1. Reagents: All commercial materials were used as received unless otherwise noted. The following solvents were obtained from a JC Meyer solvent dispe

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1 Supporting Information Pd-catalyzed Mono-selective ortho-c H Alkylation of N-Quinolyl Benzamides: Evidence for Stereo-retentive Coupling of Secondary Alkyl Iodides Shu-Yu Zhang, Qiong Li, Gang He, William A. Nack, and Gong Chen* Department of Chemistry, The Pennsylvania State University, University Park, PA United States 1. Reagents S2 2. Instruments S2 3. General procedure for the preparation of N-quinolyl benzamide substrates S2 4. Screening assay for ortho alkylation of compound 4 with npri and ipri S3 5. General procedure for Pd-catalyzed ortho alkylation with primary alkyl halides S3 6. Sequential C-H functionalization S10 7. General procedure for Pd-catalyzed ortho alkylation with secondary alkyl halides S12 8. Removal of the auxiliaries S17 9. Preliminary mechanistic studies S Alkylation of palladacycle 55 with 4-methylcyclohexyla iodides 56 and 57 S X-ray structure of compounds 55, 60, and 61 S References S NMR spectra S31 S1

2 1. Reagents: All commercial materials were used as received unless otherwise noted. The following solvents were obtained from a JC Meyer solvent dispensing system and used without further purification: CH 2 Cl 2, THF, and MeCN. Flash chromatography was performed using mesh SiliaFlash 60 silica gel (Silicycle Inc.). Pd(OAc) 2 (98%, Aldrich), (BnO) 2 PO 2 H (98%, Aldrich), (PhO) 2 PO 2 H (98%, Aldrich), pxylene (99%, Aldrich), tamyloh (99%, Aldrich), cis-4-methylcyclohexanol (98%, Alfa Aesar), and trans- 4-methylcyclohexanol (98%, Alfa Aesar) were used without further purification. 2. Instruments: NMR spectra were recorded on Bruker CDPX-300, DPX-300, DPX-400, AV-360 instruments and calibrated using residual solvent peaks as internal reference. Multiplicities are recorded as: s = singlet, d = doublet, t = triplet, dd = doublet of doublets, m = multiplet. High resolution ESI mass experiments were operated on a Waters LCT Premier instrument. 3. General procedure for the preparation of N-quinolyl benzamide substrates General procedure I: A mixture of BzCl 4-1 (1.4 g, 10 mmol, 1.0 equiv), 8-aminoquinoline (1.33 g, 9.2 mmol, 0.92 equiv), NEt 3 (1.53 ml, 11 mmol, 1.1 equiv) in anhydrous CH 2 Cl 2 (20 ml) was stirred at room temperature overnight. Water was added and the mixture was extracted with CH 2 Cl 2. The combined organic layers was washed with water and brine, dried over anhydrous Na 2 SO 4, and then concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using 25 % EtOAc in Hex as eluent to give the desired amide product 4 1 in 82 % yield. Scheme 1. List of known N-quinolyl benzamide substrates S2

3 4. Screening assay for alkylation of compound 4 with npri and ipri Compound 4 (50 mg, 0.2 mmol, 1 equiv), npri or ipri, Pd(OAc) 2, and other specified reagents were mixed in specified solvent(s) in a 10 ml glass vial (purged with O 2 or Ar, sealed with PTFE cap), and heated at 110 o C or 130 o C for 20 to 48 h. The reaction mixture was cooled to RT, filtered through a short pad of silica gel column, eluted with EtOAc, and then concentrated in vacuo. The resulting residue was dissolved in 1 ml of CDCl 3 along with Cl 2 CHCHCl 2 (21 μl, 0.2 mmol) as external standard for 1 H-NMR analysis. The composition of reaction mixture of Table 1 was based on the integration of benzylic CH 2 at 2.91 ppm (5), 2.71 ppm (6), and CH of Cl 2 CHCHCl 2 at 6.1 ppm. The composition of reaction mixture of Table 2 was based on the integration of benzylic CH at 3.53 ppm (29), 3.16 ppm (30), and CH of Cl 2 CHCHCl 2 at 6.1 ppm. 5. General procedure for Pd-catalyzed AQ-directed C H alkylation reactions with alkyl iodide General conditions A: A mixture of amide 4 (50 mg, 0.2 mmol, 1 equiv), Pd(OAc) 2 (2.2 mg, 0.01 mmol, 0.05 equiv), NaHCO 3 (25 mg, 0.3 mmol, 1.5 equiv), (BnO) 2 PO 2 H (17 mg, 0.06 mmol, 0.3 equiv), and npri (102 mg, 0.6 mmol, 3 equiv) in tamyloh/dce (1:1, 2 ml) in a 10 ml glass vial (purged with O 2, sealed with PTFE cap) was heated at 110 o C for 20 h. The reaction mixture was cooled to RT and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give the alkylated product 5 in 81 % yield (R f = 0.5, 25 % EtOAc in hexanes). 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.96 (d, J = 7.5 Hz, 1 H), (m, 1 H), 8.18 (dd, J = 8.1 and 1.5 Hz, 1 H), (m, 3 H), (m, 2 H), (m, 2 H), 2.91 (t, J = 7.8 Hz, 2 H), (m, 2 H), 0.95 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.4, 148.2, 141.3, 138.5, 136.6, 136.3, 134.8, 130.4, 130.1, 128.0, 127.4, 127.2, 126.0, 121.7, 121.6, 116.5, 35.4, 24.8, 14.1; HRMS: calculated for C 19 H 19 N 2 O [M+H + ]: ; found: General conditions B: A mixture of amide 4 (50 mg, 0.2 mmol, 1 equiv), Pd(OAc) 2 (2.2 mg, 0.01 mmol, 0.05 equiv), NaHCO 3 (59 mg, 0.7 mmol, 3.5 equiv), (BnO) 2 PO 2 H (17 mg, 0.06 mmol, 0.3 equiv), and npri (136 mg, 0.8 mmol, 4 equiv) in tamyloh/dce (1:1, 2 ml) in a 10 ml glass vial (purged with O 2, sealed with PTFE cap) was heated at 110 o C for 48 h. The reaction mixture was cooled to RT and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give the alkylated product 6 in 77 % yield (R f = 0.55, 25 % EtOAc in hexanes). 1 H NMR (CDCl 3, 300 MHz, ppm): δ 9.94 (s, 1 H), 9.01 (d, J = 6.3 Hz, 1 H), 8.74 (d, J = 2.7 Hz, 1 H), 8.20 (d, J = 7.2 Hz, 1 H), (m, 2 H), (m, 1 H), (m, 1 H), 7.17 (d, J = 7.8 Hz, 2 H), 2.71 (t, J = 7.8 Hz, 4 H), (m, 4 H), 0.91 (t, J = 7.2 Hz, 6 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.9, 148.2, 139.2, 138.5, 137.5, 136.3, 134.4, 128.9, 128.0, 127.4, 126.7, 121.8, 121.6, 116.7, 35.5, 24.6, 14.1; HRMS: calculated for C 22 H 25 N 2 O [M+H + ]: ; found: S3

