Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([O:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.C1COCC1>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([NH:9][O:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: NOc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)NOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
O-phenylhydroxylamine hydrochloride (6.9 mmol, 1.0 g), 4-methoxybenzenesulfonyl chloride (6.2 mmol, 1.29 g), diisopropylethylamine (13.1 mmol, 2.28 mL) and andhydrous THF (15 mL) were combined under nitrogen. After stirring for 2 hours at room temperature, a few crystals of 4-dimethylaminopyridine were added and the flask was re-sealed. After another 2 hours, 4 mL of N,N-dimethylformamide was injected and the reaction stirred for an additional 15 hours. The resulting red solution was concentrated to an oil and partitioned between ethyl acetate and 1N HCl. The organic layer was separated and washed with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated under vacuum. The resulting dark brown residue was purified by silica gel chromatography (3:1 hexanes/ethyl acetate) providing 360 mg (21%) of a redish solid. H1-NMR (CDCl3): δ7.89 (2H,d), 7.30-7.20 (3H,m), 7.11 (2H,d), 7.02 (1H,s), 7.00 (2H,d), 3.88 (3H,s).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])[CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1O>C1COCC1>[N:10]1([C:8]([C:5]2[CH:4]=[C:3]([CH2:2][O:1][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[CH3:47])[S:7][CH:6]=2)=[O:9])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(c1csc(CO)c1)N1CCCCC1
Reactant: Cc1ccccc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccccc1OCc1cc(C(=O)N2CCCCC2)cs1
Reaction time: 8 h
Yield: 21.1 %

Procedure:
(5-Hydroxymethyl-thiophen-3-yl)-piperidin-1-yl-nnethanone (0.068 g, 0.3 mmol) was dissolved in THF (5 mL). Triphenylphosphine (0.3 mmol), diethylazodicarboxylate (0.3 mmol) and 2-methyl-phenol (0.3 mmol) were added and the reaction stirred overnight. The reaction was quenched with saturated aqueous ammonium chloride and the solvent was reduced under vacuum. The residue was partitioned between DCM and water and the organic solution separated, dried over magnesium sulphate, filtered and the solvent evaporated. The product was purified by HPLC, eluting with acetonitrile in water (0.1% formic acid). The fractions containing the desired product were concentrated under vacuum to give the title compound (20 mg). LCMS m/z 316.20 [M+H]+RT=11.75 min (Analytical Method 1). 1H NMR (400 MHz, CHCl3-d): δ 7.45 (s, 1H), 7.2-7.1 (m, 3H), 6.9 (m, 2H), 5.2 (s, 2H), 3.6 (m, 4H), 2.25 (s, 3H), 1.7-1.6 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:23])[CH2:21][CH3:22])=[C:13]3[NH:24][C:25]2[CH:26]=[CH:27][C:28]([N:31]3[CH2:36][CH2:35][CH2:34][CH:33]([NH:37]C(=O)OC(C)(C)C)[CH2:32]3)=[N:29][CH:30]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].Cl>ClCCl.C(OCC)C>[NH2:37][CH:33]1[CH2:34][CH2:35][CH2:36][N:31]([C:28]2[N:29]=[CH:30][C:25]([NH:24][C:13]3[C:12]4[C:17](=[CH:18][CH:19]=[C:10]([C:4]5[CH:3]=[C:2]([Cl:1])[C:7]([OH:8])=[C:6]([Cl:9])[CH:5]=5)[CH:11]=4)[N:16]=[CH:15][C:14]=3[C:20](=[O:23])[CH2:21][CH3:22])=[CH:26][CH:27]=2)[CH2:32]1
Reactant: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCCC(N)C2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.7 %

