Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N=C[N:3]([C:6](N2C=NC=C2)=[S:7])C=1.[NH2:13][C:14]1[NH:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.C([O-])(=O)C.[NH4+]>C(#N)C>[NH:15]1[C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=[C:14]1[NH:13][C:6]([NH2:3])=[S:7]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc2ccccc2[nH]1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: NC(=S)Nc1nc2ccccc2[nH]1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
0.535 g (3.0 mmol) N,N′-thiocarbonyldiimidazole was dissolved in 5 ml acetonitrile, and to this yellow solution was added drop-wise 0.40 g (3.0 mmol) 2-aminobenzimidazole, suspended in 5 ml acetonitrile, at room temperature. After 30 minutes, a precipitate formed, and the mixture was stirred another 12 hours. After 0.474 g (6.0 mmol) ammonium acetate in substance (German: “in Substanz”) was added to this mixture, the mixture was heated in the microwave (at 100 Watt) 30 minutes long at 90° C. The solvent was removed under vacuum, water was added to the residue and an extraction with dichloromethane (3×30 ml) followed. The combined organic phase was washed once again with water and, after drying over MgSO4, the solvent was removed under vacuum. The product was purified by means of preparative HPLC (Merck: Chromolith RP-18E, 100-25; eluent wasser/acetonitrile/0.1 molar acetic acid). In this single pot procedure, 0.27 g of the N-1H-benzimidazole-2-ylthiourea was directly recovered without isolation of the intermediate.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[C:5]([C:15](O)=[O:16])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.ClC(N(C)C)=C(C)C.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[OH:37].C(N(C(C)C)C(C)C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C(OCC)(=O)C>[OH:37][C@@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]1[NH:30][C:15]([C:5]1[C:4]([C:18]([F:20])([F:21])[F:19])=[N:3][C:2]([Br:1])=[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1)=[O:16]
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1nc(-c2ccc(Cl)cc2)c(Br)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a yellow suspension of 1.50 g 5-bromo-6-(4-chloro-phenyl)-3-trifluoromethyl-pyrazine-2-carboxylic acid in 11 ml dichloromethane was added drop wise 0.608 g 1-chloro-N,N, 2-trimethylpropenylamine and the resulting the yellow solution was stirred at room temperature for 30 min. The resulting orange solution was added dropwise to a cooled (ice bath) solution of 0.522 g (1R,2R)-2-amino-cyclohexanol and 0.7868 g ethyldiisopropylamine in 10 ml ethyl acetate. This red solution was stirred at room temperature for 90 min. To the red solution was added 30 ml 10% aqueous citric acid solution. The layers were separated and the organic layer was purified by chromatography on silica gel with a gradient of heptane: ethyl acetate=1:1 to ethyl acetate to yield 1.56 g of the title compound as yellow crystals. MS (M−H) at 479.0 and 476.0.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9](=[O:49])[CH2:10][C:11]1[CH:48]=[CH:47][CH:46]=[CH:45][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]3[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[N:16]=1>C(Cl)Cl.C1CCCCC1>[NH:35]1[CH2:36][CH2:37][CH:32]([C:29]2[CH:28]=[CH:27][C:26]([NH:25][C:17]3[N:16]=[C:15]([CH2:14][CH2:13][C:12]4[CH:45]=[CH:46][CH:47]=[CH:48][C:11]=4[CH2:10][C:9]([NH2:8])=[O:49])[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=3)=[CH:31][CH:30]=2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: NC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCNCC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 23 h
Yield: 83.5 %

Procedure:
Trifluoroacetic acid (0.595 mL, 7.78 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I49) (90.8 mg, 0.156 mmol) in dry DCM (5 mL) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 23 hours. The volatiles were removed in vacuo and the residue partitioned between EtOAc (30 mL) and 2M NaOH (30 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic layers were washed with water (30 mL), brine (30 mL), dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a white solid which was suspended in DCM (2 mL) and cyclohexane (10 mL). The resulting precipitate was filtered to afford title compound (11) (63 mg, 84%) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.13 (s, 1H), 8.65 (s, 1H), 7.67-7.64 (m, 2H), 7.44 (s, 1H), 7.27-7.12 (m, 6H), 6.93 (s, 1H), 3.50 (s, 2H), 3.14-3.06 (m, 2H), 3.02-2.99 (m, 4H), 2.62-2.46 (m, peaks obscured by DMSO), 1.67 (d, J=11.4 Hz, 2H), 1.49 (qd, J=12.5, 3.9 Hz, 2H). LCMS Method C: rt 4.84 min; m/z 484 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][C:34]([CH:38]([CH3:40])[CH3:39])=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:41])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[ClH:42].O1CCOCC1>O1CCOCC1>[ClH:42].[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][C:34]([CH:38]([CH3:39])[CH3:40])=[CH:35][CH:36]=5)[CH:31]=[CH:30][C:29]4=[O:41])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)c1ccc2c(ccc(=O)n2CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1ccc2c(ccc(=O)n2CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.24 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-isopropyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 6 mL of 1,4-dioxane and 2 mL of 4.0 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature overnight. The solvent was removed under reduced pressure, and the resulting solid was recrystallized in methanol-ethyl acetate to give 91 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-6-isopropylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[ClH:7].[C:8](=[NH:13])(OCC)[CH3:9]>C(O)C>[ClH:7].[F:1][C:2]([F:6])([F:5])[CH2:3][NH:4][C:8](=[NH:13])[CH3:9]
Reactant: NCC(F)(F)F
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Product: CC(=N)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2,2,2-trifluoroethylamine (3 ml), ethyl acetimidate hydrochloride (4.8 g) and ethanol (12 ml) was stirred at room temperature for 90 minutes, and then stirred overnight at 80° C. The reaction mixture was concentrated under reduced pressure to obtain the title compound (6.66 g).
