Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:18].C(O)(=O)C>>[Br:18][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:16])=[O:17]
Reactant: Br
Reactant: O=C1CCCCCCCCCCCCCCO1
Solvent: CC(=O)O
Product: O=C(O)CCCCCCCCCCCCCCBr
Reaction time: 16 h

Procedure:
15-Pentadecanolide of 14.3 g (59.5 mmol), and 32% hydrogen bromide/acetic acid solution of 24.8 g (98.0 mmol, 1.6 eq) were added to 100 mL of autoclave protected with Teflon (registered trade name). After purging with nitrogen and sealing, the autoclave was placed in an oil bath at 60° C. and stirring was carried out for 16 hours. For the stirring, a magnetic stirrer was used. After cooling, 14 mL of water was added, and by using 200 mL of hot hexane the mixture was transferred to a separatory funnel. After washing with ion exchange water, it was dried over the magnesium sulfate. After filtration, 17.4 g of the target compound was obtained by crystallization using n-hexane (yield 91%).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:26][C:27]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH2:31])=[O:30]>N1C=CC=CC=1.CN(C)C=O>[NH2:26][C:27]1[C:28]([C:29](=[O:30])[NH2:31])=[CH:32][CH:33]=[CH:34][C:35]=1[NH:36][C:9]([C:7]1[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)=[O:11]
Reactant: CC(=O)c1ccc(C(=O)O)s1
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)c1ccc(C(=O)Nc2cccc(C(N)=O)c2N)s1
Temperature: 45 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
To a solution of 5-acetylthiophene-2-carboxylic acid (1.80 g, 10.55 mmol) in pyridine (12 mL) and N,N-dimethylformamide (12 mL) was added 1,1′-carbonyldiimidazole (1.88 g, 11.60 mmol) and the mixture stirred at 45° C. for 4 hours. 2,3-Diaminobenzamide dihydrochloride (synthesized as described in U.S. Pat. No. 6,737,421, column 11, EXAMPLE 2, step (e), 2.36 g, 10.55 mmol) was added and the mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and water. The resulting yellow solid was collected by filtration, washed with water and ethyl acetate and dried to give the title compound (2.91 g, 91%). MS (APCI): 304 (M+1)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[N:8]([CH3:23])[C:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[OH:21])=[CH:10][N:11]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C=O)C>[CH2:3]([C:7]1[N:8]([CH3:23])[C:9]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:10][N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCc1ncc(C(=O)c2ccc(OC)cc2O)n1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1ncc(C(=O)c2ccc(OC)cc2OCC(=O)OC(C)(C)C)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92426 %

Procedure:
To a mixture of NaH (80% oil dispersion, 41 mg, 1.35 mmol, previously washed with hexanes) in DMF (4 ml) was added dropwise a solution of 2-n-butyl-1-methyl-5-(2-hydroxy-4-methoxybenzoyl)-1H-imidazole (361 mg, 1.25 mmol) in DMF (3 ml) at 0° under argon. The cooling bath was removed and the mixture stirred for 20 min. at ambient temperature. t-Butyl bromoacetate (222 μl, 1.35 mmol) was added neat and the reaction stirred overnight. The mixture was partitioned between water and EtOAc and the layers separated. The aqueous layer was further extracted (EtOAc, 2x) and the combined organic extract was washed with water (5x) and brine. Evaporation under reduced pressure after drying (MgO4 anhydrous) afforded the title compound as a reddish oil (465 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:13][CH2:12][C:11](=[O:14])[N:10]([C@@H:15]([CH2:20][CH3:21])[C:16](OC)=[O:17])[C@@H:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Li+].CO>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:9]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[N:10]([C@@H:15]([CH2:20][CH3:21])[CH2:16][OH:17])[C:11](=[O:14])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C(=O)OC)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: CC[C@@H](CO)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 48.5 g (115 mmol) of (S)-methyl 2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate (Example 185, Step A) in ethyl ether (850 mL) was added 5.96 g (90%, 246 mmol) of lithium borohydride. The resulting light yellow solution was stirred at 0° C. for 3 h, and then MeOH (2.5 mL) and more ethyl ether (100 mL) were added. Gas evolution was observed upon the addition of MeOH. After 40 min, the reaction was quenched by cautious addition of 1 N HCl until bubbling subsided. The mixture was extracted with EtOAc (2×), and the combined organic layers were washed with saturated aqueous sodium chloride (1×). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to afford the title compound as a white foam. The crude product was used directly in the next step without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=[O:12])[CH:2]=1.S(Cl)(Cl)=O.[CH3:18]O>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13][CH3:18])=[O:12])[CH:2]=1
Reactant: CO
Reactant: O=C(O)c1cnc2ccccc2c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cnc2ccccc2c1
Temperature: 80 °C
Yield: 99 %

