Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:16]=[C:15]([N+:17]([O-])=O)[C:7]([O:8][CH2:9][C:10](OCC)=[O:11])=[C:6]([C:20]([O:22][CH3:23])=[O:21])[CH:5]=1>CN(C)C=O.[Fe]>[Cl:3][C:4]1[CH:5]=[C:6]([C:20]([O:22][CH3:23])=[O:21])[C:7]2[O:8][CH2:9][C:10](=[O:11])[NH:17][C:15]=2[CH:16]=1
Reactant: CCOC(=O)COc1c(C(=O)OC)cc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc2c1OCC(=O)N2
Yield: 90.3 %

Procedure:
A solution of 100 ml of aqueous 0.78N ammonium chloride and 50 ml of dimethylformamide is heated at 85° C. and 40 g of powdery iron is added thereto under stirring followed by addition of a solution of 63.5 g of ethyl 4-chloro-2-methoxycarbonyl-6-nitrophenoxyacetate in 150 ml of dimethylformamide over 15 minutes. The reaction temperature rises to 95° C. The resulting solution is stirred at 80°-90° C. for an hour and 400 ml of dimethylformamide is added thereto. The whole solution is filtered with suction through hot celite. The mother liquor is poured into 2 1 of ice-cold water and the precipitated crystals are collected by filtration to give 43.6 g of methyl 6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazine-8-carboxylate, melting at 239°-241° C.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][C:6](=[CH:9][O:10]C)[CH2:5][CH2:4]2)[O:2]1.C(O)(=O)C>O>[CH:9]([CH:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH2:5]1)=[O:10]
Reactant: COC=C1CCC2(CC1)OCCO2
Solvent: CC(=O)O
Solvent: O
Product: O=CC1CCC(=O)CC1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 28.2 g of 1,1-ethylenedioxy-4-(methoxymethylene)cyclohexane, 770 ml of glacial acetic acid and 385 ml of water was heated to reflux for 1 hour in a round flask while gassing with nitrogen. Thereafter, the yellowish clear solution was cooled to room temperature, diluted with 800 ml of water and extracted three times with 700 ml of methylene chloride each time. The organic phases were washed twice with 500 ml of 10% (wt./vol.) sodium carbonate solution each time, dried over sodium sulphate, filtered and concentrated. Chromatographic separation of the brownish liquid obtained (18.5 g) on silica gel with methylene chloride as the eluent finally gave 16.7 g of 4-formylcyclohexanone as a brownish liquid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[C:4]([OH:9])[CH:3]=1.[NH3:10]>O>[OH:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([OH:9])[CH:3]=1)[NH2:10]
Reactant: Oc1cc(O)cc(O)c1
Reactant: N
Solvent: O
Product: Nc1cc(O)cc(O)c1
Reaction time: 18 h
Yield: 37 %

Procedure:
To a 200-mL, 2-necked flask was added 31.5 g (250 mmol) of 1,3,5-trihydroxybenzene. After replaced with argon, 25 mL of 28% ammonia and water were added thereto, and the resulting mixture was stirred in a water bath for 18 hours. Water was removed away in vacuo and 50 mL of isopropanol was added. The obtained mixture was ice-cooled for 2 hours to precipitate a solid and the precipitated solid was obtained by filtration. The solid was washed with isopropanol and then vacuum-dried, whereby a desired product was obtained (Quantity: 11.4 g, 91.3 mmol, Yield: 37%).
Reaction SMILES: [SH:1][C:2]([C@H:5]1[O:10][C:8](=[O:9])[C@@H:7]([CH2:11][SH:12])[CH2:6]1)([CH3:4])[CH3:3].[Cl-].[NH4+]>C(Cl)Cl.C(N(CC)CC)C.C(Cl)(=O)C>[C:8]([S:1][C:2]([C@H:5]1[O:10][C:8](=[O:9])[C@@H:7]([CH2:11][S:12][C:5](=[O:10])[CH3:2])[CH2:6]1)([CH3:4])[CH3:3])(=[O:9])[CH3:7]
Reactant: CC(C)(S)[C@@H]1C[C@H](CS)C(=O)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: CC(=O)SC[C@H]1C[C@@H](C(C)(C)SC(C)=O)OC1=O
Reaction time: 0.5 h
Yield: 185.3 %

