N',3-dihydroxypropanimidamide

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

Procedure: To a solution of [(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]acetic acid (Intermediate 7, 50 mg, 0.14 mmol) in tetrahydrofuran (2 ml) was added CDI (37 mg, 0.23 mmol). The reaction mixture was stirred 1 h30. A solution of N′,3-dihydroxypropanimidamide (16 mg, 0.16 mmol), pyridine (34 ml, 0.14 mmol) in tetrahydrofuran was then added and the reaction mixture was stirred at reflux overnight The solvent was removed and ethyl acetate was added. The organic phase was washed with citric acid 5%, NH4Cl, NaHCO3 then brine. The organic phase was dried (MgSO4), concentrated and purified on silica gel column chromatography (Ethyl acetate) to afford (3EZ,5S)-1-(biphenyl-4-ylcarbonyl)-5-{[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]methyl}pyrrolidin-3-one O-methyloxime (19 mg). Yield: 27%. HPLC purity: 94% the reaction mixture was stirred at reflux overnight The solvent was removed ethyl acetate was added The organic phase was washed with citric acid 5%, NH4Cl, NaHCO3 The organic phase was dried (MgSO4) concentrated purified on silica gel column chromatography (Ethyl acetate)

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

Procedure: According to General Method 6A, 1.00 g (2.390 mmol) of the compound from Example 25A and 323 mg (3.107 mmol) of N′,3-dihydroxypropanimidamide were reacted Yield: 848 mg (69% of theory) were reacted Yield: 848 mg (69% of theory)

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

Procedure: According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 201 mg (1.938 mmol) of N′,3-dihydroxypropanimidamide were reacted Yield: 494 mg (68% of theory) were reacted Yield: 494 mg (68% of theory)

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

Procedure: According to General Method 6A, 300 mg (0.828 mmol) of the compound from Example 7A and 112 mg (1.08 mmol) of N′,3-dihydroxypropanimidamide [Graham A. Showell et al., J. Med. Chem., 1991, 34, 1086-1094] were reacted. Yield: 248 mg (66% of theory) were reacted

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

Procedure: To a solution of [(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]acetic acid (Intermediate 7, 50 mg, 0.14 mmol) in tetrahydrofuran (2 ml) was added CDI (37 mg, 0.23 mmol). The reaction mixture was stirred 1 h30. A solution of N′,3-dihydroxypropanimidamide (16 mg, 0.16 mmol), pyridine (34 ml, 0.14 mmol) in tetrahydrofuran was then added and the reaction mixture was stirred at reflux overnight The solvent was removed and ethyl acetate was added. The organic phase was washed with citric acid 5%, NH4Cl, NaHCO3 then brine. The organic phase was dried (MgSO4), concentrated and purified on silica gel column chromatography (Ethyl acetate) to afford (3EZ,5S)-1-(biphenyl-4-ylcarbonyl)-5-{[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]methyl}pyrrolidin-3-one O-methyloxime (19 mg). Yield: 27%. HPLC purity: 94% the reaction mixture was stirred at reflux overnight The solvent was removed ethyl acetate was added The organic phase was washed with citric acid 5%, NH4Cl, NaHCO3 The organic phase was dried (MgSO4) concentrated purified on silica gel column chromatography (Ethyl acetate)

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

Procedure: According to General Method 6A, 1.00 g (2.390 mmol) of the compound from Example 25A and 323 mg (3.107 mmol) of N′,3-dihydroxypropanimidamide were reacted Yield: 848 mg (69% of theory) were reacted Yield: 848 mg (69% of theory)

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

Procedure: According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 201 mg (1.938 mmol) of N′,3-dihydroxypropanimidamide were reacted Yield: 494 mg (68% of theory) were reacted Yield: 494 mg (68% of theory)

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

Procedure: According to General Method 6A, 300 mg (0.828 mmol) of the compound from Example 7A and 112 mg (1.08 mmol) of N′,3-dihydroxypropanimidamide [Graham A. Showell et al., J. Med. Chem., 1991, 34, 1086-1094] were reacted. Yield: 248 mg (66% of theory) were reacted

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

Procedure: According to General Method 6A, 1.00 g (2.390 mmol) of the compound from Example 25A and 323 mg (3.107 mmol) of N′,3-dihydroxypropanimidamide were reacted Yield: 848 mg (69% of theory) were reacted Yield: 848 mg (69% of theory)

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

Procedure: According to General Method 6A, 600 mg (1.491 mmol) of the compound from Example 16A and 201 mg (1.938 mmol) of N′,3-dihydroxypropanimidamide were reacted Yield: 494 mg (68% of theory) were reacted Yield: 494 mg (68% of theory)

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

Procedure: According to General Method 6A, 300 mg (0.828 mmol) of the compound from Example 7A and 112 mg (1.08 mmol) of N′,3-dihydroxypropanimidamide [Graham A. Showell et al., J. Med. Chem., 1991, 34, 1086-1094] were reacted. Yield: 248 mg (66% of theory) were reacted

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

Procedure: According to General Method 6A, 1.00 g (2.390 mmol) of the compound from Example 25A and 323 mg (3.107 mmol) of N′,3-dihydroxypropanimidamide were reacted Yield: 848 mg (69% of theory) were reacted Yield: 848 mg (69% of theory)