Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:23]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([NH:31][C:32]1[N:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl.O>[CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:38]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29]([C:24]4[C:23]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:30])=[N:37][CH:36]=3)=[O:39])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cn1)c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a chilled (0° C.) solution of 0.293 g of 6,11-dihydro-5H-dibenz[b,e]azepine and 625 μL triethylamine in 3.5 ml of dichloromethane is added a solution of 0.657 g of 6-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride in 1.5 ml of dichloromethane. The mixture is stirred under argon at room temperature for 16 hours and diluted with 40 ml of dichloromethane and 20 ml of water. The organic layer is separated and washed with 20 ml each of 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate concentrated to dryness under vacuum. The residual solid is chromatographed on silica gel with ethyl acetate-hexane(1:1) as solvent to give the product as a glass. Crystallization from ethyl acetate gives 0.395 g of white crystals, m.p. 134°-142° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[S:13][CH:14]=[CH:15][C:3]=12.[OH-].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CS(C)=O>[CH2:18]([NH:1][C:2]1[C:11]2[C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[S:13][CH:14]=[CH:15][C:3]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1c2c(nc3sccc13)CCCC2=O
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCCc2nc3sccc3c(NCc3ccccc3)c21
Reaction time: 0.5 h

Procedure:
4-Amino-7,8-dihydrothieno[2,3-b]quinolin-5(6H)-one (6.21 g) was dissolved in 60 ml of dimethylsulfoxide (DMSO). Potassium hydroxide (2.3 g, calculated as 85%), which had been pulverized under pentane, was added to the reaction mixture. After 30 minutes 5.0 g of benzyl bromide was added, and after an additional 30 minutes, 1.0 g of potassium hydroxide and 2.0 g of benzyl bromide were added. After a total reaction time of 90 minutes, 200 ml of water was added to the reaction mixture, causing a gummy precipitate to separate. The crude product was collected by filtration and purified by flash chromatography (10% ethyl acetate/dichloromethane) followed by recrystallization from ethyl acetate. Obtained in this manner was 2.35 g of analytically pure product, mp 159°-160°.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H-].[Na+].[Br-].[Li+].IC.[C:23](O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.COCCOC>[CH3:23][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1=[O:1]
Reactant: CCOC(=O)c1cc2ccccc2[nH]c1=O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: COCCOC
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64 %

Procedure:
3.5 g (16 mmol) of ethyl 2-oxo-1,2-dihydroquinoline-3-carboxylate was dissolved in a mixed solvent of N,N-dimethylformamide (80 mL) and 1,2-dimethoxyethane (25 mL), and under a nitrogen gas stream, 0.71 g (18 mmol) of 60% sodium hydride (oily) was added to the solution at room temperature. The mixture was stirred for 15 minutes at room temperature. 5.6 g (64 mmol) of lithium bromide was added to the above mixture at room temperature, and the resulting mixture was stirred for 15 minutes at room temperature. 4.6 g (32 mmol) of iodomethane was further added to the mixture at room temperature, and the resulting mixture was stirred for 3 hours at 60° C. The reaction mixture was poured into an aqueous solution of citric acid, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, an aqueous solution of sodium hydrogen carbonate, and brine in this order, and was dried and concentrated. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:4 to 4:1), and thus 2.4 g (yield: 64%) of the title compound was obtained as light yellow crystals.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([N+:19]([O-])=O)[CH:14]=3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:3]1>N.C(O)C.[Ni]>[NH2:19][C:15]1[CH:14]=[C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]3[CH:4]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:3][B:2]([OH:1])[C:6]=3[CH:7]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc([N+](=O)[O-])c3)cc(C)c21
