23000-14-8|2,5-Dimethyloxazole-4-carboxylic acid| Ambeed

Structure of 23000-14-8

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Quality Control of [ 23000-14-8 ] Purity: 98% SDS Specification

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Product Details of [ 23000-14-8 ]

CAS No. :	23000-14-8
Formula :	C₆H₇NO₃
M.W :	141.12
SMILES Code :	O=C(C1=C(C)OC(C)=N1)O
MDL No. :	MFCD03011595
InChI Key :	LHGRUGVXZLHYKE-UHFFFAOYSA-N
Pubchem ID :	2795465

Safety of [ 23000-14-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 23000-14-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	5
Fraction Csp3	0.33
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	33.39
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	63.33 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.32
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.0
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	0.99
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	-0.43
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.06
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	0.79

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.65
Solubility	3.17 mg/ml ; 0.0224 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.92
Solubility	1.7 mg/ml ; 0.0121 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.36
Solubility	6.15 mg/ml ; 0.0436 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.45 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.34

Application In Synthesis of [ 23000-14-8 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 23000-14-8 ]

[ 23000-14-8 ] Synthesis Path-Downstream 1~54

1
[ 23000-15-9 ]
[ 23000-14-8 ]

References: [1]Chemische Berichte,1951,vol. 84,p. 96,99.
[2]Tetrahedron Letters,1996,vol. 37,p. 675 - 678.

2
[ 63888-23-3 ]
[ 23000-14-8 ]

References: [1]Bulletin of the Chemical Society of Japan,1977,vol. 50,p. 1788 - 1792.

3
[ 23000-14-8 ]
[ 109-89-7 ]
[ 113366-45-3 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1991,p. 2417 - 2428.

4
[ 23000-14-8 ]
[ 74-88-4 ]
[ 113366-77-1 ]
[ 113366-75-9 ]

References: [1]Tetrahedron Letters,1987,vol. 28,p. 3585 - 3588.
[2]Journal of the Chemical Society. Perkin transactions I,1991,p. 2417 - 2428.
[3]Tetrahedron Letters,1987,vol. 28,p. 3585 - 3588.
[4]Journal of the Chemical Society. Perkin transactions I,1991,p. 2417 - 2428.

5
[ 23000-14-8 ]
[ 92901-94-5 ]

References: [1]Journal of Organic Chemistry,1984,vol. 49,p. 5003 - 5006.

6
[ 82123-42-0 ]
[ 23000-14-8 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 1875 - 1880.

7
5-deutero-2-methyloxazole-4-carboxylic acid [ No CAS ]
[ 74-88-4 ]
[ 23012-17-1 ]
[ 23000-14-8 ]

References: [1]Tetrahedron Letters,1981,vol. 22,p. 3163 - 3166.
[2]Tetrahedron Letters,1981,vol. 22,p. 3163 - 3166.

8
[ 23000-14-8 ]
[ 197719-27-0 ]

References: [1]Tetrahedron Letters,1996,vol. 37,p. 675 - 678.

9
[ 23000-14-8 ]
[ 174902-49-9 ]

References: [1]Tetrahedron Letters,1996,vol. 37,p. 675 - 678.

10
[ 23000-14-8 ]
[ 174902-50-2 ]

References: [1]Tetrahedron Letters,1996,vol. 37,p. 675 - 678.

11
[ 23000-14-8 ]
Ethyl 2-<2-(2,5-dimethyloxazol-4-yl)-5-methyloxazol-4-yl>-5-methyloxazole-4-carboxylate [ No CAS ]

References: [1]Tetrahedron Letters,1996,vol. 37,p. 675 - 678.

12
[ 174902-36-4 ]
[ 23000-14-8 ]

References: [1]Tetrahedron Letters,1996,vol. 37,p. 675 - 678.

13
[ 116097-67-7 ]
[ 23000-14-8 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 1875 - 1880.

14
[ 116097-66-6 ]
[ 23000-14-8 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 1875 - 1880.

15
[ 23000-14-8 ]
[ 113378-37-3 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1991,p. 2417 - 2428.

16
[ 23000-14-8 ]
[ 113366-70-4 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1991,p. 2417 - 2428.

17
[ 23000-14-8 ]
[ 113366-72-6 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1991,p. 2417 - 2428.

18
[ 23000-14-8 ]
[ 113366-71-5 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1991,p. 2417 - 2428.

19
[ 23000-14-8 ]
[ 137267-33-5 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1991,p. 2417 - 2428.

20
[ 23000-14-8 ]
[ 92901-88-7 ]

References: [1]Journal of Organic Chemistry,1984,vol. 49,p. 5003 - 5006.

21
[ 23000-14-8 ]
[ 92901-92-3 ]

References: [1]Journal of Organic Chemistry,1984,vol. 49,p. 5003 - 5006.
[2]Journal of Organic Chemistry,1984,vol. 49,p. 5003 - 5006.

