Preparation of 3,4-Substituted-5-Aminopyrazoles and 4-Substituted-2

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Preparation of 3,4-substituted-5-aminopyrazoles and 4-substituted-2-aminothiazoles. Stepan Havel, Prashant Khirsariya, Naresh Akavaram, Kamil Paruch, and Benoit Jean-Pierre Carbain J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02655 • Publication Date (Web): 21 Nov 2018 Downloaded from http://pubs.acs.org on November 21, 2018

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The Journal of Organic Chemistry

Preparation of 3,4-substituted-5-aminopyrazoles and 4-substituted-2-aminothiazoles Stepan Havel,†,‡, # Prashant Khirsariya,†,‡ Naresh Akavaram,†,‡ Kamil Paruch,†,‡ and Benoit Carbain†,‡,#,* †Department

of Chemistry, CZ Openscreen, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic. Clinical Research Center, St. Anne’s University Hospital Brno, Pekařská 53, 656 91 Brno, Czech Republic.

‡International

Abstract 3-substituted-4-aryl-1H-pyrazol-5-amine

R

O

Pd-catalyzed -arylation

R

CN

36 examples

Ar

protection

S N

Br

O

borylation

O Br

B

O N

N-Boc-thiourea condensation

O O O

Suzuki coupling

and

NH2

S

deprotection

Ar

N

NH2

21 examples

R = Boc R' = PMB X = B(MIDA)

protection

3,4-Substituted-5-aminopyrazoles

N

X

NH

4-(hetero)aryl-thiazol-2-amine R N R'

S

N

Ar

35 examples

CN

R = Boc R' = PMB X = B(Pin)

NH2

R

cyclization

4-substituted-2-aminothiazoles

are

frequently

used

intermediates in medicinal chemistry and drug discovery projects. We report an expedient flexible synthesis of 3,4-substituted-5-aminopyrazoles (35 examples), based on palladium-mediated αarylation of β-ketonitriles with aryl bromides. A library of 4-substituted-2-aminothiazoles (21 examples) was assembled by a sequence employing Suzuki coupling of newly prepared properly protected pinacol ester and MIDA ester of 4-boronic acid-2-aminothiazole with (hetero)aryl halides.

Introduction Heterocyclic 5-membered aromatic ring motifs can be found in numerous biologically active small molecules. The 5-aminopyrazole scaffold has been used in compounds with diverse pharmacological activities, e.g. kinase inhibitors, antivirals, antifungals, etc.1 Likewise, the 2aminothiazole pharmacophore is an ubiquitous medicinal chemistry building block, employed in several anticancer, neuroprotective and antiviral agents.2 Scheme 1: Typical synthetic approaches to 5-aminopyrazoles and 2-aminothiazoles. O

N

R

N 2H 4

R

4

R' O

Br2

R R'

R'

N NH NH2

S

O Br

R R'

H 2N

NH2

R' 4 R

S N

NH2

5-Aminopyrazoles are generally synthesized from -ketonitriles and hydrazine (Scheme 1). αsubstituted β-ketonitriles can be prepared by several methods, e.g. cyanation of esters,3 electrophilic ACS Paragon Plus Environment

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cyanation of silyl enol ethers4 or electrophilic cyanation of boron enolates.5 We envisioned that to create a diverse library of 4-substituted-5-aminopyrazoles, a more expedient route would be based on direct α-arylation of β-ketonitriles. Carbon nucleophiles, such as anions of active methylene compounds, can undergo copper-promoted α-arylation with aryl halides (the Hurtley reaction).6 This copper-promoted α-arylation has been extensively used for β-diketones,7 esters and malonates,7b,8 and nitriles (cyanoacetates, malononitrile, arylnitriles).7c,8e,9 Over the last three decades, palladiumcatalyzed α-arylations of β-diketones,10 esters11 and nitriles12 have been also reported. However, analogous α-arylations of β-ketonitriles are very scarce: to our knowledge, only one example of copper-mediated α-arylation of β-ketonitrile13 and two substrate-specific arylations of β-ketonitriles have been reported.14 Of palladium-mediated arylations of β-ketonitriles, only two couplings with benzoylacetonitrile and two specific electrophiles have been described in the literature.11b,15 Herein, we report a modular palladium-catalyzed α-arylation of β-ketonitriles with a relatively broad substrate scope. 4-Substituted-2-aminothiazoles are typically synthesized in 2 steps through bromination of ketones16 and subsequent condensation of the resulting α-bromoketones with thiourea17 (Scheme 1). However, in some cases, the desired ketones are not commercially available, or they are expensive. Alternatively, the desired derivatization can be achieved on the already established thiazole ring via a metal-mediated cross-coupling (i.e. Sonogashira,18 Suzuki19 and Stille20 reactions) using properly mono- or bis-protected/substituted 4-halothiazol-2-amines. Of note, the preparation of 4-boronic acid-2-aminothiazole derivatives for ‘inverse’ Suzuki coupling with aryl halides has been reported only in the patent literature.21 Hereafter, we report the rapid and flexible synthesis of a library of 4(hetero)aryl-2-aminothiazoles from 4-bromo-2-aminothiazole, which consists of protection, borylation, Suzuki coupling and deprotection steps. The preparation of the heretofore unknown protected 4-boronic acid MIDA ester-2-aminothiazole and its use in the Suzuki coupling with (hetero)aryl halides, are also described.

RESULTS AND DISCUSSION Synthesis

of

3,4-substituted-5-aminopyrazoles.

The

synthesis

of

3,4-substituted-5-

aminopyrazoles was achieved in three steps from commercially available esters and acetonitrile (Scheme 2). The synthesis commenced with the reaction of esters with acetonitrile in the presence of sodium hydride, yielding the corresponding β-ketonitriles.22 Then, we focused on the Pd-catalyzed α-arylation of β-ketonitriles, allowing derivatization prior to the formation of the pyrazole ring. Scheme 2: Synthetic route to 4-aryl-5-aminopyrazole derivatives.

O CH3CN + R

O

NaH Oalkyl

THF reflux

R

CN

1a - 1f 70 - 90 %

Pd(OAc)2 ligand Cs2CO3 ArBr DMF 150 °C

O R

CN

Aryl 2a - 2aj 18 - 85 %

ACS Paragon Plus Environment

N 2H 4 . H 2O CH3SO3H, EtOH or AcOH or HCl, EtOH reflux

N NH R

NH2 Aryl 3a - 3ai 10 - 90 %

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Three different ligands were screened: PPh3,10a Xphos and tBuMePhos.10b As shown in Table 1 (entries 8, 19, 20, 22, 24 and 36), the reactions employing tBuMePhos provided the best yields. The α-arylation was generally fast (reaction time ca. 30 min.) and provided the desired arylated ketonitriles in moderate to good yields (Table 1). The panel of successfully coupled aryl bromide substrates was relatively extensive (36 examples including bicyclic cores, electron poor/rich aromatic systems and 4-bromopyridine). As demonstrated in Table 1 (entries 1 and 2), arylbromides proved to be better coupling partners than the respective arylchlorides or iodides. α-arylations with 3bromothiophene, 5-bromopyrimidine were unsuccessful and in the particular case of 6bromoquinoline, the deacetylated product (i.e. 2-(quinolin-6-yl)acetonitrile) was isolated. The pyrazole ring closure can be achieved using hydrazine hydrate in the presence of aqueous hydrochloric acid in EtOH (entries 1, 3, 5, 6 and 30) or using a catalytic amount of methanesulfonic acid in ethanol (in most cases). However, the latter protocol provided only low yields for substrates possessing electron deficient aryls (Table 1, entries 3, 5, and 15). Moreover, in the cases of 4nitrophenyl- and 4-pyridyl-derivatives (Table 1, entries 4 and 36), only the deacetylated products, i.e. 2-(4-nitrophenyl)acetonitrile and 2-(pyridin-4-yl)acetonitrile, were isolated. Unsuccessful cyclization was also observed for hindered α-arylated β-arylacetonitriles (entries 34 and 35), in accordance to the report of Wei et al.23 Gratifyingly, when performing the cyclization in acetic acid, the reaction yielded the desired aminopyrazoles (entries 4, 34 and 35), except for the 4-pyridylderivative (entry 36). We reasoned that low-yielding/failed α-arylation coupling and cyclization reactions, could be due to unwanted deacetylation of the α-arylated β-ketonitriles. This side reaction would arise via addition of a nucleophile, e.g. dimethyl amine (from decomposition of DMF) or hydrazine, to the ketone forming a tetrahedral intermediate which would collapse through a ‘retroClaisen condensation’ to give undesired aryl-acetonitrile derivatives (Scheme 3).23 Scheme 3: Possible mechanism for the deacetylation of the α-arylated β-ketonitriles (under basic conditions). 'retro Claisen condensation' -

O R

CN + Aryl

CN

R

Nu-

O

O Nu R

Nu +

Aryl

CN

-

Aryl

Table 1: Conversion of β-ketonitriles to 4-aryl-5-aminopyrazoles: palladium-catalyzed α-arylation and cyclization.

O R

CN + Aryl halide 1a - 1f

Pd(OAc)2 (a) tBuMePhos or (b) PPh3 or (c) XPhos Cs2CO3 DMF 150 °C

O R

CN + N2H4.H2O

(d) CH3SO3H, EtOH or (e) AcOH or (f) HCl, EtOH reflux

Aryl 2a - 2aj

R

NH Aryl

NH2 3a - 3ai

α-arylated β-ketonitrile entry

Compound

N

aminopyrazole

aryl halide Compound


Yield (%)

Compound

Yield (%)


1

1a R = CH2CH3

2

1a R = CH2CH3

3 4 5 6 7

1a R = CH2CH3 1a R = CH2CH3 1a R = CH2CH3 1a R = CH2CH3 1a R = CH2CH3

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2a

X

X = I; 62a X = Br; 70a X = Cl; 28a X = I; 38a X = Br; 58a X = Cl; 0a

3a

80f

3b

90d

F

2b

Br

CF3

2c

70a

3c

Br

NO2

2d

53a

3d

Br

N

2e

26a

3e

X

10d 85f 0d 75e 35d 60f

Br

COOH

2f

46a

3f

16f

Br

O O S CH3

2g

43a

3g

70d

3h

85d

8

1a R = CH2CH3

Br

OCH3

2h

54a 23b 30c

9

1a R = CH2CH3

Br

OCF3

2i

63a

3i

80e

10

1a R = CH2CH3

Br

CH3 N CH3

2j

42a

3j

81d

11

1a R = CH2CH3

O

2k

64a

3k

62d

12

1a R = CH2CH3

O S CH3 NH

2l

45a

3l

63d

13

1a R = CH2CH3

2m

67a

3m

46d

2n

55a

3n

68d

2o

66a

3o

23d 44e

O

2p

25a

3p

72d

O

2q

63a

3q

70d

2r

75a

3r

39d

2s

65a 40b 56c

3s

36d

2t

43a 40b

3t

74d

2u

57a

3u

56e

2v

76a 63b

3v

52d

2w

66a

3w

22d

2x

65a 58c

3x

52d

Br

N

O Br

Br

O O S N

Br

O O S N

O

14

1a R = CH2CH3

15

1a R = CH2CH3

16

1a R = CH2CH3

17

1a R = CH2CH3

18

1a R = CH2CH3

19

1a R = CH2CH3

20

1a R = CH2CH3

21

1a R = CH2CH3

Br

22

1a R = CH2CH3

Br

23

1a R = CH2CH3

24

1a R = CH2CH3

Cl Br

F

O Br O Br

Br CF3 Br

COOCH3 Br

O N

N

OCF3 Br OCH3 Br


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OCH3

1a R = CH2CH3

25

2y

54a

3y

57d

2z

79a

3z

64d

2aa

27a

3aa

65d

2ab

50a

3ab

36d

2ac

18a

3ac

39f

Br

2ad

52a

3ad

66e

Br

2ae

55a

3ae

48e

Br

2af

63a

3af

47e

Br

2ag

54a

3ag

62e

F

2ah

85a

3ah

0d 33e

O O S CH3

2ai

56a

3ai

0d 30e

2aj

71a 65b 24c

-

0d,e,f

Br OCH3

26

1a R = CH2CH3

27

1a R = CH2CH3

28

1a R = CH2CH3

29

1a R = CH2CH3

OH Br

Br

F

Br F3CO Br

1b 30 R= 1c 31 R=

F3C

1d 32 R=

H3CO

1e 33 R= 1f OCH3

34

Br

R= 1f OCH3

35

Br

R= 36 a

1a R = CH2CH3

Br

N

tBuMePhos; b PPh3; c XPhos; d CH3SO3H; e AcOH; f HCl

Synthesis of 4-substituted-2-aminothiazoles. Since (hetero)aryl halides are in general more available and less expensive than the corresponding boronates, we envisioned assembling the required library of 4-(hetero)aryl-2-aminothiazoles via Suzuki couplings where the thiazole would be the boron-containing coupling partner. Our approach thus consists of the following steps: [1] preparation of N,N-protected 4-bromo-2-aminothiazole, [2] boronate formation, [3] Suzuki coupling and [4] deprotection. First, appropriate protecting groups for the aminothiazole that would be stable to aqueous basic conditions (Suzuki coupling) and easily removable at the end of the synthetic sequence, were identified. Suzuki couplings were performed on differently N,N-protected 4-bromo-2-aminothiazoles followed by deprotections (under acidic conditions). In our hands, di-Boc24 and di-ethoxymethyl25 protection could not be achieved in high yield. On the other hand, the protection with a single Boc group facilitated the second protection through alkylation of the aminothiazole moiety. The combination of Boc and ethoxymethyl protecting groups was productive for the Suzuki coupling (substrate 5a in Table 2), but the deprotection step was low yielding. Gratifyingly, the combination ACS Paragon Plus Environment


Page 6 of 64

of Boc and PMB protecting groups proved to be more satisfactory, allowing clean Suzuki coupling and deprotection reactions in high yields (substrate 5b in Table 2). Table 2: Amino-protecting groups effects on Suzuki coupling and deprotection reactions. S Br

N 5a - 5b

entry

Compound

1

5a R = EtOCH2

2

5a R = EtOCH2

Aryl boronic acid/ester Pd(dppf)Cl2 R K3PO4 N DME/H2O Boc Ar 80 °C

aryl boronic acid/ester B

N

O

N

HO B HO

N

Ar

NH2

7a - 7c

Suzuki step Compound Yield (%)

N N

B O

S

or (b) TFA 70 °C

6a - 6c'

N

O

5a R = EtOCH2 5b 4 R = PMB a HCl, EtOH, 90 °C; b TFA, 70 °C 3

N

O O

(a) HCl EtOH, 90 °C

R N Boc

S

deprotection step Compound Yield (%)

6a

88

7a

18a

6b

88

7b

27a

6c

90

6c’

78

24a 7c

N

85b

The next step consisted of the conversion of compound 5b into the corresponding boronic ester. Since the latter was needed in a relatively large quantity, 5-bromo-2-aminothiazole, which is significantly less expensive than the 4-bromo isomer, was protected (compound 9) and converted into compound 5b, via a halogen-dance reaction24 (Scheme 4). Scheme 4: Synthetic routes to 4-(hetero)aryl-2-aminothiazole derivatives. Br

S N

S Boc2O DMAP CH2Cl2, rt 80 %

Br

N

NH2

R N R'

R = R' = H 4: R = H, R' = Boc

Boc2O, DMAP CH2Cl2, rt

S Ar

N

N

LDA, THF, - 78 °C 80 % S

N

N

Br

N O B O

Boc

70 °C

Aryl halide Pd(dppf)Cl2 K3PO4 DME/H2O 80 °C

Boc

6d - 6q 36 - 80 % (2 steps)

R N Boc

5a: R = CH2OCH2CH3 5b: R = PMB

8

TFA

Boc

9

PMB

S

PMB N

N

EtOCH2Cl, DIPEA CH2Cl2, 80 °C 5a: 92 % PMBCl, Cs2CO3 DMF, 80 °C 5b: 99 %

PMB

S

then PMBCl, Cs2CO3 DMF, 80 °C 65 %

n-BuLi iPrOBPin THF, -78 °C or Pd(OAc)2 B2Pin2 PCy3 dioxane, 90 °C

Br

S Ar

N

NH2

7d - 7q 70 - 92 %

The borylation reaction was achieved either by lithium-halogen exchange or Miyaura reaction26 (Scheme 4). Of note, isolation of the boronate 8 (using standard work-up and purification by flash chromatography on silica gel) did not afford the completely pure substance. However, the Suzuki


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coupling of the crude boronate 8 with a variety of (hetero)aryl halides was productive (14 examples, Table 3). For heteroaryl chlorides (entry 12-13), the sequence Miyaura borylation-Suzuki coupling was more efficient than the sequence lithiation borylation-Suzuki coupling. Finally, the deprotection in neat TFA afforded the targeted aminothiazoles 7d – 7q in high yields (Table 3).

Table 3: Substrates and yields for the borylation-Suzuki coupling sequence and the deprotection. (a) n-BuLi iPrOBPin THF, -78 °C

PMB

S N Br

N 5b

entry

N O B O

or (b) Pd(OAc)2 B2Pin2 PCy3 dioxane, 90 °C

Boc

PMB

S N 8

Boc


S Ar

Borylation + Suzuki coupling steps Compound Yield (%)

aryl halide

PMB

TFA

Boc

70 °C

N N 6d - 6q

S Ar

NH2

N 7d - 7q


1

Br

OCH3

6d

70a

7d

80

2

Br

N

6e

65a

7e

75

6f

60a

7f

75

6g

64a

7g

89

6h

65a

7h

75

6i

60a

7i

92

6j

71a

7j

79

6k

36a

7k

84

6l

65 b

7l

75

6m

60 b

7m

70

6n

80b

7n

75

6o

30a 65b

7o

78

6p

37a 75b

7p (THP removed)

75

6q

75b

7q

80

Br

3

N

4

Br

COOEt

S

5

Br

N Br

6

CF3

7

N Br

N

N

8

O

Br

N Br

9

F Br

10

N N

N

11

Br N

12

Cl N

N

13 Cl

N

O

N N

14 a

N Cl N

lithiation borylation; b Miyaura borylation

Next, we focused on the synthesis of 4-boronic acid-2-aminothiazole MIDA ester,27 hoping that it would be sufficiently stable for purification (and easier handling). The MIDA-protected bromomethyl acylboronate was synthesized according to the published protocol from vinylboronic acid MIDA ACS Paragon Plus Environment


Page 8 of 64

ester,28 and used for condensation with N-Boc-thiourea 1029 to provide the thiazole 11 (Scheme 5). Subsequent protection with p-methoxybenzyl chloride afforded the desired MIDA ester 12, which was stable to purification on silica gel and could be stored for months at room temperature under nitrogen (Scheme 5). The structure of 12 was unambiguously confirmed by X-ray crystallography (crystallographic data are given in the Supporting Information). As shown in Table 4, MIDA ester 12 was also successfully used for Suzuki couplings with various (hetero)aryl bromides (7 examples). Of note, the Suzuki coupling of the mono-protected MIDA ester 11 was significantly less effective (entry 8), demonstrating the necessity of di-protection of the aminothiazole. Scheme 5: Preparation of aminothiazole MIDA ester boronate 12 and the following steps. O O B O O N

O R' = R'-Br NEt3

S R NaH (Boc)2O THF 0 °C to rt 32 %

N H

R=H 10: R = Boc

PMB

S N

N

B O

O

O

NH2

N

Boc

12

CH3CN 70 °C 63 %


O

PMBCl Cs2CO3

Boc NH

S

CH3CN 80 °C 71 %

N

R'

11

PMB

S N

TFA

S

70 °C

N Boc Ar 6d, 6e, 6r - 6v' 40 - 74 %

Ar

N

NH2

7d, 7e, 7r - 7v 28 - 93 %

Table 4: Substrates and yields of the Suzuki coupling with MIDA ester 12 and the deprotection. S N O

O

N

B O

12

R N Boc

Aryl bromide Pd(dppf)Cl2 K3PO4 DME/H2O 80 °C

S Ar

N

R N Boc

6d, 6e, 6r - 6v'

S

TFA 70 °C

Ar

N

NH2

7d, 7e, 7r - 7v

O

entry

R

1

PMB

2

PMB

Br

3

PMB

Br

Suzuki step Compound Yield (%)

aryl halide Br

OCH3 N


6r

71

7r

93

6d

65

7d

80

6e

71

7e

75

6s

74

7s

81

6t

55

7t

28

6u

40

7u

51

6v

71

7v

84

6v’

40

-

-

Br

4

N

PMB

N O H3CO

5

PMB

Br N

N

6

PMB

Br N

7

PMB

8

H

Br N


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CONCLUSION In summary, an efficient palladium-mediated α-arylation of β-ketonitriles with a broad panel of aryl bromides (36 examples) has been developed. This methodology enables a convenient access to 3,4-disubstituted-5-aminopyrazoles in 3 steps from readily available esters and acetonitrile. The synthesis of a library of 4-substituted-2-aminothiazoles was accomplished via effective preparation of N-Boc-N-PMB-thiazole-2-amine-4-boronic esters and their successful use in palladium-mediated cross-couplings (21 examples).



Page 10 of 64

EXPERIMENTAL SECTION General information All commercial reagents were obtained from Merck and Fluorochem and were of the highest available purity. Unless stated otherwise, chemicals were used as supplied without further purification. Anhydrous solvents were obtained from Acros and were stored under nitrogen. Unless noted otherwise, the reactions were carried out in oven-dried glassware under atmosphere of nitrogen or argon. The progress of reactions was monitored by thin layer chromatography and was conducted on plates pre-coated with silica gel (Merck 60 F254). Eluent mixture ratios are quoted as volume:volume. Visualization was done either by short wave (254 nm) or long wave (366 nm) ultraviolet light. Flash column chromatography was carried out using silica gel from Merck, (technical grade, pore size 60 Å, 230-400 mesh particle size, 40-63 μm particle size). Elution gradients are quoted as ratios between solvents at the start and end of the elution. Melting points were determined with a Stuart Scientific SMP40 apparatus and are uncorrected. 1H,

13C{1H},

and

19F{1H}

nuclear

magnetic resonance (NMR) spectra were obtained as methanol-d4, chloroform-d, or DMSO-d6 solutions and recorded at 300 or 500 MHz, 75 or 125 MHz and 282 or 471 MHz respectively, on a Bruker Avance III 500 spectrometer. Where

13C{1H}

NMR data are not quoted, insufficient material

was available or problems obtaining adequate spectra were encountered. Chemical shifts are quoted in parts per million () referenced to the appropriate deuterated solvent employed. Multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), sept (septet), m (multiplet) or (br) broad, or combinations thereof. Coupling constant values are given in Hz. Homonuclear and heteronuclear two dimensional NMR experiments were used where appropriate to facilitate assignment of chemical shifts. IR spectra were recorded on a Bruker ALPHA FT-IR spectrometer. Solid samples were measured neat and oily samples as films. High resolution mass spectra were performed on an Agilent 6224 Accurate-Mass TOF LC-MS instrument. A dual electro-spray (or multimode ion source) in positive (or negative) mode was chosen for high-resolution MS analysis and the operating parameters were set as follows: nitrogen flow 5 L; min at 350°C, nebulizer 40 psig, fragmentor voltage of 30 V, skimmer voltage of 65 V, vaporizer (only in case of MMI) 200°C or capillary voltage (only in case of dESI) of 4 kV. General procedures General procedure A: Preparation of ketonitriles with NaH To a solution of the appropriate ester (1 eq) and acetonitrile (1.2 eq, unless stated otherwise) in anhydrous THF (2 mL per 1 mmol of ester, unless stated otherwise) was added under nitrogen NaH (60 % suspension in mineral oil, 1.2 eq, unless stated otherwise) and the mixture was refluxed for 2 hours (unless stated otherwise). The reaction mixture was cooled to 0 °C, quenched with a 2M aqueous HCl until pH neutral and extracted with EtOAc (5 mL per 1 mmol of ester). The organic extracts were washed with brine (5 mL per mmol of ester), dried over MgSO4, filtered and the solvent


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was evaporated in vacuo. The crude material was purified by flash column chromatography on silica gel. General procedure B: Palladium-mediated arylation of -ketonitriles To a mixture of the appropriate -ketonitrile (1 eq), the appropriate aryl halide (1.1 or 1.2 eq), Cs2CO3 (3 eq), tBuMePhos (0.025 - 0.1 eq) or XPhos (0.1 eq) or PPh3 (0.1 eq) and Pd(OAc)2 (0.025 - 0.05 eq) was added DMF (3 mL per 1 mmol of the substrate). The mixture was degassed for 10 min by bubbling N2 or Ar. The resulting reaction mixture was refluxed for 30 min at 150 °C (unless stated otherwise). When cooled to rt, the crude mixture was filtered to remove the excess of Cs2CO3, and the filtrate was poured to a solution of 0.1 M HCl (20 mL per 1 mmol of the substrate) (unless stated otherwise) and then diluted with EtOAc (20 mL per 1 mmol of the substrate). The organic phase was extracted and washed with H2O (3 x 20 mL per 1 mmol of the substrate) and brine (3 x 20 mL per 1 mmol of the substrate). The organic phase was dried over MgSO4, filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel. General procedure C1: Pyrazole formation in presence of CH3SO3H A mixture of the appropriate 2-substituted-3-oxopentanenitrile (1 eq), N2H4.H2O (1.1 - 2 eq) and CH3SO3H (0.1 – 0.3 eq) in absolute EtOH (5 mL per 1 mmol of the substrate) was refluxed for 3 hours (unless stated otherwise). When cooled to rt, the solvent was evaporated in vacuo and the residue was quenched with a saturated aqueous solution of NaHCO3 (20 mL per 1 mmol of the substrate) and extracted with EtOAc (20 mL per 1 mmol of the substrate) (unless stated otherwise). The organic extracts were washed with brine (2 x 20 mL per 1 mmol of the substrate), dried over MgSO4, filtered and the solvent was removed in vacuo. The crude material was purified by flash column chromatography on silica gel. General procedure C2: Pyrazole formation in AcOH A mixture of the appropriate 2-substituted-3-oxopentanenitrile (1 eq) and N2H4.H2O (1.1 eq, unless stated otherwise) in AcOH (4 mL per 1 mmol of substrate) was refluxed for 4 hours (unless stated otherwise) under N2. When cooled to rt, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (40 mL per 1 mmol of the substrate) and extracted with EtOAc (40 mL per 1 mmol of the substrate) (unless stated otherwise). The organic extracts were washed with H2O (40 mL per 1 mmol of the substrate) and brine (40 mL per 1 mmol of the substrate), dried over MgSO4, filtered and the solvent was removed in vacuo. The crude material was purified by flash column chromatography on silica gel. General procedure C3: Pyrazole formation in HCl A mixture of the appropriate 2-substituted-3-oxopentanenitrile (1 eq), N2H4.H2O (5 eq) and HCl (35 %, 10 eq) in EtOH (4 mL per 1 mmol of substrate, unless stated otherwise) was refluxed for 2 hours ACS Paragon Plus Environment


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(unless stated otherwise) under an atmosphere of nitrogen. Ethanol was evaporated. The crude was dissolved in EtOAc (20 mL per 1 mmol of the substrate) and a saturated aqueous solution of NaHCO3 (20 mL per 1 mmol of the substrate) was added. The organic extract was washed with brine (20 mL per 1 mmol of the substrate), dried over MgSO4, filtered and the solvent was removed in vacuo. The crude material was purified by flash column chromatography on silica gel. General

procedure

D1:

Suzuki

coupling

with

tert-butyl

(4-bromothiazol-2-

yl)(ethoxymethyl)carbamate or tert-butyl (4-bromothiazol-2-yl)(4-methoxybenzyl)carbamate To a solution of the appropriate (hetero)aryl boronic acid or ester (1.1 eq) in DME (10 mL per 1 mmol of the substrate) and H2O (2 mL per 1 mmol of the substrate) under an atmosphere of nitrogen, were added tert-butyl (4-bromothiazol-2-yl)(ethoxymethyl)carbamate or tert-butyl (4-bromothiazol-2-yl)(4methoxybenzyl)carbamate (1 eq), K3PO4 (3.0 eq) and Pd(dppf)Cl2 (0.03 eq unless stated otherwise). The reaction mixture was stirred at 80 °C for 3 h, then diluted with water (20 mL per 1 mmol of the substrate) and extracted with EtOAc (2 × 40 mL per 1 mmol of the substrate). The combined organic extracts were washed with H2O (15 mL per 1 mmol of the substrate) and brine (15 mL per 1 mmol of the substrate), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to provide the desired target compound. General procedure D2: Suzuki coupling with tert-butyl (4-methoxybenzyl)(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate or tert-butyl (4-methoxybenzyl)(4(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)thiazol-2-yl)carbamate To a solution of tert-butyl (4-methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol2-yl)carbamate or tert-butyl (4-methoxybenzyl)(4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2yl)thiazol-2-yl)carbamate (1 eq) in DME (10 mL per 1 mmol of the substrate) and H2O (2 mL per 1 mmol of the substrate) under an atmosphere of nitrogen, were added the appropriate (hetero)aryl halide (1.1 eq), K3PO4 (3.0 eq) and Pd(dppf)Cl2 (0.1 eq). The reaction mixture was stirred at 80 °C for 3 h (unless stated otherwise), then diluted with water (20 mL per 1 mmol of the substrate), and extracted with EtOAc (2 × 40 mL per 1 mmol of the substrate). The combined organic extracts were washed with H2O (15 mL per 1 mmol of the substrate) and brine (15 mL per 1 mmol of the substrate), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to provide the desired target compound. General procedure E1: deprotection with HCl To a solution of tert-butyl (ethoxymethyl)(4-substituted thiazol-2-yl)carbamate (1 eq) in ethanol (16 mL per 1 mmol of the substrate) was added aqueous 3 M HCl (1 mL per 1 mmol of the substrate). The reaction mixture was stirred at 90 °C for 12 h (unless stated otherwise), then the solvent was evaporated under reduced pressure. The residue was stirred with 7 M NH3 in MeOH (5 mL per 1 mmol of the substrate) at 25 °C for 2 hours, then the solvent was evaporated under reduced


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pressure. The residue was purified by column chromatography to provide the desired target compound. General procedure E2: deprotection with TFA Trifluoroacetic acid (4 mL per 1 mmol of the substrate unless stated otherwise) was added to a tertbutyl (4-methoxybenzyl)(4-substitutedthiazol-2-yl)carbamate (1 eq) and stirred at 70 °C for 2 h, then the solvent was evaporated under reduced pressure. The residue was quenched with a saturated aqueous solution of NaHCO3 (30 mL per 1 mmol of the substrate) and extracted with CH2Cl2 or EtOAc (2 × 50 mL per 1 mmol of the substrate). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to provide the desired target compound. 3-oxopentanenitrile (1a). Prepared according to general procedure A with methyl propionate (3.82 g, 43.3 mmol), acetonitrile (6.8 mL, 130 mmol) and NaH (60 % suspension in mineral oil, 3.47 g, 87 mmol) in anhydrous THF (25 mL). Column chromatography (hexane:EtOAc; 4:1). The product was obtained as a colorless oil (3.5 g, 0.036 mmol, 90 %). Rf = 0.32 (Hexane:EtOAc; 2:1); IR (cm-1) 3347, 3170, 2974, 2209, 2180, 1653, 1594, 1460, 1370, 1064, 667; 1H NMR (500 MHz, Chloroform-d):  (ppm) 1.10 (t, J = 7.2 Hz, 3H), 2.62 (q, J = 7.2 Hz, 2H), 3.47 (s, 2H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 7.5, 31.7, 35.7, 114.0, 198.2; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C5H6NO 96.0455; Found 96.0462. CAS registry No. [33279-01-5]. 1H and

13C

NMR spectra were consistent with those previously

reported in the literature.30a 3-cyclohexyl-3-oxopropanenitrile (1b). Prepared according to general procedure A with methyl cyclohexanecarboxylate (1 g, 7.03 mmol), acetonitrile (0.44 mL, 8.44 mmol) and NaH (60 % suspension in mineral oil, 0.338 g, 8.44 mmol) in anhydrous THF (15 mL). Column chromatography (hexane:EtOAc; 1:0 to 1:1). The product was obtained as a yellow-brown oil (0.776 g, 5.131 mmol, 73 %). or n-BuLi (2.36 M solution in hexane, 2.57 ml, 6.08 mmol) was added under nitrogen to a solution of acetonitrile (0.48 mL, 9.11 mmol) in anhydrous THF (5 mL) at -78 ºC. The reaction mixture was stirred at at -78 ºC for 30 min, then a solution of methyl cyclohexanecarboxylate (0.432 g, 3.04 mmol) in anhydrous THF (5 mL) was added dropwise and the mixture was stired at -78 ºC for 2 hrs. The reaction mixture was quenched with saturated aqueous solution NH4Cl (10 mL) and extracted with CH2Cl2 (3 x 75 mL). The organic extracts were dried over MgSO4, filtered and the solvent was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel (hexane:EtOAc; 1:0 to 1:1). The product was obtained as yellow-brown oil (0.45 g, 2.98 mmol, 98 %). Rf = 0.27 (Hexane:EtOAc; 4:1); IR (cm-1) 2930, 2855, 1719, 1450, 1389, 1317, 1293, 1144, 1069, ACS Paragon Plus Environment


Page 14 of 64

1003, 872, 719; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.14 – 1.45 (m, 5H), 1.65 – 1.73 (m, 1H), 1.77 – 1.86 (m, 2H), 1.85 – 1.96 (m, 2H), 2.55 (tt, J = 11.1, 3.5 Hz, 1H), 3.49 (s, 2H);

13C{1H}

NMR

(126 MHz, DMSO-d6)  (ppm) 25.4, 25.7, 28.3, 30.4, 50.1, 114.1, 200.5; HRMS (APCI-MMI) m/z: [M-H]- Calcd for C9H12NO 150.0924; Found 150.0923. CAS registry No. [62455-70-3]. 1H and

13C


reported in the literature.4a 3-oxo-3-(4-(trifluoromethyl)phenyl)propanenitrile (1c). Prepared according to general procedure A with methyl 4-(trifluoromethyl)benzoate (1 g, 4.90 mmol), acetonitrile (0.306 mL, 5.88 mmol) and NaH (60 % suspension in mineral oil, 0.235 g, 5.88 mmol) in anhydrous THF (15 mL). Column chromatography (hexane:EtOAc; 1:0 to 7:3). The product was obtained as a light brown solid (0.85 g, 3.99 mmol, 81 %). Rf = 0.60 (Hexane:EtOAc; 1:1); mp= 43 45 °C; IR (cm-1) 2957, 2912, 1688, 1601, 1409, 1396, 1325, 1218, 1168, 1128, 1108, 1065, 1006, 930, 835, 768; 1H NMR (500 MHz, Chloroform-d)  (ppm) 4.13 (s, 2H), 7.80 (d, J = 8.2 Hz, 2H), 8.05 (d, J = 8.1 Hz, 2H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 29.8, 113.3, 123.3 (q, J = 272.6 Hz), 126.4 (q, J = 3.7 Hz), 129.0, 136.1 (q, J = 33.3 Hz), 137.0, 186.6;

19F{1H}

NMR (471 MHz,

Chloroform-d)  (ppm) - 63.40. HRMS (APCI-MMI) m/z: [M-H]- Calcd for C10H5F3NO 212.0329; Found 212.0327. CAS registry No. [72682-94-5]. 1H NMR spectrum was consistent with that previously reported in the literature.30b 3-(4-methoxyphenyl)-3-oxopropanenitrile (1d). Prepared according to general procedure A with methyl 4-methoxybenzoate (1 g, 6.02 mmol), acetonitrile (0.38 mL, 7.72 mmol) and NaH (60 % suspension in mineral oil, 0.309 g, 7.72 mmol) in anhydrous THF (15 mL). Column chromatography (hexane:EtOAc; 1:0 to 7:3). The product was obtained as yellow solid (0.781 g, 4.458 mmol, 74 %). Rf = 0.50 (Hexane:EtOAc; 1:1); mp = 123 126 °C; IR (cm-1) 1680, 1596, 1577, 1512,1463, 1450, 1438, 1421, 1391, 1323, 1307, 1262, 1222, 1169, 1119, 1024, 1011, 1000, 928, 845, 816, 770, 631, 604; 1H NMR (500 MHz, Chloroform-d)  (ppm) 3.89 (s, 3H), 4.01 (s, 2H), 6.95 – 7.01 (m, 2H), 7.86 – 7.93 (m, 2H). 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 29.1, 55.8, 114.2, 114.5, 127.4, 131.1, 164.9, 185.6; HRMS (APCI-MMI) m/z: [M−H]− Calcd for C10H8NO2 174.0561; Found 174.0559. CAS registry No. [3672-47-7]. 1H and reported in the

13C


literature.4a

3-(4-(tert-butyl)phenyl)-3-oxopropanenitrile (1e). Prepared according to general procedure A with methyl 4-(trifluoromethyl)benzoate (1 g, 5.2 mmol), acetonitrile (0.33 mL, 6.2 mmol) and NaH (60 % suspension in mineral oil, 0.248 g, 6.2 mmol) in anhydrous THF (15 mL). Column chromatography (hexane:EtOAc; 1:0 to 7:3). The product was ACS Paragon Plus Environment

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obtained as yellow solid (0.74 g, 3.68mmol, 70 %). Rf = 0.60 (Hexane:EtOAc; 1:1); mp = 71 - 75 °C; IR (cm-1) 2957, 2920, 2855, 1687, 1600, 1462, 1046, 1396, 1330, 1312, 1267, 1226, 1197, 1106, 1005, 930, 911, 836, 720, 585; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.35 (s, 9H), 4.05 (s, 2H), 7.49 – 7.57 (m, 2H), 7.83 – 7.91 (m, 2H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 29.4, 31.1, 35.5, 114.1, 126.3, 128.6, 131.9, 159.0, 186.8; HRMS (APCI-MMI) m/z: [M−H]− Calcd for C13H14NO 200.1081; Found 200.1079. CAS registry No. [39528-62-6]. 1H and

13C


reported in the literature.30c 3-(3-methoxynaphthalen-2-yl)-3-oxopropanenitrile (1f). Prepared according to general procedure A with methyl 3-methoxy-2-naphthoate (0.62 g, 2.87 mmol), acetonitrile (0.45 mL, 8.6 mmol) and NaH (60 % suspension in mineral oil, (230 mg, 5.7 mmol) in anhydrous THF (5 mL). Column chromatography (hexane:EtOAc; 4:1). The product was obtained as a pale white solid (520 mg, 2.3 mmol, 80 %). mp = 152 - 153 °C; IR (cm-1) 2252, 1676, 1339, 1145, 759; 1H NMR (500 MHz, DMSO-d6)  (ppm) 4.08 (s, 3H), 4.18 (s, 2H), 7.43 (m, 1H), 7.59 (m, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 8.39 (s, 1H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 34.1, 56.0, 107.0, 114.6, 125.2, 126.2, 126.7, 128.1, 129.6, 129.8, 133.5, 137.2, 155.3, 188.8; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C14H12NO2 226.0862; Found 226.0867. 3-oxo-2-phenylpentanenitrile (2a). Prepared according to general procedure B with 3-oxopentanenitrile (100 mg, 1.05 mmol), iodobenzene (257 mg, 1.26 mmol, 0.141 mL), Cs2CO3 (1.027 g, 3.15 mmol), tBuMePhos (9 mg, 0.03 mmol) and Pd(OAc)2 (7 mg, 0.03 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 5:1 to 1:1). The product was obtained as a yellow solid (113 mg, 0.651 mmol, 62 %). or Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), bromobenzene (390 mg, 2.47 mmol, 0.26 mL), Cs2CO3 (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06 mmol) and Pd(OAc)2 (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 5:1 to 1:1). The product was obtained as a yellow solid (250 mg, 1.47 mmol, 70 %). Rf = 0.45 (Hexane:EtOAc; 7:3); mp = 56 - 57 °C; IR (cm-1) 2248, 1725, 1455, 1198, 1100, 748, 695; 1H NMR (300 MHz, Chloroform-d)  (ppm) 1.03 (t, J = 7.2 Hz, 3H), 2.46 – 2.78 (m, 2H), 4.71 (s, 1H), 7.32 – 7.47 (m, 5H);

13C{1H}

NMR (75 MHz, Chloroform-d)  (ppm) 7.6, 33.2, 50.6, 116.4, 128.0, 129.2,

129.6, 130.0, 199.5; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C11H12NO 174.0913; Found [M-H]174.0913. CAS registry No. [6277-02-7]. 1H and

13C


reported in the literature.30d or



Page 16 of 64

Prepared according to general procedure B with 3-oxopentanenitrile (100 mg, 1.05 mmol), chlorobenzene (142 mg, 1.26 mmol, 0.128 mL), Cs2CO3 (1.027 g, 3.15 mmol), tBuMePhos (9 mg, 0.03 mmol) and Pd(OAc)2 (7 mg, 0.03 mmol) in DMF (3 mL). The reaction mixture was refluxed for 5 h at 150 °C. Column chromatography (hexane:EtOAc; 5:1 to 1:1). The product was obtained as a yellow solid (50 mg, 0.289 mmol, 28 %). 2-(4-fluorophenyl)-3-oxopentanenitrile (2b). Prepared according to general procedure B with 3-oxopentanenitrile (100 mg, 1.03 mmol), 1-bromo4-fluorobenzene (215 mg, 1.23 mmol), Cs2CO3 (5.87 g, 18.4 mmol), tBuMePhos (16 mg, 0.05 mmol) and Pd(OAc)2 (6 mg, 0.03 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 10:1 to 3:1). The product was obtained as yellow-orange oil (112 mg, 0.6 mmol, 58 %). Rf = 0.35 (EtOAc:MeOH; 5:1); IR (cm-1) 1730, 1632, 1604, 1460, 1419, 1350, 1228, 1161, 1103, 1068, 1016, 820; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.06 (t, J = 7.2 Hz, 3H). 2.56 – 2.74 (m, 2H), 4.68 (s. 1H), 7.09 – 7.17 (m, 2H), 7.35 – 7.42 (m, 2H);

13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm)

7.7, 33.4, 49.8, 116.4, 116.8 (d, J = 22 Hz), 125.9 (d, J = 3.4 Hz), 139.9 (d, J = 8.3 Hz), 163.3 (d. J = 249,6 Hz), 199.4; HRMS (ESI-MMI) m/z: [M-H]- Calcd for C11H9FNO 190.0674; Found 190.0672. or Prepared according to general procedure B with 3-oxopentanenitrile (100 mg, 1.03 mmol), 1-fluoro4-iodobenzene (275 mg, 1.23 mmol), Cs2CO3 (5.87 g, 18.4 mmol), tBuMePhos (16 mg, 0.05 mmol) and Pd(OAc)2 (6 mg, 0.03 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 10:1 to 3:1). The product was obtained as yellow-orange oil (75 mg, 0.4 mmol, 38 %). 3-oxo-2-(4-(trifluoromethyl)phenyl)pentanenitrile (2c). Prepared according to general procedure B with 3-oxopentanenitrile (0.156 g, 1.60 mmol), 1-bromo4-(trifluoromethyl)benzene (0.365 g, 0.244 ml, 1.77 mmol), Cs2CO3 (1.57 g, 4.82 mmol), tBuMePhos (50 mg, 0.16 mmol) and Pd(OAc)2 (9 mg, 0.04 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc; 1:0 to 2:1). The product was obtained as a yelow solid (0.273 g, 1.13 mmol, 70 %); Rf = 0.21 (hexane:EtOAc; 2:1); mp = 75 - 78 °C; IR (cm-1) 2219, 1613, 1323, 1113, 838, 538; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.33 (t, J = 7.6 Hz, 3H), 2.73 (q, J = 7.6 Hz, 2H), 6.69 (s, 1H), 7.67 (s, 4H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.9, 50.3, 115.9, 124.1 (q, J = 272.1 Hz), 126.4 (q, J = 3.6 Hz), 126.8 (q, J = 3.7 Hz), 128.7, 128.7, 198.7;

19F{1H}

NMR (471

MHz, Chloroform-d)  (ppm) -62.8; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C12H9F3NO 240.0642; Found 240.0642. 2-(4-nitrophenyl)-3-oxopentanenitrile (2d). Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 4bromonitrobenzene (0.5 g, 2.5 mmol), Cs2CO3 (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06 mmol) and Pd(OAc)2 (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 4:1 to ACS Paragon Plus Environment

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2:1). The product was obtained as a brown solid (0.24 g, 1.1 mmol, 53 %). Rf = 0.2 (EtOAc); mp = 80 - 81 °C; IR (cm-1) 2225, 1598, 1509,1334, 1107, 830, 732; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.11 (t, J = 7.2 Hz, 3H), 2.68 – 2.85 (m, 2H), 4.80 (s, 1H), 7.60 – 7.63 (m, 2H), 8.28 – 8.35 (m, 2H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 34.2, 50.1, 115.6, 124.8, 129.4, 136.7, 148.7, 198.0; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C11H9N2O3 217.0619; Found 217.0618. 4-(1-cyano-2-oxobutyl)benzonitrile (2e). Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 4bromobenzonitrile (450 mg, 2.4 mmol), Cs2CO3 (1.95 g, 6.3 mmol), tBuMePhos (19 mg,0.06 mmol) and Pd(OAc)2 (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 5:1 to 1:1). The product was obtained as a brown wax (110 mg, 0.55 mmol, 26 %). Rf = 0.10 (hexane:EtOAc; 1:1); IR (cm-1) 2224, 2196, 1727, 1656, 1583, 1398, 1066, 1012, 821, 539; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.11 (t, J = 7.2 Hz, 3H), 2.67 – 2.84 (m, 2H), 4.76 (s, 1H), 7.52 – 7.58 (m, 2H), 7.74 – 7.78 (m, 2H);

13C{1H}

NMR (500 MHz, DMSO-d6)  (ppm) 7.8, 34.1, 50.3, 113.7,

115.6, 118.0, 129.1, 133.4, 134.9, 198.2; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C12H9N2O 197.0720; Found 197.0719. 4-(1-cyano-2-oxobutyl)benzoic acid (2f). Prepared according to general procedure B with 3-oxopentanenitrile (0.21 g, 2.16 mmol), 4bromobenzoic acid (0.478 g, 2.38 mmol), Cs2CO3 (2.82 g, 8.65 mmol), tBuMePhos (68 mg, 0.216 mmol) and Pd(OAc)2 (24 mg, 0.108 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc:AcOH; 66:33:0.05 to 0:100:0.05). The product was obtained as a pale orange solid (0.218 g, 1 mmol, 46 %). Rf = 0.74 (EtOAc:AcOH; 100:1); mp = 138 - 142 °C; IR (cm-1) 2222, 1682, 1602, 1423, 1383, 1368, 1318, 1282, 1242, 1187, 1070, 939, 859, 772, 751, 730; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.24 (t, J = 7.6 Hz, 3H), 2.64 (q, J = 7.6 Hz, 2H), 7.73 – 7.80 (m, 2H), 7.90 – 7.95 (m, 2H), 12.04 (s, 1H), 12.69 (s, 1H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 12.2, 29.0, 85.3,

120.1, 126.6, 128.0, 129.4, 137.3, 166.9, 175.4; HRMS (APCI-MMI) m/z: [M-H]- Calcd for C12H10NO3 216.0666; Found 216.0665. 2-(4-(methylsulfonyl)phenyl)-3-oxopentanenitrile (2g). Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 4bromophenyl methyl sulfone (0.58 g, 2.5 mmol), Cs2CO3 (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06) and Pd(OAc)2 (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 2:1 to 0:1). The product was obtained as a brown solid (0.22 g, 0.88 mmol, 43 %). Rf = 0.4 (hexane:EtOAc; 7:3); mp = 81 - 82 °C; IR (cm-1) 3204, 3014, 2929, 2214, 1695, 1588, 1299, 1142, 1066, 960, 763, 525; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.09 (t, J = 7.2 Hz, 3H), 2.67 – 2.79 (m, 2H), 3.08 (s, 3H), 4.81 (s, 1H), 7.60 – 7.65 (m, 2H), 8.00 – 8.04 (m, 2H); 13C{1H} NMR (126 MHz,



Page 18 of 64

Chloroform-d)  (ppm) 7.8, 34.2, 44.7, 50.2, 115.8, 128.8, 129.4, 136.0, 141.8, 198.3; HRMS (APCITOF) m/z: [M-H]- Calcd for C12H12NO3S 250.0543; Found 250.0543. 2-(4-methoxyphenyl)-3-oxopentanenitrile (2h). Prepared according to general procedure B with 3-oxopentanenitrile (0.197 g, 2.03 mmol), 4bromoanisole (0.379 g, 0.25 mL, 2.03 mmol), Cs2CO3 (1.98 g, 6.08 mmol), tBuMePhos (63 mg, 0.2 mmol) and Pd(OAc)2 (11 mg, 0.05 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc; 1:0 to 1:1). The product was obtained as a pale yellow solid (0.221 g, 1.09 mmol, 54 %). Rf = 0.43 (hexane:EtOAc; 2:1); mp = 95 - 97 °C; IR (cm-1) 2246, 1727, 1508, 1260, 1175, 1026, 814, 798, 551; 1H

NMR (500 MHz, Chloroform-d)  (ppm) 1.06 (t, J = 7.2 Hz, 3H), 2.60 (q, J = 7.2 Hz, 1H), 2.66 (q,

J = 7.2 Hz, 1H), 3.84 (s, 3H), 4.64 (s, 1H), 6.94 – 6.98 (m, 2H), 7.29 – 7.34 (m, 2H);

13C{1H}

NMR

(126 MHz, Chloroform-d)  (ppm) 7.8, 33.1, 50.0, 55.6, 115.2, 116.7, 122.0, 129.3, 160.4, 199.9; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C12H12NO2 202.0874; Found 202.0875. or Prepared according to general procedure B with 3-oxopentanenitrile (0.225 g, 2.32 mmol), 4bromoanisole (0.5 g, 0.35 mL, 2.8 mmol), Cs2CO3 (1.5 g, 4.6 mmol), XPhos (35 mg, 0.07 mmol) and Pd(OAc)2 (16 mg, 0.07 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 1:0 to 1:1). The product was obtained as a pale yellow solid (0.145 g, 0.7 mmol, 30 %). or Prepared according to general procedure B with 3-oxopentanenitrile (0.175 g, 1.8 mmol), 4bromoanisole (0.371 g, 0.25 mL, 1.98 mmol), Cs2CO3 (1.76 g, 5.41 mmol), PPh3 (47 mg, 0.18 mmol) and Pd(OAc)2 (10 mg, 0.045 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc; 1:0 to 1:1). The product was obtained as a pale yellow solid (0.095 g, 0.47 mmol, 23 %). 3-oxo-2-(4-(trifluoromethoxy)phenyl)pentanenitrile (2i). Prepared according to general procedure B with 3-oxopentanenitrile (0.215 g, 2.21 mmol), 1-bromo4-(trifluoromethoxy)benzene (0.587 g, 0.362 mL, 2.43 mmol), Cs2CO3 (2.16 g, 6.64 mmol), tBuMePhos (69 mg, 0.22 mmol) and Pd(OAc)2 (25 mg, 0.11 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc; 1:0 to 1:1). The product was obtained as a brown wax (0.361 g, 1.40 mmol, 63 %). Rf = 0.31 (hexane:EtOAc; 2:1); IR (cm-1) 3111, 2219, 1631, 1508, 1363, 1259, 1204, 1151, 1069, 835, 760; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.07 (t, J = 7.2 Hz, 3H), 2.64 (dq, J = 18.6, 7.2 Hz, 1H), 2.73 (dq, J = 18.7, 7.2 Hz, 1H), 4.69 (s, 1H), 7.27 – 7.31 (m, 2H), 7.42 – 7.47 (m, 2H);

13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm) 7.7, 33.6, 49.8, 116.1, 120.50 (q, J =

259.3 Hz), 122.0, 128.6, 129.7, 150.0, 199.0; 19F{1H} NMR (471 MHz, Chloroform-d)  (ppm) -57.90; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C12H9F3NO2 256.0591; Found [M-H]- 256.0590. 2-(4-(dimethylamino)phenyl)-3-oxopentanenitrile (2j).


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Prepared according to general procedure B with 3-oxopentanenitrile (0.205 g, 2.11 mmol), 4-bromoN,N-dimethylaniline (0.465 g, 2.32 mmol), Cs2CO3 (2.06 g, 6.33 mmol), tBuMePhos (66 mg, 0.21 mmol) and Pd(OAc)2 (12 mg, 0.053 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc; 1:0 to 1:1). The product was obtained as a pale orange solid (0.193 g, 0.89 mmol, 42 %). Rf = 0.36 (hexane:EtOAc; 2:1); mp = 109 - 110 °C; IR (cm-1) 2979, 2900, 2245, 1720, 1610, 1523, 1446, 1365, 1336, 1233, 1209, 1196, 1169, 1120, 1100, 1067, 949, 804, 789, 678; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.02 (t, J = 7.2 Hz, 3H), 2.53 (dq, J = 18.5, 7.3 Hz, 1H), 2.64 (dq, J = 18.3, 7.2 Hz, 1H), 2.98 (s, 6H), 4.58 (s, 1H), 6.74 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 8.9 Hz, 2H);

13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm) 7.9, 32.9, 40.6, 50.1, 113.3, 117.0, 128.9, 150.7, 200.3; HRMS (APCI-MMI) m/z: [M+H]+ Calcd for C13H17N2O 217.1335; Found 217.1338. 2-(4-morpholinophenyl)-3-oxopentanenitrile (2k). Prepared according to general procedure B with 3-oxopentanenitrile (0.171 g, 1.76 mmol), 1-bromo3-chloro-4-fluorobenzene (0.406 g, 0.236 mL, 1.94 mmol), Cs2CO3 (1.72 g, 5.28 mmol), tBuMePhos (55 mg, 0.18 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in DMF (6 mL). No work-up, after filtration the filtrate was evaporated and the residue was loaded on silica gel. Column chromatography (hexane:EtOAc; 1:0 to 1:1). The product was obtained as an orange solid (0.293 g, 1.13 mmol, 64 %). Rf = 0.10 (hexane:EtOAc; 2:1); mp = 134 - 136 °C; IR (cm-1) 2972, 2850, 2833, 2247, 1719, 1606, 1519, 1448, 1385, 1351, 1268, 1239, 1168, 1113, 1068, 1049, 925, 824; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.03 (t, J = 7.2 Hz, 3H), 2.54 (dq, J = 18.5, 7.2 Hz, 1H), 2.65 (dq, J = 18.5, 7.2 Hz, 1H), 3.15 – 3.22 (m, 4H), 3.82 – 3.89 (m, 4H), 4.60 (s, 1H), 6.91 (d, J = 8.9 Hz, 2H), 7.26 (d, J = 8.9 Hz, 2H);

13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.0, 48.8, 50.0, 66.8, 116.1,

116.8, 120.6, 129.0, 151.8, 200.0; HRMS (APCI-MMI) m/z: [M+H]+ Calcd for C15H19N2O2 259.1441; Found 259.1448. N-(4-(1-cyano-2-oxobutyl)phenyl)methanesulfonamide (2l). Prepared according to general procedure B with 3-oxopentanenitrile (0.18 g, 1.85 mmol), N-(4bromophenyl)methanesulfonamide (0.51 g, 2.04 mmol), Cs2CO3 (1.81 g, 5.56 mmol), tBuMePhos (58 mg, 0.185 mmol) and Pd(OAc)2 (21 mg, 0.093 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc; 1:0 to 1:4). The product was obtained as an orange oil (0.224 g, 0.84 mmol, 45 %). Rf = 0.20 (hexane:EtOAc; 1:1); (cm-1) 3273, 1680, 1601, 1510, 1448, 1395, 1318, 1296, 1238, 1145, 972, 908, 771, 754, 696; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.06 (t, J = 7.2 Hz, 3H), 2.57 – 2.74 (m, 2H), 3.05 (s, 3H), 4.68 (s, 1H), 7.03 (s, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 7.7, 33.6, 40.0, 49.9, 116.4, 121.0, 126.6, 129.6, 138.1, 199.4; HRMS (APCI-MMI) m/z: [M-H]- Calcd for C12H13N2O3S 265.0652; Found 265.0652. 2-(4-(morpholinosulfonyl)phenyl)-3-oxopentanenitrile (2m).



