Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH3:10])[C:6]=2[CH:11]=1.CN(C)[C:15]1[O:16][C:17](=[O:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=1>C(O)(=O)C>[F:12][C:3]1[C:2]([N:1]2[C:17](=[O:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[NH:20][C:15]2=[O:16])=[CH:11][C:6]2[C:7]([CH3:10])=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: CN(C)c1nc(C(F)(F)F)cc(=O)o1
Reactant: Cc1noc2cc(F)c(N)cc12
Solvent: CC(=O)O
Product: Cc1noc2cc(F)c(-n3c(=O)cc(C(F)(F)F)[nH]c3=O)cc12
Temperature: 25 °C
Yield: 73.3 %

Procedure:
A mixture of 5-amino-6-fluoro-3-methyl-1,2-benzisoxazole (4.85 g, 0.029 mol) and 2-dimethylamino-4-(trifluoromethyl)-6H-1,3-oxazin-6-one (6.70 g, 0.0320 mol) in acetic acid is refluxed for 90 minutes, cooled to room temperature, and poured into an ice-water mixture. The resultant aqueous mixture is filtered to obtain a solid. The solid is air-dried and dissolved in ethyl acetate. The resultant organic solution is washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a yellow solid (7.00 g, mp 235-237° C.) which is identified by NMR spectral analyses.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2([CH2:27][NH:28][C:9](=[O:11])[CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: O=C(O)CCc1ccccc1
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CNC(=O)CCc3ccccc3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 25.9 %

Procedure:
3-Phenyl-propionic acid (30.0 mg, 0.200 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (47.1 g, 0.200 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (83.6 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (76.0 mg, 0.200 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (19.0 mg, 0.0517 mmol, 25.8%) ESI-MS m/z calc. 367.2, found 367.5 (M+1)+. Retention time of 3.05 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Fc1ccc(C2NCCc3ccccc32)cc1F
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)N1CCc2ccccc2C1c1ccc(F)c(F)c1
Reaction time: 1 h

