Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].N1C=CC=CC=1.[C:16](Cl)(=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[Br:1][C:2]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1cccc(F)c1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Nc1cccc(F)c1Br
Yield: 96 %

Procedure:
To a solution of 2-bromo-3-fluoroaniline (6.5 g, 34.17 mmol) and pyridine (2.7 g, 34.17 mmol) in 20 ml of CH2Cl2, cinnamoyl chloride (5.95 g, 35.88 mol) in 10 ml CH2Cl2 are added dropwise and mixture was refluxed for 30 min. The reaction mixture is diluted with CH2Cl2, the organic layer washed with diluted HCl, saturated Na2CO3 solution, water, and dried (Na2SO4). The solvent is removed in vacuo to give 10.5 g of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide. To a solution of N-(2-bromo-3-fluorophenyl)-3-phenylacrylamide (10.5 g, 32.8 mmol) in 70 ml of chlor-benzene at 130° C. AlCl3 (21.9 g, 0.164 mol) is added portionwise, the mixture is stirred at this temperature 2 h and poured in ice-water. The precipitate is filtered off and dried. Yield 6.05 g (76%). 6 g (24.8 mmol) of 8-bromo-7-fluoro-1H-quinolin-2-one are refluxed in 30 mL of POCl3 during 2 h, then poured on ice, extracted with benzene. the benzene extract dried (Na2SO4) to yield 6.1 g 8-bromo-2-chloro-7-fluoroquinoline after solvent removal. To a mixture of 10 ml 10%-oleum and 1.4 g (22.2 mmol) of fuming HNO3 8-bromo-2-chloro-7-fluoroquinoline (4.8 g 18.5 mmol) is added portionwise. The mixture is heated at 100° C. for 2 h. Additional HNO3 (0.17 g) is added and stirred for additional 1 h. The reaction mixture is poured in ice-water, extracted with EtOAc, filtered through silica gel, and crystallized from heptane-toluene to yield 2.3 g (50%) 8-bromo-2-chloro-7-fluoro-5-nitroquinoline. 2.3 g (7.54 mmol) of 8-bromo-2-chloro-7-fluoro-5-nitroquinoline are heated at 100° C. for 5 h in a solution containing 16 ml of CH3COOH, 3.2 ml of H2O and 5 ml of conc. HCl. The mixture is poured in water, the formed precipitate is filtered off, stirred in EtOAc and filtered to yield 1.71 g. 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one. To a suspension 1.7 g (5.92 mmol) of 8-bromo-7-fluoro-5-nitro-1H-quinolin-2-one and 2.3 g (35.5 mmol) of HCOONH4 in 10 ml of ethanol 0.1 g 10% Pd—C are added, and stirred for 2 h at 60° C. A solid disappeared and then formed again. The precipitate is filtered off, dissolved in 3 ml of DMSO and filtered through silica gel. 15 ml of water are added to the eluate, the precipitate is filtered off and dried to yield 0.5 g (47%) 5-Amino-7-fluoro-1H-quinolin-2-one. 1H-NMR (DMSO-d6); δ=6.14 (dd, 1H), 6.20 (dd, 1H), 6.23 (d, 1H), 6.27 (br, 2H), 8.06 (d, 1H), 11.50 (br., 1H).
Reaction SMILES: [CH3:1][C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10](N)[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=[O:3].C(=O)(O)[O-].[K+].Cl>O.CC(O)C>[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[CH2:10][C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:1]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1
Temperature: 0 °C

Procedure:
Solutions A and B are produced according to a method as described in Example 2, but using in solution A 18.57 g of 7-aminocephalosporanic acid instead of 18.57 g of 7-amino-3-{[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl}-3-cephem-4-carboxylic acid. While stirring the mixture obtained is poured onto an ice-cooled suspension of potassium bicarbonate in a mixture of water and 2-propanol. The pH of the two-phase system obtained is adjusted to 2.0 with 2 N HCl. The organic phase is separated off and treated with 7.5 ml of water and 3.81 g thiourea while stirring. The pH of the mixture is kept between 3.0 and 3.5 by addition of a solution of 2-amino-2,4,4-trimethylpentane in dichloromethane. A precipitate is obtained. 2-Propanol is added to the suspension obtained while stirring and the precipitate is isolated and dried. 7-[2-(Aminothiazol-4-yl)-2(Z)-methoximino)acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid is obtained.
