Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:27]2[CH2:36][CH2:35][C:30]3([O:34][CH2:33][CH2:32][O:31]3)[CH2:29][CH2:28]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[CH3:37]I.[H-].[Na+]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:27]2[CH2:36][CH2:35][C:30]3([O:34][CH2:33][CH2:32][O:31]3)[CH2:29][CH2:28]2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:21][CH2:22][C@H:23]([O:26][CH3:37])[CH2:24][CH2:25]1)[C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: CI
Reactant: COC(=O)c1sc(C2CCC3(CC2)OCCO3)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)c1sc(C2CCC3(CC2)OCCO3)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC)CC1

Procedure:
The product from Step II (922 mg, 1.77 mmol) was treated with methyl iodide (2.21 mL, 35.48 mmol) and 60% oil suspension of sodium hydride (142 mg, 3.54 mmol) using procedure described in step I of example 4 to afford 1.143 g (100%) of crude 5-(1,4-dioxa-spiro[4.5]dec-8-yl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[C:20]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:3][C:2]([CH3:19])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([CH:13]2[CH2:14][CH2:15][N:16]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:17][CH2:18]2)[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCNCC2)CC1
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(C3CCCCC3)CC2)CC1
Yield: 99 %

Procedure:
Prepared analogously to Example A19a) from 1-(1,1-dimethylethoxycarbonyl)-4-(4-piperidinyl)piperazine and cyclohexanone in a yield of 99% of theory. Colourless, highly viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[CH:24][CH:23]=1.N1C=CN=C1.[Si:39](Cl)([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].C(=O)(O)[O-].[Na+]>ClCCl>[Si:39]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]([F:33])([F:31])[F:32])=[CH:24][CH:23]=3)[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)(F)F)cc3)c2)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 111.4 %

Procedure:
To a solution of (2S,3R,4S,5S,6R)-2-[4-chloro-3-[[4-(2,2,2-trifluoroethoxyl)phenyl]methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 17e (3.5 g, 7.1 mmol) in dichloromethane (60 mL) were added imidazole (0.97 g, 14.2 mmol) and tert-butyldimethylsilyl chloride (2.14 g, 14.2 mmol) in turn at 0° C. The mixture was warmed up to room temperature and stirred for 2 hours. The reaction mixture was adjusted with saturated aqueous sodium bicarbonate to pH 7 and partitioned. The organic layer was washed with saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 17f as light yellow oil (4.8 g, 100%). This material was not further purified.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][NH2:12])=[CH:3]1.F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][NH:12][C:19]2[CH:20]=[N:21][CH:22]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])=[CH:3]1
Reactant: O=C(O)c1ccncc1F
Reactant: NCc1coc2ccccc12
Agent: Cl
Product: O=C(O)c1ccncc1NCc1coc2ccccc12
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from (1-benzofuran-3-yl)methylamine hydrochloride and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ 13.39 (br s, 1H), 8.33 (s, 1H), 7.97 (s, 1H), 7.77 (d, 1H, J=5.0 Hz), 7.68 (br s, 1H), 7.57 (d, 1H, J=7.6 Hz), 7.48-7.52 (m, 2H), 7.17-7.28 (m, 2H), 4.64 (s, 2H). [M+H] calc'd for C15H12N2O3, 267. Found 267.
Reaction SMILES: [CH3:1][NH2:2].C(O)(=O)C.[Br:7][C:8]1[CH:38]=[CH:37][C:11]([CH2:12][CH:13]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:14]([NH:16][CH2:17][C:18](=O)[CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][CH3:22])=O)=[CH:10][CH:9]=1>C1(C)C(C)=CC=CC=1>[Br:7][C:8]1[CH:38]=[CH:37][C:11]([CH2:12][CH:13]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:14]2[N:2]([CH3:1])[C:18]([CH2:19][C:20]([CH3:24])([CH3:23])[CH2:21][CH3:22])=[CH:17][N:16]=2)=[CH:10][CH:9]=1
Reactant: CN
Reactant: CCC(C)(C)CC(=O)CNC(=O)C(Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1C
Product: CCC(C)(C)Cc1cnc(C(Cc2ccc(Br)cc2)NC(=O)OCc2ccccc2)n1C
Temperature: 150 °C
Reaction time: 2 h

