Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[C:10]([OH:21])(=O)[C:11]1[CH:19]=[CH:18][C:17]2[O:16][CH2:15][O:14][C:13]=2[CH:12]=1.C([O:26][C:27](=[O:54])[CH2:28][N:29]([C:39](=[O:53])[C@@H:40]([NH:44]C(=O)C1C=CC=CC=1)[CH:41]([CH3:43])[CH3:42])[CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)(C)(C)C>>[O:16]1[C:17]2[CH:18]=[CH:19][C:11]([C:10]([NH:44][C@@H:40]([CH:41]([CH3:43])[CH3:42])[C:39]([N:29]([CH2:28][C:27]([OH:54])=[O:26])[CH:30]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31]3)=[O:53])=[O:21])=[CH:12][C:13]=2[O:14][CH2:15]1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Agent: O=C(O)c1ccccc1
Product: CC(C)[C@H](NC(=O)c1ccc2c(c1)OCO2)C(=O)N(CC(=O)O)C1Cc2ccccc2C1

Procedure:
Compound 728 was prepared by a method similar to the method used to prepare compound 724, except benzoic acid is replaced with piperonylic acid in the preparation of compound 723. ##STR107##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>C1COCC1>[CH2:12]([O:11][C:9](=[O:10])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH3:14])[CH3:13]
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(Br)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To ethyl 4-bromophenylacetate (2.137 g, 8.8 mmol) in THF (20 mL) at −78° C. was added lithium bis(trimethylsilyl)amide (1M in hexane; 11.4 mL, 11.4 mmol), and the solution was stirred for 1 hour at −78° C. Iodomethane (0.71 mL, 11.4 mmol) in THF (5 mL) was added, and the reaction was warmed to room temperature. The mixture was quenched with water and concentrated. The residue was dissolved in EtOAc and washed three times with water and once with brine. The organic layer was dried and concentrated, and the crude material was purified by silica gel chromatography (0-60% EtOAc in hexanes) to give 2-(4-bromo-phenyl)-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:13])=O>>[CH3:1][N:2]=[C:3]([Cl:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNC(=O)c1ccccc1
Reactant: O=S(Cl)Cl
Product: CN=C(Cl)c1ccccc1
Yield: 91 %

Procedure:
N-Methyl benzamide (55.97 g., 418 mmole) and thionyl chloride (114.7 g, 0.96 mole) were treated as in Example I. Yield 58.4 g (91%) of the title compound, b.p. 80°-90° C. (~0.1 mm Hg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].N1C=CC=CC=1.[C:26](Cl)(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>O1CCCC1>[C:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.7 %