Procedure:
To a stirred solution of cis-4-(1-mercapto-1-methylethyl)-2-mercaptomethyl-4-butanolide (compound No.9-3, 0.102 g) in methylene chloride (3 ml), triethylamine (0.20 ml) and acetyl chloride (0.10 ml) were added and stirred for 30 minutes under nitrogen atmosphere and ice-cooling. The mixture was poured into saturated aqueous ammonium chloride solution (30 ml) and extracted with ether. The organic layer was washed with saturated aqueous ammonium chloride solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The oily residue was purified by silica gel column chromatography to give 0.133 g (93%) of the titled compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[Li].CC(C)([O-])C.[O-]C1C=CC=CC=1.[Li+].Br[CH:27]([C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=1)[C:28]([O:30][C@@H](C)C(=O)N1CCCC1)=[O:29].OO>C1COCC1.O>[Cl:46][C:43]1[CH:42]=[CH:41][C:40]([C@@H:27]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[C:28]([OH:30])=[O:29])=[CH:45][CH:44]=1
Reactant: C[C@H](OC(=O)C(Br)c1ccc(Cl)cc1)C(=O)N1CCCC1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](Oc1cccc(C(F)(F)F)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To a solution of 3-(Trifluoromethyl)phenol 5 (10.82 g, 66.85 mmol) in THF (30 mL) was added lithium-tert-butoxide (5.34 g, 66.85 mmol) at 0° C. and stirred at RT for 30 min. The resulting lithium phenoxide solution was added drop wise to a solution of (2S)-1-oxo-1-(pyrrolidin-1-yl)propan-2-yl 2-bromo-2-(4-chlorophenyl)acetate 4 (25.0 g, 66.85 mmol) in THF (160 ml) at −5° C. The reaction mixture was stirred for 4 h at −5° C. To the solution was added a pre-mixed solution of H2O2 (30% solution, 151 g, 1336.989 mmol) and LiOH,H2O (6.8 g, 167.11 mmol) in water (150 mL) at 0-5° C. over 30 min. The reaction mixture was stirred 0-5° C. for 1 h and quenched with saturated aqueous sodium bisulfite (200 ml). The reaction mixture was made acidic (pH ˜2) with 1(N) HCl at cooling condition. The organic layer was separated and concentrated under reduced pressure. The crude residue was dissolved in ethyl acetate (150 mL) and washed with water (2×80 mL) followed by brine solution (80 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash chromatography on 100-200 mesh silica-gel (12-15% ethyl acetate-hexane) to afford (2R)-2-(4-chlorophenyl)-2-[3-(trifluoromethyl)phenoxy]acetic acid 7 (11.2 g, 51%) as off white solid.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.CS(C)=O.[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[F:1][C:2]1[C:3](=[O:9])[N:4]([C:5](=[O:8])[NH2:6])[C:21](=[O:22])[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)n1c(=O)c(F)cn(-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
10.4 g. (0.08 mole) of 5-fluorouracil was dissolved in 100 ml. of dimethyl sulfoxide, then 14.3 g. (0.12 mole) of phenyl isocyanate was added thereto and stirred at room temperature for 1 hour. The milky reaction mixture was filtered off and a fine precipitate was obtained. The precipitate was suspended in hot ethanol and again filtered. There was obtained 16.2 g. (81.4% yield) of 5-fluoro-1-phenyl carbamoyluracil melting at 280° C.
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:23])[CH3:22])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+].O1CCCC1>CO.C(#N)C>[NH2:31][CH:1]([C:4]1[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:23])[CH3:22])[CH2:16][CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)[CH3:2]
Reactant: CC(=O)NC1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)NC1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)CC1
Temperature: 65 °C

Procedure:
A mixture of N-[1-(7-acetyl-5-chloroquinolin-8-yl)piperidin-4-yl]acetamide (0.042 g, 0.12 mmol) and ammonium acetate (0.0936 g, 1.21 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.30 mL, 0.30 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C18H24ClN4O (M+H)+: m/z=347.2; Found: 347.1.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C@H:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][C:18]3[N:19]=[C:20](Br)[S:21][C:22]=3[CH3:23])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1)C.[CH3:26][CH2:27]O>C1COCC1.O>[CH:9]([C:26]1[CH:27]=[CH:7][C:6]([C:20]2[S:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[C@H:6]([CH2:5][C:4]([OH:3])=[O:25])[CH2:7][CH2:8]4)[N:19]=2)=[CH:5][CH:4]=1)([CH3:10])[CH3:8]
Reactant: CCO
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(Br)sc3C)ccc21
Solvent: C1CCOC1
Solvent: O
Product: Cc1sc(-c2ccc(C(C)C)cc2)nc1CCOc1ccc2c(c1)CC[C@H]2CC(=O)O
Reaction time: 24 h
Yield: 66 %

