methyl 2-methyloxirane-2-carboxylate

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

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

Procedure: The title compound was synthesized using an analogous procedure to that described in connection with Compound 87 except that ethyl 3-(cyclohexylamino)-2-fluoro-2-methylpropanoate, made from commercially available starting material methyl 2-methyloxirane-2-carboxylate, was used and the final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.36 (m, 2H) 1.28-2.08 (m, 17H) 2.19 (s, 3H) 2.81 (d, J=10.6 Hz, 2H) 3.26 (s, 3H) 3.60-3.85 (m, 3H) 3.95 (s, 3H) 4.45 (m, 1H) 7.47 (d, J=8.3 Hz, 1H) 7.50 (s, 1H) 7.75 (s, 1H) 7.97-8.20 (m, 2H) 8.32 (d, J=8.3 Hz, 1H). [M+H] calc'd for C29H40FN7O3, 554. found 554. the final compound was purified by reverse phase HPLC to give the free base

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-methylglycidate (3.2 mL, 30 mmol) and cyclohexylamine (5.2 mL, 45 mmol) in ethanol (50 mL) was heated at 80° C. for 24 h. The reaction mixture was then concentrated, diluted to EtOAc, washed by NaHCO3, brine and water. Organic layer was dried, concentrated to give a residue which is used for next step without further purification (6.7 g, 97%). [M+H] calc'd for C12H23NO3, 230. found 230. The reaction mixture was then concentrated diluted to EtOAc washed by NaHCO3, brine and water Organic layer was dried concentrated to give a residue which is used for next step without further purification (6.7 g, 97%)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-methylglycidate (3.18 g, 27 mmol) and cyclopentylamine (4 mL, 41 mmol) in ethanol (50 mL) was heated at 80° C. for 3 d. The reaction mixture was then concentrated, diluted to EtOAc, washed by NaHCO3, brine and water. Organic layer was dried, concentrated to give a residue which is used for next step without further purification (3.9 g, 60%). [M+H] calc'd for C11H21NO3, 216. found 216. The reaction mixture was then concentrated diluted to EtOAc washed by NaHCO3, brine and water Organic layer was dried concentrated to give a residue which is used for next step without further purification (3.9 g, 60%)

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

Procedure: Sodium hydride (23.5 mg, 0.59 mmol) at 0° C. was added to an oven-dried vial containing N-[3-methyl-5-(1H-pyrazol-4-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (75 mg, 0.24 mmol) in DMF (0.8 mL). The mixture was stirred for 10 minutes, and then methyl 2-methylglycidate (0.03 mL, 0.24 mmol) was added. The reaction was warmed to room temperature and stirred overnight, followed by subsequent heating to 70° C. overnight. The mixture was cooled to room temperature, diluted with EtOAc, washed with water (3×), then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase HPLC (45 to 85% ACN/water with 0.1% TFA modifier) to afford racemic 2-hydroxy-2-methyl-3-[4-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1H-pyrazol-1-yl]propanoic acid. MS ESI calcd. for C19H18F3N5O3 [M+H]+ 422. found 422. stirred overnight by subsequent heating to 70° C. overnight The mixture was cooled to room temperature washed with water (3×) brine, dried over sodium sulfate filtered concentrated under reduced pressure The residue was purified by reverse phase HPLC (45 to 85% ACN/water with 0.1% TFA modifier)

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

Procedure: To round bottom flask containing sodium hydrosulfide (0.582 g, 10.4 mmol) in isopropanol (20 mL) was added methyl 2-methyloxirane-2-carboxylate (1.0 mL, 9.44 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was then added water (20 ml) and the pH adjusted to 2 with 2 N HCl. The reaction mixture was extracted with diethyl ether (3×50 mL). The organic extracts were combined, dried with sodium sulfate and concentrated under reduced pressure. The resulting crude isopropyl 3-mercapto-2-methyl-2-propanoate obtained was used in the next reaction with naphthalene-1,2-dione trifluoroacetic acid as outlined for example 21. The final desired product isopropyl 2-methyl-5,6-dioxo-2,3,5,6-tetrahydronaphtho[1,2-b][1,4]oxathiine-2-carboxylate was obtained as a dark red solid (overall yield 5% for the three steps). M.p.=168-169° C.; 400 MHz 1H NMR (CDCl3) δ: 8.06 (dd, J=7.7, 1.1 Hz, 1H), 7.83 (dd, J=7.7, 0.9 Hz, 1H), 7.66 (td, J=7.7, 1.4 Hz, 1H), 7.49 (td, J=7.5, 1.1 Hz, 1H), 5.08 (septuplet, J=6.3 Hz, 1H), 3.35 (d, J=13.2 Hz, 1H), 3.03 (d, J=13.2 Hz, 1H), 1.86 (s, 3H), 1.27 (d, J=6.3 Hz, 3H), 1.26 (d, J=6.3 Hz, 3H); LCMS: 333 [M+H]; Calc. for C17H16O5S: C, 61.43; H, 4.85; N, 0. Found C, 61.93; H, 4.92; N, 0.04. The reaction mixture was extracted with diethyl ether (3×50 mL) dried with sodium sulfate concentrated under reduced pressure The resulting crude isopropyl 3-mercapto-2-methyl-2-propanoate obtained

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

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

Procedure: The title compound was synthesized using an analogous procedure to that described in connection with Compound 87 except that ethyl 3-(cyclohexylamino)-2-fluoro-2-methylpropanoate, made from commercially available starting material methyl 2-methyloxirane-2-carboxylate, was used and the final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.36 (m, 2 H) 1.28-2.08 (m, 17 H) 2.19 (s, 3 H) 2.81 (d, J=10.6 Hz, 2 H) 3.26 (s, 3 H) 3.60-3.85 (m, 3 H) 3.95 (s, 3 H) 4.45 (m, 1 H) 7.47 (d, J=8.3 Hz, 1 H) 7.50 (s, 1 H) 7.75 (s, 1 H) 7.97-8.20 (m, 2 H) 8.32 (d, J=8.3 Hz, 1 H). [M+H] calc'd for C29H40FN7O3, 554; found 554. the final compound was purified by reverse phase HPLC to give the free base

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-methylglycidate (3.2 mL, 30 mmol) and cyclohexylamine (5.2 mL, 45 mmol) in ethanol (50 mL) was heated at 80° C. for 24 h. The reaction mixture was then concentrated, diluted to EtOAc, washed by NaHCO3, brine and water. Organic layer was dried, concentrated to give a residue which is used for next step without further purification (6.7 g, 97%). [M+H] calc'd for C12H23NO3, 230; found 230. The reaction mixture was then concentrated diluted to EtOAc washed by NaHCO3, brine and water Organic layer was dried concentrated to give a residue which is used for next step without further purification (6.7 g, 97%)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-methylglycidate (3.18 g, 27 mmol) and cyclopentylamine (4 mL, 41 mmol) in ethanol (50 mL) was heated at 80° C. for 3 d. The reaction mixture was then concentrated, diluted to EtOAc, washed by NaHCO3, brine and water. Organic layer was dried, concentrated to give a residue which is used for next step without further purification (3.9 g, 60%). [M+H] calc'd for C11H21NO3, 216; found 216. The reaction mixture was then concentrated diluted to EtOAc washed by NaHCO3, brine and water Organic layer was dried concentrated to give a residue which is used for next step without further purification (3.9 g, 60%)

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

Procedure: The title compound was synthesized using an analogous procedure to that described in connection with Compound 87 except that ethyl 3-(cyclohexylamino)-2-fluoro-2-methylpropanoate, made from commercially available starting material methyl 2-methyloxirane-2-carboxylate, was used and the final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.36 (m, 2H) 1.28-2.08 (m, 17H) 2.19 (s, 3H) 2.81 (d, J=10.6 Hz, 2H) 3.26 (s, 3H) 3.60-3.85 (m, 3H) 3.95 (s, 3H) 4.45 (m, 1H) 7.47 (d, J=8.3 Hz, 1H) 7.50 (s, 1H) 7.75 (s, 1H) 7.97-8.20 (m, 2H) 8.32 (d, J=8.3 Hz, 1H). [M+H] calc'd for C29H40FN7O3, 554. found 554. the final compound was purified by reverse phase HPLC to give the free base

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methyl 2-methylglycidate (3.2 mL, 30 mmol) and cyclohexylamine (5.2 mL, 45 mmol) in ethanol (50 mL) was heated at 80° C. for 24 h. The reaction mixture was then concentrated, diluted to EtOAc, washed by NaHCO3, brine and water. Organic layer was dried, concentrated to give a residue which is used for next step without further purification (6.7 g, 97%). [M+H] calc'd for C12H23NO3, 230. found 230. The reaction mixture was then concentrated diluted to EtOAc washed by NaHCO3, brine and water Organic layer was dried concentrated to give a residue which is used for next step without further purification (6.7 g, 97%)