Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14](S(C2C=CC(C(C)(C)C)=CC=2)(=O)=O)[C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:16]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:16]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2c(OCCOc3ccc(F)cc3)nn(C)c2N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(OCCOc3ccc(F)cc3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 100 °C
Yield: 80.4 %

Procedure:
To 4-(tert-butyl)-N-{[4-(tert-butyl)phenyl]sulfonyl}-N-[3-[2-(4-fluorophenoxy)ethoxy]-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Preparation 25) (180 mg) in dioxan 5 ml) at room temperature was added 1N aqueous sodium hydroxide (5 ml) and the mixture was stirred and heated to 100° C. for 1.5 hrs. The reaction was partitioned between 2N aqueous hydrochloric acid (25 ml) and ethyl acetate (25 ml). The organic layer was separated, washed with water, then brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel (20 g), eluting with a solvent gradient of pentane:ethylacetate (19:1 changing to 7:3), to yield the title compound as a glass (106 mg).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].OC1[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1>CCCCO.CCCCO.CCCCO.CCCCO.[Ti].CO>[CH3:1][C:2]1[O:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9][CH:10]1[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1)=[O:8]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: COC(=O)c1cc(C)oc1C
Agent: [Ti]
Solvent: CCCCO
Solvent: CO
Product: Cc1cc(C(=O)OC2CC(C)(C)NC(C)(C)C2)c(C)o1

Procedure:
154 g (1 mole) of methyl 2,5-dimethylfuran-3-carboxylate and 157 g (1 mole) of 4-hydroxy-2,2,6,6-tetramethylpiperidine were heated together with 10 g of tetrabutyl orthotitanate for 10 hours at about 190° C., the methanol formed being distilled off. When the reaction is complete, the mixture is cooled and the reaction mass is dissolved in ethyl acetate. The solution is extracted by shaking, first with 10% strength sodium carbonate solution and then with water, after which it is dried and evaporated down, and the residue is distilled under reduced pressure. The desired product distils at 142° C./2 mm as a virtually colorless oil which soon solidifies to a solid of melting point 59°-61° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]([OH:24])=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:25]=2)=[N:7][CH:6]=[N:5]1.[CH3:28][NH2:29]>C1COCC1>[CH3:28][NH:29][C:22]([C:20]1[CH:19]=[CH:18][C:17]2[C:11]3[N:12]([CH:25]=[C:9]([C:8]4[N:4]([CH2:3][C:2]([F:26])([F:1])[F:27])[N:5]=[CH:6][N:7]=4)[N:10]=3)[CH2:13][CH2:14][O:15][C:16]=2[CH:21]=1)=[O:24]
Reactant: CN
Reactant: O=C(O)c1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Solvent: C1CCOC1
Product: CNC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2

Procedure:
Following the same procedure as for 133, 2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (60 mg, 0.1 mmol) was reacted with 2M methylamine (0.26 mL) in THF to provide 158. LC/MS (ESI+): m/z 393 (M+H). 1H NMR (400 MHz, DMSO) δ 8.49 (d, J=4.2, 1H), 8.42 (s, 1H), 8.11 (d, J=9.8, 1H), 7.60 (dd, J=8.4, 1.6, 1H), 7.52 (d, J=1.4, 1H), 5.90 (q, J=8.8, 2H), 4.57 (dd, J=11.5, 5.4, 4H), 2.79 (d, J=4.5, 3H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Ni].N>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH2:15])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: N#CCc1ccc(CN2CCCC2)cc1
Agent: [Ni]
Agent: N
Product: NCCc1ccc(CN2CCCC2)cc1

Procedure:
A reaction mixture of 0.73 g (3.66 mmol) of (4-pyrrolidin-1-ylmethyl-phenyl)-acetonitrile and 0.1 g Raney nickel in 25 mL of methanolic ammonia solution is hydrogenated for 9 hours at 50° C. under 3 bar hydrogen.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[CH:11][N:12]([CH3:16])[C:13]=1[CH2:14][OH:15]>O1CCOCC1.O=[Mn]=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[CH:11][N:12]([CH3:16])[C:13]=1[CH:14]=[O:15]
Reactant: COc1ccccc1-c1ncn(C)c1CO
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: COc1ccccc1-c1ncn(C)c1C=O
Temperature: 90 °C
Yield: 84.4 %

