Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].S(Cl)([Cl:18])=O>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][CH2:12][C:13]([Cl:18])=[O:15])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CCCC(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: CC(=O)N1CCC(CCCC(=O)Cl)CC1
Reaction time: 0.08 h

Procedure:
4-(1-Acetyl-4-piperidinyl)butyric acid (2.6 g, 12 mmol) was added in small portions to thionyl chloride (12 ml) with ice-bath cooling. After the mixture was stirred for 5 minutes, the excess thionyl chloride was distilled off and the residue was washed with hexane to provide 4-(1-acetyl-4-piperidinyl)butyryl chloride as light-yellow solid. Aluminum chloride (66,0 g, 0.49 mol) powders were added in small portions to a mixed solution of the above acid chloride and 3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.5 g, 10 mmol), obtained in Reference Example 3, in 1,2-dichloroethane (10 ml) with ice-bath cooling. This mixture was stirred at room temperature for 2 days, then poured in ice-water, and extracted with ethyl acetate. The extract was washed with saturated NaCl/H2O and dried over MgSO4 The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=9:1) to provide 4-(1-acetyl-4-piperidinyl)-1-(3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-butanone (3.7 g) as colorless crystals melting at 101-102° C.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH3:11])=[O:9].[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[C:25]([CH3:30])[CH:24]=1.O>CN(C)C=O>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:8](=[O:9])[O:10][CH3:11])=[C:25]([CH3:30])[CH:24]=1
Reactant: COC(=O)Cl
Reactant: Cc1cc(OCc2nc3ccccc3s2)ccc1N
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)Nc1ccc(OCc2nc3ccccc3s2)cc1C
Reaction time: 2 h
Yield: 54 %

Procedure:
82.5 ml of pyridine and 18.9 ml of methyl chloroformate were added to a solution of 55.0 g of 4-(benzothiazol-2-ylmethoxy)-2-methylaniline [prepared as described in step (b) above] in 400 ml of dimethylformamide cooled in an ice-water bath and the resulting mixture was stirred at the same temperature for 2 hours. At the end of this time, the reaction mixture was poured into water resulting in the precipitation of a crystalline solid which was washed with water and then further washed with diethyl ether to give a crude crystalline solid. This was recrystallised from a 4:1 by volume mixture of tetrachloromethane and acetone to give 36.2 g (yield 54%) of the title compound as a solid having a melting point of 147° to 149° C.
Reaction SMILES: IC.[F:3][C:4]1[CH:5]=[C:6]([SH:11])[CH:7]=[CH:8][C:9]=1[F:10].[C:12](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:3][C:4]1[CH:5]=[C:6]([S:11][CH3:12])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc(S)cc1F
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CSc1ccc(F)c(F)c1
Reaction time: 8 h