22
[ 23000-14-8 ]
[ 92901-91-2 ]

References: [1]Journal of Organic Chemistry,1984,vol. 49,p. 5003 - 5006.

23
[ 23000-14-8 ]
[ 92901-90-1 ]

References: [1]Journal of Organic Chemistry,1984,vol. 49,p. 5003 - 5006.

24
[ 23000-14-8 ]
[ 92901-89-8 ]

References: [1]Journal of Organic Chemistry,1984,vol. 49,p. 5003 - 5006.

25
[ 23000-14-8 ]
[ 92901-84-3 ]

References: [1]Journal of Organic Chemistry,1984,vol. 49,p. 5003 - 5006.

26
[ 23012-17-1 ]
[ 23000-14-8 ]

References: [1]Tetrahedron Letters,1981,vol. 22,p. 3163 - 3166.

27
[ 5431-93-6 ]
[ 23000-14-8 ]

References: [1]Chemische Berichte,1951,vol. 84,p. 96,99.

28
[ 60379-78-4 ]
[ 23000-14-8 ]

References: [1]Bulletin of the Chemical Society of Japan,1977,vol. 50,p. 1788 - 1792.

29
[ 23000-14-8 ]
[ 6346-05-0 ]
C₂₁H₂₁NO₆ [ No CAS ]

References: [1]Organic Letters,2009,vol. 11,p. 2389 - 2392.
[2]Journal of Organic Chemistry,2009,vol. 74,p. 9140 - 9151.

30
[ 23000-14-8 ]
[ 557-66-4 ]
[ 1096163-99-3 ]

References: [1]Organic and Biomolecular Chemistry,2008,vol. 6,p. 3908 - 3916.

31
[ 23000-14-8 ]
[ 75-65-0 ]
[ 63888-23-3 ]

References: [1]Organic and Biomolecular Chemistry,2008,vol. 6,p. 3908 - 3916.

32
methyl 2,5-dimethyloxazole-4-carboxylate [ No CAS ]
[ 23000-14-8 ]

References: [1]Organic and Biomolecular Chemistry,2008,vol. 6,p. 3908 - 3916.

33
C₉H₁₅NO₃Si [ No CAS ]
[ 23000-14-8 ]

References: [1]Journal of Organic Chemistry,2009,vol. 74,p. 9140 - 9151.

34
[ 23000-14-8 ]
[ 1738-69-8 ]
[ 1198280-64-6 ]

References: [1]Journal of Organic Chemistry,2009,vol. 74,p. 8988 - 8996.

35
[ 23000-14-8 ]
methyl 3-chloro-L-phenylalaninate [ No CAS ]
[ 1186415-55-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4280 - 4283.

36
[ 23000-14-8 ]
[ 1246828-91-0 ]
C₄₈H₄₀Cl₂N₄O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EDC (3 eq.) and 2,5-dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred 40 minutes. To this solution was added (S)-3-(4'-cyano-biphenyl-4-yl)-2-({(3S,8S)-3- [4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1 ,4]dioxino [2,3-g]isoquinoline-8- carbonyl}-amino)-propionic acid methyl ester (20 mg) and stirred for 12 hours. The reaction mixture was directly purified over silica (hexanes to 1 :1 hexanes EtOAc to 1 :1 hexanes EtOAc + 1% MeOH to 1 :1 hexanes EtOAc + 2% MeOH to 1 :1 hexanes EtOAc + 3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (22 mg). LCMS (m/z): 860.

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 364-365.

