Cobalt-Catalyzed Selective Synthesis of Isoquinolines Using Picolinamide as a Traceless Directing Group
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Supporting Information Cobalt-Catalyzed Selective Synthesis of Isoquinolines Using Picolinamide as a Traceless Directing Group Changsheng Kuai, Lianhui Wang, Bobin Li, Zhenhui Yang, Xiuling Cui* Engineering Research Center of Molecular Medicine, Ministry of Education, Key Laboratory of Xiamen Marine and Gene Drugs, Institute of Molecular Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen, 361021, China Email: cuixl@hqu.edu.cn Table of Contents 1.General information...s-2 2.Preparation of substrates 1...S-2 3.General procedure for the synthesis of compounds 3...S-2 4.X-ray Crystallographic Data of 3aa and 3ap...S-3 5.Characterization data of compounds 3...S-12 6.NMR spectra of compounds 3...S-23 S 1

1. General information Unless otherwise stated, all commercial materials and solvents were used directly without further purification. Commercially available chemicals were obtained from Energy Chemical, TCI, Alfa Aesar, J&K. Melting points were obtained on a Beijing Science Instrument Dianguang Instrument Factory XT4B Melting Point apparatus and are uncorrected. 1 H and 13 C NMR spectra were measured on a 400 MHz Bruker spectrometer ( 1 H 400MHz, 13 C 100MHz), using CDCl 3 as the solvent with tetramethylsilane (TMS) as the internal standard at room temperature. High-resolution mass spectra (HRMS) were recorded using Agilent 6450 spectrometer. Column chromatography was performed on silica gel (70 230 mesh ASTM) using the reported eluents. Thin-layer chromatography (TLC) was carried out on 4 15 cm plates with a layer thickness of 0.2 mm (silica gel 60 F254). 2. Preparation of substrates 1 R NH 2 + HO O N EDCI, HOBt, DIPEA DMF, rt, 24 h A solution of benzylamines (10 mmol), 2-picolinic acid (1.48 g, 12 mmol), EDCI (2.32 g, 12 mmol), HOBt (1.84 g, 12 mmol) and DIPEA (4.4 ml, 25 mmol) were dissolved in 15 ml of anhydrous DMF. The mixture was stirred at rt for 24 h. Water was then added and the mixture was extracted with EtOAc. The combined organic layers was washed with H 2 O and brine, dried over anhydrous Na 2 SO 4, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (n-hexane/etoac: 10:1) to give the desired product 1. R N H 1 O N 3. Representative procedure for the synthesis of compounds 3 O Ph Co(OAc) 2 4H 2 O (50 mol%) N N + H N PEG 400,140 o C,O 2 Ph Ph KPF 6 (50 mol%) Ph 1a 2a 3aa A mixture of 1a (0.25 mmol, 53.0 mg), 2a (0.3 mmol, 53.4mg), Co(OAc) 2 4H 2 O (0.125 mmol, 31.1 mg, 50 mol%),) KPF 6 (0.0125 mmol, 23.0 mg, 50 mol%) and PEG-400 (1.0 ml), 140 o C under O 2 (1 atm), in a 5 ml flask was heated at 140 o C for 20 hours. The reaction mixture was cooled to room temperature, and then the reaction mixture was diluted with H 2 O and extracted with t-buome (3 x 25 ml). The combined organic layers were dried over Na 2 SO 4. After filtration and evaporation of the solvents in vacuo, the crude product was purified by column chromatography on silica gel (n-hexane/etoac: 20:1) to yield 3aa (62.6 mg, 89%) as a white solid. Procedure for the synthesis of product 3a on a 1 mmol scale A mixture of 1a (1 mmol, 212.0 mg), 2a (1.2 mmol, 213.6mg), Co(OAc) 2 4H 2 O (0.5 mmol, 124.4 mg, 50 mol%), KPF 6 (0.5 mmol, 92.0 mg, 50 mol%) and PEG-400 (4.0 ml), 140 o C under O 2 (1 atm), in a 10 ml flask was heated at 140 o C for 20 hours. The reaction mixture was cooled to room temperature, diluted, washed with H 2 O and extracted with t-buome (3 x 25 ml). The combined organic layers were dried over Na 2 SO 4. After removal of the solvents in vacuo, the crude product was purified by column S 2

chromatography on silica gel (n-hexane/etoac: 20:1) to yield 3aa (194.1 mg, 69%) as a white solid. 4. X-ray Crystallographic Data of 3aa and 3ap X-ray Crystallographic Data of 3aa Figure S1. X-ray molecular structure of 3aa Table 1 Crystal data and structure refinement for exp_1025. Identification code Empirical formula C21H15N Formula weight 281.34 Temperature/K 173.6(3) Crystal system monoclinic Space group P21/c a/å 9.4624(7) b/å 9.9524(7) c/å 16.0483(11) α/ 90 β/ 102.418(7) γ/ 90 Volume/Å3 1475.97(19) Z 4 ρcalcg/cm3 1.266 μ/mm 1 0.073 F(000) 592.0 Crystal size/mm3 0.2 0.18 0.16 Radiation MoKα (λ = 0.71073) 2Θ range for data collection/ 6.05 to 58.102 Index ranges -12 h 12, -12 k 13, -21 l 21 Reflections collected 9734 Independent reflections 3449 [Rint = 0.0364, Rsigma = 0.0449] Data/restraints/parameters 3449/0/200 Goodness-of-fit on F2 1.030 Final R indexes [I>=2σ(I)] R1 = 0.0479, wr2 = 0.1080 Final R indexes [all data] R1 = 0.0642, wr2 = 0.1202 Largest diff. peak/hole / e Å-3 0.27/-0.22 S 3

Table 2 Fractional Atomic Coordinates ( 104) and Equivalent Isotropic Displacement Parameters (Å2 103) for exp_1025. Ueq is defined as 1/3 of of the trace of the orthogonalised UIJ tensor. Atom x y z U(eq) C1 8283.5(15) 4684.3(14) 3655.2(8) 28.4(3) C2 7968.6(17) 4340.6(15) 2801.8(9) 34.7(4) C3 6704.1(17) 4769.3(18) 2281.3(9) 42.2(4) C4 5777.5(17) 5590(2) 2605.7(10) 49.8(5) C5 6102.3(16) 5964.3(18) 3454.5(9) 40.0(4) C6 7347.6(14) 5492.8(14) 3990.9(8) 25.5(3) C7 7644.5(14) 5800.8(14) 4920.4(8) 24.5(3) C8 7689.4(13) 4785.7(13) 5510.4(8) 22.3(3) C9 7426.3(14) 3357.8(14) 5252.6(8) 23.3(3) C10 6058.8(15) 2931.2(15) 4834.0(8) 29.0(3) C11 5806.1(16) 1593.6(16) 4617.8(9) 34.4(4) C12 6910.7(17) 667.3(15) 4810.1(9) 34.9(4) C13 8272.0(17) 1078.0(15) 5219.3(9) 33.8(4) C14 8528.8(16) 2414.0(14) 5439.9(9) 29.6(3) C15 8358.7(15) 6896.9(16) 7478.3(9) 33.0(4) C16 8370.6(16) 5959.0(16) 8095.6(9) 35.1(4) C17 8197.3(16) 4593.4(16) 7879.5(9) 34.4(4) C18 7985.7(15) 4184.2(15) 7051.3(8) 29.3(3) C19 7947.6(13) 5134.6(14) 6394.2(8) 23.4(3) C20 8146.4(14) 6504.6(14) 6614.9(8) 26.6(3) C21 8083.7(15) 7437.4(15) 5948.3(9) 31.1(3) N1 7836.7(13) 7132.6(12) 5134.2(7) 30.2(3) Table 3 Anisotropic Displacement Parameters (Å2 103) for exp_1025. The Anisotropic displacement factor exponent takes the form: -2π2[h2a*2U11+2hka*b*U12+ ]. Atom U11 U22 U33 U23 U13 U12 C1 29.3(7) 27.1(7) 27.9(7) 1.7(6) 4.0(5) 1.9(6) C2 42.8(9) 31.6(8) 31.5(7) -3.1(6) 12.2(6) -1.8(7) C3 44.7(9) 58.1(11) 22.8(7) -1.9(7) 4.7(6) -10.9(8) C4 31.5(8) 87.7(15) 27.2(7) 8.3(8) -0.4(6) 7.2(9) C5 30.3(8) 62.0(11) 28.2(7) 7.7(7) 7.5(6) 13.5(8) C6 26.3(7) 26.7(7) 23.5(6) 4.4(5) 5.2(5) -1.8(6) C7 21.9(6) 26.1(7) 25.0(6) 1.8(5) 4.2(5) 2.1(6) C8 19.6(6) 23.2(7) 23.4(6) 0.4(5) 3.0(5) 2.0(5) C9 27.2(7) 24.8(7) 18.6(6) 1.1(5) 6.5(5) -0.7(6) C10 27.5(7) 32.0(8) 27.4(7) -2.3(6) 5.6(5) -0.6(6) C11 35.6(8) 36.9(9) 30.7(7) -6.1(6) 7.0(6) -9.5(7) C12 51.4(10) 26.0(8) 31.1(7) -5.5(6) 17.6(7) -7.7(7) C13 41.5(9) 25.8(8) 36.3(8) 3.6(6) 13.6(6) 7.4(7) C14 29.7(7) 27.3(8) 31.0(7) 0.7(6) 5.0(6) 0.9(6) C15 35.6(8) 31.6(8) 31.1(7) -7.3(6) 5.1(6) -2.8(7) C16 36.5(8) 45.3(10) 22.9(7) -5.6(6) 4.8(6) -4.6(7) S 4