Procedure:
16-Hydroxyhexadecanoic acid (5.43 g, 19.9 mmol) was dissolved in tetrahydrofuran (190 ml) and pyridine (2.36 g, 29.9 mmol) was added. Palmitoyl chloride (5.48 g, 19.9 mmol) was dissolved in tetrahydrofuran (10 ml) and added dropwise at room temperature. After stirring at room temperature for 16 hours, the mixture was filtered and the filtrate evaporated under reduced pressure. The residue was dissolved in chloroform, washed with water (3×50 ml), and the organc phase was dried (MgSO4). After evaporating under reduced pressure, the residue was purified on a silica column, eluted with chloroform with increasing methanol concentration (from 1% to 2% methanol in chloroform) to give 8.41 g (83%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 0.85 (t, 3H, CH3), 1.20-1.35 (s, 46H, --CH2 --), 1.55-1.70 (m, 6H, --CH2 --), 2.25 (t, 2H, --CH2 --C(O)--O), 2.45 (t, 2H, --CH2 --COOH), 4.05 (t, 2H, --O--CH2). 13C NMR (75 MHz, CDCl3): δ 14.01, 22.57, 24.10, 24.91, 25.82, 28.53, 28.75, 28.94, 29.08, 29.15, 29.25, 29.36, 29.54, 31.81, 34.29, 35.16, 64.27, 76.48, 76.90, 77.10, 77.32, 169.50, 173.91.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([N+:13]([O-:15])=[O:14])=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a stirred solution of N-(4-chloro-2-fluorophenyl)acetamide (180.6 g, 0.96 mol) in concentrated sulfuric acid (1L) was added a mixture of 175 mL of concentrated HNO3 and 175 mL of concentrated sulfuric acid at 0 to 5° C. in 1.5 h. After the addition was finished, the reaction mixture was stirred for another 0.5 h. The solution was poured into 5 L of ice water. After the product precipitated, it was isolated by filtration and then was dissolved in 2.5 L of ethyl acetate. After separation of the water layer, the organic layer was dried over sodium sulfate and then the solvent was evaporated. The crude product was triturated in diisopropyl ether (1.5 L), isolated by filtration, and dried under reduced pressure to afford the title compound of Step A (196.2 g, 87.6%) melting at 145-146° C. 1H NMR (Me2SO-d6) δ 10.3-10.2 (s, 1H), 8.9 (d, 1H), 7.9-7.8 (d, 2.2-2.1 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[O:24][CH2:25][CH2:26]Cl>CS(C)=O.O>[CH:7]1([NH:13][CH2:26][CH2:25][O:24][C:15]2[CH:16]=[CH:17][C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCCCC1
Reactant: ClCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc2cc(OCCNC3CCCCC3)ccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and cyclohexylamine (0.32 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 2-(2-naphthyloxy)-1-chloro ethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-cyclohexyl-[2-(naphthalen-2-yloxy)-ethyl]amine, solid, m.p. 89° C., (yield 0.56 gm, 85.6%).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1.[CH3:11][O:12][CH2:13]Cl>O1CCCC1.ClCCl>[CH3:11][O:12][CH2:13][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:4][N:3]=1
Reactant: COCCl
Reactant: COC(=O)c1cc(O)no1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCOc1cc(C(=O)OC)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A solution of 2.0 g (14.0 mmol) of methyl 3-hydroxy-5-isoxazole carboxylate and 29.2 ml (16.8 mmol) of N,N-diisopropylethylamino in 20 ml of tetrahydrofuran was treated with 1.27 ml of chloromethyl methyl ether. After being stirred at ambient temperature for 2 h, the solution was diluted with dichloromethane, washed with water, dried over MgSO4, and concentrated in vacuo. Silica gel chromatography of the residue using 10% methanol in dichloromethane provided 129.6 mg (78%) of the desired compound as a white solid. 1H NMR (CDCl3) δ3.57 (s, 3H), 3.96 (s, 3H), 5.37 (s, 2H), 6.64 (s, 1H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C(N(CC)CC)C.[OH:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=2)[N:21]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:20]=1.C([O-])(O)=O.[Na+]>C(#N)C>[O:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][O:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=3)[N:21]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:20]=2)[CH2:6][CH2:7]1
Reactant: ClCCN1CCOCC1
Reactant: CCOC(=O)n1nc(O)c2cc([N+](=O)[O-])ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)n1nc(OCCN2CCOCC2)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Yield: 42.2 %

