ethyl 3-(nitromethyl)hexanoate

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

Procedure: Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolved in absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate (1 g) are added under vigorous stirring. After 15 min, the mixture is diluted with ether (100 ml) and filtered. The solid on the filter is washed with ether (2×50 ml). A solution of aldehyde x255 (0.7 g, 1 eq, 2.3 mmol) in methanol (5 ml) is added immediately. The combined solution is evaporated in the vacuum of a rotary evaporator. The residue is dissolved in methanol (10 ml), CH(OMe)3 (0.5 ml) is added, and the obtained solution is stirred at room temperature for 16 h. An excess of NaBH4 (1 g in several small portions) is then added to the reaction solution under vigorous stirring for 20 min. The reaction mixture is evaporated in the vacuum of a rotary evaporator. The residue is partitioned between ethyl acetate and water. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is dissolved in acetonitrile (10 ml), and the solution is refluxed for 24 h to complete the cyclization. The solvent is distilled off. The residue is purified by chromatography on silicagel (CCl4/MeCN) to afford 4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}pyrrolidin-2-one x256. filtered The solid on the filter is washed with ether (2×50 ml) The combined solution is evaporated in the vacuum of a rotary evaporator The residue is dissolved in methanol (10 ml) CH(OMe)3 (0.5 ml) is added An excess of NaBH4 (1 g in several small portions) is then added to the reaction solution under vigorous stirring for 20 min The reaction mixture is evaporated in the vacuum of a rotary evaporator The residue is partitioned between ethyl acetate and water The organic phase is separated dried with anhydrous sodium sulfate evaporated The residue is dissolved in acetonitrile (10 ml) the solution is refluxed for 24 h The solvent is distilled off The residue is purified by chromatography on silicagel (CCl4/MeCN)

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

Procedure: Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolved in absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate (1 g) are added under vigorous stirring. After 15 min, the mixture is diluted with ether (100 ml) and filtered. The solid on the filter is washed with ether (2×50 ml). A solution of 3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridine-7-carbaldehyde x225 (1 g, 1 eq, 2.9 mmol) in methanol (5 ml) is added immediately. The combined solution is evaporated in the vacuum of a rotary evaporator. The residue is dissolved in methanol (10 ml), CH(OMe)3 (0.5 ml) is added and the obtained solution is stirred at room temperature for 16 h. An excess of NaBH4 (1 g in several small portions) is then added under vigorous stirring for 20 min. The reaction mixture is evaporated in the vacuum of a rotary evaporator. The residue is partitioned between ethyl acetate and water. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is dissolved in acetonitrile (10 ml), and the solution is refluxed for 24 h to complete the cyclization. The solvent is distilled off. The residue is purified by chromatography on silicagel (CCl4/MeCN) to yield 0.79 g of 1-{[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x226. filtered The solid on the filter is washed with ether (2×50 ml) The combined solution is evaporated in the vacuum of a rotary evaporator The residue is dissolved in methanol (10 ml) CH(OMe)3 (0.5 ml) is added An excess of NaBH4 (1 g in several small portions) is then added under vigorous stirring for 20 min The reaction mixture is evaporated in the vacuum of a rotary evaporator The residue is partitioned between ethyl acetate and water The organic phase is separated dried with anhydrous sodium sulfate evaporated The residue is dissolved in acetonitrile (10 ml) the solution is refluxed for 24 h The solvent is distilled off The residue is purified by chromatography on silicagel (CCl4/MeCN)

