sodium;methanethiolate

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

Procedure: Cyclohex-2-enone (3.80 g, 95% Aldrich, 39.5 mmol uncorrected), toluene (15.31 g, HPLC grade) and glacial acetic acid (2.85 g, 47.4 mmoles, 1.20 eq, 99.7+% Aldrich) were combined in a 50 mL 3-necked round bottom flask equipped with a magnetic stirrer, reflux condenser with nitrogen oil bubbler vented to a bleach scrubber, thermometer with Therm-o-watch controller and septum. To the stirred solution was added 15 wt % sodium thiomethoxide (19.4 g of solution, 2.91 g, 41.5 mmol, 1.05 eq of NaSCH3) in portions via syringe during 19 min. The reaction temperature increased from 28.0° C. to 36.4° C. during the addition. The two-phase mixture was stirred at ambient temperature overnight. The reaction mixture was heated to about 50° C. and stirred for 7.5 h. The mixture was then allowed to cool to room temperature with stirring overnight. The phases were allowed to settle for 30 min. The lower aqueous phase was removed. The upper organic phase was washed with water (2×10 mL), dried through a cone of anhydrous magnesium sulfate and concentrated on the rotary evaporator (29 in. Hg vacuum/48° C.) to afford 4.91 g of 3-(methylthio)cyclohexanone as a clear pale yellow oil. Area % conversion by GC 95%. Raw area % 91.1%. Mass recovery 86%. equipped with a magnetic stirrer reflux condenser with nitrogen oil bubbler The reaction temperature increased from 28.0° C. to 36.4° C. during the addition The reaction mixture was heated to about 50° C. stirred for 7.5 h to cool to room temperature with stirring overnight to settle for 30 min The lower aqueous phase was removed The upper organic phase was washed with water (2×10 mL) dried through a cone of anhydrous magnesium sulfate concentrated on the rotary evaporator (29 in. Hg vacuum/48° C.)

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

Procedure: To a three-neck 50 mL round bottom flask equipped with a temperature probe, magnetic stirring, and bleach scrubber was charged in sequence 3.43 g (20.39 mmol) phenyl vinyl sulfone followed by 5 mL of acetonitrile, and the mixture was then cooled in an ice-water bath. To this mixture was then added 2.53 g (42.13 mmol) of glacial acetic acid in one portion. To this mixture was con-added 10 g (21.40 mmol) of a 15 wt % sodium thiomethoxide in water solution over a 17 min period. The internal reaction temperature rose from 14° C. to 17° C. during the sodium thiomethoxide addition. The ice-water bath was removed and the reaction mixture was heated to 50-60° C. for 3.5 h at which time liquid chromatography (LC) analysis indicated about 42% (relative area) of starting phenyl vinyl sulfone in the reaction mixture. Another 4.76 g (10.19 mmol) of a 15 wt % sodium thiomethoxide in water solution was added over a 9 min period. The reaction mixture was then stirred an additional 6.5 h at 50-60° C., and then cooled to ambient temperature and allowed to stir overnight. At this time LC analysis indicated about 7% (relative area) of starting phenyl vinyl sulfone in the reaction mixture. To the reaction mixture was added 1.37 g (23.44 mmol) of sodium chloride and the reaction phases were allowed to separate. The organic layer was concentrated on a rotary evaporator to give 3.96 g of methyl 2-phenylsulfonylethyl sulfide as a yellow oil (yield was ˜90% based on theoretical yield). 1H NMR (300 MHz, CDCl3) δ 2.1 (s, 3H), 2.78 (m, 2H), 3.35 (m 2H), 7.1 (m, 2H), 7.7 (m, 1H), 7.9 (m, 2H). 13C NMR (75.5 MHz, CDCl3) δ 15.5, 26.4, 56.0, 127.9, 129.4, 134.1, 138.6. To a three-neck 50 mL round bottom flask equipped with a temperature probe, magnetic stirring, and bleach scrubber the mixture was then cooled in an ice-water bath The ice-water bath was removed Another 4.76 g (10.19 mmol) of a 15 wt % sodium thiomethoxide in water solution was added over a 9 min period cooled to ambient temperature to stir overnight to separate The organic layer was concentrated on a rotary evaporator to give

