Novel Aldosterone Synthase Inhibitors with Extended Carbocyclic Skeleton by a Combined Ligand-Based and Structure-Based Drug Design Approach

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1 Supporting Information Novel Aldosterone Synthase Inhibitors with Extended Carbocyclic Skeleton by a Combined Ligand-Based and Structure-Based Drug Design Approach Simon Lucas, Ralf Heim, Matthias Negri, Iris Antes, Christina Ries, Katarzyna E. Schewe, Alessandra Bisi, Silvia Gobbi, and Rolf W. Hartmann * Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box , D Saarbrücken, Germany; Max Planck Institute for Informatics, Stuhlsatzenhausweg 85, D Saarbrücken, Germany; Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, I Bologna, Italy * To whom correspondence should be addressed: Phone: Fax: rwh@mx.uni-saarland.de. Contents a) Inhibitory data of compounds 1 10 (S2) b) NMR spectroscopic data of compounds 11 15, 17, 18, (S3 S7) c) Synthesis and spectroscpic data of compounds 11a 16a, 19a, 20a, 26a 30a, 11b 16b, 19b, 26b 30b, 11c 16c, 19c, 11d 16d, 19d, 26d 30d, 12e 14e, 12f 14f, 12g 14g, 12h, 13h (S8 S22) d) Elemental analysis results of compounds (S23) e) Purity data (LC-MS) of compounds (S24) f) Pharmacophore modeling training set and pharmacophore geometric properties (S25) S1

2 a) Inhibitory data of compounds 1 10 (Table S1) Table S1. Inhibitory data of compounds 1 10 % inhibition a IC 50 value b (nm) V79 11B2 c V79 11B2 c V79 11B1 d selectivity compd R hcyp11b2 hcyp11b2 hcyp11b1 factor e 1 f H f OMe H NO Br OMe H Br 80 n.d. n.d. n.d. 9 NO 2 73 n.d. n.d. n.d fadrozole a Mean value of at least two experiments, standard deviation less than 10 %. b Mean value of at least four experiments, standard deviation usually less than 25 %, n.d. = not determined. c Hamster fibroblasts expressing human CYP11B2; substrate deoxycorticosterone, 100 nm. d Hamster fibroblasts expressing human CYP11B1; substrate deoxycorticosterone, 100 nm. e IC 50 CYP11B2/IC 50 CYP11B2, n.d. = not determined. f IC 50 values as described by Voets et al. 14 S2

3 b) NMR spectroscopic data of compounds 11 15, 17, 18, (3-Phenylnaphthalen-2-yl)pyridine (11). 1 H-NMR (500 MHz, CDCl 3 ): δ = 7.13 (dd, 3 J = 7.6 Hz, 3 J = 4.7 Hz, 1H), 7.19 (m, 2H), (m, 3H), 7.42 (m, 1H), (m, 2H), (m, 4H), 8.48 (m, 1H), 8.57 (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 122.6, 126.6, 126.8, 126.9, 127.7, 127.8, 128.2, , , 130.1, 132.7, 133.0, 135.3, 137.2, 139.0, 140.7, 147.8, (3-Benzylnaphthalen-2-yl)pyridine (12). 1 H-NMR (500 MHz, CDCl 3 ): δ = 4.07 (s, 2H), 6.92 (d, 3 J = 8.2 Hz, 2H), (m, 3H), 7.25 (ddd, 3 J = 7.6 Hz, 3 J = 5.0 Hz, 5 J = 0.9 Hz, 1H), (m, 3H), 7.69 (s, 1H), 7.73 (s, 1H), (m, 2H), 8.54 (dd, 4 J = 2.2 Hz, 5 J = 0.9 Hz, 1H), 8.58 (dd, 3 J = 5.0 Hz, 4 J = 1.9 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 39.9, 122.7, 126.0, 126.1, 126.4, 127.4, 127.6, 128.3, 128.8, 129.1, 129.5, 132.0, 133.1, 136.6, 136.7, 137.1, 137.2, 140.4, 148.3, (3-Benzyl-6-methoxynaphthalen-2-yl)pyridine (13). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.92 (s, 3H), 4.05 (s, 2H), 6.92 (d, 3 J = 8.2 Hz, 2H), 7.10 (d, 4 J = 2.2 Hz, 1H), (m, 4H), 7.24 (ddd, 3 J = 7.9 Hz, 3 J = 4.7 Hz, 5 J = 0.9 Hz, 1H), 7.50 (ddd, 3 J = 7.9 Hz, 4 J = 2.2 Hz, 4 J = 1.6 Hz, 1H), 7.60 (s, 1H), 7.61 (s, 1H), 7.71 (d, 3 J = 8.8 Hz, 1H), 8.54 (dd, 4 J = 2.2 Hz, 5 J = 0.9 Hz, 1H), 8.56 (dd, 3 J = 4.7 Hz, 4 J = 1.6 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 39.8, 55.3, 105.2, 119.0, 122.7, 126.0, 127.5, 128.0, 128.3, 128.8, 129.1, 129.2, 134.3, 134.8, 136.7, 137.1, 137.2, 140.5, 148.1, 150.1, [3-(2-Methoxybenzyl)naphthalen-2-yl]pyridine (14). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.67 (s, 3H), 4.03 (s, 2H), (m, 3H), 7.16 (m, 1H), 7.27 (ddd, 3 J = 7.8 Hz, 3 J = 4.8 Hz, 5 J = 0.8 Hz, 1H), (m, 2H), 7.60 (ddd, 3 J = 7.8 Hz, 4 J = 2.2 Hz, 4 J = 1.8 Hz, 1H), 7.64 (s, 1H), 7.69 (s, 1H), (m, 2H), 8.57 (dd, 3 J = 4.8 Hz, 4 J = 1.8 Hz, 1H), 8.59 (dd, 4 J = 2.2 Hz, 5 J = 0.8 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 33.4, 55.2, 110.1, 120.3, 122.7, 125.9, 126.3, 127.3, 127.4, 127.6, 128.8, 129.0, 129.2, 130.3, 131.9, 133.1, 136.6, 136.7, , , 148.1, 150.0, [3-(3-Methoxybenzyl)naphthalen-2-yl]pyridine (15). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.69 (s, 3H), 4.05 (s, 2H), 6.46 (m, 1H), 6.52 (dd, 3 J = 7.6 Hz, 4 J = 0.6 Hz, 1H), 6.69 (dd, 3 J = 8.2 Hz, 4 J = 1.9 Hz, 1H), 7.09 (m, 1H), 7.26 (ddd, 3 J = 7.6 Hz, 3 J = 4.7 Hz, 5 J = 0.6 Hz, 1H), (m, 2H), 7.52 (ddd, 3 J = 7.6 Hz, 4 J = 2.2 Hz, 4 J = 1.6 Hz, 1H), 7.69 (s, 1H), 7.73 (s, 1H), (m, 2H), 8.56 (dd, 4 J = 2.2 Hz, 5 J = 0.6 Hz, 1H), 8.59 (dd, 3 J = 4.7 Hz, 4 J = 1.6 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 39.8, 55.0, 111.3, 114.6, 121.2, 122.7, 126.1, S3