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

Procedure: Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolved in absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate (1 g) are added under vigorous stirring. After 15 min, the mixture is diluted with ether (100 ml) and filtered. The solid on the filter is washed with ether (2×50 ml). A solution of aldehyde x255 (0.7 g, 1 eq, 2.3 mmol) in methanol (5 ml) is added immediately. The combined solution is evaporated in the vacuum of a rotary evaporator. The residue is dissolved in methanol (10 ml), CH(OMe)3 (0.5 ml) is added, and the obtained solution is stirred at room temperature for 16 h. An excess of NaBH4 (1 g in several small portions) is then added to the reaction solution under vigorous stirring for 20 min. The reaction mixture is evaporated in the vacuum of a rotary evaporator. The residue is partitioned between ethyl acetate and water. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is dissolved in acetonitrile (10 ml), and the solution is refluxed for 24 h to complete the cyclization. The solvent is distilled off. The residue is purified by chromatography on silicagel (CCl4/MeCN) to afford 4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}pyrrolidin-2-one x256. filtered The solid on the filter is washed with ether (2×50 ml) The combined solution is evaporated in the vacuum of a rotary evaporator The residue is dissolved in methanol (10 ml) CH(OMe)3 (0.5 ml) is added An excess of NaBH4 (1 g in several small portions) is then added to the reaction solution under vigorous stirring for 20 min The reaction mixture is evaporated in the vacuum of a rotary evaporator The residue is partitioned between ethyl acetate and water The organic phase is separated dried with anhydrous sodium sulfate evaporated The residue is dissolved in acetonitrile (10 ml) the solution is refluxed for 24 h The solvent is distilled off The residue is purified by chromatography on silicagel (CCl4/MeCN)

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

Procedure: Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolved in absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate (1 g) are added under vigorous stirring. After 15 min, the mixture is diluted with ether (100 ml) and filtered. The solid on the filter is washed with ether (2×50 ml). A solution of 3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridine-7-carbaldehyde x225 (1 g, 1 eq, 2.9 mmol) in methanol (5 ml) is added immediately. The combined solution is evaporated in the vacuum of a rotary evaporator. The residue is dissolved in methanol (10 ml), CH(OMe)3 (0.5 ml) is added and the obtained solution is stirred at room temperature for 16 h. An excess of NaBH4 (1 g in several small portions) is then added under vigorous stirring for 20 min. The reaction mixture is evaporated in the vacuum of a rotary evaporator. The residue is partitioned between ethyl acetate and water. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is dissolved in acetonitrile (10 ml), and the solution is refluxed for 24 h to complete the cyclization. The solvent is distilled off. The residue is purified by chromatography on silicagel (CCl4/MeCN) to yield 0.79 g of 1-{[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x226. filtered The solid on the filter is washed with ether (2×50 ml) The combined solution is evaporated in the vacuum of a rotary evaporator The residue is dissolved in methanol (10 ml) CH(OMe)3 (0.5 ml) is added An excess of NaBH4 (1 g in several small portions) is then added under vigorous stirring for 20 min The reaction mixture is evaporated in the vacuum of a rotary evaporator The residue is partitioned between ethyl acetate and water The organic phase is separated dried with anhydrous sodium sulfate evaporated The residue is dissolved in acetonitrile (10 ml) the solution is refluxed for 24 h The solvent is distilled off The residue is purified by chromatography on silicagel (CCl4/MeCN)

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

Procedure: Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolved in absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate (1 g) are added under vigorous stirring. After 15 min, the mixture is diluted with ether (100 ml) and filtered. The solid on the filter is washed with ether (2×50 ml). A solution of aldehyde x255 (0.7 g, 1 eq, 2.3 mmol) in methanol (5 ml) is added immediately. The combined solution is evaporated in the vacuum of a rotary evaporator. The residue is dissolved in methanol (10 ml), CH(OMe)3 (0.5 ml) is added, and the obtained solution is stirred at room temperature for 16 h. An excess of NaBH4 (1 g in several small portions) is then added to the reaction solution under vigorous stirring for 20 min. The reaction mixture is evaporated in the vacuum of a rotary evaporator. The residue is partitioned between ethyl acetate and water. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is dissolved in acetonitrile (10 ml), and the solution is refluxed for 24 h to complete the cyclization. The solvent is distilled off. The residue is purified by chromatography on silicagel (CCl4/MeCN) to afford 4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}pyrrolidin-2-one x256. filtered The solid on the filter is washed with ether (2×50 ml) The combined solution is evaporated in the vacuum of a rotary evaporator The residue is dissolved in methanol (10 ml) CH(OMe)3 (0.5 ml) is added An excess of NaBH4 (1 g in several small portions) is then added to the reaction solution under vigorous stirring for 20 min The reaction mixture is evaporated in the vacuum of a rotary evaporator The residue is partitioned between ethyl acetate and water The organic phase is separated dried with anhydrous sodium sulfate evaporated The residue is dissolved in acetonitrile (10 ml) the solution is refluxed for 24 h The solvent is distilled off The residue is purified by chromatography on silicagel (CCl4/MeCN)