Procedure:
Iodomethane (15 mL, 0.22 mol) was added to a stirred mixture of 3,4-difluorobenzenethiol (30 g, 0.21 mol) and potassium carbonate (32.6 g, 0.24 mol) in DMF (250 mL), and left overnight. The reaction mixture was diluted with water (100 mL) and extracted with ethyl ether (100 mL×3), the organic phases were dried over Na2SO4 and evaporated under reduced pressure to give (3,4-difluorophenyl)(methyl)sulfane as a yellow liquid. Yield: 30 g, 89.3%. 3-Chloroperoxybenzoic acid (85% in purity, 62.5 g, 0.305 mol) was added in portions to a solution of (3,4-difluorophenyl)(methyl)sulfane (25 g, 0.155 mol) in dichloromethane (650 mL), and the mixture was stirred at room temperature for 2 h. The mixture was washed with saturated aqueous sodium sulfite solution (200 mL). The organic phases were sequentially washed with aqueous sodium bicarbonate solution (100 mL×2) and water (100 mL), dried over Na2SO4 and evaporated under reduced pressure to give the title compound as a white solid. Yield: 18 g, 60%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11](=O)[NH:10]1.O=P(Cl)(Cl)[Cl:24]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([Cl:24])=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(=O)NC1c1ccc(F)cc1Br
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C1=C(C)NC(Cl)=NC1c1ccc(F)cc1Br
Temperature: 110 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (3.56 g, 10 mmol) and POCl3 (15 mL) was stirred at 110° C. for 4 hours under N2, then cooled to 25° C. POCl3 was removed in vacuo and the residue was dissolved in chloroform (100 mL). Then the mixture was adjusted to pH 6-8 with strong ammonia. The organic phase was washed with brine (80 mL×3), dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=5/1) to give the title compound as a white solid (1.73 g, 46%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([NH:16][C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:3]1=[O:22].CCN(C(C)C)C(C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]([S:40]([C:37]3[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=3)(=[O:42])=[O:41])[C:17]3[S:18][CH:19]=[CH:20][N:21]=3)(=[O:14])=[O:15])=[CH:9][CH:8]=2)[C:3]1=[O:22]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N(c2nccs2)S(=O)(=O)c2ccc(N3CC[C@@H](O)C3=O)cc2)cc1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
Synthesized according to General Procedure 8. To a stirred suspension of (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzenesulfonamide (41 g, 0.121 mol) in DCM (205 mL) under N2 at 0° C. was added DIEA (15.6 g, 21 mL, 0.121 mol). To this suspension at 0° C. was added 4-methoxybenzenesulfonyl chloride (25 g, 0.121 mol) portionwise over 15 minutes. The cooling bath was removed and the suspension was allowed to warm to RT over 1 hour during which time the reaction mixture became a homogeneous solution. The solution was cooled to 0° C. and MeOH (2.05 L) was added. Stirring was continued at 0° C. After 10 minutes a precipitate formed. The resulting suspension was stirred at 0° C. for 30 minutes and then filtered. The filter cake was washed with MeOH (2×250 mL) and then dried under vacuum to constant weight to provide (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(4-methoxyphenylsulfonyl)-N-(thiazol-2-yl)benzenesulfonamide as a white solid (55.49 g, 0.109 mol, 90% yield). 1H-NMR (400 MHz, DMSO-d6) δ 7.86-7.80 (m, 4H), 7.70 (d, J=5.1 Hz, 1H), 7.60 (d, J=9.0 Hz, 2H), 7.03-6.98 (m, 3H), 5.88 (d, J=5.9 Hz, 1H), 4.38-4.32 (m, 1H), 3.85-3.77 (m, 1H), 3.81 (s, 3H), 3.70 (td, J=9.4, 5.4 Hz, 1H), 2.48-2.41 (m, 1H) and 1.92-1.82 (m, 1H) ppm. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=510.0; tR=1.22 min.
Reaction SMILES: C(O[C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1)C.[OH-].[NH4+:17].[ClH:18].CCOCC>C(O)C>[NH2:17][C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1.[ClH:18].[NH2:17][C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[NH:14][CH:15]=[C:7]([C:8]=23)[CH2:6][N:5]=1
Reactant: CCOC1=NCc2c[nH]c3cccc1c23
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: NC1=NCc2c[nH]c3cccc1c23

