Materials and Methods S2. 1. General procedure for the preparation of 2-methylaminobenzonitriles S3

A Synthesis of 1H-Indazoles via a Cu(OAc) 2 -catalyzed N-N Bond Formation Cheng-yi Chen,*, Guangrong Tang, Fengxian He, Zhaobin Wang, Hailin Jing and Roger Faessler Janssen R&D, Pharmaceutical Development and Manufacturing Sciences, Small Molecule API Switzerland, Cilag AG, Hochstrasse 201, 8205 Schaffhausen, Switzerland Porton (Shanghai) R&D Center, 1299 Ziyue Road, Zizhu Science Park, Minhang District, Shanghai 200241, China cchen117@its.jnj.com Table of Contents Materials and Methods S2 Experimental Procedures 1. General procedure for the preparation of 2-methylaminobenzonitriles S3 2. General procedure for amination of bromobenzonitriles using arylamines S4 3. Procedure for the preparation of tert-butylaminobenzonitrile S5 4. Procedure for the preparation of (1'R, 2'R)-2-((2'-benzyloxy)cyclopentyl)amino-4-bromo-6-fluorobenzonitrile S6 5. General procedure for the preparation of 1H-indazoles S7 S1

References S19 1 H NMR and 13 C NMR spectra of new compounds S21 Materials and Methods. Unless stated otherwise, all preparation of imines were carried out under nitrogen and all preparation of (methylamino)benzonitrile were prepared according to a literature procedure. 1 2-(Phenylamino)benzonitrile, 5-chloro-2-(phenylamino)benzonitrile and 2-((2,6-dimethylphenyl)amino)benzonitrile were prepared according to a literature procedure. 2 indazoles via N-N bond formation were carried out under oxygen. 2-(Methylamino)benzonitrile and 4-chloro-2-2-(tert- Butylamino)benzonitrile was prepared according to a literature procedure. 3 (1'R, 2'R)-2-(2'-Benzyloxy)cyclopentylamino-4-bromo-6- fluorobenzonitrile was prepared according to a literature procedure. 4 All commercially available reagents were used as received. Flash chromatography was carried out with Sunasiachem silica gel (200-300 mesh). 1 H NMR and 13 C NMR spectra were recorded on a Varian 300 or 400 NMR Spectrometer with chemical shifts reported in ppm relative to Me 4 Si for 1 H NMR and CDCl 3 for 13 C NMR. High resolution mass spectra were obtained using the Waters Q-Tof Ultima global instrument at the mass spectrometry facility of SIMM (Shanghai Institute of Materia Medica, Chinese Academy of Sciences). S2

Experimental Procedures: 1. General procedure for the preparation of 2-methylaminobenzonitriles The 2-methylamino benzonitriles were prepared according to a literature procedure. 1 Under nitrogen, a mixture of 2-aminobenzonitrile (1.0 equiv), dimethyl oxalate (1.5 eqiuv) and t-buok (1.25 eqiuv) in DMA was heated at 130-140 o C for 5h. The reaction was poured into ice water and extracted with MTBE. After concentration of the MTBE layer in vacuum, the crude product was purified through flash chromatography eluted with EtOAc/n-heptane = 1/50) to afford 2-methylaminobenzonitrile. 2-(methylamino)benzonitrile (6): 1 The reaction was run according to the general method using 2-aminobenzonitrile (70.8 g, 0.6 mol), dimethyl oxalate (106.2 g, 0.9 mol) and t-buok (84.0 g, 0.75 mol) in DMA (450 ml) to afford the benzonitrile (55.5 g, 70.0% yield) as white solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.43-7.37 (m, 2H), 6.70-6.64 (m, 2H), 2.93 (s, 3H). 4-chloro-2-(methylamino)benzonitrile (6 (4-Cl)): 5 The reaction was run according to the general method using 2- amino-4-chlorobenzonitrile (7.6 g, 0.05 mol), dimethyl oxalate (8.9 g, 0.075 mol) and t-buok (7.0 g, 0.063 mol) in DMA (30 ml) to afford 4-chloro-2-(metylamino)benzonitrile (4.1 g, 49.2% yield) as white solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.29 (d, J = 8.2 Hz, 1H), 6.65 (dt, J = 5.6, 1.7 Hz, 2H), 4.72 (brs, 1H), 2.92 (d, J = 5.1 Hz, 3H). S3

