tert-butyl N-[(2-aminophenyl)methyl]carbamate

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

Procedure: Following a procedure analogous to Example 1783c, 2-nitro-benzylamine was converted to 2-nitro-benzyl-carbamic acid tert-butyl ester, which following a procedure analogous to Example 1791b was converted to 2-amino-benzyl-carbamic acid tert-butyl ester. Following a procedure analogous to Example 1751b, 2-amino-benzyl-carbamic acid tert-butyl ester was converted to [2-(2,5-dichloro-pyrimidin-4-ylamino)-benzyl]-carbamic acid tert-butyl ester, which following a procedure analogous to Example 1773c was converted to N-(2-(aminomethyl)phenyl)-2,5-dichloropyrimidin-4-amine. Following a procedure analogous to Example 1792a, N-(2-(aminomethyl)phenyl)-2,5-dichloropyrimidin-4-amine was converted to N-(2-(2,5-dichloropyrimidin-4-ylamino)benzyl)acetamide, which following a procedure analogous to Example 1741e was converted to N-{2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-benzyl}-acetamide. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.12 (s, 1H), 7.4 (m, 4H), 7.32 (d, 1H), 7.20 (dd, 1H), 7.10 (d, 1H), 4.3 (m, 4H), 3.3 (s, 3H), 2.76 (t, 2H), 1.89 (s, 3H); MS (m/e) 467 (M+1).

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

Procedure: Following a procedure analogous to Example 1783c, 2-nitro-benzylamine was converted to 2-nitro-benzyl-carbamic acid tert-butyl ester, which following a procedure analogous to Example 1791b was converted to 2-amino-benzyl-carbamic acid tert-butyl ester. Following a procedure analogous to Example 1751b, 2-amino-benzyl-carbamic acid tert-butyl ester was converted to [2-(2,5-dichloro-pyrimidin-4-ylamino)-benzyl]-carbamic acid tert-butyl ester, which following a procedure analogous to Example 1773c was converted to N-(2-(aminomethyl)phenyl)-2,5-dichloropyrimidin-4-amine. Following a procedure analogous to Example 1792a, N-(2-(aminomethyl)phenyl)-2,5-dichloropyrimidin-4-amine was converted to N-(2-(2,5-dichloropyrimidin-4-ylamino)benzyl)acetamide, which following a procedure analogous to Example 1741e was converted to N-{2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-benzyl}-acetamide. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.12 (s, 1H), 7.4 (m, 4H), 7.32 (d, 1H), 7.20 (dd, 1H), 7.10 (d, 1H), 4.3 (m, 4H), 3.3 (s, 3H), 2.76 (t, 2H), 1.89 (s, 3H); MS (m/e) 467 (M+1).

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

Procedure: A mixture of 15.5 g of 2-(tert-butoxycarbonylaminomethyl)aniline, 15 g of N-t-butyloxycarbonyl-4-piperidone, 250 mL of 1,2-dichloroethane, 4.2 mL of glacial acetic acid and 25 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 500 mL chloroform and 500 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×250 mL of chloroform and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Drying overnight under vacuum gave 30.1 g of tert-butyl (2-(tert-butoxycarbonylaminomethyl)anilino)piperidine carboxylate as a solid: 1H NMR (400 MHz, CDCl3) 7.19 (t, 1H), 7.0 (d, 1H), 6.6 (dd, 2H), 4.94 (br s, 1H), 4.75 (br s, 1H), 4.23 (br m, 2H), 4.0 (br m, 2H), 3.45 (br m, 1H), 3.0 (br m, 2H), 2.0 (br m, 2H), 1.82 (br m, 1H), 1.46 (s, 9H), 1.44 (s, 9H). the layers separated The aqueous layer was extracted with 2×250 mL of chloroform the combined organic layers dried over MgSO4 concentrated under reduced pressure Drying overnight under vacuum

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

Procedure: 2-Aminobenzylamine (5.0 g, 40.9 mmol) and triethylamine (4.1 g, 40.9 mmol) were dissolved in a mixed solvent (50 ml) of dioxane-water (2:1). A dioxane solution (8.9 g/10 ml) of di-t-butyl carbonate was added dropwise to the solution under cooling with ice water. The mixture was stirred for 2 hours as it was. After the reaction mixture was diluted with ethyl acetate, an aqueous phase was removed, and an organic phase was washed 3 times with water and once with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was crystallized from diisopropyl ether-hexane to obtain 6.70 g of the title compound. an aqueous phase was removed an organic phase was washed 3 times with water once with saturated brine, and dried over anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the residue was crystallized from diisopropyl ether-hexane

