1-[(3,5-difluorophenyl)methyl]piperidin-4-amine

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl]thiophen-2-carbaldehyde is reacted with 1-(3,5-difluoro-benzyl)-piperidin-4-ylamine as described in Method A of Example 123 to give the title compound. MS: m/e 458 (M+H).

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

Procedure: The title compound was prepared (264 mg, 56%) from 4-chloro-6-isopropylthieno[2,3-d]pyrimidine (0.25 g, 1.18 mmol) and 1-(3,5-difluorobenzyl)piperidin-4-amine (0.4 g, 1.77 mmol) by following the general procedure described for Preparation 6. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 6.90 (m, 2H), 6.80 (s, 1H), 6.70 (m, 1H), 4.95 (d, 1H), 4.20 (m, 1H), 3.50 (s, 2H), 3.20 (m, 1H), 2.85 (m, 2H), 2.25 (m, 2H), 2.10 (m, 2H), 1.60 (m, 2H), 1.40 (d, 6H). MS (ESI) m/z: Calculated: 402.5; Observed: 403.1 (M++1). described for Preparation 6

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

Procedure: The title compound was prepared (140 mg, 49%) from 4,6-dichloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (175 mg, 0.59 mmol) and 1-(3,5-difluorobenzyl)piperidin-4-amine (170 mg, 0.7 mmol) by following the general procedure described for Preparation 6. 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.45 (m, 2H), 7.30 (m, 2H), 6.85 (m, 2H), 6.65 (m, 1H), 4.65 (m, 1H), 4.05 (bs, 1H), 3.40 (s, 2H), 2.40 (m, 2H), 2.15 (m, 2H), 1.85 (m, 2H), 1.15 (m, 1H). MS (ESI) m/z: Calculated: 488.1; Observed: 489.2 (M++1). described for Preparation 6

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

Procedure: The title compound was prepared (264 mg, 56%) from 4-chloro-6-isopropylthieno[2,3-d]pyrimidine (0.25 g, 1.18 mmol) and 1-(3,5-difluorobenzyl)piperidin-4-amine (0.4 g, 1.77 mmol) by following the general procedure described for Preparation 6. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 6.90 (m, 2H), 6.80 (s, 1H), 6.70 (m, 1H), 4.95 (d, 1H), 4.20 (m, 1H), 3.50 (s, 2H), 3.20 (m, 1H), 2.85 (m, 2H), 2.25 (m, 2H), 2.10 (m, 2H), 1.60 (m, 2H), 1.40 (d, 6H). MS (ESI) m/z: Calculated: 402.5; Observed: 403.1 (M++1). described for Preparation 6

Conditions: temp:180.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-chloro-4,5-dimethyl-pyridazine-3-carbonitrile (D11) (0.120 g, 0.72 mmol), 1-(3,5-difluoro-benzyl)-piperidin-4-ylamine (D5) (0.194 g, 0.86 mmol) and diisopropylethylamine (0.188 ml, 1.08 mmol) in acetonitrile was stirred at 180° C. for 20 min., under microwave irradiation (Biotage MW-oven), and then again at 180° C. for additional 30 min. Dichloromethane, water and a saturated solution of sodium carbonate were then added. The organic phase was separated, filtered over cotton and evaporated in vacuo. The residue was purified by column chromatography (silica gel; 0-1% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and the solvent evaporated in vacuo to yield E19 (0.108 g, 42%) as a solid. C19H21F2N5 requires 357. Found 358 (MH+). again at 180° C. for additional 30 min The organic phase was separated filtered over cotton evaporated in vacuo The residue was purified by column chromatography (silica gel; 0-1% ammonia in methanol (7M)/dichloromethane) The desired fractions were collected the solvent evaporated in vacuo

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-chloro-pyridazine-3-carbonitrile (D4) (1.74 g, 12.46 mmol), 1-(3,5-difluoro-benzyl)-piperidin-4-ylamine (D5) (2.35 g, 10.386 mmol) and diisopropylethylamine (2.71 ml, 15.58 mmol) in acetonitrile (30 ml) was stirred at 120° C. for 40 min., under microwave irradiation (Milestone MW-oven). Dichloromethane, water and a saturated solution of sodium carbonate were then added. The organic layers were filtered over cotton, evaporated in vacuo and the residue was purified by column chromatography (silica gel; 0-1.5% ammonia in methanol (7 M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. The residue was precipitated in heptane to yield E15 (2.065 g, 60%) as a solid. C17H17F2N5 requires 329. Found 330 (MH+); mp: 187.9° C. The organic layers were filtered over cotton evaporated in vacuo the residue was purified by column chromatography (silica gel; 0-1.5% ammonia in methanol (7 M)/dichloromethane) The desired fractions were collected evaporated in vacuo The residue was precipitated in heptane

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

Procedure: A mixture of piperidin-4-ylcarbamic acid tert-butyl ester (5 g, 24.9 mmol), 3,5-difluorobenzyl bromide (2.9 ml, 22.7 mmol) and diisoproylethylamine (5.9 ml, 34.03 mmol) in dichloromethane (50 ml) was stirred at room temperature for 2 h. After this period, trifluoroacetic acid (32 ml) was added and the reaction mixture was stirred for a further 2 h. The solvent was evaporated in vacuo and a saturated solution of sodium carbonate was added. The mixture was extracted with dichloromethane, and the separated organic layers were dried (Na2SO4), filtered, and the solvent evaporated in vacuo to yield D5 (4.5 g, 90%) as a solid. C12H16F2N2 requires 226. Found 227 (MH+) After this period the reaction mixture was stirred for a further 2 h The solvent was evaporated in vacuo a saturated solution of sodium carbonate was added The mixture was extracted with dichloromethane the separated organic layers were dried (Na2SO4) filtered the solvent evaporated in vacuo