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([N:21]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[N:22]3)=[C:16]([CH3:30])[CH:15]=2)[NH:7]S(C(C)(C)C)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:31]>CO>[ClH:31].[CH:1]1([CH:6]([C:14]2[CH:15]=[C:16]([CH3:30])[C:17]([N:21]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[N:22]3)=[C:18]([CH3:20])[CH:19]=2)[NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C(NS(=O)C(C)(C)C)C2CCCC2)cc(C)c1-n1cc(C(F)(F)F)cn1
Agent: Cl
Solvent: CO
Product: Cc1cc(C(N)C2CCCC2)cc(C)c1-n1cc(C(F)(F)F)cn1

Procedure:
To a solution of (+/−)-N-(cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methyl)-2-methylpropane-2-sulfinamide (1.184 g, 2.680 mmol) in methanol (13.4 mL) was added hydrogen chloride (4 M in dioxane, 3.35 mL, 13.4 mmol) dropwise. The reaction was concentrated under reduced pressure to provide (+/−)-cyclopentyl(3,5-dimethyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine hydrochloride. 1H NMR (400 MHz, CD3OD, δ): 8.33 (s, 1 H), 8.07 (s, 1H), 7.31 (s, 2H), 4.05 (d, J=10.6 Hz, 1H), 2.35-2.51 (m, 1H), 2.10-1.98 (m, 7H), 1.89-1.39 (m, 6H), 1.20-1.14 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[CH2:13]([OH:25])[C@H:14]([OH:24])[C@@H:15]([OH:23])[C@H:16]([OH:22])[C:17]([C:19](O)=[O:20])=[O:18]>>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].[OH:25][CH2:13][C@@H:14]([C@H:15]([C@@H:16]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:22])[OH:23])[OH:24]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO

Procedure:
Transposon mutagenesis was carried out (Manning R. F. et al., U.S. Pat. No. 5,082,785) to construct L-sorbose reductase deficient strain from 2-keto-L-gulonic acid-producing L42-9 strain. Any strains which produce L-sorbose from D-sorbitol and assimilate the resulting L-sorbose by L-sorbose reductase of the present invention can be obtained from G. melanogenus IFO 3293 by means of multi-step mutations with chemical mutagens including NTG and ICR170, ultraviolet irradiation etc. E. coli W3110 carrying P1::Tn5 maintained on LB agar plate containing 30 μg/ml of kanamycin was inoculated into 5 ml of P1 medium (LB supplemented with 0.01 M MgSO47H2O and 10 μg/ml thymine) and cultivated at 30° C. overnight. One ml of this culture was transferred to 100 ml of the same medium in a 500 ml-Erlenmyer flask and grown to OD550 of approximately 0.09 at 30° C. for 95 min. The resulting culture was cooled on ice for 10 min and centrifuged at 3500 rpm at 4° C. for 20 min. The cells were suspended in 25 ml of P1 medium and the cell suspension was transferred to a 300 ml-flask and incubated at 42° C. for 20 min without shaking. When lysis of the cell was observed by standing at 37° C. for 90 min, the cells were lysed by adding 0.5 ml of chloroform. The mixture was then vortexed thoroughly, stood at room temperature for 10 min, and centrifuged at 10,000 rpm at 4° C. for 15 min. After the supernatant was transferred into a sterile screw-top glass bottle, 0.5 ml of chloroform was added again and the lysate was stored at 4° C.
