Supporting information

Supporting information Synthesis and biological investigation of oxazole hydroxamates as highly selective histone deacetylase 6 (HDAC6) inhibitors Johanna Senger, Jelena Melesina, Martin Marek, Christophe Romier, Ina Oehme, Olaf Witt, Wolfgang Sippl and Manfred Jung *, Institute of Pharmaceutical Sciences, Albert-Ludwigs-University Freiburg, Albertstraße 25, 79104 Freiburg, Germany Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck- Straße 4, 06120 Halle (Saale), Germany Département de Biologie Structurale Intégrative, Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UDS), CNRS, INSERM, 1 rue Laurent Fries, 67404 Illkirch Cedex, France Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Centre (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany * email: manfred.jung@pharmazie.uni-freiburg.de Contents: S2-S10: additional synthetic procedures and analytical data S11: Figure S1. Western blots with BE(2)-C cells S12: Figure S2. Copies of 1 H- and 13 C-NMR-spectra of compound 4g S13: References S1

Characterization data: Ethyl 2-(4-bromophenyl)-1,3-thiazole-4-carboxylate (2b). 432 mg (2 mmol) 4-bromothiobenzamide and 301 µl (2.4 mmol) ethyl bromopyruvate were used according to method A. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.59 (s, 1H, 5-H), 7.94-7.92 (m, 2H, 2 -,6 -H), 7.75-7.72 (m, 2H, 3 -,5 -H), 4.36-4.31 (q, 2H, O-CH 2 -CH 3, 3 J = 7.1 Hz), 1.34-1.31 (t, 3H, O-CH 2 -CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz): δ 167.0 (2-C), 161.1 (COOEt), 147.4 (4-C), 132.8 (2 -,6 -C), 131.9 (4 -C), 130.1 (5-C), 128.8 (3 -,5 -C), 124.7 (1 -C), 61.5 (O-CH 2 -CH 3 ), 14.6 (O-CH 2 -CH 3 ). Ethyl 2-benzyl-1,3-thiazole-4-carboxylate (2c). 530 mg (3.5 mmol) 2-phenyl-thioacetamide and 527 µl (4.2 mmol) ethyl bromopyruvate were used according to method A. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.37 (s, 1H, 5-H), 7.38-7.33 (m, 4H, 2 -,3-5 -,6 -H), 7.31-7.26 (m, 1H, 4 -H), 4.37 (s, 2H, CH 2 ), 4.31-4.26 (q, 2H, O-CH 2 -CH 3, 3 J = 7.1 Hz), 1.31-1.26 (t, 3H, O-CH 2 - CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz): δ 171.3 (2-C), 161.2 (COOEt), 146.2 (4-C), 138.2 (1 - C), 129.7 (5-C), 192.4 (2 -,6 -C), 129.2 (3 -,5 -C), 127.5 (4 -C), 38.9 (CH 2 ), 61.5 (O-CH 2 -CH 3 ), 14.6 (O-CH 2 -CH 3 ). Ethyl 2-(diphenylmethyl)-1,3-thiazole-4-carboxylate (2d). 986 mg (4.3 mmol) 2,2-diphenylthioacetamide and 648 µl (5.2 mmol) ethyl bromopyruvate were used according to method A. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.43 (s, 1H, 5-H), 7.38-7.34 (m, 4H, 2x2 -,6 -H), 7.31-7.26 (m, 6H, 2x3 -,4-5 -H), 6.03 (s, 1H, CH(Ph) 2 ), 4.30-4.25 (q, 2H, O-CH 2 -CH 3, 3 J = 7.1 Hz), 1.30-1.26 (t, 3H, O-CH 2 -CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz): δ 174.2 (2-C), 161.2 (COOEt), 149.6 (4-C), 142.1 (2x1 -C), 129.7 (5-C), 129.1 (2x 3 -,5 -C), 129.1 (2x2 -,6 -C), 127.6 (2x4 -C), 61.2 (O-CH 2 -CH 3 ), 54.0 (CH(Ph) 2 ), 14.6 (O-CH 2 -CH 3 ). Ethyl 2-phenyl-1,3-thiazole-4-carboxylate (2e). 1 g (7.3 mmol) thiobenzamide and 1.1 ml (8.8 mmol) ethyl bromopyruvate were used according to method A. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.58 (s, 1H, 5-H), 8.00-7.98 (m, 2H, 2 -,6 -H), 7.55-7.53 (m, 3H, 3 -,4 -,5 -H), 4.37-4.32 (q, 2H, O-CH 2 -CH 3, 3 J = 7.1 Hz), 1.35-1.32 (t, 3H, O-CH 2 -CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz): δ 168.1 (2-C), 161.1 (COOEt), 147.4 (4-C), 132.8 (1 -C), 131.3 (4 -C), 129.8 (3 -,5 - C), 129.7 (5-C), 126.9 (2 -,6 -C), 61.3 (O-CH 2 -CH 3 ), 14.6 (O-CH 2 -CH 3 ). 2-(4-bromophenyl)-1,3-thiazole-4-carboxylic acid (3b). 350 mg (1.1 mmol) 2b and 4.5 ml (4.5 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 MHz): δ 13.16 (bs, 1H, COOH), 8.53 (s, 1H, 5-H), 7.95-7.92 (m, 2H, 2 -,6 -H), 7.76-7.72 (m, 2H, 3 -,5 - H). 13 C-NMR (100 MHz): δ 166.6 (2-C), 162.4 (COOH), 148.6 (4-C), 132.7 (2 -,6 -C), 132.1 (4 -C), 129.6 (5-C), 128.7 (3 -,5 -C), 124.5 (1 -C). 2-benzyl-1,3-thiazole-4-carboxylic acid (3c). 425 mg (1.7 mmol) 2c and 6.9 ml (6.9 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.30 (s, 1H, 5-H), 7.38-7.33 (m, 4H, 2 -,3-5 -,6 -H), 7.31-7.26 (m, 1H, 4 -H), 4.36 (s, 2H, CH 2 ). 13 C-NMR (100 MHz): δ 170.9 (2-C), 162.5 (COOH), 147.3 (4-C), 138.2 (1 -C), 129.4 (2 -,6 -C), 129.2 (5- C), 129.2 (3 -,5 -C), 127.5 (4 -C), 38.9 (CH 2 ). 2-(diphenylmethyl)-1,3-thiazole-4-carboxylic acid (3d). 777 mg (2.4 mmol) 2d and 9.6 ml (9.6 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 MHz): δ 13.02 (bs, 1H, COOH), 8.37 (s, 1H, 5-H), 7.38-7.26 (m, 10H, (Ph) 2 CH), 6.03 (s, 1H, CH(Ph) 2 ). 13 C-NMR (100 MHz): δ 173.7 (2-C), 162.5 (COOH), 147.7 (4-C), 142.2 (2x1 -C), 129.2 (5-C), 129.1 (2x 3 -,5 -C), 129.1 (2x2 -,6 -C), 127.6 (2x4 -C), 54.0 (CH(Ph) 2 ). S2