C17 39.6(8) 38.4(9) 24.8(7) 3.9(6) 6.1(6) -1.9(7) C18 33.6(8) 25.9(7) 28.0(7) 1.6(6) 6.0(6) 0.0(6) C19 21.1(6) 25.5(7) 23.2(6) -0.2(5) 4.0(5) 0.4(6) C20 25.1(7) 26.6(7) 27.6(7) -1.5(5) 4.3(5) 1.2(6) C21 37.7(8) 22.8(7) 32.2(7) -1.9(6) 6.4(6) -0.2(6) N1 35.6(7) 24.4(6) 30.5(6) 2.5(5) 6.6(5) 1.0(5) Table 4 Bond Lengths for exp_1025. Atom Atom Length/Å Atom Atom Length/Å C1 C2 1.3806(19) C10 C11 1.384(2) C1 C6 1.3882(19) C11 C12 1.378(2) C2 C3 1.372(2) C12 C13 1.376(2) C3 C4 1.380(2) C13 C14 1.384(2) C4 C5 1.381(2) C15 C16 1.359(2) C5 C6 1.3833(19) C15 C20 1.4118(18) C6 C7 1.4893(17) C16 C17 1.403(2) C7 C8 1.3790(18) C17 C18 1.3631(19) C7 N1 1.3714(17) C18 C19 1.4113(19) C8 C9 1.4861(19) C19 C20 1.411(2) C8 C19 1.4293(17) C20 C21 1.4080(19) C9 C10 1.3900(18) C21 N1 1.3123(17) C9 C14 1.3878(19) Table 5 Bond Angles for exp_1025. Atom Atom Atom Angle/ Atom Atom Atom Angle/ C2 C1 C6 120.60(13) C11 C10 C9 120.52(14) C3 C2 C1 120.06(14) C12 C11 C10 120.38(14) C2 C3 C4 119.76(14) C13 C12 C11 119.69(14) C3 C4 C5 120.46(14) C12 C13 C14 120.15(14) C4 C5 C6 120.08(15) C13 C14 C9 120.82(14) C1 C6 C7 120.62(12) C16 C15 C20 120.16(14) C5 C6 C1 118.97(12) C15 C16 C17 120.17(13) C5 C6 C7 120.36(12) C18 C17 C16 121.01(14) C8 C7 C6 120.55(12) C17 C18 C19 120.21(14) N1 C7 C6 115.84(11) C18 C19 C8 123.38(13) N1 C7 C8 123.60(12) C20 C19 C8 117.96(12) C7 C8 C9 122.06(11) C20 C19 C18 118.65(12) C7 C8 C19 118.48(12) C19 C20 C15 119.78(12) C19 C8 C9 119.42(11) C21 C20 C15 122.49(13) C10 C9 C8 120.63(12) C21 C20 C19 117.70(12) C14 C9 C8 120.92(12) N1 C21 C20 124.98(13) C14 C9 C10 118.44(13) C21 N1 C7 117.27(12) Table 6 Torsion Angles for exp_1025. A B C D Angle/ A B C D Angle/ C1 C2 C3 C4 2.7(2) C9 C8 C19 C18 0.80(19) C1 C6 C7 C8-62.25(18) C9 C8 C19 C20-177.97(11) C1 C6 C7 N1 118.87(15) C9 C10 C11 C12-0.4(2) S 5

C2 C1 C6 C5-0.8(2) C10 C9 C14 C13-0.34(19) C2 C1 C6 C7 176.54(13) C10 C11 C12 C13 0.0(2) C2 C3 C4 C5-1.1(3) C11 C12 C13 C14 0.3(2) C3 C4 C5 C6-1.4(3) C12 C13 C14 C9-0.1(2) C4 C5 C6 C1 2.4(2) C14 C9 C10 C11 0.60(19) C4 C5 C6 C7-175.01(15) C15 C16 C17 C18-1.3(2) C5 C6 C7 C8 115.10(16) C15 C20 C21 N1-177.39(13) C5 C6 C7 N1-63.78(18) C16 C15 C20 C19-0.1(2) C6 C1 C2 C3-1.7(2) C16 C15 C20 C21 178.16(13) C6 C7 C8 C9-0.92(19) C16 C17 C18 C19 0.4(2) C6 C7 C8 C19-178.68(11) C17 C18 C19 C8-178.14(13) C6 C7 N1 C21 179.24(12) C17 C18 C19 C20 0.6(2) C7 C8 C9 C10-68.56(17) C18 C19 C20 C15-0.82(19) C7 C8 C9 C14 112.87(14) C18 C19 C20 C21-179.11(12) C7 C8 C19 C18 178.62(12) C19 C8 C9 C10 109.18(14) C7 C8 C19 C20-0.15(18) C19 C8 C9 C14-69.40(16) C8 C7 N1 C21 0.4(2) C19 C20 C21 N1 0.9(2) C8 C9 C10 C11-178.02(12) C20 C15 C16 C17 1.1(2) C8 C9 C14 C13 178.27(12) C20 C21 N1 C7-0.9(2) C8 C19 C20 C15 178.01(12) N1 C7 C8 C9 177.87(12) C8 C19 C20 C21-0.29(18) N1 C7 C8 C19 0.1(2) Table 7 Hydrogen Atom Coordinates (Å 104) and Isotropic Displacement Parameters (Å2 103) for exp_1025. Atom x y z U(eq) H1 9130 4371 4008 34 H2 8614 3818 2580 42 H3 6472 4507 1712 51 H4 4928 5894 2250 60 H5 5483 6534 3666 48 H10 5308 3550 4698 35 H11 4885 1318 4341 41 H12 6737-2314664 42 H13 9021 456 5348 41 H14 9452 2683 5717 35 H15 8491 7799 7625 40 H16 8494 6223 8663 42 H17 8227 3958 8308 41 H18 7866 3276 6919 35 H21 8228 8338 6096 37 S 6

X-ray Crystallographic Data of 3ap Figure S1. X-ray molecular structure of 3ap Table 1 Crystal data and structure refinement for exp_1928. Identification code Empirical formula C16H13N Formula weight 219.27 Temperature/K 293(2) Crystal system orthorhombic Space group Pna21 a/å 15.5482(14) b/å 8.4957(9) c/å 18.085(4) α/ 90 β/ 90 γ/ 90 Volume/Å3 2389.0(6) Z 8 ρcalcg/cm3 1.219 μ/mm 1 0.071 F(000) 928.0 Crystal size/mm3 0.22 0.2 0.15 Radiation MoKα (λ = 0.71073) 2Θ range for data collection/ 5.464 to 58.432 Index ranges -20 h 19, -11 k 10, -22 l 9 Reflections collected 7158 Independent reflections 3907 [Rint = 0.0656, Rsigma = 0.0956] Data/restraints/parameters 3907/1/309 Goodness-of-fit on F2 1.106 Final R indexes [I>=2σ(I)] R1 = 0.1106, wr2 = 0.2433 Final R indexes [all data] R1 = 0.2060, wr2 = 0.3092 Largest diff. peak/hole / e Å-3 0.68/-0.26 Flack parameter -7.9(10) Table 2 Fractional Atomic Coordinates ( 104) and Equivalent Isotropic Displacement Parameters (Å2 103) for exp_1928. Ueq is defined as 1/3 of of the trace of the orthogonalised UIJ tensor. Atom x y z U(eq) S 7

