N-methyloxan-4-amine;hydrochloride

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

Procedure: The title compound was prepared according to Preparation 23 from benzylmethyl(tetrahydropyran-4-yl)amine (Preparation 87). Crude material was dissolved in methanol and a solution of 1M HCl in ether was added dropwise to form a precipitate. The product was filtered and washed with ether to give the title compound as the hydrochloride salt as a white crystalline solid. δH (CD3OD): 4.11–4.00 (2H, m), 3.53–3.43 (2H, m), 3.37–3.27 (11H, m), 2.74 (3H, s), 2.11–2.03 (2H, m), 1.74–1.60 (2H, m). The title compound was prepared to form a precipitate The product was filtered washed with ether

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

Procedure: The title compound was prepared according to Preparation 23 from benzylmethyl(tetrahydropyran-4-yl)amine (Preparation 87). Crude material was dissolved in methanol and a solution of 1M HCl in ether was added dropwise to form a precipitate. The product was filtered and washed with ether to give the title compound as the hydrochloride salt as a white crystalline solid. δH (CD3OD): 4.11–4.00 (2H, m), 3.53–3.43 (2H, m), 3.37–3.27 (11H, m), 2.74 (3H, s), 2.11–2.03 (2H, m), 1.74–1.60 (2H, m). The title compound was prepared to form a precipitate The product was filtered washed with ether

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of methylamine hydrochloride (5.4 g), terahydro-4H-pyran-4-one (8 g), triethylamine (2.4 g), 5% palladium on carbon (400 mg) and methanol (56 ml) were stirred at 60° C. for 3 hours under a hydrogen atmosphere. The palladium on carbon was removed by filtration through diatomaceous earth (Celite®) and the resultant filtrate evaporated in vacuo to a cream solid. To this solid were added propan-2-ol (39 ml), methanol (10 ml) and diethyl ether (20 ml), the resultant suspension then allowed to stir at room temperature for 1 hour, the solid was collected by filtration, washed with diethyl ether (10 ml) and dried in vacuo at room temperature to give N-methyl-N-(tetrahydropyran-4-yl)amine hydrochloride (9.83 g) as a white solid; NMR Spectrum: (DMSOd6) 1.62 (m, 2H); 1.94 (m, 2H); 2.53 (m, 3H); 3.14 (m, 1H); 3.3 (m, 2H); 3.91 (m, 2H); 9.24 (s, 2H). The palladium on carbon was removed by filtration through diatomaceous earth (Celite®) the resultant filtrate evaporated in vacuo to a cream solid To this solid were added propan-2-ol (39 ml), methanol (10 ml) and diethyl ether (20 ml) to stir at room temperature for 1 hour the solid was collected by filtration washed with diethyl ether (10 ml) dried in vacuo at room temperature

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

Procedure: To a stirred solution of 7.50 g (32.0(mmol) 4-bromo-2-nitro-anisole in 200 ml dioxane were added 6.86 g (45.0 mmol) methyl-(tetrahydro-pyran-4-yl)-amine hydrochloride (1:1), 1.13 g (3.0 mmol) 2-(dicyclohexylphosphino)biphenyl, 14.75 g (45.0 mmol) cesium carbonate, and 360 mg (2.0 mmol) palladium (II) acetate. The mixture was heated at reflux for 72 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/2 hexane/ethyl acetate) afforded 1.59 g (18.5%) (4-methoxy-3-nitro-phenyl)-methyl-(tetrahydro-pyran-4-yl)-amine as a red solid. ES-MS m/e (%): 267 (M+H+, 100). The mixture was heated at reflux for 72 h poured onto water extracted three times with ethyl acetate The combined organic phases were dried over sodium sulfate concentrated in vacuo

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

Procedure: To a stirred solution of 7.50 g (32.0(mmol) 4-bromo-2-nitro-anisole in 200 ml dioxane were added 6.86 g (45.0 mmol) methyl-(tetrahydro-pyran-4-yl)-amine hydrochloride (1:1), 1.13 g (3.0 mmol) 2-(dicyclohexylphosphino)biphenyl, 14.75 g (45.0 mmol) cesium carbonate, and 360 mg (2.0 mmol) palladium (II) acetate. The mixture was heated at reflux for 72 h and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/2 hexane/ethyl acetate) afforded 1.59 g (18.5%) (4-methoxy-3-nitro-phenyl)-methyl-(tetrahydro-pyran-4-yl)-amine as a red solid. ES-MS m/e (%): 267 (M+H+, 100). The mixture was heated at reflux for 72 h poured onto water extracted three times with ethyl acetate The combined organic phases were dried over sodium sulfate concentrated in vacuo

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

Procedure: Benzyl 4-(hydroxymethyl)piperidine-1-carboxylate (2.14 g, 8.57 mmol) was dissolved in dichloromethane (26 mL), to which pyridine (1.04 mL, 12.9 mmol) and p-nitrophenyl chloroformate (2.07 g, 12.9 mmol) were added, followed by stirring at room temperature for 35 minutes under a nitrogen atmosphere. Subsequently, N-methyltetrahydro-2H-pyran-4-amine hydrochloride (1.30 g, 8.57 mmol) and triethylamine (3.59 mL, 25.7 mmol) were added, followed by further stirring for 4.5 hours. Water was added to the resulting reaction liquid, and the resulting mixture was extracted with dichloromethane. The resulting organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-50:50, V/V) to give the desired title compound (2.22 g, yield 66%). were added by further stirring for 4.5 hours the resulting mixture was extracted with dichloromethane The resulting organic layer was dried over sodium sulfate the solvent was distilled off under reduced pressure The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-50:50, V/V)

