General Procedures

5.2.1 General Procedure A: synthesis of phenoxypyridines 73

A suspension of phenol (1.2 equiv), 2-bromopyridine (1.0 equiv), CuI (10 mol %), 2-picolinic acid (20 mol %) and K3PO4 (2.0 equiv) in DMSO (0.5 M) was stirred overnight at 90 °C under N2. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc (50 mL) and H2O (50 mL) and stirred for 30 minutes at ambient temperature. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with a NH4Cl / NH3 (v/v: 1/1) solution (3 x 50 mL), then with a aqueous NaOH solution (2N, 50 mL) and finally with brine (50 mL). The extracts were dried over Na2SO4, filtered and evaporated in vacuo. The remaining residue was purified by column chromatography on silica gel (n-hexane/EtOAc).

5.2.2 General Procedure B: Ruthenium-catalyzed direct arylations of phenoxypyridines 73 with aryl bromides 18 or aryl chlorides 28

A suspension of phenoxypyridine 73 (3.0 equiv), aryl bromide 18 or aryl chloride 28 (1.0 equiv), [RuCl2(p-cymene)]2 (2.5-5.0 mol %), MesCO2H (30 mol %) and K2CO3 (2.0 equiv) in PhMe (2.0 mL) was stirred at 120 °C for 20 h under N2. At ambient temperature, the reaction mixture was diluted with EtOAc (50 mL) and H2O (50 mL). The aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The remaining residue was purified by column chromatography on silica gel (n-hexane/EtOAc).

5.2.3 General Procedure C1: Synthesis of substituted phenyltetrazoles 60 from benzoic acids 103 To a solution of benzoic acid 103 (1.0 equiv) in CH2Cl2 (1.2 M) and N,N-Dimethylformamide (0.2 equiv), was added oxalylchloride (1.1 equiv) at 0 °C dropwise. The reaction mixture was stirred further at 0 °C until the gas evolution disappeared, then for one more hour at ambient temperature.

The reaction mixture was afterwards concentrated at ambient temperature in vacuo. To remove the excess of oxalylchloride, CH2Cl2 (5 mL) was added and evaporated again at ambient temperature. This operation was repeated three times. The crude acid chloride was used directly, without any further purification.

The crude acid chloride (1.0 equiv) 104 was dissolved in CH2Cl2 (1.0 M), and then added to a solution of benzylamine 105 (1.0 equiv), NEt3 (1.0 equiv) in CH2Cl2 (2.0 M) at 0 °C. The reaction mixture was allowed to warm up to 20°C and stirred under N2 till the TLC control showed complete consumption of one of the starting materials or no further evolution of the reaction. The reaction mixture was diluted with H2O (50 mL) and CH2Cl2 (50 mL). The organic phase was separated, the aqueous phase was extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. After filtration and evaporation of the solvents in vacuo, the benzamide was obtained and was used without further purification (purity was more than 95% by ¹H-NMR).

To a solution of benzamide 106 (1.0 equiv) in CH2Cl2 (0.5 M) was added PCl5 (1.2 equiv) portionwise, at a temperature below -18 °C. The reaction mixture was allowed to warm up and stirred at ambient temperature for 1 h. Then TMSN3 (1.7 equiv) was added at a rate, so that the temperature remained under -15 °C. The reaction mixture was allowed to warm up, and stirred at ambient temperature overnight. To the reaction mixture was added an aqueous saturated NaHCO3 solution (200 mL) dropwise. The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were washed with brine and dried over MgSO4. After filtration and evaporation of the solvents in vacuo, the crude reaction mixture was purified by column chromatography on silica gel (n-hexane/EtOAc) to yield the tetrazoles 60.

5.2.4 General Procedure C2: Synthesis of substituted phenyltetrazoles 60 from acid chlorides 104 To a solution of benzylamine 105 (1.0 equiv), NEt3 (1.0 equiv) in CH2Cl2 (0.67 M) was added dropwise benzoylchloride (104a) (1.0 equiv) at a temperature below 16 °C. The reaction mixture was allowed to warm up and stirred under N2 at 20 °C until the TLC control showed complete consumption of one of the two starting materials or no further evolution of the reaction. The reaction mixture was diluted with H2O (50 mL) and CH2Cl2 (50 mL). The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. After filtration and evaporation of the solvents in vacuo, the benzamide was obtained and was used without further purification (purity was superior to 95% by

1H-NMR).

To a solution of benzamide 106 (1.0 equiv) in CH2Cl2 (0.5 M) was added PCl5 (1.2 equiv) portionwise, at a temperature below -18 °C. The reaction mixture was allowed to warm up and stirred at ambient temperature for 1 h. Then TMSN3 (1.7 equiv) was added at a rate, so that the temperature remained under -15 °C. The reaction mixture was allowed to warm up, and stirred at ambient temperature

overnight. To the reaction mixture was added an aqueous saturated NaHCO3 solution (200 mL) dropwise. The organic phase was separated and the aqueous phase was extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were washed with brine and dried over MgSO4. After filtration and evaporation of the solvents in vacuo, the crude reaction mixture was purified by column chromatography on silica gel (n-hexane/EtOAc) to yield the tetrazoles.