37
[ 23000-14-8 ]
(S)-2-({(3S,8S)-3-[4-(3-chlorophenoxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride [ No CAS ]
[ 1246830-42-1 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;	(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl- ethylcarbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1 ,4]dioxino[2,3g]isoquinoline-7- carboxylic acid tert-butyl (0.1 g), 3-chlorophenylboronic acid (0.0337 g), cupric acetate (0.39 g), and 1 gram of powdered 4 A molecular seives in 5 ml. dry DCM and 0.1 ml. TEA was stirred vigorously at room temperature overnight. The reaction mixture was then filtered through celite, the celite cake was washed three times with DCM, and the filtrates combined. The solvent was then removed in vacuo, and purified by column chromatography using 2% MeOH and 1 :1 hexane and ethyl acetate as an eluents to give 50 mg of (3S,8S)-3-[4-(3-chloro-phenoxy)- phenyl]-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}- 2,3,8,9-tetrahydro-6H-[1 ,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester which was deprotected according to General Procedure C to provide (S)-2-({(3S,8S)-3-[4-(3-chloro- phenoxy^phenyl^AΘJ^Θ-hexahydro-ϖ ^dioxino^S-glisoquinoline-δ-carbonylJ-amino)^-^- (2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (0.035 g).(S)-2-({(3S,8S)-3-[4-(3-Chloro-phenoxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1 ,4]dioxino[2,3- g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (0.035 g), 2,5-dimethyl-oxazole-4-carboxylic acid (0.014 g), HBTU (0.038 g) in DCM (3.0 ml_), DIEA (0.026 g) was added. The reaction mixture was stirred at r.t for 2.0 h, poured on to a silica gel column chromatography and eluted with 1% MeOH, 1 :1 hexanes/EtOAc to provide (S)-2-[(3S,8S)-3-[4-(3-Chloro-phenoxy)-phenyl]-7-(2,5-dimethyl- oxazole^-carbonyl^^θJΛΘ-hexahydro-ϖ ^dioxino^Sgliso-quinoline-δ-carbonyO-aminoJ-S- [4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl etser (0.020 g).(S)-2-[(3S,8S)-3-[4-(3-Chloro-phenoxy)-phenyl]-7-(2,5-dimethyl-oxazole-4-carbonyl)- 2,3,6,7,8,9-hexahydro-[1 ,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl- pyridin-4-yl)-phenyl]-propionic acid methyl etser (0.020 g) dissolved in THF (0.3 ml.) and MeOH (0.3 ml.) and 0.3 ml. of 2.0 N LiOH was added at 0 C and stirred at that temperature for 30 minutes. The pH was adjusted to 6-7, and the mixture was extracted with EtOAc, dried with (Na2SO4), and evaporated and dried under vacuum to get the title compound (0.015 g). LCMS (m/z): 814.

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 319-320.

38
[ 23000-14-8 ]
(S)-2-[(3S,8S)-3-(3'-chloro-biphenyl-4-yl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride [ No CAS ]
[ 1246830-46-5 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;	(S)-2-[(3S,8S)-3-(3'-Chloro-biphenyl-4-yl)-2,3,6,7,8,9-hexahydro-[1 ,4]dioxino[2,3- g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (0.025g), 2,5-dimethyl-oxazole-4-carboxylic acid (0.010 g), HBTU (0.027 g) in DCM (3.0 ml_), DIEA (0.019 g) was added. The reaction mixture was stirred at room temperature for 2.0 hours, poured onto a silica gel column and eluted with 1 % MeOH, 1 :1 hexanes-EtOAc to provide (S)-2-[(3S,8S)-3-(3'-Chloro-biphenyl-4-yl)-7-(2,5-dimethyl-oxazole-4- carbonyl)-2,3,6,7,8,9-hexahydro-[1 ,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3- dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (0.0139 g).

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 320-321.

39
[ 23000-14-8 ]
C₄₄H₄₅N₃O₆*(x)ClH [ No CAS ]
C₅₀H₅₀N₄O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; for 12h;	(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethyl- carbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1 ,4]dioxino[2,3-g]isoquinoline-7- carboxylic acid tert-butyl ester (30 mg) was dissolved in DMF and 3,4-dimethylbenzyl bromide (2 equiv) and potassium carbonate (3 eq.) added. The reaction mixture was stirred at room temperature and was poured onto EtOAc and water. The organic layer was dried over sodium sulfate and concentrated. The mixture was purified over silica (hexanes; 1 :1 hexanes/EtOAc; 1 :1 hexanes/EtOAc + 1 % MeOH). The resulting compound was dissolved in 2 mL DCM and 1 mL 4N HCl (dioxane) was added. The mixture was stirred at room temperature for 1.5 hours and was concentrated. The residue was suspended in DCM. TEA (3 eq.) was added and the mixture used in the following reaction sequence. In a separate vial, EDC (3 eq.) and 2,5- dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred for 40 minutes. This solution was added to the above mixture and stirred for 12 hours. The reaction mixture was directly purified over silica (hexanes; 1 :1 hexanes/EtOAc; 1 :1 hexanes/EtOAc + 1% MeOH; 1 :1 hexanes/EtOAc + 2% MeOH; 1 :1 hexanes/EtOAc + 3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 822.

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 321-322.

40
[ 23000-14-8 ]
C₄₃H₄₃N₃O₆*(x)ClH [ No CAS ]
C₄₉H₄₈N₄O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; for 12h;	(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethyl- carbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1 ,4]dioxino[2,3-g]isoquinoline-7- carboxylic acid tert-butyl ester (30 mg) was dissolved in DMF and 3-methylbenzyl bromide (2 eq.) and potassium carbonate (3 eq.) added. The reaction mixture was stirred at room temperature and was then poured onto EtOAc and water. The organic layer was dried over sodium sulfate and concentrated. The mixture was purified over silica (hexanes; 1 :1 hexanes EtOAc; 1 :1 hexanes EtOAc + 1% MeOH). The resulting compound was dissolved in 2 mL DCM and 1 mL 4N HCl (dioxane) was added. The mixture stirred at room temperature for 1.5 hours and was concentrated. The residue was suspended in DCM, TEA (3 eq.) added and the mixture used in the following reaction sequence. In a separate vial EDC (3 eq.) and 2,5- dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred 40 minutes. This solution was added to the above mixture stirred 12 hours. The reaction mixture was directly purified over silica (hexanes; 1 :1 hexanes/EtOAc; 1 :1 hexanes EtOAc + 1% MeOH; 1 :1 hexanes EtOAc + 2% MeOH; 1 :1 hexanes EtOAc + 3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 808.