Procedure:
To a stirred solution of 1-(3,4-difluorophenyl)-1,2,3,4-tetrahydroisoquinoline (0.1019 g, 0.415 mmol) in 3 mL of DCM, 4-fluorophenyl isocyanate (0.0550 mL, 0.484 mmol) was added. The clear solution was stirred for 1 h. The solvent was evaporated and residue was taken into small amount of DCM. The resulting precipitate was collected to yield the title compound as a white solid. The filtrate was concentrated and purified by silica gel chromatography (0-30% EtOAc in hexanes) to afford another batch of the title compound as a white solid. MS (ESI pos. ion) m/z: 383 (M+1). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.16-7.37 (m, 6H) 6.93-7.13 (m, 5H) 6.54 (s, 1H) 6.40 (s, 1H) 3.66 (t, J=6.28 Hz, 2H) 2.77-3.08 (m, 2H).
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[C:28]([CH3:31])=[N:27][CH:26]=3)=[O:24])[CH:21]=2)[N:16]=[C:15]([CH2:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1>O1CCCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[C:28]([CH3:31])=[N:27][CH:26]=3)([C:11]3[N:7]([CH3:6])[N:8]=[N:9][CH:10]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([CH2:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=1
Reactant: CCc1nc2ccc(C(=O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1nc2ccc(C(O)(c3cnnn3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of n-butyllithium in hexanes (2.5 M, 0.17 mL, 0.43 mmol) was added dropwise to a stirring solution of 1-methyl-1H-1,2,3-triazole (38.3 mg, 0.461 mmol, prepared according to PCT Int. Appl., 2008098104) in tetrahydrofuran (1.5 mL) at −50° C. After 20 minutes at −50° C., a solution of (4-chloro-2-ethyl-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1,2-dimethyl-1H-imidazol-5-yl)methanone (0.145 g, 0.307 mmol, Intermediate 25: step b) in tetrahydrofuran (1.5 mL) was added dropwise. After 5 minutes at −50° C., the flask was allowed to warm to 0° C. After 30 minutes, the mixture was partitioned between half-saturated aqueous sodium chloride solution (25 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was dried with sodium sulfate. The dried solution was filtered. Silica gel (3 g) was added to the filtrate and the mixture was concentrated by rotary evaporation to afford a free-flowing powder. The powder was loaded onto a silica gel column for flash column chromatography purification. Elution with dichloromethane initially, grading to 10% methanol-dichloromethane provided the title compound as an off-white solid. The solid was further purified by chiral SFC (Chiralpak AD-H, 5 μm, 250×20 mm, mobile phase: 75% CO2, 25% ethanol containing 0.03% isopropylamine) to provide two enantiomers. The first eluting enantiomer was Example 25b: 1H NMR (600 MHz, CDCl3) δ ppm 8.30 (d, J=2.1 Hz, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.57-7.49 (m, 3H), 7.21 (d, J=7.9 Hz, 2H), 7.17 (s, 1H), 6.18 (s, 1H), 4.91 (s, 1H), 4.49 (s, 2H), 3.95 (s, 3H), 3.40 (s, 3H), 3.00-2.90 (m, 2H), 2.30 (s, 3H), 1.35-1.28 (m, 3H); MS (ESI): mass calcd. for C28H26ClF3N6O, 554.2. m/z found, 555.2 [M+H]+. and the second eluting enantiomer was Example 25c: 1H NMR (600 MHz, CDCl3) δ ppm 8.32 (d, J=2.1 Hz, 1H), 7.99 (d, J=8.8 Hz, 1H), 7.56-7.51 (m, 3H), 7.21 (d, J=7.9 Hz, 2H), 7.12 (s, 1H), 6.14 (s, 1H), 5.83 (s, 1H), 4.48 (s, 2H), 3.93 (s, 3H), 3.38 (s, 3H), 2.98-2.90 (m, 2H), 2.24 (s, 3H), 1.34-1.27 (m, 3H); MS (ESI): mass calcd. for C28H26ClF3N6O, 554.2. m/z found, 555.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[N:23]1([CH2:32][C:33](O)=[O:34])[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]1=[O:25].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:33](=[O:34])[CH2:32][N:23]1[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]1=[O:25])[CH3:2]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Reaction time: 5 h
Yield: 75 %

