1.1: toluene / 6.67 h / 90 °C / Industry scale 2.1: hydrogen / palladium 10 on activated carbon / toluene; methanol / 20 - 27 °C / 3102.97 Torr / Industry scale 2.2: 20 °C / pH 6.3 / Industry scale View Scheme

1: With hydrogenchloride; water in methanol 2: With sodium hydroxide; ethylenediamine in methanol; water pH=10; 0.5 h;

sodium hydroxide; water; ethylenediamine in methanol pH=10;

1.1: potassium carbonate / potassium iodide / isobutyramide / 60 - 90 °C / Industry scale 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 20.5 h / -50 - 20 °C / Industry scale 2.2: 15 °C / Industry scale 3.1: thionyl chloride / acetonitrile / 5 - 18 °C / Industry scale 4.1: potassium hydroxide / toluene; water / 0.33 h / 12.5 °C / Industry scale; Inert atmosphere 4.2: 1.65 h / 12.5 - 14.6 °C / Industry scale; Inert atmosphere 5.1: (9R)-1-[3,5-bis(trifluoromethyl)benzyl]cinchonan-1-ium-9-ol bromide / toluene; water / 16 h / 10 °C / Industry scale; Inert atmosphere 6.1: toluene / 6.67 h / 90 °C / Industry scale 7.1: hydrogen / palladium 10 on activated carbon / toluene; methanol / 20 - 27 °C / 3102.97 Torr / Industry scale 7.2: 20 °C / pH 6.3 / Industry scale View Scheme

1.1: methanesulfonic acid / 16 h / 80 °C / Inert atmosphere; Industry scale 2.1: hydrogen / palladium 10 on activated carbon / methanol / 40 °C / 3102.97 Torr / Industry scale 3.1: potassium carbonate / potassium iodide / isobutyramide / 60 - 90 °C / Industry scale 4.1: lithium aluminium tetrahydride / tetrahydrofuran / 20.5 h / -50 - 20 °C / Industry scale 4.2: 15 °C / Industry scale 5.1: thionyl chloride / acetonitrile / 5 - 18 °C / Industry scale 6.1: potassium hydroxide / toluene; water / 0.33 h / 12.5 °C / Industry scale; Inert atmosphere 6.2: 1.65 h / 12.5 - 14.6 °C / Industry scale; Inert atmosphere 7.1: (9R)-1-[3,5-bis(trifluoromethyl)benzyl]cinchonan-1-ium-9-ol bromide / toluene; water / 16 h / 10 °C / Industry scale; Inert atmosphere 8.1: toluene / 6.67 h / 90 °C / Industry scale 9.1: hydrogen / palladium 10 on activated carbon / toluene; methanol / 20 - 27 °C / 3102.97 Torr / Industry scale 9.2: 20 °C / pH 6.3 / Industry scale View Scheme

1.1: sodium t-butanolate / 2,2'-bis-(diphenylphosphino)-1,1'- binaphthyl; tris-(dibenzylideneacetone)dipalladium(0) / toluene / 20 - 90 °C / Industry scale; Inert atmosphere 2.1: n-hexyl lithium / hexane; tetrahydrofuran / 1.08 h / -10 - -5 °C / Industry scale; Inert atmosphere 2.2: 14.2 - 20 °C / Industry scale; Inert atmosphere 3.1: n-hexyl lithium / hexane; tetrahydrofuran / 0.5 h / -25 - -15 °C / Industry scale; Inert atmosphere 3.2: -20 - 15 °C / Industry scale; Inert atmosphere 4.1: hexane; tetrahydrofuran / 1.08 h / 0 - 13 °C / Industry scale; Inert atmosphere 4.2: 2 h / 20 °C / pH 3.88 - 4.28 / Industry scale 5.1: potassium hydroxide / toluene; water / 0.33 h / 12.5 °C / Industry scale; Inert atmosphere 5.2: 1.65 h / 12.5 - 14.6 °C / Industry scale; Inert atmosphere 6.1: (9R)-1-[3,5-bis(trifluoromethyl)benzyl]cinchonan-1-ium-9-ol bromide / toluene; water / 16 h / 10 °C / Industry scale; Inert atmosphere 7.1: toluene / 6.67 h / 90 °C / Industry scale 8.1: hydrogen / palladium 10 on activated carbon / toluene; methanol / 20 - 27 °C / 3102.97 Torr / Industry scale 8.2: 20 °C / pH 6.3 / Industry scale View Scheme

