Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:4][CH2:5][CH2:6][O:7][N:8]=[C:9]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:10]([O:12]CC)=[O:11])[CH:2]=[CH2:3].CO.[OH-].[Na+]>O1CCCC1>[CH2:1]([S:4][CH2:5][CH2:6][O:7][N:8]=[C:9]([C:15]1[N:16]=[C:17]([NH:20][CH:21]=[O:22])[S:18][CH:19]=1)[C:10]([OH:12])=[O:11])[CH:2]=[CH2:3]
Reactant: C=CCSCCON=C(C(=O)OCC)c1csc(NC=O)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCSCCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 35 °C
Reaction time: 5.5 h
Yield: 43.3 %

Procedure:
A mixture of ethyl 2-(2-allylthioethoxyimino)-2-(2-formamidothiazol-4-yl)acetate (syn isomer, 5.1 g.), methanol (37.2 ml.), 1 N-aqueous sodium hydroxide (37.2 ml.) and tetrahydrofuran (35 ml.) was stirred at 35° C. for 5.5 hours. After concentrating the resultant solution in vacuo, the residue was washed with ethyl acetate twice. The aqueous solution was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate twice. The extract was washed with a saturated aqueous solution of sodium chloride dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with n-hexane and the precipitates were collected by filtration to give 2-(2-allylthioethoxyimino)-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer, 2.03 g.), mp. 70° to 78° C.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:22][C:21]([CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:20][N:19]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:22][C:21]([CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[N:20][N:19]=1
Reactant: CC(C)(C)OC(=O)NCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3O)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
A mixture of tert-butyl (2-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)ethyl)carbamate (400 mg, 0.90 mmol) and 10% Pd/C (50 mg) in THF (20 mL) was stirred under H2 atmosphere at rt for 3 h. The reaction mixture was then filtered and concentrated to afford tert-butyl (2-(5-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)ethyl)carbamate (300 mg, 94%) as a white solid, which was used directly in the next step. ESI-MS (EI+, m/z): 354.24 [M+H]+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f35) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([S:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])=[CH:19][CH:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].I([O-])(=O)(=O)=[O:32].[Na+]>CO.O>[CH2:1]([S:13]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])=[CH:19][CH:18]=1)=[O:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCSCCOc1ccc(CCC(=O)C(F)(F)F)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCS(=O)CCOc1ccc(CCC(=O)C(F)(F)F)cc1
Temperature: 22 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A solution of 4-[4-[2-(dodecylthio)ethoxy]phenyl]-1,1,1-trifluoro-2-butanone (0.340 g, 0.76 mmol) in methanol (15 ml) was treated with a solution of sodium periodate (0.165 g, 0.77 mmol) in water (3 ml) and the resulting mixture was stirred at 22° C. for 18 h. The solid formed was filtered and washed with methanol. This filtrate was then concentrated under reduced pressure and then partitioned between water and ethyl acetate. The organic phase was then dried (magnesium sulfate) and concentrated. The residue was chromatographed on silica gel (elution toluene-ethyl acetate 1:1) to give 0.335 g (90%) of 4-[4-[2-(dodecylsulfinyl)ethoxy]phenyl]-1,1,1-trifluoro-2-butanone as a white solid. By 1HNMR this product was a 6:4 mixture of trifluoromethyl ketone and hydrated trifluoromethyl ketone. The pure hydrate precipitates from ethyl acetate-hexane: m.p. 98-100° C.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:43])[N:24]([CH2:32][CH2:33][O:34][CH2:35][CH:36]2[CH2:40][O:39]C(C)(C)[O:37]2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH:20]=[C:19]([Cl:44])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.O.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[Cl:44][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH2:32][CH2:33][O:34][CH2:35][CH:36]([OH:37])[CH2:40][OH:39])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[F:31])=[O:43]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCOCC2COC(C)(C)O2)c2ccccc2F)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(c1cc(Cl)cc(OCCNc2ccncc2)c1)N(CCOCC(O)CO)c1ccccc1F
Reaction time: 3 h