Procedure:
tert-butyl 1-(5-(6-(3,5-dichloro-4-hydroxyphenyl)-3-propionylquinolin-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (35 mg, 0.055 mmol) was dissolved in dichloromethane (5 mL). To this solution was added a 2.0 M HCl solution in diethyl ether (2 mL) the mixture was stirred for 16 h at room temperature where a precipitate formed. The precipitate was filtered off, washed with dichloromethane (10 mL), dried under vacuum to obtain the desired product as the HCl salt (12 mg, 33%) as a yellow solid: 1H NMR (500 MHz, MeOD) δ 9.29 (s, 1H), 8.24 (m, 2H), 8.04 (m, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.31 (s, 2H), 7.25 (d, J=8.9 Hz, 1H), 4.53 (s, 1H), 4.06 (d, J=13.3 Hz, 1H), 3.39 (m, 2H), 3.24 (q, J=14.1, 7.0 Hz, 2H), 2.22 (m, 1H), 1.98 (m, 1H), 1.74 (m, 2H), 1.25 (t, J=6.9 Hz, 3H); ESI MS m/z 536, [C28H27Cl2N5O2+H]+; HPLC 98.9% (AUC), tR=10.33 min.
Reaction SMILES: [N+:1]([C:4]1[C:12]([NH2:13])=[CH:11][C:7]2[CH2:8][CH2:9][O:10][C:6]=2[CH:5]=1)([O-])=[O:2].[N:14]#[C:15][NH2:16].[CH]Cl.[OH-].[Na+]>O>[N+:1]1([O-:2])[C:4]2[CH:5]=[C:6]3[O:10][CH2:9][CH2:8][C:7]3=[CH:11][C:12]=2[N:13]=[C:15]([NH2:16])[N:14]=1
Reactant: N#CN
Reactant: Nc1cc2c(cc1[N+](=O)[O-])OCC2
Agent: [CH]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2cc3c(cc2[n+]([O-])n1)OCC3
Temperature: 50 °C
Reaction time: 3 h
Yield: 22.7 %

Procedure:
A mixture of nitroaniline 194 (7.27 g, 40.4 mmol) and cyanamide (6.79 g, 162 mmol) were mixed together at 100° C., cooled to 50° C., cHCl (15 mL) added carefully and the mixture heated at 100° C. for 4 h. The mixture was cooled to 50° C., 7.5 M NaOH solution added until the mixture was strongly basic and the mixture stirred at 100° C. for 3 h. The mixture was cooled, diluted with water (200 mL), filtered, washed with water (3×50 mL) and dried. The aqueous fraction was extracted with CHCl3 (3×50 mL), dried and the solvent evaporated. The combined solids were purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give crude amine 195 (1.87 g, 23%) as a yellow powder: mp (MeOH/DCM) 241-246° C. Anal. calcd for C9H8N4O2: C, 52.9; H, 4.0; N, 27.4. Found: C, 53.3; H, 3.8; N, 26.4%.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8](/[C:10](=[CH:18]/[CH3:19])/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:9]=1)(=[O:3])[CH3:2].S(Cl)([Cl:23])(=O)=O>C(Cl)(Cl)(Cl)Cl.C(O)(=O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([Cl:23])=[C:8](/[C:10](=[CH:18]/[CH3:19])/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:9]=1)(=[O:3])[CH3:2]
Reactant: C/C=C(\C(=O)OC(C)(C)C)c1csc(NC(C)=O)n1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: C/C=C(\C(=O)OC(C)(C)C)c1nc(NC(C)=O)sc1Cl
Yield: 6.8 %

