Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:28]([O:30]C)=[O:29])=[C:21]5[C:25]=4[O:24][C:23]([CH3:27])([CH3:26])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:32])[C:8](=[O:33])[C@H:7]2[CH2:34][CH3:35])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O.Cl>CO>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:28]([OH:30])=[O:29])=[C:21]5[C:25]=4[O:24][C:23]([CH3:27])([CH3:26])[CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:32])[C:8](=[O:33])[C@H:7]2[CH2:34][CH3:35])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)OC)c4c3OC(C)(C)C4)nc2N1C1CCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OC(C)(C)C4)nc2N1C1CCCC1
Temperature: 50 °C
Reaction time: 12 h
Yield: 116.7 %

Procedure:
Methyl 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-3H-benzofuran-4-carboxylate 4e (1.67 g, 3.48 mmol) was dissolved in 50 mL of methanol followed by the addition of 1 M lithium hydroxide solution (17.4 mL, 17.40 mmol). The reaction solution was heated to 50° C. and stirred for 12 hours. The resulting solution was added with 10 mL of water, and added dropwise with 1 M hydrochloric acid to adjust pH to 2 to 3. The reaction solution was concentrated under reduced pressure to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,2-dimethyl-3H-benzofuran-4-carboxylic acid 4f (1.89 g, yield: 100%) as a white solid.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.Cl[CH:19]([CH3:34])[C:20]([O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:21].CN(C)C=O>O>[Cl:2][C:3]1[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:19]([CH3:34])[C:20]([O:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[O:21])=[CH:13][CH:12]=2)=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: CC(Cl)C(=O)OCCOCc1ccc(F)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)OCCOCc1ccc(F)cc1
Temperature: 25 °C

Procedure:
30.6 g of 4-(3,5-dichloro-2-pyridyloxy)phenol sodium salt and 30.5 g of 2-(4-fluorobenzyloxy)ethyl 2-chloropropionate were added to 100 ml of dimethylformamide, and the mixture was heated to 70° to 80° C. for 3 hours with stirring. After cooling to room temperature, the reaction solution was poured into 300 ml of water, then extracted with ether. The ether layer was washed successively with 1% strength by weight sodium hydroxide aqueous solution and water, followed by dehydration. Upon distilling off the ether, there were obtained 38 g of a pale yellow, viscous, oily end product, 2-(4-fluorobenzyloxy)ethyl 2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionate. nD20 1.5643
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([F:11])[CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[CH2:17]([NH:24][CH2:25][CH2:26][OH:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.O1CCCC1.O>[CH2:17]([N:24]([CH2:25][CH2:26][OH:27])[C:8](=[O:10])[C:7]1[C:2]([Br:1])=[CH:3][CH:4]=[CH:5][C:6]=1[F:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1c(F)cccc1Br
Reactant: OCCNCc1ccccc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1c(F)cccc1Br)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A solution of 6-bromo-2-fluorobenzoic acid (10.0 g, 45.7 mmol) and N,N-dimethylformamide (0.100 ml) in thionylchloride (40 ml) was stirred at 85° C. for 12 hr, and the solvent was evaporated under reduced pressure. The residue was added to a solution of N-benzylethanolamine (6.91 g, 45.7 mmol) and triethylamine (9.55 ml, 68.6 mmol) in tetrahydrofuran (100 ml) under ice-cooling, and the mixture was stirred for 1 hr under ice-cooling and at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the desired product (15.7 g, 97.5%) as an oil.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([NH:13][S:14]([C:17]([F:20])([F:19])[F:18])(=[O:16])=[O:15])=[C:7]([CH:12]=1)[C:8]([O:10]C)=[O:9].[OH-].[Li+].Cl>C1COCC1.O>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([NH:13][S:14]([C:17]([F:18])([F:19])[F:20])(=[O:16])=[O:15])=[C:7]([CH:12]=1)[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1cc(C(F)(F)F)ccc1NS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)ccc1NS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Yield: 77 %

