Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cs].[C:2]1([CH2:8][CH:9]2[NH:13][S:12](=[O:15])(=[O:14])[NH:11][C:10]2=[O:16])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:23]1([S:29][CH2:30]Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CO>[C:23]1([S:29][CH2:30][N:11]2[C:10](=[O:16])[CH:9]([CH2:8][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[NH:13][S:12]2(=[O:15])=[O:14])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: ClCSc1ccccc1
Reactant: O=C1NS(=O)(=O)NC1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Cs]
Solvent: CO
Product: O=C1C(Cc2ccccc2)NS(=O)(=O)N1CSc1ccccc1
Temperature: 0 °C
Yield: 95.9 %

Procedure:
To a mixture of 4-phenylmethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide cesium salt (prepared by reacting 11.43 g (50.52 mmol) of the dioxide in methanol with 8.23 g (25.26 mmol) of Cs2CO3 followed by removal of the solvent) in 150 ml of DMF was added in one portion phenylthiomethyl chloride (8.82 g, 55.57 mmol) and the mixture was heated at 80°-90° C. under nitrogen for 17 hours. The mixture was cooled and poured into 600 ml of ice/water. The reaction mixture was extracted with ethyl acetate (3x), the organic layer was dried over sodium sulfate, and concentrated in vacuo. The residual yellow oil was purified by silica column chromatography (5%-10% ethyl acetate in hexane) to afford 16.88 g (95.9%) of 2-phenylthiomethyl-4-phenylmethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula VI: R1 =H; R2 =CH2Ph; R3 =H) as an yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[C:15]1([CH:21]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:22]2[CH2:25][C:24](=[O:26])[CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC1C(C)=C(C)[SiH](C)[SiH-](C)(C)C=1.[Li+]>>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([C:24]2([OH:26])[CH2:25][N:22]([CH:21]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:23]2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCOC(=O)Cc1cc(F)cc(Br)c1
Agent: CC1=C[SiH-](C)(C)[SiH](C)C(C)=C1C
Agent: [Li+]
Product: CCOC(=O)[C@H](c1cc(F)cc(Br)c1)C1(O)CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared from ethyl 3-bromo-5-fluorophenylacetate and 1-[bis-phenylmethyl]azetidin-3-one (Preparation 2) by the procedure described in Step 2 of Preparation 3 except that lithium hexamethyldisilamide was used instead of butyllithium to form the ketene acetal; Mass Spectrum: m/e=498 (M+1, 79Br), 500 (M+1, 81Br)
Reaction SMILES: [CH:1]1([S:6]([NH:8][C:9]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:10]=2[O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([S:6]([NH:8][C:9]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:10]=2[O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)(=[O:39])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2NS(=O)C2CCCC2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2NS(=O)(=O)C2CCCC2)cc1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of methyl 4-(2-cyclopentylsulfinylamino-5-trifluoromethylphenoxymethyl)benzoate (305 mg; prepared in Reference Example 33.) in methylene chloride (4.0 ml), meta-chloroperbenzoic acid (456 mg) was added at 0° C. The mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, washed, dried over and concentrated under the reduced pressure to give the title compound (317 mg) having the following physical data.
Reaction SMILES: BrCC.[Mg].Br[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[CH3:21].[CH3:22][C:23]1[CH:27]=[C:26]([C:28](Cl)=[O:29])[O:25][N:24]=1.[Cl-].[NH4+]>C1COCC1>[CH3:22][C:23]1[CH:27]=[C:26]([C:28]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[O:29])[O:25][N:24]=1
Reactant: Cc1ccc(C)c(OCc2ccccc2Br)c1
Reactant: Cc1cc(C(=O)Cl)on1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCBr
Solvent: C1CCOC1
Product: Cc1ccc(C)c(OCc2ccccc2C(=O)c2cc(C)no2)c1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 17.4 %