Procedure:
The solution of quinoline-3-carboxylic acid (3 g, 17.32 mmol) in methanol (30 mL) was cooled on ice bath at 0° C. Then thionyl chloride (1.264 mL, 17.32 mmol) was added and the reaction mixture was heated to 80° C. and maintained overnight. Reaction was monitored by TLC. After completion of reaction methanol was evaporated under reduced pressure and the resultant residue was basified with saturated sodium bicarbonate to make pH (7 to 8) to get white solid which was filtered and dried to get methyl quinoline-3-carboxylate (3.2 g, yield-99%) as a white solid; m/z-187.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:18])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5]([Cl:18])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OC)c(C(=O)O)cc1OC
Solvent: c1ccccc1
Product: COc1cc(OC)c(C(=O)Cl)cc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 89.7 %

Procedure:
To a suspension of 2,4,5-trimethoxybenzoic acid (2.12 g, 10 mmol) in dry 10 mL benzene was added thionyl chloride (4.4 mL, 60 mmol). The reaction mixture was stirred at 70° C. for 5 hr. The solvent was evaporated in vacuo. The residue was washed with hexane to give 2.07 g of the title compound which was used for the next step without further purification. 1H NMR (CDCl3) δ: 7.65 (1 H, s), 6.50 (1 H, s), 4.05 (3 H, s), 3.97 (3 H, s), 3.86 (3 H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](Cl)=[O:7].[CH3:14][C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH2:17].N1C=CC=CC=1>C(Cl)Cl>[CH3:14][C:15]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:16]=1[NH:17][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Cc1ccc([N+](=O)[O-])cc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2cc([N+](=O)[O-])ccc2C)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
A solution of 3,4-dimethoxybenzoyl chloride (11.5 g) in methylene chloride (100 ml) was added dropwise to a stirred mixture of 2-methyl-5-nitroaniline (8.74 g), pyridine (18.6 ml) and methylene chloride (200 ml) and the mixture was stirred at ambient temperature for 18 hours. The mixture was washed with 2M hydrochloric acid and with water, dried over magnesium sulphate, filtered and evaporated to dryness. The resultant solid was dried under vacuum at 60° C. to yield N-(2-methyl-5-nitrophenyl)-3,4-dimethoxybenzamide (15.9 g); m.p.>300° C.; NMR: (CDCl3) 2.43 (s, 3H), 3.94 (m, 6H), 6.93 (m, 1H), 7.38 (m, 2H), 7.51 (m, 1H), 7.75 (broad s, 1H), 7.94 (d, 1H), 8.89 (broad m, 1H).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([NH:12][NH2:13])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24]([CH2:27][C:28](O)=S)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24]([CH2:27][C:28]2[O:11][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[NH:1][CH:2]=[N:3][C:4]=4[CH:9]=3)=[N:12][N:13]=2)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: NNC(=O)c1ccc2nc[nH]c2c1
Reactant: COc1ccc(S(=O)(=O)CC(O)=S)cc1OC
Product: COc1ccc(S(=O)(=O)Cc2nnc(-c3ccc4[nH]cnc4c3)o2)cc1OC

Procedure:
The compound was synthesized starting from benzimidazol-5-carbohydrazide (176 mg, 1 mmol) and 3,4-dimethoxyphenylsulfonylthioacetic acid (261 mg; 1 mmol) as described in method 2 but purified by flash chromatography on silica using a CHCl3/MeOH gradient; yield: 0.022 g (5.5%); MS m/z: 401.2 [M+H]+; 1H-NMR (DMSO d6, 400 MHz): δ 3.75 (s, 3H); 3.82 (s, 3H); 5.29 (s, 2H); 7.15 (d, 1H3J=8.7 Hz); 7.328-7.333 (m, 1H); 7.38 (dd, 1H, 4J=2.1 Hz, 3J=8.7 Hz); 7.68-7.72 (m, 1H); 7.78-7.82 (m, 1H); 8.01 (br s, 1H); 8.38 (s, 1H); 12.80 (br s, 1H); HPLC (METHOD [A]): rt 10.19 min (90.6%)
Reaction SMILES: [Na].[CH2:2]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH3:4].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32]>C(O)C>[C:26]1(=[O:27])[N:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:5]([CH2:2][CH2:3][CH3:4])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:23](=[O:32])[C:24]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:25]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCC(CCCCCN1C(=O)c2ccccc2C1=O)(C(=O)OCC)C(=O)OCC
Yield: 41 %

