Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:5]([CH:6]3[CH2:16][CH:7]3[CH2:8][O:9]2)=[CH:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=1.N1C=CC=CC=1>C(Cl)Cl>[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH:1][C:2]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]3[C:5]([CH:6]4[CH2:16][CH:7]4[CH2:8][O:9]3)=[CH:4][CH:3]=2)(=[O:26])=[O:25])=[C:20]([N+:28]([O-:30])=[O:29])[CH:19]=1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Reactant: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2[N+](=O)[O-])ccc2c1OCC1CC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 42, 0.1 g), 4-fluoro-2-nitrobenzenesulfonyl chloride (0.115 g) and pyridine (2 mL) in DCM (5 mL) was stirred at room temperature overnight. The mixture was concentrated under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was dried (Na2SO4) and filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether (20%) to give methyl (1aRS,7bSR)-5-(4-fluoro-2-nitrobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.11 g) as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:17]>C(OCC)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([Cl:17])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: CCOCC
Product: O=C(Cl)CNC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
A stirred mixture of N-benzyloxycarbonylglycine [30 g.; prepared as described in Ber., 65, 1192, (1932)] and dry diethyl ether (190 ml.) was treated at 0° C. with phosphorus pentachloride (32 g.) during 5 minutes. The mixture was stirred at between 0° and 5° C. for a further 20 minutes and the solution was then filtered and the filtrate was evaporated. The residue was triturated with petrol (b.p. 40°-60° C.) and the petrol layer was decanted off, and this procedure was repeated several times, keeping the temperature below 20° C. throughout. A solid formed, which was filtered off to give N-benzyloxycarbonylglycyl chloride (25 g.), which was used immediately in the next stage. N-Benzyloxycarbonylglycyl chloride (13.0 g.) was added in one portion to a stirred solution of 4-amino-3-(3-methoxycarbonyl-2-thioureido)diphenyl thioether (10.0 g.; prepared as hereinbefore described in Example 2) in dry dimethylformamide. The temperature of the mixture rose to 35° C., and the stirring was continued for 20 minutes. The solution was then poured into water. The resulting oil solidified on scratching. The solid was filtered off and recrystallised from a mixture of dimethylformamide and methanol to give 4-(2-benzyloxycarbonylaminoacetamido)-3-(3-methoxycarbonyl-2-thioureido)diphenyl thioether (13.0 g.), m.p. 184°-186° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=C=O.[CH3:14][S:15]([CH3:17])=O>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[S:15]([CH3:17])[CH3:14]
Reactant: CS(C)=O
Reactant: O=C=Nc1ccccc1C(F)(F)F
Product: CS(C)=Nc1ccccc1C(F)(F)F

Procedure:
The process of claim 3 in which 2-trifluoromethylphenyl isocyanate is reacted with dimethyl sulfoxide to produce N-(2-trifluoromethylphenyl)-S,S,-dimethylsulfilimine.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[C:12]2[C:7]=1[N:8]=[C:9]([O:20][CH3:21])[C:10]([O:18][CH3:19])=[N:11]2>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6]1[C:15]([Cl:16])=[C:14]([Cl:17])[CH:13]=[C:12]2[C:7]=1[N:8]=[C:9]([O:20][CH3:21])[C:10]([O:18][CH3:19])=[N:11]2)(=[O:3])[CH3:2]
Reactant: COc1nc2cc(Cl)c(Cl)c(N)c2nc1OC
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Product: COc1nc2cc(Cl)c(Cl)c(NC(C)=O)c2nc1OC
Yield: 100 %