Procedure:
78 g (0.28 mol) of tert.-butyl Z-2-(2-acetamidothiazol-4-yl)but-2-enoate are suspended in a mixture of 2 l of carbon tetrachloride and 15 ml of glacial acetic acid at 0° C. 43 g (0.32 mol) of sulphuryl chloride, dissolved in 600 ml of carbon tetrachloride, are added dropwise in the course of five hours, while stirring. The solution is extracted once with saturated sodium bicarbonate solution and once with water, dried and concentrated to about 200 ml. The product which has precipitated is filtered off with suction and washed with ether (53.4 g). The mother liquor is evaporated completely and a second fraction of the product (6 g) is obtained by crystallization of the residue with ether/ligroin. Yield: 59.4 g=67.8% of theory.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([N:22]4C(=O)C5=CC=CC=C5C4=O)=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2].CN>C1(C)C=CC=CC=1.CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([NH2:22])=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cc(COc2ccc(C#N)cc2)nc2cc(N3C(=O)c4ccccc4C3=O)ccc12
Agent: CN
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(COc2ccc(C#N)cc2)nc2cc(N)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.15 g (5.1 mmol) of 2-[(4-cyanophenyl)-oxymethyl]-4-methyl-7-phthalimido-quinoline are dissolved in 75 ml of toluene/methanol (2:1), mixed with 7.5 ml of 40% aqueous methylamine solution and stirred for 2 hours at ambient temperature. Then the solution is concentrated by evaporation in vacuo, the residue is stirred with 2N acetic acid, suction filtered and dried. The crude product is chromatographed on silica gel, eluting first with methylene chloride, later with methylene chloride/ethanol (50:1). The desired fractions are combined, concentrated by evaporation and triturated with ether.
Reaction SMILES: [N+]([O-])(O)=O.[F:5][CH:6]([F:22])[O:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([NH:15]C(=O)C)=[C:10]([N+:19]([O-])=O)[CH:9]=1.[ClH:23].FC(F)OC1C(F)=CC(N)=C([N+]([O-])=O)C=1>ClCCl.CO.C1CCCCC1>[ClH:23].[ClH:23].[F:22][CH:6]([F:5])[O:7][C:8]1[C:13]([F:14])=[CH:12][C:11]([NH2:15])=[C:10]([NH2:19])[CH:9]=1
Reactant: CC(=O)Nc1cc(F)c(OC(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: Nc1cc(F)c(OC(F)F)cc1[N+](=O)[O-]
Solvent: C1CCCCC1
Solvent: CO
Solvent: ClCCl
Product: Nc1cc(F)c(OC(F)F)cc1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
22.5 ml of 100% nitric acid are added dropwise at 20° C. within 30 min. to 20 g of the above compound in 200 ml of dichloromethane, and the mixture is stirred for a further 15 h at room temperature. Analogously to Example B7c, this gives N-(4-difluoromethoxy-5-fluoro-2-nitrophenyl)acetamide of m.p. 72°-74° C. (from cyclohexane) in 89% yield. By stirring for several hours with 1M hydrochloric acid in methanol at 60° C., 4-difluoromethoxy-5-fluoro-2-nitroaniline of m.p. 95°-97.5° C. is obtained in 95% yield and, analogously to Example B7e, 4-difluoromethoxy-5-fluoro-1,2-phenylenediamine dihydrochloride (decomposition from 210° C.) is obtained in 85% yield.
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][CH2:4][NH2:5].[SH:6][C:7]1[S:8][CH2:9][CH2:10][N:11]=1>C1C=CC=CC=1>[ClH:2].[ClH:1].[NH2:5][CH2:4][CH2:3][S:6][C:7]1[S:8][CH2:9][CH2:10][N:11]=1
Reactant: NCCCl
Reactant: SC1=NCCS1
Agent: Cl
Solvent: c1ccccc1
Product: NCCSC1=NCCS1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
In 100 ml of benzene, 0.1 mol of 2-chloroethylamine hydrochloride and 0.1 mol of 2-mercaptothiazoline were dispersed, gradually heated to 80° C., and stirred for reaction at this temperature for 30 minutes. After completion of the reaction, the reaction mixture was filtered to obtain white 2-(2-aminoethylthio)-thiazoline dihydrochloride powder in a yield of 99.7%. In 100 ml of 36 wt % hydrochloric acid, 23.5 g (0.1 mol) of 2-(2-aminoethylthio)-thiazoline dihydrochloride was dissolved. The resultant solution was refluxed for 30 hours, to obtain cysteamine hydrochloride. Then, the cysteamine hydrochloride was concentrated to dryness under a vacuum and then thoroughly dissolved by heating to a temperature above 80° C. The solution was aspired with a Pasteur pipet 2 mm in mouth diameter and dropped onto a tetrafluoroethylene plate having the opposite side thereof cooled with water to 30° C. The white solid cysteamine hydrochloride heaps consequently deposited on the plate were hemispheres 3 to 5 mm in diameter and 2 to 3 mm in height.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:44][O:45][C:46]1[C:51]2[N:52]=[C:53]([NH2:55])[S:54][C:50]=2[C:49]([CH:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)=[CH:48][CH:47]=1>C1COCC1.O1CCOCC1.CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:55][C:53]2[S:54][C:50]3[C:49]([CH:56]4[CH2:57][CH2:58][O:59][CH2:60][CH2:61]4)=[CH:48][CH:47]=[C:46]([O:45][CH3:44])[C:51]=3[N:52]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Reactant: O=C(O)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a stirred solution of 32 mg (0.23 mmol) 4-fluoro-benzoic acid in 5 ml THF were added 32 mg (0.25 mmol) HATU and 0.043 ml (0.25 mmol) N-ethyldiisopropylamine and stirring continued at room temperature for 1 h. A solution of 60 mg (0.23 mmol) 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl-amine in 5 ml dioxane and 1 ml DMF was then added and stirring continued at room temperature for 16 h. The reaction mixture was then poured into 100 ml water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (ethyl acetate) followed by trituration in hexane afforded 45 mg (51%) 4-fluoro-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-benzamide as a white crystalline solid. ES-MS m/e (%): 387 (M+H+, 100).
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[C:8]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)(=[O:10])[CH3:9].CN(C=O)C.C>C(#N)C.C(OCC)(=O)C>[C:6]([C:14]1[CH:15]=[C:11]([C:8](=[O:10])[CH3:9])[NH:12][CH:13]=1)#[N:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(=O)c1ccc[nH]1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)c1cc(C#N)c[nH]1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of chlorosulfonylisocyanate in acetonitrile (25 mL) was added dropwise to a solution of 2-acetylpyrrole (10.9 g, 100 mmol) in acetonitrile (25 mL) at 0° C. The reaction mixture turned from yellow to black and was allowed to stir at ambient temperature for 2.5 h. The reaction mixture was cooled to 0° C. and DMF (10 mL) was added. The resulting reaction mixture was then heated to 50° C. for 10 minutes and then poured onto ice to afford a dark colored product. The product was dissolved in ethyl acetate and treated with activated charcoal and filtered. The ethyl acetate was evaporated to afford a tan-colored product. Recrystallization from ethyl acetate afforded 4-cyano-2-acetylpyrrole (4.5 g) as a tan solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:10]([CH3:19])=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12](OC)=[O:13]>C1COCC1>[CH3:7][O:8][C:9]1[C:10]([CH3:19])=[C:11]([CH2:12][OH:13])[CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1cccc(OC)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(CO)c1C
Yield: 95.8 %

