Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:10]=[C:11]([C:15]3([C:21]#[N:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:31]>ClCCCl>[C:33]1([O:32][C:30](=[O:31])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([S:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]4([C:21]#[N:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH:10]=3)=[CH:4][CH:3]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: N#CC1(c2cccc(Sc3ccc(N)cc3)c2)CCOCC1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: N#CC1(c2cccc(Sc3ccc(NC(=O)Oc4ccccc4)cc3)c2)CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 4-{3-[(4-aminophenyl)thio]phenyl}tetrahydro-2H-pyran-4-carbonitrile (2.50 g, 8.06 mmol) (example 4) in 1,2-dichloroethane (20 mL) and pyridine (0.95 g, 12.097 mmol) was cooled to 0° C. Phenyl chloroformate (1.89 g, 12.097 mmol) was added dropwise to the reaction mixture at 0° C. The reaction mixture was stirred at room temperature for about 1 hour. The solvent was evaporated under vacuum, toluene was added to remove traces of pyridine, then hexane was added and the solid so obtained was filtered and dried. Yield:4.30 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([OH:18])=[C:5]2C(O)=O.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][CH:24]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]([O:18][C:23]1[C:32]3[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:24]=1)=[CH:5]2
Reactant: O=C(O)c1c(O)c(-c2ccccc2)nc2ccc(F)cc12
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4cc(F)ccc4nc3-c3ccccc3)c2cc1OC
Temperature: 160 °C
Reaction time: 11 h
Yield: 18 %