Procedure:
Acetyl chloride (5.71 mL, 6.30 g, 80.3 mmol) was added to a vigorously stirred suspension of 5-amino-6,7-dichloro-2,3-dimethoxyquinoxaline (Preparation 26, 20.49 g, 64.8 mmol) in toluene (500 mL) and the resulting mixture was heated under reflux for 2 hours. After being cooled, the product was collected by filtration, washed with toluene and dried by suction for 15 hours to yield 5-acetamido-6,7-dichloro-2,3-dimethoxyquinoxaline (20.49 g, 89%) as a beige solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26]>ClCCl>[F:23][C:24]([F:29])([F:28])[C:25]([OH:27])=[O:26].[N:14]1([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[CH:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc3ccccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(c1)ncn2C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
1-(tert-Butoxycarbonyl)-4-(1H-benzimidazol-1-yl)piperidine (192 mg) was dissolved in dichloromethane (1.9 ml), added with trifluoroacetic acid (1.9 ml) and stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure and added with diisopropyl ether, and then the produced crystals were collected by filtration to obtain 200 mg of the title compound. Yield: 100%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:33]=[CH:32][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH:60]2[CH2:62][O:61]2)=[CH:54][CH:53]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:7]3[CH:32]=[CH:33][C:4]([CH2:3][CH2:2][NH:1][CH2:62][CH:60]([OH:61])[CH2:59][O:58][C:55]4[CH:56]=[CH:57][C:52]([OH:51])=[CH:53][CH:54]=4)=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[O:16])[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(CCCCNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1OC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(CCCCNC(=O)N2CCC(Nc3ccc(CCNCC(O)COc4ccc(O)cc4)cc3)CC2)cc1OC
Yield: 52.8 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-[4-(3,4-dimethoxyphenyl)butyl]-1-piperidinecarboxamide (0.79 g, 1.42 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.36 g, 0.89 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.40 g, 0.47 mmol).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]1[S:18][C:17]2[CH2:19][CH2:20][CH2:21][CH2:22][C:16]=2[C:15]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:12])=[O:11].[CH3:28][Si:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][O:32][CH2:33]Cl>C1COCC1>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]([C:14]1[S:18][C:17]2[CH2:19][CH2:20][CH2:21][CH2:22][C:16]=2[C:15]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:33][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])(=[O:11])=[O:12]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2Br)sc2c1CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(N(COCC[Si](C)(C)C)S(=O)(=O)c2ccccc2Br)sc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in oil, 0.081 g) was added to a solution of ethyl 2-(2-bromobenzenesulphonylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (Intermediate 39, 0.700 g) in anhydrous THF at 0° C. under nitrogen. The mixture was allowed to warm to room temperature and then stirred for 15 minutes. The mixture was then cooled to 0° C., 2-trimethysilylethoxymethyl chloride (0.360 ml) was added and the resultant mixture was stirred at room temperature for a further 64 hours. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride (30 ml) and the product was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (0-20%) to give ethyl 2-[N-(2-bromobenzenesulphonyl)-N-(2-trimethylsilylethoxymethyl)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (0.800 g) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2.[N:13]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[NH:16][CH2:15][CH2:14]2.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[Cl:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[CH:3][C:2]([N:16]1[CH:17]3[CH2:20][CH2:21][N:13]([CH2:19][CH2:18]3)[CH2:14][CH2:15]1)=[CH:11]2
Reactant: Clc1ccc2ncc(Br)cc2c1
Reactant: C1CN2CCC(CC2)N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Clc1ccc2ncc(N3CCN4CCC3CC4)cc2c1

Procedure:
0.53 g (2.18 mmol) of 3-bromo-6-chloro_quinoline, 0.25 g (2 mmol) of 1,4-diazabicyclo[3.2.2]_nonane, 0.018 g (0.08 mmol) of palladium diacetate, 0.91 g (2.8 mmol) of cesium carbonate and 0.05 g (0.08 mmol) of 2,2′-bis(diphenylphosphino)-1,1′-bi_naphthyl, in 15 ml of tetrahydrofuran, are introduced consecutively into a 50 ml three-necked round-bottomed flask and the reaction mixture is heated at reflux for 26 h.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])(O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:28])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=2[F:21])([F:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2cccc(F)c2F)CCN(Cc2ccccc2)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cccc(C2(F)CCN(Cc3ccccc3)C2)c1F
Yield: 37.5 %

