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

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 (R)-pyrrolidin-2-ylmethanol and isolated as light-yellow gum (14.2 mg, 75%). MS (m/e): 401.4 (MH+).

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

Procedure: To a solution of 4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid (0.040 g, 0.111 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.042 g, 0.111 mmol), and diisopropylethylamine (0.038 mL, 0.222 mmol) in DMF (0.35 mL) was added D-prolinol (0.011 mL, 0.111 mmol) and the reaction mixture stirred at room temperature for 6 hours. The reaction was reduced in vacuo. The residue was purified by preparative HPLC to afford the white solid (R)-2-(2,6-difluorophenyl)-5-(4-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)phenylamino)oxazole-4-carboxamide (0.018 g, 0.040 mmol, 36%). 1H NMR (DMSO) δ 1.68 (1H, m), 1.90 (3H, m), 3.61-3.32 (4H, m), 4.13 (1H, br s), 4.75 (1H, t), 7.50-7.31 (8H, m), 7.64 (1H, m), 9.50 (1H, br s). LCMS (2) Rt: 2.10 min; m/z (ES+) 443. The residue was purified by preparative HPLC

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

Procedure: As described for example 223, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (120 mg, 0.37 mmol) was converted, using D-prolinol instead of L-prolinol, to the title compound (139 mg, 96%) which was obtained as a colourless oil. MS: m/e=394.1 [M+H]′.

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

Procedure: As described for example 223, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (120 mg, 0.37 mmol) was converted, using D-prolinol instead of L-prolinol, to the title compound (139 mg, 96%) which was obtained as a colourless oil. MS: m/e=394.1 [M+H]′.

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

Procedure: The product from Example 1C and (D)-prolinol were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.87 (m, 1H), 7.82 (m, 4H), 7.58 (m, 2H), 6.80 (s, 1H), 3.95 (m, 2H), 3.72 (m, 2H), 3.58 (m, 1H), 3.35-3.4 (m, 4H), 1.95-2.3 (m, 4H); MS (DCI) m/z 347 (M+H)+;

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

Procedure: Prepared as described for 2-(N-methylpropylsulfonamido)ethyl propane-1-sulfonate (example 76, step 1 using (R)-1-pyrrolidin-2-yl-methanol instead of 2-(methylamino)ethanol. Prepared

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

Procedure: 1 g of commercially available (D)-prolinol, 1.5 g of 7-chloro-[1,2,4]triazolo-[1,5-a]pyrimidine and 2.6 g of N-ethyldiisopropylamine are heated at 130° C. in a microwave for 3 h in 60 ml of 1-butanol. The butanol is subsequently removed in vacuo, the residue is taken up in ethyl acetate, mixed with water, adjusted to pH 12 using 1 N NaOH solution, phases are separated, the organic phase is dried over sodium sulfate, evaporated and chromatographed on silica gel, giving 1.7 g of ((R)-1-[1,2,4]triazolo[1,5-a]pyrimidin-7-ylpyrrolidin-2-yl)methanol as beige crystals; The butanol is subsequently removed in vacuo mixed with water are separated the organic phase is dried over sodium sulfate evaporated chromatographed on silica gel

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

Procedure: The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and (R)-1-pyrrolidin-2-yl-methanol in direct analogy to the general procedure used in example 129. MS: 477.3 (MH+).

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

Procedure: The title compound was prepared from 1-[5-Cyclopropyl-3-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carbonyl]-piperidin-4-one (Example 181B) and (R)-1-pyrrolidin-2-yl-methanol in direct analogy to the general procedure used in example 129. MS: 477.3 (MH+).

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

Procedure: The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 118 (0.033 g, 0.0779 mmol) and 3-hydroxypyrrolidine with (R)-2-(hydroxymethyl)pyrrolidine. A yellow solid 120 was obtained (0.027 g, 55%). 1H-NMR (CDCl3, 400 MHz) δ 2.06-2.11 (m, 2H), 2.16-21 (m, 2H), 3.46-3.53 (m, 1H), 3.63-3.76 (m, 3H), 4.28-4.34 (m, 4H), 4.61-4.66 (m, 1H), 6.78 (s, 1H), 6.92 (dd, J=1.4 Hz, 6.9 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.05 (dd, J=2.2 Hz, 8.0 Hz, 1H), 7.10 (d, J=2.2 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.52 (dd, J=1.9 Hz, 8.4 Hz, 1H), 7.82 (d, J=1.4 Hz, 1H), 8.13 (d, J=6.6 Hz, 1H); MS (APCI) m/z 489 (M+H)+.

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 3,4-difluoronitrobenzene (1.57 g, 9.8 mmol), (R)-2-pyrrolidinemethanol (1.0 g, 9.8 mmol) and K2CO3 (1.36 g, 9.8 mmol) in 30 mL DMF was heated at 75° C. for 20 h, whereupon the mixture was partitioned between water (100 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL), and the combined organic layers washed with brine, dried over Na2SO4, filtered, and concentrated. Flash chromatography (19:1 CH2Cl2:MeOH) afforded 2.27 g (96%) of (R)-[l-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol, an orange solid. Data for (R)-[1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol: Rf 0.17 (7:3 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.94 (dd, 1H, J=9.1, 2.6), 7.89 (dd, 1H, J=14.4, 2.6), 6.68 (t, 1H, J=9.0), 4.25-4.32 (m, 1H), 3.60-3.75 (m, 3H), 3.40-3.50 (m, 1H), 1.95-2.15 (m, 4H), 1.43 (t, 1H, J=5.8). was partitioned between water (100 mL) and EtOAc (100 mL) The aqueous layer was extracted with EtOAc (100 mL) the combined organic layers washed with brine dried over Na2SO4 filtered concentrated

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of 3,4-difluoronitrobenzene (1.57 g, 9.8 mmol), (R)-2-pyrrolidinemethanol (1.0 g, 9.8 mmol) and K2CO3 (1.36 g, 9.8 mmol) in 30 mL DMF was heated at 75° C. for 20 h, whereupon the mixture was partitioned between water (100 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL), and the combined organic layers washed with brine, dried over Na2SO4, filtered, and concentrated. Flash chromatography (19:1 CH2Cl2:MeOH) afforded 2.27 g (96%) of (R)-[l-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol, an orange solid. Data for (R)-[1-(2-fluoro-4-nitrophenyl)-2-pyrrolidinyl]-methanol: Rf 0.17 (7:3 hexanes:EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.94 (dd, 1H, J=9.1, 2.6), 7.89 (dd, 1H, J=14.4, 2.6), 6.68 (t, 1H, J=9.0), 4.25-4.32 (m, 1H), 3.60-3.75 (m, 3H), 3.40-3.50 (m, 1H), 1.95-2.15 (m, 4H), 1.43 (t, 1H, J=5.8). was partitioned between water (100 mL) and EtOAc (100 mL) The aqueous layer was extracted with EtOAc (100 mL) the combined organic layers washed with brine dried over Na2SO4 filtered concentrated