tert-butyl N-[(2S)-1-oxobutan-2-yl]carbamate

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an atmosphere of argon, benzo[d]oxazole (5 g, 42.0 mmol, Eq: 1.00) was combined with THF (100 ml) to give a light yellow solution. At −5° C. isopropylmagnesium chloride 2M in THF (21.0 ml, 42.0 mmol, Eq: 1.00) was added dropwise. The reaction was stirred for 1.5 h at −5° C. Then (S)-tert-butyl 1-oxobutan-2-ylcarbamate (4.72 g, 25.2 mmol, Eq: 0.6) diluted in 20 ml THF was added. The reaction was stirred overnight at RT. Satd. ammoniumchloride solution (6 ml) was added to the reaction. The THF was evaporated under vacuum. The reaction mixture was poured into 50 ml H2O and extracted with ethyl acetate (2×100 ml). The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 40% ethyl acetate in heptane). The title compound was obtained as a brown gum (5.08 g, 39.5%, MS (m/e)=307.2 [M+H+]). to give a light yellow solution was added The reaction was stirred overnight at RT The THF was evaporated under vacuum The reaction mixture was poured into 50 ml H2O extracted with ethyl acetate (2×100 ml) The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 40% ethyl acetate in heptane)

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an atmosphere of argon, oxalyl chloride (7.01 g, 4.75 ml, 55.3 mmol, Eq: 1.00) was combined with CH2Cl2 (100 ml) to give a colorless solution. The reaction was cooled to −60° C. Then dimethyl sulfoxide (10.8 g, 9.8 ml, 138 mmol, Eq: 2.5) diluted in CH2Cl2 (20 ml) was added dropwise at −60° C. The reaction was stirred for 10 min at −60° C. Then (S)-tert-butyl-1-hydroxybutan-2-ylcarbamate (11.62 g, 55.3 mmol, Eq: 1.00) dissolved in 20 ml CH2Cl2 was added dropwise at −70° C. The reaction was allowed to warm to −40° C. for 10 min and then cooled to −70° C. again. A solution of triethylamine (15.7 g, 21.6 ml, 155 mmol, Eq: 2.8) in 20 ml CH2Cl2 was added dropwise. The reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was poured into 100 ml satd. sodium dihydrogenphosphate solution and extracted with ethyl acetate (2×150 mL). The organic layer was back-extracted with brine (1×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as a light yellow oil (11.12 g, quant., MS (m/e)=188.2 [M+H+]). to give a colorless solution was added dropwise at −60° C was added dropwise at −70° C to warm to −40° C. for 10 min cooled to −70° C. again to warm to room temperature over 2 hours The reaction mixture was poured into 100 ml sodium dihydrogenphosphate solution and extracted with ethyl acetate (2×150 mL) The organic layer was back-extracted with brine (1×50 mL) The organic layers were dried over Na2SO4 concentrated in vacuo

Conditions: temp:-60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under an atmosphere of argon, oxalyl chloride (7.01 g, 4.75 ml, 55.3 mmol, Eq: 1.00) was combined with CH2Cl2 (100 ml) to give a colorless solution. The reaction was cooled to −60° C. Then dimethyl sulfoxide (10.8 g, 9.8 ml, 138 mmol, Eq: 2.5) diluted in CH2Cl2 (20 ml) was added dropwise at −60° C. The reaction was stirred for 10 min at −60° C. Then (S)-tert-butyl-1-hydroxybutan-2-ylcarbamate (11.62 g, 55.3 mmol, Eq: 1.00) dissolved in 20 ml CH2Cl2 was added dropwise at −70° C. The reaction was allowed to warm to −40° C. for 10 min and then cooled to −70° C. again. A solution of triethylamine (15.7 g, 21.6 ml, 155 mmol, Eq: 2.8) in 20 ml CH2Cl2 was added dropwise. The reaction mixture was allowed to warm to room temperature over 2 hours. The reaction mixture was poured into 100 ml satd. sodium dihydrogenphosphate solution and extracted with ethyl acetate (2×150 mL). The organic layer was back-extracted with brine (1×50 mL). The organic layers were dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as a light yellow oil (11.12 g, quant., MS (m/e)=188.2 [M+H+]). to give a colorless solution was added dropwise at −60° C was added dropwise at −70° C to warm to −40° C. for 10 min cooled to −70° C. again to warm to room temperature over 2 hours The reaction mixture was poured into 100 ml sodium dihydrogenphosphate solution and extracted with ethyl acetate (2×150 mL) The organic layer was back-extracted with brine (1×50 mL) The organic layers were dried over Na2SO4 concentrated in vacuo

