ethyl (2R)-4-bromo-2-methyl-2-methylsulfonylbutanoate

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

Procedure: Cesium carbonate (1.90 g, 5.84 mmol) was added to a solution of the 3,5-difluoro-4-iodopyridin-2(1H)-one (1.0 g, 3.9 mmol) and ethyl (2R)-4-bromo-2-methyl-2-(methylsulfonyl)butanoate, T1, (1.45 g, 5.06 mmol) in tetrahydrofuran:t-butanol (1:1, 50 mL). The resulting suspension was heated to reflux and was stirred at this temperature for 72 h. The reaction was filtered through celite, and the filter pad was washed with EtOAc (3×50 mL). The combined filtrates were concentrated and the crude product was purified via flash chromatography on an Analogix SF15-24 g column using an eluent of EtOAc in hexanes (0-50%) to afford the title compound as a yellow solid (575.6 mg, 32%). MS (LCMS) m/z 463.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (s, 3H) 1.58 (s, 3H) 2.20 (dt, J=13.90, 7.00 Hz, 1H) 2.52-2.62 (m, 1H) 3.14 (s, 3H) 4.00 (t, J=7.61 Hz, 2H) 4.05-4.22 (m, 2H) 7.94 (dd, J=4.20, 2.05 Hz, 1H). The resulting suspension was heated to reflux The reaction was filtered through celite the filter pad was washed with EtOAc (3×50 mL) The combined filtrates were concentrated the crude product was purified via flash chromatography on an Analogix SF15-24 g column

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

Procedure: Cesium carbonate (1.90 g, 5.84 mmol) was added to a solution of the 3,5-difluoro-4-iodopyridin-2(1H)-one (1.0 g, 3.9 mmol) and ethyl (2R)-4-bromo-2-methyl-2-(methylsulfonyl)butanoate, T1, (1.45 g, 5.06 mmol) in tetrahydrofuran:t-butanol (1:1, 50 mL). The resulting suspension was heated to reflux and was stirred at this temperature for 72 h. The reaction was filtered through celite, and the filter pad was washed with EtOAc (3×50 mL). The combined filtrates were concentrated and the crude product was purified via flash chromatography on an Analogix SF15-24 g column using an eluent of EtOAc in hexanes (0-50%) to afford the title compound as a yellow solid (575.6 mg, 32%). MS (LCMS) m/z 463.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (s, 3H) 1.58 (s, 3H) 2.20 (dt, J=13.90, 7.00 Hz, 1H) 2.52-2.62 (m, 1H) 3.14 (s, 3H) 4.00 (t, J=7.61 Hz, 2H) 4.05-4.22 (m, 2H) 7.94 (dd, J=4.20, 2.05 Hz, 1H). The resulting suspension was heated to reflux The reaction was filtered through celite the filter pad was washed with EtOAc (3×50 mL) The combined filtrates were concentrated the crude product was purified via flash chromatography on an Analogix SF15-24 g column

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

Procedure: Cesium carbonate (1.77 g, 5.44 mmol) was added to a suspension of 5-fluoro-4-iodopyridin-2(1H)-one (1.00 g, 4.2 mmol) and ethyl (2R)-4-bromo-2-methyl-2-(methylsulfonyl)butanoate (1.56 g, 5.44 mmol) in anhydrous THF (45 mL). The reaction was heated to 70° C. and stirred at this temperature overnight. The reaction was quenched with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), filtered, and concentrated. The crude product was purified via flash chromatography using a Varian SF15-24 g column and an eluent of EtOAc in n-heptane (30-80%) to afford the title compound as a yellow residue (691 mg, 37%). MS (LCMS) m/z 446.0 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (t, 3H) 1.75 (s, 3H) 2.37-2.57 (m, 2H) 3.10 (s, 3H) 3.83-4.02 (m, 1H) 4.16-4.37 (m, 3H) 7.15 (d, 1H) 7.20 (d, J=3.32 Hz, 1H). The reaction was quenched with water (100 mL) extracted with EtOAc (2×100 mL) The combined organics were washed with brine (100 mL) dried (MgSO4) filtered concentrated The crude product was purified via flash chromatography

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

Procedure: To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.8 g, 4.12 mmol) in acetonitrile (10 mL) was added cesium carbonate (3.36 g, 10.3 mmol, 2.5 eq), sodium iodide (0.124 g, 0.825 mmol, 0.2 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (1.54 g, 5.36 mmol, 1.3 eq). The mixture was heated at 50° C. overnight. The reaction mixture was filtered over a pad of diatomateous earth and the filtrate was evaporated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10-100% ethyl acetate/heptane to give ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanoate (0.810 g, 49% yield) as a white solid. LC-MS M+H+401.3. The reaction mixture was filtered over a pad of diatomateous earth the filtrate was evaporated to dryness The crude product was purified by flash chromatography on silica gel eluting with 10-100% ethyl acetate/heptane

