3-[2-(dimethylamino)ethoxy]-4-methoxyaniline

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

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

Procedure: A solution of 3-(2-dimethylaminoethoxy)-4-methoxyaniline (D11, 5.7 g, 0.027 mole) ethanol (120 ml) was treated with a solution of 2,2-dimethoxyacetaldehyde in methyl tert-butyl ether (9.5 g of approx. 40% solution, 0.036 mole) and kept at room temperature for 16 hours. The solution was then hydrogenated over 10% Pd-C (0.6 g) at atmospheric pressure and temperature for 7 hours. The catalyst was removed by filtration through kieselguhr and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed twice with water (2×60 ml), then dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5% methanol/chloroform to afford the title compound as a red oil (5.4 g, 67%). The catalyst was removed by filtration through kieselguhr the filtrate concentrated in vacuo The residue was dissolved in ethyl acetate (100 ml) washed twice with water (2×60 ml) dried (Na2SO4) concentrated in vacuo The residue was chromatographed on silica gel eluting with 5% methanol/chloroform

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

Procedure: A solution of 2-(2-dimethylaminoethoxy)-4-nitroanisole (D10, 11.8 g, 0.049 mole) in ethanol (200 ml) was hydrogenated over 10% Pd-C (1 g) at atmospheric temperature and pressure. The catalyst was filtered off through kieselguhr and the filtrate concentrated in vacuo to afford the title compound as a beige solid (10.3 g, 100%). The catalyst was filtered off through kieselguhr the filtrate concentrated in vacuo

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

Procedure: 2-Bromo-4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (100 mg, 0.28 mmol), Pd(OAc)2 (3.1 mg, 5 mol %), DPPF (15.5 mg, 10 mol %) and NaOtBu (52 mg, 0.56 mmol) were added to a microwave vial. Toluene (0.5 mL) and 3-(2-dimethylamino-ethoxy)-4-methoxy-phenylamine (118 mg, 2 mol eq) were added and the vial was evacuated and back-filled with N2. The reaction mixture was heated at 130° C. for 30 min (microwave). The reaction mixture was filtered and the solids washed with CH2Cl2. The product nitrile was purified using flash chromatography eluting with CH2Cl2 and methanol. This nitrile (32 mg, 0.66 mmol) was dissolved in ethanol (0.8 mL) and DMSO (0.2 mL) to which NaOH (5 N, 26 μL, 2 eq) and H2O2 (excess, 30% solution in H2O) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with H2O and extracted with EtOAc. The product was purified using flash chromatography eluting with CH2Cl2 and methanol. The title compound was obtained as a yellow solid (10 mg, 30%); LC/MS (m/z): M+H=506.5. the vial was evacuated back-filled with N2 The reaction mixture was filtered the solids washed with CH2Cl2 The product nitrile was purified eluting with CH2Cl2 and methanol The reaction mixture was washed with H2O extracted with EtOAc The product was purified eluting with CH2Cl2 and methanol

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

Procedure: 2-bromo-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (500 mg, 1 eq), 3-(2-dimethylamino-ethoxy)-4-methoxy-phenylamine (306 mg, 1.2 eq), Pd(OAc)2 (14 mg), DPPF (66 mg), and NaOtBu (214 mg, 2 eq) were mixed in toluene (5 mL) and microwaved at 140° C. for 25 minutes. Then 10 mL of EtOH(4)/H2O(1) were added, followed by NaOH (700 mg, 2 eq) and H2O2 (1 mL). The mixture was microwaved at 100° C. for 15 min, then concentrated to dryness, and purified by flash chromatography, eluting with 20% EtOH in dichloromethane to give the title compound (480 mg, 71% two-step yield). LCMS (m/z): M+H=560.3. microwaved at 140° C. for 25 minutes The mixture was microwaved at 100° C. for 15 min concentrated to dryness purified by flash chromatography eluting with 20% EtOH in dichloromethane

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

Procedure: 2-Bromo-4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (100 mg, 0.28 mmol), Pd(OAc)2 (3.1 mg, 5 mol %), DPPF (15.5 mg, 10 mol %) and NaOtBu (52 mg, 0.56 mmol) were added to a microwave vial. Toluene (0.5 mL) and 3-(2-dimethylamino-ethoxy)-4-methoxy-phenylamine (118 mg, 2 mol eq) were added and the vial was evacuated and back-filled with N2. The reaction mixture was heated at 130° C. for 30 min (microwave). The reaction mixture was filtered and the solids washed with CH2Cl2. The product nitrile was purified using flash chromatography eluting with CH2Cl2 and methanol. This nitrile (32 mg, 0.66 mmol) was dissolved in ethanol (0.8 mL) and DMSO (0.2 mL) to which NaOH (5 N, 26 μL, 2 eq) and H2O2 (excess, 30% solution in H2O) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with H2O and extracted with EtOAc. The product was purified using flash chromatography eluting with CH2Cl2 and methanol. The title compound was obtained as a yellow solid (10 mg, 30%); LC/MS (m/z): M+H=506.5. the vial was evacuated back-filled with N2 The reaction mixture was filtered the solids washed with CH2Cl2 The product nitrile was purified eluting with CH2Cl2 and methanol The reaction mixture was washed with H2O extracted with EtOAc The product was purified eluting with CH2Cl2 and methanol

