Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:47])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[CH:35]([F:46])[C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)[CH2:4][CH2:3]1.[CH3:48][NH2:49].CO.[BH4-].[Na+].[Cl-].[NH4+].C(=O)([O-])O.[Na+]>O1CCCC1.CO>[F:1][C:2]1([F:47])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([CH2:33][NH:49][CH3:48])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[CH:35]([F:46])[C:36]2[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:43])[F:44])=[CH:40][CH:41]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(C=O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Reactant: CN
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.8 %

Procedure:
To 165 mg (0.250 mmol) of 4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-formyl pyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example (36-1), 1.0 ml of methanol, 0.1 ml of tetrahydrofuran and 0.20 ml (about 2.5 mmol) of about 40% methylamine-methanol solution were added, and the reaction solution was stirred at room temperature for 12 hours. Then, 95 mg (2.5 mmol) of sodium borohydride was added thereto and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, saturated ammonium chloride aqueous solution was poured into the reaction solution until the bubbling disappeared. Saturated sodium hydrogencarbonate aqueous solution was poured into the reaction solution to make the reaction solution basic and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [dichloromethane/methanol/28% ammonia water=100/0/0-90/9.5/0.5 (V/V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 128 mg of the title compound as a colorless oil (yield: 76%).
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[N:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:8]=2[N:7]=[CH:6]1.[C:22]([O:26][NH2:27])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][NH:27][C:14]([C:12]1[N:11]=[CH:10][C:9]2[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:2]=3[F:1])[CH:6]=[N:7][C:8]=2[CH:13]=1)=[O:16])([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C(O)c1cc2ncn(Cc3cccc(F)c3F)c2cn1
Reactant: CC(C)(C)ON
Product: CC(C)(C)ONC(=O)c1cc2ncn(Cc3cccc(F)c3F)c2cn1

Procedure:
The title compound can be prepared by coupling of 3-(2,3-difluorobenzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-(tert-butoxy)amine under the same conditions as those in step (c) of Example 1.
Reaction SMILES: [H-].[Na+].C[O:4][CH2:5][C:6]([O:8][CH3:9])=O.[CH3:10][CH:11]([CH3:15])[C:12](=[O:14])[CH3:13]>CCOCC>[CH3:9][O:8][CH2:6][C:5](=[O:4])[CH2:13][C:12](=[O:14])[CH:11]([CH3:15])[CH3:10]
Reactant: CC(=O)C(C)C
Reactant: COCC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: COCC(=O)CC(=O)C(C)C
Reaction time: 15 h
Yield: 79.7 %

