Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH2:12]Br)[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([CH2:34][OH:35])[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1.[H-].[Na+]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[CH2:12][O:35][CH2:34][C:21]1([C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=2)[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: FC(F)(F)c1cc(Br)cc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(C(F)(F)F)c2)(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Bromo-3-(bromomethyl)-5-(trifluoromethyl)benzene (1.2 g, 3.78 mmol) and tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (0.96 g, 3.2 mmol) were combined in dimethylformamide (10 mL) and cooled to 0° C. The reaction was treated with sodium hydride (151 mg, 6.3 mmol), stirred at 0° C. for 1 h, and at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (15% ethyl acetate/hexanes) gave 1.1 g (61%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.61 (s, 1H), 7.35 (s, 1H), 7.30-7.31 (m, 2H), 7.26 (s, 1H), 7.03-7.07 (m, 2H), 4.36 (s, 2H), 3.72-3.75 (m, 2H), 3.38 (s, 2H), 3.01-3.06 (m, 2H), 2.13-2.16 (m, 2H), 1.81-1.87 (m, 2H), 1.43 (s, 9H). 13C-NMR (CDCl3, 126 MHz) δ 161.6 (d, J=245.7 Hz), 152.0, 141.9, 138.3, 133.3, 132.4 (q, J=32.6 Hz), 128.8, 127.5 123.2 (q, J=273.5 Hz), 122.8, 122.4, 115.5, 115.3, 79.7, 79.5, 71.7, 68.0, 41.4, 32.2, 28.5, 25.7. Mass spec.: 548.16 (MH)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17](I)=[C:16]3[O:21][CH2:22][O:23][C:15]=13)=[CH:10][C:9]([O:24][CH3:25])=[C:8]([O:26][CH3:27])[CH:7]=2)#[N:2].[C:28](#[N:31])[CH:29]=[CH2:30].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH:30]=[CH:29][C:28]#[N:31])=[C:16]3[O:21][CH2:22][O:23][C:15]=13)=[CH:10][C:9]([O:24][CH3:25])=[C:8]([O:26][CH3:27])[CH:7]=2)#[N:2]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(I)c4c3OCO4)c2cc1OC
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(C=CC#N)c4c3OCO4)c2cc1OC
Temperature: 115 °C

Procedure:
A mixture of 3-cyano-4-(4-iodo-2,3-methylenedioxyanilino)-6,7-dimethoxyquinoline (0.2 g), acrylonitrile (0.2 ml), triethylamine (0.2 ml), palladium(II) acetate (0.01 g) and DMF (2 ml) was stirred and heated to 115° C. for 3 hours. The reaction mixture was evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of hexane and ethyl acetate as eluent. The material so obtained was triturated under diethyl ether. There was thus obtained the title compound, in the form of a 4:1 mixture of trans and cis isomers and as a yellow solid (0.095 g); NMR Spectrum: (DMSOd6, data relating to the major trans isomer) 3.91 (s, 3H), 3.93 (s, 3H), 6.12 (s, 2H), 6.26 (d, 1H), 6.88 (d, 1H), 7.14 (d, 1H), 7.35 (s, 1H), 7.56 (d, 1H), 7.7 (s, 1H), 8.51 (s, 1H), 9.7 (s, 1H); Mass Spectrum: M+H+ 401.
Reaction SMILES: [CH3:1][C:2](=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH:21][CH2:22][CH:23]([CH2:25]O)[OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCOC1>C1(C)C=CC=CC=1.O>[CH2:3]([C:2]1([CH3:1])[O:24][CH:23]([CH2:22][OH:21])[CH2:25][O:20]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCCCCCCCCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1COCO1
Product: CCCCCCCCCCCCCCCCCC1(C)OCC(CO)O1
Reaction time: 12 h