2-phenyl-1,3-thiazole-4-carboxylic acid (3e). 528 mg (2.3 mmol) 2e and 9.1 ml (9.1 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 MHz): δ 13.02 (bs, 1H, COOH), 8.51 (s, 1H, 5-H), 8.00-7.97 (m, 2H, 2,6 -H), 7.55-7.52 (m, 3H, 3 -,4 -,5 -H). 13 C-NMR (100 MHz): δ 167.9 (2-C), 162.5 (COOH), 148.5 (4-C), 132.9 (1 -C), 131.2 (4 -C), 129.8 (3 -,5 - C), 129.2 (5-C), 126.8 (2 -,6 -C). 2-(4-bromophenyl)-1,3-thiazole-4-carbohydroxamic acid (4b). 47 mg (0.17 mmol) 3b, 20 µl (0.21 mmol) ethyl chloroformate, 25 µl (0.23 mmol) N-methylmorpholine, 18 mg (0.26 mmol) hydroxylamine hydrochloride and 15 mg (0.26 mmol) potassium hydroxide were used according to method C. Overall yield: 35 mg (6%). Mp: 207-209 C. 1 H-NMR (DMSO-d 6, 400 MHz): δ 11.31 (bs, 1H, NH-OH), 9.21 (bs, 1H, NH-OH), 8.30 (s, 1H, 5-H), 8.02-8.00 (m, 2H, 2 -,6 -H), 7.76-7.73 (m, 2H, 3 -,5 -H). 13 C-NMR (100 MHz): δ 166.5 (2-C), 158.6 (CONH), 149.6 (4-C), 132.6 (2 -,6 -C), 132.1 (4 -C), 128.8 (3 -,5 -C), 124.5 (5-C or 1 -C), 124.4 (5-C or 1 -C). MS (APCI, m/z): 298.9488 [M Br79 + H] +, 300.9466 [M Br81 + H] +. Purity >99% (16.61 min, M1). 2-benzyl-1,3-thiazole-4-carbohydroxamic acid (4c). 222 mg (1 mmol) 3c, 115 µl (1.2 mmol) ethyl chloroformate, 143 µl (1.3 mmol) N-methylmorpholine, 104 mg (1.5 mmol) hydroxylamine hydrochloride and 84 mg (1.5 mmol) potassium hydroxide were used according to method C. Overall yield: 37 mg (5%). Mp: 168-170 C. 1 H-NMR (DMSO-d 6, 400 MHz): δ 11.17 (bs, 1H, NH-OH), 9.08 (bs, 1H, NH-OH), 8.08 (s, 1H, 5-H), 7.38-7.34 (m, 4H, 2 -,3-5 -,6 -H), 7.30-7.27 (m, 1H, 4 -H), 4.36 (s, 2H, CH 2 ). 13 C-NMR (100 MHz): δ 171.0 (2-C), 158.9 (CONH), 148.6 (4-C), 138.2 (1 -C), 129.4 (2 -,6 -C), 129.2 (3 -,5 -C), 127.5 (4 -C), 124.0 (5-C), 38.9 (CH 2 ). MS (APCI, m/z): 235.0538 [M + H] +. Purity >99% (15.69 min, M3). 2-(diphenylmethyl)-1,3-thiazole-4-carbohydroxamic acid (4d). 455 mg (1.54 mmol) 3d, 176 µl (1.85 mmol) ethyl chloroformate, 220 µl (2.0 mmol) N-methylmorpholine, 161 mg (2.3 mmol) hydroxylamine hydrochloride and 130 mg (2.3 mmol) potassium hydroxide were used according to method C. Overall yield: 67 mg (5%). Mp: 174-176 C. 1 H-NMR (DMSO-d 6, 400 MHz): δ 11.18 (bs, 1H, NH-OH), 9.09 (bs, 1H, NH-OH), 8.15 (s, 1H, 5-H), 7.42-7.40 (m, 4H, 2x2 -,6 -H), 7.36-7.33 (m, 4H, 2x3 -,5 -H), 7.29-7.24 (m, 2H, 2x4 -H), 5.98 (s, 1H, CH(Ph) 2 ). 13 C-NMR (100 MHz): δ 173.2 (2-C), 158.9 (CONH), 149.2 (4-C), 142.2 (2x1 -C), 129.1 (2x 3 -,5 -C), 129.0 (2x2 -,6 -C), 127.5 (2x4 -C), 123.9 (5-C), 53.9 (CH(Ph) 2 ). MS (APCI, m/z): 311.0847 [M + H] +. Purity >99% (19.62 min, M3). 2-phenyl-1,3-thiazole-4-carbohydroxamic acid (4e). 40 mg (0.15 mmol) 3e, 17 µl (0.18 mmol) ethyl chloroformate, 22 µl (0.2 mmol) N-methylmorpholine, 16 mg (0.23 mmol) hydroxylamine hydrochloride and 13 mg (0.23 mmol) potassium hydroxide were used according to method C. Overall yield: 35 mg (2%). Mp: 141-143 C. 1 H-NMR (DMSO-d 6, 400 MHz): δ 10.30 (bs, 1H, NH-OH), 9.52 (bs, 1H, NH-OH), 8.26 (s, 1H, 5-H), 8.07-8.04 (m, 2H, 2,6 -H), 7.55-7.52 (m, 3H, 3 -,4 -,5 -H). 13 C-NMR (100 MHz): δ 167.6 (2-C), 158.7 (CONH), 149.8 (4- C), 133.0 (1 -C), 131.1 (4 -C), 129.6 (3 -,5 -C), 126.9 (2 -,6 -C), 123.7 (5-C). MS (APCI, m/z): 221.0377 [M + H] +. Purity >99% (15.80 min, M3). Ethyl 2-(4-bromphenyl)-1,3-oxazole-4-carboxylate (2g). 500 mg (2.5 mmol) 4- bromobenzamide, 375 µl (3.0 mmol) ethyl bromopyruvate and 850 mg (2.5 mmol) silver hexafluoroantimonate were used according to method D. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.97 (s, 1H, 5-H), 7.96-7.93 (m, 2H, 3 -,5 -H), 7.79-7.77 (m, 2H, 2 -,6 -H), 4.35-4.30 (q, 2H, O-CH 2 - CH 3, 3 J = 7.1 Hz), 1.33-1.30 (t, 3H, O-CH 2 -CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz, δ S3

[ppm]):161.0 (2-C), 161.0 (COOEt), 145.4 (5-C), 134.2 (4-C), 132.8 (2 -,6 -C), 128.7 (3 -,5 -C), 125.6 (4 -C or 1 -C), 125.4 (4 -C or 1 -C), 61.1 (O-CH 2 -CH 3 ), 14.6 (O-CH 2 -CH 3 ). Ethyl 2-(biphenyl-4-yl)-1,3-oxazole-4-carboxylate (2h). 1.1 g (5.6 mmol) biphenyl-4- carboxamide, 842 µl (6.7 mmol) ethyl bromopyruvate and 1.9 g (5.6 mmol) silver hexafluoroantimonate were used according to method D. 1 H-NMR ((DMSO-d 6, 400 MHz): δ 8.97 (s, 1H, 5-H), 8.11-8.08 (m, 2H, 2 -,6 -H), 7.89-7.87 (m, 2H, 3 -,5 -H), 7.77-7.75 (m, 2H, 2 -,6 -H), 7.53-7.49 (m, 2H, 3 -, 5 -H), 7.45-7.41 (m, 1H, 4 -H), 4.36-4.31 (q, 2H, O-CH 2 -CH 3, 3 J = 7.1 Hz), 1.34-1.31 (t, 3H, O-CH 2 -CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz): δ 161.6 (2-C), 161.1 (COOEt), 146.1 (5-C), 143.2 (4 -C), 139.3 (1 -C), 134.2 (4-C), 129.5 (3 -,5 -C), 128.7 (4 -C), 127.9 (3 -,5 -C), 127.4 (2 -,6 -C), 127.2 (2 -,6 -C), 125.4 (1 -C), 61.1 (O-CH 2 -CH 3 ), 14.6 (O-CH 2 -CH 3 ). Ethyl 2-(diphenylmethyl)-1,3-oxazole-4-carboxylate (2i). 