2-(2-piperazin-1-ylethoxy)ethanol

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:

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

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

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (3E)-6-fluoro-3-[4-(2-fluoropyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (50 mg, 0.15 mmol) and 2-(2-(piperazin-1-yl)ethoxy)ethanol (50 mg, 0.29 mmol) in 2 mL of DMSO was heated in 105° C. bath for 6 hours. The mixture was cooled to room temp and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-6-fluoro-3-[4-(2-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}pyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 64 mg, 89%. The mixture was cooled to room temp The precipitates were filtered washed with water dried in vacuo

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

Procedure: A mixture of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde (55 mg, 0.16 mmol), 2-(2-(piperazin-1-yl)ethoxy)ethanol (56 mg, 0.32 mmol) and 4 Å molecular sieves (100 mg) in anhydrous DMF (3 mL) was stirred at room temp for 16 hours. To this stirred mixture was added AcOH (10 mg), 1M sodium cyanoborohydride in THF solution (0.32 mL, 0.32 mmol) and 3 mL of anhydrous methanol. The reaction mixture was stirred at room temp for 5 hours and poured into 100 mL of water. Saturated NaHCO3 solution was then added until pH=9. The precipitates were filtered, washed with water, and dried in vacuo to give the crude product, which was purified through silica gel column with 5-10% MeOH/CHCl3 to give (3E)-6-fluoro-3-{4-[4-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}methyl)phenyl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one as yellow solid. Yield: 45 mg, 56%. The reaction mixture was stirred at room temp for 5 hours The precipitates were filtered washed with water dried in vacuo to give the crude product, which was purified through silica gel column with 5-10% MeOH/CHCl3

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (3E)-6-fluoro-3-[4-(2-fluoropyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one (50 mg, 0.15 mmol) and 2-(2-(piperazin-1-yl)ethoxy)ethanol (50 mg, 0.29 mmol) in 2 mL of DMSO was heated in 105° C. bath for 6 hours. The mixture was cooled to room temp and poured into 100 mL of water. The precipitates were filtered, washed with water and dried in vacuo to give (3E)-6-fluoro-3-[4-(2-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}pyridin-4-yl)-5,5-dimethylfuran-2(5H)-ylidene]-1,3-dihydro-2H-indol-2-one as a brown solid. Yield: 64 mg, 89%. The mixture was cooled to room temp The precipitates were filtered washed with water dried in vacuo

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

Procedure: A mixture of 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzaldehyde (55 mg, 0.16 mmol), 2-(2-(piperazin-1-yl)ethoxy)ethanol (56 mg, 0.32 mmol) and 4 Å molecular sieves (100 mg) in anhydrous DMF (3 mL) was stirred at room temp for 16 hours. To this stirred mixture was added AcOH (10 mg), 1M sodium cyanoborohydride in THF solution (0.32 mL, 0.32 mmol) and 3 mL of anhydrous methanol. The reaction mixture was stirred at room temp for 5 hours and poured into 100 mL of water. Saturated NaHCO3 solution was then added until pH=9. The precipitates were filtered, washed with water, and dried in vacuo to give the crude product, which was purified through silica gel column with 5-10% MeOH/CHCl3 to give (3E)-6-fluoro-3-{4-[4-({4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}methyl)phenyl]-5,5-dimethylfuran-2(5H)-ylidene}-1,3-dihydro-2H-indol-2-one as yellow solid. Yield: 45 mg, 56%. The reaction mixture was stirred at room temp for 5 hours The precipitates were filtered washed with water dried in vacuo to give the crude product, which was purified through silica gel column with 5-10% MeOH/CHCl3

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

Procedure: 2-iodobenzoic acid (20 g, 0.081 mol), toluene (20 ml) and thionyl chloride (30 ml, 0.41 mol) were charged into a reaction flask. The mixture was stirred and refluxed for 11 h. Toluene (40 ml) was added and the solvent and excess of thionylchloride were distilled off under reduced pressure. The process was repeated with 20 ml of toluene. The residue of 2-iodobenzoyl chloride was dissolved into THF (20 ml). 1-[2-(hydroxyethoxy)-ethyl]-piperazine (14.1 g, 0.081 mol), THF (100 ml), water (50 ml) and triethylamine (12.3 ml) were added into a reaction flask and stirred at icewater bath temperature. The previously prepared 2-iodobenzoyl chloride THF solution was slowly added to the reaction mixture. The temperature was kept below 20° C. during the addition. The reaction mixture was allowed to warm to room temperature and stirred 2 h at ambient temperature. 50 ml of water was added and THF was removed by distillation. The pH of the solution was checked and adjusted to 9-10. The water was extracted three times with dichloromethane (50 ml). The combined organic phase was evaporated yielding {4-[2-(2-hydroxy-ethoxy)ethyl-piperazin-1-yl}-(2-iodophenyl)-methanone as a yellowish oil, which was used without further purification. Yield 31 g. refluxed for 11 h the solvent and excess of thionylchloride were distilled off under reduced pressure The residue of 2-iodobenzoyl chloride was dissolved into THF (20 ml) stirred at icewater bath temperature The temperature was kept below 20° C. during the addition stirred 2 h at ambient temperature THF was removed by distillation The water was extracted three times with dichloromethane (50 ml) The combined organic phase was evaporated

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

Procedure: 2-iodobenzoic acid (20 g, 0.081 mol), toluene (20 ml) and thionyl chloride (30 ml, 0.41 mol) were charged into a reaction flask. The mixture was stirred and refluxed for 11 h. Toluene (40 ml) was added and the solvent and excess of thionylchloride were distilled off under reduced pressure. The process was repeated with 20 ml of toluene. The residue of 2-iodobenzoyl chloride was dissolved into THF (20 ml). 1-[2-(hydroxyethoxy)-ethyl]-piperazine (14.1 g, 0.081 mol), THF (100 ml), water (50 ml) and triethylamine (12.3 ml) were added into a reaction flask and stirred at icewater bath temperature. The previously prepared 2-iodobenzoyl chloride THF solution was slowly added to the reaction mixture. The temperature was kept below 20° C. during the addition. The reaction mixture was allowed to warm to room temperature and stirred 2 h at ambient temperature. 50 ml of water was added and THF was removed by distillation. The pH of the solution was checked and adjusted to 9-10. The water was extracted three times with dichloromethane (50 ml). The combined organic phase was evaporated yielding {4-[2-(2-hydroxy-ethoxy)ethyl-piperazin-1-yl}-(2-iodophenyl)-methanone as a yellowish oil, which was used without further purification. Yield 31 g. refluxed for 11 h the solvent and excess of thionylchloride were distilled off under reduced pressure The residue of 2-iodobenzoyl chloride was dissolved into THF (20 ml) stirred at icewater bath temperature The temperature was kept below 20° C. during the addition stirred 2 h at ambient temperature THF was removed by distillation The water was extracted three times with dichloromethane (50 ml) The combined organic phase was evaporated