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

Procedure: Following a procedure analogous to Example 1783c, 2-nitro-benzylamine was converted to 2-nitro-benzyl-carbamic acid tert-butyl ester, which following a procedure analogous to Example 1791b was converted to 2-amino-benzyl-carbamic acid tert-butyl ester. Following a procedure analogous to Example 1751b, 2-amino-benzyl-carbamic acid tert-butyl ester was converted to [2-(2,5-dichloro-pyrimidin-4-ylamino)-benzyl]-carbamic acid tert-butyl ester, which following a procedure analogous to Example 1773c was converted to N-(2-(aminomethyl)phenyl)-2,5-dichloropyrimidin-4-amine. Following a procedure analogous to Example 1792a, N-(2-(aminomethyl)phenyl)-2,5-dichloropyrimidin-4-amine was converted to N-(2-(2,5-dichloropyrimidin-4-ylamino)benzyl)acetamide, which following a procedure analogous to Example 1741e was converted to N-{2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-benzyl}-acetamide. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.12 (s, 1H), 7.4 (m, 4H), 7.32 (d, 1H), 7.20 (dd, 1H), 7.10 (d, 1H), 4.3 (m, 4H), 3.3 (s, 3H), 2.76 (t, 2H), 1.89 (s, 3H); MS (m/e) 467 (M+1).

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

Procedure: To a solution of (2-amino-benzyl)-carbamic acid tert-butyl ester [prepared from 2-aminobenzylamine and di-tert-butyl dicarbonate], (100 mg, 0.45 mmol) in acetic acid (2.46 mL), was added water (26 mL). Reaction mixture was cooled to 0° C. and a solution of sodium nitrite (62 mg, 0.9 mmol) in water (4.3 ml) was added. The reaction mixture was stirred for 30 min at the same temperature followed by addition of sodium azide (64 mg, 0.99 mmol). The reaction mixture was stirred at 0° C. for 30 min. When the reaction was complete as confirmed by TLC, reaction mixture was quenched by dropwise addition of 10 N NaOH (5.0 mL). The crude compound was extracted with ethylacetate (2×10 mL). Organic layer was separated, washed with brine, dried over Na2SO4 and the solvents were removed in vacuo to afford (2-azido-benzyl)-carbamic acid tert-butyl ester (105 mg, 96%) which was used as such without any further purification for the next step. Reaction mixture The reaction mixture was stirred at 0° C. for 30 min as confirmed by TLC, reaction mixture was quenched by dropwise addition of 10 N NaOH (5.0 mL) The crude compound was extracted with ethylacetate (2×10 mL) Organic layer was separated washed with brine dried over Na2SO4 the solvents were removed in vacuo

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

Procedure: Following a procedure analogous to Example 1783c, 2-nitro-benzylamine was converted to 2-nitro-benzyl-carbamic acid tert-butyl ester, which following a procedure analogous to Example 1791b was converted to 2-amino-benzyl-carbamic acid tert-butyl ester. Following a procedure analogous to Example 1751b, 2-amino-benzyl-carbamic acid tert-butyl ester was converted to [2-(2,5-dichloro-pyrimidin-4-ylamino)-benzyl]-carbamic acid tert-butyl ester, which following a procedure analogous to Example 1773c was converted to N-(2-(aminomethyl)phenyl)-2,5-dichloropyrimidin-4-amine. Following a procedure analogous to Example 1792a, N-(2-(aminomethyl)phenyl)-2,5-dichloropyrimidin-4-amine was converted to N-(2-(2,5-dichloropyrimidin-4-ylamino)benzyl)acetamide, which following a procedure analogous to Example 1741e was converted to N-{2-[5-chloro-2-(5-methyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-benzyl}-acetamide. TFA salt: 1H NMR (300 MHz, CD3OD) δ 8.12 (s, 1H), 7.4 (m, 4H), 7.32 (d, 1H), 7.20 (dd, 1H), 7.10 (d, 1H), 4.3 (m, 4H), 3.3 (s, 3H), 2.76 (t, 2H), 1.89 (s, 3H); MS (m/e) 467 (M+1).