ethyl (E)-hex-2-enoate

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-(−)-N-benzyl-alpha-methyl-benzylamine (50 mL, 239 mmol) in THF (150 mL) at 0° C. is added nBuLi (2.5 M in THF) (100 mL, 250 mmol) under nitrogen atmosphere. The solution is cooled to −78° C. and ethyl trans-2-hexenoate (16.6 g, 117 mmol) is added. The solution is stirred for 1 hour and saturated NH4Cl solution is added. The solution is warmed to room temperature and is extracted with EtOAc. The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by flash chromatography with 5% EtOAc in Hexane as the eluent to afford the (S)-3-[Benzyl-((S)-1-phenyl-ethyl)-amino]-hexanoic acid ethyl ester (20.8 g, 50%) as a colorless oil. The solution is warmed to room temperature is extracted with EtOAc The combined organic layer is dried with MgSO4 is filtered The filtrate is concentrated the residue is purified by flash chromatography with 5% EtOAc in Hexane as the eluent

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-(−)-N-benzyl-alpha-methyl-benzylamine (50 mL, 239 mmol) in THF (150 mL) at 0° C. is added nBuLi (2.5 M in THF) (100 mL, 250 mmol) under nitrogen atmosphere. The solution is cooled to −78° C. and ethyl trans-2-hexenoate (16.6 g, 117 mmol) is added. The solution is stirred for 1 hour and saturated NH4Cl solution is added. The solution is warmed to room temperature and is extracted with EtOAc. The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by flash chromatography with 5% EtOAc in Hexane as the eluent to afford the (S)-3-[Benzyl-((S)-1-phenyl-ethyl)-amino]-hexanoic acid ethyl ester (20.8 g, 50%) as a colorless oil. The solution is warmed to room temperature is extracted with EtOAc The combined organic layer is dried with MgSO4 is filtered The filtrate is concentrated the residue is purified by flash chromatography with 5% EtOAc in Hexane as the eluent

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-(−)-N-benzyl-alpha-methyl-benzylamine (50 mL, 239 mmol) in THF (150 mL) at 0° C. is added nBuLi (2.5 M in THF) (100 mL, 250 mmol) under nitrogen atmosphere. The solution is cooled to −78° C. and ethyl trans-2-hexenoate (16.6 g, 117 mmol) is added. The solution is stirred for 1 hour and saturated NH4Cl solution is added. The solution is warmed to room temperature and is extracted with EtOAc. The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by flash chromatography with 5% EtOAc in Hexane as the eluent to afford the (S)-3-[Benzyl-((S)-1-phenyl-ethyl)-amino]-hexanoic acid ethyl ester (20.8 g, 50%) as a colorless oil. The solution is warmed to room temperature is extracted with EtOAc The combined organic layer is dried with MgSO4 is filtered The filtrate is concentrated the residue is purified by flash chromatography with 5% EtOAc in Hexane as the eluent

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

Procedure: To a solution of (S)-(−)-N-benzyl-alpha-methyl-benzylamine (50 mL, 239 mmol) in THF (150 mL) at 0 C was added BuLi (2.5 M in THF) (100 mL, 250 mmol) under nitrogen atmosphere. The solution was cooled to −78 C and ethyl trans-2-hexenoate (16.6 g, 117 mmol) was added. The solution was stirred for 1 hour and Sat. NH4Cl solution was added. The solution was warmed to room temperature and was extracted with EtOAc. The combined organic layer was dried with MgSO4 and was filtered. The filtrate was concentrated and the residue was purified by CombiFlash with 5% EtOAc in Hexane as the eluent to afford the desirable product (S)-3-[Benzyl-((S)-1-phenyl-ethyl)-amino]-hexanoic acid ethyl ester (20.8 g, 50%) as a colorless oil. was added was extracted with EtOAc The combined organic layer was dried with MgSO4 was filtered The filtrate was concentrated the residue was purified by CombiFlash with 5% EtOAc in Hexane as the eluent