635 mg (3.0 mmol) 2,2- diphenylacetamide, 453 µl (3.6 mmol) ethyl bromopyruvate and 1 g (3.0 mmol) silver hexafluoroantimonate were used according to method D. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.83 (s, 1H, 5-H), 7.38-7.26 (m, 10H, CH-(Ph) 2 ), 5,88 (s, 1H, CH(Ph) 2 ), 4.30-4.24 (q, 2H, O-CH 2 - CH 3, 3 J = 7.1 Hz), 1.29-1.25 (t, 3H, O-CH 2 -CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz): δ 165.4 (2- C), 161.1 (COOEt), 146.2 (5-C), 140.0 (2x 1 -C), 133.0 (4-C), 129.1 (2x 3 -,5 -C), 128.9 (2x 2 -,6 -C), 127.6 (2x4 -C), 61.1 (O-CH 2 -CH 3 ), 49.8 (CH(Ph) 2 ), 14.6 (O-CH 2 -CH 3 ). Ethyl 2-(thiophene-2-yl)-1,3-oxazole-4-carboxylate (2j). 550 mg (4.3 mmol) thiophene-2- carboxamide, 650 µl (5.2 mmol) ethyl bromopyruvate and 1.5 g (4.3 mmol) silver hexafluoroantimonate were used according to method D. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.89 (s, 1H, 5-H), 7.88-7.87 (m, 1H, 3 -/4 -/5 -H), 7.80-7.79 (m, 1H, 3 -/4 -/5 -H), 7.26-7.24 (m, 1H, 3 -/4 -/5 -H), 4.34-4.28 (q, 2H, O-CH 2 -CH 3, 3 J = 7.1 Hz), 1.32-1.29 (t, 3H, O-CH 2 -CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz): δ 160.9 (COOEt), 158.0 (2-C), 145.6 (5-C) 134.0 (4-C), 131.2 (3 - /4 -/5 -C), 129.8 (3-4 -/5 -C), 129.1 (3-4 -/5 -C), 128.3 (2 -C), 61.2 (O-CH 2 -CH 3 ), 14.6 (O- CH 2 -CH 3 ). Ethyl 2-(2-bromophenyl)-1,3-oxazole-4-carboxylate (2k). 802 mg (4.0 mmol) 2- bromobenzamide, 605 µl (4.8 mmol) ethyl bromopyruvate and 1.4 g (4.0 mmol) silver hexafluoroantimonate were used according to method D. 1 H-NMR (DMSO-d 6, 400 MHz): δ 9.05 (s, 1H, 5-H), 7.93-7.91 (m, 1H, 3 -H), 7.86-7.84 (m, 1H, 6 -H), 7.60-7.56 (m, 1H, 5 -H), 7.54-7.51 (m, 1H, 4 -H), 4.36-4.31 (q, 2H, O-CH 2 -CH 3, 3 J = 7.1 Hz), 1.33-1.30 (t, 3H, O-CH 2 -CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz): δ 161.0 (COOEt), 160.4 (2-C), 146.6 (5-C), 134.6 (4-C), 133.9 (3 -C), 133.2 (4 -C), 132.3 (6 -C), 128.6 (5 -C), 127.7 (1 -C), 121.0 (2 -C), 61.2 (O-CH 2 -CH 3 ), 14.6 (O-CH 2 -CH 3 ). Ethyl 2-(4-chlorophenyl)-1,3-oxazole-4-carboxylate (2l). 578 mg (3.7 mmol) 4- chlorobenzamide, 559 µl (4.5 mmol) ethyl bromopyruvate and 1.3 g (3.7 mmol) silver hexafluoroantimonate were used according to method D. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.97 (s, 1H, 5-H), 8.03-8.01 (m, 2H, 2 -,6 -H), 7.65-7.63 (m, 2H, 3 -,5 -H), 4.35-4.29 (q, 2H, O-CH 2 - CH 3, 3 J = 7.1 Hz), 1.33-1.29 (t, 3H, O-CH 2 -CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz): δ 161.0 (COOEt), 160.8 (2-C), 145.4 (5-C), 136.5 (4 -C), 134.2 (4-C), 129.9 (3 -,5 -C), 128.6 (2 -,6 -C), 125.3 (1 -C), 61.2 (O-CH 2 -CH 3 ), 14.6 (O-CH 2 -CH 3 ). Ethyl 2-(4-fluorophenyl)-1,3-oxazole-4-carboxylate (2m). 453 mg (3.3 mmol) 4- fluorobenzamide, 621 µl (5 mmol) ethyl bromopyruvate and 1.1 g (3.3 mmol) silver S4

hexafluoroantimonate were used according to method D. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.96 (s, 1H, 5-H), 8.10-8.05 (m, 2H, 2 -,6 -H), 7.44-7.40 (m, 2H, 3 -,5 -H), 4.35-4.30 (q, 2H, O-CH 2 - CH 3, 3 J = 7.1 Hz), 1.33-1.30 (t, 3H, O-CH 2 -CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz): δ 164.2 (d, 1 J = 248.0 Hz, 4 -C), 161.0 (COOEt), 160.9 (2-C), 146.2 (5-C), 134.1 (4-C), 129.4 (d, 2C, 3 J = 9.0 Hz, 2 -,6 -C), 123.1 (d, 4 J = 3.0 Hz, 1 -C), 116.9 (d, 2C, 2 J = 22.0 Hz, 3 -,5 -C), 61.1 (O- CH 2 -CH 3 ), 14.6 (O-CH 2 -CH 3 ). Ethyl 2-(4-methoxyphenyl)-1,3-oxazole-4-carboxylate (2n). 581 mg (3.9 mmol) 4- methoxybenzamide, 580 µl (4.6 mmol) ethyl bromopyruvate and 1.3 g (3.9 mmol) silver hexafluoroantimonate were used according to method D. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.86 (s, 1H, 5-H), 7.97-7.94 (m, 2H, 2 -,6 -H), 7.12-7.10 (m, 2H, 3 -,5 -H), 4.34-4.28 (q, 2H, O-CH 2 - CH 3, 3 J = 7.1 Hz), 3.84 (s, 3H, O-CH 3 ), 1.32-1.29 (t, 3H, O-CH 2 -CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz): δ 162.0 (4 -C), 161.9 (COOEt), 161.2 (2-C), 145.5 (5-C), 133.9 (4-C), 128.6 (2 -,6 - C), 119.0 (1 -C), 115.1 (3 -,5 -C), 61.0 (O-CH 2 -CH 3 ), 55.9 (O-CH 3 ), 14.6 (O-CH 2 -CH 3 ). 2-phenyl-1,3-oxazole-4-carboxylic acid (3f). This compound has already been described. 1 591 mg (2.72 mmol) 2f and 10.9 ml (10.9 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 MHz): δ 13.05 (bs, 1H, COOH), 8.85 (s, 1H, 5-H), 8.04-7.99 (m, 2H, 2 -,6 -H), 7.59-7.56 (m, 3H, 3 -,4 -,5 -H). 13 C-NMR (100 MHz, δ [ppm]):167.7 (2-C), 162.4 (COOH), 145.8 (5-C), 134.9 (4-C), 131.7 (4 -C), 129.7 (3 -,5 -C), 126.7 (2 -,6 -C), 126.6 (1 -C). 