diphenoxymethylidenecyanamide

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

Procedure: To a solution (S)-5-amino-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentyl 6-fluoroisoquinolin-3-ylcarbamate (190 mg, 0.35 mmol) and diphenyl cyanocarbonimidate (83 mg, 0.35 mmol) in DCM (10.0 mL) was added DIEA (0.12 mL, 0.70 mmol). The reaction mixture was stirred at RT for 4 h. The mixture was concentrated under reduced pressure to give (S,Z)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-((cyanoimino)(phenoxy)methylamino)pentyl 6-fluoroisoquinolin-3-ylcarbamate, which was used without further purification. LRMS (M+H+) m/z 650.2. The mixture was concentrated under reduced pressure

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

Procedure: [6-(3-Amino-prop-1-ynyl)-quinazolin-4-yl]-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (280 mg, 0.663 mmol) is treated with diphenyl cyanocarbonimidate (163 mg, 1.031 equiv.) in a mixture of i-PrOH (12 ml) and THF (4 ml). Stir mixture overnight, then concentrate to dryness and chromatograph on silica (EtOAc/hexanes) to obtain 186.3 mg (49.6%) of pure desired product. concentrate to dryness and chromatograph on silica (EtOAc/hexanes)

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

Procedure: Diphenylcyanocarbonimidate (1.1 equiv) and 4-(2-(pyrrolidin-1-yl)ethoxy)aniline (1 equiv) were stirred in iso-propyl alcohol at ambient temperature overnight. The resulting white precipitate was filtered and washed with iso-propyl alcohol and dried to yield (Z)-phenyl N′-cyano-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)carbamimidate. 3-Hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (82 mg, 0.36 mMol) and (Z)-phenyl N′-cyano-N-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)carbamimidate (128 mg, 0.36 mMol) were suspended in isopropanol (3 mL) and subjected to microwave irradiation (150° C., 20 min). The precipitate which formed in the microwave vial was re-dissolved in hot isopropanol. The mixture was cooled to ambient temperature and then filtered to give 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N3-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine, compound #1, as a yellow solid, 23 mg. 1H NMR (CDCl3, 300 MHz) 7.90 (s, 1H), 7.83 (t, 1H), 7.43 (m, 3H), 7.29 (t, 1H), 6.93 (d, 1H), 6.83 (br s, 2H), 6.39 (s, 1H), 4.17 (m, 2H), 2.98 (m, 2H), 2.60-2.80 (m, 8H), 2.32 (m, 2H), 1.87 (m, 4H) ppm; MS (ES) 483.16 (M+H). The resulting white precipitate was filtered washed with iso-propyl alcohol dried

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

Procedure: m-Anisidine (4.56 mL, 4.06 mmol, 1 eq.), and diphenylcyanocarbonimidate (967 mg, 4.06 mmol, 1 eq.) were mixed and refluxed in acetonitrile under N2 for 1 hour. Solids precipitated. The reaction was worked up by filtering off the solids. Obtained 580 mg as product. M.P.=170.0-171.0° C. NMR (300 MHz, DMSO-d6) δ 8.70-8.50 (m, 1H); 7.43 (t, 2H, J=7 Hz); 7.40-7.20 (m, 2H); 7.14 (d, 2H, J=7 Hz); 7.00-6.80 (m, 2H); 6.80-6.70 (m, 1H); 3.80 (s, 3H). Solids precipitated by filtering off the solids Obtained 580 mg as product

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(3-Bromo-8-chloro-6,11-dihydro-5 H-benzo[5,6]-cyclohepta[1,2-b] pyridin-11-yl)-4-[(4-piperidinyl)acetyl]-piperazine (Formula 47.0) (prepared as described in Preparative Example 11) (2.5 g) (1 equivalent) and diphenylcyanocarbon-imidate (1.38 g) (1.2 equivalents) were dissolved in 2-propanol (65 ml) and the solution was heated at 80° C. under reflux and under nitrogen for 24 h. The mixture was evaporated to dryness and the product was chromatographed on a silica gel column (60×2.5 cm) using neat ethyl acetate as the eluant to give the title compound (Formula 2.0) (2.7921 g; 87%), FABMS: m/z 661 (MH+). under reflux and under nitrogen for 24 h The mixture was evaporated to dryness the product was chromatographed on a silica gel column (60×2.5 cm)

