Process toward the manufacture of (6r,10s)-10-{4-[5-chloro-2-(4-chloro-1h-1,2,3-triazol-1-yl)phenyl]-6-oxo-1(6h)-pyrimidinyl}- 1-(difluoromethyl)-6-methyl-1,4,7,8,9,10-hexahydro-11,15-(metheno)pyrazolo[4,3-b][1,7]diazacyclotetradecin-5(6h)-one

A process for preparing a compound represented by:

• comprising:
• (a) reacting Compound 17 having the structure:
• with Compound 18 having the structure:
• (b) subsequently adding a non-nucleophilic base followed by trimethylsilane chloride to afford the bis-hydrochloride salt of Compound 20 having the structure:
• (c) reacting Compound 20 with a carbamate protecting group (PG) agent followed by propionic anhydride then a non-nucleophilic base to afford Compound 21 having the structure:
• (d) reacting Compound 21 with a non-nucleophilic base to afford Compound 22 have the structure:
• (e) reacting Compound 22 with a metal hydrogenation catalyst to afford Compound 23 having the structure:
• (f) reacting Compound 23 with 1-(difluoromethyl)-4-nitro-1H-pyrazole (Compound 12) and a metal catalyst to afford Compound 24 having the structure:
• (g) reacting Compound 24 with a metal hydrogenation catalyst to afford Compound 25 having the structure:
• (h) reacting Compound 25 with a coupling agent to afford Compound 26 having the structure:
• (i) reacting Compound 26 with an acid to afford Compound C:

A process for the preparation of Compound 11 having the structure:

• comprising the steps of:
• (a) reacting Compound 27 having the structure:
• with (3-(1,3-dioxolan-2-yl)propyl)magnesium chloride to afford Compound 28 having the structure:
• (b) reacting Compound 28 with an oxidizing agent to afford Compound 29 having the structure:
• (c) reacting Compound 29 with N,O-dimethylhydroxylamine and a coupling agent to afford Compound 30 having the structure:
• (d) reacting Compound 30 with 4-chloropyridin-2-yl magnesium bromide to afford Compound 31 having the structure:
• (e) subsequently adding a strong acid/alcoholic solution to afford Compound 32:

A process for the preparation of Compound 40 having the structure of:

• comprising the steps of:
• (a) reacting Compound 34 having the structure:
• with 2-(3-bromopropyl)-1,3-dioxolane to afford Compound 35 having the structure:
• (b) reacting Compound 35 with strong base in a suitable solvent to afford Compound 36 having the structure:
• (c) reacting Compound 36 with benzyl alcohol and a coupling agent to afford Compound 37 having the structure:
• (d) reacting a strong acid with Compound 37 followed by the addition of a chiral auxiliary with a metal catalyst to afford Compound 38 having the structure:
• (e) subsequently reacting Compound 38 with (4-chloropyridin-2-yl)magnesium bromide to afford Compound 39 having the structure:
• (f) subsequently hydrolyzing the ester followed by the addition of a protecting group to afford Compound 40:

A process for preparing Compound 1 having the structure:

• comprising the steps of
• (a) reacting Compound 4 having the structure:
• (i) with sodium nitrite and an acid in a suitable solvent to form a first mixture;
• (ii) then adding the first mixture to an aqueous solution comprising sodium azide and a weak base to form a second mixture;
• (iii) reacting the second mixture with trimethylsilylacetylene and copper (I) iodide (CuI) and a ligand to afford Compound 7 having the structure:
• and
• (b) chlorinating Compound 7 with a chlorinating agent to afford Compound 1.

A process for preparing Compound 1 having the structure:

• comprising the steps of:
• (a) reacting Compound 4 having the structure:
• (i) with an acid and sodium nitrite in a suitable solvent;
• (ii) reacting with an aqueous mixture of sodium azide and an aqueous weak base to form Compound 6 having the structure:
• (b) subsequently coupling Compound 6 to chloroacetylene in the presence of a metal catalyst and a ligand to afford Compound 1.