4 R f = 0.45, 25 % EtOAc in Hex Compound 7m was isolated in 85 % yield using the general conditions A with 3 equiv of EtI. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.96 (d, J = 7.2 Hz, 1 H), (m, 1 H), 8.17 (d, J = 8.1, 1 H), (m, 3 H), (m, 2 H), (m, 2 H), 2.95 (dd, J = 15.0 and 7.5 Hz, 2 H), 1.32 (t, J = 7.5 Hz, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.4, 148.2, 142.8, 138.5, 136.4, 136.3, 134.7, 130.3, 129.7, 127.9, 127.2, 126.0, 121.7, 121.6, 116.5, 26.5, 16.0; HRMS: calculated for C 18 H 17 N 2 O [M+H + ]: ; found: R f = 0.50, 25 % EtOAc in Hex Compound 7d was isolated in 82 % yield using the general conditions B with 4 equiv of EtI. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 9.05 (dd, J = 7.2 and 1.5 Hz, 1 H), 8.75 (dd, J = 4.2 and 1.5 Hz, 1 H), 8.19 (dd, J = 8.1 and 1.5 Hz, 1 H), (m, 2 H), (m, 2 H), 7.21 (d, J = 7.5 Hz, 2 H), 2.80 (dd, J = 15.0 and 7.5 Hz, 4 H), 1.30 (t, J = 7.5 Hz, 6 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.8, 148.2, 140.6, 138.4, 137.0, 136.2, 134.4, 129.3, 127.9, 127.3, 126.0, 121.8, 121.6, 116.6, 26.4, 15.8; HRMS: calculated for C 20 H 21 N 2 O [M+H + ]: ; found: R f = 0.40, 25 % EtOAc in Hex Compound 8m was isolated in 75 % yield using the general conditions A with 3 equiv of EtI. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.90 (d, J = 7.2 Hz, 1 H), 8.76 (dd, J = 4.2 and 1.5 Hz, 1 H), 8.16 (dd, J = 8.4 and 1.5 Hz, 1 H), (m, 3 H), (m, 1 H), (m, 2 H), 3.85 (s, 3 H), 2.95 (dd, J = 15.0 and 7.5 Hz, 2 H), 1.29 (t, J = 7.5 Hz, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.1, 161.1, 148.2, 145.6, 138.6, 136.4, 134.9, 129.2, 128.9, 128.0, 127.5, 121.6, 121.5, 116.4, 115.5, 110.8, 55.3, 26,8, 15.9; HRMS: calculated for C 19 H 19 N 2 O 2 [M+H + ]: ; found: R f = 0.45, 25 % EtOAc in Hex Compound 8d was isolated in 82 % yield using the general conditions B with 4 equiv of EtI. 1 H NMR (CDCl 3, 300 MHz, ppm): δ 9.93 (s, 1 H), 8.99 (dd, J = 7.2 and 1.5 Hz, 1 H), 8.72 (dd, J = 4.2 and 1.5 Hz, 1 H), 8.17 (dd, J = 8.1 and 1.5 Hz, 1 H), (m, 2 H), (m, 1 H), 6.70 (s, 2 H), 3.86 (s, 3 H), S4

5 2.74 (dd, J = 15.0 and 7.5 Hz, 4 H), 1.27 (t, J = 7.5 Hz, 6 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.9, 160.1, 148.2, 142.7, 138.4, 136.3, 134.5, 130.2, 128.0, 127.4, 121.8, 116.6, 111.4, 55.2, 26,7, 15.8; HRMS: calculated for C 21 H 23 N 2 O 2 [M+H + ]: ; found: R f = 0.45, 25 % EtOAc in Hex Compound 9m was isolated in 76 % yield using the general conditions A with 3 equiv of EtI. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), (m, 1 H), (m, 1 H), 8.22 (d, J = 8.1 Hz, 1 H), 7.76 (d, J = 7.8 Hz, 1 H), (m, 4 H), 7.50 (dd, J = 8.4 and 4.2 Hz, 1 H), 3.01 (dd, J = 15.0 and 7.5 Hz, 2 H), 1.36 (t, J = 7.5 Hz, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 167.1, 148.4, 143.6, 139.7, 138.4, 136.5, 134.3, (q, J C-F = 29.8 Hz) , 128.0, 127.6, 127.4, (q, J C-F = Hz), 122.9, 122.2, 121.8, 116.7, 77.2, 26.5, 15.7; HRMS: calculated for C 19 H 16 F 3 N 2 O [M+H + ]: ; found: R f = 0.55, 25 % EtOAc in Hex Compound 10m was isolated in 75 % yield using the general conditions A with 3 equiv of cyclopropylmethyl iodide. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.95 (d, J = 6.9 Hz, 1 H), 8.77 (d, J = 2.7 Hz, 1 H), 8.18 (d, J = 8.1 Hz, 1 H), (m, 7 H), 2.88 (d, J = 6.9 Hz, 2 H), (m, 1 H), 0.49 (t, J = 4.8 Hz, 2 H), 0.24 (t, J = 4.8 Hz, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.5, 148.2, 140.8, 138.5, 136.5, 134.7, 130.2, 130.0, 128.0, 127.4, 127.0, 126.1, 121.8, 121.6, 115.5, 37.5, 11.9, 4.9; HRMS: calculated for C 20 H 19 N 2 O [M+H + ]: ; found: R f = 0.60, 25 % EtOAc in Hex Compound 11m was isolated in 81 % yield using the general conditions A with 3 equiv of BnCl. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.88 (dd, J = 6.9 and 1.5 Hz, 1 H), 8.12 (dd, J = 8.1 and 1.5 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 2 H), (m, 6 H), 4.25 (s, 1 H), 2.39 (s, 3 H), 2.20 (s, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 169.0, 148.1, 140.3, 138.6, 138.5, 138.4, 136.3, 136.2, 134.7, 133.5, 133.2, 128.4, 128.3, 128.2, 127.9, 127.3, 125.6, 125.5, 121.6, 121.5, 116.6, 35.5, 20.9, 20.1; HRMS: calculated for C 25 H 23 N 2 O [M+H + ]: ; found: S5

6 R f = 0.65, 25 % EtOAc in Hex Compound 11d was isolated in 82 % yield using the general conditions B with 4 equiv of BnCl. 1 H NMR (CDCl 3, 300 MHz, ppm): δ 9.76 (s, 1 H), 8.90 (d, J = 6.9 Hz, 1 H), (m, 1 H), 8.09 (d, J = 8.1 Hz, 1 H), (m, 2 H), (m, 2 H), (m, 8 H), (m, 2 H), (m, 4 H), 2.24 (s, 6 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 169.4, 147.8, 140.1, 140.0, 138.2, 136.2, 135.9, 134.1, 133.5, 132.6, 128.5, 128.2, 128.1, 127.6, 127.1, 125.5, 121.6, 121.3, 116.4, 36.6, 19.7; HRMS: calculated for C 32 H 29 N 2 O [M+H + ]: ; found: R f = 0.50, 25 % EtOAc in Hex Compound 12m was isolated in 75 % yield using the general conditions A with 1.1 equiv of MeI. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), (m, 1 H), (m, 1 H), (m, 1 H), (m, 1 H), (m, 1 H), (m, 1 H), 2.64 (s, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.2, 148.2, 136.7, 136.6, 136.4, 134.7, 131.4, 130.3, 128.0, 127.4, 127.3, 126.0, 121.8, 121.7, 116.5, 20.2; HRMS: calculated for C 17 H 15 N 2 O [M+H + ]: ; found: R f = 0.55, 25 % EtOAc in Hex Compound 12d was isolated in 82 % yield using the general conditions B with 2.2 equiv of MeI. 1 H NMR (CDCl 3, 300 MHz, ppm): δ 9.96 (s, 1 H), (m, 1 H), (m, 1 H), 8.20 (dd, J = 8.1 and 1.5 Hz, 1 H), (m, 2 H), (m, 1 H), (m, 1 H), 2.46 (s, 6 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.9, 148.3, 138.5, 138.0, 136.3, 134.5, 134.4, 128.9, 128.0, 127.7, 127.4, 121.9, 121.6, 116.7, 19.4; HRMS: calculated for C 18 H 17 N 2 O [M+H + ]: ; found: R f = 0.55, 25 % EtOAc in Hex Compound 13m was isolated in 87 % yield using the general conditions A with 1.1 equiv of MeI. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.97 (d, J = 7.2 Hz, 1 H), 8.78 (dd, J = 4.5 and 1.5 Hz, 1 H), 8.18 (d, J = 1.5 Hz, 1 H), (m, 2 H), (m, 1 H), 7.30 (s, 1 H), 7.13 (s, 1 H), 2.42 (s, 3 H), 2.38 (s, 3 H), 2.34 (s, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 169.2, 148.2, 138.5, 137.9, 137.6, 136.3, 135.2, 134.8, 132.4, 131.2, 128.0, 127.4, 125.2, 121.7, 121.6, 116.5, 20.8, 20.3, 16.1; HRMS: calculated for S6