Procedure:
In an appropriate reactor were poured 11.1 g (40 mmol) of 2-nonadecanone, 6 g--which represents an excess with regard to the stoichiometric proportions--of twice distilled glycerol and 0.6 g of p-toluenesulphonic acid dissolved in 120 ml of dry toluene. The reaction mixture was refluxed under stirring for 12 hours and the resulting water was eliminated using a Dean Stark apparatus. After cooling, the organic phase was washed with 30 ml of 5% by weight aqueous solution of potassium hydroxide and then three times with the minimum amount of water. After drying over anhydrous sodium sulphate, the solvent was removed under reduced pressure. The residue was then purified by chromatography on a silica gel column. There were successively eluted the fraction of the ketone not involved in the reaction (petroleum ether : diethyl ether, 95:5 by volume), and then the dioxolan a (petroleum ether/diethyl ether 85:15 by volume). the dioxolan is a viscous product, partially crystallized.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=O)[C:5]2[S:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][N:33]1[CH2:37][CH2:38][CH2:39][CH3:40]>C(OCC)(=O)C>[CH2:37]([N:33]1[CH2:34][CH2:35][CH2:36][CH:32]1[CH2:31][NH:30][C:13]([C:4]1[C:5]2[S:10][CH2:9][CH2:8][N:7]([CH3:11])[C:6]=2[CH:12]=[C:2]([Cl:1])[CH:3]=1)=[O:15])[CH2:38][CH2:39][CH3:40]
Reactant: CCCCN1CCCC1CN
Reactant: CN1CCSc2c(C(=O)O)cc(Cl)cc21
Agent: CC(C)(C)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCN1CCCC1CNC(=O)c1cc(Cl)cc2c1SCCN2C

Procedure:
To a solution of 1.8 g of 6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxylic acid in 30 ml of ethyl acetate was added 1.05 g of triethylamine, and then added 0.891 g of pivaloyl chloride dropwise with stirring at -10° C. to -5° C. followed by stirring the mixture at the same temperature for 30 minutes. To the resultant mixture was added 1.39 g of 2-aminomethyl-1-butylpyrrolidine at --10° C. to -5° C. and then stirred at room temperature for an hour. After the reaction solution was washed with water, dried over anhydrous sodium sulfate and concentrated, the residue thus obtained was crystallized from diisopropyl ether. The crystals were collected by filtration and recrystallized from diisopropyl ether to give N-[(1-butyl-2-pyrrolidinyl)methyl]-6-chloro-4-methyl-3,4-dihydro-2H-1,4-benzothiazine-8-carboxamide as colorless crystals. Melting point: 108°-109° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7]C)=O.[NH2:14][O:15][CH2:16][CH2:17][OH:18].C[O-].[Na+].Cl>CO.O>[Cl:1][C:2]1[C:3]([NH2:13])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([NH:14][O:15][CH2:16][CH2:17][OH:18])=[O:7]
Reactant: NOCCO
Reactant: COC(=O)c1cc(Cl)cc(Cl)c1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1c(Cl)cc(Cl)cc1C(=O)NOCCO
Temperature: 50 °C
Reaction time: 8 h

Procedure:
9 g (40.9 mmol) of methyl 3,5-dichloro-2-aminobenzoate and 6.3 g (81.8 mmol) of 2-(aminooxy)ethanol are initially charged in 90 ml of methanol, and 22.1 g (122.7 mmol) of sodium methoxide as a 30% strength solution in methanol are added dropwise at 20° C. The mixture is stirred at 50° C. overnight. The mixture is cooled and poured onto 400 ml of water, and the pH is adjusted to 3 using 1 N hydrochloric acid. The mixture is extracted 3 times with in each case 150 ml of ethyl acetate and the extracts are dried with sodium sulphate and concentrated using a rotary evaporator.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[N:7]([CH3:10])[C:8]=1[CH3:9])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([CH:26]1[O:28][CH2:27]1)Cl>CN(C)C=O>[C:1]([C:4]1[N:5]=[C:6]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:24][CH:26]3[O:28][CH2:27]3)=[CH:15][CH:16]=2)[N:7]([CH3:10])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1nc(-c2ccc(O)cc2)n(C)c1C
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1nc(-c2ccc(OCC3CO3)cc2)n(C)c1C
Reaction time: 20 h