Procedure:
THF (2 ml) and bromoethane (0.1 ml) were added to magnesium (0.49 g, 0.02 mol) in a stream of nitrogen, and the mixture was stirred at 50° C. for 10 minutes. Then, a mixture of 1-bromo-2-(2,5-dimethylphenoxymethyl)benzene (2.91 g, 0.01 mol) and THF (8 ml) was added at 50 to 60° C. over 30 minutes, and the mixture was stirred at 50 to 60° C. for 1 hour. After completion of the reaction, the reaction mixture was added to a mixture of 3-methylisoxazol-5-carbonyl chloride (1.45 g, 0.01 mol) and THF (15 ml) at −70 to −60° C. over 15 minutes, and then the mixture was stirred at −70 to −60° C. for 0.5 hours. After completion of the reaction, saturated aqueous ammonium chloride solution (150 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) and recrystallized from n-hexane to give 2-(2,5-dimethylphenoxymethyl)phenyl 3-methylisoxazol-5-yl ketone (0.56 g, 17.4%) as colorless crystals. mp. 106-108° C.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[O:8][C:9]([CH3:26])=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:11]=1)=[O:6]>O1CCCC1.CO>[C:17]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]2[CH:11]=[C:7]([C:5]([OH:6])=[O:4])[O:8][C:9]=2[CH3:26])=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(COc2ccc(-c3ccccc3)cc2)c(C)o1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(C(=O)O)cc1COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
1M Aqueous lithium hydroxide (18 mL) was added to solution of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (17) (1 g) in tetrahydrofuran/methanol (2:1 by volume, 100 mL) and the mixture stirred at room temperature for 5 h. The solvent was removed in vacuo, the residue dissolved in water (20 mL) and the solution acidified to pH6 with aqueous dilute hydrochloric acid. The mixture was evaporated to dryness and the residue was purified by HPLC to afford compound 18 as a white solid (210 mg). LC/MS System B: Rt=4.80 mins, m/z=307 ((M−1) for C19H16O4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[F:8].[Si:11]([O:18][CH2:19][C:20](N(OC)C)=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C1COCC1.CCCCCC>[Si:11]([O:18][CH2:19][C:20]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: Fc1ccc([Mg]Br)cc1Cl
Reactant: CON(C)C(=O)CO[Si](C)(C)C(C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc(F)c(Cl)c1
Reaction time: 2 h
Yield: 87.9 %

Procedure:
0.5M (3-Chloro-4-fluorophenyl)magnesium bromide in THF (27.4 mL, 13.7 mmol) was added dropwise to 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (2.00 g, 8.57 mmol) in THF (20 mL) cooled in ice. The mixture became turbid after about half of the Grignard reagent was added. This was stirred in an ice bath for 2 hours, quenched with saturated aqueous NH4Cl, and concentrated to remove the THF. The aqueous residue was extracted with 2 portions DCM. The combined DCM layers were dried over MgSO4, filtered, and evaporated to yield a crude product (3.62 g) as an oil. This was taken up in hexane and purified on a silica gel plug with hexane until product started eluting, then 15:1 hexane/EtOAc. Product-containing fractions yielded 2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethanone (2.28 g, 7.53 mmol, 87.9% yield) as an oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[N-:15]=[N+:16]=[N-:17].[Na+].CCOC(C)=O>CC(C)=O>[N:15]([CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)=[O:4])=[N+:16]=[N-:17]
Reactant: O=C(CBr)c1ccc2ccccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2-bromo-1-(2-naphthyl)ethanone in acetone was added NaN3 (1 eq.) and the mixture was stirred at RT for 24 h. EtOAc was added (10 vol.) and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash chromatography on silica eluting with 10% EtOAc/Petroleum ether to obtain the product as a white solid. 1H NMR (300 MHz, CDCl3) δ: 8.39 (1H, s), 8.02-7.82 (4H, m), 7.69-7.50 (2H, m), 4.68 (2H, s). MS (ES) C12H9N3O requires: 211, found: 212 (M+H)+.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25](O)=[O:26])=[CH:19]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([C:25]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:2][CH2:3]1)=[O:26])=[CH:19]2
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cc3cc(F)ccc3[nH]2)CC1
Reaction time: 24 h

