Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][CH:22]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].P([O-])([O-])(O)=O.[Na+].[Na+]>CN(C)C=O.O>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][C:22]=1[C:14]([F:17])([F:16])[F:15]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1
Agent: O=P([O-])([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1C(F)(F)F
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(furan-3-yl)pyrazole (0.5 g) in dimethylformamide (15 m) and water (5 ml) was added sodium dithionite (0.112 g) and disodium hydrogen phosphate (0.067 g). The mixture placed in a 400 ml Parr vessel, which was evacuated, then charged with trifluoromethylbromide gas to 20 psi. The mixture was shaken and heated at 50° C., for 2.5 hours, then left at room temperature for 16 hours. The vessel Mwas then evacuated, then charged with trifluoromethylbromide to 40 psi, then shaken and heated to 50° C. for a further 7 hours, then left at room temperature for 16 hours. Further sodium dithionite (0.120 g) and disodium hydrogen phosphate (0.080 g) was added, the vessel evacuated, then charged with trifluoromethylbromide to 40 psi, then shaken and heated to 50° C. as before for 9 hours, then left at room temperature for 48 hours. Further sodium dithionite (0.240 g) and disodium hydrogen phosphate (0.160 g) were added, the vessel was evacuated, then charged w-ith trifluoromethylbromide to 45 psi, then shaken and heated to 50° C. as before for a further 9 hours. The mixture was filtered and then poured into ether (100 ml) and water (100 ml). The organic layer was separated, washed twice with water (50 ml), dried (Na2SO4), and evaporated. The residue was purified by column chromatography on silica gel (25 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(2-trifluoromethylfuran-3-yl)pyrazole as a white solid, m.p. 155-7° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=3)[N:17]=2)[CH:9]=[N:8]1.[NH:29]1[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]1.C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:25][N:29]4[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]4)=[CH:27][CH:28]=3)[N:17]=2)[CH:9]=[N:8]1
Reactant: O=C(O)C1CNC1
Reactant: O=Cc1ccc(-c2noc(-c3cnn(-c4ccccn4)c3C(F)(F)F)n2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4cnn(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Temperature: 0 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A solution of 4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (21 g, 54.5 mmol) and azetidine-3-carboxylic acid (6.61 g, 65.4 mmol) in ethanol (750 mL) and acetic acid (20 mL) was stirred at RT for 30 min. The reaction was cooled to 0° C. and a solution of sodium cyanoborohydride (caution: potential source of cyanide generation) (1.17 g, 27.3 mmol) in ethanol was added slowly. The reaction was warmed to RT and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water. The solids were collected by filtration and washed with water. The product was purified by triturating once each with DCM:methanol (98:2), DCM:methanol (96:4) and ethyl acetate to afford 1-(4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (16 g, 34 mmol). The compound had an HPLC retention time=8.48 min.−Column: XbridgeA 4.6×150 mm Flow rate=1.0 mL/min. Buffer=0.05% TFA in water pH2.5. Solvent A=Buffer:Acetonitrile (95:5), Solvent B=Acetonitrile:Buffer (95:5). 0-100% B over 12 minutes. LC/MS M+1=471.2.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][CH2:26][CH2:27][C@H:28]([OH:32])[C:29]([OH:31])=[O:30].C[O-].[Na+]>COCCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:25][CH2:26][CH2:27][C@H:28]([OH:32])[C:29]([OH:31])=[O:30])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NCC[C@H](O)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)NCC[C@H](O)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (200 mg, 0.63 mmol), (S)-4-amino-2-hydroxybutanoic acid (372 mg, 3.13 mmol, Sigma-Aldrich) and sodium methoxide (155 mg, 2.87 mmol) were suspended in 2-methoxyethanol (7 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (20 mL) and EtOAc (20 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-20% MeOH/CH2Cl2 with 0.5% formic acid) to give the title compound in 180 mg. MS: (−) m/z 406.28 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([S:16](F)(=[O:18])=[O:17])=[CH:15][C:8]=3[C:7](=[O:20])[C:6]=2[CH:21]=1.[CH3:22][NH:23][CH3:24]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([S:16](=[O:18])(=[O:17])[N:23]([CH3:24])[CH3:22])=[CH:15][C:8]=3[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: CNC
Reactant: O=C1c2cc(Br)ccc2CCc2ccc(S(=O)(=O)F)cc21
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)c1cc(Br)ccc1CC2

