Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([CH:17]([CH3:20])[CH:18]=O)[C:13]=3[CH:21]=2)[CH:5]=[C:4]([F:22])[C:3]=1[C:23]([F:26])([F:25])[F:24].[N+:27]([C:30]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=1[NH:39][NH2:40])([O-:29])=[O:28].OS(O)(=O)=O>C(O)C.O>[N+:27]([C:30]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=1[NH:39][N:40]=[CH:18][CH:17]([CH3:20])[N:14]1[C:13]2[CH:21]=[C:9]([O:8][C:6]3[CH:5]=[C:4]([F:22])[C:3]([C:23]([F:26])([F:25])[F:24])=[C:2]([Cl:1])[CH:7]=3)[CH:10]=[CH:11][C:12]=2[N:16]=[N:15]1)([O-:29])=[O:28]
Reactant: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(C=O)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CC(C=NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21

Procedure:
A solution of 6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl) oxy]-α-methyl-1H-benzotriazol-1-acetaldehyde (0.0294 mole) in ethanol is added to a solution of 2,4-dinitrophenylhydrazine (7 g, 0.035 mole) and conc. H2SO4 (35 ml, 0.63 mole) in H2O at 50° C., allowed to come to room temperature and filtered. The solid filter cake is recrystallized from aqueous acetic acid and from ethanol to afford the title compound, mp 148°-149° C., identified by elemental and NMR analyses.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=O.[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH2:35][NH2:36])([CH3:29])([CH3:28])[CH3:27].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([NH:36][CH2:35][CH2:34][CH2:33][NH:32][C:31](=[O:37])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:25])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)c(CC(=O)NCCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
Compound 27gg, N-[3-{7-(N,N-Diethylamino)coumarin-3-carboxylamido}butyl]-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide was synthesized by the method depicted in FIG. 8. Briefly, indomethacin was complexed with tert-Butyl-3-aminopropylcarbamate for 16 hours at room temperature in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), N,N-diisopropylethylamine (DIPEA), and N,N-dimethylformamide (DMF). tert-Butyl 3-[2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamido]propylcarbamate was produced as a pale yellow solid at 70% yield. This product was then dissolved in dichloromethane and treated with HCl (gas) for 2 hours at room temperature, producing N-(4-qminobutyl)-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide hydrochloride as a brown solid with a yield of 98%, which was reacted with triethylamine (TEA) in dimethyl sulfoxide (DMSO) for 5 minutes at room temperature prior to the addition of 7-(N,N-Diethylamino)coumarin-3-carboxylic acid succinimidyl ester. The reaction proceeded for 16 hours at room temperature and produced Compound 27gg as a yellow solid (66% yield).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]([N:13]1[C:17]([OH:18])=[C:16]([C:19](=[O:39])[C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:21]=2[CH3:38])[CH:15]=[N:14]1)([CH3:12])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH3:12][C:10]([N:13]1[C:17]([O:18][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:16]([C:19](=[O:39])[C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)[C:21]=2[CH3:38])[CH:15]=[N:14]1)([CH3:9])[CH3:11]
Reactant: COc1ccc(-c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C(C)(C)C)c3O)c2C)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2c(S(C)(=O)=O)ccc(C(=O)c3cnn(C(C)(C)C)c3OCc3ccccc3)c2C)cc1
Reaction time: 8 h

Procedure:
Benzyl chloride (1.1 mL) was added with stirring under nitrogen to a mixture of 2.0 g (4.5 mmol) of 1-(1,1-dimethylethyl)-5-hydroxy-4-(2-methyl-4-methylsulfonyl-3-(4-methoxyphenyl)benzoyl)pyrazole and 1.3 g of sodium carbonate in about 20 mL of dry N,N-dimethylformamide and the resulting mixture was allowed to stir overnight. Ethyl acetate was then added and the resulting mixture was washed with water several times, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure. The residual orange oil was chromatographed on silica eluting with an 80:20 mixture and then a 60:40 mixture of hexane and ethyl acetate. The product fractions were combined and concentrated by evaporation under reduced pressure and dried to obtain 1.73 g (72 percent of theory) of the title compound as a yellow glass.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH:5]=[C:4]([CH2:8][CH2:9][CH3:10])[NH:3]1.[OH-].[Ca+2].[OH-].[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](Cl)=O.Cl>C1C=CC=CC=1.O1CCOCC1>[CH3:1][N:2]1[C:6]([OH:7])=[C:5]([CH2:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[Cl:14])[C:4]([CH2:8][CH2:9][CH3:10])=[N:3]1
Reactant: CCCc1cc(=O)n(C)[nH]1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cl
Agent: [Ca+2]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: CCCc1nn(C)c(O)c1Cc1ccccc1Cl
Temperature: 50 °C
Yield: 9.2 %