Procedure:
tert-Butyl 1,4-diazepane-1-carboxylate (2.0 g, 10 mmol, Aldrich), 5-fluoro-1H-indole-2-carboxylic acid (1.79 g, 10 mmol, Aldrich), and EDCI (1.92 g, 10 mmol) were combined in CH2Cl2 (30 mL) at room temperature and stirred for 24 hours. The mixture was concentrated under reduced pressure and the residue was purified by flash chromatography (5% MeOH/CH2Cl2) to provide the title compound. 1H NMR (CD3OD, 300 MHz) δ 1.46(s, 9H), 1.86–2.14(m, 2H), 3.40–3.58(m, 2H), 3.62–3.72(m, 2H), 3.75–4.05(m, 4H), 6.78(s, 1H), 6.99–7.09(m, 1H), 7.28–7.35(m, 2H); MS (DCI/NH3) m/z 362 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.Br[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C1CN2C(=NCCC2)C1.C(#N)C>ClCCl>[NH2:20][S:17]([C:11]1[C:10]([Cl:21])=[CH:9][C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)=[C:13]([CH:12]=1)[C:14]([O:16][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:15])(=[O:19])=[O:18]
Reactant: CCOC(=O)CCCBr
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Agent: C1CN=C2CCCN2C1
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)CCCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of furosemide (5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid (10), (Aldrich) (0.060 mole), ethyl 4-bromobutyrate (Aldrich) (0.055 mole), DBN (1,5-diazabicyclo[4.3.0]non-5-ene, Aldrich) (0.060 mole) and dry acetonitrile (100 mL) is stirred at ambient temperature for 10 hours. The reaction mixture is diluted with dichloromethane (200 mL) and extracted with sodium bicarbonate solution, washed with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give crude product, which may be purified by column chromatography on silica gel with hexanes/ethyl acetate as eluent. The fractions that contain pure product may be combined and spin evaporated in vacuo to give ethyl 4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoate (300). See eg., T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, p. 228 (1991).
Reaction SMILES: [C:1]1([CH:7]2[O:12][CH2:11][CH:10]([OH:13])[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])[N:18]=1>O1CCCC1.O>[Cl:16][C:17]1[CH:22]=[C:21]([O:13][CH:10]2[CH2:11][O:12][CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH2:9]2)[N:20]=[C:19]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])[N:18]=1
Reactant: OC1COC(c2ccccc2)OC1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(CSc2nc(Cl)cc(OC3COC(c4ccccc4)OC3)n2)c1F

Procedure:
To a solution of 2-phenyl-1,3-dioxan-5-ol (484 mg) in anhydrous tetrahydrofuran (10 ml) at 0° C. was added 60% sodium hydride (110 mg) and the mixture was heated to reflux for 25 minutes. On allowing to cool to ambient temperature 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of step (ii) (75 mg) was added and the reaction was heated to reflux for a further 90 minutes. The reaction mixture was allowed to cool, diluted with water and extracted with ethyl acetate (×3). The combined organic layers were dried with magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica using a 95:5 to 90:10 mixture of iso-hexane and ethyl acetate as eluent to give the sub-title compound as a white solid. Yield: 350 mg
Reaction SMILES: C([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)C1C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[CH:25]1[O:27][CH2:26]1>CO>[ClH:21].[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][NH:8][CH2:26][CH:25]([OH:27])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: Clc1cccc(C2CO2)c1
Reactant: COc1ccc(CCNCc2ccccc2)cc1OC
Solvent: CO
Product: COc1ccc(CCNCC(O)c2cccc(Cl)c2)cc1OC
Product: Cl
Reaction time: 1.5 h

Procedure:
A solution of 27.1 g. (0.1 mole) of N-benzyl-3,4-dimethoxyphenylethylamine and 23.3 g. (0.15 mole) of m-chlorostyrene oxide in 500 ml. of methanol is stirred and refluxed overnight. The methanol is removed in vacuo and the residual N-benzyl-N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(3-chlorophenyl)ethylamine is reduced without further purification. This sample (0.01 mole) is dissolved in ether, acidified with ethereal hydrogen chloride and hydrochloride precipitates. The latter is dissolved in 90 ml. of methanol, the solution is added to a mixture of 0.5 g. of palladium-on-carbon in 10 ml. of ethyl acetate and the mixture is hydrogenated at room temperature for 90 minutes at 60 psi. The reaction mixture is filtered and the filtrate evaporated in vacuo to yield N-[2-(3,4-dimethoxyphenyl)ethyl]-2-hydroxy-2-(3-chlorophenyl)ethylamine hydrochloride, m.p. 155°-157.5° C.
Reaction SMILES: [C:1]([O:4][C:5]1([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12]/[C:11]/2=[N:19]\[C:20]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])=S)[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[N:38]#[C:39][NH2:40]>C(#N)C.[Hg](OC(C)=O)OC(C)=O>[C:1]([O:4][C:5]1([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[S:12]/[C:11]/2=[N:19]\[C:20]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[O:29][CH3:30])=[N:40][C:39]#[N:38])[CH2:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: N#CN
Reactant: COc1ccc(Cl)cc1C(=S)/N=c1\sc(C(C)(C)C)cn1CC1(OC(C)=O)CCC1
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=NC#N)/N=c1\sc(C(C)(C)C)cn1CC1(OC(C)=O)CCC1
Yield: 76.9 %