Procedure:
Methylamine (2 M in tetrahydrofuran) (1.2 mL, 24 mmol) followed by acetic acid (1.2 mL) were added to an ambient temperature solution of benzyl {1-(4-bromobenzyl)-2-[(4,4-dimethyl-2-oxohexyl)amino]-2-oxoethyl}carbamate (for synthesis see Example 37) (600 mg, 1.2 mmol) in xylene (10 mL). After stirring at 150° C. for 2 h, the reaction mixture was concentrated in vacuo. High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid afforded benzyl {2-(4-bromophenyl)-1-[5-(2,2-dimethylbutyl)-1-methyl-1H-imidazol-2-yl]ethyl}carbamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2.C1(C)C=CC=CC=1>C(O)(=O)C>[F:14][C:13]([F:15])([F:16])[C:10]([CH:11]=[N:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2)([OH:17])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[O:20][CH3:21])([CH3:18])[CH3:19]
Reactant: Nc1cccc2[nH]ncc12
Reactant: COc1ccc(Br)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COc1ccc(Br)cc1C(C)(C)CC(O)(C=Nc1cccc2[nH]ncc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 96 h
Yield: 89.5 %

Procedure:
300 mg (0.813 mmol) of 4-(5-bromo-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal is mixed in 1.19 ml of glacial acetic acid with 108.2 mg (0.813 mmol) of 4-aminoindazole, and it is stirred for four days at room temperature. The batch is spun in until a dry state is reached, and the residue is drawn off three times with toluene. Chromatography on silica gel (mobile solvent ethyl acetate/hexane) yields 352.5 mg (89.5%) of the desired imine (together with the imine of the Desbrom compound).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[CH3:7][C:5]1[N:6]=[C:2]([C:12]#[C:11][CH2:10][CH2:9][N:13]2[N:14]=[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]3=[N:17]2)[S:3][C:4]=1[CH3:8]
Reactant: Cc1nc(Br)sc1C
Reactant: C#CCCn1nc2ccccc2n1
Product: Cc1nc(C#CCCn2nc3ccccc3n2)sc1C
Yield: 17.1 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-4,5-dimethylthiazole (100 mg, 0.52 mmol) and 2-(but-3-ynyl)-2H-benzo[d][1,2,3]triazole (89 mg, 0.52 mmol, Example 109(D)). The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 25 mg (89 μmol, 17%) of 2-(4-(4,5-dimethylthiazol-2-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a yellow solid (M.P.=96-98° C.).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10](O)[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15].CI>CC(CC)=O.O>[F:7][C:8]1[CH:9]=[C:10]([O:4][CH3:1])[CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Solvent: CI
Product: COc1ccc([N+](=O)[O-])c(F)c1
Temperature: 40 °C
Reaction time: 15 h
Yield: 96.7 %

Procedure:
Potassium carbonate (79.0 g, 0.57 mol) was added to a stirred solution of 3-fluoro-4-nitrophenol (45.0 g, 0.29 mol) and methyl iodide (50.0 mL, 0.81 mol) in methylethyl ketone (450 mL) at room temperature. The suspension was stirred at 40° C. for 15 hours and then allowed to cool. The mixture was diluted with water (200 mL) and the organic phase was separated. The aqueous phase was extracted with dichloromethane (2×200 mL). The organic extracts were combined, dried over MgSO4 and evaporated under reduced pressure to give the title compound (48.0 g, 97% yield) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH2:11]O)=[CH:10][C:4]=2[O:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34]>>[Cl:34][CH2:11][C:9]1[CH:8]=[CH:7][C:5]2[O:6][C:2]([F:13])([F:1])[O:3][C:4]=2[CH:10]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: FC1(F)Oc2ccc(CCl)cc2O1
Temperature: 80 °C

