4,4,4-trifluorobutan-2-one

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

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: To a solution of 4,4,4-trifluorobutan-2-one (12 g, 95 mmol) in THF (150 ml) was added titanium (IV) isopropoxide (42 ml, 142 mmol) and (R)-tert-butanesulfinamide (17.3 g, 142 mmol). The solution was heated to reflux for 22 h, cooled to RT, and poured into a vigorously-stirred brine solution. The mixture was filtered through a pad of Celite, the filter cake washed with EtOAc, and the filtrate separated. The aqueous layer was extracted with EtOAc, the organic layers combined and washed with brine, dried on Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (15% to 60% EtOAc in hexanes) to afford the title compound as a yellow oil (14.0 g, 65%). 1H NMR (CDCl3, 400 MHz) δ 1.25 (s, 9H), 2.45 (s, 3H), 3.19 (q, J=14.4 Hz, 2H). 19F NMR (CDCl3, 376 MHz) δ −61.03 (t, J=10.5 Hz), −62.8 (t, J=10.5 Hz). The solution was heated to reflux for 22 h The mixture was filtered through a pad of Celite the filter cake washed with EtOAc the filtrate separated The aqueous layer was extracted with EtOAc washed with brine dried on Na2SO4 concentrated in vacuo The residue was purified by column chromatography (15% to 60% EtOAc in hexanes)

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 60 (0.37 g, 1 mmol) in 11 mL of 95:5 methanol-acetic acid was treated with excess of 4,4,4-trifluorobutan-2-one (1 g, 7.9 mmol), followed by sodium cyanoborohydride (0.25 g, 4 mmol). The reaction mixture was heated at 70° C. overnight, after which a small trace of the desired product was detected by LC-MS analysis. The crude reaction mixture was directly submitted to silica gel chromatography; elution with 9:1 dichloromethane-2 M ammonia in methanol provided a small amount of impure product. Further purification by preparative thin layer chromatography afforded 10 mg of the title compound, identified by LC-MS (Method A).

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 5-chloro-N-(5-chloropyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 60 (0.37 g, 1 mmol) in 11 mL of 95:5 methanol-acetic acid was treated with excess of 4,4,4-trifluorobutan-2-one (1 g, 7.9 mmol), followed by sodium cyanoborohydride (0.25 g, 4 mmol). The reaction mixture was heated at 70° C. overnight, after which a small trace of the desired product was detected by LC-MS analysis. The crude reaction mixture was directly submitted to silica gel chromatography; elution with 9:1 dichloromethane-2 M ammonia in methanol provided a small amount of impure product. Further purification by preparative thin layer chromatography afforded 10 mg of the title compound, identified by LC-MS (Method A).

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

Procedure: A mixture of 3-amino-4-bromo-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide (90 mg, 0.313 mmol), 4,4,4-trifluorobutan-2-one (395 mg, 3.13 mmol), CSA (7.28 mg, 0.031 mmol), MgSO4 (37.7 mg, 0.313 mmol) and DMA (2 mL) was microwave-irradiated at 150° C. for 3 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc). The obtained solid was triturated with EtOAc, and the precipitate was collected by filtration to afford the title compound (29.2 mg, 24%) as a white solid: was microwave-irradiated at 150° C. for 3 h extracted with EtOAc the extract was dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) The obtained solid was triturated with EtOAc the precipitate was collected by filtration

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

Procedure: A mixture of 3-amino-4-bromo-5-(1H-pyrazol-4-yl)thiophene-2-carboxamide (90 mg, 0.313 mmol), 4,4,4-trifluorobutan-2-one (395 mg, 3.13 mmol), CSA (7.28 mg, 0.031 mmol), MgSO4 (37.7 mg, 0.313 mmol) and DMA (2 mL) was microwave-irradiated at 150° C. for 3 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc). The obtained solid was triturated with EtOAc, and the precipitate was collected by filtration to afford the title compound (29.2 mg, 24%) as a white solid: was microwave-irradiated at 150° C. for 3 h extracted with EtOAc the extract was dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) The obtained solid was triturated with EtOAc the precipitate was collected by filtration

