N,N,N',N',N",N"-hexamethylmethanetriamine

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: A mixture of 4′-methoxy-5-methyl-4-nitro-biphenyl-2-carbonitrile (118.0 mg, 0.44 mmol) and tris(dimethylamino) methane (128.0 mg, 0.88 mmol) in toluene (15 mL) was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in EtOH (1 mL) and water (0.10 mL), and treated with iron powder (64.0 mg, 1.15 mmol), followed by concentrated HCl (28.0 mg, 0.29 mmol). The reaction mixture was heated to reflux for an additional 16 hours, and quenched with 1N aqueous NaOH (0.288 mL). The solution was filtered through celite and rinsed with EtOH (10 mL). The filtrate was concentrated in vacuo to give the title compound (35 mg, 49% yield). MS (ES−) 247.1 (M−1)−. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.68 (d, J=2.73 Hz, 1H), 7.66 (s, 1H), 7.48 (d, J=8.59 Hz, 2H), 7.05 (d, J=8.59 Hz, 2H), 6.58 (d, J=2.73 Hz, 1H), 3.82 (s, 3H). was heated to reflux for 2 hours The reaction mixture was concentrated in vacuo The resulting residue was dissolved in EtOH (1 mL) The reaction mixture was heated to reflux for an additional 16 hours quenched with 1N aqueous NaOH (0.288 mL) The solution was filtered through celite rinsed with EtOH (10 mL) The filtrate was concentrated in vacuo

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

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

Procedure: A mixture of 4′-methoxy-5-methyl-4-nitro-biphenyl-2-carbonitrile (118.0 mg, 0.44 mmol) and tris(dimethylamino) methane (128.0 mg, 0.88 mmol) in toluene (15 mL) was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in EtOH (1 mL) and water (0.10 mL), and treated with iron powder (64.0 mg, 1.15 mmol), followed by concentrated HCl (28.0 mg, 0.29 mmol). The reaction mixture was heated to reflux for an additional 16 hours, and quenched with 1 N aqueous NaOH (0.288 mL). The solution was filtered through celite and rinsed with EtOH (10 mL). The filtrate was concentrated in vacuo to give the title compound (35 mg, 49% yield). MS (ES−) 247.1 (M−1)−. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1 H), 7.68 (d, J=2.73 Hz, 1 H), 7.66 (s, 1 H), 7.48 (d, J=8.59 Hz, 2 H), 7.05 (d, J=8.59 Hz, 2 H), 6.58 (d, J=2.73 Hz, 1 H), 3.82 (s, 3 H). was heated to reflux for 2 hours The reaction mixture was concentrated in vacuo The resulting residue was dissolved in EtOH (1 mL) The reaction mixture was heated to reflux for an additional 16 hours quenched with 1 N aqueous NaOH (0.288 mL) The solution was filtered through celite rinsed with EtOH (10 mL) The filtrate was concentrated in vacuo

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

Procedure: A mixture of 4′-methoxy-5-methyl-4-nitro-biphenyl-2-carbonitrile (118.0 mg, 0.44 mmol) and tris(dimethylamino) methane (128.0 mg, 0.88 mmol) in toluene (15 mL) was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in EtOH (1 mL) and water (0.10 mL), and treated with iron powder (64.0 mg, 1.15 mmol), followed by concentrated HCl (28.0 mg, 0.29 mmol). The reaction mixture was heated to reflux for an additional 16 hours, and quenched with 1 N aqueous NaOH (0.288 mL). The solution was filtered through celite and rinsed with EtOH (10 mL). The filtrate was concentrated in vacuo to give the title compound (35 mg, 49% yield). MS (ES−) 247.1 (M−1)−. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1 H), 7.68 (d, J=2.73 Hz, 1 H), 7.66 (s, 1 H), 7.48 (d, J=8.59 Hz, 2 H), 7.05 (d, J=8.59 Hz, 2 H), 6.58 (d, J=2.73 Hz, 1 H), 3.82 (s, 3 H). was heated to reflux for 2 hours The reaction mixture was concentrated in vacuo The resulting residue was dissolved in EtOH (1 mL) The reaction mixture was heated to reflux for an additional 16 hours quenched with 1 N aqueous NaOH (0.288 mL) The solution was filtered through celite rinsed with EtOH (10 mL) The filtrate was concentrated in vacuo

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of γ-butyrolactone (1 mol) and tris(dimethylamino)methane (1.5 mol) is stirred under dry nitrogen at 75° C. for 2 days to give 3-[(dimethylamino)methylene]dihydro-2(3H)-furanone. A solution containing 3-[(dimethylamino)methylene]dihydro-2(3H)-furanone (1 mol), n-butanethiol (1.1 mol) and para-toluenesulfonic acid (1 mol) in benzene is heated at reflux overnight to give upon aqueous work-up 3-[(butylthio)methylene]dihydro-2(3H)-furanone. After a solution of 3-[(butylthio)methylene]dihydro-2(3H)-furanone (1 mol) in anhydrous diethyl ether is added to a solution of lithium di-n-butylcuprate (1.1 mol) in diethyl ether at -78° C., the resulting mixture is stirred at -78° C. for an additional 0.5 hours and then quenched with methanol. Work-up affords 3-ethylidenedihydro-2(3H)-furanone. Freshly prepared W-2 Raney nickel (about 3 parts) is deactivated by refluxing in benzene for 1 hour, whereupon 3-ethylidenedihydro-2(3H)-furanone is added and the mixture is heated at reflux under nitrogen for 24-48 hours; the reaction is monitored by thin layer chromatography. After complete washing of the Raney nickel with hot benzene, the title compound is obtained.