Procedure:
6-Fluoro-3-hydroxy-2-phenyl-quinoline-4-carboxylic acid (118 mg), 4-chloro-6,7-dimethoxyquinoline (330 mg), and 4-dimethylaminopyridine (310 mg) were suspended in o-dichlorobenzene (8 ml), and the mixture was stirred at 160° C. for 11 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (32 mg, yield 18%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][O:33]C(=O)C)=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]([CH3:31])[CH2:24][CH2:25][NH:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.O[Li].O>C1COCC1.CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][OH:33])=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]([CH3:31])[CH2:24][CH2:25][NH:26][C:27](=[O:30])[CH:28]=[CH2:29])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1
Reactant: C=CC(=O)NCCN(C)c1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3COC(C)=O)cn(C)c2=O)n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: C=CC(=O)NCCN(C)c1cccc(Nc2cc(-c3cc(F)cc(-n4ncc5c6c(sc5c4=O)CCCC6)c3CO)cn(C)c2=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
A mixture of 111a (130 mg, 0.186 mmol) and LiOH.H2O (40 mg, 0.93 mmol) in THF/i-PrOH/water (2.0 mL/1.0 mL/1.0 mL) was stirred at rt for 2 h. The mixture was extracted with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by prep-TLC (DCM/MeOH=20/1) to give 111 (40 mg, 33%) as white solid. 1H NMR (400 MHz, CDCl3): δ 8.53 (s, 1H), 8.25 (s, 1H), 7.77 (s, 1H), 7.47 (s, 1H), 7.39-7.35 (t, J=8.4 Hz, 1H), 7.26-7.23 (m, 1H), 7.10-7.08 (m, 1H), 6.64 (s, 1H), 6.18-6.16 (d, J=8.4 Hz, 1H), 6.08-6.00 (m, 2H), 5.85-5.79 (m, 1H), 5.47-5.44 (d, J=10.4 Hz, 1H), 4.30-4.28 (d, J=6.4 Hz, 2H), 4.02-3.99 (t, J=6.4 Hz, 1H), 3.75-3.69 (m, 5H), 3.47-3.45 (m, 2H), 3.02-2.98 (m, 5H), 2.86 (m, 2H), 1.98 (m, 4H). ESI-LCMS: m/z=656 [C34H34FN7O4S+H]+
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Br:9][C:10]1[C:11]([S:17](Cl)(=[O:19])=[O:18])=[C:12]([Cl:16])[S:13][C:14]=1[Cl:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:17]([C:11]1[C:10]([Br:9])=[C:14]([Cl:15])[S:13][C:12]=1[Cl:16])(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1c(Cl)sc(Cl)c1Br
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2c(Cl)sc(Cl)c2Br)c1Br
Yield: 58 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dichloro-4-bromothiophene-3-sulfonamide was prepared in the same manner as described in Example 1 from 5-amino-4-bromo-3-methylisoxazole and 4-bromo-2,5-dichlorothiophene-3-sulfonyl chloride in 58% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 146-149° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])[CH3:3].CN1C=CN=C1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[N:30][O:31][C:32]=2[C:33]2[CH:38]=[C:37]([O:39][CH3:40])[C:36]([O:41][CH3:42])=[C:35]([O:43][CH3:44])[CH:34]=2)=[CH:24][C:23]=1[NH2:45]>C1COCC1>[C:2]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10](=[O:12])[NH:45][C:23]1[CH:24]=[C:25]([C:28]2[CH:29]=[N:30][O:31][C:32]=2[C:33]2[CH:34]=[C:35]([O:43][CH3:44])[C:36]([O:41][CH3:42])=[C:37]([O:39][CH3:40])[CH:38]=2)[CH:26]=[CH:27][C:22]=1[O:21][CH3:20])([CH3:1])([CH3:3])[CH3:4]
Reactant: COc1ccc(-c2cnoc2-c2cc(OC)c(OC)c(OC)c2)cc1N
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Agent: Cn1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(-c2cnoc2-c2cc(OC)c(OC)c(OC)c2)cc1NC(=O)CNC(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of N-t-Boc-glycine (357 mg, 2 mmol) and N-methyl-imidazole (0.162 mL, 2 mmol) in THF (16 mL) cooled with ice methanesulfonyl chloride (0.158 mL, 2 mmol) was added. Ice batch was removed, compound 5 (0.4 g, 1 mmol) was added as a solid, followed by thriethylamine (0.144 mL, 2.02 mmol), and the reaction mixture was stirred at 40-50° C. overnight. A resulted solution was decanted from a solid, a flask rinsed with EtOAc, and a combined organic solution was washed with saturated ammonium chloride solution, then twice with water, brine and dried over anhydrous sodium sulfate. The solution was filtered out through a celite pad, concentrated and the residue was dissolved in 2-propanol (3 mL) with heating, and hexane (1-2 mL) was added drop-wise to start precipitation. In 1 hour a solid was filtered out, washed with 1:1 Hexane:ether mixture (10 ml×2) and vacuum-dried to give compound 6, 0.49 g (93.7%), LC purity 99%. 1H NMR (DMSO-d6): δ 9.11 (s, 1H), 8.81 (s, 1H), 8.22 (s, 1H), 7.24 (m, 1H), 7.20-7.15 (m, 2H), 6.91 (s, 2H), 3.87 (s, 3H), 3.73 (m, 2H), 3.70 (s, 3H), 3.66 (s, 6H). 1.40 (s, 9H).
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:18][C:17]=1[F:37])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.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>[Cl:22][C:20]1[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:18][C:17]([F:37])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2cncnc2)cc1F
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: CN(C)C=O
Solvent: O
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cnc(-c3cccc(F)c3)cc2-c2cncnc2)cc1F
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
20 mg (0.03 mmol) of tert-butyl((5-chloro-4-((6-chloro-4-(pyrimidin-5-yl)pyridin-3-yl)oxy)-2-fluorophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 7 mg (0.05 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 3.8 mg (10 mol %) of Pd(PPh3)4, 10.6 mg (0.10 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][C:5]1[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:7]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1.[CH:37]1[CH:41]=[C:40]([CH2:42][NH2:43])[O:39][CH:38]=1.C(Cl)CCl>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][C:5]1[C:6]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:7]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:43][CH2:42][C:40]3[O:39][CH:38]=[CH:37][CH:41]=3)=[O:24])=[CH:20][CH:19]=2)[C:8]2[C:15](=[O:16])[N:14]3[C@@H:10]([CH2:11][CH2:12][CH2:13]3)[C:9]=2[N:17]=1
Reactant: CCOC(=O)c1c(Cc2ccc(F)cc2F)nc2c(c1-c1ccc(C(=O)O)cc1)C(=O)N1CCC[C@@H]21
Reactant: NCc1ccco1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cc2ccc(F)cc2F)nc2c(c1-c1ccc(C(=O)NCc3ccco3)cc1)C(=O)N1CCC[C@@H]21
Reaction time: 3 h
Yield: 57.4 %

