2-ethylsulfanylbenzaldehyde

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (1.0 g), 2-ethylsulfanylbenzaldehyde (0.96 g), sodium hydrogen sulfite (1.80 g), sodium hydrogen sulfite (1.80 g) and DMF (10 ml) was stirred with heating at 160° C. for 5 hours. The reaction mixture was ice-cooled, and water was added thereto. The precipitated crystal was collected by filtration, and washed with water, then hexane. The obtained crystal was dried under reduced pressure to give 1.09 g of 2-(2-ethylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 4). cooled The precipitated crystal was collected by filtration washed with water The obtained crystal was dried under reduced pressure

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.0 g of 2-amino-5-trifluoromethylpyridine-3-carboxylic acid amide, 810 mg of 2-ethylsulfanylbenzaldehyde, 1.01 g of sodium bisulfite and 3 ml of DMA was stirred at 150° C. for 12 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 975 mg of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-pyrido[2,3-d]pyrimidin-4-one. the mixture was extracted with ethyl acetate The organic layer was washed with water dried over anhydrous magnesium sulfate concentrated under reduced pressure

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.0 g of 3-amino-5-trifluoromethylpyridine-2-carboxylic acid amide, 850 mg of 2-ethylsulfanylbenzaldehyde, 1.60 g of sodium bisulfite and 3 ml of DMA was stirred at 150° C. for 20 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 927 mg of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-pyrido[3,2-d]pyrimidin-4-one. the mixture was extracted with ethyl acetate The organic layer was washed with water dried over anhydrous magnesium sulfate concentrated under reduced pressure

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.0 g of 2-amino-4-trifluromethylbenzamide, 813 mg of 2-ethylsulfanylbenzaldehyde, 764 mg of sodium bisulfite and 4 ml of DMA was stirred at 150° C. for 8 hours. A saturated aqueous sodium bicarbonate solution and water were added to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 1.49 g of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-quinazolin-4-one. the precipitated solid was filtered The resulting solid was washed with water and n-hexane dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Methyl triphenylphosphonium iodide (1.57 g, 3.88 mmol) was dissolved in 25 mL ether in a 50 mL round-bottomed flask under dry nitrogen. To the mixture was added in one portion at 0° C. potassium tert-butoxide (0.47 g, 4.19 mmol) and it was stirred for 10 min at room temperature. 2-(ethylsulfanyl)benzenecarbaldehyde (2.77 mmol) was added in one portion at 0° C. and the reaction mixture was stirred until complete disappearance of the reactants (22 hr) at room temperature (followed by TLC). The mixture was added to 50 mL of saturated sodium bicarbonate solution, followed by extraction with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using petroleum ether 60-80 as eluent. Yield: 0.37 g, 81%, colorless oil. 1H NMR (200 MHz, CDCl3): δ 1.29 (t, J=7.3, 3H), 2.89 (q, J=7.3, 2H), 5.34 (dd, J1=10.9, J2=1.2, 1H), 5.69 (dd, J1=17.4, J2=1.2, 1H), 7.19-7.54 (m, 5H) ppm. the reaction mixture was stirred until complete disappearance of the reactants (22 hr) at room temperature (followed by TLC) followed by extraction with 3×50 mL portions of ether The extracts were dried with magnesium sulfate evaporated The crude product was further purified by chromatography on silica gel

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-fluoro-benzaldehyde (2.00 g, 16.1 mmol), potassium carbonate (2.45 g, 17.7 mmol) and thioethanol (17.1 mmol) were dissolved in 10.0 mL DMF in a 50 mL round-bottomed flask under dry nitrogen, topped with a reflux condenser. The reaction mixture was heated to 55° C. for 3 days. After cooling, the mixture was added to 50 mL of saturated potassium carbonate solution and extracted with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using 2:1 dichloromethane/n-hexane as eluent to give a yellow oil (1.94 g, 72%). 1H NMR (200 MHz, CDCl3): δ 1.37 (t, J=7.5, 3H), 2.99 (q, J=7.5, 2H), 7.26-7.56 (m, 3H), 7.84 (dd, J1=8.0, 1H), 10.37 (s, 1H) ppm. topped with a reflux condenser After cooling extracted with 3×50 mL portions of ether The extracts were dried with magnesium sulfate evaporated The crude product was further purified by chromatography on silica gel using 2:1 dichloromethane/n-hexane as eluent

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.0 g of 2-amino-5-trifluoromethylpyridine-3-carboxylic acid amide, 810 mg of 2-ethylsulfanylbenzaldehyde, 1.01 g of sodium bisulfite and 3 ml of DMA was stirred at 150° C. for 12 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 975 mg of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-pyrido[2,3-d]pyrimidin-4-one. the mixture was extracted with ethyl acetate The organic layer was washed with water dried over anhydrous magnesium sulfate concentrated under reduced pressure

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.0 g of 3-amino-5-trifluoromethylpyridine-2-carboxylic acid amide, 850 mg of 2-ethylsulfanylbenzaldehyde, 1.60 g of sodium bisulfite and 3 ml of DMA was stirred at 150° C. for 20 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 927 mg of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-pyrido[3,2-d]pyrimidin-4-one. the mixture was extracted with ethyl acetate The organic layer was washed with water dried over anhydrous magnesium sulfate concentrated under reduced pressure

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.0 g of 2-amino-4-trifluromethylbenzamide, 813 mg of 2-ethylsulfanylbenzaldehyde, 764 mg of sodium bisulfite and 4 ml of DMA was stirred at 150° C. for 8 hours. A saturated aqueous sodium bicarbonate solution and water were added to the cooled reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 1.49 g of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-quinazolin-4-one. the precipitated solid was filtered The resulting solid was washed with water and n-hexane dried

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 114A (10.4 g, 78% yield) was prepared from 2-fluorobezaldehyde (10 g, 81 mmol) and thioethane (5.5 g, 89 mmol) using a procedure similar to that used in the preparation of 11A. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.23-1.42 (m, 3H) 2.98 (q, J=7.34 Hz, 2H) 7.17-7.37 (m, 1H) 7.38-7.64 (m, 2H) 7.81 (dd, J=7.70, 1.59 Hz, 1H) 10.30 (s, 1H).

Conditions: temp:160.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N2-methyl-5-trifluoromethylpyridin-2,3-diamine (1.0 g), 2-ethylsulfanylbenzaldehyde (0.96 g), sodium hydrogen sulfite (1.80 g), sodium hydrogen sulfite (1.80 g) and DMF (10 ml) was stirred with heating at 160° C. for 5 hours. The reaction mixture was ice-cooled, and water was added thereto. The precipitated crystal was collected by filtration, and washed with water, then hexane. The obtained crystal was dried under reduced pressure to give 1.09 g of 2-(2-ethylsulfanylphenyl)-3-methyl-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 4). cooled The precipitated crystal was collected by filtration washed with water The obtained crystal was dried under reduced pressure

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1.0 g of 2-amino-5-trifluoromethylpyridine-3-carboxylic acid amide, 810 mg of 2-ethylsulfanylbenzaldehyde, 1.01 g of sodium bisulfite and 3 ml of DMA was stirred at 150° C. for 12 hours. Water was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 975 mg of 2-(2-ethylsulfanylphenyl)-6-trifluoromethyl-3H-pyrido[2,3-d]pyrimidin-4-one. the mixture was extracted with ethyl acetate The organic layer was washed with water dried over anhydrous magnesium sulfate concentrated under reduced pressure