sodium;ethanethiolate

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

Procedure: Commercially available benzyl chloride and sodium ethanethiolate are subjected to a nucleophilic substitution reaction to produce PhCH2SC2H5 after isolation and purification. In a Parr pressure vessel, 2.0 g (0.013 moles) of PhCH2SC2H5 is added to 200 ml of t-butanol. With stirring, 2.94 g (0.026 moles) of potassium t-butoxide is slowly added. The head space is flushed with an inert gas before exposure to 60 psi NO gas. The reaction is allowed to proceed at room temperature for 24 hours or until no further consumption of NO gas is observed. The resulting diazeniumdiolate salt is filtered, washed with t-butanol and diethyl ether, and vacuum dried before analysis.

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

Procedure: Combine 6-methoxy-9-methoxymethyl-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene (0.050 g, 0.14 mmol), sodium ethanethiolate (0.037 g, 0.44 mmol), and DMF (4 mL), and reflux under nitrogen atmosphere. After 18 hours, cool the reaction to room temperature and add ethyl acetate, wash with sat ammonium chloride solution (aq), then brine several times. Concentrate, and purify using reverse phase chromatography (5% to 95% 0.001% TFA buffer in acetonitrile/water) to yield the titled compound (0.015 g, 33%) as a white solid. TLC Rf=0.27 in 3:1 hexanes:ethyl acetate. 1H NMR (d-methanol): 7.42 (d, 1H, J=8.4 Hz), 7.13 (d, 2H, J=8.4 Hz), 6.84 (s, 1H), 6.79 (d, 2H, J=8.4 Hz), 6.65 (dd, 1H, J=7.9, 1.8 Hz), 3.70 (d, 1H, J=7.0 Hz), 3.35 (m, 3H), 3.17 (s, 3H), 3.07 (m, 1H), 2.48 (d, 1H, J=14.1 Hz), 1.87 (m, 1H), 1.64 (m, 2H), 1.41 (m, 2H), 1.16 (m, 3H). cool the reaction to room temperature wash with sat ammonium chloride solution (aq) Concentrate purify

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

Procedure: To chloride 366 (0.048 g, 0.077 mmol) in dry DMF (10 mL) was added sodium ethanethiolate (100 mg, 1.19 mmol) and the mixture was heated to 50° C., for 18 h. It was cooled, partitioned between ethyl acetate and water, washed with brine, dried (MgSO4), filtered, run through a short plug of silica gel, and concentrated. The residue was suspended in 1:1 ethyl acetate/methanol (50 mL) and sodium periodate (0.060 g, 0.28 mmol) in water (5 mL) was added. The reaction mixture was stirred for 6 h, concentrated and the residue was partitioned between ethyl acetate and water. The organic phase was collected, washed with brine, dried (anhydrous MgSO4), filtered, and concentrated. Reverse phase HPLC (Aquasil C-18 column, 60-95% MeOH/H2O+HCO2H, 30 min. linear gradient elution) of the residue followed by lyophilization afforded 368 (0.015 g, 29% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.71 (s, 1H); 9.66 (s, 1H); 8.51 (d, J=5.5, 1H); 8.12 (s, 1H); 8.07 (d, J=8.8, 1H); 7.89 (dd, J=12.9, 2.2, 1H); 7.53-7.41 (m, 5H); 7.09-7.03 (m, 3H); 6.94-6.90 (m, 1H); 6.64 (dd, J=5.5, 0.5, 1H); 4.22 (t, J=6.3, 2H); 3.86 (s, 3H); 3.65 (s, 2H); 2.93-2.65 (m, 4H); 2.13 (quint, J=8.0, 2H); 1.29 (t, J=7.4, 3H). LCMS: (M+H) 662.0. It was cooled partitioned between ethyl acetate and water washed with brine dried (MgSO4) filtered concentrated was added concentrated the residue was partitioned between ethyl acetate and water The organic phase was collected washed with brine dried (anhydrous MgSO4) filtered concentrated Reverse phase HPLC (Aquasil C-18 column, 60-95% MeOH/H2O+HCO2H, 30 min. linear gradient elution) of the residue