Procedure:
The product of Example 27D (1.2 g, 2.6 mmol), triethylamine (1.4 mL, 10 mmol), cyanamide (0.32 g, 7.7 mmol) and Hg(OAc)2 (1.6 g, 5.1 mmol) in acetonitrile (20 mL) were processed as described in Example 16E to provide the title compound (0.93 g, 2.0 mmol, 77% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.38 (s, 9H), 1.73-1.96 (m, 2H), 1.99 (s, 3H), 2.22-2.46 (m, 4H), 3.91 (s, 3H), 4.76 (s, 2H), 6.63 (s, 1H), 6.94 (d, J=8.8 Hz, 1H), 7.31-7.39 (m, 2H); MS (DCI/NH3) m/z 475 (M+H)+. Anal. calculated for C23H27 ClN4O3S: C, 58.16; H, 5.73; N, 11.80. Found: C, 58.16; H, 5.66; N, 11.85.
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1.N1C=CC=CC=1.[C:31](Cl)(=[O:34])[O:32][CH3:33].Cl>C(Cl)Cl.O>[CH3:33][O:32][C:31]([NH:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][C:5]=2[O:4][CH:3]=1)=[O:34]
Reactant: COC(=O)Cl
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)Nc1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To 70 ml of methylene chloride was added 3.46 g of 3-amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. Further, 870 mg of pyridine was added thereto. The mixture was ice-cooled. To this solution was dropwise added a solution of 1.04 g of methyl chlorocarbonate dissolved in 30 ml of methylene chloride, in 10 minutes. The mixture was then stirred for 30 minutes at 20°-25° C. 50 ml of water was added thereto. The resulting mixture was adjusted to pH 4 with 4N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from acetonitrile to obtain 2.95 g (yield: 73%) of 3-methoxycarbonylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 233°-235° C.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:27]([CH2:28][NH2:29])=[CH:26][C:25]3[C:20](=[C:21]([O:30][CH3:31])[CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:15]=[CH:16][CH:17]=1.C(N(CC)C(C)C)(C)C.C(O)CCC>CCOC(C)=O>[F:11][C:12]1[CH:13]=[C:14]([C:18]2[C:27]([CH2:28][NH:29][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)=[CH:26][C:25]3[C:20](=[C:21]([O:30][CH3:31])[CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: COc1cccc2cc(CN)c(-c3cccc(F)c3)nc12
Reactant: Brc1ncnc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1cccc2cc(CNc3ncnc4[nH]cnc34)c(-c3cccc(F)c3)nc12
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 6-bromopurine (0.1418 g, 0.7125 mmol), (2-(3-fluorophenyl)-8-methoxyquinolin-3-yl)methanamine (0.2213 g, 0.7838 mmol), and N,N-diiso-propylethylamine (0.2482 mL, 1.425 mmol) in 1-butanol (7.125 mL, 0.7125 mmol) was stirred at 100° C. After 24 h, the mixture was removed from the heat and concentrated under reduced pressure. The residue was purified by flash column chromatography on a silica gel column using 50% of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 as eluent to give an off-white solid. The off-white solid was suspended in EtOAc and filtered to give N-((2-(3-fluoro-phenyl)-8-methoxyquinolin-3-yl)methyl)-9H-purin-6-amine as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.95 (1 H, s), 8.18-8.30 (2 H, m), 8.11 (2 H, s), 7.42-7.61 (5 H, m), 7.28-7.36 (1 H, m), 7.16 (1 H, dd, J=7.1, 1.7 Hz), 4.71-4.95 (2 H, m), 3.95 (3 H, s); LC-MS (ESI) m/z 401.2 [M+H]+.
Reaction SMILES: BrC[CH2:3][C:4]1[CH2:5][S:6](=[O:31])[C@@H:7]2[CH:19]([NH:20][C:21](=[O:29])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18](=[O:30])[N:8]2[C:9]=1[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[O:11].CS(C)=[O:34].O>C1C=CC=CC=1.CS(C)=O>[OH:34][CH2:3][C:4]1[CH2:5][S:6](=[O:31])[C@@H:7]2[CH:19]([NH:20][C:21](=[O:29])[CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:18](=[O:30])[N:8]2[C:9]=1[C:10]([O:12][CH2:13][C:14]([Cl:17])([Cl:15])[Cl:16])=[O:11]
Reactant: CS(C)=O
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CCBr)CS(=O)[C@H]12
Solvent: O
Solvent: c1ccccc1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=C(CO)CS(=O)[C@H]12
Reaction time: 168 h

