Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH2:18])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([C@H:19]3[CH2:24][CH2:23][C@H:22]([N:25]4[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)[CH:10]=2)=[CH:5][CH:4]=1.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>N1C=CC=CC=1.ClCCl>[NH2:18][C:16]1[C:17]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:32](=[O:39])[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:8][CH:7]=3)=[CH:10][N:11]([C@H:19]3[CH2:24][CH2:23][C@H:22]([N:25]4[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]4)[CH2:21][CH2:20]3)[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(CN)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCN([C@H]2CC[C@H](n3cc(-c4ccc(CNC(=O)c5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of trans-5-[4-(aminomethyl)phenyl]-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (50 mg, 0.119 mmol) in pyridine (2 mL) and dichloromethane (2 mL) was cooled to 0° C. then treated with benzoyl chloride (19 mg, 0.13 mmol). The mixture was allowed to warm to ambient temperature and stirred for 1 hour. The solvents were removed under reduced pressure then the residue was purified by preparative reverse phase chromatography to give trans-N1-(4-{4-amino-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}benzyl)benzamide (50 mg) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.08(t, 1H), 8.13(s, 1H), 7.91(m, 2H), 7.4-7.54(m, 8H), 6.0(bs, 2H), 4.53(m, 3H), 2.30-2.40(m, 5H), 2.15(s, 3H), 1.85-1.89(m, 10H), 1.43-1.46 (m, 2H); RP-HPLC (Hypersil HS C18, 5μm, 100 A, 250×4.6 mm; 5%-50% acetonitrile over 25 min, 1 mL/min) tr 18.20 min.; MS:MH+ 524.3.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([NH:14][C:15](=[O:17])[CH3:16])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCCCCC.C(OCC)(=O)C>CN(C)C=O>[CH2:23]([O:12][C:11](=[O:13])[C@@H:10]([NH:14][C:15](=[O:17])[CH3:16])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a mixture of N-(t-butoxycarbonyl)-2(S)-acetylamino-β-alanine (3.0 g) in dimethylformamide (60 ml) was added NaHCO3 (2.05 g) at −2° C., and a solution of benzyl bromide in dimethylformamide (60 ml) was added by using a dropping funnel under stirring. The mixture was stirred overnight around 26° C., then poured into a mixture of ice-water (300 ml) and hexane-ethyl acetate (8:2, 500 ml). After the organic layer was separated, the aqueous layer was extracted again with hexane-ethyl acetate (8:2, 300 ml). The combined organic layer was washed with water (300 ml×2), brine (300 ml) and dried over Na2SO4, and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with hexane-ethyl acetate (8:2) to give N-(t-butoxycarbonyl)-2(S)-acetylamino-β-alanine benzyl ester (3.68 g).
Reaction SMILES: C(Cl)(Cl)[Cl:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15]2[N:20]=[C:19]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[CH:50]=[CH:49][C:32]([O:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]5)=[CH:31][CH:30]=4)[CH2:25][CH2:24]3)=[O:22])[CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14].[ClH:51].C(OCC)(=O)C>C(O)C>[OH2:6].[ClH:2].[ClH:51].[ClH:2].[ClH:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:15]2[N:20]=[C:19]([C:21]([N:23]3[CH2:24][CH2:25][N:26]([C:29]4[CH:50]=[CH:49][C:32]([O:33][CH2:34][CH2:35][N:36]5[CH2:37][CH2:38][NH:39][CH2:40][CH2:41]5)=[CH:31][CH:30]=4)[CH2:27][CH2:28]3)=[O:22])[CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: ClC(Cl)Cl
Reactant: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(OCCN5CCN(C(=O)OC(C)(C)C)CC5)cc4)CC3)n2)cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(OCCN5CCNCC5)cc4)CC3)n2)cc1OC