Procedure:
To a solution of Example 174 (305 mg, 0.657 mmol) in a mixture of THF (8 mL), water (8 mL), and EtOH (4 mL), was added LiON (63 mg, 2.63 mmol). The reaction mixture was vigorously stirred for 24 hours, diluted with water (20 mL), and washed with Et2O (10 mL). The aqueous phase was then acidified to pH ˜1 using 1 N HCl, and then extracted with CH2Cl2 (4×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was then purified by silica gel flash chromatography (95:5 CH2Cl2/MeOH) to afford product (189 mg, 66%) as a white solid. (C26H29NO3S): LC-MS, RT 3.95 min., M+H 436.4; 1H NMR (CDCl3): δ 1.25 (s, 3H), 1.28 (s, 3H), 1.70-1.82 (m, 1H), 2.32-2.43 (m, 2H), 2.45 (s, 3H), 2.74-2.98 (m, 4H), 3.18 (t, 2H), 3.47-3.54 (m, 1H), 4.28 (t, 2H), 6.72 (dd, 1H), 6.78 (s, 1H), 7.08 (d, 1H), 7.51 (AB quartet, 4H).
Reaction SMILES: [CH3:1][C:2]1[N+:3]([O-])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(OC(=O)C)(=[O:15])C>>[CH3:1][C:2]1[NH:3][C:4](=[O:15])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2ccccc2c[n+]1[O-]
Product: Cc1cc2ccccc2c(=O)[nH]1
Yield: 27 %

Procedure:
3-Methyisoquinoline oxide (3.60 g, 22.6 mmol) and acetic anhydride (38 mL) are heated at reflux for 6 hr. After cooling the volatiles are removed and the residue is distilled at 220° C. under 0.5 mbar using a Kugelrohr distillation apparatus to afford 3-methyl-2H-isoquinolin-1-one (900 mg, 27% yield). LC/MS: MS m/e=160 (M+H); RT 2.45 min.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=O)[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10](=[S:40])[NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:5]=[CH:4][C:3]=1[NH:20][C@@H:21]1[CH2:26][C@@H:25]2[CH2:27][C@@H:23]([C:24]2([CH3:29])[CH3:28])[C@H:22]1[CH3:30]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NCc3ccncc3)c(=O)c1Br)C2(C)C
Solvent: Cc1ccccc1
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=S)NCc3ccncc3)c(=O)c1Br)C2(C)C
Temperature: 120 °C
Yield: 27.4 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (99 mg, 0.208 mmol) in toluene (1 mL) was mixed with Lawesson's reagent (168 mg, 0.416 mmol) and refluxed at 120° C. for 1 hour. After cooling, the reaction solution was evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol=50/1) to give the desired product (28 mg, 27% yield).
Reaction SMILES: [F:1][CH:2]([CH3:12])[CH2:3][O:4][C:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][N:6]=1.[CH3:13][O:14][C:15]([C:17]1[S:26][C:20]2[N:21]=[CH:22][N:23]=[C:24](Cl)[C:19]=2[C:18]=1[CH3:27])=[O:16].Cl.CN1CCC(=C2C3C(=CC=CC=3)C=CC3C2=CC=CC=3)CC1>O1CCOCC1>[CH3:13][O:14][C:15]([C:17]1[S:26][C:20]2[N:21]=[CH:22][N:23]=[C:24]([NH:11][C:10]3[C:5]([O:4][CH2:3][CH:2]([F:1])[CH3:12])=[N:6][CH:7]=[CH:8][CH:9]=3)[C:19]=2[C:18]=1[CH3:27])=[O:16]
Reactant: CC(F)COc1ncccc1N
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3cccnc3OCC(C)F)c2c1C

