Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Na+].[OH:4][C:5]1[CH:18]=[CH:17][C:8]2[S:9][C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=3[C:7]=2[CH:6]=1.[ClH:19].[N:20]1([CH2:26][CH2:27][CH2:28][Cl:29])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[ClH:29].[ClH:19].[N:20]1([CH2:26][CH2:27][CH2:28][O:16][C:13]2[CH:14]=[CH:15][C:10]3[S:9][C:8]4[CH:17]=[CH:18][C:5]([O:4][CH2:28][CH2:27][CH2:26][N:20]5[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]5)=[CH:6][C:7]=4[C:11]=3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: ClCCCN1CCCCC1
Reactant: Oc1ccc2sc3ccc(O)cc3c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc2sc3ccc(OCCCN4CCCCC4)cc3c2cc1OCCCN1CCCCC1

Procedure:
To 200 ml of water containing 12.0 g (0.3 mole) of sodium hydroxide and 8.5 g (0.039 mole) of 2,8-dihydroxydibenzothiophene are added 200 ml of toluene and 19.8 g (0.1 mole) of 3-piperidinopropyl chloride hydrochloride, and the heterogeneous reaction mixture is stirred and heated to reflux for 16 hours. After cooling, the organic layer is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The free base is chromatographed on alumina, using chloroform as the eluant. After removing the chloroform from the fraction collected, the oily residue is dissolved in ether and treated with ethereal hydrogen chloride. The resulting solid is purified by two recrystallizations from methanol-butanone to give 2,8-bis(3-piperidinopropoxy)dibenzothiophene dihydrochloride, M.P. 240°-242°C.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([CH3:25])[O:23][CH:24]=2)=[CH:16][CH:15]=1)C1C=CC=CC=1.C1CC=CCC=1>>[CH3:25][C:22]1[O:23][CH:24]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][CH2:11][NH2:10])=[CH:15][CH:16]=2)[N:21]=1
Reactant: Cc1nc(-c2ccc(OCCNC(=O)OCc3ccccc3)cc2)co1
Solvent: C1=CCC=CC1
Product: Cc1nc(-c2ccc(OCCN)cc2)co1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.9 %

Procedure:
A round-bottomed flask containing benzyl-{2-[4-(2-methyl-oxazol-4-yl)-phenoxy]-ethyl}-carbamate (788 mg, 2.07 mmol) was purged with nitrogen, and 10% Pd/C (200 mg, 20 wt %), ethyl acetate (15 ml), and methanol (5 ml) were added. 1,4-cyclohexadiene (0.90 ml, 9.60 mmol) was then added to the mixture, and the solution was allowed to stir at room temperature for about one hour. The reaction mixture was then filtered through a pad of diatomaceous earth and the filter cake was washed with methanol. The filtrate was concentrated in vacuo and the residue purified by column chromatography (silica gel; methylene chloride to 20% methanol/methylene chloride) to afford 456 mg (89% yield) of the desired product. LRMS ([M+H]+)=247.2.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=1[OH:27])=[O:18]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:27][C:20]1[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[C:17](=[O:18])[CH3:16]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: COc1ccc(C(C)=O)c(O)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(C(C)=O)c(Oc2ccnc3cc(OC)c(OC)cc23)c1
Temperature: 160 °C
Reaction time: 7 h
Yield: 30.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg), 2-hydroxy-4-methoxyacetophenone (873 mg), and 4-dimethylaminopyridine (619 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 7 hr. The reaction solution was cooled to room temperature, and the solvent was then removed therefrom by distillation under the reduced pressure. Chloroform was added to the residue, and the organic layer was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (53.9 mg, yield 31%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3(C#C)[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.BrC1C=C(CC(O)=[O:32])SC=1.[Cl-].[NH4+]>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]3=[O:32])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)Cc1cc(Br)cs1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCC(=O)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Product: COc1ccc(C2CCCCC2=O)cc1OC1CCCC1
Yield: 65 %