Page 20 of 64

Prepared according to general procedure B with 3-oxopentanenitrile (0.1 g, 1 mmol), 4-[(4bromophenyl)sulfonyl]morpholine (0.26 g, 0.85 mmol), Cs2CO3 (0.98 g, 3 mmol), tBuMePhos (16 mg, 0.05 mmol) and Pd(OAc)2 (12 mg, 0.05 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 2:1 to 0:1). The product was obtained as a yellow wax (0.19 g, 0.57 mmol, 67 %). Rf = 0.44 (hexane:EtOAc; 7:3); 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.10 (t, J = 7.2 Hz, 3H), 2.65 – 2.86 (m, 2H), 3.02 – 3.08 (m, 4H), 3.74 – 3.77 (m, 4H), 4.78 (s, 1H), 7.58 – 7.65 (m, 2H), 7.81 – 7.84 (m, 2H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 7.5, 34.0, 45.9, 50.0, 66.1, 115.6, 128.9, 129.0, 134.9, 136.7, 198.1; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C15H19N2O4S 323.1060; Found 323.1057. 3-oxo-2-(4-(piperidin-1-ylsulfonyl)phenyl)pentanenitrile (2n). Prepared according to general procedure B with 3-oxopentanenitrile (100 mg, 1 mmol), 1-[(4bromophenyl)sulfonyl]piperidine (300 mg, 1 mmol), Cs2CO3 (0.98 g, 3 mmol), tBuMePhos (16 mg, 0.05 mmol) and Pd(OAc)2 (12 mg, 0.05 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 2:1 to 0:1). The product was obtained as a yellow wax (170 mg, 0.55 mmol, 55 %). Rf = 0.45 (hexane:EtOAc; 7:3); IR (cm-1) 2201, 1687, 1337, 1161, 925, 737, 577; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.08 (t, J = 7.2 Hz, 3H), 1.40 – 1.49 (m, 2H), 1.61 – 1.70 (m, 4H), 2.63 – 2.82 (m, 2H), 2.97 – 3.05 (m, 4H), 4.79 (s, 1H), 7.55 – 7.60 (m, 2H), 7.80 – 7.83 (m, 2H);

13C{1H}

NMR

(126 MHz, Chloroform-d)  (ppm) 7.8, 23.6, 25.4, 34.1, 47.1, 50.2, 115.9, 128.9, 129.0, 134.6, 138.0, 198.5; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C16H21N2O3S 321.1267; Found 321.1267. 2-(3-chloro-4-fluorophenyl)-3-oxopentanenitrile (2o). Prepared according to general procedure B with 3-oxopentanenitrile (0.171 g, 1.76 mmol), 1-bromo3-chloro-4-fluorobenzene (0.406 g, 0.236 mL, 1.94 mmol), Cs2CO3 (1.72 g, 5.28 mmol), tBuMePhos (55 mg, 0.18 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc; 1:0 to 2:1). The product was obtained as yellow wax (0.262 g, 1.16 mmol, 66 %). Rf = 0.31 (hexane:EtOAc; 2:1); IR (cm-1) 2979, 2205, 1733, 1701, 1620, 1591, 1530, 1499, 1463, 1350, 1260, 1228, 1139, 1111, 1062, 945, 881, 822, 768, 710; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.08 (t, J = 7.2 Hz, 3H), 2.60 – 2.80 (m, 2H), 4.63 (s, 1H), 7.21 (dd, J = 8.5, 8.5 Hz, 1H), 7.28 (ddd, J = 8.7, 4.4, 2.4 Hz, 1H), 7.46 (dd, J = 6.6, 2.4 Hz, 1H);

13C{1H}

NMR (126 MHz, Chloroform-d) 

(ppm) 7.7, 33.7, 49.3, 115.9, 117.9 (d, J = 21.8 Hz), 122.7 (d, J = 19.1 Hz), 127.0 (d, J = 4.5 Hz), 128.0 (d, J = 7.3 Hz), 130.5, 158.7 (d, J = 252.5 Hz), 198.7; 19F{1H} NMR (471 MHz, Chloroform-d)

 (ppm) -113.68; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C11H8ClFNO 224.0284; Found 224.0283. 2-(benzo[d][1,3]dioxol-5-yl)-3-oxopentanenitrile (2p). Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 5-bromo1,3-benzodioxole (0.5 g, 0.3 mL, 2.5 mmol), Cs2CO3 (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06 mmol) and Pd(OAc)2 (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; ACS Paragon Plus Environment

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2:1). The product was obtained as a yellow solid (0.15 g, 0.67 mmol, 25 %). Rf = 0.5 (hexane:EtOAc; 2:1); IR (cm-1) 2248, 1724, 1466, 1240, 1032, 807; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.06 (t, J = 7.2 Hz, 3H), 2.54 – 2.73 (m, 2H), 4.59 (s, 1H), 6.01 (s, 2H), 6.82 – 6.88 (m, 3H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 7.9, 33.2, 50.4, 102.0, 108.4, 109.3, 116.6, 122.0, 123.6, 148.7, 149.0, 199.7; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C12H10NO3 216.0666; Found 216.0666. 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxopentanenitrile (2q). Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 6-bromo2,3-dihydro-1,4-benzodioxine (0.53 g, 0.33 mL, 2.5 mmol), Cs2CO3 (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06 mmol) and Pd(OAc)2 (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 2:1). The product was obtained as a yellow solid (0.3 g, 1.3 mmol, 63 %). Rf = 0.5 (hexane:EtOAc; 2:1); mp = 86 - 88 °C; IR (cm-1) 2218, 1626, 1508, 1344, 1283, 1063, 858, 749; 1H NMR (300 MHz, Chloroform-d)  (ppm) 1.28 (t, J = 7.6 Hz, 3H), 2.47 – 2.83 (m, 2H), 4.29 (s, 4H), 6.25 (s, 1H), 6.77 – 7.05 (m, 3H); 13C{1H} NMR (75 MHz, Chloroform-d)  (ppm) 7.8, 33.1, 50.1, 64.5, 64.5, 116.6, 117.1, 118.5, 121.1, 123.0, 144.5, 144.6, 199.7; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C13H12NO3 230.0823; Found 230.0824. 2-(naphthalen-2-yl)-3-oxopentanenitrile (2r). Prepared according to general procedure B with 3-oxopentanenitrile (0.176 g, 1.81 mmol), 2bromonaphtalene (0.413 g, 2 mmol), Cs2CO3 (1.77 g, 5.44 mmol), tBuMePhos (57 mg, 0.18 mmol) and Pd(OAc)2 (10 mg, 0.045 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc; 10:1 to 1:1). The product was obtained as a pale orange solid (0.304 g, 1.36 mmol, 75 %). Rf = 0.37 (hexane:EtOAc; 2:1); mp = 94 - 96 °C; IR (cm-1) 3365, 3184, 3140, 3075, 2957, 2923, 2855, 1631, 1601, 1585, 1522, 1491, 1463, 1444, 1343, 1115, 1044, 1025, 944, 889, 860, 822, 794, 746, 729; 1H

NMR (500 MHz, Chloroform-d)  (ppm) 1.04 (t, J = 7.2 Hz, 3H), 2.62 (dq, J = 18.6, 7.2 Hz, 1H),

2.73 (dq, J = 18.6, 7.2 Hz, 1H), 4.85 (s, 1H), 7.44 (dd, J = 8.5, 2.1 Hz, 1H), 7.52 – 7.59 (m, 2H), 7.83 – 7.89 (m, 2H), 7.89 – 7.94 (m, 2H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.3, 51.0, 116.5, 124.9, 127.3, 127.3, 127.4, 127.7, 128.0, 128.2, 129.8, 133.4, 133.5, 199.6; HRMS (APCITOF) m/z: [M+H]+ Calcd for C15H14NO 224.1070; Found 224.1072. 3-oxo-2-(3-(trifluoromethyl)phenyl)pentanenitrile (2s). Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 1-bromo3-(trifluoromethyl)benzene (0.55 g, 0.35 ml, 2.5 mmol), Cs2CO3 (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06 mmol) and Pd(OAc)2 (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 2:1). The product was obtained as a yelow oil (320 mg, 1.37 mmol, 65 %). or Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 1-bromo3-(trifluoromethyl)benzene (0.55g, 0.35 ml, 2.5 mmol), Cs2CO3 (1.95 g, 6.3 mmol), XPhos (28 mg, ACS Paragon Plus Environment


Page 22 of 64

0.06 mmol) and Pd(OAc)2 (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 2:1). The product was obtained as a yelow oil (282 mg, 1.17 mmol, 56 %). or Prepared according to general procedure B with 3-oxopentanenitrile (168 mg, 1.73 mmol), 1-bromo3-(trifluoromethyl)benzene (0.43 g, 0.27 ml, 1.9 mmol), Cs2CO3 (1.7 g, 5.2 mmol), PPh3 (44 mg, 0.17 mmol) and Pd(OAc)2 (22 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 2:1). The product was obtained as a yelow oil (170 mg, 0.69 mmol, 40 %). IR (cm-1) 2209, 1731, 1629, 1165, 1121, 1074, 800, 698; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.10 (t, J = 7.2 Hz, 3H), 2.85 – 2.59 (m, 2H), 4.75 (s, 1H), 7.64 – 7.57 (m, 2H), 7.66 (s, 1H), 7.69 (d, J = 7.2 Hz, 1H); 13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.9, 50.2, 116.0, 123.7 (q, J = 272.5 Hz), 125.1

(q, J = 3.7 Hz), 126.4 (q, J = 3.6 Hz), 130.4, 131.2, 131.6, 132.3 (q, J = 32.9 Hz), 198.7; 19F{1H} NMR (471 MHz, Chloroform-d)  -62.82; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H9F3NO2 256.0591; Found 256.0592. methyl 3-(1-cyano-2-oxobutyl)benzoate (2t). Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), methyl 3bromobenzoate (0.53 g, 2.5 mmol), Cs2CO3 (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06 mmol) and Pd(OAc)2 (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 2:1). The product was obtained as a pale yelow oil (0.2 g, 0.87 mmol, 43 %); or Prepared according to general procedure B with 3-oxopentanenitrile (134 g, 1.38 mmol), methyl 3bromobenzoate (0.31 g, 1.45 mmol), Cs2CO3 (1.41 g, 4.35 mmol), PPh3 (40 mg, 0.15 mmol) and Pd(OAc)2 (20 mg, 0.08 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 2:1). The product was obtained as a pale yelow oil (127 mg, 0.55 mmol, 40 %). IR (cm-1) 2210, 1727, 1693, 1218, 755, 670; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.08 (t, J = 7.2 Hz, 3H), 2.70 (p, J = 7.2 Hz, 2H), 3.96 (d, J = 1.1 Hz, 3H), 4.76 (s, 1H), 7.50 – 7.59 (m, 1H), 7.59 – 7.65 (m, 1H), 8.05 – 8.14 (m, 2H);

13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.8, 50.4, 52.7, 116.2, 129.3, 130.0,

130.6, 130.7, 131.9, 132.4, 166.2, 199.0; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C13H12NO3 230.0823; Found 230.0823. 2-(3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-3-oxopentanenitrile (2u). Prepared according to general procedure B with 3-oxopentanenitrile (0.205 g, 2.11 mmol), 2-(3Bromophenyl)-5-methyl-1,3,4-oxadiazole (0.605 g, 2.53 mmol), Cs2CO3 (2.06 g, 6.33 mmol), tBuMePhos (66 mg, 0.21 mmol) and Pd(OAc)2 (24 mg, 0.1 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc; 3:1 to 0:1). The product was obtained as a yellow-orange solid (0.307 g, 1.20 mmol, 57 %). Rf = 0.50 (EtOAc); Mp > 250 °C; IR (cm-1) 2196, 1624, 1580, 1555, 1493, 1450, 1420, 1381, 1344, 1288, 1265, 1239, 1071, 1044, 981, 891, 798, 753, 727, 682; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.25 (t, J = 7.6 Hz, 3H), 2.59 (s, 3H), 2.64 (q, J = 7.6 Hz, 2H), ACS Paragon Plus Environment

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7.58 (dd, J = 7.9, 7.9 Hz, 1H), 7.81 (dd, J = 13.3, 7.8 Hz, 2H), 8.29 (s, 1H), 11.97 (s, 1H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 10.6, 12.2, 28.9, 84.8, 120.1, 123.6, 123.9, 124.4, 129.5, 129.8, 133.9, 163.8, 164.0, 174.8; HRMS (APCI-MMI) m/z: [M+H]+ Calcd for C14H12N3O2 254.0935; Found 254.0934. 2-([1,1'-biphenyl]-3-yl)-3-oxopentanenitrile (2v). Prepared according to general procedure B with 3-oxopentanenitrile (0.097 g, 1 mmol), 3bromobiphenyl (0.244 g, 0.175 Ml, 1.05 mmol), Cs2CO3 (0.976 g, 3 mmol), PPh3 (27 mg, 0.1 mmol) and Pd(OAc)2 (6 mg, 0.025 mmol) in DMF (3 mL). Reaction time: 1 h. Column chromatography (hexane:EtOAc; 10:1 to 1:2). The product was obtained as a yellow-orange oil (0.136 g, 0.55 mmol, 63 %). Rf = 0.43 (hexane:EtOAc; 2:1); 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.06 (t, J = 7.2 Hz, 3H), 2.57 – 2.79 (m, 2H), 4.75 (s, 1H), 7.35 – 7.42 (m, 2H), 7.44 – 7.53 (m, 3H), 7.56 – 7.65 (m, 4H); 13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.4, 50.8, 116.5, 126.8, 127.3, 128.1, 129.1,

130.1, 130.6, 140.0, 143.0, 199.5; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C17H16NO 250.1226; Found 250.1222. or Prepared according to general procedure B with 3-oxopentanenitrile (0.139 g, 1.43 mmol), 3bromobiphenyl (0.4 g, 0.286 mL, 1.72 mmol), Cs2CO3 (1.399 g, 4.29 mmol), tBuMePhos (45 mg, 0.143 mmol) and Pd(OAc)2 (8 mg, 0.036 mmol) in DMF (3 mL). Reaction time: 1 h. Column chromatography (hexane:EtOAc; 10:1 to 1:2). The product was obtained as a yellow-orange oil (0.274 g, 1.1 mmol, 76 %). 3-oxo-2-(3-(trifluoromethoxy)phenyl)pentanenitrile (2w). Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 1-bromo3-(trifluoromethoxy)benzene (0.6 g, 0.37 mL, 2.5 mmol), Cs2CO3 (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06 mmol) and Pd(OAc)2 (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 2:1). The product was obtained as a yellow wax (0.35 g, 1.36 mmol, 66 %). Rf = 0.55 (hexane:EtOAc; 7:3); IR (cm-1) 2210, 1732, 1623, 1354, 1153, 698, 663; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.08 (t, J = 7.2 Hz, 3H), 2.61 – 2.78 (m, 2H), 4.70 (s, 1H), 7.26 – 7.30 (m, 1H), 7.35 – 7.37 (m, 1H), 7.49 (t, J = 8 Hz, 1H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.7, 50.2, 116.0, 120.6 (q, J = 258.2 Hz), 120.9, 121.8, 126.5, 131.3, 132.2, 150.1, 198.7; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C12H9F3NO2 256.0591; Found 256.0592. 2-(3-methoxyphenyl)-3-oxopentanenitrile (2x). Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 3bromoanisole (0.46 g, 0.3 mL, 2.5 mmol), Cs2CO3 (1.95 g, 6.3 mmol), XPhos (29 mg, 0.06) and Pd(OAc)2 (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 2:1). The product was obtained as a yellow oil (0.25 g, 0.12 mmol, 58 %). Rf = 0.6 (hexane:EtOAc; 7:3); IR ACS Paragon Plus Environment


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(cm-1) 2204, 1728, 1600, 1455, 1259, 1037, 780, 696; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.05 (t, J = 7.2 Hz, 3H), 2.51 – 2.80 (m, 2H), 3.84 (s, 3H), 4.66 (s, 1H), 6.91 – 6.95 (m, 2H), 6.98 (d, J = 7.7 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H);

13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm) 7.9, 33.3,

50.9, 55.6, 113.8, 115.0, 116.5, 120.3, 130.9, 131.5, 160.7, 199.6; HRMS (APCI-TOF) m/z: [M-H]Calcd for C12H12NO2 202.0874; Found 202.0874. or Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 3bromoanisole (0.46 g, 0.3 mL, 2.5 mmol), Cs2CO3 (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06 mmol) and Pd(OAc)2 (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 2:1). The product was obtained as a yellow oil (0.27 g, 1.3 mmol, 65 %). 2-(3,5-dimethoxyphenyl)-3-oxopentanenitrile (2y). Prepared according to general procedure B with 3-oxopentanenitrile (0.201 g, 2.1 mmol), 1-bromo3,5-dimethoxybenzene (0.494 g, 2.3 mmol), Cs2CO3 (2.02 g, 6.2 mmol), tBuMePhos (65 mg, 0.21 mmol) and Pd(OAc)2 (23 mg, 0.1 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc; 1:0 to 2:1). The product was obtained as a yellow oil (0.263 g, 1.13 mmol, 54 %). Rf = 0.43 (hexane:EtOAc; 2:1); IR (cm-1) 2941, 2840, 2204, 1729, 1594, 1458, 1430, 1347, 1325, 1299, 1205, 1156, 1108, 1062, 836, 693; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.05 (t, J = 7.2 Hz, 3H), 2.56 (dq, J = 18.6, 7.2 Hz, 1H), 2.69 (dq, J = 18.6, 7.3 Hz, 1H), 3.80 (s, 6H), 4.59 (s, 1H), 6.46 (dd, J = 2.2 Hz, 1H), 6.51 (d, J = 2.1 Hz, 2H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.1, 51.0, 55.7, 101.1, 106.2, 116.3, 132.0, 161.8, 199.4; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C13H14NO3 232.0979; Found 232.0979. 2-(3-hydroxyphenyl)-3-oxopentanenitrile (2z). Prepared according to general procedure B with 3-oxopentanenitrile (0.193 g, 1.99 mmol), 3bromophenol (0.378 g, 2.18 mmol), Cs2CO3 (1.94 g, 5.96 mmol), tBuMePhos (62 mg, 0.2 mmol) and Pd(OAc)2 (22 mg, 0.1 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc; 1:0 to 1:1). The product was obtained as a light brown wax (0.298 g, 1.57 mmol, 79 %). Rf = 0.21 (hexane:EtOAc; 2:1); IR (cm-1) 3395, 2982, 2257, 2209, 1722, 1591, 1489, 1456, 1349, 1277, 1220, 1190, 1162, 1108, 998, 964, 871, 781, 695; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.05 (t, J = 7.2 Hz, 3H), 2.58 (dq, J = 18.6, 7.2 Hz, 1H), 2.69 (dq, J = 18.6, 7.2 Hz, 1H), 4.65 (s, 1H), 5.49 (s, 1H), 6.87 (ddd, J = 8.1, 2.4, 1 Hz, 1H), 6.90 (dd, J = 2.1 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 7.29 (dd, J = 7.8 Hz, 1H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.3, 50.6, 114.9, 116.4, 116.6, 120.4, 131.1, 131.4, 156.9, 199.7; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C11H10NO2 188.0717; Found 188.0717. 2-(4-fluoro-2-methylphenyl)-3-oxopentanenitrile (2aa).


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Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 2-bromo5-fluorotoluene (466 mg, 2.47 mmol), Cs2CO3 (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06 mmol) and Pd(OAc)2 (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 5:1 to 1:1). The product was obtained as a yellow solid (115 mg, 0.55 mmol, 27 %). Rf = 0.50 (Hexane:EtOAc; 2:1); mp = 117 - 119 °C; IR (cm-1) 2202, 1729, 1495, 1253, 864, 815; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.01 (t, J = 7.2 Hz, 3H), 2.30 (s, 3H), 2.53 (q, J = 7.2 Hz, 2H), 4.78 (s, 1H), 6.85 – 7.00 (m, 2H), 7.23 – 7.37 (m, 1H); 13C{1H} NMR (75 MHz, Chloroform-d)  (ppm) 7.8, 19.8 (d, J = 1.7 Hz), 33.6, 47.7, 114.3 (d, J = 21.8 Hz), 116.3, 118.5 (d, J = 21.6 Hz), 125.0 (d, J = 3.3 Hz), 130.9 (d, J = 8.8 Hz), 139.2 (d, J = 8.2 Hz), 163.0 (d, J = 249.2 Hz), 199.5;

19F{1H}

NMR

(282 MHz, Chloroform-d)  (ppm) -112.4; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C12H11FNO 204.0830; Found 204.0831. 2-(naphthalen-1-yl)-3-oxopentanenitrile (2ab). Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 1bromonaphtalene (0.51 g, 0.35 mL, 2.5 mmol), Cs2CO3 (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06 mmol) and Pd(OAc)2 (14 mg, 0.06 mmol) in DMF (3 mL) for 3 h. Column chromatography (hexane:EtOAc; 2:1). The product was obtained as a brown oil (0.23 g, 1 mmol, 50 %). Rf = 0.60 (hexane:EtOAc; 2:1); IR (cm-1) 2200, 1726, 1398, 1350, 1109, 773; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.0 (t, J = 7.2 Hz, 3H), 2.5 – 2.6 (m, 2H), 5.3 (s, 1H), 7.5 – 7.7 (m, 3H), 7.7 (d, J = 7.1 Hz, 1H), 7.9 – 8.0 (m, 3H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 7.9, 33.1, 49.1, 116.6, 122.8, 125.8,

126.5, 126.9, 127.9, 128.0, 129.5, 130.5, 130.7, 134.4, 200.1; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C15H12NO 222.0924; Found 222.0924. 3-oxo-2-(2-(trifluoromethoxy)phenyl)pentanenitrile (2ac). Prepared according to general procedure B with 3-oxopentanenitrile (0.122 g, 1.26 mmol), 1-bromo2-(trifluoromethoxy)benzene (0.363 g, 1.51 mmol), Cs2CO3 (1.23 g, 3.77 mmol), tBuMePhos (0.039 g, 0.125 mmol) and Pd(OAc)2 (0.007 g, 0.03 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 0:1 to 1:1). The product was obtained as a yellow oil (0.059 g, 0.023 mmol, 18 %). Rf = 0.50 (Hexane:EtOAc; 2:1); 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.10 (t, J = 7.2 Hz, 3H), 2.56 – 2.77 (m, 2H), 5.03 (s, 1H), 7.32 – 7.37 (m, 1H), 7.38 (dd, J = 7.6, 1.4 Hz, 1H), 7.43 – 7.50 (m, 1H), 7.52 (dd, J = 7.7, 1.8 Hz, 1H);

13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm) 7.7, 34.3, 44.4,

115.6, 120.1, 120.5 (q, J = 260 Hz), 122.9, 127.6, 130.5, 131.1, 146.8, 198.1; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H11F3NO2 258.0736; Found 258.0737. 3-cyclohexyl-3-oxo-2-phenylpropanenitrile (2ad). Prepared according to general procedure B with 3-cyclohexyl-3-oxopropanenitrile(100 mg, 0.661 mmol), bromobenzene (76.4 µL, 0.727 mmol), Cs2CO3 (646 mg, 1.983 mmol), tBuMePhos (20.7 mg, 0.066 mmol) and Pd(OAc)2 (7.4 mg, 0.033mmol) in DMF (3.5 mL). Column chromatography ACS Paragon Plus Environment


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(hexane:EtOAc; 9:1 to 4:1). The product was obtained as a yellow solid (78 mg, 0.343 mmol, 52 %). Rf = 0.50 (EtOAc:MeOH; 1:1); mp = 93 − 101 °C; IR (cm-1) 3267, 3054, 2931, 2850, 2204, 1618, 1495, 1448, 1356, 1343, 1258, 1087, 1068, 1029, 929, 893, 759, 746, 691; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.14 – 1.29 (m, 3H), 1.29 – 1.47 (m, 2H), 1.60 – 1.81 (m, 5H), 2.65 (tt, J = 11.2, 3.2 Hz, 1H), 4.78 (s, 1H), 7.35 – 7.48 (m, 5H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm)

25.2, 25.5, 25.6, 28.8, 29.2, 48.6, 49.4, 116.5, 128.3, 129.3, 129.7, 129.9, 201.7; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C15H16NO 226.1237; Found 226.1236. 3-oxo-2-phenyl-3-(4-(trifluoromethyl)phenyl)propanenitrile (2ae). Prepared according to general procedure B with 3-oxo-3-(4-(trifluoromethyl)phenyl)propanenitrile (100 mg, 0.469 mmol), bromobenzene (54.3 µL, 0.516 mmol), Cs2CO3 (459 mg, 1.41 mmol), tBuMePhos (15 mg, 0.047 mmol) and Pd(OAc)2 (5 mg, 0.023 mmol) in DMF (3.5 mL). Column chromatography (hexane:EtOAc; 1:0 to 7:3). The product was obtained as light brown solid (74 mg, 0.256 mmol, 55 %). Rf = 0.40 (EtOAc:MeOH; 10:1); mp = 99 − 101 °C; IR (cm-1) 3074, 2220, 1610, 1047, 1349, 1323, 1289, 1264, 1244, jj1176, 1151, 1128, ,1115, 1069, 1053, 1014, 835, 755, 735, 696; 1H NMR (300 MHz, Chloroform-d)  (ppm) 5.55 (s, 1H), 7.37 – 7.47 (m, 5H), 7.73 (d, J = 8.3 Hz, 2H), 8.05 (d, J = 8.2 Hz, 2H);

13C{1H}

NMR (75 MHz, Chloroform-d)  (ppm) 47.3, 116.2, 123.3

(q, J = 272.9 Hz), 126.2 (q, J = 3.7 Hz), 128.4, 128.9 (q, J = 12.2 Hz), 129.6, 129.7, 129.8 (q, J = 3.4 Hz), 130.0, 136.5, 188.4; 19F{1H} NMR (282 MHz, Chloroform-d)  (ppm) -63.5; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C16H9F3NO 288.0642; Found 288.0642. 3-(4-methoxyphenyl)-3-oxo-2-phenylpropanenitrile (2af). Prepared according to general procedure B with 3-(4-methoxyphenyl)-3-oxopropanenitrile (100 mg, 0.57 mmol), bromobenzene (66 µL, 0.63 mmol), Cs2CO3 (558 mg, 1.71 mmol), tBuMePhos (18 mg, 0.057 mmol) and Pd(OAc)2 (6.4 mg, 0.029mmol) in DMF (3.5 mL). Column chromatography (hexane:EtOAc; 4:1 to 3:1). The product was obtained as light brown wax (90 mg, 0.358 mmol, 63 %). Rf = 0.60 (Hexane:EtOAc; 1:1); IR (cm-1) 2933, 2204, 1677, 1598, 1573, 1511, 1494, 1452, 1422, 1317, 1263, 1236, 1171, 1119, 1023, 934, 854, 845, 823, 750, 737, 636; 1H NMR (300 MHz, Chloroform-d)  3.83 (s, 3H), 5.58 (s, 1H), 6.87 – 6.94 (m, 2H), 7.32 – 7.47 (m, 5H), 7.89 – 7.98 (m, 2H).13C{1H} NMR (75 MHz, Chloroform-d)  46.4, 55.7, 114.4, 117.0, 126.5, 128.2, 129.0, 129.6, 131.0, 131.8, 164.6, 187.4. HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C16H14NO2 252.1019; Found 252.1019. CAS registry No. [5415-11-2]. 1H NMR spectrum was consistent with that previously reported in the literature.30e 3-(4-(tert-butyl)phenyl)-3-oxo-2-phenylpropanenitrile (2ag). Prepared according to general procedure B with 3-(4-(tert-butyl)phenyl)-3-oxopropanenitrile (100 mg, 0.497 mmol), bromobenzene (57 µL, 0.547 mmol), Cs2CO3 (487 mg, 1.49 mmol), tBuMePhos ACS Paragon Plus Environment

