Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH2:24])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][C:38]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:39])[CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccccc1N1CCN(C[C@H](N)Cc2ccncc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C[C@@H](Cc2ccncc2)NC(=O)C2CCCCC2)CC1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of (1R)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1-pyridin-4-ylmethyl-ethylamine (800 mg.; 2.45 mmol, from Example 8) in dichloromethane (30 mL) at 0° C. was added triethylamine (0.68 mL; 4.9 mmol) and cyclohexanecarbonyl chloride (0.33 mL; 2.45 mmol). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour. The mixture was washed with saturated NaHCO3 (5 mL), dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (2% methanol/chloroform) to afford the free base of the title compound as a white gummy foam (610 mg; 57%). Treatment with an equimolar amount of maleic acid in ethanol yielded the maleate salt as an off-white amorphous solid, m.p. 145–147° C.; MS (+) FAB [M+H]+ @ m/z 437, [M+Na]+ @ m/z 459; 1H NMR, 400 MHz, DMSO-d6. Analysis for C26H36N4O2.C4H4O4.0.5H2O Calculated: C, 64.15; H, 7.36; N, 9.97 Found: C, 64.23; H, 7.37; N, 9.88
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:15])=[CH:12][C:13]=1I)([CH3:4])([CH3:3])[CH3:2].[CH:17]#[C:18][CH2:19][CH3:20].C(N(CC)CC)C>C1(C)C=CC=CC=1.O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:17]([C:13]1[CH:12]=[C:11]([Cl:15])[N:10]=[CH:9][C:8]=1[NH:7][C:6](=[O:16])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])#[C:18][CH2:19][CH3:20]
Reactant: C#CCC
Reactant: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC#Cc1cc(Cl)ncc1NC(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a deoxygenated solution of (6-chloro-4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester (6.0 g, 16.9 mmol), 1-butyne (9 g, 169 mmol), CuI (160.1 mg, 0.84 mmol) and triethylamine (3.4 g, 33.2 mmol) in toluene (40 mL) and water (14 mL) was added Pd(PPh3)2Cl2 (592 mg, 0.84 mmol) under N2 in a autoclave. The mixture was heated to 70° C. and stirred for 24 h. The solid was filtered off and washed with ethyl acetate (60 mL×3). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 10/1) to give tert-butyl 4-(but-1-ynyl)-6-chloropyridin-3-ylcarbamate (3.5 g, 74%). 1H-NMR (CDCl3, 300 MHz) δ 9.13 (s, 1H), 7.22 (s, 1H), 6.98 (s, 1H), 2.53 (q, J=7.5 Hz, 2H), 1.54 (s, 9H), 1.29 (t, J=7.5 Hz, 3H).
Reaction SMILES: [K].C(OC([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:36])/[CH:23]=[CH:24]/[C:25]3[CH:26]=[N:27][C:28](/[CH:31]=[CH:32]/[C:33]([OH:35])=O)=[CH:29][CH:30]=3)=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C1C=CC2[N:45]([OH:46])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>CN(C=O)C.C(Cl)Cl>[OH:46][NH:45][C:33](=[O:35])/[CH:32]=[CH:31]/[C:28]1[CH:29]=[CH:30][C:25](/[CH:24]=[CH:23]/[C:22](=[O:36])[C:19]2[CH:20]=[CH:21][C:16]([CH2:15][N:12]3[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]3)=[CH:17][CH:18]=2)=[CH:26][N:27]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)nc3)cc2)CC1
Agent: NOC1CCCCO1
Agent: [K]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(CN3CCNCC3)cc2)cn1)NO
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.2 %

Procedure:
A mixture of 4-(4-{(E)-3-[6-((E)-2-carboxy-vinyl)-pyridin-3-yl]-acryloyl}-benzyl)-piperazine-1-carboxylic acid tert-butyl ester potassium salt (250 mg, 0.48 mmol), HOBT (130 mg, 0.96 mmol), EDC (184 mg, 0.96 mmol), TEA (0.134 ml, 0.96 mmol) and NH2OTHP (84 mg, 0.72 mmol) in DMF (4 ml) and DCM (4 ml) was stirred at room temperature for 5 h. The solution was diluted with DCM and washed with water and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by column chromatography (eluent: DCM/MeOH/NH4OH 95:5:0.1) and the resulting product was dissolved in DCM and treated with HCl/Et2O for 4 h. The resulting precipitate was filtered and purified by preparative LC-MS to give 40 mg of (E)-N-hydroxy-3-{5-[(E)-3-oxo-3-(4-piperazin-1-ylmethyl-phenyl)-propenyl]-pyridin-2-yl}-acrylamide as its formate salt.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:17]2[CH:18]=[CH:19][C:14]([C:11](=[O:13])[CH3:12])=[CH:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Product: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 97 %