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

Procedure: In a clean roundbottom flask equipped with stir bar was placed oxazolo[4,5-b]pyridine (600 mg, 5 mmol) in 30 mL THF and the reaction mixture was cooled to 0° C. under N2 atmosphere. Isopropylmagnesium chloride (2M in THF, 2.5 ml, 5 mmol ) was added. After stirring for 1 h at 0° C., (S)-2-(tert-butoxycarbonyl)aminobutyraldehyde (573 mg, 3 mmol) in 20 ml THF was added. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was quenched with saturated ammonium chloride solution and concentrated to dryness. The residue was extracted with EtOAc, then washed with brine, dried with anhyd. MgSO4, filtered and concentrated. The crude product was purified by chromatograph to yield 383 mg of the desired compound. In a clean roundbottom flask equipped After stirring for 1 h at 0° C. The ice bath was removed to warm to room temperature the reaction mixture was quenched with saturated ammonium chloride solution concentrated to dryness The residue was extracted with EtOAc washed with brine dried with anhyd MgSO4, filtered concentrated The crude product was purified by chromatograph

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

Procedure: In a clean roundbottom flask equipped with stir bar was placed oxazolo[4,5-b]pyridine (600 mg, 5 mmol) in 30 mL THF and the reaction mixture was cooled to 0° C. under N2 atmosphere. Isopropylmagnesium chloride (2M in THF, 2.5 ml, 5 mmol ) was added. After stirring for 1 h at 0° C., (S)-2-(tert-butoxycarbonyl)aminobutyraldehyde (573 mg, 3 mmol) in 20 ml THF was added. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was quenched with saturated ammonium chloride solution and concentrated to dryness. The residue was extracted with EtOAc, then washed with brine, dried with anhyd. MgSO4, filtered and concentrated. The crude product was purified by chromatograph to yield 383 mg of the desired compound. In a clean roundbottom flask equipped After stirring for 1 h at 0° C. The ice bath was removed to warm to room temperature the reaction mixture was quenched with saturated ammonium chloride solution concentrated to dryness The residue was extracted with EtOAc washed with brine dried with anhyd MgSO4, filtered concentrated The crude product was purified by chromatograph

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

Procedure: In a clean roundbottom flask equipped with stir bar was placed oxazolo[4,5-b]pyridine (600 mg, 5 mmol) in THF (30 mL) and the reaction mixture was cooled to 0° C. under N2 atomosphere. Isopropylmagnesium chloride (2 M in THF, 2.5 mL, 5 mmol) was added. After stirring for 1 h at 0° C., (S)-2-(tert-butoxycarbonyl)aminobutyraldehyde (573 mg, 3 mmol) in THF (20 mL) was added. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was quenched with saturated ammonium chloride solution and concentrated to dryness. The residue was extracted with EtOAc, then washed with brine, dried with anhyd. MgSO4, filtered and concentrated. The crude product was purified by chromatograph to yield 383 mg of the desired compound. In a clean roundbottom flask equipped After stirring for 1 h at 0° C. The ice bath was removed to warm to room temperature the reaction mixture was quenched with saturated ammonium chloride solution concentrated to dryness The residue was extracted with EtOAc washed with brine dried with anhyd MgSO4, filtered concentrated The crude product was purified by chromatograph

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

Procedure: In a clean roundbottom flask equipped with stir bar was placed oxazolo[4,5-b]pyridine (600 mg, 5 mmol) in THF (30 mL) and the reaction mixture was cooled to 0° C. under N2 atomosphere. Isopropylmagnesium chloride (2 M in THF, 2.5 mL, 5 mmol) was added. After stirring for 1 h at 0° C., (S)-2-(tert-butoxycarbonyl)aminobutyraldehyde (573 mg, 3 mmol) in THF (20 mL) was added. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was quenched with saturated ammonium chloride solution and concentrated to dryness. The residue was extracted with EtOAc, then washed with brine, dried with anhyd. MgSO4, filtered and concentrated. The crude product was purified by chromatograph to yield 383 mg of the desired compound. In a clean roundbottom flask equipped After stirring for 1 h at 0° C. The ice bath was removed to warm to room temperature the reaction mixture was quenched with saturated ammonium chloride solution concentrated to dryness The residue was extracted with EtOAc washed with brine dried with anhyd MgSO4, filtered concentrated The crude product was purified by chromatograph

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

Procedure: In a clean roundbottom flask equipped with stir bar was placed oxazolo[4,5-b]pyridine (600 mg, 5 mmol) in THF (30 mL) and the reaction mixture was cooled to 0° C. under N2 atomosphere. Isopropylmagnesium chloride (2 M in THF, 2.5 mL, 5 mmol) was added. After stirring for 1 h at 0° C., (S)-2-(tert-butoxycarbonyl)aminobutyraldehyde (573 mg, 3 mmol) in THF (20 mL) was added. The ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 h, the reaction mixture was quenched with saturated ammonium chloride solution and concentrated to dryness. The residue was extracted with EtOAc, then washed with brine, dried with anhyd. MgSO4, filtered and concentrated. The crude product was purified by chromatograph to yield 383 mg of the desired compound. In a clean roundbottom flask equipped After stirring for 1 h at 0° C. The ice bath was removed to warm to room temperature the reaction mixture was quenched with saturated ammonium chloride solution concentrated to dryness The residue was extracted with EtOAc washed with brine dried with anhyd MgSO4, filtered concentrated The crude product was purified by chromatograph

