Characterization data

Both 1H and 13C NMR spectra were recorded on a Bruker DPX-300 or DRX-500

instrument where noted. HRMS scans were recorded with a Shimadzu LCMS-IT-TOF or similar

instruments run at the Shimadzu Analytical Chemistry Center of Southeastern Wisconsin. In silico cLogP values and topological polar surface area values (tPSA) were calculated with ChemBioDraw Ultra v. 14.

(E)-3-(2-(Benzo[b]thiophen-2-yl)vinyl)-5-methoxyphenol (SK-03-92, Table 2-3, entry 3)

The NaH (60% dispersed in mineral oil, 3.6 g, 0.09 mol) was added to anhydrous DMF (100 mL) at 0° C. The CH3CH2SH (12.2 mL, 13.22 g, 0.12 mol) was then added dropwise and stirred at 0° C for 30 min. The temperature of the reaction mixture was allowed to rise to rt and the mixture stirred for 1 h. The temperature of the reaction mixture was raised to 140° C and (E)-2-(3,5-dimethoxystyryl)benzo[b]thiophene (8.90 g, 0.03 mol) in dry DMF (30 mL) was added dropwise to the reaction mixture. This mixture was held at 140° C and monitored by TLC (30%

EtOAc in hexanes). When the starting material was no longer present by TLC (~1 hr), the reaction mixture was cooled to rt and quenched by addition of aq 0.5N HCl (500 mL). The mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed sequentially with aq 0.5N HCl (3x60 mL) and brine (3 x 60 mL). The organic layer was dried over Na2S04 and the solvent was removed in vacuo. The crude solid was purified by flash column chromatography (FCC) (20% EtOAc in hexanes) to afford the pure SK-03-92 in 92%

yield as a pale yellow solid (7.79g): ¹H NMR (300 MHz, CD3COCD3) δ 8.43 (s, 1H), 7.89 – 7.77 (m, 2H), 7.52 – 7.34 (m, 4H), 6.97 (d, J = 15.9 Hz, 1H), 6.72 (m, 2H), 6.40 (t, J = 2.2 Hz, 1H),

3.81 (s, 3H); ¹³C NMR (75 MHz, CD3COCD3) δ 161.3, 158.7, 142.7, 140.3, 138.6, 130.8, 124.8, 124.5, 123.6, 123.4, 122.4, 122.0, 106.2, 103.4, 101.5, 54.6; HRMS (ESI) (M + H), Calcd. for C17H15O2S 283.0793; Found 283.0797.

(E)-3-(2-(Benzo[b]thiophen-2-yl)vinyl)-5-methoxyphenyl trifluoromethanesulfonate (22, Table 2-4, entry 1)

The (E)-3-(2-(benzo[b]thiophen-2-yl)vinyl)-5-methoxyphenol (1.00g, 3.54mmol, 1eq) was dissolved in 50mL DCM (freshly distilled) and the pyridine (310mg, 3.90mmol, 1.1eq) was added in one portion. The solution was cooled to 0 ºC and trifluoromethanesulfonic anhydride (1.1g, 3.90mmol, 1.1eq) was added dropwise at 0 ºC. The starting material was consumed after 10 min on analysis by TLC (20% EtOAc in hexanes) and the reaction was quenched with aq 0.5N HCl (50mL). DCM (40mL) was added and the organic layer extracted. The organic layer was washed with brine (50mL) and dried over Na2SO4. The solvent was removed in vacuo leaving a crude yellow solid. The solid was purified by flash column chromatography on silica gel (10% EtOAc in hexanes) to provide the pure 22 in 98% yield as a white solid (1.44g): ¹H NMR (300 MHz, CDCl3) δ 7.80 (dd, J = 8.8, 4.8 Hz, 1H), 7.75 (dd, J = 6.1, 3.0 Hz, 1H), 7.41 – 7.30 (m, 4H), 7.28 (s, 1H), 7.04 (s, 2H), 6.92 (d, J = 16.0 Hz, 1H), 6.74 (t, J = 2.1 Hz, 1H), 3.89 (s, 3H), 1.57 (s, 1H); ¹³C NMR (75 MHz, CDCl3) δ 160.97, 150.51, 141.74, 140.00, 139.80,

139.16, 128.56, 125.24, 124.89, 124.72, 124.68, 123.73, 122.30, 112.00, 111.19, 106.59, 55.82;

HRMS (ESI) (M + H), Calcd. for C18H14F3O4S2 415.0286; Found 415.0291.

