Mild and Efficient Palladium-Mediated C–N Cross-Coupling Reaction

5 days ago - Over the last 10 years, a number of DNA-compatible chemical reactions have been published and used to synthesize libraries. Among the mos...
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Letter

Mild and Efficient Palladium-mediated C-N Cross-Coupling Reaction between DNA-conjugated Aryl Bromides and Aromatic Amines Eduardo de Pedro Beato, Julian Priego, Adrián Gironda-Martínez, Fernando González, Jesús Benavides, Jesús Blas, María Dolores Martín-Ortega, Miguel A Toledo, Jesús Ezquerra, and Alicia Torrado ACS Comb. Sci., Just Accepted Manuscript • Publication Date (Web): 07 Jan 2019 Downloaded from http://pubs.acs.org on January 8, 2019

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is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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Mild and Efficient Palladium-mediated C-N Cross-Coupling Reaction between DNA-conjugated Aryl Bromides and Aromatic Amines Eduardo de Pedro Beato, Julián Priego, Adrián Gironda-Martínez, Fernando González, Jesús Benavides, Jesús Blas, María Dolores Martín-Ortega, Miguel Ángel Toledo, Jesús Ezquerra, and Alicia Torrado*

Centro de Investigación Lilly, S. A., 28108 Alcobendas, Madrid, Spain

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Abstract DNA-Encoded Library Technology (ELT) has emerged in the pharmaceutical industry as a powerful tool for hit and lead generation. Over the last 10 years, a number of DNA-compatible chemical reactions have been published and used to synthesize libraries. Among the most commonly used reactions in medicinal chemistry is the C-N bond formation and its application to DNA encoded library technology affords an alternative approach to identify high-affinity binders for biologically relevant protein targets. Herein we report a newly developed Pd promoted C-N cross coupling reactions between DNA-conjugated aryl bromides and a wide scope of aryl amines in good to excellent yields. The mild reaction conditions should facilitate the synthesis of novel DNA-encoded combinatorial libraries.

Keyword: DNA-encoded chemical libraries, C-N bond formation.

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The main principle of DNA-Encoded Library Technology (ELT), as suggested by Brenner and Lerner,1 as well as by Gallop and co-workers2 in the early 1990s, is to directly link chemical building blocks to oligonucleotides.3 Since then, great progress has been made in the field, making DNA-Encoded Libraries (DELs) a powerful tool for the discovery of ligands to several biological targets.4-10 This success depends not only on the number and characteristics of the building blocks used for the library construction but also on library design. Therefore, the development of chemical methodology for the synthesis of DELs represents an important challenge in the field.11-15 The chemical reactions described for DEL synthesis must be robust, high yielding, cover broad reactant scope, and must preserve the integrity of the DNA code.16 More than 40 reaction classes have been described “on-DNA” with moderate to high success rates,17,18 and more synthetic transformations are being recently reported expanding the “on-DNA” compatible chemistry tool-box.19-24 Among the most often used chemistry transformations in Medicinal Chemistry are the C-C and C-N crosscoupling bond formation reactions. Several libraries and methods have been already published for the Sonogashira and Suzuki C-C couplings.25,26 However, the C-N coupling remained quite difficult to adapt standard organic chemistry protocol in order to go from single reaction under controlled atmosphere in organic solvents, towards hundreds of parallel small-scale reactions under mild aqueous conditions. It was not until last year that Lu et al. published the first protocol for the copper and palladium catalyzed Narylation of amines with aryl iodides on-DNA27 and recently Ruff et al.28 published work on the coppercatalyzed amination of aryl iodides with aliphatic amines. However, the N-arylation of anilines with onDNA aryl bromides has not been reported to date. In this letter, we seek to expand the scope on the C-N cross-coupling reaction introducing the on-DNA aryl bromides as coupling partners for aromatic amines, which could complement nicely Ruff’s C-N coupling with aliphatic amines. To establish the appropriate conditions for the coupling reaction, and based on recent literature examples of N-arylation in water,29 we used DNA-conjugated aryl iodide SC130 and aniline 1 as coupling model substrates. We ran more than 300 experiments in a parallel screening of reaction conditions: 9 bases, 13 known palladium sources and 5 different temperatures were tested using water as solvent (Table 1, see supplementary information for more detail). The reactions were monitored by LCMS and the rate of conversion was estimated from LCMS analysis. Initial screening for suitable Pd sources was performed in water using tBuOK as base at a range of temperature between 50 and 80 ⁰C. Interestingly, desired coupling product was only detected with tButyl-XPhos Pd precatalyst, together with unreacted starting material SC1 and other byproducts, mainly dehalogenation. Our efforts were then focused on getting the best combination of precatalyst, base and temperature to increase the conversion to desired product and reduce dehalogenation. Finally, combination of t-Butyl-XPhos Pd precatalyst G3 (15 equiv.) and NaOH (300 equiv.) as base showed to be the most successful conditions for the C-N bond formation between DNA-conjugated aryl iodides and aromatic amines at very mild temperature (30 ⁰C) (Scheme 1a). The developed conditions afforded the desired products in medium-high yields (Table 2).

