Reaction SMILES: [N:1]1S[N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:15]=3[C:16]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=3[F:28])[CH3:20])=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.N[C:35]1C=C(Br)C=C[C:36]=1C(N[C@@H](C1C=CC(F)=CC=1F)C)=O.N1SN=C2C(S(Cl)(=O)=O)=CC=CC=12.N1C=CC=CC=1>C(Cl)Cl>[Br:33][C:31]1[CH:30]=[CH:29][C:15]([C:16]([NH:18][C@@H:19]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH3:20])=[O:17])=[C:14]([NH:13][S:10]([C:6]2[C:3]3[N:4]=[CH:35][CH:36]=[N:1][C:2]=3[CH:9]=[CH:8][CH:7]=2)(=[O:12])=[O:11])[CH:32]=1
Reactant: C[C@@H](NC(=O)c1ccc(Br)cc1N)c1ccc(F)cc1F
Reactant: C[C@@H](NC(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12)c1ccc(F)cc1F
Agent: O=S(=O)(Cl)c1cccc2nsnc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](NC(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
S—(S)-2-Methylpropane-2-sulfinic acid 2,4-difluorobenzylideneamide. A suspension of 2,4-difluorobenzaldehyde (0.61 g, 4.3 mmol), (S)-tert-butanesulfinamide (0.47 g, 3.9 mmol), and powdered anhydrous CuSO4 (1.24 g, 7.8 mmol) was stirred in DCM (8 mL) overnight. The reaction mixture was filtered, and the filter cake was washed with DCM. The filtrate was concentrated in vacuo to give the crude N-sulfinyl imine as a viscous yellow oil. Purification by flash chromatography (EtOAc/hexanes) provided 0.81 g (84%) of the N-sulfinyl imine as a pale yellow viscous oil. 1H NMR (400 MHz, CDCl3): 8.83 (s, 1H), 8.05-7.99 (m, 1H), 7.01-6.96 (m, 1H), 6.94-6.87 (m, 1H), 1.27 (s, 9H). B. S—(S)—2-Methylpropane-2-sulfinic acid 1-(R)-[1-(2,4-difluorophenyl)-ethyl]-amide. To a stirred solution of S—(S)-2-methylpropane-2-sulfinic acid 2,4-difluorobenzylideneamide (0.77 g, 3.1 mmol) in DCM (20 mL) at −50° C., was added a solution of methyl magnesium bromide (3.0 M in diethyl ether, 2.1 mL, 6.3 mmol). The reaction mixture was stirred at −50° C. for 1 h then allowed to warm slowly to room temperature overnight. The reaction was quenched by the addition of satd. aq. NH4Cl, and the mixture was poured into H2O, and extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. Purification by flash chromatography (EtOAc/hexanes) provided the title compound as a colorless, viscous oil (0.80 g, 99%, 90% de). Major diastereomer: 1H NMR (400 MHz, CDCl3): 7.37-7.28 (m, 1H), 6.88-6.83 (m, 1H), 6.82-6.76 (m, 1H), 4.82 (dq, J=6.8, 4.5 Hz, 1H), 3.32 (d, J=4.1 Hz, 1H), 1.56 (d, J=6.8 Hz, 3H), 1.19 (s, 9H). C. (R)-1-(2,4-Difluorophenyl)ethylamine hydrochloride. To a stirred solution of S—(S)-2-methylpropane-2-sulfinic acid 1-(R)-[1-(2,4-difluorophenyl)-ethyl]-amide (0.80 g, 3.1 mmol, 90% de) in methanol (7 mL) at room temperature, was added 2 mL of a satd. solution of HCl (g) in methanol. After several minutes, precipitated amine hydrochloride was visible. The reaction mixture was allowed to stir for 2 h at room temperature. The heterogeneous mixture was concentrated in vacuo until approximately 2 mL remained, and then the amine hydrochloride was fully precipitated by the addition of diethyl ether (10 mL). The HCl salt was collected by suction filtration, washed with diethyl ether, and dried in vacuo to provide fine white crystals (570 mg, 95%, 99% ee). Enantiomeric purity was determined by HPLC analysis on the benzamide derivative of the amine. Chiralcel AS column, 90:10 hexanes/isopropyl alcohol, 0.7 mL/min. R enantiomer, RT═18.1 min. S enantiomer, RT═21.0 min. [α]D20=−3.7° (c 4.37, H2O). 