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(16 mg, 0.05 mmol) and Pd(OAc)2 (6 mg, 0.025 mmol) in DMF (3.5 mL). Column chromatography (hexane:EtOAc; 9:1 to 4:1). The product was obtained as light brown oil (75 mg, 0.27 mmol, 54 %).Rf = 0.60 (Hexane:EtOAc; 3:1); IR (cm-1) 2963, 2251, 1686, 1602, 1564, 1455, 1409, 1365, 1291, 1268, 1233, 1195, 1109, 1025, 1012, 938, 861, 818, 757, 745, 720, 698; 1H NMR (300 MHz, Chloroformd)  1.32 (s, 9H), 5.60 (s, 1H), 7.30 – 7.33 (m, 3H), 7.43 – 7.51 (m, 4H), 7.87 – 7.95 (m, 2H).13C{1H} NMR (75 MHz, Chloroform-d)  31.0, 35.4, 46.6, 116.8, 126.1, 128.4, 129.1, 129.4, 129.7, 130.8, 131.2, 158.6, 188.5. HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C19H20NO 278.1539; Found 278.1539. 2-(4-fluorophenyl)-3-(3-methoxynaphthalen-2-yl)-3-oxopropanenitrile (2ah). Prepared according to general procedure B with 3-(3-methoxynaphthalen-2-yl)-3-oxopropanenitrile (0.3 g, 1.33 mmol), 1-bromo-4-fluorobenzene (0.28 mg, 0.18 mL, 1.6 mmol), Cs2CO3 (1.30 g, 4 mmol), tBuMePhos (13 mg, 0.04 mmol) and Pd(OAc)2 (9 mg, 0.04 mmol) in DMF (3 mL) for 1.5 h. Column chromatography (hexane:EtOAc; 5:1 to 1:1). The product was obtained as a white solid (0.36 g, 1.13 mmol, 85 %). Rf = 0.60 (hexane:EtOAc ; 1:1); mp = 176 - 177 °C; IR (cm-1) 2216, 1615, 1599, 1505, 1346, 1214, 830, 811; 1H NMR (500 MHz, DMSO-d6)  (ppm) 3.94 (s, 3H), 7.27 (t, J = 8.8 Hz, 2H), 7.43 (t, J = 7.5 Hz, 1H), 7.50 (s, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.82 (dd, J = 8.6, 5.5 Hz, 2H), 7.90 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 8.06 (s, 1H), 12.19 (s, 1H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm), 55.8, 88.6, 106.3, 115.2, 115.4, 120.3, 124.3, 126.5, 126.6, 127.6 (d, J = 15.5 Hz), 128.1, 129.1, 129.1, 130.2, 135.0, 154.4, 160.6 (d, J = 244.4 Hz), 165.5; HRMS (APCITOF) m/z: [M+H]+ Calcd for C20H15FNO2 320.1081; Found 320.1081. 3-(3-methoxynaphthalen-2-yl)-2-(4-(methylsulfonyl)phenyl)-3-oxopropanenitrile (2ai). Prepared according to general procedure B with 3-(3-methoxynaphthalen-2-yl)-3-oxopropanenitrile (0.21 mg, 0.93 mmol), 4-bromophenyl methyl sulfone (0.25 g, 1.12 mmol), Cs2CO3 (0.91 g, 2.8 mmol), tBuMePhos (0.01 g, 0.03 mmol) and Pd(OAc)2 (0.006 g, 0.03 mmol) in DMF (3 mL) for 1 h. Column chromatography (hexane:EtOAc; 1:1 to 0:1). The product was obtained as a white solid (0.2 g, 0.52 mmol, 56 %). Rf = 0.75 (EtOAc); mp = 143 - 144 °C; IR (cm-1) 1620, 1519, 1321, 1041, 705; 1H

NMR (500 MHz, DMSO-d6)  (ppm) 3.22 (s, 1H), 3.95 (s, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.53 (s,

1H), 7.58 (t, J = 7.5 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.94 – 8.00 (m, 3H), 8.03 – 8.08 (m, 2H), 8.10 (s, 1H), 12.87 (s, 1H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 44.2, 56.4, 89.0, 106.9, 120.5,

124.9, 126.9, 127.1, 127.4, 127.8, 128.0, 128.3, 128.6, 128.6, 130.6, 135.6, 138.7, 154.7, 169.3; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C21H18NO4S 380.0951; Found 380.0956. 3-oxo-2-(pyridin-4-yl)pentanenitrile (2aj). Prepared according to general procedure B with 3-oxopentanenitrile (0.167 g, 1.72 mmol), 4bromopyridine hydrochloride (0.368 g, 1.89 mmol), Cs2CO3 (2.24 g, 6.88 mmol), tBuMePhos (54 mg, 0.17 mmol) and Pd(OAc)2 (10 mg, 0.043 mmol) in DMF (6 mL). Column chromatography ACS Paragon Plus Environment


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(hexane:EtOAc:MeOH; 1:1:0 to 0:9:1). The product was obtained as a pale orange solid (0.232 g, 1.22 mmol, 71 %). or Prepared according to general procedure B with 3-oxopentanenitrile (0.191 g, 1.97 mmol), 4bromopyridine hydrochloride (0.421 g, 2.16 mmol), Cs2CO3 (2.56 g, 7.87 mmol), XPhos (94 mg, 0.197 mmol) and Pd(OAc)2 (11 mg, 0.049 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc:MeOH; 1:1:0 to 0:9:1). The product was obtained as a pale orange solid (0.09 g, 0.473 mmol, 24 %). or Prepared according to general procedure B with 3-oxopentanenitrile (0.214 g, 1.93 mmol), 4bromopyridine hydrochloride (0.393 g, 2.02 mmol), Cs2CO3 (2.51 g, 7.7 mmol), PPh3 (50 mg, 0.193 mmol) and Pd(OAc)2 (11 mg, 0.048 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc:MeOH; 1:1:0 to 0:9:1). The product was obtained as a pale orange solid (0.237 g, 1.25 mmol, 65 %). Rf = 0.53 (EtOAc:MeOH; 20:1); Mp > 175 °C decomp.; IR (cm-1) 2175, 1635, 1530, 1465, 1410, 1386, 1365, 1304, 1261, 1233, 1189, 1071, 1051, 885, 851, 815; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.02 (t, J = 7.5 Hz, 3H), 2.53 (q, J = 7.5 Hz, 2H), 6.49 – 9.44 (br. s, 2H), 7.98 (d, J = 7.6 Hz, 2H), 12.88 (s, 1H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 9.5, 33.8, 78.2,

114.4, 123.5, 137.2, 154.4, 193.1; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C10H11N2O 175.0866; Found 175.0868. CAS registry No. [126769-99-1]. 1H NMR spectrum was consistent with that previously reported in the literature.30f 3-ethyl-4-phenyl-1H-pyrazol-5-amine (3a). Prepared according to general procedure C1 with 3-oxo-2-phenylpentanenitrile (230 mg, 1.34 mmol), N2H4.H2O (0.4 g, 6.6 mmol, 0.4 mL) and HCl (35 %, 1.3 g, 13.4 mmol, 1.2 mL) in absolute EtOH (3 mL) for 3 hours. Column chromatography (hexane:EtOAc; 4:1 to 0:1). The product was obtained as a pale white solid (0.2 g, 1.1 mmol, 80 %). Rf = 0.1 (EtOAc); mp = 169 - 170 °C; IR (cm-1) 3371, 1603, 1477, 897, 793, 773, 697; 1H NMR (300 MHz, DMSO-d6)  (ppm) 1.03 – 1.20 (m, 3H), 2.56 (q, J = 7.6 Hz, 2H), 7.10 – 7.26 (m, 1H), 7.30 – 7.48 (m, 4H); 13C{1H} NMR (75 MHz, DMSO-d6)

 (ppm) 13.3, 18.4, 103.6, 125.0, 128.0, 128.4, 134.1; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C11H14N3 188.1182; Found 188.1182. CAS registry No. [110335-22-3]. 1H NMR spectrum was consistent with that previously reported in the literature.30g 3-ethyl-4-(4-fluorophenyl)-1H-pyrazol-5-amine (3b). Prepared according to general procedure C1 with 2-(4-fluorophenyl)-3-oxopentanenitrile (1.89 g, 9.88 mmol), N2H4.H2O (0.494 g, 0.48 mL, 9.88 mmol) and CH3SO3H (0.095 g, 0.064 mL, 0.99 mmol) in absolute EtOH (20 mL) for 1 hour. Column chromatography (hexane:EtOAc; 3:1 to 0:1). The ACS Paragon Plus Environment

Page 29 of 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


product was obtained as a white solid (1.826 g, 8.9 mmol, 90 %). Rf = 0.28 (EtOAc); mp = 163 - 166 °C; IR (cm-1) 3374, 1963, 2933, 2853, 1530, 1484, 1225, 1158, 838; 1H NMR (500 MHz, DMSO-d6)

 (ppm) 1.23 (q, 3H, J = 7.5 Hz), 2.69 (q, 2H, J = 7.5 Hz), 3.48 (s, 2H, J = 77.8 Hz), 7.27 – 7.40 (m, 2H), 7.42 – 7.52 (m, 2H), 8.51 (s, 1H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 13.2, 18.4, 102.8, 115.2 (d, J = 21.6 Hz), 129.9 (d, J = 7.9 Hz), 130.4 (d, J = 3.1 Hz), 143.1, 160.1 (d, J = 242.2 Hz); 19F{1H}

NMR (471 MHz, DMSO-d6)  (ppm) – 117.79; HRMS (APCI-TOF) m/z: [M-H]- Calcd for

C11H11FN3 204.0942; Found 204.0948. 3-ethyl-4-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (3c). Prepared according to general procedure C1 with 3-oxo-2-(4-(trifluoromethyl)phenyl)pentanenitrile (0.27 g, 1.12 mmol), N2H4.H2O (67 mg, 65 L, 1.34 mmol) and CH3SO3H (33 mg, 21 L, 0.34 mmol) in absolute EtOH (5 mL) for 3 hours. Column chromatography (EtOAc:MeOH; 1:0 to 10:1). The product was obtained as as a pale yellow solid (29 mg, 0.114 mmol, 10 %). or Prepared according to general procedure C3 with 3-oxo-2-(4-(trifluoromethyl)phenyl)pentanenitrile (90 mg, 0.37 mmol), N2H4.H2O (120 mg, 120 L, 1.86 mmol) and HCl (35 %, 337 mg, 290 L, 3.37 mmol) in absolute EtOH (5 mL) for 3 hours. Column chromatography (Hexane:EtOAc; 1:1 to 0:1 to EtOAc:MeOH; 1:0 to 10:1). The product was obtained as a pale yellow solid (80 mg, 0.31 mmol, 85 %). Rf = 0.16 (EtOAc); mp = 144 - 146 °C; IR (cm-1) 3374, 1618, 1322, 1117, 1050, 846; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.11 (td, J = 7.5, 1.4 Hz, 3H), 2.60 (qd, J = 7.6, 1.4 Hz, 2H), 4.60 (s, 2H), 7.54 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 7.9 Hz, 2H), 11.56 (s, 1H); 13C{1H} NMR (126 MHz, DMSOd6)  (ppm) 13.6, 19.2, 125.7 (q, J = 3.6 Hz), 128.7, 139.3;

19F{1H}

NMR (282 MHz, DMSO-d6) 

(ppm) -55.9; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H13F3N3 256.1056; Found 256.1056. 3-ethyl-4-(4-nitrophenyl)-1H-pyrazol-5-amine (3d). Prepared according to general procedure C2 with 2-(4-nitrophenyl)-3-oxopentanenitrile (50 mg, 0.23 mmol), N2H4.H2O (15 mg, 0.23 mmol) in AcOH (1 mL) for 4 hours. Column chromatography (hexane:EtOAc; 1:1 to 1:1 to EtOAc:MeOH; 10:1). The product was obtained as a pale orange wax (40 mg, 0.17 mmol, 75 %). Rf = 0.1 (EtOAc); IR (cm-1) 3112, 2944, 2911, 1599, 1510, 1341, 1107, 923, 858, 830, 732; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.13 (t, J = 7.6 Hz, 3H), 2.64 (q, J = 7.6 Hz, 2H), 4.84 (s, 2H), 7.57 – 7.62 (m, 2H), 8.18 – 8.24 (m, 2H), 11.84 (s, 1H);

13C{1H}

NMR (126

MHz, DMSO-d6)  (ppm) 12.9, 19.1, 101.7, 123.7, 127.8, 142.2, 143.9, 145.2; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C11H13N4O2 233.1033; Found 233.1033. 4-(5-amino-3-ethyl-1H-pyrazol-4-yl)benzonitrile (3e). Prepared according to general procedure C1 with 4-(1-cyano-2-oxobutyl)benzonitrile (80 mg, 0.4 mmol), N2H4.H2O (28 mg, 27 L, 0.44 mmol) and CH3SO3H (3 mg, 2 L, 0.03 mmol) in absolute



Page 30 of 64

EtOH (2 mL) for 3 hours. Column chromatography (hexane:EtOAc:MeOH; 4:1:0 to 0:1:0 to 0:10:1). The product was obtained as a pale yellow solid, (30 mg, 0.14 mmol, 35 %). or Prepared according to general procedure C3 with 4-(1-cyano-2-oxobutyl)benzonitrile (645 mg, 3.22 mmol), N2H4.H2O (1 g, 0.99 mL, 16 mmol) and HCl (35 %, 3.2 g, 2.86 mL, 32 mmol) in absolute EtOH (5 mL) for 3 hours. Column chromatography (hexane:EtOAc:MeOH; 4:1:0 to 0:1:0 to 0:10:1). The product was obtained as a pale yellow solid (0.4 g, 1.9 mmol, 60 %). Rf = 0.25 (EtOAc:MeOH; 10:1); mp = 169 - 171 °C; IR (cm-1) 3377, 3074, 2224, 1605, 1586, 1476, 1009, 856, 836, 551; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.11 (t, J = 7.6 Hz, 3H), 2.61 (q, J = 7.5 Hz, 2H), 7.50 – 7.54 (m, 2H), 7.75 – 7.80 (m, 2H);

13C{1H}


106.8, 119.3, 128.1, 132.3, 139.7, 144.4, 150.9; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H13N4 213.1135; Found 213.1135. 4-(5-amino-3-ethyl-1H-pyrazol-4-yl)benzoic acid (3f). Prepared according to general procedure C3 with 4-(1-cyano-2-oxobutyl)benzoic acid (150 mg, 0.69 mmol), N2H4.H2O (216 mg, 0.212 mL, 3.46 mmol) and HCl (35 %, 0.71 g, 0,6 mL, 6.9 mmol) in absolute EtOH (3 mL) for 3 hours. After cooling to rt, a saturated aqueous solution of sodium hydroxide (1 mL) was added and the mixture was stirred for 2 h at rt. The solution was neutralized by HCl (35 %) until pH neutral and the solution was extracted with EtOAc (3 × 15 mL). The organic fractions were combined, washed with brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (CH2Cl2:MeOH; 10:1 to 5:1). The sticky product after column was suspended in EtOAc:MeOH (2:0.2 mL) and the precipitate was filtered. The product was obtained as a white solid (25 mg, 0.11 mmol, 16 %). Rf = 0.5 (CH2Cl2:MeOH; 5:1); mp = 238 – 239 °C; IR (cm-1) 3401, 3180, 1673, 1606, 1383, 1313, 1279, 1266, 1180, 1007, 851, 706, 637, 519, 478; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.11 (t, J = 7.5 Hz, 3H), 2.61 (q, J = 7.6 Hz, 2H), 4.64 (s, 2H), 7.41 – 7.46 (m, 2H), 7.89 – 7.95 (m, 2H), 12.01 (s, 2H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 13.1, 18.7, 102.7, 126.8, 127.5, 127.6, 129.6, 139.1, 150.9, 167.3; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C12H12N3O2 230.0935; Found 230.0933. 3-ethyl-4-(4-(methylsulfonyl)phenyl)-1H-pyrazol-5-amine (3g). Prepared according to general procedure C1 with 2-(4-(methylsulfonyl)phenyl)-3-oxopentanenitrile (120 mg, 0.48 mmol), N2H4.H2O (33 mg, 0.53 mmol) and CH3SO3H (5 mg, 0.05 mmol) in absolute EtOH (3 mL) for 3 hours. Column chromatography (hexane:EtOAc; 1:1 to 0:1). The product was obtained as a pale yellow-orange solid (90 mg, 0.34 mmol, 70 %). Rf = 0.1 (EtOAc); mp = 166 - 167 °C; IR (cm-1) 3310, 1599, 1320, 1146, 946, 776, 550; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.12 (t, J = 7.5 Hz, 3H), 2.62 (q, J = 7.6 Hz, 2H), 3.20 (s, 3H), 4.67 (s, 2H), 7.55 – 7.61 (m, 2H), 7.85 – 7.91


Page 31 of 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

(m, 2H), 11.56 (s, 1H);


13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 13.1, 18.7, 43.7, 127.1, 128.0,

136.6, 139.9; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H16N3O2S 266.0958; Found 266.0958. 3-ethyl-4-(4-methoxyphenyl)-1H-pyrazol-5-amine (3h). Prepared according to general procedure C1 with 2-(4-methoxyphenyl)-3-oxopentanenitrile (0.205 g, 1 mmol), N2H4.H2O (61 mg, 59 L, 1.21 mmol) and CH3SO3H (29 mg, 20 L, 0.30 mmol) in absolute EtOH (4 mL) for 3 hours. Column chromatography (hexane:EtOAc:MeOH; 1:1:0 to 0:9:1). The product was obtained as a pale yellow solid (0.186 g, 0.86 mmol, 85 %). Rf = 0.15 (EtOAc); mp = 144 - 145 °C; IR (cm-1) 3375, 1508, 1277, 829, 795; 1H NMR (500 MHz, DMSO-d6)  (ppm) (t, J = 7.6 Hz, 3H), 2.48 – 2.61 (m, 2H), 3.75 (s, 3H), 4.24 (br s, 2H), 6.94 (dd, J = 8.4, 1.8 Hz, 2H), 7.14 – 7.34 (m, 2H), 11.31 (br s, 1H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 13.4, 18.3, 55.0, 114.0,

126.2, 129.3, 157.0; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H16N3O 218.1288; Found 218.1285. 3-ethyl-4-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-5-amine (3i). Prepared according to general procedure C2 with 3-oxo-2-(4-(trifluoromethoxy)phenyl)pentanenitrile (0.333 g, 1.29 mmol), N2H4.H2O (68 mg, 66 L, 1.36 mmol) in AcOH (4 mL) for 1 hour at 100 °C. Column chromatography (hexane:EtOAc:MeOH; 1:1:0 to 0:10:1). The product was obtained as an off-white solid (0.28 g, 1.03 mmol, 80 %). Rf = 0.17 (EtOAc); mp = 106 – 108 °C; IR (cm-1) 3374, 1530, 1483, 1259, 1208, 1143, 1009, 891, 853, 808, 794; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.10 (t, J = 7.6 Hz, 3H), 2.56 (q, J = 7.6 Hz, 2H), 4.49 (s, 2H), 7.31 – 7.36 (m, 2H), 7.41 – 7.46 (m, 2H), 11.51 (s, 1H).; 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 13.2, 18.5, 102.3, 120.2 (q, J = 255.8 Hz), 121.1, 129.6, 133.7, 143.5, 145.7, 150.8;

19F{1H}

NMR (471 MHz, DMSO-d6)  (ppm) -56.80;

HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H13F3N3O 272.1005; Found 272.1006. 4-(4-(dimethylamino)phenyl)-3-ethyl-1H-pyrazol-5-amine (3j). Prepared according to general procedure C1 with 2-(4-(dimethylamino)phenyl)-3-oxopentanenitrile (0.163 g, 0.75 mmol), N2H4.H2O (45 mg, 44 L, 0.9 mmol) and CH3SO3H (22 mg, 15 L, 0.23 mmol) in absolute EtOH (4 mL) for 3 hours. Column chromatography (hexane:EtOAc:MeOH; 1:1:0 to 0:10:1). The product was obtained as a brown solid (0.14 g, 0.61 mmol, 81 %). Rf = 0.43 (EtOAc:MeOH; 10:1); mp = 114 – 119 °C; IR (cm-1) 3316, 3193, 2964, 2928, 2880, 2799, 1619, 1586, 1530, 1485, 1442, 1350, 1320, 1227, 1198, 1060, 1047, 945, 823; 1H NMR (500 MHz, DMSOd6)  (ppm) 1.09 (t, J = 7.6 Hz, 3H), 2.48 – 2.53 (m, 2H), 2.89 (s, 6H), 6.76 (d, J = 8.9 Hz, 2H), 7.11 (d, J = 9 Hz, 2H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 13.5, 18.3, 40.3, 103.9, 112.8, 121.8, 128.9, 142.4, 148.4; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C13H19N4 231.1604; Found 231.1607. 3-ethyl-4-(4-morpholinophenyl)-1H-pyrazol-5-amine (3k).



Page 32 of 64

Prepared according to general procedure C1 with 2-(4-morpholinophenyl)-3-oxopentanenitrile (0.219 g, 0.85 mmol), N2H4.H2O (51 mg, 49 L, 1.02 mmol) and CH3SO3H (24 mg, 17 L, 0.25 mmol) in absolute EtOH (4 mL) for 3 hours. Column chromatography (hexane:EtOAc:MeOH:NEt3; 20:80:0:0.05 to 0:80:20:0.05). The product was obtained as a colourless wax (0.143 g, 0.53 mmol, 62 %). Rf = 0.33 (EtOAc:MeOH:NEt3; 90:10:0.05); IR (cm-1) 2964, 2925, 2853, 1606, 1587, 1525, 1450, 1258, 1231, 1119, 1050, 926, 830; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.20 (t, J = 7.6 Hz, 3H), 2.65 (q, J = 7.6 Hz, 2H), 3.16 – 3.21 (m, 4H), 3.85 – 3.90 (m, 4H), 4.49 (s, 3H), 6.93 – 6.98 (m, 2H), 7.21 – 7.27 (m, 2H);

13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.1, 50.9, 55.7,

101.1, 106.2, 116.3, 132.0, 161.8, 199.4; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C15H21N4O 273.1710; Found 273.1711. N-(4-(5-amino-3-ethyl-1H-pyrazol-4-yl)phenyl)methanesulfonamide (3l). Prepared

according

to

general

procedure

C1

with

N-(4-(1-cyano-2-

oxobutyl)phenyl)methanesulfonamide (0.21 g, 0.79 mmol), N2H4.H2O (47 mg, 46 L, 0.95 mmol) and CH3SO3H (23 mg, 15 L, 0.24 mmol) in absolute EtOH (4 mL) for 3 hours. Column chromatography (hexane:EtOAcMeOH; 1:1:0 to 0:10:1). The product was obtained as a white solid (0.139 g, 0.495 mmol, 63 %). Rf = 0.24 (EtOAc); mp = 186 – 189 °C; IR (cm-1) 3378, 3095, 1322, 1297, 1149, 1137, 971, 913, 897, 837, 753, 514; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.10 (t, J = 7.6 Hz, 3H), 2.54 (q, J = 7.6 Hz, 2H), 2.98 (s, 3H), 7.18 – 7.24 (m, 2H), 7.26 (d, J = 8.7 Hz, 2H), 9.62 (s, 1H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 13.3, 18.4, 38.9, 103.1, 120.4, 128.9, 129.9, 135.4, 142.9; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H17N4O2S 281.1067; Found 281.1068. 3-ethyl-4-(4-(morpholinosulfonyl)phenyl)-1H-pyrazol-5-amine (3m). Prepared

according

to

general

procedure

C1

with

2-(4-(morpholinosulfonyl)phenyl)-3-

oxopentanenitrile (140 mg, 0.52 mmol), N2H4.H2O (40 mg, 0.63 mmol) and CH3SO3H (6 mg, 0.06 mmol) in absolute EtOH (3 mL) for 3 hours. Column chromatography (hexane:EtOAc; 1:1 to 0:1). The product was obtained as a yellow wax (68 mg, 0.29 mmol, 46 %). Rf = 0.3 (EtOAc:MeOH; 10:1); IR (cm-1) 3342, 1594, 1342, 1159, 1068, 939, 757; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.12 (t, J = 7.5 Hz, 3H), 2.62 (q, J = 7.6 Hz, 2H), 2.87 – 2.98 (m, 4H), 3.62 – 3.73 (m, 4H), 4.70 (s, 2H), 7.56 – 7.62 (m, 2H), 7.67 – 7.71 (m, 2H), 11.62 (s, 1H); 13C{1H} NMR (125 MHz, DMSO-d6)  (ppm) 13.0, 18.8, 45.8, 65.3, 127.9, 128.0, 130.0, 139.7, 142.9, 144.2, 151.0; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C15H21N4O3S 337.1329; Found 337.1328. 3-ethyl-4-(4-(piperidin-1-ylsulfonyl)phenyl)-1H-pyrazol-5-amine (3n). Prepared

according

to

general

procedure

C1

with

3-oxo-2-(4-(piperidin-1-

ylsulfonyl)phenyl)pentanenitrile (140 mg, 0.52 mmol), N2H4.H2O (40 mg, 0.63 mmol) and CH3SO3H (6 mg, 0.06 mmol) in absolute EtOH (3 mL) for 3 hours. Column chromatography (hexane:EtOAc:MeOH; 1:1:0 to 0:1:0 to 0:10:1). The product was obtained as a pale yellow solid ACS Paragon Plus Environment

Page 33 of 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(100 mg, 0.36 mmol, 68 %). Rf = 0.3 (EtOAc:MeOH; 10:1); mp = 102 - 103 °C; IR (cm-1) 3345, 1594, 1334, 1161, 926, 755, 585; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.13 (t, J = 7.5 Hz, 3H), 1.38 (s, 2H), 1.55 (d, J = 5.8 Hz, 4H), 2.62 (q, J = 7.5 Hz, 2H), 2.91 (t, J = 5.4 Hz, 4H), 4.66 (s, 2H), 7.52 – 7.58 (m, 2H), 7.64 – 7.71 (m, 2H), 11.55 (s, 1H); 13C{1H} NMR (75 MHz MHz, DMSO-d6)  (ppm13.0, 18.8, 22.9, 24.7, 46.5, 102.1, 127.7, 127.8, 131.3, 139.2, 144.2, 150.9; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C16H23N4O2S 335.1536; Found 335.1538. 4-(3-chloro-4-fluorophenyl)-3-ethyl-1H-pyrazol-5-amine (3o). Prepared according to general procedure C1 with 2-(3-chloro-4-fluorophenyl)-3-oxopentanenitrile (0.19 g, 0.84 mmol), N2H4.H2O (51 mg, 49 L, 1.01 mmol) and CH3SO3H (24 mg, 16 L, 0.25 mmol) in absolute EtOH (4 mL) for 3 hours at reflux. Column chromatography (EtOAc:MeOH; 1:0 to 10:1). The product was obtained as a white solid (0.046 g, 0.19 mmol, 23 %). Rf = 0.30 (EtOAc); mp = 113 – 116 °C; IR (cm-1) 3317, 2969, 2931, 1682, 1623, 1524, 1490, 1469, 1372, 1296, 1258, 1237, 1140, 1064, 1032, 824, 705, 606; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.09 (t, J = 7.5 Hz, 3H), 2.54 (q, J = 7.5 Hz, 2H), 4.51 (s, 2H), 7.28 (ddd, J = 8.5, 4.7, 2.2 Hz, 1H), 7.38 (dd, J = 9.5, 8.5 Hz, 1H), 7.45 (dd, J = 7.3, 2.1 Hz, 1H), 11.46 (s, 1H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 13.1, 18.4, 101.6, 116.7 (d, J = 20.9 Hz), 119.3 (d, J = 17.3 Hz), 128.5 (d, J = 7.3 Hz), 129.6, 132.1 (d, J = 3.6 Hz), 143.3, 155.0 (d, J = 244.3 Hz); 19F{1H} NMR (471 MHz, DMSO-d6)  (ppm) -121.30; HRMS (APCITOF) m/z: [M+H]+ Calcd for C11H12ClFN3 240.0698; Found 240.0697. or Prepared according to general procedure C2 with 2-(4-fluoro-2-methylphenyl)-3-oxopentanenitrile (0.102 g, 0.45 mmol), N2H4.H2O (25 mg, 0.5 mmol) in AcOH (2 mL) for 3 hours at 100 °C. Column chromatography (EtOAc:MeOH; 1:0 to 10:1). The product was obtained as a white solid (0.048 g, 0.20 mmol, 44 %). 4-(benzo[d][1,3]dioxol-5-yl)-3-ethyl-1H-pyrazol-5-amine (3p). Prepared according to general procedure C1 with 2-(benzo[d][1,3]dioxol-5-yl)-3-oxopentanenitrile (126 mg, 0.58 mmol), N2H4.H2O (45 mg, 0.7 mmol) and CH3SO3H (6 mg, 0.06 mmol) in absolute EtOH (3 mL) for 3 hours. Column chromatography (hexane:EtOAc; 1:1 to 0:1). The product was obtained as a pale brown solid (100 mg, 0.42 mmol, 72 %). Rf = 0.3 (EtOAc); mp = 118 - 119 °C; IR (cm-1) 3367, 1475, 1223, 1037, 809; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.08 (t, J = 7.6 Hz, 3H), 2.52 (q, J = 14.8, 7.1 Hz, 5H), 4.30 (s, 2H), 6.00 (s, 2H), 6.72 (dd, J = 8.0, 1.7 Hz, 1H), 6.84 (d, J = 1.7 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 11.34 (s, 1H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm)

13.3, 18.3, 30.6, 100.6, 103.6, 108.4, 108.7, 121.4, 127.8, 144.8, 147.3; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H14N3O2 232.1081; Found 232.1082. 4-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-ethyl-1H-pyrazol-5-amine (3q).



