4-(methoxymethyl)piperidine;hydrochloride

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

Procedure: A solution of 4M hydrogen chloride in 1,4-dioxane (807 μL, 3.23 mmol) was added to tert-butyl 4-(methoxymethyl)piperidine-1-carboxylate (Intermediate 176, 74 mg, 0.323 mmol) and the mixture was stirred at room temperature for 18 h before being evaporated to dryness to provide the title compound (47.7 mg, 89%). Method B HPLC-MS: MH+ requires m/z=130 Found: m/z=130, Rt=0.24 min. before being evaporated to dryness

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 2-(4-chloro-5-phenyl-thieno[2,3-d]pyrimidin-2-yl)acetate (100 mg, 0.285 mmol), 4-(methoxymethyl)piperidine hydrochloride (52 mg, 0.314 mmol) and triethylamine (0.12 mL, 0.85 mmol) were dissolved in ethanol (4 mL) and heated to 65° C. for 6 hrs. The reaction was then heated to 150° C. in a microwave for 10 min. The reaction was poured over ice and extracted with DCM. The extracts were combined and concentrated in vacuo. The residue was dissolved in non-dry THF (2 mL) and lithium hydroxide monohydrate (48 mg) was added. The reaction was stirred at room temperature overnight then another portion of lithium hydroxide monohydrate was added (10 mg) and the reaction stirred for a further 2 hrs. The reaction mixture was purified on an Isolute NH2 SPE column (eluting ammonia in methanol) to give 2-[4-[4-(methoxymethyl)-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]acetic acid (107 mg). The reaction was then heated to 150° C. in a microwave for 10 min The reaction was poured over ice extracted with DCM concentrated in vacuo The residue was dissolved in non-dry THF (2 mL) lithium hydroxide monohydrate (48 mg) was added another portion of lithium hydroxide monohydrate was added (10 mg) the reaction stirred for a further 2 hrs The reaction mixture was purified on an Isolute NH2 SPE column (eluting ammonia in methanol)

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-[4-Chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2-yl]ethanol (150 mg, 0.0005 mol), triethylamine (0.214 mL, 0.00154 mol) and 4-(methoxymethyl)piperidine hydrochloride (0.091 g, 0.00055 mol) were dissolved in ethanol (5 mL) and warmed to 55° C. for 2 hrs. The reaction was then poured over ice and extracted with DCM. The organics were dried by passage through a PTFE frit and concentrated in vacuo to give 2-[5-(4-fluorophenyl)-4-[4-(methoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-2-yl]ethanol (180 mg). LCMS RT=4.33 min. M+1=402. The reaction was then poured over ice extracted with DCM The organics were dried by passage through a PTFE frit concentrated in vacuo

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-[4-Chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2-yl]ethanol (150 mg, 0.0005 mol), triethylamine (0.214 mL, 0.00154 mol) and 4-(methoxymethyl)piperidine hydrochloride (0.091 g, 0.00055 mol) were dissolved in ethanol (5 mL) and warmed to 55° C. for 2 hrs. The reaction was then poured over ice and extracted with DCM. The organics were dried by passage through a PTFE frit and concentrated in vacuo to give 2-[5-(4-fluorophenyl)-4-[4-(methoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-2-yl]ethanol (180 mg). LCMS RT=4.33 min. M+1=402. The reaction was then poured over ice extracted with DCM The organics were dried by passage through a PTFE frit concentrated in vacuo

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

Procedure: The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-(methoxymethyl)piperidine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 1.10 (qd, J=12.3, 4.0 Hz, 2 H) 1.59 (br. s., 1 H) 1.67 (br. s., 1 H) 1.70-1.85 (m, 1 H) 2.36 (s, 3 H) 2.74 (br. s., 1 H) 3.14 (d, J=6.3 Hz, 2 H) 3.17 (s, 3 H) 3.57 (br. s., 1 H) 4.41 (br. s., 1 H) 7.57 (dd, J=8.0, 1.4 Hz, 1 H) 7.64 (s, 1 H) 7.74 (d, J=8.1 Hz, 1 H) 7.96 (dd, J=8.6, 2.3 Hz, 1 H) 8.03-8.09 (m, 1 H) 8.31 (d, J=8.3 Hz, 1 H) 8.42-8.47 (m, 1 H) 13.03 (br. s., 1 H). MS m/z [M+H]+ 432.5.

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

Procedure: The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-(methoxymethyl)piperidine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 1.10 (qd, J=12.3, 4.0 Hz, 2H) 1.59 (br. s., 1H) 1.67 (br. s., 1H) 1.70-1.85 (m, 1H) 2.36 (s, 3H) 2.74 (br. s., 1H) 3.14 (d, J=6.3 Hz, 2H) 3.17 (s, 3H) 3.57 (br. s., 1H) 4.41 (br. s., 1H) 7.57 (dd, J=8.0, 1.4 Hz, 1H) 7.64 (s, 1H) 7.74 (d, J=8.1 Hz, 1H) 7.96 (dd, J=8.6, 2.3 Hz, 1H) 8.03-8.09 (m, 1H) 8.31 (d, J=8.3 Hz, 1H) 8.42-8.47 (m, 1H) 13.03 (br. s., 1H). MS m/z [M+H]+ 432.5.