Procedure:
To a soln. of (4-(2-methoxyphenyl)-1-methyl-1H-imidazol-5-yl)methanol (84 mg, 0.385 mmol) in 1,4-Dioxane (5 ml) was added MnO2 (147 mg, 1.693 mmol). The mixture was heated to 90° C. for 4 hrs or until LC/MS showed the completion of the reaction. The reaction mixture was Filtered through celite, and evaporated to afford 4-(2-methoxyphenyl)-1-methyl-1H-imidazole-5-carbaldehyde (78 mg, 0.325 mmol, 84% yield), which was used for the next reaction w/o purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:31])[C:14](=[O:30])[CH2:15][C:16]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:19][CH2:18][CH2:17]2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C[SiH](C)C.[F:42][CH:43]([F:45])[F:44].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O.O1CCCC1>[F:42][C:43]([F:45])([F:44])[C:14]([OH:30])([CH2:15][C:16]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]([F:29])([F:27])[F:28])[CH2:19][CH2:18][CH2:17]1)[C:13]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)=[CH:11][CH:10]=1)=[O:31]
Reactant: O=C(CC1(c2ccccc2C(F)(F)F)CCC1)C(=O)Nc1ccc(-c2ncco2)cc1
Reactant: FC(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[SiH](C)C
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2ncco2)cc1)C(O)(CC1(c2ccccc2C(F)(F)F)CCC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.4 %

Procedure:
63 mg (0.15 mmol) of N-(4-oxazol-2-yl-phenyl)-2-oxo-3-[1-(2-trifluoromethyl-phenyl)-cyclobutyl]-propionamide in 2 ml dimethylformamide is mixed at 0° C. with 48.7 mg (0.15 mmol) of cesium carbonate and 0.14 ml (0.88 mmol) of trimethylsilane-trifluoromethane (CF3.TMS). The reaction mixture was stirred overnight at room temperature. 0.1 ml of 1M tetrabutylammonium fluoride in tetrahydrofuran was added and stirred over the weekend at room temperature. The reaction was quenched with water and extracted with ethyl acetate. The combined ethyl acetate extracts were washed twice with water, dried and concentrated by evaporation. The residue was purified by preparative TLC (EtOAc-hexane 30%) to yield 3.3 mg of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][C:11]([C:16]([F:19])([F:18])[F:17])(O)[N:12]([CH3:14])[N:13]=2)=[CH:5][C:4]=1[CH3:20].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:16]([F:19])([F:17])[F:18])[N:12]([CH3:14])[N:13]=2)=[CH:5][C:4]=1[CH3:20]
Reactant: COc1ccc(C2=NN(C)C(O)(C(F)(F)F)C2)cc1C
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C(F)(F)F)n(C)n2)cc1C
Yield: 102 %

Procedure:
A mixture of 5-(4-methoxy-3-methyl-phenyl)-2-methyl-3-trifluoromethyl-3,4-dihydro-2H-pyrazol-3-ol (described in Reference preparation example 77) 2.3 g, 6N aqueous hydrochloric acid solution 4 ml and tetrahydrofuran 30 ml was stirred with heating under reflux for two hours. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate solution and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 3-(4-methoxy-3-methyl-phenyl)-1-methyl-5-trifluoromethyl-1H-pyrazole 2.2 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:25])=[CH:28][CH:29]=1
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)CCCCCC(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 7-((2-((tert-butoxycarbonyl)amino)phenyl)amino)-7-oxoheptanoic acid (1.0 g, 2.85 mmol) in DMF (20 mL) was added 4-aminophenol (0.31 g, 2.85 mmol), HBTU (1.1 g, 2.85 mmol), DIEA (2 mL, 11.4 mmol). The mixture was stirred at room temperature for 12 hours. The resulting mixture was poured into water and extracted by EtOAc (100 mL×3). The organic layers were combined and washed with saturated aqueous solution of Na2CO3, dried over Na2SO4 and then the resulting residue was used directly for the next step without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10]([CH2:17][C:18](OCC)=[O:19])[CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[Cl:14].O.[OH-].[Na+]>CCOCC>[Cl:7][C:8]1[CH:9]=[C:10]([CH2:17][CH2:18][OH:19])[CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[Cl:14]
Reactant: CCOC(=O)Cc1cc(Cl)c(Cl)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COc1cc(CCO)cc(Cl)c1Cl
Reaction time: 0.5 h