Procedure:
To the mixture of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol), (thymin-1-yl)-acetic acid (0.92 g, 5 mmol), HOBt (0.81 g, 6 mmol), and DCC (1.24 g, 6 mmol) in DMF (15 mL) was added N,N-diisopropylethylamine (1.31 mL, 7.5 mmol) at ambient temperature. The resulting reaction mixture was stirred for 5 h at the same temperature and the, solvent was removed in vacuo to 5 mL. The residue was dissolved in dichloromethane (50 mL) and the precipitate was filtered. The filtrate was washed with 1N HCl aqueous solution, saturated sodium bicarbonate solution, and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and the residue was triturated with ethyl alcohol. The resulting solid was filtered off and dried in vacuo to give the title compound (1.91 g, 75%) as a white solid. 1H NMR (500 MHz; DMSO-d6) δ 11.29 (s, 0.6H), 11.28(s, 0.4H), 8.99(brs, 0.6H), 8.82(brs, 0.4H), 8.28(m, 1H) 8.18(d, 1H) 7.66(m, 2H) 7.31(s, 0.6H) 7.42(s, 0.4H) 4.66(s, 1.2H) 4.47(s, 0.8H) 4.31(s, 0.8H), 4.05(s, 1.2H), 4.04(q, 1.2H), 3.55(t, 1.2H), 3.40˜3.34(m, 2.8H), 3.20(t, 0.8H), 1.73(s, 3H), 1.19(t, 1.2H), 1.14(t, 1.8H).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:9]=[C:10]([CH3:20])[N:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH:12]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:11]2[CH:12]=[C:8]([CH2:7][OH:6])[N:9]=[C:10]2[CH3:20])=[CH:18][CH:17]=1
Reactant: Cc1nc(C(C)(C)O[SiH2]C(C)(C)C)cn1-c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(CO)cn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole (14.7 g, 45.7 mmol) was dissolved in 200 mL THF. Tetrabutyl ammoniumfluoride (91 mL, 1M in THF, 91 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 200 mL water and extracted three times with ethyl acetate (200 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was suspended in 150 mL ethyl acetate, filtered and dried. The desired compound was obtained as a white solid (7.16 g, 76%), MS: m/e=207.1 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([OH:12])[CH:5]=1)[CH3:2].N1C=CC=CC=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.C(OCC)(=O)C>[C:21]([O:12][C:6]1[CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH2:13][CH3:14])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CC)c1ccc(C=O)c(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of 4-diethylamino-2-hydroxybenzaldehyde (300 mg, 1.55 mmol), pyridine (0.19 mL, 2.3 mmol) in 1.6 mL of dry dichloromethane was added benzoyl chloride (216 μL, 1.84 mmol) at 0° C. After being stirred at room temperature overnight, the reaction mixture was diluted with ethyl acetate. The mixture was washed with 1N HCl, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain the title compound as a white solid (432 mg, 94%).
Reaction SMILES: [S:1]1[C:5]([NH2:6])=[CH:4][N:3]=[N:2]1.N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15].O>O1CCCC1>[S:1]1[C:5]([NH:6][C:14](=[O:15])[O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[CH:4][N:3]=[N:2]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1cnns1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cnns1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,2,3-thiadiazol-5-amine and pyridine (0.129 ml, 4.00 mmol) in tetrahydrofuran (4.5 ml) was added 2,2,2-trichloroethyl chloroformate (0.220 ml, 2.00 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and 190 mg (51.6%) of the desired product was collected by filtration as a solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11](Cl)(=[O:13])=[O:12])(=[O:4])=[O:3].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([CH:23]=1)[OH:22]>>[CH3:15][O:16][C:17]1[CH:23]=[C:21]([O:22][S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([CH3:1])(=[O:4])=[O:3])(=[O:13])=[O:12])[CH:20]=[C:19]([OH:24])[CH:18]=1
Reactant: COc1cc(O)cc(O)c1
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Product: COc1cc(O)cc(OS(=O)(=O)c2ccccc2S(C)(=O)=O)c1
Yield: 80 %

Procedure:
The title compound was prepared in 80% yield from 2-methylsulfonylbenzenesulfonyl chloride and 5-methoxyresorcinol in a manner analogous to step a of Example 1. 1H-NMR (300 MHz, CDCl3) δ8.42 (d, J=7.8 Hz, 1H), 8.13 (d, J=7.8 Hz, 1H), 7.88 (t, J=7.8 Hz, 1H), 7.75 (t, J=7.7 Hz, 1H), 6.36 (s, 1H), 6.31 (s, 1H), 6.28 (s, 1H), 3.68 (s, 3H), 3.45 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][CH:35]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][CH:13]1[CH2:16][N:15]([CH:17]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30](O)=[O:31])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[CH2:14]1)=[O:11])=[O:7].CC[N:40]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.N>C(Cl)Cl.O1CCOCC1>[C:30]([CH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH:20]2[CH2:21][CH2:22][CH:17]([N:15]3[CH2:16][CH:13]([NH:12][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]4[CH:33]=[CH:34][CH:35]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:4]=4)=[O:11])[CH2:14]3)[CH2:18][CH2:19]2)=[CH:28][CH:27]=1)(=[O:31])[NH2:40]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)Cc1ccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cc1