Procedure:
1.4 g. of 1-methyl-3-n-propyl-5-pyrazolone is dissolved in 10 ml. of dioxane with heating and then 1.5 g. of calcium hydroxide is added to the resulting solution. 1.75 g. of 2-chlorobenzoyl chloride is added dropwise with stirring at 50° C. After completion of the dropwise addition, the mixture is heated under reflux for 1 hour. After completion of the reaction, the reaction mixture is allowed to cool and 100 ml. of a 2 N hydrochloric acid solution is added thereto. The mixture is extracted with 70 ml. of chloroform and an organic layer is separated. The layer is washed with water, dried over anhydrous sodium sulfate and the solvent is distilled off from the layer to give 2 g. of brown oily residue. The residue thus obtained is dissolved in a small amount of benzene and adsorbed on a silica gel column, which is then eluted with benzene: ethanol (50:1) to give 0.6 g. of crystals. The crystals are recrystallized from methanol-water (7:3) to give 0.25 g. of the desired product as colorless columns having a melting point of 125°-126° C. Yield 9.2%
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:14][O:15][C:16]([C:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17].ON1C2C=CC=CC=2N=N1.[O:35]1[CH:39]=[CH:38][C:37]([C:40](O)=[O:41])=[CH:36]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:15][C:16]([C:18]1([NH:24][C:40]([C:37]2[CH:38]=[CH:39][O:35][CH:36]=2)=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)=[O:17]
Reactant: O=C(O)c1ccoc1
Reactant: COC(=O)C1(N)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1(NC(=O)c2ccoc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
105 g (550 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 98.8 g (500 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, 84.2 g (550 mmol) of 1-hydroxybenzotriazole, 56.0 g (500 mmol) of 3-furancarboxylic acid and 152 g (1.5 mol) of triethylamine in 1000 ml of methylene chloride under ice-cooling. After the mixture was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the obtained crystal was washed with diisopropyl ether to obtain 114 g (91%) of the title compound.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25](B(O)O)[C:24]([O:30][CH3:31])=[CH:23][C:22]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:25]3[C:24]([O:30][CH3:31])=[CH:23][C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=4)=[C:21]([Cl:20])[CH:26]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1B(O)O
Reactant: Clc1ncnc2cc(SCc3ccccc3)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1ncnc2cc(SCc3ccccc3)ccc12

Procedure:
A microwave vial was charged with 7-(benzylthio)-4-chloroquinazoline (0.372 g, 1.298 mmol), (2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)boronic acid (0.364 g, 1.298 mmol), tetrakis(triphenylphosphine)palladium(0) (0.150 g, 0.130 mmol), and potassium carbonate (0.897 g, 6.49 mmol). Dioxane (3.24 ml) and Water (1.081 ml) were added; the vial was flushed with argon and sealed, and microwaved at 90° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-75% EtOAc:Heptane) to afford 7-(benzylthio)-4-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)quinazoline as a yellow solid. (ESI) 487.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(Nc2ncnc3cnc(NCCN4CCNCC4)nc23)cc1Cl
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1CCN(CCNc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(1-piperazinyl)ethylamino]pyrimido[5,4-d]pyrimidine by reaction with acetic anhydride. Melting point: 196°-198° C.; Rf : 0.59 (alumina; methylene chloride/methanol=10:0.4)
Reaction SMILES: [CH3:1][C@@H:2]([NH2:10])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.C([O:19][C@@H:20]1[C@H:24]([O:25]C(=O)C2C=CC=CC=2)[C@@H:23]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[O:22][C@H:21]1[N:44]1[CH:52]=[N:51][C:50]2[C:45]1=[N:46][C:47]([Cl:54])=[N:48][C:49]=2Cl)(=O)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.N>O1CCOCC1>[Cl:54][C:47]1[N:48]=[C:49]([NH:10][C@H:2]([CH3:1])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:50]2[N:51]=[CH:52][N:44]([C:45]=2[N:46]=1)[C@@H:21]1[O:22][C@H:23]([CH2:34][OH:35])[C@@H:24]([OH:25])[C@H:20]1[OH:19]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: C[C@@H](N)Cc1ccccc1
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H](Cc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 20.6 %