3-(2-(Benzo[b]thiophen-2-yl)ethyl)-5-methoxyphenol (21, Table 2-4, entry 2)

The (E)-3-(2-(benzo[b]thiophen-2-yl)vinyl)-5-methoxyphenol (100mg, 0.354mmol, 1eq) and 10% Pd/C (38mg, 10mol% Pd) were mixed in a sealed tube under argon. THF (4mL) was added in one portion and the sealed tube was evacuated under vacuum and backfilled with argon three consecutive times. The sealed tube was evacuated under vacuum and a balloon filled with hydrogen was attached. The starting material was consumed after 2h (TLC, silica gel) and the solution was filtered through a plug of celite. The solvent was removed in vacuo to leave a crude yellow solid. The solid was purified by flash column chromatography on silica gel (10% EtOAc in hexanes) to provide the pure 21 in 95% yield as a white solid (96 mg): ¹H NMR (300 MHz, CDCl3) δ 7.79 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.42 – 7.19 (m, 2H), 7.02 (s, 1H), 6.41 (s, 1H), 6.30 (dd, J = 5.9, 3.7 Hz, 2H), 4.83 (s, 1H), 3.77 (s, 3H), 3.33 – 3.11 (m, 2H), 3.11 – 2.83 (m, 2H); ¹³C NMR (75 MHz, CDCl3) δ 160.95, 156.59, 145.28, 143.63, 140.08, 139.31, 124.12, 123.55, 122.82, 122.15, 120.93, 107.92, 106.84, 99.32, 55.29, 37.37, 32.32; HRMS (ESI) (M + H), Calcd. for C17H17O2S 285.0949; Found 285.0947.

(E)-3-Methoxy-5-(2-(thiophen-2-yl)vinyl)phenol (29, Table 2-4, entry 3)

The NaH (60% dispersed in mineral oil, 360 mg, 0.009 mol) was added to anhydrous DMF (10 mL) at 0° C. The CH3CH2SH (1.22 mL, 1.32 g, 0.012 mol) was then added dropwise and stirred at 0° C for 30 min. The temperature of the reaction mixture was allowed to rise to rt and the mixture stirred for 1 h. The temperature of the reaction mixture was raised to 140° C and (E)-2-(3,5-dimethoxystyryl)thiophene (739 mg, 0.003 mol) in dry DMF (3 mL) was added dropwise to the reaction mixture. This mixture was held at 140° C and monitored by TLC (30% EtOAc in hexanes, silica gel). When starting material was no longer present by TLC (~2 h) the reaction mixture was cooled to rt and quenched by addition of aq 0.5N HCl (50 mL). The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed sequentially with aq 0.5N HCl (3x15 mL) and brine (3 x 15 mL). The organic layer was dried (Na2S04) and the solvent was removed in vacuo. The crude solid was purified by FCC (20% EtOAc in hexanes) to afford the pure 29 in 62% yield as an off-white solid (432 mg): ¹H NMR (300 MHz, CDCl3) δ 7.23 – 7.17 (m, 2H), 7.09 – 7.08 (m, 1H), 7.04 – 7.00 (m, 1H), 6.84 (d, J = 16.2 Hz, 1H), 6.63 (s, 1H), 6.57 (s, 1H), 6.36 (t, J = 2.1 Hz, 1H), 5.04 (s, 1H), 3.83 (s, 3H); ¹³C NMR (75 MHz,

CDCl3) δ 161.0, 156.7, 142.4, 139.3, 127.8, 127.5, 126.3, 124.5, 122.4, 105.7, 104.7, 101.0, 55.3;

HRMS (ESI) (M + H), Calcd. for C13H13O2S 233.0636; Found 233.0639.

(E)-2-(3-Methoxy-5-(methylthio)styryl)benzo[b]thiophene (24, Table 2-5, entry 1)

The (E)-3-(2-(benzo[b]thiophen-2-yl)vinyl)-5-methoxyphenyl trifluoromethanesulfonate (250mg, 0.603mmol, 1eq) and tetrakis(triphenylphosphine)palladium(0) (35mg, 5mol%) were mixed in a sealed tube under argon. Then degassed toluene (3mL), triisopropylsilanethiol (138mg, 0.724mmol, 1.2eq), and triethylamine (80mg, 0.784mmol, 1.3eq) were added and the sealed tube was heated to 100 ºC. After 2h the starting material was consumed (by TLC) and the sealed tube was cooled to rt. The solution was filtered through a plug of celite and the celite washed with EtOAc (10mL x 3). The organic layer was washed with water (10mL) and brine (10mL), then dried over Na2SO4, and the solvent removed in vacuo. The crude solid was dissolved in THF and iodomethane (171mg, 1.20mmol, 2eq) was added in one portion.