Procedure:
A solution of [4-(4-{3-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-azetidin-1-yl}-cyclohexyl)-phenyl]-acetic acid (as prepared in Example 25, 450 mg, 0.87 mmol), EDCI (240 mg, 1.25 mmol), HOBT (130 mg, 0.96 mmol) and TEA (610 μL, 4.35 mmol) in DCM (10 mL) was treated with 2N NH3 in dioxane (5 mL) at room temperature overnight. The solvent was removed in vacuo and the residue was purified by a CombiFlash® system using ethyl acetate and 7N NH3 in MeOH as eluent (from pure ethyl acetate to 5% 7N NH3 in MeOH in ethyl acetate) to afford the two title compound as white solids.
Reaction SMILES: [Cl:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]2[N:6]=[C:7]([C:9]3[N:10](S(C4C=CC(C)=CC=4)(=O)=O)[C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([CH:18]=[O:19])=[CH:13][CH:12]=4)[NH:8][C:4]=2[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:42][O:43][CH2:44]Cl.O>CN(C)C=O>[Cl:32][C:31]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:42][O:43][CH3:44])[C:7]([C:9]3[NH:10][C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([CH:18]=[O:19])=[CH:13][CH:12]=4)=[N:6][C:5]=2[CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3nc4cc(Cl)c(Cl)cc4[nH]3)cc3cc(C=O)ccc32)cc1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COCn1c(-c2cc3cc(C=O)ccc3[nH]2)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.1 %

Procedure:
To a solution of 5,6-dichloro-2-[5-formyl-1-(4-methylphenyl)sulfonylindol-2-yl]benzimidazole obtained in Example 45 (824 mg, 1.71 mmol) in dimethylformamide (10 mL) were added diisopropylethylamine (0.59 mL, 3.4 mmol) and chloromethyl methyl ether (0.16 mL, 2.1 mmol), and the mixture was stirred at room temperature for 15 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue were added methanol (80 mL) and 2 mol/L sodium hydroxide (5 mL), and the mixture was heated to reflux for 1 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was triturated with ether to afford 5,6-dichloro-2-[5-formylindol-2-yl]-1-(methoxymethyl)benzimidazole (570 mg, 89%).
Reaction SMILES: COC1C=CC([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]([NH:23][C:24](=[O:37])[C@H:25]([CH2:33][CH:34]([CH3:36])[CH3:35])[C@H:26]([CH2:30][CH2:31][CH3:32])[C:27]([NH2:29])=[O:28])[C:17]3=[O:38])[CH:14]=2)=CC=1.[F:39][C:40]([F:51])([F:50])[C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1>>[F:39][C:40]([F:51])([F:50])[C:41]1[CH:46]=[CH:45][C:44]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH2:15][N:16]3[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]([NH:23][C:24](=[O:37])[C@H:25]([CH2:33][CH:34]([CH3:35])[CH3:36])[C@H:26]([CH2:30][CH2:31][CH3:32])[C:27]([NH2:29])=[O:28])[C:17]3=[O:38])[CH:14]=2)=[CH:43][CH:42]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCC[C@H](C(N)=O)[C@@H](CC(C)C)C(=O)N[C@H]1CCCCN(Cc2cncc(-c3ccc(OC)cc3)c2)C1=O
Product: CCC[C@H](C(N)=O)[C@@H](CC(C)C)C(=O)N[C@H]1CCCCN(Cc2cncc(-c3ccc(C(F)(F)F)cc3)c2)C1=O

Procedure:
The general procedure reported for the compound of Example 30 was followed using 4-trifluoromethylphenyl boronic acid. Purification by HPLC afforded 6.0 mg of the desired product from as its trifluoroacetic acid salt. MS (M+Na)+=583.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11]Cl)[CH:3]=1.[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:9][CH2:10][CH2:11][N:27]1[CH2:28][CH2:29][CH:24]([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=2)[CH2:25][CH2:26]1
Reactant: ClCCCOc1cccc(Br)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3cccc(Br)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-bromo-3-(3-chloropropoxy)benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 459.1 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:13][CH2:12][CH2:11][CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN1C(=O)CCC1>[C:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:12][CH2:11][CH2:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cc3c(nc2-c2ccccc2)NCCC3)cc1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCCCCN1CCCc2cc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 140 °C
Reaction time: 3 h