Procedure:
To a solution of 4-(2-chloroethyl)morpholine hydrochloride (390 mg, 2.10 mmol) in acetonitrile (25 mL) was added triethylamine (0.56 mL, 4.0 mmol) and ethyl 3-hydroxy-5-nitro-1H-indazole-1-carboxylate (563 mg, 1.91 mmol) and the mixture heated to reflux for 2 days. Additional portions of 4-(2-chloroethyl)morpholine hydrochloride (178 mg, 0.955 mmol) and triethylamine (130 μL, 0.95 mmol) were added and the reaction mixture was heated at reflux for a further 3 hr and then cooled to RT. Saturated aq. NaHCO3 (50 mL) was added and the mixture was extracted with EtOAc (2×100 mL). The organic extracts were combined, dried and evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, 40 g, 0-100% EtOAc in isohexane, gradient elution) to afford ethyl 3-(2-morpholinoethoxy)-5-nitro-1H-indazole-1-carboxylate as a yellow solid (294 mg, 41%); Rt 1.26 min (Method 2, acidic); m/z 365 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([C:13](=[O:19])[C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([NH:20][C:21]2[CH:25]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[NH:23][N:22]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([C:13](=[O:19])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-yl)-2-oxoacetate (Compound 189) (50 mg, 0.12 mmol, 1.0 eq) in ethanol (15 mL) was added 1 N NaOH (0.5 mL, 0.48 mmol, 4.0 eq). The mixture was stirred at room temperature for 1 hour, then, concentrated and the residue was redissolved in water. To the solution was added 1N HCl (0.5 mL) and the mixture was stirred for 0.5 h at 23° C. The solution was filtered to afford 2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-yl)-2-oxoacetic acid Compound 190) (30 mg, 64.3%). LC-MS (m/z): 390.0 [M+]+. 1H NMR (400 MHz, DMSO-d6): δ 0.74-0.78 (m, 2H), 0.96-1.01 (m, 2H), 1.92-1.96 (m, 1H), 6.42 (s, 1H), 7.87 (d, J=4.0 Hz, 1H), 8.07 (d, J=4.4 Hz, 1H), 8.49 (s, 1H), 9.51 (s, 1H), 13.28 (bs, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])=[O:12])=[CH:7][CH:6]=1.Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:12])=[O:13])=[CH:7][CH:6]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: CCOC(=O)CNS(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc2ccccc2n1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a suspension of sodium hydride (0.84 g, 35.0 mmol) in dimethylformamide (120.0 mL), is added ethyl 2-[[4-methoxybenzenesulfonyl]amino]acetate (3.19 g, 11.67 mmol) and 2- (chloromethyl)quinoline (2.62 g, 12.26 mmol), and the reaction is stirred for three days at room temperature. Then, additional NaH (0.46 g, 11.67 mmol) is added, and the reaction is heated to 50° C. for 5 hours. The reaction is cooled to 0° C., quenched with water, and extracted well with ether. The combined organic layers are washed with brine, dried (Na2SO4), and the solvent is removed to give ethyl 2-[[4-methoxybenzenesulfonyl]-(2-quinolinylmethyl)amino]acetate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[N:17]1([CH2:23][CH2:24][CH2:25][C:26]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[NH:28][C:27]=2[CH:35]=O)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[N:17]1([CH2:23][CH2:24][CH2:25][C:26]2[C:34]3[CH2:33][CH2:32][CH2:31][CH2:30][C:29]=3[NH:28][C:27]=2[CH:35]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: O=Cc1[nH]c2c(c1CCCN1CCOCC1)CCCC2
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: O=C1Nc2cccc(C3CCNCC3)c2C1=Cc1[nH]c2c(c1CCCN1CCOCC1)CCCC2

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 3-(3-morpholin-4-yl-propyl)-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (61 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([O:17][CH3:18])=[O:16])=[O:7])=[CH:4][CH:3]=1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>>[C:38]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:25][CH2:26]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([O:17][CH3:18])=[O:16])=[O:7])=[CH:36][CH:37]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(N)cc1
Product: COC(=O)c1ccccc1N(CCN1CCC(C(=O)c2ccc(F)cc2)CC1)C(=O)c1ccc(NC(C)=O)cc1
Yield: 95.8 %

Procedure:
Using 4-amino-N-{2-[4-(4-fluorobenzoyl)piperidino]ethyl}-N-(2-methoxycarbonylphenyl)benzamide (291.0 mg, 0.58 mmol) and acetic anhydride (0.11 ml, 1.16 mmol), the procedure of Inventive Example 94 was repeated to obtain 303.0 mg (96.0%) of the title compound in a colorless amorphous form.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2].[BH4-].[Na+]>C1COCC1.CO>[N+:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH:7]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc2[nH]cc(C=C[N+](=O)[O-])c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2[nH]cc(CC[N+](=O)[O-])c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Treat a solution of 3-(2-nitrovinyl)-5-methoxycarbonyl-1H-indole (57 mg, 0.23 mmol) in 9 mL THF and 2 mL MeOH with NaBH4 (26 mg, 0.69 mmol). Stir at ambient temperature overnight, concentrate to dryness and partition between conc. NH4OH (10 mL) and dichloromethane. Extract the aqueous layer with dichloromethane, acidify with conc. HCl and extract twice with dichloromethane. Combine the organic layers, concentrate, and chromatograph on silica gel eluting with 1% MeOH in CHCl3 to give the title compound as a solid: 1H NMR (CDCl3) 8.35 (bs, 1H), 8.32 (s, 1H), 7.92–7.90 (m, 1H), 7.38–7.36 (d, 1H), 7.12–7.11 (m, 1H), 4.69–4.65 (t, 2H), 3.93 (s, 3H), 3.51–3.48 (t, 2H); ISMS 248 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=1)=[O:6].[Cl:21][C:22]1[CH:23]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1>N1C=CC=CC=1>[Cl:28][C:26]1[CH:25]=[C:24]([S:29]([NH:1][C:2]2[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([F:15])[CH:9]=2)=[O:6])(=[O:30])=[O:31])[CH:23]=[C:22]([Cl:21])[CH:27]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1N
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccc(F)c(F)c2)cc1NS(=O)(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 16 h
Yield: 94.4 %

