isocyanocyclopentane

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

Procedure: 10 μl (0.022 mmol) of 20% aq. perchloric acid, a solution of 31.8 mg (0.15 mmol) of 5-phenylethynyl-thiophene-2-carbaldehyde in a mixture of MeOH and DCM (0.5 ml, 1:1 vol/vol) and a solution of 11.1 mg (0.115 mmol) of cyclopentyl isocyanide in MeOH (0.5 ml) were added in succession to a solution of 9.5 mg (0.1 mmol) of 2-aminopyrazine in MeOH (1 ml). The reaction solution was stirred at RT for 36 h and then combined with sat. aq. NaCl solution (3 ml) and stirred at RT for a further 45 min. The phases were separated and the aq. phase was extracted with DCM (2×3 ml). The collected organic phases were dried over MgSO4, filtered and evaporated under a vacuum. The group was purified by means of preparative HPLC, wherein 18 mg (0.047 mmol, 47%) of cyclopentyl-[2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-amine were obtained. stirred at RT for a further 45 min The phases were separated the aq. phase was extracted with DCM (2×3 ml) The collected organic phases were dried over MgSO4 filtered evaporated under a vacuum The group was purified by means of preparative HPLC

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

Procedure: 3-Imidazol-1-yl-propylamine (1 mmol) and 3,4-Dihydro-2H-pyran-2-carbaldehyde (1 mmol) were combined in methanol (2 ml, dry). After 2 hours Trimethylsilylazide (5 mmol) and Isocyano-cyclopentan (1 mmol) was added. The reaction was stirred at room temperature for 48 h. After evaporation of the solvent the residue was purified with chromatographic methods. After evaporation of the solvent the residue was purified with chromatographic methods

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

Procedure: 10 μl (0.022 mmol) of 20% aq. perchloric acid, a solution of 31.8 mg (0.15 mmol) of 5-phenylethynyl-thiophene-2-carbaldehyde in a mixture of MeOH and DCM (0.5 ml, 1:1 vol/vol) and a solution of 11.1 mg (0.115 mmol) of cyclopentyl isocyanide in MeOH (0.5 ml) were added in succession to a solution of 9.5 mg (0.1 mmol) of 2-aminopyrazine in MeOH (1 ml). The reaction solution was stirred at RT for 36 h and then combined with sat. aq. NaCl solution (3 ml) and stirred at RT for a further 45 min. The phases were separated and the aq. phase was extracted with DCM (2×3 ml). The collected organic phases were dried over MgSO4, filtered and evaporated under a vacuum. The group was purified by means of preparative HPLC, wherein 18 mg (0.047 mmol, 47%) of cyclopentyl-[2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-amine were obtained. stirred at RT for a further 45 min The phases were separated the aq. phase was extracted with DCM (2×3 ml) The collected organic phases were dried over MgSO4 filtered evaporated under a vacuum The group was purified by means of preparative HPLC

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

Procedure: 3-Imidazol-1-yl-propylamine (1 mmol) and 3,4-Dihydro-2H-pyran-2-carbaldehyde (1 mmol) were combined in methanol (2 ml, dry). After 2 hours Trimethylsilylazide (5 mmol) and Isocyano-cyclopentan (1 mmol) was added. The reaction was stirred at room temperature for 48 h. After evaporation of the solvent the residue was purified with chromatographic methods. After evaporation of the solvent the residue was purified with chromatographic methods

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

Procedure: 1H-Benzoimidazol-5-ylamine (1 mmol) and 1H-Indole-5-carbaldehyde (1 mmol) were combined in methanol (2 ml, dry). After 2 hours 2 ml of a solution of KOCN (KSCN) (2 mmol) and Pyridinehydrochloride (2 mmol) in MeOH is added was added. Finally Isocyano-cyclopentane (1 mmol) is added. The reaction was stirred at room temperature for 48 h. After evaporation of the solvent the residue was purified with chromatographic methods. Yield: 0.107 g (27%); mp: 210° C., 1H-NMR (400 MHz, DMSO-D6): 1.20-1.25 (m, 1H, CH2), 1.38-1.56 (m, 5H, CH2), 1.70-1.79 (m, 1H, CH2), 1.82-1.90 (m, 1H, CH2), 4.08-4.14 (m, 1H, CH2—CH), 5.91 (s, 1H, CH—N), 6.33-6.36 (m, 1H, Ar), 6.85 (dd, 3J=8.3 Hz, 4J=1.7 Hz, 1H, Ar), 7.24-7.33 (m, 4H, 3H Ar, 1H Benzimid), 7.52 (s, 1H, Benzimid), 7.63 (s, 1H, Benzimid), 7.86 (m, 1H, NH), 8.06 (s, 1H, Benzimid), 11.05 (s, 1H, NH), MS m/z 399.4 (M+H)+, HPLC (254 nm): rt 2.56 min (100%), calc: C, 69.33; H, 5.57; N, 21.09. found.: C, 63.34; H, 6.16; N, 19.04 corresponds to C23H22N6O+2.0H2O was added After evaporation of the solvent the residue was purified with chromatographic methods rt 2.56 min (100%)