2-(4-bromphenyl)-1,3-oxazole-4-carboxylic acid (3g). 441 mg (1.49 mmol) 2g and 5.7 ml (5.7 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 MHz): δ 13.24 (bs, 1H, COOH), 8.88 (s, 1H, 5-H), 7.96-7.92 (m, 2H, 3 -,5 -H), 7.80-7.76 (m, 2H, 2 -,6 - H). 13 C-NMR (100 MHz): δ 162.3 (COOH), 160.8 (2-C), 146.1 (5-C), 135.0 (4-C), 132.8 (2 -,6 - C), 128.6 (3 -,5 -C), 125.8 (4 -C or 1 -C), 125.3 (4 -C or 1 -C). 2-(biphenyl-4-yl)-1,3-oxazole-4-carboxylic acid (3h). 417 mg (1.42 mmol) 2h and 7 ml (7 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 MHz): δ 13.21 (bs, 1H, COOH), 8.88 (s, 1H, 5-H), 8.11-8.08 (m, 2H, 2 -,6 -H), 7.90-7.87 (m, 2H, 3 -,5 -H), 7.77-7.74 (m, 2H, 2 -,6 -H), 7.53-7.49 (m, 2H, 3 -, 5 -H), 7.45-7.40 (m, 1H, 4 -H). 13 C-NMR (100 MHz): δ 162.4 (COOH), 161.4 (2-C), 145.9 (5-C), 143.0 (4 -C), 139.3 (1 -C), 135.0 (4-C), 129.5 (3 -,5 -C), 128.6 (4 -C), 127.9 (3 -,5 -C), 127.3 (2 -,6 -C), 127.2 (2 -,6 -C), 125.5 (1 - C). 2-(diphenylmethyl)-1,3-oxazole-4-carboxylic acid (3i). 189 mg (0.65 mmol) 2i and 2.4 ml (2.4 mmol) LiOH (1 M) were used according to method B. The compound was directly processed further and no NMR spectrum was recorded. 2-(thiophene-2-yl)-1,3-oxazole-4-carboxylic acid (3j). 333 mg (1.5 mmol) 2j and 6 ml (6 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.79 (s, 1H, 5-H), 7.86-7.85 (m, 1H, 3 -,4 -,5 -H), 7.78-7.77 (m, 1H, 3 -,4 -,5 -H), 7.26-7.24 (m, 1H, 3 -,4 -,5 -H). 13 C-NMR (100 MHz): δ 162.2 (COOH), 157.8 (2-C), 145.3 (5-C) 134.7 (4-C), 131.0 (3-4 -/5 -C), 129.6 (3-4 -/5 -C), 129.1 (3-4 -/5 -C), 128.5 (2 -C). 2-(2-bromophenyl)-1,3-oxazole-4-carboxylic acid (3k). 340 mg (1.15 mmol) 2k and 4.6 ml (4.6 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.96 (s, 1H, 5-H), 7.93-7.91 (m, 1H, 3 -H), 7.86-7.84 (m, 1H, 6 -H), 7.60-7.56 (m, 1H, 5 -H), S5

7.54-7.49 (m, 1H, 4 -H). 13 C-NMR (100 MHz): δ 162.3 (COOH), 160.2 (2-C), 146.3 (5-C), 134.7 (4-C), 133.1 (3 -C), 132.2 (4 -C), 128.6 (6 -C), 128.6 (5 -C), 127.8 (1 -C), 121.0 (2 -C). 2-(4-chlorophenyl)-1,3-oxazole-4-carboxylic acid (3l). 501 mg (2 mmol) 2l and 8 ml (8 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.85 (s, 1H, 5-H), 8.02-7.99 (m, 2H, 2 -,6 -H), 7.64-7.62 (m, 2H, 3 -,5 -H). 13 C-NMR (100 MHz): δ 162.3 (COOH), 160.7 (2-C), 146.0 (5-C), 136.4 (4 -C), 135.0 (4-C), 129.8 (3 -,5 -C), 128.5 (2 -,6 -C), 125.4 (1 -C). 2-(4-fluorophenyl)-1,3-oxazole-4-carboxylic acid (3m). 500 mg (2.13 mmol) 2m and 8.5 ml (8.5 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 MHz): δ 13.21 (bs, 1H, COOH), 8.86 (s, 1H, 5-H), 8.09-8.04 (m, 2H, 2 -,6 -H), 7.45-7.39 (m, 2H, 3 -,5 - H). 13 C-NMR (100 MHz): δ 163.7 (d, 1 J = 248.0 Hz, 4 -C), 162.0 (COOH), 160.4 (2-C), 145.5 (5-C), 134.5 (4-C), 128.9 (d, 2C, 3 J = 9.0 Hz, 2 -,6 -C), 122.8 (d, 4 J = 3.0 Hz, 1 -C), 116.5 (d, 2C, 2 J = 22.0 Hz, 3 -,5 -C). 2-(4-methoxyphenyl)-1,3-oxazole-4-carboxylic acid (3n). 267 mg (1.08 mmol) 2n and 4.3 ml (4.3 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.71 (s, 1H, 5-H), 7.95-7.82 (m, 2H, 2 -,6 -H), 7.11-7.08 (m, 2H, 3 -,5 -H), 3.81 (s, 3H, O- CH 3 ). 13 C-NMR (100 MHz): δ 162.6 (COOH), 161.9 (4 -C), 161.2 (2-C), 145.1 (5-C), 134.6 (4- C), 128.5 (2 -,6 -C), 119.0 (1 -C), 115.1 (3 -,5 -C), 55.8 (O-CH 3 ). 2-phenyl-1,3-oxazole-4-carbohydroxamic acid (4f). This compound has already been described. 1 236 mg (1.25 mmol) 3f, 143 µl (1.5 mmol) ethyl chloroformate, 178 µl, (1.6 mmol) N-methylmorpholine, 130 mg (1.9 mmol) hydroxylamine hydrochloride and 105 mg (1.9 mmol) potassium hydroxide were used according to method C. Overall yield: 156 mg (11%). Mp: 164-166 C. 1 H-NMR (DMSO-d 6, 400 MHz): δ 10.14 (bs, 1H, NH-OH), 9.52 (bs, 1H, NH-OH), 8.65 (s, 1H, 5-H), 8.05 (m, 2H, 2 -,6 -H), 7.58 (m, 3H, 3 -,4 -,5 -H). 13 C-NMR (100 MHz): δ 161.0 (2- C), 158.1 (CONH), 141.9 (5-C), 136.4 (4-C), 131.6 (4 -C), 129.7 (3 -,5 -C), 126.7 (1 -C), 126.7 (2 -,4 -C). MS (APCI, m/z): 205.0606 [M + H] +. Purity >98% (14.35 min, M3). 2-(4-bromphenyl)-1,3-oxazole-4-carbohydroxamic acid (4g). 200 mg (0.75 mmol) 3g, 86 µl (0.9 mmol) ethyl chloroformate, 107 µl, (1 mmol) N-methylmorpholine, 78 mg (1.13 mmol) hydroxylamine hydrochloride and 63 mg (1.13 mmol) potassium hydroxide were used according to method C. Overall yield: 120 mg (17%). Mp: 175-177 C.; 1 H-NMR (DMSO-d 6, 400 MHz): δ 11.20 (bs, 1H, NH-OH), 9.16 (bs, 1H, NH-OH), 8.70 (s, 1H, 5-H), 7.94 (m, 2H, 3 -,5 -H), 7.79 (m, 2H, 2 -,6 -H). 