Page 34 of 64

Prepared according to general procedure C1 with 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3oxopentanenitrile (267 mg, 1.15 mmol), N2H4.H2O (85 mg, 1.38 mmol) and CH3SO3H (12 mg, 0.15 mmol) in absolute EtOH (3 mL) for 3 hours. Column chromatography (Hexane:EtOAc; 1:1 to EtOAc:MeOH; 10:1). The product was obtained as a pale yellow solid (200 mg, 0.81 mmol, 70 %). Rf = 0.15 (EtOAc); mp = 147 - 149°C; IR (cm-1) 3367, 1573, 1486, 1327, 1130, 863, 812; 1H NMR (300 MHz, Chloroform-d)  (ppm) 1.09 (t, J = 7.5 Hz, 3H), 2.51 (q, J = 7.6 Hz, 2H), 4.23 (s, 6H), 6.71 – 6.77 (m, 2H), 6.84 (d, J = 8.1 Hz, 1H), 11.32 (s, 1H); 13C{1H} NMR (75 MHz, Chloroform-d)  (ppm) 13.3, 18.3, 64.0, 64.0, 116.5, 117.0, 121.2, 127.1, 141.2, 143.2, 172.4; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C13H16N3O2 246.1237; Found 246.1237. 3-ethyl-4-(naphthalen-2-yl)-1H-pyrazol-5-amine (3r). Prepared according to general procedure C1 with 2-(naphthalen-2-yl)-3-oxopentanenitrile (0.262 g, 1.17 mmol), N2H4.H2O (70 mg, 69 L, 1.4 mmol) and CH3SO3H (34 mg, 23 mL, 0.35 mmol) in absolute EtOH (4 mL) for 2 hours. Column chromatography (hexane:EtOAc:MeOH; 1:1:0 to 0:20:1). The product was obtained as a pale brown wax (0.108 g, 0.046 mmol, 39 %). Rf = 0.13 (EtOAc); IR (cm-1) 3365, 3184, 3140, 3074, 2957, 2953, 2855, 1631, 1601, 1585, 1522, 1491, 1463, 1444, 1343, 1115, 1044, 1025, 944, 889, 860, 822, 746, 729; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.24 (t, J = 7.6 Hz, 3H), 2.75 (q, J = 7.6 Hz, 2H), 5.68 (br s, 3H), 7.43 – 7.54 (m, 3H), 7.79 (s, 1H), 7.81 – 7.91 (m, 3H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 13.3, 18.9, 105.9, 125.8, 126.4, 127.3, 127.5, 127.8, 128.5, 130.8, 132.1, 133.9, 144.0, 152.3; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C15H16N3 238.1339; Found 238.1341. 3-ethyl-4-(3-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (3s). Prepared according to general procedure C1 with 3-oxo-2-(3-(trifluoromethyl)phenyl)pentanenitrile (288 mg, 1.2 mmol), N2H4.H2O (90 mg, 1.43 mmol) and CH3SO3H (3 mg, 2 L, 0.03 mmol) in absolute EtOH (3 mL) for 3 hours. Column chromatography (hexane:EtOAc; 1:1 to 0:1). The product was obtained as a pale orange solid (110 mg, 0.43 mmol, 36 %). or Prepared according to general procedure C3 with 3-oxo-2-(4-(trifluoromethyl)phenyl)pentanenitrile (300 mg, 1.24 mmol), N2H4.H2O (390 mg, 390 L, 7.15 mmol) and HCl (35 %, 1.2 g, 1 mL, 12.4 mmol) in absolute EtOH (3 mL) for 1 hour. Column chromatography (hexane:EtOAc; 10:1 to 0:1 to EtOAc:MeOH; 5:1). The product was obtained as a pale orange solid (220 mg, 0.86 mmol, 70 %). Rf = 0.15 (Hexane:EtOAc; 7:3); mp = 116 – 117 °C; IR (cm-1) 3379, 1728, 1270, 1153 802, 701; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.11 (t, J = 7.6 Hz, 3H), 2.58 (q, J = 7.6 Hz, 2H), 4.54 (s, 2H), 7.49 – 7.55 (m, 1H), 7.57 – 7.64 (m, 3H), 11.51 (s, 1H); 13C{1H} NMR (125 MHz, DMSO-d6)  (ppm) 13.1, 30.6, 121.4 (q, J = 4.2 Hz), 124.0 (q, J = 3.8 Hz), 124.3 (q, J = 272.3 Hz), 129.2 (q, J = 31.1


Page 35 of 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Hz), 129.4, 131.8, 135.3; 19F{1H} NMR (471 MHz, DMSO)  -61.1; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H13N3F3 256.1056; Found 256.1058. methyl 3-(5-amino-3-ethyl-1H-pyrazol-4-yl)benzoate (3t). Prepared according to general procedure C1 with methyl 3-(1-cyano-2-oxobutyl)benzoate (127 mg, 0.54 mmol), N2H4.H2O (40 mg, 0.6 mmol) and CH3SO3H (6 mg, 0.06 mmol) in absolute EtOH (3 mL) for 3 hours. Column chromatography (hexane:EtOAc; 1:1 to 0:1). The product was obtained as a pale pink solid (100 mg, 0.4 mmol, 74 %). Rf = 0.2 (EtOAc); mp = 112 - 114 °C; IR (cm-1) 3374, 1718, 1496, 1302, 1266, 1119, 756; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.11 (t, J = 7.6 Hz, 3H), 2.56 (q, J = 7.6 Hz, 2H), 3.86 (s, 3H), 7.47 – 7.63 (m, 2H), 7.74 – 7.81 (m, 1H), 7.88 – 7.92 (m, 1H); 13C{1H}


132.7, 134.7, 143.5, 150.8, 166.4; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C13H16N3O2 246.1237; Found 246.1238. 3-ethyl-4-(3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1H-pyrazol-5-amine (3u). Prepared according to general procedure C2 with 2-(3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-3oxopentanenitrile (0.145 g, 0.57 mmol), N2H4.H2O (30 mg, 29 L, 0.60 mmol) in AcOH (2 mL) for 3 hours at 100 °C. Column chromatography (hexane:EtOAc:MeOH; 1:1:0 to 0:10:1). The product was obtained as a pale yellow solid (0.085 g, 0.32 mmol, 56 %). Rf = 0.1 (EtOAc); mp = 74 - 78 °C; IR (cm-1) 3206, 2970, 2932, 1676, 1611, 1580, 1549, 1505, 1464, 1430, 1232, 1039, 959, 802, 765, 724, 695; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.13 (t, J = 7.6 Hz, 3H), 2.55 – 2.64 (m, 5H), 4.54 (s, 2H), 7.54 (ddd, J = 7.8, 1.6 Hz, 1H), 7.58 (dd, J = 7.6 Hz, 1H), 7.78 (ddd, J = 7.5, 1.6 Hz, 1H), 7.91 (dd, J = 1.8 Hz, 1H), 11.58 (s, 1H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 10.6, 13.2, 18.6, 122.9, 123.8, 125.6, 129.6, 131.2, 135.3, 163.8, 164.1; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C14H16N5O 270.1349; Found 270.1350. 4-([1,1'-biphenyl]-3-yl)-3-ethyl-1H-pyrazol-5-amine (3v). Prepared according to general procedure C1 with 2-([1,1'-biphenyl]-3-yl)-3-oxopentanenitrile (0.252 g, 1.01 mmol), N2H4.H2O (51 mg, 49 L, 1.01 mmol) and CH3SO3H (10 mg, 7 L, 0.101 mmol) in absolute EtOH (5 mL) for 3 hours. Column chromatography (hexane:EtOAc:MeOH; 2:1:0 to 0:9:1). The product was obtained as a pale yellow oil (0.138 g, 0.52 mmol, 52 %). Rf = 0.48 (EtOAc); 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.24 (t, J = 7.6 Hz, 3H), 2.73 (q, J = 7.6 Hz, 2H), 5.60 (br s, 3H), 7.31 – 7.39 (m, 2H), 7.43 – 7.53 (m, 4H), 7.58 – 7.64 (m, 3H);

13C{1H}

NMR (126 MHz,

Chloroform-d)  (ppm) 13.3, 18.8, 105.9, 125.2, 127.3, 127.5, 127.7, 127.9, 128.9, 129.4, 133.8, 141.2, 141.9, 143.9, 152.2; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C17H18N3 264.1495; Found 264.1496. 3-ethyl-4-(3-(trifluoromethoxy)phenyl)-1H-pyrazol-5-amine (3w). ACS Paragon Plus Environment


Page 36 of 64

Prepared according to general procedure C1 with 3-oxo-2-(3-(trifluoromethoxy)phenyl)pentanenitrile (170 mg, 0.7 mmol), N2H4.H2O (45 mg, 0.7 mmol) and CH3SO3H (7 mg, 0.07 mmol) in absolute EtOH (3 mL) for 3 hours. Column chromatography (hexane:EtOAc; 1:1 to 0:1). The product was obtained as a pale pink solid (40 mg, 0.15 mmol, 22 %). Rf = 0.1 (Hexane:EtOAc; 2:1); mp = 128 - 129 °C; IR (cm-1) 3379, 1596, 1337, 1271, 1153, 1115, 877, 803, 701; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.11 (t, J = 7.5 Hz, 3H), 2.58 (q, J = 7.6 Hz, 2H), 4.58 (s, 2H), 7.49 – 7.55 (m, 1H), 7.56 – 7.65 (m, 3H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 13.5, 19.1, 117.6, 120.4, 120.7 (q, J = 256.0 Hz),

127.3,

130.7,

137.1,

149.1,

172.9;

HRMS

(APCI-TOF)

m/z:

[M+H]+

Calcd

for

C12H13N3OF3 272.1005; Found 272.1005. 3-ethyl-4-(3-methoxyphenyl)-1H-pyrazol-5-amine (3x). Prepared according to general procedure C1 with 2-(3-methoxyphenyl)-3-oxopentanenitrile (360 mg, 1.77 mmol), N2H4.H2O (120 mg, 1.94 mmol) and CH3SO3H (18 mg, 0.18 mmol) in absolute EtOH (3 mL) for 3 hours. Column chromatography (hexane:EtOAc; 1:1 to 0:1). The product was obtained as a pale yellow solid , (200 mg, 0.92 mmol, 52 %). Rf = 0.15 (EtOAc); mp = 130 - 131 °C; IR (cm-1) 3370, 1607, 1418, 1295, 1218, 777, 699; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.10 (t, J = 7.5 Hz, 3H), 2.56 (q, J = 7.6 Hz, 2H), 3.76 (s, 3H), 4.37 (s, 2H), 6.72 – 6.79 (m, 1H), 6.83 – 6.90 (m, 2H), 7.25 – 7.30 (m, 1H), 11.39 (s, 1H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 13.3, 18.5, 54.8,

110.7, 113.4, 120.3, 129.4, 135.5, 159.4; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H16N3O 218.1288; Found 218.1288. 4-(3,5-dimethoxyphenyl)-3-ethyl-1H-pyrazol-5-amine (3y). Prepared according to general procedure C1 with 2-(3,5-dimethoxyphenyl)-3-oxopentanenitrile (0.224 g, 0.96 mmol), N2H4.H2O (53 mg, 51 L, 1.06 mmol) and CH3SO3H (28 mg, 19 L, 0.29 mmol) in absolute EtOH (4 mL) for 3 hours. Column chromatography (hexane:EtOAc:MeOH; 1:1:0 to 0:10:1). The product was obtained as a brown wax (0.136 g, 0.55 mmol, 57 %). Rf = 0.16 (EtOAc); IR (cm-1) 3378, 3314, 3206, 2963, 2933, 1591, 1452, 1416, 1349, 1202, 1153, 1027, 853, 827, 691; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.11 (t, J = 7.6 Hz, 3H), 2.57 (q, J = 7.6 Hz, 2H), 3.75 (s, 6H), 4.39 (s, 2H), 6.34 (t, J = 2.3 Hz, 1H), 6.44 (d, J = 2.3 Hz, 2H), 11.43 (s, 1H);

13C{1H}

NMR

(126 MHz, DMSO-d6)  (ppm) 13.3, 18.5, 55.0, 97.3, 103.5, 105.9, 136.0, 143.2, 150.8, 160.5; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C13H18N3O2 248.1394; Found 248.1394. 3-(5-amino-3-ethyl-1H-pyrazol-4-yl)phenol (3z). Prepared according to general procedure C1 with 2-(3-hydroxyphenyl)-3-oxopentanenitrile (0.259 g, 1.37 mmol), N2H4.H2O (82 mg, 80 L, 1.64 mmol) and CH3SO3H (39 mg, 27 L, 0.41 mmol) in absolute EtOH (4 mL) for 3 hours. Column chromatography (hexane:EtOAc:MeOH; 1:1:0 to 0:10:1). The product was obtained as a white solid (0.177 g, 0.87 mmol, 64 %). Rf = 0.15 (EtOAc); mp = 153 - 155 °C; IR (cm-1) 3416, 3299, 1610, 1587, 1524, 1506, 1442, 1284, 1214, 1030, 883, 868, 787, ACS Paragon Plus Environment

Page 37 of 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


696, 677, 629, 614, 576; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.10 (t, J = 7.6 Hz, 3H), 2.54 (q, J = 7.6 Hz, 2H), 4.29 (br s, 2H), 6.55 – 6.63 (m, 1H), 6.72 – 6.74 (m, 2H), 7.15 (dd, J = 8.2 Hz, 1H), 9.28 (br s, 1H), 11.38 (br s, 1H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 13.4, 18.4, 103.7, 112.2, 114.9, 118.8, 129.4, 135.3, 142.9, 150.7, 157.4; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C11H14N3O 204.1131; Found 204.1131. 3-ethyl-4-(4-fluoro-2-methylphenyl)-1H-pyrazol-5-amine (3aa). Prepared according to general procedure C1 with 2-(4-fluoro-2-methylphenyl)-3-oxopentanenitrile (100 mg, 0.49 mmol), N2H4.H2O (30 mg, 0.58 mmol, 36 L) and CH3SO3H (3 mg, 0.03 mmol, 1.5 L) in absolute EtOH (2 mL) for 3 hours. Column chromatography (hexane:EtOAc; 4:1 to 0:1). The product was obtained as a pale yellow oil (70 mg, 0.32 mmol, 65 %). Rf = 0.15 (EtOAc); IR (cm-1) 3195, 1600, 1481, 1223, 1149, 1012, 822; 1H NMR (300 MHz, Chloroform-d)  (ppm) 1.09 (t, J = 7.6 Hz, 3H), 2.19 (s, 3H), 2.37 – 2.54 (m, 2H), 5.97 (s, 3H), 6.84 – 6.94 (m, 1H), 6.98 (dd, J = 2.7, 9.8 Hz, 1H), 7.11 (dd, J = 6.1, 8.4 Hz, 1H); 13C{1H} NMR (75 MHz, Chloroform-d)  (ppm) 13.3, 18.8, 20.1 (d, J = 1.7 Hz), 104,4, 112.8 (d, J = 20.9 Hz), 116.9 (d, J = 21.0 Hz), 127.8 (d, J = 2.9 Hz), 133.0 (d, J = 8.3 Hz), 140.9 (d, J = 7.9 Hz), 144.6, 152.1, 162.4 (d, J = 245.5 Hz); 19F{1H} NMR (282 MHz, Chloroform-d)  (ppm) -115.7; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H15FN3 220.1245; Found 220.1244. 3-ethyl-4-(naphthalen-1-yl)-1H-pyrazol-5-amine (3ab). Prepared according to general procedure C1 with 2-(naphthalen-1-yl)-3-oxopentanenitrile (200 mg, 0.9 mmol), N2H4.H2O (67 mg, 65 L 1.1 mmol) and CH3SO3H (11 mg, 7 L, 0.11 mmol) in absolute EtOH (3 mL) for 3 hours. Column chromatography (hexane:EtOAc; 1:1 to 0:1). The product was obtained as a pale brown oil (75 mg, 0.33 mmol, 36 %). Rf = 0.2 (EtOAc); IR (cm-1) 3193, 1597, 1493, 1042, 776; 1H NMR (500 MHz, DMSO-d6)  (ppm) 0.95 (t, J = 7.6 Hz, 3H), 2.22 – 2.43 (m, 2H), 4.09 (s, 2H), 7.35 (dd, J = 7.0, 1.2 Hz, 1H), 7.44 – 7.57 (m, 3H), 7.67 – 7.73 (m, 1H), 7.84 – 7.89 (m, 1H), 7.94 (dd, J = 7.8, 1.6 Hz, 1H), 11.53 (s, 1H);

13C{1H}

NMR (126 MHz, DMSO-d6) 

(ppm) 13.3, 18.5, 125.6, 125.7, 125.9, 126.7, 128.1, 128.2, 131.2, 132.1, 133.5; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C15H16N3 238.1339; Found 238.1338. 3-ethyl-4-(2-(trifluoromethoxy)phenyl)-1H-pyrazol-5-amine (3ac). Prepared according to general procedure C3 with 3-oxo-2-(2-(trifluoromethoxy)phenyl)pentanenitrile (56 mg, 0.218 mmol), N2H4.H2O (54 mg, 53 L, 1.09 mmol) and HCl (35 %, 290 L, 2.18 mmol) in absolute EtOH (2 mL) for 3 hours. Column chromatography (hexane:EtOAc:MeOH; 1:1:0 to 0:1:0 to 0:20:1). The product was obtained as a pale yellow solid (23 mg, 0.085 mmol, 39 %). Rf = 0.45 (CH2Cl2:MeOH; 20:1); mp = 103 – 105 °C; IR (cm-1) 3382, 3146, 1470, 1280, 1236, 1216, 1195, 1011, 883, 759; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.15 (t, J = 7.6 Hz, 3H), 2.58 (q, J = 7.8



Page 38 of 64

Hz, 2H), 4.21 (s, 3H), 7.33 - 7.38 (m, 4H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 12.8, 18.8, 101.4, 120.5 (q, J = 257.9 Hz), 121.6, 126.5, 127.4, 128.7, 132.6, 144.8, 147.4, 152.5; 19F{1H} NMR (471 MHz, Chloroform-d)  (ppm) -57.62; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H13F3N3O 272.1005; Found 272.1006. 3-cyclohexyl-4-phenyl-1H-pyrazol-5-amine (3ad). Prepared according to general procedure C2 with 3-cyclohexyl-3-oxo-2-phenylpropanenitrile (20 mg, j0.088 mmol), N2H4.H2O (137 mg, 1.76mmol) in AcOH (0.4 mL) for 1.5 hours. Purified by preparative TLC (NH3 (0.7 M in MeOH):MeOH: CH2Cl2; 0.5:5.5:94). The product was obtained as a pale white solid(14 mg, 0.058 mmol, 66 %). Rf = 0.35 (0.7 M NH3 in MeOH:MeOH:CH2Cl2, 1:9.5:90); mp = 128−130 °C; IR (cm-1) 3175, 2927, 2846, 1604, 1593, 1531, 1476, 1461, 1444, 1428, 1314, 1262, 1014, 887, 763, 720, 697; 1H NMR (300 MHz, Chloroform-d)  1.20 – 1.48 (m, 5H), 1.63 – 1.74 (m, 1H), 1.74 – 1.84 (m, 2H), 1.84 – 2.00 (m, 2H), 2.63 – 2.83 (m, 1H), 5.32 (s, 3H), 7.24 – 7.36 (m, 3H), 7.37 – 7.46 (m, 2H).13C{1H} NMR (75 MHz, Chloroform-d)  25.9, 26.4, 32.7, 34.9, 105.5, 126.4, 128.8, 129.2, 133.3, 146.8, 152.2. HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C15H20N3 242.1652; Found 242.1652. 4-phenyl-3-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (3ae). Prepared

according

to

general

procedure

C2

with

3-oxo-2-phenyl-3-(4-

(trifluoromethyl)phenyl)propanenitrile (20 mg, 0.069 mmol), N2H4.H2O (108 mg, 1.382 mmol) in AcOH (0.4 mL) for 1.5 hours. Purified by preparative TLC (0.7 M NH3 in MeOH:MeOH:CH2Cl2, 0.5:5.5:94). The product was obtained as a light brown wax (10 mg, 0.0329 mmol, 48 %). Rf = 0.30 (NH3 (0.7 M in MeOH):MeOH:CH2Cl2; 1:9:90); IR (cm-1) 3188, 2924, 1618, 1606, 1509, 1321, 1165, 1107, 1065, 1016, 844, 700; 1H NMR (300 MHz, Chloroform-d)  5.54 (br. s, 3H), 7.22 – 7.33 (m, 3H), 7.34 – 7.41 (m, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H);13C{1H} NMR (75 MHz, Chloroform-d)  125.8 (q, J = 3.8 Hz), 127.3, 127.8, 128.0, 129.3, 129.7, 130.1, 130.6, 132.2, 134.1; 19F{1H}

NMR (282 MHz, Chloroform-d)  -62.8. HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C16H13F3N3

304.1056; Found 304.1055. 3-(4-methoxyphenyl)-4-phenyl-1H-pyrazol-5-amine (3af). Prepared

according

to

general

procedure

C2

with

3-(4-methoxyphenyl)-3-oxo-2-

phenylpropanenitrile (20 mg, 0.0795 mmol), N2H4.H2O (124 mg, 1.59 mmol) in AcOH (0.4 mL) for 1.5 hours. Purified by preparative TLC (0.7 M NH3 in MeOH:MeOH:CH2Cl2; 0.5:5.5:94).The product was obtained as a colorless wax (10 mg, 0.038 mmol, 47 %). Rf = 0.25 (MeOH:CH2Cl2; 1:9); IR (cm-1) 2922, 1605, 1506, 1475, 1425,1323, 1301, 1245, 1176, 1108, 1031, 1013, 832, 775, 730, 699, 681; 1H NMR (300 MHz, Chloroform-d)  (ppm) 3.79 (s, 3H), 6.76 – 6.90 (m, 2H), 7.20 – 7.39 (m, 7H);13C{1H} NMR (75 MHz, Chloroform-d)  (ppm) 55.4, 114.4, 122.9, 126.6, 128.9, 129.0, 129.7, 133.0, 159.9; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C16H16N3O 266.1288; Found 266.1288. ACS Paragon Plus Environment

Page 39 of 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


CAS registry No. [1159606-24-2]. 1H and

13C


reported in the literature.30e 3-(4-(tert-butyl)phenyl)-4-phenyl-1H-pyrazol-5-amine (3ag). Prepared

according

to

general

procedure

C2

with

3-(4-(tert-butyl)phenyl)-3-oxo-2-

phenylpropanenitrile (20 mg, 0.072 mmol), N2H4.H2O (112 mg, 1.44 mmol) in AcOH (0.4 mL) for 1.5 hours. purified by preparative TLC (NH3 (0.7 M in MeOH):MeOH:CH2Cl2; 0.5:5.5:94). The product was obtained as a light brown gum (13 mg, 0.0446 mmol, 62 %). Rf = 0.30 (0.7 M NH3 in MeOH:MeOH:CH2Cl2; 0.5:5.5:94); IR (cm-1) 3185, 2960, 1603, 1506, 1475, 1362, 1267, 1098, 1014, 837, 729, 700; 1H NMR (300 MHz, Chloroform-d)  (ppm) 1.29 (s, 9H), 5.68 (s, 3H), 7.25 – 7.39 (m, 9H).13C{1H} NMR (75 MHz, Chloroform-d)  (ppm) 31.4, 34.8, 125.8, 126.7, 127.1, 127.4, 129.0, 129.8, 133.0, 151.6. HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C19H22N3 292.1808; Found 292.1808. 4-(4-fluorophenyl)-3-(3-methoxynaphthalen-2-yl)-1H-pyrazol-5-amine (3ah). Prepared according to general procedure C2 with 2-(4-fluorophenyl)-3-(3-methoxynaphthalen-2-yl)3-oxopropanenitrile (200 mg, 0.63 mmol), N2H4.H2O (70 mg, 68 L, 1.4 mmol) in AcOH (2 mL) for 24 hours. Column chromatography (hexane:EtOAc; 4:1 to 0:1). The product was obtained as a yellow solid (70 mg, 0.21 mmol, 33 %). Rf = 0.1 (EtOAc); Mp > 200 °C decomp.; IR (cm-1) 3325, 1679, 1634, 1472, 1217, 840, 540; 1H NMR (500 MHz, DMSO-d6)  (ppm) 3.55 (s, 3H), 6.99 – 7.05 (m, 2H), 7.08 – 7.15 (m, 2H), 7.30 – 7.33 (m, 1H), 7.33 – 7.36 (m, 1H), 7.44 – 7.49 (m, 1H), 7.75 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.81 (d, J = 8.2 Hz, 1H), 11.80 (s, 2H); 13C{1H} NMR (126 MHz, DMSOd6)  (ppm) 55.0, 106.0, 114.7, 114.9, 114.9 (d, J = 21.0 Hz), 115.2 (d, J = 21.0 Hz), 123.8, 126.3, 126.6, 127.6, 127.9, 129.2 (d, J = 7.8 Hz), 129.8 (d, J = 7.6 Hz), 129.9 (d, J = 8.2 Hz), 130.9, 134.1, 155.0, 159.9 (d, J = 241.8 Hz);

19F{1H}

NMR (471 MHz, DMSO-d6)  (ppm) -118.0; HRMS (APCI-

TOF) m/z: [M+H]+ Calcd for C20H17FN3O 334.1350; Found 334.1351. 3-(3-methoxynaphthalen-2-yl)-4-(4-(methylsulfonyl)phenyl)-1H-pyrazol-5-amine (3ai). Prepared

according

to

general

procedure

C2

with

3-(3-methoxynaphthalen-2-yl)-2-(4-

(methylsulfonyl)phenyl)-3-oxopropanenitrile (135 g, 0.35 mmol), N2H4.H2O (30 mg, 29 L, 0.85 mmol) in AcOH (2 mL) for 24 hours. Column chromatography (hexane:EtOAc; 4:1 to 0:1). The product was obtained as a pale white solid (40 mg, 0.10 mmol, 29 %). Rf = 0.1 (Hexane:EtOAc; 1:1); mp = 181 - 182 °C; IR (cm-1) 3324, 1635, 1610, 1463, 1245, 746, 457; 1H NMR (500 MHz, DMSOd6)  (ppm) 1.93 (s, 3H), 3.97 (s, 3H), 7.38 – 7.45 (m, 1H), 7.48 (s, 1H), 7.50 – 7.60 (m, 1H), 7.88 (d, J = 8.3 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 10.08 (d, J = 2.6 Hz, 1H), 10.18 (d, J = 2.6 Hz, 1H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 20.5, 55.8, 106.6, 123.7, 124.3, 126.4, 127.4,

127.9, 128.4, 130.7, 135.1, 154.2, 163.7, 167.0; HRMS (ESI-TOF) m/z: [M-H]- Calcd for C21H18N3O3S 392.1147; Found 392.1146.