Procedure:
To a stirred slurry of NaH (1.02 g, 26 mmol, washed with anhydrous hexanes) in ether (10 mL) was added methyl methoxyacetate (2.3 mL, 23 mmol) followed by 3-methyl-2-butanone (2.4 mL, 23 mmol) in ether (5 mL). The resulting mixture was stirred for 15 h and became a clear yellow solution. The reaction was quenched with saturated aqueous NH4Cl. The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layer was washed with H2O, brine, dried with Na2SO4 and concentrated under reduced pressure to provide 1-methoxy-5-methylhexane-2,4-dione (2.90 g, 80%) as a mixture of keto and enol form.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:22])([CH3:21])[CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=1>[Ag]=O.[N+]([O-])([O-])=O.[Ag+].O>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:22])([CH3:21])[CH2:18][C:19]([OH:1])=[O:20])=[CH:13][CH:12]=1
Reactant: CC(O)(CCO)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: [OH-]
Agent: O=[Ag]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CC(O)(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Silver oxide, freshly prepared from 3.2 g. of AgNO3 and 0.8 g. of NaOH in 25 ml. of water, is added to a mixture of 2.78 g. of 3-(2',4'-difluoro-4-biphenylyl)butane-1,3-diol and 2 g. of NaOH in 20 ml. of water. The mixture is heated under reflux for 2 hours and filtered. The filtrate is worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)-3-hydroxybutyric acid, m.p. 121°-123°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]([C:9]2[CH:10]=[C:11]([NH:15][C:16]([N:18]3[CH2:27][C:26]4[CH:25]=[N:24][C:23]5[N:28](CC6C=CC(OC)=CC=6)[N:29]=[CH:30][C:22]=5[C:21]=4[CH2:20][CH2:19]3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[N:2]1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]([C:9]2[CH:10]=[C:11]([NH:15][C:16]([N:18]3[CH2:27][C:26]4[CH:25]=[N:24][C:23]5[NH:28][N:29]=[CH:30][C:22]=5[C:21]=4[CH2:20][CH2:19]3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[O:8])=[N:2]1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Nc2cccc(C(=O)Nc3ccon3)c2)CC4)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccon1)c1cccc(NC(=O)N2CCc3c(cnc4[nH]ncc34)C2)c1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
Step 2 To the crude N-(3-(isoxazol-3-ylcarbamoyl)phenyl)-3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide obtained above was added trifluoroacetic acid (1 mL). The reaction mixture was shaken at 65° C. for 16 hours. On completion of the reaction, toluene (1 mL) was added and solvent removed under reduced pressure. The crude product was purified reverse phase HPLC to give the desired product, N-(3-(isoxazol-3-ylcarbamoyl)phenyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide. LCMS [M+H]: 404.
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)[C:6]([O-:8])=[O:7])[CH3:2].[C:15](OC(=O)C)(=[O:17])C>C(O)=O>[CH2:1]([O:3][N:4]=[C:5]([C:9]1[N:10]=[C:11]([NH:14][CH:15]=[O:17])[S:12][CH:13]=1)[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCON=C(C(=O)[O-])c1csc(N)n1
Solvent: O=CO
Product: CCON=C(C(=O)O)c1csc(NC=O)n1
Yield: 87.3 %

Procedure:
2-Ethoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate acid (syn isomer) (100 g.), formic acid (85.5 g.) and acetic anhydride (190.1 g.) were treated according to a similar manner to that of Example 7(a) (5) to give 2-ethoxyimino-2-(2-formamido-1,3-thiazol-4-yl)acetic acid (syn isomer) (99.1 g.).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[S:5][CH2:4][CH2:3]1.C([Li])(C)(C)C.[C:19](=[O:21])=[O:20].O>CCOCC.CCCCC>[CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:19]([OH:21])=[O:20])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: O=C=O
Reactant: CC1(C)CCSc2ccc(Br)cc21
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCCCC
Solvent: CCOCC
Product: CC1(C)CCSc2ccc(C(=O)O)cc21
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 5.14 g (0.02 mmol) of 4,4-dimethyl-6-bromothiochroman in 40 ml of dry ether at -78° C. was added dropwise 28.2 ml of 1.7 M 0.048 mmol) tert-butyllithium in pentane. The mixture was stirred at -78° C. for 2.5 hours and then treated with an excess of solid carbon dioxide. The mixture was warmed to room temperature and treated with sufficient water to dissolve the solids. The aqueous layer was then separated, acidified with dilute sulfuric acid and extracted with three portions of ether. The ether extracts were combined and washed successively with water and saturated NaCl solution and then dried (MgSO4). The solution was filtered and the solvent removed in-vacuo and the residue recrystallized from ethyl acetate and hexane to give the title compound as a white solid. PMR (CDCl3): δ1.37 (6H, s), 1.97 (2H, m), 3.08 (2H, m), 7.17 (1H, d, J~ 8.0 Hz), 7.74 (1H dd, J~8.0, 1.9 Hz), 8.11 (1H, d, J~1.9 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[CH:8]=[C:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28]Cl>CN(C)C=O>[CH3:25][N:26]([CH3:30])[CH2:27][CH2:28][N:11]1[CH2:12][CH2:13][C:9](=[CH:8][C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)[C:10]1=[O:14]
Reactant: CN(C)CCCl
Reactant: CC(C)(C)c1cc(C=C2CCNC2=O)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN1CCC(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O
Yield: 48.5 %