Procedure:
From 4-nitro-bromobenzene and 4-acetylphenyl boronic acid, yield 97%; mp 144-146° C. (lit.,7 150-151° C.); IR: 1681, 1530, 1497, 1361 and 1280; 1H NMR (400 MHz; CDCl3): 8.02 (2H, d, J 8.5), 7.64-7.56 (4H, m), 7.16 (2H, t, J 8.5) and 2.63 (3H, s); 13C NMR (CDCl3): 197.5, 164.2, 144.7, 136, 128.9, 127, 116, 115.7 and 26.6; m/z (EI) 199 (30%, M+−C2H2O), 131 (50) and 69 (100)(Found: M+−C2H2O, 199.062).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[CH3:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[C:30]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:29]=1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][N:38]([C:30]3[CH:29]=[C:28]([CH3:27])[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Cc1cc(N2CCNCC2)nc2ccccc12
Product: Cc1cc(N2CCN(CCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)nc2ccccc12

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 4-methyl-2-piperazin-1-yl-quinoline.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)[CH:10]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Oc1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.1 %

Procedure:
Tetrakis(triphenylphosphine)palladium (139 mg, 0.12 mmol) was added to a flask containing 4-bromophenol (519 mg, 3.0 mmol), 3-pyridyl boronic acid (553 mg, 4.5 mmol) and sodium carbonate (1.27 g 12.0 mmol). The flask was flushed with nitrogen and ethanol (6 mL) and water (0.6 mL), were added. The mixture was placed in an oil bath at 80° C. for 16 h. Upon cooling to RT the mixture was partitioned between water and chloroform. The aqueous layer was extracted with chloroform (3×) and the combined organic layers were dried (Na2SO4), filtered and concentrated. The crude residue was purified by chromatography (Biotage, 40S) eluting with 50% ethyl acetate in hexanes to afford 165 mg (32%) of 4-pyridin-3-yl-phenol as a white solid: mp=194.6° C., MS (Cl) m/z 172.1 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].C(O)=[O:40]>C(O)CO.C(OCC)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:24][N:25]=[N:26][N:27]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34][CH2:35][CH2:36][OH:40])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=CO
Reactant: CCCCc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: OCCO
Solvent: CCOC(C)=O
Product: CCCCc1nc2cccc(C(=O)OCCO)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of ethyl 2-butyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.72 g) in ethylene glycol (15 ml) was added, while stirring at room temperature, sodium hydride (60% oil, 0.25 g) and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added ice-water (100 ml), which was made acidic with formic acid. Precipitates then formed were dissolved in ethyl acetate (100 ml) and the solution was washed with water, dried and concentrated to dryness to give a crystalline product. The crystals were recrystallized from acetone to afford colorless crystals (0.49 g, 66%), m.p. 145°-147° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].Cl.[NH2:6][C:7]1[C:15]2[S:14][C:13]([Cl:16])=[N:12][C:11]=2[C:10]([Cl:17])=[CH:9][C:8]=1[F:18]>C1(C)C=CC=CC=1>[Cl:16][C:13]1[S:14][C:15]2[C:7]([N:6]=[C:1]=[O:2])=[C:8]([F:18])[CH:9]=[C:10]([Cl:17])[C:11]=2[N:12]=1
Reactant: Nc1c(F)cc(Cl)c2nc(Cl)sc12
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1c(F)cc(Cl)c2nc(Cl)sc12
Temperature: 100 °C

Procedure:
31 ml of a 20% solution of phosgene in toluene was added, dropwise, at room temperature to a suspension of 5.1 g 7-amino-2,4-dichloro-6-fluorobenzothiazole hydrochloride in 30 ml abs. toluene. The mixture was heated for 8 hours at 100° C. and the toluene removed in vacuo. The residue was triturated with hexane. Yield: 4.8 g=90% of theory m.p.: 95°-98° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[S:5][C@@H:6]2[C@@H:23]([O:24][CH3:25])[C:22](=[O:26])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:32]>CN(C=O)C.C(Cl)Cl>[CH2:1]([S:3]([C:4]1[S:5][C@@H:6]2[C@@H:23]([O:24][CH3:25])[C:22](=[O:26])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)=[O:10])=[O:32])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H](OC)[C@H]2S1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCS(=O)C1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H](OC)[C@H]2S1
Reaction time: 1 h

