Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([Cl:12])[N:6]=1)=[O:4].Cl.[F:14][C:15]1([F:20])[CH2:19][CH2:18][NH:17][CH2:16]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:17]2[CH2:18][CH2:19][C:15]([F:20])([F:14])[CH2:16]2)=[C:7]([Cl:12])[N:6]=1)=[O:4]
Reactant: FC1(F)CCNC1
Reactant: COC(=O)c1ccc(Br)c(Cl)n1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CCC(F)(F)C2)c(Cl)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
Under nitrogen atmosphere, a suspension of 5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (Example 9 c, 1.5 g, 6 mmol), 3,3-difluoropyrrolidine hydrochloride (CAN 163457-23-6, 0.64 g, 6 mmol), tris(dibenzylideneacetone)dipalladium (CAN 51364-51-3, 120 mg, 0.12 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (CAN 76189-55-4, 150 mg, 0.24 mmol) and cesium carbonate (3.9 g, 12 mmol) in toluene (30 mL) was stirred at 110° C. overnight. After concentration, the residue was partitioned between water (30 mL) and ethyl acetate (30 mL). The aqueous phase was extracted with ethyl acetate (2×30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography (silica gel, 15 g, 10% ethyl acetate in petroleum ether) to give the target compound (0.5 g, 30%) as light-yellow solid; MS (EI): m/e=277.0 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[C:16]1([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][N:31]([C:8]([NH:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:15])[CH2:30][CH2:29]3)[CH:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2ccnc(N3CCNCC3)c2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCN(c2cc(-c3ccccc3)ccn2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (113 mg, 0.418 mmol), 1-(4-phenylpyridin-2-yl)piperazine (100 mg, 0.418 mmol), diisopropylethylamine (0.146 ml, 0.836 mmol) and dimethylsulfoxide (2 ml) was stirred at 70° C. for 12 hours, then the reaction solution was poured into water, and extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled away under reduce pressure, and the residue was purified by basic silica gel column chromatography (ethyl acetate) to give the titled compound as solid product. This was recrystallized from a mixed solvent of hexane and ethyl acetate to give the titled compound 67.2 mg (44.8%) as solid product.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:11]([NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])([CH3:10])([CH3:9])[CH3:8].[C:25]1(=[O:29])[O:28][CH2:27][CH2:26]1.C(OCC)(=O)C>C1COCC1.O>[C:7]([C:11]([NH:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:27][CH2:26][C:25]([OH:29])=[O:28])[C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C1CCO1
Reactant: COC(=O)c1c(O)cccc1NC(=O)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(NC(=O)C(C)(C)C)cccc1OCCC(=O)O
Reaction time: 8 h
Yield: 67.2 %

Procedure:
Potassium tert-butoxide (1.81 g) was added to a solution of methyl 2-tert-butylcarbonylamino-6-hydroxybenzoate (Intermediate 79, 4.06 g) in THF (30 mL) and the mixture was heated at 60° C. β-propiolactone (1.16 g) was added dropwise and the resultant mixture was heated at 60° C. for 25 minutes, then left to stand at room temperature overnight. Ethyl acetate and water were added and the layers were separated. The aqueous phase was extracted with more ethyl acetate and acidified to pH 2 using 1M hydrochloric acid. This was extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane, with a gradient of 50-100% to give methyl 2-tert-butylcarbonylamino-6-(2-carboxyethoxy)-benzoate (3.5 g) as a white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH2:33][CH2:34][CH3:35])=[C:7]([CH:27]=[CH:28][C:29]=1[C:30](=[O:32])[CH3:31])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:15][C:14]=1[Br:26])(=[O:3])[CH3:2].Cl>O1CCOCC1>[C:1]([O:4][C:5]1[C:6]([CH2:33][CH2:34][CH3:35])=[C:7]([CH:27]=[CH:28][C:29]=1[C:30](=[O:32])[CH3:31])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:25]=[CH:24][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[Br:26])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)OC(C)(C)C)cc2Br)ccc(C(C)=O)c1OC(C)=O
Agent: Cl
Solvent: C1COCCO1
Product: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Br)ccc(C(C)=O)c1OC(C)=O
Temperature: 20 °C
Yield: 26 %