Procedure:
A solution of 6,7-diphenyl-1,2,3,4-tetrahydro-[1,8]naphthyridine (Intermediate B) (200 mg, 0.698 mmol) in dry NMP (1 ml) under N2 was treated with cesium carbonate (910 mg, 2.79 mmol) and ethyl 7-bromoheptanoate (0.544 ml, 2.79 mmol). The reaction mixture was stirred at 120° C. for 1 h and a further 3 h at 140° C. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic portion was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 4:1 iso-hexane/EtOAc afforded a pink oil residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:22])[NH:10][CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1.[OH-:23].[Na+].[CH2:25]=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:22])[N:10]([CH2:25][OH:23])[CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:6][CH:7]=1
Reactant: C=O
Reactant: [OH-]
Reactant: O=c1[nH]cc2c(c1-c1ccc(Cl)cc1)Nc1ccccc1S2
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccccc1N2
Yield: 93 %

Procedure:
To 5.0 g. of 4-(4-chlorophenyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3-(2H)-one (15.3 mmol.) in 50 ml. of dimethylformamide was added 30 ml. of a 5% sodium hydroxide solution (37.5 mmol.), and the resulting suspension was heated on a steam bath until a solution formed. To the solution was then added 50 ml. of a 36% formaldehyde solution (60.0 mmol.), and the resulting reaction mixture was heated until a yellow precipitate formed. The hot reaction mixture was filtered, and the precipitate was washed well with water and dried under high vacuum at room temperature to yield 4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one complexed with water (4:1) as a yellow powder (5.15 g.; 93% yield) having the structural formula, ##STR9## a melting point of greater than 300° C. and the following elemental analysis:
Reaction SMILES: C(S[C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:16]2=[O:19])=[CH:11][C:10]=1[O:29][C@@H:30]1[CH2:35][CH2:34][C@H:33]([NH:36][C:37](=[O:39])[CH3:38])[CH2:32][CH2:31]1)C1C=CC=CC=1.C(O)(=O)C.O.[S:45]([Cl:49])(Cl)(=[O:47])=[O:46].[Cl:50]CCl>C(OCC)(=O)C>[C:37]([NH:36][C@@H:33]1[CH2:34][CH2:35][C@H:30]([O:29][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][C:9]=2[S:45]([Cl:49])(=[O:47])=[O:46])[C:16](=[O:19])[N:15]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:14]=[C:13]3[Cl:50])[CH2:31][CH2:32]1)(=[O:39])[CH3:38]
Reactant: ClCCl
Reactant: COc1ccc(Cn2ccc3cc(O[C@H]4CC[C@@H](NC(C)=O)CC4)c(SCc4ccccc4)cc3c2=O)cc1
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc(Cl)c3cc(O[C@H]4CC[C@@H](NC(C)=O)CC4)c(S(=O)(=O)Cl)cc3c2=O)cc1
Reaction time: 0.5 h

Procedure:
37 mg of N-{4-[7-benzylsulfanyl-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6-yloxy]-cyclohexyl}-acetamide (128, crude product) were dissolved in 5 ml of dichloromethane. At 0° C., 16.4 mg (0.273 mmol) of acetic acid, 4.9 mg (0.273 mmol) of water and 273 μl (0.273 mmol) of sulfuryl chloride (1 M in dichloromethane) were added. After 30 minutes, ethyl acetate was added and the solution was washed with sodium bicarbonate solution (2%), water and saturated sodium chloride solution. The organic layer was dried with Na2SO4 and evaporated. The so obtained crude product was used without further purification. Rt=1.55 min (Method C). Detected mass: 553.5 (M+H+).
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=1)[CH3:5])C.[NH:16]([C:18]1[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[NH2:17].O>ClCCl.CO>[F:14][C:10]1[CH:9]=[C:8]([C:7]2[N:16]([C:18]3[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[N:17]=[C:4]([CH3:5])[N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(C)=NC(=O)c1cccc(F)c1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1nc(-c2cccc(F)c2)n(-c2ccc(S(N)(=O)=O)cn2)n1
Reaction time: 8 h
Yield: 53.1 %

Procedure:
N-(1-ethoxy-ethylidene)-3-fluoro-benzamide 438 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-[5-(3-fluoro-phenyl)-3-mehtyl-[1,2,4]triazole-1-yl]-pyridine-3-sulfonic acid amide (370 mg, yield: 53%) was obtained as a solid phase.