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

Procedure: Benzyl 4-(hydroxymethyl)piperidine-1-carboxylate (2.14 g, 8.57 mmol) was dissolved in dichloromethane (26 mL), to which pyridine (1.04 mL, 12.9 mmol) and p-nitrophenyl chloroformate (2.07 g, 12.9 mmol) were added, followed by stirring at room temperature for 35 minutes under a nitrogen atmosphere. Subsequently, N-methyltetrahydro-2H-pyran-4-amine hydrochloride (1.30 g, 8.57 mmol) and triethylamine (3.59 mL, 25.7 mmol) were added, followed by further stirring for 4.5 hours. Water was added to the resulting reaction liquid, and the resulting mixture was extracted with dichloromethane. The resulting organic layer was dried over sodium sulfate and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-50:50, V/V) to give the desired title compound (2.22 g, yield 66%). were added by further stirring for 4.5 hours the resulting mixture was extracted with dichloromethane The resulting organic layer was dried over sodium sulfate the solvent was distilled off under reduced pressure The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-50:50, V/V)

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

Procedure: Imidazole-1-sulfonic acid methyl-(tetrahydro-pyran-4-yl)-amide was prepared in accordance with step A of the general method described in example 76 from methyl-(tetrahydro-pyran-4-yl)amine hydrochloride and 3-(1H-imidazol-1-ylsulfonyl)-1-methyl-1H-imidazolium trifluoromethanesulfonate; MS: m/e=246.8 (M+H+).

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

Procedure: A solution of 0.100 g (0.20 mmol) of 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(4-iodo-butyl)-[1,4]diazepan-5-one (example 9B) in 3.1 ml of DMA was treated with free methyl-(tetrahydro-pyran-4-yl)-amine in 1 ml of toluene [0.035 g (0.22 mmol) methyl-(tetrahydro-pyran-4-yl)-amine hydrochloride were dissolved in 0.8 ml of 0.5 N NaOH was extracted with toluene (2 ml). The organic phase was dried over Na2SO4] and stirred for 22 h at RT, 0.06 ml (0.40 mmol) of Et3N was added and stirring was continued for 18 h at 50° C. Again methyl-(tetrahydro-pyran-4-yl)-amine in 1 ml of CH2Cl2 [0.035 g (0.22 mmol) methyl-(tetrahydro-pyran-4-yl)-amine hydrochloridewere dissolved in 0.5 ml aqueous 10% NaCl solution/0.4 ml of 1 N NaOH was extracted with CH2Cl2 (1 ml). The organic phase was dried over Na2SO4] was added and heated for 9 h at 50° C. The reaction was extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4), concentrated and evaporated. Purification by catridges, Si-Amine, 70 ml, 20 g (n-heptane/EtOAc 1:4 to 1:9) gave 0.004 g (4%) of the title compound as a light yellow semisolid. MS: 482.3 (MH+, 2Cl). was extracted with toluene (2 ml) The organic phase was dried over Na2SO4] and stirring was continued for 18 h at 50° C was extracted with CH2Cl2 (1 ml) The organic phase was dried over Na2SO4] was added heated for 9 h at 50° C The reaction was extracted with aqueous saturated NaHCO3/Et2O (3×) The organic phases were washed with aqueous 10% NaCl dried (Na2SO4) concentrated evaporated Purification by catridges, Si-Amine, 70 ml, 20 g (n-heptane/EtOAc 1:4 to 1:9)

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

Procedure: The title compound was prepared according to Preparation 23 from benzylmethyl(tetrahydropyran-4-yl)amine (Preparation 87). Crude material was dissolved in methanol and a solution of 1M HCl in ether was added dropwise to form a precipitate. The product was filtered and washed with ether to give the title compound as the hydrochloride salt as a white crystalline solid. δH (CD3OD): 4.11-4.00 (2H, m), 3.53-3.43 (2H, m), 3.37-3.27 (1H, m), 2.74 (3H, s), 2.11-2.03 (2H, m), 1.74-1.60 (2H, m). The title compound was prepared to form a precipitate The product was filtered washed with ether

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

Procedure: Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and methylamine hydrochloride with N-methyl-N-(tetrahydro-2H-pyran-4-yl)amine hydrochloride, the title compound was obtained. Proton NMR for the product was consistent with the titled compound. ESI+ MS: 416.2 [M+H]+.

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

Procedure: The title compound was prepared according to Preparation 23 from benzylmethyl(tetrahydropyran-4-yl)amine (Preparation 87). Crude material was dissolved in methanol and a solution of 1M HCl in ether was added dropwise to form a precipitate. The product was filtered and washed with ether to give the title compound as the hydrochloride salt as a white crystalline solid. δH (CD3OD): 4.11–4.00 (2H, m), 3.53–3.43 (2H, m), 3.37–3.27 (11H, m), 2.74 (3H, s), 2.11–2.03 (2H, m), 1.74–1.60 (2H, m). The title compound was prepared to form a precipitate The product was filtered washed with ether