3-(dimethylamino)benzaldehyde

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

Procedure: (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 3-dimethylamino-benzaldehyde (31.6 mg, 0.212 mmol) were combined with ammonium acetate (29.7 mg, 0.386 mmol) and heated in ethanol (2.5 mL) at 70° C. for 18 h. The reaction mixture was concentrated and chromatographed by reverse phase preparative HPLC. The desired fractions were neutralized with bicarb solution and extracted into EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. This residue was triturated in ethyl ether and filtered to yield 28 mg (37%) of the title compound. mp: 200-204° C., 1H NMR (300 MHz, DMSO-d6): 13.02 (s, 1H), 7.90 (d, 1H), 7.66 (s, 1H), 7.50 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.30 (t, J=8 Hz, 1H), 7.15 (s, 1H), 6.86 (m, 1H), 6.81 (d, J=8 Hz, 1H), 6.40 (d, J=5 Hz, 1H), 6.33 (s, 2H), 2.98 (s, 6H), 2.87 (s, 1H), 2.77 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). HPLC: 1.63 min (G method), MS: 389 (M+H). The reaction mixture was concentrated chromatographed by reverse phase preparative HPLC extracted into EtOAc The organic layer was dried over MgSO4 filtered concentrated This residue was triturated in ethyl ether filtered

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

Procedure: In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (1.30 mg, 0.386 mmol) and 3-(dimethylamino)benzaldehyde were reacted to produce 105 mg (58%) of the title compound. mp: 220-221° C., 1H NMR (300 MHz, DMSO-d6): 13.02 (s, 1H), 7.90 (d, 1H), 7.66 (s, 1H), 7.50 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.30 (t, J=8 Hz, 1H), 7.15 (s, 1H), 6.86 (m, 1H), 6.81 (d, J=8 Hz, 1H), 6.40 (d, J=5 Hz, 1H), 6.33 (s, 2H), 2.98 (s, 6H), 2.87 (s, 1H), 2.77 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). MS: 467, 469 (M+H), HPLC: 2.13 min (G method).

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

Procedure: In a similar fashion to Compound LXXVI, (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (1.30 mg, 0.386 mmol) and 3-(dimethylamino)benzaldehyde were reacted to produce 105 mg (58%) of the title compound. mp: 220-221° C., 1H NMR (300 MHz, DMSO-d6): 13.02 (s, 1H), 7.90 (d, 1H), 7.66 (s, 1H), 7.50 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.30 (t, J=8 Hz, 1H), 7.15 (s, 1H), 6.86 (m, 1H), 6.81 (d, J=8 Hz, 1H), 6.40 (d, J=5 Hz, 1H), 6.33 (s, 2H), 2.98 (s, 6H), 2.87 (s, 1H), 2.77 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). MS: 467, 469 (M+H), HPLC: 2.13 min (G method).

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

Procedure: In the same fashion as for Compound III, (1R,2R,3S,4S)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-Dimethylamino-benzaldehyde were reacted to produce the title compound (58%). 1H NMR (d-chloroform): 16.03 (br s, 1H), 8.36 (d, J=9 Hz, 1H), 7.82 (s, 1H), 7.74 (s, 1H), 7.61 (d, J=9 Hz, 1H), 7.45 (t, J=8 Hz, 1H), 7.09 (t, J=8 Hz, 1H), 6.50 (m, 1H), 6.42 (m, 1H), 6.04 (m, 1H), 5.69 (m, 1H), 5.37 (t, J=7 Hz, 1H), 3.17 (s, 1H), 3.13 (s, 6H), 3.04 (s, 1H), 2.71 (d, J=9 Hz, 1H), 2.33 (d, J=9 Hz, 1H), 1.68 (d, J=9 Hz, 1H). MS: 423.15 (M+H). HPLC retention time: 2.05 minutes (G Method).

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

Procedure: In the same fashion as for Compound III, (1R,2R,3S,4S)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-Dimethylamino-benzaldehyde were reacted to produce the title compound (58%). 1H NMR (d-chloroform): 16.03 (br s, 1H), 8.36 (d, J=9 Hz, 1H), 7.82 (s, 1H), 7.74 (s, 1H), 7.61 (d, J=9 Hz, 1H), 7.45 (t, J=8 Hz, 1H), 7.09 (t, J=8 Hz, 1H), 6.50 (m, 1H), 6.42 (m, 1H), 6.04 (m, 1H), 5.69 (m, 1H), 5.37 (t, J=7 Hz, 1H), 3.17 (s, 1H), 3.13 (s, 6H), 3.04 (s, 1H), 2.71 (d, J=9 Hz, 1H), 2.33 (d, J=9 Hz, 1H), 1.68 (d, J=9 Hz, 1H). MS: 423.15 (M+H). HPLC retention time: 2.05 minutes (G Method).