C0AA 4088(8) 452(11) 6176(7) 77(4) C1' 2551(6) 6131(12) 5369(6) 62(3) C2' 1928(6) 7296(14) 5213(8) 69(4) C3' 1679(6) 8304(12) 5750(8) 71(3) C4' 2044(7) 8178(11) 6452(7) 62(3) C5' 2621(7) 7057(11) 6599(7) 63(3) C6' 2900(5) 6016(9) 6087(6) 47(2) C7' 3562(5) 4767(9) 6248(5) 46(2) C8' 3466(6) 3172(11) 6121(6) 55(3) C9' 4115(6) 2154(11) 6316(7) 53(3) C10' 4850(6) 2740(12) 6653(7) 51(3) C11' 4875(6) 4376(11) 6787(6) 62(3) C13' 4741(8) -455(13) 6392(8) 84(4) C14' 5472(8) 205(12) 6728(7) 79(4) C15' 5539(7) 1740(14) 6859(6) 67(3) C16' 2609(6) 2495(10) 5789(9) 66(4) N1' 4267(5) 5360(8) 6600(5) 59(2) C1 4917(7) 3648(12) 4544(7) 67(3) C2 5494(7) 2501(11) 4702(8) 62(3) C3 5784(7) 1514(13) 4162(8) 75(3) C4 5449(7) 1658(13) 3441(8) 77(3) C5 4835(6) 2768(10) 3303(7) 53(3) C6 4572(5) 3863(10) 3855(6) 48(2) C7 3935(5) 5098(10) 3679(5) 50(2) C8 4040(5) 6662(11) 3862(6) 50(2) C9 3358(5) 7684(10) 3691(6) 43(2) C10 2624(6) 7210(12) 3320(7) 52(3) C11 2613(6) 5541(12) 3130(6) 63(3) C12' 3375(7) 9365(13) 3854(8) 80(4) C13 2715(9) 10339(13) 3677(9) 95(4) C14 1988(8) 9737(15) 3323(8) 83(4) C15 1936(7) 8142(16) 3132(6) 69(3) C16 4809(7) 7339(12) 4245(10) 86(5) N1 3232(5) 4569(9) 3305(5) 61(2) Table 3 Anisotropic Displacement Parameters (Å2 103) for exp_1928. The Anisotropic displacement factor exponent takes the form: -2π2[h2a*2U11+2hka*b*U12+ ]. Atom U11 U22 U33 U23 U13 U12 C0AA 107(8) 47(5) 79(10) -16(6) -7(8) 14(6) C1' 60(6) 71(6) 53(7) -4(6) 6(5) 13(5) C2' 42(6) 97(8) 67(9) -3(7)-13(6) 16(5) C3' 58(6) 59(6) 96(10) 15(7) 4(7) 10(5) C4' 85(7) 46(5) 55(7) -8(6) 0(6) 4(5) C5' 87(8) 44(5) 59(8) -1(6) 20(6) 3(5) C6' 48(5) 45(4) 48(6) 2(5) 1(5) -4(4) S 8

C7' 55(5) 41(4) 43(6) -2(4) 3(5) -9(4) C8' 57(5) 55(5) 54(7) -9(5) 1(5) -14(5) C9' 56(6) 48(5) 55(7) 12(5) 16(6) 10(5) C10' 35(5) 75(7) 42(7) -3(6) 7(5) 3(4) C11' 65(6) 62(6) 58(8) -8(6)-27(6) -1(5) C13' 101(9) 49(5) 103(11) 16(7) -10(8) 5(6) C14' 102(8) 56(6) 79(10) 12(7) 14(8) 27(6) C15' 73(7) 74(7) 56(7) 9(7) 3(6) 12(6) C16' 44(6) 60(6) 94(11) -6(6)-24(7) -1(4) N1' 63(4) 49(4) 65(6) 1(4) -15(5) -2(4) C1 67(6) 75(7) 60(8) -12(6) 9(6) 13(5) C2 64(7) 76(7) 46(7) 3(6) -3(6) 10(5) C3 68(7) 76(7) 81(9) 26(7) -2(7) 7(6) C4 89(8) 61(6) 80(10) -14(7) 10(8) 18(6) C5 47(5) 60(5) 52(7) -5(6)-18(5) 2(4) C6 46(5) 50(5) 48(6) 6(5) -1(5)-5(4) C7 53(5) 55(5) 42(6) -2(5)-6(5)-8(4) C8 36(4) 62(6) 52(6) 0(5) 0(5) 4(4) C9 30(4) 60(5) 39(6) 1(5) -3(4) 0(4) C10 51(6) 67(6) 38(6) 4(5) 1(5) 6(5) C11 49(5) 77(7) 63(8) -15(6) -7(5)-4(5) C12' 64(6) 73(7) 103(12) -3(8) 3(7) 0(6) C13 110(9) 56(6) 118(13) 21(8) -7(9) 27(7) C14 75(7) 89(8) 86(10) 15(8) 3(7) 26(6) C15 61(6) 96(8) 50(7) 13(7) -1(5) 6(6) C16 50(6) 72(7) 137(17) -20(8) -27(8) 1(5) N1 50(4) 64(5) 68(6) -6(5) -6(5)-2(4) Table 4 Bond Lengths for exp_1928. Atom Atom Length/Å Length/Å C0AA C9' 1.469(12) C1 C2 1.356(14) C0AA C13' 1.333(14) C1 C6 1.369(14) C1' C2' 1.412(14) C2 C3 1.365(16) C1' C6' 1.411(14) C3 C4 1.408(17) C2' C3' 1.351(17) C4 C5 1.365(14) C3' C4' 1.395(16) C5 C6 1.425(14) C4' C5' 1.335(14) C6 C7 1.478(12) C5' C6' 1.352(14) C7 C8 1.379(12) C6' C7' 1.507(12) C7 N1 1.360(11) C7' C8' 1.383(11) C8 C9 1.405(12) C7' N1' 1.364(10) C8 C16 1.497(14) C8' C9' 1.375(13) C9 C10 1.384(13) C8' C16' 1.569(13) C9 C12' 1.459(13) C9' C10' 1.388(14) C10 C11 1.459(13) C10' C11' 1.412(12) C10 C15 1.373(14) Atom Atom S 9

C10' C15' 1.417(14) C11 N1 1.307(12) C11' N1' 1.306(11) C12' C13 1.357(14) C13' C14' 1.406(15) C13 C14 1.395(17) C14' C15' 1.330(14) C14 C15 1.401(17) Table 5 Bond Angles for exp_1928. Atom Atom Atom Angle/ Atom Atom Atom Angle/ C13' C0AA C9' 119.8(11) C2 C1 C6 123.2(11) C6' C1' C2' 119.7(11) C1 C2 C3 120.6(12) C3' C2' C1' 119.9(12) C2 C3 C4 119.1(10) C2' C3' C4' 119.3(10) C5 C4 C3 119.2(11) C5' C4' C3' 120.5(11) C4 C5 C6 121.6(11) C4' C5' C6' 123.1(12) C1 C6 C5 116.0(8) C1' C6' C7' 119.4(9) C1 C6 C7 123.7(10) C5' C6' C1' 117.5(9) C5 C6 C7 120.3(9) C5' C6' C7' 123.1(10) C8 C7 C6 123.5(8) C8' C7' C6' 125.7(8) N1 C7 C6 114.3(8) N1' C7' C6' 112.4(7) N1 C7 C8 122.2(8) N1' C7' C8' 121.8(8) C7 C8 C9 117.0(8) C7' C8' C16' 121.0(8) C7 C8 C16 125.2(8) C9' C8' C7' 119.6(8) C9 C8 C16 117.9(8) C9' C8' C16' 119.4(8) C8 C9 C12' 123.2(9) C8' C9' C0AA 123.6(10) C10 C9 C8 123.3(8) C8' C9' C10' 119.5(9) C10 C9 C12' 113.4(8) C10' C9' C0AA 116.9(9) C9 C10 C11 114.0(8) C9' C10' C11' 116.8(9) C15 C10 C9 126.5(10) C9' C10' C15' 121.5(10) C15 C10 C11 119.6(10) C11' C10' C15' 121.6(9) N1 C11 C10 123.2(9) N1' C11' C10' 124.5(8) C13 C12' C9 122.4(11) C0AA C13' C14' 120.8(11) C12' C13 C14 119.8(11) C15' C14' C13' 122.1(10) C13 C14 C15 121.0(10) C14' C15' C10' 118.8(11) C10 C15 C14 116.9(10) C11' N1' C7' 117.8(8) C11 N1 C7 120.2(8) Table 6 Torsion Angles for exp_1928. A B C D Angle/ A B C D Angle/ C0AA C9' C10' C11' -180.0(11) C1 C2 C3 C4-2.6(17) C0AA C9' C10' C15' -0.6(16) C1 C6 C7 C8 50.3(14) C0AA C13' C14' C15' 1(2) C1 C6 C7 N1-130.7(10) C1' C2' C3' C4' 0.0(17) C2 C1 C6 C5 1.9(15) C1' C6' C7' C8' -54.3(13) C2 C1 C6 C7 179.3(9) C1' C6' C7' N1' 130.8(9) C2 C3 C4 C5-0.8(17) C2' C1' C6' C5' -0.7(14) C3 C4 C5 C6 4.8(16) C2' C1' C6' C7' 179.8(9) C4 C5 C6 C1-5.4(14) C2' C3' C4' C5' -1.3(17) C4 C5 C6 C7 177.2(9) C3' C4' C5' C6' 1.6(17) C5 C6 C7 C8-132.4(10) C4' C5' C6' C1' -0.6(15) C5 C6 C7 N1 46.6(12) S 10