Product: O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a chloroform (3 ml) solution of t-butyl 4-[2-(4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenoxy)ethyl]piperazine-1-carboxylate was added 0.427 ml of a 4M hydrogen chloride/ethyl acetate solution, followed by 2 days of stirring at room temperature. Further, 2 ml of chloroform and 1 ml of a 4M hydrogen chloride/ethyl acetate solution were added thereto, and the whole was stirred at room temperature overnight. Ethanol was added to the reaction mixture and crude crystals were collected by filtration and recrystallized from methanol to obtain 114 mg of 1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-[4-(2-piperazin-1-ylethoxy)phenyl]piperazine tetrahydrochloride hydrate as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[O:16][C:15]2=[O:25])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl[C:27]1[N:36]=[C:35]2[C:30]([C:31](=[O:43])[C:32]([C:40]([OH:42])=[O:41])=[CH:33][N:34]2[CH:37]2[CH2:39][CH2:38]2)=[CH:29][C:28]=1[F:44]>>[CH:37]1([N:34]2[C:35]3[C:30](=[CH:29][C:28]([F:44])=[C:27]([N:11]4[CH2:12][CH2:13][N:8]([C:7]5[CH:6]=[CH:5][C:4]([N:14]6[CH2:18][C@H:17]([CH2:19][NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[O:16][C:15]6=[O:25])=[CH:3][C:2]=5[F:1])[CH2:9][CH2:10]4)[N:36]=3)[C:31](=[O:43])[C:32]([C:40]([OH:42])=[O:41])=[CH:33]2)[CH2:38][CH2:39]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: CS(=O)(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)c(F)c2)C(=O)O1
Product: CS(=O)(=O)NC[C@H]1CN(c2ccc(N3CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
This compound was synthesized in analogy to the procedure described in Example 10 using 0.082 g N-[(5R)-3-(3-fluoro-4-piperazin-1-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-methansulfonamide (0.22 mmol) and 0.067 g 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-[1,8]naphthyridine-3-carboxylic acid (0.22 mmol)
Reaction SMILES: C([O:5][C:6](=[O:40])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:32]2[N:37]=[CH:36][C:35]([CH2:38][CH3:39])=[CH:34][N:33]=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:22][CH:21]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH2:38]([C:35]1[CH:36]=[N:37][C:32]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:40])=[O:5])[S:12][CH:13]=2)=[N:33][CH:34]=1)[CH3:39]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(-c3cccnc3)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2ccc(-c3cccnc3)cc2)nc1

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)(4-pyridin-3-ylbenzyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 407-1 was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water:0.05% trifluoroacetic acid-acetonitrile=75:25 to 30:70) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH2:9])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>O1CCCC1>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:4]=1
Reactant: Nc1nccc(C(F)(F)F)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Nc1nccc(C(F)(F)F)n1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
According to the procedure described in Example 113B, to a solution of 4-(trifluoromethyl)pyrimidin-2-amine (500 mg, 3.1 mmoles) in 20 mL of tetrahydrofuran was added potassium carbonate (533 mg, 4 mmoles) followed by phenyl chloroformate (626 mg, 4 mmoles). The mixture was stirred at room temperature overnight. After 24 hours, and additional portion of phenyl chloroformate was added and the reaction heated to 60° C. for 3 days. This solution was concentrated to dryness and purified by silica chromatography (eluted with a gradient of 0-5% ethyl acetate/dichloromethane) to afford phenyl 4-(trifluoromethyl)pyrimidin-2-ylcarbamate. 1H NMR (300 MHz, DMSO-d6) δ 11.50 (s, 1H), 9.05 (s, 1H), 7.69 (m, 1H), 7.46 (m, 2H), 7.25 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]([F:29])([F:28])[F:27])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]4([C:23]#N)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)[C:6]=2[CH:25]=1.C[Mg]Br>O1CCCC1>[ClH:1].[Cl:1][C:2]1[C:3]([C:26]([F:27])([F:28])[F:29])=[CH:4][C:5]2[NH:9][C:8](=[O:10])[N:7]([CH:11]3[CH2:12][CH2:13][N:14]([C:17]4([CH3:23])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)[CH2:15][CH2:16]3)[C:6]=2[CH:25]=1