Procedure:
3-Bromo-7-fluorosulfonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (2.5 g., 0.00677 mole) together with 30 ml. of 25% aqueous dimethylamine and 30 ml. of p-dioxane is heated to refluxing for 3 hours. The brown solution is evaporated to dryness under reduced pressure and the residue partitioned between benzene and water. After washing with water, the benzene layer is evaporated to dryness under reduced pressure, leaving 3-bromo-7-dimethylsulfamoyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one as a tan solid, m.p. 142°-145°C., in a yield of 2.1 g. (80%). An analytical sample melts at 146°-148°C. after crystallizations from mixtures of benzene and hexane and from methanol.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([O:14]CC)=[O:13])[O:9]2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].N1C=CC=CC=1>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:12]([OH:14])=[O:13])[O:9]2)=[CH:4][C:3]=1[C:17](=[O:19])[CH3:18]
Reactant: CCOC(=O)C1CCc2ccc(O)cc2O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)c1cc2c(cc1O)OC(C(=O)O)CC2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A 1.1 g sample of racemic ethyl 7-hydroxychroman-2-carboxylate was treated with 10 ml of 1:1 acetic anhydride - pyridine and stirred for 17 hours at room temperature. After removal of the solvents, the residual product (1.2 g) was dissolved in 12 ml of glacial acetic acid and treated with 1.26 ml of borontrifluoride etherate. The reaction mixture was gently refluxed for 17 hours, cooled, poured carefully into a mixture of sodium bicarbonate and ice and the product extracted with 1:1 tetrahydrofuran-ether. After evaporation of the solvent, 1.1 g of crude racemic-7-hydroxy-6-acetylchroman-2-carboxylic acid was obtained. Conversion of this material into the corresponding ethyl ester was achieved by refluxing 1.1 g of the crude acid in absolute ethanol in the presence of 10 mg of p-toluenesulfonic acid for 17 hours. After removal of most of the solvent, the product was extracted with 1:1 tetrahydrofuran-ether, washed with saturated sodium bicarbonate solution, water, dried and the solvents concentrated to give 1.2 g of crude ethyl ester as a mixture of the 6-acetyl and 8-acetyl derivatives in a ratio of about 7:1. This material was purified by column chromatography on silica gel to afford 0.7 g (53.5%) of racemic-6-acetyl-3,4-dihydro-7-hydroxy-2H-1-benzopyran-2-carboxylic acid ethyl ester as a colorless crystalline material mp 93.5°-95.5° C. (from ethyl acetate-hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:20]O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:14])[C:11]([O:13][CH3:20])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccc([N+](=O)[O-])cc1

Procedure:
2-(4-Nitrophenyl)propionic acid is refluxed in methanol in the presence of sulfuric acid, to give methyl 2-(4-nitrophenyl)propanoate.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5](O)=[O:6].[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([N:41]1[CH:2]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=4)[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[CH2:3][CH2:4][C:5]1=[O:6])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)CCC(=O)c1ccc(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Reactant: NCc1ccccc1
Product: O=C1CCC(c2ccc(CCCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)cc2)N1Cc1ccccc1

Procedure:
4-Oxo-4-[4-(4-(4-(3-trifluoromethylphenyl)piperazin-1-yl)butyl)phenyl]butyric acid and benzylamine are reacted together to give N-benzyl-5-[4-(4-(4-(3-trifluoromethylphenyl)piperazin-1-yl)butyl)phenyl ]pyrrolidin-2-one.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH2:9])=[C:4]([CH3:10])[CH:3]=1.N1C=CC=CC=1.[C:17]([CH2:21][C:22](Cl)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([NH:9][C:22](=[O:23])[CH2:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:4]([CH3:10])[CH:3]=1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1cc(Br)nc(C)c1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(Br)nc(C)c1NC(=O)CC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a mixture of 1c (0.364 g, 1.81 mmol) and pyridine (0.158 ml, 2 mmol) in dichloromethane (5 ml) was added tert-butylacetyl chloride (0.242 g, 1.8 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield 1d (0.361 g, 1.64 mmol, 91%).
Reaction SMILES: [CH3:1][C:2]([OH:10])([CH:4]=[CH:5][C:6]([CH3:9])([OH:8])[CH3:7])[CH3:3].[CH:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:12]([CH:11]1[O:10][C:2]([CH3:3])([CH3:1])[CH:4]=[CH:5][C:6]([CH3:9])([CH3:7])[O:8]1)[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(C)(O)C=CC(C)(C)O
Reactant: CCCCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1OC(C)(C)C=CC(C)(C)O1
Yield: 70.3 %