13 C-NMR (100 MHz): δ 160.3 (2-C), 158.0 (CONH), 142.4 (5-C), 136.3 (4-C), 132.8 (2 -,6 -C), 128.6 (3 -,5 -C), 125.9 (4 -C), 125.2 (1 -C). MS (APCI, m/z): 282.9710 [M Br79 + H] +, 284.9689 [M Br81 + H] +. Purity >98% (15.38 min, M1). For 4g as an representative member, the IR spectral data are shown in an exemplary manner. The significant groups are listed and very similar values are obtained for the other target compounds. IR (cm 1 ): 3456 (N-H), 3160 (O H), 3017 (C-H), 1738 (C=O). 2-(biphenyl-4-yl)-1,3-oxazole-4-carbohydroxamic acid (4h). 246 mg (0.93 mmol) 3h, 106 µl (1.11 mmol) ethyl chloroformate, 132 µl, (1.20 mmol) N-methylmorpholine, 97 mg (1.4 mmol) hydroxylamine hydrochloride and 79 mg (1.4 mmol) potassium hydroxide were used according to method C. Overall yield: 29 mg (2%). Mp: 196-198 C. 1 H-NMR (CD 3 OD, 400 MHz): δ 8.48 (s, 1H, 5-H), 8.23-8.16 (m, 2H, 2 -,6 -H), 7.86-7.80 (m, 2H, 3 -,5 -H), 7.75-7.69 (m, 2H, 2 -,6 -H), 7.55-7.47 (m, 2H, 3 -, 5 -H), 7.46-7.39 (m, 1H, 4 -H). 13 C-NMR (100 S6

MHz): δ 161.8 (2-C), 159.4 (CONH), 143.9 (4 -C), 141.2 (5-C), 139.8 (1 -C), 135.4 (4-C), 128.6 (3 -,5 -C), 127.7 (4 -C), 127.1 (3 -,5 -C), 126.8 (2 -,6 -C), 126.6 (2 -,6 -C), 125.2 (1 - C). MS (APCI, m/z): 281.0918 [M + H] +. Purity >98% (17.81 min, M1). 2-(diphenylmethyl)-1,3-oxazole-4-carbohydroxamic acid (4i). 60 mg (0.21 mmol) 3i, 25 µl (0.26 mmol) ethyl chloroformate, 30 µl, (0.27 mmol) N-methylmorpholine, 46 mg (0.7 mmol) hydroxylamine hydrochloride and 37 mg (0.7 mmol) potassium hydroxide were used according to method C. Overall yield: 10 mg (1%). Mp: 181-183 C. 1 H-NMR (DMSO-d 6, 400 MHz): δ 11.08 (bs, 1H, NH-OH), 9.07 (bs, 1H, NH-OH), 8.55 (s, 1H, 5-H), 7.37-7.33 (m, 8H, 2x 2 -,3 -,5 -,6 -H), 7.31-7.24 (m, 2H, 2x 4 -H), 5,82 (s, 1H, CH-Ph 2 ). 13 C-NMR (100 MHz): δ 164.1 (2- C), 157.8 (CONH), 141.6 (5-C), 139.7 (2x 1 -C), 134.7 (4-C), 128.7 (2x 3 -,5 -C), 128.4 (2x 2 -,6 -C), 127.2 (4 -C), 49.5 (CH-Ph 2 ). MS (APCI, m/z): 295.1075 [M + H] +. Purity >99% (18.73 min, M3). 2-(thiophene-2-yl)-1,3-oxazole-4-carbohydroxamic acid (4j). 200 mg (1.02 mmol) 3j, 117 µl (1.23 mmol) ethyl chloroformate, 147 µl, (1.33 mmol) N-methylmorpholine, 107 mg (1.54 mmol) hydroxylamine hydrochloride and 86 mg (1.54 mmol) potassium hydroxide were used according to method C. Overall yield: 16 mg (2%). Mp: 168-170 C. 1 H-NMR (DMSO-d 6, 400 MHz): δ 11.19 (bs, 1H, NH-OH), 9.17 (bs, 1H, NH-OH), 8.61 (s, 1H, 5-H), 7.88-7.82 (m, 1H, 3 -,4 -,5 -H), 7.78-7.73 (m, 1H, 3 -,4 -,5 -H), 7.28-7.21 (m, 1H, 3 -,4 -,5 -H). 13 C-NMR (100 MHz): δ 158.0 (2-C), 157.4 (CONH), 141.7 (5-C) 136.1 (4-C), 131.0 (3-4 -/5 -C), 129.6 (3-4 - /5 -C), 129.1 (3-4 -/5 -C), 128.6 (2 -C). MS (APCI, m/z): 211.0173 [M + H] +. Purity >99% (13.83 min, M3). 2-(2-bromophenyl)-1,3-oxazole-4-carbohydroxamic acid (4k). 248 mg (0.93 mmol) 3k, 106 µl (1.11 mmol) ethyl chloroformate, 132 µl (1.2 mmol) N-methylmorpholine, 100 mg (1.43 mmol) hydroxylamine hydrochloride and 78 mg (1.43 mmol) potassium hydroxide were used according to method C. Overall yield: 34 mg (3%). Mp: 157-159 C. 1 H-NMR (DMSO-d 6, 400 MHz): δ 11.17 (bs, 1H, NH-OH), 9.15 (bs, 1H, NH-OH), 8.78 (s, 1H, 5-H), 7.94-7.88 (m, 1H, 3 - H), 7.87-7.80 (m, 1H, 6 -H), 7.61-7.56 (m, 1H, 5 -H), 7.55-7.48 (m, 1H, 4 -H). 13 C-NMR (100 MHz): δ 159.8 (2-C), 158.0 (CONH), 142.6 (5-C), 135.9 (4-C), 134.5 (3 -C), 133.1 (4 -C), 132.3 (6 -C), 128.5 (5 -C), 128.0 (1 -C), 121.1 (2 -C). MS (ESI, m/z): 282.9714 [M Br79 + H] +, 284.9693 [M Br81 + H] +, 304.9534 [M Br79 + Na] +, 306.9511 [M Br81 + Na] +. Purity >99% (16.23 min, M3). 2-(4-chlorophenyl)-1,3-oxazole-4-carbohydroxamic acid (4l). 386 mg (1.7 mmol) 3l, 197 µl (2.07 mmol) ethyl chloroformate, 247 µl (2.24 mmol) N-methylmorpholine, 240 mg (3.45 mmol) hydroxylamine hydrochloride and 194 mg (3.45 mmol) potassium hydroxide were used according to method C. Overall yield: 35 mg (4%). Mp: 180-182 C. 1 H-NMR (DMSO-d 6, 400 MHz): δ 11.19 (bs, 1H, NH-OH), 9.16 (bs, 1H, NH-OH), 8.69 (s, 1H, 5-H), 8.02-8.00 (m, 2H, 2 -,6 -H), 7.67-7.64 (m, 2H, 3 -,5 -H). 13 C-NMR (100 MHz): δ 159.8 (2-C), 157.6 (CONH), 141.9 (5-C), 135.9 (4-C), 135.9 (4 -C), 129.4 (3 -,5 -C), 128.0 (2 -,6 -C), 125.1 (1 -C). MS (ESI, m/z): 239.0219 [M Cl35 + H] +, 241.0191 [M Cl37 + H] +, 261.0039 [M Cl35 + Na] +, 263.0009 [M Cl37 + Na] +. Purity >98% (16.61 min, M2). 2-(4-fluorophenyl)-1,3-oxazole-4-carbohydroxamic acid (4m). 300 mg (1.45 mmol) 3m, 166 µl (1.74 mmol) ethyl chloroformate, 207 µl (1.88 mmol) N-methylmorpholine, 202 mg (2.9 mmol) hydroxylamine hydrochloride and 163 mg (2.9 mmol) potassium hydroxide were used according to method C. Overall yield: 31 mg (4%). Mp: 174-176 C. 1 H-NMR (DMSO-d 6, 400 MHz): δ 11.18 (bs, 1H, NH-OH), 9.15 (bs, 1H, NH-OH), 8.68 (s, 1H, 5-H), 8.09-8.03 (m, 2H, 2 - S7