Procedure:
4-[(9aS)-2-(2,4-Difluorobenzyl)-3-(ethoxycarbonyl)-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-α]pyrrolizin-4-yl]benzoic acid (0.120 g, 0.244 mmol) was dissolved in 2 mL DCM. 2-Furfurylamine (0.035 g, 0.365 mmol) was added followed by EDC (0.070 g, 0.365 mmol). After 3 h, the reaction mixture was diluted with EtOAc and washed with pH 4.0 buffer (3×), saturated NaHCO3, brine, and dried over MgSO4. Purification on SiO2 (hexanes:EtOAc 1:1 to 1:2) provided the title compound as a white solid (0.082 g, 0.14 mmol, 59%): 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.17 (m, 1H), 6.78 (m, 2H), 6.43 (t, J=5.2 Hz, 1H), 6.34 (m, 1H), 6.30 (m, 1H), 4.69 (dd, J=12.4, 6.4 Hz, 1H), 4.64 (d, J=5.6 Hz, 2H), 4.31 (AB, J=15.6, 2H), 3.90 (dq, J=7.2, 2.0 Hz, 2H), 3.68 (m, 1H), 3.35 (m, 1H), 2.45 (m, 1H), 2.30 (m, 2H), 1.38 (m, 1H), 0.85 (t, J=7.2 Hz, 3H) ppm. ESMS m/z 572 (M+H)+, 604 (M+Na)+. Anal. calcd. for C32H27F2N3O5.¼H2O: C, 66.72; H, 4.81; N, 7.29; found: C, 66.70; H, 4.70; N, 7.21.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13]C)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]([O:17]C)=O.[CH3:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].[H-].[Na+].Cl>O1CCCC1>[CH3:22][C:21]([CH3:24])([CH3:23])[C:20](=[O:25])[CH2:19][C:11]([C:7]1[CH:8]=[CH:9][C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:15](=[O:17])[CH2:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:1]=2)[CH:6]=1)=[O:13]
Reactant: COC(=O)c1ccc2cc(C(=O)OC)ccc2c1
Reactant: CC(=O)C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(=O)c1ccc2cc(C(=O)CC(=O)C(C)(C)C)ccc2c1
Yield: 67.4 %

Procedure:
To 2.0 gm of dimethyl 2,6-naphthalene dicarboxylate and 2.8 gm of pinacolone, which had been dissolved in 25 ml of anhydrous tetrahydrofuran, 1.1 gm of 60% sodium hydride was added. The mixture was reacted at 60° C. for 4 hours while stirring. The reaction mixture was poured into ice-cooled 2N hydrochloric acid. Organic substances were extracted using chloroform and, after evaporating the solvent, recrystallized in a mixed solvent of chloroform-methanol to obtain 2.1 gm of the target compound as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:16]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:17]=[CH:18][N:19]=4)[S:8][C:7]=3[C:6]=2[N:28]=1.[CH3:29][N:30]([CH3:34])[CH2:31][C:32]#[CH:33].C([O-])([O-])=O.[K+].[K+].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2].O>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[N:16]1[C:15]([C:9]2[S:8][C:7]3[C:6]4[N:28]=[C:2]([C:33]#[C:32][CH2:31][N:30]([CH3:34])[CH3:29])[CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][C:11]=3[CH:10]=2)=[N:19][CH:18]=[N:17]1
Reactant: C#CCN(C)C
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC#Cc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 110 °C
Yield: 95.3 %

Procedure:
To a mixture of 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (500 mg, 1.2 mmol), and dimethyl-prop-2-ynyl-amine (150 mg, 1.8 mmol) in dry DMF (3 mL) under nitrogen was added K2CO3 (498 mg, 3.6 mmol), CuI (11 mg, 0.06 mmol), 1,3-bis(diphenylphosphino)propane (99 mg, 0.24 mmol) and Pd(OAc)2 (27 mg, 0.12 mmol). The reaction mixture was heated at 110° C. for 40 min under microwave. Cooled to room temperature, the resulting mixture was poured into water and extracted with EtOAc. Dried organics over sodium sulfate and purified by column chromatography (Hexanes/EtOAc=1:1) to give (3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-prop-2-ynyl)-dimethyl-amine as a yellow solid (530 mg, yield 95%). 1H NMR (DMSO-d6, 400 MHz): δ8.31 (s, 1H), 7.91 (dd, J=3.2, 8.8 Hz, 1H), 7.73-7.68 (m, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.4 Hz, 1H), 7.07 (s, 1H), 4.31 (t, J=4.8 Hz, 2H), 3.50 (s, 2H), 3.14 (t, J=4.8 Hz, 2H), 2.27 (s, 6H). ESI-MS: (m/z)=464 [M+H]+
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]3[NH:16][CH:17]=[C:18]([NH:19][C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[C:10]=23)[CH2:4]1.Br[CH2:26][CH2:27][F:28].CCN(C(C)C)C(C)C.O>CN(C=O)C>[ClH:1].[Br:15][C:14]1[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][CH2:26][CH2:27][F:28])[CH2:4]2)=[C:10]2[C:18]([NH:19][C:20]([CH:22]3[CH2:23][CH2:24]3)=[O:21])=[CH:17][NH:16][C:11]2=[N:12][CH:13]=1
Reactant: FCCBr
Reactant: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)C4CC4)c23)C1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NCCF)C3)c12)C1CC1
Temperature: 80 °C
Yield: 15.8 %

