Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[NH2:17][CH2:16][CH2:15][NH:18][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Product: CC(C)(C)OC(=O)c1ccc(NCCN)cc1
Temperature: 120 °C
Yield: 96 %

Procedure:
tert-Butyl p-fluorobenzoate (750 mg, 3.93 mmol, 1 equiv) was dissolved in ethylenediamine (4 mL), and heated to 120° C. for 24 h. All solvent was evaporated, and then the residue was dry-loaded onto silica gel and purified by flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 92:7:1) to furnish tert-butyl 4-(2-amino-ethylamino)-benzoate as a white powder (891 mg, 96%): δH (400 MHz, CD2Cl2) 1.59 (s, 9H, CO2(CH3)3), 2.98 (t, J=5.8 Hz, 2H, H2NCH2CH2NH), 3.23 (q, J=5.8 Hz, 2H, H2NCH2CH2NH), 4.67 (br, 1H, H2NCH2CH2NH), 6.62 (d, J=8.6 Hz, 2H, 2 CH (Ar)), 7.81 (d, J=8.6 Hz, 2H, 2 CH (Ar)); δC (125 MHz, CD2Cl2) 28.9, 41.7, 46.6, 80.3, 112.1, 120.9, 131.9, 152.9, 166.7; HRMS (EI+) m/z calcd for [C13H20N2O2] 236.1525. found 236.1527. tert-Butyl 4-(2-amino-ethylamino)-benzoate (700 mg, 3.03 mmol, 1 equiv) was then sulfonylated with 1-methyl-1H-imidazole-4-sulfonyl chloride. The appropriate sulfonyl chloride (1.2 equiv) was added to a solution of the amine (1 equiv) and DIPEA (2 equiv) in anhydrous CH3CN (0.1 M) at 0° C. The reaction was warmed to room temperature and stirred for 16 h, at which time the solvent was evaporated. The residue was re-dissolved in CH2Cl2, washed with 5% NaHCO3, water, brine, dried (Na2SO4), filtered and concentrated. The crude material was dry-loaded onto silica gel, and then purified by flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to give tert-butyl 4-[2-(1-methyl-1H-imidazole-4-sulfonylamino)-ethylamino]-benzoate as a white powder (1.04 g, 90%): δH (500 MHz, CDCl3) 1.56 (s, 9H, CO2(CH3)3), 3.17 (m, 2H, SO2NHCH2CH2NH), 3.28 (m, 2H, SO2NHCH2CH2NH), 3.67 (s, 3H, CH3 (Im)), 6.51 (d, J=8.5 Hz, 2H, 2 CH (Ar)), 7.46 (s, 1H, CH (Im)), 7.51 (s, 1H, CH (Im)), 7.75 (d, J=8.5 Hz, 2H, 2 CH (Ar)); δC (125 MHz, MeOH-d4) 28.7, 34.6, 42.4, 43.1, 80.8, 111.9, 120.5, 125.2, 131.8, 140.1, 140.3, 152.4, 167.4; HRMS (ES+) calcd for [C17H24N4O4S+H] 381.1597. found 381.1573. tert-Butyl 4-[2-(1-methyl-1H-imidazole-4-sulfonylamino)-ethylamino]-benzoate (610 mg, 1.63 mmol, 1 equiv) was then chemoselectively benzylated on the sulfonamide NH with benzyl bromide. To a solution of the sulfonamide (1 equiv) and Cs2CO3 (2 equiv) in DMF (0.1 M) at 0° C. was added the appropriate alkyl bromide or chloride (1.1 equiv). The resulting mixture was stirred at room temperature overnight. The reaction was diluted with water, then extracted into EtOAc (×3). The combined EtOAc extractions were washed with 5% NaHCO3 (×3), brine, dried (Na2SO4), filtered and concentrated. The crude material was then flash chromatographed over silica gel to furnish tert-butyl 4-{2-[benzyl-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-ethylamino}-benzoate as a white solid (703 mg, 92%): δH (400 MHz, CDCl3) 1.52 (s, 9H, CO2(CH3)3), 3.13 (t, J=6.2 Hz, 2H, (Bn)NCH2CH2NH), 3.43 (t, J=6.2 Hz, 2H, (Bn)NCH2CH2NH), 3.68 (s, 3H, CH3 (Im)), 4.32 (s, 2H, CH2Ph), 6.30 (d, J=8.8 Hz, 2H, 2 CH (Ar)), 7.23-7.30 (m, 5H, 5 CH (Ph)), 7.42 (s, 1H, CH (Im)), 7.49 (s, 1H, CH (Im)), 7.70 (d, J=8.8 Hz, 2H, 2 CH (Ar)); δC (500 MHz, CDCl3) 28.1, 33.9, 41.6, 46.6, 52.6, 79.6, 111.1, 119.9, 124.4, 127.9, 128.3, 128.6, 131.1, 136.0, 139.0, 139.8, 151.1, 166.1; HRMS (ES+) calcd for [C24H30N4O4S+H] 471.2066. found 471.2053. tert-Butyl 4-{2-[benzyl-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-ethylamino}-benzoate (220 mg, 0.473 mmol, 1 equiv) was alkylated on the aniline NH with 5-chloromethyl-1-methyl-1H-imidazole.HCl. The secondary aniline (1 equiv) was dissolved in DMF (0.07 M), then the reaction was cooled to 0° C. After 15 min, NaH (3 eq.) was added in one portion. After a further 15 min, 5-chloromethyl-1-methyl-1H-imidazole.HCl (1.1 eq) was added. The reaction was allowed to stir at 0° C. from 2-3 h, when TLC indicated the reaction was complete or had stalled. Upon quenching the reaction with brine (approximately 1 mL), the reaction was diluted with water and extracted with EtOAc (×3). The EtOAc extractions were combined, and washed with 5% NaHCO3 (×3), brine, dried (Na2SO4), filtered and concentrated. The crude material was flash chromatographed over silica gel (eluent CH2Cl2/MeOH/NH4OH, 192:7:1) to afford the title compound 10 as a colourless foam (200 mg, 76%): δH (500 MHz, CDCl3) 1.53 (s, 9H, C(CH3)3), 3.09-3.15 (m, 2H, CH2CH2NSO2), 3.29-3.34 (m, 2H, CH2CH2NSO2), 3.43 (s, 3H, CH3), 3.73 (s, 3H, CH3), 4.26 (s, 2H, CH2Ph), 4.30 (s, 2H, CH2Im), 6.35 (d, J=9.0 Hz, 2H, 2 CH (Ar)), 6.69 (s, 1H, CH (Im)), 7.31-7.37 (m, 5H, 5 CH (Ph)), 7.39 (s, 1H, CH (Im)), 7.42 (s, 1H, CH (Im)), 7.46 (s, 1H, CH (Im)), 7.68 (d, J=9.0 Hz, 2H, 2 CH (Ar)); δC (125 MHz, CDCl3) 28.2, 31.6, 33.9, 44.1, 45.0, 49.7, 54.3, 79.8, 111.0, 120.0, 124.4, 127.5, 128.1, 128.6, 128.7, 128.9, 131.1, 136.2, 138.5, 139.0, 139.1, 150.3, 165.8; HRMS calcd for [C29H36N6O4S+H] 565.2597. found 565.2576; HPLC (I) tR=12.53 min (100%), (II) tR=18.77 min (100%).