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1. (WO2015143154) ANTIFUNGAL COMPOUND PROCESS
ملاحظة: نص مبني على عمليات التَعرف الضوئي على الحروف. الرجاء إستخدام صيغ PDF لقيمتها القانونية

WHAT IS CLAIMED:

1. A process to prepare morpholine amide 2b:


2;

to provide 2b;

wherein each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)- aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0- aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or - 0(S02)-substituted aryl.

. A process to prepare ketone 3


comprising aryl substitution of morpholine amide 2b:


2b ;

to provide ketone 3;

wherein each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)- aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0- aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or - 0(S02)-substituted aryl.

3. A process to prepare a compound of formula II:


II

of a compound of formula I:


I ;

to provide a compound of formula II;

wherein each R2 is independently
, halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.

4. A process to prepare amino alcohol 1-6 or 1-7, or a mixture thereof


com risin ar lation of ridine 4b or 4c, or a mixture thereof:


4b 4c

to provide compound 1-6 or 1-7, or a mixture thereof;

wherein each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.

5. A process of enriching the enantiomeric purity of an enantiomeric compound mixture, comprising:

(i) crystallizing said enantiomeric compound mixture with a chiral acid in a suitable solvent or solvent mixture, wherein:

the suitable solvent or solvent mixture is selected from acetonitrile,


each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl;

(ii) isolating the enantio-enriched chiral salt mixture; and

(iii) free-basing the enantio-enriched chiral salt mixture to provide the enantio-enriched compound mixture.

6. The process of claim 5, further comprising reslurrying the enantio-enriched chiral salt mixture in a slurrying solvent or slurrying solvent mixture

7. The process of claim 5, wherein the suitable solvent or solvent mixture is a) acetonitrile b) a mixture of acetonitrile and methanol.

8. The process of claim 6, wherein the slurrying solvent or slurrying solvent mixture is a) acetonitrile or b) a mixture of acetonitrile and methanol.

9. The process of claim 7, wherein the mixture of acetonitrile and methanol comprises 80-90% acetonitrile and 10-20% methanol.

10. The process of claim 8, wherein the mixture of acetonitrile and methanol comprises 80-90% acetonitrile and 10-20% methanol.

11. The process of claim 5, wherein the chiral acid is selected from the group consisting of tartaric acid, di-benzoyltartaric acid, malic acid, camphoric acid, camphorsulfonic acid, ascorbic acid, and di-p-toluoyltartaric acid.

12. The process of claim 6, wherein the chiral acid is selected from the group consisting of tartaric acid, di-benzoyltartaric acid, malic acid, camphoric acid, camphorsulfonic acid, ascorbic acid, and di-p-toluoyltartaric acid.

. A process to prepare compound 1 or la, or a mixture thereof:


1 la

comprising convertin morpholine amide 2b:


2b ;

to compound 1 or la, or a mixture thereof;

wherein Rj is halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, - 0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, 0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.

14. The proces reacting morpholine amide 2b:


2b

with


wherein M is Mg or MgX, Li, A1X2; and X is halogen, alkyl, or aryl;

Rj is halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-O-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl;

to provide compound 1 or la, or a mixture thereof:


la.

15. The process of claim 14, wherein M is Mg or MgX, and X is halogen.

16. The further comprising amidation of ester 2:


to provide morpholine amide 2b:


2b

wherein each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, - 0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, - 0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, - 0(S02)-aryl, or -0(S02)-substituted aryl.

comprising reacting ester 2:


with morpholine to provide morpholine amide 2b:


2b;

wherein each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, - 0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, - 0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, - 0(S02)-aryl, or -0(S02)-substituted aryl.

18. The process of claim 13, further comprising:


ylating ketone 3,
to provide aryl-pyridine 1-4,


(iii) forming the epoxide of aryl-pyridine 1-4, , tO

, to provide amino-alcohol

(v) enriching the enantiomeric purity of amino-alcohol ±1-6,


, to provide enantio-enriched amino-alcohol 1-6* or 1-7*,


, or a mixture thereof; and

(vi) forming the tetrazole of enantio-enriched amino-alcohol 1-6* or 1-7*,


or , or a mixture

F; F


thereof, to provide compound 1 or la, or


, or a mixture thereof;

wherein each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, 0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.