Page 40 of 64

tert-butyl (4-bromothiazol-2-yl)carbamate (4). Di-tert-butyl dicarbonate (2.43 g, 11.17 mmol) was added to a mixture of 4-bromothiazol-2-amine (2.00 g, 11.17 mmol) and DMAP (136 mg, 1.11 mmol) in CH2Cl2 (25 mL) and the mixture was stirred at 25 °C for 24 hours. The resulting solution was quenched with a saturated aqueous solution of NaHCO3 (100 mL) and the mixture was extracted with CH2Cl2 (2 × 200 mL). The organic extracts were combined, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane:EtOAc; 1:0 to 9.5:0.5) to afford tert-butyl (4bromothiazol-2-yl)carbamate (2.50 g, 8.955 mmol, 80 %) as a white solid. Rf = 0.50 (Hexane:EtOAc; 9:1); mp = 150 – 152 °C; IR (cm-1) 3143, 2971, 2931, 1707, 1547, 1486, 1391, 1365, 1298, 1279, 1248, 1156, 1083, 1064, 900, 870, 827, 785; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.54 (s, 9H), 6.79 (s, 1H), 8.83 (s, 1H);

13C{1H}


152.1, 160.7; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C8H12BrN2O2S 280.9777; Found 280.9774. CAS registry No. [1159606-24-2]. 1H NMR spectrum was consistent with that previously reported in the literature.30h tert-butyl (4-bromothiazol-2-yl)(ethoxymethyl)carbamate (5a). Ethoxymethyl chloride (0.981 mL, 10.57 mmol) was added to a solution of tert-butyl (4-bromothiazol2-yl)carbamate (2.46 g, 8.81 mmol) and DIPEA (4.60 mL, 26.43 mmol) in 1,2-dichloroethane (45 mL) and the mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled to 25 °C, quenched with water (100 mL), and extracted with CH2Cl2 (3 × 200 mL). The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane:EtOAc; 1:0 to 9.5:0.5) to afford tert-butyl (4-bromothiazol-2yl)(ethoxymethyl)carbamate (2.72 g, 8.065 mmol, 92 %) as a pale yellow wax. Rf = 0.48 (Hexane:EtOAc; 9:1); IR (cm-1) 2976, 1705, 1486, 1455, 1416, 1368, 1282, 1254, 1143, 1094, 881, 847; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.20 (t, J = 7.02 Hz, 3H), 1.58 (s, 9H), 3.65 (q, J = 7.02 Hz, 2H), 5.53 (s, 2H), 6.83 (s, 1H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 15.3, 28.3, 65.3, 76.1, 84.4, 112.4, 120.7, 152.8, 161.6; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C11H18BrN2O3S 339.0196; Found 339.0190. tert-butyl (4-bromothiazol-2-yl)(4-methoxybenzyl)carbamate (5b). 4-Methoxybenzyl chloride (2.72 mL, 20.09 mmol) was added to a solution of tert-butyl (4bromothiazol-2-yl)carbamate (5.10 g, 18.26 mmol) and Cs2CO3 (11.90 g, 36.53 mmol) in DMF (40 mL) and the mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled to 25 °C, quenched with water (100 mL), and extracted with EtOAc (3 × 300 mL). The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane:EtOAc; 1:0 to 9.5:0.5) to afford tert-butyl (4-bromothiazol-2yl)(4-methoxybenzyl)carbamate (7.20 g, 18.03 mmol, 99 %) as a pale yellow wax. Rf = 0.57 (Hexane:EtOAc; 9:1); IR (cm-1) 3103, 2976, 2928, 2833, 1698, 1616, 1512, 1482, 1429, 1381, 1296, ACS Paragon Plus Environment

Page 41 of 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1236, 1183, 1137, 1023, 880, 814; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.52 (s, 9H), 3.78 (s, 3H), 5.21 (s, 2H), 6.81 (s, 1H), 6.81 – 6.85 (m, 2H), 7.31 – 7.36 (m, 2H);

13C{1H}

NMR (126 MHz,

Chloroform-d)  (ppm) 28.3, 49.7, 55.4, 84.1, 112.1, 113.8, 120.5, 129.6, 129.7, 153.0, 159.1, 161.9; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C16H20BrN2O3S 401.0353; Found 401.0359. or Diisopropylamine (0.6 g, 0.84 mL, 6 mmol) was diluted with anhydrous THF (5 mL) and cooled -78 °C. n-BuLi (2.5 M in hexane, 2.4 mL, 6 mmol) was slowly added and the mixture was stirred at -78 °C for 10 min, and left to warm up to 0 °C. Then, the latter solution was added to a solution of tertbutyl (5-bromothiazol-2-yl)(4-methoxybenzyl)carbamate (2.0 g, 5 mmol) in dry THF (2 mL) at -78 °C and the mixture was stirred at -78 °C for 30 min. The reaction mixture was quenched with a saturated solution of NH4Cl (25 mL) and extracted with EtOAc (3 × 25 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane:EtOAc; 1:0 to 4:1) to afford tert-butyl (4-bromothiazol-2yl)(4-methoxybenzyl)carbamate (1.6 g, 4.0 mmol, 80 %) as a colourless oil. tert-butyl (ethoxymethyl)(4-(6-morpholinopyridin-3-yl)thiazol-2-yl)carbamate (6a). The compound was prepared according to General procedure D1 from tert-butyl (4-bromothiazol-2yl)(ethoxymethyl)carbamate (0.210 g, 0.622 mmol), 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)pyridin-2-yl)morpholine (0.198 g, 0.684 mmol), K3PO4 (0.396 g, 1.86 mmol), Pd(dppf)Cl2 (0.045 g, 0.062 mmol), DME (6 mL) and H2O (1.5 mL); the reaction time was 24 hours at 80 °C. The product, purified by flash column chromatography (hexane:EtOAc; 1:0 to 1:1), was obtained as a yellow solid (0.230 g, 0.546 mmol, 88 %). Rf = 0.42 (Hexane:EtOAc; 1:1); mp = 124 – 126 °C; IR (cm-1) 2973, 2850, 1701, 1503, 1395, 1368, 1357, 1282, 1251, 1146, 1117, 1097, 1048, 945, 846, 817, 763, 721; 1H

NMR (500 MHz, Chloroform-d)  (ppm) 1.22 (t, J = 7.02 Hz, 3H), 1.60 (s, 9H), 3.51 – 3.60 (m,

4H), 3.71 (q, J = 7.04 Hz, 2H), 3.81 – 3.87 (m, 4H), 5.66 (s, 2H), 6.67 (d, J = 8.82 Hz, 1H), 6.99 (s, 1H), 7.93 – 8.03 (m, 1H), 8.73 (d, J = 2.28 Hz, 1H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 15.5, 28.4, 45.9, 65.3, 66.9, 76.4, 83.9, 106.6, 121.6, 135.5, 145.9, 147.4, 153.1,161.3; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C20H29N4O4S 421.1904; Found 421.1906. tert-butyl (ethoxymethyl)(4-(1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)carbamate (6b). The compound was prepared according to General procedure D1 from tert-butyl (4-bromothiazol-2yl)(ethoxymethyl)carbamate

(0.490

g,

1.45

mmol),

1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-

dioxaborolan-2-yl)-1H-pyrazole (0.332 g, 1.59 mmol), K3PO4 (0.925 g, 4.35 mmol), Pd(dppf)Cl2 (0.106 g, 0.145 mmol) DME (16 mL) and H2O (4 mL); the reaction time was 3 hours at 80 °C. The product, purified by flash column chromatography (hexane:EtOAc; 1:0 to 2:3), was obtained as a colourless wax (0.433 g, 1.279 mmol, 88 %). Rf = 0.37 (Hexane:EtOAc; 1:2); IR (cm-1) 2976, 2934, 1706, 1602, 1493, 1416, 1394, 1367, 1254, 1144, 1093, 1052, 982, 849; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.21 (t, J = 7.11 Hz, 3H), 1.59 (s, 9H), 3.69 (q, J = 7.02 Hz, 2H), 3.91 (s, 3H), ACS Paragon Plus Environment


Page 42 of 64

5.63 (s, 2H), 6.81 (s, 1H), 7.69 (s, 1H), 7.76 (s, 1H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 15.4, 28.3, 65.1, 75.1, 76.2, 83.9, 106.3, 119.0, 128.1, 137.1, 143.0, 153.0, 161.0; HRMS (APCITOF) m/z: [M+H]+ Calcd for C15H23N4O3S 339.1485; Found 339.1487. tert-butyl (ethoxymethyl)(4-(pyrimidin-5-yl)thiazol-2-yl)carbamate (6c). The compound was prepared according to General procedure D1 from tert-butyl (4-bromothiazol-2yl)(ethoxymethyl)carbamate (0.500 g, 1.48 mmol), pyrimidin-5-ylboronic acid (0.202 g, 1.63 mmol), K3PO4 (0.944 g, 4.44 mmol), Pd(dppf)Cl2 (0.108 g, 0.148 mmol) and DME/H2O (16 + 4 mL); reaction time was 3 hours at 80 °C. The product, purified by flash column chromatography (CH2Cl2: MeOH; 1:0 to 9.6:0.4), was obtained as a white solid (0.448 g, 1.33 mmol, 90 %). Rf = 0.3 (Hexane:EtOAc; 1:1); mp = 119 – 121 °C; IR (cm-1) 3085, 2981, 1697, 1518, 1498, 1422, 1402, 1368, 1298, 1146, 1097, 1048, 899, 846, 769;1H NMR (500 MHz, Chloroform-d)  (ppm) 1.23 (t, J = 6.99 Hz, 3H), 1.61 (s, 9H), 3.72 (q, J = 7.02 Hz, 2H), 5.66 (s, 2H), 7.33 (s, 1H), 9.15 (s, 1H), 9.19 (s, 2H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 15.4, 28.3, 65.4, 76.4, 84.4, 111.3, 128.6, 143.7, 153.0, 154.2, 157.5, 162.3; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C15H21N4O3S 337.1329; Found 337.1325. tert-butyl (4-methoxybenzyl)(4-(pyrimidin-5-yl)thiazol-2-yl)carbamate (6c’). The compound was prepared according to General procedure D1 from tert-butyl (4-bromothiazol-2yl)(4-methoxybenzyl)carbamate (0.22 g, 0.55 mmol), pyrimidin-5-ylboronic acid (0.075 g, 0.606 mmol), K3PO4 (0.35 g, 1.65 mmol), Pd(dppf)Cl2 (0.04 g, 0.055 mmol) and DME/H2O (8 + 2 mL); reaction time was 3 hours at 80 °C. The product, purified by flash column chromatography (CH2Cl2: EtOAc; 1:0 to 6:4), was obtained as a white solid (0.170 g, 0.426 mmol, 78 %). mp = 172 – 174 °C; Rf = 0.4 (CH2Cl2:EtOAc; 1:1); IR (cm-1) 3082, 2988, 2968, 1692, 1498, 1435, 1391, 1353, 1306, 1248, 1235, 1153, 1139, 1030, 1004, 899, 766; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.52 (s, 9H), 3.70 (s, 3H), 5.28 (s, 2H), 6.86 – 6.93 (m, 2H), 7.32 – 7.39 (m, 2H), 8.00 (s, 1H), 9.13 (s, 1H), 9.27 – 9.33 (m, 2H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 27.7, 49.3, 55.0, 83.6, 112.6, 113.7,

127.8, 129.1, 129.5, 142.6, 152.5, 153.7, 157.2, 158.5, 161.3; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C20H23N4O3S 399.1485; Found 399.1488. tert-butyl (4-methoxybenzyl)(4-(4-methoxyphenyl)thiazol-2-yl)carbamate (6d). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(4-methoxyphenyl)thiazol-2-yl)carbamate (310 mg, 0.70 mmol) (from lithiation borylation), 1-bromo-4-methoxybenzene (157 mg, 0.84 mmol, 0.1 mL), K3PO4 (445 mg, 2.1 mmol), Pd(dppf)Cl2 (25 mg, 0.035 mmol) and DME/H2O (4 + 1 mL); reaction time was 4 hours at 80 °C. The product, purified by flash column chromatography (hexane:EtOAc; 10:1 to 5:1), was obtained as a colourless wax (205 mg, 0.5 mmol, 71 %). Rf = 0.36 (hexane:EtOAc; 5:1); mp = 88 - 89 °C; IR (cm1)

1698, 1610, 1496, 1241, 1153, 1014, 814, 744; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.55

(s, 9H), 3.78 (s, 3H), 3.84 (s, 3H), 5.35 (s, 2H), 6.81 – 6.86 (m, 2H), 6.92 – 6.96 (m, 2H), 6.99 (s, ACS Paragon Plus Environment

Page 43 of 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1H), 7.42 (d, J = 8.7 Hz, 2H), 7.80 – 7.86 (m, 2H);

13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm)

28.4, 49.8, 55.4, 55.5, 83.5, 106.5, 113.8, 114.1, 127.3, 128.1, 129.7, 130.5, 149.4, 153.3, 159.0, 159.5, 161.1; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C23H27N2O4S 427.1686; Found 427.1685. or The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)thiazol-2-yl)carbamate

(0.155

g, 0.326 mmol), 4-bromoanisole (73 mg, 49 L, 0.39 mmol), K3PO4 (0.28 g, 1.3 mmol), Pd(dppf)Cl2 (24 mg, 0.03 mmol) and DME/H2O (2 + 0.5 mL); reaction time was 16 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 1:0 to 2:1), was obtained as a white solid (91 mg, 0.213 mmol, 65 %). tert-butyl (4-(4-cyanophenyl)thiazol-2-yl)(4-methoxybenzyl)carbamate (6e). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate

(310

mg,

0.70 mmol) (from lithiation borylation), 4-bromobenzonitrile (152 mg, 0.84 mmol), K3PO4 (445 mg, 2.1 mmol), Pd(dppf)Cl2 (25 mg, 0.035 mmol) and DME/H2O (4 + 1 mL); reaction time was 4 hours at 80 °C. The product, purified by flash column chromatography (hexane:EtOAc; 10:1 to 3:1), was obtained as a white solid (195 mg, 0.46 mmol, 65 %). or The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)thiazol-2-yl)carbamate

(0.159

g, 0.335 mmol), 4-bromobenzonitrile (0.073 g, 0.4 mmol), K3PO4 (0.284 g, 1.34 mmol), Pd(dppf)Cl2 (24 mg, 0.033 mmol) and DME/H2O (2 + 0.5 mL); reaction time was 16 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 1:0 to 3:1), was obtained as a white solid (0.1 g, 0.237 mmol, 71 %). Rf = 0.41 (hexane:EtOAc; 4:1); mp = 145 - 146 °C ; IR (cm-1) 2223, 1694, 1513, 1230, 1151, 998, 848, 766, 546; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.56 (s, 9H), 3.78 (s, 3H), 5.33 (s, 2H), 6.84 (d, J = 8.9 Hz, 2H), 7.27 (s, 1H), 7.36 – 7.40 (m, 2H), 7.63 – 7.73 (m, 2H), 7.93 – 8.02 (m, 2H);

13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm) 28.4, 49.9, 55.4, 83.9, 110.9,

111.4, 113.9, 119.2, 126.5, 129.5, 130.0, 132.6, 139.0, 147.7, 153.3, 159.1, 161.8; HRMS (APCITOF) m/z: [M+H]+ Calcd for C23H24N3O3S 422.1533; Found 422.1533. tert-butyl (4-(3-cyanophenyl)thiazol-2-yl)(4-methoxybenzyl)carbamate (6f). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate

(310

mg,

0.73 mmol) (from lithiation borylation), 3-bromobenzonitrile (152 mg, 0.84 mmol), K3PO4 (445 mg, 2.1 mmol), Pd(dppf)Cl2 (25 mg, 0.035 mmol) and DME/H2O (4 + 1 mL); reaction time was 4 hours at 80 °C. The product, purified by flash column chromatography (hexane:EtOAc; 10:1 to 3:1), was obtained as a colourless wax (180 mg, 0.44 mmol, 60 %). Rf = 0.60 (Hexane:EtOAc; 7:3); IR (cm-1) ACS Paragon Plus Environment


Page 44 of 64

2227, 1697, 1512, 1481, 1140, 1016, 750; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.57 (s, 9H), 3.79 (s, 3H), 5.35 (s, 2H), 6.83 – 6.92 (m, 2H), 7.21 (s, 1H), 7.35 – 7.41 (m, 2H), 7.47 – 7.51 (m, 1H), 7.54 – 7.59 (m, 1H), 8.05 – 8.11 (m, 1H), 8.16 – 8.22 (m, 1H);

13C{1H}

NMR (126 MHz,

Chloroform-d)  (ppm) 28.4, 50.0, 55.5, 84.0, 110.1, 113.0, 113.9, 119.1, 129.6, 129.6, 129.9, 130.1, 131.0, 136.2, 147.4, 153.4, 159.2, 161.9; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C23H24N3O3S 422.1533; Found 422.1532. ethyl 4-(2-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)thiazol-4-yl)benzoate (6g). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate

(0.35

g,

0.784 mmol) (from lithiation borylation), ethyl 4-bromobenzoate (0.115 mL, 0.705 mmol), K3PO4 (0.5 g, 2.35 mmol), Pd(dppf)Cl2 (0.058 g, 0.078 mmol) and DME/H2O (8 + 2 mL); reaction time was 3 hours at 80 °C. The product, purified by flash column chromatography (hexane:EtOAc; 1:0 to 9:1), was obtained as a colourless wax (0.188 g, 0.401 mmol, 64 %). Rf = 0.62 (Hexane:EtOAc; 9:1); IR (cm-1) 2978, 2933, 1701, 1609,1512, 1498, 1386, 1367, 1270, 1231, 1153, 1101,1018, 728; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.41 (t, J = 7.11 Hz, 3H), 1.56 (s, 9H), 3.78 (s, 3H), 4.39 (q, J = 7.12 Hz, 2H), 5.35 (s, 2H), 6.81 – 6.87 (m, 2H), 7.26 (s, 1H), 7.38 – 7.46 (m, 2H), 7.92 – 7.99 (m, 2H), 8.04 – 8.12 (m, 2H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 14.5, 28.4, 49.9, 55.4, 61.0, 110.4, 113.8, 125.8, 129.5, 129.7, 130.1, 130.2, 139.0, 148.6, 159.1, 161.5, 166.6; HRMS (APCITOF) m/z: [M+H]+ Calcd for C25H29N2O5S 469.1792; Found 469.1791. tert-butyl (4-methoxybenzyl)(4-(thiophen-2-yl)thiazol-2-yl)carbamate (6h). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate

(0.350

g,

0.784 mmol) (from lithiation borylation), 2-bromothiophene (0.068 mL, 0.705 mmol), K3PO4 (0.500 g, 2.35 mmol), Pd(dppf)Cl2 (0.058 g, 0.0784 mmol) and DME/H2O (8 + 2 mL); reaction time was 3 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 1:0 to 9:1), was obtained as a colourless wax (0.164 g, 0.407 mmol, 65 %). Rf = 0.44 (Hexane:EtOAc; 9:1); IR (cm-1) 2932, 1698, 1611, 1511, 1437, 1386, 1366, 1282, 1231, 1151, 1031, 819, 753; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.57 (s, 9H), 3.78 (s, 3H), 5.30 (s, 2H), 6.81 – 6.86 (m, 2H), 6.98 (s, 1H), 7.04 (dd, J = 5.08, 3.58 Hz, 1H), 7.24 (dd, J = 5.04, 1.19 Hz, 1H), 7.39 (dd, J = 3.55, 1.20 Hz, 1H), 7.45 – 7.50 (m, 2H);

13C{1H}


107.0, 113.7, 123.4, 124.8, 127.7, 130.2, 130.2, 139.6, 144.4, 159.1, 161.1; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C20H23N2O3S2 403.1145; Found 403.1145. tert-butyl (4-methoxybenzyl)(4-(4-(trifluoromethyl)pyridin-2-yl)thiazol-2-yl)carbamate (6i). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate ACS Paragon Plus Environment

(0.558

g,

Page 45 of 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


1.25 mmol) (from lithiation borylation), 2-bromo-4-(trifluoromethyl)pyridine (0.31 g, 1.37 mmol), K3PO4 (0.796 g, 3.75 mmol), Pd(dppf)Cl2 (0.91 g, 0.125 mmol) and DME/H2O (12 + 3 mL); reaction time was 3 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 1:0 to 9:1), was obtained as a white solid (0.35 g, 0.751 mmol, 60 %). Rf = 0.55 (Hexane:EtOAc; 9:1); mp = 120 – 122 °C; IR (cm-1) 2973, 1699, 1612, 1511, 1382, 1352, 1322, 1252, 1232, 1131, 847, 766, 697; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.57 (s, 9H), 3.78 (s, 3H), 5.34 (s, 2H), 6.82 – 6.87 (m, 2H), 7.36 – 7.42 (m, 3H), 7.81 (s, 1H), 8.25 (d, J = 1.57 Hz, 1H), 8.74 (d, J = 5.04 Hz, 1H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 28.4, 50.1, 55.4, 83.9, 113.9, 114.3, 116.6, 117.7 (d, J = 3.64 Hz), 122.1, 124.2 (q, J = 272.6 Hz), 129.6, 130.1, 139.2, 148.3, 150.3, 154.4, 159.1, 161.7; 19F{1H} NMR (471 MHz, Chloroform-d)  (ppm) -64.96; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C22H23F3N3O3S 466.1407; Found 466.1409. tert-butyl (4-(5-cyanopyridin-2-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate (6j). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate

(0.782

g,

2.62 mmol) (from lithiation borylation), 6-bromonicotinonitrile (0.352 g, 1.92 mmol), K3PO4 (1.15 g, 5.25 mmol), Pd(dppf)Cl2 (0.128 g, 0.175 mmol) and DME/H2O (12 + 3 mL); reaction time was 3 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 1:0 to 8:2), was obtained as a white solid (0.530 g, 1.25 mmol, 71 %). Rf = 0.34 (Hexane:EtOAc; 9:1); mp = 129 – 131 °C; IR (cm-1) 3114, 2975, 2931, 2225, 1694, 1587, 1512, 1367, 1291, 1242, 1151, 1019, 849; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.55 (s, 9H), 3.78 (s, 3H), 5.33 (s, 2H), 6.80 – 6.88 (m, 2H), 7.33 – 7.40 (m, 2H), 7.91 (s, 1H), 7.98 (dd, J = 8.28, 2.17 Hz, 1H), 8.15 (d, J = 8.28 Hz, 1H), 8.82 (d, J = 2.05 Hz, 1H);

13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm) 28.4, 50.0, 55.4, 84.2, 107.8,

113.9, 116.5, 117.3, 120.4, 129.4, 130.0, 140.2, 148.0, 152.3, 155.8, 159.2, 162.0; HRMS (APCITOF) m/z: [M+H]+ Calcd for C22H23N4O3S 423.1485; Found 423.1482. tert-butyl (4-(6-acetylpyridin-3-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate (6k). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate (0.7 g, 1.56 mmol) (from lithiation borylation), 1-(5-bromopyridin-2-yl)ethan-1-one (0.313 g, 1.56 mmol), K3PO4 (0.998 g, 4.7 mmol), Pd(dppf)Cl2 (0.114 g, 0.156 mmol) and DME/H2O (8 + 2 mL); reaction time was 3 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 1:0 to 4:1), was obtained as a white solid (0.2 g, 0.455 mmol, 36 %). Rf = 0.46 (Hexane:EtOAc; 2:1); mp = 110 – 112 °C; IR (cm-1) 2976, 2933, 1692, 1511, 1382, 1352, 1294, 1229, 1137, 1022, 847, 763, 746; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.56 (s, 9H), 2.74 (s, 3H), 3.77 (s, 3H), 5.33 (s, 2H), 6.82 – 6.86 (m, 2H), 7.34 (s, 1H), 7.37 – 7.45 (m, 2H), 8.07 (d, J = 8.12 Hz, 1H), 8.24 (dd, J = 8.20, 2.19 Hz, 1H), 9.19 (d, J = 2.09 Hz, 1H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 26.0, 28.4, 50.0,



Page 46 of 64

55.4, 84.0, 111.8, 113.9, 121.9, 129.6, 129.9, 133.7, 133.7, 145.9, 146.7, 152.3, 153.3, 159.1, 162.0, 199.7; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C23H26N3O4S 440.1639; Found 440.1639. tert-butyl (4-(3-fluoropyridin-2-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate (6l). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate

(334

mg,

0.75 mmol) (from Miyaura borylation), 2-bromo-3-fluoropyridine (158 mg, 0.9 mmol), K3PO4 (0.49 g, 2.25 mmol), Pd(dppf)Cl2 (30 mg, 0.038 mmol) and DME/H2O (4 + 1 mL); reaction time was 4 hours at 80 °C. The product, purified by flash column chromatography (hexane:EtOAc; 10:1 to 3:1), was obtained as a white solid (0.2 g, 0.48 mmol, 65 %). Rf = 0.45 (Hexane:EtOAc; 7:3); mp = 109 – 110 °C; IR (cm-1) 1696, 1509, 1499, 1439, 1225, 1137, 797, 741; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.55 (s, 9H), 3.76 (d, J = 1.6 Hz, 3H), 5.39 (s, 2H), 6.76 – 6.84 (m, 2H), 7.21 – 7.26 (m, 1H), 7.43 – 7.47 (m, 2H), 7.47 – 7.51 (m, 1H), 7.68 (d, J = 1.2 Hz, 1H), 8.48 – 8.52 (m, 1H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 28.4, 50.0, 55.4, 83.6, 113.7, 116.4 (d, J = 8.2 Hz), 123.6 (d, J = 4.2 Hz), 124.4 (d, J = 20.0 Hz), 130.2 (d, J = 36.2 Hz), 141.7 (d, J = 9.2 Hz), 145.3 (d, J = 5.2 Hz), 153.5, 156.2, 158.3, 159.1, 161.3;

13F{1H}

NMR (451 MHz, Chloroform-d)  (ppm) -120.3; HRMS

(APCI-TOF) m/z: [M+H]+ Calcd for C21H23FN3O3S 416.1439; Found 416.1438. tert-butyl (4-(6-cyanopyridin-2-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate (6m). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate

(350

mg,

0.78 mmol) (from Miyaura borylation), 6-bromopicolinonitrile (143 mg, 0.78 mmol), K3PO4 (520 mg, 2.34 mmol), Pd(dppf)Cl2 (17 mg, 0.02 mmol) and DME/H2O (4 + 1 mL); reaction time was 4 hours at 80 °C. The product, purified by flash column chromatography (hexane:EtOAc; 10:1 to 3:1), was obtained as a white solid (0.2 g, 0.47 mmol, 60 %). Rf = 0.4 (Hexane:EtOAc; 7:3); mp = 153 - 154 °C; IR (cm-1) 2230, 1698, 1584, 1386, 1235, 1150, 1000, 749, 639; 1H NMR (500 MHz, Chloroformd)  (ppm) 1.6 (s, 9H), 3.8 (s, 3H), 5.3 (s, 2H), 6.9 (d, J = 8.7 Hz, 2H), 7.4 (d, J = 8.7 Hz, 2H), 7.6 (dd, J = 1.1, 7.6 Hz, 1H), 7.8 – 7.9 (m, 2H), 8.3 (dd, J = 1.1, 8.1 Hz, 1H);

13C{1H}

NMR (126 MHz,

Chloroform-d)  (ppm) 28.4, 50.0, 55.4, 84.0, 113.9, 115.2, 117.6, 124.0, 126.7, 129.5, 130.1, 133.6, 138.0, 147.7, 154.6, 159.2, 162.0; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C22H23N4O3S 423.1485; Found 423.1486. tert-butyl (4-(3-cyanopyridin-2-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate (6n). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate

(350

mg,

0.78 mmol) (from Miyaura borylation), 2-bromonicotinonitrile (143 mg, 0.78 mmol), K3PO4 (520 mg, 2.34 mmol), Pd(dppf)Cl2 (17 mg, 0.02 mmol) and DME/H2O (4 + 1 mL); reaction time was 4 hours at 80 °C. The product, purified by flash column chromatography (hexane:EtOAc; 10:1 to 3:1), was ACS Paragon Plus Environment

Page 47 of 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


obtained as a colourless wax (265 mg, 0.63 mmol, 80 %). Rf = 0.65 (Hexane:EtOAc; 7:3); IR (cm-1) 3114, 2222, 1698, 1501, 1390, 1240, 1158, 749, 654, 531; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.56 (s, 9H), 3.75 (s, 3H), 5.45 (s, 2H), 6.77 – 6.84 (m, 2H), 7.28 (dd, J = 4.7, 7.9 Hz, 1H), 7.39 – 7.45 (m, 2H), 7.90 (s, 1H), 8.04 (dd, J = 1.8, 7.9 Hz, 1H), 8.74 (dd, J = 1.8, 4.7 Hz, 1H); 13C{1H}


121.6, 129.5, 130.1, 142.3, 142.9, 146.8, 152.1, 153.5, 158.8, 161.5; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C22H23N4O3S 423.1485; Found 423.1486. tert-butyl (4-(4-(tert-butyl)pyridin-2-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate (6o). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate (0.7 g, 1.56 mmol) (from lithiation borylation), 4-(tert-butyl)-2-chloropyridine (0.266 g, 1.56 mmol), K3PO4 (0.998 g, 4.7 mmol), Pd(dppf)Cl2 (0.114 g, 0.156 mmol) and DME/H2O (8 + 2 mL); reaction time was 4 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 1:0 to 7.5:2.5), was obtained as a colourless wax (0.167 g, 0.368 mmol, 30 %). Rf = 0.43 (Hexane:EtOAc; 3:2); IR (cm1)

3361, 2965, 1702, 1601, 1512, 1382, 1246, 1153, 1030, 832, 767, 736; 1H NMR (500 MHz,

Chloroform-d)  (ppm) 1.38 (s, 9H), 1.59 (s, 9H), 3.78 (s, 3H), 5.33 (s, 2H), 6.81 – 6.86 (m, 2H), 7.21 (dd, J = 5.33, 1.99 Hz, 1H), 7.43 – 7.49 (m, 2H), 7.76 (s, 1H), 8.11 (d, J = 1.89 Hz, 1H), 8.49 (dd, J = 5.32, 0.75 Hz, 1H);

13C{1H}


55.4, 83.7, 113.8, 118.2, 119.7, 129.8, 130.4, 133.5, 148.9, 152.5, 153.3, 159.1, 161.2, 198.1; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C25H32N3O3S 454.2159; Found 454.2159. or The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate (0.35 g, 0.78 mmol) (from Miyaura borylation), 4-(tert-butyl)-2-chloropyridine (0.132 g, 0.78 mmol), K3PO4 (0.52 g, 2.34 mmol), Pd(dppf)Cl2 (0.017 g, 0.02mmol) and DME/H2O (4 + 1 mL); reaction time was 2 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 10:1 to 7:3), was obtained as a colourless wax (0.23 g, 0.51 mmol, 65 %). tert-butyl(4-methoxybenzyl)(4-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)thiazol-2-yl)carbamate (6p). The compound was prepared according to General procedure G from tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate (0.7 g, 1.56 mmol) (from lithiation borylation), 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.374 g, 1.56 mmol), K3PO4 (0.998 g, 4.70 mmol), Pd(dppf)Cl2 (0.114 g, 0.156 mmol) and DME/H2O (8 + 2 mL); reaction time was 3 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 1:0 to 3:7), was obtained as a pale yellow wax (0.243 g, 0.464 mmol, 37 %). Rf = 0.34 (Hexane:EtOAc; 1:1); IR (cm-1) 3110, 2933, 2857, 1698, 1578, 1512, 1487, 1439, 1386, 1243, 1227, ACS Paragon Plus Environment


Page 48 of 64

1146, 1083, 848, 810, 767, 727, 644; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.53 (s, 9H), 1.65 – 1.71 (m, 1H), 1.75 – 1.87 (m, 2H), 2.02 – 2.15 (m, 2H), 2.15 – 2.22 (m, 1H), 3.75 (s, 3H), 3.81 (td, J = 11.87, 2.77 Hz, 1H), 4.20 (ddt, J = 11.60, 4.06, 1.74 Hz, 1H), 5.48 (s, 2H), 5.85 (dd, J = 10.32, 2.49 Hz, 1H), 6.76 – 6.83 (m, 2H), 7.47 (d, J = 8.43 Hz, 2H), 8.34 (s, 1H), 8.72 (s, 1H), 9.08 (s, 1H); 13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm) 14.2, 22.8, 22.9, 25.1, 28.4, 31.7, 32.1, 50.1, 55.3,

69.0, 82.2, 83.8, 113.7, 123.0, 130.0, 130.3, 130.5, 142.5, 151.6, 152.8, 159.0, 161.8; HRMS (APCITOF) m/z: [M+H]+ Calcd for C26H31N6O4S 523.2122; Found 523.2122. or The compound was prepared according to General procedure G from tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate

(0.700

g,

1.56 mmol) (from Miyaura borylation), 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.374 g, 1.56 mmol), K3PO4 (0.998 g, 4.70 mmol), Pd(dppf)Cl2 (0.03 g, 0.05 mmol) and DME/H2O (4 + 1 mL); reaction time was 2 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 1:0 to 3:7), was obtained as a pale yellow wax (0.622 g, 1.19 mmol, 76 %). tert-butyl (4-methoxybenzyl)(4-(pyrazin-2-yl)thiazol-2-yl)carbamate (6q). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate

(350

mg,

0.78 mmol) (from Miyaura borylation), 2-chloropyrazine (90 mg, 0.78 mmol), K3PO4 (520 mg, 2.34 mmol), Pd(dppf)Cl2 (17 mg, 0.02 mmol) and DME/H2O (4 + 1 mL); reaction time was 4 hours at 80 °C. The product, purified by flash column chromatography (hexane:EtOAc; 10:1 to 3:1), was obtained as a colourless wax (230 mg, 0.59 mmol, 75 %). Rf = 0.55 (Hexane:EtOAc; 7:3); IR (cm-1) 1694, 1511, 1383, 1235, 1150, 769, 747; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.58 (s, 9H), 3.78 (d, J = 1.0 Hz, 3H), 5.35 (s, 2H), 6.77 – 6.93 (m, 2H), 7.34 – 7.47 (m, 2H), 7.79 (s, 1H), 8.45 – 8.49 (m, 1H), 8.51 – 8.55 (m, 1H), 9.24 – 9.37 (m, 1H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 28.4, 50.0, 55.4, 84.0, 113.9, 114.7, 129.7, 130.0, 142.9, 143.2, 144.1, 147.0, 148.5, 153.4, 159.2, 162.0; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C20H23N4O3S 399.1485; Found 399.1485. tert-butyl (4-methoxybenzyl)(4-phenylthiazol-2-yl)carbamate (6r). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)thiazol-2-yl)carbamate

(0.101

g, 0.212 mmol), bromobenzene (0.04 g, 27 L, 0.255 mmol), K3PO4 (0.18 g, 0.85 mmol), Pd(dppf)Cl2 (16 mg, 0.021 mmol) and DME/H2O (2 + 0.5 mL); reaction time was 16 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 1:0 to 5:1), was obtained as a white solid (0.059 g, 0.149 mmol, 71 %). Rf = 0.35 (hexane:EtOAc; 10:1); mp = 90 - 93 °C; IR (cm-1) 1696, 1512, 1497, 1433, 1392, 1385, 1288, 1241, 1175, 1157, 1143, 1027, 1016, 899, 853, 731, 720; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.56 (s, 9H), 3.78 (s, 3H), 5.36 (s, 2H), 6.79 – 6.88 (m, 2H), 7.13 (s, 1H), 7.27 – 7.34 (m, 1H), 7.36 – 7.47 (m, 4H), 7.86 – 7.94 (m, 2H); ACS Paragon Plus Environment

13C{1H}

NMR (126 MHz,

Page 49 of 64 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Chloroform-d)  (ppm) 28.4, 49.9, 55.4, 108.3, 113.8, 126.1, 127.8, 128.8, 129.8, 130.4, 135.1, 149.6, 159.1, 161.3; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C22H25N2O3S 397.1580; Found 397.1580. tert-butyl (4-methoxybenzyl)(4-(6-morpholinopyridin-2-yl)thiazol-2-yl)carbamate (6s). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)thiazol-2-yl)carbamate

(160

mg, 0.337 mmol), 2-bromo-6-morpholinopyridine (90 mg, 0.37 mmol), K3PO4 (0.286 g, 1.35 mmol), Pd(dppf)Cl2 (25 mg, 0.034 mmol) and DME/H2O (6 + 1.5 mL); reaction time was 16 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 1:0 to 1:1), was obtained as a white solid (0.121 g, 0.251 mmol, 74 %). Rf = 0.30 (hexane:EtOAc; 2:1); mp = 141 - 143 °C ; IR (cm-1) 1699, 1512, 1462, 1388, 1244, 1229, 1151, 1130, 1122, 1004, 848, 758; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.55 (s, 9H), 3.54 – 3.63 (m, 4H), 3.77 (s, 3H), 3.80 – 3.91 (m, 4H), 5.35 (s, 2H), 6.57 (d, J = 8.3 Hz, 1H), 6.77 – 6.88 (m, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 7.4 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.65 (s, 1H);

13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm) 28.4, 45.8,

49.8, 55.3, 67.0, 83.5, 106.1, 111.0, 112.1, 113.7, 129.7, 130.4, 138.5, 150.2, 151.1, 153.3, 159.0, 159.1, 161.1; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C25H31N4O4S 483.2061; Found 483.2061. tert-butyl (4-methoxybenzyl)(4-(3-methoxypyridin-2-yl)thiazol-2-yl)carbamate (6t). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)thiazol-2-yl)carbamate

(0.172

g, 0.484 mmol), 2-bromo-3-methoxypyridine (0.1 g, 0.53 mmol), K3PO4 (0.411 g, 1.94 mmol), Pd(dppf)Cl2 (35 mg, 0.048 mmol) and DME/H2O (4 + 1 mL); reaction time was 16 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 1:0 to 1:1), was obtained as a colourless oil (0.113 g, 0.264 mmol, 55 %). Rf = 0.20 (hexane:EtOAc; 1:1); IR (cm-1) 2983, 1700, 1497, 1461, 1387, 1278, 1240, 1156, 1143, 1120, 1006, 792, 655; 1H NMR (500 MHz, Chloroformd)  (ppm) 1.51 (s, 9H), 3.75 (s, 3H), 3.91 (s, 3H), 5.40 (s, 2H), 6.75 – 6.83 (m, 2H), 7.20 (dd, J = 8.2, 4.6 Hz, 1H), 7.28 (dd, J = 8.3, 1.4 Hz, 1H), 7.41 (d, J = 8.9 Hz, 2H), 7.69 (s, 1H), 8.34 (dd, J = 4.6, 1.4 Hz, 1H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 28.4, 49.9, 55.3, 55.7, 83.3, 113.6, 116.4, 118.8, 122.9, 129.8, 130.6, 141.6, 142.9, 146.6, 153.5, 153.9, 158.9, 160.5; HRMS (APCITOF) m/z: [M+H]+ Calcd for C22H26N3O4S 428.1639; Found 248.1639. tert-butyl (4-(4-cyanopyridin-2-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate (6u). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)thiazol-2-yl)carbamate

(172

mg, 0.484 mmol), 2-bromo-4-cyanopyridine (98 mg, 0.53 mmol), K3PO4 (411 mg, 1.94 mmol), Pd(dppf)Cl2 (35 mg, 0.048 mmol) and DME/H2O (4 + 1 mL); reaction time was 16 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 1:0 to 2:1), was obtained as ACS Paragon Plus Environment


Page 50 of 64

a white solid (0.081 g, 0.192 mmol, 40 %). Rf = 0.31 (hexane:EtOAc; 3:1); mp = 160 - 162 °C ; IR (cm-1) 1704, 1591, 1509, 1434, 1296, 1145, 1026, 769; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.56 (s, 9H), 3.78 (s, 3H), 5.35 (s, 2H), 6.86 (d, J = 8.9 Hz, 2H), 7.33 – 7.41 (m, 3H), 7.81 (s, 1H), 8.24 (t, J = 1.3 Hz, 1H), 8.70 – 8.74 (m, 1H);

13C{1H}

NMR (126 MHz, Chloroform-d)  (ppm) 28.4,

50.0, 55.4, 84.0, 113.9, 114.8, 117.0, 121.3, 122.5, 123.4, 129.3, 130.0, 147.7, 150.3, 153.3, 154.3, 159.1, 162.0; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C22H23N4O3S 423.1485; Found 423.1485. tert-butyl (4-methoxybenzyl)(4-(6-phenylpyridin-2-yl)thiazol-2-yl)carbamate (6v). The compound was prepared according to General procedure D2 from tert-butyl (4methoxybenzyl)(4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)thiazol-2-yl)carbamate (90 mg, 0.189 mmol), 2-bromo-6-phenylpyridine (49 mg, 0.208 mmol), K3PO4 (161 mg, 0.757 mmol), Pd(dppf)Cl2 (14 mg, 0.019 mmol) and DME/H2O (4 + 1 mL); reaction time was 16 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 1:0 to 2:1), was obtained as a white solid (0.081 g, 0.192 mmol, 40 %). Rf = 0.44 (hexane:EtOAc; 5:1); mp = 152 - 154 °C; IR (cm-1) 1693, 1564, 1513, 1500, 1427, 1388, 1242, 1154, 1141, 1016, 754, 740; 1H NMR (300 MHz, Chloroform-d)  (ppm) 1.57 (s, 9H), 3.78 (s, 3H), 5.38 (s, 2H), 6.80 – 6.87 (m, 2H), 7.39 – 7.54 (m, 5H), 7.66 (dd, J = 7.9, 1.0 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.93 (s, 1H), 8.02 (dd, J = 7.7, 1.1 Hz, 1H), 8.10 – 8.16 (m, 2H); 13C{1H} NMR (75 MHz, Chloroform-d)  (ppm) 28.4, 49.9, 55.4, 83.6, 112.9, 113.8, 119.1, 119.1, 127.1, 128.8, 129.1, 129.7, 130.4, 137.7, 139.6, 149.9, 152.8, 153.3, 156.7, 159.1, 161.4; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C27H28N3O3S 474.1846; Found 474.1846. tert-butyl (4-(6-phenylpyridin-2-yl)thiazol-2-yl)carbamate (6v’). The compound was prepared according to General procedure D2 from tert-butyl (4-(6-methyl-4,8dioxo-1,3,6,2-dioxazaborocan-2-yl)thiazol-2-yl)carbamate (91 mg, 0.256 mmol), 2-bromo-6phenylpyridine (63 mg, 0.269 mmol), K3PO4 (163 mg, 0.769 mmol), Pd(dppf)Cl2 (19 mg, 0.026 mmol) and DME/H2O (4 + 1 mL); reaction time was 24 hours at 80 °C. The product, purified by flash column chromatography (hexane: EtOAc; 1:0 to 4:1), was obtained as a colourless wax (0.036 g, 0.102 mmol, 40 %). Rf = 0.33 (hexane:EtOAc; 4:1); IR (cm-1) 2978, 1719, 1566, 1437, 1369, 1324, 1244, 1153, 1075, 751; 1H NMR (300 MHz, Chloroform-d)  (ppm) 1.38 (s, 9H), 7.39 – 7.54 (m, 3H), 7.64 – 7.71 (m, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.86 – 7.93 (m, 2H), 8.07 – 8.15 (m, 2H), 9.78 (s, 1H); HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C19H20N3O2S 354.1271; Found 354.1271. 4-(6-morpholinopyridin-3-yl)thiazol-2-amine (7a). The compound was prepared according to General procedure E1 from tert-butyl (ethoxymethyl)(4(6-morpholinopyridin-3-yl)thiazol-2-yl)carbamate (0.226 g, 0.53 mmol), ethanol (8.5 mL), aqueous 3 M HCl (0.5 mL) and 7 M NH3 in MeOH (5.3 mL); the reaction time was 12 hours at 90 °C and then 25 °C for 2 hours. The product, purified by flash column chromatography (CH2Cl2:MeOH:7 M NH3 in MeOH; 1:1:0.5 % to 9.5:0.5:0.5 %); was obtained as a pale yellow solid (0.025 g, 0.095 mmol, 18 ACS Paragon Plus Environment

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%). Rf = 0.58 (CH2Cl2:MeOH:7 M NH3 in MeOH; 9:1:0.1 %); 1H NMR (500 MHz, DMSO-d6)  (ppm) 3.42 – 3.49 (m, 4H), 3.67 – 3.74 (m, 4H), 6.82 (d, J = 1.97 Hz, 2H), 7.02 (s, 2H), 7.91 (dd, J = 8.84, 2.45 Hz, 1H), 8.56 (d, J = 2.30 Hz, 1H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 45.1, 65.9, 98.9, 106.5, 121.1, 134.7, 144.9, 147.6, 158.0, 168.3; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H15N4OS 263.0961; Found 263.0959. 4-(1-methyl-1H-pyrazol-4-yl)thiazol-2-amine (7b). The compound was prepared according to General procedure E1 from tert-butyl (ethoxymethyl)(4(1-methyl-1H-pyrazol-4-yl)thiazol-2-yl)carbamate (0.280 g, 0.827 mmol), ethanol (13 mL), aqueous 3 M HCl (0.8 mL) and 7 M NH3 in MeOH (8.3 mL); the reaction time was 5 hours at 90 °C and then 25 °C for 2 hours. The product, purified by flash column chromatography (CH2Cl2:MeOH; 1:0 to 9.5:0.5); was obtained as a white solid (40 mg, 0.22 mmol, 27 %). Rf = 0.58 (CH2Cl2:MeOH:7 M NH3 in MeOH; 9:1:0.1); IR (cm-1) 3281, 3107, 2941, 1637, 1532, 1512, 1384, 1343, 1315, 1267, 1171, 1067, 990, 849, 819, 707; 1H NMR (500 MHz, DMSO-d6)  (ppm) 3.82 (s, 3H), 6.53 (s, 1H), 6.91 (s, 2H), 7.64 (s, 1H), 7.84 (s, 1H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 38.4, 98.0, 118.4, 127.8, 136.2, 143.5, 168.1; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C7H9N4S 181.0542; Found 181.0539. 4-(pyrimidin-5-yl)thiazol-2-amine (7c). The compound was prepared according to General procedure E1 from tert-butyl (ethoxymethyl)(4(pyrimidin-5-yl)thiazol-2-yl)carbamate (0.40 g, 1.18 mmol), ethanol (19 mL), aqueous 3 M HCl (1 mL) and 7 M NH3 in MeOH (11.8 mL); the reaction time was 24 hours at 90 °C and then 25 °C for 2 hours. The product, purified by flash column chromatography (CH2Cl2:MeOH; 1:0 to 9.3:0.7); was obtained as a brown solid (50 mg, 0.28 mmol, 24 %). Rf = 0.58 (CH2Cl2:MeOH; 9:1); mp = > 210 °C (decomposed); IR (cm-1) 3249, 3085, 1657, 1544, 1431, 1405, 1221, 1033, 912, 841, 725, 691; 1H NMR (500 MHz, DMSO-d6)  (ppm) 7.25 (s, 2H), 7.36 (s, 1H), 9.07 (s, 1H), 9.15 (s, 2H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 104.7, 128.3, 143.8, 153.4, 156.6, 169.1; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C7H7N4S 179.0386; Found 179.0384. CAS registry No. [1159606-24-2]. 1H and reported in the

13C


literature.30i

or The compound was prepared according to General procedure E2 from tert-butyl (4methoxybenzyl)(4-(pyrimidin-5-yl)thiazol-2-yl)carbamate (80 mg, 0.200 mmol) and trifluoroacetic acid (2 mL); the reaction time was 1 hour at 70 °C. The product, purified by flash column chromatography (CH2Cl2:MeOH; 1:0 to 9.4:0.6); was obtained as a brown solid (30 mg, 0.168 mmol, 85 %). 4-(4-methoxyphenyl)thiazol-2-amine (7d).



Page 52 of 64

The compound was prepared according to General procedure E2 from tert-butyl (4methoxybenzyl)(4-(4-methoxyphenyl)thiazol-2-yl)carbamate (0.1 g, 0.23 mmol) and trifluoroacetic acid (2 mL); the reaction time was 2 hours at 70 °C. The product, purified by flash column chromatography (CH2Cl2:MeOH; 1:0 to 5:1); was obtained as a white solid (40 mg, 0.18 mmol, 80 %). Rf = 0.5 (Hexane:EtOAc; 1:1); mp = 162 - 195 °C; IR (cm-1) 3437, 1624, 1492, 1241, 1175, 1030, 833; 1H NMR (500 MHz, DMSO-d6)  (ppm) 3.76 (s, 3H), 6.81 (s, 1H), 6.88 – 6.95 (m, 2H), 6.96 (s, 2H), 7.67 – 7.75 (m, 2H);

13C{1H}


127.8, 149.7, 158.5, 168.0; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C10H11N2OS 207.0587; Found 207.0585. CAS registry No. [2104-04-3]. 1H and

13C


reported in the literature.30i 4-(2-aminothiazol-4-yl)benzonitrile (7e). The compound was prepared according to General procedure E2 from tert-butyl (4-(4cyanophenyl)thiazol-2-yl)(4-methoxybenzyl)carbamate (0.15 g, 0.35 mmol) and trifluoroacetic acid (2 mL); the reaction time was 2 hours at 70 °C. The product, purified by flash column chromatography (CH2Cl2:MeOH; 1:0 to 5:1); was obtained as a white solid (53 mg, 0.26 mmol, 75 %). Rf = 0.1 (EtOAc); mp = 200 - 201 °C; IR (cm-1) 3373, 2226, 1641, 1539, 1340, 1041, 836, 707; 1H NMR (500 MHz, DMSO-d6)  (ppm) 7.14 – 7.19 (m, 2H), 7.32 (s, 1H), 7.79 – 7.83 (m, 2H), 7.94 – 7.99 (m, 2H); 13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 105.4, 109.1, 119.0, 126.1, 132.5, 138.9, 148.1, 168.0;

HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C10H8N3S 202.0433; Found 202.0433. CAS registry No. [436151-85-8]. 1H and

13C


reported in the literature.30j 3-(2-aminothiazol-4-yl)benzonitrile (7f). The compound was prepared according to General procedure E2 from tert-butyl (4-(3cyanophenyl)thiazol-2-yl)(4-methoxybenzyl)carbamate (0.15 g, 0.35 mmol) and trifluoroacetic acid (2 mL); the reaction time was 2 hour at 70 °C. The product, purified by flash column chromatography (CH2Cl2:MeOH; 1:0 to 5:1); was obtained as a white solid (53 mg, 0.26 mmol, 75 %). Rf = 0.1 (EtOAc); mp = 191 - 192 °C; IR (cm-1) 3395, 2233, 1630, 1532, 1342, 1052, 724; 1H NMR (500 MHz, DMSOd6)  (ppm) 7.13 (s, 2H), 7.25 (s, 1H), 7.55 – 7.61 (m, 1H), 7.69 – 7.72 (m, 1H), 8.09 – 8.14 (m, 1H), 8.18 – 8.21 (m, 1H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 103.8, 111.6, 118.8, 128.8, 129.8, 129.9, 130.4, 135.9, 147.6, 168.5; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C10H8N3S 202.0433; Found 202.0433. CAS registry No. [202664-32-2]. 1H NMR spectrum was consistent with that previously reported in the literature.30k ethyl 4-(2-aminothiazol-4-yl)benzoate (7g). ACS Paragon Plus Environment

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The compound was prepared according to General procedure E2 from ethyl 4-(2-((tertbutoxycarbonyl)(4-methoxybenzyl)amino)thiazol-4-yl)benzoate

(0.15

g,

0.32

mmol)

and

trifluoroacetic acid (1.30 mL); the reaction time was 2 hours at 70 °C. The product, purified by flash column chromatography (CH2Cl2:MeOH; 1:0 to 30:1); was obtained as a white solid (70 mg, 0.282 mmol, 89 %). Rf = 0.57 (CH2Cl2:MeOH; 9:1); mp = 210 – 212 °C; IR (cm-1) 3398, 3287, 3112, 1691, 1635, 1608, 1539, 1524, 1274, 1106, 1016, 859, 706; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.33 (t, J = 7.10 Hz, 3H), 4.31 (q, J = 7.07 Hz, 2H), 7.13 (br s, 2H), 7.22 (s, 1H), 7.89 – 8.01 (m, 4H); 13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 14.2, 60.5, 104.4, 125.5, 128.1, 129.4, 139.0, 148.7,

165.5, 168.3; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H13N2O2S 249.0692; Found 249.0692. CAS registry No. [651042-69-2]. 1H and

13C


reported in the literature.30l 4-(thiophen-2-yl)thiazol-2-amine (7h). The compound was prepared according to General procedure E2 from tert-butyl (4methoxybenzyl)(4-(thiophen-2-yl)thiazol-2-yl)carbamate (150 mg, 0.372 mmol) and trifluoroacetic acid (1.50 mL); the reaction time was 2 hours at 70 °C. The product, purified by flash column chromatography (CH2Cl2:MeOH; 1:0 to 30:1); was obtained as a white solid (50 mg, 0.274 mmol, 75 %). Rf = 0.47 (CH2Cl2:MeOH; 9:1); mp = 114 – 116 °C; IR (cm-1) 3423, 3269, 3114, 3099, 2929, 1621, 1518, 1221, 1184, 1016, 803, 701; 1H NMR (500 MHz, DMSO-d6)  (ppm) 6.83 (s, 1H), 7.03 (dd, J = 5.05, 3.63 Hz, 1H), 7.12 (br s, 2H), 7.37 (dd, J = 3.68, 1.13 Hz, 1H), 7.39 (dd, J = 5.05, 1.18 Hz, 1H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 99.7, 122.7, 124.6, 127.7, 139.1, 144.4, 168.2; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C7H7N2S2 183.0045; Found 183.0046. CAS registry No. [28989-50-6]. 1H and

13C


reported in the literature.30m 4-(4-(trifluoromethyl)pyridin-2-yl)thiazol-2-amine (7i). The compound was prepared according to General procedure E2 from tert-butyl (4methoxybenzyl)(4-(4-(trifluoromethyl)pyridin-2-yl)thiazol-2-yl)carbamate (0.450 g, 0.966 mmol) and trifluoroacetic acid (4 mL); the reaction time was 2 hour at 70 °C. The product, purified by flash column chromatography (CH2Cl2: MeOH; 1:0 to 9.3:0.7); was obtained as a light yellow solid (0.230 g, 0.937 mmol, 92 %). Rf = 0.28 (CH2Cl2:MeOH; 9:1); mp = 128 – 130 °C; IR (cm-1) 3263, 3133, 1701, 1613, 1528, 1391, 1352, 1312, 1261, 1171, 1134, 1084, 1041, 758, 697; 1H NMR (500 MHz, DMSO-d6)  (ppm) 7.23 (s, 2H), 7.41 (s, 1H), 7.63 (dd, J = 5.00, 1.72 Hz, 1H), 8.03 (s, 1H), 8.81 (d, J = 5.03 Hz, 1H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 107.3, 114.4 – 115.8 (m), 117.0 –

117.6 (m), 124.1 (q, J = 273.5 Hz), 137.5, 148.4, 151.0, 153.6, 168.8;

19F{1H}

NMR (471 MHz,

DMSO-d6)  (ppm) -63.81; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C9H7F3N3S 246.0307; Found 246.0310.