4 126.4, 127.4, 127.6, 129.1, 129.2, 129.4, 132.0, 133.1, 136.4, 136.6, 137.1, 142.0, 148.2, 149.9, (3-Pyridin-3-yl-naphthalen-2-ylmethyl)benzonitrile (17). 1 H-NMR (500 MHz, DMSOd 6 ): δ = 4.24 (s, 2H), 7.04 (d, 3 J = 8.5 Hz, 2H), 7.56 (m, 1H), 7.60 (d, 3 J = 8.5 Hz, 2H), (m, 5H), 8.35 (m, 1H), 8.82 (d, 4 J = 1.3 Hz, 1H), 8.85 (d, 3 J = 5.1 Hz). 13 C-NMR (125 MHz, DMSO-d 6 ): δ = 38.8, 108.8, 118.8, 126.0, 126.6, 127.2, 127.3, 127.8, 129.3, 129.6, 130.1, 131.6, 132.2, 133.0, 134.0, 135.1, 138.9, 142.0, 142.8, 144.2, [3-(4-Trifluoromethoxybenzyl)naphthalen-2-yl]pyridine (18). 1 H-NMR (500 MHz, CDCl 3 ): δ = 4.08 (s, 2H), 6.88 (d, 3 J = 8.5 Hz, 2H), 6.99 (d, 3 J = 8.3 Hz, 2H), 7.23 (dd, 3 J = 7.6 Hz, 3 J = 4.7 Hz, 1H), 7.44 (m, 1H), (m, 2H), 7.69 (s, 1H), 7.72 (s, 1H), (m, 2H), 8.54 (d, 4 J = 1.9 Hz, 1H), 8.58 (dd, 3 J = 4.7 Hz, 4 J = 1.6 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 39.3, (q, 1 J = 257 Hz), 120.8, 122.8, 126.3, 126.6, 127.4, 127.7, 129.2, , 132.2, 133.1, 136.1, 136.6, , , 137.1, 139.2, 148.4, [7-Methoxy-3-(4-methoxybenzyl)naphthalen-2-yl]pyridine (20) C. 1 H- NMR (500 MHz, CDCl 3 ): δ = 3.74 (s, 3H), 3.91 (s, 3H), 3.96 (s, 2H), 6.71 (d, 3 J = 8.5 Hz, 2H), 6.81 (d, 3 J = 8.8 Hz, 2H), 7.11 (d, 4 J = 2.5 Hz, 1H), 7.15 (dd, 3 J = 9.1 Hz, 4 J = 2.5 Hz, 1H), 7.26 (dd, 3 J = 7.6 Hz, 3 J = 4.7 Hz, 1H), 7.51 (m, 1H), 7.57 (s, 1H), 7.62 (s, 1H), 7.70 (d, 3 J = 8.8 Hz, 1H), 8.54 (d, 4 J = 1.6 Hz, 1H), 8.57 (dd, 3 J = 4.9 Hz, 4 J = 1.6 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 38.8, 55.2, 55.4, 105.5, 113.7, 119.4, 122.8, 128.4, 128.7, 128.8, 128.9, 129.7, 131.5, 132.7, 133.1, 134.7, 136.8, 137.4, 137.5, 148.0, 149.7, Methoxy-5-[3-(4-methoxybenzyl)naphthalen-2-yl]pyridine (21). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.71 (s, 3H), 3.75 (s, 3H), 4.00 (s, 2H), 6.72 (d, 3 J = 8.7 Hz, 2H), 6.83 (d, 3 J = 8.7 Hz, 2H), 6.94 (dd, 4 J = 3.1 Hz, 4 J = 1.8 Hz, 1H), (m, 2H), 7.69 (s, 1H), 7.71 (s, 1H), (m, 2H), 8.16 (d, 4 J = 1.8 Hz, 1H), 8.29 (d, 4 J = 2.9 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 39.0, 55.2, 55.3, 113.7, 121.0, 126.0, 126.4, 127.4, 127.6, 129.0, 129.3, 129.7, 131.9, 132.7, 133.1, 136.5, 136.9, 137.0, 137.6, 142.1, 155.0, Methoxy-5-[6-methoxy-3-(4-methoxybenzyl)naphthalen-2-yl]pyridine (22). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.72 (s, 3H), 3.75 (s, 3H), 3.92 (s, 3H), 3.98 (s, 2H), 6.73 (d, 3 J = 8.7 Hz, 2H), 6.85 (d, 3 J = 8.7 Hz, 2H), 6.95 (dd, 4 J = 2.8 Hz, 4 J = 1.8 Hz, 1H), 7.09 (d, 4 J = 2.4 Hz, 1H), 7.13 (dd, 3 J = 8.8 Hz, 4 J = 2.4 Hz, 1H), 7.58 (s, 1H), 7.61 (s, 1H), 7.71 (d, 3 J = 8.8 Hz, 1H), 8.16 (d, 4 J = 1.8 Hz, 1H), 8.27 (d, 4 J = 2.7 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 39.0, 55.2, 55.33, 55.36, 105.2, 113.7, 119.0, 121.1, 127.4, 127.9, , , 129.8, 132.8, 134.3, 134.6, 136.3, 137.5, 137.7, 142.3, 155.0, 157.8, S4

5 3-(3-Benzyl-6-methoxynaphthalen-2-yl)5-methoxypyridine (23). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.68 (s, 3H), 3.92 (s, 3H), 4.05 (s, 2H), 6.92 (dd, 4 J = 2.8 Hz, 4 J = 1.9 Hz, 1H), (m, 2H), 7.10 (m, 1H), 7.14 (m, 2H), 7.19 (m, 2H), 7.61 (s, 1H), 7.62 (s, 1H), 7.72 (d, 3 J = 9.1 Hz, 1H), 8.16 (d, 4 J = 1.8 Hz, 1H), 8.27 (d, 4 J = 2.8 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 39.9, 55.3, 105.2, 119.1, 121.0, 126.0, 127.5, 128.2, 128.3, 128.8, , , 134.4, 134.6, 136.5, 137.0, 137.6, 140.8, 142.3, 155.0, [3-(4-Methoxybenzyl)naphthalen-2-yl]isoquinoline (24). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.68 (s, 3H), 3.72 (d, 2 J = 15.5 Hz, 1H), 3.83 (d, 2 J = 15.5 Hz, 1H), 6.56 (d, 3 J = 8.7 Hz, 2H), 6.64 (d, 3 J = 8.7 Hz, 2H), 7.35 (dd, 3 J = 8.2 Hz, 4 J = 0.6 Hz, 1H), 7.48 (m, 1H), 7.50 (m, 1H), 7.52 (m, 1H), 7.57 (m, 1H), 7.74 (s, 1H), 7.75 (s, 1H), 7.81 (d, 3 J = 7.9 Hz, 1H), 7.85 (d, 3 J = 7.9 Hz, 1H), 8.02 (d, 3 J = 8.2 Hz, 1H), 8.34 (s, 1H), 9.27 (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 39.2, 55.2, 113.5, 120.0, 125.0, 126.0, 126.4, 127.1, , , 128.4, 129.8, 130.2, 130.4, 131.9, 132.1, 133.4, 135.1, 135.2, 138.9, 143.2, [6-Methoxy-3-(4-methoxybenzyl)naphthalen-2-yl]isoquinoline (25). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.68 (s, 3H), 3.70 (d, 2 J = 15.6 Hz, 1H), 3.80 (d, 2 J = 15.4 Hz, 1H), 3.94 (s, 3H), 6.58 (d, 3 J = 8.7 Hz, 2H), 6.67 (d, 3 J = 8.7 Hz, 2H), (m, 2H), 7.37 (dd, 3 J = 8.4 Hz, 4 J = 0.7 Hz, 1H), 7.51 (m, 1H), 7.57 (m, 1H), 7.62 (s, 1H), 7.66 (s, 1H), 7.70 (d, 3 J = 9.4 Hz, 1H), 8.01 (d, 3 J = 8.5 Hz, 1H), 8.35 (s, 1H), 9.26 (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 39.1, 55.2, 55.4, 105.4, 113.5, 118.9, 125.1, 127.0, 127.3, 127.4, 127.6, 128.1, 129.1, 129.8, 129.9, 130.3, 132.2, 132.4, 132.7, 134.6, 135.3, 139.4, 143.3, 151.9, 157.7, (4-Methoxyphenyl)(3-pyridin-3-yl-naphthalen-2-yl)methanone (26). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.81 (s, 3H), 6.81 (d, 3 J = 9.2 Hz, 2H), 7.17 (m, 1H), 7.57 (m, 1H), 7.61 (m, 1H), 7.65 (m, 1H), 7.72 (d, 3 J = 8.8 Hz, 2H), 7.90 (d, 3 J = 7.9 Hz, 1H), 7.91 (s, 1H), 7.94 (d, 3 J = 8.2 Hz, 1H), 8.01 (s, 1H), 8.49 (dd, 3 J = 4.7 Hz, 4 J = 1.3 Hz, 1H), 8.49 (d, 4 J = 2.2 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 55.4, 113.7, 122.9, 127.2, , , 128.4, 129.3, 129.6, 130.4, 131.8, 132.5, 133.8, 134.7, 136.1, 136.2, 137.3, 148.4, 149.5, 163.7, (3-Fluoro-4-methoxyphenyl)(3-pyridin-3-yl-naphthalen-2-yl)methanone (27). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.89 (s, 3H), 6.84 (m, 1H), 7.19 (dd, 3 J = 7.9 Hz, 4 J = 5.0, 1H), 7.46 (d, 3 J = 8.8 Hz, 1H), 7.51 (dd, 3 J = 11.7 Hz, 3 J = 1.9 Hz, 1H), (m, 3H), (m, 2H), 7.94 (d, 3 J = 8.2 Hz, 1H), 8.02 (s, 1H), 8.46 (dd, 3 J = 4.7 Hz, 4 J = 1.3 Hz, 1H), 8.62 (d, 4 J = 1.6 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 56.3, 112.1, (d, 2 J = 19.3 Hz), 122.6, 127.4, (d, 3 J = 2.8 Hz), 128.0, 128.2, 128.4, 129.4, 129.7, (d, 3 J = 4.6 Hz), S5