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 322.

41
[ 23000-14-8 ]
C₄₄H₄₃N₃O₆*(x)ClH [ No CAS ]
C₅₀H₄₈N₄O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; for 16h;	(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethyl- carbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1 ,4]dioxino[2,3g]isoquinoline-7- carboxylic acid tert-butyl ester (30 mg) was dissolved in DCM and indan-2-ol (5 eq.), triphenyl phosphine (5 eq.) and DIAD (4.6 eq.) added at 0 C. The reaction mixture stirred at room temperature for 16 hours and was directly purified over silica (hexanes; 1 :1 hexanes/EtOAc; 1 :1 hexanes EtOAc + 1% MeOH). The resulting compound was dissolved in 2 ml. DCM and 1 ml_ 4N HCl (dioxane) was added. The mixture stirred at room temperature for 1.5 hours and was concentrated. The residue was suspended in DCM, TEA (3 eq.) was added and the mixture was conentrated. In a separate vial, EDC (3 eq.) and 2,5-dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred for 40 minutes. This solution was added to the above mixture and stirred for 16 hours. The reaction mixture was directly purified over silica (hexanes; 1 :1 hexanes/EtOAc; 1 :1 hexanes EtOAc + 1 % MeOH). This compound was dissolved in THF (0.3 ml.) and MeOH (0.3 ml.) and 0.3 ml. of 2.0 N LiOH was added at 0 C and stirred at that temperature for 30 minutes. Then, pH was was adjusted to 6-7, and the mixture was extracted with EtOAc, dried (Na2SO4), and evaporated and dried under vacuum to give the title compound (0.008 g) LCMS (m/z) 820.

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 322323.

42
[ 23000-14-8 ]
C₄₂H₃₉Cl₂N₃O₆*(x)ClH [ No CAS ]
C₄₈H₄₄Cl₂N₄O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl- ethylcarbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1 ,4]dioxino[2,3-g]isoquinoline-7- carboxylic acid tert-butyl ester was dissolved in DMF and 2,6-dichlorobenzyl bromide (2 eq.) and potassium carbonate (3 eq.) were added. The reaction mixture stirred at room temperature and was poured onto EtOAc and water. The organic layer was dried over sodium sulfate and concentrated. The mixture was purified over silica (hexanes to 1 :1 hexanes EtOAc to 1 :1 hexanes EtOAc + 1% MeOH). The resulting compound was dissolved in 2 mL DCM and 1 ml_ 4N HCl (dioxane) was added. The mixture was stirred at room temperature for 1.5 hours and was concentrated. The residue was suspended in DCM, TEA (3 eq.) added and the mixture used in the following reaction sequence. In a separate vial EDC (3 eq.) and 2,5-dimethyl- oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred 40 minutes. This solution was added to the above mixture stirred for 12 hours. The reaction mixture was directly purified over silica (hexanes to 1 :1 hexanes EtOAc to 1 :1 hexanes EtOAc + 1 % MeOH to 1 :1 hexanes EtOAc + 2% MeOH to 1 :1 hexanes EtOAc + 3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (6 mg). LCMS (m/z):862.

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 350-351.

43
[ 23000-14-8 ]
C₄₃H₄₂ClN₃O₆*(x)ClH [ No CAS ]
C₄₉H₄₇ClN₄O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl- ethylcarbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1 ,4]dioxino[2,3-g]isoquinoline-7- carboxylic acid tert-butyl ester (30 mg) was dissolved in DCM and 2(4-chloro-phenyl)-ethanol (5 equiv), triphenyl phosphine (5 eq.) and DIAD (4.5 eq.) added. The reaction mixture stirred at room temperature and was directly purified over silica (hexanes to 1 :1 hexanes EtOAc to 1 :1 hexanes EtOAc + 1% MeOH). The resulting compound was dissolved in 2 ml. DCM and 1 ml_ 4N HCl (dioxane) added. The mixture stirred at room temperature for 1.5 hours and was concentrated. The residue was suspended in DCM, TEA (3 eq.) added the mixture used in the following reaction sequence. In a separate vial EDC (3 eq.) and 2,5-dimethyl-oxazole-4- carboxylic acid (6 eq.) were dissolved in DCM and stirred 40 minutes. This solution was added to the above mixture stirred 12 hours. The reaction mixture was directly purified over silica (hexanes to 1 :1 hexanes EtOAc to 1 :1 hexanes EtOAc + 1% MeOH to 1 :1 hexanes EtOAc + 2% MeOH to 1 :1 hexanes EtOAc + 3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 842.

