(4-chlorophenyl)-piperazin-1-ylmethanone

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

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

Procedure: This is an example of Procedure B in Scheme 1 above. 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.5 g 1 eq) and (4-Chloro-phenyl)-piperazin-1-yl-methanone (0.6 g 1 eq) were dissolved in CH3CN (5 mL). Ca(OTf)2 (0.456 g, 0.5 eq) was added into the mixture. Reaction mixture was stirred at RT for overnight, then 80-85° C. for 8 h. After concentrating and adding EtOAc 20 mL to the residue, the organic phase was washed with H2O, dried over Na2SO4. The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01) to give 1.01 g of desired product as a sticky oil (92% yield). * It is important to note that during workup, the organic phase should be washed with H2O and saturated NaCl solution, not saturated NaHCO3 solution. Reaction mixture 80-85° C. for 8 h After concentrating adding EtOAc 20 mL to the residue the organic phase was washed with H2O dried over Na2SO4 The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01)

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

Procedure: This is an example of Procedure B in Scheme 1 above. 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.5 g 1 eq) and (4-Chloro-phenyl)-piperazin-1-yl-methanone (0.6 g 1 eq) were dissolved in CH3CN (5 mL). Ca(OTf)2 (0.456 g, 0.5 eq) was added into the mixture. Reaction mixture was stirred at RT for overnight, then 80-85° C. for 8 h. After concentrating and adding EtOAc 20 mL to the residue, the organic phase was washed with H2O, dried over Na2SO4. The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01) to give 1.01 g of desired product as a sticky oil (92% yield). * It is important to note that during workup, the organic phase should be washed with H2O and saturated NaCl solution, not saturated NaHCO3 solution. Reaction mixture 80-85° C. for 8 h After concentrating adding EtOAc 20 mL to the residue the organic phase was washed with H2O dried over Na2SO4 The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01)

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

Procedure: This is an example of Procedure A in Scheme 1 above. 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.85 g 1 eq) and (4-Chloro-phenyl)-piperazin-1-yl-methanone (2.2 g 1 eq) were added into a sealed tube. The mixture was heated to 130° C. for 5 h. The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01) to give 3.38 g of desired product as a sticky oil (84% yield). 1H-NMR (300 MHz, DMSO): δ 1.43 (s, 9H), 2.40-2.80 (m, 4H), 3.15-3.85 (m, 9H), 4.26-4.30 (m, 1H), 7.35 (d, 2H), 7.38 (d, 2H) Retention Time (LC, method: Formic acid polar): 1.19 min. MS (M+H+): 410 The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01)

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

Procedure: This is an example of Procedure A in Scheme 1 above. 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.85 g 1 eq) and (4-Chloro-phenyl)-piperazin-1-yl-methanone (2.2 g 1 eq) were added into a sealed tube. The mixture was heated to 130° C. for 5 h. The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01) to give 3.38 g of desired product as a sticky oil (84% yield). 1H-NMR (300 MHz, DMSO): δ 1.43 (s, 9H), 2.40-2.80 (m, 4H), 3.15-3.85 (m, 9H), 4.26-4.30 (m, 1H), 7.35 (d, 2H), 7.38 (d, 2H) Retention Time (LC, method: Formic acid polar): 1.19 min. MS (M+H+): 410 The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01)

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

Procedure: 4-(4-Chloro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (26 g) was dissolved in CH2Cl2 (350 mL). 4M HCL/Dioxane (150 mL) was added. The mixture was stirred at RT for 4 h. White precipitate was formed. The mixture was concentrated. The white solid was washed with Et2O. After the white solid was treated with 1N NaOH (200 mL) and extracted with Ethyl acetate (3×100 mL), the combined organic phase was dried over Na2SO4 and concentrated to give 17.79 g of desired product (99% yield). 1H-NMR (for HCl salt) (300 MHz, MeOD): δ 2.80-2.90 (m, 4H), 3.20-3.80 (m, 4H), 7.29-7.36 (m, 4H). White precipitate was formed The mixture was concentrated The white solid was washed with Et2O After the white solid was treated with 1N NaOH (200 mL) extracted with Ethyl acetate (3×100 mL) the combined organic phase was dried over Na2SO4 concentrated

