Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][C:12]2([CH3:17])[OH:16])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.Cl[Si](CC)(CC)CC.N1C(C)=CC=CC=1C.FC(F)(F)S([O:44][Si:45]([CH2:50][CH3:51])([CH2:48][CH3:49])[CH2:46][CH3:47])(=O)=O>C(Cl)Cl>[CH3:17][C:12]1([OH:16])[CH2:13][CH2:14][CH2:15][CH:11]1[CH2:10][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([S:7]([CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][C:12]2([CH3:17])[O:44][Si:45]([CH2:46][CH3:47])([CH2:48][CH3:49])[CH2:50][CH3:51])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1(O)CCCC1CS(=O)(=O)c1ccccc1
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC1(O)CCCC1CSc1ccccc1
Product: CC[Si](CC)(CC)OC1(C)CCCC1CS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10a (2.69 g, crude) and imidazole (5.6 g, 82.3 mmol) in CH2Cl2 (50 mL) was added chlorotriethylsilane (1.7 mL, 10.1 mmol), and the mixture was stirred at ambient temperature overnight. To the mixture were added 2,6-lutidine (1.9 mL, 16.3 mmol) and triethylsilyl trifluoromethanesulfonate (1.9 mL, 8.40 mmol), and the mixture was stirred at ambient temperature for 35 min, then heated under reflux. Heating and stirring were continued with further addition of triethylsilyl trifluoromethanesulfonate (0.8 mL) overnight. Ice was added to the mixture, and the organic layer was separated. The aqueous layer was extracted with n-hexane, and the combined organic layers were washed with cold diluted HCl , water, NaHCO3 solution and NaCl solution, and dried over Na2SO4. Filtration and concentration, followed by chromatographic purification (SiO2 gel 50 g, EtOAc in n-hexane 5%), to give 3.21 g (quantitative yield from 9a) of 11a, as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][C:3]=1[O:11][CH3:12].C([O:15][C:16](=O)[CH:17]=[C:18]([NH2:22])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:22][C:18]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([O:11][CH3:12])[CH:4]=2)[C:16](=[O:15])[CH:17]=1
Reactant: COc1cc(CNN)ccc1Cl
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: COc1cc(Cn2[nH]c(N)cc2=O)ccc1Cl
Reaction time: 8 h