,6 -H), 7.46-7.40 (m, 2H, 3 -,5 -H). 13 C-NMR (100 MHz): δ 165.3 (2-C), 161.6 (d, 1 J = 257.2 Hz, 4 -C), 158.1 (CONH), 142.2 (5-C), 136.2 (4-C), 129.2 (d, 2C, 3 J = 9.1 Hz, 2 -,6 -C), 123.4 (d, 4 J = 3.0 Hz, 1 -C), 116.9 (d, 2C, 2 J = 22.4 Hz, 3 -,5 -C). MS (ESI, m/z): 223.0515 [M + H] +, 245.0334 [M + Na] +. Purity >97% (15.01 min, M2). 2-(4-methoxyphenyl)-1,3-oxazole-4-carbohydroxamic acid (4n). 145 mg (0.66 mmol) 3n, 76 µl (0.80 mmol) ethyl chloroformate, 95 µl (0.86 mmol) N-methylmorpholine, 70 mg (1 mmol) hydroxylamine hydrochloride and 56 mg (1 mmol) potassium hydroxide were used according to method C. Overall yield: 29 mg (3%). Mp: 187-189 C. 1 H-NMR (DMSO-d 6, 400 MHz): δ 11.12 (bs, 1H, NH-OH), 9.12 (bs, 1H, NH-OH), 8.60 (s, 1H, 5-H), 7.95 (m, 2H, 2 -,6 -H), 7.12 (m, 2H, 3 -,5 -H), 3.84 (s, 3H, O-CH 3 ). 13 C-NMR (100 MHz): δ 161.9 (4 -C), 161.2 (2-C), 158.3 (CONH) 141.4 (5-C), 136.0 (4-C), 128.5 (2 -,6 -C), 119.3 (1 -C), 115.1 (3 -,5 -C), 55.9 (O-CH 3 ). MS (APCI, m/z): 235.0715 [M + H] +. Purity >97% (13.32 min, M1). Ethyl 2-(6-methoxynaphthalen-2-yl)-1,3-oxazole-4-carboxylate (2p). 241 mg (1.1 mmol) ethyl 2-bromo-1,3-oxazole-4-carboxylate, 332 mg (1.6 mmol) 6-methoxy-2-naphthylboronic acid, 127 mg (0.11 mmol) Pd(P(Ph) 3 ) 4 and 5.5 ml (11.0 mmol) Na 2 CO 3 (2 M) were used according to method E. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.93 (s, 1H, 5-H), 8.55-8.54 (m, 1H, 1 -H), 8.05-7.95 (m, 3H, 3 -,4 -,8 -H), 7.41 (m, 1H, 5 -H), 7.27-7.24 (m, 1H, 7 -H), 4.35-4.30 (q, 2H, O-CH 2 -CH 3, 3 J = 7.1 Hz), 3.91 (s, 3H, O-CH 3 ), 1.34-1.30 (t, 3H, O-CH 2 -CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz): δ 162.1 (COOEt), 161.2 (2-C), 159.2 (6 -C), 145.9 (5-C), 136.0 (Ar- C), 134.1 (4-C), 130.9 (Ar-C), 128.3 (Ar-C), 128.2 (Ar-C), 126.8 (Ar-C), 123.8 (Ar-C), 121.5 (Ar-C), 120.2 (7 -C), 106.6 (5 -C), 61.1 (O-CH 2 -CH 3 ), 55.8 (O-CH 3 ), 14.6 (O-CH 2 -CH 3 ). Ethyl 2-(4-methylphenyl)-1,3-oxazole-4-carboxylate (2q). 207 mg (0.9 mmol) ethyl 2- bromo-1,3-oxazole-4-carboxylate, 192 mg (1.4 mmol) p-tolylboronic acid, 109 mg (0.09 mmol) Pd(P(Ph) 3 ) 4 and 4.7 ml (9.4 mmol) Na 2 CO 3 (2 M) were used according to method E. The compound was directly processed further and no NMR-spectra was recorded. Ethyl 2-(biphenyl-3-yl)-1,3-oxazole-4-carboxylate (2r). 407 mg (1.9 mmol) ethyl 2-bromo- 1,3-oxazole-4-carboxylate, 550 mg (2.8 mmol) biphenyl-3-boronic acid, 214 mg (0.19 mmol) Pd(P(Ph) 3 ) 4 and 9.5 ml (19.0 mmol) Na 2 CO 3 (2 M) were used according to method E. 1 H-NMR (DMSO-d 6, 400 MHz): δ 9.00 (s, 1H, 5-H), 8.24-8.23 (m, 1H, 2 -H), 8.04-8.01 (m, 1H, 6 -H), 7.90-7.88 (m, 1H, 4 -H), 7.77-7.76 (m, 2H, 2 -,6 -H), 7.70-7.66 (m, 1H, 5 -H), 7.54-7.50 (m, 2H, 3 -,5 -H), 7.45-7.44 (m, 1H, 4 -H), 4.36-4.31 (q, 2H, O-CH 2 -CH 3, 3 J = 7.1 Hz), 1.34-1.31 (t, 3H, O-CH 2 -CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz): δ 161.6 (2-C), 161.0 (COOEt), 146.3 (5- C), 141.6 (1 -C), 139.5 (3 -C), 134.2 (4-C), 130.5 (Ar-C), 130.1 (Ar-C), 129.6 (2C, 3 -,5 -C), 128.5 (Ar-C), 127.3 (2C, 2 -,6 -C), 127.1 (1 -C), 125.8 (Ar-C), 124.8 (Ar-C), 61.2 (O-CH 2 - CH 3 ), 14.6 (O-CH 2 -CH 3 ). 2-(naphthalene-2-yl)-1,3-oxazole-4-carboxylic acid (3o). 170 mg (0.63 mmol) 2o and 2.5 ml (2.5 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 MHz): δ 13.19 (bs, 1H, COOH), 8.92 (s, 1H, 5-H), 8.64 (m, 1H, 1 -H), 8.15-8.12 (m, 1H, Ar-H), 8.10-8.09 (m, 2H, Ar-H), 8.02-8.00 (m, 1H, Ar-H), 7.66-7.60 (m, 2H, Ar-H). 13 C-NMR (100 MHz): δ 162.5 (COOH), 161.7 (2-C), 146.0 (5-C), 135.1 (4-C), 134.3 (Ar-C), 133.0 (Ar-C), 129.5 (Ar-C), 129.2 (Ar-C), 128.3 (Ar-C), 128.2 (Ar-C), 127.6 (Ar-C), 126.9 (1 -C), 123.9 (2 -C), 123.3 (3 -C). 2-(6-methoxynaphthalen-2-yl)-1,3-oxazole-4-carboxylic acid (3p). 120 mg (0.4 mmol) 2p and 1.6 ml (1.6 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 S8

MHz): δ 13.15 (bs, 1H, COOH), 8.88 (s, 1H, 5-H), 8.56 (m, 1H, 1 -H), 8.07-7.97 (m, 3H, 3 -,4 -,8 -H), 7.43 (m, 1H, 5 -H), 7.29-7.26 (m, 1H, 7 -H), 3.92 (s, 3H, O-CH 3 ). 13 C-NMR (100 MHz): δ 162.5 (COOH), 161.9 (2-C), 159.2 (6 -C), 145.7 (5-C), 136.0 (Ar-C), 135.0 (4-C), 130.9 (Ar- C), 128.4 (Ar-C), 128.2 (Ar-C), 126.7 (Ar-C), 123.9 (Ar-C), 121.7 (Ar-C), 120.2 (7 -C), 106.6 (5 -C), 55.8 (O-CH 3 ). 2-(4-methylphenyl)-1,3-oxazole-4-carboxylic acid (3q). 69 mg (0.3 mmol) 2q and 1.2 ml (1.2 mmol) LiOH (1 M) were used according to method B. The compound was directly processed further and no NMR-spectra were recorded. 2-(biphenyl-3-yl)-1,3-oxazole-4-carboxylic acid (3r). 275 mg (0.94 mmol) 2r and 4 ml (4 mmol) LiOH (1 M) were used according to method B. The compound was directly processed further and no NMR-spectra were recorded. 