Procedure:
A mixture of 720 g (5 moles) of 2,5-dimethylhex-3-ene-2,5-diol, 3 g of p-toluenesulfonic acid, 500 g (5 moles) of n-hexanal and 1 l of toluene was refluxed, and the resulting water of reaction (115 ml) was separated off in the course of 5.5 h. The mixture was then left to cool, 10 ml of a 25% strength aqueous sodium hydroxide solution were added, the mixture was washed neutral with a little water and the toluene was removed under reduced pressure at from 50° to 60° C. The residue obtained was distilled under 0.1 mbar to give 796 g of 2-pentyl-4,4,7,7-tetramethyl-4,7-dihydro-1,3-dioxepin of boiling point 75° C./0.1 mbar.
Reaction SMILES: ClC(Cl)(Cl)C([C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:30]([O:32]C(C)(C)C)=O)[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:29])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)=O.Cl>C(O)C>[F:28][C:22]([F:27])([C:23]([F:26])([F:24])[F:25])[C:21]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:14][C:10]2[N:9]3[C:5](=[CH:6][N:7]=[C:8]3[CH:13]=[CH:12][CH:11]=2)[C:30]1=[O:32])=[O:29]
Reactant: CC(C)(C)OC(=O)N(CCCCNC(=O)C(F)(F)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Agent: Cl
Solvent: CCO
Product: O=C1c2cnc3cccc(n23)CN1CCCCNC(=O)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 5.00 g (8.2 mmol) of 3-trichloroacetyl-5-[N-tert-butoxycarbonyl-N-(4-pentafluoropropionamidobutan-1-yl)aminomethyl]imidazo[1,2-a]pyridine in 100 ml of ethanol was added 3.4 ml (41.0 mmol) of 12N hydrochloric acid. The mixture was stirred for one hour at room temperature. The solvent and an excess volume of hydrochloric acid were distilled off under reduced pressure. The residue was dissolved in a mixture of 50 ml of purified water and 50 ml of ethanol. The solution was neutralized with 2N aqueous solution of sodium hydroxide. This solution was extracted with 150 ml of dichloromethane. The organic layer was washed with 150 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to afford 2.11 g of the desired compound (66.1%, a pale yellow solid).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>Cl>[Cl:23][C:21]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([NH:13][C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:22]=1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Product: O=C(O)c1ccc(Cl)cc1Nc1ccnc2cc(Cl)ccc12