Procedure:
To a solution of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-ethynylcyclohexan-1-one (0.25 g, 0.8 mmol) and 4-bromo-2-carboxymethylthiophene (0.27 g, 1.2 mmol) in triethylamine (3.5 mL) under an argon atmosphere were added tetrakis(triphenylphosphine)palladium(0) (0.038 g, 4%) and copper(I) iodide (0.010 g, 6%), and the mixture was heated at 80°-85° C. for 0.5 h. Ammonium chloride was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate:hexanes, provided 4-(2-carbomethoxythien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenylcyclohexan-1-one as a yellow glass (0.15 g, 42%). 1H-NMR (400 MHz, CDCl3) δ 7.81 (d, J=1.3 Hz, 1H), 7.60 (d, J=1.3 Hz, 1H), 7.16 (d, J=2.2 Hz, 1H), 7.10 (dd, J=8.5, 2.2 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 4.80 (m, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 2.98 (dt, J=14.8, 5.7 Hz, 2H), 2.48 (br d, J=14.8 Hz, 2H), 3.33 (m, 2H), 2.26 (dt, J=13.6, 4 Hz, 2H), 1.9-2.0 (m, 6H), 1.6 (m, 2H) ppm. Anal. (C26H28O5S) calcd: C, 69.00; H, 6.24; found: C, 68.82; H, 6.04.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH2:17]([C:19]1[NH:23][C:22]([CH:24]=O)=[C:21]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[NH:23][C:22]([CH:24]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])=[C:21]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:20]=1)[CH3:18]
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Reactant: CCc1cc(CCC(=O)O)c(C=O)[nH]1
Product: CCc1cc(CCC(=O)O)c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)[nH]1

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 3-(5-ethyl-2-formyl-1H-pyrrol-3-yl)-propionic acid (0.23 mmol) to give the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[CH3:14][C:15]1[C:16](B(O)O)=[CH:17][S:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[C:16]1[C:15]([CH3:14])=[CH:19][S:18][CH:17]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1ccc(Br)c(OC)c1
Reactant: Cc1cscc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C(=O)O)ccc1-c1cscc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
A suspension of methyl 4-bromo-3-methoxybenzoate (2.5 g; 10.2 mmol; 1.00 eq.), 4-methyl-3-thiopheneboronic acid (Aldrich 542393; 1.59 g; 11.2 mmol; 1.1 eq.), potassium carbonate (7.05 g; 51 mmol; 5 eq.) and Pd(PPh3)4 (1.18 g; 1 mmol; 0.1 eq.) in toluene (12.5 mL) and water (12.5 mL) was refluxed for 5 hours. The reaction mixture was cooled down to room temperature and filtered through a pad of Celite® which was further washed with toluene (200 mL). The filtrate was concentrated in vacuo and the residue taken up in Ethyl acetate (400 mL). The organic layer was washed with sat. aq. NaHCO3 (100 mL), water (100 mL) and brine (100 mL) then dried over magnesium sulfate and concentrated in vacuo. The residue (2.3 g; 8.77 mmol; 1 eq.) was taken up in EtOH (69 mL), sodium hydroxide (5M; 5.26 mL; 26.3 mmol; 3 eq.) was added and the reaction mixture was stirred at 60° C. for one hour. After concentration in vacuo, the residue was taken up in water (200 mL) and the aqueous phase was washed with Ethyl acetate then acidified to pH 2 with conc. HCl. The solution was concentrated to ca. 100 mL and the precipitate filtered off and dried to afford the title compound (1.81 g, 71%) as a brown solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[N:31]=[CH:30][C:29]([C:32]([O:34]C3C=CC=CC=3)=O)=[CH:28][N:27]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>O>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[N:27]=[CH:28][C:29]([C:32]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:34])=[CH:30][N:31]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncc(C(=O)Oc3ccccc3)cn2)CC1
Reactant: C1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncc(C(=O)N3CCCCC3)cn2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.3 %

Procedure:
Piperidine (0.02 ml, 0.20 mmol) was added to a dimethylformamide solution (1.0 ml) of 2-(1-t-butoxycarbonylpiperidin-4-yloxy)-5-(phenoxycarbonyl)pyrimidine (40 mg, 0.100 mmol), and stirred at room temperature for 12 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified through partitioning thin-layer chromatography (hexane:ethyl acetate=3:7) to obtain the entitled compound (38 mg, 97%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=C(C)O[N:11]=2)=[CH:6][C:5]=1[NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34]>>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([C:29]([F:28])([F:39])[F:40])[CH:31]=2)=[C:5]([NH:16][CH2:17][C:18]([OH:20])=[O:19])[CH:6]=1)(=[NH:11])[NH2:14]
Reactant: Cc1nc(-c2ccc(CN)c(NCC(=O)OCc3ccccc3)c2)no1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: Cl
Product: N=C(N)c1ccc(CNC(=O)c2cccc(C(F)(F)F)c2)c(NCC(=O)O)c1