Procedure:
A solution of (2,2-difluoro-benzo[1,3]dioxol-5-yl)-methanol (1.0 g, 5.32 mmol) in carbon tetrachloride (10.6 mL) is added to polymer-supported triphenylphospine (3.5 g, 3 mmol/g, 10.6 mmol) at room temperature. The reaction is heated for 3 h at 80° C., cooled to room temperature, filtered, and the solids washed with dichloromethane. The filtrate is concentrated in vacuo to yield the title compound, 0.79 g (72%), as a clear, orange oil.
Reaction SMILES: C([O:5][C:6](=[O:51])[CH2:7][C@H:8]([NH:24][C:25](=[O:50])[CH2:26][N:27]([C:35](=[O:49])[C@@H:36]([NH:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:37]([CH3:39])[CH3:38])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:9]([C:11]1[O:12][CH:13]=[C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])[N:15]=1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:41]([NH:40][C@@H:36]([CH:37]([CH3:39])[CH3:38])[C:35]([N:27]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:26][C:25]([NH:24][C@H:8]([C:9]([C:11]1[O:12][CH:13]=[C:14]([C:16]2[C:17]([Cl:23])=[CH:18][CH:19]=[CH:20][C:21]=2[Cl:22])[N:15]=1)=[O:10])[CH2:7][C:6]([OH:51])=[O:5])=[O:50])=[O:49])(=[O:48])[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)N[C@@H](CC(=O)O)C(=O)c1nc(-c2c(Cl)cccc2Cl)co1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 709 in CH2Cl2 (4.0 mL) was added TFA (2.0 mL) and the reaction stirred at rt for 1 hr. The reaction was concentrated in vacuo and the residue co-concentrated with toluene. Prep-HPLC provided 35 mg of compound 710: 1H NMR (500 MHz, CD3 OD) δ 8.90 (m), 8.52 (m), 8.35 (m), 7.83 (m), 7.62-7.39 (m), 7.38-7.16 (m), 5.52 (m), 5.01 (m), 5.01 (m), 4.99-4.53 (m), 4.42 (m), 4.33-3.82 (m), 3.16-2.93 (m), 2.91-2.48 (m), 2.24 (m), 1.09-0.85 (m). ##STR89##
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:16](=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([C:12]([O:14]C)=O)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][NH2:30]>C(O)C.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:30][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[C:12](=[O:14])[C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1
Reactant: CCOC(=O)C(=O)c1c(C(=O)OC)n(C)c2cc(F)ccc12
Reactant: NNc1ccccn1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1nn(-c2ccccn2)c(=O)c2c1c1ccc(F)cc1n2C

Procedure:
A solution of 0.40 g (1.36 mmol) of ethyl 6-fluoro-2-(methoxycarbonyl)-1-methyl-α-oxo-1H-indole-3-acetate (obtained in stage 1.4.) in 30 ml of absolute ethanol, a few drops of glacial acetic acid and 0.60 g (5.5 mmol) of 2-pyridinylhydrazine is brought to reflux for 17 h.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[NH:21][CH2:22][CH2:23][N:24]=1.[H][H].Cl[C:28](OCC)=[O:29]>O1CCCC1.O.C(O)(=O)C>[F:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]2=[N:21][CH2:22][CH2:23][N:24]2[C:28]1=[O:29]
Reactant: [H][H]
Reactant: CCOC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Nc2ccccc2C2=NCCN2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C1N2CCN=C2c2ccccc2N1c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C

Procedure:
1.1 g (25 mmol) of sodium hydride were added to a solution of 3.47 g (11.6 mmol) of 2-(2-(2-fluoro-4-nitrophenylamino)-phenyl)-2-imidazoline in 60 ml of absolute tetrahydrofuran, and the mixture was warmed to 50° C. until the evolution of hydrogen had ended. After the reaction mixture had been cooled to room temperature, 5.8 ml (60 mmol) of ethyl chloroformate in 10 ml of absolute tetrahydrofuran were added dropwise to it and it was warmed to 50° C. for 90 minutes. The reaction mixture was allowed to cool to room temperature, acidified with glacial acetic acid, diluted with water and extracted with dichloromethane. The organic phase was concentrated by evaporation, water was added to the residue, and the solution was adjusted to a pH of 1-2 with hydrochloric acid and was extracted with dichloromethane. The precipitate which occurred on addition of KHCO3 solution to the aqueous phase was filtered off under suction, washed with water and dried.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[C@@H:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:22])([CH3:21])[C@H:10]1[OH:23])#[N:2].[C:24](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[C:1]([N:3]=[C:4]1[N:8]([CH3:24])[CH2:7][CH2:6][N:5]1[C@@H:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:21])([CH3:22])[C@H:10]1[OH:23])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCNC2=NC#N)[C@@H]1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN1CCN([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1=NC#N
Temperature: 80 °C
Reaction time: 5 h
Yield: 19.1 %