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 354.

44
[ 23000-14-8 ]
C₄₂H₃₇Cl₂N₃O₇ [ No CAS ]
C₄₈H₄₂Cl₂N₄O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 2h;	(S)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester and 4- carbamoylphenyl boronic acid (2 eq.) were coupled in 7:2 toluene-H2O with Na2CO3 (3 eq.) and Pd(PPh3)4 (0.1 eq.). After heating for 4 hours at 80 C, the reaction mixture was purified by flash chromatography to provide (S)-2-tert-butoxycarbonylamino-3-(4'-carbamoyl-biphenyl-4-yl)- propionic acid methyl ester. The product was deprotected according to General Procedure C to provide an amine-HCl salt, which was coupled with (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)- phenyl]-2,3,8,9-tetrahydro-6H-[1 ,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester according to General Procedure L. The product was deprotected according to General Procedure C to provide an amine-HCl salt, which was treated with excess NEt3 in DCM to produce a free amine. The free amine was coupled with <strong>[23000-14-8]2,5-dimethyloxazole-4-carboxylic acid</strong> (2 eq.) in dry DCM with HBTU (2.2 eq.) and NEt3 (3 eq.). After reacting for 2 hours at room temperature, the reaction mixture was purified by flash chromatography to provide the product, which was hydrolyzed acording to general procedure B to give the title compound (11 mg). LCMS (m/z) 876.

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 359.

45
[ 23000-14-8 ]
[ 1246829-54-8 ]
[ 1246830-52-3 ]

Yield	Reaction Conditions	Operation in experiment
		2,5-Dimethyl-oxazole-4-carboxylic acid (5 mg) and EDCI (8 mg), HOBT (6 mg) were taken up in 1 ml. of anhydrous DCM and stirred for 5 min. DIEA (10 mg) and (S)-2-({(3S,8S)-3- [3-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1 ,4]dioxino[2,3-g]isoquinoline-8- carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (20 mg in 0.5ml_ DCM) were added to the reaction mixture and stirred for 6 hours. After completion of the reaction, it was loaded onto a silica gel column (1 :3 EtOAc/hexanes to 5% MeOH in 1 :1 EtOAc/ hexanes) to get pure compound (17 mg), which was hydrolyzed according to General Procedure B to give the title compound (13 mg). LCMS (m/z): 862.

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 365-366.

46
[ 23000-14-8 ]
(S)-2-[(3S,8S)-3-(3-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride [ No CAS ]
[ 1246830-55-6 ]

Yield	Reaction Conditions	Operation in experiment
		(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl- ethylcarbamoyl}-3-(3-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1 ,4]dioxino[2,3-g]isoquinoline-7- carboxylic acid tert-butyl ester (25 mg), cyclohexyl methanol (12 mg), triphenyl phosphine (38 mg) were taken in 1 mL of anhydrous DCM and cooled to 0 C. Diisobutyl azodicarboxylate (22 mg) was added and reaction was warmed to room temperature and stirred for 4 hours. After the completion, reaction was loaded onto a silica gel column (1 :1 EtOAc:hexanes to 4% MeOH in 1 :1 EtOAc:hexanes) gave (3S,8S)-3-(3-cyclohexylmethoxy-phenyl)-8-{(S)-2-[4-(2,3-dimethyl- pyridin^-ylJ-phenylJ-1-methoxycarbonyl-ethylcarbamoyl^.S.δ.θ-tetrahydro-ΘH-ti ^Jdioxinop.S- g]isoquinoline-7-carboxylic acid tert-butyl ester (27 mg). This was taken in 2 mL anhydrous DCM and cooled 0 C, HCl (0.5 ml_, 4N in dioxane) was added and stirred at room temperature for 1 hour. All volatiles were evaporated and the residue was precipitated from DCM/hexanes to get (S)-2-[(3S,8S)-3-(3-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1 ,4]dioxino[2,3- g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (25mg).2,5-Dimethyl-oxazole-4-carboxylic acid (6 mg) was taken in 1 ml. of anhydrous DCM and EDCI (9 mg), HOBT (7 mg) and (S)-2-[(3S,8S)-3-(3-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9- hexahydro-[1 ,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)- phenyl]-propionic acid methyl ester dihydrochloride (25 mg) and stirred for 5 minutes. The reaction mixture was cooled to 0 C and DIEA (25 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction was complete, it was loaded onto a silica gel column (1 :3 EtOAc/hexanes to 4% MeOH in 1 :1 EtOAc/hexanes) to get pure (S)-2-[(3S,8S)-3- (3-cyclohexylmethoxy-phenyl)-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro- [1 ,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]- propionic acid methyl ester (22mg). This product was hydrolyzed according to General Procedure B to the title compound (17mg). LCMS (m/z): 800.