Procedure:
Preparation B6, Step 4: To a solution of methyl 5-(trifluoromethyl)-2-(trifluoromethylsulfonamido)benzoate (2.7 g, 7.7 mmol) in 55 ml of THF was added lithium hydroxide (0.97 g, 23.1 mmol) in 55 ml of water and stirred at RT over night. The reaction mixture was acidified with 1.5N HCl and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated to give 5-(trifluoromethyl)-2-(trifluoromethylsulfonamido)benzoic acid (2 g) as white solid. 1H NMR (DMSO-d6, 400 MHz) δ 7.77 (m, 2H), 8.18 (s, 1H). MS found: (M−H)−=336.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.C([Li])CCC.O1CCCC1.Br[CH2:27][CH2:28][CH2:29][N:30]1[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]1[CH3:36]>C(OCC)C.CCCCCC>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:27][CH2:28][CH2:29][N:30]2[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]2[CH3:36])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: Cc1ccc(C)n1CCCBr
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc(CCCCn2c(C)ccc2C)nc(-n2c(C)ccc2C)c1
Temperature: -17.5 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A solution of 297 mg (1.49 mmol) of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine (from Example 53, Step A) in 1.5 mL of ethyl ether was added to a -20° C. solution prepared from 3.0 mL of ethyl ether and 1.2 mL (1.7 mmol) of 1.4 M n-butyllithium in hexane. The mixture was stirred for 1 h at -20 to -15° C. with the formation of a preciptate. Tetrahydrofuran (1.0 mL) was added, the resulting orange-red solution was cooled to .BECAUSE.45° C., and 400 mg (1.85 mmol) of 1-(3-bromopropyl)-2,5-dimethylpyrrole (S. P. Bruekelman, S. E. Leach, G. D. Meakins, and M. D. Tirel, J. Chem. Soc., Perkin Trans. 1, 1984, 2801-7) was added in one portion. The mixture was allowed to warm to 10° C. over 1.75 h, quenched with 10 mL of saturated aqueous ammonium chloride, and extracted with 20 mL of ethyl acetate. The organic layer was washed with 10 mL of saturated aqueous sodium chloride, dried (sodium sulfate), decanted, and evaporated. The residue was purified by flash column chromatography on 50 g of silica gel, eluting with 1.2 L of 5% ethyl acetate in hexane to give 402 mg (80% yield) of 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(4-(2,5-dimethylpyrrol-1-yl)butyl)pyridine as an almost colorless oil.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[C:14]([Cl:20])[CH:13]=1)[CH2:2][CH2:3][CH3:4].C([O-])(O)=O.[Na+].C(OCC)(=O)C.[C:42](#[N:44])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([C:5]1[N:6]=[C:7]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[S:8][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:42]#[N:44])=[C:14]([Cl:20])[CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC#N
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CCl)c(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [C-]#N
Solvent: CCOC(C)=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(CC#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.1 g crude 4-Butyl-5-(3-chloro-4-chloromethyl-phenoxymethyl)-2-(4-trifluoromethyl-phenyl)-thiazole was dissolved in 50 ml acetonitrile. 2.0 g tetrabutylammonium cyanide were added and the reaction mixture stirred at room temperature for one hour. Then a mixture of saturated NaHCO3 solution, ice and ethyl acetate was added. The aqueous phase was separated and extracted three times with portions of 30 ml ethylacetate. The combined organic layers were washed with ice cold water and brine and dried over MgSO4. The solvent was removed in vacuo. The residue was purified by flash chromatography with the eluent n-heptane:ethyl acetate=4:1 to provide 2.2 g {4-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-2-chloro-phenyl}-acetonitrile as oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:28][CH2:27][CH2:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NCCC1CCOCC1
