potassium carbonate in N,N-dimethyl-formamide T=90 - 92°C; 1 h; Inert atmosphere;

1: [14C]-Ambrisentan With potassium carbonate in acetone 0.5 h; 2: methyl iodide in acetone 3 h;

in tetrahydrofuran; methanol; hexane T=20°C; 0.5 h;

1.1: toluene-4-sulfonic acid / 48 h / 25 - 35 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 0.67 h / 25 - 35 °C 2.2: 4 h / 90 - 95 °C View Scheme

1.1: sodium hydroxide; water / 2 h / 95 - 100 °C 1.2: 40 - 45 °C / pH 1.3 2.1: sodium methylate; (S)-2-carbomethoxypyrrolidine hydrochloride / tert-butyl methyl ether; methanol / 1.25 h / 25 - 60 °C / Reflux 3.1: toluene-4-sulfonic acid / 48 h / 25 - 35 °C 4.1: potassium carbonate / N,N-dimethyl-formamide / 0.67 h / 25 - 35 °C 4.2: 4 h / 90 - 95 °C View Scheme

1.1: sodium methylate; (S)-2-carbomethoxypyrrolidine hydrochloride / tert-butyl methyl ether; methanol / 1.25 h / 25 - 60 °C / Reflux 2.1: toluene-4-sulfonic acid / 48 h / 25 - 35 °C 3.1: potassium carbonate / N,N-dimethyl-formamide / 0.67 h / 25 - 35 °C 3.2: 4 h / 90 - 95 °C View Scheme

1.1: sodium methylate / tetrahydrofuran / 2 h / -10 - -4 °C 1.2: 2.75 h / 0 - 35 °C 2.1: sodium hydroxide; water / 2 h / 95 - 100 °C 2.2: 40 - 45 °C / pH 1.3 3.1: sodium methylate; (S)-2-carbomethoxypyrrolidine hydrochloride / tert-butyl methyl ether; methanol / 1.25 h / 25 - 60 °C / Reflux 4.1: toluene-4-sulfonic acid / 48 h / 25 - 35 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 0.67 h / 25 - 35 °C 5.2: 4 h / 90 - 95 °C View Scheme

1.1: potassium carbonate / N,N-dimethyl-formamide / 0.5 h / 20 °C 1.2: 15 h / 20 - 90 °C 2.1: water; sodium hydroxide / 1,4-dioxane / 20 - 90 °C 2.2: pH Ca. 1 3.1: tetrahydrofuran; methanol; hexane / 0.5 h / 20 °C View Scheme

1: magnesium sulfate; NADP; keto-reductase enzyme KRED-P1-B12; potassium phosphate / water; dimethyl sulfoxide; isopropyl alcohol / 25 - 30 °C / |Enzymatic reaction 2: potassium carbonate / N,N-dimethyl-formamide / 1 h / 90 - 92 °C / |Inert atmosphere View Scheme