[ CAS No. 54221-93-1 ] {[proInfo.proName]}

Name: 54221-93-1|2,6-Dimethylisonicotinic acid|98%
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SKU: A145681
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Quality Control of [ 54221-93-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 54221-93-1 ]

SDS Specification

Alternatived Products of [ 54221-93-1 ]

Product Details of [ 54221-93-1 ]

CAS No. :	54221-93-1	MDL No. :	MFCD03731176
Formula :	C₈H₉NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JRJLLMLYUFAZOM-UHFFFAOYSA-N
M.W :	151.16	Pubchem ID :	4531896
Synonyms :

Calculated chemistry of [ 54221-93-1 ] Expand+

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	41.13
TPSA :	50.19 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.38 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.38
Log Po/w (XLOGP3) :	1.18
Log Po/w (WLOGP) :	1.4
Log Po/w (MLOGP) :	-0.45
Log Po/w (SILICOS-IT) :	1.62
Consensus Log Po/w :	1.03

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-1.86
Solubility :	2.1 mg/ml ; 0.0139 mol/l
Class :	Very soluble
Log S (Ali) :	-1.83
Solubility :	2.24 mg/ml ; 0.0148 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.15
Solubility :	1.06 mg/ml ; 0.007 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.3

Safety of [ 54221-93-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 54221-93-1 ]

* 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.

Upstream synthesis route of [ 54221-93-1 ]
Downstream synthetic route of [ 54221-93-1 ]

[ 54221-93-1 ] Synthesis Path-Upstream 1~9

1
[ 39965-81-6 ]
[ 54221-93-1 ]

Reference： [1] Chemistry - A European Journal, 2006, vol. 12, # 4, p. 1097 - 1113
[2] Roczniki Chemii, 1959, vol. 33, p. 387,392[3] Chem.Abstr., 1959, p. 18954
[4] Patent: US2004/92726, 2004, A1, . Location in patent: Page 7
[5] Patent: JP2004/509075, 2004, A, . Location in patent: Page 22-23

2
[ 1073-23-0 ]
[ 54221-93-1 ]

Reference： [1] Chemistry - A European Journal, 2006, vol. 12, # 4, p. 1097 - 1113

3
[ 87117-15-5 ]
[ 54221-93-1 ]

Reference： [1] Chemistry - A European Journal, 2006, vol. 12, # 4, p. 1097 - 1113

4
[ 108-75-8 ]
[ 54221-93-1 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1958, vol. 613, p. 153,155, 162
[2] Collection of Czechoslovak Chemical Communications, 1958, vol. 23, p. 1083,1087
[3] Chemische Berichte, 1955, vol. 88, p. 1276,1281

5
[ 18206-06-9 ]
[ 54221-93-1 ]

Reference： [1] Chemische Berichte, 1955, vol. 88, p. 1276,1281

6
[ 13959-27-8 ]
[ 54221-93-1 ]

Reference： [1] Collection of Czechoslovak Chemical Communications, 1958, vol. 23, p. 1083,1087

7
[ 3512-80-9 ]
[ 54221-93-1 ]

Reference： [1] Roczniki Chemii, 1959, vol. 33, p. 387,392[2] Chem.Abstr., 1959, p. 18954

8
[ 110-86-1 ]
[ 108-75-8 ]
[ 7446-08-4 ]
[ 54221-93-1 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1958, vol. 613, p. 153,155, 162

9
[ 67-56-1 ]
[ 54221-93-1 ]
[ 142896-15-9 ]

Reference： [1] Chemische Berichte, 1955, vol. 88, p. 1276,1281
[2] Patent: US2004/92726, 2004, A1, . Location in patent: Page 7
[3] Patent: JP2004/509075, 2004, A, . Location in patent: Page 23

[ 54221-93-1 ] Synthesis Path-Downstream 1~66

1
[ 108-75-8 ]
[ 54221-93-1 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1958,vol. 613,p. 153,155, 162
[2]Collection of Czechoslovak Chemical Communications,1958,vol. 23,p. 1083,1087
[3]Chemische Berichte,1955,vol. 88,p. 1276,1281

2
[ 18206-06-9 ]
[ 54221-93-1 ]