Procedure:
A mixture of 11.5 g of 4-acetyl-1,5-dimethyl-2-(4-hydroxyphenyl)-1H-imidazole, 13.8 g of potassium carbonate, 7.0 g of epichlorohydrin and 120 ml of dimethylformamide is stirred for 20 hours in a bath at 60°-70°. The insoluble material is filtered off, the filtrate is concentrated by evaporation and the residue is divided between ethyl acetate and water. From the organic phase there is obtained, by concentration by evaporation, an oil which is chromatographed on silica gel with ethyl acetate. 4-acetyl-1,5-dimethyl-2-[4-(2,3-epoxypropoxy)-phenyl]-1H-imidazole is obtained from the first six fractions eluted in the form of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16](NC1C=C2OCOC2=CC=1C(=O)C)=[O:17])(=[O:10])=[O:9].[CH3:32][O:33][C:34](=[O:46])[C:35]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[CH:37][C:36]=1[NH2:45]>>[Cl:1][C:2]1[C:3]([CH3:31])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1[C:16]([NH:45][C:36]1[CH:37]=[C:38]([O:43][CH3:44])[C:39]([O:41][CH3:42])=[CH:40][C:35]=1[C:34]([O:33][CH3:32])=[O:46])=[O:17])(=[O:9])=[O:10].[S:13]1[CH:14]=[CH:15][C:11]([S:8]([NH2:7])(=[O:10])=[O:9])=[CH:12]1
Reactant: COC(=O)c1cc(OC)c(OC)cc1N
Reactant: CC(=O)c1cc2c(cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl)OCO2
Product: COC(=O)c1cc(OC)c(OC)cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Product: NS(=O)(=O)c1ccsc1
Yield: 13 %
Yield: 1 %

Procedure:
The title compounds were prepared by the method set forth for N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide (EXAMPLE 148) except that methyl-2-amino-4,5-dimethoxybenzoate was used instead of 2'-amino-4',5'-(methylenedioxy)acetophenone. The crude product was purified via HPLC to give N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5-dimethoxy-2-methoxycarbonylphenyl)aminocarbonyl]thiophene-3-sulfonamide as a yellow powder (13% yield, m.p. 167°-168° C.) and N-(4-chloro-3-methyl-5-isoxazolyl)2-{[4,5-dimethoxy-2,4,5-dimethoxy-2-methoxycarbonyl)phenyl]phenylaminocarbonyl}thiophene-3-sulfonamide as a dull yellow solid (1% yield, m.p. 228°-230° C.).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([CH2:14][CH:15]2[CH2:20][NH:19][CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].Cl>C(Cl)Cl>[CH:8]1([CH2:14][CH:15]2[CH2:20][N:19]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:18][CH:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(=O)C1CNCC(CC2CCCCC2)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(CC2CCCCC2)CN(S(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (340 mL, 2.4 mmol) was added to a solution of ethyl 5-(cyclohexylmethyl)piperidine-3-carboxylate (155 mg, 0.60 mmol) and methanesulfonyl chloride (75 mL, 0.90 mmol) in CH2Cl2 (6 mL) cooled to 0° C. The reaction was maintained at this temperature for 15 min at which point the whole was allowed to warm to RT and stir for an additional 3 h. The reaction was diluted with CH2Cl2 (20 mL) and poured into HCl (1 N, 20 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were sequentially washed with H2O (10 mL) and brine before being dried over Na2SO4. Concentration under reduced pressure provided the title compound. MS m/z: 332.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[C:3]=1[CH2:22][OH:23].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[C:31]([O:23][CH2:22][C:3]1[C:4]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: O=C1c2cc3c(n2CCN1c1nccc(Cl)c1CO)CCCC3
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1c(Cl)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 25 °C
Yield: 0.1 %

Procedure:
To a mixture of 2-(4-chloro-3-(hydroxymethyl)pyridin-2-yl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 190f (900 mg, 2.7 mol) and triethylamine (900 mg, 9.0 mol) in dichloromethane (25 mL) was added dropwise acetyl chloride (600 mg, 6.0 mol) while stirring at room temperature. The reaction mixture was stirred for 1 h and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with dichloromethane to afford 190g as white solid (950 mg, 94%). MS-ESI: [M+H]+ 374.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)=[N:6][CH:7]=1>C1COCC1.C(OCC)(=O)C.[Ni]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reaction time: 8 h
Yield: 84.1 %

