4,4-difluorocyclohexane-1-carbonyl chloride

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

Procedure: The title compound was prepared in a manner similar to that described in Preparation 9 for the synthesis of (S)-3-((R)-cyclohexylhydroxymethyl) pyrrolidine-1-carboxylic acid t-butyl ester. (S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester and LiHMDS were dissolved in THF under nitrogen and cooled at −78° C. 4,4-Difluoro-cyclohexanecarbonyl chloride (prepared by treatment of 4,4-difluorocyclohexane carboxylic acid with thionyl chloride in THF at 50° C. for 2 hours), was then added and the resulting mixture was stirred at −78° C. then allowed to reach room temperature overnight. BH3.Me2S in THF was added and the resulting mixture stirred at room temperature for 1 hour, then refluxed for 1 hour. The solids (1.03 g) were separated and dissolved in 1:1 AcOH:H2O (20 mL) and purified by preparative HPLC (BDS, 40-60%). This was repeated twice to yield: the resulting mixture stirred at room temperature for 1 hour refluxed for 1 hour The solids (1.03 g) were separated dissolved in 1:1 AcOH H2O (20 mL) and purified by preparative HPLC (BDS, 40-60%)

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

Procedure: The title compound was prepared in a manner similar to that described in Preparation 9 for the synthesis of (S)-3-((R)-cyclohexylhydroxymethyl) pyrrolidine-1-carboxylic acid t-butyl ester. (S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester and LiHMDS were dissolved in THF under nitrogen and cooled at −78° C. 4,4-Difluoro-cyclohexanecarbonyl chloride (prepared by treatment of 4,4-difluorocyclohexane carboxylic acid with thionyl chloride in THF at 50° C. for 2 hours), was then added and the resulting mixture was stirred at −78° C. then allowed to reach room temperature overnight. BH3.Me2S in THF was added and the resulting mixture stirred at room temperature for 1 hour, then refluxed for 1 hour. The solids (1.03 g) were separated and dissolved in 1:1 AcOH:H2O (20 mL) and purified by preparative HPLC (BDS, 40-60%). This was repeated twice to yield: the resulting mixture stirred at room temperature for 1 hour refluxed for 1 hour The solids (1.03 g) were separated dissolved in 1:1 AcOH H2O (20 mL) and purified by preparative HPLC (BDS, 40-60%)

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

Procedure: 4,4-Difluorocyclohexanecarboxylic acid (118.2 g, 0.72 mol) was dissolved in toluene (296 ml). To the clear solution was added thionyl chloride (261 ml, 3.6 mol) and the resultant solution was heated under reflux for 1.5 hours. A sample was taken and concentrated and 1H-NMR indicated complete conversion to the title compound. The reaction was cooled to room temperature and the thionyl chloride was removed under reduced pressure and replaced with toluene to give the title compound as a toluene concentrate at a total volume of 591 ml. under reflux for 1.5 hours concentrated the thionyl chloride was removed under reduced pressure

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

Procedure: 4,4-Difluorocyclohexanecarboxylic acid (118.2 g, 0.72 mol) was dissolved in toluene (296 ml). To the clear solution was added thionyl chloride (261 ml, 3.6 mol) and the resultant solution was heated under reflux for 1.5 hours. A sample was taken and concentrated and 1H-NMR indicated complete conversion to the title compound. The reaction was cooled to room temperature and the thionyl chloride was removed under reduced pressure and replaced with toluene to give the title compound as a toluene concentrate at a total volume of 591 ml. under reflux for 1.5 hours concentrated the thionyl chloride was removed under reduced pressure

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

Procedure: 4,4-Difluorocyclohexanecarboxylic acid (118.2 g, 0.72 mol) was dissolved in toluene (296 ml). To the clear solution was added thionyl chloride (261 ml, 3.6 mol) and the resultant solution was heated under reflux for 1.5 hours, A sample was taken and concentrated and 1H-NMR indicated complete conversion to the title compound. The reaction was cooled to room temperature and the thionyl chloride was removed under reduced pressure and replaced with toluene to give the title compound as a toluene concentrate at a total volume of 591 ml. under reflux for 1.5 hours concentrated the thionyl chloride was removed under reduced pressure