7 C 19 H 19 N 2 O [M+H + ]: ; found: R f = 0.45, 25 % EtOAc in Hex Compound 14m was isolated in 81 % yield using the general conditions A with 3 equiv of Ph(CH 2 ) 2 I. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 9.00 (d, J = 5.7 Hz, 1 H), 8.81 (d, J = 2.1 Hz, 1 H), 8.22 (d, J = 6.6 Hz, 1 H), (m, 3 H), (m, 4 H), (m, 4 H), (m, 1 H), (m, 2 H), 3.07 (d, J = 6.0 Hz, 2 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.2, 148.2, 141.7, 140.5, 136.6, 136.3, 134.7, 130.7, 130.3, 128.5, 128.4, 128.2, 128.0, 127.4, 127.2, 126.3, 125.8, 121.8, 121.6, 116.5, 38.1, 35.6; HRMS: calculated for C 24 H 21 N 2 O [M+H + ]: ; found: R f = 0.40, 35 % EtOAc in Hex Compound 15 was isolated in 82 % yield using the general conditions A with 3 equiv of methyl-5- iodovalerate. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 9.01 (dd, J = 7.5 and 1.5 Hz, 1 H), 8.76 (dd, J = 4.2 and 1.8 Hz, 1 H), 8.18 (dd, J = 8.4 and 1.5 Hz, 1 H), (m, 2 H), 7.45 (dd, J = 4.2 and 1.8 Hz, 1 H), 7.35 (t, J = 8.1 Hz, 1 H), 6.89 (dd, J = 18.0 and 7.8 Hz, 2 H), 3.84 (s, 3 H), 3.58 (s, 3 H), 2.78 (t, J = 7.5 Hz, 2 H), 2.27 (t, J = 7.2 Hz, 2 H), (m, 4 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 173.9, 166.4, 156.3, 148.0, 141.3, 138.4, 136.3, 134.6, 130.1, 127.9, 127.4, 126.8, 121.8, 121.6, 121.5, 116.8, 108.6, 55.7, 51.3, 33.8, 32.8, 30.8, 24.7; HRMS: calculated for C 23 H 25 N 2 O 4 [M+H + ]: ; found: R f = 0.50, 25 % EtOAc in Hex Compound 16 was isolated in 85 % yield using the general conditions A with 3 equiv of EtI. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.97 (dd, J = 6.9 and 1.5 Hz, 1 H), (m, 1 H), 8.14 (d, J = 8.7 Hz, 1 H), (m, 5 H), 7.41 (dd, J = 8.4 and 4.5 Hz, 1 H), (m, 2 H), 1.28 (t, J = 7.5 Hz, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 165.6, 148.3, 142.7, 138.3, 136.3, 134.1, 132.6, 129.4, 127.9, 127.3, (q, J C-F = Hz), 123.6, 122.0, 121.7, 116.8, 26.2, 15.7; HRMS: calculated for C 19 H 16 F 3 N 2 O [M+H + ]: ; found: R f = 0.55, 25 % EtOAc in Hex S7

8 Compound 17 was isolated in 93 % yield using the general conditions A with 1.1 equiv of CD 3 I. 1 H NMR (CDCl 3, 300 MHz, ppm): δ 9.97 (s, 1 H), 9.02 (dd, J = 7.2 and 1.8 Hz, 1 H), 8.76 (dd, J = 7.2 and 1.5 Hz, 1 H), 8.21 (dd, J = 8.4 and 1.5 Hz, 1 H), (m, 2 H), (m, 1 H), (m, 1 H), (m, 2 H), 2.46 (s, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.9, 162.3, 148.2, 138.4, 138.0, 136.5, 134.5, 134.4, 129.0, 128.0, 127.7, 127.5, 121.9, 121.6, 118.9, 19.5; HRMS: calculated for C 18 H 14 D 3 N 2 O [M+H + ]: ; found: R f = 0.60, 25 % EtOAc in Hex Compound 18 was isolated in 44 % yield using the general conditions A with 3 equiv of 6-bromo-1-hexene and recovered 15-1 in 49% yield. No rearranged side products were formed. 1 H NMR (CDCl 3, 360 MHz, ppm): δ 9.97 (s, 1 H), 8.94 (d, J = 7.2 Hz, 1 H), (m, 1 H), 8.10 (d, J = 7.9 Hz, 1 H), (m, 2 H), (m, 1 H), (m, 1 H), 6.84 (d, J = 7.6 Hz, 1 H), 6.77 (d, J = 7.6 Hz, 1 H), (m, 1 H), 4.80 (d, J = 17.3 Hz, 1 H), 4.71 (d, J = 9.7 Hz, 1 H), 3.76 (s, 3 H), 2.67 (t, J = 7.6, 2 H), (m, 2 H), (m, 2 H), (m, 2 H); 13 C NMR (CDCl 3, 90 MHz, ppm) δ 166.5, 156.3, 148.1, 141.8, 138.8, 138.5, 136.3, 134.7, 130.1, 128.0, 127.5, 126.9, 121.8, 121.6, 121.5, 116.7, 114.2, 108.5, 55.8, 33.5, 33.1, 30.9, 28.7; HRMS: calculated for C 23 H 25 N 2 O 2 [M+H + ]: ; found: R f = 0.55, 25 % EtOAc in Hex Compound 19 was isolated in 61 % yield using the general conditions A with 3 equiv of BnBr. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.85 (d, J = 7.2 Hz, 1 H), (m, 1 H), 8.18 (d, J = 8.1 Hz, 1 H), (m, 3 H), (m, 6 H), 6.90 (s, 1 H), 4.17 (s, 2 H), 2.70 (s, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 162.8, 156.3, 148.2, 139.5, 139.0, 138.6, 136.3, 134.7, 128.8, 128.4, 128.0, 127.5, 126.2, 124.5, 121.6, 121.4, 117.7, 116.4, 31.0, 14.2; HRMS: calculated for C 22 H 19 N 2 O 2 [M+H + ]: ; found: R f = 0.40, 25 % EtOAc in Hex Compound 20 was isolated in 63 % yield using the general conditions A with 3 equiv of BrCH 2 CO 2 Me. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), (m, 1 H), (m, 1 H), 8.23 (dd, J = 8.1 and 1.5 Hz, 1 H), (m, 3 H), (m, 3 H), (m, 1 H), 4.23 (s, 2 H), 4.07 (s, 3 H), 3.80 (s, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 171.8, 160.7, 148.4, 139.1, 138.0, 136.3, 134.5, 132.1, 128.1, S8

9 127.2, 126.6, 124.5, 122.4, 121.7, 120.3, 120.0, 117.8, 110.1, 109.9, 52.4, 31.6, 31.2; HRMS: calculated for C 22 H 20 N 3 O 3 [M+H + ]: ; found: R f = 0.45, 25 % EtOAc in Hex Compound 21 was isolated in 81 % yield using the general conditions A with 3 equiv of 1-iodooctane. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), (m, 1 H), (m, 1 H), 8.18 (d, J = 8.4 Hz, 1 H), 7.74 (d, J = 2.1 Hz, 1 H), (m, 4 H), 7.20 (d, J = 8.1 Hz, 1 H), (m, 2 H), (m, 2 H), (m, 10 H), (t, J = 6.3 Hz, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 166.8, 148.3, 140.3, 138.5, 136.4, 134.4, 133.1, 132.0, 130.0, 128.0, 127.4, 122.1, 121.7, 119.4, 116.7, 32.8, 31.8, 31.5, 29.4, 29.3, 29.1, 22.5, 14.0; HRMS: calculated for C 24 H 28 BrN 2 O [M+H + ]: ; found: R f = 0.45, 25 % EtOAc in Hex Compound 22 was isolated in 93 % yield using the general conditions A with 3 equiv of BnCl. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.93 (d, J = 7.2 Hz, 1 H), (m, 1 H), 8.17 (d, J = 8.4 Hz, 1 H), (m, 3 H), (m, 1 H), (m, 5 H), 6.70 (s, 1 H), 4.38 (s, 2 H), 3.81 (s, 3 H), 2.29 (s, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.0, 159.2, 148.1, 141.0, 139.3, 138.5, 136.2, 134.9, 129.8, 129.0, 128.6, 128.3, 127.9, 127.4, 125.9, 124.7, 121.5, 121.4, 116.4, 112.3, 55.3, 38.8, 15.9; HRMS: calculated for C 25 H 23 N 2 O 2 [M+H + ]: ; found: O NHAQ 23 R f = 0.45, 25 % EtOAc in Hex Compound 23 was isolated in 42 % yield using the general conditions A with 3 equiv of 3, 3-dimethylallyl bromide. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.99 (d, J = 6.6 Hz, 1 H), 8.77 (d, J = 2.7 Hz, 1 H), (m, 2 H), (m, 3 H), (m, 5 H), 5.41 (t, J = 6.9 Hz, 1 H), 3.81 (d, J = 6.9 Hz, 2 H), 1.66 (s, 3 H), 1.64 (s, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.4, 148.2, 138.6, 137.1, 136.3, 135.6, 134.8, 134.2, 133.3, 131.2, 128.3, 128.1, 127.9, 127.4, 127.3, 127.2, 127.0, 126.0, 122.6, 121.8, 121.6, 116.6, 32.1, 25.7, 17.9; HRMS: calculated for C 25 H 23 N 2 O [M+H + ]: ; found: S9

