methyl 4-(pyrrolidin-1-ylmethyl)benzoate

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

Procedure: A solution of 4-formyl-benzoic acid methyl ester (10 g), pyrrolidine (5.6 mL), and acetic acid (3.5 mL) in DCM (200 mL) was treated with sodium triacetoxyborohyride (20.65 g) and stirred at rt for 16 hours. The reaction mixture was then quenched with 3N NaOH (70 mL). The organic layer was dried over sodium sulfate and concentrated to yield the titled compound without purification. The reaction mixture was then quenched with 3N NaOH (70 mL) The organic layer was dried over sodium sulfate concentrated

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

Procedure: A solution of 4-formyl-benzoic acid methyl ester (10 g), pyrrolidine (5.6 mL), and acetic acid (3.5 mL) in DCM (200 mL) was treated with sodium triacetoxyborohyride (20.65 g) and stirred at rt for 16 hours. The reaction mixture was then quenched with 3N NaOH (70 mL). The organic layer was dried over sodium sulfate and concentrated to yield the titled compound without purification. The reaction mixture was then quenched with 3N NaOH (70 mL) The organic layer was dried over sodium sulfate concentrated

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

Procedure: The title compound was synthesized from (R)-2-(methoxymethyl)pyrrolidine (0.175 g, 1.52 mmol) according to a procedure similar to that used for compound 56. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H), 4.16 (d, J=13.6 Hz, 1H), 3.91 (s, 3H), 3.42 (m, 2H), 3.33 (m, 4H), 2.92 (m, 1H), 2.73 (m, 1H), 2.19 (m, 1H), 1.93 (m, 1H), 1.70 (m, 3H). 13C NMR (100 MHz, CDCl3): δ 166.7, 144.7, 129.1, 128.4, 128.3, 76.0, 62.8, 58.9, 58.7, 54.2, 51.6, 28.0, 22.4. ESI-LRMS: [M+H]+=264 m/z.

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

Procedure: The title compound was synthesized from (S)-2-(methoxymethyl)pyrrolidine (0.175 g, 1.52 mmol) according to a procedure similar to that used for compound 56. 1H NMR (400 MHz, CDCl3): δ 7.99 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 4.17 (d, J=13.6 Hz, 1H), 3.92 (s, 3H), 3.45 (m, 2H), 3.35 (m, 4H), 2.92 (m, 1H), 2.74 (m, 1H), 2.21 (m, 1H), 1.95 (m, 1H), 1.69 (m, 3H).

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

Procedure: Pyrrolidine (0.12 mL, 1.52 mmol), methyl 4-formylbenzoate (0.250 g, 1.52 mmol), NaBH(OAc)3 (0.52 g, 2.4 mmol) and 5 Å molecular sieves were dissolved in 1,2-dichloroethane (5 mL) under Ar atmosphere and stirred for 24 h at RT. Then, the reaction was diluted with 2 N NaOH (30 mL) and extracted with EtOAc (3×20 mL). The combined organic fractions were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified via automated column chromatography (50-100% EtOAc/hexane, 25 g cartridge) to yield the title compound as a clear oil (0.166 g, 50%). 1H NMR (400 MHz, CDCl3): δ 8.00 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 3.92 (s, 3H), 3.69 (s, 2H), 2.54 (br, 4H), 1.81 (t, J=3.2 Hz, 4H). extracted with EtOAc (3×20 mL) The combined organic fractions were washed with brine (15 mL) dried over Na2SO4 filtered concentrated in vacuo The crude product was purified

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

Procedure: A solution of 6.20 mL (44.5 mmol) of TEA and 4.70 g (21.8 mmol) of 4-carboxybenzyl bromide in 50 mL of DMF was treated with 2.10 mL (25.2 mmol) of pyrrolidine at 50° C. for 3 h. The reaction mixture was cooled, evaporated in vacuo, and the residue was taken up in 50 mL of MeOH. The solution was treated with a rapid stream of HCl (g) for 15 min, the reaction vessel was sealed and the reaction stirred at ambient temperature for 16 h. Evaporation of the solvent afforded 2.56 g of an oil which was purified by radial chromatography (SiO2; 80:18:2 hexanes-THF-TEA) to afford 2.30 g (10.5 mmol; 48%) of the title compound as an oil. The reaction mixture was cooled evaporated in vacuo The solution was treated with a rapid stream of HCl (g) for 15 min the reaction vessel was sealed Evaporation of the solvent

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

Procedure: A solution of 4-formyl-benzoic acid methyl ester (10 g), pyrrolidine (5.6 mL), and acetic acid (3.5 mL) in DCM (200 mL) was treated with sodium triacetoxyborohyride (20.65 g) and stirred at rt for 16 hours. The reaction mixture was then quenched with 3N NaOH (70 mL). The organic layer was dried over sodium sulfate and concentrated to yield the titled compound without purification. The reaction mixture was then quenched with 3N NaOH (70 mL) The organic layer was dried over sodium sulfate concentrated