Author: Lena Dolghih
Company: UF

Supplementary Methods

Chemical shifts are reported in δ units (ppm) relative to TMS as an internal standard. Coupling constants (J) are reported in Hertz (Hz). Characterization data are reported as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, br=broad, m=multiplet), coupling constants, number of protons, mass to charge ratio.

Benzyl N-[(1S)-1-[(cyanomethyl)carbamoyl]-2-(dimethylamino)ethyl]carbamate (2) was prepared in 47% yield over two steps according to the general procedure described in Synthetic Methods and employing N,N-dimethyltrimethylsilylamine (2 equivalents) in the first reaction. 

^1H NMR (400 MHz, CDCl_3) δ 9.10 (br. s., 1H), 7.25 - 7.47 (m, 5H), 5.75 - 5.97 (m, 1H), 5.01 - 5.19 (m, 2H), 4.03 - 4.29 (m, 3H), 2.65 (d, J = 9.34 Hz, 1H), 2.44 - 2.56 (m, 1H), 2.34 (br. s., 6H);  ^13C NMR (100 MHz, CDCl_3) δ 171.5, 156.0, 136.1, 128.6, 128.2, 128.1, 116.0, 67.1, 60.5, 50.7, 45.0, 27.2;   MS (m/z): [M+H]^+ = 306 

Benzyl N-[(1S)-1-[(cyanomethyl)carbamoyl]-3-phenylpropyl]carbamate (3) was prepared in 29% according to the general procedure described in Synthetic Methods.

^1H NMR (400 MHz, CDCl_3) δ 7.29 - 7.40 (m, 4H), 7.22 - 7.29 (m, 2H), 7.15 - 7.22 (m, 2H), 7.09 - 7.15 (m, 2H), 5.60 (d, J = 8.24 Hz, 1H), 5.02 - 5.16 (m, 2H), 4.15 (m, 1H), 4.02 (d, J = 5.68 Hz, 2H), 2.58 - 2.74 (m, 2H), 2.08 - 2.21 (m, 1H), 1.96-1.91 (m, 1H);  ^13C NMR (100 MHz, CHLOROFORM-d) δ 172.0, 156.5, 140.1, 135.8, 128.6, 128.6, 128.4, 128.4, 128.0, 126.4, 115.8, 67.5, 54.2, 33.3, 31.6, 27.4;  MS (m/z): [M+H]^+ = 352

Benzyl N-[(1S)-1-[(cyanomethyl)carbamoyl]-2-[methyl(phenyl)amino]ethyl] carbamate (4) was prepared in 18% yield over two steps according to the general procedure described in Synthetic Methods and employing N-methylaniline (10 equivalents) in the first reaction. 

^1H NMR (400 MHz, CDCl_3) δ 7.23 - 7.41 (m, 6H), 6.78 - 6.91 (m, 4H), 5.57 - 5.66 (m, 1H), 5.07 - 5.15 (m, 2H), 4.47 (s, 1H), 4.07 - 4.16 (m, 1H), 3.98 - 4.07 (m, 1H), 3.68 - 3.77 (m, 1H), 3.44 - 3.51 (m, 1H), 2.95 (s, 3H);  ^13C NMR (100 MHz, CHLOROFORM-d) δ 171.0, 156.0, 148.8, 135.8, 129.6, 129.6 128.6, 128.6 128.4, 128.1, 128.1, 118.5, 115.3, 113.3, 77.3, 77.2, 76.7, 67.4, 55.5, 52.5, 39.7, 27.5; MS (m/z): [M+H]^+ = 367

Benzyl N-[(1S)-1-[(cyanomethyl)carbamoyl]-2-(1,2,3,4-tetrahydroquinolin-1-yl)ethyl]carbamate (5)  was prepared in 30% yield over two steps according to the general procedure described in Synthetic Methods and employing tetrahydroquinoline (3 equivalents) in the first reaction. 

^1H NMR (400 MHz, CDCl_3) δ 7.28 - 7.44 (m, 5H), 7.11 (br. s., 1H), 6.99 (d, J = 7.33 Hz, 1H), 6.90 (br. s., 1H), 6.84 (br. s., 1H), 6.69 (t, J = 7.33 Hz, 1H), 5.58 - 5.74 (m, 1H), 5.12 (s, 2H), 4.41 - 4.59 (m, 1H), 4.14 (dd, J = 6.04, 17.40 Hz, 1H), 4.00 (dd, J = 5.59, 17.49 Hz, 1H), 3.68 (d, J = 10.26 Hz, 1H), 3.40 (dd, J = 9.34, 14.47 Hz, 1H), 3.19 - 3.34 (m, 2H), 2.77 (t, J = 6.04 Hz, 2H), 1.88 - 1.99 (m, 2H);  ^13C NMR (100 MHz, CDCl_3) δ 171.6, 156.4, 145.0, 136.1, 129.8, 128.8, 128.6, 128.2, 127.6, 123.4, 117.6, 115.8, 111.5, 67.5, 54.7, 52.6, 51.1, 28.0, 27.7, 22.4;  MS (m/z): [M+H]^+ = 393

Benzyl N-[(1S)-1-[(cyanomethyl)carbamoyl]-2-(1H-indol-3-yl)ethyl]carbamate (6) was prepared in 60% yield according to the general procedure described in Synthetic Methods. 