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

Procedure: Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolved in absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate (1 g) are added under vigorous stirring. After 15 min, the mixture is diluted with ether (100 ml) and filtered. The solid on the filter is washed with ether (2×50 ml). A solution of 3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridine-7-carbaldehyde x225 (1 g, 1 eq, 2.9 mmol) in methanol (5 ml) is added immediately. The combined solution is evaporated in the vacuum of a rotary evaporator. The residue is dissolved in methanol (10 ml), CH(OMe)3 (0.5 ml) is added and the obtained solution is stirred at room temperature for 16 h. An excess of NaBH4 (1 g in several small portions) is then added under vigorous stirring for 20 min. The reaction mixture is evaporated in the vacuum of a rotary evaporator. The residue is partitioned between ethyl acetate and water. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is dissolved in acetonitrile (10 ml), and the solution is refluxed for 24 h to complete the cyclization. The solvent is distilled off. The residue is purified by chromatography on silicagel (CCl4/MeCN) to yield 0.79 g of 1-{[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x226. filtered The solid on the filter is washed with ether (2×50 ml) The combined solution is evaporated in the vacuum of a rotary evaporator The residue is dissolved in methanol (10 ml) CH(OMe)3 (0.5 ml) is added An excess of NaBH4 (1 g in several small portions) is then added under vigorous stirring for 20 min The reaction mixture is evaporated in the vacuum of a rotary evaporator The residue is partitioned between ethyl acetate and water The organic phase is separated dried with anhydrous sodium sulfate evaporated The residue is dissolved in acetonitrile (10 ml) the solution is refluxed for 24 h The solvent is distilled off The residue is purified by chromatography on silicagel (CCl4/MeCN)

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

Procedure: Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolved in absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate (1 g) are added under vigorous stirring. After 15 min, the mixture is diluted with ether (100 ml) and filtered. The solid on the filter is washed with ether (2×50 ml). A solution of aldehyde x255 (0.7 g, 1 eq, 2.3 mmol) in methanol (5 ml) is added immediately. The combined solution is evaporated in the vacuum of a rotary evaporator. The residue is dissolved in methanol (10 ml), CH(OMe)3 (0.5 ml) is added, and the obtained solution is stirred at room temperature for 16 h. An excess of NaBH4 (1 g in several small portions) is then added to the reaction solution under vigorous stirring for 20 min. The reaction mixture is evaporated in the vacuum of a rotary evaporator. The residue is partitioned between ethyl acetate and water. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is dissolved in acetonitrile (10 ml), and the solution is refluxed for 24 h to complete the cyclization. The solvent is distilled off. The residue is purified by chromatography on silicagel (CCl4/MeCN) to afford 4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}pyrrolidin-2-one x256. filtered The solid on the filter is washed with ether (2×50 ml) The combined solution is evaporated in the vacuum of a rotary evaporator The residue is dissolved in methanol (10 ml) CH(OMe)3 (0.5 ml) is added An excess of NaBH4 (1 g in several small portions) is then added to the reaction solution under vigorous stirring for 20 min The reaction mixture is evaporated in the vacuum of a rotary evaporator The residue is partitioned between ethyl acetate and water The organic phase is separated dried with anhydrous sodium sulfate evaporated The residue is dissolved in acetonitrile (10 ml) the solution is refluxed for 24 h The solvent is distilled off The residue is purified by chromatography on silicagel (CCl4/MeCN)