Procedure:
59 g of 4-chloro-3-methoxybenzylhydrazine were added dropwise, under nitrogen, to a solution of 50.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulphonic acid in 250 ml of ethanol. After standing overnight, the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 148°, 30 g. (38%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)=[CH:10][CH:9]=1)=[O:7])C.Cl>O1CCCC1.CO.C(OCC)(=O)C>[C:21]([O:20][C:18]([N:16]1[CH2:15][CH:14]([C:11]2[CH:10]=[CH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:13][CH:12]=2)[CH2:17]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1ccc(C2CN(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(c2ccc(C(=O)O)cc2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A 2 M sodium hydroxide solution (28.5 mL, 57.0 mmol) was added to a solution of tert-butyl 3-(4-(ethoxycarbonyl)phenyl)azetidine-1-carboxylate described in Production Example 26-4 (4.35 g, 14.2 mmol) in tetrahydrofuran (32 mL) and methanol (7 mL) at 25° C. The reaction liquid was stirred at 60° C. for 1 hour. 2 M hydrochloric acid (28.5 mL) was added to the reaction liquid, and the mixture was diluted with ethyl acetate. The organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1) to obtain the title compound (3.4 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:10]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][N:11]3[CH:23]=2)[CH:5]=[CH:6][CH:7]=1.ClS([N:33]=[C:34]=O)(=O)=O.CN(C)C=O.[OH-].[Na+]>ClCCl>[C:34]([C:23]1[N:11]2[CH2:12][CH2:13][N:14]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:15][C:10]2=[C:9]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)#[N:33]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(-c2cccc(F)c2)cn2c1CN(C(=O)OC(C)(C)C)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(-c2cccc(F)c2)c(C#N)n2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
To a solution, under argon and cooled to 10° C., of 2.52 g (6.49 mmol) of 2-tert-butyl 8-ethyl 7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate in 20 ml of dichloromethane is added dropwise 0.62 ml (7.14 mmol) of chlorosulfonyl isocyanate (CAS 1189-71-5) and the mixture is left stirring at 0° C. for 1 hour. 3.3 ml (65 mmol) of dimethylformamide are then added dropwise to the mixture, cooled to −10° C. After stirring for 5 hours at room temperature, the mixture is poured into 60 ml of aqueous 1N sodium hydroxide solution and the product is extracted with dichloromethane. The solution is dried over sodium sulfate and the solvent is evaporated off under reduced pressure, to give a yellow oil, which is chromatographed on a column of g of silica gel, eluting with a mixture of 20% ethyl acetate in cyclohexane, to give 1.24 g of 2-tert-butyl 8-ethyl 6-cyano-7-(3-fluorophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2,8(1H)-dicarboxylate in the form of a white powder after crystallizing from diisopropyl ether, filtering off and drying.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[Br:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27]O)=[N:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[C:10]([CH3:11])[N:2]([CH3:1])[N:3]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[N:25][CH:26]=1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Reactant: OCc1ccc(Br)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4ccc(Br)cn4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (5-bromopyridin-2-yl)methanol (74 mg) and triphenylphosphine (154 mg) in tetrahydrofuran (5 ml) was added bis(2-methoxyethyl)azodicarboxylate (138 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was washed with ethyl acetate, and recrystallized from ethanol-hexane to give the title compound (51 mg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.C([Li])CCC.CON(C)[C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)C>C1COCC1.CCCCCC>[C:17]1([C:16]([C:3]2([C:2]([F:7])([F:6])[F:1])[CH2:4][O:5]2)=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)C1CO1
Reactant: CON(C)C(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccccc1)C1(C(F)(F)F)CO1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
2.3 ml (26 mmol) 1,1,1-trifluoro-2,3-epoxypropane in 30 ml THF and 8 ml hexane are cooled to −100° C. and 6.3 ml of a 2.5 M n-butyl lithium solution (16 mmol) in hexane are added over 15 minutes while the temperature does not exceed −95° C. 10 Minutes after complete addition 2.0 (12 mmol) g N-methoxy-N-methylbenzamid in 38 ml THF are added over 15 minutes while the temperature does not exceed −95° C. After 5 hours at −100° C. 12 ml diethyl ether are added and the reaction mixture is warmed to room temperature over 14 hours. The reaction is quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer is extracted twice with ethyl acetate, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated to yield 2.59 g of Phenyl-[2-(trifluoromethyl)oxiranyl]methanone. 1H-NMR (CDCl3); δ=3.07 (dq, 1H), 3.38 (d, 1H), 7.50 (t, 2H), 7.65 (tt, 1H), 8.07 (d, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.C(OCC)(=O)C.CCCCCC>CO>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH:10]2[CH2:9][CH2:8][N:7]([C:3]3[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=3)[CH2:12][CH2:11]2)=[CH:14][CH:15]=1
Reactant: Cn1ccnc1N1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCCCCC
Product: Cn1ccnc1N1CCC(c2ccc(N)cc2)CC1

Procedure:
Hydrogenation of the product from part (iii) above (0.50 g) in methanol (30 ml) according to the method of Example 1(ii) gave the title compound, (0.43 g), m.p. 187°-188° from ethyl acetate/hexane.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.C(Cl)Cl.[NH2:28][C:29]1[N:33]=[CH:32][NH:31][N:30]=1.N1C=CC=CC=1>>[NH:31]1[CH:32]=[N:33][C:29]([NH:28][S:17]([C:14]2[CH:15]=[CH:16][C:11]([C:9]([NH:8][CH2:7][C:6]3[CH:21]=[CH:22][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:4][CH:5]=3)=[O:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])=[N:30]1
Reactant: Nc1nc[nH]n1
Reactant: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(NCc1ccc(C(F)(F)F)cc1)c1ccc(S(=O)(=O)Nc2nc[nH]n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.5 %

