2,2,2-trifluoroacetaldehyde;hydrate

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: This compound was prepared in a similar fashion as that described in Example 2, General Procedure IV but using 2-amino-5-nitroanisole and trifluoroacetaldehyde hydrate in place of Compound 200 and propionaldehyde. Compound 465 was isolated as a light brown crystalline solid after recrystallization (1:1 EtOAc:hexanes, 30 mL): Rf 0.52 (2:1 hexanes:EtOAc); 1H NMR (400 MHz, acetone-d6) 7.87 (dd, J=8.9, 2.4, 1H), 7.69 (d, J=2.4, 1H), 6.96 (d, J=8.9, 1H), 6.38 (broad s, 1H), 4.20 (qd, J=9.3, 7.1, 2H), 4.00 (s, 3H). This compound was prepared in a similar fashion as

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: This compound was prepared in a similar fashion as that described in Example 2, General Procedure IV but using 2-amino-5-nitroanisole and trifluoroacetaldehyde hydrate in place of Compound 200 and propionaldehyde. Compound 465 was isolated as a light brown crystalline solid after recrystallization (1:1 EtOAc:hexanes, 30 mL): Rf 0.52 (2:1 hexanes:EtOAc); 1H NMR (400 MHz, acetone-d6) 7.87 (dd, J=8.9, 2.4, 1H), 7.69 (d, J=2.4, 1H), 6.96 (d, J=8.9, 1H), 6.38 (broad s, 1H), 4.20 (qd, J=9.3, 7.1, 2H), 4.00 (s, 3H). This compound was prepared in a similar fashion as

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: This compound was prepared in a similar fashion as that described in Example 2, General Procedure IV but using 2-amino-5-nitroanisole and trifluoroacetaldehyde hydrate in place of Compound 200 and propionaldehyde. Compound 465 was isolated as a light brown crystalline solid after recrystallization (1:1 EtOAc:hexanes, 30 mL): Rf 0.52 (2:1 hexanes:EtOAc); 1H NMR (400 MHz, acetone-d6) 7.87 (dd, J=8.9, 2.4, 1H), 7.69 (d, J=2.4, 1H), 6.96 (d, J=8.9, 1H), 6.38 (broad s, 1H), 4.20 (qd, J=9.3, 7.1, 2H), 4.00 (s, 3H). This compound was prepared in a similar fashion as

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: This compound was prepared by General Method 7 (EXAMPLE 5) from (±)-3-ethyl-3,4-dihydro-7-nitro-2H-1,4-benzoxazine (200 mg, 0.96 mmol), 2,2,2-trifluoroacetaldehyde monohydrate (1.12 g, 9.6 mmol) and NaBH3CN (292 mg, 4.6 mmol) to afford 100 mg (36%) of 3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine, a yellow solid. Data for (±)-3-ethyl-3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine: Rf 0.69 (2:3 EtOAc:hexanes); 1H NMR (500 MHz, CDCl3) δ 7.80 (dd, 1H, J=8.9, 2.6), 7.71 (d, 1H, J=2.6), 6.72 (d, 1H, J=9.0), 4.34 (dd, 1H, J=10.9, 1.4), 4.19-4.05 (m, 1H), 4.02 (dd, 1H, J=11.0, 2.3), 3.87-3.72 (m, 1H), 1.72-1.62 (m, 2H), 1.00 (t, 34H, J=7.4).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: This compound was prepared by General Method 7 from 3,4-dihydro-7-nitro-2H-1,4-benzoxazine (EXAMPLE 1) (388 mg, 2.1 mmol), 2,2,2-trifluoroacetaldehyde monohydrate (2.51 g, 21.6 mmol) and NaBH3CN (656 mg, 10.4 mmol) to afford 500 mg (88%) of 3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine, a yellow solid. Data for 3,4-dihydro-7-nitro-4-(2,2,2-trifluoroethyl)-2H-1,4-benzoxazine: Rf 0.59 (3:2 EtOAc:hexanes); 1H NMR (400 MHz, CDCl3) δ 7.81 (dd, 1H, J=8.8, 2.6), 7.72 (d, 1H, J=2.6), 6.72 (d, 1H, J=9.1), 4.27 (t, 2H, J=4.5), 3.94 (2H, J=8.6), 3.61 (t, 2H, J=4.5).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3-amino-4-(4'-cyanophenyl)aminopyridine (420 mg, 2.0 mmol) (prepared as above), trifluoroacetaldehyde hydrate (232 mg, 2.0 mmol), and sodium metabisulphite (475 mg, 2.5 mmol) in N,N-dimethylacetamide (10 ml) was heated under reflux for 16 hours. After being cooled, the mixture was diluted with ethyl acetate (200 ml), washed with saturated aqueous sodium bicarbonate (50 ml) and water (5×50 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with ethyl acetate) to give 1-(4-cyanophenyl)-2-trifluoromethylimidazo[4,5-c]pyridine, 337 mg. was heated under reflux for 16 hours After being cooled washed with saturated aqueous sodium bicarbonate (50 ml) and water (5×50 ml) The organic layer was dried (MgSO4) concentrated under reduced pressure The residue was purified by flash chromatography (eluting with ethyl acetate)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 3-amino-4-(4'-cyanophenyl)aminopyridine (420 mg, 2.0 mmol) (prepared as above), trifluoroacetaldehyde hydrate (232 mg, 2.0 mmol), and sodium metabisulphite (475 mg, 2.5 mmol) in N,N-dimethylacetamide (10 ml) was heated under reflux for 16 hours. After being cooled, the mixture was diluted with ethyl acetate (200 ml), washed with saturated aqueous sodium bicarbonate (50 ml) and water (5×50 ml). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (eluting with ethyl acetate) to give 1-(4-cyanophenyl)-2-trifluoromethylimidazo[4,5-c]pyridine, 337 mg. was heated under reflux for 16 hours After being cooled washed with saturated aqueous sodium bicarbonate (50 ml) and water (5×50 ml) The organic layer was dried (MgSO4) concentrated under reduced pressure The residue was purified by flash chromatography (eluting with ethyl acetate)