5.2.5 General Procedure D1: Ruthenium-catalyzed direct arylation of phenyltetrazoles 60

A mixture of tetrazole 60 (1.00 equiv), arylbromide 18 (1.05 equiv), [RuCl2(p-cymene)]2 (5.0 mol %), MesCO2H (30 mol %) and K2CO3 (2.00 equiv) in PhMe (2.0 mL) was stirred at 120 °C for 18 h under N2. At ambient temperature, the reaction mixture was diluted with CH2Cl2 (50 mL) and water (50 mL).

The aqueous phase was extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The remaining residue was purified by column chromatography on silica gel (n-hexane/EtOAc).

5.2.6 General Procedure D2: Ruthenium-catalyzed direct arylation of phenyltetrazoles 60 with KOAc as a base

A mixture of tetrazole 60 (1.00 equiv), arylbromide 18 (1.05 equiv), [RuCl2(p-cymene)]2 (5.0 mol %), and KOAc (2.00 equiv) in PhMe (2.0 mL) was stirred at 120 °C for 18 h under N2. At ambient temperature, the reaction mixture was diluted with CH2Cl2 (50 mL) and water (50 mL). The aqueous phase was extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The remaining residue was purified by column chromatography on silica gel (n-hexane/EtOAc).

5.2.7 General Procedure E1: Copper-catalyzed synthesis of benzyltriazoles and alkyltriazoles 109 Alkyl/benzylbromide (1.0 equiv) was added to a solution of sodium azide (1.0 equiv) in degassed DMSO (0.5 M). The reaction mixture was stirred overnight at ambient temperature. Degassed water (2xVDMSO) was then added, followed by Cu(SO4)2.

5H2O (20 mol %), sodium ascorbate (10 mol %) and finally the alkyne (1.0 equiv). After an exothermic reaction, the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was then diluted with an aqueous solution of NH3/NH4Cl (1/1, v/v) and EtOAc. The aqueous phase was extracted with EtOAc. The gathered organic phases were washed with NH3/NH4Cl (1/1, v/v), until disappearance of the blue color, brine, dried over Na2SO4, and finally evaporated in vacuo. Purity was checked with ¹H-NMR spectroscopy and the product was used without further purification.

5.2.8 General Procedure E2: Copper catalyzed synthesis of phenyltriazoles 109c-d

A mixture of aryl iodide (1.00 equiv), NaN3 (1.05 equiv), sodium ascorbate (10.0 mol %), CuI (10.0 mol

%), alkyne (1.00 equiv) in a mixture of degassed DMSO and H2O (0.3 M, 5/1, v/v) was stirred at ambient temperature. DMEDA (15.0 mol %), was then added at ambient temperature. The reaction mixture was further stirred at ambient temperature overnight, and afterwards diluted with an

aqueous solution of NH3/NH4Cl (1/1, v/v) and EtOAc. The aqueous phase was extracted with EtOAc.

The gathered organic phases were washed with NH3/NH4Cl (1/1, v/v) until disappearance of the blue color, brine, dried over Na2SO4 and finally evaporated in vacuo. Purity was checked with ¹H-NMR and the product was used without further purification.

5.2.9 General Procedure F1: Synthesis of benzamides 78 from acid chlorides 104

The acid chloride 104 was added at 0 °C to a solution of amine (1.0 equiv) and NEt3 (1.0 equiv) in CH2Cl2 (1.0 M). The reaction mixture was allowed to warm up to ambient temperature and stirred under N2 overnight. The reaction mixture was diluted with water and EtOAc. The organic phase was separated, the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. After filtration and evaporation of the solvents in vacuo, the residue was purified either by column chromatography on silica gel or by recrystallization.

5.2.10 General Procedure F2: Synthesis of benzamides 78 from the acids 103

To a solution of benzoic acid 103 (1.0 equiv) in CH2Cl2 (1.2 M) and N,N-Dimethylformamide (0.2 equiv), was added oxalylchloride (1.1 equiv) at 0 °C dropwise. The reaction mixture was stirred further at 0 °C until the gas evolution disappeared, then for one more hour at ambient temperature.

The reaction mixture was afterwards concentrated at ambient temperature in vacuo. To remove the excess of oxalylchloride, CH2Cl2 (5 mL) was added and evaporated again at ambient temperature. This operation was repeated three times. The crude acid chloride was used directly, without any further purification.

The crude acid chloride 104 was dissolved in CH2Cl2 (1.0 M), and then added at 0 °C to a solution of amine (1.0 equiv), and NEt3 (1.0 equiv) in CH2Cl2 (2.0 M). The reaction mixture was allowed to warm up to ambient temperature and stirred under N2 overnight. The reaction mixture was diluted with H2O (50 mL) and EtOAc (50 mL). The organic phase was separated, and the aqueous phase was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over Na2SO4. After filtration and evaporation of the solvents in vacuo, the residue was purified either by column chromatography on silica gel or by recrystallization.

5.2.11 General Procedure G: Ruthenium-catalyzed direct arylation of benzamides 78.

A mixture of benzamide 78 (1.00 equiv), arylbromide 18 (1.05 equiv), [RuCl2(PPh3)3] (2.5 mol %) Na2CO3 (1.50 equiv) and o-xylene (2.0 mL) was stirred at 120 °C for 22 h under N2. At ambient temperature, the reaction mixture was diluted with CH2Cl2 (50 mL) and saturated aqueous NaHCO3

(50 mL). The aqueous phase was extracted with CH2Cl2 (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The remaining residue was purified by column chromatography on silica gel (n-hexane/EtOAc).