10 6. Sequential C-H Functionalization Compound 24: A mixture of amide 7m (55 mg, 0.2 mmol, 1 equiv), Pd(OAc) 2 (2.2 mg, 0.01 mmol, 0.05 equiv), NaHCO 3 (25 mg, 0.3 mmol, 1.5 equiv), (BnO) 2 PO 2 H (17 mg, 0.3 equiv) and ICH 2 CO 2 Et (129 mg, 0.6 mmol, 3 equiv) in tamyloh/dce (1:1, 2 ml) in a 10 ml glass vial (purged with O 2, sealed with PTFE cap) was heated at 110 o C for 20 h. The reaction mixture was cooled to RT and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give the alkylated product 24 in 91 % yield (R f = 0.35, 25 % EtOAc in hexanes). 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 9.01 (dd, J = 6.9 and 1.8 Hz, 1 H), 8.76 (dd, J = 4.2 and 1.5 Hz, 1 H), 8.19 (dd, J = 8.4 and 1.5 Hz, 1 H), (m, 2 H), (m, 2 H), (m, 2 H), 3.97 (dd, J = 14.4 and 7.2 Hz, 2 H), 3.79 (s, 2 H), 2.79 (dd, J = 15.0 and 7.5 Hz, 2 H), 1.29 (t, J = 7.5 Hz, 3 H), 0.99 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 171.3, 168.1, 148.2, 141.1, 138.5, 137.6, 136.2, 134.3, 131.0, 129.4, 127.9, 127.7, 127.3, 122.0, 121.6, 116.8, 60.8, 38.9, 26.5, 15.8, 13.8; HRMS: calculated for C 22 H 23 N 2 O 3 [M+H + ]: ; found: Compound 25: A mixture of amide 7m (55 mg, 0.2 mmol, 1 equiv), Pd(OAc) 2 (2.2 mg, 0.01 mmol, 0.05 equiv), NaHCO 3 (25 mg, 0.3 mmol, 1.5 equiv), (BnO) 2 PO 2 H (17 mg, 0.06 mmol, 0.3 equiv), and MeI (43 mg, 0.3 mmol, 1.5 equiv) in tamyloh/dce (1:1, 2 ml) in a 10 ml glass vial (purged with O 2, sealed with PTFE cap) was heated at 110 o C for 20 h. The reaction mixture was cooled to RT and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give the alkylated product 25 in 88 % yield (R f = 0.55, 25 % EtOAc in hexanes). 1 H NMR (CDCl 3, 300 MHz, ppm): δ 9.97 (s, 1 H), 9.03 (dd, J = 7.2 and 1.5 Hz, 1 H), 8.76 (dd, J = 4.2 and 1.5 Hz, 1 H), 8.21 (d, J = 8.4 Hz, 1 H), (m, 2 H), 7.48 (dd, J = 8.1 and 4.2 Hz, 1 H), 7.33 (t, J = 7.5 Hz, 1 H), 7.18 (dd, J = 13.2 and 7.5 Hz, 1 H), 2.79 (dd, J = 15.0 and 7.5 Hz, 2 H), 2.47 (s, 3 H), 1.30 (t, J = 7.5 Hz, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.9, 148.3, 140.8, 138.5, 137.6, 136.3, 134.5, 129.1, 128.0, 127.7, 127.4, 126.1, 121.9, 121.6, 116.7, 26.5, 19.4, 15.9; S10

11 HRMS: calculated for C 19 H 19 N 2 O [M+H + ]: ; found: Compound 26: A mixture of amide 7m (55 mg, 0.2 mmol, 1 equiv), Pd(OAc) 2 (4.4 mg, 0.02 mmol, 0.1 equiv), Ag 2 CO 3 (84 mg, 0.3 mmol, 1.5 equiv), (BnO) 2 PO 2 H (11 mg, 0.2 equiv) and p-iodoanisole (70 mg, 0.3 mmol, 1.5 equiv) in tamyloh (2 ml) in a 10 ml glass vial (purged with Ar, sealed with PTFE cap) was heated at 110 o C for 12 h. The reaction mixture was cooled to RT and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give the arylated product 26 in 76 % yield (R f = 0.55, 25 % EtOAc in hexanes). 1 H NMR (CDCl 3, 300 MHz, ppm): δ 9.64 (s, 1 H), 8.78 (dd, J = 7.2 and 1.8 Hz, 1 H), 8.61 (dd, J = 4.2 and 1.5 Hz, 1 H), 8.09 (dd, J = 8.4 and 1.5 Hz, 1 H), (m, 8 H), 6.75 (d, J = 8.7 Hz, 2 H), 3.64 (s, 3 H), 2.86 (dd, J = 15.0 and 7.5 Hz, 2 H), 1.31 (t, J = 7.5 Hz, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.5, 158.8, 148.0, 141.9, 139.2, 138.4, 136.4, 136.1, 134.4, 132.9, 129.8, 129.3, 127.8, 127.6, 127.5, 127.3, 121.6, 121.4, 116.5, 113.6, 55.1, 26.6, 15.9; HRMS: calculated for C 25 H 23 N 2 O 2 [M+H + ]: ; found: Compound 27 3 : A mixture of amide 7m (55 mg, 0.2 mmol, 1 equiv), Pd(OAc) 2 (4.4 mg, 0.02 mmol, 0.1 equiv), KHCO 3 (40 mg, 0.4 mmol, 2 equiv), and opba (8.0 mg, 0.04 mmol, 20 mol %) and (2- bromoethynyl)triisopropylsilane (104 mg, 0.4 mmol, 2 equiv) in DCE (2 ml) in a 10 ml glass vial (purged with Ar, sealed with PTFE cap) was heated at 100 o C for 24 h. The reaction mixture was cooled to RT and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give product 27 in 86 % yield (R f = 0.6, 25 % EtOAc in hexanes). 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 9.03 (d, J = 1.8 Hz, 1 H), 8.76 (dd, J = 4.2 and 1.5 Hz, 1 H), 8.17 (d, J = 1.5 Hz, 1 H), (m, 2 H), (m, 2 H), (m, 2 H), 2.81 (t, J = 7.5 Hz, 2 H), 1.31 (t, J = 7.5 Hz, 3 H), (m, 21 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 167.2, 148.1, 141.7, 139.8, 138.5, 136.1, 134.7, 130.4, 129.0, 128.9, 127.8, 127.3, 121.7, 121.4, 120.9, 116.8, 103.9, 94.8, 26.5, 18.2, 15.8, 11.0; HRMS: calculated for C 29 H 37 N 2 OSi [M+H + ]: ; found: Compound 28 1,8 : A mixture of amide 7m (55 mg, 0.2 mmol, 1 equiv), Pd(OAc) 2 (2.2 mg, 0.01 mmol, 0.05 equiv), PhI(OAc) 2 (128 mg, 0.4 mmol, 2.0 equiv) in AcOH/p-xylene (1: 2, 2 ml) in a 10 ml glass vial (purged with Ar, sealed with PTFE cap) was heated at 110 o C for 20 h. The reaction mixture was cooled to RT and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give the acetoxylated product 28 in 72 % yield (R f = 0.3, 25 % EtOAc in hexanes). 1 H NMR (CDCl 3, 300 MHz, ppm): δ 9.93 (s, 1 H), 8.86 (dd, J = 6.6 and 2.4 Hz, 1 H), 8.70 (dd, J = 3.9 and 1.5 Hz, 1 H), 8.10 (dd, J = 8.4 and 1.5 Hz, 1 H), (m, 2 H), (m, 2 H), (m, 1 H), 6.98 (d, J = 8.1 Hz, 1 H), 2.75 (dd, J = 15.0 and 7.5 Hz, 2 H), 2.02 (s, 2 H), 1.31 (t, J = 7.5 Hz, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 169.6, 164.9, 148.4, 147.2, 143.6, 138.4, 136.2, 134.3, 130.3, 130.2, 127.9, 127.3, 126.6, 122.1, 121.7, 120.3, 116.8, 26.4, 20.8, 15.7; HRMS: calculated for C 20 H 19 N 2 O 3 [M+H + ]: ; found: S11