6 131.8, 133.9, 134.6, 136.0, 136.2, 136.6, 148.5, 149.4, (d, 1 J = 248 Hz), (d, 2 J = 11.0 Hz), (3-Pyridin-3-yl-naphthalene-2-carbonyl)benzonitrile (28). 1 H-NMR (500 MHz, CDCl 3 ): δ = 7.16 (ddd, 3 J = 7.8 Hz, 3 J = 4.7 Hz, 4 J = 0.9 Hz, 1H), (m, 4H), 7.65 (m, 1H), 7.73 (ddd, 3 J = 8.5 Hz, 4 J = 1.9 Hz, 3 J = 1.6 Hz, 1H), (m, 3H), 8.08 (s, 1H), 8.44 (dd, 3 J = 5.0 Hz, 4 J = 1.6 Hz, 1H), 8.55 (dd, 4 J = 2.0 Hz, 4 J = 0.7 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 116.1, 117.7, 123.0, 127.6, 128.0, 128.6, 128.7, , , 130.4, 131.7, 132.1, 134.2, 134.4, 135.6, 135.7, 136.1, 140.8, 148.6, 149.5, (3-Pyridin-3-yl-naphthalen-2-yl)(4-trifluoromethoxyphenyl)methanone (29). 1 H-NMR (500 MHz, CDCl 3 ): δ = (m, 3H), (m, 3H), 7.76 (d, 3 J = 8.8 Hz, 2H), 7.93 (s, 1H), 7.95 (d, 3 J = 8.8 Hz, 1H), 8.07 (s, 1H), 8.46 (dd, 3 J = 4.7 Hz, 4 J = 1.6 Hz, 1H), 8.59 (dd, 4 J = 2.2 Hz, 5 J = 0.6 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 120.1, (q, 1 J = 259 Hz), 123.0, 127.5, 128.0, 128.4, 128.5, 129.9, 130.0, 131.8, 132.0, 134.1, 134.8, 135.8, 135.9, 136.2, 136.3, 148.6, 149.5, 152.6, (4-Methoxyphenyl)(6-methoxy-3-pyridin-3-yl-naphthalen-2-yl)methanone (30). 1 H- NMR (500 MHz, CDCl 3 ): δ = 3.78 (s, 3H), 3.93 (s, 3H), 6.79 (d, 3 J = 8.8 Hz, 2H), 7.14 (ddd, 3 J = 7.9 Hz, 3 J = 4.7 Hz, 5 J = 0.9 Hz, 1H), (m, 2H), 7.62 (ddd, 3 J = 7.9 Hz, 4 J = 2.2 Hz, 3 J = 1.6 Hz, 1H), 7.70 (d, 3 J = 8.8 Hz, 2H), (m, 2H), 7.93 (s, 1H), 8.43 (dd, 3 J = 7.4 Hz, 4 J = 1.6 Hz, 1H), 8.62 (dd, 4 J = 2.1 Hz, 5 J = 0.8 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 55.4, 105.8, 113.5, 120.2, 122.8, 127.1, 128.4, 129.5, 129.9, 130.6, 132.4, 134.8, 135.3, 135.4, 136.2, 136.3, 148.2, 149.3, 159.3, 163.5, (4-Methoxyphenyl)(3-pyridin-3-yl-naphthalen-2-yl)methanol (31). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.74 (s, 3H), 5.89 (s, 1H), 6.72 (d, 3 J = 8.8 Hz, 2H), 6.93 (d, 3 J = 8.8 Hz, 2H), 7.22 (ddd, 3 J = 7.7 Hz, 3 J = 4.9 Hz, 5 J = 0.6 Hz, 1H), 7.42 (m, 1H), 7.50 (m, 1H), 7.53 (m, 1H), 7.63 (s, 1H), 7.81 (m, 1H), 7.91 (m, 1H), 8.23 (s, 1H), 8.42 (d, 4 J = 2.0 Hz, 1H), 8.55 (dd, 3 J = 4.9 Hz, 4 J = 1.8 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 55.2, 73.1, 113.8, 122.7, 125.7, , , 127.6, 128.1, 128.6, 129.6, 132.4, 133.0, 135.3, 135.6, 136.6, 136.9, 139.5, 148.3, 149.9, (3-Fluoro-4-methoxyphenyl)(3-pyridin-3-yl-naphthalen-2-yl)methanol (32). 1 H-NMR (500 MHz, CDCl 3 ): δ = 2.78 (bs, 1H), 3.82 (s, 3H), 5.87 (s, 1H), 6.69 (m, 1H), 6.76 (m, 1H), 6.82 (dd, 3 J = 12.0 Hz, 4 J = 1.9 Hz, 1H), 7.24 (ddd, 3 J = 7.9 Hz, 3 J = 5.0 Hz, 5 J = 1.0 Hz, 1H), 7.46 (m, 1H), (m, 2H), 7.64 (s, 1H), 7.81 (m, 1H), 7.90 (m, 1H), 8.16 (s, 1H), 8.41 (d, 4 J = 1.9 Hz, 1H), 8.52 (dd, 3 J = 5.0 Hz, 4 J = 1.6 Hz, 1H). 13 C-NMR (125 MHz, S6

7 CDCl 3 ): δ = 56.2, 72.5, 113.0, (d, 2 J = 19.3 Hz), 122.8, (d, 3 J = 3.7 Hz), 126.0, , , 127.6, 128.1, 129.7, 132.4, 133.0, 135.4, (d, 3 J = 5.5 Hz), 136.5, 136.9, 139.1, (d, 2 J = 10.8 Hz), 148.8, 149.8, (d, 1 J = 247 Hz). 4-[Hydroxy-(3-pyridin-3-yl-naphthalen-2-yl)methyl]benzonitrile (33). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.65 (bs, 1H), 6.02 (s, 1H), 7.21 (d, 3 J = 8.2 Hz, 2H), 7.26 (ddd, 3 J = 7.6 Hz, 3 J = 4.7 Hz, 5 J = 0.9 Hz, 1H), 7.49 (d, 3 J = 8.5 Hz, 2H), (m, 3H), 7.67 (s, 1H), (m, 2H), 7.99 (s, 1H), 8.48 (dd, 3 J = 4.7 Hz, 4 J = 1.6 Hz, 1H), 8.51 (dd, 4 J = 2.2 Hz, 5 J = 0.8 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 72.5, 111.2, 118.7, 123.1, 126.9, 127.0, 127.1, 127.5, 127.6, 128.0, 130.0, 132.1, 132.6, 133.0, 135.4, 136.5, 137.1, 138.6, 148.3, 148.7, (3-Pyridin-3-yl-naphthalen-2-yl)(4-trifluoromethoxyphenyl)methanol (34). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.08 (bs, 1H), 5.97 (s, 1H), (m, 4H), 7.22 (ddd, 3 J = 7.6 Hz, 3 J = 5.0 Hz, 5 J = 0.6 Hz, 1H), 7.43 (m, 1H), (m, 2H), 7.65 (s, 1H), 7.82 (m, 1H), 7.90 (m, 1H), 8.14 (s, 1H), 8.48 (d, 4 J = 1.6 Hz, 1H), 8.50 (dd, 3 J = 5.1 Hz, 4 J = 1.6 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 72.6, (q, 1 J = 257 Hz), 120.8, 122.9, 126.3, 126.7, 126.9, 127.6, 128.1, 128.5, 129.8, 132.5, 133.0, 135.5, 136.6, 137.0, 139.1, 141.9, 148.3, 148.5, {3-[Methoxy-(4-methoxyphenyl)methyl]naphthalen-2-yl}pyridine (35). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.26 (s, 3H), 3.75 (s, 3H), 5.27 (s, 1H), 6.74 (d, 3 J = 8.7 Hz, 2H), 6.93 (d, 3 J = 8.8 Hz, 2H), 7.27 (ddd, 3 J = 7.9 Hz, 3 J = 4.8 Hz, 5 J = 0.8 Hz, 1H), 7.45 (m, 1H), 7.49 (m, 1H), 7.51 (m, 1H), 7.64 (s, 1H), 7.81 (m, 1H), 7.90 (m, 1H), 8.06 (s, 1H), 8.49 (d, 4 J = 1.8 Hz, 1H), 8.60 (dd, 3 J = 4.8 Hz, 4 J = 1.6 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 55.2, 56.8, 82.1, 113.7, 122.7, 126.1, , , 127.5, 128.1, 129.1, 129.5, 132.3, 132.7, 133.0, 136.2, 136.8, 136.9, 137.9, 148.4, 150.0, S7

8 c) Synthesis and spectroscopic data of compounds 11a 16a, 19a, 20a, 26a 30a, 11b 16b, 19b, 26b 30b, 11c 16c, 19c, 11d 16d, 19d, 26d 30d, 12e 14e, 12f 14f, 12g 14g, 12h, 13h Procedure E. To a 0.5 or 1.0 M solution of Grignard reagent ( equivalents) was added dropwise a 1.0 M solution of carbaldehyde (1 equivalent) at 0 C. The mixture was stirred 1 h and then poured onto ice water. NH 4 Cl was added and the whole mixture was extracted three times with ethyl acetate, washed with brine and dried over MgSO 4. The filtrate was concentrated in vacuo and the arylnaphthyl carbinols were used without further puification in the next step. Procedure F. To a stirred mixture of anhydrous AlCl 3 (3 equivalents) and fine powdered NaBH 4 (5 equivalents) in dry THF was added a solution of arylnaphthyl carbinol (1 equivalent) in THF at reflux temerature over the course of 1 8 h. The overall volume of solvent should generate a 0.1 M solution of arylnaphthyl carbinol. After complete addition the mixture was refluxed for 2 h, then cooled and water was carefully added. The whole mixture was extracted three times with ethyl acetate, washed with brine and dried over MgSO 4. The filtrate was concentrated in vacuo, and the residue was flash chromatographed on silica gel (petroleum ether/ethyl acetate mixtures) to afford the corresponding diarylmethanes. Procedure G. To a 0.1 M solution of benzyl protected naphthol (1 equivalent) in THF/methanol 1/1 was added ammonium formate (3 6 equivalents) and Pd(10%)/C (10% w/w) and the whole mixture was heated under reflux for 1 3 h. After cooling to room temperature, the solution was filtered through a short pad of silica and the filtrate was concentrated in vacuo. The crude products were analytically pure and could be used without further puification. Procedure H. The napthol (2.0 mmol, 1 equivalent), N- phenylbis(trifluoromethanesulfonimide) (785 mg, 2.2 mmol, 1.1 equivaletns), K 2 CO 3 (830 mg, 6.0 mmol, 3 equivalents), and 3 ml of THF were mixed in a microwave reaction tube. The mixture was irradiated with microwaves for 10 min at a temperature of 120 C with an initial irradiation power of 100 W. After the reaction, the vial was cooled to 40 C by gas jet cooling, the crude mixture was partitioned between diethyl ether and water and the aqueous layer was extracted three times with diethyl ether. The combined organic layers were dried over MgSO 4, filtered through a short pad of silica and the filtrate was concentrated in vacuo. The crude products were analytically pure and could be used without further puification. S8