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

Procedure: 4-(4-Chloro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (26 g) was dissolved in CH2Cl2 (350 mL). 4M HCL/Dioxane (150 mL) was added. The mixture was stirred at RT for 4 h. White precipitate was formed. The mixture was concentrated. The white solid was washed with Et2O. After the white solid was treated with 1N NaOH (200 mL) and extracted with Ethyl acetate (3×100 mL), the combined organic phase was dried over Na2SO4 and concentrated to give 17.79 g of desired product (99% yield). 1H-NMR (for HCl salt) (300 MHz, MeOD): δ 2.80-2.90 (m, 4H), 3.20-3.80 (m, 4H), 7.29-7.36 (m, 4H). White precipitate was formed The mixture was concentrated The white solid was washed with Et2O After the white solid was treated with 1N NaOH (200 mL) extracted with Ethyl acetate (3×100 mL) the combined organic phase was dried over Na2SO4 concentrated

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

Procedure: This is an example of Procedure B in Scheme 1 above. 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.5 g 1 eq) and (4-Chloro-phenyl)-piperazin-1-yl-methanone (0.6 g 1 eq) were dissolved in CH3CN (5 mL). Ca(OTf)2 (0.456 g, 0.5 eq) was added into the mixture. Reaction mixture was stirred at RT for overnight, then 80-85° C. for 8 h. After concentrating and adding EtOAc 20 mL to the residue, the organic phase was washed with H2O, dried over Na2SO4. The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01) to give 1.01 g of desired product as a sticky oil (92% yield). * It is important to note that during workup, the organic phase should be washed with H2O and saturated NaCl solution, not saturated NaHCO3 solution. Reaction mixture 80-85° C. for 8 h After concentrating adding EtOAc 20 mL to the residue the organic phase was washed with H2O dried over Na2SO4 The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01)

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

Procedure: This is an example of Procedure A in Scheme 1 above. 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.85 g 1 eq) and (4-Chloro-phenyl)-piperazin-1-yl-methanone (2.2 g 1 eq) were added into a sealed tube. The mixture was heated to 130° C. for 5 h. The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01) to give 3.38 g of desired product as a sticky oil (84% yield). 1H-NMR (300 MHz, DMSO): δ 1.43 (s, 9H), 2.40-2.80 (m, 4H), 3.15-3.85 (m, 9H), 4.26-4.30 (m, 1H), 7.35 (d, 2H), 7.38 (d, 2H) Retention Time (LC, method: Formic acid polar): 1.19 min. MS (M+H+): 410 The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0.01)

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

Procedure: 4-(4-Chloro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (26 g) was dissolved in CH2Cl2 (350 mL). 4M HCL/Dioxane (150 mL) was added. The mixture was stirred at RT for 4 h. White precipitate was formed. The mixture was concentrated. The white solid was washed with Et2O. After the white solid was treated with 1N NaOH (200 mL) and extracted with Ethyl acetate (3×100 mL), the combined organic phase was dried over Na2SO4 and concentrated to give 17.79 g of desired product (99% yield). 1H-NMR (for HCl salt) (300 MHz, MeOD): δ 2.80-2.90 (m, 4H), 3.20-3.80 (m, 4H), 7.29-7.36 (m, 4H). White precipitate was formed The mixture was concentrated The white solid was washed with Et2O After the white solid was treated with 1N NaOH (200 mL) extracted with Ethyl acetate (3×100 mL) the combined organic phase was dried over Na2SO4 concentrated

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

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

Procedure: This is an example of Procedure A in Scheme 1 above. 6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (1.85 g 1 eq) and (4-Chloro-phenyl)-piperazin-1-yl-methanone (2.2 g 1 eq) were added into a sealed tube. The mixture was heated to 130° C. for 5 h. The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0,01) to give 3.38 g of desired product as a sticky oil (84% yield). 1H-NMR (300 MHz, DMSO): δ 1.43 (s, 9H), 2.40-2.80 (m, 4H), 3.15-3.85 (m, 9H), 4.26-4.30 (m, 1H), 7.35 (d, 2H), 7.38 (d, 2H) Retention Time (LC, method: Formic acid polar): 1.19 min. MS (M+H+): 410 The resulting oil was purified by column chromatography (EtOAc:MeOH:Et3N 10:1:0,01)