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture 1,3-dibromo-5-methoxy-benzene (2.65 g, 10 mmol) and sodium thioethoxide (1.01 g, 12 mmol) was added dimethylformamide (30 mL) at room temperature. Then, the resulting light yellow solution was heated to 105° C. and stirred for 2 h at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was cooled to room temperature and diluted with water (50 mL) and brine solution (50 mL). Then, the organic compound was extracted into ethyl acetate (3×50 mL). The combined extracts were washed with brine solution (150 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and the concentration of the solution under reduced pressure gave the crude residue which was purified by using an ISCO 120 g column chromatography, eluting with 0-20% ethyl actetate in hexanes to obtain 1-bromo-3-ethylsulfanyl-5-methoxy-benzene (1.35 g, 55%) as a white solid: EI(+)-HRMS m/e calcd for C9H11BrOS (M)+ 245.9715, found 245.9713. The reaction mixture was cooled to room temperature Then, the organic compound was extracted into ethyl acetate (3×50 mL) The combined extracts were washed with brine solution (150 mL) dried over anhydrous magnesium sulfate Filtration of the drying agent the concentration of the solution under reduced pressure gave the crude residue which was purified eluting with 0-20% ethyl actetate in hexanes

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (−)-4-benzo[b]thiophen-5-yl-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (10.00 g, 32.3 mmol) which was obtained according to Step F in the preparation of Example 98 and sodium ethanethiolate (11.3 g, 134.3 mmol) in DMF (250 mL) was heated at 140° C. under an N2 atmosphere for 14 hours. The reaction mixture was cooled in an ice bath before addition of saturated NH4Cl (250 mL). The aqueous phase was extracted with DCM (3×750 mL) and the combined organic extracts washed with water (3×500 mL), brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by silica gel column chromatography (eluent: 5% MeOH/CH2Cl2) to afford (−)-4-benzo[b]thiophen-5-yl-2-methyl-1,2,3,4-tetrahydroisoquinoline-7-ol (6.64 g, 70%) as an orange-brown solid: 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=8.3 Hz, 1H), 7.62 (s, 1H), 7.40 (d, J=5.4 Hz, 1H), 7.26-7.20 (m, 2H), 7.13 (d, J=8.4 Hz, 1H), 6.66 (d, J=8.3 Hz, 1H), 6.50-6.40 (m, 2H), 4.34 (dd, J=9.0, 6.0 Hz, 1H), 3.68 (d, J=15.0 Hz, 1H), 3.54 (d, J=15.0 Hz, 1H), 3.11 (dd, J=11.5, 5.7 Hz, 1H), 2.58 (dd, J=11.3, 9.7 Hz, 1H), 2.43 (s, 3H); ESI-MS m/z=296 [M+H]+. was obtained The aqueous phase was extracted with DCM (3×750 mL) the combined organic extracts washed with water (3×500 mL), brine dried over Na2SO4 concentrated in vacuo The crude material was purified by silica gel column chromatography (eluent: 5% MeOH/CH2Cl2)

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

Procedure: To a solution of the mesylate from Step F (3.6 g, 8.3 mmol) in 100 mL of DMF at 0° C. was added sodium ethanethiolate (1.4 g, 16.6 mmol). After 2 hours, the reaction was poured into EtOAc, washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product which was used in the next step without further purification. washed with sat. NaHCO3 and brine dried (Na2SO4) filtered concentrated in vacuo

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

Procedure: A mixture of 4-(chloromethyl)-1-methyl-1H-pyrazole (2.0 g, 15 mmol) (prepared according to Intermediate 5 Step A) and sodium ethanethiolate (2.6 g, 31 mmol) in N,N-dimethylformamide (20.0 mL) was stirred at room temperature overnight. The reaction mixture was quenched with brine and extracted with EtOAc (3×). The combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give an oil residue which was purified by combi-flash chromatography eluted with 20% EtOAc in hexane to give 1.9 g (79% yield) of the desired product. LC-MS found: 157.1 (M+H)+. The reaction mixture was quenched with brine extracted with EtOAc (3×) The combined extracts were dried over Na2SO4 filtered concentrated under reduced pressure to give an oil residue which was purified by combi-flash chromatography eluted with 20% EtOAc in hexane