Procedure:
500 mg of 3-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-pyrrolidone was dissolved in 5 ml of dimethylformamide and 0.2 g of sodium hydride and 0.2 g of 2-dimethylaminoethyl chloride were successively added thereto under ice-cooling. Then the obtained mixture was allowed to react for one hour at room temperature. The reaction mixture was extracted with ethyl acetate, washed with water followed by a saturated saline solution and dried over anhydrous magnesium sulfate. After distilling the ethyl acetate off, the residue was purified by column chromatography with the use of silica gel and benzene/acetone and recrystallized from ethyl acetate/hexane to give 300 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[C:8]([C:11](=[O:15])[CH2:12][CH2:13][CH3:14])[S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br-:16].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>O1CCCC1>[Br:16][CH:12]([CH2:13][CH3:14])[C:11]([C:8]1[S:7][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[CH:9]=1)=[O:15]
Reactant: [Br-]
Reactant: CCCC(=O)c1cc2c(Cl)cccc2s1
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CCC(Br)C(=O)c1cc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 66 h
Yield: 148.6 %

Procedure:
A mixture of 1-(4-chlorobenzo[b]thiophen-2-yl)butan-1-one (0.93 g), phenyltrimethylammonium tribromide (1.47 g) and tetrahydrofuran (20 ml) was stirred under nitrogen at ambient temperature for 66 hours, then it was filtered and diluted with water (50 ml). The product was extracted into dichloromethane (3×30 ml), the combined extracts were dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to leave 2-bromo-1-(4-chlorobenzo[b]thiophen-2-yl)butan-1-one (1.07 g) which was used without further purification.
Reaction SMILES: CC1C=CC(S(OCC2CC3C(F)=CC=C(C4C=CC=CC=4C)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:34]([CH2:37][CH:38]1[CH2:42][C:41]2[C:43]([F:54])=[CH:44][CH:45]=[C:46]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[CH3:53])[C:40]=2[O:39]1)=[N+]=[N-].[N-]=[N+]=[N-]>[Pd]>[F:54][C:43]1[C:41]2[CH2:42][CH:38]([CH2:37][NH2:34])[O:39][C:40]=2[C:46]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[CH3:53])=[CH:45][CH:44]=1
Reactant: Cc1ccccc1-c1ccc(F)c2c1OC(CN=[N+]=[N-])C2
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)ccc(-c4ccccc4C)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Product: Cc1ccccc1-c1ccc(F)c2c1OC(CN)C2
Yield: 57 %

Procedure:
Treatment of (±)-[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.38 g, 3.35 mmol) with sodium azide (0.87 g, 13.38 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-4-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.083 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.561 g (57%) of (±)-1-[4-fluoro-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 228-231° C.; Anal. calcd. for C16H16FNOHCl: C, 65.42; H, 5.83; N, 4.77. Found: C, 66.01; H, 5.88; N, 4.51.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:18]=1[NH2:19]>C(O)C>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:18]=1[NH:19][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1
Reactant: COc1ccc(OC)c(N)c1
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2cc(OC)ccc2OC)[nH]c1=O
Reaction time: 17 h
Yield: 59 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (10 g) and 2,5-dimethoxyaniline (8.6 g) are added to ethanol (200 ml), and the mixture is refluxed with stirring for 17 hours. After cooling, the precipitate is collected by filtration and recrystallized from a mixture of DMF and water to give ethyl 1,6-dihydro-2-(2,5-dimethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (8.8 g). M.p. 221°-223° C.
Reaction SMILES: C([O:8][C:9]([CH2:11][CH2:12][C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=1[N:19]1[C:24](=[O:25])[CH:23]=[CH:22][C:21]([C:26]2[C:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:28][N:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=23)=[N:20]1)=[O:10])C1C=CC=CC=1.[OH-].[Na+]>O1CCCC1>[C:9]([CH2:11][CH2:12][C:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=1[N:19]1[C:24](=[O:25])[CH:23]=[CH:22][C:21]([C:26]2[C:27]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[N:28][N:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=23)=[N:20]1)([OH:10])=[O:8]
Reactant: O=C(CCC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCC1=C(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CCCC1
Reaction time: 5 h
Yield: 87.9 %