Procedure:
In 10 ml of dioxane was dissolved 1.5 g of tert-butyl 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]-3-bromobenzoate. To the solution was added under stirring at 20° C., 10 ml of a dioxane solution (2 N) of hydrogen chloride which was previously ice-cooled. The mixture was further stirred for 30 minutes at room temperature, and then to the mixture was added 10 ml of the dioxane solution of hydrogen chloride. The mixture was stirred for 1.5 hours, and concentrated urder reduced pressure. The resultant was dissolved in 30 ml of chloroform, and the solution was washed with 30 ml of water and then dried over with magnesium sulfate. Chloroform was removed by evaporation under reduced pressure, and the resultant was dissolved in isopropyl ether. The solution was subjected to a treatment using activated charcoal, and to the solution was added hexane for crystallization. The crystals were collected by filtration, subjected to purification by silica gel column chromatography, and then recrystallized from aqueous ethanol to give 0.35 g of 4-[3-(3-acetoxy-4-acetyl 2-propylphenoxy)propoxy]-3-bromobenzoic acid as colorless crystals. m.p. 154°-156° C.
Reaction SMILES: Cl.[NH2:2]O.[F:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:17])[C:12]([NH:14][C:15]#[N:16])=[O:13])[CH:8]=[CH:7][C:6]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>N1C=CC=CC=1.C(O)C>[NH2:16][C:15]1[N:14]=[C:12]([CH:11]([C:9]2[CH:8]=[CH:7][C:6]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:5]([F:4])[CH:10]=2)[CH3:17])[O:13][N:2]=1
Reactant: NO
Reactant: CC(C(=O)NC#N)c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(N)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A mixture of 2-(2-fluoro-4-biphenylyl)propionic acid (5.00 g, 20.5 mmol) and thionyl chloride (10 ml) in benzene (50 ml) was stirred under reflux for 4 hr and the solution was evaporated under reduced pressure to afford the acid chloride. After the acid chloride was dissolved in acetone (15 ml), the solution was added to cyanamide (1.44 g, 30.8 mmol) in 2N-NaOH (16 ml) by portions at 0°-5° C. The mixture was controlled above pH 10 by 2N-NaOH during addition. After the addition, the mixture was stirred at room temperature for 15 hr, then diluted with water, acidified with 1N-HCl to pH 6 and extracted with ether. The water phase was acidified with 1N-HCl to pH 3 and then extracted with chloroform. The chloroform extracts were washed with saturated NaCl aq., dried with magnesium sulfate, then evaporated under reduced pressure to a residue, which was chlomatographed to afford N-(2-(2-fluoro-4-biphenylyl)propionyl)cyanamide. To hydroxylamine hydrochloride (2.20 g, 30.4 mmol) in pyridine (5 ml) was added N-(2-(2-fluoro-4-biphenylyl)propionyl)cyanamide in ethanol (15 ml) by portion under cooling for 15 minute and the mixture was stirred at room temperature for 1 hr, then standed at room temperature overnight. To the reaction mixture was added 2N-NaOH (40 ml) to afford the precipitates. The precipitates were collected, washed with water, dried and recrystallized with ethyl acetate to afford 3-amino-5-(1-(2-fluoro-4-biphenylyl)ethyl)-1,2,4-oxadiazole (3.00 g, 52% yield): mp 174.5°-175.0° C.
Reaction SMILES: [F:1][C:2]1[C:7](OS(C(F)(F)F)(=O)=O)=[CH:6][CH:5]=[C:4]([F:16])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=1.[CH3:27][Zn]C>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:1][C:2]1[C:7]([CH3:27])=[CH:6][CH:5]=[C:4]([F:16])[C:3]=1[C:17]1[N:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1cccc(-c2c(F)ccc(OS(=O)(=O)C(F)(F)F)c2F)n1
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2c(F)ccc(C)c2F)n1
Temperature: 80 °C