2. General procedure for amination of bromobenzonitriles using arylamines The 2-arylamino benzonitriles were prepared by a slightly modified literature procedure. 2 Under nitrogen, a mixture of 2- bromobenzonitrile (1.0 equiv), aniline (1.5 eqiuv), Pd(dppf)Cl 2 (0.05 eqiuv), PPh 3 (0.3 eqiuv) and Cs 2 CO 3 (2 equiv) in 1,4-dioxane was heated at 90-100 o C for 24h. The reaction was quenched with water and extracted with EtOAc. After concentration of the organic solution in vacuum, the crude product was purified through flash chromatography (EtOAc/n-heptane = 1/50) to afford 2- aminobenzonitriles. 2-(phenylamino)benzonitrile (1, R = Ph): 2 The reaction was run according to the general method using 2- bromobenzonitrile (18.2 g, 0.1 mol), aniline (14.0 g, 0.15 mol), PPh 3 (7.8 g, 0.03 mol), Pd(dppf)Cl 2 (3.6 g, 5 mmol), and Cs 2 CO 3 (65.2 g, 0.2 mol) in 1,4-dioxane (400 ml) to afford 2-(phenylamino)benzonitrile (13.8 g, 71.1% yield) as white solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.50 (dd, J = 7.8, 1.5 Hz, 1H), 7.37 (ddd, J = 9.0, 3.6, 1.7 Hz, 3H), 7.23-7.17 (m, 3H), 7.14 (t, J = 7.4 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 6.46 (brs, 1H). 2-((2,6-dimethylphenyl)amino)benzonitrile (1, R = 2,6-dimethylphenyl): The reaction was run according to the general method using 2-bromobenzonitrile (9.1 g, 0.05 mol), 2,6-dimethylaniline (9.1 g, 0.075 mol), PPh 3 (3.9 g, 0.015 mol), Pd(dppf)Cl 2 (1.8 g, 2.5 mmol), and Cs 2 CO 3 (32.6 g, 0.1 mol) in 1,4-dioxane (120 ml) to afford the 2- S4

arylaminobenzonitrile (4.0 g, 35.7% yield) as white solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.45 (dd, J = 7.8, 1.5 Hz, 1H), 7.27-7.20 (m, 1H), 7.14 (d, J = 2.8 Hz, 3H), 6.71 (t, J = 7.5 Hz, 1H), 6.17 (d, J = 8.5 Hz, 1H), 5.91 (brs, 1H), 2.19 (s, 6H). 13 C NMR (100 MHz, CDCl 3 ): δ 149.24, 136.98, 135.91, 134.36, 132.84, 128.88, 127.49, 117.99, 117.63, 111.99, 95.84, 18.31. HRMS (ESI): calcd. for C 15 H 15 N 2 [M+H] + : 223.1235, found: 223.1231. 5-chloro-2-(phenylamino)benzonitrile (1 (5-Cl), R = Ph): The reaction was run according to the general method using 2-bromo-5-chlorobenzonitrile (4.4 g, 0.02 mol), aniline (2.8 g, 0.03 mol), PPh 3 (1.6 g, 6 mmol), Pd(dppf)Cl 2 (0.7 g, 1 mmol), and Cs 2 CO 3 (12.8 g, 0.04 mol) in 1,4-dioxane (80 ml) to afford the benzonitrile (2.6 g, 44.8% yield) as greenish yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.46 (d, J = 2.4 Hz, 1H), 7.38 (dd, J = 10.6, 5.2 Hz, 2H), 7.31 (dd, J = 9.1, 2.5 Hz, 1H), 7.21-7.08 (m, 4H), 6.32 (brs, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ 146.27, 139.49, 134.32, 132.10, 129.91, 124.90, 123.64, 122.18, 116.50, 115.50, 99.42. HRMS (ESI): calcd. for C 13 H 10 ClN 2 [M+H] + : 229.0532, found: 229.0535. 3. Procedure for the preparation of tert-butylaminobenzonitrile 2-(tert-butylamino)benzonitrile (1, R = tert-bu): This substituted benzonitrile was prepared according to a literature procedure. 3 2-Bromobenzonitrile (2.36 g, 0.02 mol), tert-butyl 2,2,2-trichloroacetimidate (10.9 g, 0.05 mol), and S5

Cu(OTf) 2 (0.36 g, 0.001 mol) were charged into nitromethane and stirred at 25-30 o C for 7h under nitrogen. The reaction was quenched with water and extracted with EtOAc. After concentration of the EtOAc solution in vacuum, the crude product was purified through flash chromatography eluted with EtOAc/n-heptane = 1/100) to afford the 2-(tert-butylamino)benzonitrile (1.3 g, 37.4% yield) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.40-7.28 (m, 2H), 6.93 (d, J = 8.6 Hz, 1H), 6.63 (td, J = 7.7, 0.9 Hz, 1H), 4.54 (brs, 1H), 1.42 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ): δ 149.29, 133.59, 133.10, 116.12, 113.30, 97.19, 51.71, 29.62. HRMS (ESI): calcd. for C 11 H 15 N 2 [M+H] + : 175.1235, found: 175.1238. 4. Procedure for the preparation of (1'R, 2'R)-2-((2'-benzyloxy)cyclopentyl)amino-4-bromo-6-fluorobenzonitrile (1'R, 2'R)-2-((2'-(benzyloxy)cyclopentyl)amino)-4-bromo-6-fluorobenzonitrile (19): This substituted benzonitrile was prepared according to a literature procedure. 4 4-bromo-2,6-difluorobenzonitrile (2.0 g, 9.2 mmol), (1R, 2R)-2-(benzyloxy)cyclopentanamine (1.93 g, 10.1 mmol), DIPEA (1.3 g, 10.1 mmol) were charged into DMSO (10mL) and stirred at 120 o C for 3 h under nitrogen. Then the reaction was quenched with saturated aq. NH 4 Cl solution and extracted with EtOAc. After concentration in vacuum, the crude product was purified through flash chromatography (EtOAc/n-heptane = 1/30) to afford the benzonitrile (2.7 g, 75.6% yield) as white solid. Mp.: 80.7 o C. 1 H NMR (400 MHz, CDCl 3 ): δ 7.42-7.27 (m, 5H), 6.90 (s, 1H), 6.61 (dd, J = 8.4, 1.5 Hz, 1H), 4.66 (d, J = 5.3 Hz, 1H), 4.60 (d, J = 11.5 Hz, 1H), 4.45 (d, J = 11.5 Hz, 1H), 3.86-3.72 (m, 2H), 2.29 (td, J = 13.2, 6.9 Hz, 1H), 2.02-1.72 (m, 4H), 1.57-1.41 (m, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ: 163.58 S6