9 Procedure I. To a 0.1 M solution of the benzoyl chloride (1.0 equivalents) in CH 2 Cl 2 was added N,O-dimethylhydroxylamine hydrochloride (1.1 equivalents). The mixture was cooled to 0 C and then triethylamine (2.2 equivalents) was added dropwise. The resulting solution was warmed to room temperature and stirred over night. After washing twice with 1 N HCl, the organic layer was dried over MgSO 4 and then evaporated to yield the crude Weinreb amides that were analytically pure and could be used without further puification. Procedure J. To a 0.5 M solution of 2-methoxynaphthalene (1.0 equivalents) in dry THF was added TMEDA (2.0 equivalents). nbuli (1.2 equivalents, 2.5 M in hexanes) was added dropwise at 0 C and the resulting solution was stirred for 3 h at room and then recooled to 0 C again. Thereupon a 1.0 M solution of N-methoxy-N-methylbenzamide (0.9 equivalents) in THF was added to the raction mixture and allowed to warm to room temperature overnight. The reaction was quenched by adding 1 N HCl and stirring for 1 h. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO 4, and concentrated. The obtained crude product of the obtained phenyl naphthylketone (1.0 equiv) was added to a 0.2 M solution of nbu 4 NI (1.0 equivalents) in dry CH 2 Cl 2 at -78 C. The mixture was then treated with BCl 3 solution (2.5 equivalents, 1.0 M in hexanes), stirred for 30 min, and then allowed to warm to room temperature within 1 h. The reaction was quenched by addition water and stirring for 10 min. Then, a solution of saturated aqueous NaHCO 3 was added dropwise until gas evolution ceased. The organic layer was separated and the aqueous layer was extracted twice with CH 2 Cl 2. The combined organic layers were dried over MgSO 4 and concentrated. The residue was crystallized from EtOH to afford the deprotected phenyl naphthylketone. Procedure K. A 1.5 M solution of triflic anhydride (1.2 equivalents) in dry CH 2 Cl 2 was added to a 0.5 M solution of naphthol (1 equivalent) in CH 2 Cl 2 and pyridine (5 equivalents) at 0 C over a period of 1 h. Stirring was continued for 1 h at ambient temperature before the reaction was quenched with saturated aqueous NaHCO 3. The aqueous layer was extracted twice with ethyl acetate, washed with 1 N HCl and brine and then dried over MgSO 4. Evaporation of the solvent afford the trifluoromethanesulfonate in analytically pure form. (3-Methoxynaphtalene-2-yl)boronic acid (11d). To a stirred solution of 2- methoxynaphthalene (8.30 g, 53.0 mmol) in 300 ml dry THF was added nbuli (25.2 ml, 63.0 mmol, 2.5 M in hexanes) at room temperature. After stirring for 3 h, the solution was cooled to -78 C and trimethylborate (4.2 ml, 76.0 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature over 12 h before 150 ml 2 N HCl was S9

10 added and stirred for one additional hour. Three times extraction with ethyl acetate, followed by washing with saturated aqueous NH 4 Cl solution, drying over MgSO 4 and evaporation of the solvent gave the boronic acid as crude product. The residue was crystallized from toluene/petroleum ether to afford 11d as white crystals (9.2 g, 45.5 mmol, 91 %). 1 H-NMR (500 MHz, acetone-d 6 ): δ = 4.03 (s, 3H), 7.15 (s, 2H), 7.33 (s, 1H), 7.35 (m, 1H), 7.47 (m, 1H), 7.79 (d, 3 J = 7.9 Hz, 1H), 7.86 (d, 3 J = 8.2 Hz, 1H), 8.38 (s, 1H). 3-(3-Methoxynaphthalen-2-yl)pyridine (11c) was obtained according to procedure B from 11d (5.0 g, 24.8 mmol) and 3-bromopyridine (2.61 g, 16.5 mmol) after crystallization from ethyl acetate/petroleum ether as yellow solid (3.67 g, 15.6 mmol, 95 %), 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.93 (s, 3H), 7.24 (s, 1H), (m, 2H), 7.47 (m, 1H), 7.76 (s, 1H), 7.77 (d, 3 J = 8.2 Hz, 1H), 7.80 (d, 3 J = 7.9 Hz, 1H), 7.92 (m, 1H), 8.59 (dd, 3 J = 4.6 Hz, 4 J = 1.5 Hz, 1H), 8.84 (d, 4 J = 1.8 Hz, 1H). 3-(3-Hydroxynaphthalen-2-yl)pyridine (11b). A solution of 11c (3.55 g, 15.1 mmol) in 100 ml concentrated HBr (48 %) was refluxed for 18 h. After cooling to room temperature the mixture was diluted with 200 ml water and neutralized with 6 N NaOH. Three times extraction with ethyl acetate, followed by washing with brine, drying over MgSO 4 and evaporation of the solvent afforded 11b as a pale yellow solid (2.18 g, 9.84 mmol, 65 %). 1 H- NMR (500 MHz, DMSO-d 6 ): δ = (m, 2H), 7.41 (m, 1H), 7.45 (ddd, 3 J = 7.9 Hz, 3 J = 4.9 Hz, 5 J = 0.6 Hz, 1H), 7.71 (d, 3 J = 8.2 Hz, 1H), 7.83 (d, 3 J = 8.2 Hz, 1H), 7.89 (s, 1H), 8.04 (m, 1H), 8.55 (dd, 3 J = 4.7 Hz, 4 J = 1.6 Hz, 1H), 8.82 (d, 3 J = 1.6 Hz, 1H), (bs, 1H). 3-pyridin-3-ylnaphthalen-2-yl trifluoromethanesulfonate (11a) was obtained according to procedure H from 11b (443 mg, 2.0 mmol) and N-phenyltriflimide (785 mg, 2.2 mmol) as a pale yellow solid (657 mg, 1.86 mmol, 93 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 7.42 (ddd, 3 J = 7.9 Hz, 3 J = 4.7 Hz, 5 J = 0.6 Hz, 1H), (m, 2H), 7.87 (m, 1H), (m, 4H), 8.69 (dd, 3 J = 4.7 Hz, 4 J = 1.6 Hz, 1H), 8.79 (d, 4 J = 1.9 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = (q, 2 J = 321 Hz), 120.4, 123.2, 127.8, 127.9, 128.0, 130.1, 131.5, 131.8, 132.4, 132.9, 136.9, 144.6, 149.5, Methyl 3-hydroxynaphthalene-2-carboxylate (12h). 3-Hydroxynaphthalene-2- carboxylicacid (18.8 g, 100 mmol) was dissolved in 100 ml dry methanol and 1.1 ml concentrated H 2 SO 4 (98%) was added. The whole mixture was refluxed for 10 h and thereafter the excess methanol was distilled off. The residue was taken up in 350 ml ethyl acetate and the organic layer was washed several times with 5 % aqueous Na 2 CO 3 solution, S10

11 water and brine. After drying over MgSO 4, the solvent was evaporated in vacuo to yield 12h as yellow solid (17.8 g, 88.0 mmol, 88 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 4.02 (s, 3H), (m, 2H), 7.49 (m, 1H), 7.68 (d, 3 J = 8.2 Hz, 1H), 7.79 (d, 3 J = 8.2 Hz, 1H), 8.49 (s, 1H), (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 52.6, 111.7, 114.2, 124.0, 126.3, 127.0, 129.1, 129.2, 132.4, 137.9, 156.3, Methyl 3-hydroxy-7-methoxynaphthalene-2-carboxylate (13h) was prepared as described for 12h starting from 3-hydroxy-7-methoxynaphthalene-2-carboxylicacid (17.3 g, 79.3 mmol) yielding 13h as yellow solid (13.1 g, 56.4 mmol, 71 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.88 (s, 3H), 4.01 (s, 3H), 7.07 (d, 4 J = 2.5 Hz, 1H), 7.18 (dd, 3 J = 9.1 Hz, 4 J = 2.5 Hz, 1H), 7.26 (s, 1H), 7.58 (d, 3 J = 8.8 Hz, 1H), 8.37 (s, 1H), (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 52.5, 55.3, 106.2, 111.9, 114.3, 122.7, 127.8, 130.6, 133.6, 155.0, 156.2, Methyl 3-methoxynaphthalene-2-carboxylate (12g). To a solution of 12h (16.8 g, 82.5 mmol) in 300 ml dry acetone was added K 2 CO 3 (17.3 g, 125 mmol) and 18-crown-6 (26 mg, 0.10 mmol). The mixture was stirred for 2 h at room temperature before methyl iodide (17.8 g, 125 mmol) was added dropwise and then refluxed for 32 h. After cooling to room temperature again, the mixture was filtered through a pad of celite and concentrated. The residue was taken up in 300 ml ethyl acetate and washed twice with 1 N NaOH, water and brine. Drying over MgSO 4 and evaporation of the solvent afforded 12g as yellow oil (15.0 g, 69.3 mmol, 84 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.95 (s, 3H), 3.99 (s, 3H), 7.19 (s, 1H), 7.36 (m, 1H), 7.50 (m, 1H), 7.72 (d, 3 J = 7.9 Hz, 1H), 7.80 (d, 3 J = 8.2 Hz, 1H), 8.29 (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 52.2, 56.0, 106.8, 121.7, 124.4, 126.4, 127.5, 128.4, 128.7, 132.8, 136.1, 155.7, Methyl 3-(benzyloxy)naphthalene-2-carboxylate (13g). To a solution of 12h (22.2 g, 110 mmol) in 350 ml dry acetone was added K 2 CO 3 (18.6 g, 135 mmol) and 18-crown-6 (26 mg, 0.10 mmol). The mixture was stirred for 2 h at room temperature before benzyl bromide (23.1 g, 135 mmol) was added dropwise and then refluxed for 32 h. After cooling to room temperature again, the mixture was filtered through a pad of celite and concentrated. The residue was taken up in 350 ml ethyl acetate and washed twice with 1 N NaOH, water and brine. Drying over MgSO 4 and evaporation of the solvent afforded 13g as yellow oil (27.9 g, 95.4 mmol, 87 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 4.00 (s, 3H), 5.30 (s, 2H), 7.30 (s, 1H), 7.37 (m, 1H), 7.44 (m, 3H), 7.54 (m, 1H), 7.59 (d, 3 J = 7.3 Hz, 2H), 7.74 (d, 3 J = 8.2 Hz, 1H), 7.85 (d, 3 J = 8.2 Hz, 1H), 8.38 (s, 1H). S11