Procedure:
A solution of 3-amino-4-methoxy-N-(3,4-difluorophenyl)-benzamide from Example 15 (0.834 g, 3.00 mmol), 3,5-dichlorobenzenesulfonyl chloride (0.736 g, 3.00 mmol) and a catalytic amount of 4-dimethylaaminopyridine in pyridine (10 mL) was stirred under nitrogen at room temperature. After 16 hours, the solvent was removed in vacuo and the residue shaken with a mixture of ethyl acetate and 1N HCl then filtered. The layers were separated and the organic layer washed with brine, dried with MgSO4, concentrated to dryness, triturated in hexanes and filtered to afford a solid which was combined with that obtained in the filtration step to afford the product (1.38 g); m.p. 228-231° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:13][NH:14][C:15](=[O:16])[C:11]=2[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[H-].[Na+].[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[CH2:33]Cl.[I-].[Na+]>CN(C)C=O.C(O)(=O)C>[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([Cl:38])[CH:37]=1)[CH2:33][N:14]1[C:15](=[O:16])[C:11]2[C:10]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:9]3[C:4]([CH:5]=[CH:6][CH:7]=[N:8]3)=[C:3]([O:2][CH3:1])[C:12]=2[CH2:13]1
Reactant: ClCc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(COc2c3c(c(OC)c4cccnc24)CNC3=O)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(COc2c3c(c(OC)c4cccnc24)CN(Cc2cc(Cl)cc(Cl)c2)C3=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 28 %

Procedure:
5-Methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 304 (17 mg, 0.049 mmol) was dissolved in dimethylformamide (0.3 ml) and cooled to 0° C. After adding sodium hydride (2.5 mg, 0.064 mmol), the reaction was stirred for 5 minutes at 0° C. 3,5-Dichlorobenzylchloride (11.5 mg, 0.059 mmol) and a catalytic amount of sodium iodide were then added. The reaction mixture was warmed to room temperature and stirred at room temperature for 30 minutes. It was then cooled to 0° C., acidified with acetic acid (0.030 ml), and concentrated in vacuo. The resulting residue was diluted with ethyl acetate, washed twice with water, once with brine, and concentrated in vacuo. The residue was purified by silica gel chromatography (99/1-ethyl acetate/acetic acid) to afford 7-(3,5-dichloro-benzyl)-5-methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 307 (7 mg, 40%). 1H NMR (CDCl3) δ 9.0 (dd, 1H), 8.40 (dd, 1H), 7.60 (d, 2H), 7.55 (m, 1H), 7.20 (m, 3H), 6.80 (d, 2H), 5.60 (s, 2H), 4.75(s, 2H), 4.40 (s, 2H), 3.95 (s, 3H), 3.75 (s, 3H). MS: 509.1 (M+1).
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[C:13](=O)[C:12](=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][S:10](=[O:23])(=[O:22])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([NH:27][NH2:28])[CH2:25][CH3:26]>CO.C(Cl)(Cl)(Cl)Cl>[C:1]1([CH:7]2[N:27]([CH2:24][CH2:25][CH3:26])[N:28]=[C:13]3[C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:11][S:10](=[O:23])(=[O:22])[CH2:9][CH:8]23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C(=Cc2ccccc2)CS(=O)(=O)CC1=Cc1ccccc1
Reactant: CCCNN
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: CCCN1N=C2C(=Cc3ccccc3)CS(=O)(=O)CC2C1c1ccccc1
Yield: 48.7 %