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Table 1: Pd source, base and temperature range conditions for parallel screening.

O

N H2

I N H

Catalyst Base temperature

+

SC1

O N H

N H

1

Pd source

Base

Temperature (⁰C)

Pd2(dba)3

Na2CO3

30*

[Pd(cinnamyl)Cl]2

K2CO3

40

[Pd(allyl)Cl]2

Cs2CO3

50

t-Butyl-XPhos Pd G3*a

K3PO4

60a

BrettPhos Pd G3

NaOH*a

80

t-BuBrettPhos Pd G3

KOH

AdBrettPhos Pd G3

LiOH

Pd CatacXium Pd G3

DBU

Pd MorDalPhos G3

t-BuOK

Pd PEPPSI-i-Pr Pd(OAc)2 water activation Pd 173 Pd 174 *Optimal Pd source/base/temperature for the N-C coupling between DNA-conjugated aryl iodides and aromatic amines. aOptimal Pd source/base/temperature for the C-N coupling between DNA-conjugated aryl bromides and aromatic amines. During the process of optimization, we observed that higher temperature increased dehalogenation byproduct and T>80 ⁰C together with high amount of t-Butyl-XPhos precatalyst G3 afforded less clear LCMS with traces of DNA degradation visible. It was found that the quantity of the precatalyst reagent was crucial since, although a loading of 5-10 equiv. was enough for most of the aryl iodides tested to react, less reactive aryl iodides as SC-2 (Table 2) showed less conversion and higher dehalogenation rate (55% desired product, 25% SM and 20% dehalogenation). However, when the amount of Pd-precatalyst was increased to 15 equiv., we were able to see conversion higher than 80% with SC-2. Unfortunately, when the same conditions were applied to another very low reactive DNA-coupled aryl iodide as SC-3, only SM 4 ACS Paragon Plus Environment

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was recovered. When the Pd-precatalyst loading increased up to 20 equiv., the conversion to product was similar; however, the reaction afforded less clean LCMS with traces of DNA degradation detected. Taking in account all the variables, 15 equiv. was the optimal amount of t-Butyl-XPhos precatalyst G3 for this reaction to proceed at mild temperature (30 ⁰C). Final concentration of the reaction also played a critical role in the C-N coupling conversion and 0.7 mM was optimal for higher conversion to desired product. To achieve that final concentration, the starting concentration of the DNA conjugated aryl iodide was 1.5 mM. The election of the base was also very important, as NaOH was basic enough to facilitate the deprotonation of the aromatic amines. Motivated by the mild conditions found to run the C-N coupling reaction with DNA-conjugated aryl iodides, we next explored the scope of the reaction testing DNA-conjugated aryl bromides as coupling partners, which are less reactive electrophiles. As expected, the conditions were not optimal for aryl bromides. For our delight, slight modifications to the above coupling conditions, as higher equivalents of aniline (150 equiv.) and doubling the temperature from 30 to 60 ⁰C, resulted in comparable catalytic abilities for DNAconjugated aryl bromides (Scheme1, 1b). However, in less aromatic rings as SC-9 (Table 2), we observed a phenol by-product coming from the SNAr reaction with NaOH when using 300 equiv. of base. To avoid this inconvenience, the quantity of base employed was decreased to half (150 equiv.), resulting not only in a comparable conversion, but also in a higher selectivity to the desired coupling product over the phenol by-product. Scheme 1: Coupling conditions for on-DNA aryl halides and aromatic amines. O