Reaction SMILES: [CH3:1][C:2]([O-])(C)[CH3:3].[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=1.C([O-])([O-])=O.[K+].[K+].IC(C)C>COCCOC.C(Cl)(Cl)Cl.CCCCCC>[Br:7][C:8]1[CH:9]=[CH:10][C:11](=[O:14])[N:12]([CH:2]([CH3:3])[CH3:1])[CH:13]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: COCCOC
Solvent: ClC(Cl)Cl
Product: CC(C)n1cc(Br)ccc1=O
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
t-BuOK (32.2 g) was added to the suspension of 5-bromo-2(1H)-pyridone (50 g) in DME (500 ml). The mixture was stirred for 30 minutes. To the mixture was added K2CO3 (27.8 g) and 2-iodopropane (81.6 g). The reaction mixture was refluxed with stirring for 3 hours. The above mixture was cooled to 20-25° C. The precipitated salt was removed by filtration and washed with DME (100 ml). Evaporation of solvent in vacuo gave solidly residue. The residue was dissolved in CHCl3 (150 ml). The solution was washed with 0.1N HCl and brine, and dried over MgSO4. Evaporation of solvent in vacuo gave solidly residue. To the residue was added n-hexane (150 ml) to pulverize the residue. The precipitate was collected by filtration and dried in vacuo to give 5-bromo-1-isopropyl-2(1H)-pyridone (41.2 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH3:9])[CH:4]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH2:8]([C:5]1[CH:4]=[C:3]([CH2:2][N:1]=[CH:12][N:13]([CH3:15])[CH3:14])[O:7][N:6]=1)[CH3:9]
Reactant: CCc1cc(CN)on1
Reactant: COC(OC)N(C)C
Product: CCc1cc(CN=CN(C)C)on1

Procedure:
9 g of 5-aminomethyl-3-ethyl-isoxazole is stirred in 12 ml of dimethylformamide-dimethylacetal with exclusion of moisture for 8 hours at 80° C. (bath temperature). After distillation on a bulb tube at 145° C. and 0.03 torr, 12.8 g (98% of theory) of the desired product is obtained.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:19][C:20]2[C:21]3[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:22]=3[S:23][CH:24]=2)[C:11]1=[O:30])[CH2:7][CH2:8][CH3:9])C.[OH-].[Na+].Cl.O>CO>[CH3:29][C:28]1[C:21]2[C:20]([CH2:19][N:12]3[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[N:10]([CH:6]([CH2:7][CH2:8][CH3:9])[CH2:5][C:4]([OH:31])=[O:3])[C:11]3=[O:30])=[CH:24][S:23][C:22]=2[CH:25]=[CH:26][CH:27]=1
Reactant: CCCC(CC(=O)OCC)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(CC(=O)O)n1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 91.4 %

Procedure:
To a solution of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (65 mg, 0.15 mmol) in MeOH (3.0 mL) is added 2.0 N NaOH (0.5 mL). The reaction mixture is stirred at room temperature for 3.5 h and then 1.0M HCl (1.5 mL) and water (50 mL) are added. The mixture is extracted with EtOAc (3×50 mL). The organic layers are combined, dried over MgSO4 and concentrated to give crude product. Purification by flash column chromatography affords 56 mg (92%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid.
