General Procedures

5.2.1 General Procedure A: Ruthenium-Catalyzed meta-Selective Bromination

A microwave vial was charged with purine 123 or heteroarene 68, 139, 147 (0.30 mmol), NBS (62, 107 mg, 0.60 mmol) and 152 (0.14 mmol[Ru]/g, 214 mg, 10 mol %) in DMA (0.6 mL) and the mixture was stirred open to air at 80–100 °C. After 20 h, the resulting mixture was filtered and washed with CH2Cl2 (20 mL). The filtrate was concentrated in vacuo. Purification of the residue by column chromatography (SiO2, n-hexane/EtOAc) yielded meta-brominated products 133 or 153.

5.2.2 General Procedure B: Ruthenium(II)-Catalyzed Remote meta-C–H Alkylations of Ketimines using 1-AdCO

H as the Ligand

Ketimine 135 (0.50 mmol), [RuCl2(p-cymene)]2 (15.3 mg, 25.0 μmol, 5.0 mol %), 1-AdCO2H (12, 27.3 mg, 0.15 mmol, 30 mol %) and K2CO3 (138 mg, 1.00 mmol) were placed in a pre-dried 25 mL pressure tube. The tube was evacuated and purged with N2 for three times. Alkyl bromide 136 (1.50 mmol) and PhCMe3 (2.0 mL) were then added and the mixture was stirred at 120 °C for 20 h.

At ambient temperature, HCl (2 N, 3.0 mL) was added, and the resulting mixture was stirred for an additional 3 h, and then extracted with EtOAc or Et2O (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification of the residue by column chromatography (SiO2, n-hexane/EtOAc or n-pentane/Et2O) yielded phenone 154.

5.2 General Procedures

5.2.3 General Procedure C: Ruthenium(II)-Catalyzed Remote meta-C–H Alkylations of Ketimines using Piv-Ile-OH as the Ligand

Ketimine 135 (0.50 mmol), [RuCl2(p-cymene)]2 (15.3 mg, 25.0 μmol, 5.0 mol %), Piv-Ile-OH (155, 32.3 mg, 0.15 mmol, 30 mol %) and K2CO3 (138 mg, 1.00 mmol) were placed in a pre-dried 25 mL pressure tube. The tube was evacuated and purged with N2 for three times. Alkyl bromide 136 (1.50 mmol) and PhCMe3 (2.0 mL) were then added and the mixture was stirred at 120 °C for 20 h.

At ambient temperature, HCl (2 N, 3.0 mL) was added, and the resulting mixture was stirred for an additional 3 h, and then extracted with EtOAc or Et2O (3 × 20 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification of the residue by column chromatography (SiO2, n-hexane/EtOAc or n-pentane/Et2O) yielded phenone 154.

5.2.4 General Procedure D: Ruthenium(II)-Catalyzed Remote meta-C–H Alkylations of Ketimines Followed by Reduction in One-Pot Fashion

Ketimine 135 (0.50 mmol), [RuCl2(p-cymene)]2 (15.3 mg, 25.0 μmol, 5.0 mol %), 1-AdCO2H (12, 27.3 mg, 0.15 mmol, 30 mol %) and K2CO3 (138 mg, 1.00 mmol) were placed in a pre-dried 25 mL pressure tube. The tube was evacuated and purged with N2 for three times. Alkyl bromide 136 (1.50 mmol) and PhCMe3 (2.0 mL) were then added and the mixture was stirred at 120 °C for 20 h.

Then, a solution of ZnCl2 in THF (1.0 M, 0.50 mmol), NaBH3CN (63.5 mg, 2.00 mmol) and MeOH (1.5 mL) were successively added to the reaction mixture at ambient temperature. The reaction mixture was stirred at ambient temperature for 16 h and then distributed between Et2O (8 mL) and sat. aq. K2CO3 (8 mL). The aqueous phase was extracted with Et2O (2 × 10 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (SiO2, n-hexane/EtOAc) yielded 157.

