oxan-2-ylmethanamine

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

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

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

Procedure: A solution of 2-aminomethyltetrahydropyran (51 g, 0.44 mole) and ethanol (50 ml) was slowly added to a heated suspension of 6-nitroveratraldehyde (84 g, 0.4 mole) and ethanol (600 ml). The resulting solution was refluxed for 1.5 hrs and cooled overnight. The solution was concentrated to dryness and the oil was dissolved in chloroform and washed with water. The chloroform extract was concentrated leaving a dark oil which crystallized upon standing. The solid was suspended in hexane and filtered (117 g, 95%), m.p. 89°-96°. The resulting solution was refluxed for 1.5 hrs cooled overnight The solution was concentrated to dryness the oil was dissolved in chloroform washed with water The chloroform extract was concentrated leaving a dark oil which crystallized filtered (117 g, 95%), m.p. 89°-96°

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

Procedure: The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (tetrahydro-2H-pyran-2-yl)methanamine 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.31 (m, 2 H) 1.32-1.45 (m, 2 H) 1.77-1.91 (m, 4 H) 2.40-2.46 (m, 3 H) 3.37-3.49 (m, 1 H) 3.65-3.82 (m, 1 H) 4.58 (br. s., 1 H) 7.65 (dd, J=7.83, 1.52 Hz, 1 H) 7.73 (s, 1 H) 7.77 (d, J=7.83 Hz, 1 H) 8.16 (br. s., 1 H) 8.25-8.65 (m, 3 H) 8.80-9.01 (m, 1 H) 12.36-13.83 (m, 1 H). MS m/z [M+H]+ 418.2.

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

Procedure: The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (tetrahydro-2H-pyran-2-yl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.31 (m, 2H) 1.32-1.45 (m, 2H) 1.77-1.91 (m, 4H) 2.40-2.46 (m, 3H) 3.37-3.49 (m, 1H) 3.65-3.82 (m, 1H) 4.58 (br. s., 1H) 7.65 (dd, J=7.83, 1.52 Hz, 1H) 7.73 (s, 1H) 7.77 (d, J=7.83 Hz, 1H) 8.16 (br. s., 1H) 8.25-8.65 (m, 3H) 8.80-9.01 (m, 1H) 12.36-13.83 (m, 1H). MS m/z [M+H]+418.2.

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

Procedure: The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (tetrahydro-2H-pyran-2-yl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.31 (m, 2H) 1.32-1.45 (m, 2H) 1.77-1.91 (m, 4H) 2.40-2.46 (m, 3H) 3.37-3.49 (m, 1H) 3.65-3.82 (m, 1H) 4.58 (br. s., 1H) 7.65 (dd, J=7.83, 1.52 Hz, 1H) 7.73 (s, 1H) 7.77 (d, J=7.83 Hz, 1H) 8.16 (br. s., 1H) 8.25-8.65 (m, 3H) 8.80-9.01 (m, 1H) 12.36-13.83 (m, 1H). MS m/z [M+H]+418.2.

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

Procedure: 2-Fluoro-5-chloronitrobenzene (0.762 g; 4.341 mmol), tetrahydropyran methyl amine (0.5 g; 4.341 mmol), N,N-diisopropylethylamine (0.756 mL; 4.341 mmol) and dimethylsulfoxide (2 mL) are heated at 80° C. in an oil bath for 4 days. After this time the reaction is cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organics are washed with water and brine and concentrated in vacuo to afford title compound as an orange oil which solidified upon standing and was used crude in subsequent reactions. ESI m/z 271 [M+H]+ extracted with ethyl acetate The combined organics are washed with water and brine concentrated in vacuo

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

Procedure: A solution of 2-aminomethyltetrahydropyran (51 g, 0.44 mole) and ethanol (50 ml) was slowly added to a heated suspension of 6-nitroveratraldehyde (84 g, 0.4 mole) and ethanol (600 ml). The resulting solution was refluxed for 1.5 hrs and cooled overnight. The solution was concentrated to dryness and the oil was disolved in chloroform and washed with water. The chloroform extract was concentrated leaving a dark oil which crystallized upon standing. The solid was suspended in hexane and filtered (117 g. 95%), m.p. 89°-96°. The resulting solution was refluxed for 1.5 hrs cooled overnight The solution was concentrated to dryness washed with water The chloroform extract was concentrated leaving a dark oil which crystallized filtered (117 g. 95%), m.p. 89°-96°

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

Procedure: A solution of 2-aminomethyltetrahydropyran (51 g, 0.44 mole) and ethanol (50 ml) was slowly added to a heated suspension of 6-nitroveratraldehyde (84 g, 0.4 mole) and ethanol (600 ml). The resulting solution was refluxed for 1.5 hrs and cooled overnight. The solution was concentrated to dryness and the oil was disolved in chloroform and washed with water. The chloroform extract was concentrated leaving a dark oil which crystallized upon standing. The solid was suspended in hexane and filtered (117 g. 95%), m.p. 89°-96°. The resulting solution was refluxed for 1.5 hrs cooled overnight The solution was concentrated to dryness washed with water The chloroform extract was concentrated leaving a dark oil which crystallized filtered (117 g. 95%), m.p. 89°-96°

