Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14](Cl)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1>>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[C:14]([C:22]3[CH:23]=[CH:24][O:20][CH:21]=3)[N:13]=[CH:12][C:11]=2[C:10]([CH3:19])([CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccoc1
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(Cl)cc21
Product: CC(C)(C)OC(=O)N1CC(C)(C)c2cnc(-c3ccoc3)cc21

Procedure:
Prepared from 6-chloro-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester and furan-3-boronic acid using an analogous procedure to that of Preparation 161. MS: [M+H]+=315.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH2:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH2:17][CH:18]([CH3:20])[CH3:19]>C(#N)C>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][NH:6][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH3:2]
Reactant: CC(C)CCBr
Reactant: CCOC(CN)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(CNCCC(C)C)OCC
Temperature: 65 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution of 2,2-diethoxyethanamine 2.91 ml (20 mmol) in acetonitrile 50 ml, potassium carbonate 2.0 g (15 mmol) and a solution of isoamylbromide 1.26 ml (10 mmol) in acetonitrile 20 ml were added and the mixture was stirred at 65° C. overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate 100 ml and washed with water 100 ml and brine 100 ml. The organic phase was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on Büch silica gel column chromatography (n-hexane:ethyl acetate=90:10 to 80:20) to obtain the title compound 1.57 g (77%).
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH:3]([F:5])[F:4].C1C(=O)N([Br:22])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:14])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][Br:22])[CH:3]([F:4])[F:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1OC(F)(F)C(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)C(F)(F)Oc1ccccc1CBr

Procedure:
To a stirred solution of 2-(1,1,2,2-tetrafluoroethoxy)toluene (2.5 g, 12.2 mmol) in CCl4 (75 mL) was added NBS (2.1 g, 13 mmol) and AIBN (0.65 g, 3 mmol). The mixture was refluxed for 6 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (75 mL) and water (50 mL). The organic phase was separated, dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using hexanes as eluant to give 2-(1,1,2,2-tetrafluoroethoxy)benzyl bromide as a colorless liquid (TLC Rf =0.7 (hexanes)).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=3)[C:6](=[C:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:5]=2[CH:4]=1.[OH:26][C@@H:27]1[CH2:32][CH2:31][C@H:30]([CH2:33][C:34](O)=O)[CH2:29][CH2:28]1.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O>C(Cl)Cl>[OH:26][C@@H:27]1[CH2:32][CH2:31][C@H:30]([CH2:33][CH2:34][N:21]2[CH2:20][CH2:19][C:18](=[C:6]3[C:5]4[CH:4]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:16]=[CH:15][C:14]=4[S:13][C:12]4[C:7]3=[CH:8][CH:9]=[C:10]([F:17])[CH:11]=4)[CH2:23][CH2:22]2)[CH2:29][CH2:28]1
Reactant: O=C(O)C[C@H]1CC[C@@H](O)CC1
Reactant: Fc1ccc2c(c1)Sc1ccc(C(F)(F)F)cc1C2=C1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: ClCCl
Product: O[C@H]1CC[C@@H](CCN2CCC(=C3c4ccc(F)cc4Sc4ccc(C(F)(F)F)cc43)CC2)CC1
Reaction time: 8 h