(d, J = 259.0 Hz), 151.22 (d, J = 4.6 Hz), 137.88, 129.51 (d, J = 12.6 Hz), 128.64, 127.94, 112.97 (d, J = 1.9 Hz), 110.89 (d, J = 2.9 Hz), 107.32, 107.09, 85.28, 84.93 (d, J = 18.9 Hz), 71.57, 60.70, 31.75, 30.18, 21.98. HRMS (ESI): calcd. for C 19 H 19 BrFN 2 O [M+H] + : 389.0674, found: 389.0659. 5. General procedure for the preparation of 1H-indazoles To a cooled solution of corresponding 2-aminobenzonitrile (1.0 equiv) in THF was added the corresponding Grignard reagent (3.3 equiv) or organolithium reagent (3.3 eqiuv) at 10 o C (for Grignard reagent) or -50 o C (for organolithium reagent) under nitrogen. After addition, the reaction was stirred for 3h at 30 o C (for Grignard reagent) or 10 o C (for organolithium reagent). This reaction mixture was poured into brine and extracted with MTBE. The organic layer was dried over Na 2 SO 4 and concentrated in vacuum to afford the corresponding NHketimine. To the mixture of DMSO with Cu(OAc) 2 (0.2 equiv) was added the solution of the corresponding NH ketimine in DMSO at 85 o C under oxygen over 10min. The resulted mixture was stirred at 85 o C for 3h. The reaction was poured into water and extracted with EtOAc. After concentration in vacuum, the crude product was purified through flash chromatography (EtOAc/n-heptane = 1/20). S7

1-methyl-3-phenyl-1H-indazole (8): 6 The reaction was run according to the general method using 2- (methylamino)benzonitrile (1.00 g, 7.5 mmol), phenyllithium (1.0 M in Et 2 O, 25 ml, 25 mmol) and Cu(OAc) 2 (0.27 g, 1.5 mmol) in DMSO (20 g) to afford the indazole (1.23 g, 77.8% yield) as yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 8.03 (d, J = 8.2 Hz, 1H), 8.01-7.96 (m, 2H), 7.56-7.48 (m, 2H), 7.44-7.38 (m, 3H), 7.22 (ddd, J = 8.0, 5.0, 2.8 Hz, 1H), 4.13 (s, 3H). The reaction was also run according to the general method using 2-(dimethylamino)benzonitrile (1.46 g, 10 mmol), phenyllithium (1.0 M in Et 2 O, 22 ml, 22 mmol) and Cu(OAc) 2 (0.36 g, 2 mmol) in DMSO (20 g) to afford the 1H-indazole (1.06 g, 51.0% yield) as yellow solid. 3-(3-fluorophenyl)-1-methyl-1H-indazole (10a): The reaction was run according to the general procedure using 2-(methylamino)benzonitrile (1.05 g, 7.9 mmol), (3-fluorophenyl) magnesium bromide (1.0 M in THF, 26 ml, 26 mmol) and Cu(OAc) 2 (0.27 g, 1.5 mmol) in DMSO (20 g) to afford the 1H-indazole (1.50 g, 83.3% yield) as yellow solid. Mp.: 59.6-59.7 o C. 1 H NMR (400 MHz, CDCl 3 ): δ 8.01 (dt, J = 8.2, 0.9 Hz, 1H), 7.78-7.73 (m, 1H), 7.68 (ddd, J = 10.1, 2.5, 1.6 Hz, 1H), 7.50-7.41 (m, 3H), 7.26-7.21 (m, 1H), 7.08 (tdd, J = 8.5, 2.6, 0.9 Hz, 1H), 4.13 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ: 163.16 (d, J = 245.3 Hz), 142.36 (d, J = 2.7 Hz), 141.45, 135.88 (d, J = 8.3 Hz), 130.26 (d, J = 8.4 Hz), 126.37, 122.86 (d, J = 2.8 S8