19. A process to prepare epoxide 5,
, the method comprising i) displacing the morpholino portion of morpholine amide 2b,


, to provide ketone 3,

wherein each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.

ep

wherein each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0- aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or · 0(S02)-substituted aryl.

21. A process to prepare enantio-enriched amino-alcohol 1-6* or 1-7*,


or , or a mixture thereof, the method comprising:

(i) displacing the morpholino portion of morpholine amide 2b,


, to provide ketone 3,

4,


(iii) forming the epoxide of aryl-pyridine 1-4, , tO

F3cc

provide epoxide 5,

(iv) ring-opening epoxide 5,
, to provide amino-alcohol


(v) enriching the enantiomeric purity of amino-alcohol ±1-6,

-6* or 1-7*,


or 5 or a mixture thereof;

wherein each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.

22. A process to prepare enantio-enriched amino-alcohol 1-6* or 1-7*,


or , or a mixture thereof, the method comprising:

thereof;

wherein each Rj is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or 0(S02)-substituted aryl.

23. The process of claim 13, further comprising:

(i) displacing the morpholino portion of morpholine amide 2b,

(iv) enriching the enantiomeric purity of amino-alcohol ±4b,

pyridine 1-6* or 1-7*,


, or a mixture thereof; and

(vi) forming the tetrazole of enantio-enriched aryl-pyridine 1-6* or 1-7*,


or , or a mixture

thereof, to provide compound 1 or la,
or


or a mixture thereof;

wherein each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl,

0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, - 0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.

24. A process to prepare enantio-enriched aryl-pyridine 1-6* or 1-7*,


or 5 or a mixture thereof, the method comprising:

(i) displacing the morpholino portion of morpholine amide 2b,

epoxide 4,


ring-opening epoxide 4, , to provide amino-alcohol +4b,


(iv) enriching the enantiomeric purity of amino-alcohol ±4b,


and

(v) arylating enantio-enriched amino-alcohol 4b or 4c,
or


, or a mixture thereof, to provide enantio-enriched aryl-

pyridine 1-6* or 1-7*,


, or a mixture thereof;

wherein each Rj is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.

25. A process to prepare enantio-enriched aryl-pyridine 1-6* or 1-7*,


, or a mixture thereof, the method comprising:

ring-opening epoxide 4,
to provide amino- alcohol +4b,

(ii) enriching the enantiomeric purity of amino-alcohol +4b,


(iii) arylating enantio-enriched amino-alcohol 4b or 4c,

vide enantio-enriched aryl-

pyridin
1-6* or 1-7*,


, or a mixture thereof;

wherein each Rj is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0- aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.

26. A process to prepare enantio-enriched amino-alcohol XV or XVa:


, or a mixture thereof, the method comprising:

( l

+XVII,

(ii) enric
hing the enantiomeric purity of amino-alcohol +XVII, , to provide enantio-enriched amino-alcohol XV or XVa:


or 5 or a mixture thereof;

wherein each R3 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, haloalkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and haloalkoxy;

each each n is independen 4, or 5; and

each Rio is independently
, halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted

alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.

XV or XVa,


or a mixture thereof, the method comprising:

enantiomeric purity of amino-alcohol +XVII,

lcohol XV or XVa:


or 5 or a mixture thereof;

wherein each R3 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, haloalkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and haloalkoxy;

each n is 1, 2, 3, 4, or 5; and

each Rio is independently
, halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.

28. The process of any one of claims 26-27, wherein Rio is halo or 4- (trifluoromethoxy)phenyl.

29. The process of claim 28, wherein Rio is bromo or 4-(trifluoromethoxy)phenyl.

30. The process of claim 13, further comprising:

(i) displacing the morpholino portion of morpholine amide 2b,

provide epoxide 4,


-opening epoxide 4, , to provide amino-alcohol +4b,

(iv) enriching the enantiomeric purity of amino-alcohol ±4b,


(v) forming the tetrazole of enantio-enriched amino-alcohol 4b or 4c:

, or a mixture thereof;

wherein each Rj is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, 0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.