Reference： [1]Chemische Berichte,1955,vol. 88,p. 1276,1281

3
[ 39965-81-6 ]
[ 54221-93-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; at 100℃; for 5h;	A mixture of 1 g (7.56 mmol) of (1) and 5 ml of concentrated sulfuric acid is heated at 100 C. for 5 hours. The resulting solution is then cooled on an ice bath, brought to pH 3.5 with 10 N sodium hydroxide and then concentrated to dryness. Extraction with ether for 48 hours (soxhlet) of a portion of the residue obtained gives 50 mg of 2,6-dimethylisonicotinic acid (2) for analysis. The remaining crude reaction product, not treated with ether, is used in its present form in the esterification reaction without further purification. [0133] NMR: 1H (D20); internal reference tBuOH 1.29 ppm. [0134] 2.82 (s, 6H, CH3); 8.05 (s, 2H, Py). [0135] MS (EI): 151 (M+, 100); 134 (M+-OH, 7.2); 106 (M+-CO2H, 16.4) [0136] MA: C8H9NO2+0.1 NaHSO4 (163.16) [0137] calculated: C 58.89H 5.62 N 8.58 O 23.53 [0138] found: C 58.73H 5.90 N 8.37 O 23.7
	With sulfuric acid; at 100℃; for 5h;	2,6-??????????(2)1g(7.56mmol)?(1)???5ml????????5??100?????????????????????????10N????????pH3.5??????????????????????????48????????(??????)??????????50mg?2,6-??????????(2)?????????????(????????????)?????????????????????????????????

Reference： [1]Chemistry - A European Journal,2006,vol. 12,p. 1097 - 1113
[2]Roczniki Chemii,1959,vol. 33,p. 387,392
Chem.Abstr.,1959,p. 18954
[3]Patent: US2004/92726,2004,A1 .Location in patent: Page 7
[4]Patent: JP2004/509075,2004,A .Location in patent: Page 22-23

4
[ 13959-27-8 ]
[ 54221-93-1 ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1958,vol. 23,p. 1083,1087

5
[ 67-56-1 ]
[ 54221-93-1 ]
[ 142896-15-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; for 24h;Heating / reflux;	A mixture of 2 g of 2,6-dimethylisonicotinic acid (2) (unpurified), 100 ml of methanol and 1 ml of 98% sulfuric acid is refluxed for 24 hours. After cooling, the reaction medium is neutralized with saturated NaHCO3 solution and then extracted five times with 60 ml of CHCl3. The combined chloroform phases are then dried over Na2SO4 and then concentrated. The resulting solid is then extracted four times with 50 ml of ether, after which the ether phase is concentrated. Chromatography on alumina [gradient: cyclohexane/CH2Cl2 (50/50) to pure CH2Cl2] of the white residue obtained gives 1 g of 4-methyl-2,6-dimethyl isonicotinate (3). [0141] m.p.: 45-47 C. [0142] TLC: Rf: 0.3 [SiO2/CH2Cl2-MeOH (97/3)][0143] HPLC: Tr: 2.4 [0144] UV: CHCl3: 290.6 nm (3650) [0145] NMR: 1H CDCl3; internal reference TMS [0146] 2.59 (s, 6H, CH3); 3.93 (s, 3H, CO2CH3); 7.51 (s, 2H, Py) [0147] 13C CDCl3; internal reference 77.0 ppm [0148] 24.5 (CH3); 52.5 (OCH3); 119.5 (Ct); 137.9, 158.9 (Cq); [0149] 166.1 (CO). [0150] MS (EI): 165 (M+, 24); 134 (M+-OCH3, 13); 106 (M+-CO2Me)
	With sulfuric acid; for 24h;Heating / reflux;	4-???2,6-????????????(3)2g?2,6-??????????(2)(??)?100ml?????????1ml?98%??24????????????????NaHCO3???????????60ml?CHCl3?5??????????????????????Na2SO4?????????????????????????50ml??????4????????????????????????????????????????????[?:???????/CH2Cl2(50/50)?CH2Cl2]????1g?4-???2,6-????????????(3)????

Reference： [1]Chemische Berichte,1955,vol. 88,p. 1276,1281
[2]Patent: US2004/92726,2004,A1 .Location in patent: Page 7
[3]Patent: JP2004/509075,2004,A .Location in patent: Page 23

6
[ 64-17-5 ]
[ 54221-93-1 ]
[ 39965-80-5 ]

Reference： [1]Journal of the American Chemical Society,1959,vol. 81,p. 704,707

7
[ 54221-93-1 ]
[ 98491-79-3 ]

Reference： [1]Chemische Berichte,1955,vol. 88,p. 1276,1281

8
[ 54221-93-1 ]
[ 151427-26-8 ]

Reference： [1]Journal of Heterocyclic Chemistry,1992,vol. 29,p. 1245 - 1273

10
[ 110-86-1 ]
[ 108-75-8 ]
[ 7446-08-4 ]
[ 54221-93-1 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1958,vol. 613,p. 153,155, 162

11
[ 54221-93-1 ]
[ 3883-94-1 ]
5-(4'-methoxyphenyl)-2-(2,6-dimethyl-4-pyridyl)oxazole [ No CAS ]