Hz), 121.44, 121.24, 121.00, 114.53 (d, J = 21.3 Hz), 114.05 (d, J = 22.6 Hz), 109.32, 35.56. HRMS (ESI): calcd. for C 14 H 11 FN 2 [M+H] + : 227.0984, found: 227.0986. 6-chloro-3-(3-fluorophenyl)-1-methyl-1H-indazole (10b): The reaction was run according to the general method using 4-chloro-2-(methylamino)benzonitrile (0.83g, 5.0 mmol), (3-fluorophenyl) magnesium bromide (1.0 M in THF, 16.5 ml, 16.5 mmol) and Cu(OAc) 2 (0.18g, 1.0 mmol) in DMSO (20 g) to afford the 1Hindazole (1.17 g, 90.0% yield) as yellow solid. Mp.: 65.5-66.5 o C. 1 H NMR (400 MHz, CDCl 3 ): δ 7.86 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 7.62 (dd, J = 10.0, 1.9 Hz, 1H), 7.45 (td, J = 8.0, 6.1 Hz, 1H), 7.41-7.38 (m, 1H), 7.17 (dd, J = 8.7, 1.5 Hz, 1H), 7.09 (td, J = 8.5, 2.6 Hz, 1H), 4.06 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 163.26 (d, J = 245.7 Hz), 142.77, 141.94, 135.35 (d, J = 8.3 Hz), 132.97, 130.50 (d, J = 8.5 Hz), 122.94 (d, J = 2.9 Hz), 122.37, 122.11, 120.14, 115.03 (d, J = 21.2 Hz), 114.17 (d, J = 22.7 Hz), 109.23, 35.81. HRMS (ESI): calcd. for C 14 H 10 ClFN 2 [M+H] + : 261.0595, found: 261.0600. 3-(4-fluorophenyl)-1-methyl-1H-indazole (10c): 7 The reaction was run according to the general method using 2- (methylamino)benzonitrile (1.06 g, 8.0 mmol), (4-fluorophenyl)magnesium bromide (1.0 M in THF, 26 ml, 26 mmol) and Cu(OAc) 2 (0.29 g, 1.6 mmol) in DMSO (20 g) to afford the 1H-indazole (1.44 g, 79.3% yield) as yellow solid. 1 H S9

NMR (400 MHz, CDCl 3 ): δ 7.99-7.89 (m, 3H), 7.48-7.40 (m, 2H), 7.25-7.15 (m, 3H), 4.13 (s, 3H). 3-(4-methoxyphenyl)-1-methyl-1H-indazole (10d): 6 The reaction was run according to the general method using 2-(methylamino)benzonitrile (1.08 g, 8.2 mmol), (4-methoxyphenyl)magnesium bromide (1.0 M in THF, 27 ml, 27 mmol) and Cu(OAc) 2 (0.29 g, 1.6 mmol) in DMSO (20 g) to afford the indazole (1.49 g, 76.4% yield) as yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.99 (dt, J = 8.2, 0.9 Hz, 1H), 7.93-7.87 (m, 2H), 7.45-7.38 (m, 2H), 7.23-7.16 (m, 1H), 7.08-7.01 (m, 2H), 4.11 (s, 3H), 3.88 (s, 3H). 3-(2-methoxyphenyl)-1-methyl-1H-indazole (10e): The reaction was run according to the general method using 2-(methylamino)benzonitrile (1.02 g, 7.7 mmol), (2-methoxyphenyl) magnesium bromide (1.0 M in THF, 25 ml, 25 mmol) and Cu(OAc) 2 (0.27 g, 1.5 mmol) in DMSO (20 g) to afford the 1H-indazole (1.40 g, 76.1% yield) as yellow solid. Mp.: 69.1 o C. 1 H NMR (400 MHz, CDCl 3 ): δ 7.74 (d, J = 8.2 Hz, 1H), 7.63 (dd, J = 7.5, 1.7 Hz, 1H), 7.42 (dd, J = 11.9, 2.9 Hz, 3H), 7.19-7.11 (m, 1H), 7.08 (dd, J = 14.2, 7.5 Hz, 2H), 4.14 (s, 3H), 3.86 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 157.18, 142.03, 140.87, 131.38, 129.49, 126.02, 123.07, 122.57, 122.43, 120.80, 120.10, 111.18, 108.84, 55.47 (d, J = 1.8 Hz), 35.47. HRMS (ESI): calcd. for C 15 H 14 N 2 O [M+H] + : 239.1184, found: 239.1178. S10

1-methyl-3-(o-tolyl)-1H-indazole (10f): 8 The reaction was run according to the general method using 2- (methylamino)benzonitrile (1.05 g, 7.9 mmol), o-tolylmagnesium bromide (1.0 M in THF, 26 ml, 26 mmol) and Cu(OAc) 2 (0.29 g, 1.6 mmol) in DMSO (20 g) to afford the 1H-indazole (1.38 g, 78.0% yield) as yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 7.64 (d, J = 8.2 Hz, 1H), 7.54-7.49 (m, 1H), 7.47-7.39 (m, 2H), 7.37-7.27 (m, 3H), 7.16 (ddd, J = 7.9, 5.6, 2.0 Hz, 1H), 4.14 (s, 3H), 2.40 (s, 3H). 1-methyl-3-(pyridin-3-yl)-1H-indazole (10g): 6 The reaction was run according to the general method using 2- (methylamino)benzonitrile (1.00 g, 7.5 mmol), pyridin-3-ylmagnesium bromide (0.7 M in THF, 36 ml, 25 mmol) and Cu(OAc) 2 (0.27 g, 1.6 mmol) in DMSO (20 g) to afford the 1H-indazole (1.05 g, 65.9% yield) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ 9.24-9.13 (m, 1H), 8.56 (d, J = 4.7 Hz, 1H), 8.22-8.11 (m, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.34 (dt, J = 13.4, 8.5 Hz, 3H), 7.21-7.10 (m, 1H), 4.02 (s, 3H). 1,3-dimethyl-1H-indazole (10h): 9 The reaction was run according to the general method using 2- (methylamino)benzonitrile (1.05 g, 7.9 mmol), methyllithium (1.6 M in Et 2 O, 16 ml, 26 mmol) and Cu(OAc) 2 (0.29 g, 1.6 mmol) in DMSO (20 g) to afford the 1H-indazole (0.84 g, 72.4% yield) as yellow solid. 1 H NMR (400 MHz, S11