31. A process to prepare compound 1 or la, or a mixture thereof:

to rovide a compound of formula II, VIII or Villa:


substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.

. A process to prepare compound 1 or la, or a mixture thereof:


la

omprising the arylation of substituted pyridine 4b or 4c, or a mixture thereof:


wherein each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, - 0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, - 0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, - 0(S02)-aryl, or -0(S02)-substituted aryl.

33. A compound that is 2-(5-bromopyridin-2-yl)-2,2-difluoro-l-morpholinoethanone (2b).

34. A compound of formula IX or IXa, or a mixture thereof:


wherein each Z is independently aryl, substituted aryl, alkyl, or substituted alkyl.

35. The compound of claim 34, wherein Z is phenyl, p-tolyl, methyl, or ethyl.

36. A process to prepare a compound of formula IX or IXa, or a mixture thereof, comprising:

IX IXa;

(i) combining compound 1 or la,


1 la , or a mixture thereof, a o

Z-S-OH

sulfonic acid o , and a crystallization solvent or crystallization solvent mixture;

(ii) diluting the mixture from step (i) with a crystallization co-solvent or

crystallization co-solvent mixture; and

(iii) isolating a compound of formula IX or IXa, or a mixture thereof;

wherein Z is aryl, substituted aryl, alkyl, or substituted alkyl.

37. The process of claim 36, wherein Z is phenyl, p-tolyl, methyl, or ethyl.

38. The process of claim 36, wherein the crystallization solvent or crystallization solvent mixture is ethyl acetate, isopropyl acetate, ethanol, methanol, or acetonitrile, or combinations thereof.

39. The process of claim 36, wherein the crystallization co-solvent or crystallization co-solvent mixture is pentane, methyl ieri-butylether, hexane, heptane, or toluene, or combinations thereof.

40. The process of claim 30, further comprising:

(i) combining compound 1 or la,


la , or a mixture thereof, a o

Z-S-OH

sulfonic acid o , and a crystallization solvent or crystallization solvent mixture;

(ii) diluting the mixture from step (i) with a crystallization co-solvent or crystallization co-solvent mixture; and

(iii) isolating a compound of formula IX or IXa,


thereof;

wherein each Z is independently aryl, substituted aryl, alkyl, or substituted alkyl.

41. The process of claim 40, wherein Z is phenyl, p-tolyl, methyl, or ethyl.

42. The process of claim 40, wherein the crystallization solvent or crystallization solvent mixture is ethyl acetate, isopropyl acetate, ethanol, methanol, or acetonitrile, or combinations thereof.

43. The process of claim 40, wherein the crystallization co-solvent or crystallization co-solvent mixture is pentane, methyl ieri-butylether, hexane, heptane, or toluene, or combinations thereof.

. A process to prepare compound 13 or 13a, or a mixture thereof, comprising:

127 to


a mixture thereof;

(vi) arylating enantio-enriched alcohol 11 or 11a,
or


or a mixture thereof; and

ant -enriched aryl-pyridine 12 or 12b,



wherein each n is independently 1, 2, 3, 4, or 5;

each o is independently 1, 2, 3, 4, or 5;

each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl;

each R3 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, haloalkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and haloalkoxy;

each R4 is independently H or halo;

each R5 is independently H or fluoro;

each R6 is independently H or fluoro;

each R7 is independently N3, NHRs, or NR8R9; and

each Rs and R9 are each independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

45. The process of claim 39, further comprising:

(i) combining compound 13
or


, or a mixture thereof, a sulfonic acid o

Z-S-OH

o , and a crystallization solvent or crystallization solvent mixture;

(ii) diluting the mixture from step (i) with a crystallization co- solvent or crystallization co-solvent mixture; and

(iii)


thereof;

wherein each Z is independently aryl, substituted aryl, alkyl, or substituted alkyl.

46. The process of claim 45, wherein Z is phenyl, p-tolyl, methyl, or ethyl.

47. The process of claim 45, wherein the crystallization solvent or crystallization solvent mixture is ethyl acetate, isopropyl acetate, ethanol, methanol, or acetonitrile, or combinations thereof.

