2,2,2-trifluoro-N-methoxy-N-methylacetamide

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

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

Procedure: Starting materials (2R,6S)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 3) and 2,2,2-trifluoro-N-methoxy-N-methylacetamide. Compound exists in the hydrated form.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a chilled (−78° C.) solution of 4-(4-bromothiazol-2-yl)morpholine (249 mg, 1.00 mmol) in dry diethyl ether (10 mL) was added n-BuLi (480 μL, 2.5 M in hexanes, 1.20 mmol). After 20 minutes, a solution of 2,2,2-trifluoro-N-methoxy-N-methylacetamide (224 μL, 2 mmol) in THF (10 mL) was added over 10 minutes. After 30 minutes, the mixture was warmed to 0° C. After 30 minutes, the mixture was quenched with 10 mL of water, warmed to room temperature, and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was twice purified on SiO2 using ethyl acetate-hexanes (20-100% gradient) to afford 125 mg (47%) of the title compound. After 30 minutes After 30 minutes the mixture was quenched with 10 mL of water warmed to room temperature extracted with three 10 mL portions of ethyl acetate The combined organic layers were dried over magnesium sulfate filtered concentrated in vacuo The residue was twice purified on SiO2

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a chilled (−78° C.) solution of 4-(4-bromothiazol-2-yl)morpholine (249 mg, 1.00 mmol) in dry diethyl ether (10 mL) was added n-BuLi (480 μL, 2.5 M in hexanes, 1.20 mmol). After 20 minutes, a solution of 2,2,2-trifluoro-N-methoxy-N-methylacetamide (224 μL, 2 mmol) in THF (10 mL) was added over 10 minutes. After 30 minutes, the mixture was warmed to 0° C. After 30 minutes, the mixture was quenched with 10 mL of water, warmed to room temperature, and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was twice purified on SiO2 using ethyl acetate-hexanes (20-100% gradient) to afford 125 mg (47%) of the title compound. After 30 minutes After 30 minutes the mixture was quenched with 10 mL of water warmed to room temperature extracted with three 10 mL portions of ethyl acetate The combined organic layers were dried over magnesium sulfate filtered concentrated in vacuo The residue was twice purified on SiO2

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

Procedure: The reaction of 5-bromo-2,2,3,3-tetrafluorobenzofuran (5.3 g, 0.02 mole) with magnesium turnings (0.48 g) in dry diethyl ether was followed by reaction with N-methoxy-N-methyltrifluoroacetamide (3.5 g, 0.022 mole), yielding 5.3 g of 1-(2,2,3,3-tetrafluorobenzofuran-5-yl)-2,2,2-trifluoroethanone.

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

Procedure: 3-Bromopyridine (11.28 g, 0.0714 mol) in dry ether (50 ml) was added dropwise to a solution of n-butyl lithium (49.1 ml of a 1.6M solution in hexane, 0.0785 mol) in ether (150 ml) at -78° C. over 15 minutes. The resulting suspension was stirred for a further 15 minutes before N-methyl-N-methoxytrifluoroacetamide (D4, 11.22 g, 0.0715 mol) in ether (15 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature over 1 h then poured into stirred ice-cold 2M hydrochloric acid (200 ml). The aqueous layer was separated and washed with ether (2×100 ml). The combined organic layers were extracted with 2M hydrochloric acid (150 ml). The combined aqueous layers were then carefully made basic then saturated with potassium carbonate and extracted with chloroform (4×250 ml). The combined chloroform extracts were dried (Na2SO4) and evaporated to give a semi-crystalline solid which was taken-up in toluene (300 ml) and treated with methoxylamine hydrochloride (18 g, 0.216 mol) at reflux under Dean-Stark conditions for 2 h. The reaction mixture was cooled and extracted with 2M hydrochloric acid (3×150 ml). The combined aqueous extracts were washed with ether (2×200 ml) then basified and partially saturated with potassium carbonate then extracted with chloroform (2×300 ml). The combined organic fractions were dried (Na2SO4) and evaporated to give an oil which was distilled to give the title compound (D7) as a colourless oil (11.64 g, 80%) b.p. 135° C. at 120 mmHg. was added dropwise then poured The aqueous layer was separated washed with ether (2×100 ml) The combined organic layers were extracted with 2M hydrochloric acid (150 ml) carefully made basic then saturated with potassium carbonate and extracted with chloroform (4×250 ml) The combined chloroform extracts were dried (Na2SO4) evaporated to give a semi-crystalline solid which at reflux under Dean-Stark conditions for 2 h The reaction mixture was cooled extracted with 2M hydrochloric acid (3×150 ml) The combined aqueous extracts were washed with ether (2×200 ml) then extracted with chloroform (2×300 ml) The combined organic fractions were dried (Na2SO4) evaporated to give an oil which was distilled

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

Procedure: 3-Bromopyridine (11.28 g, 0.0714 mol) in dry ether (50 ml) was added dropwise to a solution of n-butyl lithium (49.1 ml of a 1.6M solution in hexane, 0.0785 mol) in ether (150 ml) at -78° C. over 15 minutes. The resulting suspension was stirred for a further 15 minutes before N-methyl-N-methoxytrifluoroacetamide (D4, 11.22 g, 0.0715 mol) in ether (15 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature over 1 h then poured into stirred ice-cold 2M hydrochloric acid (200 ml). The aqueous layer was separated and washed with ether (2×100 ml). The combined organic layers were extracted with 2M hydrochloric acid (150 ml). The combined aqueous layers were then carefully made basic then saturated with potassium carbonate and extracted with chloroform (4×250 ml). The combined chloroform extracts were dried (Na2SO4) and evaporated to give a semi-crystalline solid which was taken-up in toluene (300 ml) and treated with methoxylamine hydrochloride (18 g, 0.216 mol) at reflux under Dean-Stark conditions for 2 h. The reaction mixture was cooled and extracted with 2M hydrochloric acid (3×150 ml). The combined aqueous extracts were washed with ether (2×200 ml) then basified and partially saturated with potassium carbonate then extracted with chloroform (2×300 ml). The combined organic fractions were dried (Na2SO4) and evaporated to give an oil which was distilled to give the title compound (D7) as a colourless oil (11.64 g, 80%) b.p. 135° C. at 120 mmHg. was added dropwise then poured The aqueous layer was separated washed with ether (2×100 ml) The combined organic layers were extracted with 2M hydrochloric acid (150 ml) carefully made basic then saturated with potassium carbonate and extracted with chloroform (4×250 ml) The combined chloroform extracts were dried (Na2SO4) evaporated to give a semi-crystalline solid which at reflux under Dean-Stark conditions for 2 h The reaction mixture was cooled extracted with 2M hydrochloric acid (3×150 ml) The combined aqueous extracts were washed with ether (2×200 ml) then extracted with chloroform (2×300 ml) The combined organic fractions were dried (Na2SO4) evaporated to give an oil which was distilled

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution (0.2 M) of 1,3-thiazole-5-carboxylic acid (from Combi-blocks) in dry THF a solution of BuLi (1.6 M solution in hexane, 2.2 eq.) was added dropwise at −78° C. and stirred at −78° C. for 45 min. A solution (1 M) of N-methyl-N-methoxytrifluoroacetamide (1.5 eq.) in dry THF was added at −78° C. to the reaction mixture and stirred for 1 h at −60° C. The reaction mixture was quenched by adding NH4Cl solution, then extracted with DCM. The combined organic layer was washed with brine and dried. Evaporation of the solvent gave a residue (LC-MS (ES+) C6H2F3NO3S requires: 225, found: 226 (M+H)+. Retention time: 2.26 min) that was dissolved in DMF. To the resulting solution (0.5 M), HOBt (1.5 eq.) and EDCI (1.5 eq.) were added and stirring was continued for 1 h. N-benzylmethylamine (1.5 eq.) was added and the reaction mixture was stirred at RT O/N. The crude was purified by RP-HPLC to yield (3%) the title compound as a solid. stirred for 1 h at −60° C The reaction mixture was quenched by adding NH4Cl solution extracted with DCM The combined organic layer was washed with brine dried Evaporation of the solvent gave a residue (LC-MS (ES+) C6H2F3NO3S requires: 225, found: 226 (M+H)+. Retention time: 2.26 min) that stirring was continued for 1 h the reaction mixture was stirred at RT O/N The crude was purified by RP-HPLC

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution (0.2 M) of 1,3-thiazole-5-carboxylic acid (from Combi-blocks) in dry THF a solution of BuLi (1.6 M solution in hexane, 2.2 eq.) was added dropwise at −78° C. and stirred at −78° C. for 45 min. A solution (1 M) of N-methyl-N-methoxytrifluoroacetamide (1.5 eq.) in dry THF was added at −78° C. to the reaction mixture and stirred for 1 h at −60° C. The reaction mixture was quenched by adding NH4Cl solution, then extracted with DCM. The combined organic layer was washed with brine and dried. Evaporation of the solvent gave a residue (LC-MS (ES+) C6H2F3NO3S requires: 225, found: 226 (M+H)+. Retention time: 2.26 min) that was dissolved in DMF. To the resulting solution (0.5 M), HOBt (1.5 eq.) and EDCI (1.5 eq.) were added and stirring was continued for 1 h. N-benzylmethylamine (1.5 eq.) was added and the reaction mixture was stirred at RT O/N. The crude was purified by RP-HPLC to yield (3%) the title compound as a solid. stirred for 1 h at −60° C The reaction mixture was quenched by adding NH4Cl solution extracted with DCM The combined organic layer was washed with brine dried Evaporation of the solvent gave a residue (LC-MS (ES+) C6H2F3NO3S requires: 225, found: 226 (M+H)+. Retention time: 2.26 min) that stirring was continued for 1 h the reaction mixture was stirred at RT O/N The crude was purified by RP-HPLC

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

Procedure: A solution of 4-fluorophenylmagnesium bromide (3.64 mL, 1.1 M in THF, 4.0 mmol) in THF (3.6 mL) was stirred on a dry ice/acetone bath under argon while a solution of 4-fluoro-3-iodobenzaldehyde (1.00 g, 4.00 mmol, Intermediate 35: step a) in THF (6.4 mL) was added rapidly dropwise over 1.5 minutes, and the reaction was then immediately transferred to a room temperature water bath and stirred for 5 minutes. The clear, ˜colorless reaction was then cooled in the dry ice/acetone bath and treated with iPrMgCl (2.04 mL, 2.06 M in THF, 4.20 mmol) rapidly dropwise over 2.5 minutes. The yellow reaction was stirred for 30 minutes, and was then treated with 2,2,2-trifluoro-N-methoxy-N-methylacetamide dropwise over ˜30 seconds. The homogeneous yellow reaction was then immediately removed from the cold bath and allowed to warm to room temperature with stirring. After 2.5 hours, the dark yellow homogeneous reaction was chilled in a dry ice/acetone bath and quenched with 1 M aqueous NaH2PO4 (10 mL) in one portion. The reaction was warmed to room temperature and extracted with MTBE (1×10 mL, 1×5 mL), and the combined organic layers were washed with 5 M NaCl (1×3 mL), dried (Na2SO4), filtered, and concentrated twice from DCM to provide the crude title compound as a clear yellow oil. was then immediately transferred to a room temperature The clear, ˜colorless reaction The yellow reaction was stirred for 30 minutes The homogeneous yellow reaction was then immediately removed from the cold bath with stirring After 2.5 hours the dark yellow homogeneous reaction was chilled in a dry ice/acetone bath quenched with 1 M aqueous NaH2PO4 (10 mL) in one portion The reaction was warmed to room temperature extracted with MTBE (1×10 mL, 1×5 mL) the combined organic layers were washed with 5 M NaCl (1×3 mL) dried (Na2SO4) filtered concentrated twice from DCM

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-Bromo-6-(4-tert-butyl-cyclohexyloxy)-naphthalene (2 g, 0.006 mol) in 15 mL dry THF stirring at −78° C., was added dropwise. The reaction was then stirred at −78° C. for 15 minutes, yellow color results. 2,2,2-Trifluoro-N-methoxy-N-methyl-acetamide (1.0 mL, 0.0083 mol) in 10 mL THF was then added dropwise while the reaction was stirred at −78° C. Once all of the starting material was added reaction the reaction was allowed to warm to room temperature while stirring for 2 hours. The Reaction was then quenched with water and extracted three times with EtOAc. Organics were dried over MgSO4, filtered, and concentrated to dryness under reduced pressure. Crude NMR shows about 80% purity (looks like des-bromostarting material). Material was purified via column chromatography using a gradient of hexanes for one column volume followed by 0-10% EtOAC/Hexanes on 25 g of SiO2 to give the title compound as a yellow solid. Material will be carried on without additional purification yellow color results was stirred at −78° C Once all of the starting material was added reaction the reaction to warm to room temperature while stirring for 2 hours The Reaction was then quenched with water extracted three times with EtOAc Organics were dried over MgSO4 filtered concentrated to dryness under reduced pressure Material was purified via column chromatography

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2-Bromo-6-(4-tert-butyl-cyclohexyloxy)-naphthalene (2 g, 0.006 mol) in 15 mL dry THF stirring at −78° C., was added dropwise. The reaction was then stirred at −78° C. for 15 minutes, yellow color results. 2,2,2-Trifluoro-N-methoxy-N-methyl-acetamide (1.0 mL, 0.0083 mol) in 10 mL THF was then added dropwise while the reaction was stirred at −78° C. Once all of the starting material was added reaction the reaction was allowed to warm to room temperature while stirring for 2 hours. The Reaction was then quenched with water and extracted three times with EtOAc. Organics were dried over MgSO4, filtered, and concentrated to dryness under reduced pressure. Crude NMR shows about 80% purity (looks like des-bromostarting material). Material was purified via column chromatography using a gradient of hexanes for one column volume followed by 0-10% EtOAC/Hexanes on 25 g of SiO2 to give the title compound as a yellow solid. Material will be carried on without additional purification yellow color results was stirred at −78° C Once all of the starting material was added reaction the reaction to warm to room temperature while stirring for 2 hours The Reaction was then quenched with water extracted three times with EtOAc Organics were dried over MgSO4 filtered concentrated to dryness under reduced pressure Material was purified via column chromatography