Reference： [1]Chemistry - A European Journal,2006,vol. 12,p. 1097 - 1113

12
[ 1073-23-0 ]
[ 54221-93-1 ]

Reference： [1]Chemistry - A European Journal,2006,vol. 12,p. 1097 - 1113

13
[ 87117-15-5 ]
[ 54221-93-1 ]

Reference： [1]Chemistry - A European Journal,2006,vol. 12,p. 1097 - 1113

14
[ 54221-93-1 ]
[ 151427-27-9 ]

Reference： [1]Journal of Heterocyclic Chemistry,1992,vol. 29,p. 1245 - 1273

15
[ 3512-80-9 ]
[ 54221-93-1 ]

Reference： [1]Roczniki Chemii,1959,vol. 33,p. 387,392
Chem.Abstr.,1959,p. 18954

16
[ 54221-93-1 ]
[ 100050-00-8 ]

Reference： [1]Journal of the American Chemical Society,1959,vol. 81,p. 704,707

17
[ 54221-93-1 ]
[ 100247-55-0 ]

Reference： [1]Journal of the American Chemical Society,1959,vol. 81,p. 704,707

18
[ 870-46-2 ]
[ 54221-93-1 ]
[ 1122092-41-4 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a solution of 2,6-dimethyl-isonicotinic acid (1.59 g, 10.5 mmol), hydrazinecarboxylic acid tert-butyl ester (1.42 g, 10.7 mmol) and DIPEA (6.06 g, 31.5 mmol) in DMF (33 mL), TBTU (4.05 g, 12.6 mmol) is added. The suspension is stirred at rt for 2 h before it is diluted with EA:diethyl ether 1 :1 and washed with 1 N aq. NaOH solution. The washing is extracted three times with DCM, acidified and extracted again with DCM. The combined org. extracts are dried over MgSO4, filtered and concentrated to give crude N'-(2,6-dimethyl-pyridine-4-carbonyl)- hydrazinecarboxylic acid tert-butyl ester (2.79 g) as a brown oil. This material is dissolved 5 M HCI in dioxane (14 mL) and the resulting solution is stirred at rt for 3 h. The solvent is removed in vacuo and the residue is purified by MPLC on RP-Ci8 <n="101"/>silica gel to give 2,6-dimethyl-isonicotinic acid hydrazide hydrochloride (1.71 g) as a beige solid; LC-MS: tR = 0.15 min, [IVM]+ = 166.10.
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a solution of 2,6-dimethyl-isonicotinic acid (1.59 g, 10.5 mmol), hydrazinecarboxylic acid tert-butyl ester (1.42 g, 10.7 mmol) and DIPEA (6.06 g, 31.5 mmol) in DMF (33 mL), TBTU (4.05 g, 12.6 mmol) is added. The suspension is stirred at rt for 2 h before it is diluted with EA:diethyl ether 1:1 and washed with 1 N aq. NaOH solution. The washing is extracted three times with DCM, acidified and extracted again with DCM. The combined org. extracts are dried over MgSO4, filtered and concentrated to give crude N'-(2,6-dimethyl-pyridine-4-carbonyl)-hydrazinecarboxylic acid tert-butyl ester (2.79 g) as a brown oil.

Reference： [1]Patent: WO2009/24905,2009,A1 .Location in patent: Page/Page column 99-100
[2]Patent: US2011/212998,2011,A1 .Location in patent: Page/Page column 36

19
[ 1122092-45-8 ]
[ 54221-93-1 ]
C₁₉H₂₄N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General Method for the Preparation of 2,5-dipyridyl-[1,3,4]thiadiazolesTo a solution of the appropriate pyridine-carboxylic acid (1 eq.) and DIPEA (3 eq.) in DCM (20 mL/mmol), TBTU (1 eq.) is added. The mixture is stirred for 5 min before the appropriate pyridine-carboxylic acid hydrazide (1 eq.) is added. The mixture is stirred at rt for 1 h before it is diluted with DCM, washed with water, dried over MgSO4, filtered and concentrated. The remaining residue is dissolved in THF, Lawesson's reagent (2 eq.) is added and the mixture is stirred at 1100C for 6 min under microwave irradiation. The mixture is diluted with EA, washed with sat. aq. NaHCO3, and concentrated. The crude product is purified by chromatography on prep. TLC plates or by prep. HPLC to give the desired 2,5-dipyridyl- [1 ,3,4]thiadiazole in 3-44% yield.