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

Procedure: The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-(methoxymethyl)piperidine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 1.10 (qd, J=12.3, 4.0 Hz, 2H) 1.59 (br. s., 1H) 1.67 (br. s., 1H) 1.70-1.85 (m, 1H) 2.36 (s, 3H) 2.74 (br. s., 1H) 3.14 (d, J=6.3 Hz, 2H) 3.17 (s, 3H) 3.57 (br. s., 1H) 4.41 (br. s., 1H) 7.57 (dd, J=8.0, 1.4 Hz, 1H) 7.64 (s, 1H) 7.74 (d, J=8.1 Hz, 1H) 7.96 (dd, J=8.6, 2.3 Hz, 1H) 8.03-8.09 (m, 1H) 8.31 (d, J=8.3 Hz, 1H) 8.42-8.47 (m, 1H) 13.03 (br. s., 1H). MS m/z [M+H]+ 432.5.

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

Procedure: A solution of 4M hydrogen chloride in 1,4-dioxane (807 μL, 3.23 mmol) was added to tert-butyl 4-(methoxymethyl)piperidine-1-carboxylate (Intermediate 176, 74 mg, 0.323 mmol) and the mixture was stirred at room temperature for 18 h before being evaporated to dryness to provide the title compound (47.7 mg, 89%). Method B HPLC-MS: MH+ requires m/z=130 Found: m/z=130, Rt=0.24 min. before being evaporated to dryness

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

Procedure: 3′-({4-[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy}methyl)-2-methylbiphenyl-4-carboxylic acid (10.8 mg) was dissolved in a THF-methanol [1 ml, 4:1 (v/v)] mixed solution, and the solution was added to 4-(methoxymethyl)piperidine hydrochloride (7.5 mg). DMT-MM (12 mg) and triethylamine (20 μl) were added, followed by overnight stirring at room temperature. Thereafter, chloroform was added to the reaction liquid, and the organic layer was washed with 1 M hydrochloric acid. The organic layer was concentrated, and the residue was purified by a fractional HPLC (Waters, product name: Waters SunFire™ Prep C18OBD™ (19×100 mm, 5 μm)) to obtain 2-{4-[(4′-{[4-(methoxymethyl)piperidin-1-yl]carbonyl}-2′-methylbiphenyl-3-yl)methoxy]benzyl}-1,2,4-oxadiazolidine-3,5-dione (9.0 mg). mixed solution the organic layer was washed with 1 M hydrochloric acid The organic layer was concentrated the residue was purified by a fractional HPLC (Waters, product name: Waters SunFire™ Prep C18OBD™ (19×100 mm, 5 μm))

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Ethyl 2-(4-chloro-5-phenyl-thieno[2,3-d]pyrimidin-2-yl)acetate (100 mg, 0.285 mmol), 4-(methoxymethyl)piperidine hydrochloride (52 mg, 0.314 mmol) and triethylamine (0.12 mL, 0.85 mmol) were dissolved in ethanol (4 mL) and heated to 65° C. for 6 hrs. The reaction was then heated to 150° C. in a microwave for 10 min. The reaction was poured over ice and extracted with DCM. The extracts were combined and concentrated in vacuo. The residue was dissolved in non-dry THF (2 mL) and lithium hydroxide monohydrate (48 mg) was added. The reaction was stirred at room temperature overnight then another portion of lithium hydroxide monohydrate was added (10 mg) and the reaction stirred for a further 2 hrs. The reaction mixture was purified on an Isolute NH2 SPE column (eluting ammonia in methanol) to give 2-[4-[4-(methoxymethyl)-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]acetic acid (107 mg). The reaction was then heated to 150° C. in a microwave for 10 min The reaction was poured over ice extracted with DCM concentrated in vacuo The residue was dissolved in non-dry THF (2 mL) lithium hydroxide monohydrate (48 mg) was added another portion of lithium hydroxide monohydrate was added (10 mg) the reaction stirred for a further 2 hrs The reaction mixture was purified on an Isolute NH2 SPE column (eluting ammonia in methanol)

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-[4-Chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-2-yl]ethanol (150 mg, 0.0005 mol), triethylamine (0.214 mL, 0.00154 mol) and 4-(methoxymethyl)piperidine hydrochloride (0.091 g, 0.00055 mol) were dissolved in ethanol (5 mL) and warmed to 55° C. for 2 hrs. The reaction was then poured over ice and extracted with DCM. The organics were dried by passage through a PTFE frit and concentrated in vacuo to give 2-[5-(4-fluorophenyl)-4-[4-(methoxymethyl)-1-piperidyl]thieno[2,3-d]pyrimidin-2-yl]ethanol (180 mg). LCMS RT=4.33 min. M+1=402. The reaction was then poured over ice extracted with DCM The organics were dried by passage through a PTFE frit concentrated in vacuo

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

Procedure: The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 4-(methoxymethyl)piperidine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 1.10 (qd, J=12.3, 4.0 Hz, 2 H) 1.59 (br. s., 1 H) 1.67 (br. s., 1 H) 1.70-1.85 (m, 1 H) 2.36 (s, 3 H) 2.74 (br. s., 1 H) 3.14 (d, J=6.3 Hz, 2 H) 3.17 (s, 3 H) 3.57 (br. s., 1 H) 4.41 (br. s., 1 H) 7.57 (dd, J=8.0, 1.4 Hz, 1 H) 7.64 (s, 1 H) 7.74 (d, J=8.1 Hz, 1 H) 7.96 (dd, J=8.6, 2.3 Hz, 1 H) 8.03-8.09 (m, 1 H) 8.31 (d, J=8.3 Hz, 1 H) 8.42-8.47 (m, 1 H) 13.03 (br. s., 1 H). MS m/z [M+H]+ 432.5.