C4' C5' C6' C7' 178.9(9) C6 C1 C2 C3 2.0(17) C5' C6' C7' C8' 126.2(11) C6 C7 C8 C9-176.9(10) C5' C6' C7' N1' -48.7(12) C6 C7 C8 C16 1.5(18) C6' C1' C2' C3' 0.9(16) C6 C7 N1 C11 178.5(10) C6' C7' C8' C9' -178.0(10) C7 C8 C9 C10-3.4(16) C6' C7' C8' C16' -0.8(16) C7 C8 C9 C12' 179.7(10) C6' C7' N1' C11' 178.1(9) C8 C7 N1 C11-2.5(15) C7' C8' C9' C0AA -177.4(10) C8 C9 C10 C11 0.8(15) C7' C8' C9' C10' 1.4(16) C8 C9 C10 C15-179.8(12) C8' C7' N1' C11' 3.0(14) C8 C9 C12' C13 179.2(13) C8' C9' C10' C11' 1.2(15) C9 C10 C11 N1 1.1(16) C8' C9' C10' C15' -179.5(11) C9 C10 C15 C14 1.2(18) C9' C0AA C13' C14' -2(2) C9 C12' C13 C14 0(2) C9' C10' C11' N1' -1.8(17) C10 C9 C12' C13 2.1(18) C9' C10' C15' C14' -0.4(17) C10 C11 N1 C7-0.3(17) C10' C11' N1' C7' -0.3(16) C11 C10 C15 C14-179.4(11) C11' C10' C15' C14' 178.9(11) C12' C9 C10 C11 178.0(11) C13' C0AA C9' C8' -179.1(12) C12' C9 C10 C15-2.6(16) C13' C0AA C9' C10' 2.0(17) C12' C13 C14 C15-1(2) C13' C14' C15' C10' 0.1(18) C13 C14 C15 C10 1.0(19) C15' C10' C11' N1' 178.9(11) C15 C10 C11 N1-178.3(11) C16' C8' C9' C0AA 5.3(18) C16 C8 C9 C10 178.1(11) C16' C8' C9' C10' -175.9(11) C16 C8 C9 C12' 1.2(18) N1' C7' C8' C9' -3.5(15) N1 C7 C8 C9 4.2(15) N1' C7' C8' C16' 173.7(10) N1 C7 C8 C16-177.4(11) Table 7 Hydrogen Atom Coordinates (Å 104) and Isotropic Displacement Parameters (Å2 103) for exp_1928. Atom x y z U(eq) H0AA 3617 8 5937 93 H1' 2730 5444 4999 74 H2' 1690 7368 4743 82 H3' 1269 9073 5652 85 H4' 1884 8882 6822 75 H5' 2841 6988 7076 76 H11' 5357 4781 7025 74 H13' 4712-1537 6320 101 H14' 5923-4546863 95 H15' 6030 2150 7081 81 H16A 2689 2274 5273 99 H16B 2157 3254 5847 99 H16C 2458 1543 6044 99 H1 4746 4321 4923 81 H2 5695 2385 5184 74 H3 6198 756 4267 90 H4 5643 1005 3064 92 S 11

H5 4582 2811 2838 64 H11 2142 5148 2872 76 H12' 3856 9785 4088 96 H13 2746 11405 3791 114 H14 1532 10405 3213 100 H15 1458 7734 2890 83 H16D 5106 8035 3914 129 H16E 5187 6502 4392 129 H16F 4626 7913 4674 129 5. Characterization data of compounds 3 3,4-diphenylisoquinoline (3aa) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3aa (62.5mg, 89%), colorless solid, mp 153-154ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.41 (s, 1H), 8.12 8.03 (m, 1H), 7.72 (dd, J = 5.2, 4.4 Hz, 1H), 7.68 7.60 (m, 2H), 7.46 7.36 (m, 5H), 7.32 7.21 (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.8, 150.7, 140.8, 137.3, 136.0, 131.3, 130.6, 130.5, 130.3, 128.3, 127.7, 127.6, 127.4, 127.4, 127.1, 126.9, 125.6. HRMS (APCI) m/z calcd for C 21 H 16 N [M + H] + : 282.1283; Found: 282.1288. 6-methyl-3,4-diphenylisoquinoline (3ba) The representative procedure was following using N-(4-methylbenzyl)picolinamide (1b) (56.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 30:1) yielded compound 3ba (64.2 mg, 87%), white solid, mp 170-172ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.35 (s, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 7.1 Hz, 2H), 7.43 7.38 (m, 5H), 7.30 7.21 (m, 5H), 2.48 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.4, 150.7, 141.1, 140.9, 137.4, 136.2, 131.3, 130.3, 130.2, 129.2, 128.3, 127.7, 127.5, 127.3, 127.1, 125.9, 124.4, 22.4. HRMS (APCI) m/z calcd for C 22 H 18 N [M + H] + : 296.1439; Found: 296.1440. 6-methoxy-3,4-diphenylisoquinoline (3ca) The representative procedure was following using N-(4-methoxybenzyl)picolinamide (1c) (60.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 30:1) yielded compound 3ca (69.2 mg, 89%), colorless solid, mp 103-105ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.23 (s, 1H), 7.93 (d, J = 8.9 Hz, 1H), 7.39 7.30 (m, 5H), 7.27 7.23 (m, 2H), 7.22 7.15 (m, 3H), 6.91 (d, J = 1.9 Hz, 1H), 3.72 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 161.3, 151.0, 150.7, 140.8, 138.0, 137.5, 131.1, 130.3, 130.0., 129.5, 128.4, 127.6, 127.4, 127.1, 123.3, 119.7, 103.7, 55.3. HRMS (APCI) m/z calcd for C 22 H 18 NO [M + H] + : 312.1388; Found: 312.1389. 6-(tert-butyl)-3,4-diphenylisoquinoline (3da) The representative procedure was following using N-(4-(tert-butyl)benzyl)picolinamide (1d) (67.0mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 30:1) yielded compound 3da (79.2 mg, 94%), S 12