Procedure:
To a solution of 1-benzyl-3-(2,3-difluorophenyl)pyrrolidin-3-ol (5.3 g, 18.3 mmol) in dichloromethane (30 mL) at 0° C. was added drop wise, a solution of diethylaminosulfur trifluoride (2.93 mL, 22.4 mmol) in dichloromethane. The cooling was removed and the mixture was stirred at ambient temperature for 2 h after which an additional amount of diethylaminosulfur trifluoride (0.1 mL, 0.76 mmol) was added. The mixture was stirred for 1 h at ambient temperature after which aqueous sodium hydrogen carbonate (10%) was added and the mixture was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (isooctane/ethyl acetate, 1:0 to 1:1) gave the title compound (2 g). MS m/z (relative intensity, 70 eV) 291 (M+, 32), 200 (18), 133 (54), 91 (bp), 65 (20).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([Cl:8])=[N:5][CH:4]=1.CN(C)C=O.[CH3:14][N:15]1[C:20](=[N:21][N+:22]([O-:24])=[O:23])[NH:19][CH2:18][O:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[Cl:8][C:6]1[S:7][C:3]([CH2:2][N:19]2[CH2:18][O:17][CH2:16][N:15]([CH3:14])[C:20]2=[N:21][N+:22]([O-:24])=[O:23])=[CH:4][N:5]=1
Reactant: Clc1ncc(CBr)s1
Reactant: CN1COCNC1=N[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CN1COCN(Cc2cnc(Cl)s2)C1=N[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 5 h

Procedure:
3.18 g of 5-bromomethyl-2-chloro-thiazole, 12 ml of dimethylformamide, 1.99 g of 3-methyl-4-nitroimino-perhydro-1,3,5-oxadiazine and 3.79 g of potassium carbonate are combined and the mixture is stirred for 5 hours at 50° C. The mixture is cooled to room temperature and 50 ml of water and 50 ml of dichloromethane are added. The organic phase is separated off and dried over magnesium sulfate; the solvent is evaporated off in vacuo. The residue is purified by column chromatography on silica gel using hexane/ethyl acetate (1:1), yielding the title compound (compound 2-2).
Reaction SMILES: [ClH:1].[CH:2]1[C:12]2[CH2:11][CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[C:7](=[CH:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26](O)=[O:27])[CH2:21]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.O[N:30]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[NH4+]>CN(C)C=O.C(OCC)(=O)C>[ClH:1].[CH:13]1[C:9]2[CH2:10][CH2:11][C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[CH:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH2:23][C@@H:22]([C:26]([NH2:30])=[O:27])[CH2:21]3)[C:8]=2[CH:16]=[CH:15][CH:14]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)[C@@H]1CCCN(CCC=C2c3ccccc3CCc3ccccc32)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)[C@@H]1CCCN(CCC=C2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
(R)-1-(3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid hydrochloride (4.96 g, 12.5 mmol, prepared as described in WO 9518793) was dissolved in N,N-dimethylformamide (60 ml). N-Hydroxybenzotriazole (1.86 g, 13.8 mmol) and 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (2.64 g, 13.8 mmol) were added, and the resulting mixture was stirred at room temperature for 20 minutes. Ammonium hydrogencarbonate (1.98 g, 25 mmol) was added and the mixture was stirred 1 day at room temperature. Ethyl acetate (200 ml) was added and the resulting mixture was extracted with water (200 ml), 5% aqueous citric acid (200 ml), and saturated sodium hydrogencarbonate (200 ml). The combined aqueous phases were evaporated to dryness in vacuo and the residue was extracted with dichloromethane (200 ml). The resulting dichloromethane suspension was filtered and evaporated. The residue was purified by column chromatography on silica gel (600 ml) using a mixture of ethyl acetate and triethyl amine (95:5) as eluent. This afforded 1.92 g (43%) of the free base as an oil, which was converted to the hydrochloride by dissolution in diethyl ether (25 ml) and addition of 1 N hydrochloric acid in diethyl ether (5.9 ml). Filtration followed by drying in vacuo, afforded 1.53 g, (31%) of the title compound as a solid.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30][NH2:31]>>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30][NH:31][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: NCCc1ccc2ccccc2c1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cn1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccc4ccccc4c3)cc2)cn1
Yield: 50.3 %