Procedure:
To a mixture of trans-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.50 g) and potassium carbonate (0.66 g) in N,N-dimethylformamide (5 ml) was added methyl iodide (0.30 ml). The reaction mixture was stirred at 80° C. for 5 hours, poured into water (50 ml) and extracted with ethyl acetate (50 ml). The organic layer was washed successively with aqueous sodium bisulfite (25 ml) and brine (25 ml), dried over magnesium sulfate, and then evaporated in vacuo. The residue was subjected to column chromatography on silica gel (15 g) and eluted with chloroform and then a mixture of chloroform and methanol (50:1). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from isopropyl alcohol to give trans-4-(2-cyanoimino-3-methylimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.10 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].CC(O)=O>C1COCC1.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:20])[C:9]([N:11]2[C@@H:15]([CH:16]([CH3:17])[CH3:18])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)Cc1ccc(F)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](C)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of (4S)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one (2.81 g, 10.6 mmol) in dry THF (40 mL) at −78° C. under argon, was added dropwise 1.0M solution of NaHMDS in THF (11.7 mL, 11.7 mmol) over a period of 10 min. After stirring at −78° C. for 1 h, Mel (3.30 mL, 53.0 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 1 h and −40° C. for 2 h, quenched with HOAc (32 mmol) in ether (20 mL), filtered over celite. The filtrate was concentrated in vacuo and the residue was dissolved in CH2Cl2 (100 mL) and washed with H2O following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (5%–10% EtOAc in hexane) to give 2.40 g (8.60 mmol, 81%) of (4S)-3-[(2S)-2-(4-fluorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCl3) δ 7.34–7.31 (m, 2H), 7.02–6.96 (m, 2H), 5.13 (q, 1H, J=7.7 Hz), 4.38–4.33 (m, 1H), 4.18–4.13 (m, 2H), 2.48–2.37 (m, 1H), 1.49 (d, 3H, J=7.3 Hz), 0.91 (apparent t, 6H, J=6.9 Hz); ESMS m/e: 280.2 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1.C(O)(=[O:10])C.[CH:12]([CH:25]1[CH2:27][O:26]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(C1C=C(C=N[C@H]2[C@H](N=CC3C([O-])=C(C(C)(C)C)C=C(C(C)(C)C)C=3)CCCC2)C([O-])=C(C(C)(C)C)C=1)(C)C.[Co+2].O>[CH:12]([C@@H:25]1[CH2:27][O:26]1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]1([CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C@H:25]([OH:10])[CH2:27][OH:26])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)O
Reactant: c1ccc(C(c2ccccc2)C2CO2)cc1
Agent: [Co+2]
Agent: CC(C)(C)c1cc(C=N[C@@H]2CCCC[C@H]2N=Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2[O-])c([O-])c(C(C)(C)C)c1
Solvent: O
Solvent: Cc1ccccc1
Product: OC[C@@H](O)C(c1ccccc1)c1ccccc1
Product: c1ccc(C(c2ccccc2)[C@@H]2CO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (R,R)-(−)-N,N′-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexane diaminocobalt (II) (0.22 g, 0.37 mmol, 0.8%), toluene (5 ml), and acetic acid (0.044 g, 0.74 mmol) was stirred for 1 h at room temperature. The solvent was removed in vacuo and the residue was dried. 2-Benzhydryl-oxirane (9.6 g, 45.7 mmol) was added in one portion and stirred, the mixture was then cooled by means of an ice-bath. H2O (0.58 g, 32 mmol) was slowly added over a 30-min period. After water addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 72 h. Compounds were separated via flash chromatography on silica gel column to give (2R)-2-benzhydryl-oxirane (23a) 4.5 g ([α]D=(+)9.58, c=1, MeOH) and (2S)-3,3-diphenyl-propane-1,2-diol 24 3.53 g ([α]D=(+)48, c-=1, MeOH, ee=97%). The proton and carbon NMR data of (2R)-2-benzhydryl-oxirane was identical to the racemate 2-benzhydryl-oxirane.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:28]=2[C:37]#[N:38])=[CH:22][C:18]=1[C:19](Cl)=[O:20])([O-:16])=[O:15]>C1(C)C=CC=CC=1>[N+:14]([C:17]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][C:28]=2[C:37]#[N:38])=[CH:22][C:18]=1[C:19]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:20])([O-:16])=[O:15]
Reactant: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)Cl)c1
Reactant: OC1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#Cc1cc(C(F)(F)F)ccc1Oc1ccc([N+](=O)[O-])c(C(=O)OC2CCOC2)c1
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-nitro-5-(2-cyano-4-trifluoromethylphenoxy)benzoate.
Reaction SMILES: [CH:1]([O:4][SiH:5]([O:10][CH:11]([CH3:13])[CH3:12])[O:6][CH:7]([CH3:9])[CH3:8])([CH3:3])[CH3:2].[CH:14]([Si:16]([O:25][CH:26]([CH3:28])[CH3:27])([O:21][CH:22]([CH3:24])[CH3:23])[O:17][CH:18]([CH3:20])[CH3:19])=[CH2:15]>C1(C)C(C)=CC=CC=1>[CH:7]([O:6][Si:5]([O:4][CH:1]([CH3:3])[CH3:2])([O:10][CH:11]([CH3:13])[CH3:12])[CH:15]=[CH:14][Si:16]([O:17][CH:18]([CH3:20])[CH3:19])([O:21][CH:22]([CH3:24])[CH3:23])[O:25][CH:26]([CH3:28])[CH3:27])([CH3:9])[CH3:8]
Reactant: C=C[Si](OC(C)C)(OC(C)C)OC(C)C
Reactant: CC(C)O[SiH](OC(C)C)OC(C)C
Solvent: Cc1ccccc1C
Product: CC(C)O[Si](C=C[Si](OC(C)C)(OC(C)C)OC(C)C)(OC(C)C)OC(C)C
Temperature: 225 °C

