ethyl 1H-indole-3-carboxylate

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 3-bromo-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (2.0 g, 5.5 mmol), 1H-Indole-3-carboxylic acid ethyl ester (1.3 g, 6.6 mmol), copper iodide (0.11 g, 0.55 mmol), K3PO4 (2.5 g, 11.6 mmol) in toluene (5 mL) was added (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (0.16 g, 1.1 mmol). After being flushed with N2, the resulting mixture was heated at 110° C. overnight, cooled to room temperature, filtered through celite and concentrated under reduced pressure to give an oil. This oil was purified by silica gel column chromatography using 30-50% EtOAc/heptane to give the titled compound as a light yellow foam (2.0 g, 77%). After being flushed with N2 cooled to room temperature filtered through celite and concentrated under reduced pressure to give an oil This oil was purified by silica gel column chromatography

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

Procedure: A solution of 3.15 g of ethyl indole-3-carboxylate, 4.36 g of di-tert-butylcarbonate and 0.02 g of 4-DMAP in 30 ml of acetonitrile is stirred at room temperature for 15 min. The reaction mixture is then diluted with 200 ml of ethyl acetate. The organic phase is washed with dilute hydrochloric acid, water and saturated sodium chloride solution in succession, dried over sodium sulfate and concentrated. Purification by means of FC over 80 g of silica gel with a 15:1 mixture of hexane and ethyl acetate as the mobile phase gives 5.1 g of the title compound: Rf (G)=0.41. The organic phase is washed with dilute hydrochloric acid, water and saturated sodium chloride solution in succession dried over sodium sulfate concentrated Purification by means of FC over 80 g of silica gel with a 15:1 mixture of hexane and ethyl acetate as the mobile phase

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

Procedure: The title compound is prepared starting from indole-3-carboxylic acid (commercially available from Aldrich) by esterification with ethanol using standard methods of organic synthesis (e.g. J. March, Advanced Organic Chemistry, Reactions, Mechanisms and Structure (1992, 4th edition) 393–394 (Wiley interscience, New York).

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

Procedure: Indole-3-carboxylic acid ethyl ester, R5X=benzyl bromide, NH2A=3-(2-amino-thiazol-4-yl)-propionic acid ethyl ester

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

Procedure: To a suspension of 1H-indole-3-carboxylic acid ethyl ester (800 mg, 4.23 mmol) and potassium carbonate (1.34 g, 9.72 mmol) in CH3CN (21 mL) under nitrogen was added tert-butyl bromoacetate (875 μL, 5.92 mmol) and the reaction mixture was heated at reflux overnight. The reaction mixture was allowed to cool to RT, EtOAc and water were added and the layers were separated, the aqueous one being re-extracted with EtOAc. The organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography (c-hexane to c-hexane/EtOAc 1:1) to afford the desired compound. TLC, Rf (EtOAc)=0.77; MS (LC/MS): 304.1 [M+H]+, 302.0 [M−H]−; tR (HPLC conditions a): 4.01 min. the reaction mixture was heated at reflux overnight the layers were separated the aqueous one being re-extracted with EtOAc The organic layers were washed with brine dried (Na2SO4) filtered concentrated The crude residue was purified by flash column chromatography (c-hexane to c-hexane/EtOAc 1:1)

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

Procedure: Indole-3-carboxylic acid ethyl ester, R5X=benzyl bromide, NH2A=3-(2-amino-thiazol-4-yl)-propionic acid ethyl ester

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a suspension of 3-bromo-5-{(S)-1-[(R)-1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (2.0 g, 5.5 mmol), 1H-Indole-3-carboxylic acid ethyl ester (1.3 g, 6.6 mmol), copper iodide (0.11 g, 0.55 mmol), K3PO4 (2.5 g, 11.6 mmol) in toluene (5 mL) was added (1S,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (0.16 g, 1.1 mmol). After being flushed with N2, the resulting mixture was heated at 110° C. overnight, cooled to room temperature, filtered through celite and concentrated under reduced pressure to give an oil. This oil was purified by silica gel column chromatography using 30-50% EtOAc/heptane to give the titled compound as a light yellow foam (2.0 g, 77%). After being flushed with N2 cooled to room temperature filtered through celite and concentrated under reduced pressure to give an oil This oil was purified by silica gel column chromatography

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

Procedure: A solution of 3.15 g of ethyl indole-3-carboxylate, 4.36 g of di-tert-butylcarbonate and 0.02 g of 4-DMAP in 30 ml of acetonitrile is stirred at room temperature for 15 min. The reaction mixture is then diluted with 200 ml of ethyl acetate. The organic phase is washed with dilute hydrochloric acid, water and saturated sodium chloride solution in succession, dried over sodium sulfate and concentrated. Purification by means of FC over 80 g of silica gel with a 15:1 mixture of hexane and ethyl acetate as the mobile phase gives 5.1 g of the title compound: Rf (G)=0.41. The organic phase is washed with dilute hydrochloric acid, water and saturated sodium chloride solution in succession dried over sodium sulfate concentrated Purification by means of FC over 80 g of silica gel with a 15:1 mixture of hexane and ethyl acetate as the mobile phase