48. The process of claim 45, wherein the crystallization co-solvent or crystallization co-solvent mixture is pentane, methyl teri-butylether, hexane, heptane, or toluene, or

combinations thereof.

49. A compound of formula 18:


18 ;

wherein Rj is halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl;

R5 is H or fluoro; and

R6 is H or fluoro.

50. A compound of formula 11 or 11a, or a mixture thereof:


wherein each o is independently 1, 2, 3, 4, or 5;

each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl;

each R4 is independently H or halo;

each R5 is independently H or fluoro;

each R6 is independently H or fluoro;

each R7 is independently N3, NHRs, or NR8R9; and

each Rs and R9 are each independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

51. The compound of claim 50, wherein o is 2, Ri is bromo, each R4 is fluoro, R5 is fluoro, R6 is fluoro, R7 is NHRs, and Rs is H.

52. The com ound of claim 51, wherein the compound is


53. A compound of formula 12 or 12a, or a mixture thereof:


12 12a;

wherein each n is independently 1, 2, 3, 4, or 5;

each o is independently 1, 2, 3, 4, or 5;

each R3 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, haloalkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and haloalkoxy;

each R4 is independently H or halo;

each R5 is independently H or fluoro;

each R6 is independently H or fluoro;

each R7 is independently N3, NHRs, or NR8R9; and

each Rs and R9 are each independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

54. The compound of claim 53, wherein each n is 1, each o is 2, each R3 is trifluoromethoxy, each R4 is F, each R5 is F, each R6 is F, each R7 is NHRs, and each Rs is H.

, or a mixture thereof.

56. A compound of formula 14:


wherein n is 1, 2, 3, 4, or 5;

o is 1, 2, 3, 4, or 5;

each R3 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, haloalkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and haloalkoxy;

each R4 is independently H or halo;

R5 is H or fluoro;

R6 is H or fluoro;

with the proviso that when R4 is F, o is 2, R5 and R6 are fluoro, n is 1, then R3 is not /?-OCF3 or p-OCH2CF3.

57. A compound of formula X or Xa, or a mixture thereof:

wherein each n is independently 1, 2, 3, 4, or 5;

each o is independently 1, 2, 3, 4, or 5;

each R3 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, haloalkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and haloalkoxy;

each R4 is independently H or halo;

each R5 is independently H or fluoro;

each R6 is independently H or fluoro; and

each Z is independently aryl, substituted aryl, alkyl, or substituted alkyl.

58. The compound of claim 57, wherein Z is phenyl, p-tolyl, methyl, or ethyl.

59. A process to prepare a compound of formula X or Xa, or a mixture thereof, comprising:


X Xa


, an a crysta zat on so vent or crysta zat on so vent m xture;

(ii) diluting the mixture from step (i) with a crystallization co-solvent or

crystallization co-solvent mixture; and

(iii) isolating a compound of formula X or Xa, or a mixture thereof;

wherein each n is independently 1, 2, 3, 4, or 5;

each o is independently 1, 2, 3, 4, or 5;

each R3 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, haloalkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and haloalkoxy;

each R4 is independently H or halo;

each R5 is independently H or fluoro;

each R6 is independently H or fluoro; and

each Z is independently aryl, substituted aryl, alkyl, or substituted alkyl.

60. The process of claim 59, wherein Z is phenyl, p-tolyl, methyl, or ethyl.

61. The process of claim 59, wherein the crystallization solvent or crystallization solvent mixture is ethyl acetate, isopropyl acetate, ethanol, methanol, or acetonitrile, or combinations thereof.

62. The process of claim 59, wherein the crystallization co-solvent or crystallization co-solvent mixture is pentane, methyl ieri-butylether, hexane, heptane, or toluene, or combinations thereof.