Procedure:
7.3 Grams of 4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine were dissolved in 50 milliliters of dry methylene chloride. Then 3.8 grams of cis-4-hydroxycyclohexane acetic cid (J.Am.Ch.Soc. 70, pg. 1898-99 (1948)) and 5 grams of dicyclohexylcarbodiimide were added. The mixture was heated at temperatures from 22 to 30 degrees Centigrade during which the dicyclohexylurea formed separated out and was then left standing overnight. The precipitate was filtered from the solution which was then evaporated, and the residue was dissolved in ether. The solution was washed with dilute hydrochloric acid, dried over anhydrous potassium carbonate, filtered and evaporated. The residue, which was an oil, wad dried by evaporation in vacuum with toluene and consisted of somewhat impure 1-(cis-4-hydroxycyclohexylmethylcarbonyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine which was used without further purification in the next step. The oil was dissolved in dry ether, and 2 grams of lithium aluminum hydride were added in small portions. The mixture was heated under reflux for one hour. Then water was added dropwise until the precipitate formed clotted. The ether phase was decanted, the precipitate washed thoroughly with ether, the combined ether phases were dried over anhydrous potassium carbonate and treated with active carbon and filtered. The ether was evaporated, and 1-(cis-4-hydroxycyclohexylethyl)-4-(2-trifluoromethyl-6-fluoro-9-thioxanthenylidene)piperidine was obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:4][CH:3]=1.[CH2:17]([O:19]P(CC(OCC)=O)(OCC)=O)[CH3:18]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:19])[CH:18]=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(C=NNc1ccc(Cl)cc1)C(F)(F)F
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Solvent: CCN(CC)CC
Product: O=c1cc(C(F)(F)F)cnn1-c1ccc(Cl)cc1
Reaction time: 24 h
Yield: 52.9 %

Procedure:
First, 2 g of 3,3,3-trifluoro-2-oxo-1-propanal 1-(4-chlorophenylhydrazone) and 2 g of ethyl diethylphosphonoacetate were mixed with 20 ml of triethylamine, and the reaction was allowed to proceed at 50° C. for 24 hours. The solvent was distilled out under reduced pressure, and the residue was subjected to column chromatography, which afforded 1.16 g of 2-(4-chlorophenyl)-5-trifluoromethylpyridazin-3-one (compound 1-332).
Reaction SMILES: [CH3:1][N:2]([CH3:59])[CH2:3][CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][N:41]4[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]4)=[CH:35][C:34]=3[O:54][CH3:55])=[CH:29][CH:28]=2)=[O:26])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:56]([O-:58])=[O:57])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCOCC1.Cl>[CH3:59][N:2]([CH3:1])[CH2:3][CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][N:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)=[CH:35][C:34]=3[O:54][CH3:55])=[CH:29][CH:28]=2)=[O:26])(=[O:22])=[O:23])=[CH:17][C:16]=1[N+:56]([O-:58])=[O:57])[CH2:6][S:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1cc(CCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@H](CCN(C)C)CSc3ccccc3)c([N+](=O)[O-])c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(CCN2CCNCC2)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@H](CCN(C)C)CSc3ccccc3)c([N+](=O)[O-])c2)cc1

Procedure:
A solution of Example 491F (284 mg, 0.34 mmol) in 1,4-dioxane (1.5 mL) and 4M HCl (1.5 mL) at room temperature was stirred for 16 hours. The solution was purified by flash column chromatography on silica gel with 80:20:0.5 dichloromethane/methanol/concentrated ammonium hydroxide to provide the desired product. MS (ESI) m/e 745, 747 (M−H)−, (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ2.11 (m, 2H), 2.62 (s, 6H), 2.67 (m, 4H), 2.77 (m, 2H), 3.00 (m, 2H), 3.06 (m, 4H), 3.16 (d, 2H), 3.33 (t, 2H), 3.75 (s, 3H), 4.09 (m, 1H), 6.88 (d, 1H), 6.95 (d, 1H), 6.98 (s, 1H), 7.15-7.22 (m, 2H), 7.24-7.33 (m, 4H), 7.38 (d, 2H), 7.82 (dd, 1H), 7.88 (d, 2H), 8.17 (d, 1H), 8.47 (d, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[CH3:30].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:33])[CH:27]=[CH:28][C:29]=1[CH3:30]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(N=C=O)cc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1Cl
Temperature: 40 °C
Yield: 86.6 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol), 3-chloro-4-methylphenyl isocyanate (0.26 g, 1.6 mmol), and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at the same temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed, eluting with 95:5 methylene chloride-methanol, to provide 0.63 g of the product in 90% yield: mp 238-240° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H), 2.22 (s, 3H), 2.49-2.65 (m, 2H), 2.84-2.97 (m, 1H), 4.70 (d, J=6.0 Hz, 2H), 5.17 (dd, J=12.5 Hz, d=5.3 Hz, 1H), 6.81 (t, J=6.0 Hz, 1H), 7.10 (dd, J=8.3 Hz, J=2.0 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 7.65 (d, J=2.0 Hz, 1H), 7.75-7.85 (m, 3H), 8.90 (s, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 18.7, 22.0, 30.9, 38.7, 48.9, 116.4, 117.6, 121.9, 127.2, 127.5, 131.0, 131.6, 133.0, 133.7, 134.7, 139.5, 140.1, 155.1, 167.0, 167.6, 169.8, 172.8; Anal. calcd. for C22H19ClN4O5.0.25H2O: C, 57.52; H, 4.27; N, 12.19. Found: C, 57.80; H, 4.33; N, 11.83.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([O:9][CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH:4][N:3]=1.CC(C)([O-])C.[K+].[N:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1[NH:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([OH:41])[CH:39]=2)[N:34]=[CH:33][N:32]=1.[Cl-].[NH4+]>CN(C)C(=O)C>[Cl:8][C:7]1[C:2]([O:41][C:38]2[CH:39]=[C:40]3[C:35](=[CH:36][CH:37]=2)[N:34]=[CH:33][N:32]=[C:31]3[NH:30][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][N:24]=2)=[N:3][CH:4]=[C:5]([O:9][CH2:10][CH:11]([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH:6]=1
Reactant: CCOC(COc1cnc(Cl)c(Cl)c1)OCC
Reactant: Oc1ccc2ncnc(Nc3cnccn3)c2c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(COc1cnc(Oc2ccc3ncnc(Nc4cnccn4)c3c2)c(Cl)c1)OCC
Temperature: 200 °C
Reaction time: 24 h
Yield: 9.9 %