CDCl 3 ): δ 7.65 (d, J = 8.1 Hz, 1H), 7.35 (ddd, J = 19.8, 13.7, 4.6 Hz, 2H), 7.11 (ddd, J = 7.7, 6.7, 0.8 Hz, 1H), 3.99 (s, 3H), 2.58 (s, 3H). 3-isopropyl-1-methyl-1H-indazole (10i): The reaction was run according to the general method using 2- (methylamino)benzonitrile (1.00 g, 7.5 mmol), isopropylmagnesium bromide (1.0 M in THF, 25 ml, 25 mmol) and Cu(OAc) 2 (0.27 g, 1.5 mmol) in DMSO (20 g) to afford the 1H-indazole (0.99 g, 75.0% yield) as yellow oli. 1 H NMR (400 MHz, CDCl 3 ): δ 7.76 (d, J = 8.1 Hz, 1H), 7.35 (dt, J = 15.0, 7.9 Hz, 2H), 7.15-7.06 (m, 1H), 4.01 (s, 3H), 3.49-3.37 (m, 1H), 1.49 (d, J = 7.0 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ): δ 150.56, 141.03, 126.00, 121.62, 120.77, 119.31, 108.90, 35.09, 27.76, 22.40. HRMS (ESI): calcd. for C 11 H 15 N 2 [M+H] + : 175.1235, found: 175.1248. 3-cyclopropyl-1-methyl-1H-indazole (10j): The reaction was run according to the general method using 2- (methylamino)benzonitrile (1.00 g, 7.5 mmol), cyclopropyl magnesium bromide (1.0 M in THF, 25 ml, 25 mmol) and Cu(OAc) 2 (0.27 g, 1.5 mmol) in DMSO (20 g) to afford the 1H-indazole (1.09 g, 84.5% yield) as yellow solid. Mp.: S12

41.0-41.4 o C. 1 H NMR (400 MHz, CDCl 3 ): δ 7.74 (d, J = 8.1 Hz, 1H), 7.40-7.28 (m, 2H), 7.14-7.06 (m, 1H), 3.97 (s, 3H), 2.25-2.19 (m, 1H), 1.11-0.98 (m, 4H); 13 C NMR (100 MHz, CDCl 3 ): δ 146.75, 141.30, 126.47, 123.10, 120.64 (d, J = 5.2 Hz), 119.78, 109.14, 35.38 (d, J = 7.8 Hz), 8.42, 7.27. HRMS (ESI): calcd. for C 11 H 13 N 2 [M+H] + : 173.1078, found: 173.1075. 1,3-diphenyl-1H-indazole (11a): 10 The reaction was run according to the general method using 2- (phenylamino)benzonitrile (2.00 g, 10.3 mmol), phenyllithium (1.0 M in Et 2 O, 34 ml, 34 mmol) and Cu(OAc) 2 (0.37 g, 2.1 mmol) in DMSO (40 g) to afford the 1H-indazole (1.96 g, 70.4% yield) as yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 8.10 (d, J = 8.2 Hz, 1H), 8.07-8.03 (m, 2H), 7.84-7.76 (m, 3H), 7.58-7.51 (m, 4H), 7.47 (m, 2H), 7.39 (ddd, J = 13.8, 4.9, 1.1 Hz, 1H), 7.34-7.27 (m, 1H). 3-(4-methoxyphenyl)-1-phenyl-1H-indazole (11b): 10 The reaction was run according to the general method using 2-(phenylamino)benzonitrile (1.94 g, 10 mmol), (4-methoxy phenyl)magnesium bromide (1.0 M in THF, 33 ml, 33 mmol) and Cu(OAc) 2 (0.37 g, 2 mmol) in DMSO (50 g) to afford the 1H-indazole (1.53 g, 51.0% yield) as yellow solid. 1 H NMR (300 MHz, CDCl 3 ): δ 8.05 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.78 (t, J = 6.8 Hz, 3H), 7.54 (t, J = 6.9 Hz, 2H), 7.44 (t, J = 7.1 Hz, 1H), 7.37 (d, J = 6.9 Hz, 1H), 7.31-7.22 (m, 1H), 7.06 (d, J = 8.1 Hz, 2H), 3.88 (s, 3H). S13