12 7. General procedure for ortho alkylation with secondary alkyl iodide General conditions C: A mixture of benzamide 4 (50 mg, 0.2 mmol, 1 equiv), Pd(OAc) 2 (4.4 mg, 0.02 mmol, 0.1 equiv), NaHCO 3 (35 mg, 0.4 mmol, 2 equiv), (PhO) 2 PO 2 H (15 mg, 0.06 mmol, 0.3 equiv), and ipri (102 mg, 0.6 mmol, 3 equiv) in t-amyloh/p-xylene (1:1, 2 ml) in a 10 ml glass vial (purged with O 2, sealed with PTFE cap) was heated at 130 o C for 24 h. The reaction mixture was cooled to RT and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give the alkylated product 29 in 85 % yield (R f = 0.5, 25 % EtOAc in hexanes). 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.97 (d, J = 7.2 Hz, 1 H), 8.76 (dd, J = 3.9 and 1.5 Hz, 1 H), 8.18 (dd, J = 8.1 and 1.5 Hz, 1 H), (m, 3 H), (m, 3 H), (m, 1 H), (m, 1 H), 1.33 (d, J = 6.6 Hz, 6 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.7, 148.2, 147.0, 138.5, 136.4, 136.3, 134.7, 130.3, 128.0, 127.4, 126.9, 126.3, 125.8, 121.8, 121.6, 116.5, 30.0, 24.3; HRMS: calculated for C 19 H 19 N 2 O [M+H + ]: ; found: General conditions D: A mixture of amide 4 (50 mg, 0.2 mmol, 1 equiv), Pd(OAc) 2 (4.4 mg, 0.02 mmol, 0.1 equiv), K 2 CO 3 (97 mg, 0.7 mmol, 3.5 equiv), (PhO) 2 PO 2 H (15 mg, 0.06 mmol, 0.3 equiv), and ipri (204 mg, 1.2 mmol, 6 equiv) in t-amyloh/p-xylene (1:1, 2 ml) in a 10 ml glass vial (purged with O 2, sealed with PTFE cap) was heated at 130 o C for 48 h. The reaction mixture was cooled to RT and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give the alkylated product 30 in 84 % yield (R f = 0.55, 25 % EtOAc in hexanes). 1 H NMR (CDCl 3, 300 MHz, ppm): δ 9.99 (s, 1 H), 9.02 (dd, J = 6.9 and 1.5 Hz, 1 H), (m, 1 H), 8.20 (dd, J = 8.4 and 1.5 Hz, 1 H), (m, 1 H), (m, 2 H), (m, 2 H), (m, 2 H), 1.30 (t, J = 5.7 Hz, 12 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 169.1, 148.3, 145.3, 138.5, 136.3, 136.2, 134.4, 129.5, 128.0, 127.4, 123.1, 121.9, 121.6, 116.7, 31.1, 24.5; HRMS: calculated for C 22 H 25 N 2 O [M+H + ]: ; found: R f = 0.50, 25 % EtOAc in Hex Compound 31 was isolated in 77 % yield using the general conditions C with 3 equiv of ipri. 1 H NMR (CDCl 3, 360 MHz, ppm): δ (s, 1 H), 8.95 (d, J = 6.8 Hz, 1 H), 8.74 (s, 1 H), 8.16 (d, J = 7.6 Hz, 1 H), (m, 4 H), 7.26 (s, 1 H), 7.11 (d, J = 7.2 Hz, 1 H), (m, 1 H), 2.42 (s, 3 H), 1.31 (d, J = 6.5 Hz, 6 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.8, 148.2, 147.2, 140.4, 138.5, 136.3, 134.8, 133.6, 127.9, 127.4, 127.0, 127.0, 126.5, 121.7, 121.6, 29.8, 24.3, 21.6; HRMS: calculated for C 20 H 21 N 2 O [M+H + ]: ; found: S12

13 R f = 0.40, 25 % EtOAc in Hex Compound 32 was isolated in 73 % yield using the general conditions C with 3 equiv of ipri. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.96 (d, J = 6.9 Hz, 1 H), 8.79 (t, J = 1.8 Hz, 1 H), 8.19 (d, J = 8.4 Hz, 1 H), 7.90 (d, J = 7.8 Hz, 1 H), (m, 2 H), (m, 1 H), (m, 2 H), 7.16 (d, J = 7.2 Hz, 1 H), 3.94 (s, 3 H), 3.69 (t, J = 6.9 Hz, 1 H),1.61 (d, J = 6.9 Hz, 6 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 161.5, 148.3, 138.5, 138.4, 136.3, 134.4, 130.4, 128.0, 127.4, 125.2, 123.6, 123.5, 122.1, 122.0, 121.8, 119.3, 116.4, 110.2, 31.1, 26.7, 23.5; HRMS: calculated for C 22 H 22 N 3 O [M+H + ]: ; found: R f = 0.5, 25 % EtOAc in Hex Compound 33 was isolated in 34 % yield using the general conditions C with 3 equiv of ipri. 1 H NMR (CDCl 3, 360 MHz, ppm): δ (s, 1 H), 8.91 (d, J = 2.1 and 6.4 Hz, 1 H), 8.76 (dd, J = 1.8 and 4.3 Hz, 1 H), 8.18 (dd, J = 1.4 and 7.9 Hz, 1 H), 7.81 (s, 1 H), 7.70 (d, J = 7.9 Hz, 1 H), (m, 3 H), 7.45 (dd, J = 4.3 and 8.3 Hz, 1 H), (m, 1 H), 1.32 (d, J = 6.8 Hz, 6 H); 13 C NMR (CDCl 3, 90 MHz, ppm) δ 167.2, 151.0, 148.4, 138.4, 136.9, 136.4, 134.3, 128.0, 127.3, 127.1, (q, J C-F = Hz), 122.3, 121.8, 116.8, 30.3, 24.1; HRMS: calculated for C 20 H 18 F 3 N 2 O [M+H + ]: ; found: R f = 0.60, 25 % EtOAc in Hex Compound 34 was isolated in 84 % yield using the general conditions D with 6 equiv of ipri and 3.5 equiv of K 2 CO 3. 1 H NMR (CDCl 3, 360 MHz, ppm): δ 9.96 (s, 1 H), 8.99 (d, J = 7.2 Hz, 1 H), 8.69 (s, 1 H), 8.17 (d, J = 8.3 Hz, 1 H), (m, 2 H), (m, 1 H), 7.05 (s, 1 H), 3.11 (t, J = 6.5 Hz, 2 H), 2.40 (s, 3 H), 1.26 (s, 12 H); 13 C NMR (CDCl 3, 90 MHz, ppm) δ 169.4, 148.2, 145.2, 139.1, 138.5, 136.2, 134.5, 133.7, 128.0, 127.4, 123.8, 121.8, 121.6, 116.6, 31.0, 24.5, 21.7; HRMS: calculated for C 23 H 27 N 2 O [M+H + ]: ; found: R f = 0.55, 25 % EtOAc in Hex Compound 35 was isolated in 76 % yield using the general conditions C with 3 equiv of ipri. 1 H NMR S13

