METHODS OF PREPARING 4-PHENYL-6-(2,2,2-TRIFLUORO-1-PHENYLETHOXY)PYRIMIDINE-BASED COMPOUNDS

1 . A method of preparing a compound of formula I:

or a salt thereof, which comprises contacting a compound of formula II:

with a compound of formula III:

under conditions sufficient for the formation of the compound of formula I, wherein:

A 1 is optionally substituted heterocycle;

Y 1 is halogen or pseudohalogen;

each R 1 is independently amino, halogen, hydrogen, C(O)R A , OR A , NR B R C , S(O 2 )R A , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

R 2 is independently amino, halogen, hydrogen, C(O)R A , OR A , NR B R C , S(O 2 )R A , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

R 3 is hydrogen, C(O)R A , C(O)OR A , or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

R 4 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

each R A is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R B is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R C is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and

m is 1-4.

2 . (canceled)

3 . (canceled)

4 . (canceled)

5 . The method of claim 1 , wherein the compound of formula I is of formula I(a):

6 . The method of claim 5 , wherein the compound of formula I(a) is formula I(b):

wherein: each R 5 is independently amino, halogen, hydrogen, C(O)R A , OR A , NR B R C , S(O 2 )R A , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and n is 1-3.

7 . (canceled)

8 . (canceled)

9 . The method of claim 1 , wherein R 2 is hydrogen or amino.

10 . The method of claim 1 , wherein R 3 is hydrogen or lower alkyl.

11 . The method of claim 1 , wherein R 3 is C(O)OR A and R A is alkyl.

12 . The method of claim 1 , wherein R 4 is hydrogen or lower alkyl.

13 . The method of claim 1 , wherein R 5 is hydrogen or lower alkyl.

14 . The method of claim 1 , wherein n is 1.

15 . The method of claim 6 , wherein the compound of formula I(a) is (S)-ethyl 2-amino-3-(4-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)phenyl)propanoate.

16 . The method of claim 1 , wherein the compound of formula II is of formula II(a):

17 . The method of claim 16 , wherein R 1 is chloro.

18 . The method of claim 16 , wherein m is 1.

19 . The method of claim 16 , wherein the compound of formula II is (R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanol.

20 . (canceled)

21 . (canceled)

22 . (canceled)

23 . The method of claim 1 , wherein the compound of formula II is prepared by reducing a compound of formula IV:

24 - 29 . (canceled)

30 . The method of claim 23 , wherein the compound of formula IV is 1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethanone.

31 . The method of claim 23 , wherein the compound of formula IV is prepared by reacting a compound of formula V with a trifluoroacetylating agent under transmetalation conditions

wherein X is bromine or iodine.

32 . The method of claim 31 , wherein the compound of formula V is 1-(2-bromo-5-chlorophenyl)-3-methyl-1H-pyrazole.

33 - 36 . (canceled)

37 . A method of preparing a compound of formula III:

which comprises contacting a compound of formula III(a):

with 2-amino-4,6-dichloropyrimidine and a palladium catalyst under conditions sufficient to provide the compound of formula III, wherein:

Y 1 is halogen or pseudohalogen;

each R′ is independently hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle, or are taken together with the oxygen atoms to which they are attached to provide a cyclic dioxaborolane;

R 2 is independently amino, halogen, hydrogen, C(O)R A , OR A , NR B R C , S(O 2 )R A , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

R 3 is hydrogen, C(O)R A , C(O)OR A , or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

R 4 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

each R A is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and

the palladium catalyst is not bis(triphenylphosphine)-palladium(II) chloride.

38 . The method of claim 37 , wherein Y 1 is chloro.

39 . The method of claim 37 , wherein the compound of formula III(a) is of the formula:

40 . (canceled)

41 . (canceled)

42 . A method of crystallizing a compound of formula I:

or a salt thereof, which comprises contacting a compound of formula I with a pharmaceutically acceptable amino acid under conditions sufficient to provide a co-crystal of the compound of formula I and the amino acid, wherein:

A 1 is optionally substituted heterocycle;

each R 1 is independently amino, halogen, hydrogen, C(O)R A , OR A , NR B R C , S(O 2 )R A , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

R 2 is independently amino, halogen, hydrogen, C(O)R A , OR A , NR B R C , S(O 2 )R A , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

R 3 is hydrogen, C(O)R A , C(O)OR A , or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

R 4 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

each R A is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R B is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R C is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and

m is 1-4.

43 . A compound of the formula:

44 . A compound of the formula:

45 . A compound of the formula:

46 . The compound of formula 45, which is of the formula:

47 . (canceled)

48 . (canceled)

49 . (canceled)

50 . A compound of the formula:

51 . (canceled)

52 . (canceled)

53 . (canceled)

54 . A compound of the formula:

55 . (canceled)

56 . (canceled)

57 . (canceled)