Procedure:
The title compound was prepared by reacting L-amphetamine (0.49 g, 3.6 mmol) with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.9 g, 3.0 mmol) in dioxan (25 ml) in the presence of diisopropylethylamine (0.58 g, 4.5 mmol) followed by deprotection of the purified product using methanolic ammonia. Evaporation of the reaction mixture provided a gummy residue which crystallized on addition of dichloromethane (10 ml), to provide the title compound (0.26 g, 38%) as a solid, m.p. 132.5°-135.5° C. A further sample of the title compound (0.26 g) was obtained by flash chromatography of the mother liquors. 1H NMR (DMSO-d6)δ 1.22 (3H, d, -- CH3), 2.67-2.79 & 2.92-3.03 (2H, 2m, -- CH2 --), 3.51-3.58 (1H, m, H-5'a), 3.62-3.68 (1H, m, H-5'b), 3.94 (1H, q, H-4'), 4.12 (1H, m, H-3'), 4.41-4.54 (2H, m, H-2' and CH3C H--), 5.06 (1H, t, 5'-OH), 5.22, 5.49 (2H, 2d, 2' and 3'-OH), 5.82 (1H, d, H-1'), 7.10-7.33 (5H, m, Ar--H), 8.28-8.44 (2H, m, H-8 and N--H).
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:36]=[CH:35][C:10]([NH:11][C:12]2[CH:24]=[C:23]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-])=O)[CH:22]=[CH:21][C:13]=2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=1>[C].[Pd].C(OCC)(=O)C>[NH2:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:23]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([F:6])=[CH:36][CH:35]=2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1Nc1ccc(F)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2N)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
To a mixed solution of tetrahydrofuran 10 mL and ethyl acetate 5.0 mL of tert-butyl 2-(4-fluoroanilino)-4-(2-nitroanilino)benzoate 0.35 g was added 10% palladium-carbon 74 mg, it was stirred under hydrogen atmosphere at room temperature for 4 hours and 30 minutes, and subsequently it was stirred at 34° C. for 4 hours. After the reaction mixture was cooled to room temperature, insoluble matter was filtrated, and the solvent was removed under reduced pressure. Hexane was added to the obtained residue, and solid matter was filtrated to give tert-butyl 4-((2-aminophenyl)amino)-2-(4-fluoroanilino)benzoate 0.15 g of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](O)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([Cl:20])[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccc(Cl)cc2)nc2c1CCC2
Product: Clc1ccc(-c2nc(Cl)c3c(n2)CCC3)cc1
Reaction time: 3 h