1a

N H

I n

+

Ar

N H2

80 eq. (400 mM DMA)

n= 0,1, 2 1.5 mM in water

t-BuXPhos Pd G3 (15 eq., 100 mM DMA)

Ar

O N H

N H

n

H N H

NaOH (300 eq, 1M water) 30 ºC, 2h

t-Bu

O Pd O S O P

t-Bu

i-Pr i-Pr

O

1b

N H

Br X

X= C, N 1.5 mM in water

+

Ar

N H2

150 eq. (400 mM DMA)

t-BuXPhos Pd G3 (15 eq., 100 mM DMA)

H N

O N H

X

Ar

i-Pr t-BuXPhos Pd G3

NaOH (150 eq, 1M water) 60 ºC, 2h

We further tested the coupling efficiency between seven representative aromatic amines (electron-rich, electron-poor and sterically hindered anilines) and 14 DNA-coupled aryl halide (SC1 to SC14) with different chemical features (Table 2), according to the reaction conditions described in Scheme 1. Table 2. C-N coupling between 14 different DNA-conjugated aryl halide with six representative aromatic amines, according to the reaction conditions described in Scheme 1.

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DNA HN O

DNA HN O

DNA HN O

X

SC1 a, X=I, n=0 SC4 b, X=Br, n=0 SC7 a, X=I, n=2

1 H 2N

O

2

DNA HN O

DNA HN O

Br

N

X Br

SC2 a, X=I SC5 b, X=Br

SC3 a, X=I SC6 b, X=Br

SC1 (90%) SC4 (91%) SC7 (90%)

SC2 (85%) SC5 (88%)

SC1 (80%) SC4 (75%)

N

Br

Br

N

DNA HN O

DNA HN O

DNA HN O

X

n

H 2N

DNA O HN

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N

N Br

DNA HN O

N Br

Br

SC8 b

SC9 b

SC10 b

SC11 b

SC12 b

SC13 b

SC14 b

SC3 (0%) SC6 (0%)

80%

80%

72%

70%

76%

90%

25%

SC2 (90%) SC5 (73%)

SC3 (0%) SC6 (0%)

84%

75%

80%

76%

81%

78%

23%

SC1 (84%) SC4 (80%)

SC2 (85%) SC5 (75%)

SC3 (NT) SC6 (0%)

86%

74%

74%

77%

80%

75%

22%

SC1 (92%) SC4 (86%*)

SC2 (88%) SC5 (85%*)

SC3 (NT) SC6 (0%)

73%*

82%*

70%*

82%*

80%*

88%*

25%*

SC1 (70%) SC4 (72%*)

SC2 (90%) SC5 (65%*)

SC3 (NT) SC6 (0%)

60%*

32%*

70%*

71%*

80%*

70%*

23%*

SC1 (92%) SC4 (75%)

SC2 (95%) SC5 (80%)

SC3 (NT) SC6 (0%)