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

Procedure: The reaction was carried out under argon. 4-(1,3-Dioxan-2-yl)-3-fluorobenzonitrile (4.14 g, 20 mmol) and sodium ethanethiolate (1.68 g, 20 mmol; 1 eq.) were initially charged in DMF (100 ml). Potassium carbonate (6.91 g, 50 mmol; 2.5 eq.) was added at RT, and the mixture was stirred at 100° C. for 5 h. TLC control then showed complete conversion. The mixture was concentrated and the residue was subjected to flash chromatography on silica gel (mobile phase: cyclohexane→cyclohexane/ethyl acetate 4:1). The title compound was obtained as a solid (4.8 g, 97% of theory). The mixture was concentrated

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

Procedure: Sodium ethanethiolate (1.6 g, 17.2 mmol) was added to a solution of methyl 5-nitropicolinate (2.8 g, 16 mmol) in DMF (30 mL), and the resulting mixture was stirred a room temperature. After 3 hours, acetic acid (1 mL) was added, and the mixture was evaporated to dryness. The residue was suspended in methanol (50 mL) and treated with 3N NaOH. The resulting mixture was stirred at room temperature for 16 hours and then evaporated. The residue was dissolved in water (100 mL), washed with ethyl acetate (2×100 mL), and acidified to pH 3-4 (conc. HCl), resulting in precipitation of the product. The precipitate was filtered, rinsed with water (100 mL) and dried under vacuum, providing 2.3 g of 5-(ethylthio)picolinic acid, in 79% yield; 1H NMR (DMSO-d6) δ 1.23 (t, 3H, J=7.3 Hz), 3.14 (q, 2H, J=7.3 Hz), 7.86 (dd, 1H, J=8.4 Hz, J=2.4 Hz), 7.95 (dd, 1H, J=8.4 Hz, J=0.9 Hz), 8.57 (dd, 1H, J=2.4 Hz, J=0.9 Hz), 13.09 (br, 1H). the mixture was evaporated to dryness treated with 3N NaOH The resulting mixture was stirred at room temperature for 16 hours evaporated The residue was dissolved in water (100 mL) washed with ethyl acetate (2×100 mL) resulting in precipitation of the product The precipitate was filtered rinsed with water (100 mL) dried under vacuum

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

Procedure: 3-Methoxy-6-oxamorphinan (VIII) is demethylated using sodium thioethoxide in dimethylformamide by the general procedure of Example 2 to produce the title product.

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

Procedure: 3-Methoxy-6-oxamorphinan (VIII) is demethylated using sodium thioethoxide in dimethylformamide by the general procedure of Example 2 to produce the title product.

Conditions: temp:23.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a freshly prepared, stirred solution of 0.25 mole of sodium ethanethiolate in 250 ml. of N,N-dimethylformamide at 0° C. is added 34 g. (0.10 mole) of 4-(4-methoxybenzoyl)-2,6-di(t-butyl)phenol, and the resulting solution is refluxed for 3 hours. The solution is stirred at 23° C. for about 16 hours, then acidified with 10 percent hydrochloric acid and extracted with dichloromethane. The organic extracts are washed twice with 10 percent hydrochloric acid, then with water, then dried and evaporated to provide an oil residue. The residue is dissolved in benzene an cooled. A solid crystallizes after many hours. It is recrystallized from a benzene-hexane mixture, then sublimed to provide white crystals of 4-(4-hydroxybenzoyl)-2,6-di(t-butyl)phenol, m.p. 188°-189.5° C. To a freshly prepared extracted with dichloromethane The organic extracts are washed twice with 10 percent hydrochloric acid with water, then dried evaporated to provide an oil residue A solid crystallizes after many hours It is recrystallized from a benzene-hexane mixture