3-(4-fluorophenyl)-1-phenyl-1H-indazole (11c): 10 The reaction was run according to the general method using 2- (phenylamino)benzonitrile (1.94 g, 10 mmol), (4-fluorophenyl)magnesium bromide (1.0 M in THF, 33 ml, 33 mmol) and Cu(OAc) 2 (0.37 g, 2 mmol) in DMSO (50 g) to afford the 1H-indazole (2.00 g, 69.4% yield) as yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 8.07-7.99 (m, 3H), 7.83-7.76 (m, 3H), 7.61-7.53 (m, 2H), 7.51-7.44 (m, 1H), 7.42-7.36 (m, 1H), 7.31 (ddd, J = 7.9, 7.0, 0.8 Hz, 1H), 7.27-7.20 (m, 2H). 3-(3-fluorophenyl)-1-phenyl-1H-indazole (11d): The reaction was run according to the general method using 2- (phenylamino)benzonitrile (1.46g, 7.5 mmol), (3-fluorophenyl)magnesium bromide (1.0 M in THF, 25 ml, 25 mmol) and Cu(OAc) 2 (0.27 g, 1.5 mmol) in DMSO (20 g) to afford the 1H-indazole (1.45 g, 67.0% yield) as yellow solid. Mp.: 114 o C. 1 H NMR (400 MHz, CDCl 3 ): δ 8.08 (d, J = 8.2 Hz, 1H), 7.88-7.83 (m, 1H), 7.79 (tdd, J = 4.0, 2.7, 1.4 Hz, 4H), 7.57 (dd, J = 10.7, 5.2 Hz, 2H), 7.53-7.44 (m, 2H), 7.40 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.17-7.09 (m, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ 163.27 (d, J = 245.5 Hz), 144.89 (d, J = 2.7 Hz), 140.50, 140.05, 135.51 (d, J = 8.3 Hz), 130.48 (d, J = 8.4 Hz), 129.63, 127.38, 127.03, 123.42 (d, J = 2.9 Hz), 123.18, 123.01, 122.36, 121.41, 115.21 (d, J = 21.2 Hz), 114.64 (d, J = 22.6 Hz), 110.96. HRMS (ESI): calcd. for C 19 H 13 FN 2 [M+H] + : 289.1141, found: 289.1136. S14

1-phenyl-3-(prop-1-en-1-yl)-1H-indazole (11e): The reaction was run according to the general method using 2- (phenylamino)benzonitrile (1.46 g, 7.5 mmol), propenylmagnesiumbromide (1.0 M in THF, 25 ml, 25 mmol) and Cu(OAc) 2 (0.27 g, 1.5 mmol) in DMSO (20 g) to afford the E/Z mixture of 1H-indazoles 0.88 g, 50.0% yield) as yellow oil. HRMS (ESI): calcd. for C 16 H 15 N 2 [M+H] + : 235.1235, found: 235.1229. Z-isomer: 1 H NMR (400 MHz, CDCl 3 ): δ 7.82-7.71 (m, 4H), 7.57-7.48 (m, 2H), 7.46-7.39 (m, 1H), 7.33 (t, J = 7.4 Hz, 1H), 7.22 (dd, J = 10.8, 3.8 Hz, 1H), 6.70 (dq, J = 11.4, 1.7 Hz, 1H), 6.12 (dq, J = 11.5, 7.1 Hz, 1H), 2.25 (dd, J = 7.1, 1.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 144.25, 140.54, 139.01, 131.37, 129.51, 127.18, 126.36, 125.32, 122.55, 121.39, 120.73, 118.09, 110.53, 16.48. E-isomer: 1 H NMR (400 MHz, CDCl 3 ): δ 7.95 (d, J = 8.1 Hz, 1H), 7.77-7.69 (m, 3H), 7.58-7.48 (m, 2H), 7.46-7.38 (m, 1H), 7.38-7.30 (m, 1H), 7.24 (dd, J = 11.2, 4.0 Hz, 1H), 6.88-6.68 (m, 2H), 2.09-1.94 (m, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 144.58, 140.04, 139.88, 129.95, 129.39, 127.04, 126.43, 123.15, 122.76, 122.45, 121.48, 121.23, 110.49, 19.11. 3-cyclopropyl-1-phenyl-1H-indazole (11f): The reaction was run according to the general method using 2- (phenylamino)benzonitrile (1.46 g, 7.5 mmol), cyclopropylmagnesium bromide (1.0 M in THF, 25 ml, 25 mmol) and Cu(OAc) 2 (0.27 g, 1.5 mmol) in DMSO (20 g) to afford the 1H-indazole (1.12 g, 63.6% yield) as yellow solid. Mp.: 65.9 o C. 1 H NMR (400 MHz, CDCl 3 ): δ 7.82 (dd, J = 8.1, 0.8 Hz, 1H), 7.74-7.66 (m, 3H), 7.51 (dd, J = 11.1, 4.8 Hz, 2H), 7.41 (ddd, J = 8.1, 7.0, 0.9 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.20 (dd, J = 7.9, 7.1 Hz, 1H), 2.30 (tt, J = 8.4, 5.1 Hz, 1H), 1.22- S15