12 Methyl 3-(benzyloxy)-7-methoxynaphthalene-2-carboxylate (14g) was prepared as described for 13g starting from 13h (22.4 g, 96.2 mmol), K 2 CO 3 (16.5 g, 120 mmol), benzyl bromide (20.6 g, 120 mmol) and 18-crown-6 (26 mg, 0.10 mmol). Crystallization from ethyl acetate/petroleum ether afforded 14g as pale yellow solid (24.5 g, 76.1 mmol, 79 %). 1 H- NMR (500 MHz, CDCl 3 ): δ = 3.89 (s, 3H), 3.95 (s, 3H), 5.42 (s, 2H), 7.12 (d, 4 J = 2.5 Hz, 1H), 7.18 (dd, 3 J = 8.8 Hz, 4 J = 2.5 Hz, 1H), 7.23 (s, 1H), 7.31 (m, 1H), 7.40 (m, 2H), 7.54 (d, 3 J = 7.6 Hz, 2H), 7.61 (d, 3 J = 9.1 Hz, 1H), 8.23 (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 51.2, 55.3, 70.6, 106.5, 109.1, 121.3, 122.4, 126.8, 127.7, 127.9, 128.5, 128.6, 131.3, 131.4, 137.0, 153.2, 156.7, (3-Methoxynaphthalen-2-yl)methanol (12f). 12g (17.4 g, 80.5 mmol) was dissolved in 50 ml THF and 30 ml toluene before LiBH 4 (964 mg, 44.3 mmol) was added under an atmosphere of dry nitrogen. The soluion was then heated to 100 C and held at that temperature for 2 h. After cooling to room temperature 150 ml 0.5 N HCl were added and the mixture was extracted three times with diethyl ether. The organic extracts were washed with water and brine, dried over MgSO 4 and evaporated to afford 12f as pale yellow solid (12.8 g, 68.0 mmol, 84 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.96 (s, 3H), 4.82 (s, 2H), 7.12 (s, 1H), 7.35 (m, 1H), 7.43 (m, 1H), (m, 2H), 7.76 (d, 3 J = 8.2 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 55.3, 62.4, 105.2, 123.9, 126.3, 126.4, 127.5, 127.6, 128.7, 130.5, 134.1, (3-Benzyloxynaphthalen-2-yl)methanol (13f) was prepared as described for 12f starting from 13g (20.8 g, 71.3 mmol) and LiBH 4 (887 mg, 40.7 mmol) yielding 13f after crystallization from ethyl acetate/petroleum ether as yellow solid (15.6 g, 59.1 mmol, 83 %). 1 H-NMR (500 MHz, CD 3 OD): δ = 4.81 (s, 2H), 5.15 (s, 2H), 7.23 (s, 1H), 7.28 (m, 2H), 7.36 (m, 3H), 7.46 (d, 3 J = 7.6 Hz, 2H), 7.69 (d, 3 J = 8.2 Hz, 1H), 7.74 (d, 3 J = 8.2 Hz, 1H), 7.84 (s, 1H). 13 C-NMR (125 MHz, CD 3 OD): δ = 60.8, 70.9, 107.3, 124.8, 127.0, 127.4, 127.6, 128.4, 128.5, 128.9, 129.5, 130.3, 132.7, 135.4, 138.6, (3-Benzyloxy-7-methoxynaphthalen-2-yl)methanol (14f) was prepared as described for 12f starting from 14g (24.5 g, 76.1 mmol) and LiBH 4 (914 mg, 42.0 mmol) yielding 14f as yellow oil (21.6 g, 73.3 mmol, 96 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 2.49 (bs, 1H), 3.88 (s, 3H), 4.85 (bs, 2H), 5.17 (s, 2H), 7.09 (d, 4 J = 2.4 Hz, 1H), 7.12 (dd, 3 J = 8.8 Hz, 4 J = 2.4 Hz, 1H), 7.16 (s, 1H), 7.35 (m, 1H), 7.41 (m, 2H), 7.46 (d, 3 J = 7.3 Hz, 2H), 7.61 (d, 3 J = 8.5 Hz, 1H), 7.66 (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 55.3, 62.5, 70.0, 106.2, 106.6, 118.7, 126.4, 127.3, 127.9, 128.1, 128.7, 129.1, 129.6, 131.0, 136.7, 153.4, S12

13 3-Methoxynaphthalene-2-carbaldehyde (12e). A solution of 12f (2.82 g, 15.0 mmol), TBACl (417 mg, 1.5 mmol), TEMPO (236 mg, 1.5 mmol) in 100 ml CH 2 Cl 2 and 100 ml of an aqueous solution of NaHCO 3 (0.5 M) and Na 2 CO 3 (0.05 M) was stirred at room temperature. NCS (2.60 g, 19.5 mmol) was then added in small portions and stirred for 2 h. The mixture was extracted twice with CH 2 Cl 2, washed with brine and dried over MgSO 4. Evaporation of the solvent followed by washing of the residue with petroleum ether afforded 12e as a pale yellow solid (2.41 g, 12.9 mmol, 86 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 4.01 (s, 3H), 7.17 (s, 1H), 7.37 (m, 1H), 7.53 (m, 1H), 7.73 (d, 3 J = 8.2 Hz, 1H), 7.86 (d, 3 J = 8.2 Hz, 1H), 8.34 (s, 1H), (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 55.6, 106.3, 124.6, 125.6, 126.6, 127.7, 129.2, 129.9, 130.9, 137.5, 157.6, Benzyloxynaphthalene-2-carbaldehyde (13e). To a solution of 13f (10.6 g, 40.1 mmol) in 50 ml DMSO and NEt 3 (28 ml, 200 mmol) was slowly added SO 3 pyridine complex (14.0 g, 88.0 mmol) and the internal temperature maintained at C by a water bath. After 2 h stirring at room temperature the mixture was poured into 200 ml water and extracted twice with 200 ml ethyl acetate. The combined organic layers were washed with water (3 x 200 ml), 1 N HCl (3 x 100 ml) and brine, dried over MgSO 4 and concentrated. The residue was crystallized from petroleum ether/ethyl acetate to afford 13e as a yellow solid (7.88 g, 30.1 mmol, 75 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 5.27 (s, 2H), 7.27 (s, 1H), (m, 4H), (m, 3H), 7.72 (d, 3 J = 8.2 Hz, 1H), 7.88 (d, 3 J = 8.2 Hz, 1H), 8.39 (s, 1H), (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 70.4, 107.7, 124.8, 125.7, 126.7, 127.3, 127.9, 128.2, 128.7, 129.2, 129.9, 130.7, 136.2, 137.4, 156.7, Benzyloxy-7-mezhoxynaphthalene-2-carbaldehyde (14e) was prepared as described for 13e starting from 14f (21.2 g, 72.0 mmol) and SO 3 pyridine complex (25.2 g, 158 mmol) yielding 14e after crystallization from petroleum ether/ethyl acetate as a yellow solid (18.4 g, 63.0 mmol, 88 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.90 (s, 3H), 5.25 (s, 2H), 7.17 (d, 4 J = 2.5 Hz, 1H), 7.21 (dd, 3 J = 8.8 Hz, 4 J = 2.5 Hz, 1H), 7.24 (s, 1H), 7.36 (m, 1H), 7.42 (m, 2H), 7.49 (d, 3 J = 6.9 Hz, 2H), 7.63 (d, 3 J = 8.8 Hz, 1H), 8.28 (s, 1H), (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 55.4, 70.5, 107.3, 108.1, 122.4, 125.9, 127.4, 128.1, 128.2, 128.7, 128.8, 129.1, 133.0, 136.3, 155.5, 156.8, (3-Methoxynaphthalen-2-yl)phenylmethanol (12d). Grignard reaction of 12e (3.5 g, 18.8 mmol) and phenylmagnesiumbromide solution (1.0 M in THF, 21.0 ml, 21.0 mmol) according to procedure E yielded 12d as a yellow oil (4.72 g, 17.8 mmol, 95 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.11 (d, 3 J = 5.5 Hz, 1H), 3.89 (s, 3H), 6.15 (d, 3 J = 5.5 Hz, 1H), 7.13 S13