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(N)c3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(1-hydroxy-4-methyl-6-(2-nitropyridin-4-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in 2M ammonia in ethanol was added 1 ml Raney-Nickel (slurry in water). The mixture was stirred at room temperature for 8 hours and then filtered through Celite. The filtrate was evaporated to yield desired product. MS (ESI) m/z=343 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(Cl)(=O)OCC.C(N(CC)CC)C.[NH:39]1[CH2:44][CH2:43][S:42][CH2:41][CH2:40]1>C1COCC1.O>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([N:39]3[CH2:44][CH2:43][S:42][CH2:41][CH2:40]3)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Reactant: C1CSCCN1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)N3CCSCC3)cc2)=C(C)C1=O
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a solution of 3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (27 mg, 0.078 mmol) obtained in Example 1 and ethyl chlorocarbonate (15 mg, 0.139 mmol) in THF (10 ml) was added triethylamine (14 mg, 0.139 mmol) at −10° C. followed by stirring for 30 minutes, and then thiomorpholine (20 mg, 0.194 mmol) was added thereto followed by stirring at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with ether. The extract was washed with water, dried, and then the solvent was distilled off. The resulting residue was purified by a middle-pressure column chromatography using silica gel (hexane:ethyl acetate=1:1). The yellow powder thus obtained was crystallized from methylene chloride-diethylether to yield the title compound (26 mg, 0.061 mmol, yield 77%) as a yellow crystal.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:41][CH2:42][CH2:43][N:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[N:45]1>CC(=O)CC>[N:44]1([CH2:43][CH2:42][CH2:41][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=4)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]=[N:45]1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: ClCCCn1nnc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4nnc5ccccc54)CC3)C2=O)c1
Temperature: 78 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To a solution of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2 g, 0.47 mmol), potassium carbonate (0.097 g, 0.7 mmol) and sodium iodide (0.021 g, 0.14 mmol) in 2-butanone (5 mL), was added 1-(3-chloropropyl)-1H-benzo[d][1,2,3]triazole (0.093 g, 0.47 mmol). After stirring at 78° C. for 18 hours, the reaction mixture was filtered, concentrated and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.21 g, 77%); 1H NMR (DMSO-d6): δ 1.51 (s, 9H), 1.58 (d, 2H, J=13.2 Hz), 2.13 (t, 2H, J=6.4 Hz), 2.30 (t, 2H, J=6.4 Hz), 2.49-2.53 (m, 2H), 2.66 (d, 4H, J=7.6 Hz), 4.58 (d, 4H, J=9.6 Hz), 4.80 (t, 2H, J=6.4 Hz), 6.78 (t, 1H, J=6.8 Hz), 6.84 (d, 2H, J=8 Hz), 7.25 (t, 2H, J=8 Hz), 7.39 (t, 1H, J=7.2 Hz), 7.47-7.54 (m, 3H), 7.78 (s, 1H), 7.82 (dt, 1H, J=6.8 and 2 Hz), 7.93 (d, 1H, J=8.4 Hz), 8.03 (d, 1H, J=8.4 Hz); MS for C34H40N6O3 m/z 581.20 (M+H)+.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12](F)[CH:11]=1>>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([S:7][C:12]2[CH:13]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:15]=[C:10]([Br:9])[CH:11]=2)=[CH:3][CH:2]=1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(Sc2cc(Br)cc(C(F)(F)F)c2)cc1
Yield: 63 %

Procedure:
Using a similar procedure to that described in the 1st paragraph of Note a. above 4-toluenethiol was reacted with 1-bromo-3-fluoro-5-trifluoromethylbenzene to give 3-bromo-5-trifluoromethylphenyl 4-tolyl sulphide in 63% yield as an oil.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[C:18](=[O:19])[CH2:17][S:16][C:15]3=[O:20])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:21](=O)[CH2:22][CH2:23][CH3:24].N1CCCCC1>C(O)C>[CH:21](=[C:17]1[S:16][C:15](=[O:20])[N:14]([CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:18]1=[O:19])[CH2:22][CH2:23][CH3:24]
Reactant: O=C1CSC(=O)N1CCCCc1cccc2nccn12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCCCc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.00 g (3.46 mmol) of 3-[4-(imidazo-[1,2-a]pyridin-5-yl)butyl]thiazolidine-2,4-dione and 0.31 ml (3.46 mmol) of n-butyraldehyde in 25 ml of ethanol, 0.03 ml (0.35 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate→ethyl acetate/ethanol=10/1) to yield 1.08 g (90.8%, light yellow oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:32])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([O:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:16]=3[O:30][CH3:31])[N:14]=2)[CH:5]=[C:4]([Cl:33])[C:3]=1/[CH:34]=[C:35](\[CH3:41])/[C:36]([O:38]CC)=[O:37].[OH-].[Na+].Cl>C1COCC1.C(O)C>[Cl:33][C:4]1[CH:5]=[C:6]([C:8](=[O:32])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C@@H:21]([O:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:16]=3[O:30][CH3:31])[N:14]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1/[CH:34]=[C:35](\[CH3:41])/[C:36]([OH:38])=[O:37]
Reactant: CCCCCC[C@H](OC)c1cccc(-c2csc(NC(=O)c3cc(Cl)c(/C=C(\C)C(=O)OCC)c(Cl)c3)n2)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCC[C@H](OC)c1cccc(-c2csc(NC(=O)c3cc(Cl)c(/C=C(\C)C(=O)O)c(Cl)c3)n2)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
Ethyl (S)-(E)-3-(2,6-dichloro-4-(4-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylate (14, 6.76 g) obtained in the fifth step was dissolved in THF (20 mL) and ethanol (20 mL), a 4 mol/L sodium hydroxide aqueous solution (13.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with hydrochloric acid, and extracted with ethyl acetate. The extraction residue was recrystallized with methanol to obtain (S)-(E)-3-(2,6-dichloro-4-(4-(2-methyloxy-3-(1-methyloxyheptyl)phenyl)thiazol-2-ylcarbamoyl)phenyl)-2-methylacrylic acid (C-1B, 5.8 g, yield 88%).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].C([O-])([O-])=O.[Na+].[Na+].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>[OH-].[Na+].O1CCOCC1>[CH2:20]([O:19][C:17]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
L-Pyroglutamic acid (2.02 g, 13.83 mmol) was dissolved in 1 N NaOH (13.84 mL) and the solution was cooled to 0° C. After 30 min stirring, Na2CO3 (3.63 g) and benzyl chloroformate (4.82 mL) in dioxane (21.23 mL) were gradually added in equal portions. Stirring was continued at 0° C. for 1 h, then the solution was stirred overnight at room temperature and extracted with ethyl ether (2×20 mL). The aqueous solution was acidified with 2N HCl to pH 5 and extracted with ethyl acetate (3×50 mL). The ethyl acetate layer was dried over sodium sulfate and evaporated to give an oil, which crystallized overnight. Recrystallization of the crude product gave white crystalline material (2.86 g, 87%): FABMS 240.1 (M+H): HRFABMS Calcd for C13H14NO5 (M+H) 264.0872, Found 264.0866; Calcd for C13H13NaNO5 (M+Na) 286.0691, Found 286.0694.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:20][CH3:21])[C@H:3]([NH:8][C:9]([N:11]([CH3:19])[CH2:12][C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)=[O:10])[C:4]([O:6]C)=[O:5].[OH-].[Li+].Cl>O1CCOCC1>[CH3:1][C@@H:2]([CH2:20][CH3:21])[C@H:3]([NH:8][C:9]([N:11]([CH3:19])[CH2:12][C:13]1[N:14]=[C:15]([CH3:18])[S:16][CH:17]=1)=[O:10])[C:4]([OH:6])=[O:5]