2-(naphthalene-2-yl)-1,3-oxazole-4-carbohydroxamic acid (4o). 125mg (0.52 mmol) 3o, 60 µl (0.63 mmol) ethyl chloroformate, 75 µl (0.67 mmol) N-methylmorpholine, 55 mg (0.78 mmol) hydroxylamine hydrochloride and 44 mg (0.78 mmol) potassium hydroxide were used according to method C. Overall yield: 34 mg (13%). 1 H-NMR (DMSO-d 6, 400 MHz): δ 11.22 (bs, 1H, NH-OH), 9.17 (bs, 1H, NH-OH), 8.74 (s, 1H, 5-H), 8.62 (s, 1H, 1 -H), 8.14-8.09 (m, 3H, 3 -,4 -,8 -H), 8.04-7.99 (m, 1H, 5 -H), 7.67-7.61 (m, 2H, 7 -H). 13 C-NMR (100 MHz): δ 161.3 (2_C), 158.2 (CONH), 142.3 (5-C), 136.4 (4-C), 134.3 (Ar-C), 133.0 (Ar-C), 129.4 (Ar-C), 129.2 (Ar-C), 128.3 (Ar-C), 128.3 (Ar-C), 127.6 (Ar-C), 126.7 (1 -C), 124.0 (2 -C), 123.4 (3 -C). MS (APCI, m/z): 255.0765 [M + H] +. Purity >99% (18.78 min, M3). 2-(6-methoxynaphthalen-2-yl)-1,3-oxazole-4-carbohydroxamic acid (4p). 83 mg (0.31 mmol) 3p, 35 µl (0.37 mmol) ethyl chloroformate, 44 µl (0.40 mmol) N-methylmorpholine, 32 mg (0.46 mmol) hydroxylamine hydrochloride and 26 mg (0.46 mmol) potassium hydroxide were used according to method C. Overall yield: 15 mg (5%). 1 H-NMR (DMSO-d 6, 400 MHz): δ 10.05 (bs, 1H, NH-OH), 9.52 (bs, 1H, NH-OH), 8.55 (s, 1H, 5-H), 8.52 (s, 1H, 1 -H), 8.07-7.96 (m, 3H, 3 -,4 -,8 -H), 7.41 (m, 1H, 5 -H), 7.27 (m, 1H, 7 -H), 3.92 (s, 3H, O-CH 3 ). 13 C-NMR (100 MHz): δ 161.2 (2-C), 159.1 (6 -C), 158.3 (CONH), 140.7 (5-C), 137.4 (Ar-C), 135.8 (4-C), 130.7 (Ar-C),, 128.3 (2 -C), 128.1 (Ar-C), 126.4 (1 -C), 124.0 (Ar-C), 122.0 (Ar-C), 120.1 (7 - C), 106.6 (5 -C), 55.8 (O-CH 3 ). MS (ESI, m/z): 285.0872 [M + H] +, 307.0693 [M + Na] +. Purity >95% (18.99 min, M3). 2-(4-methylphenyl)-1,3-oxazole-4-carbohydroxamic acid (4q). 44 mg (0.22 mmol) 3q, 25 µl (0.26 mmol) ethyl chloroformate, 31 µl (0.28 mmol) N-methylmorpholine, 23 mg (0.33 mmol) hydroxylamine hydrochloride and 18 mg (0.33 mmol) potassium hydroxide were used according to method C. Overall yield: 18 mg (9%). Mp: 171-173 C. 1 H-NMR (CD 3 OD, 400 MHz): δ 8.42 (s, 1H, 5-H), 8.02-7.97 (m, 2H, 2-6 -H), 7.39-7.33 (m, 2H, 3-5 -H), 2.44 (s, 3H, CH 3 ). 13 C-NMR (100 MHz): δ 162.1 (2-C), 159.4 (CONH), 141.6 (5-C), 140.9 (4 -C), 135.2 (4- C), 129.3 (3 -,5 -C), 126.3 (2 -,6 -C), 123.7 (1 -C), 20.1 (CH 3 ). MS (APCI, m/z): 219.0766 [M + H] +. Purity >98% (16.90 min, M3). 2-(biphenyl-3-yl)-1,3-oxazole-4-carbohydroxamic acid (4r). 204 mg (0.8 mmol) 3r, 88 µl (0.9 mmol) ethyl chloroformate, 110 µl (1.0 mmol) N-methylmorpholine, 80 mg (1.2 mmol) hydroxylamine hydrochloride and 67 mg (1.2 mmol) potassium hydroxide were used according to method C. Overall yield: 15 mg (3%). 1 H-NMR (CD 3 OD, 400 MHz): δ 8.46 (s, 1H, 5-H), 8.35 (s, 1H, 2 -H), 8.08-8.06 (m, 1H, 6 -H), 7.82-7.80 (m, 1H, 4 -H), 7.71-7.69 (m, 2H, 2 -,6 -H), S9

7.64-7.60 (m, 1H, 5 -H), 7.52-7.49 (m, 2H, 3 -,5 -H), 7.43-7.40 (m, 1H, 4 -H). 13 C-NMR (100 MHz): δ 161.8 (2-C), 159.2 (CONH), 142.0 (5-C), 141.1 (4-C), 139.9 (3 -C), 135.5 (1 -C), 129.4 (Ar-C), 129.2 (Ar-C), 128.6 (2C, 3 -,5 -C), 127.5 (Ar-C), 127.0 (1 -C), 126.6 (2C, 2 -,6 -C), 125.0 (Ar-C), 124.7 (Ar-C). MS (ESI, m/z): 303.1 [M + Na] +. Purity >97% (19.39 min, M3). Ethyl 5-(4-bromophenyl)-1,2,4-oxadiazole-3-carboxylate (2t). 584 mg (2.9 mmol) 4- bromoobenzoic acid, 632 µl (8.7 mmol) thionyl chloride, 384 mg (2.9 mmol) ethyl 2- oximinooxamate and 605 µl (4.4 mmol) triethylamine were used according to method F. 1 H- NMR (DMSO-d 6, 400 MHz): δ 8.11-8.09 (m, 2H, 2 -,6 -H), 7.90-7.87 (m, 2H, 3 -,5 -H), 4.48-4.42 (q, 2H, O-CH 2 -CH 3, 3 J = 7.1 Hz), 1.38-1.34 (t, 3H, O-CH 2 -CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz): δ 176.3 (5-C), 162.6 (COOEt), 157.5 (3-C), 133.2 (3 -,5 -C), 130.4 (2 -,6 -C), 128.2 (4 -C), 122.4 (1 -C), 63.1 (O-CH 2 -CH 3 ), 14.3 (O-CH 2 -CH 3 ). Ethyl 5-(biphenyl-4-yl)-1,2,4-oxadiazole-3-carboxylate (2u). 560 mg (2.8 mmol) 4- biphenylcarboxylic acid, 615 µl (8.5 mmol) thionyl chloride, 374 mg (2.8 mmol) ethyl 2- oximinooxamate and 589 µl (4.3 mmol) triethylamine were used according to method F. 1 H- NMR (DMSO-d 6, 400 MHz): δ 8.22-8.20 (m, 2H, 2 -,6 -H), 7.95-7.93 (m, 2H, 3 -,5 -H), 7.78-7.76 (m, 2H, 2 -,6 -H), 7.54-7.50 (m, 2H, 3 -,5 -H), 7.47-7.44 (m, 1H, 4 -H), 4.47-4.42 (q, 2H, O-CH 2 -CH 3, 3 J = 7.1 Hz), 1.38-1.35 (t, 3H, O-CH 2 -CH 3, 3 J = 7.1 Hz). 13 C-NMR (100 MHz): δ 176.8 (5-C), 162.6 (COOEt), 157.6 (3-C), 145.5 (4 -C), 138.9 (1 -C), 129.6 (3 -,5 -C), 129.2 (4 -C), 129.2 (3 -,5 -C), 128.2 (2 -,6 -C), 127.4 (2 -,6 -C), 122.0 (1 -C), 63.1 (O-CH 2 -CH 3 ), 14.4 (O-CH 2 -CH 3 ). 5-phenyl-1,2,4-oxadiazole-3-carboxylic acid (3s). This compound has already been described. 