14 (s, 1H), 7.27 (m, 1H), (m, 3H), (m, 3H), (m, 3H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 55.4, 72.7, 105.7, 123.9, , , 126.7, 127.1, 127.3, 127.9, 128.2, 128.6, 133.2, 133.9, 143.0, (3-Benzyloxy-7-methoxynaphthalen-2-yl)phenylmethanol (13d). Grignard reaction of 14e (7.36 g, 25.0 mmol) and phenylmagnesiumbromide solution (1.0 M in THF, 30.0 ml, 30.0 mmol) according to procedure E yielded 13d as a yellow oil (8.78 g, 23.7 mmol, 95 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.06 (d, 3 J = 6.0 Hz, 1H), 3.88 (s, 3H), 5.08 (s, 2H), 6.13 (d, 3 J = 6.0 Hz, 1H), (m, 2H), (m, 3H), (m, 6H), 7.37 (m, 2H), 7.60 (d, 3 J = 7.6 Hz, 1H), 7.69 (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 55.3, 70.2, 73.2, 106.3, 107.2, 119.0, 126.1, 126.8, 127.3, 127.5, 127.8, 128.0, 128.2, 128.5, 129.0, 129.6, 133.6, 136.4, 143.2, 152.9, (3-Benzyloxynaphthalen-2-yl)(2-methoxyphenyl)methanol (14d). Grignard reaction of 13e (7.87 g, 30.0 mmol) and 2-methoxyphenylmagnesiumbromide solution (1.0 M in THF, 33.0 ml, 33.0 mmol) according to procedure E yielded 14d as a yellow oil (9.67 g, 26.1 mmol, 87 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.25 (d, 3 J = 5.0 Hz, 1H), 3.77 (s, 3H), 5.10 (d, 2 J = 11.7 Hz, 1H), 5.15 (d, 2 J = 11.7 Hz, 1H), 6.55 (d, 3 J = 5.0 Hz, 1H), (m, 2H), 7.13 (dd, 3 J = 7.6 Hz, 4 J = 1.6 Hz, 1H), 7.19 (s, 1H), (m, 3H), (m, 4H), 7.41 (m, 1H), 7.70 (d, 3 J = 7.9 Hz, 1H), 7.76 (d, 3 J = 8.2 Hz, 1H), 7.85 (s, 1H). (3-Benzyloxynaphthalen-2-yl)(3-methoxyphenyl)methanol (15d). Grignard reaction of 13e (8.60 g, 32.8 mmol) and 3-methoxyphenylmagnesiumbromide solution (1.0 M in THF, 34.0 ml, 34.0 mmol) according to procedure E yielded 15d as a yellow oil (11.3 g, 90.5 mmol, 93 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.28 (bs, 1H), 3.72 (s, 3H), 5.10 (s, 2H), 6.15 (s, 1H), 6.84 (dd, 3 J = 8.2 Hz, 4 J = 2.5 Hz, 1H), 6.95 (d, 3 J = 7.3 Hz, 1H), 7.01 (d, 4 J = 2.0 Hz, 1H), (m, 4H), (m, 3H), 7.38 (m, 1H), 7.46 (m, 1H), 7.73 (d, 3 J = 7.9 Hz, 1H), 7.80 (d, 3 J = 8.2 Hz, 1H), 7.87 (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 55.0, 70.0, 72.9, 106.9, 112.1, 113.0, 119.1, 124.0, 126.3, 127.1, 127.5, 127.9, 128.0, 128.5, 128.6, 129.1, 133.1, 133.8, 136.2, 144.9, 154.3, (3-Benzyloxynaphthalen-2-yl)(4-methoxyphenyl)methanol (16d). Grignard reaction of 13e (6.56 g, 25.0 mmol) and 4-methoxyphenylmagnesiumbromide solution (0.5 M in THF, 53.0 ml, 26.5 mmol) according to procedure E yielded 16d as a yellow oil (8.47 g, 22.9 mmol, 91 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.13 (bs, 1H), 3.83 (s, 3H), 5.13 (s, 2H), 6.17 (s, 1H), 6.88 (d, 3 J = 8.8 Hz, 2H), 7.22 (s, 1H), (m, 2H), 7.32 (d, 3 J = 8.7 Hz, 2H), S14

15 (m, 4H), 7.47 (m, 1H), 7.75 (d, 3 J = 8.2 Hz, 1H), 7.82 (d, 3 J = 7.9 Hz, 1H), 7.90 (s, 1H). (3-Benzyloxy-7-methoxynaphthalen-2-yl)(4-methoxyphenyl)methanol (19d). Grignard reaction of 14e (5.85 g, 20.0 mmol) and 4-methoxyphenylmagnesiumbromide solution (1.0 M in THF, 21.0 ml, 21.0 mmol) according to procedure E yielded 19d as a yellow oil (7.55 g, 18.9 mmol, 94 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.08 (d, 3 J = 5.7 Hz, 1H), 3.80 (s, 3H), 3.88 (s, 3H), 5.07 (s, 2H), 6.12 (d, 3 J = 5.4 Hz, 1H), 6.85 (d, 3 J = 8.8 Hz, 2H), (m, 2H), 7.14 (s, 1H), (m, 2H), 7.29 (d, 3 J = 8.2 Hz, 2H), (m, 3H), 7.60 (d, 3 J = 8.2 Hz, 1H), 7.72 (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 55.2, 55.3, 70.1, 72.4, 106.3, 107.0, 113.5, 118.8, 125.7, 127.4, 127.8, 128.0, 128.1, 128.5, 128.9, 129.5, 133.9, 135.4, 136.5, 152.8, 156.4, Benzyl-3-methoxynaphthalene (12c) was obtained via hydrogenolysis of 12d (6.52 g, 24.7 mmol) according to procedure F after flash chromatography on silica gel (petroleum ether/ethyl acetate, 9/1, R f = 0.46) as a colorless solid (3.25 g, 13.1 mmol, 53 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.94 (s, 3H), 4.16 (s, 2H), 7.14 (s, 1H), 7.24 (m, 1H), (m, 5H), 7.43 (m, 1H), 7.52 (s, 1H), 7.71 (d, 3 J = 8.2 Hz, 1H), 7.75 (d, 3 J = 8.2 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 36.4, 55.3, 105.0, 123.5, 125.7, 125.9, 126.3, 127.2, 128.3, 128.8, 128.9, 129.1, 131.4, 133.5, 140.6, Benzyl-2-benzyloxy-6-methoxynaphthalene (13c) was obtained via hydrogenolysis according of 13d (9.22 g, 24.9 mmol) according to procedure F after flash chromatography on silica gel (petroleum ether/ethyl acetate, 9/1, R f = 0.30) as a colorless solid (3.84 g, 10.8 mmol, 44 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.86 (s, 3H), 4.15 (s, 2H), 5.12 (s, 2H), 7.02 (d, 4 J = 2.5 Hz, 1H), 7.06 (dd, 3 J = 8.8 Hz, 3 J = 2.5 Hz, 1H), 7.13 (s, 1H), 7.20 (m, 1H), (m, 4H), (m, 4H), 7.35 (m, 1H), 7.42 (s, 1H), 7.59 (d, 3 J = 9.0 Hz, 1H). 13 C- NMR (125 MHz, CDCl 3 ): δ = 36.8, 55.3, 69.8, 105.7, 106.5, 118.2, 125.9, 127.3, 127.7, 127.8, 128.0, 128.3, 128.4, 128.6, 129.2, 129.6, 132.0, 137.1, 140.7, 153.8, Benzyloxy-3-(2-methoxybenzyl)naphthalene (14c) was obtained via hydrogenolysis of 14d (11.1 g, 30.0 mmol) according to procedure F after flash chromatography on silica gel (petroleum ether/ethyl acetate, 4/1, R f = 0.56) as a colorless solid (5.20 g, 14.7 mmol, 49 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.74 (s, 3H), 4.12 (s, 2H), 5.13 (s, 2H), 6.80 (m, 1H), 6.84 (d, 3 J = 8.2 Hz, 1H), 6.99 (dd, 3 J = 7.3 Hz, 4 J = 1.6 Hz, 1H), 7.13 (s, 1H), 7.16 (m, 1H), 7.24 (m, 1H), 7.25 (m, 1H), (m, 4H), 7.32 (m, 1H), 7.42 (s, 1H), 7.61 (d, 3 J = 7.9 Hz, 1H), 7.65 (d, 3 J = 8.2 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 30.5, 55.3, 69.8, 106.0, S15