Procedure:
2,3-Dichloro-5-(2,2-diethoxyethoxy)pyridine (810 mg, 2.9 mmol) and potassium tert-butoxide (350 mg, 3.1 mmol) were added to an N,N-dimethylacetamide suspension (3 ml) of 4-(pyrazin-2-ylamino)quinazolin-6-ol (300 mg, 1.25 mmol), and stirred for 24 hours in a sealed tube at 200° C. The reaction solution was cooled to room temperature, aqueous saturated ammonium chloride solution was added, filtered, and washed with a mixed solution of chloroform/methanol (9:1). The obtained filtrate was extracted with chloroform, the organic layer was washed with water and saturated saline water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by reversed-phase liquid chromatography (YMC CombiPrep Pro C18 AS-360-cc) to obtain 6-{[3-chloro-5-(2,2-diethoxyethoxy)pyridin-2-yl]oxy}-N-pyrazin-2-ylquinazoline-4-amine (60 mg, yield: 10%) as a pale yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH3:23]O>>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([O:13][CH3:23])=[O:12])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccccc1-c1ccc(CO)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccccc1-c1ccc(CO)cc1
Yield: 89 %

Procedure:
4.0 g (17.5 mmol) of 2-(4'-hydroxymethylphenyl)benzoic acid was dissolved in methanol (50 ml). Sulfuric acid (1 ml) was added thereto, followed by heating under reflux for 8 hours. After conducting vacuum concentration, water was added thereto, followed by the extraction with chloroform. After the organic phase was washed with water and dried, it was subjected to vacuum concentration. The residue was purified by silica gel column chromatography (a n-hexane/ethyl acetate system) to give 3.8 g of the title compound as an oil (yield 89%).
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[C:19]([C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32])(=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[C:19]([C:29]1[CH:30]=[C:31]([NH:32][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:33]=[CH:34][CH:35]=1)(=[O:28])[CH:20]=[CH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(C(=O)C=Cc2ccccc2)c1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(C=Cc1ccccc1)c1cccc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (8.8 g) is added, at a temperature between 60° and 75° C., to a solution of 3-cinnamoylaniline (6.57 g) and triethylamine (5.95 g) in dioxane (165 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 10 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and 30 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. The residue is dissolved in methylene chloride (500 cc). The solution obtained is washed 4 times with distilled water (650 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (13.5 g) is thereby obtained, which is dissolved in boiling acetonitrile (300 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 16 hours. The crystals formed are separated by filtration, washed 3 times with acetonitrile (60 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(3- cinnamoylphenyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole -7-carboxamide (7.1 g) in the form of beige-coloured crystals, m.p. 190° C., is thereby obtained.
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][CH2:8][C:9]([OH:11])=O)[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.Cl.[NH:19]1[CH2:30][CH2:29][CH2:28][C@H:20]1[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]>C(Cl)(Cl)Cl.C(Cl)(=O)C(C)(C)C.C(N(CC)CC)C>[C:4]1(=[O:12])[N:5]([CH2:6][CH2:7][CH2:8][C:9]([N:19]2[CH2:30][CH2:29][CH2:28][C@H:20]2[C:21]([N:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)=[O:22])=[O:11])[C:1](=[O:17])[C:2]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:3]12
Reactant: O=C([C@@H]1CCCN1)N1CCCC1
Reactant: O=C(O)CCCN1C(=O)c2ccccc2C1=O
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C([C@@H]1CCCN1C(=O)CCCN1C(=O)c2ccccc2C1=O)N1CCCC1
Yield: 57.2 %

