N,N-dimethylmethanamine;hydrochloride

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added trimethylamine hydrochloride (0.1 eq), tosyl chloride (1.3 eq) and toluene (5 vols) under a nitrogen atmosphere and the reaction mixture agitated to form an oily slurry. The slurry was cooled to −5° C., then (2R)-1-methoxypropan-2-ol (1.0 eq) was added drop-wise over 30 minutes. Toluene (2.5 vols) was added as a line wash followed by triethylamine (1.5 eq), which was added drop-wise via addition funnel over 30 minutes maintaining the reaction temperature<8° C. Further toluene (2.5 vols) was added as a line wash and the reaction mixture held at −5° C. to 5° C. for 4.5 hours. N,N-dimethyl-1,3-propane-diamine, (0.3 eq) was added over 10 minutes at −5° C. The reaction mixture was agitated at −5° C. to 5° C. for 30 minutes, then 2N hydrochloric acid (0.55 eq) and 70 ml water were added. The reaction mixture was agitated for 30 minutes at 22° C. and the aqueous layer was separated off and discarded. The mixture was washed twice more with water (10 vols each wash) then the toluene layer was distilled to an oil on the rotary evaporator. Toluene (20 vols) was added to the oil and the solution evaporated to an oil to give the title compound as a dry light brown oil. Yield corrected for assay 93-97%. 1H NMR δ (400 MHz CDCl3): 7.78-7.75 (d, 2H), 7.45-7.43 (d, 2H), 4.66-4.62 (m, 1H), 3.35-3.26 (m, 2H), 3.16 (s, 3H), 2.4 (s, 3H), 1.13-1.11 (d, 3H). To a flask fitted with overhead stirrer, condenser to form an oily slurry wash was added drop-wise via addition funnel over 30 minutes maintaining the reaction temperature<8° C wash The reaction mixture was agitated at −5° C. to 5° C. for 30 minutes The reaction mixture was agitated for 30 minutes at 22° C. the aqueous layer was separated off The mixture was washed twice more with water (10 vols each wash) then the toluene layer was distilled to an oil on the rotary evaporator Toluene (20 vols) was added to the oil the solution evaporated to an oil

Conditions: temp:8.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flask was added under a nitrogen atmosphere trimethylamine hydrochloride (0.1 eq), tosyl chloride (1.3 eq) and toluene (5 vols) and the reaction mixture agitated to form an oily slurry. The slurry was cooled to −5° C. (2R)-1-Methoxypropan-2-ol (1.0 eq) was added drop-wise over 30 minutes. Toluene (2.5 vols) was added as a wash followed by triethylamine (1.5 eq), which was added drop-wise via addition funnel over 30 minutes maintaining the reaction temperature<8° C. Further toluene (2.5 vols) was added as a wash and the reaction mixture held at −5° C. to 5° C. for 4.5 hours. N,N-Dimethyl-1,3-propane-diamine (0.3 eq) was added over 10 minutes at −5° C. The mixture was agitated at −5° C. to 5° C. for 30 minutes. Then 2N hydrochloric acid (0.55 eq) and 70 ml water were added. The mixture was agitated for 30 minutes at 22° C. and the aqueous layer was separated off and discarded. The mixture was washed twice more with water (10 vols each wash) and after separation of the aqueous wash, the toluene layer was distilled to an oil on the rotary evaporator. Toluene (20 vols) was added to the oil and the solution evaporated to give the title compound as a dry light brown oil. Yield (corrected for assay) 93-97%. to form an oily slurry was added drop-wise over 30 minutes was added drop-wise via addition funnel over 30 minutes a wash The mixture was agitated at −5° C. to 5° C. for 30 minutes The mixture was agitated for 30 minutes at 22° C. the aqueous layer was separated off The mixture was washed twice more with water (10 vols each wash) and after separation of the aqueous wash the toluene layer was distilled to an oil on the rotary evaporator Toluene (20 vols) was added to the oil the solution evaporated