Procedure:
A solution/suspension of 4-(4-trifluoromethyl-benzylcarbamoyl)-benzenesulfonyl chloride (200 mg, 0.5 mmol) in methylene chloride (1.0 mL, 16 mmol) was added portion-wise to a 0° C. solution of 3-amino-1,2,4-triazole (48.9 mg, 0.581 mmol) in pyridine (1.0 mL, 12 mmol). After addition was complete, the ice-bath was removed, and the reaction mixture was warmed to rt. After 16 h, the reaction mixture was diluted with methylene chloride and partitioned with 1 N HCl. The layers were separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with water, diluted with ethyl acetate, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was loaded onto Celite and purified on the Isco (12 g cartridge, chloroform to 12% MeOH in chloroform) to afford the title compound (150 mg, 60%).
Reaction SMILES: [CH3:1][CH:2]1[O:7][C@:6]2([C@@H:11]([O:12][C:13]([CH3:15])=[O:14])[C@:10]3([OH:31])[CH2:16][C@@:17]45[S:28]S[S:26][C@@:21]([CH2:29][OH:30])([N:22]([CH3:25])[C:23]4=[O:24])[C:19](=[O:20])[N:18]5[C@@H:9]3[CH2:8]2)[C:4](=[O:5])[C:3]1([CH3:33])[CH3:32].S(Cl)(Cl)=O.O>N1C=CC=CC=1>[CH3:1][CH:2]1[O:7][C:6]2([CH:11]([O:12][C:13]([CH3:15])=[O:14])[C:10]3([OH:31])[CH2:16][C:17]45[S:28][S:26][C:21]([CH2:29][OH:30])([N:22]([CH3:25])[C:23]4=[O:24])[C:19](=[O:20])[N:18]5[CH:9]3[CH2:8]2)[C:4](=[O:5])[C:3]1([CH3:33])[CH3:32]
Reactant: CC(=O)O[C@H]1[C@]2(O)C[C@]34SSS[C@](CO)(C(=O)N3[C@@H]2C[C@@]12OC(C)C(C)(C)C2=O)N(C)C4=O
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: CC(=O)OC1C2(CC3N4C(=O)C5(CO)SSC4(CC31O)C(=O)N5C)OC(C)C(C)(C)C2=O
Reaction time: 0.25 h

Procedure:
Sirodesmin C (5.0 mg.) in dry pyridine (0.1 ml.) was treated with thionyl chloride (0.01 ml.) for 10 minutes at 0°C., then added to iced-water (5 ml.) and left for 15 minutes. The solution was adjusted to pH 2 with 2N.sulphuric acid, then extracted with chloroform (3 × 5 ml.). The extracts were dried over sodium sulphate, then concentrated to yield Sirodesmin A as an oil (4.3 mg.).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=1)=[O:4].[C:23]1([C:29]2[N:30]=[C:31]([N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[S:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:23]1([C:29]2[N:30]=[C:31]([N:34]3[CH2:39][CH2:38][N:37]([C:13]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:21])[F:22])=[CH:11][CH:10]=4)=[O:20])[CH2:36][CH2:35]3)[S:32][CH:33]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccc(NC(=O)C(F)(F)F)cc1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(NC(=O)C(F)(F)F)cc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1
Yield: 39.9 %

Procedure:
A solution of 2,2,2-trichloroethyl {4-[(trifluoroacetyl)amino]phenyl}carbamate (200 mg, 0.527 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (129 mg, 0.527 mmol), diisopropylethylamine (0.184 ml, 1.05 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 100 mg (39.8%) of the desired product as a solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([N+:26]([O-:28])=[O:27])[CH:17]=1.Cl>C(OCC)(=O)C.CN(C)C=O>[N+:26]([C:18]1[CH:17]=[C:16]([CH2:15][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])([O-:28])=[O:27]
Reactant: COC(=O)c1ccc(CBr)cc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(COc2ccccc2)cc1[N+](=O)[O-]
Reaction time: 10 h
Yield: 101.1 %

Procedure:
To N,N-dimethylformamide 5.0 mL solution of phenol 0.18 g were added potassium carbonate 0.50 g and methyl 4-(bromomethyl)-2-nitrobenzoate 0.50 g at room temperature, and it was stirred at same temperature for 10 hours. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and collected,dried over anhydrous magnesium sulfate after washing with saturated sodium chloride aqueous solution, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [eluent; hexane:ethyl acetate=6:1] to give methyl 2-nitro-4-(phenoxymethyl)benzoate 0.53 g of colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][C:18]2[N:22]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]3[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:20]=3[N:19]=2)[C:9]1=[O:34])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:37][OH:38].C([O-])([O-])=O.[K+].[K+]>CCO>[C:1]([O:5][C:6](=[O:35])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][C:18]2[N:22]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]3[CH:28]=[CH:29][C:30]([C:32](=[NH:33])[NH:37][OH:38])=[CH:31][C:20]=3[N:19]=2)[C:9]1=[O:34])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CCn1c(Cn2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)nc2cc(C#N)ccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)CCn1c(Cn2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)nc2cc(C(=N)NO)ccc21
Yield: 54.2 %

