(2S,6S)-4-benzyl-2,6-dimethylmorpholine

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

Procedure: 1-Chloroethyl chloroformate (292 μL, 2.68 mmol, Aldrich) is added to a solution of (2S,6S)-4-benzyl-2,6-dimethylmorpholine (in CH2Cl2 (6 mL) with stirring in an ice bath. The solution is allowed to warm to room temperature and stirred for 2.5 hours. The solvent is removed by rotary evaporation and the residue is dissolved in methanol (6 mL). This solution is heated to reflux for 2.5 hours and the methanol is removed by rotary evaporation. The residue is dissolved in CH3CN (5 mL) and treated with N,N-diisopropylethylamine (244 μL, 1.4 mmol, Aldrich). K2CO3 (190 mg, 1.37 mmol, Mallinkrodt) and 2-fluoro-5-nitrobenzaldehyde (230 mg, 1.36 mmol, Oakwood) are added and the mixture is heated at 60° C. for 21 hours. The mixture is filtered and the solvent is removed by rotary evaporation. The residue is dissolved in CH2Cl2 (100 mL) and washed sequentially with water (75 mL) and brine (75 mL). The organic layer is purified on a Biotage Flash 25M+ using a 40% EtOAc in heptane as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum yielding a yellow syrup. stirred for 2.5 hours The solvent is removed by rotary evaporation the residue is dissolved in methanol (6 mL) This solution is heated to reflux for 2.5 hours the methanol is removed by rotary evaporation The residue is dissolved in CH3CN (5 mL) the mixture is heated at 60° C. for 21 hours The mixture is filtered the solvent is removed by rotary evaporation The residue is dissolved in CH2Cl2 (100 mL) washed sequentially with water (75 mL) and brine (75 mL) The organic layer is purified on a Biotage Flash 25M+ The product containing fractions the solvent is removed by rotary evaporation The product is dried under vacuum yielding a yellow syrup

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

Procedure: (2S,6S)-4-benzoyl-2,6-dimethylmorpholine (759 mg, 3.46 mmol) is dissolved in anhydrous THF (40 mL) and treated with LiAlH4 (1.0M in THF, 6.9 mL, Aldrich). The mixture is stirred with heating at 55° C. for 18 hours. An additional equivalent of LiAlH4 is added and the mixture is stirred with heating at 55° C. for an additional 6 hours. The reaction is quenched by adding water (0.4 mL) followed by 6.0M NaOH (0.4 mL) followed by water (1.2 mL). The white slurry is diluted with Et2O and filtered. The inorganic salts are washed with and additional portion of Et2O and the combined ethereal washes are dried over Na2SO4. The product is purified on a Biotage Flash 40M+ using a 15% Et2O in pentane as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum yielding a colorless oil. the mixture is stirred with heating at 55° C. for an additional 6 hours The reaction is quenched by adding water (0.4 mL) The white slurry is diluted with Et2O filtered The inorganic salts are washed with and additional portion of Et2O the combined ethereal washes are dried over Na2SO4 The product is purified on a Biotage Flash 40M+ The product containing fractions the solvent is removed by rotary evaporation The product is dried under vacuum yielding a colorless oil

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

Procedure: 1-Chloroethyl chloroformate (292 μL, 2.68 mmol, Aldrich) is added to a solution of (2S,6S)-4-benzyl-2,6-dimethylmorpholine (in CH2Cl2 (6 mL) with stirring in an ice bath. The solution is allowed to warm to room temperature and stirred for 2.5 hours. The solvent is removed by rotary evaporation and the residue is dissolved in methanol (6 mL). This solution is heated to reflux for 2.5 hours and the methanol is removed by rotary evaporation. The residue is dissolved in CH3CN (5 mL) and treated with N,N-diisopropylethylamine (244 μL, 1.4 mmol, Aldrich). K2CO3 (190 mg, 1.37 mmol, Mallinkrodt) and 2-fluoro-5-nitrobenzaldehyde (230 mg, 1.36 mmol, Oakwood) are added and the mixture is heated at 60° C. for 21 hours. The mixture is filtered and the solvent is removed by rotary evaporation. The residue is dissolved in CH2Cl2 (100 mL) and washed sequentially with water (75 mL) and brine (75 mL). The organic layer is purified on a Biotage Flash 25M+ using a 40% EtOAc in heptane as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum yielding a yellow syrup. stirred for 2.5 hours The solvent is removed by rotary evaporation the residue is dissolved in methanol (6 mL) This solution is heated to reflux for 2.5 hours the methanol is removed by rotary evaporation The residue is dissolved in CH3CN (5 mL) the mixture is heated at 60° C. for 21 hours The mixture is filtered the solvent is removed by rotary evaporation The residue is dissolved in CH2Cl2 (100 mL) washed sequentially with water (75 mL) and brine (75 mL) The organic layer is purified on a Biotage Flash 25M+ The product containing fractions the solvent is removed by rotary evaporation The product is dried under vacuum yielding a yellow syrup