Procedure:
A solution of p-nitrobenzyl (5R,6S)-2-ethylthio-6-methoxy-pen-2-em-3-carboxylate (96 mg, 0.24 mmol) in anhydrous DMF (1.2 ml) is diluted with CH2Cl2 (2.4 ml) and cooled in an ice-bath. A solution of 85% m-chloroperoxybenzoic acid (51 mg, 0.25 mmol) in CH2Cl2 (1.2 ml) is added dropwise over 2 minutes to the cold, stirring solution. The resulting mixture is kept at 0° for 60 minutes, and then treated with excess Amberlyst-21 resin and stirred and additional 5 minutes. The mixture is filtered and the filtrate is diluted with CH2Cl2 and washed with 5 portions of H2O. The organic phase is dried over MgSO4, filtered, and evaporated under vacuum to give a crude residue of the title compound which is purified by rapid chromatography on silica gel.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].I[CH:13]1[C:18](OC)([O:19]C)[CH2:17][CH2:16][O:15][CH2:14]1>>[O:19]=[C:18]1[CH2:17][CH2:16][O:15][CH2:14][CH:13]1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: COC1(OC)CCOCC1I
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(C2COCCC2=O)cc1

Procedure:
4-cyanophenylboronic acid was reacted as described in Intermediate X(2) with 3-iodo-4,4-dimethoxytetrahydro-2H-pyran (Intermediate X(1)) to give 4-(4-oxotetrahydro-2H-pyran-3-yl)benzonitrile (Intermediate AA(2)). LC-MS (M+H)+=202.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.66 (d, J=8.24 Hz, 2 H) 7.38 (d, J=8.55 Hz, 2 H) 4.23-4.31 (m, 2 H) 3.94-4.02 (m, 2 H) 3.85-3.92 (m, 1 H) 2.55-2.65 (m, 1 H) 2.52 (t, J=5.80 Hz, 1 H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:11]=1[O:12][C:13]1[C:14]2[N:15]([CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:17][CH:18]=1>C(Cl)(Cl)Cl>[Br:1][C:21]1[CH:20]=[CH:19][N:15]2[C:14]=1[C:13]([O:12][C:11]1[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:10]=1[F:9])=[CH:18][CH:17]=[N:16]2
Reactant: O=[N+]([O-])c1ccc(Oc2ccnn3cccc23)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(Oc2ccnn3ccc(Br)c23)c(F)c1
Reaction time: 4 h
Yield: 28.4 %

Procedure:
N-Bromosuccinimide (1.49 g, 8.42 mmol) was added to a solution of 4-(2-fluoro-4-nitrophenoxy)pyrrolo[1,2-b]pyridazine (2.30 g, 8.42 mmol) in anhydrous chloroform (70 mL) at 0° C. and stirred for 4 hours. Upon completion of the reaction, the resulting mixture was washed by adding water thereto. The organic layer was separated, dried with magnesium sulfate, and then filtered. The filtrate was concentrated by distillation under reduced pressure. The resulting residue was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to give the target compound as a yellow solid (840 mg, 2.39 mmol, 28% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[N+:11]([O-])([OH:13])=[O:12].[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: Clc1ccc2nccn2n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Reaction time: 4.5 h
Yield: 90.8 %

Procedure:
6-Chloroimidazo[1,2-b]pyridazine (4.95 g, 31.6 mmol) [purchased from Combi-Blocks] was dissolved in 60 mL concentrated sulfuric acid, cooled in an ice bath, and nitric acid (9.9 mL, 158 mmol) was added dropwise while stirring. The reaction was stirred at 0° C. for 30 minutes, then at ambient temperature for 4.5 hours to reach completion. The reaction was poured onto ice, and the resulting aqueous mixture was neutralized with 50% NaOH aqueous solution and then extracted with EtOAc (3×400 mL). The organic layers were combined and washed with water (2×400 mL) and brine (400 mL), dried (Na2SO4), filtered and concentrated to yield the product as a yellowish powder (5.7 g, 91% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](Cl)=[O:23]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)=[O:23])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: O=C(Cl)c1ccccn1
Product: O=C(NC1CCCc2c1[nH]c1ccc(Br)cc21)c1ccccn1