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

Procedure: A solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-ethylazepan-2-one (135 mg, 0.503 mmol) in dichloromethane was treated N,N-diisopropylethylamine (65 mg, 0.503 mmol) and diphenyl N-cyanocarbonimidate (204 mg, 0.855 mmol). After 5 h, the reaction was quenched with 0.5N NaOH and the organic layer washed with water and brine. The combined aqueous layers were extracted with EtOAc. The combined organics were dried, filtered and concentrated. Purification by silica gel chromatography (EtOAc/hexanes) gave the title compound (166 mg). MS 413.3 (M+1). the reaction was quenched with 0.5N NaOH the organic layer washed with water and brine The combined aqueous layers were extracted with EtOAc The combined organics were dried filtered concentrated Purification by silica gel chromatography (EtOAc/hexanes)

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

Procedure: A solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-ethylazepan-2-one (135 mg, 0.503 mmol) in dichloromethane was treated N,N-diisopropylethylamine (65 mg, 0.503 mmol) and diphenyl N-cyanocarbonimidate (204 mg, 0.855 mmol). After 5 h, the reaction was quenched with 0.5N NaOH and the organic layer washed with water and brine. The combined aqueous layers were extracted with EtOAc. The combined organics were dried, filtered and concentrated. Purification by silica gel chromatography (EtOAc/hexanes) gave the title compound (166 mg). MS 413.3 (M+1). the reaction was quenched with 0.5N NaOH the organic layer washed with water and brine The combined aqueous layers were extracted with EtOAc The combined organics were dried filtered concentrated Purification by silica gel chromatography (EtOAc/hexanes)

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

Procedure: CHART B, Step B-1. To a solution of 3-azido-5-iodoaniline (A-4, 2.42 g, 9.31 mmol) in chloroform (8 mL) is added diphenyl cyanocarbonimidate (2.21g, 9.31 mmol). The solvent is allowed to evaporate at a temperature of 70° C. overnight. The resulting solid is washed with ether, filtered and dried to afford 3.558 g of N-(3-azido-5-iodophenyl)-N'-cyanocarbamimidic acid, phenyl ester (B-1) which is used without further purification. A small analytical sample is recrystallized from ethyl acetate in hexane. Mp=195° C. (dec). IR (mull) 3094, 3078, 2954, 2925, 2867, 2854, 2208, 2121, 2106, 1652, 1600, 1590, 1565, 1504, 1491, 1446, 1433, 1401, 1302, 1219, 1195, 833 cm -1 ; 1H NMR (DMSO) δ10.57 (bs (1 H), 7.50 (t, 1 H, J=2 Hz), 7.28 (m, 2 H), 7.10 (m, 5 H); 13C NMR (DMSO) δ151.4, 141.3, 138.6, 129.9, 128.2, 126.4, 124.6, 120.8, 113.6, 95.0; Mass Spec (70eV, EI) m/z 404 (parent), 376, 249 (base), 222, 207, 194, 155, 145, 128, 118, 103, 94, 77, 65, 51; Exact mass calculated for C14H9IN6O: 403.9884. Found: 403.9877. Melt solvate: 3.6% ethyl acetate; Analysis calculated for C14H9IN6O plus 3.6% C4H8O2 : C, 42.07; H, 2.49; N, 20.04; Found; C, 41.95; H, 2.25; N, 19.76. to evaporate at a temperature of 70° C. overnight The resulting solid is washed with ether filtered dried

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

Procedure: CHART B, Step B-1. To a solution of 3-azido-5-iodoaniline (A-4, 2.42 g, 9.31 mmol) in chloroform (8 mL) is added diphenyl cyanocarbonimidate (2.21g, 9.31 mmol). The solvent is allowed to evaporate at a temperature of 70° C. overnight. The resulting solid is washed with ether, filtered and dried to afford 3.558 g of N-(3-azido-5-iodophenyl)-N'-cyanocarbamimidic acid, phenyl ester (B-1) which is used without further purification. A small analytical sample is recrystallized from ethyl acetate in hexane. Mp=195° C. (dec). IR (mull) 3094, 3078, 2954, 2925, 2867, 2854, 2208, 2121, 2106, 1652, 1600, 1590, 1565, 1504, 1491, 1446, 1433, 1401, 1302, 1219, 1195, 833 cm -1 ; 1H NMR (DMSO) δ10.57 (bs (1 H), 7.50 (t, 1 H, J=2 Hz), 7.28 (m, 2 H), 7.10 (m, 5 H); 13C NMR (DMSO) δ151.4, 141.3, 138.6, 129.9, 128.2, 126.4, 124.6, 120.8, 113.6, 95.0; Mass Spec (70eV, EI) m/z 404 (parent), 376, 249 (base), 222, 207, 194, 155, 145, 128, 118, 103, 94, 77, 65, 51; Exact mass calculated for C14H9IN6O: 403.9884. Found: 403.9877. Melt solvate: 3.6% ethyl acetate; Analysis calculated for C14H9IN6O plus 3.6% C4H8O2 : C, 42.07; H, 2.49; N, 20.04; Found; C, 41.95; H, 2.25; N, 19.76. to evaporate at a temperature of 70° C. overnight The resulting solid is washed with ether filtered dried