Page 54 of 64

6-(2-aminothiazol-4-yl)nicotinonitrile (7j). The compound was prepared according to General procedure E2 from tert-butyl (4-(5-cyanopyridin2-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate (0.53 g, 1.25 mmol) and trifluoroacetic acid (4 mL); the reaction time was 2 hours at 70 °C. The product, purified by flash column chromatography (CH2Cl2:MeOH; 1:0 to 9.2:0.8); was obtained as a yellow solid (0.2 g, 0.99 mmol, 79 %). Rf = 0.28 (CH2Cl2:MeOH; 9:1); mp = > 230 °C (decomposed); IR (cm-1) 3395, 3297, 3146, 2221, 1639, 1586, 1535, 1356, 1126, 1040, 1020, 846, 714; 1H NMR (500 MHz, DMSO-d6)  (ppm) 7.22 (s, 2H), 7.50 (s, 1H), 7.92 (dd, J = 8.26, 0.89 Hz, 1H), 8.28 (dd, J = 8.28, 2.19 Hz, 1H), 8.94 (dd, J = 2.23, 0.88 Hz, 1H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 106.5, 109.7, 117.3, 119.7, 140.9, 148.7, 152.2, 154.9, 168.7; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C9H7N4S 203.0386; Found 203.0383. 1-(5-(2-aminothiazol-4-yl)pyridin-2-yl)ethan-1-one (7k). The compound was prepared according to General procedure E2 from tert-butyl (4-(6-acetylpyridin3-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate (0.385 g, 0.875 mmol) and trifluoroacetic acid (3.5 mL); the reaction time was 2 hour at 70 °C. The product, purified by flash column chromatography (CH2Cl2:MeOH; 1:0 to 30:1); was obtained as a yellow solid (0.162 g, 0.738 mmol, 84 %). Rf = 0.5 (CH2Cl2:MeOH; 9:1); mp = > 214 °C (decomposed); IR (cm-1) 3371, 3321, 3148, 3089, 1678, 1652, 1582, 1545, 1331, 1294, 1248, 1047, 854, 761, 724; 1H NMR (500 MHz, DMSO-d6)  (ppm) 2.63 (s, 3H), 7.23 (br s, 2H), 7.41 (s, 1H), 7.96 (d, J = 8.23 Hz, 1H), 8.29 (dd, J = 8.21, 2.18 Hz, 1H), 9.12 (d, J = 2.08 Hz, 1H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 25.6, 105.9, 121.3, 133.3, 133.5,

146.2, 151.2, 168.8, 198.7; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C10H10N3OS 220.0539; Found 220.0539. 4-(3-fluoropyridin-2-yl)thiazol-2-amine (7l). The compound was prepared according to General procedure E2 from tert-butyl (4-(3-fluoropyridin2-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate (0.15 g, 0.36 mmol) and trifluoroacetic acid (2 mL); the reaction time was 2 hours at 70 °C. The product, purified by flash column chromatography (CH2Cl2:MeOH; 1:0 to 5:1); was obtained as a white solid (53 mg, 0.27 mmol, 75 %). Rf = 0.2 (EtOAc); mp = 163 - 164 °C; IR (cm-1) 3294, 1531, 1424, 1340, 1257, 1221, 1176, 1101, 808, 640, 547; 1H NMR (500 MHz, DMSO-d6)  (ppm) 7.09 (s, 2H), 7.19 (d, J = 1.1 Hz, 1H), 7.35 – 7.41 (m, 1H), 7.72 (ddd, J = 1.4, 8.3, 11.7 Hz, 1H), 8.38 – 8.44 (m, 1H);

13C{1H}

NMR (126 MHz, DMSO-d6)

 (ppm) 108.7 (d, J = 7.1 Hz), 123.9 (d, J = 4.3 Hz), 124.4 (d, J = 20.0 Hz), 140.8 (d, J = 9.9 Hz), 145.1 (d, J = 5.3 Hz), 146.1 (d, J = 7.3 Hz), 156.1 (d, J = 262.4 Hz), 167.9; 13F{1H} NMR (451 MHz, Chloroform-d)  (ppm) -120.5; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C8H7FN3S 196.0339; Found 196.0339. CAS registry No. [1044270-53-2]. 1H NMR spectrum was consistent with that previously reported in the literature.30n


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6-(2-aminothiazol-4-yl)picolinonitrile (7m). The compound was prepared according to General procedure E2 from tert-butyl (4-(6-cyanopyridin2-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate (0.15 g, 0.36 mmol) and trifluoroacetic acid (2 mL); the reaction time was 2 hours at 70 °C. The product, purified by flash column chromatography (CH2Cl2:MeOH; 1:0 to 3:1); was obtained as a white solid (51 mg, 0.25 mmol, 70 %). Rf = 0.1 (Hexane:EtOAc; 0:1); Mp > 225 °C;IR (cm-1) 3373, 2223, 1664, 1620, 1585, 1389, 1351, 1062, 741, 571, 454; 1H NMR (500 MHz, DMSO-d6)  (ppm) 7.12 (s, 2H), 7.80 (s, 1H), 7.88 (d, J = 7.3 Hz, 1H), 7.91 – 8.01 (m, 2H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 107.2, 119.8, 122.2, 138.4, 149.3, 149.7, 151.3, 165.9, 168.5; HRMS (APCI-TOF) m/z: [M+H2O+H]+ Calcd for C9H9N4OS 221.0492; Found 221.0499. 2-(2-aminothiazol-4-yl)nicotinonitrile (7n). The compound was prepared according to General procedure E2 from tert-butyl (4-(3-cyanopyridin2-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate (0.2 g, 0.47 mmol) and trifluoroacetic acid (1.5 mL); the reaction time was 2 hour at 70 °C. The product, purified by flash column chromatography (CH2Cl2: MeOH; 1:0 to 3:1); was obtained as a white solid (73 mg, 0.35 mmol, 75 %). Rf = 0.15 (EtOAc); Mp > 200 °C decomp.; IR (cm-1) 3229, 2227, 1608, 1569, 1426, 1044, 713, 421; 1H NMR (500 MHz, DMSO-d6)  (ppm) 7.17 (s, 2H), 7.41 (s, 1H), 7.47 (dd, J = 4.7, 7.9 Hz, 1H), 8.26 (dd, J = 1.7, 7.9 Hz, 1H), 8.78 (dd, J = 1.7, 4.7 Hz, 1H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 105.0,

110.1, 117.5, 122.1, 143.2, 147.8, 152.5, 152.8, 168.2; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C9H7N4S 203.0386; Found 203.0387. 4-(4-(tert-butyl)pyridin-2-yl)thiazol-2-amine (7o). The compound was prepared according to General procedure E2 from tert-butyl (4-(4-(tertbutyl)pyridin-2-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate (0.34 g, 0.749 mmol) and trifluoroacetic acid (3 mL); the reaction time was 2 hours at 70 °C. The product, purified by flash column chromatography (CH2Cl2:MeOH; 1:0 to 30:1); was obtained as a white solid (0.136 g, 0.582 mmol, 78 %). Rf = 0.33 (CH2Cl2:MeOH; 9:1); mp = 190 – 192 °C; IR (cm-1) 3094, 2964, 1643, 1599, 1539, 1346, 1058, 997, 844, 829, 629; 1H NMR (500 MHz, DMSO-d6)  (ppm) 1.29 (s, 9H), 7.11 (br s, 2H), 7.22 (s, 1H), 7.27 (dd, J = 5.22, 2.08 Hz, 1H), 7.85 (d, J = 1.99 Hz, 1H), 8.43 (d, J = 5.16 Hz, 1H); 13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 30.2, 34.4, 105.1, 116.8, 119.2, 149.1, 150.3, 152.4,

160.1,168.4; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H16N3S 234.1059; Found 234.1059. 4-(9H-purin-6-yl)thiazol-2-amine (7p). The compound was prepared according to General

procedure

D2 from tert-butyl(4-

methoxybenzyl)(4-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)thiazol-2-yl)carbamate (750 mg, 1.44 mmol) and trifluoroacetic acid (5 mL); the reaction time was 2 hours at 70 °C. TFA was neutralized with a saturated aqueous solution of NaHCO3 until pH = 8. The precipitate was filtered, washed with ACS Paragon Plus Environment


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water (10 mL) and Et2O (2 × 10 mL). The product was obtained as a white solid (240 mg, 1.1 mmol, 76 %). mp > 250 °C; IR (cm-1) 3136, 1582, 1537, 1398, 1225, 876, 805, 640; 1H NMR (500 MHz, DMSO-d6)  (ppm) 7.09 (s, 2H), 7.76 (s, 1H), 8.65 (s, 1H), 8.92 (s, 1H), 12.51 (s, 1H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 110.2*, 147.1*, 147.6, 151.1*, 151.9, 161.7*, 169.0* (*detected by HMBC); HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C8H7N6S 219.0447; Found 219.0447. 4-(pyrazin-2-yl)thiazol-2-amine (7q). The compound was prepared according to General procedure E2 from tert-butyl (4methoxybenzyl)(4-(pyrazin-2-yl)thiazol-2-yl)carbamate (0.21 g, 0.53 mmol) and trifluoroacetic acid (2 mL); the reaction time was 2 hours at 70 °C. The product, purified by flash column chromatography (CH2Cl2:MeOH; 1:0 to 5:1); was obtained as a white solid (75 mg, 0.42 mmol, 80 %). Rf = 0.3 (EtOAc); Mp > 163 °C decomp.; IR (cm-1) 3345, 1631, 1504, 1352, 1211, 1064, 1015, 847, 688; 1H NMR (500 MHz, DMSO-d6)  (ppm) 7.24 (s, 2H), 7.39 (s, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.59 (dd, J = 2.5, 1.4 Hz, 1H), 9.00 (d, J = 1.5 Hz, 1H);

13C{1H}

NMR (126 MHz, DMSO-d6)  (ppm) 107.6, 141.6, 143.1,

144.2, 147.6, 169.1, 183.9; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C7H7N4S 179.0386; Found 179.0386. CAS registry No. [19847-11-1]. 1H and

13C


reported in the literature.30o 4-phenylthiazol-2-amine (7r). The compound was prepared according to General procedure E2 from tert-butyl (4methoxybenzyl)(4-phenylthiazol-2-yl)carbamate (82 mg, 0.207 mmol) and trifluoroacetic acid (1 mL); the reaction time was 3 hours at 70 °C. The product, purified by flash column chromatography (hexane:EtOAc; 10:1 to 1:1); was obtained as a white solid (34 mg, 0.193 mmol, 93 %). Rf = 0.32 (Hexane:EtOAc; 2:1); IR (cm-1) 3434, 3251, 1598, 1531, 1516, 1483, 1340, 1330, 1038, 1022, 772, 713, 687, 667, 657; 1H NMR (300 MHz, DMSO-d6)  (ppm) 6.99 (s, 1H), 7.01 (s, 2H), 7.18 – 7.29 (m, 1H), 7.31 – 7.41 (m, 2H), 7.79 (d, J = 7.0 Hz, 2H). HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C9H9N2S 177.0481; Found 177.0481. CAS registry No. [2010-06-2]. 1H NMR spectrum was consistent with that previously reported in the literature.30i 4-(6-morpholinopyridin-2-yl)thiazol-2-amine (7s). The compound was prepared according to General procedure E2 from tert-butyl (4methoxybenzyl)(4-(6-morpholinopyridin-2-yl)thiazol-2-yl)carbamate (0.109 g, 0.226 mmol) and trifluoroacetic acid (1 mL); the reaction time was 3 hours at 70 °C. The product, purified by flash column chromatography (hexane:EtOAc; 2:1 to 1:3); was obtained as a white solid (48 mg, 0.183 mmol, 81 %). Rf = 0.57 (hexane:EtOAc; 1:3); mp = 88 - 92 °C; IR (cm-1) 2852, 1591, 1566, 1528, 1516, 1440, 1328, 1243, 1214, 1112, 1068, 983, 972, 910, 797, 758, 739, 692; 1H NMR (500 MHz, ACS Paragon Plus Environment

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Chloroform-d)  (ppm) 3.53 – 3.59 (m, 4H), 3.82 – 3.87 (m, 4H), 6.57 (d, J = 8.4 Hz, 1H), 7.26 (s, 1H), 7.29 (d, J = 7.5 Hz, 1H), 7.55 (dd, J = 8.5, 7.3 Hz, 1H); 13C{1H} NMR (126 MHz, Chloroform-d)

 (ppm) 45.8, 67.0, 106.2, 107.1, 111.1, 138.5, 150.7, 151.9, 159.1, 167.3; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C12H15N4OS 263.0961; Found 263.0961. 4-(3-methoxypyridin-2-yl)thiazol-2-amine (7t). The compound was prepared according to General procedure E2 from tert-butyl (4methoxybenzyl)(4-(3-methoxypyridin-2-yl)thiazol-2-yl)carbamate (0.101 g, 0.237 mmol) and trifluoroacetic acid (1 mL); the reaction time was 3 hours at 70 °C. The product, purified by flash column chromatography (EtOAc:MeOH; 1:0 to 4:1); was obtained as a light brown wax (14 mg, 0.088 mmol, 28 %). Rf = 0.1 (CH2Cl2:MeOH; 10:1); IR (cm-1) 1674, 1470, 1434, 1288, 1181, 1128, 1014, 841, 800, 723; 1H NMR (500 MHz, Methanol-d4)  (ppm) 4.08 (s, 3H), 7.41 (dd, J = 8.3, 5.1 Hz, 1H), 7.60 (s, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.83 (s, 1H);

13C{1H}

NMR (126 MHz, Methanol-d4)  (ppm)

56.8, 113.6, 123.2, 126.4, 138.9, 142.5, 156.4, 172.3; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C9H10N3OS 208.0539; Found 208.0539. 2-(2-aminothiazol-4-yl)isonicotinonitrile (7u). The compound was prepared according to General procedure E2 from tert-butyl (4-(4-cyanopyridin2-yl)thiazol-2-yl)(4-methoxybenzyl)carbamate (82 mg, 0.194 mmol) and trifluoroacetic acid (1 mL); the reaction time was 3 hours at 70 °C. The product, purified by flash column chromatography (hexane:EtOAc; 1:1 to 0:1); was obtained as a white solid (20 mg, 0.099 mmol, 51 %). Rf = 0.23 (hexane:EtOAc; 1:3); Mp > 225 °C decomp.; IR (cm-1) 1755, 1698, 1613, 1481, 1281, 1231, 1151, 1133, 1052, 1026, 992, 954, 894, 852, 776, 757; 1H NMR (500 MHz, DMSO-d6)  (ppm) 7.19 (s, 2H), 7.39 (s, 1H), 7.71 (dd, J = 4.9, 1.7 Hz, 1H), 8.02 (s, 1H), 8.78 (dd, J = 5.0, 1.0 Hz, 1H); 13C{1H} NMR (126 MHz, DMSO-d6)  (ppm) 107.7, 116.9, 120.2, 121.4, 123.6, 148.3, 150.6, 153.3, 168.8; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C9H7N4S 203.0386; Found 203.0386. 4-(6-phenylpyridin-2-yl)thiazol-2-amine (7v). The compound was prepared according to General procedure E2 from tert-butyl (4methoxybenzyl)(4-(6-phenylpyridin-2-yl)thiazol-2-yl)carbamate

(71

mg,

0.145

mmol)

and

trifluoroacetic acid (1 mL); the reaction time was 3 hours at 70 °C. The product, purified by flash column chromatography (hexane:EtOAc; 1:1 to 0:1); was obtained as a white solid (32 mg, 0.126 mmol, 84 %). Rf = 0.34 (hexane:EtOAc; 1:2); mp = 126 - 128 °C; IR (cm-1) 3434, 1624, 1592, 1564, 1527, 1495, 1438, 1330, 1036, 763, 743, 717, 693, 683; 1H NMR (500 MHz, DMSO-d6)  (ppm) 7.11 (s, 2H), 7.42 (s, 1H), 7.43 – 7.47 (m, 1H), 7.49 – 7.54 (m, 2H), 7.78 (dd, J = 7.6, 1.1 Hz, 1H), 7.81 – 7.85 (m, 1H), 7.90 (t, J = 7.8 Hz, 1H), 8.14 – 8.19 (m, 2H);


13C{1H}

NMR (126 MHz, DMSO-


Page 58 of 64

d6)  (ppm) 105.7, 118.5, 118.8, 126.5, 128.7, 129.0, 138.0, 138.6, 150.2, 152.2, 155.3, 168.5; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C14H12N3S 254.0746; Found 254.0746. tert-butyl (4-methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate (8). Boronate formation using n-BuLi: n-BuLi (1.6 M in hexane) (0.82 mL, 2.50 mmol) was added dropwise to a solution of tert-butyl (4bromothiazol-2-yl)(4-methoxybenzyl)carbamate

(0.5

g,

1.25

mmol),

2-isopropoxy-4,4,5,5-

tetramethyl-1,3,2-dioxaborolane (0.383 mL, 1.87 mmol) and THF (8 mL) at -78 °C and stirred for 1 h at -78 °C. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (10 mL) at -78 °C. The reaction mixture was warmed up to room temperature and extracted with EtOAc (2 × 50 mL). The combined organic extracts were washed with H2O (20 mL) and brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude tert-butyl (4methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate as a pale yellow wax (0.558 g, 1.25 mmol), which was used into the next step without further purification. Boronate formation using Palladium: In dioxane (25 mL) were dissolved tert-butyl (4-bromothiazol-2-yl)(4-methoxybenzyl)carbamate (5.3 g, 13.25 mmol), Pd(OAc)2 (60 mg, 0.26 mmol), PCy3 (150 mg, 0.42 mmol), bis(pinacolato)diboran (4 g, 14.7 mmol), KOAc (3.3 g, 33 mmol). This mixture was degassed with Ar (10 min). The reaction mixture was stirred at 90 °C for 2 h, then cooled down to room temperature. The mixture was poured into water (30 ml) and extracted with EtOAc (3 × 20 mL). The organic fractions were combined, washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude tert-butyl (4-methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol2-yl)carbamate as a brownwish solid (5.92 g, 13.27 mmol), which was used into the next step without further purification. IR (cm-1) 1702, 1510, 1369, 1242, 1160, 822, 619; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.36 (s, 12H), 1.48 (s, 9H), 3.78 (s, 3H), 5.37 (s, 2H), 6.75 – 6.84 (m, 2H), 7.28 – 7.31 (m, 2H), 7.64 (s, 1H).

13C{1H}


83.7, 84.3, 113.7, 128.1, 129.5, 130.7, 153.5, 158.9, 162.2; 11B NMR (96 MHz, Chloroform-d)  (ppm) 30.80; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C22H32BN2O5S 447.2124; Found 447.2128. tert-butyl (5-bromothiazol-2-yl)(4-methoxybenzyl)carbamate (9). 5-bromothiazol-2-amine hydrobromide (8.58 g, 33 mmol) was extracted between a saturated solution of NaHCO3 (50 mL) and EtOAc (3 × 50 mL). The combined organic extracts were washed with brine (50 mL), dried over MgSO4, filtered, concentrated under reduced pressure and dried under high vacuum. The residue was dissolved in CH2Cl2 (40 mL). To the solution were added DMAP (40 mg, 0,33 mmol) and di-tert-butyl dicarbonate (8.0 g, 36.0 mmol). The mixture was stirred at 25 °C for 24 hours. The solvent was evaporated and tert-butyl (5-bromothiazol-2-yl)carbamate was used in the next step without purification. ACS Paragon Plus Environment

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tert-butyl (5-bromothiazol-2-yl)carbamate was dissolved in DMF (40 mL). To the solution were added Cs2CO3 (18.0 g, 56.0 mmol) followed by 4-Methoxybenzyl chloride (5.1 g, 33.0 mmol). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was cooled to 25 °C, quenched with water (100 mL), and extracted with Et2O (3 × 100 mL). The organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (hexane:EtOAc; 1:0 to 7:3) to afford tert-butyl (5-bromothiazol-2-yl)(4methoxybenzyl)carbamate (8.7 g, 21.75 mmol, 66 %) as a colorless oil. Rf = 0.57 (Hexane:EtOAc; 9:1); IR (cm-1) 3095, 2984, 1693, 1509, 1475, 1387, 1227, 1110, 845, 771, 744, 627; 1H NMR (500 MHz, Chloroform-d)  (ppm) 1.60 (s, 9H), 3.80 (s, 3H), 5.22 (s, 2H), 6.82 – 6.88 (m, 2H), 7.28 – 7.33 (m, 2H), 7.36 (s, 1H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 28.4, 49.0, 55.4, 84.1, 103.6, 113.9, 129.4, 129.8, 138.4, 153.3, 159.2, 161.6; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C16H20BrN2O3S 399.0373; Found 399.0371. CAS registry No. [881402-27-3]. 1H NMR spectrum was consistent with that previously reported in the literature.30p N-Bocthiourea (10). To a solution of thiourea (4.4 g, 57.8 mmol) in anhydrous THF (300 mL) at 0 °C under an atmosphere of nitrogen was added NaH (60 % in mineral oil, 5.4 g, 0.133 mmol). The mixture was stirred 15 min after which di-tert-butyldicarbonate (13.25 g, 0.061 mmol) was slowly added as a solution in THF (50 mL). The mixture was left to warm up to room temperature and stirred for 2 hours. CH2Cl2 (300 mL) was added and the organic phase was washed with a saturated aqueous solution of NaHCO3 (2 x 200 mL), H2O (200 mL) and brine (200 mL), dried over MgSO4, filtered and evaporated in vacuuo. The crude residue was triturated with heptane (500 mL) and the precipitate was filtered. The product was obtained as a white solid (3.243 g, 0.18 mmol, 32 %). mp = 132 - 134 °C; IR (cm-1) 3363, 3236, 3166, 1725, 1603, 1539, 1510, 1448, 1369, 1227, 1144, 1103, 994, 885, 760, 576; 1H NMR (300 MHz, DMSO-d6)  (ppm) 1.44 (s, 9H), 8.96 (s, 1H), 9.13 (s, 1H), 10.49 (s, 1H);

13C{1H}

NMR (75 MHz, DMSO-d6)  (ppm) 27.6, 81.9, 152.2, 181.5; HRMS (APCI-TOF) m/z: [M-H]- Calcd for C6H11N2O2S 175.0547; Found 175.0548. CAS registry No. [268551-65-1]. 1H and

13C


reported in the literature.29 tert-butyl (4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)thiazol-2-yl)carbamate (11). To a mixture of 2-(2-bromoacetyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (1.13 g, 4.07 mmol) and N-Bocthiourea (788 mg, 4.47 mmol) in CH3CN (50 mL) was added NEt3 (1.23 g, 1.7 mL, 12.2 mmol) and the mixture was stirred at 70 °C for 50 min. The reaction mixture was diluted with EtOAc (100 mL) and washed with a saturated aqueous solution of NaHCO3 (50 mL). The aqueous phase was extracted with EtOAc (2 x 75 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered, and the solvent was evaporated in vacuo. The product, purified by ACS Paragon Plus Environment


Page 60 of 64

flash column chromatography (40 mL of silica gel, hexane:EtOAc; 1:2 to 0:1), was obtained as a white solid (0.905 g, 2.55 mmol, 63 %). Rf = 0.31 (EtOAc); mp = 103 – 105 °C; IR (cm-1) 2978, 1756, 1716, 1539, 1277, 1236, 1149, 1048, 1006, 954, 857, 759; 1H NMR (300 MHz, Chloroform-d)  (ppm) 1.51 (s, 9H), 2.64 (s, 3H), 3.91 (d, J = 16.8 Hz, 2H), 4.13 (d, J = 17.0 Hz, 2H), 7.23 (s, 1H); 13C{1H}


168.8; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C13H19BN3O6S 356.1085; Found 356.1085. tert-butyl

(4-methoxybenzyl)(4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)thiazol-2-

yl)carbamate (12). To a mixture of tert-butyl (4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)thiazol-2-yl)carbamate (0.371 g, 1.045 mmol), Cs2CO3 (0.851 g, 2.61 mmol) in anhydrous CH3CN (4 mL) was added 4methoxybenzyl chloride (0.204 g, 0.177 mL, 1.31 mmol) and the mixture was stirred at 80 °C for 1 h. The product, purified by flash column chromatography (hexane:EtOAc:CH3CN; 1:1:0 to 0:1:0 to 0:1:1), was obtained as a white solid (0.353 g, 0.74 mmol, 71 %). Rf = 0.36 (EtOAc); mp = 174 - 176 °C; IR (cm-1) 1769, 1699, 1512, 1481, 1282, 1243, 1154, 1134, 1055, 1027, 993, 954, 852, 775, 747; 1H

NMR (500 MHz, Chloroform-d)  (ppm) 1.56 (s, 9H), 2.26 (s, 3H), 3.64 (d, J = 16.2 Hz, 2H), 3.76

(s, 3H), 3.80 (d, J = 16.2 Hz, 2H), 5.20 (s, 2H), 6.79 – 6.84 (m, 2H), 7.13 – 7.17 (m, 2H), 7.27 (s, 1H); 13C{1H} NMR (126 MHz, Chloroform-d)  (ppm) 28.4, 46.2, 50.2, 55.5, 61.9, 114.0, 121.3, 128.1, 130.6, 158.8, 162.2, 167.5; HRMS (APCI-TOF) m/z: [M+H]+ Calcd for C21H27BN3O7S 476.1661; Found 476.1661; Crystallized from iPrOH:hexane; 1:1, CCDC ref. No. 1871943. AUTHOR INFORMATION #these

authors contributed equally to this work

Corresponding author *E-mail: [email protected]; [email protected] ORCID Benoit Carbain: 0000-0001-7654-925X SUPPORTING INFORMATION The supporting information is available on the ACS Publications website at DOI: 1H

spectra of all compounds; selected

13C{1H}

. Copies of

NMR, IR and HRMS spectra; crystallographic data

(CIF files) for compound 12.


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ACKNOWLEDGEMENT This work was supported by the following grants: CZ-OPENSCREEN: National Infrastructure for Chemical Biology (Identification code: LM2015063), Preclinical Progression of New Organic Compounds with Targeted Biological Activity (CZ CZ.02.1.01/0.0/0.0/16_025/0007381), the National Program of Sustainability II (MEYS CR, project No. LQ1605), and the Czech Science Foundation grant project 16-23955Y. CIISB research infrastructure project LM2015043 funded by MEYS CR is gratefully acknowledged for the financial support of the measurements at the CF X-ray diffraction and Bio-SAXS. The authors would like to thank Dr. Jakub Švenda and Dr. Andrey Mikhaylov for helpful comments and review of the manuscript. REFERENCES (1)

(2)

(3) (4)

(5) (6)

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