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

Procedure: Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolved in absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate (1 g) are added under vigorous stirring. After 15 min, the mixture is diluted with ether (100 ml) and filtered. The solid on the filter is washed with ether (2×50 ml). A solution of 3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridine-7-carbaldehyde x225 (1 g, 1 eq, 2.9 mmol) in methanol (5 ml) is added immediately. The combined solution is evaporated in the vacuum of a rotary evaporator. The residue is dissolved in methanol (10 ml), CH(OMe)3 (0.5 ml) is added and the obtained solution is stirred at room temperature for 16 h. An excess of NaBH4 (1 g in several small portions) is then added under vigorous stirring for 20 min. The reaction mixture is evaporated in the vacuum of a rotary evaporator. The residue is partitioned between ethyl acetate and water. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is dissolved in acetonitrile (10 ml), and the solution is refluxed for 24 h to complete the cyclization. The solvent is distilled off. The residue is purified by chromatography on silicagel (CCl4/MeCN) to yield 0.79 g of 1-{[3-(4-methoxybenzyl)-2-phenyl-3H-imidazo[4,5-b]pyridin-7-yl]methyl}-4-propylpyrrolidin-2-one x226. filtered The solid on the filter is washed with ether (2×50 ml) The combined solution is evaporated in the vacuum of a rotary evaporator The residue is dissolved in methanol (10 ml) CH(OMe)3 (0.5 ml) is added An excess of NaBH4 (1 g in several small portions) is then added under vigorous stirring for 20 min The reaction mixture is evaporated in the vacuum of a rotary evaporator The residue is partitioned between ethyl acetate and water The organic phase is separated dried with anhydrous sodium sulfate evaporated The residue is dissolved in acetonitrile (10 ml) the solution is refluxed for 24 h The solvent is distilled off The residue is purified by chromatography on silicagel (CCl4/MeCN)

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

Procedure: 300 g (1.476 mol) of 3-nitromethyl-hexanoic acid ethyl ester (B) are diluted in methanol (500 ml). The mixture is transferred to an autoclave of 1 L. The reaction mixture is allowed to react at 55° C. under 50 bars of hydrogen pressure for 28 h. The catalyst is filtered on celite and washed with methanol. The filtrate is recovered with 500 ml of dichloromethane. Then, the solution is extracted with water (2×400 ml). The organic layers are dried with MgSO4, filtered and concentrated to afford an oil residue (177.12 g, HPLC purity=82.6%) which is purified by distillation (110° C., 7.10−2 mbar). 147.82 g of (C) are obtained (Yield=78.7%). The catalyst is filtered on celite washed with methanol The filtrate is recovered with 500 ml of dichloromethane Then, the solution is extracted with water (2×400 ml) The organic layers are dried with MgSO4 filtered concentrated to afford an oil residue (177.12 g, HPLC purity=82.6%) which is purified by distillation (110° C., 7.10−2 mbar)

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

Procedure: To a stirred solution of hex-2-enoic acid ethyl ester (A) (450 g, 3.164 mol, 1 eq) in nitromethane (858 ml, 15.822 mol, 5 eq) cooled at 0° C., is added dropwise, under nitrogen, 481.8 g (3.164 mol, 1 eq.) of 1.8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction mixture is allowed to react at room temperature for 3 h and is quenched with a 6M aqueous hydrogen chloride solution to obtain pH=4. The solution is extracted with diethyl ether (500 ml+2×300 ml). The organic layers are dried with MgSO4, filtered and concentrated to obtain an oil residue (672.13 g, HPLC purity=78.9%) which is purified by liquid chromatography eluting with dichloromethane. 639.41 g of 3-nitromethyl-hexanoic acid ethyl ester (B) are obtained (yield=99.4%). is added dropwise, under nitrogen to react at room temperature for 3 h is quenched with a 6M aqueous hydrogen chloride solution to obtain pH=4 The solution is extracted with diethyl ether (500 ml+2×300 ml) The organic layers are dried with MgSO4 filtered concentrated to obtain an oil residue (672.13 g, HPLC purity=78.9%) which is purified by liquid chromatography eluting with dichloromethane