colorless solid, mp 154-155ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.35 (s, 1H), 8.03 (d, J = 8.6 Hz, 1H), 7.73 (dd, J = 8.6, 1.7 Hz, 1H), 7.67 (s, 1H), 7.43 7.36 (m, 5H), 7.32 7.28 (m, 2H), 7.23 (d, J = 7.5 Hz, 3H), 1.33 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) δ 153.7, 151.1, 150.7, 141.0, 137.4, 136.0, 131.3, 130.8, 130.3, 128.3, 127.6, 127.3, 127.2, 127.0, 125.9, 125.8, 120.6, 35.5, 31.0. HRMS (APCI) m/z calcd for C 25 H 24 N [M + H] + : 338.1909; Found: 338.1910. 6-fluoro-3,4-diphenylisoquinoline (3ea) The representative procedure was following using N-(4-fluorobenzyl)picolinamide (1e) (57.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 60:1) yielded compound 3ea (61.2 mg, 82%), colorless solid, mp 135-137ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.37 (s, 1H), 8.09 (dd, J = 8.9, 5.7 Hz, 1H), 7.40 (d, J = 6.5 Hz, 5H), 7.37 7.29 (m, 2H), 7.28 7.21 (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 164.9, 162.4, 151.4, 151.3, 140.5, 137.8 (d, J = 10.0 Hz), 136.8, 131.1, 130.6 (d, J = 9.8 Hz), 130.3 (d, J = 5.6 Hz), 130.3, 128.6, 127.7, 127.5 (d, J = 29.3 Hz), 124.6, 117.5 (d, J = 25.9 Hz), 109.4 (d, J = 22.6 Hz). 19 F NMR (376 MHz, CDCl3) δ -105.7 (s). HRMS (APCI) m/z calcd for C 21 H 15 FN [M + H] + : 300.1189; Found: 300.1188. 6-chloro-3,4-diphenylisoquinoline (3fa) N The representative procedure was following using Cl Ph N-(4-chlorobenzyl)picolinamide (1f) (61.5mg, 0.25mmol) and Ph 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 60:1) yielded compound 3fa (61.4 mg, 78%), white solid, mp 160-162ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.37 (s, 1H), 8.01 (d, J = 8.7 Hz, 1H), 7.71 7.66 (m, 1H), 7.57 (dd, J = 8.7, 1.9 Hz, 1H), 7.43 7.36 (m, 5H), 7.25 (ddd, J = 6.8, 5.1, 2.3 Hz, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.7, 151.4, 140.4, 137.0, 136.9, 136.5, 131.1, 130.2, 129.9, 129.3, 128.6, 128.0, 127.7, 127.7, 127.4, 125.6, 124.6. HRMS (APCI) m/z calcd for C 21 H 15 ClN [M + H] + : 316.0893; Found: 316.0893. 6-bromo-3,4-diphenylisoquinoline (3ga) N The representative procedure was following using Br Ph N-(4-bromobenzyl)picolinamide (1g) (72.5mg, 0.25mmol) and Ph 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3ga (64.5 mg, 72%), colorless solid, mp 150-153ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.36 (s, 1H), 7.93 (d, J = 8.6 Hz, 1H), 7.86 (s, 1H), 7.70 (dd, J = 8.6, 1.6 Hz, 1H), 7.39 (dt, J = 6.7, 3.9 Hz, 5H), 7.27 7.21 (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.7, 151.5, 140.4, 137.1, 136.5, 131.1, 130.6, 130.2, 129.7, 129.2, 128.6, 127.9, 127.7, 127.4, 125.7. HRMS (APCI) m/z calcd for C 21 H 15 BrN [M + H] + : 360.0388; Found: 360.0389. 3,4-diphenyl-6-(trifluoromethoxy)isoquinoline (3ha) The representative procedure was following using N-(4-(trifluoromethoxy)benzyl)picolinamide (1h) (74.0mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After20h, purification by column chromatography on silica gel (n-hexane/etoac: 30:1) yielded compound 3Ha (57.5 mg, 63%), white solid, mp 71-73ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.41 (s, 1H), 8.14 (d, J = 9.4 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.40 (td, J = 6.5, 1.8 Hz, 5H), 7.28 7.21 (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.7, 151.3, 150.4, 140.3, 137.0, 136.4, 131.0, 130.6, 130.2, 130.1, 128.6, 127.8, 127.8, S 13

127.4, 125.5, 120.8, 116.0. 19 F NMR (376 MHz, CDCl3) δ -57.49 (s). HRMS (APCI) m/z calcd for C 22 H 15 F 3 NO [M + H] + : 366.1106; Found: 366.1106. 3,4-diphenyl-6-(trifluoromethyl)isoquinoline (3ia) N The representative procedure was following using F 3 C Ph N-(4-(trifluoromethyl)benzyl)picolinamide (1i) (70.0mg, 0.25mmol) and Ph 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 50:1) yielded compound 3ia (36.7 mg, 42%), white solid, mp 100-101ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.49 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.03 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.48 7.38 (m, 5H), 7.35 7.13 (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.1, 151.6, 140.2, 136.1, 135.3, 132.1 (d, J = 32.3 Hz), 131.3, 131.1, 130.3, 128.7, 128.4 (d, J = 94.5 Hz), 128.0, 127.8, 127.5, 123.8 (d, J = 272.9 Hz), 123.4 (d, J = 4.6 Hz), 122.7 (d, J = 3.0 Hz). 19 F NMR (376 MHz, CDCl3) δ -62.80 (s). HRMS (APCI) m/z calcd for C 22 H 15 F 3 N [M + H] + : 350.1157; Found: 350.1159. 3,4-diphenylisoquinolin-6-ol (3ja) The representative procedure was following using N-(4-hydroxybenzyl)picolinamide (1j) (57.0mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 6:1) yielded compound 3ja (39.8 mg, 54%), yellow solid, mp 256-259ºC. 1 H NMR (400 MHz, DMSO) δ 10.33 (s, 1H), 9.22 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.48 7.33 (m, 3H), 7.30 (d, J = 3.5 Hz, 2H), 7.27 7.03 (m, 6H), 6.77 (s, 1H). 13 C NMR (100 MHz, DMSO) δ 160.0, 151.2, 150.3, 141.4, 137.9, 137.9, 131.3, 130.5, 130.4, 129.1, 128.9, 127.8, 127.7, 127.3, 122.6, 120.2, 106.5. HRMS (APCI) m/z calcd for C 21 H 16 NO [M + H] + : 298.1232; Found: 298.1231. 8-methyl-3,4-diphenylisoquinoline (3ka) The representative procedure was following using N-(2-methylbenzyl)picolinamide (1k) (56.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3ka (55.0 mg, 75%), white solid, mp 128-130ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.64 (s, 1H), 7.58 7.49 (m, 2H), 7.46 7.35 (m, 6H), 7.32 7.21 (m, 5H), 2.90 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 150.3, 148.5, 140.7, 137.5, 136.3, 135.4, 131.3, 131.0, 130.4, 130.3, 128.3, 127.8, 127.7, 127.3, 127.1, 126.3, 124.0, 18.8. HRMS (APCI) m/z calcd for C 22 H 18 N [M + H] + : 296.1439; Found: 296.1441. 8-methoxy-3,4-diphenylisoquinoline (3la) The representative procedure was following using N-(2-methoxybenzyl)picolinamide (1l) (60.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3la (63.7 mg, 82%), white solid, mp 113-115ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.80 (d, J = 0.5 Hz, 1H), 7.56 7.48 (m, 1H), 7.43 7.34 (m, 5H), 7.30 7.19 (m, 6H), 6.91 (d, J = 7.7 Hz, 1H), 4.09 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ 156.6, 151.2, 146.8, 140.9, 137.6, 137.2, 131.3, 130.9, 130.3, 130.1, 128.2, 127.6, 127.3, 127.1, 119.5, 117.6, 104.8, 55.8. HRMS (APCI) m/z calcd for C 22 H 18 NO [M + H] + : 312.1388; Found: 312.1388. 8-fluoro-3,4-diphenylisoquinoline (3ma) S 14

The representative procedure was following using N-(2-fluorobenzyl)picolinamide (1m) (57.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 100:1) yielded compound 3ma (38.1 mg, 51%), white solid, mp 144-145ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.70 (s, 1H), 7.59 7.53 (m, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.40 (dd, J = 6.4, 3.2 Hz, 5H), 7.26 (ddd, J = 8.2, 7.2, 2.1 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 160.6, 158.0, 151.6, 145.4 (d, J = 5.8 Hz), 140.4, 137.5 (d, J = 3.2 Hz), 136.9, 131.1, 130.6 (d, J = 8.7 Hz), 130.3, 128.4, 127.7, 127.6, 127.4, 121.7 (d, J = 4.3 Hz), 118.0 (d, J = 15.4 Hz), 110.6 (d, J = 19.0 Hz). 19 F NMR (376 MHz, CDCl3) δ -123.32 (s). HRMS (APCI) m/z calcd for C 21 H 15 FN [M + H] + : 300.1189; Found: 300.1193. 8-chloro-3,4-diphenylisoquinoline(3na) The representative procedure was following using N-(2-chlorobenzyl)picolinamide (1n) (61.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 100:1) yielded compound 3na (46.5mg, 59%), colorless solid, mp 110-111ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.85 (s, 1H), 7.66 7.59 (m, 2H), 7.50 (dd, J = 8.5, 7.4 Hz, 1H), 7.45 7.38 (m, 5H), 7.28 7.22 (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.5, 148.7, 140.4, 137.5, 136.9, 132.6, 131.2, 130.4, 130.3, 128.5, 127.8, 127.6, 127.4, 127.2, 125.0, 124.5. HRMS (APCI) m/z calcd for C 21 H 15 ClN [M + H] + : 316.0893; Found: 316.0892. 8-bromo-3,4-diphenylisoquinoline (3oa) The representative procedure was following using N-(2-bromobenzyl)picolinamide (1o) (72.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 100:1) yielded compound 3oa (59.7 mg, 66%), white solid, mp 142-143ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.79 (d, J = 0.6 Hz, 1H), 7.85 (dd, J = 7.4, 0.7 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.48 7.44 (m, 1H), 7.42 7.38 (m, 5H), 7.28 7.21 (m, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.5, 151.2, 140.3, 137.7, 136.8, 131.2, 130.9, 130.7, 130.3, 128.4, 127.7, 127.6, 127.4, 125.7, 125.5, 122.7. HRMS (APCI) m/z calcd for C 21 H 15 BrN [M + H] + : 360.0388; Found: 360.0387. 7-methyl-3,4-diphenylisoquinoline (3pa) The representative procedure was following using N-(3-methylbenzyl)picolinamide (1p) (56.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 100:1) yielded compound 3pa (47.1 mg, 73%), white solid, mp 138-140ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.32 (s, 1H), 7.84 (s, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.48 (dd, J = 8.7, 1.5 Hz, 1H), 7.42 7.36 (m, 5H), 7.28 7.18 (m, 5H), 2.59 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.2, 149.9, 140.8, 137.4, 136.9, 134.2, 132.8, 131.2, 130.5, 130.3, 128.3, 127.6, 127.3, 127.0, 126.4, 125.5, 21.6. HRMS (APCI) m/z calcd for C 22 H 18 N [M + H] + : 296.1439; Found: 296.1444. 7-methoxy-3,4-diphenylisoquinoline (3qa) The representative procedure was following using N-(3-methoxybenzyl)picolinamide (1q) (60.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3qa (46.8 mg, 60%), white solid, mp 124-126ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.31 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.56 (t, S 15