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 366-367.

47
[ 23000-14-8 ]
(S)-2-[(3S,8S)-3-(3-cyclopentylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride [ No CAS ]
[ 1246830-58-9 ]

Yield	Reaction Conditions	Operation in experiment
		(3S,8S)-8-{(S)-2-[4-(2,3-Dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethyl- carbamoyl}-3-(3-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1 ,4]dioxino[2,3-g]isoquinoline-7- carboxylic acid tert-butyl ester (25 mg), cyclopentyl methanol (11 mg), triphenyl phosphine (38 mg) were taken in 1 ml. of anhydrous DCM and cooled to 0 C. Diisobutyl azodicarboxylate (22 mg) was added and reaction was warned to room temperature and stirred for 4 hours. After the completion of the reaction, the reaction mixture was loaded onto a silica gel column (1 :1 EtOAc:hexanes to 4% MeOH in 1 :1 EtOAc:hexanes) to give (3S,8S)-3-(3-cyclopentylmethoxy- phenyl)-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}- 2,3,8,9-tetrahydro-6H-[1 ,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (24 mg). This was taken up in 2 ml. anhydrous DCM and cooled 0 "C, HCl (0.5 ml_, 4N in dioxane) was added and stirred at room temperature for 1 hour. All volatiles are evaporated and residue was precipitated from DCM/hexanes to get (S)-2-[(3S,8S)-3-(3-cyclopentylmethoxy-phenyl)- 2,3,6,7,8,9-hexahydro-[1 ,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl- pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (22 mg).2,5-Dimethyl-oxazole-4-carboxylic acid (6 mg) was taken in 1 mL of anhydrous DCM and EDCI (9 mg), HOBT (7 mg) and (S)-2-[(3S,8S)-3-(3-cyclopentylmethoxy-phenyl)-2,3,6,7,8,9- hexahydro-[1 ,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)- phenyl]-propionic acid methyl ester dihydrochloride (22 mg) and stirred for 5 minutes. The reaction mixture was cooled to 0 C and DIEA (25 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction completed, the reaction mixture was loaded onto a silica gel column (1 :3 EtOAc:hexanes to 4% MeOH in 1 :1 EtOAc:hexanes) to get purified (S)-2-[(3S,8S)-3-(3-cyclopentylmethoxy-phenyl)-7-(2,5-dimethyl-oxazole-4-carbonyl)- 2,3,6,7,8,9-hexahydro-[1 ,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl- pyridin-4-yl)-phenyl]-propionic acid methyl ester (20mg). This was hydrolyzed according to General Procedure B to get the title compound (16mg). LCMS (m/z): 786.

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 367-368.

48
[ 23000-14-8 ]
(S)-2-({(3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride [ No CAS ]
[ 1246830-61-4 ]

Yield	Reaction Conditions	Operation in experiment
		(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-8-{(S)-2-[4-(2,3-dimethy l-pyridin-4-yloxy)- phenyO-1-methoxycarbonyl-ethylcarbamoyl^^^^-tetrahydro-ΘH-fi ^ldioxinoP^-g]- isoquinoline-7-carboxylic acid tert-butyl ester (50 mg) was taken in 2 ml. of DCM and cooled to 0 C, HCl (0.5 ml_, 4N in dioxane) was added and stirred at room temperature for 2 hours. All volatiles were evaporated and residue was washed with hexanes and dried under vacuum to get (S)-2-({(3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1 ,4]dioxino[2,3- g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride (46 mg).2,5-Dimethyl-oxazole-4-carboxylic acid (6mg) was taken in 1 ml. of anhydrous DCM and EDCI (9 mg), HOBT (7 mg) and (S)-2-({(3S,8S)-3-[3-(3,4-dichloro-benzyloxy)-phenyl]- 2,3,6,7,8,9-hexahydro-[1 ,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl- pyridin-4-yloxy)-phenyl]-propionic acid methyl ester dihydrochloride (25 mg) and stirred for 5 minutes. The reaction mixture was cooled to 0 C and DIEA (25 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was loaded onto a silica gel column (1 :3 EtOAc:hexanes to 4%MeOH in 1 :1 EtOAc:hexanes) to get purified (S)-2-[(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-7-(2,5- dimethyl-oxazole^-carbonyl^^βJΛΘ-hexahydro-ϖ ^dioxino^S-glisoquinoline-δ-carbonyl]- amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (23mg). This was hydrolyzed according to General Procedure B to give the title compound (19mg ). LCMS (m/z): 878.

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 369.

