[(2S)-pyrrolidin-2-yl]methanol

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

Procedure: Using general procedure 1 and purification method D with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.10 g, 0.38 mmol) and (2S)-2-hydroxymethyl-pyrrolidine (0.077 g, 0.76 mmol) gives the title compound.

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

Procedure: 0.1 g (0.37 mmol) of 2-(3-methylbenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile is heated with 0.11 g (1.1 mmol) of (S)-(+)-2-pyrrolidinemethanol in 3 ml of acetonitrile at 90° C. under argon for five days. After cooling to room temperature, the crude product is purified by preparative HPLC. 0.035 g (29% of theory) of the title compound is obtained as a colourless solid. the crude product is purified by preparative HPLC

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

Procedure: This compound was prepared by using procedure analogous to those described for the synthesis of Example 98, Step 9 starting from 2-(4-{3-[3-({[(2,2,2-trifluoro ethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}phenyl)propanoic acid and (2S)-pyrrolidin-2-ylmethanol. LCMS (M+H)+: m/z=567.3 This compound was prepared

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-pyrrolidin-2-ylmethanol and isolated as light-yellow gum (14.6 mg, 77%). MS (m/e): 401.4 (MH+).

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 2(S)-hydroxymethylpyrrolidine (25.32 g, 250.3 mmol) in CH2Cl2 (720 mL) under argon was added Et3N (38.0 mL, 273 mmol). After cooling this mixture to -20° C., chloroacetyl chloride (20.0 mL, 251 mmol) was added dropwise over 0.75 h maintaining the reaction temperature at -20 ±3° C. The reaction was stirred at ambient temperature for 18 h and evaporated in vacuo. An impurity which precipitated during concentration was removed by filtration. The crude product was purified by chromatography (silica gel, 1:39 to 1:19 MeOH/CH2Cl2) to give the title compound as a yellow oil. 1H NMR (CDCl3, 400 MHz): δ4.37 (dd, J=8, 3 Hz, 1H), 4.22 (qd, J=7, 3 Hz, 1H), 4.08 (s, 2H), 3.71 (td, J=8, 3 Hz, 1H), 3.68-3.50 (m, 3H), 2.14-1.86 (m, 3H), 1.72-1.62 (m, 1H). maintaining the reaction temperature at -20 ±3° C evaporated in vacuo An impurity which precipitated during concentration was removed by filtration The crude product was purified by chromatography (silica gel, 1:39 to 1:19 MeOH/CH2Cl2)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 13 ml of ethanol, 4.71 g of (S)-2-pyrrolidinemethanol was dissolved, followed by the addition of 4.6 ml of acrylonitrile. The resulting mixture was heated under reflux for 2 hours. After the solvent was evaporated, the residue was dissolved in 70 ml of toluene, followed by the addition of 13 ml of triethylamine under ice-cooling. To the resulting mixture, 4.3 ml of methanesulfonyl chloride was added dropwise, followed by stirring at 0° C. for 10 minutes and then at room temperature for 30 minutes. After the addition of 15.7 g of potassium tert-butoxide, the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the toluene layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated and the resulting residue was subjected to silica gel column chromatography, whereby 5.22 g of (5S)-1-azabicyclo[3.3.0]octane-3-carbonitrile was obtained as a diastereomer mixture from the fraction eluted with chloroform-methanol-29% aqueous ammonia (100:10:1). The resulting mixture was heated under reflux for 2 hours After the solvent was evaporated the residue was dissolved in 70 ml of toluene followed by the addition of 13 ml of triethylamine under ice- cooling To the resulting mixture, 4.3 ml of methanesulfonyl chloride was added dropwise at room temperature for 30 minutes After the addition of 15.7 g of potassium tert-butoxide the mixture was stirred at room temperature for 16 hours Water was added to the reaction mixture the toluene layer was separated dried over anhydrous sodium sulfate The solvent was evaporated