Procedure:
(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide hydrochloride (0.112 g, 0.248 mmol; Example 29, Step C), 1-bromo-2-fluoroethane (0.0222 mL, 0.298 mmol) and DIEA (0.173 mL, 0.993 mmol, d 0.742) were placed in DMF (2 mL) and heated to 80° C. for 36 hours. The reaction was then cooled to room temperature, poured into water, and extracted with EtOAc. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by reverse phase chromatography (Biotage SP4, C-18 40M+, 5-50% water:ACN). The product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirring solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(5-bromo-4-(3-(2-fluoroethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide hydrochloride (0.018 g, 15% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.23 (s, 1H), 7.26 (s, 1H), 4.69-4.67 (m, 1H), 4.56-4.55 (m, 1H), 3.84-3.81 (m, 1H), 3.57-3.54 (m, 1H), 3.42-3.16 (m, 5H), 2.22-2.19 (m, 1H), 1.80-1.73 (m, 3H), 1.57-1.55 (m, 1H), 0.90-0.80 (m, 4H). LCMS (APCI+) m/z 424, 426 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].CC[N:13](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)([O-])[O-].[NH4+].[NH4+]>CC#N.O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:13])=[O:6]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cccc(I)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: NC(=O)c1cccc(I)c1
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
To a stirred solution of 3-iodobenzoic acid (2.00 g, 8.06 mmol) and DIPEA (562 mL, 32.3 mmol) in MeCN (100 mL) at room temperature was added HOBT (1.63 g, 12.1 mmol) and EDCI.HCl (2.32 g, 12.1 mmol). After stirring for 10 minutes, ammonium carbonate (4.65 g, 48.4 mmol) was added and the resulting solution was stirred overnight. The volatiles were removed in vacuo to yield a crude solid which was suspended in water (100 mL). The resulting suspension was sonicated for 10 minutes then the solid collected by filtration. The filter cake was washed with water (20 mL) and dried to yield the title compound (I29) (1.65 g 83%) as a brown solid; 1H NMR (400 MHz, CDCl3) δ 8.13 (t, J=1.6 Hz, 1H), 7.83 (ddd, J=7.9, 1.7, 1.1 Hz, 1H), 7.73 (ddd, J=7.8, 1.7, 1.1 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.18-5.49 (m, J=137.3 Hz, 2H). LCMS Method C: rt=5.04 min; m/z=248 [M+1]+.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:18][N:19]1[CH2:24][C:23](=[O:25])[N:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[C:29]([NH2:35])[CH:28]=2)[CH:21]([C:36]([O:38]C)=[O:37])[CH2:20]1)=O)(C)(C)C.C1COCC1.CO.O>CC(O)=O>[NH2:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[C:33]#[N:34])[CH2:26][N:22]1[C:23](=[O:25])[CH2:24][N:19]([CH2:18][C:9]2[NH:8][C:16]3[C:11]([CH:10]=2)=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=3)[CH2:20][CH:21]1[C:36]([OH:38])=[O:37]
Reactant: COC(=O)C1CN(Cc2cc3cc(Cl)ccc3n2C(=O)OC(C)(C)C)CC(=O)N1Cc1ccc(C#N)c(N)c1
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: N#Cc1ccc(CN2C(=O)CN(Cc3cc4cc(Cl)ccc4[nH]3)CC2C(=O)O)cc1N
Reaction time: 16 h
Yield: 47.7 %

Procedure:
LiOH monohydrate (380 mg, 9.06 mmol) is added at ambient temperature to a solution containing (±)-2-[4-(3-amino-4-cyano-benzyl)-3-methoxycarbonyl-5-oxo-piperazin-1-ylmethyl]-5-chloro-indole-1-carboxylic acid tert-butyl ester (1.0 g, 1.81 mmol), EXAMPLE 784, Part E, in 1:1:1 THF/MeOH/water (30 mL). After 16 h, HOAc (0.5 mL) is added and the reaction mixture is concentrated in vacuo. The residue is dissolved in CH3CN/water and purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 378 mg (48%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.03 (m, 1H), 3.48 (m, 1H), 3.51 (ABq, ΔAB=69.2 Hz, JAB=16.4 Hz, 2H), 3.78 (d, J=15.9 Hz, 1H), 4.05-4.09 (m, 2H), 5.04 (d, J=15.9 Hz, 1H), 6.41 (m, 2H), 6.58 (s, 1H), 7.04 (dd, J=8.6, 2.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.6 Hz, 1H), 7.51, d, J=2.0 Hz, 1H) ppm; MS (ISP loop): m/z 438 (M+H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17](Br)[CH:16]=1)[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]1[S:30][N:29]=[C:28]([CH3:31])[CH:27]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([NH:25][C:26]2[S:30][N:29]=[C:28]([CH3:31])[CH:27]=2)[CH:16]=1)[C:11]([NH2:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N)sn1
Reactant: N#Cc1ccc(N[C@H](COCc2ccccc2)C(N)=O)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N[C@H](COCc3ccccc3)C(N)=O)ccc2C#N)sn1
Reaction time: 18 h