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

Procedure: A solution of 2,5-dibromopyridine (1.0 g, 4.22 mmol) in DMF (15 mL) was treated with sodium thiomethoxide (0.69 g, 95%, 9.29 mmol) at ambient temperature. The reaction mixture was stirred for 30 minutes, was diluted water and then extracted with ether. The combined organic extract was washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give crude sulfide as a colorless oil. The crude sulfide was dissolved in acetone (120 mL) and was treated with water (50 mL) followed by Oxone® (7.80 g, 12.7 mmol). The reaction mixture was stirred at ambient temperature for 2 h. After more water was added, the mixture was extracted with ether (200 mL) and EtOAc (150 mL). The organic layers were combined and washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light brown oil. The crude product was purified by chromatography on ISCO silica gel column eluted with a 0 to 45% EtOAc:hexane gradient to give 0.54 g (54% from 2,5-dibromopyridine) of 5-bromo-2-(methylsulfonyl)pyridine as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.78 (d, 1H, J=2.2 Hz), 8.10 (dd, 1H, Ja=8.3 Hz, Jb=2.2 Hz), 7.98 (d, 1H, J=8.3 Hz), 3.22 (s, 3H); LRMS (ESI), m/z 236/238 (M+H). extracted with ether The combined organic extract was washed with brine dried over Na2SO4 filtered the filtrate was concentrated to give crude sulfide as a colorless oil The reaction mixture was stirred at ambient temperature for 2 h the mixture was extracted with ether (200 mL) and EtOAc (150 mL) washed with water and brine dried over Na2SO4 filtered the filtrate was concentrated to give the crude product as a light brown oil The crude product was purified by chromatography on ISCO silica gel column eluted with a 0 to 45% EtOAc

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 4-(2-iodoethyl)-1-[2-methyl-5-(methyloxy)-4-nitrophenyl]piperidine (40.6 g, 100 mmol) was added sodium thiomethoxide (7.75 g, 111 mmol) and diluted with DMF (201 mL). The reaction was stirred at 50° C. overnight. The solution was diluted with EtOAc and washed with H2O. The organic layer was dried (MgSO4), filtered, and rotovapped down to provide the title compound of step H (33.5 g) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.72 (s, 1H), 6.64 (s, 1H), 3.86 (s, 3H), 3.23 (d, J=12.1 Hz, 2H), 2.60-2.72 (m, 2H), 2.46-2.52 (m, 2H), 2.14 (s, 3H), 2.01 (s, 3H), 1.75 (d, J=12.1 Hz, 2H), 1.50 (t, J=5.7 Hz, 3H), 1.16-1.35 (m, 2H). washed with H2O The organic layer was dried (MgSO4) filtered

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To 1,1-dimethylethyl 4-(2-iodoethyl)-1-piperidinecarboxylate (Example 101, Step A) (23.6 g, 69.5 mmol) in DMF (100 mL) was added sodium thiomethoxide (5.37 g, 76.4 mmol). The mixture was stirred at 50° C. overnight. The mixture was diluted with EtOAc, washed with H2O (6×), dried (MgSO4), and rotovapped down to provide the title compound of Step A (17.9 g, 68.8 mmol, 99%). 1H NMR (400 MHz, CDCl3) δ 1.09 (dd, 2H), 1.44 (s, 9H), 1.53 (t, J=5.6 Hz, 3H), 1.65 (d, J=12.6 Hz, 2H), 2.08 (s, 3H), 2.51 (t, J=6.9 Hz, 2H), 2.67 (t, J=12.6 Hz, 2H), 4.06 (d, J=13.2 Hz, 2H). washed with H2O (6×) dried (MgSO4)

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

Procedure: To 1,1-dimethylethyl 4-(2-iodoethyl)-1-piperidinecarboxylate (3.13 g, 9.23 mmol) in DMF (50 mL) was added sodium thiomethoxide (661 mg, 10.4 mmol) in one portion. The reaction was stirred for 3 days. Upon completion by TLC, the reaction was diluted with EtOAc (250 mL), washed with H2O (4 times), dried (MgSO4) and concentrated to provide the title compound of step B (2.37 g, 9.20 mmol, 99%, approximately 93% pure, used without further purification). 1H NMR (400 MHz, CDCl3) δ ppm 1.02-1.13 (m, 2H), 1.42 (s, 9H), 1.48-1.55 (m, 3H), 1.63 (d, J=12.5 Hz, 2H), 2.07 (s, 3H), 2.45-2.53 (m, 2H), 2.65 (td, J=12.8, 2.6 Hz, 2H), 4.02-4.09 (m, 2H). washed with H2O (4 times) dried (MgSO4) concentrated