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

Procedure: A solution of 31.4 g (144 mmol) di-tert-butyl dicarbonate in dichloromethane was added to a solution of 14.6 g (144 mmol) L-prolinol and 22.1 ml (159 mmol) triethyl amine in dichloromethane at 0° C. The reaction was left overnight at rt. The dichloromethane phase was washed with 30% citric acid aq, saturated NaCl aq and saturated NaHCO3 aq. The organic phase was dried with Na2SO4 and evaporated. Yield 27.71 g (138 mmol, 96%). 27.71 g (138 mmol) BOC-L-prolinol was oxidized to the corresponding aldehyde according to procedure G. Yield of crude product 22.63 g. The product was purified with a silica column using 20% ethyl acetate in petroleum ether as eluent. Yield 18.4 g (92 mmol, 67%). The dichloromethane phase was washed with 30% citric acid aq, saturated NaCl aq and saturated NaHCO3 aq. The organic phase was dried with Na2SO4 evaporated The product was purified with a silica column

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Triethylamine (4.0 ml) and isobutyl chloroformate (1.86 ml) were added dropwise to a solution of 3-(N-benzyl-N-methylcarbamoyl) propionic acid (2.5 g) in THF (30 ml) cooled to -20° C. The mixture was stirred for 30 mins at the same temperature. Triethylamine (4 ml) was added to a solution of (S)-2-pyrrolidinemethanol (1.45 g) in THF (30 ml). To the solution cooled to -25° C., the above solution was added dropwise. The mixture was stirred for 1 hr at the same temperature. After reaction, water was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2 --CH3OH) to give the title compound (2.59 g) having the following physical data: To the solution cooled to -25° C. the above solution was added dropwise The mixture was stirred for 1 hr at the same temperature was added to the reaction solution The mixture was extracted with EtOAc The extract was washed dried evaporated The residue was purified by column chromatography on silica gel (CH2Cl2 --CH3OH)

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

Procedure: Benzoyl chloride (18.5 ml) and an aqueous (50 ml) solution of sodium carbonate (17.0 g) were added dropwise to a solution of (S)-2-pyrrolidinemethanol (12.0 g) in a mixture of acetone (70 ml) and water (14 ml). After addition, the reaction mixture was stirred for 30 mins at room temperature. The reaction mixture was filtered. Water was added to the filtrate. The mixture was extracted with methylene chloride. The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica-gel (hexane-EtOAc) to give the title compound (24.1 g) having the following physical data: After addition The reaction mixture was filtered Water was added to the filtrate The mixture was extracted with methylene chloride The extract was washed dried evaporated The residue was purified by column chromatography on silica-gel (hexane-EtOAc)

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

Procedure: ((2S)-1-(1-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethyl)pyrrolidin-2-yl)methanol was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and (S)-pyrrolidin-2-ylmethanol (commercially available) following the procedures described for Example 182, 1H NMR (Acetone-d6) TFA Salt: δ 8.83 (s, 1H), 8.80 (s, 1H), 8.43 (d, 1H), 7.36-7.53 (m, 6H), 4.68 (m, 1H), 3.69 (m, 2H), 3.19-3.21 (m, 4H), 2.55 (m, 4H), 1.75-1.78 (m, 6H), 1.74 (d, 3H). LRMS [M+H]=441.2

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

Procedure: A mixture of 2,4,6-trichloro-5-methoxy-pyrimidine (1.2 g, 5.62 mmol), (S)-1-pyrrolidin-2-yl-methanol (1.1 mL, 11.3 mmol) and triethylamine (1.08 mL, 7.75 mmol) in IMS (36 mL) was stirred at RT for 20 mins, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane) affording [(S)-1-(2,6-Dichloro-5-methoxy-pyrimidin-4-yl)-pyrrolidin-2-yl]-methanol (1.08 mg, 70%). LCMS (method A): RT=2.98 min, [M+H]+=278/280. concentrated in vacuo The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane)

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

Procedure: As described for example 220, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (120 mg, 0.37 mmol) was converted, using L-prolinol instead of 3-amino-1-propanol, to the title compound (122 mg, 84%) which was obtained as a colourless oil. MS: m/e=394.1 [M+H]+.