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

Procedure: (2S,6S)-4-benzoyl-2,6-dimethylmorpholine (759 mg, 3.46 mmol) is dissolved in anhydrous THF (40 mL) and treated with LiAlH4 (1.0 M in THF, 6.9 mL, Aldrich). The mixture is stirred with heating at 55° C. for 18 hours. An additional equivalent of LiAlH4 is added and the mixture is stirred with heating at 55° C. for an additional 6 hours. The reaction is quenched by adding water (0.4 mL) followed by 6.0 M NaOH (0.4 mL) followed by water (1.2 mL). The white slurry is diluted with Et2O and filtered. The inorganic salts are washed with and additional portion of Et2O and the combined ethereal washes are dried over Na2SO4. The product is purified on a Biotage Flash 40M+ using a 15% Et2O in pentane as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum yielding a colorless oil. the mixture is stirred with heating at 55° C. for an additional 6 hours The reaction is quenched by adding water (0.4 mL) The white slurry is diluted with Et2O filtered The inorganic salts are washed with and additional portion of Et2O the combined ethereal washes are dried over Na2SO4 The product is purified on a Biotage Flash 40M+ The product containing fractions the solvent is removed by rotary evaporation The product is dried under vacuum yielding a colorless oil

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

Procedure: 1-Chloroethyl chloroformate (292 μL, 2.68 mmol, Aldrich) is added to a solution of (2S,6S)-4-benzyl-2,6-dimethylmorpholine (in CH2Cl2 (6 mL) with stirring in an ice bath. The solution is allowed to warm to room temperature and stirred for 2.5 hours. The solvent is removed by rotary evaporation and the residue is dissolved in methanol (6 mL). This solution is heated to reflux for 2.5 hours and the methanol is removed by rotary evaporation. The residue is dissolved in CH3CN (5 mL) and treated with N,N-diisopropylethylamine (244 μL, 1.4 mmol, Aldrich). K2CO3 (190 mg, 1.37 mmol, Mallinkrodt) and 2-fluoro-5-nitrobenzaldehyde (230 mg, 1.36 mmol, Oakwood) are added and the mixture is heated at 60° C. for 21 hours. The mixture is filtered and the solvent is removed by rotary evaporation. The residue is dissolved in CH2Cl2 (100 mL) and washed sequentially with water (75 mL) and brine (75 mL). The organic layer is purified on a Biotage Flash 25M+ using a 40% EtOAc in heptane as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum yielding a yellow syrup. stirred for 2.5 hours The solvent is removed by rotary evaporation the residue is dissolved in methanol (6 mL) This solution is heated to reflux for 2.5 hours the methanol is removed by rotary evaporation The residue is dissolved in CH3CN (5 mL) the mixture is heated at 60° C. for 21 hours The mixture is filtered the solvent is removed by rotary evaporation The residue is dissolved in CH2Cl2 (100 mL) washed sequentially with water (75 mL) and brine (75 mL) The organic layer is purified on a Biotage Flash 25M+ The product containing fractions the solvent is removed by rotary evaporation The product is dried under vacuum yielding a yellow syrup

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

Procedure: (2S,6S)-4-benzoyl-2,6-dimethylmorpholine (759 mg, 3.46 mmol) is dissolved in anhydrous THF (40 mL) and treated with LiAlH4 (1.0M in THF, 6.9 mL, Aldrich). The mixture is stirred with heating at 55° C. for 18 hours. An additional equivalent of LiAlH4 is added and the mixture is stirred with heating at 55° C. for an additional 6 hours. The reaction is quenched by adding water (0.4 mL) followed by 6.0M NaOH (0.4 mL) followed by water (1.2 mL). The white slurry is diluted with Et2O and filtered. The inorganic salts are washed with and additional portion of Et2O and the combined ethereal washes are dried over Na2SO4. The product is purified on a Biotage Flash 40M+ using a 15% Et2O in pentane as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum yielding a colorless oil. the mixture is stirred with heating at 55° C. for an additional 6 hours The reaction is quenched by adding water (0.4 mL) The white slurry is diluted with Et2O filtered The inorganic salts are washed with and additional portion of Et2O the combined ethereal washes are dried over Na2SO4 The product is purified on a Biotage Flash 40M+ The product containing fractions the solvent is removed by rotary evaporation The product is dried under vacuum yielding a colorless oil