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

Procedure: A mixture of 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one (0.1 g, 0.27 mmol) and tris(dimethylamino)methane (0.077 g, 0.54 mmol) is heated at 60° C. in a sealed tube for 6 hours. The volatile material is removed in vacuo. EtOH (5 mL) and methyl hydrazine (1.1 mmol) are added to the residue. The mixture is heated at 120° C. for 2 hours. The solvent is removed. NaHCO3 (aq.) (10 mL) and DCM (30 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×15 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (ethyl acetate/Hexanes 1:1) to give 5-bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole and 5-bromo-1-ethyl-2-[5-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole. 5-bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole: 1H NMR (CDCl3) δ 7.88 (s, 1H), 7.27-7.42 (m, 4H), 7.00-7.20 (m, 3H), 4.21 (s, 2H), 3.95 (t, 2H), 3.83 (s, 3H), 1.15 (t, 3H). 5-bromo-1-ethyl-2-[5-(3-fluoro-phenyl)-1-methyl-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole: 1H NMR (CDCl3) δ 7.81 (s, 1H), 7.38-7.45 (m, 2H), 7.32 (dd, 1H), 7.00-7.18 (m, 4H), 4.00 (s, 2H), 3.90 (q, 2H), 3.78 (s, 3H), 1.15 (t, 3H). The volatile material is removed in vacuo The mixture is heated at 120° C. for 2 hours The solvent is removed NaHCO3 (aq.) (10 mL) and DCM (30 mL) are added to the residue The organic layer is separated the aqueous layer is extracted with DCM (2×15 mL) The combined organic layers are dried the solvent removed The crude is purified by PTLC (ethyl acetate/Hexanes 1:1)

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

Procedure: A mixture of 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one (0.1 g, 0.27 mmol) and tris(dimethylamino)methane (0.077 g, 0.54 mmol) is heated at 60° C. in a sealed tube for 6 hours. The volatile material is removed in vacuo. EtOH (5 mL) and hydrazine acetate (1.1 mmol) are added to the residue. The mixture is heated at 120° C. for 2 hours. The solvent is removed. NaHCO3 (aq.) (10 mL) and DCM (30 mL) are added to the residue. The organic layer is separated and the aqueous layer is extracted with DCM (2×15 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (ethyl acetate/Hexanes 1:1) to give 5-bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-1H-pyrazol-4-ylmethyl]-1H-benzoimidazole as a solid. LRMS: calcd 399.3, found [M+1] 401.0. The volatile material is removed in vacuo The mixture is heated at 120° C. for 2 hours The solvent is removed NaHCO3 (aq.) (10 mL) and DCM (30 mL) are added to the residue The organic layer is separated the aqueous layer is extracted with DCM (2×15 mL) The combined organic layers are dried the solvent removed The crude is purified by PTLC (ethyl acetate/Hexanes 1:1)

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

Procedure: A mixture of 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one (0.1 g, 0.27 mmol) and tris(dimethylamino)methane (0.077 g, 0.54 mmol) is heated at 60° C. in a sealed tube for 6 hours. The volatile material is removed in vacuo. To the residue is added EtOH (5 mL) and hydroxylamine (1.1 mmol). The mixture is heated at 120° C. for 2 hours. The solvent is removed. To the residue is added NaHCO3 (aq.) (10 mL) and DCM (30 mL). The organic layer is separated and the aqueous layer is extracted with DCM (2×15 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (ethyl acetate/Hexanes 1:1) to give 5-Bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-isoxazol-4-ylmethyl]-1H-benzoimidazole as a solid. 1H NMR (CDCl3) δ 8.40 (s, 1H), 7.88 (s, 1H), 7.31-7.52 (m, 4H), 7.18-7.22 (m, 2H), 4.14 (s, 2H), 4.04 (q, 2H), 1.18 (t, 3H). The volatile material is removed in vacuo The mixture is heated at 120° C. for 2 hours The solvent is removed To the residue is added NaHCO3 (aq.) (10 mL) and DCM (30 mL) The organic layer is separated the aqueous layer is extracted with DCM (2×15 mL) The combined organic layers are dried the solvent removed The crude is purified by PTLC (ethyl acetate/Hexanes 1:1)

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

Procedure: A mixture of 3-(5-Bromo-1-ethyl-1H-benzoimidazol-2-yl)-1-(3-fluoro-phenyl)-propan-1-one (0.1 g, 0.27 mmol) and tris(dimethylamino)methane (0.077 g, 0.54 mmol) is heated at 60° C. in a sealed tube for 6 hours. The volatile material is removed in vacuo. To the residue is added EtOH (5 mL) and hydroxylamine (1.1 mmol). The mixture is heated at 120° C. for 2 hours. The solvent is removed. To the residue is added NaHCO3 (aq.) (10 mL) and DCM (30 mL). The organic layer is separated and the aqueous layer is extracted with DCM (2×15 mL). The combined organic layers are dried and the solvent removed. The crude is purified by PTLC (ethyl acetate/Hexanes 1:1) to give 5-Bromo-1-ethyl-2-[3-(3-fluoro-phenyl)-isoxazol-4-ylmethyl]-1H-benzoimidazole as a solid. 1H NMR (CDCl3) δ 8.40 (s, 1H), 7.88 (s, 1H), 7.31-7.52 (m, 4H), 7.18-7.22 (m, 2H), 4.14 (s, 2H), 4.04 (q, 2H), 1.18 (t, 3H). The volatile material is removed in vacuo The mixture is heated at 120° C. for 2 hours The solvent is removed To the residue is added NaHCO3 (aq.) (10 mL) and DCM (30 mL) The organic layer is separated the aqueous layer is extracted with DCM (2×15 mL) The combined organic layers are dried the solvent removed The crude is purified by PTLC (ethyl acetate/Hexanes 1:1)