Procedure:
Compound 58d was reacted with 3-trifluoromethylbenzoic acid and subsequently hydrogenated according to the procedure described in Example 58, to give Example 63. ESI-MS m/e 395.4 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[C:22]([O:24]CC)=[O:23]>C(O)C>[OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:13])[F:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]=1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1c(-c2ccccc2)nc2c(C(F)(F)F)cccc2c1O
Solvent: CCO
Product: O=C(O)c1c(-c2ccccc2)nc2c(C(F)(F)F)cccc2c1O
Yield: 77.7 %

Procedure:
Using the procedure of Step E of Example 6, 12.64 g of the product of Step D in 35 ml of 36° Be sodium hydroxide and 70 ml of 95% ethanol were refluxed for 51/2 hours to obtain 9.06 g of 4-hydroxy-2-phenyl-8-trifluoromethyl-quinoline-3-carboxylic acid melting at 204° C which was used as is for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH2:7][S:8]([NH2:11])(=[O:10])=[O:9])=[O:4].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[N:21]=[C:20]([N:26]=[C:27]=[S:28])[N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][CH:13]=[CH:12][C:6]=1[CH2:7][S:8]([NH:11][C:27]([NH:26][C:20]1[N:19]=[C:18]([O:17][CH3:16])[CH:23]=[C:22]([O:24][CH3:25])[N:21]=1)=[S:28])(=[O:10])=[O:9])=[O:4]
Reactant: COc1cc(OC)nc(N=C=S)n1
Reactant: COC(=O)c1ccccc1CS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccccc1CS(=O)(=O)NC(=S)Nc1nc(OC)cc(OC)n1
Temperature: 55 °C
Reaction time: 8.5 h
Yield: 771.9 %

Procedure:
A mixture of 2.5 g of (2-methoxycarbonylbenzyl)sulfonamide, 21.5 g of 4,6-dimethoxy-2-isothiocyanatopyrimidine and 15.1 g of anhydrous potassium carbonate in 400 ml of acetone is stirred for 8.5 hours at 55° C., and then filtered to collect precipitated crystals. To the filtrate, further 2 g of anhydrous potassium carbonate is added and stirred for 2 hours at 60° C. The precipitated crystals are collected. The combined crystals are suspended in 1.5 of water and adjusted to pH 2 with hydrochloric acid. After stirring the mixture for an hour, the crystals are collected by filtration, washed with water, dried and recrystallized from acetonitrile to give 35.9 g of the title compound, as white powder.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[C:4]([C:13]([O:15][CH3:16])=[O:14])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=1.CO.[CH:20]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[C:3]([O:17][CH3:20])=[C:4]([C:13]([O:15][CH3:16])=[O:14])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1sc(-c2ccnn2C)c(Br)c1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1sc(-c2ccnn2C)c(Br)c1OC
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of methyl 4-bromo-3-hydroxy-5-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (175 mg, 0.554 mmol), MeOH (26 μL, 0.609 mmol), PPh3 (189 mg, 0.720 mmol) in THF (6 mL) at 25° C. was added DEAD (113 μL, 0.720 mmol) in one portion. After 30 min, the reaction was concentrated and purified via column chromatography (silica, 20% EtOAc in hexanes) affording the title compound (135 mg, 74%) as a white solid: LC-MS (ES) m/z=332 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=O)[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)[CH:3]=1.B.[CH3:24]SC.NC1C=C(C)C=C(C)N=1.CI.[H-].[Na+]>C1COCC1.[Ni].CO>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][N:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]=2)[CH3:24])=[CH:14][CH:15]=1
Reactant: CSC
Reactant: Cc1cc(C)nc(NC(=O)COc2ccc([N+](=O)[O-])cc2)c1
Agent: [Ni]
Agent: B
Agent: Cc1cc(C)nc(N)c1
Solvent: CO
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc(C)nc(N(C)CCOc2ccc(N)cc2)c1