51%

60%

82%

70%

74%

60%

22%

F H 2N

3 CO2 Me

H 2N

4 EtO2C H 2N

5 O H 2N

6

Table indicates conversion by LCMS, not isolated yield. aReaction conditions: 1 equiv. of SC (1.5 mM in H2O), 80 equiv. of aromatic amine (400 mM in DMA), 15 equiv. of Pd t-BuXPhos G3 (100 mM in DMA), 300 equiv. of NaOH (1 M in H2O), 30 ⁰C, 1h. bReaction conditions: 1 equiv. of SC (1.5 mM in H2O), 150 equiv. of aromatic amine (400 mM in DMA), 15 equiv. of Pd t-BuXPhos G3 (100 mM in DMA), 150 equiv. of NaOH (1 M in H2O), 60 ⁰C, 1h. *Indicated conversion corresponds to the sum of desired product and the product of ester hydrolysis. NT= no tested. In general, all the reactions proceeded in good to excellent yields (50-90%) for the six aromatic amines with the exception of the coupling with highly sterically hindered SC3 and SC6 (0%), both having the DNA moiety in ortho position to the halide. Other combinations of sterically hindered anilines as 5 and 6 with a hindered halide as SC8 were not highly successful either. Surprisingly, SC11, also an ortho-substituted DNA-coupled aryl bromide, afforded excellent results with all the amines, meaning that the reactivity is not influenced only by the steric hindrance of the molecule, but also by the electronic nature of the ring. Presumably, SC11 is highly activated for the oxidative addition of Pd and that is translated in a higher reactivity. The by-product (phenol) identified in the reaction with SC14 was the responsible for the low yields observed with that DNA-coupled aryl bromide. Finally, it is clear that the linker length to the DNA (SC1 vs. SC7) does not influence the coupling efficiency. Overall, this protocol provided good to excellent yields for C-N coupling of non-sterically hindered aryl halides with non-sterically hindered anilines. The coupling with heteroaryl bromides afforded variable yields depending on the nature of the heterocycle. 6 ACS Paragon Plus Environment

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The newly developed conditions worked well, not only with a short DNA piece (AOP-HP, MW= 5184), but also with full length DNA up to 3 Tags (MW= 34000). The C-N coupling was also tested before and after Tag3 ligation, affording the same product in both experiments (see supporting information), which ensured us that our protocol was compatible with DEL synthesis. A wide spectrum of different aromatic amines (867, see some structures in the supporting information) and DNA-conjugated aryl bromides (471, see some structures a in the supporting information) were tested under the described C-N coupling conditions (Scheme 1, 1b), and the conversion was determined by LC/MS. The aromatic amines were validated against one unique DNA-coupled aryl bromide SC15 (MW= 11892), and the on-DNA-conjugated aryl bromides against one unique aniline (3-fluoroaniline). Aromatic amines displaying functional groups such as free phenol, aromatic thiol, carboxylic acid or nucleophilic free amines behave poorly, since all of them are susceptible to deprotonation under highly basic conditions as described here. However, anilines containing aliphatic alcohol, sulfonamide, ester functionality and tertiary basic amines showed successful C-N coupling. In general, the ester function hydrolyzed in the medium giving access to free carboxylic acid that could be used to further introduce another point of diversity in a library. Furthermore, diverse hetero aromatic amines containing heterocycles as thiazole, pyrazine, pyridine, oxadiazole, benzoxazole, benzimidazole or pyrazole among others (see Figure 1) were successful coupling partners for this reaction. Remarkable is the successful coupling of unreactive amines such as 2-aminothiazoles on-DNA, which was not reported to date. However, the electronic nature of the ring seems to influence its reactivity as 4- & 5-substituted 2-aminothiazole (mono- or di-functionalized), afforded the desired product in good yield, whereas plain 2-aminothiazole failed to give the C-N coupling reaction. Figure 1: Scope of the amines validation with SC15 and some examples of heteroaromatic amines validated. Conversion calculated by LCMS signal integration, not isolated yield. O

O Br N H

+

Ar N H 2

tBuXPhos Pd G3 NaOH

N H

N H

Ar

60 ºC, 2h

SC15 F F

N H 2N

465 Invalid 92 Moderate

H 2N

< 50%

50-70%

N

N N N 72%

310 Valid

> 70%

N

50%

O

N

N N

N

90%

75%

N

N H2 H 2N

F S

O O

70%

N H2

O N

N H2

60%

The carboxylic acid aryl bromides were double validated: carboxylic acid to form an amide and Br to perform the C-N coupling reaction (Figure 2). From this validation, we observed that the DNA-conjugated aryl bromide moiety was able to tolerate functional groups not allowed in the aromatic amine moiety, as 7 ACS Paragon Plus Environment

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phenols and aromatic amines, which opens a wide scope in the BBs amenable to run this C-N coupling reaction. Figure 2: Scope of the bromide validation and some examples of carboxylic acid aryl bromides validated. Conversions calculated by LCMS integration after the two step validation.