14 (CDCl 3, 300 MHz, ppm): δ (s, 1 H), (m, 2 H), 8.18 (dd, J = 8.1 and 1.5 Hz, 1 H), (m, 4 H), 7.15 (d, J = 5.4 Hz, 1 H), (m, 1 H), 1.37 (d, J = 6.9 Hz, 6 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 161.4, 153.4, 148.2, 138.5,136.3, 134.7, 130.8, 127.9, 127.7, 127.5, 127.4, 121.6, 121.5, 116.4, 28.1, 23.9; HRMS: calculated for C 17 H 17 N 2 OS [M+H + ]: ; found: MeO O NHAQ 36 R f = 0.45, 25 % EtOAc in Hex Compound 36 was isolated in 88 % yield using the general conditions C with 3 equiv of ipri. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.97 (d, J = 6.9 Hz, 1 H), (m, 1 H), 8.20 (dd, J = 8.1 and 1.5 Hz, 1 H), (m, 2 H), (m, 1 H), 7.39 (d, J = 8.7 Hz, 1 H), 7.13 (d, J = 2.4 Hz, 1 H), 7.05 (dd, J = 8.4 and 2.7 Hz, 1 H), 3.86 (s, 3 H), (m, 1 H), 1.31 (d, J = 6.9 Hz, 6 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.5, 157.3, 148.2, 138.8, 138.5, 137.2, 136.3, 134.6, 127.9, 127.5, 127.4, 121.8, 121.7, 116.5, 116.3, 111.9, 55.4, 29.4, 24.5; HRMS: calculated for C 20 H 21 N 2 O 2 [M+H + ]: ; found: R f = 0.50, 25 % EtOAc in Hex Compound 37 was isolated in 56 % yield using the general conditions C with 3 equiv of sec-butyl iodide. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), (m, 1 H), 8.71 (dd, J = 4.2 and 1.5 Hz, 1 H), 8.14 (dd, J = 8.4 and 1.5 Hz, 1 H), (m, 2 H), (m, 1 H), (m, 1 H), 7.07 (d, J = 2.7 Hz, 1 H), 6.99 (dd, J = 8.7 and 2.7 Hz, 1 H), 3.81 (s, 3 H), 3.10 (dd, J = 14.1 and 6.9 Hz, 1 H), (m, 2 H), 1.25 (d, J = 6.9 Hz, 3 H), 0.79 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.5, 157.3, 148.2, 138.5, 138.0, 137.6, 136.3, 134.7, 128.0, 127.8, 127.4, 121.8, 121.6, 116.6, 116.5, 111.8, 55.4, 36.4, 31.2, 22.5, 12.3; HRMS: calculated for C 21 H 23 N 2 O 2 [M+H + ]: ; found: R f = 0.55, 25 % EtOAc in Hex Compound 38 was isolated in 31 % yield using the general conditions C with 3 equiv of sec-pentyl iodide. 9 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.97 (d, J = 7.2 Hz, 1 H), (m, 1 H), (m, 1 H), (m, 2 H), 7.46 (dd, J = 8.4 and 4.2 Hz, 1 H), 7.34 (d, J = 8.7 Hz, 1 H), 7.12 (d, J = 2.7 Hz, 1 H), 7.65 (dd, J = 8.7 and 2.7 Hz, 1 H), 3.86 (s, 3 H), (m, 1 H), (m, 2 H), (m, 5 H), 0.82 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.5, 157.3, 148.2, 138.5, 137.8, 137.7, S14

15 136.3, 134.6, 127.9, 127.8, 127.4, 121.8, 121.6, 116.5, 116.4, 111.7, 55.4, 40.7, 34.5, 22.9, 20.8, 14.1; HRMS: calculated for C 22 H 25 N 2 O 3 [M+H + ]: ; found: R f = 0.5, 25 % EtOAc in Hex Compound 39 was isolated in 72 % yield using the general conditions C with 3 equiv of cyclohexyl iodide. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 9.00 (d, J = 6.6 Hz, 1 H), 8.78 (d, J = 3.9 Hz, 1 H), 8.22 (d, J = 7.2 Hz, 1 H), (m, 3 H), (m, 3 H), (m, 1 H), (m, 1 H), (m, 2 H), (m, 3 H), (m, 2 H), (m, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.7, 148.2, 146.0, 138.5, 136.6, 136.3, 134.8, 130.3, 128.0, 127.4, 127.3, 127.1, 125.9, 121.8, 121.7, 116.6, 40.5, 34.7, 26.7, 26.1; HRMS: calculated for C 22 H 23 N 2 O [M+H + ]: ; found: R f = 0.45, 25 % EtOAc in Hex Compound 40 was isolated in 54 % yield using the general conditions C with 3 equiv of cyclohexyl iodide. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 9.00 (d, J = 7.2 Hz, 1 H), (m, 1 H), (m, 1 H), 8.12 (s, 1 H), (m, 3 H), (m, 5 H), (m, 1 H), (m, 2 H), (m, 3 H), (m, 2 H), (m, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.6, 148.3, 143.3, 138.6, 136.3, 135.7, 134.9, 134.2, 131.0, 128.0, 127.9, 127.5, 127.4, 127.1, 127.0, 125.9, 125.7, 121.8, 121.7, 116.6, 40.2, 35.0, 26.9, 26.2; HRMS: calculated for C 26 H 25 N 2 O [M+H + ]: ; found: R f = 0.55, 25 % EtOAc in Hex Compound 41 was isolated in 69 % yield using the general conditions C with 3 equiv of cyclohexyl iodide. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 9.00 (d, J = 7.2 Hz, 1 H), 8.75 (d, J = 3.6 Hz, 1 H), 8.16 (d, J = 8.1 Hz, 1 H), (m, 2 H), (m, 2 H), 7.16 (s, 1 H), 7.05 (dd, J = 2.4 and 8.7 Hz, 1 H), 3.85 (s, 3 H), 3.08 (t, J = 11.4 Hz, 1 H), (m, 2 H), (m, 3 H), (m, 5 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.2, 157.2, 148.1, 138.3, 137.7, 137.2, 136.1, 134.5, 128.1, 127.8, 127.2, 121.7, 121.5, 116.4, 116.1, 112.1, 55.2, 39.7, 34.8, 26.6, 25.9; HRMS: calculated for C 23 H 25 N 2 O 2 [M+H + ]: ; found: S15

16 R f = 0.55, 35 % EtOAc in Hex Compound 42 was isolated in 42 % yield using the general conditions C with 3 equiv of 1-iodocyclopentane and 3 equiv of NaHCO 3. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.96 (d, J = 6.9 Hz, 1 H), 8.80 (d, J = 4.2 Hz, 1 H), 8.22 (d, J = 8.4 Hz, 1 H), (m, 2 H), 7.49 (dd, J = 8.4 and 4.2 Hz, 1 H), 7.15 (s, 1 H), 6.94 (s, 1 H), 3.98 (s, 3 H), 3.95 (s, 3 H), 3.55 (t, J = 7.5 Hz, 1 H), (m, 2 H), (m, 2 H), (m, 4 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 73.7, 71.4, 71.1, 70.9, 69.7, 69.5, 69.3, 68.6, 68.5, 68.4, 67.7, 67.6, 67, 59.3, 59.2, 57.5, 56.7, 55.4; HRMS: calculated for C 23 H 25 N 2 O 3 [M+H + ]: ; found: R f = 0.50, 25 % EtOAc in Hex Compound 43 was isolated in 63 % yield using the general conditions C with 3 equiv of 1-iodocyclopentane. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.86 (d, J = 7.2 Hz, 1 H), 8.81 (d, J = 2.7 Hz, 1 H), 8.18 (d, J = 8.1 Hz, 1 H), (m, 4 H), 7.11 (d, J = 5.1 Hz, 1 H), (m, 1 H), 2.28 (bs, 2 H), (m, 6 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 161.5, 150.4, 148.2, 138.6, 136.3, 134.7, 132.3, 128.1, 128.0, 127.8, 127.4, 121.6, 116.5, 39.8, 34.8, 25.6; HRMS: calculated for C 19 H 19 N 2 OS [M+H + ]: ; found: R f = 0.45, 25 % EtOAc in Hex Compound 44 was isolated in 84 % yield using the general conditions C with 1.3 equiv NaHCO 3 and 3 equiv of α-methylbenzyl bromide. 1 H NMR (CDCl 3, 300 MHz, ppm): δ (s, 1 H), 8.96 (d, J = 6.9 Hz, 1 H), 8.73 (d, J = 2.7 Hz, 1 H), 8.19 (d, J = 8.1 Hz, 1 H), (m, 2 H), (m, 1 H), (m, 4 H), (m, 3 H), (m, 2 H), 4.78 (dd, J = 14.1 and 6.9 Hz, 1 H), 3.87 (s, 3 H), 1.70 (d, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 168.3, 157.6, 148.2, 146.0, 138.5, 137.7, 136.8, 136.2, 134.5, 129.4, 128.1, 127.9, 127.6, 127.3, 125.7, 121.9, 121.6, 116.6, 116.1, 112.0, 55.4, 29.6, 22.2; HRMS: calculated for C 25 H 23 N 2 O 2 [M+H + ]: ; found: S16

