Process for preparing BTK inhibitors

A method of preparing compound 200, or a salt thereof,

• the method comprising:
• (i) (1) forming a first reaction mixture comprising compound 170, compound 181, a palladium catalyst, a solvent system comprising water, and a base, wherein the ratio of solvent volume to compound 170 weight in the reaction mixture is less than 20:1 liters per kg, the equivalent ratio of compound 181 to compound 170 is greater than 1:1, and the equivalent ratio of the palladium catalyst to compound 170 is from about 0.005:1 to about 0.05:1,
• (2) reacting the first reaction mixture to form a first reaction product mixture comprising compound 190 according to the following scheme:
• and
• (3) isolating compound 190 from the first reaction product mixture;
• and
• (ii) (1) forming a second reaction mixture comprising compound 190, a reducing agent, a base and a solvent, (2) reacting the second reaction mixture to reduce the aldehyde moiety of compound 190 and form a second reaction product mixture comprising compound 200, or salt thereof, and (3) isolating compound 200, or salt thereof, from the second reaction product mixture,
• wherein the yield of compound 190 is at least 60% based on compound 170, and the yield of compound 200 or salt thereof is at least 60% based on compound 190.