Procedure:
8.0 g of 2-(4-chlorophenyl)-4-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidine are heated to 100° C. in 10 ml of phosphorus oxychloride. After 3 hours, the cooled solution was cautiously poured onto ice water. The crystalline product was filtered off with suction, washed well with water and dried in vacuo at room temperature. Yield: 6.5 g. M.p.: 1450° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Br:22]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Br:22])[CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)cc2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of intermediate (b), N-BOC-(R)-2-(4-hydroxybenzyl)morpholine (1.0 g, 3.41 mmol) in anhydrous N,N-dimethyl formamide (10 mL), under at atmosphere of nitrogen at room temperature was added N-bromosuccinimide (0.63 g, 3.58 mmol). The resulting solution was stirred at room temperature for 2 hrs and then poured into water (50 mL) and extracted with ethyl acetate (70 mL×2). Combined organic layers were washed with water (2×50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The material was concentrated onto sodium sulfate and purified by column chromatography (silica; 17% ethyl acetate/isohexane) to yield the desired intermediate (a), N-BOC-(R)-2-(3-bromo-4-hydroxybenzyl)morpholine, as a white solid (0.89 g).
Reaction SMILES: [O:1]=[C:2]1[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[NH:6][CH2:5][C@@H:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]1[CH2:18][C:19]([O:21]CC)=[O:20].[Li+].[OH-].[ClH:26]>C1COCC1.O>[ClH:26].[O:1]=[C:2]1[C:7]2([CH2:8][CH2:9][CH2:10][CH2:11]2)[NH:6][CH2:5][C@@H:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]1[CH2:18][C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)CN1C(=O)C2(CCCC2)NC[C@H]1c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1C(=O)C2(CCCC2)NC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl [(8R)-10-oxo-8-phenyl-6,9-diazaspiro[4.5]dec-9-yl]acetate from Step B (407 mg, 1.29 mmol) in THF (8 mL) and H2O (2 mL) was added 1 N aqueous LiOH (1.54 mL, 1.54 mmol) and the resulting mixture was stirred at ambient temperature for 4 h. The mixture was adjusted to pH 4 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=289 (M+1).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:13]2[CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][C:9](=O)[C:8]=2[C:7]([CH3:21])=[CH:6]1)(=[O:4])=[O:3].[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].[ClH:27].Cl.O>C(O)C>[ClH:27].[NH:25]([N:26]=[C:9]1[CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:13]2[N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]([CH3:21])[C:8]1=2)[C:22]([NH2:24])=[NH:23]
Reactant: N=C(N)NN
Reactant: Cc1cn(S(C)(=O)=O)c2c1C(=O)CC(c1ccccc1)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cn(S(C)(=O)=O)c2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Reaction time: 12 h
Yield: 46.7 %

Procedure:
A mixture of 1-methanesulfonyl-3-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.41 g), aminoguanidine hydrochloride (0.16 g), concentrated hydrochloric acid (0.068 ml), water (0.068 ml) and ethanol (30 ml) was refluxed for 20 minutes. The reaction solution was allowed to stand in a refrigerator for 12 hours, and precipitated crystals were filtered, which were washed with ethanol and recrystallized from water to give 4-guanidinoimino-1-methanesulfonyl-3-methyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 13) (0.25 g) as colorless crystals.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:19]([O:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)([CH3:21])[CH3:20].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:18][O:17][C:11]1[CH:10]=[C:9]([CH2:8][CH:2]([NH:1][C:27]([C:26]2[CH:30]=[CH:31][C:23]([O:22][CH:19]([CH3:21])[CH3:20])=[CH:24][CH:25]=2)=[O:28])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:13][C:12]=1[O:15][CH3:16]
Reactant: CCOC(=O)C(N)Cc1ccc(OC)c(OC)c1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OC)c(OC)c1)NC(=O)c1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-amino-3-(3,4-dimethoxyphenyl)propionate (the compound obtained in Example 1-(1)) (15.2 g), 4-isopropyloxybenzoic acid (10.8 g), and 1-hydroxybenzotriazole monohydrate (9.2 g) are dissolved in methylene chloride (120 ml), and thereto is added 1,3-dicyclohexylcarbodiimide (12.4 g) under ice-cooling, and the mixture is stirred at room temperature overnight. The insoluble materials are removed by filtration, and the filtrate is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals are collected by filtration with diethyl ether to give ethyl 3-(3,4-dimethoxyphenyl)-2-{[4-(isopropyloxy)phenyl]carbonylamino}propionate (24.2 g).
Reaction SMILES: C([NH:4][C@H:5]1[C@H:10]([C:11]([O:13]C)=[O:12])[C@@H:9]([CH3:15])[O:8][C:6]1=[O:7])(=O)C>Cl>[NH2:4][C@H:5]1[C@H:10]([C:11]([OH:13])=[O:12])[C@@H:9]([CH3:15])[O:8][C:6]1=[O:7]
Reactant: COC(=O)[C@H]1[C@H](NC(C)=O)C(=O)O[C@@H]1C
Agent: Cl
Product: C[C@H]1OC(=O)[C@@H](N)[C@@H]1C(=O)O
Temperature: 0 °C