Procedure:
4,7-Dichloroquinoline and 2-amino-4-chloro benzoic acid are refluxed in dilute hydrochloric acid for 1 hour to give 4-chloro-2-(7-chloro-4-quinolylamino)benzoic acid.
Reaction SMILES: [Cl:1][C:2](OC(Cl)(Cl)Cl)=[O:3].[N:9]1([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[Cl:1][C:2]([N:12]1[CH2:13][CH2:14][N:9]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10][CH2:11]1)=[O:3]
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Cl)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trichloromethyl chloroformate (5.45 mmol, 0.657 ml) in tetrahydrofuran (20 ml) was cooled to 0° C. and a solution of benzyl 1-piperazinecarboxylate (4.54 mmol, 0.876 ml) and N,N-diisopropylethylamine (9.99 mmol, 1.651 ml) in tetrahydrofuran (20 ml) was added dropwise. After stirring for one hour at 0° C. the solids were removed by filtration over decalite and the filtrate was concentrated in vacuo to give crude benzyl 4-(chlorocarbonyl)piperazine-1-carboxylate. The latter compound was added to 2-aminomethyl-3-chloropyrazine hydrochloride (content 69%; 3.49 mmol, 0.91 g) in dichloromethane (15 ml) and triethylamine (10.46 mmol, 1.458 ml) and the reaction mixture was stirred over night at room temperature. Then the reaction mixture was filtered over decalite (washed with dichloromethane). The filtrate was concentrated and the crude product was purified using column chromatography (silica gel; dichloromethane with gradient 0 to 10% methanol) to give benzyl 4-((3-chloropyrazin-2-yl)methylcarbamoyl)piperazine-1-carboxylate (1.15 g).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17].[C:21]([NH:29][CH:30]1[C:42](=[O:43])[N:32]2[C:33]([C:39](O)=[O:40])=[C:34]([CH3:38])[CH2:35][S:36](=[O:37])[C@H:31]12)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:21]([NH:29][CH:30]1[C:42](=[O:43])[N:32]2[C:33]([C:39]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:40])=[C:34]([CH3:38])[CH2:35][S:36](=[O:37])[C@H:31]12)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)O
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)C(NC(=O)c3ccccc3)[C@H]2S(=O)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 48 %

Procedure:
A mixture of 103.2 g of dicyclohexylcarbodiimide, 43.5 g of t-butyl alcohol and 1.1 g of cuprous chloride was held at room temperature for 3 days and the mixture was then dissolved in 200 ml of methylene chloride. The resulting solution was added dropwise to a suspension of 35 g of 7-benzamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide in 500 ml of methylene chloride and after stirring for 24 hours at room temperature, the precipitated N,N'-dicyclohexyl urea was removed by filtration and the precipitate washed with methylene chloride. The combined filtrates were washed sequentially with 2 N hydrochloric acid, saturated sodium bicarbonate solution (three times) and with water (twice). Methylene chloride was removed by evaporation in vacuo and toluene was added to the residue. The crystalline solid was isolated by filtration and washed with toluene. Upon crystallization from a methylene chloride/toluene mixture, 19.6 g (48% yield) of t-butyl 7-benzamido-3-methyl-3-cephem-4-carboxylate 1-oxide were obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[NH:15][CH2:14][CH2:13][NH:12][C:11]2=[O:16])=[CH:2]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13][NH:12][C:11]2=[O:16])=[CH:2]1
Reactant: O=C1NCCNC1c1c[nH]c2ccccc12
Reactant: ClCc1ccccc1
Product: O=C1NCCN(Cc2ccccc2)C1c1c[nH]c2ccccc12

Procedure:
21.5 g (0.1 mol) of 3-(3-indolyl)-piperazin-2-one, prepared in accordance with Example 30, are alkylated with benzyl chloride as described in Example 2.
Reaction SMILES: [CH3:1][C:2]1([CH2:14][OH:15])[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4][CH2:3]1.[I:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.[H-].[Na+]>>[I:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:15][CH2:14][C:2]1([CH3:1])[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4][CH2:3]1
Reactant: BrCc1cccc(I)c1
Reactant: CC1(CO)CCn2cc([N+](=O)[O-])nc2O1
Agent: [H-]
Agent: [Na+]
Product: CC1(COCc2cccc(I)c2)CCn2cc([N+](=O)[O-])nc2O1
Yield: 69 %