Procedure:
To a suspension of 5-ethoxy-1,3-dihydropyrrolo[4,3,2-de]isoquinoline (200 mg, 1 mmole), described in Example 5, in ethanol (2 ml), aqueous ammonium hydroxide (25%, 0.5 ml, 1.4 mmole) is added followed by 2.3 N HCl in ethanol (0.5 ml). The mixture is heated at reflux for 0.5 hour, then ether is added and the light green crystalline precipitate collected to give the hydrochloride salt of the title compound, 5-amino-1,3-dihydropyrrol[4,3,2-de]isoquinoline hydrochloride, mp 227° - 228°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([C:24]([CH3:26])=[CH2:25])[C:16]2=[O:27])=[C:12]2[C:8]([C:9]([CH3:29])=[C:10]([CH3:28])[NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[CH3:32]I.[NH4+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:13]([CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([C:24]([CH3:26])=[CH2:25])[C:16]2=[O:27])=[C:12]2[C:8]([C:9]([CH3:29])=[C:10]([CH3:28])[N:11]2[CH3:32])=[CH:7][CH:6]=1)=[O:4]
Reactant: C=C(C)n1c(=O)n(Cc2c(C(=O)OC)ccc3c(C)c(C)[nH]c23)c2ccccc21
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)n1c(=O)n(Cc2c(C(=O)OC)ccc3c(C)c(C)n(C)c23)c2ccccc21
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
To a solution of 7-(3-Isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-2,3-dimethyl-1H-indole-6-carboxylic acid methyl ester (107 mg, 0.3 mmol) in THF (10 mL) was added NaH (60% in mineral oil) (22 mg, 0.55 mmol) at 0 C under nitrogen atmosphere. The solution was stirred at the same temperature for 15 minutes. MeI (0.034 mL, 0.55 mmol) was added and the solution was stirred at 0 C for 2 hour. Sat. NH4Cl solution was added and the solution was extracted with EtOAc. The combined organic layer was dried with MgSO4 and was filtered. The filtrate was concentrated and the residue was purified by CombiFlash with 10% EtOAc in Hexane as the eluent to afford the desirable product 7-(3-Isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1,2,3-trimethyl-1H-indole-6-carboxylic acid methyl ester (100 mg. 90%) as a colorless oil.
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH:10](Br)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:3]([O:5][CH2:6][CH3:7])=[O:4].O.O.O.O.O.O.O.O.O.[Na+].[Na+].[SH-:28].C(OCC)C.O>CN(C)C=O>[CH2:6]([O:5][C:3]([CH:2]1[CH2:8][CH2:9][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:28]1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(Br)CCC(Br)C(=O)OCC
Reactant: [SH-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCC(C(=O)OCC)S1
Reaction time: 5 h
Yield: 72.3 %

Procedure:
To a stirred solution of diethyl 2,5-dibromoadipate (4.5 g) in dimethylformamide (15 ml), sodium sulfide enneahydrate (3.9 g) was added under nitrogen atmosphere and the mixture was stirred for 5 hours under ice-cooling. To the reaction mixture, diethyl ether and water were added. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 2.1 g (72%) of 2,5-diethoxycarbonyltetrahydrothiophene.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]#[CH:23])[CH:18]=3)[NH:13][C:12](=[S:24])[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:25]([S:24][C:12]1[N:11]=[C:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH2:21][C:22]#[CH:23])[CH:18]=2)[N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: C#CCOc1ccc2[nH]c(=S)nc(-c3ccc(C(C)C)cc3)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C#CCOc1ccc2nc(SCc3ccccc3)nc(-c3ccc(C(C)C)cc3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 100 mg (299 μmol) 4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione in 2 ml THF are added 35.5 μl (299 μmol) benzyl bromide and 76 μl (448 μmol) DIEA. After stirring for 18 h at r.t. the reaction mixture is extracted with dichloromethane and water. After evaporation of the organic layers the crude product is purified by flash chromatography using hexanes/ethyl acetate 20:1 as eluent.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[N:9][N:8]=1.[CH3:34][NH2:35].C([O-])([O-])=O.[K+].[K+]>CCOCC>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([S:13]([NH:12][C:10]2[S:11][C:7]([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:35][CH3:34])=[N:8][N:9]=2)(=[O:15])=[O:14])=[CH:17][CH:18]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CCCCCBr)s2)cc1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CCCCCNC)s2)cc1
Yield: 61 %