N H2

O HO

+

Ar Br

DMT-MM Ar Br

N H

rt, 16 h

F

3-F-aniline tBuXPhos Pd G3 NaOH

O

O N H

60 ºC, 2h

Ar N H

83 Invalid 225 Valid

246 Invalid

37 Moderate 105 Valid

>70%

70%

Validation in acylation

50-70%

98% tags detected, see supporting information), which confirms that, the residual DNA damage observed in a few examples by LCMS does not prevent from getting reliable results. Future plans include to develop additional conditions for the C-N coupling between DNA-conjugated aryl bromides and aliphatic amines.

Supporting Information Detailed experimental procedures for the synthesis of SC1 to SC16 and for the C-N coupling reaction, representative LCMS for some of the coupled products, structures of some anilines and carboxylic acid aryl-halides and oligonucleotide sequences are described in the Supporting Information. Author information E.D.P.B. and A.T. conceived the work, designed the experiments, analyzed data and drafted the manuscript with input from all authors. E.D.P.B., J.P., J.B., A.G-M, F.G., J.B. and M.D.M-O. performed the experiments. M.A.T. and J.E. guided aspects of this work. All the authors contributed invaluably to the revision and formatting of the final manuscript. Corresponding Author *E-mail: [email protected] Tel.: (+34)916633423 Notes The authors declare no competing financial interest. Alicia Torrado, Julián Priego, Jesús Blas, María Dolores Martín-Ortega and Miguel Ángel Toledo are all employees of Eli Lilly & Company. Eduardo de Pedro Beato, Adrián Gironda-Martínez, Fernando González, Jesús Benavides & Jesús Ezquerra are former employees of Eli Lilly & Company. Funding The authors received no financial support for the research, authorship, and/or publication of this article.

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Acknowledgements The authors thank Theodore Curtis Jessop for advice; Craig Ruble, Jeff Richardson and Graham Cumming for valuable suggestions on palladium coupling conditions; and Alfonso Rivera, Tamara Salamanca, Ramón Rama and José Pablo Román for technical support.