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

Procedure: The title compound was prepared in a manner similar to that described in Preparation 9 for the synthesis of (S)-3-((R)-cyclohexylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester. (S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester and LiHMDS were dissolved in THF under nitrogen and cooled at −78° C. 4,4-Difluoro-cyclohexanecarbonyl chloride (prepared by treatment of 4,4-difluorocyclohexane carboxylic acid with thionyl chloride in THF at 50° C. for 2 hours), was then added and the resulting mixture was stirred at −78° C. then allowed to reach room temperature overnight. BH3.Me2S in THF was added and the resulting mixture stirred at room temperature for 1 hour, then refluxed for 1 hour. The solids (1.03 g) were separated and dissolved in 1:1 AcOH:H2O (20 mL) and purified by preparative HPLC (BDS, 40-60%). This was repeated twice to yield: the resulting mixture stirred at room temperature for 1 hour refluxed for 1 hour The solids (1.03 g) were separated dissolved in 1:1 AcOH H2O (20 mL) and purified by preparative HPLC (BDS, 40-60%)

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

Procedure: The title compound was prepared in a manner similar to that described in Preparation 9 for the synthesis of (S)-3-((R)-cyclohexylhydroxymethyl) pyrrolidine-1-carboxylic acid t-butyl ester. (S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester and LiHMDS were dissolved in THF under nitrogen and cooled at −78° C. 4,4-Difluoro-cyclohexanecarbonyl chloride (prepared by treatment of 4,4-difluorocyclohexane carboxylic acid with thionyl chloride in THF at 50° C. for 2 hours), was then added and the resulting mixture was stirred at −78° C. then allowed to reach room temperature overnight. BH3.Me2S in THF was added and the resulting mixture stirred at room temperature for 1 hour, then refluxed for 1 hour. The solids (1.03 g) were separated and dissolved in 1:1 AcOH:H2O (20 mL) and purified by preparative HPLC (BDS, 40-60%). This was repeated twice to yield: the resulting mixture stirred at room temperature for 1 hour refluxed for 1 hour The solids (1.03 g) were separated dissolved in 1:1 AcOH H2O (20 mL) and purified by preparative HPLC (BDS, 40-60%)

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

Procedure: 4,4-Difluorocyclohexanecarboxylic acid (118.2 g, 0.72 mol) was dissolved in toluene (296 ml). To the clear solution was added thionyl chloride (261 ml, 3.6 mol) and the resultant solution was heated under reflux for 1.5 hours. A sample was taken and concentrated and 1H-NMR indicated complete conversion to the title compound. The reaction was cooled to room temperature and the thionyl chloride was removed under reduced pressure and replaced with toluene to give the title compound as a toluene concentrate at a total volume of 591 ml. under reflux for 1.5 hours concentrated the thionyl chloride was removed under reduced pressure

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

Procedure: 4,4-Difluorocyclohexanecarboxylic acid (118.2 g, 0.72 mol) was dissolved in toluene (296 ml). To the clear solution was added thionyl chloride (261 ml, 3.6 mol) and the resultant solution was heated under reflux for 1.5 hours. A sample was taken and concentrated and 1H-NMR indicated complete conversion to the title compound. The reaction was cooled to room temperature and the thionyl chloride was removed under reduced pressure and replaced with toluene to give the title compound as a toluene concentrate at a total volume of 591 ml. under reflux for 1.5 hours concentrated the thionyl chloride was removed under reduced pressure

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

Procedure: 4,4-Difluorocyclohexanecarboxylic acid (118.2 g, 0.72 mol) was dissolved in toluene (296 ml). To the clear solution was added thionyl chloride (261 ml, 3.6 mol) and the resultant solution was heated under reflux for 1.5 hours. A sample was taken and concentrated and 1H-NMR indicated complete conversion to the title compound. The reaction was cooled to room temperature and the thionyl chloride was removed under reduced pressure and replaced with toluene to give the title compound as a toluene concentrate at a total volume of 591 ml. under reflux for 1.5 hours concentrated the thionyl chloride was removed under reduced pressure