Procedure:
Into a 45 cc Parr bomb was added 2.5 g (0.012 mol) triisopropoxysilane, 5.7 g (0.024 mol) vinyltriisopropoxysilane, 1.0 xylene and 200 ppm Ru3CO12 (20 mg). The reaction was heated for 4 hours at 225° C. in a fluidized sand bath. A single product, 1,2-bis(triisopropoxysilyl)ethylene was formed.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CC(C)([O-])C.[Na+].[C:19]([C:23]1[O:27]/[C:26](=[N:28]\[C:29](=[O:41])[C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=2F)/[N:25]([CH2:42][C@H:43]2[CH2:47][CH2:46][CH2:45][O:44]2)[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>C1COCC1.O>[C:19]([C:23]1[O:27]/[C:26](=[N:28]\[C:29]([C:30]2[CH:35]=[C:34]([C:36]([F:38])([F:37])[F:39])[CH:33]=[CH:32][C:31]=2[O:1][CH:2]2[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]2)=[O:41])/[N:25]([CH2:42][C@H:43]2[CH2:47][CH2:46][CH2:45][O:44]2)[CH:24]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)o1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2C(=O)/N=c2\oc(C(C)(C)C)cn2C[C@H]2CCCO2)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 94.8 %

Procedure:
To a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (167 mg, 0.965 mmol) in THF (2 mL) was added sodium tert-butoxide (93 mg, 0.965 mmol). The reaction was stirred at room temperature for 20 min. The reaction was cooled to 0° C. and a solution of Example 95A (200 mg, 0.483 mmol) in THF (1 mL) was added. The reaction was stirred at 0-5° C. for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The organic layer was combined and dried over MgSO4, filtered and concentrated to afford the title compound 260 mg (93%). MS (DCI/NH3) m/z 568 (M+H)+.