PMC

Reagents and conditions: (i) 10% DMF in PBS buffer pH 7.5, overnight, 80%.

(a) Synthesis sequence for the preparation of building blocks 4 and 5; (b) Retrosynthetic analysis for the preparation of 1.

Reagents and conditions. (i) TMSOTf, DCM, −10 °C, 80%; (ii) NaOMe, MeOH; then KOH, MeOH, 60 °C; then Pd/C, H₂, AcOH, MeOH, THF, H₂O, rt, 76% over three steps.

Reagents and conditions: (i) PhI(OAc)_2, BF₃·Et₂O, CH₂Cl_2, −40 °C; then Ac₂O, pyridine; (ii) N₂H₄·AcOH, DMF; (iii) CF₃C(NPh)Cl, Cs₂CO₃, CH₂Cl₂, DCM, 66% over three steps for 4 (for a detailed description of the synthesis of compound 4 see the supporting information of []); 62% over three steps for 5.

Automated synthesis of 16. Reagents and conditions: (i) (a) NIS, TfOH, dioxane, DCM, −40 to −20 °C, 40 min; (b) piperidine, DMF. (ii) (a) TMSOTf, DCM, 0 °C, 2 h; (b) piperidine, DMF. (iii) NaOMe, MeOH, DCM, 1.5 h. (iv) KOH, MeOH, H₂O, THF, 60 °C, 40%. (v) Pd/C, H₂, MeOH/H₂O, cat. AcOH, 91% (for experimental details see the supporting information of []).

Automated synthesis of 20. Reagents and conditions: (i) (a) NIS, TfOH, dioxane, DCM, −40 to −20 °C, 40 min; (b) piperidine, DMF. (ii) (a) TMSOTf, DCM, 0 °C, 2 h; (b) piperidine, DMF. (iii) AIBN (cat.), Bu₃SnH (10 equiv), xylene, 90 °C. (iv) NaOMe, MeOH, DCM, 1.5 h, 33%. (v) Pd/C, H₂, MeOH/H₂O, cat. AcOH, 78% (for experimental details see the supporting information of []).

Automated synthesis of 30. Reagents and conditions: (i) (a) NIS, TfOH, dioxane, DCM, −40 to −20 °C, 40 min; (b) piperidine, DMF. (ii) NIS, TfOH, dioxane, DCM, −40 to −20 °C, 40 min. (iii) TMSOTf, Et₂O, 0 °C, 2 h. (iv) AIBN (cat.), Bu₃SnH (10 equiv), xylene, 90 °C. (v) NaOMe, MeOH, DCM, 1.5 h. (vi) KOH, MeOH, H₂O, THF, 60 °C, 16%. (vii) Pd/C, MeOH/H₂O/EtOAc, cat. AcOH, 51%.

Automated synthesis of 27. Reagents and conditions: (i) (a) NIS, TfOH, dioxane, DCM, −40 to −20 °C, 40 min; (b) piperidine, DMF. (ii) (a) TMSOTf, DCM, 0 °C, 2 h; (b) NH₂NH₂·H₂O, AcOH, pyridine, DCM. (iii with 24) TMSOTf, Et₂O, −10 °C, 1 h. (iii with 25) NIS, TfOH, dioxane, DCM, −40 °C to −20 °C, 40 min. (iv) AIBN (cat.), Bu₃SnH (10 equiv), xylene, 90 °C. (v) NaOMe, MeOH, DCM, 1.5 h. (vi) KOH, MeOH, H₂O, THF, 60 °C, 51%. (vii) Pd/C, H₂, MeOH/H₂O, cat. AcOH, 30% (for experimental details see the supporting information of []).