Reactant: N#CC1(N2CCC(n3c(=O)[nH]c4cc(C(F)(F)F)c(Cl)cc43)CC2)CCOCC1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(N2CCC(n3c(=O)[nH]c4cc(C(F)(F)F)c(Cl)cc43)CC2)CCOCC1
Product: Cl

Procedure:
A solution of 4-{4-[6-chloro-2-oxo-5-(trifluoromethyl)-2,3-dihydro-1H-benzimidazol-1-yl]-1-piperidinyl}tetrahydro-2H-pyran-4-carbonitrile (D65, 1160 mg, 0.37 mmol) in tetrahydrofuran (5 ml) was treated with methylmagnesium bromide (3M in diethyl ether, 1.0 ml, 3.0 mmol). After 2 h at room temperature the solution was partitioned between aqueous Rochelle salt solution and dichloromethane, and the organic layer was dried (MgSO4) and evaporated The residue was chromatographed on silica gel eluting with methanol-dichloromethane mixtures to afford the title compound, which was isolated as the hydrochloride salt triturated from diethyl ether (110 mg). MH+=418 and 420,
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].[O:8]=[C:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=2)[NH:10]1>C1COCC1>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[S:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:8])[CH2:17]2)(=[O:19])=[O:20]
Reactant: CNCCN(C)C
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: C1CCOC1
Product: CN(C)CCN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reaction time: 3 h

Procedure:
To a solution of N1,N1,N2-trimethylethane-1,2-diamine (26 uL, 0.20 mmol) in THF (2 mL) was added 2-oxoindoline-5-sulfonyl chloride (30 mg, 0.130 mmol) and the reaction stirred for 3 hours. The solvent was removed and the crude material used for the next step. MS ESI 298.0 [M+H]+, calcd for [C13H19N3O3S+H]+ 298.12.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH2:17][CH2:16][O:15][C:14](=[O:18])[CH:13]=2)=[C:6]2[C:10]=1[C@@H:9](O)CC2.O[C:20]1C=CC2[C@H](CC(OC)=O)COC=2C=1.Br[C:35]1[CH:43]=[CH:42][C:41]([F:44])=[C:40]2[C:36]=1[CH2:37][CH2:38][C@H:39]2[O:45][C:46]1[CH:59]=[CH:58][C:49]2[C@H:50]([CH2:53][C:54]([O:56][CH3:57])=[O:55])[CH2:51][O:52][C:48]=2[CH:47]=1>>[CH3:20][C:3]1[CH:4]=[C:5]([C:12]2[CH2:17][CH2:16][O:15][C:14](=[O:18])[CH:13]=2)[CH:6]=[C:10]([CH3:9])[C:2]=1[C:35]1[CH:43]=[CH:42][C:41]([F:44])=[C:40]2[C:36]=1[CH2:37][CH2:38][C@H:39]2[O:45][C:46]1[CH:59]=[CH:58][C:49]2[C@H:50]([CH2:53][C:54]([O:56][CH3:57])=[O:55])[CH2:51][O:52][C:48]=2[CH:47]=1
Reactant: O=C1C=C(c2ccc(F)c3c2CC[C@@H]3O)CCO1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(C6=CC(=O)OCC6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from (S)-4-(7-fluoro-1-hydroxy-2,3-dihydro-1H-inden-4-yl)-5,6-dihydro-2H-pyran-2-one and (S)-methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate following a procedure analogous to that described in Step 3 of Intermediate 1. LC (method 7): tR=1.18 min; Mass spectrum (ESI+): m/z=543 [M+H]+.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[Na].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[N:9]=1>C1COCC1.CCOC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: OC1CCC1
Reactant: Brc1cccc(Br)n1