Procedure:
A suspension of 4.5 g (0.118 mol) of lithium aluminum hydride in 100 mL of THF was treated dropwise with a solution of 14.22 g (78.9 mmol) of methyl 3-methoxy-2-methylbenzoate in 120 mL of THF. The mixture was heated at reflux for 2.5 hours, then cautiously decomposed with 1NH2SO4. The mixture was extracted with EtOAc, and the EtOAc washed with dilute HCl, H2O, saturated NaHCO3, and saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 11.5 g (95.8% yield) of the product as a tan solid, mp 63-64° C. The structure was confirmed by NMR and mass spectroscopy MS n/z 153 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH2:2][CH3:3].O.[N-:12]=[C:13]=[O:14].[Na+]>C(O)(=O)C>[CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:13]([NH2:12])=[O:14])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(N)cc1
Reactant: [N-]=C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCc1ccc(NC(N)=O)cc1
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A solution of 31.4 g of p-n-propylaniline dissolved in 116 ml of acetic acid and 232 ml of water was added dropwise into 200 ml of a mixed solution comprising 130 g of sodium isocyanate and 900 ml of water, and then stirred in an ice-bath for 30 minutes. The crystals precipitated were filtered, washed with water and dried to give 38.88 g of 4-n-propylphenylurea. After the 4-n-propylphenylurea was added in portions into 107.6 ml of 20% fuming sulfuric acid, the reaction was carried out at 60° C. for 2 hours. Under cooling in an ice-bath, about 400 ml of ice was added into the reaction mixture, followed by heating under reflux for 4 hours. The crystals precipitated by cooling were filtered, washed with water and then dried to give 30.09 g of the above title product (yield: 64.1%). Melting point: 30 261.7°-262.3° C.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][S:9][C:8]=1[NH2:18])=[O:6])C.[C:19]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])#[N:20]>>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:19]1[NH:20][C:5](=[O:6])[C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][S:9][C:8]=2[N:18]=1)[CH3:26]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)c1c(-c2ccccc2)csc1N
Agent: Cl
Product: CCOC(=O)Cc1nc2scc(-c3ccccc3)c2c(=O)[nH]1
Reaction time: 18 h