Reactant: CC[C@H](C)[C@H](NC(=O)N(C)Cc1csc(C)n1)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC[C@H](C)[C@H](NC(=O)N(C)Cc1csc(C)n1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the product from Example 109D (0.38 g, 1.2 mmol) in dioxane (5 mL) was treated with an aqueous solution of lithium hydroxide (5.0 mL, 0.5 M), stirred for 0.5 hours at 25° C., treated with aqueous HCl (2.5 mL, 1 N), and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over Na2SO4, filtered and concentrated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2S[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)([CH3:4])([CH3:3])[CH3:2].[S:20]([O-:25])(O[O-])(=O)=[O:21].[K+].[K+].C([O-])(=O)C.[Na+].C(O)(C)(C)C>O>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[S:20](=[O:25])(=[O:21])[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)([O-])O[O-]
Reactant: CC(C)(C)Oc1ccc2c(c1)Oc1ccccc1S2
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)Oc1ccc2c(c1)Oc1ccccc1S2(=O)=O
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of 1.05 gm (3.85 mmole) of 3-tert-butoxyphenoxathiin, 3.53 gm (11.5 mmole) of potassium peroxymonosulfate compound [OXONE™] (Dupont), 1.14 gm (14 mmole) of sodium acetate, 20 mL of water, and 20 mL of tert-butanol was stirred overnight. The reaction was diluted with 50 mL of water and extracted with 3×75 mL of chloroform. The combined organic layers were then washed with 2×100 mL of water and concentrated in vacuo (water pump). The residue was then chromatographed on silica gel using methylene chloride to yield 0.89 gm of 3-tert-butoxyphenoxathiin 10,10-dioxide, m.p. 108-110°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[I:11][CH:12]1[CH2:16][O:15][CH2:14][CH:13]1[O:17][CH2:18][CH2:19][CH2:20][OH:21].CCN(CC)CC.P([O-])([O-])([O-])=O>C(Cl)Cl>[I:11][CH:12]1[CH2:16][O:15][CH2:14][CH:13]1[O:17][CH2:18][CH2:19][CH:20]=[O:21]
Reactant: OCCCOC1COCC1I
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCCOC1COCC1I
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
Oxalyl chloride (580 mg, 392 μL, 4.6 mmol) was diluted in CH2Cl2 (12 mL) under argon and the solution was cooled to −78° C. Dry DMSO (715 mg, 650 μL, 9.15 mmol) in CH2Cl2 (3 mL) was added to the cold solution dropwise and the mixture was stirred for 30 min. A solution of alcohol 23 (500 mg, 1.83 mmol) in CH2Cl2 (4 mL) was then added slowly, and the mixture was kept stirring for an additional hour at −78° C. Et3N (1.3 g, 1.8 mL, 12.8 mmol) was then introduced, the white suspension was stirred at −78° C. for 20 min and slowly warmed to rt. A 0.5 M phosphate buffer solution pH 5.5 (20 mL) was added, the two phases were separated and the resulting aqueous phase was extracted with Et2O (4×). The combined organic phase was dried (MgSO4), filtered, and evaporated. The residue was purified by flash column chromatography using hexanes/EtOAc (6:1 to 4:1) to yield the desired aldehyde 24 (433 mg, 86%) as a light yellow oil. TLC: Rf=0.76 (hexanes/EtOAc=1:1); 1H NMR (CDCl3, 300 MHz) δ 9.77 (t, J=1.3 Hz, 1H), 4.35 (m, 1H), 4.30-4.19 (m, 3H), 4.04 (dd, J=2.3, 9.8 Hz, 1H), 3.92 (ddd, J=5.3, 6.7, 9.5 Hz, 1H), 3.77 (dd, J=1.7, 10.1 Hz, 1H), 3.75 (ddd, J=5.2, 6.2, 9.5 Hz, 1H), 2.69 (m, 2H); 13C NMR (CDCl3, 75 MHz) δ 200.1, 88.3, 76.1, 71.8, 63.1, 43.7, 23.3.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:24]1[N:25]=[C:26]([NH:29]C(=O)C(F)(F)F)[S:27][CH:28]=1)[C:5]([NH:7][CH:8]1[C:22](=[O:23])[N:10]2[C:11]([C:19]([OH:21])=[O:20])=[C:12]([CH2:15][S:16][CH:17]=[CH2:18])[CH2:13][S:14][C@H:9]12)=[O:6].C([O-])(=O)C.[Na+].[ClH:41]>O>[ClH:41].[NH2:29][C:26]1[S:27][CH:28]=[C:24]([C:4](=[N:3][O:2][CH3:1])[C:5]([NH:7][CH:8]2[C:22](=[O:23])[N:10]3[C:11]([C:19]([OH:21])=[O:20])=[C:12]([CH2:15][S:16][CH:17]=[CH2:18])[CH2:13][S:14][C@H:9]23)=[O:6])[N:25]=1
Reactant: C=CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)C(F)(F)F)n3)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C=CSCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1

Procedure:
A solution of 7-[2-methoxyimino-2-{2-(2,2,2-trifluoroacetamido)thiazol-4-yl}acetamido]-3-vinylthiomethyl-3-cephem-4-carboxylic acid (syn isomer) (380 mg) and sodium acetate (937 mg) in water (8 ml) was stirred at ambient temperature overnight. The mixture was adjusted to pH 1.6 with 6N-hydrochloric acid. This solution was subjected to column chormatography on macroporous non-ionic adsorption resin "Diaion HP 20" (15 ml). After the column was washed with water, the elution was carried out with 25% aqueous isopropyl alcohol. The eluates containing the object compound were collected, evaporated to remove isopropyl alcohol under reduced pressure and lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinylthiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (170 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[C:14]([Br:16])[N:15]=[C:10]3[N:9]([CH:17]3[CH2:19][CH2:18]3)[C:8]2=[O:20])[CH2:4]1.CS(C)=O.C(N(CC)C(C)C)(C)C.Cl[C:35]1[S:36][C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1>O.CO>[S:36]1[C:37]2[CH:43]=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=[C:35]1[NH:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3=[N:12][CH:13]=[C:14]([Br:16])[N:15]=[C:10]3[N:9]([CH:17]3[CH2:18][CH2:19]3)[C:8]2=[O:20])[CH2:4]1
Reactant: N[C@H]1C[C@H](n2c(=O)n(C3CC3)c3nc(Br)cnc32)C1
Reactant: Clc1nc2ccccc2s1
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=c1n(C2CC2)c2nc(Br)cnc2n1[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 100 °C

Procedure:
A glass microwave reaction vessel was charged with 1-(trans-3-aminocyclobutyl)-5-bromo-3-cyclopropyl-1H-imidazo[4,5-b]pyrazin-2(3H)-one hydrochloride (Intermediate 82, 0.128 g, 0.355 mmol) and DMSO (2 mL). N,N-Diisopropylethylamine (0.250 ml, 1.437 mmol) was added followed by 2-chlorobenzothiazole (0.060 ml, 0.461 mmol) and the reaction mixture was sealed under argon and heated at 100° C. for 24 h. The reaction mixture was diluted with water and a small amount of MeOH. The resultant solid was filtered, washed with water and dried in vacuo to give 94 mg (58%) of an off-white crystalline solid. ESI MS 456.8, 458.8 [M+1]. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.53 (d, J=6.28 Hz, 1 H), 8.16 (s, 1 H), 7.63-7.75 (m, 1 H), 7.42 (d, J=7.45 Hz, 1 H), 7.15-7.30 (m, 1 H), 6.96-7.09 (m, 1 H), 5.12 (quin, J=8.29 Hz, 1 H), 4.41-4.65 (m, 1 H), 3.14-3.29 (m, 2 H), 2.87-3.01 (m, 1 H), 2.39-2.57 (m, 2 H), 0.91-1.11 (m, 4 H)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH3:18][N:19]([CH3:28])[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:18][N:19]([CH3:28])[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[CH:4][N:3]=2)[CH2:24][CH2:23]1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nc2)cc1
Reactant: CN(C)CCN1CCNCC1
Product: CN(C)CCN1CCN(c2ccc(-c3ccc(C(F)(F)F)cc3)cn2)CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(4-trifluoromethylphenyl)pyridine and (2-dimethylaminoethyl)piperazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[NH:14][C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:12]1.[F:21][C:22]1[CH:23]=[C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36](=[O:43])(=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:25]=[CH:26][C:27]=1[CH2:28]Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[S:36](=[O:42])(=[O:43])[NH:37][C:38]([CH3:41])([CH3:39])[CH3:40])=[CH:23][C:22]=2[F:21])[C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:12]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)c(F)c1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)[nH]1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 93 %

Procedure:
The alkylation of 2-(2-bromo-5-nitrophenyl)-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 30, Step A) with [3-fluoro-2'-(N-t-butylsulfamoyl)-biphenyl-4-yl]methyl bromide (from Step B) was carried out according to the procedure of Example 8, Step A, to give a 93% yield of the title compound as a stiff, brownish foam, mp 137°-139° C., homogeneous by TLC in 98:2 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 666, 668 (M+Li)+.