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-bromo-3-(ethylamino)thiophene-2-carboxamide (250 mg, 1.0 mmol), 4,4,4-trifluorobutan-2-one (1.0 mL), CSA (23 mg, 0.10 mmol), MgSO4 (192 mg, 2.0 mmol) and DMA (0.5 mL) was microwave-irradiated at 150° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to 50:50 hexane/EtOAc) to give a brown crystalline solid. A flask was charged with this solid, 1,2-dimethoxyethane (3 mL), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (555 mg, 1.8 mmol), sodium carbonate (180 mg, 3.0 mmol) and water (1.5 mL). The flask was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (49 mg, 0.060 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 100° C. for 6 h, organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 50:50 hexane/EtOAc to EtOAc), then crystallized from MeOH/EtOAc/heptane) to give the title compound (37 mg, 10%) as a pale brown solid: was microwave-irradiated at 150° C. for 1 h The organic materials were extracted with EtOAc The combined extracts were washed with water and brine dried over Na2SO4 filtered After removal of the solvent at reduced pressure the residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to 50:50 hexane/EtOAc) to give a brown crystalline solid The flask was purged with argon The flask was purged with argon again organic materials were extracted with EtOAc The combined extracts were washed with brine dried over Na2SO4 filtered After removal of the solvent at reduced pressure the residue was purified by column chromatography (Purif, silica gel, 50:50 hexane/EtOAc to EtOAc) crystallized from MeOH/EtOAc/heptane)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-bromo-3-(ethylamino)thiophene-2-carboxamide (250 mg, 1.0 mmol), 4,4,4-trifluorobutan-2-one (1.0 mL), CSA (23 mg, 0.10 mmol), MgSO4 (192 mg, 2.0 mmol) and DMA (0.5 mL) was microwave-irradiated at 150° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to 50:50 hexane/EtOAc) to give a brown crystalline solid. A flask was charged with this solid, 1,2-dimethoxyethane (3 mL), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (555 mg, 1.8 mmol), sodium carbonate (180 mg, 3.0 mmol) and water (1.5 mL). The flask was purged with argon. Then, 1,1′-bis(diphenylphosphino)ferrocenepalladium (II) dichloride dichloromethane adduct (49 mg, 0.060 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 100° C. for 6 h, organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 50:50 hexane/EtOAc to EtOAc), then crystallized from MeOH/EtOAc/heptane) to give the title compound (37 mg, 10%) as a pale brown solid: was microwave-irradiated at 150° C. for 1 h The organic materials were extracted with EtOAc The combined extracts were washed with water and brine dried over Na2SO4 filtered After removal of the solvent at reduced pressure the residue was purified by column chromatography (Purif, silica gel, 90:10 hexane/EtOAc to 50:50 hexane/EtOAc) to give a brown crystalline solid The flask was purged with argon The flask was purged with argon again organic materials were extracted with EtOAc The combined extracts were washed with brine dried over Na2SO4 filtered After removal of the solvent at reduced pressure the residue was purified by column chromatography (Purif, silica gel, 50:50 hexane/EtOAc to EtOAc) crystallized from MeOH/EtOAc/heptane)

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,2-dimethyl-6-(5-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one, 1 M HCl (1.2 mL, 1.2 mmol) and MeOH (4 mL) was stirred at 50° C. for 2 h. Then, the reaction mixture was poured into excess saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was mixed with 4,4,4-trifluorobutan-2-one (0.433 g, 3.43 mmol), CSA (7.97 mg, 0.034 mmol), MgSO4 (0.041 g, 0.343 mmol) and DMA (1 mL). The mixture was microwave-irradiated at 140° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH). The obtained oil was purified again by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) to give yellow oil. This oil was dissolved with small amount of EtOAc and poured into heptane (100 mL) with stirring. After 5 min, the precipitate was collected by filtration to afford the title compound (33.5 mg, 30%) as a yellow solid: extracted with EtOAc the extract was dried over MgSO4 filtered concentrated under reduced pressure The mixture was microwave-irradiated at 140° C. for 1 h extracted with EtOAc the extract was dried over MgSO4 filtered concentrated under reduced pressure The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc The obtained oil was purified again by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) to give yellow oil with stirring After 5 min the precipitate was collected by filtration

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

Procedure: A mixture of 5-bromo-3-(methylamino)thiophene-2-carboxamide (940 mg, 4.0 mmol), 4,4,4-trifluorobutan-2-one (5.04 g, 40 mmol), CSA (93 mg, 0.40 mmol), MgSO4 (576 mg, 6.0 mmol) and DMA (4 mL) was microwave-irradiated at 150° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3. The organic materials were extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, NH, 90:10 hexane/EtOAc to 50:50 hexane/EtOAc) to give a yellow solid. The solid was purified by crystallization from EtOAc/heptane to give the title compound (431 mg, 31%) as a yellow solid: was microwave-irradiated at 150° C. for 1 h The organic materials were extracted with EtOAc The combined extracts were washed with water and brine dried over Na2SO4 filtered After removal of the solvent at reduced pressure the residue was purified by column chromatography (Purif, NH, 90:10 hexane/EtOAc to 50:50 hexane/EtOAc) to give a yellow solid The solid was purified by crystallization from EtOAc/heptane