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

Procedure: The mixture of diastereomers of (S)-2-((2R,3R)-3-(4-chlorophenyl)-2-(5-chloropyridin-3-yl)-3-hydroxypropyl)-N-((S)-1-hydroxybutan-2-yl)-2-methylpent-4-enamide and (R)-2-((2S,3S)-3-(4-chlorophenyl)-2-(5-chloropyridin-3-yl)-3-hydroxypropyl)-N-((S)-1-hydroxybutan-2-yl)-2-methylpent-4-enamide (Example 400, Step G, 6.34 g,) was combined in DCM (68 ml) and triethylamine (13.3 ml, 95 mmol). After cooling in an ice bath, trimethylamine hydrochloride (1.953 g, 20.43 mmol) was added. 4-Methylbenzenesulfonic anhydride (17.78 g, 54.5 mmol) was added slowly as a solid, keeping the temperature below 10° C. The brownish colored solution was allowed to slowly warm to room temperature, and then stirred over night. The next day more trimethyl amine hydrochloride (0.271 mg, 2.91 mmol) was added and the solution was stirred for another day. The reaction was quenched with ice water. The layers were partitioned and the aqueous layer was washed with DCM. The combined organics were dried over MgSO4, filtered, and concentrated to provide a brown oil. The oil was dissolved in MeCN (100 ml) and then heated to 60° C. for 4 hours. The solution was concentrated and the residue dissolved in 100 ml of DCM. To this was added 100 ml of sat. NaHCO3 and the biphasic solution was stirred at rt. for 5 days. The solution was partitioned and the aqueous layer was washed with DCM. The organics were dried over MgSO4, filtered and concentrated. The product was purified by silica gel chromatography to give (3S,5R,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one as the second eluting diastereomer. After cooling in an ice bath the temperature below 10° C the solution was stirred for another day The reaction was quenched with ice water The layers were partitioned the aqueous layer was washed with DCM The combined organics were dried over MgSO4 filtered concentrated to provide a brown oil heated to 60° C. for 4 hours The solution was concentrated the residue dissolved in 100 ml of DCM To this was added 100 ml of sat. NaHCO3 the biphasic solution was stirred at rt The solution was partitioned the aqueous layer was washed with DCM The organics were dried over MgSO4 filtered concentrated The product was purified by silica gel chromatography

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

Procedure: A mixture of 7-nitrospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (10 g.), formalin (37% formaldehyde, 10 ml.), trimethylamine hydrochloride (2 g.) and Raney nickel (10 g.) in ethanol (500 ml.) was subjected to reduction at 49°-56° C. for 3 hours under hydrogen pressure of 50 kg/cm2. After removing the catalyst by filtration, and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in dichloromethane and the solution was washed with 5% aqueous solution of sodium hydrogen carbonate then with water, followed by drying. The solvent was evaporated off and the residue was subjected to column-chromatography on silica-gel. The first fraction eluted with hexane-ethyl acetate (9:1) was recrystallized from ethanol to give 7-dimethylaminospiro[benzo[b]furan-2(3H),1'-cyclopropane]-3-one (5.87 g.) as yellow needles melting at 68.3° C. After removing the catalyst by filtration the filtrate was concentrated under reduced pressure The concentrate was dissolved in dichloromethane the solution was washed with 5% aqueous solution of sodium hydrogen carbonate by drying The solvent was evaporated off The first fraction eluted with hexane-ethyl acetate (9:1) was recrystallized from ethanol

Conditions: temp:-5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added trimethylamine hydrochloride (0.1 eq), tosyl chloride (1.3 eq) and toluene (5 vols) under a nitrogen atmosphere and the reaction mixture agitated to form an oily slurry. The slurry was cooled to −5° C., then (2R)-1-methoxypropan-2-ol (1.0 eq) was added drop-wise over 30 minutes. Toluene (2.5 vols) was added as a line wash followed by triethylamine (1.5 eq), which was added drop-wise via addition funnel over 30 minutes maintaining the reaction temperature <8° C. Further toluene (2.5 vols) was added as a line wash and the reaction mixture held at −5° C. to 5° C. for 4.5 hours. N,N-dimethyl-1,3-propane-diamine, (0.3 eq) was added over 10 minutes at −5° C. The reaction mixture was agitated at −5° C. to 5° C. for 30 minutes, then 2N hydrochloric acid (0.55 eq) and 70 ml water were added. The reaction mixture was agitated for 30 minutes at 22° C. and the aqueous layer was separated off and discarded. The mixture was washed twice more with water (10 vols each wash) then the toluene layer was distilled to an oil on the rotary evaporator. Toluene (20 vols) was added to the oil and the solution evaporated to an oil to give the title compound as a dry light brown oil. Yield corrected for assay 93-97%. 1H NMR δ (400 MHz CDCl3): 7.78-7.75 (d, 2H), 7.45-7.43 (d, 2H), 4.66-4.62 (m, 1H), 3.35-3.26 (m, 2H), 3.16 (s, 3H), 2.4 (s, 3H), 1.13-1.11 (d, 3H). To a flask fitted with overhead stirrer, condenser to form an oily slurry wash was added drop-wise via addition funnel over 30 minutes maintaining the reaction temperature <8° C wash The reaction mixture was agitated at −5° C. to 5° C. for 30 minutes The reaction mixture was agitated for 30 minutes at 22° C. the aqueous layer was separated off The mixture was washed twice more with water (10 vols each wash) then the toluene layer was distilled to an oil on the rotary evaporator Toluene (20 vols) was added to the oil the solution evaporated to an oil