Procedure:
From 4-nitrophenol by etherification with bromoacetic acid in the presence of sodium hydride in THF, acid chloride formation with thionyl chloride and catalytic DMF and amide formation with 2-amino-4,6-dimethylpyridine in triethylamine and chloroform to give N-(4,6-dimethyl-pyridin-2-yl)-2-(4-nitro-phenoxy)-acetamide. The amide is the reduced with borane-dimethylsulfide in THF at reflux, the resulting amine methylated with methyl iodide in the presence of sodium hydride in THF, and finally catalytic hydrogenation over Raney nickel in methanol gives the required aniline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:10])[C:8]=1[F:9])[NH2:5].[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21](OCC)=[O:22])[N:20]=2)[CH:17]=1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([C:21]([NH:5][C:4]3[CH:3]=[C:2]([F:1])[C:8]([F:9])=[C:7]([F:10])[CH:6]=3)=[O:22])[N:20]=2)[CH:17]=1
Reactant: Nc1cc(F)c(F)c(F)c1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Product: O=C(Nc1cc(F)c(F)c(F)c1)c1cn2cc(Br)ccc2n1

Procedure:
The title compound was prepared by using procedures analogous to those described for the synthesis of Intermediate I, using 3,4,5-trifluoroaniline and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate as starting materials.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]([F:15])[CH:2]=1.S(=O)(=O)(O)[OH:17]>O=[Mn]=O.O>[F:15][C:3]1[CH:2]=[CH:1][C:6]([C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:17])=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: Fc1ccc(Cc2ccc(F)cc2)cc1
Agent: O=[Mn]=O
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 54 %

Procedure:
The procedure of Example 2 is used except that the 4,4'-difluorodiphenylmethane, water, and sulfuric acid are first mixed, then heated before the MnO2 is added. The yield is 54% 4,4'-difluorobenzophenone that is 95% pure.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N+:24]([O-])=O)(=[O:17])=[O:16])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Ni]>[C:1]([O:5][C:6](=[O:27])[C:7]1[CH:8]=[CH:9][C:10]([CH2:13][NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH2:24])(=[O:17])=[O:16])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(CNS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(CNS(=O)(=O)c2ccccc2N)cc1
Reaction time: 28 h

Procedure:
4-[(2-Nitro-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester (14.4 g, 40 mmol) was dissolved in 100 mL of tetrahydrofuran containing 10 g of Raney Nickel. The reaction was pressurized with 100 psi of hydrogen gas and stirred for 28 hours at 25° C. to 60° C. The reaction was filtered, and the filtrate was rotary evaporated to give a thick oil. Chromatography (20% ethyl acetate/hexanes, SiO2) of the oil gave 12.2 (92%) of 4-[(2-Amino-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester as a clear oil. 1H-NMR (CDCl3); δ 7.85 (d, 2H), 7.70 (dd, 1H), 7.27 (m, 3H), 6.78 (m, 2H), 5.18 (bt, 1H), 4.82 (bs, 2H), 4.08 (d, 2H), and 1.57 (s, 9H). MS: M+=363.1 Da Step (3): Synthesis of 4-[(2-Amino-5-bromo-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester
Reaction SMILES: O(Cl)[Cl:2].[P+5].[CH3:5][C:6]1[CH:7]=[C:8]([N:13]2[C:17]3[N:18]=[CH:19][NH:20][C:21](=O)[C:16]=3[CH:15]=[N:14]2)[CH:9]=[C:10]([CH3:12])[CH:11]=1>C(Cl)(Cl)Cl>[Cl:2][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:13]([C:8]3[CH:7]=[C:6]([CH3:5])[CH:11]=[C:10]([CH3:12])[CH:9]=3)[N:14]=[CH:15][C:16]=12
Reactant: Cc1cc(C)cc(-n2ncc3c(=O)[nH]cnc32)c1
Reactant: ClOCl
Agent: [P+5]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)cc(-n2ncc3c(Cl)ncnc32)c1
Temperature: 106.5 °C
Yield: 86.6 %