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)pyridine-2-carboxamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and picolinoyl chloride in a similar manner as described above to give an off-white solid (64% yield). 1H-NMR (CDCl3): δ 8.96 (s, 1H), 8.52 (m, 1H), 8.37 (d, 1H), 8.21 (m, 1H), 7.86 (m, 1H), 7.61 (m, 1H), 7.43 (m, 1H), 7.22 (dd, 1H), 7.17 (d, 1H), 5.31 (m, 1H), 2.72 (m, 2H), 2.31 (m, 1H), 1.98 (m, 3H); MS m/z 370 (M−1).
Reaction SMILES: Br[C:2]1[C:3]([N:27]2[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:5]2=[N:6][CH:7]=1.[CH:41]1(B(O)O)[CH2:43][CH2:42]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:37]([O:36][C:34]([NH:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][N:27]([C:3]2[C:2]([CH:41]3[CH2:43][CH2:42]3)=[CH:7][N:6]=[C:5]3[N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:9]=[C:10]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[C:4]=23)[CH2:28]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3c2c(NC(=O)c2cccnc2)cn3C(=O)OC(C)(C)C)C1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(C3CC3)cnc3c2c(NC(=O)c2cccnc2)cn3C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Yield: 50.9 %

Procedure:
A mixture of (R)-tert-butyl 5-bromo-4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (170 mg, 0.276 mmol), cyclopropylboronic acid (95 mg, 1.10 mmol), K3PO4 (205 mg, 0.967 mmol), Pd(OAc)2 (6.20 mg, 0.0276 mmol), and tricyclohexylphosphine (9.3 mg, 0.033 mmol) in toluene/water (10:1 mixture, 4.4 mL) was degassed under argon and heated at 80° C. for 15 hours. The reaction mixture was then allowed to cool to room temperature. The mixture was poured into water and extracted with CH2Cl2. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 5 to 95% CH3CN/water gradient; 30 CV) to provide (R)-tert-butyl 4-(3-(tert-butoxycarbonylamino)piperidin-1-yl)-5-cyclopropyl-3-(nicotinamido)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (81 mg, 51% yield). LCMS (APCI+) m/z 577.2 (M+H)+, Retention time=4.01 minutes (Method 2).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9]CC[CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=[O:44])C=CC=2)N=1.Cl.N1CC[C@@H]1C(OC)=O>>[S:24]([CH2:23][C:19]1[CH:18]=[C:17]([NH:16][C:12]2[N:13]=[CH:14][N:15]=[C:10]([N:5]3[CH2:6][CH2:9][C@@H:4]3[C:3]([O:2][CH3:1])=[O:44])[N:11]=2)[CH:22]=[CH:21][CH:20]=1)(=[O:26])(=[O:25])[NH2:27]
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Agent: COC(=O)[C@H]1CCN1
Agent: Cl
Product: COC(=O)[C@H]1CCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B36 was prepared following the general procedure reported for B4 using A1 and A7 and obtained as white crystals; yield: 60 mg (18%). MS (ES) C15H18N16O4S requires: 378. found: 379 (M+H)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:15]2[C:14]([Cl:16])=[N:13][CH:12]=[N:11][C:10]=2[N:9]([CH:17]([CH3:19])[CH3:18])[CH:8]=1.CON(C)[C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[C:25]=1[CH3:33]>C(OCC)C>[Cl:16][C:14]1[C:15]2[C:7]([C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-:32])=[O:31])[C:25]=3[CH3:33])=[O:34])=[CH:8][N:9]([CH:17]([CH3:19])[CH3:18])[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: CC(C)n1cc(Br)c2c(Cl)ncnc21
Reactant: CON(C)C(=O)c1cccc([N+](=O)[O-])c1C
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1c(C(=O)c2cn(C(C)C)c3ncnc(Cl)c23)cccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 37.7 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 14.3 mmol) was added dropwise to a suspension of 5-Bromo-4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidine (3.7 g, 13.6 mmol) and ethyl ether (75 mL), cooled to −78 C, and stirred for 1 h. N-Methoxy-2,N-dimethyl-3-nitro-benzamide (4.0 g, 17.7 mmol) was added to the reaction mixture, stirred for 2 h, quenched with aqueous NH4Cl (100 mL), and extracted with EtOAc (3×100 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash column chromatography (silica, 3:7 EtOAc:hexanes) provided the title compound as an yellow solid (1.84 g, 38%). MS: 357.5 (MH−); HPLC Rf: 2.0 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:17][CH2:18][OH:19])[CH3:16])=[O:14])=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=2)[C:5](=[O:25])[N:4]([CH3:26])[CH:3]=1.[CH3:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[CH:30][C:29]=1[NH:43][C:44]([C:46]1[S:50][C:49]2[CH2:51][CH2:52][CH2:53][CH2:54][C:48]=2[CH:47]=1)=[O:45].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:19][CH2:18][CH2:17][N:15]([CH3:16])[C:13]([C:12]1[CH:20]=[CH:21][C:9]([NH:8][C:6]2[C:5](=[O:25])[N:4]([CH3:26])[CH:3]=[C:2]([C:33]3[C:28]([CH3:27])=[C:29]([NH:43][C:44]([C:46]4[S:50][C:49]5[CH2:51][CH2:52][CH2:53][CH2:54][C:48]=5[CH:47]=4)=[O:45])[CH:30]=[CH:31][CH:32]=3)[N:7]=2)=[CH:10][C:11]=1[N+:22]([O-:24])=[O:23])=[O:14]
Reactant: CN(CCO)C(=O)c1ccc(Nc2nc(Br)cn(C)c2=O)cc1[N+](=O)[O-]
Reactant: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)c2cc3c(s2)CCCC3)cccc1-c1cn(C)c(=O)c(Nc2ccc(C(=O)N(C)CCO)c([N+](=O)[O-])c2)n1
Yield: 61.8 %