^1H NMR (400 MHz, DMSO-d_6) δ 10.83 (br. s., 1H), 8.79 (t, J = 5.59 Hz, 1H), 7.62 (d, J = 7.87 Hz, 1H), 7.54 (d, J = 8.42 Hz, 1H), 7.23 - 7.36 (m, 6H), 7.14 (s, 1H), 7.04 - 7.09 (m, 1H), 6.95 - 7.00 (m, 1H), 4.95 (s, 2H), 4.27 (dd, J = 4.94, 9.71 Hz, 1H), 4.12 - 4.16 (m, 2H), 3.11 (dd, J = 4.94, 14.47 Hz, 1H), 2.93 (dd, J = 9.89, 14.47 Hz, 1H); ^13C NMR (100 MHz, DMSO-d_6) δ 172.6, 155.9, 136.9, 136.1, 128.3, 127.7, 127.5, 127.1, 123.9, 120.9, 118.4, 118.3, 117.6, 111.3, 109.8, 65.4, 55.3, 27.5, 27.2; MS (m/z): [M+H]^+ = 377

Benzyl N-[(1S)-1-[(cyanomethyl)carbamoyl]-2-(2H-indazol-2-yl)ethyl]carbamate (7) was prepared in 19% yield over two steps according to the general procedure described in Synthetic Methods and employing indazole (1.05 equivalents) with heating at 60 ^oC in the first reaction. 

^1H NMR (400 MHz, DMSO-d_6) δ 8.95 (t, J = 5.31 Hz, 1H), 8.27 (s, 1H), 7.82 (d, J = 8.61 Hz, 1H), 7.69 (d, J = 8.61 Hz, 1H), 7.59 (d, J = 8.79 Hz, 1H), 7.15 - 7.32 (m, 5H), 7.01 - 7.06 (m, 1H), 4.89 - 4.99 (m, 2H), 4.80 (dd, J = 4.03, 13.00 Hz, 1H), 4.65 - 4.73 (m, 1H), 4.55 - 4.64 (m, 1H), 4.15 (d, J = 5.68 Hz, 2H); ^13C NMR (100 MHz, CDCl_3) δ 169.6, 156.3, 148.9, 135.6, 128.6, 128.5, 128.2, 127.2, 125.5, 122.3, 121.6, 120.6, 116.7, 115.2, 67.7, 55.3, 53.5, 27.5; MS: (m/z): [M+H]^+ = 379

Benzyl N-[(1S)-1-[(cyanomethyl)carbamoyl]-2-(1H-indol-1-yl)ethyl]carbamate (8) was prepared in 4% yield over three steps according to the general procedure described in Synthetic Methods and employing indoline (1.05 equivalents) in the first reaction. 

^1H NMR (400 MHz, CDCl_3CHLOROFORM) δ 7.63 (d, J = 7.87 Hz, 1H), 7.30 - 7.46 (m, 5H), 7.22 (br. s., 1H), 7.10 - 7.18 (m, 1H), 6.97 - 7.05 (m, 1H), 6.53 (d, J = 3.11 Hz, 1H), 6.01 (br. s., 1H), 5.49 (br. s., 1H), 5.10 (s, 2H), 4.62 (br. s., 2H), 4.28 - 4.41 (m, 1H), 3.91 (dd, J = 5.77, 17.49 Hz, 1H), 3.77 (dd, J = 5.68, 17.40 Hz, 1H); ^13C NMR (100 MHz, CDCl_3) δ 169.9, 155.9, 135.9, 135.6, 128.7, 128.5, 128.1, 122.4, 121.3, 120.2, 115.0, 109.2, 102.8, 77.3, 76.7, 67.6, 54.5, 47.4, 27.4
MS: (m/z): [M+H]^+ = 377

Benzyl N-[(1S)-1-[(cyanomethyl)carbamoyl]-2-(1H-imidazol-5-yl)ethyl]carbamate (9) was obtained in 20% yield according to the general procedure provided described in Synthetic Methods.

^1H NMR (400 MHz, DMSO-d_6) δ 11.80 (br. s., 1H), 8.65 (t, J = 5.40 Hz, 1H), 7.53 (s, 1H), 7.19 - 7.39 (m, 5H), 6.77 (br. s., 1H), 4.91 - 5.08 (m, 2H), 4.16 - 4.31 (m, 1H), 4.01 - 4.15 (m, 2H), 2.85-2.97 (m, 1H), 2.73-2.81 (m,1H); ^13C NMR (100 MHz, DMSO-d_6) δ 171.7, 155.8, 136.8, 134.5, 132.3, 128.4, 127.8, 127.6, 117.5, 116.6, 65.6, 54.4, 28.5, 27.2;  MS: (m/z): [M+H]^+ = 328

Benzyl N-[(1S)-1-[(cyanomethyl)carbamoyl]-2-(1H-pyrazol-1-yl)ethyl]carbamate (10) was prepared in 13% yield over two steps according to the general procedure described in Synthetic Methods and employing pyrazole (1.05 equivalents) with heating at 55 ^oC in the first reaction. 

^1H NMR (400 MHz, CDCl_3) δ 7.53 (d, J = 1.83 Hz, 1H), 7.29 - 7.48 (m, 6H), 6.58 (d, J = 6.78 Hz, 1H), 6.28 (s, 1H), 5.15 (s, 2H), 4.58 - 4.76 (m, 2H), 4.41 (dd, J = 4.49, 13.64 Hz, 1H), 4.11 (dd, J = 5.95, 17.67 Hz, 1H), 4.00 (dd, J = 5.49, 17.40 Hz, 1H);  ^13C NMR (100 MHz, CDCl_3) δ 170.0, 156.5, 140.7, 135.9, 131.6, 128.9, 128.7, 128.5, 115.5, 106.4, 67.8, 55.6, 52.3, 27.7; MS (m/z): [M+H]^+ = 329