Procedure:
A mixture of N-(5-(5-bromopentyl)-1,3,4-thiadiazol-2-yl)-4-dodecylbenzenesulfonamide (100 mg, 0.18 mmol), CH3NH2 (0.42 mL, 40% solution in water, 5.4 mmol), K2CO3 (25 mg, 0.18 mmol), and KI (30 mg, 0.18 mmol) was heated at reflux for 2 d. The reaction mixture was diluted with ether (50 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The crude product was purified by chromatography over silica gel 60 (70-230 mesh) eluted with CH2Cl2:methanol 2:3 to give the product as a solid, mp 158-160° C., in 61% yield (56 mg, 0.11 mmol). 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3, J=7.2 Hz), 1.25-1.36 (m, 18), 1.53-1.67 (m, 8), 2.57-2.61 (m, 5), 2.68 (t, 2, J=7.2 Hz), 2.96 (t, 2, J=6.9 Hz), 7.20 (d, 2, J=8.4 Hz), 7.75 (d, 2, J=8.1 Hz); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.7, 25.5, 28.3, 29.3, 29.4, 29.5, 29.7, 30.5, 31.2, 31.9, 33.1, 35.8, 60.0, 126.1, 128.5, 140.7, 146.7, 163.7, 170.7; HRMS (ESI+, m/z) calculated for C26H45N4O2S2 509.2984. observed 509.2972 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[C:8]([N:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[C:9]3[CH:15]=[CH:14][N:13](S(C4C=CC=CC=4)(=O)=O)[C:10]3=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.CO.[Li+].[OH-]>O>[C:1]1([C:7]2[C:8]([N:25]3[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]3)=[C:9]3[CH:15]=[CH:14][NH:13][C:10]3=[N:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1
Temperature: 50 °C
Yield: 49.9 %

Procedure:
tert-Butyl 4-(5-phenyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (1.10 g, 2.12 mmol) was placed in 1:1 THF:MeOH (20 mL). LiOH (3.54 mL, 10.6 mmol) was then added, and the reaction was heated to 50° C. for 1 hour. The reaction was cooled to room temperature, poured into water, and extracted with DCM (3×50 mL). The combined organic fractions were dried, filtered, concentrated, and then purified by column chromatography (500:5 DCM:MeOH) to give tert-butyl 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.40 g, 49.8% yield).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[C:8]([CH2:10][C:11]([O:13]CC)=[O:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].CO.[OH-].[K+]>O>[CH2:1]([C:5]1[O:6][C:7]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[C:8]([CH2:10][C:11]([OH:13])=[O:12])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(CC(=O)OCC)c(-c2ccco2)o1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCc1nc(CC(=O)O)c(-c2ccco2)o1
Yield: 83.4 %

Procedure:
4.0 g of ethyl 2-[2-n-butyl-5-(2-furyl)-4-oxazolyl]acetate, 50 ml of methanol, 5 ml of water and 4.75 g of potassium hydroxide are treated in the same manner as described in Example 16. 3.0 g of 2-[2-n-butyl-5-(2-furyl)-4-oxazolyl]acetic acid are thereby obtained. Yield: 83.3%
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[C:8]=2[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+].O.Cl>CO.O1CCCC1>[O:15]=[C:11]1[C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[C:7]=2[CH2:14][CH2:13][CH2:12]1
Reactant: CCOC(=O)c1csc2c1CCCC2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1csc2c1CCCC2=O
Reaction time: 0.75 h
Yield: 95.8 %