Reaction SMILES: [F:1][C:2]([F:35])([CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[CH:3]=[CH:4]/[C@H:5]1[C@H:9]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH2:8][C@H:7](O)[C@@H:6]1[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].C1C=C(SSC2N=CC=CC=2)N=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]([F:35])([CH2:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)/[CH:3]=[CH:4]/[C@@H:5]1[C@@H:6]2[C@@H:7]([O:25][C:24](=[O:26])[CH2:23][CH2:22][CH2:21][CH:20]=[CH:19][CH2:18]2)[CH2:8][C@H:9]1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](/C=C/C(F)(F)COc2ccccc2)[C@H](OC2CCCCO2)C[C@@H]1O
Agent: O=C1CCC/C=C\C[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: Cc1ccccc1C
Product: O=C1CCCC=CC[C@@H]2[C@@H](/C=C/C(F)(F)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (Z)-7-((1R,2R,3R,5S)-2-((E)-3,3-difluoro-4-phenoxybut-1-en-1-yl)-5-hydroxy-3-((tetrahydro-2H-pyran-2-yl)oxy)cyclopentyl)hept-5-enoic acid (145.0 g from Example 32) in xylene (2 L) was treated with 2,2′-dipyridyl disulfide (90.0 g, 0.41 mol.) and triphenylphosphine (123.0 g, 0.47 mol.). This mixture was then stirred for 1 hr at room temperature under an atmosphere of nitrogen. The resulting mixture was heated to 80° C. for 18 hr (TLC monitoring), followed by removal of xylene under reduced pressure. The residue was diluted with saturated aqueous solution of sodium bicarbonate (1.6 L) and extracted with ethyl acetate (1.6 L). The organic layer is dried over magnesium sulfate and concentrated under reduced pressure to give 322.0 g of crude product. The crude product was purified by column chromatography providing 26.0 g of the title compound (48% yield, 3 steps).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:13]O)[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.S(Cl)([Cl:17])=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:13][Cl:17])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)Cc2cc(Br)cc(CO)c2O1
Solvent: ClCCl
Product: CC1(C)Cc2cc(Br)cc(CCl)c2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methanol (669) (390 mg, 1.51 mmol) in dichloromethane (15 mL) was added thionyl chloride (0.56 mL, 7.58 mmol). The reaction was stirred at room temperature for 2 hours and then concentrated to afford 5-bromo-7-(chloromethyl)-2,2-dimethyl-2,3-dihydrobenzofuran (670).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:22][C:21]([C:23]([OH:25])=O)=[CH:20][N:19]=3)=[O:17])=[CH:8]2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([C:18]3[NH:22][C:21]([C:23]([N:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[O:25])=[CH:20][N:19]=3)=[O:17])=[CH:8]2)=[CH:26][CH:27]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1cnc(C(=O)c2cn(Cc3ccc(Cl)cc3)c3ccccc23)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1ncc(C(=O)N2CCOCC2)[nH]1)c1cn(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A mixture of 2-[1-(4-chloro-benzyl)-1H-indole-3-carbonyl]-3H-imidazole-4-carboxylic acid (10 mg, 0.026 mmol), 4-(dimethylamino)pyridine (DMAP) (30 mg, 0.25 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (30 mg, 0.16 mmol) in CH2Cl2 (2 mL) was stirred at room temperature under N2 for 1 hour. Then morpholine (0.1 mL) in CH2Cl2 (2 mL) was added followed by stirring overnight at room temperature. After removal of solvent, product {2-[1-(4-Chloro-benzyl)-1H-indole-3-carbonyl]-3H-imidazol-4-yl}-morpholin-4-yl-methanone (8 mg, yield 68%) was purified by column chromatography (ethyl acetate:methanol=10:1). 1H NMR (CD3OD) δ3.7 (m, 8H), 5.58 (s, 2H), 7.3-7.45 (m, 7H), 7.80 (s, 1H), 8.42 (m, 1H), 9.05 (s, 1H) ppm; ESMS calcd (C24H21ClN4O3): 448.13; found: 449.1 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[N:14]3[C:9]([C:10](=[O:28])[NH:11][C:12]([C:15]4[CH:16]=[C:17]([S:24](Cl)(=[O:26])=[O:25])[CH:18]=[CH:19][C:20]=4[O:21][CH2:22][CH3:23])=[N:13]3)=[C:8]([CH2:29]C)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>ClCCl.CN(C)C1C=CN=CC=1>[CH2:22]([O:21][C:20]1[CH:19]=[CH:18][C:17]([S:24]([N:35]2[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]2)(=[O:25])=[O:26])=[CH:16][C:15]=1[C:12]1[NH:11][C:10](=[O:28])[C:9]2=[C:8]([CH3:29])[N:7]=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:14]2[N:13]=1)[CH3:23]