J = 7.9 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.26 (d, J = 1.4 Hz, 1H), 7.19 (ddd, J = 12.8, 6.1, 3.5 Hz, 8H), 6.99 (d, J = 7.6 Hz, 1H), 3.46 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 156.4, 152.3, 151.4, 141.4, 140.8, 130.4, 130.2, 129.4, 129.2, 127.5, 127.4, 127.3, 126.6, 126.6, 126.0, 120.2, 110.3, 55.6. HRMS (APCI) m/z calcd for C 22 H 18 NO [M + H] + : 312.1388; Found: 312.1391. 5-methoxy-3,4-diphenylisoquinoline (3qa ) The representative procedure was following using N-(3-methoxybenzyl)picolinamide (1q) (60.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3q a (18.2 mg, 19%), white solid, mp 138-140ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.30 (s, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.38 (d, J = 6.9 Hz, 5H), 7.33 (d, J = 2.3 Hz, 1H), 7.30 (d, J = 2.5 Hz, 1H), 7.27 (dd, J = 6.5, 4.4 Hz, 3H), 7.23 (s, 1H), 7.21 (s, 1H), 4.01 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 158.2, 150.3, 149.0, 140.8, 137.4, 131.5, 131.2, 130.7, 130.2, 128.7, 128.3, 127.6, 127.4, 127.3, 126.9, 123.5, 104.6, 55.6. HRMS (APCI) m/z calcd for C 22 H 18 NO [M + H] + : 312.1388; Found: 312.1391. 7-fluoro-3,4-diphenylisoquinoline (3ra) The representative procedure was following using N-(3-fluorobenzyl)picolinamide (1r) (57.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 50:1) yielded compound 3ra (25.4 mg, 34%), white solid, mp 130-132ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.35 (s, 1H), 7.70 (ddd, J = 11.0, 8.9, 3.8 Hz, 2H), 7.39 (dd, J = 6.7, 5.5 Hz, 6H), 7.25 (ddd, J = 10.7, 5.0, 2.8 Hz, 5H). 13 C NMR (100 MHz, CDCl 3 ) δ 160.8 (d, J = 249.8 Hz), 150.9 (d, J = 5.4 Hz), 150.3 (d, J = 2.9 Hz), 140.4, 136.9, 133.1, 131.1, 130.7, 130.2, 128.7 (d, J = 8.4 Hz), 128.4, 128.2 (d, J = 8.6 Hz), 127.7, 127.6, 127.2, 120.9 (d, J = 25.0 Hz), 110.4 (d, J = 20.5 Hz). 19 F NMR (376 MHz, CDCl3) δ -112.41 (s). HRMS (APCI) m/z calcd for C 21 H 15 FN [M + H] + : 300.1189; Found: 300.1192. 5-fluoro-3,4-diphenylisoquinoline (3ra ) The representative procedure was following using N-(3-fluorobenzyl)picolinamide (1r) (57.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 50:1) yielded compound 3r a (27.7 mg, 37%), white solid, mp 138-140ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.40 (d, J = 2.2 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.59 (td, J = 7.9, 4.3 Hz, 1H), 7.35 7.29 (m, 6H), 7.27 (d, J = 5.6 Hz, 2H), 7.25 7.16 (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 158.6 (d, J = 258.7 Hz), 152.7, 151.5 d, J = 2.3 Hz), 140.5, 138.9 (d, J = 3.5 Hz), 130.5, 130.4, 130.2, 129.3 (d, J = 2.6 Hz), 127.6, 127.4, 127.3, 127.1, 127.0, 125.9 (d, J = 10.3 Hz), 124.0 (d, J = 4.7 Hz), 116.1 (d, J = 22.1 Hz). 19 F NMR (376 MHz, CDCl3) δ -106.91 (s). HRMS (APCI) m/z calcd for C 21 H 15 FN [M + H] + : 300.1189; Found: 300.1191. 3,4-diphenylbenzo[g]isoquinoline (3sa) The representative procedure was following using N-(naphthalen-2-ylmethyl)picolinamide (1s) (65.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 50:1) yielded compound 3sa (43.2 mg, 52%), white solid, mp 200-202ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 10.21 (s, 1H), 8.91 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 9.2 Hz, 1H), 7.84 7.77 (m, 1H), 7.74 7.68 (m, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.43 (dd, J = 8.2, 6.6 Hz, 5H), 7.34 7.22 (m, 5H). 13 C NMR (100 MHz, S 16

CDCl 3 ) δ 152.8, 145.8, 140.7, 137.4, 135.6, 131.7, 131.7, 131.6, 131.4, 130.2, 129.3, 128.8, 128.4, 128.1, 127.7, 127.6, 127.5, 127.3, 123.6, 123.5, 122.2. HRMS (APCI) m/z calcd for C 25 H 18 N [M + H] + : 332.1439; Found: 332.1444. 1-methyl-3,4-diphenylisoquinoline (3ta) The representative procedure was following using N-(1-phenylethyl)picolinamide (1t) (56.5mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 60:1) yielded compound 3ta (50.0 mg, 68%), white solid, mp 157-159ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 8.28 8.21 (m, 1H), 7.71 (dt, J = 6.9, 3.2 Hz, 1H), 7.65 7.60 (m, 2H), 7.44 7.35 (m, 5H), 7.31 7.20 (m, 5H), 3.13 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 157.8, 149.5, 141.1, 137.6, 136.0, 131.5, 130.3, 130.0, 129.2, 128.3, 127.7, 127.2, 127.0, 126.6, 126.3, 126.2, 125.6, 22.8. HRMS (APCI) m/z calcd for C 22 H 18 N [M + H] + : 296.1439; Found: 296.1443. 1,3,4-triphenylisoquinoline (3ua) The representative procedure was following using N-benzhydrylpicolinamide (1u) (72.0mg, 0.25mmol) and 1,2-diphenylethyne (2a) (53.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 100:1) yielded compound 3ua (68.7 mg, 77%), white solid, mp 156-159ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 8.23 (d, J = 8.3 Hz, 1H), 7.91 7.84 (m, 2H), 7.77 (d, J = 8.4 Hz, 1H), 7.65 7.53 (m, 5H), 7.45 (ddd, J = 21.0, 11.3, 4.7 Hz, 5H), 7.38 7.31 (m, 2H), 7.28 7.13 (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 159.9, 149.7, 140.9, 139.8, 137.6, 137.0, 131.4, 130.5, 130.3, 130.0, 129.8, 128.6, 128.4, 127.6, 127.6, 127.3, 127.0, 126.6, 126.0, 125.5. HRMS (APCI) m/z calcd for C 27 H 20 N [M + H] + : 358.1596; Found: 358.1602. 3,4-di-p-tolylisoquinoline (3ab) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-di-p-tolylethyne (2b) (61.8mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3ab (58.0 mg, 75%), white solid, mp 135-137ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.38 (s, 1H), 8.08 8.03 (m, 1H), 7.74 7.69 (m, 1H), 7.65 7.58 (m, 2H), 7.32 (d, J = 8.1 Hz, 2H), 7.19 (dd, J = 20.1, 8.0 Hz, 4H), 7.06 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H), 2.33 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.5, 150.5, 137.9, 136.9, 136.7, 136.2, 134.3, 131.1, 130.4, 130.2, 129.1, 128.4, 127.6, 127.3, 126.7, 125.7, 21.4, 21.3. HRMS (APCI) m/z calcd for C 23 H 20 N [M + H] + : 310.1596; Found: 310.1597. 3,4-bis(4-methoxyphenyl)isoquinoline (3ac) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(4-methoxyphenyl)ethyne (2c) (71.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 10:1) yielded compound 3ac (61.7 mg, 72%), yellow solid, mp 163-165ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.36 (s, 1H), 8.04 (dd, J = 7.0, 2.0 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.64 7.58 (m, 2H), 7.39 7.34 (m, 2H), 7.19 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), 6.79 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 3.80 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 158.8, 158.6, 151.5, 150.3, 136.4, 133.3, 132.3, 131.6, 130.4, 129.8, 129.6, 127.6, 127.2, 126.6, 125.6, 113.9, 113.2, 55.3, 55.2. HRMS (APCI) m/z calcd for C 23 H 20 NO 2 [M + H] + : 342.1494; Found: 342.1497. S 17