Procedure:
To a mixture solution of 7-Oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester (21.6 g) in methanol (50 mL) and tetrahydrofuran (50 mL) was added in several portions an aqueous solution of 2N sodium hydroxide (77 mL) on an ice bath. After the solution was stirred for 45 minutes and the pH of solution was adjusted to 2 with 2N hydrochloric acid water, the organic solvent was removed by evaporation. Water was added to the residue to suspend, the solid was collected by filtration, and washed with water and then with ethanol, and then was dried to provide the title compound (18.1 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[NH3:15]>O1CCCC1>[NH2:15][C:13]([NH:12][S:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])(=[O:10])=[O:11])=[O:14]
Reactant: O=C=NS(=O)(=O)c1cccc(Cl)c1Cl
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)NS(=O)(=O)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10.0 g of 2,3-dichlorobenzenesulfonyl isocyanate in 200 mL of dry tetrahydrofuran was cooled to 0° C. and treated with 5.0 mL of anhydrous liquid ammonia, added in a dropwise manner at a rate that maintained the temperature between 0° and 10° C. The resultant white mixture was allowed to warm to room temperature and was stirred overnight. The precipitate was collected by filtration, dissolved in 250 mL of water, and acidified with concentrated hydrochloric acid to yield a white solid. Filtration and air drying gave 7.0 g of the title compound, m.p. 197°-200° C.; NMR (DMSO-d6): δ6.0-6.8 (br s, 2H), 7.6 (t, 1H), 7.8-8.1 (m, 2H), 11.1 (br s, 1H); IR (nujol): 1690 cm-1.
Reaction SMILES: Cl.[C:2]([S:21][CH2:22][CH2:23][NH2:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:25][C:26]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)(=[O:38])=[O:37])=[C:31]2[C:27]=1[CH:28]=[C:29]([C:44](O)=[O:45])[NH:30]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH3:25][C:26]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)(=[O:38])=[O:37])=[C:31]2[C:27]=1[CH:28]=[C:29]([C:44]([NH:24][CH2:23][CH2:22][S:21][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:45])[NH:30]2
Reactant: Cc1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)O)cc12
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 94.6 %

Procedure:
To a mixture of 2-(tritylthio)ethylamine hydrochloride (0.93 g), triethylamine (0.37 mL) and N,N-dimethylformamide (15 mL) were added 4-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.73 g), 1H-1,2,3-benzotriazol-1-ol (0.47 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.59 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (1.31 g, yield 95%) as pale-yellow crystals. melting point 241-242° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([CH3:14])[CH:8]=2)=[O:4].Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH3:14][C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:5]([C:3]([OH:2])=[O:4])[N:6]2[CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc2ccc(C)cc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: Cc1ccc2cc(C(=O)O)n(Cc3cccc4ccccc34)c2c1

Procedure:
Using general procedure B, 6-methyl-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 314.1 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[Br:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:23]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cccc(Br)c4)nc23)CC1
Yield: 89.3 %

Procedure:
Beginning with 0.015 gm (0.065 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.0095 mL (0.072 mMol) 3-bromobenzoyl chloride, 0.024 gm (90%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[CH2:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].C(OCC)(OCC)O[CH2:23][CH3:24]>C(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([O:16][CH2:23][CH3:24])=[CH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)N1c2ccccc2CC(=O)c2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC1=Cc2ccccc2N(C(=O)OC)c2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
A suspension of 10-oxo-10,11-dihydro-dibenzo[b,f]azepine-5-carboxylic acid methyl ester (15 g, 56 mmol) in ethanol (75 ml) is heated to 60° C. and a catalytic amount of p-toluene sulfonic acid (0.213 g, 1.1 mmol) is added. After addition of triethyl ortho-formate (8.73 g, 58.9 mmol) the solution is stirred at 60–70° C. for 4 hours. During this reaction the product precipitates as white crystals. The mixture is cooled to room temperature, filtered and dried to yield 16.0 g of pure title compound (97%).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=12.S(Cl)([Cl:15])=O.CN(C=O)C>C1(C)C=CC=CC=1>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([Cl:15])=[O:12])[CH:7]=[CH:6][C:5]=12
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2nonc2c1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccc2nonc2c1
Yield: 79.8 %

Procedure:
In a 500 ml reactor fitted with mechanical stirring, thermometer, addition funnel, reflux condenser and nitrogen inlet, 2,1,3-benzoxadiazole-5-carboxylic acid (28 g) was suspended in toluene (245 ml). To this suspension was added thionyl chloride (39.4 g) and DMF (0.35 ml). The resulting mixture was heated to reflux and maintained for 3 hours. A short pass column was installed and toluene was distilled (atmospheric pressure, 124 ml) off to remove excess reagent. After cooling the remaining toluene was distilled off, which resulted in a thick oil. This oil was distilled (90° C., 2 mm Hg) to remove impurities and the product crystallized on standing (79.8% yield), mp: 55-58° C.