(3R)-4,4,4-trifluorobutane-1,3-diol

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

Procedure: 6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 100 mg, 506 μmol), (R)-4,4,4-trifluorobutane-1,3-diol (219 mg, 1.52 mmol) and potassium tert-butoxide (114 mg, 1.01 mmol) were combined with DMF (2 mL) to give a white suspension. The reaction mixture was heated to 140° C. and stirred for 20 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2×75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (8 mg, 5.2%) and its regioisomer; MS (EI) 304.2 (M+H)+. to give a white suspension After cooling the mixture extracted with ethyl acetate (2×75 mL) dried with Na2SO4 concentrated in vacuo The residue was purified by preparative HPLC

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

Procedure: 6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 100 mg, 506 μmol), (R)-4,4,4-trifluorobutane-1,3-diol (219 mg, 1.52 mmol) and potassium tert-butoxide (114 mg, 1.01 mmol) were combined with DMF (2 mL) to give a white suspension. The reaction mixture was heated to 140° C. and stirred for 20 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2×75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (8 mg, 5.2%) and its regioisomer; MS (EI) 304.2 (M+H)+. to give a white suspension After cooling the mixture extracted with ethyl acetate (2×75 mL) dried with Na2SO4 concentrated in vacuo The residue was purified by preparative HPLC

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

Procedure: 6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 100 mg, 506 μmol), (R)-4,4,4-trifluorobutane-1,3-diol (219 mg, 1.52 mmol) and potassium tert-butoxide (114 mg, 1.01 mmol) were combined with DMF (2 mL) to give a white suspension. The reaction mixture was heated to 140° C. and stirred for 20 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2×75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (12 mg, 7.8%) and its regioisomer; MS (EI) 304.2 (M+H)+. to give a white suspension After cooling the mixture extracted with ethyl acetate (2×75 mL) dried with Na2SO4 concentrated in vacuo The residue was purified by preparative HPLC

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

Procedure: 6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 100 mg, 506 μmol), (R)-4,4,4-trifluorobutane-1,3-diol (219 mg, 1.52 mmol) and potassium tert-butoxide (114 mg, 1.01 mmol) were combined with DMF (2 mL) to give a white suspension. The reaction mixture was heated to 140° C. and stirred for 20 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2×75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (12 mg, 7.8%) and its regioisomer; MS (EI) 304.2 (M+H)+. to give a white suspension After cooling the mixture extracted with ethyl acetate (2×75 mL) dried with Na2SO4 concentrated in vacuo The residue was purified by preparative HPLC

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

Procedure: 6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 100 mg, 506 μmol), (R)-4,4,4-trifluorobutane-1,3-diol (219 mg, 1.52 mmol) and potassium tert-butoxide (114 mg, 1.01 mmol) were combined with DMF (2 mL) to give a white suspension. The reaction mixture was heated to 140° C. and stirred for 20 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2×75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (8 mg, 5.2%) and its regioisomer; MS (EI) 304.2 (M+H)+. to give a white suspension After cooling the mixture extracted with ethyl acetate (2×75 mL) dried with Na2SO4 concentrated in vacuo The residue was purified by preparative HPLC

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

Procedure: 6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 100 mg, 506 μmol), (R)-4,4,4-trifluorobutane-1,3-diol (219 mg, 1.52 mmol) and potassium tert-butoxide (114 mg, 1.01 mmol) were combined with DMF (2 mL) to give a white suspension. The reaction mixture was heated to 140° C. and stirred for 20 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2×75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (8 mg, 5.2%) and its regioisomer; MS (EI) 304.2 (M+H)+. to give a white suspension After cooling the mixture extracted with ethyl acetate (2×75 mL) dried with Na2SO4 concentrated in vacuo The residue was purified by preparative HPLC