16 110.3, 120.4, 123.5, 125.5, 126.3, 127.2, 127.7, 128.4, , , 129.0, 130.5, 131.2, 133.4, 137.1, 155.6, Benzyloxy-3-(3-methoxybenzyl)naphthalene (15c) was obtained via hydrogenolysis of 15d (13.0 g, 35.1 mmol) according to procedure F after flash chromatography on silica gel (petroleum ether/ethyl acetate, 4/1, R f = 0.46) as a colorless solid (4.30 g, 12.1 mmol, 35 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.72 (s, 3H), 4.17 (s, 2H), 5.17 (s, 2H), 6.77 (dd, 3 J = 7.2 Hz, 4 J = 2.5 Hz, 1H), 6.82 (m, 1H), 6.85 (d, 3 J = 7.6 Hz, 1H), (m, 2H), 7.31 (m, 1H), (m, 5H), 7.41 (m, 1H), 7.68 (s, 1H), (m, 2H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 36.9, 55.0, 69.8, 106.2, 111.4, 114.7, 121.5, 123.7, 125.7, 126.3, 127.2, 127.3, 127.8, 128.4, 128.9, 129.2, 131.4, 133.5, 137.0, 142.3, 155.3, Benzyloxy-3-(4-methoxybenzyl)naphthalene (16c) was obtained via hydrogenolysis of 16d (9.30 g, 25.1 mmol) according to procedure F after flash chromatography on silica gel (petroleum ether/ethyl acetate, 4/1, R f = 0.53) as a colorless solid (7.06 g, 19.9 mmol, 80 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.80 (s, 3H), 4.12 (s, 2H), 5.17 (s, 2H), 6.83 (d, 3 J = 8.5 Hz, 2H), 7.16 (d, 3 J = 8.8 Hz, 2H), 7.18 (s, 1H), 7.32 (m, 1H), (m, 5H), 7.39 (m, 1H), 7.53 (s, 1H), 7.69 (m, 1H), 7.71 (m, 1H). 2-Benzyloxy-6-methoxy-3-(4-methoxybenzyl)naphthalene (19c) was obtained via hydrogenolysis of 19d (8.0 g, 20.0 mmol) according to procedure F after flash chromatography on silica gel (petroleum ether/ethyl acetate, 4/1, R f = 0.42) as a colorless solid (7.19 g, 18.7 mmol, 94 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.79 (s, 3H), 3.87 (s, 3H), 4.10 (s, 2H), 5.13 (s, 2H), 6.82 (d, 3 J = 8.8 Hz, 2H), 7.02 (d, 4 J = 2.5 Hz, 1H), 7.07 (dd, 3 J = 9.0 Hz, 4 J = 2.5 Hz, 1H), 7.13 (s, 1H), 7.16 (d, 3 J = 8.5 Hz, 2H), 7.33 (m, 1H), (m, 4H), 7.40 (s, 1H), 7.59 (d, 3 J = 9.0 Hz, 1H). 3-Benzylnaphthalene-2-ol (12b). A solution of 12c (990 mg, 3.98 mmol) in 15 ml dry CH 2 Cl 2 was treated with BBr 3 (8.0 ml, 8.0 mmol, 1.0 M in CH 2 Cl 2 ) at -78 C. The solution was then warmed to room temperature and an aqueous 1 M solution of NaHCO 3 was added slowly. Extraction with CH 2 Cl 2, drying over MgSO 4 and concentration afforded 12b as a yellow oil. The crude product was filtered through a pad of silica to yield 12b as pale yellow solid (802 mg, 3.42 mmol, 86 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 4.17 (s, 2H), 5.01 (bs, 1H), 7.11 (s, 1H), (m, 6H), 7.38 (m, 1H), 7.58 (s, 1H), 7.64 (d, 3 J = 8.2 Hz, 1H), 7.71 (d, 3 J = 8.2 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 36.9, 110.0, 125.8, 125.9, 126.4, 127.3, 128.6, 128.8, 129.1, 129.4, 129.7, 133.7, 139.7, S16

17 3-Benzyl-6-methoxynaphthalen-2-ol (13b) was obtained according to procedure G from 13c (3.0 g, 8.46 mmol) and ammonium formate (2.68 g, 42.5 mmol) as a pale yellow solid (2.06 g, 7.78 mmol, 92 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.37 (s, 3H), 4.15 (s, 2H), 4.90 (bs, 1H), 7.03 (d, 4 J = 2.5 Hz, 1H), (m, 2H), 7.23 (m, 1H), (m, 4H), 7.46 (s, 1H), 7.54 (d, 3 J = 8.8 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 36.8, 55.3, 105.7, 110.2, 118.6, 126.4, 127.4, 128.4, 128.6, 128.7, 129.8, 129.9, 139.8, 150.8, (2-Methoxybenzyl)naphthalen-2-ol (14b) was obtained according to procedure G from 14c (5.20 g, 14.7 mmol) and ammonium formate (4.73 g, 75.0 mmol) as a pale yellow solid (3.61 g, 13.7 mmol, 93 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.97 (s, 3H), 4.11 (s, 2H), (m, 3H), (m, 2H), 7.27 (m, 1H), 7.31 (dd, 3 J = 7.3 Hz, 4 J = 1.6 Hz, 1H), 7.35 (m, 1H), 7.63 (d, 3 J = 8.2 Hz, 1H), (m, 2H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 30.9, 55.7, 110.7, 121.8, 123.4, 125.7, 126.1, 127.2, 127.9, 128.0, 129.0, 129.3, 130.8, 134.0, 152.7, (3-Methoxybenzyl)naphthalen-2-ol (15b) was obtained according to procedure G from 15c (4.30 g, 12.1 mmol) and ammonium formate (4.45 g, 70.5 mmol) as a pale yellow solid (3.15 g, 11.9 mmol, 98 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.76 (s, 3H), 4.14 (s, 2H), 6.78 (dd, 3 J = 8.2 Hz, 4 J = 2.5 Hz, 1H), 6.84 (m, 1H), 7.88 (d, 3 J = 7.6 Hz, 1H), 7.09 (s, 1H), 7.23 (m, 1H), 7.31 (m, 1H), 7.39 (m, 1H), 7.58 (s, 1H), 7.63 (d, 3 J = 8.2 Hz, 1H), 7.71 (d, 3 J = 7.9 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 36.8, 55.1, 110.0, 111.6, 114.7, 121.2, 123.6, 125.9, 127.3, 129.1, 129.3, , , 133.7, 141.4, 152.5, (4-Methoxybenzyl)naphthalen-2-ol (16b) was obtained according to procedure G from 16c (5.0 g, 14.1 mmol) and ammonium formate (4.45 g, 70.5 mmol) as a pale yellow solid (3.21 g, 12.1 mmol, 86 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.64 (s, 3H), 3.99 (s, 2H), 6.72 (d, 3 J = 8.6 Hz, 2H), 6.96 (s, 1H), 7.08 (d, 3 J = 8.8 Hz, 2H), 7.14 (m, 1H), 7.22 (m, 1H), 7.39 (s, 1H), 7.46 (d, 3 J = 7.9 Hz, 1H), 7.55 (d, 3 J = 8.2 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 35.9, 55.3, 109.6, 113.9, 123.2, 125.6, 125.7, 127.4, 128.3, 129.2, 130.1, 131.0, 132.5, 133.7, 153.5, Methoxy-3-(4-methoxybenzyl)naphthalen-2-ol (19b) was obtained according to procedure G from 19c (7.0 g, 18.2 mmol) and ammonium formate (5.74 g, 91.0 mmol) as a pale yellow solid (4.92 g, 16.7 mmol, 92 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.79 (s, 3H), 3.87 (s, 3H), 4.08 (s, 2H), 6.86 (d, 3 J = 8.8 Hz, 2H), 7.03 (d, 4 J = 2.5 Hz, 1H), 7.05 (s, 1H), 7.07 (dd, 3 J = 8.8 Hz, 4 J = 2.5 Hz, 1H), 7.19 (d, 3 J = 8.8 Hz, 2H), 7.44 (s, 1H), 7.53 (d, 3 J = S17

18 8.8 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 36.0, 55.2, 105.6, 110.2, 114.0, 118.5, 127.3, 128.2, 128.8, 129.8, 130.3, 131.8, 150.9, 156.0, Benzylnaphthalen-2-yl trifluoromethanesulfonate (12a) was obtained according to procedure H from 12b (496 mg, 2.0 mmol) and N-phenyltriflimide (785 mg, 2.2 mmol) as a pale yellow solid (654 mg, 1.76 mmol, 88 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 4.13 (s, 2H), (m, 3H), 7.25 (m, 2H), (m, 2H), 7.52 (s, 1H), 7.67 (m, 1H), 7.69 (s, 1H), 7.74 (m, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 36.4, (q, 2 J = 320 Hz), 119.2, 126.7, 127.0, 127.2, 127.5, 127.7, 128.7, 129.2, 130.8, 132.0, 132.2, 132.4, 138.4, benzyl-6-methoxynaphthalen-2-yl trifluoromethanesulfonate (13a) was obtained according to procedure H from 13b (529 mg, 2.0 mmol) and N-phenyltriflimide (785 mg, 2.2 mmol) as a pale yellow solid (720 mg, 1.82 mmol, 91 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.87 (s, 3H), 4.17 (s, 2H), 7.01 (d, 4 J = 2.5 Hz, 1H), 7.15 (dd, 3 J = 8.8 Hz, 4 J = 2.5 Hz, 1H), (m, 4H), 7.32 (m, 2H), 7.44 (s, 1H), 7.66 (s, 1H), 7.69 (d, 3 J = 8.8 Hz, 1H). 13 C- NMR (125 MHz, CDCl 3 ): δ = 36.3, 55.4, 105.4, 119.1, 120.1, 126.6, 127.5, 128.7, 129.1, 129.3, 129.4, 132.5, 133.8, 138.5, 144.8, (2-Methoxybenzyl)naphthalen-2-yl trifluoromethanesulfonate (14a) was obtained according to procedure H from 14b (529 mg, 2.0 mmol) and N-phenyltriflimide (785 mg, 2.2 mmol) as a pale yellow solid (705 mg, 1.78 mmol, 89 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.78 (s, 3H), 4.20 (s, 2H), (m, 2H), 7.12 (dd, 3 J = 7.6 Hz, 4 J = 1.6 Hz, 1H), 7.27 (m, 1H), (m, 2H), 7.52 (s, 1H), 7.70 (m, 1H), 7.76 (s, 1H), 7.82 (m, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 30.3, 55.3, 110.5, (d, 2 J = 321 Hz) 118.8, 120.6, 126.7, , , 127.5, 127.7, 128.2, 130.4, 130.7, 131.8, 132.1, 132.4, 146.8, (3-Methoxybenzyl)naphthalen-2-yl trifluoromethanesulfonate (15a) was obtained according to procedure H from 15b (529 mg, 2.0 mmol) and N-phenyltriflimide (785 mg, 2.2 mmol) as a pale yellow solid (650 mg, 1.64 mmol, 82 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.78 (s, 3H), 4.18 (s, 2H), (m, 3H), 7.24 (m, 1H), (m, 2H), 7.62 (s, 1H), 7.75 (m, 1H), 7.76 (s, 1H), 7.82 (m, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 36.4, 55.2, 112.1, 114.9, (q, 2 J = 320 Hz), 119.9, 121.6, 127.0, 127.2, 127.5, 127.7, 129.6, 130.8, 131.8, 132.2, 132.4, 140.0, 146.4, (4-Methoxybenzyl)naphthalen-2-yl trifluoromethanesulfonate (16a) was obtained according to procedure H from 16b (529 mg, 2.0 mmol) and N-phenyltriflimide (785 mg, 2.2 mmol) as a pale yellow solid (770 mg, 1.94 mmol, 97 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.81 (s, 3H), 4.16 (s, 2H), 6.88 (d, 3 J = 8.5 Hz, 2H), 7.16 (d, 3 J = 8.5 Hz, 2H), (m, S18