Procedure:
To a solution of methyl 6-(2,6-difluoro-3-(trifluoromethylsulfonyloxy)-phenyl)picolinate (1.0 equiv.) in toluene was added Pd(dppf)Cl2-DCM (0.1 equiv.) followed by dimethyl zinc (3.0 equiv.). The solution turned from orange to bright yellow. The reaction was heated to 80° C. for 2 hours at which time, LC/MS analysis indicated complete conversion to product. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with brine. The organic layer was dried with magnesium sulfate, filtered, and concentrated in vacuo to provide methyl 6-(2,6-difluoro-3-methylphenyl)picolinate as a brown oil in quantitative yield. LC/MS=264.0 (M+H), Rt=0.90 min.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][CH2:8][NH:9][C:10]1[N:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]([NH2:14])=O)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.O=P(Cl)(Cl)Cl.[OH-].[Na+]>C(#N)C.CCOC(C)=O>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][CH2:8][NH:9][C:10]1[N:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[C:12]#[N:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCNc1nc(Cl)ccc1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCNc1nc(Cl)ccc1C#N
Temperature: 60 °C
Yield: 73.5 %

Procedure:
To a solution of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethylamino]-6-chloro-nicotinamide (3, 300 mg, 0.96 mmol) in acetonitrile (anhydrous, 50 mL) were added pyridine (0.62 mL, 7.65 mmol) and POCl3 (0.35 mL, 382 mmol). The reaction was heated at 60° C. for 1 hour. After cooling to room temperature, NaOH solution (10% aq.) was slowly added till pH 9. EtOAc (200 mL) was added and the layers separated. The aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification was accomplished by silica gel chromatography, eluting with 1%-20% EtOAc/hexanes gradient, to afford 220 mg (78% yield) of the titled product.
Reaction SMILES: C[O-].[Na+].C([CH:6](CC)[C:7]([NH:9][CH:10]([C:14]([O-])=O)[C:11]([O-:13])=[O:12])=[O:8])C.Cl.ClC[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[OH-].[Na+]>CO.O>[C:7]([NH:9][CH:10]([C:11]([OH:13])=[O:12])[CH2:14][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)(=[O:8])[CH3:6]
Reactant: ClCc1ccccn1
Reactant: CCC(CC)C(=O)NC(C(=O)[O-])C(=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)NC(Cc1ccccn1)C(=O)O
Temperature: 45 °C
Yield: 55.1 %

Procedure:
A solution of sodium methoxide (65.8 g, 1.22 mol) in methanol (300 ml) was treated portionwise with diethylacetamidomalonate (132.3 g, 0.61 mol) maintaining a temperature of ca. 45° C. The mixture was then heated under reflux for 15 min. The mixture was cooled to 50° C. then treated slowly with a suspension of 2-chloromethylpyridine hydrochloride (100 g, 0.61 mol), the pink suspension was then heated under reflux for a further 6 h. Water (500 ml) was added followed by 10M sodium hydroxide (122 ml, 1.22 mol) and the pH was maintained at ca. 11 while heating the mixture at 70° C. overnight. The mixture was cooled to RT and the methanol removed in vacuo. The aqueous residue was washed with ethyl acetate (2×500 ml), then acidified to pH 5 and further washed with ethyl acetate (2×500 ml), before evaporating in vacuo to provide a semi-solid. The residue was triturated with hot ethanol (500 ml) and the sodium chloride removed by filtration. The filtrate was then evaporated in vacuo and the residue crystallised from methanol-ethyl acetate to provide the title compound (70 g, 66%) as a yellow solid.
Reaction SMILES: [I:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:18]([CH3:20])[CH3:19].O>CN(C=O)C>[I:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[N:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: CC(C)I
Reactant: Ic1c[nH]c2ccncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(I)c2cnccc21
Reaction time: 6 h
Yield: 105.9 %

Procedure:
To a suspension of 3-iodo-1H-pyrrolo[3,2-c]pyridine (Preparation 47, 82 g, 340 mmol) and cesium carbonate (164 g, 504 mmol) in DMF (650 mL) was added 2-iodopropane (30.7 mL, 307 mmol) dropwise over 25 minutes at room temperature and the reaction was stirred for 6 hours. The reaction was poured into water (500 mL), stirred for 10 minutes and extracted into EtOAc (4×350 mL). The organic layers were combined, washed with brine, passed through a phase separation cartridge and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with DCM followed by 50% EtOAc in DCM to afford the title compound as a pale brown gum (93 g, 61%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)ccc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) (182 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous light brown substance (316 mg).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][O:21][CH2:22][NH:23][C:24]([C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([CH:33]([C:44]2[CH:49]=[C:48]([F:50])[CH:47]=[CH:46][C:45]=2[F:51])[S:34]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])=[CH:28][N:27]=1)=[O:25])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[F:51][C:45]1[CH:46]=[CH:47][C:48]([F:50])=[CH:49][C:44]=1[CH:33]([S:34]([C:37]1[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=1)(=[O:36])=[O:35])[C:29]1[C:30]([CH3:32])=[CH:31][C:26]([C:24]([NH:23][CH2:22][O:21][CH2:20][CH2:19][OH:18])=[O:25])=[N:27][CH:28]=1
Reactant: Cc1cc(C(=O)NCOCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cc(C(=O)NCOCCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 93.4 %