. A process to prepare compound 13 or 13a comprising:



-enriched alcohol 20 or 20a,


mixture thereof; and

(vii) forming the tetrazole of enantio-enriched alcohol 20 or 20a,


wherein each n is independently 1, 2, 3, 4, or 5;

each o is independently 1, 2, 3, 4, or 5;

each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl;

each R3 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, haloalkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and haloalkoxy;

each R4 is independently H or halo;

each R5 is independently H or fluoro;

each R6 is independently H or fluoro;

each R7 is independently N3, NHRs, or NR8R9; and

each Rs and R9 are each independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

64. The process of claim 63, further comprising:

(i) combining compound 13
or


, or a mixture thereof, a sulfonic acid o

Z-S-OH

o , and a crystallization solvent or crystallization solvent mixture;

(ii) diluting the mixture from step (i) with a crystallization co- solvent or crystallization co-solvent mixture; and

(iii) isolating a compound of formula X or Xa,


thereof;

wherein each Z is independently aryl, substituted aryl, alkyl, or substituted alkyl.

. A process to prepare morpholine morpholine amide 7


7

comprising amidation of ester 6:

6;

to provide 7;

wherein each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl;

each R5 is independently H or fluoro; and

each R6 is independently H or fluoro.

. A process to prepare ketone 8:


7 ;

to provide ketone 8;

wherein each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl;

o is 1, 2, 3, 4, or 5;

each R4 is independently H or halo;

each R5 is independently H or fluoro; and

each R6 is independently H or fluoro.

. A process to prepare a compound of formula XIII


XIII

of a compound of formula I:


XII

to provide a compound of formula XIII;

wherein each o is independently 1, 2, 3, 4, or 5;

each R3 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, haloalkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and haloalkoxy;

each R4 is independently H or halo;

each R5 is independently H or fluoro;

each R6 is independently H or fluoro;

R7 is N3, NHR8, or NR8R9; and

each R 10
-0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl.


20 20a

comprising arylation of pyridine 11 or 11a, or a mixture thereof:

to provide compound 20 or 20a, or a mixture thereof;

wherein each n is independently 1, 2, 3, 4, or 5;

each o is independently 1, 2, 3, 4, or 5;

each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl;

each R3 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, haloalkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and haloalkoxy;

each R4 is independently H or halo;

each R5 is independently H or fluoro;

each R6 is independently H or fluoro;

each R7 is independently N3, NHRs, or NR8R9; and

each Rs and R9 are each independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

69. A process to prepare compound 1 or la, or a mixture thereof:


1 la

rpholine amide 7:


7;

to compound 1 or la, or a mixture thereof;

wherein Rj is halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, - 0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, - 0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or - 0(S02)-substituted aryl;

R5 is H or fluoro; and

R6 is H or fluoro.

, further comprising amidation of ester 6:

de 7:


7

wherein each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, - 0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, - 0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, - 0(S02)-aryl, or -0(S02)-substituted aryl;

each R5 is independently H or fluoro; and

each R6 is independently H or fluoro.

aim 70, comprising reacting ester 6:


with morpholine to provide morpholine amide 7:

7;

wherein each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl;

each R5 is independently H or fluoro; and

each R6 is independently H or fluoro.

72. The process of claim 70, further comprising

(i) displacing line amide 7,

, to provide aryl-pyridine 14,


(iii) forming the epoxide of aryl-pyridine 14,

, to provide


or 11a,

or a mixture thereof; and ohol 11 or 11a,


or a mixture thereof, to provide compound 1 or la,
, or a mixture thereof;

wherein each n is independently 1, 2, 3, 4, or 5;

each o is independently 1, 2, 3, 4, or 5;

each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl;

each R3 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, haloalkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and haloalkoxy;

each R4 is independently H or halo;

each R5 is independently H or fluoro;

each R6 is independently H or fluoro;

each R7 is independently N3, NHRs, or NR8R9; and

each Rs and R9 are each independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

73. The process of claim 70, further comprising:

(i) displacing the morpholino portion of morpholine amide 7,

to provide ketone 8,

, to provide epoxide
-opening epoxide 9, , to provide alcohol 10,
(iv) enriching the enantiomeric purity of alcohol 10, , to

11 or 11a,


a mixture thereof;

a,


or a mixture thereof, to provide enantio-enriched aryl-pyridine 12 or 12b,
or


r a mixture thereof; and

(vi) forming the tetrazole of enantio-enriched ar l- ridinel2 or 12b


mixture thereof, to provide compound 1 or la,
or


wherein each n is independently 1, 2, 3, 4, or 5;

each o is independently 1, 2, 3, 4, or 5;

each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or 0(S02)-substituted aryl;

each R3 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, haloalkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and haloalkoxy;

each R4 is independently H or halo;

each R5 is independently H or fluoro;

each R6 is independently H or fluoro;

each R7 is independently N3, NHRs, or NR8R9; and

each Rs and R9 are each independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