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cccc(OC2CCC2)n1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To cyclobutanol (1 mL), was added sodium (36 mg, 1.56 mmol). When the sodium was consumed, the mixture was diluted with 1 mL THF and 2,6-dibromopyridine (250 mg, 1.06 mmol). The mixture was stirred at 90° C. for 3 h, then was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 106 mg of 158.1 as a colorless oil. LCMS (2 min gradient) RT=1.87 min, 228.17 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[F:29])[N:22]=[C:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:20]=1[CH3:36].[H-].[Na+]>CN(C=O)C>[CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][CH:9]=2)[N:4]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[F:29])[N:22]=[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:20]=2[CH3:36])[CH2:3]1
Reactant: CC1(C)CNc2cc(N3CCOCC3)ccc21
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CC(C)(C)c2ccc(N3CCOCC3)cc21
Temperature: 130 °C

Procedure:
Prepared according to procedure M using 3,3-dimethyl-6-morpholinoindoline (348 mg, 1496 μmol), 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (340 mg, 1247 μmol) in DMF (12 mL), and sodium hydride (72 mg, 2992 μmol) and heating at 130° C. overnight. After purification 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-indol-1-yl)-5-fluoro-3-methyl-2-(2-pyridinyl)quinoline was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.76 (1H, dd, J=3.5, 1.2 Hz), 8.02 (1H, d, J=8.2 Hz), 7.83-7.96 (2H, m), 7.60 (1H, td, J=8.1, 5.3 Hz), 7.40 (1H, ddd, J=7.0, 5.1, 2.0 Hz), 7.08-7.17 (1H, m), 7.04 (1H, d, J=8.2 Hz), 6.26 (1H, dd, J=8.0, 2.2 Hz), 5.50 (1H, d, J=2.3 Hz), 3.76-3.85 (1H, m), 3.60-3.76 (5H, m), 2.86-3.02 (4H, m), 2.42 (3H, s), 1.50 (3H, s), 1.44 (3H, s). Mass Spectrum (ESI) m/e=469 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21]4(C(O)=O)[CH:26]=[CH:25][CH:24]=[CH:23][NH:22]4)=[CH:19][C:12]=3[N:11]=2)=[CH:5][CH:4]=1)[CH3:2].[N:30]1([CH2:35][CH2:36][NH2:37])[CH2:34][CH2:33][CH2:32][CH2:31]1.CN([C:41]([O:45]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:14]([CH3:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21]4([CH:33]5[CH2:34][N:30]([CH2:35][CH2:36][NH:37][CH:41]=[O:45])[CH2:31][CH2:32]5)[CH:26]=[CH:25][CH:24]=[CH:23][NH:22]4)=[CH:19][C:12]=3[N:11]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NCCN1CCCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCc1ccc(Nc2nc3cc(OC4(C(=O)O)C=CC=CN4)ccc3n2C)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1ccc(Nc2nc3cc(OC4(C5CCN(CCNC=O)C5)C=CC=CN4)ccc3n2C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-(2-{[4-ethylpheylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid (1 eq) in tetrahydrofuran was added 2-pyrrolidinylethylamine (2 eq), HBTU (2 eq) and N,N-diisopropylethylamine (4 eq) and stir at ambient temperature for 16 h. The mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was concentrated and preparative chromatography yielded [4-(2-{[4-ethylphenyl]amino-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-(2-pyrrolidinyl-ethyl)carboxamide. MS: MH+=484.
Reaction SMILES: Br[C:2]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=2[CH3:20])=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.BrC1C(Br)=CSC=1C=O.OC1C=CC(B(O)O)=CC=1.[Cl:40][C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[C:43]([O:50][CH3:51])[CH:42]=1>CCOC(C)=O>[Cl:40][C:41]1[CH:46]=[CH:45][C:44]([C:2]2[C:3]([C:9]3[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=3[CH3:20])=[C:4]([CH:7]=[O:8])[S:5][CH:6]=2)=[C:43]([O:50][CH3:51])[CH:42]=1
Reactant: COc1cc(Cl)ccc1B(O)O
Reactant: Cc1cc(NS(C)(=O)=O)ccc1-c1c(Br)csc1C=O
Agent: O=Cc1scc(Br)c1Br
Agent: OB(O)c1ccc(O)cc1
Solvent: CCOC(C)=O
Product: COc1cc(Cl)ccc1-c1csc(C=O)c1-c1ccc(NS(C)(=O)=O)cc1C
Yield: 365.2 %

Procedure:
Followed the procedure described in General Scheme II, with modification. Step 1 was followed where the starting material was N-(4-(4-bromo-2-formylthiophen-3-yl)-3-methylphenyl)methanesulfonamide (Intermediate 4) instead of 3,4-dibromothiophene-2-carbaldehyde (Intermediate I), starting material 8A was 4-chloro-2-methoxyphenylboronic acid. After purification by column chromatography (PE:EtOAc=3:1) N-(4-(4-(4-chloro-2-methoxyphenyl)-2-formylthiophen-3-yl)-3-methylphenyl)methanesulfonamide (380 mg, yield 365.2%) was obtained. Step 3 of Scheme II was then followed with column conditions (PE: EtOAc=3:1) to afford (E)-ethyl 3-(4-(4-chloro-2-methoxyphenyl)-3-(2-methyl-4-(methylsulfonamido)phenyl)thiophen-2-yl)acrylate (280 mg, yield 63.4%). Step 4 of Scheme II gave 200 mg of product (yield 71%) followed by Step 5 (with purification by prep-HPLC) gave Example 10 (41.9 mg, 13% yield). 1H NMR (DMSO-d6 400 MHz): δ 9.73 (s, 1H), 7.38 (s, 1H), 6.93 (m, 4H), 6.90 (s, 1H), 6.86 (m, 1H), 3.5 (d, 3H), 2.95 (s, 1H), 2.75 (m, 2H), 7.01 (t, J=7.2 Hz, 2H), 1.82 (s, 3H); MS (ESI): m/z 502.0 [M+23]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=2)[C:5]([CH:22]=O)=[CH:4][CH:3]=1.Cl.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[C:30](=[NH:32])[NH2:31].O=[C:34]([CH3:41])[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:22]2[C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:34]([CH3:41])[NH:31][C:30]([C:26]3[S:25][CH:29]=[CH:28][N:27]=3)=[N:32]2)=[C:6]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:9]=2)[CH:7]=1
Reactant: N=C(N)c1nccs1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccc(F)cc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 25.8 %

Procedure:
5-fluoro-3′,5′-bis(trifluoromethyl)-[1,1′-biphenyl]-2-carbaldehyde (2.34 g, 6.96 mmol) was reacted with thiazole-2-carboximidamide hydrochloride (1.14 g, 6.96 mmol) and ethyl 3-oxobutanoate (1.1 g, 8.35 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (1 g, 26%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27]N)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:14]1([CH2:13][O:20][C:21]2[CH:26]=[CH:25][C:24]3[NH:27][C:2]4[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C:3]=4[C:23]=3[CH:22]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)N1CCc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Temperature: 0 °C
Yield: 63.3 %

Procedure:
A mixture of ethyl 4-oxo-1-piperidinecarboxylate (0.23 mol) and 4-(benzyloxy)-phenyl hydrazine (0.23 mol) in ethanol (400 ml) was stirred and refluxed for 5 hours. The reaction mixture was stirred overnight at room temperature. The solid was filtered off and washed on filter with H2O/2-propanol (200 ml). The precipitate was dissolved in CHCl3 (300 ml), washed with water (2×50 ml), dried, filtered and the solvent was evaporated. The residue was crystallized from CH3CN (300 ml) and cooled to 0° C. The resulting precipitate was filtered off and dried, yielding 51.0 g (63%) of ethyl 1,3,4,5-tetrahydro-8-(phenylmethoxy)-2H-pyrido[4,3-b]indole-2-carboxylate (intermediate 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1)=O.CN(C)CCN>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([NH:26][CH2:27][CH2:28][N:24]([CH3:25])[CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: CN(C)CCN
Solvent: C1CCOC1
Product: C[C@@H](C(=O)NCCN(C)C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo [4,5-b]pyridine-3-acetic acid (5.0 g, 0.0166 mole), 1,1'-carbonyldiimidazole (3.21 g, 0.0198 mole) in tetrahydrofuran (100 ml) was stirred at room temperature for two hours with nitrogen bubbling through it. A solution of N,N-dimethylethylenediamine (4.41 g, 0.050 mole) in tetrahydrofuran (5.5 ml) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The solvents were removed under reduced pressure and the solid was triturated in water (100 ml). The solid was collected by filtration, rinsed once with water, twice with 5% potassium hydroxide solution and twice with water. The solid was recrystallized from hot isopropyl ether to give 1.99 g (32%) of a solid. A 0.5-g sample was dried under high vacuum to give 0.49 g of title compound, mp 130°-133° C.