5.2.5 General Procedure E: Ruthenium(II)-Catalyzed Remote meta-C–H Alkylations using PPh

as the Ligand

Heteroarene 68b, 123a, 139, or 147 (0.50 mmol), [Ru(O2CAd)2(p-cymene)] (163, 29.7 mg, 50.0 μmol, 10 mol %), PPh3 (13.1 mg, 50.0 μmol, 10 mol %) and K2CO3 (138 mg, 1.00 mmol) were placed in a pre-dried 25 mL Schlenk tube. The tube was evacuated and purged with N2 for three times. Alkyl bromide 140 (1.50 mmol) and 1,4-dioxane (2.0 mL) were then added and the mixture was stirred at 40 °C. After 20 h, the resulting mixture was filtered through a pad of silica gel and

5 Experimental Part

washed with EtOAc. The filtrate was concentrated in vacuo. Purification of the residue by column chromatography (SiO2, n-hexane/EtOAc) yielded meta-alkylated product 141.

5.2.6 General Procedure F: Ruthenium(II)-Catalyzed Sequential meta-Alkylation/ortho-Arylation

Heteroarene 123a or 147 (0.50 mmol), [Ru(O2CAd)2(p-cymene)] (163, 29.7 mg, 50.0 μmol, 10 mol %), PPh3 (13.1 mg, 50.0 μmol, 10 mol %) and K2CO3 (276 mg, 2.00 mmol) were placed in a pre-dried 25 mL Schlenk tube. The tube was evacuated and purged with N2 for three times. Alkyl bromide 140 (1.50 mmol) and 1,4-dioxane (2.0 mL) were then added and the mixture was stirred at 60 °C. After 20 h, bromoarene 165 (1.00 or 1.50 mmol) was added to the reaction mixture at ambient temperature and the mixture was stirred at 120 °C for an additional 20 h. The resulting mixture was filtered through a pad of silica gel and washed with EtOAc. The filtrate was pre-dried 25 mL Schlenk tube. The tube was evacuated and purged with N2 for three times. Alkyl bromide 140a (1.50 mmol), bromoarene 165 (1.50 mmol), and 1,4-dioxane (2.0 mL) were then added and the mixture was stirred at 40 °C. After 18 h, the reaction mixture was stirred at 120 °C for an additional 18 h. Afterwards, the resulting mixture was filtered through a pad of silica gel and washed with EtOAc. The filtrate was concentrated in vacuo. Purification of the residue by column chromatography (SiO2, n-hexane/EtOAc) yielded product 166.

5.2.8 General Procedure H: Photocatalytic Decarboxylation

Carboxylic acid 175 or 178 (0.20 mmol), bis(4-chlorophenyl)disulfide (5.8 mg, 20.0 μmol, 10 mol %), and photocatalyst [Mes-Acr-Me][ClO4] (176, 1.0–4.8 mol %) were placed in 10 mL vial.

The vial was evacuated and purged with N2 for three times. To the reaction mixture was added 2,6-lutidine (5 μL, 40.0 μmol, 20 mol %) and 1,2-DCE (8.0 mL). The mixture was degassed for

5.2 General Procedures 5 min. The reaction mixture was stirred under blue LED irradiation (8 W). After 16 h, the solvent was removed in vacuo. Purification of the residue by column chromatography (SiO2, n-hexane/EtOAc or CH2Cl2/HOAc) yielded product 177 or 179.

5.2.9 General Procedure I: Ruthenium(II)-Catalyzed meta-C–H Benzylation of Heteroarenes

Heteroarene 68, 139 or purine 123 (0.50 mmol), [Ru(OAc)2(p-cymene)] (181, 17.7 mg, 50.0 μmol, 10 mol %), PPh3 (13.1 mg, 50.0 μmol, 10 mol %) and K2CO3 (138 mg, 1.00 mmol) were placed in a pre-dried 25 mL Schlenk tube. The tube was evacuated and purged with N2 three times. Benzyl chloride 142 (1.50 mmol) and 1,4-dioxane (2.0 mL) were then added and the mixture was stirred at 60 °C. After 20 h, the resulting mixture was filtered through a pad of silica gel and washed with EtOAc. The filtrate was concentrated in vacuo. Purification of the residue by column chromatography (SiO2, n-hexane/EtOAc) yielded meta-benzylated product 143 or 185.