Procedure:
Sodium (0.5 g) was dissolved in ethanol (7 ml) and diethyl propylmalonate (4.4 g) was added to the solution. The resulting mixture was heated under reflux for 15 minutes. To the mixture was added N-(5-bromopentyl)phthalimide (6.4 g) and the mixture was further heated under reflux for 4 hours. Then, ethanol was removed by distillation. The residue was treated with ether and filtered. The filtrate was concentrated and the residue was chromatographed on silica gel column. A fraction eluted with 5% methanol in chloroform was recrystallized from a mixture of ether and hexane to give colorless crystals of diethyl 2-(5-phthalimidopentyl)-2-propylmalonate (m.p. 51°-52° C., yield 3.7 g).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]2[C:5]([C:6](=[O:13])[NH:7][S:8]2(=[O:10])=[O:9])=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:23]1([S:29][CH2:30]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[CH:14]([C:4]1[CH:3]=[C:2]([OH:1])[CH:12]=[C:11]2[C:5]=1[C:6](=[O:13])[N:7]([CH2:30][S:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[S:8]2(=[O:10])=[O:9])([CH3:16])[CH3:15]
Reactant: ClCSc1ccccc1
Reactant: CC(C)c1cc(O)cc2c1C(=O)NS2(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: CC(C)c1cc(O)cc2c1C(=O)N(CSc1ccccc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69.9 %

Procedure:
6-hydroxy-4-isopropylsaccharin (30.0 g, 0.12 mol) in methanol was treated with Cs2CO3 (20.28 g, 0.062 mol). The mixture was stirred at ambient temperature for 3-4 hours, the excess methanol was removed under reduced pressure and the residue was dried under high vacuum. The residue was dissolved in DMF and chloromethyl phenyl sulfide (21.72 g, 0.14 mol) was added. The mixture was heated at 70°-80° C. for 24 hours, cooled, treated with ice-water and extracted with ethyl acetate/ether. The organic layer was washed with water, then brine and was dried. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with ethyl acetate/hexane to afford 30.5 g (67%) of 4-isopropyl-6-hydroxy-2-phenylthiomethylsaccharin.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:2][NH:1][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][C:7]=1[C:13]([F:15])([F:16])[F:14])#[N:10]
Reactant: N#Cc1ccc(N(CCN)CC(F)(F)F)cc1C(F)(F)F
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: N#Cc1ccc(N(CCNC(=O)c2ccccc2)CC(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.4 %

Procedure:
A solution of crude 4-[(2-aminoethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.018 mg, 0.058 mmol) in CH2Cl2 (3 mL) was treated with TEA (0.0064 g, 0.063 mmol) and benzoyl chloride (0.0089 mg, 0.063 mmol) and stirred at rt for 1 h. The mixture was partitioned between EtOAc and 0.1N HCl. The organic phase was washed with 0.1N HCl and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (5-70% EtOAc/hexanes gradient) and the product crystallized from CH2Cl2/hexanes to give the title compound as a white solid (0.016 g, 66% yield): MS (ES) mlz 416 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19])[C:5]([O:7]N1C(=O)CCC1=O)=O.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1)[CH2:27][NH2:28].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:28][CH2:27][C:26]2[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=[C:24]([O:23][CH3:22])[CH:25]=2)=[O:7])[CH:15]=[CH:16][C:17]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: COc1cc(CN)cc(OC)c1
Reactant: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NCc2cc(OC)cc(OC)c2)cc1Cl
Yield: 72.6 %

Procedure:
A solution of 1-[[3-chloro-4-(methoxycarbonyl)benzoyl]oxy]-2,5-pyrrolidinedione (Example 5; 2.00 g, 6.4 mmol), 3,5-dimethoxybenzylamine (1.25 g, 7.5 mmol) and triethylamine (1.00 g, 9.9 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature overnight. The solvent was evaporated (<0.5 mm Hg, 40° C.), ethyl acetate (200 mL) was added, and the solution was allowed to stand over the weekend at room temperature. The white solid was filtered off and discarded. Silica gel was added, the solvent was evaporated and the residue was chromatographed (30-50% ethyl acetate/hexanes) to give 2-chloro-4-[[[(3,5-dimethoxyphenyl) methyl]amino]carbonyl]benzoic acid, methyl ester (1.69 g, 72%) as a white solid, mp 101-103° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:20])[F:19])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:22]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>CC(O)C>[C:22]([C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:18]([F:21])([F:20])[F:19])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:31][CH:32]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: FC(F)(F)c1ccccc1-c1ccc2c(Cl)ccnc2c1
Solvent: CC(C)O
Product: CC(C)(C)c1ccc(Nc2ccnc3cc(-c4ccccc4C(F)(F)F)ccc23)cc1