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

Procedure: 6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 100 mg, 506 μmol), (R)-4,4,4-trifluorobutane-1,3-diol (219 mg, 1.52 mmol) and potassium tert-butoxide (114 mg, 1.01 mmol) were combined with DMF (2 mL) to give a white suspension. The reaction mixture was heated to 140° C. and stirred for 20 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2×75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (12 mg, 7.8%) and its regioisomer; MS (EI) 304.2 (M+H)+. to give a white suspension After cooling the mixture extracted with ethyl acetate (2×75 mL) dried with Na2SO4 concentrated in vacuo The residue was purified by preparative HPLC

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

Procedure: 6-Chloro-5-cyclopropyl-2-pyridinecarboxylic acid (CAN 1211530-95-8; 100 mg, 506 μmol), (R)-4,4,4-trifluorobutane-1,3-diol (219 mg, 1.52 mmol) and potassium tert-butoxide (114 mg, 1.01 mmol) were combined with DMF (2 mL) to give a white suspension. The reaction mixture was heated to 140° C. and stirred for 20 h. After cooling the mixture was poured into cold 1 M HCl (15 mL) and extracted with ethyl acetate (2×75 mL). The phases were combined, dried with Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (12 mg, 7.8%) and its regioisomer; MS (EI) 304.2 (M+H)+. to give a white suspension After cooling the mixture extracted with ethyl acetate (2×75 mL) dried with Na2SO4 concentrated in vacuo The residue was purified by preparative HPLC

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

Procedure: The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and (R)-toluene-4-sulfonic acid 4,4,4-trifluoro-3-hydroxy-butyl ester (prepared from commercially available (R)-4,4,4-trifluoro-butane-1,3-diol in analogy to M. Tordeux et. al, J. Fluorine Chem. 20, 301 (1982) and U.S. Pat. No. 5,405,967) to give the desired product as a light yellow oil (5%).

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

Procedure: The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride and (R)-toluene-4-sulfonic acid 4,4,4-trifluoro-3-hydroxy-butyl ester (prepared from commercially available (R)-4,4,4-trifluoro-butane-1,3-diol in analogy to M. Tordeux et. al, J. Fluorine Chem. 20, 301 (1982) and U.S. Pat. No. 5,405,967) to give the desired product as a light yellow oil (5%).

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

Procedure: Triphenylphosphine (5.09 g, 19.4 mmol) was dissolved in dichloromethane (66 mL) and treated with imidazole (1.33 g, 19.5 mmol) and iodine (4.92 g, 19.4 mmol), respectively, to give an orange suspension. A solution of (R)-4,4,4-trifluoro-1,3-butanediol (2.34 g, 16.2 mmol) in dichloromethane (18 mL) was added to the suspension and stirred for 30 minutes. The reaction mixture was placed on a silica gel flash column and eluted with 100% dichloromethane to give the product as a pale purple oil (3.30 g, 80%). respectively, to give an orange suspension eluted with 100% dichloromethane

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

Procedure: A solution of ethyl (R)-(+)-4,4,4trifluoro-3-hydroxybutyrate (3.12 g, 16.8 mmol) in diethyl ether (8 mL) was added to a 0–5° C. suspension of lithium aluminium hydride (1.01 g, 26.6 mmol) in diethyl ether (17 mL) over 25 minutes. Upon complete addition, the mixture was stirred at ambient temperature for 20 h. The mixture was cooled to 0–5° C. and quenched by dropwise addition of 3N HCl (17 mL), followed by stirring at ambient temperature for 3 h. The liquid portion was decanted away and the salts were washed with additional diethyl ether. The combined organic portions were washed (brine), dried, and evaporated to give the product as a cloudy, colourless oil (2.34 g, 96%). Upon complete addition The mixture was cooled to 0–5° C. quenched by dropwise addition of 3N HCl (17 mL) by stirring at ambient temperature for 3 h The liquid portion was decanted away the salts were washed with additional diethyl ether The combined organic portions were washed (brine) dried evaporated