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: This compound was prepared in a similar fashion as that described in Example 2, General Procedure IV but using 2-amino-5-nitroanisole and trifluoroacetaldehyde hydrate in place of Compound 200 and propionaldehyde. Compound 465 was isolated as a light brown crystalline solid after recrystallization (1:1 EtOAc:hexanes, 30 mL): Rf 0.52 (2:1 hexanes:EtOAc); 1H NMR (400 MHz, acetone-d6) 7.87 (dd, J=8.9, 2.4, 1H), 7.69 (d, J=2.4, 1H), 6.96 (d, J=8.9, 1H), 6.38 (broad s, 1H), 4.20 (qd, J=9.3, 7.1, 2H), 4.00 (s, 3H). This compound was prepared in a similar fashion as

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: This compound was prepared in a similar fashion as that described in Example 2, General Procedure IV but using 2-amino-5-nitroanisole and trifluoroacetaldehyde hydrate in place of Compound 200 and propionaldehyde. Compound 465 was isolated as a light brown crystalline solid after recrystallization (1:1 EtOAc:hexanes, 30 mL): Rf 0.52 (2:1 hexanes:EtOAc); 1H NMR (400 MHz, acetone-d6) 7.87 (dd, J=8.9, 2.4, 1H), 7.69 (d, J=2.4, 1H), 6.96 (d, J=8.9, 1H), 6.38 (broad s, 1H), 4.20 (qd, J=9.3, 7.1, 2H), 4.00 (s, 3H). This compound was prepared in a similar fashion as

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2.55 g (0.01 mole) of 2,3-bis(4-fluorophenyl)-1H-pyrrole and 1.3 g (0.011 mole) of trifluoroacetaldehyde hydrate in 75 ml toluene was heated at reflux for 3.5 hours. The mixture was concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel to give 1.9 g of product, m.p. 121°-122°. was heated at reflux for 3.5 hours The mixture was concentrated on a rotary evaporator The residue was purified by chromatography on silica gel

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A mixture of 2.55 g (0.01 mole) of 2,3-bis(4-fluorophenyl)-1H-pyrrole and 1.3 g (0.011 mole) of trifluoroacetaldehyde hydrate in 75 ml toluene was heated at reflux for 3.5 hours. The mixture was concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel to give 1.9 g of product, m.p. 121°-122°. was heated at reflux for 3.5 hours The mixture was concentrated on a rotary evaporator The residue was purified by chromatography on silica gel

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: step 3—To a solution of 318 (201 mg, 0.402 mmol) in TFA (4 mL) at RT was added trifluoroacetaldehyde hydrate (98 mg, 0.845 mmol) and H2O (2 drops). The reaction mixture was stirred at RT for 5 min, and then sodium cyanoborohydride (33 mg, 0.523 mmol) was added. Gas evolution was briefly observed. The reaction mixture was stirred at RT for 4.5 h, then diluted with H2O and EtOAc and carefully poured into sat'd NaHCO3. The layers were separated, and the organic phase was subsequently twice washed sequentially with sat'd. NaHCO3, H2O and brine. The organic layer was dried (MgSO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography, eluting with an EtOAc/hexane gradient (0% to 30% EtOAc) to afford 89 mg (38%) of N-[5-(2-benzyloxy-pyridin-3-yl)-3-tert-butyl-2-methoxy-phenyl]-3-fluoro-4-(2,2,2-trifluoro-ethylamino)-benzamide (320) as a foamy, light yellow solid. The reaction mixture was stirred at RT for 4.5 h The layers were separated the organic phase was subsequently twice washed sequentially with sat'd The organic layer was dried (MgSO4) filtered concentrated The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (0% to 30% EtOAc)