Procedure:
Using a method similar to Example 405, using 5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.0366 g, 0.151 mmol) and 2-naphthalen-2-ylethylamine (0.0286 g, 0.166 mmol) gives the title compound (0.0302 g, 50.3%): TOF MS ES+ 398.2 (M+H)+, HRMS calcd for C25H24N3O2 398.1869 (M+H)+, found 398.1833, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 30-99% over 19 min], tR=9.2 min, 98.0% purity.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[N:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[N:15][C:14]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[C:23](=[O:27])[C:22]([CH2:33][C:34]([O:36]CC)=[O:35])([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:21][CH2:20]4)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1>C(O)C.O>[CH3:3][C:4]1[N:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[N:15][C:14]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[C:23](=[O:27])[C:22]([CH2:33][C:34]([OH:36])=[O:35])([CH2:28][C:29]([F:31])([F:32])[F:30])[CH2:21][CH2:20]4)=[CH:13][CH:12]=2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)CC1(CC(F)(F)F)CCc2cc(-c3ccc(Nc4ccc(C)nc4)nn3)ccc2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(Nc2ccc(-c3ccc4c(c3)CCC(CC(=O)O)(CC(F)(F)F)C4=O)nn2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Lithium hydroxide (0.042 g, 1 mmol) was added to a solution of 22B1 (0.125 g, 0.25 mmol) in 6 mL of ethanol-water (3:1) mixture, and the reaction mixture was stirred at room temperature for 8 h. After the solvent was removed in vacuo, the residue was dissolved in water. The aqueous layer was acidified by addition of saturated solution of citric acid until pH 4 was attained. The resulting solution was cooled to 0° C., and solids obtained were filtered off and dried under vacuum to afford the title compound (0.105 g, 89%) as a solid. 1H NMR (300 MHz, DMSO-d6): δ 12.4 (bs, 1H), 9.59 (s, 1H), 8.76 (d, J=2.7 Hz, 1H), 8.22 (dd, J1=2.7 Hz, J2=8.4 Hz, 1H), 8.11 (d, J=9.6 Hz, 1H), 8.05-7.97 (m, 3H), 7.25 (d, J=3.0 Hz, 1H), 7.23 (s, 1H), 3.15-2.95 (m, 3H), 2.84 (d, J=16.2 Hz, 1H), 2.78-2.65 (m, 1H), 2.58 (d, J=16.5 Hz, 1H), 2.46 (m, 1H), 2.43 (s, 3H), 2.19 (m, 1H). ESI-MS m/z: 471 (M+H)+; HPLC purity: 98%.
Reaction SMILES: [NH2:1][C@@H:2]1[C:30](=[O:31])[N:4]2[C:5]([C:17]([O:19]CC3C=CC([N+]([O-])=O)=CC=3)=[O:18])=[C:6]([O:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:12])=[O:11])[CH2:7][CH2:8][C@H:3]12.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38](Cl)=[O:39].C1OC1C>C(Cl)Cl>[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38]([NH:1][C@@H:2]1[C:30](=[O:31])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([O:9][S:10]([C:13]([F:16])([F:15])[F:14])(=[O:11])=[O:12])[CH2:7][CH2:8][C@H:3]12)=[O:39]
Reactant: O=C(Cl)Cc1cccs1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12
Agent: CC1CO1
Solvent: ClCCl
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)=C(OS(=O)(=O)C(F)(F)F)CC[C@H]12

Procedure:
p-Nitrobenzyl 7β-amino-3-trifluoromethylsulfonyloxy-1-carba-3-cephem-4-carboxylate is acylated in methylene chloride with 2-thienylacetyl chloride in the presence of propylene oxide and then is deesterified to provide the title compound.
Reaction SMILES: Cl.[CH:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:26]1([S:32]([NH2:35])(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[Na]>CC(N(C)C)=O>[CH:2]1([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH:35][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])=[O:22])=[CH:19][CH:18]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(=O)N(C)C
Product: O=C(NS(=O)(=O)c1ccccc1)c1ccc(NCCCCCCCCC2CCCCC2)cc1
Reaction time: 0.5 h