49
[ 23000-14-8 ]
[ 1246829-72-0 ]
C₄₈H₄₄Cl₂N₄O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(S)-2-({(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro- [1 ,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]- propionic acid methyl ester (35 mg) was dissolved in 2 mL DCM. In a separate vial EDC (5 equiv) and 2,5-dimethyl-oxazole-4-carboxylic acid (10 equiv) were dissolved in DCM and stirred 40 min. This solution was added to the above mixture stirred 4 hours. The reaction mixture was directly purified over silica (hexanes to 1 :1 hexanes EtOAc to 1 :1 hexanes EtOAc + 2% MeOH). The resulting compound was hydrolyzed according to General Procedures B to give the title compound (10 mg). LCMS (m/z): 862.

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 372.

50
[ 23000-14-8 ]
C₄₁H₃₅Cl₂FN₂O₆ [ No CAS ]
C₄₇H₄₀Cl₂FN₃O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 2h;	(S)-2-amino-3-(4'-fluoro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride was coupled with (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H- [1 ,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester according to General Procedure L. The product was deprotected according to General Procedure C to provide amine-HCl salt, which was treated with excess NEt3 in DCM to produce the free amine. The free amine was coupled with <strong>[23000-14-8]2,5-dimethyloxazole-4-carboxylic acid</strong> (2 eq) in dry DCM with HBTU (2.2 eq) and NEt3 (3 eq). After 2 hour reaction at RT the reaction mixture was purified by flash chromatography to provide the product, which was hydrolyzed acording to general procedure B to give the title compound (6 mg). LCMS (m/z): 851.

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 377.

51
[ 23000-14-8 ]
C₄₂H₃₈Cl₂N₂O₇ [ No CAS ]
C₄₈H₄₃Cl₂N₃O₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 2h;	(S)-2-amino-3-(4'-methoxy-biphenyl-4-yl)-propionic acid methyl ester hydrochloride was coupled with (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1 ,4]dioxino- [2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester according to General Procedure L. The product was deprotected according to General Procedure C to provide amine-HCl salt, which was treated with excess NEt3 in DCM to produce the free amine. The free amine was coupled with <strong>[23000-14-8]2,5-dimethyloxazole-4-carboxylic acid</strong> (2 eq) in dry DCM with HBTU (2.2 eq) and NEt3 (3 eq). After 2 hour reaction at RT the reaction mixture was purified by flash chromatography to provide the product, which was hydrolyzed according to General Procedure B to give the title compound (21 mg). LCMS (m/z): 863.

References: [1]Patent: WO2010/114824,2010,A1 .Location in patent: Page/Page column 377.

52
[ 23000-14-8 ]
[ 1309785-54-3 ]
[ 1310556-55-8 ]

Yield	Reaction Conditions	Operation in experiment
		2,5-Dimethyl-1 ,3-oxazole-4-carboxylic acid was dissolved in THF (0.2 ml) and 1 -chloro- /V,/V,2-trimethyl-1 -propen-1 -amine (15 μΙ) was added. The mixture was shaken and left to stand for 30 min. 3-Fluoro-6-{1 -[(4-methylphenyl)sulfonyl]-1 /-/-pyrazolo[3,4-t)]pyridin-5-yl}- 1 -(phenylsulfonyl)-1 /-/-indazol-4-amine (0.338 g) was suspended in THF (2.4 ml) and 0.4 ml of this suspension was added to the acid mixture, followed by pyridine (16 μΙ). The reaction mixture was shaken and left to stand for 2 h. 2,5-Dimethyl-1 ,3-oxazole-4- carboxylic acid was dissolved in THF (0.2 ml) and 1 -chloro-/V,/V,2-trimethyl-1 -propen-1 - amine (15 μΙ) was added. This mixture was shaken and left to stand for 30 min, then added to the reaction mixture followed by pyridine (16 μΙ). The reaction was left to stand overnight. 2,5-Dimethyl-1 ,3-oxazole-4-carboxylic acid was dissolved in THF (0.2 ml) and 1 -chloro-/V,/V,2-trimethyl-1 -propen-1 -amine (15 μΙ) was added. This mixture was shaken and left to stand for 30 min then added to the reaction, followed by pyridine (16 μΙ). The reaction was were stirred for more than 3 h. 2,5-Dimethyl-1 ,3-oxazole-4-carboxylic acid was dissolved in chloroform (0.2 ml) and 1 -chloro-/V,/V,2-trimethyl-1 -propen-1 -amine (15 μΙ) was added. This mixture was shaken and left to stand for 30 min then added to the reaction, followed by pyridine (16 μΙ). The mixture was stirred for 30 min before blowing down under a stream of nitrogen. The sample was dissolved in DMSO (0.5 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo using the Genevac to give the required intermediate. This was dissolved in I PA (300 μΙ) and 2M NaOH (aq) (300 μΙ) was added. The reaction was left over the weekend at RT. The solution was neutralised with 2M HCI (aq) and blown down under a stream of nitrogen. The sample was dissolved in DMSO (0.5 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo using the Genevac to give the title compound, 2 mg.LCMS (method A) Rt = 2.4 min, MH+ = 392.

