4-Chloro-3-(methylthio)phenol

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

Procedure: 2-Chloro-5-fluoro-N-(trans-4-hydroxycyclohexyl)nicotinamide (150 mg, 0.55 mmol) was added to a solution of 4-chloro-3-(methylsulfanyl)phenol (96 mg, 0.55 mmol), caesium carbonate (358 mg, 1.1 mmol) in N,N-dimethylformamide (2 ml). The reaction was stirred under nitrogen at 55° C. for 18 h, cooled, and quenched with 1:1 water:sat. ammonium chloride solution and passed through a chemelute™ cartridge. The solvent. The residue was purified by flash column chromatography using dichloromethane:methanol (100:0 to 96:4) as eluant to afford 2-[4-chloro-3-(methylsulfanyl)phenoxy]-5-fluoro-N-(trans-4-hydroxycyclohexyl)nicotinamide as an amorphous glass (37 mg). cooled quenched with 1:1 water The residue was purified by flash column chromatography

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

Procedure: Boron tribromide (1M in dichloromethane, 31 ml, 31 mmol) was added dropwise to a solution of 1-chloro-4-methoxy-2-(methylsulfanyl)benzene (2.88 g, 15 mmol) in dichloromethane (80 ml) at 0° C. The mixture was allowed to warm to room temperature, stirred for 72 h then cooled to 0° C. A solution of diethanolamine (10 ml) in dichloromethane (20 ml) was added dropwise (Caution—strong exotherm!) and the mixture was stirred at ambient temperature for 15 min once addition was complete, then partitioned between dichloromethane and 2N hydrochloric acid. The organic phase was washed with water, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (10:90 to 85:15) as eluant to give 4-chloro-3-(methylsulfanyl)phenol (2.12 g) as a brown oil. then cooled to 0° C the mixture was stirred at ambient temperature for 15 min once addition partitioned between dichloromethane and 2N hydrochloric acid The organic phase was washed with water dried over MgSO4 the solvent removed under reduced pressure The residue was purified by flash column chromatography

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

Procedure: 50 g of 4-chloro-3-methylmercaptophenol, 62 g of 3,4-dichlorobenzotrifluoride and 12 g of sodium hydroxide are stirred in 150 ml of dimethyl sulphoxide for 6 hours at 142° C. The reaction mixture is then poured onto ice and extracted with toluene. Distillation of the organic phase yields 81 g of 3-(2'-chloro-4-trifluoromethylphenoxy)-6-chlorothioanisole with a boiling point of 158° C./0.4 mbar. The reaction mixture is then poured onto ice extracted with toluene Distillation of the organic phase

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

Procedure: 2-Chloro-5-fluoro-N-(trans-4-hydroxycyclohexyl)nicotinamide (150 mg, 0.55 mmol) was added to a solution of 4-chloro-3-(methylsulfanyl)phenol (96 mg, 0.55 mmol), caesium carbonate (358 mg, 1.1 mmol) in N,N-dimethylformamide (2 ml). The reaction was stirred under nitrogen at 55° C. for 18 h, cooled, and quenched with 1:1 water:sat. ammonium chloride solution and passed through a chemelute™ cartridge. The solvent. The residue was purified by flash column chromatography using dichloromethane:methanol (100:0 to 96:4) as eluant to afford 2-[4-chloro-3-(methylsulfanyl)phenoxy]-5-fluoro-N-(trans-4-hydroxycyclohexyl)nicotinamide as an amorphous glass (37 mg). cooled quenched with 1:1 water The residue was purified by flash column chromatography

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

Procedure: Boron tribromide (1M in dichloromethane, 31 ml, 31 mmol) was added dropwise to a solution of 1-chloro-4-methoxy-2-(methylsulfanyl)benzene (2.88 g, 15 mmol) in dichloromethane (80 ml) at 0° C. The mixture was allowed to warm to room temperature, stirred for 72 h then cooled to 0° C. A solution of diethanolamine (10 ml) in dichloromethane (20 ml) was added dropwise (Caution—strong exotherm!) and the mixture was stirred at ambient temperature for 15 min once addition was complete, then partitioned between dichloromethane and 2N hydrochloric acid. The organic phase was washed with water, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (10:90 to 85:15) as eluant to give 4-chloro-3-(methylsulfanyl)phenol (2.12 g) as a brown oil. then cooled to 0° C the mixture was stirred at ambient temperature for 15 min once addition partitioned between dichloromethane and 2N hydrochloric acid The organic phase was washed with water dried over MgSO4 the solvent removed under reduced pressure The residue was purified by flash column chromatography