Procedure:
A solution of (2-{3-chloro-5-[[2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-ethyl]-(2-fluoro-phenyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.035 g) and water (0.010 ml) in mixture of trifluoroacetic acid (1 ml) and dichloromethane (1 ml) was stored at room temperature for 3 h and then the solvent removed under reduced pressure. The residue was subjected to preparative hplc to give the title compound (0.022 g) as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(NC(C)C)(C)C.[C:19]1([CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][NH2:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:27][CH2:26][CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
2,6-Dichloropurine (20.00 g, 106 mmol) is dissolved in THF (250 ml) under an atmosphere of argon. Diisopropylamine (16.38 g, 127 mmol) is added followed by 2,2-diphenylethylamine (25.00 g, 127 mmol) and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 6 hours. 50% of the solvent is removed in vacuo and replaced with MeOH. The resulting precipitate is filtered off and dried to give the title compound. 1H nmr (d6-DMSO, 400 MHz); 8.05(br s, 1H), 7.35-7.10(m, 10H), 4.55(m, 1H), 4.10(rri, 2H), MS (ES+) m/e 350 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[C:15](=[O:16])[CH2:14][C@@H:13]([C:17]([OH:19])=O)[CH2:12]2)[CH3:10])=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(C(C)C)CC)(C)C.[CH3:41][NH:42][O:43][CH3:44].Cl>CC1OCCC1>[CH3:44][O:43][N:42]([CH3:41])[C:17]([C@@H:13]1[CH2:14][C:15](=[O:16])[N:11]([C@@H:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH3:10])[CH2:12]1)=[O:19]
Reactant: CNOC
Reactant: COc1ccc([C@@H](C)N2C[C@H](C(=O)O)CC2=O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC1CCCO1
Product: COc1ccc([C@@H](C)N2C[C@H](C(=O)N(C)OC)CC2=O)cc1
Reaction time: 1.25 h

Procedure:
To a suspension of (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carboxylic acid 1.01 (1.0 g, 3.80 mmol) in 2-MeTHF (5 mL) was added CDI (925 mg, 5.70 mmol) and the mixture was stirred for 75 minutes over which time the reaction became homogenous. Diisopropylethyl amine (800 μL, 4.56 mmol) and N,O-dimethylhydroxylamine (445 mg, 4.56 mmol) were added and the reaction was stirred for 3 hours. 3M HCl (4 mL, 12 mmol) was added and the mixture was stirred for 5 minutes. The layers were separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organics were dried (MgSO4), filtered and concentrated to afford (R)-N-methoxy-1-((R)-1-(4-methoxyphenyl)ethyl)-N-methyl-5-oxopyrrolidine-3-carboxamide 1.02.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34]I)=[CH:29][CH:28]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH2:3]([C:5]([CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:28][CH:29]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:4]
Reactant: ICCc1ccc(OCCCCc2ccccc2)cc1
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC)(CCc1ccc(OCCCCc2ccccc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a suspension of sodium hydride (4.3 g) in dimethylformamide (212 ml) was added diethyl ethylmalonate (20 g) at 0° C. and the mixture was stirred at room temperature for an hour. To the solution, 2-(4-(4-phenylbutyloxy)phenyl)ethyl iodide (40 g) was dropwise added at 0° C., and the mixture was stirred for 20 minutes and allowed to stand at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure and the residue obtained was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:1) to give the subject compound (46 g).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][C:6](=[O:9])[NH:7][CH:8]=1.[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1.O>CN(C=O)C>[F:30][C:29]([F:31])([F:32])[CH:28]([CH3:33])[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:7]2[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=[CH:5][C:6]2=[O:9])=[CH:21][CH:20]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(c1ccc(CBr)cc1)C(C)C(F)(F)F
Reactant: O=c1ccc(C(F)(F)F)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(c1ccc(Cn2cc(C(F)(F)F)ccc2=O)cc1)C(C)C(F)(F)F
Reaction time: 0.5 h

Procedure:
1.80 g (11.04 mmol) of 5-(trifluoromethyl)pyridin-2(1H)-one were initially charged in 2.5 ml of DMF, and 0.44 g (11.04 mmol, 60% pure) of sodium hydride was added. The mixture was stirred for 30 min, and 3.0 g (8.49 mmol) of ethyl 2-[4-(bromomethyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate were then added. After a further 2 h at RT, water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 10:1 to 4:1). This gave 2.89 g (78.2% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18](=O)[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[CH2:23][CH2:22]2)=O)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:8][C:6]1[CH:5]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][N:21]2[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)[CH2:23][CH2:22]2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccccc3c2C(=O)C(=O)N2CCC(c3ccncc3)CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN2CCC(c3ccncc3)CC2)c1
Yield: 51.2 %

Procedure:
To a solution of 1-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]-2-(3,4,5,6-tetrahydro-2H-[4,4']bipyridinyl-1-yl)ethane-1,2-dione (148 mg in dry tetrahydrofuran) was added dropwise 2.71 mL of a 1M solution of lithium aluminum hydride in tetrahydrofuran and the mixture heated to reflux on an oil bath. After 1.5 hours the mixture was cooled and quenched by the sequential addition of 30 mL water and 4 mL ammonium hydroxide and 25 mL ethyl acetate. The mixture was filtered to remove the solids. The organic portion was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give the title compound (71 mg). m/e=410 (M+H).
Reaction SMILES: Cl[CH2:2][S:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>>[CH2:11]([O:13][P:14]([CH2:2][S:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: ClCSCc1ccccc1
Product: CCOP(=O)(CSCc1ccccc1)OCC
Temperature: 155 °C
Reaction time: 8 h