Procedure:
Hydrogen chloride gas was bubbled through a stirred reaction mixture of 2-amino-4-phenylthiophene-3-carboxylic acid ethyl ester (4.94 g, 0.02 mol) in ethyl cyanoacetate (50 ml) for 2 hours. A thick suspension formed initially which slowly dissolved on gentle warming. The mixture was allowed to stand at ambient temperature for 18 hours. Excess hydrogen chloride was removed by bubbling nitrogen through the reaction mixture and most of the excess ethyl cyanoacetate was distilled out at reduced pressure. The solid residue was recrystallised from ethanol to give (4-oxo-5-phenyl-3,4-dihydrothieno[2,3-d]pyrimidin-2-yl)acetic acid ethyl ester (3.64 g), which was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[NH:10][C:9]=2[C:8]([O:22]C)=[CH:7][CH:6]=1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:11]1[NH:10][C:9]2[C:8]([OH:22])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=2[N:12]=1
Reactant: COC(=O)c1ccc(OC)c2[nH]c(-c3ccc(Cl)cc3Cl)nc12
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
2-(2,4-dichloro-phenyl)-7-methoxy-1H-benzoimidazole-4-carboxylic acid methyl ester (1.9 g, 5.47 mmol) obtained in step 2 was dissolved in 100 ml of toluene, aluminum chloride (3.61 g, 27.05 mmol) was added thereto and refluxed for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding 3 N HCl thereto and stirred for 30 min. The precipitate formed was filtered, washed with benzene and dried to obtain the title compound (1.63 g, 5.03 mmol) in a yield of 92%.
Reaction SMILES: FC(F)(F)S([CH:6](S(C(F)(F)F)(=O)=O)[CH2:7][CH:8]([S:16]([C:19]([F:22])([F:21])[F:20])(=[O:18])=[O:17])[S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(=O)=O.[C:32]([C:36]1[CH:41]=C[C:39]([OH:42])=[CH:38][CH:37]=1)([CH3:35])([CH3:34])[CH3:33]>C(#N)C>[F:21][C:19]([F:20])([F:22])[S:16]([CH:8]([S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])[CH2:7][C:6]1[CH:41]=[C:36]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:37]=[CH:38][C:39]=1[OH:42])(=[O:17])=[O:18]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=S(=O)(C(CC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: CC(C)(C)c1ccc(O)c(CC(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)c1
Reaction time: 1 h

Procedure:
1,1,3,3-Tetrakis(trifluoromethylsulfonyl)propane [4] (148.8 mg, 0.264 mmol) was added to an acetonitrile (0.25 ml) solution of 4- t-butylphenol (43.6 mg, 0.29 mmol) at room temperature. After 1 hour of stirring, the reaction solution was concentrated under a reduced pressure. An obtained residue was purified by Kugelrohr distillation (190-210° C./5 mmHg) thereby obtaining 2-(2,2-bis(trifluoromethylsulfonyl)ethyl-4- t-butylphenol [1o] with an approximately quantitative yield (97.0 mg, 0.24 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].C([N-]C(C)C)(C)C.[Li+].[F:21][C:22]1[CH:29]=[CH:28][C:25](C#N)=[CH:24][C:23]=1[O:30][CH3:31].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:6]2[C:5]([CH:12]=[C:10]([C:25]3[CH:28]=[CH:29][C:22]([F:21])=[C:23]([O:30][CH3:31])[CH:24]=3)[NH:9][C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: COc1cc(C#N)ccc1F
Reactant: CNC(=O)c1cc(Cl)ccc1C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2cc3ccc(Cl)cc3c(=O)[nH]2)ccc1F
Temperature: -78 °C
Reaction time: 2.5 h
Yield: 45.2 %