Procedure:
A mixture of 3-[2-{2-(2-benzyloxycarbonylethyl)-1-cyclohexenyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (74 mg) and 1N-sodium hydroxide (0.28 ml) in tetrahydrofuran (4 ml) was refluxed with stirring for 5 hours. The mixture was evaporated under reduced pressure. The residue was dissolved in water. The aqueous layer was washed with ethyl acetate, acidified with 1N-hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethanol-water to give 3-[2-{2-(2-carboxyethyl)-1-cyclohexenyl}-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]-pyridine (54 mg).
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([CH3:30])[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:16])[C:11]1[N:17]([CH3:29])[C:18](=[O:28])[C:19]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:20][C:10]2=1)=O.O.[NH2:33]N>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[C:18](=[O:28])[N:17]([CH3:29])[C:11]3[N:12]([CH3:16])[C:13]4[C:9]([C:10]=3[CH:20]=2)=[CH:8][C:7]([C:5]2[NH:33][N:2]=[CH:3][C:4]=2[CH3:30])=[CH:15][CH:14]=4)=[CH:26][CH:25]=1
Reactant: NN
Reactant: CC(=CN(C)C)C(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3)c(=O)n(C)c1n2C
Solvent: O
Product: Cc1cn[nH]c1-c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3)c(=O)n(C)c1n2C

Procedure:
The process is carried out as indicated in Example 36 above, with compound B, 6-(3-dimethylamino-2-methyl-acryloyl)-3-(4-chlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and hydrazine hydrate.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([O:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.[O:27]1[CH2:32][CH2:31][CH:30]([CH:33]=O)[CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([O:25][CH3:26])=[N:8][N:9]3[C:14]([C:15]4[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=4[O:23][CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[CH2:2][CH2:3]1
Reactant: O=CC1CCOCC1
Reactant: COc1cc(C)cc(C)c1-c1cccc2c(NCC3CC3)c(OC)nn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C)cc(C)c1-c1cccc2c(N(CC3CCOCC3)CC3CC3)c(OC)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
After dissolving N-cyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine (134 mg) in tetrahydrofuran (10 mL), tetrahydro-2H-4-pyrancarbaldehyde (131 mg) and sodium triacetoxyborohydride (243 mg) were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the obtained reaction mixture, extraction was performed with ethyl acetate, and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (120 mg) was obtained from the n-hexane:ethyl acetate (4:1) fraction as a yellow amorphous.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[CH3:11].C1C(=O)N([Br:27])C(=O)C1>C(#N)C>[Br:27][C:17]1[CH:18]=[C:13]([O:12][CH:10]([C:3]2[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[Cl:1])[CH3:11])[C:14]([NH2:19])=[N:15][CH:16]=1
Reactant: CC(Oc1cccnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 0.25 h
Yield: 76 %