Procedure:
{3-[5-Cyano-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazol-1-yl}-acetic acid tert-butyl ester (1.5 g, 3.17 mmol), hydroxylamine hydrochloride (660 mg, 9.5 mmol) and K2CO3 (657 mg, 4.75 mmol) are dissolved in EtOH (40 ml) and heated to reflux for 12 h. The reaction mixture was cooled and the product was isolated by filtration to give 870 mg (54%) of {3-[5-(N-Hydroxycarbamimidoyl)-1-(3-methyl-butyl)-1H-benzoimidazol-2-ylmethyl]-2-oxo-2,3-dihydro-benzoimidazol-1-yl}-acetic acid tert-butyl ester as a white solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].CO[C:7](OC)([N:9]([CH3:11])[CH3:10])[CH3:8].[CH2:14]1COCC1.IC>C(Cl)Cl>[CH3:10][N:9]([CH3:11])[C:7](=[N:1][C:2](=[NH:4])[S:3][CH3:14])[CH3:8]
Reactant: C1CCOC1
Reactant: NC(N)=S
Reactant: COC(C)(OC)N(C)C
Solvent: ClCCl
Solvent: CI
Product: CSC(=N)N=C(C)N(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the slurry of thiourea (13.6 g, 178.6 mmol) in 130 mL DCM was added N,N-dimethylacetamide dimethylacetal (25 g, 187.6 mmol). The reaction mixture was stirred at room temperature for 5 hours. The mixture was condensed under reduced pressure providing an orange residue. To the residue was added 100 mL THF resulting orange suspension. To the suspension was added iodomethane (14.5 mL) under ice bath, and it was warmed to room temperature. The mixture was further stirred at room temperature for 2 hours resulting precipitates. The reaction was monitored by TLC. The precipitates obtained from the solution were filtered and washed with cold THF yielding pale brown solids (44.89 g, 87.5%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=O)[CH2:4][C:5]([O:7]CC)=O.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1>>[F:12][C:2]([F:1])([F:11])[C:3]1[CH:4]=[C:5]([OH:7])[C:20]2[C:18](=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:21]=2)[N:19]=1
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Product: COc1ccc2nc(C(F)(F)F)cc(O)c2c1

Procedure:
Ethyl trifluoroacetoacetate and 4-methoxyaniline were reacted together in presence of polyphosphoric acid to give 2-trifluoromethyl-4-hydroxy-6-methoxyquinoline (cf. Jouillie and Dey). The latter was converted to 2-trifluoromethyl-4-chloro-6-methoxy-quinoline by analogy with Example IV. This was in turn converted first to 2-trifluoromethyl-6-methoxyquinoline by hydrogenation in the presence of palladium on charcoal and thence to 2-trifluoromethyl-6-hydroxyquinoline by reaction with aqueous hydrobromic acid. The latter was reacted with (8-bromo-1-tetrahydro pyranyloxy)octane according to Example BIII, 8(2-trifluoromethyl-6-quinolinyloxy)octane-1-ol was prepared and used in Stage b.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([C:9](=[N:40][O:41][CH3:42])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([O:24]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1)=[O:2].C(OC(C)C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[CH:1]([NH:3][C:4]1[S:5][C:6]([C:9](=[N:40][O:41][CH3:42])[C:10]([NH:12][CH:13]2[C:38](=[O:39])[N:15]3[C:16]([C:22]([OH:24])=[O:23])=[C:17]([CH:20]=[CH2:21])[CH2:18][S:19][C@H:14]23)=[O:11])=[CH:7][N:8]=1)=[O:2]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3cnc(NC=O)s3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3cnc(NC=O)s3)[C@H]2SC1
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
A solution of benzhydryl 7-[2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (2.7 g) in anisole (3.5 ml) and trifluoroacetic acid (10.8 ml) was stirred under ice-cooling for 15 minutes. The reaction mixture was poured into diisopropyl ether (140 ml), followed by stirring for 10 minutes. The precipitated solid was collected by filtration, washed with diisopropyl ether and then dried to give 7-[2-(2-formamidothiazol-5-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (2.0 g), mp 147° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][CH2:20][Cl:21]>C(C(C)=O)C>[Cl:21][CH2:20][CH2:19][CH2:18][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=[N+]([O-])c1ccc(OCCCCl)cc1