1.13 (m, 2H), 1.08 (ddd, J = 6.7, 5.3, 3.9 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ 149.28, 140.45, 139.81, 129.49, 127.22, 126.15, 124.61, 122.57, 120.85, 120.71, 110.55, 8.26, 7.55. HRMS (ESI): calcd. for C 16 H 15 N 2 [M+H] + : 235.1235, found: 235.1231. 5-chloro-1,3-diphenyl-1H-indazole (11g): 11 The reaction was run according to the general method using 5- chloro-2-(phenylamino)benzonitrile (1.01 g, 4.4 mmol), phenyl magnesium bromide (3.0 M in Et 2 O, 5.0 ml, 15 mmol) and Cu(OAc) 2 (0.16 g, 0.9 mmol) in DMSO (20 g) to afford the 1H-indazole (0.84 g, 62.6% yield) as yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 8.05 (d, J = 1.8 Hz, 1H), 8.01-7.96 (m, 2H), 7.79-7.74 (m, 2H), 7.70 (d, J = 8.9 Hz, 1H), 7.55 (dd, J = 16.6, 8.0 Hz, 4H), 7.46 (d, J = 7.2 Hz, 1H), 7.44-7.37 (m, 2H). 1-(2,6-dimethylphenyl)-3-phenyl-1H-indazole (11h): The reaction was run according to the general method using 2-((2,6-dimethylphenyl)amino)benzonitrile (1.01 g, 4.5 mmol), phenyllithium (1.0 M in Et 2 O, 15 ml, 15 mmol) and Cu(OAc) 2 (0.16 g, 0.9 mmol) in DMSO (20 g) to afford the 1H-indazole (1.15 g, 85.0% yield) as yellow solid. Mp.: 75.4 o C. 1 H NMR (400 MHz, CDCl 3 ): δ 8.14 (dt, J = 8.1, 0.9 Hz, 1H), 8.10-8.05 (m, 2H), 7.57-7.50 (m, 2H), 7.46-7.19 (m, 6H), 7.07 (dt, J = 8.4, 0.8 Hz, 1H), 2.00 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ): δ 145.32, 141.89, 137.54, 137.08, 133.77, 129.40, 128.93, 128.58, 128.16, 127.74, 126.96, 121.53, 121.50, 121.47, 110.09, 17.74. HRMS (ESI): calcd. for C 21 H 18 N 2 [M+H] + : 299.1548, found: 299.1555. S16

1-(tert-butyl)-3-(3-fluorophenyl)-1H-indazole (11i): The reaction was run according to the general method using 2-(tert-butylamino)benzonitrile (1.05g, 6.0 mmol), (3-fluorophenyl)magnesium bromide (1.0 M in THF, 20 ml, 20 mmol) and Cu(OAc) 2 (0.22g, 1.2 mmol) in DMSO (20 g) to afford the 1H-indazole (1.37 g, 85.1% yield) as yellow solid. Mp.: 74.0-74.5 o C. 1 H NMR (400 MHz, CDCl 3 ): δ 8.04 (d, J = 8.2 Hz, 1H), 7.78 (dd, J = 9.8, 8.4 Hz, 2H), 7.74-7.69 (m, 1H), 7.46 (dt, J = 14.1, 7.1 Hz, 1H), 7.38 (ddd, J = 8.1, 7.0, 0.8 Hz, 1H), 7.23 (dd, J = 14.8, 7.2 Hz, 1H), 7.08 (td, J = 8.4, 2.3 Hz, 1H), 1.85 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ 163.32 (d, J = 244.8 Hz), 140.69 (d, J = 2.7 Hz), 139.79, 136.54 (d, J = 8.3 Hz), 130.30 (d, J = 8.5 Hz), 125.50, 123.20, 123.14 (d, J = 2.8 Hz), 121.26, 120.86, 114.46 (d, J = 3.7 Hz), 114.25 (d, J = 4.9 Hz), 112.68, 60.14, 29.83. HRMS (ESI): calcd. for C 17 H 17 FN 2 [M+H] + : 269.1454, found: 269.1451. 1,3-dimethyl-1H-indazole (15a): 12 The reaction was run according to the general method using 2-aminobenzonitrile (1.18 g, 10 mmol), phenylmagnesium bromide (3.0 M in Et 2 O, 11 ml, 33 mmol) and Cu(OAc) 2 (0.36 g, 2 mmol) in DMSO (20 g) to afford the 1H-indazole (1.48 g, 76.3% yield) as red solid. 1 H NMR (400 MHz, CDCl 3 ): δ 8.08-8.00 (m, 3H), 7.55 (t, J = 7.5 Hz, 2H), 7.46 (dd, J = 8.4, 6.4 Hz, 1H), 7.37 (dd, J = 11.0, 4.1 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.23 (dd, J = 11.3, 4.4 Hz, 1H). S17

