Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2.N1CCCCC1>C(O)C>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:25]3[C:24]4[C:28](=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=4)[NH:27][C:26]3=[O:31])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
A stirred solution of 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (74 mg, 0.237 mmol), 5-fluoro-1,3-dihydro-indol-2-one (40 mg, 0.267 mmol, commercially available from Aldrich) in 0.66 ml of ethanol was added dropwise with anhydrous piperidine (0.1 ml). The mixture was stirred at room temperature overnight. The resulting solid was filtered under reduced pressure, washed with anhydrous ethanol (1 ml×3), purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (60 mg, 54.8%) as a yellow solid
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:37])[N:24]=[CH:25][C:26]=3[CH:27]([CH3:29])[CH3:28])=[CH:16][C:15]=2[CH3:38])[CH:9]=[CH:10][C:11]=1[CH:12]=[O:13])[CH2:2][CH2:3][CH3:4].[O-:39]Cl=O.[Na+]>CC(O)(C)C.CC(=CC)C.O>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[N:23]([C:30]4[C:31]([Cl:37])=[CH:32][CH:33]=[CH:34][C:35]=4[Cl:36])[N:24]=[CH:25][C:26]=3[CH:27]([CH3:28])[CH3:29])=[CH:16][C:15]=2[CH3:38])[CH:9]=[CH:10][C:11]=1[C:12]([OH:39])=[O:13])[CH2:2][CH2:3][CH3:4]
Reactant: [O-][Cl+][O-]
Reactant: CCCCOc1cc(-c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)ccc1C=O
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCOc1cc(-c2ccc(OCc3c(C(C)C)cnn3-c3c(Cl)cccc3Cl)cc2C)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A solution of 3-butoxy-4′-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2′-methyl-biphenyl-4-carbaldehyde (0.125 g, 0.227 mmol) in t-BuOH (2.0 mL) and 2-methyl-2-butene (1.0 mL) at 0° C. is treated with a solution of NaClO2 (205 mg, 2.27 mmol) and NaH2PO4—H2O (313 mg, 2.27 mmol) in water (2.0 mL). The mixture is stirred at 0° C. for 60 minutes. The organic layer is separated, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified using silica gel chromatography eluting with 50%-100% ethyl acetate in hexanes to give the title compound (0.120 g, 93%). ES/MS m/e 566.8; 568.7 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:16][C:17]1[C:18](=[O:37])[N:19]([CH2:24][CH2:25][C@@:26]([CH3:36])([S:32]([CH3:35])(=[O:34])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[CH:21][C:22]=1I.O>O1CCOCC1.[Pd]>[F:16][C:17]1[C:18](=[O:37])[N:19]([CH2:24][CH2:25][C@@:26]([CH3:36])([S:32]([CH3:35])(=[O:33])=[O:34])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:20]=[CH:21][C:22]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)[C@@](C)(CCn1ccc(I)c(F)c1=O)S(C)(=O)=O
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@@](C)(CCn1ccc(-c2ccccc2)c(F)c1=O)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
Pd EnCat™ (172 mg, 0.067 mmol) was added to a mixture of potassium carbonate (298 mg, 2.16 mmol), phenylboronic acid (132 mg, 1.08 mmol), and ethyl (2R)-4-(3-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (288 mg, 0.647 mmol) in 1,4-dioxane:water (10 ml, 4:1) in a 20 ml vial. The vial was sealed and the reaction was heated to 80° C. and allowed to stir overnight at that temperature. The reaction was allowed to cool to RT, filtered and the catalyst was washed with methanol (20 mL) and dichloromethane (20 mL). The combined filtrates were concentrated and the crude product was purified via flash chromatography using an Analogix SF15-12g column and an eluant of ethyl acetate in heptane (60-100%) to afford the title compound as a white solid (131 mg, 51.2%). LC-MS m/z 396.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (t, J=7.12 Hz, 3H) 1.79 (s, 3H) 2.46-2.67 (m, 2H) 3.14 (s, 3H) 3.99-4.16 (m, 1H) 4.22-4.44 (m, 3H) 6.24-6.39 (m, 1H) 7.10-7.22 (m, 1H) 7.38-7.55 (m, 3H) 7.54-7.63 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:44])[CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([F:43])=[CH:16][C:17]2[N:21]=[C:20]([C:22]3[C:26]([NH:27][C:28]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:29])=[CH:25][N:24](C4CCCCO4)[N:23]=3)[NH:19][C:18]=2[CH:42]=1>ClCCl>[CH3:44][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([F:43])=[CH:16][C:17]2[N:21]=[C:20]([C:22]3[C:26]([NH:27][C:28]([N:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:29])=[CH:25][NH:24][N:23]=3)[NH:19][C:18]=2[CH:42]=1
Reactant: CN(C)CCCOc1cc2[nH]c(-c3nn(C4CCCCO4)cc3NC(=O)N3CCCCC3)nc2cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCOc1cc2[nH]c(-c3n[nH]cc3NC(=O)N3CCCCC3)nc2cc1F
Temperature: 22 °C
Reaction time: 16 h
Yield: 170.8 %