Procedure:
Heat a mixture of 4-chloro-7-(2-trifluoromethyl-phenyl)-quinoline (42 mg, 0.14 mmol) and 4-(tert-butyl)aniline (41 mg, 0.29 mmol) in 2-propanol (10 mL) at reflux for 3 hours. Evaporate the mixture, add 1M NaOH (10 mL), extract twice with EtOAc (10 mL each), dry (Na2SO4), and evaporate to provide the crude product. Purify by silica gel chromatography, eluting with 75% hexane-EtOAc to provide (4-tert-Butyl-phenyl)-[7-(2-trifluoromethyl-phenyl)-quinolin-4-yl]-amine as a white solid. Mass spec. 420.2.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Pt]=O>[CH:1]1([CH:7]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:8][C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C(O)CC(C1CCCCC1)C1CCCCC1
Reaction time: 24 h

Procedure:
A solution of 15 g (0.066 mol) of 3,3-diphenylpropionic acid in 200 ml of acetic acid was treated with 2.25 g of platinum oxide and shaken on the Parr hydrogenator for 24 hours at a starting pressure of 60 lbs. Whenever the pressure dropped to approximately 45 lbs., the system was repressurized to 60 lbs. After heating on the steam bath to redissolve solid which had separated, the solution was decanted from the catalyst which had settled, filtered under argon, and the catalyst washed with additional acetic acid by decantation. The acetic acid was removed on a rotary evaporator to give a colorless solid (remaining acetic acid azeotroped with toluene). The solid was taken up in 250 ml of chloroform, filtered to clarify, and the chloroform evaporated. The product was suspended in ether and the evaporation repeated. After drying at reduced pressure for 2 hours, the solid weighed 15.25 g, melting point 118°-120° C. (s, 114° C.).
Reaction SMILES: N[N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:5][CH2:4][CH2:3]1.[ClH:19].[NH:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1>>[ClH:19].[C:13]1([CH:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[C:9]4[C:22]5[CH2:21][NH:20][CH2:25][CH2:24][C:23]=5[N:2]([C:8]=34)[CH2:3][CH2:4][O:5]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CCNCC1
Reactant: NN1CCOC(c2ccccc2)c2ccccc21
Agent: Cl
Product: c1ccc(C2OCCn3c4c(c5cccc2c53)CNCC4)cc1

Procedure:
1-Amino-1,2,3,5-tetrahydro-5-phenyl-4,1-benzoxazepine [Testa and Fontanella, Il Farmaco, 18, 815 (1963)] is reacted with 4-piperidone hydrochloride as described in Example 110 to yield the title compound, m.p. 297°-299°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[C:8]=2[CH:21]=1)([O-])=O>C(O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[O:13])[C:8]=2[CH:21]=1
Reactant: CCCN(CCC)C(=O)c1csc2ccc([N+](=O)[O-])cc12
Agent: [Fe]
Solvent: CCO
Product: CCCN(CCC)C(=O)c1csc2ccc(N)cc12

Procedure:
80 g of 5-nitro-N,N-dipropyl-3-benzothiophencarboxamide were reduced with Fe-powder in 90% ethanol as in Example 11. Yield of title compound: 75 g as a semicrystalline product. 1H NMR(CDCl3): 7.0 ppm(d, 1H); 6.5 ppm(d, 1H); 6.3 ppm(s, 1H); 4.4 ppm(dd, 1H); 3.0-3.9 ppm(m, 8H); 1.4-1.9 ppm(m, 4H); 0.9 ppm(d. t., 6H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10]C(C1C=CC=C2C=1CN(C1SC(CCCOC3C=CC(C4C(C#N)=CSC=4)=CC=3)=C(C(O)=O)N=1)CC2)=O.[N+:48]([C:51]1[CH:52]=[C:53]([S:57]([NH:60][CH2:61][CH2:62][C:63]2[S:67][C:66]([N:68]3[CH2:77][CH2:76][C:75]4[C:70](=[C:71]([C:78](=[O:97])/C=C5/SC6C=CC=CC=6N/5COCC[Si](C)(C)C)[CH:72]=[CH:73][CH:74]=4)[CH2:69]3)=[N:65][C:64]=2[C:98]([O:100]CC)=[O:99])(=[O:59])=[O:58])[CH:54]=[CH:55][CH:56]=1)([O-:50])=[O:49]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:78]([C:71]1[CH:72]=[CH:73][CH:74]=[C:75]2[C:70]=1[CH2:69][N:68]([C:66]1[S:67][C:63]([CH2:62][CH2:61][NH:60][S:57]([C:53]3[CH:54]=[CH:55][CH:56]=[C:51]([N+:48]([O-:50])=[O:49])[CH:52]=3)(=[O:59])=[O:58])=[C:64]([C:98]([OH:100])=[O:99])[N:65]=1)[CH2:77][CH2:76]2)=[O:97]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)/C=C4/Sc5ccccc5N4COCC[Si](C)(C)C)c3C2)sc1CCNS(=O)(=O)c1cccc([N+](=O)[O-])c1
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1nc(C(=O)O)c(CCNS(=O)(=O)c3cccc([N+](=O)[O-])c3)s1)CC2