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

Procedure: Chart B, Step B-1. To a stirred solution of 3-azido-5-chloroaniline (A-4, 0.706 g, 4.18 mmol) in 6 mL of chloroform, is added diphenyl cyanocarbonimidate (0.997 g, 4.18 mmol). The solvent is allowed to evaporate at a temperature of 75° C. overnight. The resulting solid is triturated with ether and filtered. The solid is recrystallized from ethyl acetate/hexane to afford 0.808 g of N-(3-azido-5-chlorophenyl)-N'-cyanocarbamimidic acid, phenyl ester. (B-1) Mp 193°-194° C. (dec); IR (mull) 3084, 2954, 2925, 2210, 2117, 2104, 1652, 1608, 1581, 1500, 1449, 1438, 1405, 1222, 1197, 1002, 892 cm-1 ; 1H NMR (DMSO) δ10.9 (bs, 1 H), 7.45-7.20 (bm, 8 H), 7.07 (bs, 1 H); 13C NMR (DMSO) δ151.3, 141.5, 138.6, 134.0, 129.8, 126.4, 120.8, 119.4, 116.2, 112.8, 112.5; Analysis calculated for C14H9ClN6O: C, 53.77; H, 2.90; N, 26.87; Cl, 11.34. Found: C, 53.39; H, 2.71; N, 26.54; Cl, 11.32. to evaporate at a temperature of 75° C. overnight The resulting solid is triturated with ether filtered The solid is recrystallized from ethyl acetate/hexane

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

Procedure: Chart B, Step B-1. To a stirred solution of 3-azido-5-chloroaniline (A-4, 0.706 g, 4.18 mmol) in 6 mL of chloroform, is added diphenyl cyanocarbonimidate (0.997 g, 4.18 mmol). The solvent is allowed to evaporate at a temperature of 75° C. overnight. The resulting solid is triturated with ether and filtered. The solid is recrystallized from ethyl acetate/hexane to afford 0.808 g of N-(3-azido-5-chlorophenyl)-N'-cyanocarbamimidic acid, phenyl ester. (B-1) Mp 193°-194° C. (dec); IR (mull) 3084, 2954, 2925, 2210, 2117, 2104, 1652, 1608, 1581, 1500, 1449, 1438, 1405, 1222, 1197, 1002, 892 cm-1 ; 1H NMR (DMSO) δ10.9 (bs, 1 H), 7.45-7.20 (bm, 8 H), 7.07 (bs, 1 H); 13C NMR (DMSO) δ151.3, 141.5, 138.6, 134.0, 129.8, 126.4, 120.8, 119.4, 116.2, 112.8, 112.5; Analysis calculated for C14H9ClN6O: C, 53.77; H, 2.90; N, 26.87; Cl, 11.34. Found: C, 53.39; H, 2.71; N, 26.54; Cl, 11.32. to evaporate at a temperature of 75° C. overnight The resulting solid is triturated with ether filtered The solid is recrystallized from ethyl acetate/hexane

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

Procedure: To a stirred solution of naphthalene-2-carboxylic acid hydrazide (0.7 g, 3.76 mmol) in isopropanol (40 ml) was added triethylamine (630 μl, 4.51 mmol) and diphenyl cyanocarbonimidate (0.99 g, 4.14 mmol) and the resulting reaction mixture was stirred at room temperature for 1.5 h. The volatiles were evaporated in vacuo and to the residue was added water (50 ml) and diethyl ether (50 ml). The organic phase was separated and the aqueous phase was acidified to pH=1 with concentrated hydrochloric acid. The precipitate was filtered off and washed with water (3×10 ml) and diethyl ether (2×10 ml) and dried in vacuo at 50° C. which afforded 0.45 g (51%) of the title compound as a solid. the resulting reaction mixture The volatiles were evaporated in vacuo and to the residue was added water (50 ml) and diethyl ether (50 ml) The organic phase was separated The precipitate was filtered off washed with water (3×10 ml) and diethyl ether (2×10 ml) dried in vacuo at 50° C. which