1.1: lithium aluminium tetrahydride / tetrahydrofuran / 20.5 h / -50 - 20 °C / Industry scale 1.2: 15 °C / Industry scale 2.1: thionyl chloride / acetonitrile / 5 - 18 °C / Industry scale 3.1: potassium hydroxide / toluene; water / 0.33 h / 12.5 °C / Industry scale; Inert atmosphere 3.2: 1.65 h / 12.5 - 14.6 °C / Industry scale; Inert atmosphere 4.1: (9R)-1-[3,5-bis(trifluoromethyl)benzyl]cinchonan-1-ium-9-ol bromide / toluene; water / 16 h / 10 °C / Industry scale; Inert atmosphere 5.1: toluene / 6.67 h / 90 °C / Industry scale 6.1: hydrogen / palladium 10 on activated carbon / toluene; methanol / 20 - 27 °C / 3102.97 Torr / Industry scale 6.2: 20 °C / pH 6.3 / Industry scale View Scheme

1.1: thionyl chloride / acetonitrile / 5 - 18 °C / Industry scale 2.1: potassium hydroxide / toluene; water / 0.33 h / 12.5 °C / Industry scale; Inert atmosphere 2.2: 1.65 h / 12.5 - 14.6 °C / Industry scale; Inert atmosphere 3.1: (9R)-1-[3,5-bis(trifluoromethyl)benzyl]cinchonan-1-ium-9-ol bromide / toluene; water / 16 h / 10 °C / Industry scale; Inert atmosphere 4.1: toluene / 6.67 h / 90 °C / Industry scale 5.1: hydrogen / palladium 10 on activated carbon / toluene; methanol / 20 - 27 °C / 3102.97 Torr / Industry scale 5.2: 20 °C / pH 6.3 / Industry scale View Scheme

1.1: n-hexyl lithium / hexane; tetrahydrofuran / 1.08 h / -10 - -5 °C / Industry scale; Inert atmosphere 1.2: 14.2 - 20 °C / Industry scale; Inert atmosphere 2.1: n-hexyl lithium / hexane; tetrahydrofuran / 0.5 h / -25 - -15 °C / Industry scale; Inert atmosphere 2.2: -20 - 15 °C / Industry scale; Inert atmosphere 3.1: hexane; tetrahydrofuran / 1.08 h / 0 - 13 °C / Industry scale; Inert atmosphere 3.2: 2 h / 20 °C / pH 3.88 - 4.28 / Industry scale 4.1: potassium hydroxide / toluene; water / 0.33 h / 12.5 °C / Industry scale; Inert atmosphere 4.2: 1.65 h / 12.5 - 14.6 °C / Industry scale; Inert atmosphere 5.1: (9R)-1-[3,5-bis(trifluoromethyl)benzyl]cinchonan-1-ium-9-ol bromide / toluene; water / 16 h / 10 °C / Industry scale; Inert atmosphere 6.1: toluene / 6.67 h / 90 °C / Industry scale 7.1: hydrogen / palladium 10 on activated carbon / toluene; methanol / 20 - 27 °C / 3102.97 Torr / Industry scale 7.2: 20 °C / pH 6.3 / Industry scale View Scheme

1.1: potassium hydroxide / toluene; water / 0.33 h / 12.5 °C / Industry scale; Inert atmosphere 1.2: 1.65 h / 12.5 - 14.6 °C / Industry scale; Inert atmosphere 2.1: (9R)-1-[3,5-bis(trifluoromethyl)benzyl]cinchonan-1-ium-9-ol bromide / toluene; water / 16 h / 10 °C / Industry scale; Inert atmosphere 3.1: toluene / 6.67 h / 90 °C / Industry scale 4.1: hydrogen / palladium 10 on activated carbon / toluene; methanol / 20 - 27 °C / 3102.97 Torr / Industry scale 4.2: 20 °C / pH 6.3 / Industry scale View Scheme