Procedure:
3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-aminopyridine (24.0 g, 79.9 mmol) was dissolved in acetonitrile (250 mL), and to which was added NBS (14.2 g, 79.9 mmol) under the cooling of ice bath. After 15 min, the solvent in the resultant mixture was evaporated under reduced pressure, and then purified via silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to yield the target product as solid powder of soil colour (23.2 g, 61.1 mmol; yield=76%).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:43][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[CH:18][C:17]([CH2:22][NH:23][CH2:24][CH:25]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:26][NH:27][C:28]1([C:33]([O:35]C)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[CH:16]3.[OH-].[Na+]>CO>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:43][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[CH:18][C:17]([CH2:22][NH:23][CH2:24][CH:25]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH2:26][NH:27][C:28]1([C:33]([OH:35])=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32]1)=[CH:16]3
Reactant: COC(=O)C1(NCC(CNCc2cnc3cc4c(cc3c2)C[C@@]2(C4)C(=O)Nc3ncccc32)c2ccccc2)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1(NCC(CNCc2cnc3cc4c(cc3c2)C[C@@]2(C4)C(=O)Nc3ncccc32)c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Into a solution of methyl 1-{[3-({[(7S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-3-yl]methyl}amino)-2-phenylpropyl]amino}cyclopentanecarboxylate from Step E (0.136 g, 0.236 mmol) in methanol (2 mL) was added NaOH (0.472 mL, 1 M in water). The solution is then allowed to stir for 18 h at ambient temperature. Additional NaOH (0.472 mL, 1 M in water) was then added to the reaction, which was completed after another 24 h of stirring. The solution was then concentrated in vacuo and neutralized by addition of HCl (0.944 mL, 1 M in water). The resulting precipitate was filtered to yield the title compound. MS: m/z=562 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[O:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[CH:9]=1)([O-])=O.[H][H]>[Pd].COCCO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[O:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=2)[CH:9]=1
Reactant: O=[N+]([O-])c1cccc(Oc2cc(Oc3cccc([N+](=O)[O-])c3)cc(C(F)(F)F)c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: COCCO
Product: Nc1cccc(Oc2cc(Oc3cccc(N)c3)cc(C(F)(F)F)c2)c1
Temperature: 90 °C
Yield: 87 %

Procedure:
To a reducing apparatus equipped with a thermometer, reflux condenser and stirrer, 55 g (0.131 mol) of 1,3-bis(3-nitrophenoxy)-5-trifluoromethylbenzene, 150 g of methyl cellosolve and 5 g of 5% Pd/c having a moisture content of 50% were charged and reacted in a hydrogen atmosphere at 70°~80° C. for 4 hours. After finishing the reaction, the catalyst was filtered off. The filtrate was heated to 90° C., mixed with 140 g of water and cooled to room temperature. The precipitated crystals were filtered and dried under reduced pressure to obtain 1,3-bis(3-aminophenoxy)-5-trifluoromethyl benzene as colorless solid. The product was 41 g (87% yield) and had a melting point of 98.0°~98.6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11]C)[CH:6]=[O:7].S(=O)(=O)(O)O>>[CH:6](=[O:7])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([OH:11])=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: O=S(=O)(O)O
Product: COc1cc(C=O)cc(OC)c1O

Procedure:
Monodemethylation of 3,4,5-trimethoxy benzaldehyde using sulphuric acid at 40° C. for 8 hours as described above in Example 1 yields syringaldehyde. Condensation of 3,5-Dimethoxy-4-hydroxy benzaldehyde (syringaldehyde) with ethyl acetoacetate in the presence of piperidine—acetic acid and benzene as the reaction medium at reflux temperature yields the title product. The reaction takes about 3.5 hours for completion.
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])SC)#[N:2].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:1]([N:3]=[C:4]([NH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[NH:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)#[N:2]
Reactant: COC(=O)c1cccc(NC(=NC#N)SC)c1
Reactant: NCc1ccccc1
Solvent: CCO
Product: COC(=O)c1cccc(NC(=NC#N)NCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
A stirred mixture of the compound from Example D (1.0 g) and benzylamine (440 mg) in ethanol (15 ml) was heated at reflux under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature. On standing overnight at room temperature a white solid was obtained and isolated by filtration (720 mg). The crude filtrate was further purified by chromatography on silica (eluant; ethyl acetate/hexane, 1:1) to afford the title compound (550 mg) as a white solid.