74. The process of claim 70, further comprising:

e


-opening epoxide 9, , to provide alcohol 10,

(iv) enriching the enantiomeric purity of alcohol 10,
to provide enantio-enriched alcohol 11 or 11a,
or


or a mixture thereof;

(v) forming the tetrazole of enantio-enriched alcohol 11 or 11a,


mixture thereof; and

or , or a mixture thereof; wherein each n is independently 1, 2, 3, 4, or 5;

each o is independently 1, 2, 3, 4, or 5;

each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl;

each R3 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, haloalkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and haloalkoxy;

each R4 is independently H or halo;

each R5 is independently H or fluoro;

each R6 is independently H or fluoro;

each R7 is independently N3, NHRs, or NR8R9; and

each Rs and R9 are each independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

75. A process to prepare compound 1 or la, or a mixture thereof:


1 la

comprising the arylation of substituted pyridine 11 or 11a, or a mixture thereof:


11


, or a mixture thereof;

wherein each n is independently 1, 2, 3, 4, or 5;

each o is independently 1, 2, 3, 4, or 5;

each Ri is independently halo, -0(C=0)-alkyl, -0(C=0)-substituted alkyl, -0(C=0)-aryl, -0(C=0)-substituted aryl, -0(C=0)-0-alkyl, -0(C=0)-0-substituted alkyl, -0(C=0)-0-aryl, -0(C=0)-0-substituted aryl, -0(S02)-alkyl, -0(S02)-substituted alkyl, -0(S02)-aryl, or -0(S02)-substituted aryl;

each R3 is independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, haloalkyl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, and haloalkoxy;

each R4 is independently H or halo;

each R5 is independently H or fluoro;

each R6 is independently H or fluoro;

each R7 is independently N3, NHRs, or NR8R9; and

each Rs and R9 are each independently H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.

76. A compound of formula XXIV or XXIVa, or a mixture thereof:


wherein:

each R12 is independently H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; each Ri3 is independently H, OH, optionally substituted alkyl, optionally substituted alkoxy, or OC(0)Ri6;

each Ri4 is independently H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; each Ri5 is independently H, OH, optionally substituted alkyl, optionally substituted alkoxy, or OC(0)Ri4;

each Ri6 is independently H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; and each t is independently 0, 1, 2, or 3.

77. The compound of claim 76, wherein R12 is H and t is 1.

78. The compound of claim 76, wherein R14 is H and t is 1.

79. The compound of claim 76, wherein R12 is H, R14 is H, and t is 1.

80. The compound of claim 76, wherein R13 is OH or OC(0)Ri6 and t is 1.

81. The compound of claim 76, wherein R15 is OH or OC(0)Ri6 and t is 1.

82. The compound of claim 76, wherein Rl3 is OH or OC(0)R16, R15 is OH or OC(0)R16, and t is 1.

83. The compound of claim 76, wherein R12 is H, RJ3 is OH or OC(0)Ri6, Ri4 is H, R15 is H, OH, or OC(0)R16, and t is 1.

84. The compound of claim 76, wherein Ri2 is H, Rl3 is OH or OC(0)Ri6, Rw is H, R15 is OH

85. The compound of claim 76, wherein Ri2 is H, RJ3 is OC(0)Ri6, Ri4 is H, R15 is OC(0)Ri6, and t is l.

86. The compound of claim 76, wherein Ri2 is H, R13 is OC(0)Ri6, Ri4 is H, R15 is OC(0)Ri6, each Ri6 is independently optionally substituted arylalkyl, and t is 1.

87. The compound of claim 86, wherein each R]6 is p-tolyl.

88. The compound of claim 77, wherein RJ3 is OH, R15 is H, and t is 1.

89. The compound of claim 77, wherein Ri2 is H, Rl3 is OH, Ru is H, R15 is H, and t is 1.