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

Procedure: To a solution of 1-isopropenyl-2-benzimidazolinone (2 g, 11.5 mmol) in DMF (10 mL) were added ethyl trans-2-hexenoate (2 g, 14 mmol) and the benzyltrimethylammonium hydroxide (40% in MeOH) (0.4 mL, 2.3 mmol) at room temperature. The solution was heated to 60 C for 12 hours. The solution was cooled down and sat.NH4Cl sol was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4 and filtered. The filtrate was concentrated and the residue was purified by CombiFlash with 20% EtOAc in Hexane to afford the desirable product 3-(3-Isopropenyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (2 g, 55%) as an colorless oil. at room temperature The solution was heated to 60 C for 12 hours The solution was cooled down The solution was extracted with EtOAc the combined organic layer was dried with MgSO4 filtered The filtrate was concentrated the residue was purified by CombiFlash with 20% EtOAc in Hexane

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1-1,2-benzisoxazol-3-ylmethyl-1,3-dihydro-benzimidazol-2-one (100 mg, 0.38 mmol) in DMF (5 ml) was added ethyl trans-2-hexenoate (80 mg, 0.57 mmol) followed by benzyltrimethylammonium hydroxide (Triton B, 40 wt % in MeOH, 17.0 ul). The resulting mixture was warmed to 60° C. for 12 h and cooled to ambient temperature. The reaction was diluted with NH4Cl (sat.) and the product was extracted into ethyl acetate (2×). The combined organics were dried (MgSO4), filtered and concentrated to give the crude product which was purified via column chromatography (silica gel, 5% EtOAc/dichloromethane). The product-containing fractions were combined and concentrated to give 70 mg (46%) of the desired product. cooled to ambient temperature the product was extracted into ethyl acetate (2×) The combined organics were dried (MgSO4) filtered concentrated to give the crude product which was purified via column chromatography (silica gel, 5% EtOAc/dichloromethane) concentrated

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (50 mg, 0.17 mmol) in dry DMF (1.0 mL) are added (E)-Hex-2-enoic acid ethyl ester (27 mg, 0.19 mmol) and 40% benzyltrimethyl ammonium hydroxide in MeOH (0.008 mL, 0.017 mmol). The resulting mixture is warmed up to 60° C. for 16 hr. Then another 27 mg of (E)-Hex-2-enoic acid ethyl ester is added the heating is continued for another 8 hr. Then saturated NH4Cl (2 mL) and water (10 mL) are added and the mixture is extracted with EtOAc (3×25 mL). The organic layers are combined, dried over MgSO4 and concentrated to give the crude product. Purification with flash column chromatography using 20% EtOAc in Hexanes affords 70 mg (95%) of 3-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester. the mixture is extracted with EtOAc (3×25 mL) dried over MgSO4 concentrated to give the crude product Purification with flash column chromatography

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 1-(1,4-Dimethyl-1H-indol-3-ylmethyl)-5,6-dimethyl-1,3-dihydro-benzimidazol-2-one (0.1 g, 0.31 mmol), K2CO3 (87 mg, 0.63 mmol) and ethyl trans-2-hexenoate (0.45 g, 3.1 mmol) was heated to 130° C. for 20 min in a microwave. Since the starting material was not soluble in ethyl trans-2-hexenoate even after heating, DMA (2 mL) was added to the reaction mixture and heated again at 150° C. for 30 min. Although the un-reacted starting material was present, the reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting heterogeneous residue was purified by silica gel prep TLC using 4:1 hexanes:ethyl acetate as an eluent to afford 25 mg of the desired product as an oil. LCMS (ESMS): m/z 462.88 (M+H+). after heating heated again at 150° C. for 30 min washed with water (×4) The organic phase was dried over Na2SO4 concentrated The resulting heterogeneous residue was purified by silica gel prep TLC

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (S)-(−)-N-benzyl-alpha-methyl-benzylamine (50 mL, 239 mmol) in THF (150 mL) at 0° C. is added nBuLi (2.5 M in THF) (100 mL, 250 mmol) under nitrogen atmosphere. The solution is cooled to −78° C. and ethyl trans-2-hexenoate (16.6 g, 117 mmol) is added. The solution is stirred for 1 hour and saturated NH4Cl solution is added. The solution is warmed to room temperature and is extracted with EtOAc. The combined organic layer is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by flash chromatography with 5% EtOAc in Hexane as the eluent to afford the (S)-3-[Benzyl-((S)-1-phenyl-ethyl)-amino]-hexanoic acid ethyl ester (20.8 g, 50%) as a colorless oil. The solution is warmed to room temperature is extracted with EtOAc The combined organic layer is dried with MgSO4 is filtered The filtrate is concentrated the residue is purified by flash chromatography with 5% EtOAc in Hexane as the eluent