Procedure:
Lithium aluminum hydride (1.2 g., 0.032 moles) is suspended in dry ether (100 ml.) in a flask equipped with a stirrer, dropping funnel and protected from moisture. To this is added dropwise with stirring a solution of ethyl 3,4-dichloro-5-methoxyphenylacetate (4.1 g., 0.0156 mole) in dry ether (150 ml.) over a 20-minute period. The mixture is stirred for an additional 30 minutes. Then, with vigorous stirring 1.2 g. of water is added carefully followed by 15% sodium hydroxide (1.5 ml.) and an additional 4.5 ml. of water. The ether solution is filtered from the granular inorganic salts which then are washed with additional ether. The combined ether solutions are washed with water and dried (Na2SO4). Upon evaporation of the ether, 2-(3,4-dichoro-5-methoxyphenyl)ethanol remains.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH:6]=[C:5]([CH2:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(Cl)Cl.O>[S:10]1[CH:11]=[CH:12][N:13]=[C:9]1[CH2:8][C:5]1[CH2:4][CH2:3][N:2]([C:21](=[O:24])[CH:22]=[CH2:23])[CH2:7][CH:6]=1
Reactant: C=CC(=O)Cl
Reactant: C1=C(Cc2nccs2)CCNC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CC=C(Cc2nccs2)CC1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 25.6 %

Procedure:
To a stirred suspension of 2-((1,2,3,6-tetrahydropyridin-4-yl)methyl)thiazole hydrochloride (Intermediate-2) (1.57 g, 5.34 mmol) in anhydrous CH2Cl2 (20 mL) was added triethylamine (4.4 mL, 32.0 mmol), followed by acryloyl chloride (1.3 mL, 16.0 mmol) at 0° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. Then the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using a mixture of 20% ethyl acetate/hexane as an eluent to get the desired compound as a light brown liquid (320 mg, 26%); 1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, J=3.4 Hz, 1H), 7.60 (d, J=2.9 Hz, 1H), 6.88-6.70 (m, 1H), 6.14-6.08 (m, 1H), 5.72-5.60 (m, 2H), 4.12-4.08 (m, 1H), 4.06-3.96 (m, 1H), 3.74-3.70 (m, 2H), 3.66-3.54 (m, 2H), 2.12-2.02 (m, 2H); ES-MS: 235.1 (M+1)+.
Reaction SMILES: [Br:1][CH2:2][N:3]([C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][C:5]([O:7]C(C)(C)C)=[O:6].FC(F)(F)C(O)=O>>[Br:1][CH2:2][N:3]([C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CC(C)(C)OC(=O)CN(CBr)C(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN(CBr)C(=O)c1ccccc1
Yield: 70 %