Procedure:
To a solution of 0.461 (0.82 mmole) of 2,2,2-trichloroethyl 3-bromoethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide in 20 ml of 1:1 benzene-dimethylsulfoxide (DMSO) is added 0.150 ml (8.2 mmoles) of water and the mixture is stirred at 25° for 7 days. Then the mixture is poured into 100 ml of H2O and extracted with ethyl acetate. The ethyl acetate is dried (MgSO4) and evaporated in vacuo to yield 2,2,2-trichloroethyl 3-hydroxymethyl-7-phenylacetamido-3-cephem-4-carboxylate-1-oxide, which can be purified by recrystallization from methanol.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[Li]CCCC.[CH:36](=O)[CH2:37][CH2:38]/[CH:39]=[CH:40]/[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:8]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:30][CH:29]=1)[CH:9]=[CH:36][CH2:37][CH2:38]/[CH:39]=[CH:40]/[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: COc1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCC/C=C/CCC=O
Agent: [Br-]
Agent: [Li]CCCC
Product: CCCCC/C=C/CCC=CCc1ccc(OC)cc1
Yield: 47.7 %

Procedure:
Starting from p-methoxyphenethyltriphenylphosphonium bromide (3.12 g, 6.54 mmol, 1.0 equiv.), n-BuLi (1.6 M in hexanes, 4.1 mL, 6.54 mmol, 1.0 equiv.) and (E)-dec-4-enal (1.51 g, 9.80 mmol, 1.5 equiv.), 0.85 g (48%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (hexanes/EtOAc 992:8).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][S:7][C:8]([F:21])([F:20])[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[O:11][CH2:10]1)(=[O:3])[CH3:2].[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.C(OCC)C>[C:1]([O:4][CH2:5][CH2:6][S:7][C:8]([F:21])([F:20])[C:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[F:19])([OH:11])[CH2:10][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(=O)OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.3 %

Procedure:
To a solution of 1-(2-acetoxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-2,3-epoxypropane (24.0 g, 0.07 mol) in DMF (250 ml), 1,2,4-triazole (16.6 g, 0.24 mol) and potassium carbonate (33.2 g, 0.24 mol) were added, followed by stirring at room temperature for 12 hours and then at an external temperature of 50° C. for one hour. After the completion of the reaction, the reaction mixture was diluted with ethyl ether and an insoluble matter was filtered off. The ether solution was washed with water, dried over magnesium sulfate and then distilled off under reduced pressure. The residue so obtained was recrystallized from isopropyl ether--ethyl acetate, whereby 1-(2-acetoxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (12.2 g, yield: 37.8%) was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=1.C([Li])CCC.[CH3:19][S:20]SC>C(OCC)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[S:20][CH3:19])[CH:4]=1
Reactant: COc1ccnc(-c2cccs2)c1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1ccnc(-c2sccc2SC)c1
Temperature: 25 °C

Procedure:
The product of step (b) above (5 g) dissolved in dry diethyl ether (100 ml) was cooled to -50° and treated with butyl lithium in hexane (2.2M, 13 ml) dropwise during 0.5 hour. The mixture was warmed to -10° for 10 minutes, then cooled to -30°. Dimethyl disulphide (3.5 ml) was then added dropwise. The mixture was maintained at -30° for 0.5 hour then warmed up to room temperature during several hours. Aqueous work-up and ethyl acetate extraction gave the sub-title compound as an oil.