3,4-bis(4-fluorophenyl)isoquinoline (3ad) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(4-fluorophenyl)ethyne (2d) (64.2mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3ad (58.1 mg, 73%), colorless solid, mp 157-159ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.38 (s, 1H), 8.09 (d, J = 6.7 Hz, 1H), 7.66 (d, J = 7.8 Hz, 3H), 7.35 (dd, J = 8.6, 5.6 Hz, 2H), 7.23 (dd, J = 8.4, 5.5 Hz, 2H), 7.12 (t, J = 8.6 Hz, 2H), 6.95 (t, J = 8.7 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 163.4 (d, J = 14.3 Hz), 160.9 (d, J = 14.1 Hz), 152.0 (s), 149.8, 136.7 (d, J = 3.3 Hz), 135.9, 133.0 (d, J = 3.5 Hz), 132.8 (d, J = 8.0 Hz), 132.0 (d, J = 8.1 Hz), 130.9, 129.6, 127.7, 127.4, 127.1, 125.3, 115.6 (d, J = 21.4 Hz), 114.8 (d, J = 21.5 Hz). 19 F NMR (376 MHz, CDCl3) δ -114.18 (s), -114.75 (s). HRMS (APCI) m/z calcd for C 21 H 14 F 2 N [M + H] + : 318.1094; Found: 318.1097. 3,4-bis(4-chlorophenyl)isoquinoline (3ae) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(4-chlorophenyl)ethyne (2e) (73.8mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3ae (68.6 mg, 79%), colorless solid, mp 196-197ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.39 (s, 1H), 8.09 (dd, J = 5.1, 2.3 Hz, 1H), 7.71 7.62 (m, 3H), 7.40 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.22 (dd, J = 13.4, 8.4 Hz, 4H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.2, 149.4, 138.9, 135.7, 135.4, 133.7, 133.4, 132.5, 131.6, 131.0, 129.5, 128.9, 128.1, 127.8, 127.4, 127.3, 125.2. HRMS (APCI) m/z calcd for C 21 H 14 Cl 2 N [M + H] + : 350.0503; Found: 350.0505. 3,4-bis(4-(trifluoromethyl)phenyl)isoquinoline (3af) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(4-(trifluoromethyl)phenyl)ethyne (2f) (94.3mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3af (72.4 mg, 70%), colorless solid, mp 131-132ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.44 (s, 1H), 8.13 (dd, J = 6.3, 3.0 Hz, 1H), 7.71 (dd, J = 8.7, 3.2 Hz, 4H), 7.65 7.60 (m, 1H), 7.54 7.48 (m, 4H), 7.43 (d, J = 8.0 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.6, 149.1, 143.9, 140.7, 135.4, 131.6, 131.3, 130.6, 130.0 (d, J = 32.7 Hz), 129.8, 129.4 (d, J = 32.4 Hz), 127.9, 127.7, 127.6, 125.8 125.5 (m), 125.4 (d, J = 7.3 Hz), 125.2, 125.0 124.6 (m), 122.4 122.4 (m). 19 F NMR (376 MHz, CDCl3) δ -62.50 (s), -62.55 (s). HRMS (APCI) m/z calcd for C 23 H 14 F 6 N [M + H] + : 418.1030; Found: 418.1031. diethyl 4,4'-(isoquinoline-3,4-diyl)dibenzoate (3ag) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(4-(ethylperoxy)phenyl)ethyne (2g) (89.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 10:1) yielded compound 3ag (54.8 mg, 55%), colorless solid, mp 102-104ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.43 (s, 1H), 8.14 8.06 (m, 3H), 7.92 (d, J = 8.4 Hz, 2H), 7.73 7.62 (m, 3H), 7.46 (s, 2H), 7.36 (d, J = 8.3 Hz, 2H), 4.40 (dq, J = 25.5, 7.1 Hz, 4H), 1.42 (dt, J = 17.4, 7.1 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ) δ 166.5, 166.3, 152.4, 149.5, 144.8, 141.8, 135.4, 131.3, 131.1, 130.3, 130.3, 129.8, 129.7, 129.2, 129.1, 127.8, 127.5, S 18

127.5, 125.3, 61.2, 61.0, 14.4, 14.3. HRMS (APCI) m/z calcd for C 27 H 23 NO 4 [M + H] + : 426.1705; Found: 426.1702. 3,4-di-m-tolylisoquinoline (3ah) N The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-di-m-tolylethyne (2h) (61.8 mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3ah (55.2 mg, 72%), white solid, mp 100-102ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.39 (s, 1H), 8.06 (dd, J = 6.0, 3.2 Hz, 1H), 7.74 7.69 (m, 1H), 7.63 (dq, J = 5.8, 2.0 Hz, 2H), 7.36 (s, 1H), 7.29 7.25 (m, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.13 7.09 (m, 2H), 7.07 (ddd, J = 19.8, 11.2, 4.7 Hz, 4H), 2.36 (s, 3H), 2.30 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.6, 150.6, 140.7, 137.8, 137.2, 137.2, 136.1, 131.8, 131.0, 130.7, 130.4, 128.3, 128.2, 128.0, 127.8, 127.5, 127.4, 127.3, 126.8, 125.8, 21.5, 21.5. HRMS (APCI) m/z calcd for C 23 H 20 N [M + H] + : 310.1596; Found: 310.1596. 3,4-bis(3-methoxyphenyl)isoquinoline (3ai) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(3-methoxyphenyl)ethyne (2i) (71.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3ai (66.7 mg, 78%), yellow solid, mp 97-98ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.39 (s, 1H), 8.07 (dd, J = 6.2, 3.0 Hz, 1H), 7.78 7.72 (m, 1H), 7.68 7.61 (m, 2H), 7.33 (t, J = 7.9 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.00 6.96 (m, 1H), 6.95 6.89 (m, 2H), 6.85 6.76 (m, 2H), 3.74 (s, 3H), 3.66 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 159.6, 158.9, 151.8, 150.3, 142.0, 138.7, 135.9, 130.6, 130.5, 129.4, 128.7, 127.6, 127.4, 127.0, 125.7, 123.7, 122.8, 116.7, 114.9, 113.9, 113.2, 55.3, 55.1. HRMS (APCI) m/z calcd for C 23 H 20 NO 2 [M + H] + : 342.1494; Found: 342.1493. 3,4-bis(3-fluorophenyl)isoquinoline (3aj) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(3-fluorophenyl)ethyne (2j) (64.2mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3aj (60.7 mg, 77%), colorless solid, mp 87-89ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.40 (s, 1H), 8.15 8.04 (m, 1H), 7.71 7.63 (m, 3H), 7.44 7.36 (m, 1H), 7.23 7.19 (m, 1H), 7.17 7.13 (m, 2H), 7.11 (d, J = 2.3 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 7.01 (dd, J = 9.3, 1.9 Hz, 1H), 6.98 6.91 (m, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 163.8 (d, J = 38.6 Hz), 161.3 (d, J = 36.5 Hz), 152.3 (s), 149.3 (d, J = 2.4 Hz), 142.7 (d, J = 7.8 Hz), 139.1 (d, J = 7.8 Hz), 135.6, 131.0, 130.1 (d, J = 8.5 Hz), 129.6 (d, J = 1.8 Hz), 129.2 (d, J = 8.3 Hz), 127.7, 127.5, 127.4, 127.0 (d, J = 2.9 Hz), 125.9 (d, J = 2.9 Hz), 125.3, 118.1 (d, J = 21.5 Hz), 117.1 (d, J = 22.6 Hz), 114.7 (d, J = 20.9 Hz), 114.4 (d, J = 21.1 Hz). 19 F NMR (376 MHz, CDCl3) δ -112.65 (s), -113.78 (s). HRMS (APCI) m/z calcd for C 21 H 14 F 2 N [M + H] + : 318.1094; Found: 318.1096. 3,4-bis(3-chlorophenyl)isoquinoline (3ak) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1,2-bis(3-chlorophenyl)ethyne (2k) (73.8mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3ak (67.6 mg, S 19