17 8. Removal of the auxiliaries. Compound 45: A mixture of compound 25 (58 mg, 0.2 mmol, 1 equiv) and BF 3 OEt 2 (240 mg, 4 mmol, 10 equiv) in MeOH (1 ml) was stirred at 110 o C under Ar for 48 h 11. The reaction mixture was cooled to RT, quenched with Et 3 N (280 μl, 2.0 mmol, 10 equiv), and then concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give the desired methyl ester in 72% yield. Compound 46: A mixture of 1-naphthoyl chloride (1.9 g, 10 mmol, 1.0 equiv), 8-Amino-5-methoxyquinoline hydrochloride 13 (1.93 g, 9.2 mmol, 0.92 equiv), NEt 3 (3.06 ml, 22 mmol, 2.2 equiv) in anhydrous CH 2 Cl 2 (20 ml) was stirred at room temperature overnight. Water was added and the mixture was extracted with CH 2 Cl 2. The combined organic layers was washed with water and brine, dried over anhydrous Na 2 SO 4, and then concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using 25 % EtOAc in Hex as eluent to give the desired amide product 46 in 74 % yield. (R f = 0.55, 25 % EtOAc in hexanes). 1 H NMR (CDCl 3, 400 MHz, ppm): δ (s, 1 H), 8.98 (d, J = 8.4 Hz, 1 H), (m, 1 H), 8.61 (d, J = 8.4, 1 H), 8.53 (d, J = 7.6, 1 H), 8.00 (d, J = 8.0 Hz, 1 H), (m, 2 H), (m, 3 H), (m, 1 H), 6.95 (d, J = 8.4, 1 H), 4.04 (s, 3 H); 13 C NMR (CDCl 3, 90 MHz, ppm) δ 167.4, 150.6, 148.7, 139.3, 134.9, 133.8, 131.3, 130.9, 130.4, 128.3, 128.2, 127.2, 126.4, 125.6, 125.4, 124.9, 120.8, 120.5, 117.0, 104.3, 55.81; HRMS: calculated for C 21 H 17 N 2 O 2 [M+H + ]: ; found: Compound 46-1: A mixture of 46 (66 mg, 0.2 mmol, 1 equiv), Pd(OAc) 2 (2.2 mg, 0.01 mmol, 0.05 equiv), NaHCO 3 (25 mg, 0.3 mmol, 1.5 equiv), (BnO) 2 PO 2 H (17 mg, 0.06 mmol, 0.3 equiv), and ICH 2 CO 2 Et (128 mg, 0.6 mmol, 3 equiv) in tamyloh/dce (1:1, 2 ml) in a 10 ml glass vial (purged with O 2, sealed with PTFE cap) was heated at 110 o C for 20 h. The reaction mixture was cooled to RT and then concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give the alkylated product 46-1 in 86 % yield (R f = 0.4, 25 % EtOAc in hexanes). 1 H NMR (CDCl 3, 300 MHz, ppm): δ 9.06 (s, 1 H), 9.03 (d, J = 5.7 Hz, 1 H), 8.70 (dd, J = 3.0 and 1.5 Hz, 1 H), (m, 1 H), (m, 1 H), (m, 2 H), (m, 3 H), (m, 1 H), 6.97 (dd, J = 8.7 and 2.4 Hz, 1 H), (m, 7 H), (m, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 171.1, 167.2, 150.9, 148.7, 139.3, 135.4, 132.5, 131.2, 130.3, 129.5, 128.8, 128.0, 127.8, 127.7, 126.2, 125.3, 120.8, 120.5, 117.4, 104.2, 61.0, 55.9, 39.4, 13.9; HRMS: calculated for C 25 H 23 N 2 O 4 [M+H + ]: ; found: Compound : Compound 46-1 (82 mg, 0.2 mmol, 1 equiv) was dissolved in a mixture of CH 3 CN and H 2 O S17

18 (5:1, 1mL) at RT. CAN (178 mg, 0.33 mmol, 3.0 equiv) was added, the reaction mixture was stirred at RT for 5 h. The mixture was diluted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous Na 2 SO 4, and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using 30% acetone in hexanes as eluent to give product 47 in 71 % yield as an orange solid (R f = 0.2, 30% acetone in hexanes). 1 H NMR (CDCl 3, 300 MHz, ppm): δ 8.07 (d, J = 8.1 Hz, 1 H), (m, 2 H), (m, 2 H), 7.36 (d, J = 8.7 Hz, 1 H), 6.75 (s, 1 H), 6.18 (s, 1 H), 4.20 (dd, J = 14.4 and 4.2 Hz, 1 H), 3.92 (s, 2 H), 1.31 (t, J = 7.2 Hz, 3 H); 13 C NMR (CDCl 3, 75 MHz, ppm) δ 172.2, 170.9, 134.3, 132.5, 130.0, 129.7, 128.0, 127.9, 127.3, 127.1, 126.3, 125.3, 61.4, 39.4, 14.1; HRMS: calculated for C 15 H 16 NO3 [M+H + ]: ; found: Preliminary mechanistic studies 1) Kinetic isotope effect (KIE) of the alkylation of substrate 4 and 48 with npri under condition A Substrate 4 or 48 was subjected to the alkylation reaction with npri under the general reaction condition A for 3 h. The alkylation reaction was worked up as described in part 4 and analyzed by 1 H NMR (average of 3 runs). k H /k D is based on the ratio of alkylation yield using substrates 4 and 48. 2) Kinetic isotope effect (KIE) of the alkylation of substrate 4 and 48 with ipri under condition C Substrate 4 or 48 was subjected to the alkylation reaction with ipri under the general reaction condition C for 3 h. The alkylation reaction was worked up as described in part 4 and analyzed by 1 H NMR (average of 2 runs). k H /k D is based on the ratio of alkylation yield using substrates 4 and 48. S18

19 3) Time course analysis of alkylation of compound 4 with npri under conditions A. One set of parallel alkylation reactions of substrate 4 with npri at a 0.2 mmol scale were performed under the general conditions A. Individual alkylation reaction was stopped at specified reaction time (4, 12, and 20 h), worked up as described in part 4, and analyzed by 1 H NMR. Another set of parallel alkylation reactions of substrate 4 with npri were conducted under the general conditions A for 20 h. Additional 2 equiv of NaHCO 3 was added and the alkylation reaction continued for another 8 and 16 h. The reaction mixture was then worked up as described in part 4 and analyzed by 1 H NMR. 10. Alkylation of palladacycle 55 with 4-methylcyclohexyl iodides 56 and 57. O MeO O Pd(OAc) 2 (1 equiv) NHAQ CH 3 CN, 60 o C, 4 h MeO N 54 N Pd CH 3 CN 55 Preparation of the palladacycle compound 55 under the general conditions E 14 : A mixture of compound 54 (1.39 g, 5 mmol, 1.0 equiv) and Pd(OAc) 2 (1.12 g, 5 mmol, 1 equiv) in anhydrous MeCN (10 ml) was stirred at 60 o C for 4 h. The reaction mixture was cooled to RT; the resulting yellowish precipitate was collected by filtration, washed with 10 ml of MeCN, and then re-dissolved in 150 ml CH 2 Cl 2. The solution was then filtered through a short pad of Celite to remove residual solids, and concentrated in vacuo to give the desired palladacycle 55 in 90 % yield. Single crystals of 55 were obtained by slow evaporation of its solution in MeCN/CH 2 Cl 2 (1:4) at RT. 1 H NMR (DMSO-D6, 400 MHz, ppm): δ 8.42 (s, 1 H), 8.18 (d, J = 7.6 Hz, 1 H), 8.10 (d, J = 7.6 Hz, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 6.80 (d, J = 4.4 Hz, 1 H), 6.70 (t, J = 7.6 Hz, 1 H), 6.63 (d, J = 7.6 Hz, 1 H), 6.20 (d, J = 8.4 Hz, 1 H), 5.88 (d, J = 8.0 Hz, 1 H), 2.89 (s, 3 H), 1.22 (s, 3 S19

