4-chloro-1-fluoro-2-methylbenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: (S)-3-((R)-1-Hydroxy-2-methylsulfanylethyl)pyrrolidine-1-carboxylic acid t-butyl ester (20 mg, 80 μmol) was dissolved in DMF (367 μL). NaH (3.7 mg, 153 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 5-Chloro-2-fluorotoluene (33.2 mg mg, 230 μmol) was added and the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to room temperature, concentrated then dissolved in 1.2M HCl in EtOH (2.2 mL, 2.7 mmol) and stirred overnight at room temperature. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (0.6 mg, purity 85%). MS m/z: [M+H]+ calcd for C14H20ClNOS, 286.10; found 286.0. the mixture was stirred at 100° C. for 1 hour The mixture was cooled to room temperature concentrated stirred overnight at room temperature The product was concentrated purified by preparative HPLC

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

Procedure: (S)-3-((R)-1-Hydroxy-2-methylsulfanylethyl)pyrrolidine-1-carboxylic acid t-butyl ester (20 mg, 80 μmol) was dissolved in DMF (367 μL). NaH (3.7 mg, 153 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 5-Chloro-2-fluorotoluene (33.2 mg mg, 230 μmol) was added and the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to room temperature, concentrated then dissolved in 1.2M HCl in EtOH (2.2 mL, 2.7 mmol) and stirred overnight at room temperature. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (0.6 mg, purity 85%). MS m/z: [M+H]+ calcd for C14H20ClNOS, 286.10; found 286.0. the mixture was stirred at 100° C. for 1 hour The mixture was cooled to room temperature concentrated stirred overnight at room temperature The product was concentrated purified by preparative HPLC

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

Procedure: (S)-3-((R)-1-Hydroxy-2-methylsulfanylethyl)pyrrolidine-1-carboxylic acid t-butyl ester (20 mg, 80 μmol) was dissolved in DMF (367 μL). NaH (3.7 mg, 153 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 5-Chloro-2-fluorotoluene (33.2 mg mg, 230 μmol) was added and the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to room temperature, concentrated then dissolved in 1.2M HCl in EtOH (2.2 mL, 2.7 mmol) and stirred overnight at room temperature. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (0.6 mg, purity 85%). MS m/z: [M+H]+ calcd for C14H20ClNOS, 286.10; found 286.0. the mixture was stirred at 100° C. for 1 hour The mixture was cooled to room temperature concentrated stirred overnight at room temperature The product was concentrated purified by preparative HPLC

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

Procedure: A mixture of 5-chloro-2-fluorotoluene (2.9 g; prepared by a modified Schiemann reaction on 4-chloro-2-methylaniline), NBS (3.6 g) benzoyl peroxide (100 mg) and carbon tetrachloride (25 ml) was refluxed 2h. The mixture was cooled, filtered and the solvent removed. Distillation gave 5-chloro-2-fluorobenzyl bromide (3 g), b.p. 104°/15 mm. was refluxed 2h The mixture was cooled filtered the solvent removed Distillation

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Chloro-2-fluoro-toluene (100 g, 692 mmol) was dissolved in ethylacetate (300 ml) at 20° C. To this solution N-bromosuccinimide (147.7 g, 830 mmol) and dibenzoyl peroxide (2 g, 8.25 mmol) was added. The mixture was stirred at 80° C. for 3 hours. Heptane (300 ml) was added and the solution was cool to 0° C. whereupon succinimide precipitates. After filtration and washing with heptane, the residue was washed with water (1500 ml). The filtrate was concentrated in vacuo to dryness, yielding 162 grams of crude 5-chloro-2-fluoro-benzylbromide. Purification of the crude product (141 grams) was done by vacuum distillation at 99° C. and 33 mbar, this 5-chloro-2-fluoro-benzylbromide (99 grams, 75%). Purity according to GC is 87.1% a/a. precipitates After filtration washing with heptane the residue was washed with water (1500 ml) The filtrate was concentrated in vacuo to dryness

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

Procedure: (S)-3-((R)-1-Hydroxy-2-methylsulfanylethyl)pyrrolidine-1-carboxylic acid t-butyl ester (20 mg, 80 μmol) was dissolved in DMF (367 μL). NaH (3.7 mg, 153 μmol) was added and the mixture was stirred at room temperature for 15 minutes. 5-Chloro-2-fluorotoluene (33.2 mg mg, 230 tμmol) was added and the mixture was stirred at 100° C. for 1 hour. The mixture was cooled to room temperature, concentrated then dissolved in 1.2M HCl in EtOH (2.2 mL, 2.7 mmol) and stirred overnight at room temperature. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (0.6 mg, purity 85%). MS m/z: [M+H]+ calcd for C14H20ClNOS, 286.10. found 286.0. the mixture was stirred at 100° C. for 1 hour The mixture was cooled to room temperature concentrated stirred overnight at room temperature The product was concentrated purified by preparative HPLC

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

Procedure: A mixture of 5-chloro-2-fluorotoluene (2.9 g; prepared by a modified Schiemann reaction on 4-chloro-2-methylaniline), NBS(3.6 g) benzoyl peroxide (100 mg) and carbon tetrachloride (25 ml) was refluxed 2 h. The mixture was cooled, filtered and the solvent removed. Distillation gave 5-chloro-2-fluorobenzyl bromide (3 g), b.p. 104°/15 mm. was refluxed 2 h The mixture was cooled filtered the solvent removed Distillation