1 240 mg (1.1 mmol) 2s and 4.4 ml (4.4 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 MHz): δ 12.99 (bs, 1H, COOH), 8.17-8.15 (m, 2H, 2 -,6 - H), 7.78-7.73 (m, 1H, 4 -H), 7.69-7.64 (m, 2H, 3 -,5 -H). 13 C-NMR (100 MHz): δ 176.7 (5-C), 167.7 (COOH), 159.0 (3-C), 134.1 (4 -C), 130.1 (3 -,5 -C), 128.4 (2 -,6 -C), 123.4 (1 -C). 5-(4-bromophenyl)-1,2,4-oxadiazole-3-carboxylic acid (3t). 80 mg (0.27 mmol) 2t and 1.1 ml (1.1 mmol) LiOH (1 M) were used according to method B. 1 H-NMR (DMSO-d 6, 400 MHz): δ 8.10-8.07 (m, 2H, 2 -,6 -H), 7.90-7.88 (m, 2H, 3 -,5 -H). 13 C-NMR (100 MHz): δ 176.1 (5-C), 167.0 (COOH), 158.9 (3-C), 133.2 (3 -,5 -C), 130.4 (2 -,6 -C), 128.1 (4 -C), 122.6 (1 -C). 5-(biphenyl-4-yl)-1,2,4-oxadiazole-3-carboxylic acid (3u). 240 mg (0.82 mmol) 2u and 3.3 ml (3.3 mmol) LiOH (1 M) were used according to method B. The compound was directly processed further and no NMR spectra were recorded.5-phenyl-1,2,4-oxadiazole-3- carbohydroxamic acid (4s). This compound has already been described. 1 201mg (1.06 mmol) 3s, 121 µl (1.27 mmol) ethyl chloroformate, 151 µl (1.4 mmol) N-methylmorpholine, 147 mg (2.12 mmol) hydroxylamine hydrochloride and 119 mg (2.12 mmol) potassium hydroxide were used according to method C. Overall yield: 29 mg (4%). Mp: 173-175 C. 1 H-NMR (DMSO-d 6, 400 MHz): δ 11.89 (bs, 1H, NH-OH), 9.66 (bs, 1H, NH-OH), 8.17-8.14 (m, 2H, 2 -,6 -H), 7.78-7.74 (m, 1H, 4 -H), 7.69-7.65 (m, 2H, 3 -,5 -H). 13 C-NMR (100 MHz): δ 176.3 (5-C), 163.7 (CONH), 154.1 (3-C), 134.2 (4 -C), 130.1 (3 -,5 -C), 128.5 (2 -,6 -C), 123.3 (1 -C). MS (ESI, m/z): 206.0563 [M + H] +, 228.0383 [M + Na] +. Purity >97% (13.23 min, M1). 5-(4-bromophenyl)-1,2,4-oxadiazole-3-carbohydroxamic acid (4t). 125mg (0.52 mmol) 3t, 43 µl (0.45 mmol) ethyl chloroformate, 50 µl (0.45 mmol) N-methylmorpholine, 368 mg (5.3 S10

mmol) hydroxylamine hydrochloride and 295 mg (5.3 mmol) potassium hydroxide were used according to method C. Overall yield: 80 mg (10%). Mp: 160-162 C. 1 H-NMR (DMSO-d 6, 400 MHz): δ 11.91 (bs, 1H, NH-OH), 9.70 (bs, 1H, NH-OH), 8.09-8.07 (m, 2H, 2 -,6 -H), 7.90-7.88 (m, 2H, 3 -,5 -H). 13 C-NMR (100 MHz): δ 175.6 (5-C), 163.7 (CONH), 153.9 (3-C), 133.3 (3 -,5 -C), 130.4 (2 -,6 -C), 128.2 (4 -C), 122.6 (1 -C). MS (APCI, m/z): 283.9668 [M Br79 + H] +, 285.9647 [M Br81 + H] +. Purity >97% (14.77 min, M1). 5-(biphenyl-4-yl)-1,2,4-oxadiazole-3-carbohydroxamic acid (4u). 105mg (0.4 mmol) 3u, 46 µl (0.48 mmol) ethyl chloroformate, 57 µl (0.52 mmol) N-methylmorpholine, 449 mg (8 mmol) hydroxylamine hydrochloride and 556 mg (8 mmol) potassium hydroxide were used according to method C. Overall yield: 90 mg (11%). Mp: 188-190 C. 1 H-NMR (DMSO-d 6, 400 MHz): δ 11.91 (bs, 1H, NH-OH), 9.86 (bs, 1H, NH-OH), 8.25-8.22 (m, 2H, 2 -,6 -H), 8.00-7.97 (m, 2H, 3 -,5 -H), 7.82-7.79 (m, 2H, 2 -,6 -H), 7.56-7.52 (m, 2H, 3 -,5 -H), 7,49-7.45 (m, 1H, 4 -H). 13 C-NMR (100 MHz): δ 176.2 (5-C), 163.7 (CONH), 154.1 (3-C), 145.4 (4 -C), 138.9 (1 -C), 129.6 (3 -,5 -C), 129.5 (4 -C), 129.1 (3 -,5 -C), 128.2 (2 -,6 -C), 127.4 (2 -,6 -C), 122.2 (1 - C). MS (ESI, m/z): 282.0875 [M + H] +, 304.0695 [M + Na] +. Purity >99% (17.48 min, M1). Figure S1. Western blot with the neuroblastoma cell line BE(2)-C. 5*10 5 cells were seeded in a 10 cm cell culture dish and incubated with DMSO or 10 µm of compounds for 24 hours. Cells were lysed in SDS Sample Buffer (2% w/v SDS, 1 mm dithothreitol, 10% v/v glycerol, 62.5 mm Tris-HCl (ph 6.8 at 25 C), 0.05% bromophenol blue). 20 µg were loaded onto the SDS-gel and run, followed by the transfer to a nitrocellulose membrane via semi dry transfer. The following procedure was already described in the experimental section. Antibodies used were anti-acetylated α-tubulin (Sigma Aldrich, 1:1000), anti-acetyl-histone H4 (Millipore, 1:2000) and anti-actin (Sigma-Aldrich, 1:20000). Detection was performed after ECL Prime incubation with the chemi-capt software (peqlab). S11

Figure S2. 1 H- and 13 C-NMR-spectra of compound 4g. 160.29 157.98 142.38 136.30 132.76 128.59 125.85 125.17 40.54 40.34 40.13 39.92 39.71 39.71 DMSO 39.50 39.29 0.98 0.99 1.00 2.08 2.12 11.20 9.17 8.71 7.96 7.96 7.95 7.94 7.93 7.93 7.82 7.81 7.81 7.79 7.79 7.78 2.50 DMSO S12

References 1. Huguet, F.; Melet, A.; Alves de Sousa, R.; Lieutaud, A.; Chevalier, J.; Maigre, L.; Deschamps, P.; Tomas, A.; Leulliot, N.; Pages, J. M.; Artaud, I. Hydroxamic acids as potent inhibitors of Fe(II) and Mn(II) E. coli methionine aminopeptidase: biological activities and X-ray structures of oxazole hydroxamate-ecmetap-mn complexes. ChemMedChem 2012, 7 (6), 1020-1030. S13