Procedure:
To a solution of N-[[2-(tert-butyldiphenylsilyloxy)ethoxy]methyl]-5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxamide (56 mg, 0.076 mmol) and acetic acid (5 μl, 0.091 mmol) in tetrahydrofuran (5 ml), tetrabutylammonium fluoride (1 M tetrahydrofuran solution) (91 μl, 0.091 mmol) was added, and the mixture was stirred for 6 hours at room temperature. Acetic acid (5 μl, 0.091 mmol) and tetrabutylammonium fluoride (1 M tetrahydrofuran solution) (91 μl, 0.091 mmol) were further added to the reaction solution, and the mixture was stirred for 16 hours at room temperature. Acetic acid (5 μl, 0.091 mmol) and tetrabutylammonium fluoride (1 M tetrahydrofuran solution) (91 μl, 0.091 mmol) were further added to the reaction solution, and the mixture was stirred for 5 hours at room temperature. Saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, subsequently dried over anhydrous sodium sulfate, and filtered, and then the filtrate was concentrated under reduced pressure. The resulting concentration residue was subjected to flash silica gel column chromatography, and the fraction obtained from an elution with 70% ethyl acetate/hexane was concentrated under reduced pressure. Ether was added to the resulting concentration residue to precipitate a solid, and ether was distilled off to obtain the title compound (35 mg, 0.071 mmol, 93%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:30])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:19]=3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.Cl.FC1C=C([CH:59]([C:63]([NH:65][C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)=[O:64])[C:60](N)=[O:61])C=CC=1OC1C2=C(C)C(OCCN3CCOCC3)=CN2N=CN=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:30][C:60](=[O:61])[CH2:59][C:63]([NH:65][C:66]2[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=2)=[O:64])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[CH:19]=3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Oc2ncnn3cc(-c4ccnc(N5CCOCC5)c4)cc23)c(F)c1
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(C(C(N)=O)C(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)Nc1ccc(Oc2ncnn3cc(-c4ccnc(N5CCOCC5)c4)cc23)c(F)c1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
To a solution of 3-fluoro-4-(6-(2-morpholinopyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (15 mg, 0.037 mmol) and 3-(4-fluorophenylamino)-3-oxopropanoic acid (8 mg, 0.04 mmol, Compound A of Example 25) in DMF (1 mL) were added DIEA (0.1 mL, 0.57 mmol) and TBTU (13 mg, 0.04 mmol). The reaction mixture was stirred at room temperature overnight and then purified using preparative HPLC. The fraction containing the desired product was collected and concentrated in vacuo. The residue was neutralized with 1 N NH4OH and concentrated again. The solid that formed was filtered, washed with 1 N NH4OH, dissolved in MeOH/H2O, and lyophilized to give the title compound (8 mg, 37%). 1H NMR (DMSO-d6) δ 10.49 (s, 1H), 10.23 (s, 1H), 8.63 (s, 1H), 8.55 (s, 1H), 8.06 (s, 1H), 8.00 (d, 1H, J=7.5 Hz), 7.70 (m, 1H), 7.50 (m, 2H), 7.30–7.45 (m, 3H), 7.04–7.17 (m, 3H), 6.85–6.92 (m, 2H), 3.36 (s, 4H), 3.44 (s, 6H); MS(ESI) m/z 586.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][C:18]([CH:22]=[O:23])=[N:19]2)=[CH:14][C:13]=1[Br:24])([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[OH:25]O>C(O)=O>[Br:24][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[C:9]([P:4]([O:5][CH2:6][CH3:7])([O:3][CH2:1][CH3:2])=[O:8])([F:10])[F:11])[N:19]=[C:18]([C:22]([OH:25])=[O:23])[CH:17]=[CH:16]2
Reactant: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C=O)ccc2cc1Br
Reactant: OO
Solvent: O=CO
Product: CCOP(=O)(OCC)C(F)(F)c1cc2nc(C(=O)O)ccc2cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
As described in the literature (Synthesis, 1993, 295), to the product of step 4 (105 mg, 0.25 mmol) in 1 ml formic acid was added 30% hydrogen peroxide (0.13 mL, 1 mmol) dropwise and the mixture was stirred overnight at rt. The solvent was evaporated and absolute ethanol was added. This was repeated 3 times and after evaporation of the remaining ethanol yielded the title product as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1.Cl>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][O:1][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH2:4][CH2:5][CH2:6][C:7]4=[O:12])[CH2:22][CH2:21]2)=[CH:28][CH:27]=1
Reactant: O=C1CCCc2c(O)cccc21
Reactant: COc1ccc(N2CCN(CCCCl)CC2)cc1
Agent: Cl
Product: COc1ccc(N2CCN(CCCOc3cccc4c3CCCC4=O)CC2)cc1
Yield: 84.5 %