Procedure:
4-Nitrophenol (69.56 g, 0.5 mol), potassium carbonate (138.21 g, 1 mol) and 1-bromo-3-chloro propane (236.16 g, 1.5 mol) are refluxed in methyl ethyl ketone (800 ml) for 24 h. After filtration solvents are removed, the residue dissolved in ethyl acetate (1000 ml) and washed with NaOH (1M, 150 ml) and water (2×200 ml). Drying over sodium sulfate and concentration in vacuo yields 1-(3-Chloro-propoxy)-4-nitro-benzene as a yellow liquid.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([O-:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.[Na+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(O)CO>O>[N+:22]([C:19]1[CH:20]=[CH:21][C:16]([S:11]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)(=[O:13])=[O:12])=[CH:17][CH:18]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=S([O-])c1cccc2cnccc12
Agent: [Na+]
Solvent: OCCO
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)c2cccc3cnccc23)cc1
Yield: 19.1 %

Procedure:
A mixture of sodium 5-isoquinolinesulfinate 100 mg (0.5 mmol), 4-fluoronitrobenzene 70 mg (0.5 mmol), ethylene glycol 0.1 ml and ethyleneglycoldiethylether 0.1 ml was heated and refluxed for 3.5 hours. Water was added to the reaction mixture, and the solution was extracted with ethyl acetate, the organic layer washed with a saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was recrystallized from methanol to give 5-(4-nitrophenylsulfonyl)isoquinoline 30 mg (20.3%).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[C:5]([C:15]#[N:16])=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([O:9]CC)=[O:8]>O1CCOCC1.O>[Cl:3][C:4]1[C:5]([C:15]#[N:16])=[C:6]([CH:12]=[CH:13][CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cccc(Cl)c1C#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1c(Cl)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Lithium hydroxide (44.0 mg, 1.049 mmol) was added to a solution of the ethyl 3-chloro-2-cyanobenzoate (200 mg, 0.954 mmol) in 1,4-dioxane (2 mL) and water (2.000 mL) and the reaction was stirred at room temperature for 18 h. LCMS: No SM remains. The solvent was evaporated and the residue was dissolved in water. This was washed with Et2O and then carefully acidified (2M HCl) to pH ˜1. The resulting pink solid was collected, washed with water and dried invacuo to afford desired product in 153 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:23][S:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1C=C(Cl)C=C(C(OO)=[O:41])C=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:23][S:24]([CH2:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:41]
Reactant: Cc1c(CSCCc2ccccc2)oc2cccc(OCCCNCc3cccnc3)c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(CS(=O)CCc2ccccc2)oc2cccc(OCCCNCc3cccnc3)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.5 %

Procedure:
To a solution of the compound in Example 56 (20 mg, 0.04 mmol) in CH2Cl2/TFA (8/2) (1 ml) was added m-CPBA (14 mg, 80%, 0.06 mmol) at 0° C. The mixture was stirred for 2 hours at room temperature. The solvent was removed under reduced pressure. The residue was purified over preparative TLC (CH2Cl2/MeOH=100/1) to give the desired compound (7.5 mg, 36%) as a colorless oil. FAB-MS: m/z 463 (MH+); 1H-NMR (CDCl3): δ 1.97 (2H, m), 2.24 (3H, s), 2.81 (2H, t, J=6.9 Hz), 2.88-3.07 (4H, m), 3.77 (2H, s), 4.04-4.10 (4H, m), 6.52 (1H, d, J=7.6 Hz), 6.91 (1H, d, J=7.6 Hz), 7.05-7.22 (7H, m), 7.58 (1H, d, J=7.8 Hz) 8.41 (1H, brd, J=4.5 Hz), 8.48 (1H, brs).