methyl (E)-3-phenylprop-2-enoate

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

Procedure: A mixture of methyl trans-cinnamate (5.0 g, 31 mmol), tetrakis(triphenylphosphine) palladium(0) (2.6 g, 2.3 mmol), 1,2-bis(diphenylphosphino)ethane (0.70 g, 1.8 mmol) and 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (6.90 g, 37 mmol) in THF (60 mL) under argon was heated to reflux for 4 h. An additional aliquot of 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (3.40 g) was added and the reaction was continued for another 16 h. The volatiles were then removed in vacuo and the residue was purified by FC (10% ethyl acetate in hexanes) to afford the title compound (6.2 g). was heated to reflux for 4 h The volatiles were then removed in vacuo the residue was purified by FC (10% ethyl acetate in hexanes)

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

Procedure: A mixture of methyl trans-cinnamate (5.0 g, 31 mmol), tetrakis(triphenylphosphine) palladium(0) (2.6 g, 2.3 mmol), 1,2-bis(diphenylphosphino)ethane (0.70 g, 1.8 mmol) and 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (6.90 g, 37 mmol) in THF (60 mL) under argon was heated to reflux for 4 h. An additional aliquot of 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (3.40 g) was added and the reaction was continued for another 16 h. The volatiles were then removed in vacuo and the residue was purified by FC (10% ethyl acetate in hexanes) to afford the title compound (6.2 g). was heated to reflux for 4 h The volatiles were then removed in vacuo the residue was purified by FC (10% ethyl acetate in hexanes)

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

Procedure: To a solution of indole (2.88 g, 25 mmol) and methyl trans-cinnamate (3.98 g, 25 mmol) in anhydrous DMF (50 mL) was added a suspension of 60% NaH (0.29 g, 7 mmol) at room temperature. The reaction mixture was allowed to stir for 6 hours at room temperature. The reaction mixture was poured into water (300 mL) and product was extracted with EtOAc (2×200 mL). The combined organic extracts were washed with water (5×200 ml), dried over Na2SO4 and evaporated under vacuum. Purification by chromatography (SiO2, benzene-hexane, 1:9) afforded 1.51 g (22% yield) of 3-indol-1-yl-3-phenyl-propionic acid methyl ester as a white powder: MS 280 (M+H)+. was extracted with EtOAc (2×200 mL) The combined organic extracts were washed with water (5×200 ml) dried over Na2SO4 evaporated under vacuum Purification by chromatography (SiO2, benzene-hexane, 1:9)

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

Procedure: To a solution of indole (2.88 g, 25 mmol) and methyl trans-cinnamate (3.98 g, 25 mmol) in anhydrous DMF (50 mL) was added a suspension of 60% NaH (0.29 g, 7 mmol) at room temperature. The reaction mixture was allowed to stir for 6 hours at room temperature. The reaction mixture was poured into water (300 mL) and product was extracted with EtOAc (2×200 mL). The combined organic extracts were washed with water (5×200 ml), dried over Na2SO4 and evaporated under vacuum. Purification by chromatography (SiO2, benzene-hexane, 1:9) afforded 1.51 g (22% yield) of 3-indol-1-yl-3-phenyl-propionic acid methyl ester as a white powder: MS 280 (M+H)+. was extracted with EtOAc (2×200 mL) The combined organic extracts were washed with water (5×200 ml) dried over Na2SO4 evaporated under vacuum Purification by chromatography (SiO2, benzene-hexane, 1:9)

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

Procedure: According to the general procedure, a solution of methyl trans cinnamate (49 mg, 0.30 mmol) and rac-32 (9.8 mg, 0.0062 mmol, 2.0 mol %) in CH2Cl2 (3 mL) was pressurized with H2 to 62 bar and stirred for 48 h. Filtration of the reaction mixture and evaporation of the solvent gave 40 as a clear oil (48 mg, 95%). 1H NMR26 (300 MHz, CDCl3): δ 7.33-7.19 (m, 5H), 3.68 (s, 3H), 2.97 (t, 2H, J=8.1 Hz), 2.65 (t, 2H, J=7.8 Hz); 13C NMR (75.5 MHz, CDCl3): δ 173.4, 140.6, 128.6, 128.4, 126.4, 51.7, 35.8, 31.0. Filtration of the reaction mixture and evaporation of the solvent

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

Procedure: A mixture of methyl trans-cinnamate (5.0 g, 31 mmol), tetrakis(triphenylphosphine) palladium(0) (2.6 g, 2.3 mmol), 1,2-bis(diphenylphosphino)ethane (0.70 g, 1.8 mmol) and 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (6.90 g, 37 mmol) in THF (60 mL) under argon was heated to reflux for 4 h. An additional aliquot of 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (3.40 g) was added and the reaction was continued for another 16 h. The volatiles were then removed in vacuo and the residue was purified by FC (10% ethyl acetate in hexanes) to afford the title compound (6.2 g). was heated to reflux for 4 h The volatiles were then removed in vacuo the residue was purified by FC (10% ethyl acetate in hexanes)

