(1S,2S)-cyclohexane-1,2-diamine

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Diisopropylethylamine and (1S,2S)-1,2-cyclohexandiamine were added to 2-chloro-6-(trifluoromethyl)nicotinic acid, followed by stirring at 100° C. for 30 minutes and at 140° C. for 10 minutes using a microwave reaction device. The reaction liquid was dissolved in acetonitrile, potassium carbonate and 1,4-dibromobutane were added, followed by stirring at 50° C. for 8 hours. By dissolving the residue extracted with chloroform in methanol and THF, adding 1 M sodium hydroxide aqueous solution thereto and carrying out the reaction at 50° C., 2-{[(1S,2S)-2-pyrrolidin-1-ylcyclohexyl]amino}-6-(trifluoromethyl)nicotinic acid was obtained. a microwave reaction device The reaction liquid by stirring at 50° C. for 8 hours By dissolving the residue extracted with chloroform in methanol and THF adding 1 M sodium hydroxide aqueous solution the reaction at 50° C.

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of (S)-tert-butyl 3-(4-bromo-2,5-difluorophenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (700 mg, 1.39 mmol), and sodium methanesulfinate (219 mg, 2.08 mmol) in DMSO (5.55 mL), was deoxygenated and purged with nitrogen. Cu(I) triflate benzene complex (77.6 mg, 0.139 mmol) and (1S,2S)-cyclohexane-1,2-diamine (63.4 mg, 0.555 mmol) were introduced and the heterogeneous mixture was sealed and heated to 110° C. in an oil bath and stirred for 18 hours. The mixture was cooled to ambient temperature, diluted with EtOAc (75 mL), washed with water (30 mL) and brine (three 50 mL washes), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified over silica gel (EtOAc) to afford (S)-tert-butyl 3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (305 mg, 0.606 mmol, 44% yield) as a light yellow oil that solidified. Mass spectrum (apci) m/z=389.1 (M+H-Boc). was deoxygenated purged with nitrogen the heterogeneous mixture was sealed The mixture was cooled to ambient temperature washed with water (30 mL) and brine (three 50 mL washes) dried (Na2SO4) filtered concentrated in vacuo The residue was purified over silica gel (EtOAc)

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

Procedure: 3,5-Di-t-butylsalicylaldehyde (2.0 equivalents) (prepared from the inexpensive, commercially available 2,4-di-t-butylphenol according to Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M. J Org Chem 1994, 59, 1939) was added as a solid to a 0.2 M solution of (S,S)-1,2-diaminocyclohexane (1.0 equivalent) (Aldrich Chemical Co., Milwaukee, Wis.) in absolute ethanol. The mixture was heated to reflux for 1 hr. and then H2O was added dropwise to the cooled bright yellow solution. The resulting yellow crystalline solid was collected by filtration and washed with a small portion of 95% ethanol. The yield of analytically pure salen ligand 2 obtained in this manner was 90-97%. The mixture was heated to reflux for 1 hr The resulting yellow crystalline solid was collected by filtration washed with a small portion of 95% ethanol

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

Procedure: 3,5-Di-t-butylsalicylaldehyde (2.0 equivalents) (prepared from the inexpensive, commercially available, 2,4-di-t-butylphenol according to Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M. J. Org. Chem. 1994, 59, 1939) was added as a solid to a 0.2 M solution of (S,S)-1,2-diaminocyclohexane (1.0 equivalent) (Aldrich Chemical Co., Milwaukee, Wis.) in absolute ethanol. The mixture was heated to reflux for 1 hr. and then H2O was added dropwise to the cooled bright yellow solution. The resulting yellow crystalline solid was collected to filtration and washed with a small portion of 95% ethanol. The yield of analytically pure salen ligand 2 obtained in this manner was 90-97%. The mixture was heated to reflux for 1 hr The resulting yellow crystalline solid was collected to filtration washed with a small portion of 95% ethanol