Procedure:
To a solution of N-(5-chloropyridin-2-yl)-2-nitrobenzamide (2 g, 7.2 mmol) in THF (50 mL) and ethyl acetate (50 mL) was added Raney Ni (0.2 g) and the mixture was placed under hydrogen (4.1 bar) in a high pressure apparatus. After shaking overnight, the mixture was filtered and concentrated in vacuo and purified by flash chromatography to give 1.5 g (83%) of an off-white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[NH2:25]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(N)cc1OC
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1OC

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3,4-dimethoxyaniline were reacted to yield N2-(3,4-dimethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 20.98 min.; purity: 74%; MS (m/e): 399 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8]C)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C[O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[CH2:20])=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>[N+:10]([C:3]1[CH:4]=[C:5]([OH:8])[CH:6]=[CH:7][C:2]=1/[CH:20]=[CH:19]/[C:18]1[CH:21]=[CH:22][C:15]([OH:14])=[CH:16][CH:17]=1)([O-:12])=[O:11]
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Reactant: C=Cc1ccc(OC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(O)ccc1/C=C/c1ccc(O)cc1
Temperature: 80 °C
Yield: 79.2 %

Procedure:
To a stirred solution of 2-bromo-5-methoxynitrobenzene (5 g, 21.6 mmol) in dry acetonitrile (60 mL) were added 4-methoxystyrene (3.04 g, 22.6 mmol), N,N-diisopropylethylamine (8.36 g, 64.6 mmol), biphenyl-2-yl-di-t-butyl phosphine (385 mg, 1.3 mmol) and palladium acetate (290 mg, 1.3 mmol). The resulting mixture was heated at 80° C. overnight under N2. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, washed with water, brine, and dried over magnesium sulfate. Concentration under reduced pressure gave the crude product which was purified by column chromatography using ethyl acetate in hexane (5%-10%) to give the protected nitro-stilbene (4.4 g, 72%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:11]=[C:12]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]([F:43])([F:42])[F:41])[CH:13]=[CH:14][C:15]=3[O:16][C:17]3[C:22]([Cl:23])=[CH:21][C:20]([S:24]([NH:27][C:28]4[S:29][CH:30]=[N:31][N:32]=4)(=[O:26])=[O:25])=[C:19]([F:33])[CH:18]=3)=[CH:8][CH:7]=[N:6]2)[CH2:2]1.C=O.[C:46](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl.C(O)(=O)C>[Cl:23][C:22]1[C:17]([O:16][C:15]2[CH:14]=[CH:13][C:12]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]([F:42])([F:43])[F:41])=[CH:11][C:10]=2[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([CH3:46])[CH2:4]3)[N:6]=[CH:7][CH:8]=2)=[CH:18][C:19]([F:33])=[C:20]([S:24]([NH:27][C:28]2[S:29][CH:30]=[N:31][N:32]=2)(=[O:26])=[O:25])[CH:21]=1
Reactant: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(-c3ccccc3C(F)(F)F)cc2-c2ccnn2C2CNC2)cc1F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CN1CC(n2nccc2-c2cc(-c3ccccc3C(F)(F)F)ccc2Oc2cc(F)c(S(=O)(=O)Nc3nncs3)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 132.3 %