Reaction SMILES: [C:1]([O:11]C)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].S(=O)(=O)(O)O>>[C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)C=Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C=Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
100 g of crude methyl cinnamate and 926.8 g of 2.8% caustic soda were placed in a 2-liter flask equipped with a thermometer and a stirrer, and the solution was then stirred at 80° C. for 30 minutes to carry out hydrolysis. Furthermore, the solution which had been subjected to the hydrolysis was passed through a 2.5-cm-diameter, 2.5-cm-high column packed with 25 g of powdery active carbon (Taiko Active Carbon SGA). The thus treated solution was placed in a 2-liter flask equipped with a thermometer and a stirrer and then maintained at 40° C., and 137.1 g of 25% sulfuric acid was added dropwise to precipitate the crystals of cinnamic acid. After the addition of sulfuric acid had been over, the temperature of the solution was lowered to 20° C., followed by filtering through Nutsche. The resultant filter cake was washed with 1000 g of water, and then vacuum-dried at 50° C. to obtain 86.1 g of cinnamic acid. The purity of cinnamic acid was 98.6%, and the content of each of palladium, copper and manganese was 5 ppm or less. In the filtrate and the washing solution with which cinnamic acid had been washed, metallic components of palladium, copper and manganese were each contained in an amount of 5 ppm or less.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[C:6]([Cl:15])[C:3]=1[CH:4]=[O:5].[Mn]([O-])(=O)(=O)=[O:17].[K+]>CC(C)=O.O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[C:6]([Cl:15])[C:3]=1[C:4]([OH:17])=[O:5]
Reactant: COCCOc1cc(Cl)c(C=O)c(Cl)c1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COCCOc1cc(Cl)c(C(=O)O)c(Cl)c1
Temperature: 25 °C

Procedure:
2,6-Dichloro-4-(2-methoxyethoxy)benzaldehyde (0.5 g, 2.0 mmol) in acetone (20 mL) were cooled down in ice bath and then potassium permanganate (0.47 g, 3.0 mmol) in water (5 mL) was added slowly under vigorous stirring. The reaction mixture was warmed up slowly to room temperature and reacted over 24 h. The reaction mixture was filtered through celite and washed with acetone. The organic phase was evaporated and then re-dissolved in EtOAc to be extracted with 1N HCl aqueous solution. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum to afford the compound 2,6-dichloro-4-(2-methoxyethoxy)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](Cl)=[N:26][CH:25]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]([C:22]([O:21][CH3:20])=[O:23])=[CH:25][N:26]=3)=[CH:16][CH:17]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(O)cc1
Reactant: COC(=O)c1cnc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c2ccccc12
Temperature: 60 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A suspension of N-[2-(4-chlorophenyl)ethyl]-4-hydroxy benzamide (605 mg) and 1-chloro-isoquinoline-4-carboxylic acid methyl ester (443 mg) and potassium carbonate (332 mg) in DMF (4 ml) was stirred at 60° C. for two hours. Ethyl acetate was added thereto, and the reaction solution was washed with water, and then washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting crude product was purified by column chromatography (NH type silica gel, chloroform/n-hexane=50 to 80%) to give methyl 1-(4-{[2-(4-chlorophenyl)ethyl]carbamoyl}phenoxy)isoquinoline-4-carboxylate (782 mg) as a colorless solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][Si:26]([CH3:49])([CH3:48])[CH2:27][CH2:28][C:29]([F:47])([F:46])[C:30]([F:45])([F:44])[C:31]([F:43])([F:42])[C:32]([F:41])([F:40])[C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C.C(OCC)(=O)C>[CH3:49][Si:26]([CH3:48])([CH2:27][CH2:28][C:29]([F:47])([F:46])[C:30]([F:44])([F:45])[C:31]([F:42])([F:43])[C:32]([F:40])([F:41])[C:33]([F:38])([F:39])[C:34]([F:35])([F:36])[F:37])[CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[N:11]=[CH:10][C:9]([OH:8])=[CH:14][N:13]=2)=[CH:16][CH:17]=1
Reactant: C[Si](C)(CCCCOc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[Si](C)(CCCCOc1ccc(-c2ncc(O)cn2)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of compound 46 (2.232 g, 3.02 mmol), palladium on charcoal (0.095 g, 0.091 mmol) in ethanol/ethyl acetate (6.5 ml, 1:2) was stirred under an atmosphere of hydrogen at room temperature for 24 hours. The reaction mixture was filtered (celite), the solvent removed in vacuo and the residues recrystallized from acetonitrile to yield colorless crystals.
Reaction SMILES: [C:1]([CH:5]1[N:8](CC2C=CC(OC)=CC=2)[C:7](=[O:18])[CH:6]1[N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29])([O:3][CH3:4])=[O:2].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P(O)([O-])([O-])=O.[Na+].[Na+]>C(#N)C.O>[C:1]([CH:5]1[NH:8][C:7](=[O:18])[CH:6]1[N:19]1[C:20](=[O:29])[C:21]2=[CH:28][CH:27]=[CH:26][CH:25]=[C:22]2[C:23]1=[O:24])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1C(N2C(=O)c3ccccc3C2=O)C(=O)N1Cc1ccc(OC)cc1
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C1NC(=O)C1N1C(=O)c2ccccc2C1=O

Procedure:
A solution of 2.45 g (6.22 mmol) of the azetidinone in 250 ml of acetonitrile and 75 ml of water was degassed with argon. At 80°, a degassed solution of 23.5 g (87.2 mmol) of potassium persulfate and 7.77 g (55 mmol) of disodium phosphate was added in 6 portions over 1 hour. The mixture was cooled, the acetonitrile removed in vacuum, the aqueous residue saturated with sodium chloride and extracted with warm (40°) hexane (3×100 ml) then with ethyl acetate (5×125 ml). The ethyl acetate extract was washed with sodium bicarbonate, brine, dried and evaporated to dryness. Titration with ether gave 4-carbomethoxy-3-phthalimido-azetidin-2-one, m.p. 124°-6°.