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

Procedure: 1H-Benzoimidazol-5-ylamine (1 mmol) and 4-Chlorobenzaldehyde (1 mmol) were combined in methanol (2 ml, dry). After 2 hours 2 ml of a solution of KOCN (KSCN) (2 mmol) and Pyridinehydrochloride (2 mmol) in MeOH is added was added. Finally 3-Isocyano-cyclopentane (1 mmol) is added. The reaction was stirred at room temperature for 48 h. After evaporation of the solvent the residue was purified with chromatographic methods. was added After evaporation of the solvent the residue was purified with chromatographic methods

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

Procedure: To a clear light brown solution of 3,4,5-trimethoxybenzaldehyde (600 mg, 3.06 mmol) and 5-amino-1H-pyrazole-4-carbonitrile (331 mg, 3.06 mmol) in methanol (10 mL) in a 20 mL vial were added cyclopentyl isonitrile (294 mg, 342 μL, 3.06 mmol) and perchloric acid (61.4 mg, 54.9 μL, 0.612 mmol) at RT under nitrogen atmosphere. Then, the nitrogen line was disconnected and the resulting brown suspension was stirred for 15 h at RT. The off-white solids were collected by filtration and washed with methanol. After drying in the air, 375 mg (32%) of 3-(cyclopentylamino)-2-(3,4,5-trimethoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile was isolated as an off-white solid. LC/MS calcd. for C20H23N5O3 (m/e) 381.434, obsd. 382.0 (M+H, ES+). The off-white solids were collected by filtration washed with methanol After drying in the air

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

Procedure: To a mixture of 5-amino-1H-pyrazole-4-carbonitrile (193 mg, 1.79 mmol) and 4-(benzyloxy)-2-methoxybenzaldehyde (433 mg, 1.79 mmol) in a vial under nitrogen atmosphere were added methanol (10 mL) followed by cyclopentyl isonitrile (172 mg, 200 μL, 1.79 mmol) and perchloric acid (35.9 mg, 32.1 μL, 0.358 mmol) at RT. Then, the resulting brown solution was stirred for 15 h by which time lot of solids precipitated. These solids were collected by filtration and washed with methanol. After air drying, 320 mg of (42%) 2-(4-benzyloxy-2-methoxyphenyl)-3-(cyclopentylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile, the desired product was isolated as a white solid. LC/MS calcd. for C25H25N5O2 (m/e) 427.5, obsd. 428.1 (M+H, ES+). precipitated These solids were collected by filtration washed with methanol After air drying

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

Procedure: To a mixture of 5-amino-1H-pyrazole-4-carbonitrile (193 mg, 1.79 mmol) and 6-methoxy-2,3-dihydro-1H-indene-5-carbaldehyde (315 mg, 1.79 mmol) in a vial under nitrogen atmosphere were added methanol (10 mL) followed by cyclopentyl isonitrile (172 mg, 200 μL, 1.79 mmol) and perchloric acid (35.9 mg, 32.1 μL, 0.358 mmol) at RT. Then, the resulting light yellow suspension was stirred for 15 h and the resulting solids were collected by filtration and washed with methanol. After air drying, 55 mg (8.5% yield) of 3-(cyclopentylamino)-2-(6-methoxy-2,3-dihydro-1H-inden-5-yl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile was isolated as an off-white solid. LC/MS calcd. for C21H23N5O (m/e) 361.44, obsd. 362.1 (M+H, ES+). the resulting solids were collected by filtration washed with methanol After air drying