Procedure:
2-(2-Fluoropropoxy)pyridin-3-amine (153 mg) was dissolved in dioxane (30 ml), 4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (174.54 mg) and HCl in dioxane (4M; 25 μl) was added. The reactin was stirred at 60° C. for three days. The reaction was concentrated in vacuo.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([NH2:16])[CH2:14][CH3:15].C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:11]=[C:10]([NH:16][CH2:13][CH2:14][CH3:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: CCCN
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCNc1nc(Cl)nc2ccccc12
Temperature: 25 °C

Procedure:
2,4-Dichloroquinazoline (600 mg, 3.01 mmol) was dissolved in acetonitrile (10 mL). Propylamine (200 mg, 3.3 mmol) and triethylamine (2.1 mL, 15 mmol) were added. The mixture was stirred at room temperature over-night. Filtration and evaporation of the filtrate gave a yellow solid, which was dissolved in ethyl acetate and washed three times with water. Drying (magnesium sulphate), filtration and evaporation gave (2-chloro-quinazolin-4-yl)-propylamine as a yellow solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([C:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([C:18]([O:20][CH3:21])=[O:19])=[C:10](O)[N:9]=1)[CH3:7].C(=O)([O-])O.[Na+]>C(#N)C>[Cl:3][C:10]1[C:11]([C:18]([O:20][CH3:21])=[O:19])=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:8]([CH2:6][CH3:7])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nc(O)c(C(=O)OC)cc1C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCc1nc(Cl)c(C(=O)OC)cc1C(=O)OC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Phosphoryl trichloride (17.3 ml) was added to a solution of dimethyl 2-ethyl-6-hydroxypyridine-3,5-dicarboxylate (22.3 g) in acetonitrile (250 mL) at room temperature. The mixture was stirred at 90° C. under nitrogen atmosphere for 3 hours. The mixture was neutralized with aqueous saturated sodium hydrogen carbonate solution at 0° C. and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (24.0 g).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([O:18]CC1C=CC=CC=1)=[O:17])[CH2:10][CH2:9]2)(=[O:4])=[O:3]>CO.O.[Pd]>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([OH:18])=[O:17])[CH2:10][CH2:9]2)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)CCN2CC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc2c(c1)CCN2CC(=O)O
Yield: 82.8 %

Procedure:
A solution of benzyl 2-(5-(methylsulfonamido)indolin-1-yl)acetate (0.565 g, 1.568 mmol) in methanol was added to a suspension of 10% w/w Pd/C (a catalytic amount) in water and the mixture was hydrogenated in a Parr apparatus at 30 psi overnight. The catalyst was filtered off and the filtrate was evaporated to dryness affording 2-(5-(methylsulfonamido)indolin-1-yl)acetic acid (0.351 g, 1.299 mmol, 83% yield). MS/ESI+ 271.0 [MH]+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14](SC)=[C:15]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C(N)(C)C>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([NH:13][CH:5]([CH3:6])[CH3:4])=[C:15]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[C:16]#[N:17])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CSC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Solvent: CC(C)N
Product: CC(C)NC(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Yield: 124.1 %