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[N:13][C:14]=1I)=[O:7])(C)(C)C.[Cl:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH2:31][C:32]2[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]([F:40])[C:33]=2[F:41])=[CH:24][C:22]=1[NH2:23].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)(=O)C>[Cl:20][C:21]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH2:31][C:32]2[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]([F:40])[C:33]=2[F:41])=[CH:24][C:22]=1[N:23]1[C:14]2=[N:13][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:10]=[C:9]2[NH:8][C:6]1=[O:7]
Reactant: COc1cc(Cl)c(N)cc1OCc1c(OC)ccc(F)c1F
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)c(I)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2[nH]c(=O)n(-c3cc(OCc4c(OC)ccc(F)c4F)c(OC)cc3Cl)c2n1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
A mixture of methyl 5-(tert-butoxycarbonylamino)-6-iodopyridine-2-carboxylate (0.14 g), 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.18 g), tris-(dibenzylideneacetone)dipalladium(0) (10 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13 mg) and sodium tert-butoxide (48 mg) in tetrahydrofuran (3 mL) was heated at reflux for 22 hours. The reaction mixture was cooled to room temperature. To the reaction mixture was added acetic acid (0.02 mL), and the mixture was directly purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/2−1/3) to give the title compound (81 mg).
Reaction SMILES: [Br-].[CH2:2]([O:4][C:5]([CH2:7][N+:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)=[O:6])[CH3:3].[BH4-].[Na+]>>[CH2:2]([O:4][C:5](=[O:6])[CH2:7][N:8]1[CH2:13][CH:12]=[CH:11][CH:10]([CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)[CH3:3]
Reactant: CCOC(=O)C[n+]1cccc(C(c2ccccc2)c2ccccc2)c1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Product: CCOC(=O)CN1CC=CC(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
To an ice cooled solution of 0.206 g (0.5 mmol) 1-ethoxycarbonylmethyl-3-diphenylmethylpyridinium bromide (from step 1) was added 0.034 g (0.92 mmol) sodium borohydride in small portions with stirring over one hour. The solvent was evaporated, the residue dissolved in diethyl ether, washed with water and dried with magnesium sulphate. After evaporation of the solvent, the residue was chromatographed on silica gel column with 30% ethyl acetate in hexanes to give 0.107 g (64%) 3-diphenylmethyl-1,2,3,6-tetrahydropyridin-1-yl acetic acid ethyl ester (compound C1) as a pale yellow oil. NMR spectra showed: 1H NMR (CDCl3, 300 MHz) δ 7.40-7.10 (m, 10 H), 5.22 (br. s,1 H), 4.61 (s, 1 H), 4.12 (q, 2 H), 3.25 (s, 2 H), 3.03 (s, 2 H), 2.68 (t, 2 H), 2.22 (br. s, 2 H), 1.19 (t, 3 H); 13C NMR (CDCl3 75 MHz) δ 170.24, 141.86, 137.89, 129.11, 128.10, 126.19, 123.24, 60.31, 58.79, 56.24, 55.13, 49.51, 25.64, 14.05. El-MS: 335 (10, M+, C22H25NO2), 262 (50).