Procedure:
4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-N-(2-hydroxy-ethyl)-N-methyl-2-nitro-benzamide (4) (250 mg, 0.59 mmol, 1.0 equiv), 4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-amide (257 mg, 0.65 mmol) and tetrakis(triphenylphosphine)palladium (68 mg, 0.06 mmol) are dissolved in 1,4-dioxane (2.0 mL) and sodium carbonate (1N, 1.0 mL) and heated in a microwave glass reactor for 6 minutes at 140° C. Once completed the reaction is transferred to a seperatory funnel with ethyl acetate (50 mL) and washed with saturated sodium bicarbonate (1×100 mL), then washed with saturated sodium chloride (1×100 mL) and dried over sodium sulfate. The solution is then filtered and concentrated under reduced pressure. The resulting residue is then triturated with DCM and hexane to give 4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid [3-(6-{4-[(2-hydroxy-ethyl)-methyl-carbamoyl]-3-nitro-phenylamino}-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl)-2-methyl-phenyl]-amide (5) as a light yellow solid (225 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.CO[C:11](OC)([CH3:13])[CH3:12].C(=O)(O)[O-].[Na+]>O.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[CH3:12][C:11]1([CH3:13])[N:7]2[C:6](=[O:8])[CH2:5][CH2:4][C@@H:3]2[CH2:2][O:1]1
Reactant: COC(C)(C)OC
Reactant: O=C1CC[C@H](CO)N1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1(C)OC[C@H]2CCC(=O)N21
Temperature: 75 °C
Yield: 78.5 %

Procedure:
To a mixture consisting of (R)-5-hydroxymethyl-2-pyrrolidinone (20 g, 174 mmol) in 2,2-dimethoxypropane (1.4 L, 11,400 mmol) was added camphorsulfonic acid (1.0 g, 4.3 mmol). The stirring mixture was heated to 75° C. for 20 hours. The reaction mixture was treated with a saturated aqueous solution of sodium bicarbonate, diluted with water, and extracted with ethyl acetate. The combined organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography. Elution with methanol-dichloromethane (1:70 v/v) afforded the title compound as a white solid (21.2 g, 78%); TLC Rf 0.6 (solvent system: 25:75 v/v ethyl acetate-hexane); MS (ESI+) m/z 156.1 (M+H)+, 178.1 (M+Na)+; 1H-NMR (CDCl3) δ 4.3-4.2 (m, 1H), 4.1 (dd, 1H), 3.5 (t, 1H), 2.9-2.7 (m, 1H), 2.6-2.5 (m, 1H), 2.2-2.1 (m, 1H), 1.9-1.7 (m, 1H), 1.7 (s, 3H), 1.5 (s, 3H).