Procedure:
A mixture of (R)-3-(benzyloxy)-2-(3-bromo-4-cyanophenylamino)propanamide (66 mg, 0.176 mmol), 5-amino-3-methylisothiazole hydrochloride (35 mg, 0.232 mmol), BINAP (20 mg, 0.032 mmol), Pd(OAc)2 (15 mg, 0.066 mmol) and K2CO3 (100 mg, 0.724 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 120 C for 18 h. Water and EtOAc were added. After being filtered, the organic phase was separated, dried over Na2SO4, concentrated in vacuo to give (R)-3-(benzyloxy)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)propanamide as a crude residue (73 mg).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:19])=[O:18])=[C:13]([F:20])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3].N([CH2:24][C@H]1OC(=O)N(C2C=CC(SCC)=C(F)C=2)C1)=[N+]=[N-].ClC1C=C(C=CC=1)C(OO)=O>>[N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH2:19][CH3:24])=[O:18])=[C:13]([F:20])[CH:12]=2)[CH2:6]1)=[N+:2]=[N-:3]
Reactant: CS(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Reactant: CCSc1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F
Agent: O=C(OO)c1cccc(Cl)c1
Product: CCS(=O)c1ccc(N2C[C@@H](CN=[N+]=[N-])OC2=O)cc1F

Procedure:
This compound was prepared analogously to the synthesis of 5-(S)-azidomethyl-3-[4′-methylsulfinyl-3′-fluorophenyl]oxazolidine-2-one from 5-(S)-azidomethyl-3-[4′-ethylthio-3′-fluorophenyl]oxazolidine-2-one (0.250 g, 0.844 mmol) and m-chloroperoxybenzoic acid (77%, 0.189 g, 0.844 mmol). Yield 0.235 g (89%). MS (m/z): [M+H]+=313.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([NH2:32])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH:33]([CH3:35])[CH3:34])[C:15]=2[N:16]=[CH:17][N:18]=1>N1C=CC=CC=1>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([NH:32][S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])(=[O:10])=[O:9])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH:33]([CH3:35])[CH3:34])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: COc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(N)n1
Solvent: c1ccncc1
Product: COc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(NS(=O)(=O)c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
2-Fluoro-benzenesulfonyl chloride (0.05 mL, 0.37 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-amino-6-methoxy-pyridin-4-yl)-methanone (100 mg, 0.31 mmol) in pyridine (2 mL) and stirred for 2 h at room temperature. The reaction mixture was quenched with H2O (100 mL) and extracted with hot EtOAC/MeOH (95:5 3×100 mL). The combined organic extracts were cooled to room temperature and the solid was filtered and dried to provide the title compound as a white solid (69 mg, 47%). MS: 485.3 (MH+); HPLC Rf: 2.7 min. (HPLC method 2); HPLC purity: 100%.
Reaction SMILES: [CH3:1][C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:3].[H-].[Na+].[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14].CCOCC>CN(C=O)C>[CH:4]1([C:2](=[O:3])/[CH:1]=[C:12](\[OH:18])/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(=O)C1CCCCC1
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)/C(O)=C/C(=O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 93.6 %

Procedure:
To a solution of cyclohexyl methyl ketone (10.4 g, 82.4 mmol) in DMF (90 ml) at rt, was added 60% NaH (3.96 g, 98.9 mmol). The mixture was stirred 45 min, cooled to 0° C., diethyl oxalate (13.4 ml, 98.9 mmol) was added and the temperature allowed to warm and stay at rt for 3 h. The reaction mixture was poured into Et2O, extracted with H2O (3×), and the aqueous phase was acidified with conc. HCl and extracted with EtOAc (3×). The organic extracts were washed with brine, dried (Na2SO4), and concentrated to afford 17.45 g (94%) of 9.1. MS (ESI) 225.2 (MH+).