Procedure:
The title compound 70 was prepared in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 70A: 1H NMR (DMSO-d6): δ 8.39-8.44 (m, 2H), 8.11-8.15 (m, 2H), 8.04 (d, J=7.98 Hz, 1H), 7.78-7.84 (m, 2H), 7.68 (d, J=7.36 Hz, 1H), 7.34-7.50 (m, 4H), 6.90 (d, J=8.29 Hz, 1H), 4.79 (s, 2H), 3.69 (d, J=5.98 Hz, 2H), 3.06-3.10 (m, 4H), 3.03 (t, J=5.98 Hz, 2H). ESI (+)/MS: 665 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.CN(C)CCCN=C=NCC.[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][NH:37]2>CN(C=O)C.N1C=CC=CC=1>[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH2:35][CH2:36][N:37]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=S
Reactant: Fc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CCc3c(F)cccc32)nc(N2CCOCC2)cc1=S

Procedure:
The product is prepared by following the procedure described in example 4e (step 4e) using 250 mg of sodium (1-methyl-4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)acetate in 6 ml of DMF and 6 ml of pyridine are added 512 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 141 mg of 4-fluoro-2,3-dihydro-1H-indole.
Reaction SMILES: [CH3:1][N:2]([CH:19]([CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)[CH2:20][CH2:21][C:22](O)=[O:23])[C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1.[NH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:36]1([NH:35][C:22](=[O:23])[CH2:21][CH2:20][CH:19]([N:2]([CH3:1])[C:3](=[O:18])[C:4]2[CH:5]=[C:6]([C:14]([F:16])([F:17])[F:15])[CH:7]=[C:8]([C:10]([F:12])([F:11])[F:13])[CH:9]=2)[CH2:25][C:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[NH:28][CH:27]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ccccc1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)O)Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CCC(=O)Nc1ccccc1)Cc1c[nH]c2ccccc12
Reaction time: 16 h

Procedure:
A mixture consisting of 42.9 mg of 4[N'-methyl-N'-(3,5-bis-trifluoromethyl-benzoyl)-amino]-5-(1H-indol-3-yl)-pentanoic acid, 8.9 mg of aniline, 36.65 mg of propanephosphonic acid anhydride, 60 μl of triethylamine and 1.5 ml of methylene chloride is left to stand at room temperature for 16 hours. 0.5 ml of 1N potassium carbonate solution is then added and the mixture is shaken vigorously. After separation of the phases, the organic phase is separated off and concentrated by evaporation. In this way the title compound is obtained in the form of a white foam. Rf value=0.26 (ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[C:6]([SH:8])[CH:7]=1.[C:10](OCC)(=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12].O.Cl>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[S:8][C:6]=2[CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1ccc(F)cc1S
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nc2ccc(F)cc2s1

Procedure:
A solution of 5-fluoro-2-aminobenzenethiol (0.94 g, 6.6 mmol) in diethyl oxalate (1.8 mL, 13 mmol) is heated at reflux for overnight. The solution is poured into a mixture of water (9.8 mL), conc. HCl (3.3 mL), and EtOH (4.6 mL). The material is extracted with CHCl3 (3×100 mL). The combined organic extracts are dried over MgSO4, filtered and concentrated to yield an oil. The material is purified by chromatography (25% hexanes/75% CHCl3) to afford a solid that is recrystallized from petroleum ether (0.16 g, 11%). MS for C10H8NO2SF: m/z 226 (M+H)+.