Procedure:
To a suspension of 4-{[3-(1-azetidin-3-yl-1H-pyrazol-5-yl)-2′-(trifluoromethyl)biphenyl-4-yl]oxy}-5-chloro-2-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 46, 42.9 mg, 0.0659 mmol) in methanol (0.10 mL), dichloromethane (1.72 mL) and acetic acid (0.10 mL) was added formaldehyde (37% w/w, 16.7 μL, 0.224 mmol). The reaction was then stirred under nitrogen at room temperature for 45 minutes. Sodium triacetoxyborohydride (42.6 mg, 0.201 mmol) was added to the reaction which was stirred for 18 hours at room temperature. The reaction was diluted with dichloromethane (20 mL) and washed with water (3×2 mL). The combined aqueous phases were extracted with dichloromethane (3×5 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a white solid (58.0 mg). The solid was purified by B-HPLC to afford the title compound.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]1([CH2:14][C:15]([NH:17][CH:18]2[C:43](=[O:44])[N:20]3[CH:21]([C:27]([O:29][CH:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH:22]([CH2:25][OH:26])[CH2:23][S:24][C@H:19]23)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.C(OCC)(=O)C>CS(C)=O>[C:8]1([CH2:14][C:15]([NH:17][CH:18]2[C:43](=[O:44])[N:20]3[CH:21]([C:27]([O:29][CH:30]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[O:28])[C:22](=[CH:25][O:26][C:1](=[O:3])[CH3:2])[CH2:23][S:24][C@H:19]23)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CO)CS[C@H]12
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(=O)OC=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Acetic anhydride (20 ml.) was added to a solution of diphenylmethyl 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylate (10.0 g.) in dimethylsulfoxide (20 ml.), and stirred at room temperature for 15 hours. The resultant solution was poured into a solution of water (400 ml.) and ethyl acetate (400 ml.). The organic layer was separated and adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. The solution was concentrated under reduced pressure to give diphenylmethyl 7-(2-phenylacetamido)-3-acetoxymethylenecepham-4-carboxylate (5.3 g.).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[O:11][C:10]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH:33](Cl)[C:34](OCC)=[O:35])=[CH:28][CH:27]=1)([CH3:23])[CH2:9][CH2:8]2)(=O)C.[NH2:40][C:41](N)=[S:42].S1(CCCC1)(=O)=[O:45].Cl>COCCO>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20])[O:11][C:10]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH:33]3[S:42][C:41](=[O:45])[NH:40][C:34]3=[O:35])=[CH:28][CH:27]=1)([CH3:23])[CH2:9][CH2:8]2
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3cc(OC(C)=O)c(C(C)(C)CC(C)(C)C)cc3O2)cc1
Reactant: O=S1(=O)CCCC1
Agent: Cl
Solvent: COCCO
Product: CC(C)(C)CC(C)(C)c1cc2c(cc1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
The procedure described in Example 3 was repeated, but using 7.0 g of ethyl 3-{4-[6-acetoxy-2-methyl-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]phenyl}-2-chloropropionate (prepared as described in Preparation 23), 1.2 g of thiourea, 9 ml of sulfolane, 13 ml of 2N hydrochloric acid and 20 ml of ethylene glycol monomethyl ether, to give the title compound as a slightly yellow glassy solid, softening at 80°-85° C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:16]=[CH:15][NH:14][C:13]3=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[N:2]1.CN1CCCC1=O.[H-].[Na+].[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C@@:35]1([CH2:39][N:40]2[CH:44]=[N:43][CH:42]=[N:41]2)[C@H:37]([CH3:38])[O:36]1>C(OCC)(=O)C>[F:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[C@@:35]([OH:36])([CH2:39][N:40]1[CH:44]=[N:43][CH:42]=[N:41]1)[C@H:37]([N:14]1[CH:15]=[CH:16][N:12]([C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[N:2]3)=[CH:7][CH:8]=2)[C:13]1=[O:17])[CH3:38]
Reactant: O=c1[nH]ccn1-c1ccc(-n2ccnn2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(-n3ccnn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a mixture of 1-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (2.72 g) and 1-methyl-2-pyrrolidone (100 ml) was added sodium hydride (70% in oil, 0.40 g), and the mixture was stirred at room temperature for 1 hour. (2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (2.51 g) was added thereto, and the mixture was stirred at 100° C. for 8 hours under an argon atmosphere. After cooling, the reaction solution was diluted with ethyl acetate (400 ml), and washed with water (100 ml), 1N-hydrochloric acid (100 ml×2) and a saturated aqueous solution of sodium chloride (50 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate to ethyl acetate/acetone=5/1) and recrystallized from ethyl acetate-diisopropyl ether to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,3-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (Compound 11; 1.82 g) as a pale yellow crystalline powder.