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

Procedure: To a solution of 2-(1H-pyrazol-4-yl)-1,3-benzoxazole (0.250 g, 1.35 mmol) in acetonitrile (10 mL) was added cesium carbonate (1.10 g, 3.38 mmol, 2.5 eq), sodium iodide (0.041 g, 0.270 mmol, 0.2 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (0.504 g, 1.76 mmol, 1.3 eq). The mixture was heated at 50° C. overnight. The reaction mixture was filtered over a pad of diatomateous earth. The filtrate was evaporated and the crude was purified by flash chromatography on silica gel eluting with 10-100% ethyl acetate/heptane to give ethyl (2R)-4-[4-(1,3-benzoxazol-2-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoate (0.482 g, 91% yield) as a white solid. LC-MS M+H+392.1. The reaction mixture was filtered over a pad of diatomateous earth The filtrate was evaporated the crude was purified by flash chromatography on silica gel eluting with 10-100% ethyl acetate/heptane

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

Procedure: To a solution of 2-(1H-pyrazol-4-yl)-1,3-benzoxazole (0.250 g, 1.35 mmol) in acetonitrile (10 mL) was added cesium carbonate (1.10 g, 3.38 mmol, 2.5 eq), sodium iodide (0.041 g, 0.270 mmol, 0.2 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (0.504 g, 1.76 mmol, 1.3 eq). The mixture was heated at 50° C. overnight. The reaction mixture was filtered over a pad of diatomateous earth. The filtrate was evaporated and the crude was purified by flash chromatography on silica gel eluting with 10-100% ethyl acetate/heptane to give ethyl (2R)-4-[4-(1,3-benzoxazol-2-yl)-1H-pyrazol-1-yl]-2-methyl-2-(methylsulfonyl)butanoate (0.482 g, 91% yield) as a white solid. LC-MS M+H+392.1. The reaction mixture was filtered over a pad of diatomateous earth The filtrate was evaporated the crude was purified by flash chromatography on silica gel eluting with 10-100% ethyl acetate/heptane

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

Procedure: To a solution of 2-(1H-pyrazol-4-yl)quinoxaline (0.400 g, 1.39 mmol) in acetonitrile (10 mL) was added cesium carbonate (8.73 g, 2.68 mmol, 2.5 eq), sodium iodide (0.032 g, 0.214 mmol, 0.2 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (0.400 g 1.39 mmol, 1.3 eq). The reaction mixture was heated at 50° C. overnight. The reaction was filtered over a pad of diatomateous earth. The filtrate was evaporated and the crude was purified by flash chromatography on silica gel eluting with 40-100% ethyl acetate/heptane to give ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(quinoxalin-2-yl)-1H-pyrazol-1-yl]butanoate (0.078 g, 14% yield) as a colorless oil. LC-MS M+H+403.1. The reaction was filtered over a pad of diatomateous earth The filtrate was evaporated the crude was purified by flash chromatography on silica gel eluting with 40-100% ethyl acetate/heptane

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

Procedure: To a solution of 2-(1H-pyrazol-4-yl)quinoxaline (0.400 g, 1.39 mmol) in acetonitrile (10 mL) was added cesium carbonate (8.73 g, 2.68 mmol, 2.5 eq), sodium iodide (0.032 g, 0.214 mmol, 0.2 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (0.400 g 1.39 mmol, 1.3 eq). The reaction mixture was heated at 50° C. overnight. The reaction was filtered over a pad of diatomateous earth. The filtrate was evaporated and the crude was purified by flash chromatography on silica gel eluting with 40-100% ethyl acetate/heptane to give ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(quinoxalin-2-yl)-1H-pyrazol-1-yl]butanoate (0.078 g, 14% yield) as a colorless oil. LC-MS M+H+403.1. The reaction was filtered over a pad of diatomateous earth The filtrate was evaporated the crude was purified by flash chromatography on silica gel eluting with 40-100% ethyl acetate/heptane