Procedure:
Bromomethylbenzoyl-glycine. t-butyl ester was treated with trifluoroacetic acid and the product, a solid melting at 162°-164°, was purified in 70% yield by preparative thin layer chromatography. NMR (CHCl3) δ 8.86 (t, 1H, NH, J=5.8 Hz), 7.86 (d, 2H, Ar-2,6), 7.53 (d, 2H, Ar-3,5), 4.81 (s, 2H, CH2Br), 3.91 (d, 2 H, J=5.9 Hz), 3.6 (br, 1H, COOH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=O)[C:6]([CH:11]([CH3:13])[CH3:12])=[CH:7][N:8](C)C)C.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25]N.Cl>CCO>[CH3:1][O:3][C:4]([C:5]1[N:25]([C:19]2[C:18]([Cl:17])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:24])[N:8]=[CH:7][C:6]=1[CH:11]([CH3:13])[CH3:12])=[O:15]
Reactant: CCOC(=O)C(=O)C(=CN(C)C)C(C)C
Reactant: NNc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCO
Product: COC(=O)c1c(C(C)C)cnn1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 4-methyl-2-oxo-pentanoic acid methyl ester (3.8 g, 26 mmol) in N,N-dimethylformamide dimethyl acetal (7 mL, 52 mmol) is added p-toluenesulfonic acid monohydrate (30 mg). The mixture is stirred at 80° C. overnight. The reaction mixture is concentrated under reduced pressure to give 3-isopropyl-4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester as an orange oil. To a solution of 3-isopropyl-4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester and 2,6-dichlorophenylhydrazine hydrochloride (2.8 g, 13 mmol) in EtOH (40 mL) is added concentrated HCl (0.5 mL). The mixture is stirred at ambient temperature for 2 h followed by refluxing overnight. The reaction mixture is concentrated and the residue is partitioned between EtOAc and 1N HCl. The organic phase is dried (Na2SO4) and concentrated to a residue. The residue is purified by column chromatography (0-15% EtOAc in hexanes) to give the title compound as an oil (2.2 g, 52%). 1H NMR (CDCl3): δ 7.76 (s, 1H), 7.43 (d, 2H), 7.34 (dd, 1H), 3.75 (s, 3H), 3.48 (m, 1H), 1.32 (d, 6H).
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:17])=[CH:12][C:13]=32)[CH2:6]1)=O.C([O-])([O-])=O.[Na+].[Na+].[ClH:26].CCOC(C)=O>CO.O>[ClH:26].[CH:14]12[CH2:16][CH:7]([CH2:6][NH:5][CH2:15]1)[C:8]1[CH:9]=[CH:10][C:11]([OH:17])=[CH:12][C:13]2=1
Reactant: O=C(N1CC2CC(C1)c1cc(O)ccc12)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Oc1ccc2c(c1)C1CNCC2C1
Temperature: 65 °C

Procedure:
2,2,2-Trifluoro-1-(4-hydroxy-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7), 3,5-trien-10-yl)-ethanone (50 mg, 0.184 mmol) was dissolved in MeOH/H2O (3/1, 5 mL), treated with Na2CO3(s) (40 mg, 0.369 mmol) and warmed to 65° C. for 2 hours. The mixture was concentrated, diluted with H2O and extracted with CH2Cl2 (3×20 mL) then dried through a cotton plug. Filtration through a Silica gel plug provided an oil (10% MeOH/CH2Cl2) which was treated with 3N HCl EtOAc (3 mL) then concentrated, dissolved in a minimum of MeOH which was saturated with Et2O and stirred. After 18 hours the white crystalline product was collected by filtration (10 mg, 26%). 1H NMR (400 MHz, CDOD3) δ 7.16 (d, J=8.0 Hz, 1H), 6.80 (d, J=2.0 Hz, 1H), 6.72 (dd, J=8.0,2.0 Hz, 1H), 3.32-3.28 (4H), 3.09 (dd, J=14.5,12.0 Hz, 2H), 2.32 (m, 1H), 2.03 (d, J=11.0 Hz, 1H) APCl MS m/e 176.2 [(M+1)+]. mp 308 (dec.) ° C.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[C:14]([Cl:22])[CH:13]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]=O>C(O)C.O>[C:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[C:14]([Cl:22])[CH:13]=3)[CH2:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNc2ccccc2)cc1Cl
Reactant: C=O
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccc(N2CN(c3ccccc3)CC2=O)cc1Cl