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

Procedure: Sodium hydroxide solution (2N, 0.4 mL) was added to 3-(3-chlorophenyl)-7-trifluoromehyl-imidazo[1,2-a]pyrimidine-6-carboxylic acid ethyl ester (137 mg, 0.370 mmol) in THF (1.6 mL) and methanol (0.4 mL) at room temperature. The resulting solution was stirred for 2 hours then concentrated to dryness. Ethyl acetate was added and removed in vacuo three times. The crude residue was diluted in DMF (1.5 mL) and EDC (3 eq, 1.11 mmol, 213 mg), HOBt (3 eq, 1.11 mmol, 150 mg) were added. The mixture was stirred for 15 minutes, then tetrahydropyran-methylamine (1.5 eq, 64 mg) and triethyl amine (3 eq, 1.11 mmol, 0.16 mL) were added. The resulting mixture was stirred overnight. The reaction mixture was quenched by the addition of aqueous NH4Cl solution and the product was extracted with ethyl acetate. The crude product was purified using column chromatography (using 2% methanol/EtOAc as eluent) to afford 3-(3-chlorophenyl)-7-trifluoromehyl-imidazo[1,2-a]pyrimidine-6-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide in 43% yield. 1H NMR (DMSO-d6) δ 11.65 (1H), 8.50-8.52 (2H), 8.19 (1H), 8.01 (1H), 7.48 (1H), 7.41 (1H), 3.92 (2H), 372 (2H), 3.31 (2H), 1.92 (1H), 1.58 (2H), 1.31 (2H); m/z (M+H)=439.3. then concentrated to dryness Ethyl acetate was added removed in vacuo three times The crude residue was diluted in DMF (1.5 mL) The mixture was stirred for 15 minutes The resulting mixture was stirred overnight The reaction mixture was quenched by the addition of aqueous NH4Cl solution the product was extracted with ethyl acetate The crude product was purified

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

Procedure: To a solution of 2-(3-chloro-phenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid sodium salt (141 mg, 0.481 mmol) in DMF (2 mL) were added EDC (3 eq, 1.44 mmol, 277 mg) and HOBt (3 eq, 1.44 mmol, 195 mg). The mixture was stirred at room temperature for 15 minutes then tetrahydropyran-methylamine (1.5 eq, 0.72 mmol, 83 mg) and triethyl amine (3 eq, 1.44 mmol, 0.21 mL) were added. The reaction mixture was stirred at room temperature for 3 hours then quenched by the addition of water. The product was extracted three times with ethyl acetate and the crude product was purified by column chromatography to afford 2-(3-chloro-phenyl)-imidazo[1,2-a]pyridine-7-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide in 65% yield. 1H NMR (DMSO-d6) δ 8.69 (1H), 8.61 (2H), 8.16 (1H), 8.11 (1H), 7.98 (1H), 7.51 (1H), 7.41 (1H), 7.38 (1H), 3.92 (2H), 3.18 (2H), 3.11 (2H), 1.95 (1H), 1.31 (2H), 1.12 (2H); m/z (M+H)=370.3 The reaction mixture was stirred at room temperature for 3 hours then quenched by the addition of water The product was extracted three times with ethyl acetate the crude product was purified by column chromatography

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

Procedure: Sodium hydroxide solution (2N, 0.3 mL) was added to 3-(2,4-dichloro-phenyl)-7-trifluoromehyl-imidazo[1,2-a]pyrimidine-6-carboxylic acid ethyl ester (113 mg, 0.28 mmol) in THF (1.2 mL) and methanol (0.3 mL) at room temperature. The resulting solution was stirred for 2 hours then concentrated to dryness. Ethyl acetate was added and removed in vacuo three times. The crude residue was diluted in DMF (1.5 mL) and EDC (3 eq, 0.84 mmol, 162 mg), HOBt (3 eq, 0.843 mmol, 114 mg) were added. The mixture was stirred for 15 minutes, then tetrahydropyran-methylamine (1.5 eq, 55 mg) and triethylamine (3 eq, 0.84 mmol, 0.12 mL) were added. The resulting mixture was stirred overnight. The reaction mixture was quenched by the addition of aqueous NH4Cl solution and the product was extracted with ethyl acetate. The crude product was purified using column chromatography (using 2% methanol/EtOAc as eluent) to afford 3-(2,4-dichlorophenyl)-7-trifluoromethyl-imidazo[1,2-a]pyrimidine-6-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide in 43% yield. 1H NMR (DMSO-d6) δ 11.62 (1H), 8.54 (1H), 8.62 (1H), 8.41 (1H), 7.82 (1H), 7.60 (1H), 3.94 (2H), 3.72 (2H), 3.35 (2H), 1.98 (1H), 1.56 (2H), 1.34 (2H); m/z (M+H)=474.3. then concentrated to dryness Ethyl acetate was added removed in vacuo three times The crude residue was diluted in DMF (1.5 mL) The mixture was stirred for 15 minutes The resulting mixture was stirred overnight The reaction mixture was quenched by the addition of aqueous NH4Cl solution the product was extracted with ethyl acetate The crude product was purified