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

Procedure: A pyridine solution of 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-phenylpyrrolidine which had been synthesized from methyl trans-cinnamate, in accordance with the technique of Ling et al. (“Tetrahedron”, 2001, vol. 57,p. 6579-6588) and the method of International Patent Publication WO 2000/59502, was mixed with acetic anhydride and stirred at room temperature for 2Hours. After completion of the reaction, this was concentrated under a reduced pressure with toluene azeotropy, and THF and 1 M THF solution of TBAF were added to the thus obtained residue and stirred overnight at room temperature. Thereafter, its work-up and purification were carried out in the standard method to obtain (1-acetyl-4-phenylpyrrolidin-3-yl)methanol. EP: 220. After completion of the reaction this was concentrated under a reduced pressure with toluene azeotropy, and THF and 1 M THF solution of TBAF were added to the thus obtained residue stirred overnight at room temperature Thereafter, its work-up and purification

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

Procedure: A solution of 4-toluenesulphonylmethyl isocyanide (4.9 g, 25.2 mmol) and methyl trans-cinnamate (4.0 g, 24.7 mmol) in diethyl ether (40 ml) and dimethyl sulphoxide (20 ml) was added drop-wise over 30 minutes to a stirred suspension of sodium hydride (60% dispersion, 1.25 g, 31.3 mmol) in diethyl ether (100 ml) under nitrogen. After 20 minutes a further portion of dimethyl sulphoxide (25 ml) was added to the reaction vessel. The mixture was stirred for 1 hour then water (200 ml) was cautiously added. The product was extracted into dichloromethane (1×400 ml and 1×250 ml) then the combined dichloromethane layers were dried (Na2SO4) and the solvent removed in vacuo. The residue was purified by flash chromatography over silica gel eluting with a gradient of heptane:ethyl acetate:dichloromethane 2:1:0→1:1:1. Appropriate fractions were combined and the solvents removed in vacuo to leave 4-phenyl-1H-pyrrole-3-carboxylic acid methyl ester as a white solid (1.55 g, 31%). TLC (single spot, Rf=0.25, heptane:ethyl acetate 2:1), HPLC-MS (main UV peak with Rt=7.849 mins, 202.1 [M+H]+, 425.1 [2M+Na]+). The product was extracted into dichloromethane (1×400 ml and 1×250 ml) the combined dichloromethane layers were dried (Na2SO4) the solvent removed in vacuo The residue was purified by flash chromatography over silica gel eluting with a gradient of heptane:ethyl acetate:dichloromethane 2:1:0→1:1:1 the solvents removed in vacuo

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

Procedure: A mixture of methyl trans-cinnamate (5.0 g, 31 mmol), tetrakis(triphenylphosphine) palladium(0) (2.6 g, 2.3 mmol), 1,2-bis(diphenylphosphino)ethane (0.70 g, 1.8 mmol) and 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (6.90 g, 37 mmol) in THF (60 mL) under argon was heated to reflux for 4 h. An additional aliquot of 2-((trimethylsilyl)methyl)-2-propen-1-yl acetate (3.40 g) was added and the reaction was continued for another 16 h. The volatiles were then removed in vacuo and the residue was purified by FC (10% ethyl acetate in hexanes) to afford the title compound (6.2 g). was heated to reflux for 4 h The volatiles were then removed in vacuo the residue was purified by FC (10% ethyl acetate in hexanes)

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

Procedure: To a solution of indole (2.88 g, 25 mmol) and methyl trans-cinnamate (3.98 g, 25 mmol) in anhydrous DMF (50 mL) was added a suspension of 60% NaH (0.29 g, 7 mmol) at room temperature. The reaction mixture was allowed to stir for 6 hours at room temperature. The reaction mixture was poured into water (300 mL) and product was extracted with EtOAc (2×200 mL). The combined organic extracts were washed with water (5×200 ml), dried over Na2SO4 and evaporated under vacuum. Purification by chromatography (SiO2, benzene-hexane, 1:9) afforded 1.51 g (22% yield) of 3-indol-1-yl-3-phenyl-propionic acid methyl ester as a white powder: MS 280 (M+H)+. was extracted with EtOAc (2×200 mL) The combined organic extracts were washed with water (5×200 ml) dried over Na2SO4 evaporated under vacuum Purification by chromatography (SiO2, benzene-hexane, 1:9)

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

Procedure: Methyl trans-cinnamate (1.0 g) and hydrazine (1.2 mL) were heated in methanol (25 mL) at 60° C. for 20 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (ethyl acetate/methanol=95/5)to obtain a mixture of the entitled compound and an olefin-unreduced compound (2/1) (499 mg). The reaction solution was concentrated under reduced pressure the resulting residue was purified through silica gel column chromatography (ethyl acetate/methanol=95/5)to obtain a mixture of the entitled compound

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

Procedure: A solution of methyl (2E)-3-phenylacrylate (500 mg, 0.003 mol) in ACN (2 mL, 0.04 mol) was slowly added to a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.5 g, 0.002 mol) in ACN (2 mL, 0.04 mol) and DBU (500 μL, 0.003 mol). The reaction was stirred at room temperature over the weekend. The reaction was partitioned between water and EtOAc. The organic layer was washed with saturated sodium chloride, dried over MgSO4, filtered and concentrated to give an oil. The product was purified by FCC on silica gel using EtOAc/Hexane (1:2 to 1:1) gave methyl 3-phenyl-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanoate (500 mg, 70%) as a semisolid residue. The reaction was partitioned between water and EtOAc The organic layer was washed with saturated sodium chloride dried over MgSO4 filtered concentrated to give an oil The product was purified by FCC on silica gel