Procedure:
To a solution prepared by dissolving 1,17 g (5,0 mM) 4-phtalimido-butyric acid and 0,56 g (5,5 mM) triethylamin in 20 ml chloroform 0,61 g (5,0 mm) pivaloylchlorid were dropped at −15° C. under stirring. The reaction mixture was stirred for 1 hour at the above temperature and then a solution prepared by dissolving 1,03 g (5,0 mM) L-prolyl-pyrrolidin-hydrochloric acid salt in a mixture of 5 ml chloroform and 1,5 ml (1,1 g, 11,0 mM) triethylamine were dropwise added to it. Reaction mixture was stirred at room temperature for 4 hours, then it was washed successively with water, 30% cc. citric acid solution, saturated aqueous sodium bicarbonate solution, water and with saturated sodium chloride solution. The organic phase was dried on calcinated magnesium sulfate and it was evaporated. Crystallisation of the residue from a mixture of 5 ml chloroform and 10 ml petrolether yielded 1,1 g (53%) N-(4-phtalimido-butanoyl)-L-prolyl-pyrrolidin which melted at 148-149° C. The compounds of the general formula I were synthetised by the method as explained above starting from the corresponding compounds having general Formulas (II) and (III).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17].CO>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([C:12]([F:11])([F:22])[F:23])[CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1cccc([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a solution of 3-nitroaniline (13.8 g, 99.9 mmol) in pyridine (200 mL) were added 3-(trifluoromethyl)benzoyl chloride (21.4 g, 103 mmol) and N,N-dimethylpyridine-4-amine (69.1 mg, 566 μmol), and the mixture was stirred at room temperature for 1.5 hr. Methanol (50 mL) was added to the reaction solution to stop the reaction, and the solvent was evaporated under reduced pressure. The residue was suspended in ethyl acetate (300 mL), washed with water (200 mL×2), 0.1N hydrochloric acid (200 mL×2), saturated aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (31.0 g, 100%) as a colorless solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=2)[CH:3]=[N:2]1.[F:20][C:21]([F:36])([F:35])[C:22]([C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)([OH:27])[C:23]([F:26])([F:25])[F:24].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:16]([C:17]([NH:34][C:31]4[CH:30]=[CH:29][C:28]([C:22]([OH:27])([C:21]([F:20])([F:35])[F:36])[C:23]([F:24])([F:25])[F:26])=[CH:33][CH:32]=4)=[O:19])=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=C(O)c1cccnc1Nc1ccc2cn[nH]c2c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1)c1cccnc1Nc1ccc2cn[nH]c2c1