Procedure:
0.5 mL of trifluoroacetic acid is added to a solution of 28 mg of piperidine-1-carboxylic acid [3-[6-(3-dimethylaminopropoxy)-5-fluoro-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide in solution in 1.5 mL of dichloromethane. The reaction medium is stirred at 22° C. for 16 hours. The reaction medium is concentrated under reduced pressure in a rotary evaporator, taken up several times with isopropyl ether and concentrated under reduced pressure in a rotary evaporator each time. 40 mg of N-{3-[6-(3-dimethylaminopropoxy)-5-fluoro-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}piperidine-1-carboxamide are obtained in the form of trifluoroacetic acid salt. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.47 to 1.72 (m, 6H); 2.19 (m, 2H); 2.84 (s, 6H); 3.27 (m, 2H); 3.42 (m, 4H); 4.22 (t, J=6.0 Hz, 2H); 7.40 (d, J=7.5 Hz, 1H); 7.65 (d, J=10.0 Hz, 1H); 8.00 (s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[Si:19]([CH3:22])([CH3:21])[CH3:20].[B:23](OC)([O:26]C)[O:24]C>C1COCC1>[Cl:13][C:14]1[CH:18]=[C:17]([B:23]([OH:26])[OH:24])[S:16][C:15]=1[Si:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: C[Si](C)(C)c1sccc1Cl
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)c1sc(B(O)O)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of diisopropyl amine (1.8 ml, 13 mmol) at 0° C. in 50 mL anhdrous THF under nitrogen was added butyllithium, 2.5 M in hexanes (4.6 ml, 12 mmol). The solution was allowed to stir 5 min and then was cooled to −78° C. (3-Chlorothiophen-2-yl)trimethylsilane (2.0 g, 10 mmol) in 5 mL THF at RT was added slowly via cannula, dropwise, over about 10 min. The resulting solution was allowed to stir for 30 min, at which point trimethyl borate (2.4 ml, 21 mmol) was added dropwise. The solution was allowed to stir for 1 h, and was then warmed to 0° C. and quenched by the addition of 25 mL of 2NHCl, and warmed to ambient temperature with stirring. The mixture was extracted three times with DCM, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a semisolid. Purification by silica gel chromatography, (0-40% EtOAc/hexanes) provided 4-chloro-5-(trimethylsilyl)thiophen-2-ylboronic acid as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16]>>[C:11]1(=[O:16])[C:10]2[NH:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:15]=2[CH2:14][CH2:13][CH2:12]1
Reactant: O=C1CCCCC1=CO
Reactant: Nc1ccccc1
Product: O=C1CCCc2c1[nH]c1ccccc21

Procedure:
2,3,4,9-Tetrahydro-1H-carbazol-1-one was prepared from aniline (2.9 g, 31 mmol) and 2-(hydroxymethylene)cyclohexanone (3.5 g, 28 mmol) in a similar manner as described above to give 2.5 g (49%). of a brown solid. 1H-NMR (DMSO-d6): δ 11.6 (s, 1H), 7.66 (d, 1H), 7.38 (d, 1H), 7.30 (t, 1H), 7.07 (t, 1H), 2.90 (t, 2H), 2.56 (t, 2H), 2.15 (m, 2H); MS m/z 186 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=O)[CH3:11].[N-:13]=[N+:14]=[N-:15].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]([CH3:11])=[N:15][N:14]=[N:13]1
Reactant: CC(=O)Nc1ccc(I)cc1F
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Product: Cc1nnnn1-c1ccc(I)cc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
A suspension of N-(2-fluoro-4-iodo-phenyl)-acetamide (5 g, 18.24 mmol) in acetoritrile (100 mL) was cooled to 0° C. and then treated with sodium azide (3.56 g, 54.7 mmol). The reaction mixture was then treated with trifluoromethanesulfonic anhydride (13.6 g, 48 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred overnight, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The resulting residue was diluted with ethyl acetate (100 mL) and water (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 4/1 hexanes/ethyl acetate) afforded 1-(2-fluoro-4-iodo-phenyl)-5-methyl-1H-tetrazole (3.45 g, 62%) as a white solid: mp 122-124° C.; EI-HRMS m/e calcd for C8H6FIN4 (M+) 303.9621, found 303.9615.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19](=[O:27])[CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13]1)[CH:6]=[CH:5]2.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3]([NH:18][C:19](=[O:27])[CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([O:17][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@H](O)C3)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reaction time: 12 h