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C3CCCC3)nc(CC)c2c(=O)[nH]1
Reactant: CN1CCNCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
0.42 g (0.92 mmol) of 3-(7-cyclopentyl-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulphonyl chloride are dissolved in 15 ml of dichloromethane and cooled to 0° C. After addition of a spatula tip of 4-dimethylaminopyridine, 0.28 g (2.76 mmol) of N-methylpiperazine are added, and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with dichloromethane, the organic phase is washed with ammonium chloride solution and dried over sodium sulphate and the solvent is removed under reduced pressure. Crystallization from ether gives 0.395 g (80%) of a colourless solid.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]12([C:22]([NH:24][NH2:25])=[O:23])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:25]/[NH:24][C:22]([C:12]23[CH2:21][CH:16]4[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]4)[CH2:19]2)[CH2:13]3)=[O:23])/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NNC(=O)C12CC3CC(CC(C3)C1)C2
Product: CCCCCCN1C(=O)/C(=N\NC(=O)C23CC4CC(CC(C4)C2)C3)c2ccccc21
Yield: 59 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and adamantanecarbohydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 59%. 1H NMR (DMSO-d6): δ 0.85 (t, J=6.9 Hz, 3H), 1.27 (m, 6H), 1.60-1.65 (m, 2H), 1.72 (s, 6H), 1.91 (s, 6H), 2.05 (s, 3H), 3.75 (t, J=7.2 Hz, 2H), 7.16 (t, J=7.5 Hz, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.59 (d, J=7.5 Hz, 1H), 13.28 (br s, 1H). 13C NMR (DMSO-d6): δ 14.32 (CH3), 22.44 (CH2), 26.38 (CH2), 27.41 (CH2), 27.85 (CH), 31.31 (CH2), 36.32 (CH), 38.80 (CH2), 39.52 (CH2), 110.59 (CH), 119.75 (C), 121.03 (CH), 123.61 (CH), 131.96 (CH), 143.27 (C═N), 161.39 (C═O). HRMS (ES+) calcd for C25H34N3O2 (M+H+), m/e, 408.2660. found, 408.2646.
Reaction SMILES: COC[O:4][CH:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[CH:7]([C:8](=[O:32])[O:9][C:10]3[C@H:11]4[C@:23]([CH3:31])([CH2:24][CH2:25][C:26]=32)[C@@H:14]([C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]4)[CH2:6]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)(C)(C)C>[OH:4][C@@H:5]1[CH2:6][C@@H:7]2[C:8](=[O:32])[O:9][C:10]3[C@H:11]4[CH2:12][CH2:13][C@H:14]([C@@H:15]([CH2:16][CH2:17][CH2:18][CH:19]([CH3:20])[CH3:21])[CH3:22])[C@@:23]4([CH3:31])[CH2:24][CH2:25][C:26]=3[C@@:27]2([CH3:30])[CH2:28][CH2:29]1
Reactant: COCOC1CC[C@]2(C)C3=C(OC(=O)C2C1)[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@@H]2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C[C@@H]1C(=O)O3
Temperature: 80 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
Compound 56 (110 mg, 0.250 mmol) in obtained in Example 46 was dissolved in tert-butanol (5 mL), and pyrimidium p-toluenesulfonate (1.9 g; 7.4 mmol) was added thereto, followed by stirring at 80° C. for 1 hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate twice. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography to obtain the title compound (84 mg, 85%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1>CN(C=O)C>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([OH:25])[N:12]2[CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([O:24][CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)=[O:23])=[CH:20][CH:21]=2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClCc1cccnc1
Reactant: CCCCOc1nc(N)c2nc(OC)n(Cc3ccc(C(=O)O)cc3)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(O)n(Cc3ccc(C(=O)OCc4cccnc4)cc3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.8 %

Procedure:
After 2-butoxy-9-(4-carboxybenzyl)-8-methoxyadenine (0.05 g, 0.13 mmol) prepared in accordance with the method of Reference example 5 and potassium carbonate (0.03 g, 0.22 mmol) were added to DMF (10 ml), 3-chloromethylpyridine hydrochloride (0.03 g, 0.18 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hours. After removing the solvent, the residue was poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=300/1˜30/1) and the resulting solid was added to methanol (10 ml) and concentrated hydrochloric acid (10 ml). The mixture was stirred at room temperature for 18 hours. After being neutralized with saturated sodium hydrogencarbonate, the solution was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated and washed with methanol to give the captioned compound (0.03 g, 0.07 mmol, yield: 52%) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[O:7].CC([O-])(C)C.[K+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1.[Cl-].[NH4+]>C1COCC1>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:1]2[CH:5]=[CH:4][CH:3]=[C:2]2[CH:6]=[O:7])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc[nH]1
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cn2cccc2C=O)cc1
Yield: 65.5 %

Procedure:
To pyrrole-2-carboxaldehyde (1.0 g, 10.5 mmol) in THF (60 mL) was added KOtBu (1.2 g, 10.5 mmol), Et4N+I− (100 mg) and 4-methoxybenzyl chloride (1.4 mL, 10.5 mmol). After 1 day saturated aqueous ammonium chloride was added and the mixture was extracted with EtOAc. The organic extract was dried over Na2SO4 and concentrated. Column chromatography (EtOAc/hexanes, 1:9) provided 1.48 g (65%) of 1-(4-methoxybenzyl)-1H-pyrrole-2-carbaldehyde as an oil.
Reaction SMILES: ClC1C=C2C(C3(C(OC)CC(=O)CC3C3C=CC=C(Cl)C=3)C(=O)N2)=CC=1.[N-]=[N+]=[N-].[Na+].[Cl:31][C:32]1[CH:40]=[C:39]2[C:35]([C@:36]3([C@@H:47]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[CH:49]=4)[CH2:46][C:45](=[O:55])[NH:44][CH2:43][C@H:42]3[O:56][CH3:57])[C:37](=[O:41])[NH:38]2)=[CH:34][CH:33]=1>C(#N)C.Cl[Ti](Cl)(Cl)Cl>[Cl:31][C:32]1[CH:40]=[C:39]2[C:35]([C@@:36]3([C@H:47]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[CH:49]=4)[CH2:46][C:45](=[O:55])[NH:44][CH2:43][C@@H:42]3[O:56][CH3:57])[C:37](=[O:41])[NH:38]2)=[CH:34][CH:33]=1
Reactant: CO[C@@H]1CNC(=O)C[C@H](c2cccc(Cl)c2)[C@@]12C(=O)Nc1cc(Cl)ccc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: COC1CC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [N-]=[N+]=[N-]
Solvent: CC#N
Product: CO[C@H]1CNC(=O)C[C@@H](c2cccc(Cl)c2)[C@]12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in example 2 (method A), rac-(1R,2S,6S)-6′-chloro-2-(3-chlorophenyl)-6-methoxyspiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (156 mg, 0.4 mmol) was reacted with NaN3 (52 mg, 0.8 mmole) in the presence of TiCl4 (1.0 M in CH2Cl2, 0.8 mL) (Aldrich) in acetonitrile (10 mL) followed by chiral chromatograph to give (3R,4R,5S)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-methoxy-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (17.6 mg) and (3S,4S,5R)-6′-chloro-5-(3-chlorophenyl)-1,1′,2,2′,3,5,6,7-octahydro-3-methoxy-spiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14](=O)/[CH:15]=[C:16](/[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:20][CH:19]=1)\[CH3:17])C>C(Cl)Cl>[N:25]1[CH:26]=[CH:27][CH:28]=[N:29][C:24]=1[C:21]1[CH:22]=[CH:23][C:18](/[C:16](/[CH3:17])=[CH:15]/[CH2:14][OH:13])=[CH:19][CH:20]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2ncccn2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: C/C(=C\CO)c1ccc(-c2ncccn2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.2 %

Procedure:
Diisobutylaluminum hydride (1.0 M solution in THF, 3.4 mL, 3.40 mmol) was added dropwise to a 0° C. solution of the product from step A (300 mg, 1.12 mmol) in methylene chloride (10 mL). The resulting solution was stirred for 20 min at 0° C., quenched with methanol (0.2 mL) followed by 15% aq. Rochelle salt (20 mL) and dichloromethane (10 mL), and allowed to stir at room temperature for 18 h. The layers were separated and the aqueous layer was extracted with methylene chloride (10 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 3:2 hexane/ethyl acetate) provided 221 mg (87%) of the title compound as an off-white solid. MS 227 (M+H)+.