Procedure:
2-Phenylamino-N-(3-chloro-4-sulphamoylphenyl)-acetamide (34 g) was dissolved in ethanol (300 ml) and paraformaldehyde (6.0 g) in water (600 ml) added. The mixture was refluxed 4 hrs and cooled. The product was worked up as in Example 1(c) to yield: 18 g, m.p. 257°-259°.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]([C:8]1[CH:9]=[C:10]2[N:15]([C:16]=1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6].Cl>ClCCl.C(S)C>[CH:5]([C:8]1[CH:9]=[C:10]2[N:15]([C:16]=1[S:17]([C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1)(=[O:19])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11]2)([CH3:7])[CH3:6]
Reactant: COc1ccc(S(=O)(=O)c2c(C(C)C)cc3ccccn23)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CC(C)c1cc2ccccn2c1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6.7 g (0.050 mole) of aluminium chloride are suspended in 100 ml of dichloromethane and 25 ml of ethanethiol. This suspension is stirred and cooled to 0° C. while 2.5 g of 2-isopropyl 3-p-methoxyphenylsulfonyl indolizine in dichloromethane are added. The addition takes about 15 minutes. The reaction mixture is allowed to warm to room temperature and maintained there for 45 minutes. It is poured onto ice, then 5 ml of concentrated hydrochloric acid are added with stirring. The mixture is extracted with 2 fractions of ethyl ether and the ethereal extracts are pooled. They are washed with 3 fractions of 30 ml of a 10% aqueous solution of sodium bicarbonate and the aqueous phase is acidified.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](O)=[S:7])(=[O:3])[CH3:2].[C:13]([O:17][C:18](=[O:26])[CH2:19][NH:20][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([O:17][C:18](=[O:26])[CH2:19][N:20]([C:6](=[S:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=1[C:1](=[O:3])[CH3:2])[CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)CNC1CCCC1
Reactant: CC(=O)c1ccccc1C(O)=S
Solvent: ClCCl
Product: CC(=O)c1ccccc1C(=S)N(CC(=O)OC(C)(C)C)C1CCCC1
Reaction time: 8 h

Procedure:
N,N1 -Dicyclohexylcarbodiimide (15.9 g, 77 mmol) in methylene chloride was added slowly to a mixture of 2-acetylthiobenzoic acid (15.2 g, 77 mmol) and N-cyclopentylglycine t-butyl ester (15.4 g) in methylene chloride maintained at 0°-5°. The mixture was brought to room temperature overnight, filtered, and the filtrate washed successively with dilute hydrochloric acid, saturated sodium bicarbonate and saturated sodium chloride solutions. After drying, the organic portion was concentrated, the residue dissolved in ether and the resulting solution filtered. Concentration of the filtrate gave crude N-(2-acetylthiobenzoyl)-N-cyclopentylglycine t-butyl ester as an oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[CH2:10][CH2:11][CH2:12][C:13](=[O:17])[C:14]=2[C:15]=1[OH:16])=[O:5])C.[OH-].[Na+].Cl>O>[OH:16][C:15]1[C:14]2[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]=2[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2c(c1O)C(=O)CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cnc2c(c1O)C(=O)CCC2
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To 25 ml of water were added 4.0 g of 4-hydroxy-5,6,7,8-tetrahydro-5-oxo-3-quinolinecarboxylic acid ethyl ester and 2.9 g of sodium hydroxide. The resulting reaction mixture was stirred at 90°-95° C. for 2 hours. After being allowed to cool, the reaction mixture was adjusted to pH 2 with 6 N hydrochloric acid. The crystals so precipitated were separated by filtration, washed with water and ethyl alcohol, and then dried at 120° C. under reduced pressure for 4 hours to obtain a yield of 3.3 g of the desired compound. This compound melted (and decomposed) at 278°-279° C. Its infrared absorption spectrum (KBr tablet) had absorption peaks at 3420, 1740, 1690, 1640, 1500, and 820 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=[N:27][OH:28])[CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:36]([CH3:38])[CH3:37].O>CN(C)C=O>[Cl:1][C:2]1[C:3](/[C:12](=[N:27]/[O:28][CH:36]([CH3:38])[CH3:37])/[CH2:13][NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:25])[F:23])=[N:4][CH:5]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:7]=1
Reactant: O=C(NCC(=NO)c1ncc(C(F)(F)F)cc1Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)O/N=C(\CNC(=O)c1ccccc1C(F)(F)F)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 50.1 %

Procedure:
To a suspension of 20.00 g of N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide and 19.48 g of potassium carbonate in 105 ml of N,N-dimethylformamide, 10.38 g of 2-iodopropane was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was mixed with 200 ml of water and extracted with ethyl acetate (100 ml×3), the resulting organic layers were combined, washed with water (100 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 11.00 g of the desired product as white crystals.