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

Procedure: 3,5-Di-t-butylsalicylaldehyde (2.0 equivalents) (prepared from the inexpensive, commercially available 2,4-di-t-butylphenol according to Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M. J. Org Chem 1994, 59, 1939) was added as a solid to a 0.2 M solution of (S,S)-1,2-diaminocyclohexane (1.0 equivalent) (Aldrich Chemical Co., Milwaukee, Wis.) in absolute ethanol. The mixture was heated to reflux for 1 hr. and then H2O was added dropwise to the cooled bright yellow solution. The resulting yellow crystalline solid was collected by filtration and washed with a small portion of 95% ethanol. The yield of analytically pure salen ligand obtained in this manner was 90-97%. The mixture was heated to reflux for 1 hr The resulting yellow crystalline solid was collected by filtration washed with a small portion of 95% ethanol

Conditions: temp:18.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 22 L flask was charged with 1,1′-carbonyldimidazole (1.7 Kg, 10.48 mol) and THF (7.5 L). Solid picolinic acid (1.36 Kg, 11 mol) was added to the slurry at room temperature. The reaction was endothermic causing the mixture to cool from 18° C. to 12° C. The reaction mixture was then warmed to 18-19° C. The resulting clear solution was stirred for 1 h and molten (1S,2S)-(+)-1,2-diaminocyclohexane (0.5 Kg, 4.38 mol) was added while keeping the temperature below 50° C. The beaker and funnel were rinsed with 2.5 L of THF. The reaction was stirred at rt for 15 h. Water (0.5 L) was added to the thin slurry giving a clear solution and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated to an orange semi-solid by rotary evaporation. The reaction product was slurried in 5 L of ethanol and concentrated by rotary evaporation. The reaction product was dissolved in ethanol (5 L) at 64-65° C. The solution was allowed to cool. The solution turned hazy around 58° C. At this temperature, the hazy solution was seeded (10 g) and cooled to −8° C. The resulting white crystals were isolated by filtration on a sintered glass funnel, washed with 5 L of cold ethanol (−8 to −10° C.), dried under house vacuum with nitrogen sweep, and then dried in a vacuum oven (35° C.). This resulted in the isolation of 1.23 Kg (86.3%) of white crystalline solid. to cool from 18° C. to 12° C the temperature below 50° C The beaker and funnel were rinsed with 2.5 L of THF The reaction was stirred at rt for 15 h Water (0.5 L) was added to the thin slurry giving a clear solution the reaction mixture was stirred for 1 h The reaction mixture was concentrated to an orange semi-solid by rotary evaporation concentrated by rotary evaporation The reaction product was dissolved in ethanol (5 L) at 64-65° C to cool turned hazy around 58° C cooled to −8° C The resulting white crystals were isolated by filtration on a sintered glass funnel washed with 5 L of cold ethanol (−8 to −10° C.) dried under house vacuum with nitrogen sweep dried in a vacuum oven (35° C.)

Conditions: temp:18.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 22 L flask was charged with 1,1′-carbonyldimidazole (1.7 Kg, 10.48 mol) and THF (7.5 L). Solid picolinic acid (1.36 Kg, 11 mol) was added to the slurry at room temperature. The reaction was endothermic causing the mixture to cool from 18° C. to 12° C. The reaction mixture was then warmed to 18-19° C. The resulting clear solution was stirred for 1 h and molten (1S,2S)-(+)-1,2-diaminocyclohexane (0.5 Kg, 4.38 mol) was added while keeping the temperature below 50° C. The beaker and funnel were rinsed with 2.5 L of THF. The reaction was stirred at rt for 15 h. Water (0.5 L) was added to the thin slurry giving a clear solution and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated to an orange semi-solid by rotary evaporation. The reaction product was slurried in 5 L of ethanol and concentrated by rotary evaporation. The reaction product was dissolved in ethanol (5 L) at 64-65° C. The solution was allowed to cool. The solution turned hazy around 58° C. At this temperature, the hazy solution was seeded (10 g) and cooled to −8° C. The resulting white crystals were isolated by filtration on a sintered glass funnel, washed with 5 L of cold ethanol (−8 to −10° C.), dried under house vacuum with nitrogen sweep, and then dried in a vacuum oven (35° C.). This resulted in the isolation of 1.23 Kg (86.3%) of white crystalline solid. to cool from 18° C. to 12° C the temperature below 50° C The beaker and funnel were rinsed with 2.5 L of THF The reaction was stirred at rt for 15 h Water (0.5 L) was added to the thin slurry giving a clear solution the reaction mixture was stirred for 1 h The reaction mixture was concentrated to an orange semi-solid by rotary evaporation concentrated by rotary evaporation The reaction product was dissolved in ethanol (5 L) at 64-65° C to cool turned hazy around 58° C cooled to −8° C The resulting white crystals were isolated by filtration on a sintered glass funnel washed with 5 L of cold ethanol (−8 to −10° C.) dried under house vacuum with nitrogen sweep dried in a vacuum oven (35° C.)