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

Procedure: To a flask was added under a nitrogen atmosphere trimethylamine hydrochloride (0.1 eq), tosyl chloride (1.3 eq) and toluene (5 vols) and the reaction mixture agitated to form an oily slurry. The slurry was cooled to −5° C. (2R)-1-Methoxypropan-2-ol (1.0 eq) was added drop-wise over 30 minutes. Toluene (2.5 vols) was added as a wash followed by triethylamine (1.5 eq), which was added drop-wise via addition funnel over 30 minutes maintaining the reaction temperature <8° C. Further toluene (2.5 vols) was added as a wash and the reaction mixture held at −5° C. to 5° C. for 4.5 hours. N,N-Dimethyl-1,3-propane-diamine (0.3 eq) was added over 10 minutes at −5° C. The mixture was agitated at −5° C. to 5° C. for 30 minutes. Then 2N hydrochloric acid (0.55 eq) and 70 ml water were added. The mixture was agitated for 30 minutes at 22° C. and the aqueous layer was separated off and discarded. The mixture was washed twice more with water (10 vols each wash) and after separation of the aqueous wash, the toluene layer was distilled to an oil on the rotary evaporator. Toluene (20 vols) was added to the oil and the solution evaporated to give the title compound as a dry light brown oil. Yield (corrected for assay) 93-97%. 1H NMR (400 MHz CDCl3): δ 7.78-7.75 (d, 2H), 7.45-7.43 (d, 2H), 4.66-4.62 (m, 1H), 3.35-3.26 (m, 2H), 3.16 (s, 3H), 2.4 (s, 3H), 1.13-1.11 (d, 3H) to form an oily slurry was added drop-wise over 30 minutes was added drop-wise via addition funnel over 30 minutes maintaining the reaction temperature <8° C a wash The mixture was agitated at −5° C. to 5° C. for 30 minutes The mixture was agitated for 30 minutes at 22° C. the aqueous layer was separated off The mixture was washed twice more with water (10 vols each wash) and after separation of the aqueous wash the toluene layer was distilled to an oil on the rotary evaporator Toluene (20 vols) was added to the oil the solution evaporated

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

Procedure: To a solution of (1-methylcyclobutyl)methanol (32 mmol) in CH2Cl2 (100 mL) are added triethylamine (65 mmol), trimethylamine hydrochloride (6 mmol), and a solution of p-toluenesulfonyl chloride (49 mmol) in CH2Cl2 (50 mL) at 0° C., then the mixture is stirred at 0° C. for 0.5 h. The reaction is quenched by the addition of water, and the mixture is extracted with CH2Cl2. The combined organic extracts are washed with water and brine. The organic layer is dried over Na2SO4, filtered, and concentrated in vacuo to give toluene-4-sulfonic acid 1-methylcyclobutylmethyl ester, which is directly used for the next reaction without further purification. The reaction is quenched by the addition of water the mixture is extracted with CH2Cl2 The combined organic extracts are washed with water and brine The organic layer is dried over Na2SO4 filtered concentrated in vacuo

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

Procedure: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxa mide (381 mg) and trimethylamine hydrochloride (191 mg) were suspended in acetonitrile (10 mL) and triethylamine (1.20 mL) was added to the suspension. While this mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added dropwise. The mixture was stirred at the same temperature for 1 hour and trifluoroacetic anhydride (0.34 mL) was added dropwise. The mixture was further stirred for 1 hour. Subsequently, water (10 mL) was added to the reaction mixture and acetonitrile was evaporated under reduced pressure. The resulting crystal was collected by filtration, resuspended in diethylether (10 mL) and collected again by filtration. The collected crystal was dried under reduced pressure to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carbonitrile as a white crystal (472 mg, 75% yield). This compound was identical to the compound obtained in Example 3. While this mixture was cooled in a salt-ice bath The mixture was further stirred for 1 hour was evaporated under reduced pressure The resulting crystal was collected by filtration collected again by filtration The collected crystal was dried under reduced pressure