Procedure:
3-(3,5-Bis(trifluoromethyl)phenylamino)-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.400 g, 0.8 mmol) was stirred in isopropylamine (2 ml) at 80° C. in a sealed flask for 20 h. Work up as described in Example 1, 2) gave 254 mg (62%) of the title compound as white crystals. Mp 197-198.5° C. 1H NMR (300 MHz, CDCl3): δ=1.5 (d, 6H), 3.37 (m, 1H), 7.42 (s, 2H), 7.48 (d, 2H), 7.67 (s, 1H), 7.79 (d, 2H); MA calc for C20H16ClF6N3O2S: C, 46.93%; H, 3.15%; N, 8.21%. Found: C, 47.16%; H, 3.14%; N, 8.10%.
Reaction SMILES: [NH2:1][CH:2]([CH3:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1>CN(C)C=O>[CH3:5][CH:2]([NH2:1])[CH2:3][O:4][C:9]1[N:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Clc1ncccn1
Reactant: CC(N)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(N)COc1ncccn1
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
2.0 g of 2-amino-1-propanol was added dropwise to a stirred mixture of 1.3 g of 60% sodium hydride and 30 mL of N,N-dimethylformamide at room temperature. After the reaction mixture was stirred for 30 minutes, a solution containing 3.7 g of 2-chloropyrimidine dissolved in N,N-dimethylformamide was added dropwise to the reaction mixture. The mixture was stirred for 2 hours at 100° C. After completion of the reaction, the reaction mixture was cooled. The solids were filtered off. The solvent in the filtrate was removed under reduced pressure. The residue was purified by column chromatography on silica gel to obtain 2.1 g of the desired product (yield: 50%). Refractive index: 1.5481.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])[NH:8]2)=[CH:4][C:3]=1[C:29]([OH:31])=O.Cl.[NH2:33][C:34]1([C:37]#[N:38])[CH2:36][CH2:35]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=3)[C:14]([F:16])([F:17])[F:15])=[O:28])[NH:8]2)=[CH:4][C:3]=1[C:29]([NH:33][C:34]1([C:37]#[N:38])[CH2:36][CH2:35]1)=[O:31]
Reactant: N#CC1(N)CC1
Reactant: O=C(NC(c1cccc(C(F)(F)F)c1)C(F)(F)F)c1cc2cc(C(=O)O)c(Cl)cc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: N#CC1(NC(=O)c2cc3cc(C(=O)NC(c4cccc(C(F)(F)F)c4)C(F)(F)F)[nH]c3cc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylic acid (2.74 g, 5.07 mmol, 86% pure) was dissolved in N,N-dimethylformamide (14 ml), and 1-aminocyclopropanecarbonitrile hydrochloride (0.78 g, 6.59 mmol), N-[(1H-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate (2.12 g, 5.07 mmol) and 4-methylmorpholine (1.54 g, 15.2 mmol) were added. The reaction mixture was stirred at room temperature for 16 h and then ethyl acetate was added. The organic phase was washed with hydrochloric acid (1 mol/l) and the aqueous phase was once again extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution and the portion which was insoluble in both phases was filtered off. The filtercake is triturated with boiling ethyl acetate (15 ml) and the precipitate is washed with warm ethyl acetate. This leaves 2.01 g (74% of theory) of 6-chloro-N5-(1-cyanocyclopropyl)-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide.
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][S:3](=[O:5])(=[O:4])[NH:2][CH3:1])=[CH:10][CH:9]=1
Reactant: CNS(=O)(=O)Cl
Reactant: Oc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNS(=O)(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
A solution of 18.1 g (0.14 mole) of N-methylsulfamoyl chloride (Preparation 24) in 20 ml methylene chloride was added at 10°-20° C. to a solution of 12.8 g (0.10 mole) of 4-chlorophenol and 15 g (0.15 mole) of triethylamine in 50 ml of methylene chloride. The cooling was removed and the mixture stirred at ambient temperature for four hours. The mixture was filtered to remove the triethylamine hydrochloride. The filtrate was extracted with dilute HCl (6 ml of 37% hydrochloric acid in 60 ml water) followed by a water wash. The organic layer was then extracted with dilute potassium carbonate (8.0 g in 80 ml water) followed by a water wash. The methylene chloride layer was concentrated to 21.7 g of yellow oil which crystallized on cooling. The solid was stirred in a mixture of 10 ml toluene and 63 ml petroleum ether to obtain 20.3 g of yellow solid. The 20.3 g was recrystallized from 1:2 toluene: petroleum ether to give 8.73 g of white solid, mp 61°-62° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([N:29]=[C:30]=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>CN(C)C=O>[CH2:23]([NH:29][C:30]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCN=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 84 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in N,N-dimethylformamide (3 ml), hexyl isocyanate (0.2 ml) was added, and the admixture was stirred at 60° C. for 15 hours. After the addition of water, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 63 mg of the title compound (yield: 84%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:14][O:13]C(C)(C)[O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(=O)(O)(O)O.[OH-].[Na+]>O>[CH2:1]([O:8][CH2:9][CH:10]([OH:11])[CH2:14][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(COCc2ccccc2)O1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCC(O)COCc1ccccc1
Temperature: 70 °C

Procedure:
To 222 g (1.0 mol) of 4-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolane was added 400 g of distilled water, and the whole was adjusted to pH 2 with phosphoric acid. With introduction of nitrogen thereinto, the solution was heated to 70° C. After 2 hours of reaction, the solution was adjusted to pH 7.0 with sodium hydroxide. Thereto was charged 1 L of chloroform and extraction was carried out. Then, the chloroform layer was dried over magnesium sulfate and concentrated. Thereafter, the concentrate was filtrated to remove salts, and thereby 3-benzyloxy-1,2-propanediol was obtained. The NMR data thereof are the same as those in Example 1-2.