Procedure:
To a stirred solution of N-[6-chloro-2-[(3S)-3-hydroxy-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 29) (0.4 g) in dichloromethane was added methanesulphonyl chloride (0.104 mL) and triethylamine (0.215 mL). The reaction was stirred for 12 hours under nitrogen and then purified (Varian Chem elute cartridge, saturated sodium hydrogen carbonate solution and dichloromethane as eluant) to afford the sub-title compound (0.45 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[CH:26]=[C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=5)[S:28][C:21]=34)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1>>[NH:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[CH:26]=[C:27]([C:29]5[CH:36]=[CH:35][C:32]([CH2:33][NH:9][CH2:8][CH2:7][N:1]6[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]6)=[CH:31][CH:30]=5)[S:28][C:21]=34)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1
Reactant: O=Cc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: NCCN1CCNCC1
Product: c1cc(Nc2ccc3[nH]ccc3c2)c2sc(-c3ccc(CNCCN4CCNCC4)cc3)cc2n1

Procedure:
The title compound was prepared from 2-piperazin-1-yl-ethylamine and 4-[7-(1H-indol-5-ylamino)-thieno(3,2-b]pyridin-2-yl]-benzaldehyde by a procedure analogous to example 17. LC-MS: 483 (MH+); HPLC RT: 3.41 minutes.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][N:19]([C:23]5[C:32]6[C:27](=[CH:28][C:29]([OH:33])=[CH:30][CH:31]=6)[N:26]=[C:25]([CH3:34])[N:24]=5)[CH2:18][C:17]=4[CH:35]=3)[CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:2].[CH2:36](I)[CH3:37]>>[CH2:1]([NH:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]4[O:22][CH2:21][CH2:20][N:19]([C:23]5[C:32]6[C:27](=[CH:28][C:29]([O:33][CH2:36][CH3:37])=[CH:30][CH:31]=6)[N:26]=[C:25]([CH3:34])[N:24]=5)[CH2:18][C:17]=4[CH:35]=3)[CH:11]=[CH:12][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCI
Reactant: CCNc1nc2ccc(-c3ccc4c(c3)CN(c3nc(C)nc5cc(O)ccc35)CCO4)cc2[nH]1
Product: CCNc1nc2ccc(-c3ccc4c(c3)CN(c3nc(C)nc5cc(OCC)ccc35)CCO4)cc2[nH]1

Procedure:
Prepared according to the method of example 10 using 4-{7-[2-(ethylamino)-1H-benzimidazol-6-yl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl}-2-methylquinazolin-7-ol (example 11) and ethyl iodide in step 2. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 7.91-7.82 (m, 1H), 7.63 (dd, 1H), 7.52-7.36 (m, 2H), 7.26-7.13 (m, 2H), 6.99 (dd, 1H), 6.94-6.86 (m, 2H), 6.70 (q, 1H), 4.96 (s, 2H), 4.45-4.35 (m, 2H), 4.16-3.98 (m, 4H), 3.46-3.36 (m, 2H), 2.44-2.37 (m, 3H), 1.28-1.17 (m, 6H); MS (EI) for C29H30N6O2: 495 (MH+).
Reaction SMILES: IC.[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([OH:27])=[O:26])[CH:23]=3)[NH:18][CH:17]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:28](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH:12]=[C:13]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=3)[NH:18][CH:17]=2)[CH2:14][CH2:15]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(C(=O)O)cc23)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc2[nH]cc(C3=CCN(C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
Iodomethane (1.22 mL, 19.63 mmol) was added in one portion to 3-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole-5-carboxylic acid (6.72 g, 19.63 mmol) and potassium carbonate (3.26 g, 23.55 mmol) in DMF (60 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 3 hours then quenched in water (200 mL) and extracted with MTBE (2×100 mL). The extract was washed sequentially with water (3×100 mL) and saturated brine, dried over MgSO4 and concentrated by evaporation then purified by flash silica chromatography, elution gradient 20 to 35% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 3-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1H-indole-5-carboxylate (5.09 g, 73%) as a colourless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[CH:8]=2)[CH:6]=1.[BH4-].[Na+]>CO.C1COCC1.Cl[Ni]Cl>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[S:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH:8]=2)[CH:6]=1
Reactant: Cc1cnn(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4)c3s2)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cnn(-c2cc3nccc(Oc4ccc(N)cc4)c3s2)c1
Reaction time: 0.17 h
Yield: 87.3 %