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

Procedure: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxa mide (381 mg) and trimethylamine hydrochloride (191 mg) were suspended in acetonitrile (10 mL) and triethylamine (1.20 mL) was added to the suspension. While this mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added dropwise. The mixture was stirred at the same temperature for 1 hour and trifluoroacetic anhydride (0.34 mL) was added dropwise. The mixture was further stirred for 1 hour. Subsequently, water (10 mL) was added to the reaction mixture and acetonitrile was evaporated under reduced pressure. The resulting crystal was collected by filtration, resuspended in diethylether (10 mL) and collected again by filtration. The collected crystal was dried under reduced pressure to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carbonitrile as a white crystal (472 mg, 75% yield). This compound was identical to the compound obtained in Example 3. While this mixture was cooled in a salt-ice bath The mixture was further stirred for 1 hour was evaporated under reduced pressure The resulting crystal was collected by filtration collected again by filtration The collected crystal was dried under reduced pressure

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

Procedure: Process A: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (381 mg) and trimethylamine hydrochloride (191 mg) were suspended in acetonitrile (10 mL) and triethylamine (0.56 mL) was added to the suspension. While this mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added drop wise. The mixture was stirred for 1 hour at the same temperature, after which water (5 mL) was added and the mixture was extracted with ethyl acetate (2×40 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1) to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a white solid (528 mg, 80% yield). Process B: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (381 mg) was suspended in acetonitrile (10 mL). To this suspension, N,N,N′,N′-tetramethyl-1,3-propanediamine (34.0 μL) and triethylamine (0.56 mL) were added. While the mixture was cooled in a salt-ice bath, benzenesulfonyl chloride (0.28 mL) was added dropwise. The mixture was then stirred at the same temperature for 1 hour, followed by the addition of saturated brine (5 mL) and extraction with ethyl acetate (2×40 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1) to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a white solid (599 mg, 91% yield). Process C: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboxamide (100 mg) and triethylamine (74 mg) were suspended in acetonitrile (1 mL). While the suspension was cooled in an ice bath, benzenesulfonic anhydride (188 mg) was added and the mixture was stirred for 10 minutes. Subsequently, the mixture was stirred at room temperature for 1 hour, followed by the addition of water (2 mL) and extraction with ethyl acetate (2×4 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (2S,4S)-1-[2-(benzenesulfonyloxy)acetyl]-4-fluoropyrrolidine-2-carboxamide as a brown oil (147 mg, 85% yield). While this mixture was cooled in a salt-ice bath the mixture was extracted with ethyl acetate (2×40 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified on a silica gel column (eluant=ethyl acetate:methanol=10:1)

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

Procedure: (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carboni trile (259 mg), triethylamine (0.42 mL), trimethylamine hydrochloride (143 mg) and acetonitrile (5 mL) were mixed together. While this mixture was cooled in a salt-ice bath, 4-chlorobenzenesulfonyl chloride (350 mg) was added in portions and the mixture was further stirred for 1 hour. Subsequently, water (5 mL) was added and the mixture was extracted with ethyl acetate (2×30 mL). The ethyl acetate extracts were combined, washed with saturated brine (2×5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified on a silica gel column (eluant=ethyl acetate) to give (2S,4S)-1-[2-[(4-chlorophenyl)sulfonyloxy]acetyl]-4-fluoropyrr olidine-2-carbonitrile as a white solid (256 mg, 49% yield). While this mixture was cooled in a salt-ice bath the mixture was extracted with ethyl acetate (2×30 mL) washed with saturated brine (2×5 mL) dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting residue was purified on a silica gel column (eluant=ethyl acetate)

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

Procedure: Trimethylamine hydrochloride (128 mg, 1.34 mmol) and triethylamine (0.39 mL, 2.81 mmol) were added to a solution of (±)-cis-2-(3-fluorotetrahydro-2 H-pyran-4-yl)ethanol obtained (198 mg, 1.34 mmol) in toluene (5 mL). Subsequently, p-toluenesulfonyl chloride (382 mg, 2.00 mmol) was added thereto while cooling in ice, and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane only→hexane:ethyl acetate=1:1) to afford the title compound (354 mg) as a colorless oil. while cooling in ice the mixture was extracted with ethyl acetate The organic layer was washed with brine dried over anhydrous magnesium sulfate After the desiccant was filtered off the solvent was distilled off under reduced pressure The resulting residue was purified by silica gel column chromatography (hexane only→hexane