Procedure:
2-(1H-Indazol-6-ylamino)pyridine-3-carboxylic acid (500 mg, Step A) was reacted with 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenylamine (340 mg) and EDC (500 mg) and HOBt (270 mg) in DMF at RT overnight. The reaction was diluted with CH2Cl2 and washed with H2O followed by brine. The organic layer was dried with Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography to give the title compound. MS (ES+): 496(M+H)+; (ES−): 394(M−H). Calc'd. for C22H15F6N5O2−495.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2C)[N:5]=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[CH:3]=1.ClC1C=C(Cl)N=C(N2CCOCC2)N=1>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)[N:5]=[C:4]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])=[CH:19][CH:20]=2)[CH:3]=1
Reactant: CCNC(=O)Nc1ccc(-c2cc(Cl)nc(N3CCOC[C@@H]3C)n2)cc1
Agent: Clc1cc(Cl)nc(N2CCOCC2)n1
Product: CCNC(=O)Nc1ccc(-c2cc(Cl)nc(N3CCOCC3)n2)cc1

Procedure:
Method as described for Intermediate 2 using 4-(4,6-dichloropyrimidin-2-yl)morpholine.
Reaction SMILES: [C:1]1([C:7](=[O:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO>[C:1]1([C@@H:7]([OH:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CCO)c1ccccc1
Solvent: CO
Product: OCC[C@H](O)c1ccccc1
Temperature: 30 °C
Reaction time: 20 h
Yield: 74.7 %

Procedure:
In a 500 ml stainless steel-made autoclave were charged 65 g (400 mmole) of 3-phenyl-3-oxopropanol and 550 mg (0.4 mmole) of [RuI(p-cymene)((R)-BINAP)]I3 synthesized in Example 1 in a nitrogen atmosphere, and 300 ml of methanol was added thereto, followed by stirring the mixture at 30° C. for 20 hours under a hydrogen pressure of 30 atm. The reaction mixture was concentrated and subjected to silica gel column chromatography (eluent: hexane/isopropanol=9/1 by volume) to eliminate the complex. The obtained hydrogenation product was dissolved in a 6-fold amount of diisopropyl ether by heating and allowed to stand at 0° C. for 24 hours. The resulting precipitate was collected by filtration and dried (room temperature, 1 mmHg), and 45.5 g of (1S)-phenyl-1,3-propanediol was obtained as a colorless crystal (percent yield: 70.0%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH2:18])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])=[CH:4][CH:3]=1.C([NH:29][CH2:30][C:31](O)=[O:32])(OCC1C=CC=CC=1)=O.C1(N=C=NC2CCCCC2)CCCCC1.Cl>C(Cl)(Cl)Cl.CO.[Pd]>[NH2:29][CH2:30][C:31]([NH:18][C:9]([C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)([CH3:10])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:32]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(N)(Cc1ccc(F)cc1)c1ccc(F)cc1
Agent: [Pd]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc(F)cc1)(NC(=O)CN)c1ccc(F)cc1
Yield: 29.8 %

Procedure:
To a stirred solution of 1,2-bis(4-fluorophenyl)-2-propylamine (12.0 g, 0.049 mol) in chloroform (200 ml) under nitrogen was added N-CBZ-glycine (10.16 g, 0.049 mol) and then a solution of dicyclohexylcarbodiimide (11.35 g, 0.055 mol) in chloroform (100 ml) and the mixture stirred for 30 minutes, then filtered and the solvent evaporated. The residue was treated with ethyl acetate (200 ml), filtered, an additional 200 ml of ethyl acetate added, and then washed with cold 1% HCl (200 ml), brine (200 ml), dried, and the solvent evaporated to give a pale yellow oil. This was dissolved in methanol (400 ml) and 10% HCl (35 ml) and hydrogenated at 40 psi in a Parr apparatus over 2.5 g of 5% Pd/C catalyst for 2.5 hours. The catalyst was removed by filtration, solvent evaporated and the residue dissolved in water (300 ml) and chloroform (500 ml), basified to pH 11 with 50% NaOH, shaken and separated. The aqueous phase was extracted with chloroform (2×200 ml) and the combined organic phases washed with water (2×150 ml), brine (150 ml), dried and evaporated to a pale yellow oil which solidified on standing. The solid was recrystallised three times from cyclohexane (150 ml) and ethanol (10 ml) and vacuum dried to give 4.44 g of 2-amino-N-[1,2bis(4-fluorophenyl)-1-methylethyl]acetamide, mp 130°-131° C.