Procedure:
from 5-hydroxy-1-oxotetraline and 1-(3-chloropropyl)-4-(4-methoxyphenyl)-piperazine; yield 84.5% of theory; m.p. of the hydrochloride (recrystallized from ethanol) 191°-192°C;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:21])=[C:11]([C:13]3[C:14](=[O:20])[CH2:15][CH2:16][C:17]=3[O:18][CH3:19])[N:12]=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[O:30]1[CH2:35][CH2:34][CH:33]([CH:36]=O)[CH2:32][CH2:31]1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH3:21])=[C:11]([C:13]3[C:14](=[O:20])/[C:15](=[CH:36]/[CH:33]4[CH2:34][CH2:35][O:30][CH2:31][CH2:32]4)/[CH2:16][C:17]=3[O:18][CH3:19])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC1=C(c2nc(-c3ccc(Cl)cc3)sc2C)C(=O)CC1
Reactant: O=CC1CCOCC1
Agent: CC(C)(C)[O-]
Agent: CC(C)[N-]C(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC1=C(c2nc(-c3ccc(Cl)cc3)sc2C)C(=O)/C(=C/C2CCOCC2)C1
Temperature: 78 °C
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-3-methoxy-cyclopent-2-enone (640 mg, 2 mmol) in anhydrous tetrahydrofuran (12 ml) at −78° C. under an atmosphere of nitrogen was added lithium diisopropylamide (1.8M in THF/heptanes/ethylbenzene; 1.1 ml, 2 mmol) dropwise over a period of 5 minutes, and the reaction allowed to stir at 78° C. for 30 minutes. A solution of tetrahydro-pyran-4-carbaldehyde (228 mg, 2 mmol) in anhydrous tetrahydrofuran (1 ml) was then added dropwise over a period of 5 minutes before the reaction is allowed to warm to room temperature and stirred for a further 30 minutes. Potassium tert-butoxide (337 mg, 3 mmol) was then added in one portion and the reaction stirred for a further 90 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl acetate (50 ml) and the organic later separated, dry loaded onto silica and purified by flash chromatography to give 2-[2-(4-Chloro-phenyl)-5-methyl-thiazol-4-yl]-3-methoxy-5-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-cyclopent-2-enone (195 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:17][NH2:18])[CH3:16])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:20]=[S:21].CO.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:17][NH:18][C:20]([NH:19][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[S:21])[CH3:16])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CN=C=S
Reactant: CC(=NN)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)CNC(=S)NN=C(C)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 0.72 %

Procedure:
A solution of 2-(3,4-dichlorophenyl)-4-(1-hydrazonoethyl)thiophen-3-ol (30 mg, 0.10 mmol) prepared in Reference Synthetic Example 1 and methyl 2-isothiocyanatoacetate (20 mg, 0.15 mmol) in dimethyl formamide (300 μL) was stirred at room temperature, 40° C. and 50° C. for 2 hours, respectively. After addition of methanol-water, the solution was stirred at room temperature for 0.5 hour, and the resulting crystals were collected by filtration as the desired product (yield 0.72%).