Reactant: NC(=O)c1cnc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cnc(Oc2ccc(CNCCC3CCOCC3)cc2F)cn1
Reaction time: 8 h
Yield: 67.2 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyrazine-2-carboxamide (Example 737, Part E) (0.400 g, 1.53 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.217 g, 1.68 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (7.7 mL), cap and stir overnight. Add NaBH4 (0.058 g, 1.53 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 30% (2.0 M NH3 in methanol) in 80% (ethyl acetate in hexanes) to give the title compound (0.385 g, 67%): TOF MS ES+ 375.2 (M+H)+, HRMS calcd for C19H24N4O3F 375.1832 (M+H)+, found 375.1847, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=8.6 min, 95.4% purity.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C@:11]12[CH2:28][CH2:27][C@H:26]3[C@@H:16]([CH2:17][CH2:18][C@@H:19]4[C@:24]3([CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20]4)[C@@H:15]1[CH2:14][CH2:13][C@@H:12]2[NH2:29].C([BH3-])#N.[Na+].O1CCCC1>CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:29][C@H:12]2[CH2:13][CH2:14][C@H:15]3[C@H:16]4[C@H:26]([CH2:27][CH2:28][C@:11]23[CH3:10])[C@:24]2([CH3:25])[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17]4)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](N)CC[C@@H]12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NCc3ccc(Cl)cc3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chlorobenzaldehyde (0.464 g), 5α-androstan-17β-amine(4.40g) glacial acetic acid (0.99 g), sodium cyanoborohydride (0.21 g) and tetrahydrofuran (5 ml) were added to methanol (11 ml). The resulting mixture was warmed to dissolve the solid in solution and allowed to stir overnight at room temperature. Excess solvent was removed under reduced pressure. Water was added and made basic (pH 9) with 50% aqueous NAOH. The mixture was extracted with ether and the organic layer became cloudy. Celite was used to filter the organic layer. The aqueous layer was washed with ether and the combined organic layers were dried (NaSO4), filtered and concentrated. The crude solid was mixed with 10 g of flash silica gel and dissolved in ethyl acetate. The solvent was removed and the silica was poured on top of the chromatographic column. The compound was eluted with 50% ethyl acetate-hexane. The title compound was obtained as a solid which was recrystallized from acetone (0.364 g) mp 101°-102° C. (PLA2, diabetes)
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[C:12]1([S:18]([N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[CH:2]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridine (20 g, 169 mmol, (available from, for example Sigma Aldrich) in tetrahydrofuran (THF) (250 mL) was added sodium hydride (10.16 g, 254 mmol) portionwise during 5 min under nitrogen at 0° C. The reaction mixture was stirred at 0° C. for 30 min, then benzenesulfonyl chloride was added dropwise under nitrogen at 0° C. then stirred for 2 h at r.t., until the starting material had been completely consumed (TLC, EtOAc:PE=1:1). The mixture was poured into H2O (200 mL) and extracted with EtOAc (3×200 mL). The organic layers were washed with brine (3×150 mL), dried over Na2SO4 and filtered. The solvent was evaporated in vacuo to give the crude product, which was purified by recrystallization with (EtOAc and PE) to give desired product as a white solid (30 g, 69%)
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1[Cl:8].[OH-:12].[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[C:3](=[O:12])[NH:4][C:5]([F:10])=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: Fc1nc(F)c(Cl)c(Cl)c1Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1[nH]c(F)c(Cl)c(Cl)c1Cl
Reaction time: 2 h

Procedure:
A solution of 3,4,5-trichlorodifluoropyridine (21.8 g.) in dioxan (220 ml.) was refluxed with a solution of sodium hydroxide (8 g.) in water (40 ml.). After 2 hours a further 8 g. of sodium hydroxide in water (40 ml.) was added (4 molar equivalents of sodium hydroxide in toto). After a further 2 hours, water was added to produce a homogeneous solution which was acidified to precipitate the product (17.6 g., m.p. 170°-4°). After initial purification by charcoal and silica gel column, crystallisation from benzene gave 3,4,5-trichloro-6-fluoro-2-pyridone, m.p. 172°-6°(11.8 g.), having a pale yellow colour. After vacuum sublimation at 100°-120°, the white microcrystals melted at 173°-4° (10.65 g/.).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:5][CH:6]=1.[C:15]([Li])(C)(C)C.IC>C1COCC1.CCCCC>[C:9]1([C:8]#[C:7][C:4]2[S:5][C:6]([CH3:15])=[CH:2][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Brc1csc(C#Cc2ccccc2)n1
Reactant: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cnc(C#Cc2ccccc2)s1
Temperature: -78 °C

Procedure:
4-Bromo-2-(phenylethynyl)-1,3-thiazole (500 mg, 1.89 mmol) was dissolved in dry THF (10 mL) under argon, cooled to −78° C., then t-butyllithium (1.7 mL of a 1.7M solution in pentane, 2.8 mmol) was added. After 30 min 0.4 mL of the reaction mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. GC/MS of the crude product from this workup and comparison with a GC/MS of authentic 2-(2-phenylethynyl)-thiazole showed the two to be identical. This confirmed that the initial coupling with phenylacetylene (in Example 9) took place at the bromine at the 2 position rather than at the 4 position. The GC/MS also showed that the reaction was not complete. Additional t-butyllithium (1.7 mL of a 1.7M solution in pentane, 2.8 mmol) was added. After 30 minutes iodomethane (0.36 mL, 5.7 mmol) was added to the reaction mixture, and the reaction was allowed to warm to ambient temperature for 16 h. The solvents were then removed in vacuo, and residue dissolved in ethyl acetate (50 mL), washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography eluting with hexane, 99:1, 98:2, 97.5:2.5 hexane:ethyl acetate to afford 2-(2-phenylethynyl)-5-methyl-1,3-thiazole (90 mg). 1H NMR analysis of the material showed it to be impure, despite its apparent homogeneity by TLC analysis. The crude compound was dissolved in DMSO and purified by preparative HPLC with a 30 min gradient from 70:30 water:acetonitrile to 100% acetonitrile to afford pure 5-methyl-2-(phenylethynyl)-1,3-thiazole as a white powder (44 mg, 24% yield). M.p. 82–83° C. 1H NMR (CDCl3, 300 MHz) δ 7.85–7.55 (m, 2H), 7.49 (d, J=0.6 Hz, 1H), 7.37–7.32 (m, 3H), 2.49 (s, 3H). MS (ESI) 200.1 (M++H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)([O-:7])=[O:6].[C:17]1([CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>C(=S)=S.O>[CH3:23][C:17]1[CH:22]=[CH:21][C:20]([C:12]([C:11]2[CH:15]=[CH:16][C:8]([N+:5]([O-:7])=[O:6])=[CH:9][CH:10]=2)=[O:13])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: Cc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
Aluminum chloride (9.3 g) was added in a single portion to a mixture of 4-nitrobenzoyl chloride (10 g) and toluene (6.3 mL) dissolved in carbon disulfide (35 mL). The mixture was warmed from room temperature to reflux and heated for 3 hours. Concentrated hydrochloric acid (19 mL) was slowly added, and the mixture stirred for an additional 30 minutes, poured into water, and extracted with dichloromethane (3×). The extract was washed with dilute ammonium hydroxide and water, dried (Na2SO4), and evaporated. Recrystallization from ethyl acetate gave 4-(4-methylbenzoyl)-nitrobenzene (10.6 g, 82%) as a pale yellow solid, m.p. 122.4-123.1° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Cl[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[N:16][CH:17]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(-c2ccc(Cl)cn2)cc1

Procedure:
Repeating the operations of Production Example 14 using 4-(methoxycarbonyl)phenylboronic acid and 2,5-dichloropyridine, methyl 4-(5-chloro-2-pyridyl)benzoate was obtained. Hydrolyzing the same with 5N aqueous sodium hydroxide solution, the title compound was obtained as white solid.