Procedure:
A mixture of benzyl chloromethyl sulfide (20 g., 0.116 mole), prepared according to the method of Bohme, Fischer and Frank [Ann., 563, 54 (1949)], and triethylphosphite (26.9 g., 0.162 mole) was heated with stirring at 155° C. (bath temperature) for 8 hours under a nitrogen atmosphere. The temperature of the oil bath was then raised to 170° C. and the volatile materials removed by distillation under reduced pressure. The residue was chromatographed on silica by eluting with ethyl acetate/benzene mixtures which gave 21.5 g. of the title compound as a liquid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][S:12]([CH:15]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:16]([NH:18][CH:19]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])=[O:17])(=[O:14])=[O:13].[C:43]([O-])([O-])=O.[K+].[K+].IC.ClCl>CN(C)C=O.O>[CH3:43][N:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[S:12]([CH:15]([CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:16]([NH:18][CH:19]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[CH:32][CH:33]=1)[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:21])=[O:17])(=[O:14])=[O:13]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(CC(NC(=O)C(Cc2ccccc2)S(=O)(=O)Nc2ccc3ccccc3c2)C(=O)N2CCCC2)cc1
Agent: ClCl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1ccc2ccccc2c1)S(=O)(=O)C(Cc1ccccc1)C(=O)NC(Cc1ccc(C#N)cc1)C(=O)N1CCCC1
Reaction time: 24 h
Yield: 86.1 %

Procedure:
2 g of compound 4 are dissolved in 20 ml of dimethylformamide at 0° C. and 0.475 g of K2CO3 and 0.214 ml of ICH3 are added. After 24 hours at 5° C., 20 ml of H2O and 40 ml of CH2 Cl2 are added. The organic phase decanted is washed, dried and concentrated to dryness. The residue is recrystallized from (CH3)2CHOH to give 1.76 g of final product which melts at 186° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2].IC.[OH-].[K+].[CH3:20]S(C)=O>O>[CH3:20][N:12]1[CH2:13][CH2:14][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[C:11]1=[O:15]
Reactant: CS(C)=O
Reactant: O=C1NCCN1c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
A mixture of 21 parts of 1-(4-nitrophenyl)-2-imidazolidinone, 16 parts of iodomethane, 10 parts of potassium hydroxide and 200 parts of dimethyl sulfoxide was stirred for 3 hours at room temperature. Another portion of 16 parts of iodomethane and 10 parts of potassium hydroxide were added. Stirring was continued overnight. 300 Parts of water were added to the reaction mixture and the whole was stirred. The precipitated product was filtered off and crystallized from 4-methyl-2-pentanone, yielding 16.5 parts (74%) of 1-methyl-3-(4-nitrophenyl)-2-imidazolidinone; mp. 214.1°-215.5° C. (7).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-])=O)=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)([OH:3])=[O:2].[C:18](OC(=O)C)(=[O:20])[CH3:19]>[Ni].C(O)(=O)C>[C:18]([NH:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[CH:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[CH2:7][CH2:8]2)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CCC1CCc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)CCC2CCC(=O)O
Reaction time: 30 h

Procedure:
A mixture of 2-carboxyethyl-5-nitroindane (34 g, 0.15 mol), Raney nickel (5 g), acetic anhydride (25 mL) and acetic acid (225 mL) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (50 psi) for 30 h. After removing the catalyst, the filtrate was evaporated to give a dark syrup. The residue was purified by column chromatography (3:2 hexane:EtOAc).
Reaction SMILES: S(Cl)(Cl)=O.Cl.[CH3:6][C:7]1[NH:8][C:9]2[CH2:15][CH:14]([C:16]([OH:18])=O)[CH2:13][CH2:12][C:10]=2[N:11]=1.[CH3:19][O:20][C:21]1[C:22]([NH2:27])=[CH:23][CH:24]=[CH:25][CH:26]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][C:16]([CH:14]1[CH2:13][CH2:12][C:10]2[N:11]=[C:7]([CH3:6])[NH:8][C:9]=2[CH2:15]1)=[O:18]
Reactant: Cc1nc2c([nH]1)CC(C(=O)O)CC2
Reactant: COc1ccccc1N
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)C1CCc2nc(C)[nH]c2C1
Temperature: 90 °C
Reaction time: 16 h
Yield: 36.1 %