Procedure:
650.0 g of Phosphorus (V) oxychloride (POCl3) was charged into a 2.0 L 4 necked round bottom flask connected to a mechanical stirrer, thermo meter socket, and condenser under nitrogen atmosphere. 60.0 g (0.25 mol) of 1-(3,5-Dimethyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidine-4-one (Compound No. 78) was charged. Reaction mass temperature was raised to reflux (105-108° C.). Maintained the mass temperature at reflux for 8-9 hour's. Reaction mass temperature was cooled to 25-30° C. and 600.0 ml of chloroform was charged. Maintained the mass temperature at 25-30° C. for 30-45 min. 2.0 kg's of crushed ice was charged into a 5.0 L 4 necked round bottom flask connect to a mechanical stirrer, thermo meter socket, and condenser. Reaction mass was added slowly at maintaining the mass temperature below 10° C. Maintained the mass temperature at 0-10° C. for 30-45 min. Mass temperature was raised to 25-30° C. 600.0 ml of Chloroform was charged. Maintained the mass temperature at 25-30° C. for 30-45 min and settled the mass for 20-30 min. Separated the bottom organic layer. Organic layer was dried with sodium sulphate upto obtaining the moisture content is not more than 0.20% w/v. 15.0 g of carbon was charged. Mass temperature was raised to 45-50° C. Maintained the mass temperature at 45-50° C. for 30-45 min. Carbon and sodium sulphate was filtered through hyflow bed and bed was washed with 300.0 ml of chloroform. Filtrate was collected into a flask. Chloroform was distilled completely under vacuum at mass temperature not crossing 60° C. Finally applied high vacuum to complete remove the traces of chloroform at mass temperature not crossing 60° C. Mass temperature was cooled to 25-30° C. and release the vacuum. 250.0 ml of isopropyl ether was charged. Maintained the mass temperature at 25-30° C. for 45-60 min. Solid was filtered and the solid was washed with 50.0 ml of isopropyl ether. Compound was dried under vacuum at 55-60° C. Dry weight of the compound: 56.0 g (yield 86.6%).
Reaction SMILES: [NH:1]1[C:6]2[S:7][C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:5]=2[C:4](=[O:14])[O:3][C:2]1=[O:15].[C:16](=O)([O-])[O-].[K+].[K+].CN(C=O)C.CI>O>[CH3:16][N:1]1[C:6]2[S:7][C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:5]=2[C:4](=[O:14])[O:3][C:2]1=[O:15]
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c2sc3c(c2c(=O)o1)CCCC3
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)oc(=O)c2c3c(sc21)CCCC3
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.5 %

Procedure:
To 5,6,7,8-tetrahydro-2H-[1]benzothieno[2,3-d][1,3]oxazine-2,4(1H)-dione (1.5 g) and potassium carbonate (1.4 g) was added DMF (15 mL), and methyl iodide (1.2 m) was added thereto under ice-cooling, followed by stirring at room temperature for 6 hours. Methyl iodide (0.61 mL) was added thereto, followed by stirring at room temperature overnight, water (15 mL) was added to the reaction mixture, and the solid was collected by filtration, washed with water, and dried under reduced pressure to obtain 1-methyl-5,6,7,8-tetrahydro-2H-[1]benzothieno[2,3-d][1,3]oxazine-2,4(1H)-dione (1.3 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]1([N:18]=[C:19]=[S:20])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:19]([NH:18][CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[S:20])(=[O:10])=[O:11]
Reactant: S=C=NC1CCCC1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: Nc1cc(Cl)sc1S(=O)(=O)NC(=S)NC1CCCC1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and cyclopentyl isothiocyanate by a procedure analogous to the procedure described in example 3-a (yield 46%); 1H-NMR (DMSO-d6): δ1.30-1.70 (m, 6H), 1.90 (m, 2H), 4.40 (sextet, 1H, CH), 6.55 (br, 2H, NH2), 6.65 (s, 1H, H-4), 8.15 (br d, 1H, NH), 11.2 (br s, 1H, NH).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[N+:13]([CH3:16])([O-:15])=[O:14].[OH-].[Na+].Cl>CO.O>[N+:13](/[CH:16]=[CH:5]/[C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[C:2]([F:12])([F:11])[F:1])([O-:15])=[O:14]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])/C=C/c1ccccc1C(F)(F)F
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 41.3 %

Procedure:
2-(Trifluoromethyl)benzaldehyde (0.758 mL, 5.74 mmol) was dissolved in MeOH (5 mL) and nitromethane (0.370 mL, 6.89 mmol) was added. The mixture was cooled to −10° C. and a solution of NaOH (0.241 g, 6.03 mmol) in Water (2 mL) was added slowly keeping the temperature below −5° C. The mixture stirred at −5° C. for 15 minutes then warmed to 0° C. and stirred for two hours. Ice water (6 mL) was added followed by HCl (6 N, 3 mL). The mixture was extracted with DCM (×2) and washed with brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to give (E)-1-(2-nitrovinyl)-2-(trifluoromethyl)benzene (1.12 g, 2.373 mmol, 41%).