Procedure:
To a solution of 256 (168.4 mg, 0.478 mmol) and NiCl2×6H2O (226 mg, 0.956 mmol) in MeOH/THF (10/10 mL) NaBH4 (72 mg, 1.92 mmol) was carefully added. The reaction mixture was stirred for 10 min, concentrated to dryness and the resultant solid was suspended in 10% HCl. The aqueous solution was basified (pH ˜11) with concentrated aqueous NH4OH and extracted with EtOAc. The organic extract was collected, dried over anhydrous Na2SO4 and concentrated under reduced pressure, to afford title compound 257 (134.6 mg, 87% yield) as a white solid. MS (m/z): 322.09 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CCN(CC)CC.[C:33]1([CH3:63])[CH:38]=[CH:37][C:36]([S:39]([CH2:42][CH2:43][O:44][C:45](=[O:62])[CH2:46][O:47][C:48]2[CH:53]=[C:52]([CH3:54])[C:51]([S:55](Cl)(=[O:57])=[O:56])=[C:50]([CH:59]([CH3:61])[CH3:60])[CH:49]=2)(=[O:41])=[O:40])=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:33]1([CH3:63])[CH:38]=[CH:37][C:36]([S:39]([CH2:42][CH2:43][O:44][C:45](=[O:62])[CH2:46][O:47][C:48]2[CH:53]=[C:52]([CH3:54])[C:51]([S:55]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:3]3[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:13])([F:11])[F:12])[CH:6]=[CH:5][N:4]=3)=[O:16])(=[O:56])=[O:57])=[C:50]([CH:59]([CH3:60])[CH3:61])[CH:49]=2)(=[O:40])=[O:41])=[CH:35][CH:34]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)c(S(=O)(=O)Cl)c(C(C)C)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)CCOC(=O)COc2cc(C)c(S(=O)(=O)n3c(S(=O)Cc4nccc(OCC(F)(F)F)c4C)nc4ccccc43)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a heterogeneous solution of 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl]-1H-benzimidazole (LANSOPRAZOLE 1.0 g, 2.71 mmol) and 2 mL of Et3N in 20 mL of CH2Cl2 was added 4-chlorosulfonyl-3-isopropyl-5-methylphenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester the (Intermediate 65, 1.6 g, 3.25 mmol, 1.2 eq). About 1 g of solid NaHCO3 was added after the chlorosulfonyl ester has dissolved completely in the reaction mixture. The mixture was stirred at room temperature for 2 h. Thereafter the solvent was removed by evaporation and the residual oil was purified by column chromatography (silica gel, CH2Cl2 to 1% MeOH in CH2Cl2) to give 4-[2-{3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl-methanesulfinyl}-benzimidazole-1-sulfonyl]-3-isopropyl-5-methylphenoxyacetic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 68, 1.76 g, 79%) as a white foam.
Reaction SMILES: [CH3:1][CH:2]=[CH:3][C:4](Cl)=[O:5].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>>[O:5]=[C:4]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH:3]=[CH:2][CH3:1]
Reactant: CC=CC(=O)Cl
Reactant: C1CCNC1
Product: CC=CC(=O)N1CCCC1

Procedure:
3-Methylacryloyl chloride was reacted with pyrrolidine by the method of Example 14 to give the title amide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:9])[CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(C2CO2)c1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(OCC(O)c2cccc(F)c2)cc1
Temperature: 78 °C
Yield: 16.9 %

