(2S)-2-(trifluoromethyl)oxirane

Conditions: temp:-30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a pre-cooled −30° C. solution of tert-butyl [(3S,5S)-5-(2,3-difluorophenyl)-2-oxopiperidin-3-yl]carbamate (described in Intermediate 11, step B, 56 mg, 0.172 mmol) in tetrahydrofuran:N-methyl-2-pyrrolidinone (2:1, 0.8 mL) was added lithium bis(trimethylsilyl)amide (0.22 mL, 0.22 mmol, 1 M in THF) and the mixture was stirred at −30° C. for 30 min. (2S)-2-(Trifluoromethyl)oxirane (19 mg, 0.172 mmol) was added and the resulting mixture was stirred at −30° C. for 2 h. The mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate→90% ethyl acetate/hexane) afforded the title compound. MS: m/z=461.2 (M+Na). was added extracted with ethyl acetate (3×) The combined organic extracts were washed with water, brine dried over sodium sulfate filtered concentrated Purification by silica gel chromatography (0% ethyl acetate→90% ethyl acetate/hexane)

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

Procedure: 7-Methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (215 mg, 0.967 mmol) was placed into a sealable vial, suspended in Acetonitrile (10 mL) then (S)-2-Trifluoromethyl-oxirane (130 uL, 1.5 mmol) was added, followed by Macroporous carbonate resin (3.16 mmol/g loading; 0.810 g, 2.56 mmol). The reaction was stirred at room temperature for 24 h, filtered and concentrated in vacuo to afford (S)-1,1,1-Trifluoro-3-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-propan-2-ol as an orange oil (316 mg, 97%), which was used without further purification. 1H-NMR (CDCl3, 400 MHz) δ 7.67 (s, 1H), 6.83 (s, 1H), 4.05 (m, 1H), 3.95 (s, 3H), 2.6-3.0 (m, 10H); 19F-NMR (CDCl3, 376 MHz) δ −78.7 (s). filtered concentrated in vacuo

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

Procedure: 7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine nitric acid salt (2.01 g, 7.88 mmol, 1.0 eq), was placed in THF (100 mL) and MP-carbonate (7.1 g) was added. The reaction was stirred in a sealable vessel for 1 hour and then (S)-2-trifluoromethyl-oxirane (1.30 g, 11.59 mmol, 1.00 mL, 1.47 eq) was added. The reaction vessel was sealed, stirred at room temperature for 1 hour, and then heated at 50° C. overnight. The reaction was then cooled to room temperature and filtered. The resin was washed with CH2Cl2 (150 mL) and the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-50% EtOAc/hex as the eluting solvent to obtain (S)-1,1,1-trifluoro-3-(7-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-propan-2-ol as an orange solid (2.27 g, 95%). m.p.=82-85° C.; LCMS (m/e) 305 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.06-7.99 (m, 2H), 7.31-7.26 (m, 1H), 4.16-4.02 (m, 2H), 3.15-2.97 (m, 4H), 2.96-2.81 (m, 3H), 2.81-2.67 (m, 3H). The reaction vessel was sealed stirred at room temperature for 1 hour The reaction was then cooled to room temperature filtered The resin was washed with CH2Cl2 (150 mL) the filtrate was concentrated under reduced pressure Purification by silica gel chromatography

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

Procedure: To a solution of N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-5-methyl-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine hydrochloride (36.0 mg, 0.084 mmol) in DMF (0.5 mL) were added TEA (23.4 μL, 0.168 mmol) and (S)-2-(trifluoromethyl)oxirane (72.8 μL, 0.84 mmol). The reaction mixture was stirred at room temperature overnight, and purified by preparative RP-HPLC to provide (S)-3-(4-(2,5-dimethyl-4-(5-methyl-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)phenyl)piperidin-1-yl)-1,1,1-trifluoropropan-2-ol; ESMS m/z 504.3 (M+H+). purified by preparative RP-HPLC

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

Procedure: To a solution of N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-5-methyl-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine hydrochloride (36.0 mg, 0.084 mmol) in DMF (0.5 mL) were added TEA (23.4 μL, 0.168 mmol) and (S)-2-(trifluoromethyl)oxirane (72.8 μL, 0.84 mmol). The reaction mixture was stirred at room temperature overnight, and purified by preparative RP-HPLC to provide (S)-3-(4-(2,5-dimethyl-4-(5-methyl-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)phenyl)piperidin-1-yl)-1,1,1-trifluoropropan-2-ol; ESMS m/z 504.3 (M+H+). purified by preparative RP-HPLC

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

Procedure: In a 2 ml vial, thiomorpholine 1,1-dioxide (200 mg, 1.48 mmol) was combined with acetonitrile (5.33 ml) to give a colorless solution. (S)-2-(trifluoromethyl)oxirane (332 mg, 257 μl, 2.96 mmol) was added and the resultant mixture was stirred at room temperature for 2 h. The crude reaction mixture was concentrated in vacuo to afford 120 mg of (S)-3-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-1,1,1-trifluoro-propan-2-ol as an oil, which was used without further purification. to give a colorless solution The crude reaction mixture was concentrated in vacuo

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

Procedure: 2-(3,5-Dichlorophenyl)morpholine oxalate (1 g) from Chem-Impex was added to 5% aq NaOH and dichloromethane and extracted (3×100 mL dichloromethane). Combined extracts were dried over Na2SO4, filtered and concentrated to afford 728 mg of 2-(3,5-dichlorophenyl)morpholine as the free-base. In a 100 mL round-bottom flask, 2-(3,5-dichlorophenyl)morpholine (728 mg, 3.14 mmol) and (S)-2-(trifluoromethyl)oxirane (527 mg, 4.7 mmol) were combined with acetonitrile (10.0 ml) to give a yellow solution. Stirring was continued at room temperature for 3 days. Reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 20% EtOAc in hexanes) to afford (2S)-3-(2-(3,5-dichlorophenyl)morpholino)-1,1,1-trifluoropropan-2-ol (1.06 g, 98%) as a colorless oil. (M+H)+=344, 346 m/e. Used as is. to give a yellow solution Reaction mixture was concentrated in vacuo The crude material was purified by flash chromatography (silica gel, 40 g, 5% to 20% EtOAc in hexanes)

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

Procedure: To a solution of 2-(4-fluorophenyl)morpholine oxalate (50 mg, 184 μmol) and triethylamine (128 μL, 922 μmole) in 2.5 mL of acetonitrile was added (S)-2-(trifluoromethyl)oxirane (82.6 mg, 737 μmol) at room temperature. The mixture was stirred at this temperature for 4 days. The solution was purified by reverse phase column chromatography (30-100% acetonitrile in water). The desired fractions were pooled and lyophilized to give (2S)-1,1,1-trifluoro-3-(2-(4-fluorophenyl)morpholino)propan-2-ol (39 mg, 73%). Used as is in the next step. The solution was purified by reverse phase column chromatography (30-100% acetonitrile in water)

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

Procedure: In a 25 mL round-bottomed flask was placed 2-(3-methoxyphenyl)-thiomorpholine-1,1-dioxide (252 mg, 1.04 mmol), followed by (S)-2-(trifluoromethyl)oxirane (129 mg, 1.15 mmol). The reaction mixture was stirred overnight. Reaction was not complete. An additional 100 mg of the (S)-2-(trifluoromethyl)oxirane was added followed by a small amount of dichloromethane. Reaction mixture was stirred at room temperature for an additional 2 h. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 40% EtOAc in hexanes) afforded (S)-1,1,1-trifluoro-3-[2-(3-methoxyphenyl)-1,1-dioxo-1λ6-thiomorpholin-4-yl]-propan-2-ol (240 mg) as a white foam. (M+H)+=354 m/e. In a 25 mL round-bottomed flask was placed Reaction Reaction mixture was stirred at room temperature for an additional 2 h The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 40% EtOAc in hexanes)

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

Procedure: In a 50 mL round-bottomed flask, 2-(3-(trifluoromethyl)phenyl)morpholine hydrochloride (515 mg, 1.92 mmol) and DIPEA (249 mg, 336 μl, 1.92 mmol) were combined with acetonitrile (10 ml) to give a white suspension. (S)-2-(trifluoromethyl)oxirane (323 mg, 2.89 mmol) was added. The reaction mixture was stirred at room temperature for 3 days and then was concentrated in vacuo. The reaction mixture was taken up in 100 mL dilute aqueous NaHCO3 and extracted with dichloromethane (3×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to afford 528 mg (80%) of (2S)-1,1,1-trifluoro-3-(2-(3-(trifluoromethyl)phenyl)morpholino)propan-2-ol, which was used as is in the next step. (M+H)+=344 m/e. to give a white suspension was concentrated in vacuo extracted with dichloromethane (3×50 mL) The organic layers were dried over Na2SO4 concentrated in vacuo

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

Procedure: In a 50 mL round-bottomed flask, 2-(3-(trifluoromethyl)phenyl)morpholine hydrochloride (515 mg, 1.92 mmol) and DIPEA (249 mg, 336 μl, 1.92 mmol) were combined with acetonitrile (10 ml) to give a white suspension. (S)-2-(trifluoromethyl)oxirane (323 mg, 2.89 mmol) was added. The reaction mixture was stirred at room temperature for 3 days and then was concentrated in vacuo. The reaction mixture was taken up in 100 mL dilute aqueous NaHCO3 and extracted with dichloromethane (3×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo to afford 528 mg (80%) of (2S)-1,1,1-trifluoro-3-(2-(3-(trifluoromethyl)phenyl)morpholino)propan-2-ol, which was used as is in the next step. (M+H)+=344 m/e. to give a white suspension was concentrated in vacuo extracted with dichloromethane (3×50 mL) The organic layers were dried over Na2SO4 concentrated in vacuo

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

Procedure: In a 25 mL round-bottom flask was placed 2-benzylmorpholine (354 mg, 2 mmol,), followed by (S)-2-(trifluoromethyl)oxirane (224 mg, 2.00 mmol). The mixture was stirred for 30 min. Another 100 uL of (S)-2-(trifluoromethyl)oxirane was added. Reaction mixture was continued at room temperature overnight, then concentrated in vacuo to afford (S)-3-(2-benzyl-morpholin-4-yl)-1,1,1-trifluoro-propan-2-ol a colorless oil (600 mg). In a 25 mL round-bottom flask was placed Reaction mixture was continued at room temperature overnight concentrated in vacuo