3-(4-methoxyphenyl)-1H-indazole (15b): 12 The reaction was run according to the general method using 2- aminobenzonitrile (1.18 g, 10 mmol), (4-methoxyphenyl)magnesium bromide (1.0 M in THF, 33 ml, 33 mmol) and Cu(OAc) 2 (0.36 g, 2 mmol) in DMSO (20 g) to afford the 1H-indazole (1.89 g, 84.3% yield) as yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 8.04-7.95 (m, 3H), 7.32 (dd, J = 11.2, 4.0 Hz, 1H), 7.23-7.13 (m, 2H), 7.11 (t, J = 5.8 Hz, 2H), 3.90 (s, 3H). 3-(3-fluorophenyl)-1H-indazole (15c): 13 The reaction was run according to the general method using 2- aminobenzonitrile (1.18 g, 10 mmol), (3-fluorophenyl)magnesium bromide (1.0 M in THF, 33 ml, 33 mmol) and Cu(OAc) 2 (0.36 g, 2 mmol) in DMSO (20 g) to afford the 1H-indazole (1.70 g, 80.2% yield) as yellow solid. 1 H NMR (400 MHz, CDCl 3 ): δ 10.68 (brs, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.83-7.77 (m, 1H), 7.72 (ddd, J = 10.0, 2.5, 1.6 Hz, 1H), 7.53-7.39 (m, 3H), 7.26 (ddd, J = 7.9, 6.3, 1.5 Hz, 1H), 7.13 (tdd, J = 8.5, 2.6, 0.9 Hz, 1H). 1-((1'R,2'R)-2-(benzyloxy)cyclopentyl)-6-bromo-3-cyclopropyl-4-fluoro-1H-indazole (21): The reaction was run according to the general method using (1'R,2'R)-2-((2'-benzyloxy)cyclopentyl)amino-4-bromo-6- fluorobenzonitrile (1.23 g, 3.16 mmol), cyclopropyl magnesium bromide (1.0 M in THF, 10.5 ml, 10.5 S18

mmol) and Cu(OAc) 2 (0.12 g, 0.63 mmol) in DMSO (20 g) to afford the 1H-indazole (1.01 g, 73.8% yield) as yellow oil. 1 H NMR (400 MHz, CDCl 3 ): δ 7.35 (s, 1H), 7.28-7.18 (m, 3H), 7.13-7.06 (m, 2H), 6.86 (d, J = 9.8 Hz, 1H), 4.66 (td, J = 8.2, 5.7 Hz, 1H), 4.40 (d, J = 11.9 Hz, 1H), 4.28 (d, J = 11.8 Hz, 1H), 4.25-4.20 (m, 1H), 2.38-2.26 (m, 1H), 2.15 (dt, J = 13.9, 7.3 Hz, 3H), 1.86 (ddd, J = 29.6, 10.1, 5.6 Hz, 3H), 1.06-0.91 (m, 4H); 13 C NMR (100 MHz, CDCl 3 ): δ 156.18 (d, J = 256.2 Hz), 145.76 (d, J = 4.3 Hz), 143.91 (d, J = 10.4 Hz), 138.20, 128.40, 127.66, 127.58, 119.66 (d, J = 9.5 Hz), 112.21 (d, J = 21.3 Hz), 108.75, 108.61 (d, J = 19.7 Hz), 84.43, 71.81, 65.16, 30.62, 29.61, 21.75, 9.05 (d, J = 2.1 Hz), 8.49, 8.34. HRMS (ESI): calcd. for C 22 H 23 BrFN 2 O [M+H] + : 429.0978, found: 429.0975. References (1) Bergman, J.; Brynolf, A.; Vuorinen, E. Tetrahedron 1986, 42, 3689. (2) Chen, Y. K.; Kanouni, T.; Nie, Z.; Stafford, J. A.; Veal, J. M.; Wallace, M. B. WO 2014/100818 A1, 2014. (3) Cran, J. W.; Vidhani, D. V.; Krafft, M. E. Syn. Lett. 2014, 25, 1550. (4) Huang, K. H.; Ommen, A. J.; Barta, T. E.; Hughes, P. E.; Veal, J. M.; Ma, W.; Smith, E. D.; Woodward, A. R.; Mccall, W. S. WO 2008/130879 A2, 2008. (5) Dong, J.; Wu, Z.; Liu, Z.; Liu, P.; Sun, P. J. Org. Chem. 2015, 80, 12588. (6) Markina, N. A.; Dubrovskiy, A. V.; Larock, R.C. Org. Biomol. Chem. 2012, 10, 2409. (7) Ye, M.; Edmunds, A. J. F.; Morris, J. A.; Sale, D.; Zhang, Y.; Yu, J.-Q. Chem. Sci. 2013, 4, 2374. (8) Ali, B.-Y.; Mohammed, N.; Said, E. K.; Mokhtar, E. E.; Gerald, G. Eur. J. Org. Chem. 2012, 36, 7075. S19

(9) Vina, D.; Del Olmo, E.; Lopez-Perez, J. L.; Feliciano, A. S. Org. Lett. 2007, 9, 525. (10) Spiteri, C.; Keeling, S.; Moses, J. E. Org. Lett. 2010, 12, 3368. (11) Wray, B. C.; Stambuli, J. P. Org. Lett. 2010, 12, 4576. (12) Li, P.; Zhao, J.; Wu, C.; Larock, R. C; Shi, F. Org. Lett. 2011, 13, 3340. (13) Duefert, M. A.; Billingsley, K. L; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 12877. S20