Procedure:
A mixture of 3.24g of tetrahydro-3,5-bis-(phenylmethylene)-4H-thiopyran-4-one-1,1-dioxide and 0.6g of n-propyl hydrazine in 100ml of absolute methanol is heated at reflux temperature for 2 hours. The mixture is allowed to cool, and is then filtered to give 2.8g of crude product. The crude material is stirred for about 16 hours in 200ml of carbon tetrachloride and filtered. The mother liquor is concentrated in vacuo and the residue is crystallized from methanol to give 1.5g of the title compound, melting point 197°-199°C.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:12][C:13]([C:15]2[CH:34]=[CH:33][C:18]3[N:19]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:20]([CH2:22][C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[N:21][C:17]=3[CH:16]=2)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].C1COCC1.[OH-].[Na+].Cl>C(O)C>[CH2:29]([CH:28]([N:19]1[C:18]2[CH:33]=[CH:34][C:15]([C:13]([NH:12][C:5]3([C:3]([OH:4])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)=[O:14])=[CH:16][C:17]=2[N:21]=[C:20]1[CH2:22][C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)[CH2:31][CH3:32])[CH3:30]
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)NC3(C(=O)OC)CCCCCC3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)NC3(C(=O)O)CCCCCC3)ccc21
Temperature: 25 °C
Yield: 25.7 %

Procedure:
400 mg of 1-{[1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-cycloheptanecarboxylic acid methyl ester were dissolved in 4 ml ethanol and 2 ml THF and 4 ml of 2 M aqueous sodium hydroxide solution were added. After stirring at room temperature over night, the reaction mixture was brought to pH 3 by addition of 2 M aqueous hydrochloric acid and extracted with ethyl acetate three times. The combined organic phases were dried over magnesium sulphate and concentrated to yield 100 mg (26%) of 1-{[1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-cycloheptanecarboxylic acid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=2)[C:10]([OH:12])=O)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].C(Cl)CCl.ON1C2N=CC=CC=2N=N1.[C:38]([NH:41][NH2:42])(=[O:40])[CH3:39]>CN(C=O)C>[C:38]([NH:41][NH:42][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=[C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH:8]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)NN
Reactant: O=C(O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: On1nnc2cccnc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(=O)NNC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Temperature: 23 °C
Reaction time: 18 h

Procedure:
A screw-cap vial was charged with 3-morpholino-5-nitrobenzoic acid (0.250 g, 0.991 mmol), sodium bicarbonate (0.250 g, 2.97 mmol), EDC (0.285 g, 1.487 mmol), 1-hydroxy-7-azabenzotriazole (0.202 g, 1.487 mmol), acetic hydrazide (0.088 g, 1.189 mmol), and DMF (2.0 mL). The orange solution was stirred at 23° C. for 18 h, then partitioned between EtOAc and water. The organic phase was washed with brine, dried over magnesium sulfate, and concd, affording N′-acetyl-3-morpholino-5-nitrobenzohydrazide as an orange oil. Mass Spectrum (ESI) m/e=309.2 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=[O:8])=O.[NH2:14]/[C:15](/[CH3:21])=[CH:16]\[C:17]([O:19][CH3:20])=[O:18]>CO>[CH3:20][O:19][C:17]([C:16]1[CH:1]([C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[O:5][CH2:6][C:7]([OH:9])=[O:8])[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:21])[NH:14][C:15]=1[CH3:21])=[O:18]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1ccccc1OCC(=O)O
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1OCC(=O)O

Procedure:
A solution of 5 g of 2-formylphenoxyacetic acid and 6.4 g of methyl 3-aminocrotonate in methanol was refluxed for 24 hours and evaporated. The residue was dissolved in a solution of sodium carbonate in water. This solution was washed twice with ethyl acetate and acidified to pH 2 with dilute hydrochloric acid, after which the solution was again extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated. The residue was crystallized from ethyl acetate/petroleum ether 60-80.