Procedure:
A solution of 5-chloro-2,N-dimethylbenzamide (5.0 g, 27.2 mmol) in THF (28 mL) was cooled to −78° C. and a solution of 2M lithium diisopropylamide in THF (40.8 mL, 82 mmol) diluted with THF (68 mL) added. 4-Fluoro-3-methoxybenzonitrile (4.12 g, 27.2 mmol) in THF (28 mL) was added and the mixture stirred at −78° C. for 2.5 h. Sat. NH4Cl (aq.) was added and the mixture extracted with EtOAc (2×50 mL). A precipitate formed in the aqueous which was collected by filtration to afford 7-chloro-3-(4-fluoro-3-methoxyphenyl)-2H-isoquinolin-1-one (3.74 g, 12.3 mmol, 45%).
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13](Cl)(=[O:15])=[O:14])[CH:8]=2)[NH:3]1.[CH3:17][NH:18][CH3:19]>>[CH3:17][N:18]([CH3:19])[S:13]([C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[NH:3][C:2](=[O:1])[C:11](=[O:12])[NH:10]2)(=[O:15])=[O:14]
Reactant: O=c1[nH]c2ccc(S(=O)(=O)Cl)cc2[nH]c1=O
Reactant: CNC
Product: CN(C)S(=O)(=O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 35 %

Procedure:
A mixture of 3.91 g (0.015 mole) of 1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxalinesulfonyl chloride and 30 ml of 25% aqueous dimethylamine is stirred at room temperature for 6 hours. Then it is filtered, the separated crystals are washed successively with water and acetone, filtered, dried and recrystallized from water. Thus 1.40 g (35%) of N,N-dimethyl-1,2,3,4-tetrahydro-2,3-dioxo-6-quinoxaline sulfonamide is obtained, m.p.: 258-266° C.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:10])[CH2:8][NH2:9])([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.F[C:19]1[CH:24]=[C:23]([F:25])[C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=1[N+:30]([O-:32])=[O:31]>C(OCC)(=O)C.C1COCC1.CN(C=O)C>[C:2]([O:6][C:7](=[O:10])[CH2:8][NH:9][C:19]1[CH:24]=[C:23]([F:25])[C:22]([C:26]([F:29])([F:27])[F:28])=[CH:21][C:20]=1[N+:30]([O-:32])=[O:31])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(F)cc1F
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNc1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 97.5 %

Procedure:
To a mixture of 4.84 g (29 mmol) of glycine tert-butyl ester hydrochloride, 20 ml of THF, 4.1 ml of triethylamine and 3 ml of DMF, a mixture of 6.57 g of 2,4-difluoro-5-trifluoromethylnitrobenzene and 5 ml of THF was added dropwise under stirring. After stirring for 3 hours, 50 ml of ethyl acetate was added to the reaction mixture, followed by filtration. The filtrate was concentrated under reduced pressure. The concentrate was extracted by adding ethyl acetate and water. The organic layer was washed successively with water, a 1% aqueous solution of sodium bicarbonate and brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluting solvent: hexane:ethyl acetate=10:1.5) to give 9.54 g (98%) of N-(5-fluoro-2-nitro-4-trifluoromethylphenyl)glycine tert-butyl ester.
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:7][C:5]1[N:6]=[C:2]([S:1][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[S:3][CH:4]=1
Reactant: Cc1csc(S)n1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1csc(SCCCCCCO)n1
Yield: 99 %

Procedure:
The mixture of 2-mercapto-4-methylthiazole (2.62 g, 0.02 mol), 6-bromo-1-hexanol (3.62 g, 0.02 mol), potassium carbonate (2.76 g, 0.02 mol) and acetone (50 mL) was refluxed for 14 h. After cooling, the mixture was filtered and the filtrate was evaporated. The residual oil was purified by elution from a silica gel column using ethylacetate-methanol (99:1, v./v) as eluant to give 6-(4-methylthiazol-2-yl)thiohexan-1-ol (29) (99%) as a yellowish oil. IR (neat) 3608 (OH)cm-1 ; NMR (CDCl3) 1.25-2.10 (m, 8H, (CH2)4), 2.38 (S, 3H, Me-Het), 3.18 (t, J=9 Hz, 2H, CH2 --S), 3 65 (t, J=9 Hz, 2H, CH2 --O), 6.75 (S, 1H, H-Het). Analysis found: C, 51.98; H, 7.49; N, 5.92; S, 27.65. Required: C, 51.90; H, 7.40; N, 6.08; S, 27.71 (C10H17NOS2). ##STR11##