Reaction SMILES: C(=O)(O)[O-:2].[Na+].[C:6]([O:9][CH2:10][C:11]1[CH2:12][S:13][C@@H:14]2[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25](=O)[CH2:26][S:27][C:28]#[N:29])[C:20](=[O:32])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])(=[O:8])[NH2:7].C(OCC)(=O)C.P(=O)(O)(O)O>P([O-])([O-])([O-])=O>[C:6]([O:9][CH2:10][C:11]1[CH2:12][S:13][C@@H:14]2[CH:21]([NH:22][C:23](=[O:31])[CH2:24][C:25]3[NH:29][C:28](=[O:2])[S:27][CH:26]=3)[C:20](=[O:32])[N:15]2[C:16]=1[C:17]([OH:19])=[O:18])(=[O:8])[NH2:7]
Reactant: N#CSCC(=O)CC(=O)NC1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12
Reactant: O=C([O-])O
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)[nH]3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 30.3 %

Procedure:
To a solution of sodium bicarbonate (0.067 g.) in pH 6.4 phosphate buffer (5 ml.) was gradually added 3-carbamoyloxymethyl-7-(3-oxo-4-thiocyanatobutyramido)-3-cephem-4-carboxylic acid (0.33 g.) with stirring at room temperature, and then the mixture was allowed to stand for 30 hours at room temperature. After the reaction, to the reaction mixture was added ethyl acetate (50 ml.). The reaction mixture was adjusted to pH 2 with 50% phosphoric acid, and then the ethyl acetate layer was separated therefrom. The remaining aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined together, washed with a saturated aqueous solution of sodium chloride dried over magnesium sulfate, treated with activated carbon and then the solvent was distilled off. The residue was pulverized in diethyl ether, collected by filtration and then dried to give 3-carbamoyloxymethyl-7-(2-oxo-2,3-dihydrothiazol-4-yl)acetamido-3-cephem-4-carboxylic acid (0.1 g.). The IR Spectrum and NMR Spectrum of this object compound were identical as those of the object compound obtained in Example 15.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:22]1([C@H:28](O)[CH3:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(#N)C>[Br:1][C@H:28]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:29]
Reactant: C[C@@H](O)c1ccccc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C[C@H](Br)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Bromine (3.2 g, 20.0 mmol) was added to a suspension of triphenylphosphine (5.2 g, 19.8 mmol) stirring in ACN at −15° C. The reaction was warmed to room temperature and stirred for 50 minutes then cooled to −35° C. and (R)-(+)-1-phenylethanol (1.6 g, 13.1 mmol) was added. The reaction was allowed to warm to −10° C. over 70 minutes and was then quenched with H2O and submitted to standard aqueous workup to afford the title compound which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]=[O:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]1([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][CH:31]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([CH2:20][CH:21]([C:33]2[CH:32]=[CH:31][C:30]([CH2:29][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:35][CH:34]=2)[OH:22])=[CH:11][C:12]([Cl:19])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCc1cc(Cl)c2cccnc2c1OCc1ccccc1
Reactant: Br[Mg]c1ccc(CN2CCOCC2)cc1
Solvent: C1CCOC1
Product: OC(Cc1cc(Cl)c2cccnc2c1OCc1ccccc1)c1ccc(CN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
To a stirring solution of [8-(benzyloxy)-5-chloroquinolin-7-yl]acetaldehyde (12.50 mmol) in tetrahydrofuran (100 mL) at 0° C. was dropwise added a 0.25M solution of [4-(4-morpholinylmethyl)phenyl]magnesium bromide in tetrahydrofuran (12.50 mmol, 1.0 eq.) and stirring at 0° C. was continued for 30 min. The reaction mixture was then allowed to warm to room temperature and was stirred 20 min then quenched with saturated aqueous sodium bicarbonate solution (100 mL). After stirring 5 min the reaction mixture was extracted with ethyl acetate (3×75 mL) and the combined organic layers were dried (MgSO4), filtered and concentrated to give a thick brown syrup that was purified by column chromatography using 30% acetone/dichloromethane to give the final product as a white solid (1.50 mmol, 12%). MS (ESI) m/z 489.3; HRMS: calcd for C29H29ClN2O3+H+, 489.19395; found (ESI, [M+H]+ Obs'd), 489.1941.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[S:9]1C[C:13](=[O:14])[NH:12][C:10]1=[S:11].C([O-])(=O)C.[Na+].O>C(O)(=O)C.CCOCC>[CH3:1][C:2]1[O:6][C:5](=[C:7]2[S:11][C:10](=[S:9])[NH:12][C:13]2=[O:14])[CH2:4][CH:3]=1
Reactant: O=C1CSC(=S)N1
Reactant: Cc1ccc(C=O)o1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: CC1=CCC(=C2SC(=S)NC2=O)O1
Yield: 94.2 %

Procedure:
A mixture of 5-methylfuran-2-carboxaldehyde (5.51 g, 50 mmol, purchased from Wako Junyaku Kogyo), rhodanine (6.66 g, 50 mmol, purchased from Tokyo Kase), and anhydrous sodium acetate (12.3 g, 150 mmol, purchased from Kokusan Kagaku) in 35 ml of acetic acid (purchased from Wako Junyaku Kogyo) was refluxed for 30 minutes. After being cooled, the reaction mixture was poured into 500 ml of water. The precipitate was collected and washed with water, with ethanol, and then with ether to give 10.04 g (yield: 89.1%) of (5-methylfurylidene)rhodanine as an orange-brown color crystalline.