2-(oxan-4-yl)acetyl chloride

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: A 0° C. solution of tetrahydropyran-4-ylacetyl chloride (0.500 g, 3.07 mmol) in THF (25 mL) was treated drop-wise with NH4OH (˜15M, 2.05 mL, ˜30.7 mmol), allowed to warm to RT and stirred overnight. The mixture was concentrated to dryness, co-evaporated with IPA (2×), then suspended in IPA and the solids removed via filtration. The filtrate was concentrated to dryness to afford 2-(tetrahydro-2H-pyran-4-yl)acetamide (510 mg, 116%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (s, 1H), 6.73 (s, 1H), 3.78 (dd, J=11.4, 4.1 Hz, 2H), 3.29-3.19 (m, 2H), 2.15-1.92 (m, 2H), 1.91-1.78 (m, 1H), 1.58-1.48 (m, 2H), 1.23-1.06 (m, 2H); MS (ESI) m/z: 144.1 (M+H+). The mixture was concentrated to dryness, co-evaporated with IPA (2×) the solids removed via filtration The filtrate was concentrated to dryness

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

Procedure: A 0° C. solution of tetrahydropyran-4-ylacetyl chloride (0.500 g, 3.07 mmol) in THF (25 mL) was treated drop-wise with NH4OH (˜15M, 2.05 mL, ˜30.7 mmol), allowed to warm to RT and stirred overnight. The mixture was concentrated to dryness, co-evaporated with IPA (2×), then suspended in IPA and the solids removed via filtration. The filtrate was concentrated to dryness to afford 2-(tetrahydro-2H-pyran-4-yl)acetamide (510 mg, 116%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.25 (s, 1H), 6.73 (s, 1H), 3.78 (dd, J=11.4, 4.1 Hz, 2H), 3.29-3.19 (m, 2H), 2.15-1.92 (m, 2H), 1.91-1.78 (m, 1H), 1.58-1.48 (m, 2H), 1.23-1.06 (m, 2H); MS (ESI) m/z: 144.1 (M+H+). The mixture was concentrated to dryness, co-evaporated with IPA (2×) the solids removed via filtration The filtrate was concentrated to dryness

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

Procedure: Commercially available (tetrahydro-pyran-4-yl)-acetic acid and oxalyl chloride were processed as described for example 9A to afford the title compound. MS (DCI/NH3) m/z 159 (M+H)+.

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

Procedure: A solution of tetrahydropyran-4-yl acetic acid (Combi-Blocks, Inc., 0.18 g, 1.2 mmol) in thionyl chloride (7 mL, 96 mmol, excess) was refluxed for 1 h then was cooled to ambient temperature and concentrated under reduced pressure. The residue was azeotroped twice with 10 mL of benzene to remove any remaining thionyl chloride. The resulting acid chloride was used without further purification. concentrated under reduced pressure The residue was azeotroped twice with 10 mL of benzene to remove any remaining thionyl chloride The resulting acid chloride was used without further purification

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

Procedure: In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (715 mg, 3.0 mmol) in DMF (20 mL) was added sodium hydride (purity of about 60%, 120 mg, 3.0 mmol, 1.0 eq.). The mixture was stirred until no more hydrogen was generated, to obtain a solution. Then, tetrahydro-2H-pyran-4-ylacetyl chloride (1.2 eq.) was added thereto, and the mixture was stirred at a room temperature for 1 hour. To the mixture was added a saturated sodium hydrogencarbonate aqueous solution, and the resulting precipitate was separated by filtration, washed with water, and dried to give 1-phenyl-4-(tetrahydro-2H-pyran-4-ylacetoxy)-1,8-naphthyridin-2(1H)-one as a form of crystal (738 mg, yield 67%). was synthesized to obtain a solution the resulting precipitate was separated by filtration washed with water dried

