Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH2:11][N:12]([CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:15])=[O:14])=[C:5]([F:29])[CH:4]=1)#[N:2].ClCC1NC=NC=1.Cl.[H-].[Na+].Cl[CH2:41][C:42]1[N:46]([CH3:47])[CH:45]=[N:44][CH:43]=1>CN(C=O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:41][C:42]2[N:46]([CH3:47])[CH:45]=[N:44][CH:43]=2)[CH2:10][CH2:11][N:12]([CH2:22][CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]2)[S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)(=[O:15])=[O:14])=[C:5]([F:29])[CH:4]=1)#[N:2]
Reactant: Cn1cncc1CCl
Reactant: N#Cc1ccc(NCCN(CC2CCCCC2)S(=O)(=O)c2ccccn2)c(F)c1
Agent: Cl
Agent: ClCc1cnc[nH]1
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cncc1CN(CCN(CC1CCCCC1)S(=O)(=O)c1ccccn1)c1ccc(C#N)cc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The primary amine of N-(2-aminoethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide (19) was arylated with 3,4-difluorobenzonitrile on a 0.337 mmol scale. To a stirring solution of the primary amine (1 equiv) in DMSO (0.2 M) were added the aryl fluoride (1.2 equiv) and DIPEA (3 equiv). The reaction mixture was heated to 120° C. for 48 h. After allowing the reaction to cool, H2O was added, and the crude product was extracted with EtOAc (×3). The EtOAc extractions were combined, washed with water (×3), brine, dried (Na2SO4), filtered and concentrated. After work-up and purification by silica gel flash column chromatography (eluent CH2Cl2/MeOH/NH4OH, 192:7:1), N-(2-(4-cyano-2-fluorophenylamino)ethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide was obtained as a white foam (111 mg, 79%): δH (500 MHz, DMSO-d6) 0.83-0.77 (m, 2H, 2 CH (cyclohexylmethyl)), 1.09 (br, 3H, 3 CH (cyclohexylmethyl)), 1.62-1.51 (m, 6H, 6 CH (cyclohexylmethyl)), 3.06 (d, J=7.5 Hz, 2H, NCH2CH (cyclohexyl)), 3.42-3.34 (m, 4H, SO2NCH2CH2N), 6.54 (br, 1H, NHAr), 6.80 (t, J=8.5 Hz, 1H, CH (Ar)), 7.45 (dd, J=11.5, 1.5 Hz, 1H, CH (Ar)), 7.53 (dd, J=8.5, 1.5 Hz, 1H, CH (Ar)), 7.66 (m, 1H, CH (Py)), 7.93 (m, 1H, CH (Py)), 8.07 (m, 1H, CH (Py)), 8.71 (m, 1H, CH (Py)); δC (125 MHz, DMSO-d6) 25.1, 25.9, 30.0, 35.7, 37.1, 41.3, 47.5, 55.5, 61.8, 94.4, 122.2, 127.1, 130.4, 138.7, 140.7, 142.5, 150.1, 156.9, 179.7; HRMS (ES+) calcd for [C21H25FN4O2S+H] 417.1760. found 417.1749. N-(2-(4-Cyano-2-fluorophenylamino)ethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide was then alkylated with 5-chloromethyl-1H-imidazole.HCl on a 0.216 mmol scale. 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. After work-up and chromatography over silica gel (eluent CH2Cl2/MeOH/NH4OH, 192:7:1), the title compound N-(2-((4-cyano-2-fluorophenyl)((1-methyl-1H-imidazol-5-yl)methyl)amino)ethyl)-N-(cyclohexylmethyl)pyridine-2-sulfonamide was afforded as a white foam (90 mg, 81%): δH (500 MHz, CDCl3) 0.68-0.75 (m, 2H, 2 CH (cyclohexylmethyl)), 1.03 (br, 3H, 3 CH (cyclohexylmethyl)), 1.23-1.32 (m, 1H, CH (cyclohexylmethyl)), 1.50-1.60 (m, 5H, 5 CH (cyclohexylmethyl)), 2.80 (s, 2H, NCH2CH (cyclohexylmethyl)), 3.34-3.47 (m, 4H, SO2NCH2CH2N), 3.54 (s, 3H, CH3 (Im)), 4.46 (s, 2H, CH2Im), 6.61 (br, 1H, CH (Ar)), 6.95 (s, 1H, CH (Im)), 7.11 (m, 1H, CH (Ar)), 7.26 (br, 1H, CH (Ar)), 7.53 (m, 2H, CH (Py), CH (Im)) 7.65 (br, 1H, CH (Py)), 8.26 (m, 1H, CH (Py)), 8.69 (m, 1H, CH (Py)); δC (125 MHz, CDCl3) 25.5, 26.1, 30.5, 31.3, 31.8, 36.6, 45.7, 47.3, 50.4, 56.4, 102.9, 118.1, 119.5, 120.2, 122.4, 126.5, 128.7, 129.3, 138.8, 141.3, 149.8, 153.9, 157.6, 162.4; HRMS (ES+) calcd for [C26H31FN6O2S+H] 511.2291. found 511.2265; HPLC (I) tR=18.69 min (99.3%), (II) tR=36.03 min (99.7%).