Procedure:
To the resulting oily residue of p-(8-cyclohexyloctyl)aminobenzoyl chloride hydrochloride is added, in one portion, the previously prepared mixture of sodium benzenesulfonamide in dimethylacetamide. The mixture is stirred for 30 minutes, without cooling, and is then filtered through a bed of diatomaceous earth. The filtrate is poured into 2 l. of water, and 250 ml. of saturated sodium chloride solution is added to coagulate the precipitate. The mixture is filtered and the product is washed with water and partially air dried. The product is dissolved in methylene chloride, the mixture is filtered through diatomaceous earth, and brine is added to break the emulsion. The layers are separated, the organic phase is dried over anhydrous sodium sulfate and filtered through a bed of 300 g. of hydrous magnesium silicate. The product is eluted with an additional 3 l. of methylene chloride. The first approx. 1 l. of filtrate is set aside and the remainder is evaporated to dryness. The residue is crystallized three times from toluene to yield the product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[N+](C1C=CC([O:14][C:15]([NH:17][C@@H:18]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:19](=[O:40])[CH2:20][N:21]([CH3:39])[C:22]([N:24]2[CH2:38][CH2:37][CH2:36][C@H:25]2[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[O:23])=O)=CC=1)([O-])=O.N1CCC[C@H]1C(OCC1C=CC=CC=1)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:39][N:21]([CH2:20][C:19](=[O:40])[C@@H:18]([NH:17][C:15]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:14])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:22]([N:24]1[CH2:38][CH2:37][CH2:36][C@H:25]1[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])=[O:23]
Reactant: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: C1COCCN1
Agent: O=C(OCc1ccccc1)[C@@H]1CCCN1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(CC(=O)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
Morpholine (1 ml., 11.4 mmole) is added to a stirring solution of 1-[[[(S)-3-[[(4-nitrophenoxy)carbonyl]amino]-2-oxo-4-phenylbutyl]methylamino]carbonyl]-L-proline, phenylmethyl ester (0.9 g., 1.58 mmole) in toluene at 0° in one portion. The reaction mixture turns yellow in 15 minutes and TLC indicates complete loss of starting material after 30 minutes. The resulting solution is washed sequentially with water, 1N hydrochloric acid, and 10% sodium bicarbonate. The organic layer is dried (MgSO4) and concentrated. The crude product is purified by preparative layer chromatography to give 0.26 g. of 1-[[methyl[(S)-3-[(4-morpholinylcarbonyl)amino]carbonyl]-2-oxo-4-phenylbutyl]amino]carbonyl]-L-proline, phenylmethyl ester as a yellow oil. TLC (ethyl acetate) Rf =0.18.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[N:15](=[C:17]([C:27](=O)[CH3:28])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[OH:16]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:27]([CH3:28])[C:17](=[N:15][OH:16])[C:18]([NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19]
Reactant: CC(=O)C(=NO)C(=O)Nc1ccccc1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Product: CC(=NNc1c(Cl)cc(C(F)(F)F)cc1Cl)C(=NO)C(=O)Nc1ccccc1

Procedure:
2,6-Dichloro-4-trifluoromethylphenylhydrazine was reacted with 2,3-dioxobutyranilide 2-oxime, in a similar manner to above to give 2,3-dioxobutyranilide 3-(2,6-dichloro-4-trifluoromethylphenylhydrazone) 2-oxime, m.p. 185°-186°. This was then treated with acetic anhydride in acetic acid to give 2,3-dioxobutyranilide 2-acetyloxime 3-(2,6-dichloro-4-trifluoromethylphenylhydrazone). This was cyclised with caesium carbonate to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-2H-1,2,3-triazole-4-carboxanilide, m.p. 185°-186°.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]([CH3:12])([CH3:11])[CH:8]([OH:10])[CH3:9].C(N(CC)CC)C>>[Cl:1][CH2:2][C:3]([O:10][CH:8]([C:7]([CH3:12])([CH3:11])[CH3:6])[CH3:9])=[O:4]
Reactant: CC(O)C(C)(C)C
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Product: CC(OC(=O)CCl)C(C)(C)C
Reaction time: 4 h

Procedure:
47.5 g (0.42 mole) of chloracetyl chloride was slowly added to a mixture of 40.9 g (0.4 mole) of 3,3-dimethyl 2-butanol and 58 ml (0.42 mole) of triethylamine. The reaction mixture kept at 10° C. during the running in of the acid chloride, was brought to ordinary temperature and stirred for about 4 hours. After filtration and washing with ether of triethylamine hydrochloride, the solution was washed with water then dried over sodium sulfate. After evaporation of the solvent and distillation of the vacuum, 64 g namely 89% was obtained of a pure liquid of b.p.t =79°/81° C. under 20 mm Hg.