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

Procedure: 1-Bromo-2,5-pyrrolidinedione (0.11 g) was added to a solution of the product from Example 27 step b) (0.2 g) in DMF (2 ml), and the solution stirred for 10 min. Sodium thiomethoxide (43 mg) was then added and the mixture stirred for a further 3 hours. The solvents were evaporated in vacuo and the residue purified by reverse phase HPLC. The residue was triturated with ether to give a solid, which was filtered and dried to yield the title compound as a white solid (40 mg). the mixture stirred for a further 3 hours The solvents were evaporated in vacuo the residue purified by reverse phase HPLC The residue was triturated with ether to give a solid, which was filtered dried

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1,3-Dibromo-5-(4-methoxy-benzyloxy)-benzene (4.0 g) was dissolved in DMF (60 mL), followed by addition of sodium thiomethoxide (829 mg). The resulting mixture was stirred at 75° C. for 5 h. Over the period of 4 hours additional amount of sodium methoxide (total 754 mg) was added in two equal portions. When the starting material was completely consumed the reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified on a silica gel column using ethyl acetate and hexanes to yield the title compound (2.1 g, 60% yield). HRMS calcd for C15H15O2BrS [M+H]+ 339.0049, observed 339.0047. When the starting material was completely consumed the reaction mixture was diluted with ethyl acetate washed with water and brine The organic extract was dried over anhydrous sodium sulfate concentrated under reduced pressure purified on a silica gel column

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-benzyloxy-3,5-dibromo-benzene (9.6 g, 28.1 mmol) in dry DMF (55 mL) was added sodium thiomethoxide (1.97 g, 28.1 mmol). The reaction mixture was then stirred at 100° C. for 1 h. After cooling to room temperature, the reaction mixture was poured into a mixture of diethyl ether (50 mL) and water (20 mL) along with intense stirring. The organic layer was separated and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica using hexanes-acetone (5:0.2) as eluent to afford 3.68 g (42%) of title compound as an yellow oil. 1H NMR (CDCl3, 300 MHz): δ 7.41-7.26 (m, 5H); 6.96 (s, 1H); 6.90 (s, 1H); 6.80 (s, 1H); 5.05 (s, 2H); 2.46 (s, 3H). After cooling to room temperature The organic layer was separated washed with water and brine The organic phase was dried over magnesium sulfate filtered concentrated under reduced pressure The residue was purified by column chromatography on silica

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

Procedure: To a suspension of sodium thiomethoxide (1.47 g) in anhydrous tetrahydrofuran (50 ml) was added dropwise a solution of N-(2-nitro-5-chlorophenyl)-N-methylcarbamic acid t-butyl ester (6.0 g) in anhydrous tetrahydrofuran (120 ml) while cooling at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. At the end of this time anhydrous DMF (30 ml) was added and the resulting mixture stirred at room temperature for 1 hour. DMF (20 ml) was added and then sodium thiomethoxide (0.73 g) and further DMF (50 ml) were added. The resulting mixture was stirred at room temperature for 7 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and aqueous sodium hydrogencarbonate solution. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to afford the desired compound (6.15 g). the resulting mixture stirred at room temperature for 1 hour The resulting mixture was stirred at room temperature for 7 hours The reaction mixture was concentrated in vacuo the residue was partitioned between ethyl acetate and aqueous sodium hydrogencarbonate solution The extract was washed with saturated aqueous sodium chloride solution dried over anhydrous sodium sulfate concentrated

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

Procedure: Sodium thiomethoxide (5.18 g, 73.8 mmol) was added slowly portion-wise via powder addition funnel to a stirring solution of 2,4-dichloropyrimidine (10 g, 67.1 mmol) in THF (150 mL) at room temperature. After stirring overnight, the reaction was taken up in ethyl acetate, washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate and hexanes to give 2-chloro-4-(methylsulfanyl)pyrimidine (10.127 g, 47.3 mmol, 70.4%) as a white solid. washed with water, brine dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The residue was purified by column chromatography on silica gel eluting with ethyl acetate and hexanes

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 5-chloro-2-nitro-4-trifluoromethyl-phenylamine (2.02 g, 8.40 mmol) and DMF (40 mL) was added sodium thiomethoxide (0.618 g, 8.82 mmol). The mixture was heated to 90° C. for 50 min, then poured into brine. Water was added to bring the total volume to 300 mL and the orange precipitate was collected to yield the titled compound (2.02 g, 95%). 1H NMR (400 MHz, CDCl3): 8.42 (s, 1H), 6.51 (s, 1H), 6.39 (br s, 2H), 2.53 (s, 3H). the orange precipitate was collected