Reaction SMILES: C([O:4][C:5]1([C:8]([NH:10][C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([NH:27][C:28]([C:30]5[N:34]([CH3:35])[N:33]=[C:32]([CH3:36])[CH:31]=5)=[O:29])[CH:21]=4)=[N:15][N:14]3[CH:37]=2)=[O:9])[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].Cl.C(OCC)(=O)C>O1CCCC1>[OH:4][C:5]1([C:8]([NH:10][C:11]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([NH:27][C:28]([C:30]5[N:34]([CH3:35])[N:33]=[C:32]([CH3:36])[CH:31]=5)=[O:29])[CH:21]=4)=[N:15][N:14]3[CH:37]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: CC(=O)OC1(C(=O)Nc2cn3nc(Oc4ccc(C)c(NC(=O)c5cc(C)nn5C)c4)ccc3n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5(O)CC5)cn4n3)ccc2C)n(C)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To a solution of 1-({[6-(3-{[(1,3-dimethyl-1H-pyrazol-5-yl)carbonyl]amino}-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]amino}carbonyl)cyclopropyl acetate (130 mg, 0.25 mmol) in tetrahydrofuran (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at room temperature for 2 hr. 1N Hydrochloric acid (2.5 mL) and ethyl acetate were added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate (×3). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (99 mg, 86%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[O:13])=[CH:8][CH:7]=1.[B-].[Na+].Cl>CO>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[CH:8][CH:7]=1
Reactant: COC(=O)COc1ccc(C=O)cc1
Agent: Cl
Agent: [B-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1ccc(CO)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a solution of (4-Formylphenoxy)acetic acid methyl ester 68 (160 grams, 825 mmol) in methanol (800 mL) at 0° C. was added Sodium borohydrate (18 grams, 476 mmol) in small portions, further stirred at 0° C. for 2 hours and poured on to ice water (1500 mL). The pH of mixture was adjusted to 2 with concentrated hydrochloric acid. Crude 69 was extracted into chloroform, dried over Na2SO4, distilled and purified by column chromatography on silica gel using hexane:ethyl acetate (7:3) to give 69 (100 grams, 62%) as white powder
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:5]2[C:10]([C:11]=1[CH3:12])=[CH:9][C:8]([C:13](O)=[O:14])=[CH:7][CH:6]=2)[CH3:2].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH2:50]>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH:50][C:13]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=1)[C:3]([CH2:1][CH3:2])=[C:11]2[CH3:12])=[O:14]
Reactant: CN(C)CCN
Reactant: CCc1c(C)c2cc(C(=O)O)ccc2n1Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCc1c(C)c2cc(C(=O)NCCN(C)C)ccc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 250 mg portion of 2-ethyl-1-(4-fluorobenzyl)-3-methyl-1H-indole-5-carboxylic acid, 231 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 54 mg of 1-hydroxybenzotriazole were dissolved in 8 ml of N,N-dimethylformamide, and then 106 mg of N,N-dimethyl-1,2-ethanediamine was added, followed by overnight stirring at room temperature. The reaction liquid was diluted with chloroform and then washed with a 1 M sodium hydroxide aqueous solution and saturated brine, and dried over anhydrous sodium sulfate. After evaporation of the solvent under a reduced pressure, the residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=100:1:0.1 to 50:1:0.1 to 30:1:0.1) to obtain 257 mg of N-[2-(dimethylamino)ethyl]-2-ethyl-1-(4-fluorobenzyl)-3-methyl-1H-indole-5-carboxamide as a colorless oily material. This product was dissolved in 2.5 ml of acetonitrile at 80° C., and 67 mg of oxalic acid was added, followed by stirring at 80° C. for 10 minutes and then stirring at room temperature for 2 hours. The resulting solid was collected by filtration and then washed with acetonitrile to obtain 236 mg of N-[2-(dimethylamino)ethyl]-2-ethyl-1-(4-fluorobenzyl)-3-methyl-1H-indole-5-carboxamide oxalate as a pale purple solid.
Reaction SMILES: [OH:1][C@@:2]([CH3:11])([CH2:9][OH:10])[C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].CO[C:14](OC)([CH3:16])[CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:8][O:7][N:5]([CH3:6])[C:3]([C@:2]1([CH3:11])[CH2:9][O:10][C:14]([CH3:16])([CH3:15])[O:1]1)=[O:4]
Reactant: COC(C)(C)OC
Reactant: CON(C)C(=O)[C@@](C)(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: CON(C)C(=O)[C@]1(C)COC(C)(C)O1

Procedure:
The compound prepared in Example 130(a) (12.4 g), acetone (150 mL), acetone dimethylacetal (18 mL) and p-toluenesulfonic acid monohydrate (290 mg) were stirred at room temperature for an hour. The reaction mixture was concentrated, poured into a cold aqueous solution of sodium hydrogen carbonate and extracted with a mixed solution of ethyl acetate-hexane (1:1). The obtained organic layer was washed with an aqueous saturated sodium hydrogen carbonate solution, water and brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuum condition and dried to give the title compound (8.4 g) having the following physical data.