1H NMR (400 MHz, CD3OD): 7.60-7.53 (m, 1H), 7.14-7.06 (m, 2H), 4.72 (q, J=7.0 Hz, 1H), 1.65 (d, J=6.8 Hz, 3H). D. (R)-4-Bromo-N-[1-(2,4-difluorophenyl)ethyl]-2-(quinoxaline-5-sulfonylamino)-benzamide. 4-Bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G; 21 mg, 0.052 mmol) was coupled with (R)-1-(2,4-difluoro-phenyl)ethylamine hydrochloride (27 mg, 0.14 mmol) according to the general procedure described in EXAMPLE 1, Step K to provide the desired amide (24 mg, 89%). mp=200-200.5° C.; MS (ESI): mass calculated for C23H17BrF2N4O3S, 546.0; m/z found, 547/549 [M+H]+. HPLC (reverse phase): RT═9.76 min. Anal. calcd. for C23H17BrF2N4O3S: C, 50.47; H, 3.13; N 10.24, S 5.86; found: C 50.10, H 3.18, N 10.06, S 5.88. 1H NMR (500 MHz, CDCl3): 11.33 (s, 1H), 8.83 (d, J=1.8 Hz, 1H), 8.78 (d, J=1.8 Hz, 1H), 8.55 (dd, J=7.4, 1.4 Hz, 1H), 8.30 (dd, J=7.4, 1.4 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 7.86 (dd, J=8.4, 7.4 Hz, 1H), 7.30 (dd, J=8.5, 2.2 Hz, 1H), 7.16 (d, J=8.4, 1H), 7.08 (dd, J=8.4, 1.8 Hz, 1H), 6.92-6.80 (m, 2H), 6.33 (br d, J=6.5 Hz, 1H), 5.31 (quint, J=7.5 Hz, 1H), 1.53 (d, J=7.0 Hz, 3H). Alternatively, the title compound can be prepared via the following procedure: Method 2. A. (R)-4-Bromo-N-[1-(2,4-difluorophenyl)ethyl]-2-nitrobenzamide. A suspension of 4-bromo-2-nitrobenzoic acid (EXAMPLE 1, Step G; 8.0 g, 32 mmol) in thionyl chloride (25 mL) was heated at reflux for 30 min. The reaction became homogeneous. The mixture was cooled to room temperature and concentrated in vacuo to provide the acid chloride as a yellow liquid. The liquid was re-concentrated from DCM (3×) to ensure complete removal of thionyl chloride. 1H NMR (400 MHz, CDCl3): 8.20 (d, J=1.9 Hz, 1H), 7.92 (dd, J=8.3, 1.9 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H). To a solution of the acid chloride (32.5 mmol) in DCM (60 mL) at 0° C. was added (R)-1-(2,4-difluorophenyl)-ethylamine hydrochloride (6.61 g, 34.1 mmol) and Hünig's base (14 mL, 81 mmol). The mixture was allowed to warm to room temperature and was stirred for 1 h. The reaction mixture was washed twice with 1 N HCl, and each aqueous wash was back-extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to give the desired amide as a pale yellow solid (12.3 g, 98%). HPLC (reverse phase): RT═9.190 min. 1H NMR (500 MHz, CDCl3): 8.20 (d, J=1.8 Hz, 1H), 7.79 (dd, J=8.1, 1.8 Hz, 1H), 7.35 (ddd, J=8.6, 8.6, 6.3 Hz, 1H), 6.91-6.85 (m, 2H), 6.20 (br d, J=6.7 Hz, 1H), 5.38 (quint, J=7.5 Hz, 1H), 1.61 (d, J=7.0 Hz, 3H). B. (R)-2-Amino-4-bromo-N-[1-(2,4-difluorphenyl)ethyl]-benzamide. To a stirred solution of (R)4-bromo-N-[1-(2,4-difluorophenyl)-ethyl]-2-nitro-benzamide (12.3 g, 32.0 mmol) in 1:1 DCM/EtOAc (400 mL) at room temperature was added SnCl2.2H2O (29.0 g, 128 mmol). A mild exotherm was observed as the tin chloride slowly dissolved. The mixture was stirred for 14 h at room temperature. The reaction mixture was made basic by the addition of satd. NaHCO3 (800 mL), causing precipitation of tin salts. Diatomaceous earth (30 g) was added and the slurry was mixed thoroughly. The mixture was filtered through a pad of diatomaceous earth, washing with excess EtOAc. The biphasic filtrate was separated, and the aqueous layer was extracted once with EtOAc. The combined organic layers were dried (Na2SO4) and concentrated to give the desired aminobenzamide as a pale yellow solid (11.1 g, 98%). TLC (silica, 66% EtOAc/hexanes): Rf═0.39. HPLC (reverse phase): RT═9.461 min. 1H NMR (500 MHz, CDCl3): 7.30 (ddd, J=8.6, 8.6, 6.