Methods of manufacturing a bifunctional compound

A method comprising reductively aminating Intermediate I-9:

• with salt Intermediate I-8:
• a base, and a reducing agent in a solvent to provide Compound 1:
• wherein Intermediate I-9 is prepared by a method comprising mixing Intermediate I-6:
• and an acid in a solvent to provide Intermediate I-9:
• wherein Intermediate I-6 is prepared by a method comprising
• (a) combining racemic Intermediate I-5:
• with an additive in a solvent to prepare a reaction mixture (“step (a) reaction mixture”);
• (b) heating the step (a) reaction mixture at reflux to prepare a solution (“step (b) solution”), followed by cooling the step (b) solution to a temperature of about 50° C. to about 100° C.;
• (c) combining (R)-proline and water to prepare a solution (“step (c) solution”), wherein the molar ratio of (R)-proline to the total amount of Intermediate I-5 is about 0.40:1 to about 1.00:1;
• (d) adding about 1% to less than about 50% by volume of the step (c) solution to the step (b) solution to prepare a reaction mixture (“step (d) reaction mixture”);
• (e) adding an amount of an agent that induces nucleation to the step (d) reaction mixture to prepare a reaction mixture (“step (e) reaction mixture”);
• (f) adding about 1% to less than about 50% by volume of the step (c) solution to the step (e) reaction mixture to prepare a reaction mixture (“step (f) reaction mixture”);
• (g) adding an amount of the agent that induces nucleation to the step (f) reaction mixture to prepare a reaction mixture (“step (g) reaction mixture”);
• and
• (h) adding the remainder of the step (c) solution to the step (g) reaction mixture to prepare a reaction mixture (“step (h) reaction mixture”) to provide Intermediate I-6:

A method, comprising:

• (a) reacting Intermediate I-2A:
• a hydrogen source, and, optionally, a catalyst, in a solvent to provide Intermediate I-3A:
• (b) reducing Intermediate I-2:
• in a solvent in the presence of a reducing agent to provide Intermediate I-3:
• (c) reacting Intermediate I-3:
• with Intermediate I-3A:
• in a solvent in the presence of a reducing agent to provide Intermediate I-4:
• (d) reacting Intermediate I-4:
• and camphorsulfonic acid in a solvent to provide salt Intermediate I-8:
• and one or more byproducts;
• (e1) combining racemic Intermediate I-5:
• with an additive in a solvent to prepare a reaction mixture (“step (e1) reaction mixture”);
• (e2) heating the step (e1) reaction mixture at reflux to prepare a solution (“step (e2) solution”), followed by cooling the step (e2) solution to a temperature of about 50° C. to about 100° C.;
• (e3) combining (R)-proline and water to prepare a solution (“step (e3) solution”), wherein the molar ratio of (R)-proline to the total amount of Intermediate I-5 is about 0.40:1 to about 1.00:1;
• (e4) adding about 1% to less than about 50% by volume of the step (e3) solution to the step (e2) solution to prepare a reaction mixture (“step (e4) reaction mixture”);
• (e5) adding an amount of an agent that induces nucleation to the step (e4) reaction mixture to prepare a reaction mixture (“step (e5) reaction mixture”);
• (e6) adding about 1% to less than about 50% by volume of the step (e5) solution to the step (e5) reaction mixture to prepare a reaction mixture (“step (e6) reaction mixture”);
• (e7) adding an amount of the agent that induces nucleation to the step (e6) reaction mixture to prepare a reaction mixture (“step (e7) reaction mixture”);
• and
• (e8) adding the remainder of the step (e3) solution to the step (e7) reaction mixture to prepare a reaction mixture (“step (e8) reaction mixture”) to provide Intermediate I-6:
• (h) reacting Intermediate I-6:
• with an acid to provide Intermediate I-9:
• (i) reductively aminating Intermediate I-9:
• with salt Intermediate I-8:
• in the presence of a base and a reducing agent to provide Compound 1: