[(2R)-oxiran-2-yl]methyl butanoate

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

Procedure: 1 M Lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.1 mL, 1.1 mmol) was added dropwise with stirring at −78° C. to 5-benzyloxycarbonylamino-1-tritylindazole (0.510 g, 1 mmol) in tetrahydrofuran (10 mL) under nitrogen atmosphere. The mixture was stirred at −78° C. for 1.5 h. (R)-Glycidyl butyrate (0.160 mL, 1.2 mmol) was added dropwise with stirring. The mixture was allowed to warm to r.t. overnight. Saturated aq. NH4Cl (10 mL) was added, and the mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried (MgSO4). Solvent was evaporated to 3 mL, and the residue was triturated with hexanes (50 mL). White crystalline product was filtered off, washed with hexanes, and dried in vacuo. Yield 0.440 g (93%). MS (m/z): 232.1 [M-Trt]−. 1H NMR. was added dropwise the mixture was extracted with EtOAc (2×20 mL) The combined organic layers were washed with water (10 mL), brine (10 mL) dried (MgSO4) Solvent was evaporated to 3 mL the residue was triturated with hexanes (50 mL) White crystalline product was filtered off washed with hexanes dried in vacuo

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

Procedure: A solution of amine 102 (39.2 g, 160.0 mmol) in anhydrous THF (300 mL) was cooled to −78° C. in a dry-ice/acetone bath before a solution of n-butyl lithium (n-BuLi, 2.5 M solution in hexane, 70.4 mL, 176 mmol, 1.1 equiv) was dropwise added under N2. The resulting reaction mixture was subsequently stirred at −78° C. for 1 h before a solution of (R)-(−)-glycidyl butyrate (25.37 g, 24.6 mL, 176 mmol, 1.1 equiv) in anhydrous THF (100 mL) was dropwise added into the reaction mixture at −78° C. under N2. The resulting reaction mixture was stirred at −78° C. for 30 min before being gradually warmed to room temperature for 12 h under N2. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was quenched with H2O (200 mL), and the resulting mixture was stirred at room temperature for 1 h before EtOAc (200 mL) was added. The two layers were separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO4, and concentrated in vacuo. White crystals precipitated from the concentrated solution when most of the solvent was evaporated. The residue was then treated with 20% EtOAc/hexane (100 mL) and the resulting slurry was stirred at room temperature for 30 min. The solids were collected by filtration and washed with 20% EtOAc/hexane (2×50 mL) to afford the desired (5R)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one 103 (24.4 g, 72.3% yield) as white crystals. This product was directly used in subsequent reactions without further purification. 1H NMR (300 MHz, DMSO-d6) δ 3.34-3.72 (m, 2H), 3.83 (dd, 1H, J=6.2, 9.0 Hz), 4.09 (t, 111, J=12.0 Hz), 4.68-4.75 (m, 1H), 5.23 (t, 1H, J=5.6 Hz, OH), 6.96 (m, 1H), 7.32-7.56 (m, 3H). C10H10FNO3, LCMS (EI) m/e 212 (M++H). was dropwise added under N2 The resulting reaction mixture was dropwise added into the reaction mixture at −78° C. under N2 The resulting reaction mixture before being gradually warmed to room temperature for 12 h under N2 the reaction mixture was quenched with H2O (200 mL) the resulting mixture was stirred at room temperature for 1 h before EtOAc (200 mL) was added The two layers were separated the aqueous layer was extracted with EtOAc (2×100 mL) The combined organic extracts were washed with H2O (2×100 mL) and saturated aqueous NaCl (100 mL) dried over MgSO4 concentrated in vacuo White crystals precipitated from the concentrated solution when most of the solvent was evaporated The residue was then treated with 20% EtOAc/hexane (100 mL) the resulting slurry was stirred at room temperature for 30 min The solids were collected by filtration washed with 20% EtOAc/hexane (2×50 mL) to afford the

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

Procedure: A solution of 4-fluoro-4-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 74, Step 2, 2.03 g, contaminated with the elimination side product) in dry tetrahydrofuran (21 mL) at −78° C. under N2 is treated with n-butyllithium (2.80 mL, 1.6M in hexanes) dropwise over 5 mins. The resulting mixture is stirred at −78° C. for 1.25 hrs and is then treated with (R)-(−)-glycidyl butyrate (0.63 mL) dropwise. The resulting solution is stirred at −78° C. for 1 hr, warmed to ambient temperature and stirred for an additional 20 hrs, after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (10 mL), and the layers are separated. The organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 250 g), eluting with methanol/methylene chloride (3/97). Pooling and concentration of those fractions with an Rf=0.51 by TLC (methanol/chloroform, 10/90) and repurification by silica gel chromatography (230-400 mesh, 100 g, methanol/methylene chloride (4/96) eluent) gives the title compound (contaminated with the elimination side product from the starting material). An analytical sample is prepared by radial chromatography (2000 m silica gel rotor, ethyl acetate/hexane (60/40) eluent), NMR (400 MHz, CDCl3) 7.45, 7.34, 7.18, 5.16, 4.74, 4.17, 3.97, 3.72, 3.22, 2.25 and 1.90δ and HRMS calculated for C23H24F2N2O5: 446.1653. Found: 446.1660. at −78° C. The resulting solution is stirred at −78° C. for 1 hr warmed to ambient temperature stirred for an additional 20 hrs after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL) diluted with water (10 mL) the layers are separated The organic phase is washed with saline (10 mL) dried over anhydrous magnesium sulfate concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 250 g) eluting with methanol/methylene chloride (3/97) Pooling and concentration of those fractions with an Rf=0.51 by TLC (methanol/chloroform, 10/90) and repurification by silica gel chromatography (230-400 mesh, 100 g, methanol/methylene chloride (4/96) eluent)

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

Procedure: A solution of 4-fluoro-4-[4-[[(phenylmethoxy)carbonyl]amino]-2-fluorophenyl]-1-piperidinecarboxylic acid phenylmethyl ester (EXAMPLE 74, Step 2, 2.03 g, contaminated with the elimination side product) in dry tetrahydrofuran (21 mL) at −78° C. under N2 is treated with n-butyllithium (2.80 mL, 1.6M in hexanes) dropwise over 5 mins. The resulting mixture is stirred at −78° C. for 1.25 hrs and is then treated with (R)-(−)-glycidyl butyrate (0.63 mL) dropwise. The resulting solution is stirred at −78° C. for 1 hr, warmed to ambient temperature and stirred for an additional 20 hrs, after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (10 mL), and the layers are separated. The organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 250 g), eluting with methanol/methylene chloride (3/97). Pooling and concentration of those fractions with an Rf=0.51 by TLC (methanol/chloroform, 10/90) and repurification by silica gel chromatography (230-400 mesh, 100 g, methanol/methylene chloride (4/96) eluent) gives the title compound (contaminated with the elimination side product from the starting material). An analytical sample is prepared by radial chromatography (2000 m silica gel rotor, ethyl acetate/hexane (60/40) eluent), NMR (400 MHz, CDCl3) 7.45, 7.34, 7.18, 5.16, 4.74, 4.17, 3.97, 3.72, 3.22, 2.25 and 1.90δ and HRMS calculated for C23H24F2N2O5: 446.1653. Found: 446.1660. at −78° C. The resulting solution is stirred at −78° C. for 1 hr warmed to ambient temperature stirred for an additional 20 hrs after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL) diluted with water (10 mL) the layers are separated The organic phase is washed with saline (10 mL) dried over anhydrous magnesium sulfate concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 250 g) eluting with methanol/methylene chloride (3/97) Pooling and concentration of those fractions with an Rf=0.51 by TLC (methanol/chloroform, 10/90) and repurification by silica gel chromatography (230-400 mesh, 100 g, methanol/methylene chloride (4/96) eluent)

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

Procedure: A solution of 3,6-dihydro-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step 2, 0.500 g) in dry tetrahydrofuran (5.7 mL) at −78° C. under N2 is treated with n-butyllithium (0.73 mL, 1.6M in hexanes) dropwise over five minutes. The resulting mixture is stirred at −78° C. for 45 minutes and is then treated with (R)-(−)-glycidyl butyrate dropwise. The resulting solution is allowed to warm to ambient temperature over approximately 45 minutes and is stirred for an additional 20 hours, after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (20 mL) and extracted with ethyl acetate (2×15 mL). The combined organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 40 g), eluting with methanol/methylene chloride (1/99). Pooling and concentration of those fractions with an Rf=0.37 by TLC (methanol/chloroform, 5/95) gives the title compound, mp 131.5-133.5° C. to warm to ambient temperature over approximately 45 minutes is stirred for an additional 20 hours after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL) diluted with water (20 mL) extracted with ethyl acetate (2×15 mL) The combined organic phase is washed with saline (10 mL) dried over anhydrous magnesium sulfate concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 40 g) eluting with methanol/methylene chloride (1/99)

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

Procedure: A solution of 3,6-dihydro-4-[4-[[(phenylmethoxy)carbonyl]amino]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step 2, 0.500 g) in dry tetrahydrofuran (5.7 mL) at −78° C. under N2 is treated with n-butyllithium (0.73 mL, 1.6M in hexanes) dropwise over five minutes. The resulting mixture is stirred at −78° C. for 45 minutes and is then treated with (R)-(−)-glycidyl butyrate dropwise. The resulting solution is allowed to warm to ambient temperature over approximately 45 minutes and is stirred for an additional 20 hours, after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL), diluted with water (20 mL) and extracted with ethyl acetate (2×15 mL). The combined organic phase is washed with saline (10 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 40 g), eluting with methanol/methylene chloride (1/99). Pooling and concentration of those fractions with an Rf=0.37 by TLC (methanol/chloroform, 5/95) gives the title compound, mp 131.5-133.5° C. to warm to ambient temperature over approximately 45 minutes is stirred for an additional 20 hours after which the reaction is quenched with saturated aqueous ammonium chloride (10 mL) diluted with water (20 mL) extracted with ethyl acetate (2×15 mL) The combined organic phase is washed with saline (10 mL) dried over anhydrous magnesium sulfate concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 40 g) eluting with methanol/methylene chloride (1/99)

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

Procedure: The 1-(tert-butoxycarbonyl)-4-[2,6-difluoro-4-(benzyloxycarbonyl)aminophenyl]piperazine (14.05 g, 31 mmol) was dissolved in dry THF (150 mL) and then cooled to -78° C. (dry ice/acetone). The reaction was next treated with with n-BuLi (21.6 mL, 35 mmol) dropwise over a 25 minute period. The reaction was allowed to stir at -78° C. for 30 minutes and then (R)-(-)-glycidylbutyrate (4.89 mL, 35 mmol) was added dropwise over 7 minutes. The reaction was maintained at -78° C. for an additional 15 minutes and then the bath was removed, allowing the reaction to slowly warm up to room temperature overnight. The reaction was determined to be complete by TLC (5% MeOH/CHCl3, UV short wave). The reaction mixture was diluted with 500 mL CH2Cl2 and then washed with both H2O (3×300 mL) and brine (300 mL). The aqueous portions were back-extracted with more CH2Cl2 (3×400 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give a creamy yellow solid. The crude solid was purified by recrystallization from hot EtOAc/hexane to give 11.063 g (85%) of the title compound as a white solid with mp 164°-166° C. The reaction was maintained at -78° C. for an additional 15 minutes the bath was removed the reaction to slowly warm up to room temperature overnight washed with both H2O (3×300 mL) and brine (300 mL) The aqueous portions were back-extracted with more CH2Cl2 (3×400 mL) The combined organic extracts were dried over Na2SO4 filtered concentrated to give a creamy yellow solid The crude solid was purified by recrystallization from hot EtOAc/hexane

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

Procedure: The 1-(tert-butoxycarbonyl)-4-[2,6-difluoro-4-(benzyloxycarbonyl)aminophenyl]piperazine (14.05 g, 31 mmol) was dissolved in dry THF (150 mL) and then cooled to -78° C. (dry ice/acetone). The reaction was next treated with with n-BuLi (21.6 mL, 35 mmol) dropwise over a 25 minute period. The reaction was allowed to stir at -78° C. for 30 minutes and then (R)-(-)-glycidylbutyrate (4.89 mL, 35 mmol) was added dropwise over 7 minutes. The reaction was maintained at -78° C. for an additional 15 minutes and then the bath was removed, allowing the reaction to slowly warm up to room temperature overnight. The reaction was determined to be complete by TLC (5% MeOH/CHCl3, UV short wave). The reaction mixture was diluted with 500 mL CH2Cl2 and then washed with both H2O (3×300 mL) and brine (300 mL). The aqueous portions were back-extracted with more CH2Cl2 (3×400 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give a creamy yellow solid. The crude solid was purified by recrystallization from hot EtOAc/hexane to give 11.063 g (85%) of the title compound as a white solid with mp 164°-166° C. The reaction was maintained at -78° C. for an additional 15 minutes the bath was removed the reaction to slowly warm up to room temperature overnight washed with both H2O (3×300 mL) and brine (300 mL) The aqueous portions were back-extracted with more CH2Cl2 (3×400 mL) The combined organic extracts were dried over Na2SO4 filtered concentrated to give a creamy yellow solid The crude solid was purified by recrystallization from hot EtOAc/hexane

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

Procedure: The title compound is prepared in analogy to Example 89 from Example 12 with (2R)-3-butanoyloxy-1,2-epoxypropane and subsequent hydrolysis of the butyrate with 1 equivalent of a 1M lithium hydroxide solution at 70° C. for 1 h. For the work-up the solvent is removed on a rotary evaporator, the residue is adjusted to a neutral pH using 1N hydrochloric acid and buffer pH 7 and extracted with dichloromethane. Purification takes place by RP-HPLC (Method 6). For the work-up the solvent is removed on a rotary evaporator extracted with dichloromethane Purification

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

Procedure: The title compound is prepared in analogy to Example 89 from Example 12 with (2R)-3-butanoyloxy-1,2-epoxypropane and subsequent hydrolysis of the butyrate with 1 equivalent of a 1M lithium hydroxide solution at 70° C. for 1 h. For the work-up the solvent is removed on a rotary evaporator, the residue is adjusted to a neutral pH using 1N hydrochloric acid and buffer pH 7 and extracted with dichloromethane. Purification takes place by RP-HPLC (Method 6). For the work-up the solvent is removed on a rotary evaporator extracted with dichloromethane Purification

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

Procedure: To a solution of 144 g (1 mol) of 1-naphthol and 7.4 g (0.02 mol) of tetrabutylammonium iodide in 200 ml of toluene was added 144 g (1 mol) of (R)-glycidyl butyrate over a period of 15 min at a temperature of 120° C., and the mixture was kept at this temperature for a further 4 h. Conventional subsequent treatment of the reaction mixture gave the required compound as an oil, yield about 75%.

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

Procedure: To a solution of 144 g (1 mol) of 1-naphthol and 7.4 g (0.02 mol) of tetrabutylammonium iodide in 200 ml of toluene was added 144 g (1 mol) of (R)-glycidyl butyrate over a period of 15 min at a temperature of 120° C., and the mixture was kept at this temperature for a further 4 h. Conventional subsequent treatment of the reaction mixture gave the required compound as an oil, yield about 75%.