METHODS OF MAKING TOLEBRUTINIB

1 . A method of preparing a compound of Formula (I):

comprising:

reacting a compound of Formula A-oxalate:

to form the compound of Formula (I), wherein the reaction conditions are chosen from:

(i) reacting the compound of Formula A-oxalate with acryloyl chloride in the presence of diisopropylethylamine in toluene; or

(ii) reacting the compound of Formula A-oxalate with 3-chloropropanoic acid in the presence of potassium carbonate, diisopropylethylamine, and propylphosphonic anhydride in dichloromethane, followed by 1,8-diazabicyclo[5.4.0]undec-7-ene in hydrochloride, and finally sodium bicarbonate.

2 . The method of claim 1 , wherein the compound of Formula A-oxalate is prepared by reacting a compound of Formula A:

with oxalic acid in a mixture of ethanol and water.

3 . The method of any one of claim 1 or 2 , wherein the compound of Formula A is prepared by reacting a compound of Formula 1-f:

with Pd/C and methanesulfonic acid in ethanol.

4 . The method of claim 3 , wherein the compound of Formula 1-f is prepared by reacting a compound of Formula 1-e:

with allylamine in the presence of RuPhos Pd G2 and sodium tert-butoxide in dioxane.

5 . The method of claim 4 , wherein the compound of Formula 1-e is prepared by reacting a compound of Formula 1-d:

with carbonyldiimidazole in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in toluene.

6 . The method of claim 5 , wherein the compound of Formula 1-d is prepared by reacting a compound of Formula 1-c:

with 4-bromodiphenylether in the presence of Pd 2 (dba) 3 , DavePhos, and sodium tert-butoxide in toluene.

7 . The method of claim 6 , wherein the compound of Formula 1-c is prepared by reacting a compound of Formula 1-b:

with iron and ammonium chloride in a mixture of ethanol and water.

8 . The method of claim 7 , wherein the compound of Formula 1-b is prepared by reacting a compound of Formula 1-a:

with tert-butyl (3R)-3-amino-piperidine-1-carboxylate in the presence of triethylamine in dimethylformamide.

9 . The method of either claim 1 or 2 , wherein the compound of Formula A is prepared by reacting a compound of Formula 2-d:

with trifluoroacetic acid in dichloromethane.

10 . The method of claim 9 , wherein the compound of Formula 2-d is prepared by reacting a compound of Formula 2-c:

with Boc 2 O in the presence of 4-dimethylaminopyridine in dimethylformamide.

11 . The method of claim 10 , wherein the compound of Formula 2-c is prepared by reacting a compound of Formula 2-b:

with 4-bromodiphenylether in the presence of potassium carbonate, cesium carbonate, Pd 2 (dba) 3 , and BrettPhos in tert-amyl methyl ether.

12 . The method of claim 11 , wherein the compound of Formula 2-b is prepared by reacting a compound of Formula 2-a:

with Pd/C and H 2 in ethyl acetate.

13 . The method of claim 12 , wherein the compound of Formula 2-a is prepared by reacting a compound of Formula 1-b:

with bis(4-methoxybenzyl)amine.

14 . The method of claim 13 , wherein the compound of Formula 1-b is prepared by reacting a compound of Formula 1-a:

with tert-butyl (R)-3-aminopiperidine-1-carboxylate in the presence of triethylamine and HOBt in dimethylformamide.

15 . The method of either claim 1 or 2 , wherein the compound of Formula A is prepared by reacting a compound of Formula 3-h:

with trifluoroacetic acid.

16 . The method of claim 15 , wherein the compound of Formula 3-h is prepared by reacting a compound of Formula 3-e:

with a compound of Formula 3-g:

and N,O-bis(trimethylsilyl)acetamide in dioxane, followed by zinc in acetic acid.

17 . The method of claim 16 , wherein the compound of Formula 3-g is prepared by reacting a compound of Formula 3-f:

with N-Boc-hydroxylamine in the presence of triethylamine in tetrahydrofuran.

18 . The method of claim 16 , wherein the compound of Formula 3-e is prepared by reacting a compound of Formula 3-d:

with 4-phenoxyphenylboronic acid in the presence of copper (II) acetate, 2,2′-bipyridine, and cesium carbonate in dichloromethane.

19 . The method of claim 18 , wherein the compound of Formula 3-d is prepared by reacting a compound of Formula 3-c:

with carbonyldiimidazole in dimethylformamide.

20 . The method of claim 19 , wherein the compound of Formula 3-c is prepared by reacting a compound of Formula 3-b:

with iron and ammonium chloride in ethanol.

21 . The method of claim 20 , wherein the compound of Formula 3-b is prepared by reacting a compound of Formula 3-a:

with tert-butyl (R)-3-aminopiperidine-1-carboxylate in the presence of triethylamine in dimethylformamide.

22 . A compound selected from:

or a salt thereof.