5.2.10 General Procedure J: Late-Satge Diversification through Ruthenium(II)-Catalyzed meta-C–H Activation

Purine 123 (0.25 mmol), [Ru(OAc)2(p-cymene)] (181, 8.9 mg, 25.0 μmol, 10 mol %), PPh3 (6.6 mg, 25.0 μmol, 10 mol %) and K2CO3 (69 mg, 1.00 mmol) were placed in a pre-dried 25 mL Schlenk tube. The tube was evacuated and purged with N2 three times. Alkyl halide 186 (0.50 mmol) and 1,4-dioxane (1.0 mL) were then added and the mixture was stirred at 60 °C. After 20 h, the resulting mixture was filtered through a pad of silica gel and washed with EtOAc. The filtrate was concentrated in vacuo. Purification of the residue by column chromatography (SiO2, n-hexane/EtOAc) yielded meta-alkylated product 187.

5.2.11 General Procedure K: Ruthenium(II)-Catalyzed C–C Alkylation of Acids 144

Carboxylic acid 144 (0.50 mmol), [RuCl2(p-cymene)]2 (7.7 mg, 12.5 µmol, 2.5 mol %), MesCO2H (31, 24.6 mg, 0.15 mmol, 30 mol %) and K2CO3 (138 mg, 1.00 mmol) were placed in a pre-dried 25 mL Schlenk tube. The tube was evacuated and purged with N2 three times. Alkyl bromide 136 (1.50 mmol) and o-xylene (1.0 mL) were then added. The Schlenk tube was degassed and filled with N2 three times and the mixture was stirred at 120 °C. After 16 h, the resulting mixture was filtered through a pad of silica gel and washed with EtOAc. The filtrate was concentrated in vacuo.

5 Experimental Part

Purification of the residue by column chromatography (SiO2, n-hexane/EtOAc) yielded alkylated product 145 or 146.

5.2.12 General Procedure L: Ruthenium(II)-Catalyzed C–C Alkylation of Acids 144 using PPh

as the Ligand

Carboxylic acid 144 (0.50 mmol), [RuCl2(p-cymene)]2 (7.7 mg, 12.5 µmol, 2.5 mol %), MesCO2H (31, 24.6 mg, 0.15 mmol, 30 mol %), PPh3 (6.6 mg, 25.0 μmol, 5 mol %) and K2CO3 (138 mg, 1.00 mmol) were placed in a pre-dried 25 mL Schlenk tube. The tube was evacuated and purged with N2 three times. Alkyl bromide 140 or benzyl chloride 142 (1.50 mmol) and PhCMe3 (1.0 mL) were then added. The Schlenk tube was degassed and filled with N2 three times and the mixture was stirred at 120 °C. After 16 h, the resulting mixture was filtered through a pad of silica gel and washed with EtOAc. The filtrate was concentrated in vacuo. Purification of the residue by column chromatography (SiO2, n-hexane/EtOAc) yielded meta-alkylated product 141g or 202.

5.2.13 General Procedure M: Ruthenium-Catalyzed C–H Alkylations of Pyrazoles

Pyrazole 147 (0.50 mmol), [RuCl2(p-cymene)]2 (7.7 mg, 12.5 µmol, 2.5 mol %), MesCO2H (31, 24.6 mg, 0.15 mmol, 30 mol %) and K2CO3 (138 mg, 1.00 mmol) were placed in a pre-dried 25 mL Schlenk tube. The tube was evacuated and purged with N2 three times. Alkyl bromide 136 (0.75–

1.50 mmol) and PhCMe3 (1.0 mL) were then added and the mixture was stirred at 120 °C. After 16 h, the resulting mixture was filtered through a pad of silica gel and washed with EtOAc. The filtrate was concentrated in vacuo. Purification of the residue by column chromatography (SiO2, n-hexane/EtOAc) yielded alkylated product 145 or 146.

5.2.14 General Procedure N: Photo-Induced Ruthenium-Catalyzed C–H Arylations at Room Temperature

Heteroarene 68, 123, 139, or 147 (0.50 mmol), [Ru(OAc)2(p-cymene)] (181, 17.7 mg, 50.0 μmol, 10 mol %) and K2CO3 (138 mg, 1.00 mmol) were placed in a 10 mL vial. The vial was capped with a septum and wrapped with parafilm. The vial was evacuated and purged with N2 three times. Aryl iodide 46 (0.75 mmol) and 1,4-dioxane (2.0 mL) were then added and the mixture was stirred under visible light irradiation (2 × Kessil A360N, temperature was maintained between 30 °C and 35 °C). After 24 h, the resulting mixture was filtered through a pad of silica gel and washed with

5.3 Experimental Procedures and Analytical Data