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

Procedure: To a clear solution of 3-methoxy-2-naphthaldehyde (484 mg, 2.6 mmol) and 5-amino-1H-pyrazole-4-carbonitrile (281 mg, 2.6 mmol) in methanol (5 mL) were added cyclopentyl isonitrile (250 mg, 291 μL, 2.6 mmol) followed by perchloric acid (26.1 mg, 23.3 μL, 260 μmol) at RT under nitrogen atmosphere. The resulting dark brown solution was stirred for 15 h at RT by which time LC/MS analysis indicated the presence of the desired peak. There are no solids formed after dilution with diethyl ether. Then, the solvent was removed under vacuum. The brown solid residue was dissolved in minimum methanol and then it was diluted with diethyl ether. The resulting solution was stored in the refrigerator for 15 h, but there were no solids formed. Then, the solvent was removed under vacuum and the brown residue was purified using an ISCO (80 g) column chromatography eluting with 0-50% ethyl acetate in hexanes. The desired fractions were combined and the solvent was removed under vacuum to obtain 416 mg (43% yield) of 3-(cyclopentylamino)-2-(3-methoxynaphthalen-2-yl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile as an off-white solid. LC/MS calcd. for C22H21N5O (m/e) 371.44, obsd. 372.0 (M+H, ES+). Then, the solvent was removed under vacuum The brown solid residue was dissolved in minimum methanol it was diluted with diethyl ether The resulting solution was stored in the refrigerator for 15 h formed Then, the solvent was removed under vacuum the brown residue was purified eluting with 0-50% ethyl acetate in hexanes the solvent was removed under vacuum

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

Procedure: To a clear light brown solution of 2,4,5-trimethoxybenzaldehyde (600 mg, 3.06 mmol) and 5-amino-1H-pyrazole-4-carbonitrile (331 mg, 3.06 mmol) in methanol (10 mL) in a 20 mL vial were added cyclopentyl isonitrile (294 mg, 342 μL, 3.06 mmol) and perchloric acid (61.4 mg, 54.9 μL, 0.612 mmol) at RT under nitrogen atmosphere. Then, the nitrogen line was disconnected and the resulting dark brown solution slowly became a suspension within few hours which was then stirred for 15 h at RT. The off-white solids were collected by filtration and washed with methanol and the solids were not the desired product. The filtrate was removed under vacuum and the resulting residue was purified using an ISCO (120 g) column chromatography eluting with 0-60% ethyl acetate in hexanes. The desired fractions were combined and the solvent was removed under vacuum to isolate 165 mg (14% yield) of 3-(cyclopentylamino)-2-(2,4,5-trimethoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile as a dark brown solid. LC/MS calcd. for C20H23N5O3 (m/e) 381.434, obsd. 382.1 (M+H, ES+). The off-white solids were collected by filtration washed with methanol The filtrate was removed under vacuum the resulting residue was purified eluting with 0-60% ethyl acetate in hexanes the solvent was removed under vacuum

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

Procedure: To a clear light yellow solution of 2-fluoro-4-methoxybenzaldehyde (802 mg, 5.2 mmol) and 5-amino-1H-pyrazole-4-carbonitrile (562 mg, 5.2 mmol) in methanol (20 mL) were added a neat cyclopentyl isonitrile (500 mg, 5.2 mmol) and perchloric acid (104 mg, 93.3 μL, 1.04 mmol) at RT under nitrogen atmosphere. Lots of brown solids were precipitated within 1 h and the resulting suspension was stirred for 15 h. After 15 h, it became a dark brown solution without any solids. Then, the solvent was removed under vacuum and the residue was purified using an ISCO (120 g) column chromatography eluting with 0-50% EA in hexanes. The desired fractions were combined and the solvent was removed under vacuum to obtain 203 mg (11.5% yield) of 3-(cyclopentylamino)-2-(2-fluoro-4-methoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile as an yellow solid. LC/MS calcd. for C18H18FN5O (m/e) 339.37, obsd. 340.2 (M+H, ES+). Lots of brown solids were precipitated within 1 h After 15 h Then, the solvent was removed under vacuum the residue was purified eluting with 0-50% EA in hexanes the solvent was removed under vacuum