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

Procedure: In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-Dimethylamino-benzaldehyde were reacted to produce the title compound (86%). 1H NMR (d-chloroform): 16.5 (br s, 1H), 8.37 (d, J=8 Hz, 1H), 7.83 (s, 1H), 7.72 (s, 1H), 7.61 (d, J=8 Hz, 1H), 7.45 (t, J=8 Hz, 1H), 7.06 (dd, J=2.8 Hz, 1H), 6.51 (m, 1H), 6.42 (m, 1H), 5.98 (m, 1H), 5.62 (m, 1H), 5.38 (t, J=8 Hz, 1H), 3.17 (s, 1H), 3.13 (s, 6H), 3.06 (s, 1H), 2.71 (d, J=8 Hz, 1H), 2.33 (d, J=8 Hz, 1H), 1.68 (d, J=8 Hz, 1H). MS: 424.04 (M+H). HPLC retention time: 2.06 minutes (G Method).

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

Procedure: In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 3-Dimethylamino-benzaldehyde were reacted to produce the title compound (86%). 1H NMR (d-chloroform): 16.5 (br s, 1H), 8.37 (d, J=8 Hz, 1H), 7.83 (s, 1H), 7.72 (s, 1H), 7.61 (d, J=8 Hz, 1H), 7.45 (t, J=8 Hz, 1H), 7.06 (dd, J=2.8 Hz, 1H), 6.51 (m, 1H), 6.42 (m, 1H), 5.98 (m, 1H), 5.62 (m, 1H), 5.38 (t, J=8 Hz, 1H), 3.17 (s, 1H), 3.13 (s, 6H), 3.06 (s, 1H), 2.71 (d, J=8 Hz, 1H), 2.33 (d, J=8 Hz, 1H), 1.68 (d, J=8 Hz, 1H). MS: 424.04 (M+H). HPLC retention time: 2.06 minutes (G Method).

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

Procedure: The same installation as in Example 1 is used. Using a similar method to Example 1, a mixture of 320 parts of m-dimethylaminobenzyl alcohol and 50 parts of water with 300 parts of air is passed per hour over the catalyst at 530° C. and 1.2 bar. The residence time is 0.035 second and the throughput 0.45 tonne/m2.h. 228 parts of m-dimethylaminobenzaldehyde (in the form of an 88 percent strength by weight organic phase) are obtained per hour, corresponding to a yield of 72% of theory. The conversion is 94 percent and the space-time yield is 11 grams of m-dimethylaminobenzaldehyde per cm3 of catalyst volume per hour. is passed per hour over the catalyst at 530° C.

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

Procedure: The same installation as in Example 1 is used. Using a similar method to Example 1, a mixture of 320 parts of m-dimethylaminobenzyl alcohol and 50 parts of water with 300 parts of air is passed per hour over the catalyst at 530° C. and 1.2 bar. The residence time is 0.035 second and the throughput 0.45 tonne/m2.h. 228 parts of m-dimethylaminobenzaldehyde (in the form of an 88 percent strength by weight organic phase) are obtained per hour, corresponding to a yield of 72% of theory. The conversion is 94 percent and the space-time yield is 11 grams of m-dimethylaminobenzaldehyde per cm3 of catalyst volume per hour. is passed per hour over the catalyst at 530° C.

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

Procedure: Prepared by Procedure F and Scheme R using 3-(dimethylamino)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 380.2 (M+H)+. Prepared by Procedure F and Scheme R

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

Procedure: Prepared by Procedure F and Scheme R using 3-(dimethylamino)benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 380.2 (M+H)+. Prepared by Procedure F and Scheme R

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

Procedure: (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 3-dimethylamino-benzaldehyde (31.6 mg, 0.212 mmol) were combined with ammonium acetate (29.7 mg, 0.386 mmol) and heated in ethanol (2.5 mL) at 70° C. for 18 h. The reaction mixture was concentrated and chromatographed by reverse phase preparative HPLC. The desired fractions were neutralized with bicarb solution and extracted into EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. This residue was triturated in ethyl ether and filtered to yield 28 mg (37%) of the title compound. mp: 200-204° C., 1H NMR (300 MHz, DMSO-d6): 13.02 (s, 1H), 7.90 (d, 1H), 7.66 (s, 1H), 7.50 (s, 1H), 7.47 (d, J=8 Hz, 1H), 7.30 (t, J=8 Hz, 1H), 7.15 (s, 1H), 6.86 (m, 1H), 6.81 (d, J=8 Hz, 1H), 6.40 (d, J=5 Hz, 1H), 6.33 (s, 2H), 2.98 (s, 6H), 2.87 (s, 1H), 2.77 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). HPLC: 1.63 min (G method), MS: 389 (M+H). The reaction mixture was concentrated chromatographed by reverse phase preparative HPLC extracted into EtOAc The organic layer was dried over MgSO4 filtered concentrated This residue was triturated in ethyl ether filtered