20 H); 13 C NMR (DMSO-D6, 90 MHz, ppm) δ 175.4, 157.3, 149.9, 148.7, 145.9, 145.1, 139.3, 135.7, 133.1, 129.9, 128.7, 121.7, 119.0, 118.9, 116.2, 113.0, 55.0, 1.2; HRMS: calculated for C 19 H 16 N 3 O 2 Pd [M+H + ]: ; found: HO I 2 (1 equiv) PPh 3 (1.2 equiv) Im (1.2 equiv) I CH Cl 2,0 o C to r.t. 56 Synthesis of cis-4-methylcyclohexyl iodide : To a solution of triphenylphosphine (3.15 g, 12 mmol, 1.2 equiv) and imidazole (0.816 g, 12 mol, 1.2 equiv) in anhydrous CH 2 Cl 2 (50 ml) at 0 o C was added iodine (2.54 g, 10 mmol, 1 equiv) portion-wise. A solution of trans-4-methylcyclohexanol (98% from Alfa Aesar, 1.14g, 10 mmol, 1 equiv) in CH 2 Cl 2 (10 ml) was then added at 0 o C dropwise. The reaction mixture was allowed to warm to RT and reacted overnight. The reaction was quenched with aq. NaHSO 3 solution. The aqueous layer was extracted with CH 2 Cl 2. The combined organic layers were dried over anhydrous Na 2 SO 4, concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using hexanes as eluent to give the desired product 56 in 74% yield (R f = 0.7, 100 % Hex). Note: compound 56 has a low boiling point, use caution when concentrating compound 56 in vacuo. Cis- and trans-4-methylcyclohexyl iodides have distinct 1 H-NMR spectra and cannot be separated by silica gel chromatography. Compound 56 was obtained in >30/1 cis/trans selectivity based on 1 H-NMR analysis. 1 H NMR (CDCl 3, 360 MHz, ppm): δ 4.80 (bs, 1 H), (m, 2 H), (m, 7 H), 0.96 (d, J = 5.8 Hz, 3 H); 13 C NMR (CDCl 3, 90 MHz, ppm) δ 36.6, 36.2, 31.6, 31.3, HO I 2 (1 equiv) PPh 3 (1.2 equiv) NMI (1.2 equiv) I CH Cl 2,-5 o C 57 Synthesis of trans-4-methylcyclohexyl iodide : A solution of I 2 (2.54 g, 10 mmol, 1 equiv) and PPh 3 (3.15 g, 12 mmol, 1.2 equiv) in 50 ml anhydrous CH 2 Cl 2 was stirred for 1 h at 0 o C. N-methyl-imidazole (0.984 g, 12 mmol, 1.2 equiv) was then added. The reaction mixture (a bright yellow suspension) was cooled to -10 o C; a solution of cis-4-methylcyclohexanol (98% from Alfa Aesar, 1.14 g, 10 mmol, 1 equiv) in CH 2 Cl 2 (10 ml) was then added dropwise. The resulting mixture was stirred for 15 h at -5 o C, and then quenched by aq. NaHSO 3. The aqueous layer was extracted with CH 2 Cl 2. The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel flash chromatography using hexanes as eluent to give the desired product 57 in 32% yield (R f = 0.7, 100 % Hex). Note: compound 57 has a low boiling point, use caution when concentrating compound 57 in vacuo. Transand cis-4-methylcyclohexyl iodides have distinct 1 H-NMR spectra and cannot be separated by silica gel chromatography. Compound 57 was obtained in >30/1 trans/cis selectivity based on 1 H-NMR analysis. 1 H NMR (CDCl 3, 400 MHz, ppm): δ (m, 1 H), (m, 2 H), (m, 2 H), (m, 2 H), 1.44 (d, J = 4.4 Hz, 1 H); (m, 2 H), 0.83 (dd, J = 1.5 and 6.4 Hz, 3 H); 13 C NMR (CDCl 3, 90 MHz, ppm) δ 40.5, 37.4, 31.2, 30.5, S20

21 A mixture of palladacycle compound 55 (85 mg, 0.2 mmol, 1 equiv) and cis-4-methylcyclohexyl iodide 56 (0.6 mmol, 3 equiv) in tamyloh (1 ml)/pxylene (1 ml) in a 10 ml glass vial (sealed with PTFE cap) was stirred at 130 o C for 1 h. The reaction mixture was cooled to RT, diluted with dichloromethane (2.0 ml). aq. HI (47% in water, 30 μl) was added and the mixture was stirred for 1 h and then concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give the alkylated product 58 (25 mg, 33 % yield (R f = 0.55, 25 % EtOAc in Hex, cis: trans > 15:1, see below) and recovered 54 (32 mg, in 59% yield). 1 H NMR (CDCl 3, 400 MHz, ppm): δ (s, 1 H), 8.95 (d, J = 7.2 Hz, 1 H), (m, 1 H), 8.18 (d, J = 8.4 Hz, 1 H), (m, 2 H), 7.44 (dd, J = 4.4 and 8.4 Hz, 1 H), 7.36 (dd, J = 8.8 and 16.8 Hz, 1 H), 7.12(d, J = 2.4 Hz, 1 H), 7.01 (dd, J = 2.4 and 8.4 Hz, 1 H), 3.84 (s, 3 H), (m, 1 H), 1.90 (bs, 1 H), (m, 4 H), (m, 4 H), 1.04 (d, J = 7.2 Hz, 3 H, CH 3 -cis), a little grease at δ1.3 and 1.05; 13 C NMR (CDCl 3, 100 MHz, ppm) δ 168.4, 157.4, 148.2, 138.6, 137.9, 137.4, 136.3, 134.7, 128.3, 128.0, 127.4, 121.8, 121.7, 116.6, 116.3, 112.3, 55.5, 40.0, 32.0, 28.8, 26.6, 17.7 (CH 3 -cis); HRMS: calculated for C 24 H 27 N 2 O 2 [M+H + ]: ; found: Small peaks at δ 1.25 and 0.85 in 1 H NMR spectrum come from residual grease. These two peaks show no correlation with the carbon scaffold of 58 in HSQC NMR. Cis- and trans-iodides 58 and 59 have the same R f value on TLC and cannot be separated by silica gel chromatography. They show readily distinguishable signals in both 1 H- and 13 C-NMR. 1 H-NMR: The CH 3 group of cis compound 58 shows up at δ 1.04 (d, 3 H), while the CH 3 group of trans compound 59 shows up at δ 0.85 (d, 3 H). 13 C NMR: CH 3 of 58 shows up at δ 17.7 and CH 3 of 59 shows up at δ The estimated ratio of cis/trans is based on the integration of the CH 3 peak in both 1 H and 13 C-NMR spectra. Preparation of the palladacycle 60 under the general conditions E Palladacycle 60 was prepared from compound 58 obtained above under the general conditions E. Single crystal 60 was obtained by slow evaporation of its solution in MeCN/CH 2 Cl 2 (1:4) at RT. See page 25 for its X-ray structure. S21

22 A mixture of palladacycle compound 55 (85 mg, 0.2 mmol, 1 equiv) and trans-1-iodo-4-methylcyclohexane 57 (0.6 mmol, 3 equiv) in tamyloh (1 ml)/pxylene (1 ml) in a 10 ml glass vial (sealed with PTFE cap) was stirred at 130 o C for 1 h. The reaction mixture was cooled to RT, diluted with dichloromethane (2.0 ml). aq. HI (47% in water, 30 μl) was added and the mixture was stirred for 1 hour and then concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography to give the alkylation product 59 in 35 % yield (R f = 0.55, 25 % EtOAc in Hex, trans: cis >15:1) and recovered 54 in 52 % yield. 1 H NMR (CDCl 3, 400 MHz, ppm): δ (s, 1 H), 8.95 (d, J = 7.8 Hz, 1 H), (m, 1 H), 8.18 (d, J = 8.4 Hz, 1 H), (m, 2 H), 7.45 (dd, J = 4.0 and 8.0 Hz, 1 H), 7.34 (d, J = 8.8 Hz, 1 H), 7.11 (d, J = 2.4 Hz, 1 H), 7.00 (dd, J = 2.8 and 8.4 Hz, 1 H ), 3.83 (s, 3 H), 3.00 (t, J = 12.0 Hz, 1 H), (m, 2 H), (m, 2 H), (m, 2 H), (m, 1 H), (m, 2 H), 0.85 (d, J = 6.4 Hz, 3 H, CH 3 -trans); 13 C NMR (CDCl 3, 90 MHz, ppm) δ 168.4, 157.3, 148.2, 138.5, 137.6, 137.4, 136.3, 134.7, 128.1, 128.0, 127.4, 121.8, 121.7, 116.6, 116.2, 112.2, 55.4, 39.4, 35.4, 34.7, 32.3, 22.6 (CH 3 -trans); HRMS: calculated for C 24 H 27 N 2 O 2 [M+H + ]: ; found: Preparation of the palladacycle 60 under the general conditions E Palladacycle 61 was prepared from compound 59 obtained above under the general conditions E. Single crystal 61 was obtained by slow evaporation of its solution in MeCN/CH 2 Cl 2 (1:4) at RT. See page 27 for its X-ray structure. 11. Crystal structure information for compound 55, 60, and 61 A yellow block shaped crystal of 55 (C19 H15 N3 O2 Pd) with approximate dimensions 0.10 x 0.11 x 0.21 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured at 298(2) K, on a Bruker SMART APEX CCD area detector system equipped with a graphite monochromator and a MoK fine-focus sealed tube (λ = Å) operated at 1600 watts power (50 kv, 32 ma). The detector S22

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