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

Procedure: To a solution of 2-(1H-pyrazol-4-yl)pyrazine (0.157 g, 1.07 mmol) in acetonitrile (10 mL) was added cesium carbonate (0.873 g, 2.78 mmol, 2.5 eq), sodium sulfate (0.032 g, 0.214 mmol, 0.2 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (0.4 g 1.39 mmol, 1.3 eq). The mixture was heated at 50° C. overnight. The reaction mixture was filtered over a pad of diatomateous earth. The filtrate was evaporated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with 40-100% ethyl acetate/heptane to give ethyl (2R)-2-methyl-2-(methylsulfonyl)-4-[4-(pyrazin-2-yl)-1H-pyrazol-1-yl]butanoate (0.320 g, 1.39 mmol, 65% yield). LC-MS M+H+353.2. The reaction mixture was filtered over a pad of diatomateous earth The filtrate was evaporated in vacuo The crude product was purified by flash chromatography on silica gel eluting with 40-100% ethyl acetate/heptane

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

Procedure: To a solution of 4-cyanopyrazole (0.150 g, 1.61 mmol, 1 eq) in acetonitrile (10 mL) was added cesium carbonate (1.31 g, 4.03 mmol, 2.5 eq), sodium iodide (0.048 mg, 0.322 mmol, 0.2 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (0.555 g, 1.93 mmol, 1.2 eq). The mixture was heated at 50° C. overnight. The reaction mixture was cooled to room temperature and was filtered via Buchner funnel, and eluted with EtOAc. The filtrate was concentrated under reduced pressure and was diluted with up in tetrahydrofuran (5 mL) and water (5 mL). Lithium hydroxide (0.116 g, 4.83 mmol, 3 eq) was added, and the reaction mixture was allowed to stir at room temperature for four hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (10 mL), and concentrated again. This yielded (2R)-4-(4-cyano-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoic acid as a yellow oil, which was carried on crude in the next step. LC-MS M+H+272.2. The reaction mixture was cooled to room temperature was filtered via Buchner funnel eluted with EtOAc The filtrate was concentrated under reduced pressure was diluted with up in tetrahydrofuran (5 mL) and water (5 mL) The reaction mixture was concentrated under reduced pressure diluted with ethyl acetate (10 mL) concentrated again

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

Procedure: To a solution of 4-cyanopyrazole (0.150 g, 1.61 mmol, 1 eq) in acetonitrile (10 mL) was added cesium carbonate (1.31 g, 4.03 mmol, 2.5 eq), sodium iodide (0.048 mg, 0.322 mmol, 0.2 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (0.555 g, 1.93 mmol, 1.2 eq). The mixture was heated at 50° C. overnight. The reaction mixture was cooled to room temperature and was filtered via Buchner funnel, and eluted with EtOAc. The filtrate was concentrated under reduced pressure and was diluted with up in tetrahydrofuran (5 mL) and water (5 mL). Lithium hydroxide (0.116 g, 4.83 mmol, 3 eq) was added, and the reaction mixture was allowed to stir at room temperature for four hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (10 mL), and concentrated again. This yielded (2R)-4-(4-cyano-1H-pyrazol-1-yl)-2-methyl-2-(methylsulfonyl)butanoic acid as a yellow oil, which was carried on crude in the next step. LC-MS M+H+272.2. The reaction mixture was cooled to room temperature was filtered via Buchner funnel eluted with EtOAc The filtrate was concentrated under reduced pressure was diluted with up in tetrahydrofuran (5 mL) and water (5 mL) The reaction mixture was concentrated under reduced pressure diluted with ethyl acetate (10 mL) concentrated again

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of the 4-methylpyrazole (143 mg, 1.74 mmol, 1 eq) and (R)-ethyl 4-bromo-2-methyl-2-(methylsulfonyl)butanoate (500 mg 1.74 mmol, 1 eq) in THF (10 mL) was added cesium carbonate (2.27 g, 6.96 mmol, 4 eq). The resulting suspension was heated to 55° C. and allowed to stir overnight. The reaction was then diluted with EtOAc (10 mL) and the mixture filtered through a pad of celite, which was eluted with ˜10 mL of EtOAc. The crude material was purified by flash chromatography on a 40 g silica gel column eluting with an heptane/ethyl acetate/MeOH gradient) to give ethyl (2R)-2-methyl-4-(4-methyl-1H-pyrazol-1-yl)-2-(methylsulfonyl)butanoate which was used directly in the next step. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.27 (s, 1H), 7.13 (s, 1H), 4.30-4.11 (m, 2H), 3.03 (s, 3H), 2.80-2.71 (m, 1H), 2.51-2.41 (m, 1H), 2.04 (s, 3H), 1.66 (s, 3H). LC-MS M+H+289.4. the mixture filtered through a pad of celite, which was eluted with ˜10 mL of EtOAc The crude material was purified by flash chromatography on a 40 g silica gel column eluting with an heptane/ethyl acetate/MeOH gradient)