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(13) Kunig, V.; Potowski, M.; Gohla, A.; Brunschweiger, A. DNA-encoded libraries – an efficient small molecule discovery technology for the biomedical sciences. Biol. Chem. 2018, 399, 691-710. (14) Goodnow, R. A., Jr.; Dumelin, C. E.; Keefe, A. D. DNA-encoded chemistry: enabling the deeper sampling of chemical space. Nature Reviews Drug Discovery 2017, 16, 131-147. (15) Yuen, L. H.; Franzini, R. M. Achievements, Challenges, and Opportunities in DNA-Encoded Library Research: An Academic Point of View. ChemBiochem. 2017, 18, 829-836. (16) Malone, M. L.; Paegel, B. M. What is a "DNA-Compatible" Reaction? ACS Comb. Sci. 2016, 18, 182-187. (17) Kin-Chun Luk, Alexander Lee Satz. DNA-Compatible Chemistry. Handbook for DNA Encoded Chemistry: Theory and Applications for Exploring Chemical Space and Drug Discovery, First Edition. Edited by Robert A. Goodnow, Jr., John Willey & Sons, Inc., Hoboken, New Jersey, 2014, Chapter 4, 67-98. (18) Satz, A. L.; Cai, J.; Yi, C.; Goodnow, R.; Gruber, F.; Kowalczyk, A.; Petersen, A.; Naderi-Oboodi, G.; Orzechowski, L.; Strebel, Q. DNA Compatible Multistep Synthesis and Applications to DNA Encoded Libraries. Bioconjugate Chem. 2015, 26, 1623-1632. (19) Kölmel, D. K.; Loach, R. P.; Knauber, T.; Flanagan, M. Employing Photoredox Catalysis for DNA-Encoded Chemistry: Decarboxylative Alkylation of -Amino Acids. ChemMedChem. 10.1002/cmdc.201800492. (20) Wang, J.; Lundberg, H.; Asai, S.; Martín-Acosta, P.; Chen, J. S.; Brown, S.; Farrell, W.; Dushin, R. G.; O’Donnell, C. J.; Ratnayake, A. S.; Richardson, P.; Liu, Z.; Qin, T.; Blackmond, D. G.; Baran, P. S. Kinetically guided radical-based synthesis of C(sp3)-C(sp3) linkages on DNA. Proc. Natl Acad. Sci. USA 2018, 115, E6404-E6410. (21) Ding, Y.; Chai, J.; Centrella, P. A.; Gondo, C.; DeLorey, J. L.; Clark, M. A. Development and Synthesis of DNAEncoded Benzimidazole Library. ACS Comb. Sci. 2018, 20, 251-255. (22) Du, H-C.; Huang, H. DNA-Compatible Nitro Reduction and Synthesis of Benzimidazoles. Bioconjugate Chem. 2017, 28, 2575-2580. (23) Škopić, M. K.; Salamon, H.; Bugain, O.; Jung, K.; Gohla, A.; Doetsch, L. J.; dos Santos, D.; Bhat, A.; Wagnera, B.; Brunschweiger, A. Acid- and Au(I)-mediated synthesis of hexathymidine-DNA-heterocycle chimeras, an efficient entry to DNA-encoded libraries inspired by drug structures. Chem. Sci. 2017, 8, 3356-3361. (24) Tian, X.; Basarab, G. S.; Selmi, N.; Kogej, T.; Zhang, Y.; Clark, M.; Goodnow Jr. R. A. Development and design of the tertiary amino effect reaction for DNA-encoded library synthesis. Med. Chem. Commun. 2016, 7, 1316-1322. (25) Ding, Y.; Franklin, G. J.; DeLorey, J. L.; Centrella, P. A.; Mataruse, S.; Clark, M. A.; Skinner, S. R.; Belyanskaya, S. Design and synthesis of biaryl DNA-encoded libraries. ACS Comb. Sci. 2016, 18, 625−629. (26) Ding, Y.; Clark, M. A. Robust Suzuki-Miyaura cross-coupling on DNA-linked substrates. ACS Comb. Sci. 2015, 17, 1−4. (27) Lu, X.; Roberts, S. E.; Franklin, G. J.; Davie, C. P. On-DNA Pd and Cu Promoted C-N Cross-Coupling Reactions. Med. Chem. Commun. 2017, 8, 1614-1617. (28) Ruff, Y.; Berst, f. Efficient copper-catalyzed amination of DNA-conjugated aryl iodides under mild aqueous conditions. Med. Chem. Commun. 2018, 9, 1188-1193. (29) Surry, D. S.; Buchwald, S. L. Dialkylbiaryl phosphines in Pd-catalyzed amination: a user’s guide. Chem. Sci., 2011, 2, 27-50. (30) Clark, M. A.; Acharya, R. A.; Arico-Muendel, C. C.; Belyanskaya, S. L.; Benjamin, D. R.; Carlson, N. R.; Centrella, P. A.; Chiu, C. H.; Creaser, S. P.; Cuozzo, J. W.; Davie, c. F.; Ding, Y.; Franklin, G. J.; Franzen, K. D.; Gefter, M. L.; Hale, S. P.; Hansen, N. J. V.; Israel, D. I.; Jiang, J.; Kavarana, M. J.; Kelley, M. S.; Kollmann, C. DS.; Li, F.; Lind, K.; Mataruse, S.; Medeiros, P. F.; Messer, J. A.; Myers, P.; O’Keefe, H.; Oliff, M. C.; Rise, C. E.; Satz, A. L.; Skinner, S. R.; Svendsen, J. L.; Tang, L.; van Vloten, K.; Wagner, R. W.; Yao, G.; Morgan, B. A. Design, synthesis and selection of DNA-encoded small-molecule libraries. Nat. Chem. Biol. 2009, 5, 647-654.

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O N H

Ar NH

O

Br X + N H2 Ar

"Pd"

N H

X

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