References: [1]Patent: WO2011/67364,2011,A1 .Location in patent: Page/Page column 94-95.

53
[ 23000-14-8 ]
(3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethylpiperidine-2-thione [ No CAS ]
N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4 fluorophenyl)-2,5-dimethyloxazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 47 N-(3-((2R,5S)-6-amino-3,3,5-trifluoro-2,5-dimethyl-2,3,4,5-tetrahydropyridin-2-yl)-4 fluorophenyl)-2,5-dimethyloxazole-4-carboxamide Prepared from (3S,6R)-6-(5-amino-2-fluorophenyl)-3,5,5-trifluoro-3,6-dimethylpiperidine-2-thione and <strong>[23000-14-8]2,5-dimethyloxazole-4-carboxylic acid</strong> LC-MS (m/z) 413.1 (MH+) tR=0.51 minutes (Method A) 1H NMR (600 MHz, DMSO-d6) δ 9.90 (s, 1H), 7.80 (dd, J=7.2, 2.7 Hz, 1H), 7.75 (ddd, J=8.7, 3.8, 2.9 Hz, 1H), 7.08 (dd, J=12.0, 8.8 Hz, 1H), 6.21 (s, 2H), 2.71-2.60 (m, 1H), 2.57 (s, 3H), 2.47-2.40 (m, 1H), 2.45 (s, 3H), 1.67 (d, J=22.8 Hz, 3H), 1.61 (s, 3H)

References: [1]Patent: US2015/232449,2015,A1 .

54
[ 23000-14-8 ]
[ 1309785-54-3 ]
C₃₂H₂₄FN₇O₆S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 85 N-[3-Fluoro-6-(1H-pyrazolo[3,4-b]pyridin-5-yl)-1H-indazol-4-yl]-2,5-dimethyl-1,3-oxazole-4-carboxamide 2,5-Dimethyl-1,3-oxazole-4-carboxylic acid was dissolved in THF (0.2 ml) and 1-chloro-N,N,2-trimethyl-1-propen-1-amine (15 μl) was added. The mixture was shaken and left to stand for 30 min. 3-Fluoro-6-{1-[(4-methylphenyl)sulfonyl]-1H-pyrazolo[3,4-b]pyridin-5-yl}-1-(phenylsulfonyl)-1H-indazol-4-amine (0.338 g) was suspended in THF (2.4 ml) and 0.4 ml of this suspension was added to the acid mixture, followed by pyridine (16 μl). The reaction mixture was shaken and left to stand for 2 h. 2,5-Dimethyl-1,3-oxazole-4-carboxylic acid was dissolved in THF (0.2 ml) and 1-chloro-N,N,2-trimethyl-1-propen-1-amine (15 μl) was added. This mixture was shaken and left to stand for 30 min, then added to the reaction mixture followed by pyridine (16 μl). The reaction was left to stand overnight. 2,5-Dimethyl-1,3-oxazole-4-carboxylic acid was dissolved in THF (0.2 ml) and 1-chloro-N,N,2-trimethyl-1-propen-1-amine (15 μl) was added. This mixture was shaken and left to stand for 30 min then added to the reaction, followed by pyridine (16 μl). The reaction was were stirred for more than 3 h. 2,5-Dimethyl-1,3-oxazole-4-carboxylic acid was dissolved in chloroform (0.2 ml) and 1-chloro-N,N,2-trimethyl-1-propen-1-amine (15 μl) was added. This mixture was shaken and left to stand for 30 min then added to the reaction, followed by pyridine (16 μl). The mixture was stirred for 30 min before blowing down under a stream of nitrogen. The sample was dissolved in DMSO (0.5 ml) and purified by MDAP (method L). The solvent was evaporated in vacuo using the Genevac to give the required intermediate. This was dissolved in IPA (300 μl) and 2M NaOH (aq) (300 μl) was added. The reaction was left over the weekend at RT. The solution was neutralised with 2M HCl (aq) and blown down under a stream of nitrogen. The sample was dissolved in DMSO (0.5 ml) and purified by MDAP (method L). The solvent was evaporated in vacuo using the Genevac to give the title compound, 2 mg.LCMS (method B) R=2.4 mi MH=392.

References: [1]Patent: US9326987,2016,B2 .Location in patent: Page/Page column 225; 226.

Historical Records

Technical Information

• Arndt-Eistert Homologation • Hunsdiecker-Borodin Reaction • Passerini Reaction • Preparation of Amines • Preparation of Carboxylic Acids • Reactions of Amines • Reactions of Carboxylic Acids • Schmidt Reaction • Specialized Acylation Reagents-Ketenes • Ugi Reaction

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H401	Toxic to aquatic life
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H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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CAS No.: 23000-14-8

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CAS No.: 23000-14-8

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