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

Procedure: 3,5-Di-t-butylsalicylaldehyde (2.0 equivalents) (prepared from the inexpensive, commercially available 2,4-di-t-butylphenol according to Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M. J Org Chem 1994, 59, 1939) was added as a solid to a 0.2 M solution of (S,S)-1,2-diaminocyclohexane (1.0 equivalent) (Aldrich Chemical Co., Milwaukee, Wis.) in absolute ethanol. The mixture was heated to reflux for 1 hr. and then H2O was added dropwise to the cooled bright yellow solution. The resulting yellow crystalline solid was collected by filtration and washed with a small portion of 95% ethanol. The yield of analytically pure salen ligand 2 obtained in this manner was 90-97%. The mixture was heated to reflux for 1 hr The resulting yellow crystalline solid was collected by filtration washed with a small portion of 95% ethanol

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

Procedure: Benzaldehyde (6.36 g, 60 mmol) was added dropwise over a period of 2 minutes to a solution of (S,S)-cyclohexane-1,2-diamine (3.42 g, 30 mmol) in 50 mL of anhydrous MeOH at refluxing temperature. After stirring for 30 min, the solution was allowed to cool to room temperature and NaBH3CN (2.4 g, 63 mmol) was added in portions. After the vigorous effervescence subsided down, the mixture was brought to refluxing and stirred for 20 min. The reaction was quenched by water and extracted with dichloromethane. The organic phase was dried and concentrated to give 8.5 g of crude product (yield 95%) which was used in the next step reaction without further purification. at refluxing temperature to refluxing stirred for 20 min The reaction was quenched by water extracted with dichloromethane The organic phase was dried concentrated

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

Procedure: (S,S)-1,2-Diaminocyclohexane (1.14 g) and 2.96 g of methyl oleate were reacted in the same manner as in Reference Example 26 to obtain 2.41 g of the objective compound (yield: 65%)

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

Procedure: 3,5-Di-t-butylsalicylaldehyde (2.0 equivalents) (prepared from the inexpensive, commercially available 2,4-di-t-butylphenol according to Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M. J. Org Chem 1994, 59, 1939) was added as a solid to a 0.2 M solution of (S,S)-1,2-diaminocyclohexane (1.0 equivalent) (Aldrich Chemical Co., Milwaukee, Wis.) in absolute ethanol. The mixture was heated to reflux for 1 hr. and then H2O was added dropwise to the cooled bright yellow solution. The resulting yellow crystalline solid was collected by filtration and washed with a small portion of 95% ethanol. The yield of analytically pure salen ligand 2 obtained in this manner was 90-97%. The mixture was heated to reflux for 1 hr The resulting yellow crystalline solid was collected by filtration washed with a small portion of 95% ethanol

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

Procedure: 3,5-Di-t-butylsalicylaldehyde (2.0 equivalents) (prepared from the inexpensive, commercially available 2,4-di-t-butylphenol according to Larrow, J. F.; Jacobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C. M. J. Org Chem 1994, 59, 1939) was added as a solid to a 0.2 M solution of (S,S)-1,2-diaminocyclohexane (1.0 equivalent) (Aldrich Chemical Co., Milwaukee, Wis.) in absolute ethanol. The mixture was heated to reflux for 1 hr. and then H2O was added dropwise to the cooled bright yellow solution. The resulting yellow crystalline solid was collected by filtration and washed with a small portion of 95% ethanol. The yield of analytically pure salen ligand 2 obtained in this manner was 90-97%. The mixture was heated to reflux for 1 hr The resulting yellow crystalline solid was collected by filtration washed with a small portion of 95% ethanol