19 2H), 7.59 (s, 1H), 7.75 (m, 1H), 7.76 (s, 1H), 7.82 (m, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 35.5, 55.2, 114.1, (q, 2 J = 320 Hz), 119.2, 126.9, 127.2, 127.5, 127.6, 130.2, 130.3, 130.6, 132.2, , , 146.5, Methoxy-3-(4-methoxybenzyl)naphthalen-2-yl trifluoromethanesulfonate (19a) was obtained according to procedure H from 19b (589 mg, 2.0 mmol) and N-phenyltriflimide (785 mg, 2.2 mmol) as a pale yellow solid (795 mg, 1.86 mmol, 93 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.80 (s, 3H), 3.88 (s, 3H), 4.12 (s, 2H), 6.87 (d, 3 J = 8.8 Hz, 2H), 7.01 (d, 4 J = 2.5 Hz, 1H), (m, 3H), 7.43 (s, 1H), 7.66 (s, 1H), 7.69 (d, 4 J = 9.0 Hz, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 35.4, 55.4, 100.0, 105.4, 114.1, (d, 2 J = 321 Hz), 119.1, 120.0, 127.4, 129.1, 129.2, 130.3, 130.5, 133.0, 133.9, 144.8, 158.4, N,4-Dimethoxy-N-methylbenzamide (26d) was obtained according to procedure I starting from 4-methoxybenzoyl chloride (5.12 g, 30.0 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.22 g, 33.0 mmol) as a colorless oil (4.94 g, 25.3 mmol, 84 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.33 (s, 3H), 3.54 (s, 3H), 3.82 (s, 3H), 6.88 (d, 3 J = 8.8 Hz, 2H), 7.71 (d, 3 J = 8.8 Hz, 2H). 3-Fluoro-N,4-dimethoxy-N-methylbenzamide (27d) was obtained according to procedure I starting from 3-fluoro-4-methoxybenzoyl chloride (9.43 g, 50.0 mmol) and N,Odimethylhydroxylamine hydrochloride (5.36 g, 55.0 mmol) as a colorless oil (9.41 g, 44.1 mmol, 88 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.31 (s, 3H), 3.52 (s, 3H), 3.88 (s, 3H), 6.93 (m, 1H), (m, 2H). 4-Cyano-N-methoxy-N-methylbenzamide (28d) was obtained according to procedure I starting from 4-cyanobenzoyl chloride (5.0 g, 30.2 mmol) and N,O-dimethylhydroxylamine hydrochloride (3.24 g, 33.2 mmol) as a colorless oil (4.59 g, 24.1 mmol, 80 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.36 (s, 3H), 3.51 (s, 3H), 7.69 (d, 3 J = 8.5 Hz, 2H), 7.76 (d, 3 J = 8.5 Hz, 2H). N-Methoxy-N-methyl-4-(trifluoromethoxy)benzamide (29d) was obtained according to procedure I starting from 4-trifluoromethoxybenzoyl chloride (8.98 g, 40.0 mmol) and N,Odimethylhydroxylamine hydrochloride (4.29 g, 44.0 mmol) as a colorless oil (9.0 g, 36.1 mmol, 90 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.32 (s, 3H), 3.50 (s, 3H), 7.20 (d, 3 J = 8.6 Hz, 2H), 7.72 (d, 3 J = 8.8 Hz, 2H). (3-Hydroxynaphthalen-2-yl)(4-methoxyphenyl)methanone (26b) was obtained according to procedure J from 2-methoxynaphthalene (4.40 g, 27.8 mmol) and 26d (4.90 g, S19

20 25.0 mmol) after crystallization from ethanol as yellow needles (4.40 g, 15.8 mmol, 63 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.92 (s, 3H), 7.03 (d, 3 J = 8.8 Hz, 2H), 7.31 (m, 1H), 7.52 (m, 1H), 7.70 (d, 3 J = 8.2 Hz, 1H), 7.72 (d, 3 J = 8.2 Hz, 1H), 7.80 (d, 3 J = 8.8 Hz, 2H), 8.17 (s, 1H), (s, 1H). (3-Fluoro-4-methoxyphenyl)(3-hydroxynaphthalen-2-yl)methanone (27b) was obtained according to procedure J from 2-methoxynaphthalene (7.58 g, 48.0 mmol) and 27d (9.20 g, 43.1 mmol) after crystallization from ethanol as yellow needles (4.91 g, 16.6 mmol, 39 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 4.00 (s, 3H), 7.08 (m, 1H), 7.32 (m, 1H), 7.37 (s, 1H), 7.53 (m, 1H), (m, 2H), 7.70 (d, 3 J = 8.5 Hz, 1H), 7.74 (d, 3 J = 8.8 Hz, 1H), 8.16 (s, 1H), (s, 1H). 4-[(3-Hydroxynaphthalen-2-yl)carbonyl]benzonitrile (28b) was obtained according to procedure J from 2-methoxynaphthalene (4.24 g, 26.8 mmol) and 28d (4.59 g, 24.2 mmol) after flash chromatography on silica gel (petroleum ether/ethyl acetate, 4/1, R f = 0.38) as orange needles (2.28 g, 8.34 mmol, 35 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 7.33 (m, 1H), 7.39 (s, 1H), 7.55 (m, 1H), (m, 2H), (m, 4H), 8.01 (s, 1H), (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 112.8, 115.7, 117.8, 120.4, 124.4, 126.4, 126.7, 129.5, 129.7, 130.3, 132.3, 136.4, 138.3, 141.6, 157.1, (3-Hydroxynaphthalen-2-yl)[4-(trifluoromethoxy)phenyl]methanone (29b) was obtained according to procedure J from 2-methoxynaphthalene (6.33 g, 40.0 mmol) and 29d (9.0 g, 36.1 mmol) after crystallization from ethanol as yellow needles (4.85 g, 14.6 mmol, 40 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 7.32 (m, 1H), (m, 3H), 7.54 (m, 1H), 7.71 (d, 3 J = 8.2 Hz, 1H), 7.74 (d, 3 J = 8.2 Hz, 1H), 7.83 (d, 3 J = 8.8 Hz, 2H), 8.12 (s, 1H), (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 112.6, (q, 2 J = 259 Hz), 120.5, 120.8, 124.3, 126.3, 126.7, 129.5, 130.0, 131.5, 136.2, 136.3, 138.1, 152.1, 157.2, (3-Hydroxy-6-methoxynaphthalen-2-yl)(4-methoxyphenyl)methanone (30b) was obtained according to procedure J from 2,7-dimethoxynaphthalene (5.0 g, 26.6 mmol) and 26d (4.67 g, 23.9 mmol) after crystallization from ethanol as yellow needles (2.17 g, 7.03 mmol, 29 %). 1 H-NMR (500 MHz, CDCl 3 ): δ = 3.92 (s, 3H), 3.93 (s, 3H), (m, 2H), 7.02 (d, 3 J = 8.8 Hz, 2H), 7.23 (s, 1H), 7.61 (d, 3 J = 7.3 Hz, 1H), 7.77 (d, 3 J = 8.8 Hz, 2H), 8.08 (s, 1H), (s, 1H). 13 C-NMR (125 MHz, CDCl 3 ): δ = 55.4, 55.5, 103.8, 111.1, 113.8, 117.5, 119.2, 122.3, 130.7, 131.2, 132.0, 135.9, 139.7, 158.3, 160.8, 163.0, (4-Methoxyphenyl)(6-methoxy-3-pyridin-3-yl-naphthalen-2-yl)methanol (20a) was obtained via reduction according to procedure D from 30 (585 mg, 1.58 mmol) and sodium S20