Procedure:
To a stirring solution of 2-(3-fluorophenyl)oxirane (5.60 g, 40.5 mmol) in toluene (65 ml) was added 4-hydroxybenzaldehyde (7.40 g, 61.0 mmol), 1M NaOH (65 ml) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78° C. overnight. The reaction mixture was allowed to cool to RT and then extracted with EtOAc (2×150 ml). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light brown oil was chromatographed eluting with 30-40% EtOAc/hexanes. There are 2 major spots. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.78 g (17%) of the title compound as a white solid. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 0.90 g (9%) of the regioisomer as a nearly colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]([C:30]3[N:31]=[CH:32][C:33]4[C:38]([C:39]=3[CH3:40])=[CH:37][CH:36]=[CH:35][CH:34]=4)[S:16]([C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][N:15]([C:30]3[N:31]=[CH:32][C:33]4[C:38]([C:39]=3[CH3:40])=[CH:37][CH:36]=[CH:35][CH:34]=4)[S:16]([C:19]3[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(-c3ccc(F)cc3)cc2)c2ncc3ccccc3c2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(N(Cc2ccc(-c3ccc(F)cc3)cc2)S(=O)(=O)c2ccc(C(=O)O)cc2)ncc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A suspension of ethyl 4-{[[(4′-fluorobiphenyl-4-yl)methyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoate (88.0 mg, 0.16 mmol) prepared in Example 7 and 1 mol/L aqueous sodium hydroxide solution (320 μl, 0.32 mmol) in methanol (1.6 ml) was stirred at room temperature overnight, and then to the reaction solution was added 2 mol/L hydrochloric acid solution (400 μl). The mixture was extracted with chloroform twice. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=10:0→9:1) to give 4-{[[(4′-fluorobiphenyl-4-yl)methyl](4-methylisoquinolin-3-yl)amino]sulfonyl}benzoic acid (62.1 mg, 74%) as a colorless powder.
Reaction SMILES: S([CH2:11][CH:12]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13](=[CH2:19])[CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[CH2:43][NH:42][CH2:41][CH2:40]2>O>[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[CH2:43][N:42]([CH2:11][CH:12]([C:13]([CH2:14][Si:15]([CH3:16])([CH3:18])[CH3:17])=[CH2:19])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH2:41][CH2:40]2
Reactant: C=C(C[Si](C)(C)C)C(CC(C)C)CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C[Si](C)(C)C)C(CC(C)C)CN1CCc2cc(OC)c(OC)cc2C1
Temperature: 80 °C
Reaction time: 30 h
Yield: 70.1 %

Procedure:
(3-(tosylmethyl)-5-methyl-2-methylenehexyl)trimethylsilane (Formula 4; 72.0 mg, 0.195 mmol) and Na2CO3 (41.4 mg, 0.391 mmol) were added to DMF (2 mL). Then, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (Formula 3; 75.4 mg, 0.391 mmol) was added thereto, and the mixture was heated up to 80° C. and stirred for 30 hr. Distilled water was put into the reaction solution to complete the reaction, and then the temperature was increased to normal temperature. An organic layer was extracted, the organic layer collected was washed with distilled water and a brine solution, and the remaining solvent was distilled under reduced pressure. Anhydrous magnesium sulfate was used to dry the organic layer, filtration under reduced pressure and evaporation under reduced pressure were performed, and then column chromatography was used to obtain 53.3 mg (yield 75%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:29][CH3:30])[C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10]C23C=CC=CC2C(NC3=O)=O)=[C:6]([O:24][CH3:25])[C:5]=1[N+:26]([O-:28])=[O:27].O.[NH2:32]N.O>C(O)C>[CH3:1][O:2][CH:3]([O:29][CH3:30])[C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][NH2:32])=[C:6]([O:24][CH3:25])[C:5]=1[N+:26]([O-:28])=[O:27]
Reactant: NN
Reactant: COc1c(OCCC23C=CC=CC2C(=O)NC3=O)ccc(C(OC)OC)c1[N+](=O)[O-]
Solvent: CCO
Solvent: O
Product: COc1c(OCCN)ccc(C(OC)OC)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 116.4 %

Procedure:
A solution of 2-[2-(4-dimethoxymethyl-2-methoxy-3-nitrophenoxy)ethyl]phtalimide (0.05 g, 0.12 mmol) obtained in Step 2 in ethanol (1.0 mL) was added with hydrazine monohydrate (6.4 μL, 0.13 mmol) and heated under reflux for 3 hours. The reaction mixture was cooled to room temperature and added with water, followed by extracting with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain 2-(4-dimethoxymethyl-2-methoxy-3-nitrophenoxy)ethylamine (0.04 g, 100%).