Tetrabutyl-ammonium fluoride trihydrate (381mg, 1.20mmol, 2eq) was added slowly in 3 portions. Analysis by TLC (20% EtOAc in hexanes, silica gel) confirms the reaction was complete 0.5h after the addition. The reaction was quenched with water (10mL) and extracted with EtOAc (10mL x 2). The organic layer was washed with brine (10mL) and dried over Na2SO4. The solvent was removed in vacuo leaving an orange solid. The solid was purified by flash column chromatography on silica gel (10% EtOAc in hexanes) to provide the pure 24 in 47% yield as a yellow solid (89 mg): ¹H NMR (300 MHz, CDCl3) δ 7.85 – 7.76 (m, 1H), 7.76 – 7.69 (m, 1H), 7.42 – 7.24 (m, 4H), 7.00 (d, J = 10.2 Hz, 1H), 6.94 (d, J = 16.0 Hz, 1H), 6.84 (s,

1H), 6.80 – 6.70 (m, 1H), 3.87 (s, 3H), 2.55 (s, 3H); ¹³C NMR (75 MHz, CDCl3) δ 160.18, 142.58, 140.32, 140.15, 138.98, 138.36, 130.25, 124.88, 124.55, 123.69, 123.50, 123.18, 122.25, 117.29, 111.87, 108.61, 55.39, 15.77; HRMS (ESI) (M + H), Calcd. for C18H17OS2 313.0721;

Found 313.0718.

(E)-3-(2-(Benzo[b]thiophen-2-yl)vinyl)-5-(methylthio)phenol (25, Table 2-5, entry 2)

The NaH (60% dispersed in mineral oil, 40mg, 1.00 mmol, 8eq) was added to anhydrous DMF (2 mL) at 0° C. Then CH3CH2SH (0.1 mL 1.39 mmol, 11eq) was added dropwise and stirred at 0° C for 30 min. The temperature of the reaction mixture was allowed to rise to rt and the mixture stirred for 1 h. The temperature of the reaction mixture was raised to 140° C and (E)-2-(3-methoxy-5-(methylthio)styryl)benzo[b]thiophene (38.7 mg, 0.124 mmol, 1eq) in dry DMF (0.5 mL) was added dropwise to the reaction mixture. This mixture was held at 140° C and monitored by TLC (30% EtOAc in hexanes). When the starting material was no longer present by TLC (~1 hr) the reaction mixture was cooled to 0 ºC and quenched by addition of aq 0.5N HCl (10 mL). The mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed sequentially with aq 0.5N HCl (2 x 10 mL) and brine (2 x 10 mL). The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. The crude solid was purified by FCC (20% EtOAc in hexanes) to afford the pure product in 82% yield as a pale yellow solid (30 mg): ¹H NMR (300 MHz, CDCl3) δ 7.78 (dd, J = 7.9, 4.8 Hz, 1H), 7.75 – 7.66 (m, 1H), 7.40

– 7.29 (m, 2H), 7.29 – 7.23 (m, 2H), 6.96 (s, 1H), 6.89 (d, J = 16.0 Hz, 1H), 6.76 (s, 1H), 6.68 (t, J = 1.8 Hz, 1H), 2.52 (s, 3H); ¹³C NMR (75 MHz, CDCl3) δ 160.52, 142.48, 140.46, 140.10, 138.76, 138.32, 130.22, 124.87, 124.45, 123.70, 123.40, 123.15, 122.20, 117.19, 111.67, 108.71, 15.57; HRMS (ESI) (M + H), Calcd. for C17H15OS2 299.0564; Found 299.0568.

(E)-3-(2-(Benzo[b]thiophen-2-yl)vinyl)-5-methoxybenzonitrile (26, Table 2-5, entry 3)

The (E)-3-(2-(benzo[b]thiophen-2-yl)vinyl)-5-methoxyphenyl trifluoromethanesulfonate (250mg, 0.603mmol, 1eq), tetrakis(triphenylphosphine)palladium(0) (35mg, 5mol%), sodium cyanide (59.10mg, 1.21mmol, 2eq), and copper iodide (11.5mg, 10mol%) were mixed in a sealed tube under argon. Then degassed toluene (3mL) was added and the sealed tube was heated to 100 ºC. After 2hr the starting material was consumed (by TLC) and the sealed tube was cooled to rt. The solution was filtered through a plug of celite and the celite washed with EtOAc (10mL x 3). The organic layer was washed with water (10mL) and brine (10mL), dried over Na2SO4, and the solvent removed in vacuo to furnish a red solid. The solid was purified by flash column chromatography on silica gel (20% EtOAc in hexanes) to provide the pure 26 in 35% yield as a yellow solid (61.5 mg): ¹H NMR (300 MHz, CDCl3) δ 7.80 (dd, J = 8.6, 5.0 Hz, 1H), 7.77 – 7.70 (m, 1H), 7.46 – 7.29 (m, 5H), 7.22 (s, 1H), 7.05 (s, 1H), 6.89 (d, J = 16.0 Hz, 1H), 3.89 (s, 3H);

13C NMR (75 MHz, CDCl3) δ 160.03, 141.69, 139.97, 139.36, 139.16, 128.11, 125.30, 124.98,

124.81, 124.72, 123.76, 122.52, 122.31, 118.60, 116.83, 115.88, 113.65, 55.68; HRMS (ESI) (M + H), Calcd. for C18H14NOS 292.0796; Found 292.0792.