78%), colorless solid, mp 140-141ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.40 (s, 1H), 8.14 8.04 (m, 1H), 7.69 (dd, J = 8.0, 6.1 Hz, 3H), 7.51 (s, 1H), 7.41 7.30 (m, 3H), 7.25 7.09 (m, 4H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.3, 149.2, 142.1, 138.7, 135.6, 134.4, 133.9, 131.1, 131.0, 130.4, 129.9, 129.6, 129.4, 128.9, 128.4, 127.9, 127.8, 127.6, 127.5, 127.5, 125.3. HRMS (APCI) m/z calcd for C 21 H 14 Cl 2 N [M + H] + : 350.0503; Found: 350.0507. 3,4-dipropylisoquinoline (3al) N The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and oct-4-yne (2l) (33.1mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3al (46.5 mg, 87%), colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 9.10 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.74 7.66 (m, 1H), 7.53 (t, J = 7.5 Hz, 1H), 3.08 3.01 (m, 2H), 3.01 2.95 (m, 2H), 1.84 (dd, J = 15.4, 7.6 Hz, 2H), 1.75 1.67 (m, 2H), 1.12 (t, J = 7.3 Hz, 3H), 1.07 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.9, 150.1, 135.4, 130.0, 128.2, 128.1, 127.2, 125.6, 123.0, 37.3, 29.9, 24.1, 23.7, 14.6 14.4. HRMS (APCI) m/z calcd for C 15 H 20 N [M + H] + : 214.1596; Found: 214.1594. 3,4-diethylisoquinoline(3am) N The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and hex-3-yne (2m) (24.6mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3am (42.1 mg, 91%), colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 9.12 (s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.71 7.67 (m, 1H), 7.53 (t, J = 7.5 Hz, 1H), 3.09 (dt, J = 7.9, 6.7 Hz, 2H), 3.07 3.01 (m, 2H), 1.39 (td, J = 7.5, 1.4 Hz, 3H), 1.32 (td, J = 7.5, 1.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 153.6, 150.1, 135.2, 130.2, 129.2, 128.3, 127.3, 125.7, 122.8, 28.2, 20.8, 15.0, 14.6. HRMS (APCI) m/z calcd for C 13 H1 5 N [M + H] + : 186.1283; Found: 186.1283. 3-phenylisoquinoline (3an) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and ethynylbenzene (2n) (30.6mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3an (38.7 mg, 76%), white solid, mp 97-98ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.37 (s, 1H), 8.16 (d, J = 7.4 Hz, 2H), 8.09 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 7.45 (t, J = 7.3 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.5, 151.3, 139.6, 136.7, 130.6, 128.8, 128.6, 127.8, 127.6, 127.1, 127.0, 126.9, 116.6. HRMS (APCI) m/z calcd for C 15 H 12 N [M + H] + : 206.0970; Found: 206.0978. 3-(pyridin-3-yl)isoquinoline (3ao) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 3-ethynylpyridine (2o) (30.9mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 5:1) yielded compound 3ao (30.1 mg, 58%), white solid, mp 77-79ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.37 (s, 1H), 9.34 (d, J = 1.6 Hz, 1H), 8.72 8.64 (m, 1H), 8.51 8.43 (m, 1H), 8.12 (s, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.75 (dd, J = 11.2, 3.9 Hz, 1H), 7.65 (t, J = 7.5 Hz, 1H), 7.45 (dd, J = 7.9, 4.8 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.9, 149.5, 148.5, 148.3, 136.5, 135.2, 134.4, 130.9, 128.0, 127.7, 127.0, 123.7, 117.0. HRMS (APCI) m/z calcd for C 14 H 11 N 2 [M + H] + : 207.0922; Found: 207.0920. S 20

3-(thiophen-2-yl)isoquinoline (3ap) N The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 2-ethynylthiophene (2p) (32.4mg, 0.3mmol). After S 20h, purification by column chromatography on silica gel (n-hexane/etoac: 50:1) yielded compound 3ap (25.2 mg, 48%), white solid, mp 107-108ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.25 (s, 1H), 8.01 (s, 1H), 7.97 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 7.71 (dd, J = 12.5, 5.6 Hz, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 5.0 Hz, 1H), 7.23 7.14 (m, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.5, 146.6, 145.1, 136.5, 130.8, 128.2, 127.8, 127.8, 126.9, 126.9, 126.7, 123.9, 114.4. HRMS (APCI) m/z calcd for C 13 H 10 NS [M + H] + : 212.0534; Found: 212.0530. 4-methyl-3-phenylisoquinoline(3aq) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and prop-1-yn-1-ylbenzene (2q) (34.8mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 20:1) yielded compound 3aq (50 mg, 91%), white solid, mp 80-82ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.24 (s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.79 (t, J = 7.3 Hz, 1H), 7.64 (dd, J = 14.7, 7.4 Hz, 3H), 7.52 (t, J = 7.4 Hz, 2H), 7.44 (t, J = 7.2 Hz, 1H), 2.69 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.7, 150.1, 141.2, 136.3, 130.5, 129.9, 128.2, 127.6, 127.3, 126.7, 124.2, 123.6, 15.5. HRMS (APCI) m/z calcd for C 16 H 14 N [M + H] + : 220.1126; Found: 220.1124. 4-ethyl-3-phenylisoquinoline (3ar) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and but-1-yn-1-ylbenzene (2r) (39.0mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 50:1) yielded compound 3ar (50.5 mg, 87%), white solid, mp 112-1135ºC. 1 H NMR (400 MHz, CDCl 3 ) δ 9.21 (s, 1H), 8.12 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.81 7.77 (m, 1H), 7.64 (dd, J = 11.1, 3.9 Hz, 1H), 7.58 7.54 (m, 2H), 7.51 (t, J = 7.3 Hz, 2H), 7.45 (dd, J = 8.4, 6.0 Hz, 1H), 3.09 (q, J = 7.5 Hz, 2H), 1.33 (t, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 151.9, 150.2, 141.6, 135.2, 130.4, 130.3, 129.2, 128.4, 128.2, 127.9, 127.6, 126.6, 123.6, 21.8, 15.7. HRMS (APCI) m/z calcd for C 17 H 16 N [M + H] + : 234.1283; Found: 234.1283. 4-butyl-3-phenylisoquinoline (3as) The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and hex-1-yn-1-ylbenzene (2s) (47.4mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3as (51.5 mg, 79%), colorless oil. 1 H NMR (400 MHz, CDCl 3 ) δ 9.21 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.81 7.75 (m, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.58 7.53 (m, 2H), 7.51 (dd, J = 11.1, 4.1 Hz, 2H), 7.43 (dd, J = 10.3, 4.0 Hz, 1H), 3.12 3.00 (m, 2H), 1.73 1.63 (m, 2H), 1.39 (dt, J = 14.7, 7.3 Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ 152.1, 150.1, 141.6, 135.4, 130.3, 129.3, 129.2, 128.3, 128.1, 127.8, 127.5, 126.6, 123.7, 33.4, 28.4, 23.0, 13.8. HRMS (APCI) m/z calcd for C 19 H 20 N [M + H] + : 262.1596; Found: 262.1596. 4-(4-nitrophenyl)-3-(p-tolyl)isoquinoline (3at) N The representative procedure was following using N-benzylpicolinamide (1a) (53.0mg, 0.25mmol) and 1-methyl-4-((4-nitrophenyl)ethynyl)benzene (2t) (71.1mg, 0.3mmol). After 20h, purification by column chromatography on silica gel (n-hexane/etoac: 40:1) yielded compound 3at (30.9 mg, NO 2 S 21

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