Procedure:
Thionyl chloride, 5 ml, was added to 0.50 g (0.97 mmols) of 2-methyl-4,5,6,7-tetrahydrobenzimidazole-5carboxylic acid hydrochloride (including 58 w/w % of NaCl) obtained in Reference Example 2 and the mixture was heated at 90° C. for 3 hours. After thionyl chloride was distilled off under reduced pressure, 10 ml of methylene chloride was added to the residue and at 0° to 5° C., 0.20 ml (1.78 mmol) of o-anisidine and 0.40 ml (2.89 mmols) of triethylamine were added to the mixture followed by stirring at room temperature for 16 hours. After 50 ml of methylene chloride was supplemented, the mixture was washed with 1 N sodium hydroxide solution and then dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with methylene chloride-methanol-ammonia water (10 : 1 : 0.1). The solvent was distilled off and the resulting colorless crystals were recyrstallized from ethyl acetate to give 0.10 g (37.0%) of N-(2-methyoxyphenyl)-2-methyl -4,5,6,7-tetrahydrobenzimidazole-5-carboxamide monhydrate.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:9])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26](Cl)(=[O:28])=[O:27])([O-:19])=[O:18].O>CN(C)C=O>[OH:9][CH:4]([CH2:3][NH:2][S:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[N+:17]([O-:19])=[O:18])(=[O:27])=[O:28])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(O)CN
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a solution of methyl 3-amino-2-hydroxypropanoate hydrochloride (0.8 g) in N,N-dimethylformamide (10 mL) were added triethylamine (1.1 mL) and 2-nitrobenzenesulfonyl chloride (1.1 g) at 0° C., and the mixture was stirred at 0° C. for 2 hr and then at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.1 g, 89%) as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)/[C:8](=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)/[C:7]1=[O:24])=[O:5])[CH3:2].[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:27]=1[CH:33]=[N:34][C:35]([O:37][Si](C)(C)C)=[CH2:36]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[C:8]2([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:36][C:35](=[O:37])[NH:34][CH:33]2[C:27]2[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:26]=2[CH3:25])[C:7]1=[O:24])=[O:5])[CH3:2]
Reactant: C=C(N=Cc1c(C)cccc1C)O[Si](C)(C)C
Reactant: CCOC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1c(C)cccc1C
Yield: 70.6 %

Procedure:
In a manner similar to the method described in example 4c, E/Z-6-chloro-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester (0.4 g, 1.08 mmol) prepared in example 4b was reacted with 1-(2,6-dimethylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (2.9 g, 11.7 mmol) prepared in example 27a, in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,6-dimethylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (Yield 0.41 g, 71%).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[C:10]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH3:11].CC(C1C=CC=C(C(C)C)C=1N1C=[N+](C2C(C(C)C)=CC=CC=2C(C)C)CC1)C.[Cl-].Br[C:49]1[S:58][C:57]2[C:56](=[C:59]3[CH2:64][CH2:63][N:62]([CH3:65])[CH2:61][CH2:60]3)[C:55]3[CH:66]=[CH:67][CH:68]=[CH:69][C:54]=3[O:53][CH2:52][C:51]=2[CH:50]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O>[CH3:65][N:62]1[CH2:63][CH2:64][C:59](=[C:56]2[C:55]3[CH:66]=[CH:67][CH:68]=[CH:69][C:54]=3[O:53][CH2:52][C:51]3[CH:50]=[C:49]([CH2:11][C:10]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[S:58][C:57]2=3)[CH2:60][CH2:61]1
Reactant: CN1CCC(=C2c3ccccc3OCc3cc(Br)sc32)CC1
Reactant: CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)c1cccc(C(C)C)c1N1C=[N+](c2c(C(C)C)cccc2C(C)C)CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: O
Product: CN1CCC(=C2c3ccccc3OCc3cc(CC(=O)OC(C)(C)C)sc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
Hexamethyldisilazane (11.97 g, 74.2 mmol) was ice-cooled in an argon atmosphere, and a 1.6 mol/L n-butyllithium-hexane solution (46.6 mL, 74.6 mmol) was added dropwise thereto. t-Butyl acetate (4.9 mL, 36.7 mmol) was added dropwise to the solution, and the mixture was stirred for 30 minutes. Pd(dba)2 (1.05 g, 1.8 mmol), N,N′-(2,6-diisopropylphenyl)dihydroimidazolium chloride (0.80 g, 1.9 mmol), and the compound obtained in Example 27 (7.0 g, 18.6 mmol) were added thereto, and the mixture was heated to room temperature, and stirred overnight. Water was added to the reaction mixture, and the product was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The organic layer was distilled off under a reduced pressure, and the residue was purified by column chromatography (hexane:ethyl acetate=9:1), to give 3.30 g (43%) of the captioned compound in the form of an oily product.