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 6.90-6.78 (m, 3H), 6.75 (dd, J=8.4, 1.8 Hz, 1H), 6.35 (br d, J=7.0 Hz, 1H), 5.60 (br s, 2H), 5.34 (quint, J=7.2 Hz, 1H), 1.57 (d, J=7.00 Hz, 3H). C. (R)-2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-[1-(2,4-difluoro-phenyl)ethyl]-benzamide. To a solution of (R)-2-amino-4-bromo-N-[1-(2,4-difluoro-phenyl)-ethyl]-benzamide (11.1 g, 31.2 mmol) and benzo[1,2,5]thiadiazole-4-sulfonyl chloride (11 g, 44 mmol) in DCM (100 mL) at 0° C. was added pyridine (12.6 mL, 156 mmol) slowly via syringe. The resulting orange mixture was allowed to stir for 16 h at room temperature then was washed with 1 N HCl (2×100 mL). Each aqueous wash was back-extracted with DCM. The combined organic layers were dried (Na2SO4) and concentrated to give the crude sulfonamide. The crude tan solid was purified by trituration with diethyl ether (300 mL). The product was collected by suction filtration, washed with additional diethyl ether, and dried in vacuo to provide the pure sulfonamide as a tan solid (15.3 g, 88%). MS (ESI): mass calculated for C21H15BrF2N4O3S2, 552.0; m/z found, 553 [M+H]+. HPLC (reverse phase): RT=10.17 min. 1H NMR (500 MHz, CDCl3): (rotameric broadening) 11.52 (s, 1H), 8.35 (dd, J=7.0, 1.0 Hz, 1H), 8.20 (dd, J=8.8, 1.0 Hz, 1H), 70 (d, J=1.8 Hz, 1H), 7.70 (dd, J=8.8, 7.0 Hz, 1H), 7.31 (dt, J=8.4, 6.2 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.10 (dd, J=8.4, 1.8 Hz, 1H), 6.92-6.80 (m, 2H), 6.37 (d, J=7.6 Hz, 1H), 5.33 (quint, J=7.5 Hz, 1H), 1.56 (d, J=7.0 Hz, 3H). D. (R)-4-Bromo-N-[1-(2,4-difluorophenyl)-ethyl]-2-(quinoxaline-5-sulfonylamino)-benzamide. To a solution of (R)-2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-N-[1-(2,4-difluorophenyl)ethyl]benzamide (15.3 g, 27.6 mmol) in ACOH (200 mL) at 50° C. was added zinc dust (18.0 g, 275 mmol) in small portions. After addition was complete, the reaction was stirred at 50° C. for 2 h. The reaction mixture was filtered through a pad of diatomaceous earth with excess methanol. The filtrate was concentrated in vacuo to provide the reduced phenylene diamine as a yellow-orange heterogeneous mixture containing zinc salts and AcOH. HPLC (reverse phase): RT 9.15 min (single peak). The unpurified mixture was combined with glyoxal bisulfite adduct (22 g, 83 mmol), NaOAc (2.3 g, 28 mmol), H2O (80 mL), ACOH (12 mL), and methanol (240 mL) and heated at reflux for 4 h. The dark orange suspension was filtered through a pad of diatomaceous earth and washed with excess DCM (˜1.5 L). The filtrate was concentrated in vacuo and partitioned between H2O and DCM. The layers were separated, and the aqueous layer was extracted with DCM (4×). The combined organic layers were dried (Na2SO4) and concentrated to give a dark orange oil. The oil was passed through a plug of silica gel and eluted with a mixture of EtOAc/hexanes (gradient from 30 to 70%), and then was triturated with methanol to provide the title compound as a dark tan solid (8.80 g, 58%).