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

Procedure: To a mixture of N2-(3-chlorophenyl)-4-(trifluoromethyl)pyrimidine-2,5-diamine (147 mg), pyridine (62 μL), and dichloromethane (1 mL) was added a solution of the above crude tetrahydro-2H-pyran-4-ylacetyl chloride in dichloromethane (2 mL) under ice-cooling, followed by stirring at room temperature for 6 hours. To the reaction mixture was added ethyl acetate (50 mL), the organic layer was washed with a 10% aqueous citric acid solution, and then the solvent was evaporated under reduced pressure. The obtained residue was washed with warmed ethyl acetate to obtain N-{2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}-2-(tetrahydro-2H-pyran-4-yl)acetamide (176 mg) as a colorless powder. cooling the organic layer was washed with a 10% aqueous citric acid solution the solvent was evaporated under reduced pressure The obtained residue was washed with warmed ethyl acetate

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

Procedure: To a mixture of tetrahydro-2H-pyran-4-ylacetic acid (89 mg), N,N-dimethyl formamide (1 μL), and dichloromethane (1 mL) was added oxalylchloride (54 μL), and the mixture was stirred at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, and then toluene (1 mL) was added thereto, followed by further concentration under reduced pressure, to obtain crude tetrahydro-2H-pyran-4-yl acetyl chloride. The reaction liquid was concentrated under reduced pressure toluene (1 mL) was added followed by further concentration under reduced pressure

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

Procedure: A solution of tetrahydropyran-4-yl acetic acid (Combi-Blocks, Inc., 0.18 g, 1.2 mmol) in thionyl chloride (7 mL, 96 mmol, excess) was refluxed for 1 h then was cooled to ambient temperature and concentrated under reduced pressure. The residue was azeotroped twice with 10 mL of benzene to remove any remaining thionyl chloride. The resulting acid chloride was used without further purification. concentrated under reduced pressure The residue was azeotroped twice with 10 mL of benzene to remove any remaining thionyl chloride The resulting acid chloride was used without further purification

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

Procedure: In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (715 mg, 3.0 mmol) in DMF (20 mL) was added sodium hydride (purity of about 60%, 120 mg, 3.0 mmol, 1.0 eq.). The mixture was stirred until no more hydrogen was generated, to obtain a solution. Then, tetrahydro-2H-pyran-4-ylacetyl chloride (1.2 eq.) was added thereto, and the mixture was stirred at a room temperature for 1 hour. To the mixture was added a saturated sodium hydrogencarbonate aqueous solution, and the resulting precipitate was separated by filtration, washed with water, and dried to give 1-phenyl-4-(tetrahydro-2H-pyran-4-ylacetoxy)-1,8-naphthyridin-2(1H)-one as a form of crystal (738 mg, yield 67%). was synthesized to obtain a solution the resulting precipitate was separated by filtration washed with water dried

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

Procedure: To a mixture of N2-(3-chlorophenyl)-4-(trifluoromethyl)pyrimidine-2,5-diamine (147 mg), pyridine (62 μL), and dichloromethane (1 mL) was added a solution of the above crude tetrahydro-2H-pyran-4-ylacetyl chloride in dichloromethane (2 mL) under ice-cooling, followed by stirring at room temperature for 6 hours. To the reaction mixture was added ethyl acetate (50 mL), the organic layer was washed with a 10% aqueous citric acid solution, and then the solvent was evaporated under reduced pressure. The obtained residue was washed with warmed ethyl acetate to obtain N-{2-[(3-chlorophenyl)amino]-4-(trifluoromethyl)pyrimidin-5-yl}-2-(tetrahydro-2H-pyran-4-yl)acetamide (176 mg) as a colorless powder. cooling the organic layer was washed with a 10% aqueous citric acid solution the solvent was evaporated under reduced pressure The obtained residue was washed with warmed ethyl acetate

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

Procedure: To a mixture of tetrahydro-2H-pyran-4-ylacetic acid (89 mg), N,N-dimethyl formamide (1 μL), and dichloromethane (1 mL) was added oxalylchloride (54 μL), and the mixture was stirred at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, and then toluene (1 mL) was added thereto, followed by further concentration under reduced pressure, to obtain crude tetrahydro-2H-pyran-4-yl acetyl chloride. The reaction liquid was concentrated under reduced pressure toluene (1 mL) was added followed by further concentration under reduced pressure