(1-benzylpyrrolidin-2-yl)methanol

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

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: Following the procedures of Example 1, the title compound is prepared from 3-chloro-4-(1H-imidazol-1-yl)-1,2,5-thiadiazole and 1-benzyl-2-(hydroxymethyl)pyrrolidine.

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

Conditions: temp:35.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (1-benzylpyrrolidin-2-yl)methanol was slowly added to thionyl chloride (45 eq) and the resulting mixture was stirred for 15 h at 35° C. All the volatiles were removed in vacuo. The yellow oil residue was treated with Et2O and re-evaporated to drive off excess thionyl chloride. The crude material was then dried at the high vacuum pump for 2 h to afford the product (100%). 1H NMR (400 MHz, CDCl3) 1.85-2.01 (m, 1H), 2.15-2.32 (m, 3H), 2.85-3.05 (m, 1H), 3.43-3.54 (m, 1H), 3.65-3.79 (m, 1H), 3.92-4.02 (m, 2H), 4.20-4.22 (m, 1H), 4.41-4.43 (m, 1H), 7.44-7.62 (m, 5H). All the volatiles were removed in vacuo The yellow oil residue was treated with Et2O re-evaporated The crude material was then dried at the high vacuum pump for 2 h

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

Procedure: A solution (0.06M) of benzyl 1-benzylprolinate in THF was cooled in an ice bath and treated with LiAlH4 (3 eq). The resulting mixture was stirred at RT for 3 h, before being quenched by the addition of H2O. The resulting mixture was stirred at RT for 30 min and then filtered through a pad of Solka-Floc and the filtrate concentrated in vacuo. The crude was purified by FC (PE/EtOAc 6:4+1% NEt3) to afford the title compound as an off-white solid (62%). 1H NMR (400 MHz, CDCl3) 1.66-1.81 (m, 2H), 1.82-1.97 (m, 2H), 2.25-2.34 (m, 1H), 2.40-2.53 (m, 1H), 2.71-2.77 (m, 1H), 2.94-3.01 (m, 1H), 3.34-3.39 (m, 1H), 3.40-3.45 (m, 1H), 3.63-3.68 (m, 1H), 3.95-3.99 (m, 1H), 7.26-7.30 (m, 5H). before being quenched by the addition of H2O The resulting mixture was stirred at RT for 30 min filtered through a pad of Solka-Floc the filtrate concentrated in vacuo The crude was purified by FC (PE/EtOAc 6:4+1% NEt3)

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

Procedure: Into a 5,000 ml 3-necked roundbottom flask, was placed a solution of (1-benzylpyrrolidin-2-yl)methanol (250. g, 1.30 mol) in chloroform (2,500 ml). This was followed by the dropwise addition of a solution of thionyl chloride (232. g, 1.95 mol) in chloroform (500 ml), while maintaining the internal temperature at room temperature (60 minute addition time). The resulting solution was heated to reflux for 2 hours. After cooling to ambient temperature, the mixture was concentrated, and the resulting residue was dissolved in 3,000 ml of ethyl acetate. Adjustment of the pH to 7 was accomplished by the addition of triethylamine. The resulting mixture was filtered and the filtrate was concentrated and the residue was purified by flash column chromatography (ethylacetate/petroleum ether gradient) to afford 1-benzyl-2-(chloromethyl)pyrrolidine. Into a 5,000 ml 3-necked roundbottom flask, was placed (60 minute addition time) The resulting solution was heated to reflux for 2 hours After cooling to ambient temperature the mixture was concentrated the resulting residue was dissolved in 3,000 ml of ethyl acetate Adjustment of the pH to 7 was accomplished by the addition of triethylamine The resulting mixture was filtered the filtrate was concentrated the residue was purified by flash column chromatography (ethylacetate/petroleum ether gradient)

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

Procedure: Into a 5,000 ml 3-necked roundbottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of lithium aluminum hydride (54.0 g, 1.42 mol) in tetrahydrofuran (3,500 ml) at 0° C. This was followed by the dropwise addition of a solution of ethyl 1-benzylprolinate (330 g, 1.42 mol) in tetrahydrofuran (500 ml), maintaining an internal temperature of 0° C. (2 hours total addition time). The resulting solution was allowed to stir for 2 hours while the temperature was maintained at 0° C. The reaction mixture was then quenched by the addition of water. The solution was filtered, and the filtration residue was washed once with 500 ml of tetrahydrofuran. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The residue was dissolved in 3,000 ml of ethyl acetate, dried over sodium sulfate, filtered and concentrated to afford 1-benzylpyrrolidin-2-yl)methanol, which was used without further purification. Into a 5,000 ml 3-necked roundbottom flask purged maintained with an inert atmosphere of nitrogen at 0° C was maintained at 0° C The reaction mixture was then quenched by the addition of water The solution was filtered the filtration residue was washed once with 500 ml of tetrahydrofuran The filtrate was concentrated by evaporation under vacuum a rotary evaporator The residue was dissolved in 3,000 ml of ethyl acetate dried over sodium sulfate filtered concentrated to afford 1-benzylpyrrolidin-2-yl)methanol, which was used without further purification

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

Procedure: Following the procedures of Example 1, the title compound is prepared from 3-chloro-4-(1H-imidazol-1-yl)-1,2,5-thiadiazole and 1-benzyl-2-(hydroxymethyl)pyrrolidine.