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

Procedure: tert-Butyl [(1S)-1-formylpropyl]carbamate (24.00 g) and ethyl bromodifluoroacetate (77.0 g) were dissolved in tetrahydrofuran (220 mL), and to a suspension of a zinc powder (25.4 g) in tetrahydrofuran (50 mL) was added dropwise the solution at room temperature. After heating under reflux for 1 hr, the mixture was cooled to room temperature, 1 mol/L aqueous potassium hydrogen sulfate solution (400 mL) was added, and the mixture was extracted with ethyl acetate. The extracted organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=10→40%), the obtained oil was dissolved in 4 mol/L hydrogen chloride/ethyl acetate solution (150 mL), and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (600 mL). Diisopropylethylamine (32.8 mL) was added, and the mixture was heated under reflux for 4 hr. The reaction solution was concentrated under reduced pressure, the residue was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate/hexane to give the title compound as a white powder (yield: 7.20 g, 54%). was added dropwise the solution at room temperature After heating under reflux for 1 hr the mixture was extracted with ethyl acetate The extracted organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=10→40%) the obtained oil was dissolved in 4 mol/L hydrogen chloride/ethyl acetate solution (150 mL) The reaction solution was concentrated under reduced pressure the residue was dissolved in tetrahydrofuran (600 mL) Diisopropylethylamine (32.8 mL) was added the mixture was heated under reflux for 4 hr The reaction solution was concentrated under reduced pressure the residue was filtered through silica gel the filtrate was concentrated under reduced pressure The obtained residue was recrystallized from ethyl acetate/hexane

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

Procedure: A solution of tert-butyl[(1S)-1-(hydroxymethyl)propyl]carbamate (30.0 g) in dimethyl sulfoxide (300 mL) was ice-cooled under a nitrogen atmosphere, and triethylamine (64.4 mL) and a solution of sulfur trioxide pyridine complex (80.7 g) in dimethyl sulfoxide (300 mL) were successively added. The mixture was stirred at the same temperature for 30 min and then at room temperature for 3 hr, 1 mol/L aqueous citric acid solution (500 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%) to give the title compound as a white powder (yield: 24.3 g, 85%). cooled under a nitrogen atmosphere at room temperature for 3 hr the mixture was extracted with diethyl ether The obtained organic layer was washed with water and saturated brine dried over anhydrous magnesium sulfate concentrated under reduced pressure The residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=0→30%)

Conditions: temp:-45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Alternative procedure: To a stirred solution of the oxazolo[4,5-b]pyridine (12 g, 100 mmol) in THF (300 ml) was added n-BuLi (1.6M solution in 62.5 ml of hexane) drop wise under N2 at −78° C. After 1 hour, MgBr.Et2O (25.8 g, 100 mmol) was added and the reaction mixture was allowed to warm to −45° C. for 1 hour before being treated with (S)-(1-formyl-propyl)-carbamic acid tert-butyl ester (11.46 g, 60 mmol) in THF (50 ml). The reaction mixture was stirred for 1 hour, quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4 and concentrated. The residue was purified by silica gel column chromatography to yield (S)-[1-(hydroxy-oxazolo[4,5-b]pyridin-2-yl-methyl)-propyl]-carbamic acid tert-butyl ester (14.1 g). quenched with saturated NH4Cl extracted with ethyl acetate The organic layer was washed with brine dried with MgSO4 concentrated The residue was purified by silica gel column chromatography

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

Procedure: To a solution of LiAlH4 (0.453 g, 11.9 mmol) in Et2O (20 mL) at 0° C. was added dropwise a solution of 1,1-dimethylethyl ((1S)-1-{[methyl(methyloxy)amino]carbonyl}-propyl)carbamate (2.67 g, 10.8 mmol) in Et2O (15 mL). The reaction mixture was stirred for 30 min at 0° C. and quenched with EtOAc (6.5 mL) followed by 5% aq. potassium bisulfate (6.5 mL). The reaction mixture was washed with 1 M aq. HCl (3×10 mL), saturated aq. NaHCO3 (3×10 mL), and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound as a clear, colorless oil. quenched with EtOAc (6.5 mL) The reaction mixture was washed with 1 M aq. HCl (3×10 mL), saturated aq. NaHCO3 (3×10 mL), and brine (10 mL) The organic layer was dried over Na2SO4 filtered concentrated in vacuo