1,1,1-trifluoro-N-phenylmethanesulfonamide

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:

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

Procedure: Diisopropylamine (18.0 mL, 128 mmol) was taken up in 50 mL of THF and chilled to −78° C. Butyllithium, 2.5 M in hexanes (51.0 mL, 128 mmol) was added dropwise. After 10 min, 1-acetylpiperidin-4-one (15.0 g, 106 mmol) was added in 60 mL of THF with rigorous stirring. After 30 min, n-phenyltriflamide (41.8 g, 117 mmol) was added in 120 mL of THF. The reaction mixture was stirred at −78° C. to RT for 16 h. The reaction mixture was quenched by saturated NaHCO3, followed by extraction with EtOAc and 5% citric acid. The organic layer was washed with 1 N NaOH (2×), water (2×), and brine, then dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (0% to 60% EtOAc/hexanes) afforded 1-acetyl-1,2,3,6-tetrahydropyridin-4-yl trifluoromethanesulfonate as a yellow oil. After 30 min The reaction mixture was quenched by saturated NaHCO3 followed by extraction with EtOAc and 5% citric acid The organic layer was washed with 1 N NaOH (2×), water (2×), and brine dried over MgSO4 Filtration and concentration under reduced pressure

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

Procedure: To a solution of diisopropylamine, (6.24 mL, 44.2 mmol) in THF (60 mL) at −78° C. under argon was slowly added n-butyllithium (17.7 mL, 44.2 mmol, 2.5 M in hexanes). The mixture was stirred for 30 min at that temperature before 1,4-cyclohexanedione mono-ethylene ketal (6.00 g, 38.4 mmol) was added slowly as a solution in THF (20 mL). The mixture was stirred for an additional 30 min at −78° C. and then n-phenyltriflamide (13.7 g, 38.4 mmol) was slowly added as a suspension in THF (50 mL). This mixture was stirred overnight with gradual warming to room temperature. The solvent was removed in vacuo and the remaining oil was partitioned between 3:1 ethyl acetate/hexane and water. The layers were separated and the organic layer was washed with water (3×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate. at −78° C. This mixture was stirred overnight with gradual warming to room temperature The solvent was removed in vacuo the remaining oil was partitioned between 3:1 ethyl acetate/hexane and water The layers were separated the organic layer was washed with water (3×) dried over anhydrous magnesium sulfate filtered concentrated in vacuo

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

Procedure: To a stirring solution of diisopropylamine (38.7 mL, 275 mmol) in THF (900 mL) at 0° C. was added dropwise via an addition funnel a solution of n-BuLi in hexanes (1.6 MN 171.5 mL, 276 mmol). After 25 min, the solution was cooled to −78° C. To this solution was added dropwise via an addition funnel a solution of 1-Boc-4-piperidinone (50 g, 250.9 mmol) in THF (300 mL). After 30 min, a solution of N-phenyltrifluoromethanesulfonamide (95.9 g, 268.5 mmol) in THF (300 mL) was added and the solution was warmed to 0° C. After 3 h, the solvents were evaporated in vacuo and the residue was loaded into a silica gel column with a minimal amount of dichloromethane and eluted with 5% ethyl acetate/hexanes. The product containing fractions were combined and concentrated in vacuo to give 74.84 g (90%) of a light yellow oil. After 30 min the solution was warmed to 0° C After 3 h the solvents were evaporated in vacuo eluted with 5% ethyl acetate/hexanes The product containing fractions concentrated in vacuo

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

Procedure: To a −70° C. stirred solution of N-Boc-piperidone (500 mg, 2.5 mmol) in tetrahydrofuran (11 mL) was added lithium diisopropylamine (1.37 mL of a 2 M solution in tetrahydrofuran, 2.75 mmol). The reaction mixture was stirred for 2 h, warmed to 0° C., and N-phenyltriflamide (955 mg, 2.67 mmol) was added. The solution was allowed to warm to room temperature and was stirred for 12 h. The reaction mixture was concentrated under reduced pressure. Purification by flash column chromatography (3:1 hexanes/ethyl acetate) afforded tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (240 mg): 1H NMR (300 MHz, CDCl3) δ 5.77 (s, 1H), 4.05 (m, 2H), 3.63 (m, 2H), 2.45 (m, 2H), 1.48 (s, 9H). to warm to room temperature was stirred for 12 h The reaction mixture was concentrated under reduced pressure Purification by flash column chromatography (3:1 hexanes/ethyl acetate)

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

Procedure: A vial charged with (S)-2′-amino-3-(3,3-dimethylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-7-ol (0.200 g, 0.572 mmol) and potassium carbonate (0.087 g, 0.630 mmol) was treated with 2 mL DMF and was allowed to stir for 15 minutes. The reaction mixture was cooled to 0° C. and n-phenyltriflamide (0.245 g, 0.630 mmol) was added. After stirring for one hour the reaction mixture was poured into water and extracted with EtOAc. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by column chromatography gave (S)-2′-amino-3-(3,3-dimethylbut-1-ynyl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-7-yl trifluoromethanesulfonate (0.183 g, 0.380 mmol, 66.4% yield) After stirring for one hour the reaction mixture extracted with EtOAc The organics were dried over MgSO4 concentrated Purification of the crude residue by column chromatography

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

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

Procedure: To a stirred, cooled (0° C.) solution of 6-hydroxy-8-propionyl-2,3-dihydroindolizin-5-(1H)-one (1.10 g, 4.53 mmol) in CH2Cl2 (10 mL) was added Et3N. After stirring for 20 min., N-phenyltrifluoromethane sulfonamide was added in one portion. The mixture was stirred at RT for 6 h and quenched with H2O. the mixture was extracted with CH2Cl2 (3×) and the combined organic layers were dried over MgSO4, concentrated and purified by ISCO (40% EtOAc/Hexanes) to give the title compound as a white solid (1.50 g, 99%). The mixture was stirred at RT for 6 h quenched with H2O the mixture was extracted with CH2Cl2 (3×) the combined organic layers were dried over MgSO4 concentrated purified by ISCO (40% EtOAc/Hexanes)

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

Procedure: To a stirred, cooled (0° C.) solution of 6-hydroxy-8-propionyl-2,3-dihydroindolizin-5-(1H)-one (1.10 g, 4.53 mmol) in CH2Cl2 (10 mL) was added Et3N. After stirring for 20 min., N-phenyltrifluoromethane sulfonamide was added in one portion. The mixture was stirred at RT for 6 h and quenched with H2O. the mixture was extracted with CH2Cl2 (3×) and the combined organic layers were dried over MgSO4, concentrated and purified by ISCO (40% EtOAc/Hexanes) to give the title compound as a white solid (1.50 g, 99%). The mixture was stirred at RT for 6 h quenched with H2O the mixture was extracted with CH2Cl2 (3×) the combined organic layers were dried over MgSO4 concentrated purified by ISCO (40% EtOAc/Hexanes)