Procedure:
Alkylation of oxazine alcohol 149 (see Example 2OO) with 3-iodobenzyl bromide (1.6 equiv.) and NaH (1.8 equiv.) as in Example 2UU above for 3.5 h, followed by chromatography of the product on silica gel, eluting with CH2Cl2 (foreruns) and then with 0-2% EtOAc/CH2Cl2, gave 7-{[(3-iodobenzyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (155) (69%) as a cream solid: mp (CH2Cl2/pentane) 122-125° C. (dec); 1H NMR (CDCl3) δ 7.63 (br d, J=7.9 Hz, 1H), 7.58 (m, 1H), 7.40 (s, 1H), 7.19 (br d, J=7.7 Hz, 1H), 7.06 (t, J=7.7 Hz, 1H), 4.49 (s, 2H), 4.11 (ddd, J=12.4, 7.3, 5.8 Hz, 1H), 4.01 (ddd, J=12.5, 6.7, 6.0 Hz, 1H), 3.63 (d, J=10.2 Hz, 1H), 3.60 (d, J=10.2 Hz, 1H), 2.37 (ddd, J=14.4, 6.7, 6.0 Hz, 1H), 2.12 (ddd, J=14.4, 7.3, 6.0 Hz, 1H), 1.47 (s, 3H). Anal. (C15H16IN3O4) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[C:6]([CH:9]=1)[CH:7]=O.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1.N1CCCC1>CO>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18](/[C:19](=[CH:7]/[C:6]3[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH:11]([CH3:13])[CH3:12])/[C:20](=[O:24])[NH:21]2)=[CH:17][CH:16]=1
Reactant: CC(C)Oc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 77.5 %

Procedure:
5-Chloro-2-isopropoxy-benzaldehyde (3 g, 15.1 mmol) and 6-chlorooxindole (2 g, 12.6 mmol) were mixed in anhydrous methanol (30 mL) at room temperature. Then pyrrolidine (1.07 g, 15.1 mmol) was added slowly. The reaction mixture was heated at 70° C. for 3 h. Then the mixture was cooled to room temperature and filtered. The precipitate was dried and collected to give E/Z-6-chloro-3-(5-chloro-2-isopropoxy-benzylidene)-1,3-dihydro-indol-2-one as a yellow solid (3.4 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[N:11]([CH3:19])[C:10](=[O:20])[C:9]([C:21]([OH:23])=O)=[CH:8]2)(=[O:3])[CH3:2].S(Cl)([Cl:26])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[N:11]([CH3:19])[C:10](=[O:20])[C:9]([C:21]([Cl:26])=[O:23])=[CH:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2cc(C(=O)O)c(=O)n(C)c2cc1OC(C)=O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc2cc(C(=O)Cl)c(=O)n(C)c2cc1OC(C)=O

Procedure:
A mixture of 6,7-diacetoxy-1-methyl-1,2-dihydro-2-oxoquinoline-3-carboxylic acid (60 mg), thionyl chloride (40 μL), and dimethylformamide (one drop) was heated under reflux for 2 hours in 40 mL of benzene, and the solvent was distilled off. Benzene (30 mL) was added to the residue and the benzene was distilled off again, followed by vacuum drying, to yield 6,7-diacetoxy-1-methyl-1,2-dihydro-2-oxoquinoline-3-carbonyl chloride.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[O:6][C@H:5]1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[NH3:16]>CO>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C@@H:5]2[O:6][C@H:4]2[C:3]([NH2:16])=[O:2])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H]1O[C@H]1c1ccc(OC)cc1
Reactant: N
Solvent: CO
Product: COc1ccc([C@@H]2O[C@H]2C(N)=O)cc1
Reaction time: 2 h

Procedure:
(2R,3S)-3-(4-Methoxyphenyl)-2,3-epoxypropionic acid methyl ester (10.4 g) is mixed with 15.3 wt % solution of ammonia in methanol (56 g), and the mixture is reacted at 15° C. for 2.5 hours. The mixture is concentrated under reduced pressure until the total weight of the mixture becomes 44 g. To the mixture is added ice-water (112 g), and the mixture is stirred for two hours under ice-cooling. The precipitated crystals are collected by filtration, washed with water, and dried at 50° C. to give (2R,3S)-3-(4-methoxyphenyl)-2,3-epoxypropionamide (8.99 g).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].C[O-].[CH2:27]([N+:34]([CH3:37])([CH3:36])[CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.CO>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O-:12])=[O:11].[CH2:27]([N+:34]([CH3:37])([CH3:36])[CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: C[O-]
Solvent: CO
Solvent: O
Product: O=C([O-])c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 20 %

Procedure:
A 20% aqueous methanolic solution of the salt is prepared by slurrying 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (22.2 g, 90% pure) in water (50 g) and adding a 40% solution of benzyltrimethylammonium methoxide (27 g) in methanol to pH 8. Additional water (0.8 g) is then added to give the desired concentration.