1-(2-METHOXYETHYL)-2-THIOUREA

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

Procedure: To a stirring solution of 1-(2-methoxyethyl)thiourea (21.38 g, 159.3 mmol) and ethyl 3,3-diethoxypropanoate (46.5 mL, 239.0 mmol) in MeOH (300 mL) was added a freshly prepared solution of 0.96N sodium methoxide in MeOH (250 mL, 239.0 mmol) dropwise over 30 minutes at room temperature under argon. The reaction mixture was heated to 60° C. for 45 minutes and cooled to room temperature. Solvent was removed under reduced pressure and toluene (250 mL) was added to the residue. The mixture was stirred at reflux for an additional 3 hours and then cooled to room temperature. Water (200 mL) was added and the layers were separated. The aqueous layer was washed with CH2Cl2 (50 mL), neutralized with 2N aqueous HCl and extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from i-PrOH (200 mL) to give the title compound (13.3 g, 45%) as a light yellow crystalline solid. cooled to room temperature Solvent was removed under reduced pressure and toluene (250 mL) was added to the residue at reflux for an additional 3 hours cooled to room temperature Water (200 mL) was added the layers were separated The aqueous layer was washed with CH2Cl2 (50 mL) extracted with CH2Cl2 (3×200 mL) The combined organic layers were dried over Na2SO4 concentrated in vacuo The residue was recrystallized from i-PrOH (200 mL)

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

Procedure: The process is carried out as for Example 21 above, using the compound from preparation 1.2, 6-(bromoacetyl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one and 1-(2-methoxyethyl)-2-thiourea.

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

Procedure: The process is carried out as for Example 21 above, using the compound from preparation 1.2, 6-(bromoacetyl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one and 1-(2-methoxyethyl)-2-thiourea.

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

Procedure: To a stirring solution of 1-(2-methoxyethyl)thiourea (21.38 g, 159.3 mmol) and ethyl 3,3-diethoxypropanoate (46.5 mL, 239.0 mmol) in MeOH (300 mL) was added a freshly prepared solution of 0.96N sodium methoxide in MeOH (250 mL, 239.0 mmol) dropwise over 30 minutes at room temperature under argon. The reaction mixture was heated to 60° C. for 45 minutes and cooled to room temperature. Solvent was removed under reduced pressure and toluene (250 mL) was added to the residue. The mixture was stirred at reflux for an additional 3 hours and then cooled to room temperature. Water (200 mL) was added and the layers were separated. The aqueous layer was washed with CH2Cl2 (50 mL), neutralized with 2N aqueous HCl and extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from i-PrOH (200 mL) to give the title compound (13.3 g, 45%) as a light yellow crystalline solid. cooled to room temperature Solvent was removed under reduced pressure and toluene (250 mL) was added to the residue at reflux for an additional 3 hours cooled to room temperature Water (200 mL) was added the layers were separated The aqueous layer was washed with CH2Cl2 (50 mL) extracted with CH2Cl2 (3×200 mL) The combined organic layers were dried over Na2SO4 concentrated in vacuo The residue was recrystallized from i-PrOH (200 mL)

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

Procedure: To a stirring solution of 1-(2-methoxyethyl)thiourea (21.38 g, 159.3 mmol) and ethyl 3,3-diethoxypropanoate (46.5 mL, 239.0 mmol) in MeOH (300 mL) was added a freshly prepared solution of 0.96N sodium methoxide in MeOH (250 mL, 239.0 mmol) dropwise over 30 minutes at room temperature under argon. The reaction mixture was heated to 60° C. for 45 minutes and cooled to room temperature. Solvent was removed under reduced pressure and toluene (250 mL) was added to the residue. The mixture was stirred at reflux for an additional 3 hours and then cooled to room temperature. Water (200 mL) was added and the layers were separated. The aqueous layer was washed with CH2Cl2 (50 mL), neutralized with 2N aqueous HCl and extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from i-PrOH (200 mL) to give the title compound (13.3 g, 45%) as a light yellow crystalline solid. cooled to room temperature Solvent was removed under reduced pressure and toluene (250 mL) was added to the residue at reflux for an additional 3 hours cooled to room temperature Water (200 mL) was added the layers were separated The aqueous layer was washed with CH2Cl2 (50 mL) extracted with CH2Cl2 (3×200 mL) The combined organic layers were dried over Na2SO4 concentrated in vacuo The residue was recrystallized from i-PrOH (200 mL)

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

Procedure: The title compound (800 mg) was prepared from 750 mg (5.59 mmol) of 2-methoxyethyl thiourea and 1.17 g (5.59 mmol) of methyl 4-bromo-3-oxo-pentanoate according to the method of Intermediate 60, followed by the procedure outlined for the preparation of Intermediate 43 nd purification via silica gel flash column chromatography using chloroform/MeOH 9/1 as eluent: 1H NMR (CDCl3, 400 MHz) δ 3.82 (t, 2H, J=5.5), 3.58 (t, 2H, J=6.9), 3.41 (m, 2H), 3.36 (s, 3H), 2.65 (t, 2H, J=6.9), 2.19 (s, 3H).

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

Procedure: To a stirring solution of 1-(2-methoxyethyl)thiourea (21.38 g, 159.3 mmol) and ethyl 3,3-diethoxypropanoate (46.5 mL, 239.0 mmol) in MeOH (300 mL) was added a freshly prepared solution of 0.96N sodium methoxide in MeOH (250 mL, 239.0 mmol) dropwise over 30 minutes at room temperature under argon. The reaction mixture was heated to 60° C. for 45 minutes and cooled to room temperature. Solvent was removed under reduced pressure and toluene (250 mL) was added to the residue. The mixture was stirred at reflux for an additional 3 hours and then cooled to room temperature. Water (200 mL) was added and the layers were separated. The aqueous layer was washed with CH2Cl2 (50 mL), neutralized with 2N aqueous HCl and extracted with CH2Cl2 (3×200 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was recrystallized from i-PrOH (200 mL) to give the title compound (13.3 g, 45%) as a light yellow crystalline solid. cooled to room temperature Solvent was removed under reduced pressure and toluene (250 mL) was added to the residue at reflux for an additional 3 hours cooled to room temperature Water (200 mL) was added the layers were separated The aqueous layer was washed with CH2Cl2 (50 mL) extracted with CH2Cl2 (3×200 mL) The combined organic layers were dried over Na2SO4 concentrated in vacuo The residue was recrystallized from i-PrOH (200 mL)

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

Procedure: The process is carried out as for Example 21 above, using the compound from preparation 1.2, 6-(bromoacetyl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one and 1-(2-methoxyethyl)-2-thiourea.