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

Procedure: 2-Bromo-4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (100 mg, 0.28 mmol), Pd(OAc)2 (3.1 mg, 5 mol %), DPPF (15.5 mg, 10 mol %) and NaOtBu (52 mg, 0.56 mmol) were added to a microwave vial. Toluene (0.5 mL) and 3-(2-dimethylamino-ethoxy)-4-methoxy-phenylamine (118 mg, 2 mol eq) were added and the vial was evacuated and back-filled with N2. The reaction mixture was heated at 130° C. for 30 min (microwave). The reaction mixture was filtered and the solids washed with CH2Cl2. The product nitrile was purified using flash chromatography eluting with CH2Cl2 and methanol. This nitrile (32 mg, 0.66 mmol) was dissolved in ethanol (0.8 mL) and DMSO (0.2 mL) to which NaOH (5 N, 26 μL, 2 eq) and H2O2 (excess, 30% solution in H2O) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with H2O and extracted with EtOAc. The product was purified using flash chromatography eluting with CH2Cl2 and methanol. The title compound was obtained as a yellow solid (10 mg, 30%); LC/MS (m/z): M+H=506.5. the vial was evacuated back-filled with N2 The reaction mixture was filtered the solids washed with CH2Cl2 The product nitrile was purified eluting with CH2Cl2 and methanol The reaction mixture was washed with H2O extracted with EtOAc The product was purified eluting with CH2Cl2 and methanol

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

Procedure: 2-bromo-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (500 mg, 1 eq), 3-(2-dimethylamino-ethoxy)-4-methoxy-phenylamine (306 mg, 1.2 eq), Pd(OAc)2 (14 mg), DPPF (66 mg), and NaOtBu (214 mg, 2 eq) were mixed in toluene (5 mL) and microwaved at 140° C. for 25 minutes. Then 10 mL of EtOH(4)/H2O(1) were added, followed by NaOH (700 mg, 2 eq) and H2O2 (1 mL). The mixture was microwaved at 100° C. for 15 min, then concentrated to dryness, and purified by flash chromatography, eluting with 20% EtOH in dichloromethane to give the title compound (480 mg, 71% two-step yield). LCMS (m/z): M+H=560.3. microwaved at 140° C. for 25 minutes The mixture was microwaved at 100° C. for 15 min concentrated to dryness purified by flash chromatography eluting with 20% EtOH in dichloromethane

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

Procedure: A solution of 3-(2-dimethylaminoethoxy)-4-methoxyaniline (D11, 5.7 g, 0.027 mole) ethanol (120 ml) was treated with a solution of 2,2-dimethoxyacetaldehyde in methyl tert-butyl ether (9.5 g of approx. 40% solution, 0.036 mole) and kept at room temperature for 16 hours. The solution was then hydrogenated over 10% Pd-C (0.6 g) at atmospheric pressure and temperature for 7 hours. The catalyst was removed by filtration through kieselguhr and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed twice with water (2×60 ml), then dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5% methanol/chloroform to afford the title compound as a red oil (5.4 g, 67%). The catalyst was removed by filtration through kieselguhr the filtrate concentrated in vacuo The residue was dissolved in ethyl acetate (100 ml) washed twice with water (2×60 ml) dried (Na2SO4) concentrated in vacuo The residue was chromatographed on silica gel eluting with 5% methanol/chloroform

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

Procedure: A solution of 2-(2-dimethylaminoethoxy)-4-nitroanisole (D10, 11.8 g, 0.049 mole) in ethanol (200 ml) was hydrogenated over 10% Pd-C (1 g) at atmospheric temperature and pressure. The catalyst was filtered off through kieselguhr and the filtrate concentrated in vacuo to afford the title compound as a beige solid (10.3 g, 100%). The catalyst was filtered off through kieselguhr the filtrate concentrated in vacuo

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

Procedure: A solution of 3-(2-dimethylaminoethoxy)-4-methoxyaniline (D11, 5.7 g, 0.027 mole) ethanol (120 ml) was treated with a solution of 2,2-dimethoxyacetaldehyde in methyl tert-butyl ether (9.5 g of approx. 40% solution, 0.036 mole) and kept at room temperature for 16 hours. The solution was then hydrogenated over 10% Pd-C (0.6 g) at atmospheric pressure and temperature for 7 hours. The catalyst was removed by filtration through kieselguhr and the filtrate concentrated in vacuo. The residue was dissolved in ethyl acetate (100 ml), washed twice with water (2×60 ml), then dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5% methanol/chloroform to afford the title compound as a red oil (5.4 g, 67%). The catalyst was removed by filtration through kieselguhr the filtrate concentrated in vacuo The residue was dissolved in ethyl acetate (100 ml) washed twice with water (2×60 ml) dried (Na2SO4) concentrated in vacuo The residue was chromatographed on silica gel eluting with 5% methanol/chloroform

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