Procedure:
114.4 g of 2(S)-acetamido-3(S)-methoxycarbonyl-4(R)-pentanolide are heated at 120° C. for 24 hours in semi-concentrated hydrochloric acid. The solution is slowly cooled to 0° C., and the precipitate is filtered off, washed with ethyl acetate, dried under a high vacuum and recrystallised from methanol. Hydrochloride of the title compound, [α]D20 =-21.5° (1% in H2O), m.p. >250° C. The free title compound is obtained by treating the hydrochloride with an excess of propylene oxide in hot methanol, [α]D20 =-23.1° (1% in 1N HCl), m.p. 196°-200° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:16](=[O:17])[C:10]3([CH2:14][CH2:13][O:12][C:11]3=[O:15])[S:9][C:8]=2[CH:18]=1)([O-])=[O:2]>C(OCC)(=O)C.C(O)(=O)C.[C].[Pd]>[OH:2][NH:1][C:4]1[CH:5]=[CH:6][C:7]2[C:16](=[O:17])[C:10]3([CH2:14][CH2:13][O:12][C:11]3=[O:15])[S:9][C:8]=2[CH:18]=1
Reactant: O=C1OCCC12Sc1cc([N+](=O)[O-])ccc1C2=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1OCCC12Sc1cc(NO)ccc1C2=O

Procedure:
In 35 ml of ethyl acetate and 3.5 ml of acetic acid was dissolved 356.3 mg of 6-nitro-4',5'-dihydrospiro[benzo[b]thiophen-2(3H),3'(2'H)-furan]-3,2'-dione as obtained in Reference Example 7, and was subjected to catalytic reduction under atmospheric pressure at room temperature in the presence of 113.3 mg of 5% palladium carbon. After absorption of hydrogen stopped, the catalyst was filtered off, and the filtrate was evaporated to dryness under reduced pressure. Recrystallization of the residue from water-acetone (7:3) yielded yellow needles of 6-hydroxyamino-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dione. Melting point: 184°-186° C.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([S:28][CH2:29][CH2:30][CH2:31]Cl)[CH:24]=2)[CH:19]=1.O>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28][CH2:29][CH2:30][CH2:31][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]1=[O:1])[CH:22]=[CH:21]2
Reactant: ClCCCSc1ccc2cc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCCSc2ccc3cc(Cl)ccc3c2)C(=O)C1
Yield: 92.4 %

Procedure:
tert-Butyl 3-oxopiperazine-1-carboxylate (2.0 g) was dissolved in DMF (30 mL), and sodium hydride (0.5 g) was added thereto. With ice cooling, 2-chloro-6-((3-chloropropyl)thio)naphthalene (2.7 g) was added thereto, and the mixture was mixed at 60° C. for 3 hours. The reaction solution was poured into water, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified with a silica gel column to give the title compound (4.0 g) as a pale brown oily matter.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([C:22](O)=[O:23])=[CH:14]1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:22]([C:15]3[C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[S:13][CH:14]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1csc2ccccc12
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1csc2ccccc12

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 1-benzothiophene-3-carboxylic acid (Maybridge) according to methods A and C; yield 58 mg, 0.17 mmol (56%): 1H NMR (300 MHz, methanol-d4) δ 1.98 (d, J=13 Hz, 2H), 2.20 (s, 1H), 2.36 (d, J=14 Hz, 2H), 2.48 (s, 2H), 3.57 (s, 2H), 3.69 (d, J=2 Hz, 4H), 4.47 (s, 1H), 7.38-7.48 (m, 2H), 7.92-7.96 (m, 1H), 8.27 (s, 1H), 8.27-8.32 (m, 1H); MS (DCI/NH3) m/z 313 (M+H)+; Anal. C18H20N2OS.HCl.0.13H2O: C, H, N.