Reference： [1]Patent: WO2009/24905,2009,A1 .Location in patent: Page/Page column 102; 130

20
[ 54221-93-1 ]
[ 1186513-25-6 ]

Reference： [1]Patent: US2011/212998,2011,A1

21
[ 54221-93-1 ]
2,6-dimethyl-isonicotinoyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; at 85℃; for 2h;	3.1 N-(2-amino-1 -cyano-2-oxoethyl)-2,6-dimethylisonicotinamide2-amino 2-cyano acetamide (1 .4 g, 0.01473 mol, 1 eq) in pyridine (15ml) is stirred for 1 h at room temperature, to this 2,6-dimethyl isonicotinyl chloride (2.5 g, 0.1473 mol, 1 eq) [prepared by stirring a mixture of 2,6-dimethyl isonicotinic acid (2.5g, 0.0465 mol,1 eq) in thionyl chloride (15 ml) at 85 C for 2 hr, thionyl chloride was removed in vacuum under nitrogen] is added at 0 C and the reaction mixture is stirred at room temperature for 14 h, after the completion of the reaction pyridine is removed under vacuum and the crude product is purified by column chromatography to afford (1 .5 g) of the titled compound;yield: 39%; MS (ESI+): 233.05.

Reference： [1]Patent: WO2012/161879,2012,A1 .Location in patent: Page/Page column 54-55

22
[ 54221-93-1 ]
[ 1414935-84-4 ]

Reference： [1]Patent: WO2012/161879,2012,A1

23
[ 54221-93-1 ]
[ 1414935-85-5 ]

Reference： [1]Patent: WO2012/161879,2012,A1

24
[ 54221-93-1 ]
[ 1414935-86-6 ]

Reference： [1]Patent: WO2012/161879,2012,A1

25
[ 54221-93-1 ]
[ 1414935-35-5 ]

Reference： [1]Patent: WO2012/161879,2012,A1

26
[ 54221-93-1 ]
(R)-N-(1-(azepan-3-yl)-7-chloro-1H-benzo[d]imidazol-2-yl)-2,6-dimethylisonicotinamide hydrochloride [ No CAS ]

Reference： [1]Patent: WO2013/184757,2013,A1

27
[ 54221-93-1 ]
(R,E)-N-(7-chloro-1-(1-(4-(dimethylamino)but-2-enoyl)azepan-3-yl)-1H-benzo[d]imidazol-2-yl)-2,6-dimethylisonicotinamide [ No CAS ]

Reference： [1]Patent: WO2013/184757,2013,A1

28
(R)-tert-butyl 3-(2-amino-7-chloro-1H-benzo[d]imidazol-1-yl)azepane-1-carboxylate [ No CAS ]
[ 54221-93-1 ]
(R)-tert-butyl 3-(7-chloro-2-(2,6-dimethylisonicotinamido)-1H-benzo[d]imidazol-1-yl)azepane-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step A: A mixture of <strong>[54221-93-1]2,6-dimethylisonicotinic acid</strong> (927 mg, 6.1 mmol) and 0- benzotriazole-N,N,N’ ,N’ -tetramethyl-uronium-hexafluoro-phosphate (HBTU) (4.65 g, 12.3 mmol) in DMF (15 ml) was treated with hydroxybenzotriazole (HOBt) (1.82 g, 13.5 mmol) and stirred at room temperature for 10 mm. The resulting mixture was then added to a solution of 1-26 (1.12 g, 3.1 mmol) in DMF (4 mL), followed by addition of NEt3(1.7 mL, 12.3 mmol). The reaction was stuffed overnight, quenched with H20 (2 mL) and concentrated under reduced pressure. The crude was partitioned between EtOAc and iN NaOH, and extracted with EtOAc. The combined organic phase was dried over Na2504, and concentrated under reduced pressure. The crude material was purified by column chromatography (0-100% EtOAc/Hexanes) to afford (R)-tert-butyl 3-(7-chloro-2-(2,6-dimethylisonicotinamido)- 1 H-benzo [djimidazol- 1 -yl)azepane- 1 -carboxylate (I-30a). MS calculated for C26H33C1N503 (M+Hj 498.22, found: 498.2.

Reference： [1]Patent: WO2013/184757,2013,A1 .Location in patent: Page/Page column 95

29
1-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methylpropan-2-aminium chloride [ No CAS ]
[ 54221-93-1 ]
[ 1622458-34-7 ]

Yield	Reaction Conditions	Operation in experiment
57%		Example 3 N-(1-((4-amino-2,2-dioxide-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2-methylpropan-2-yl)-2,6-dimethylisonicotinamide To a stirred suspension of 5-(2-amino-2-methylpropoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide hydrochloride (320.8 mg, 1 mmol) in DMF (8 mL) was added triethylamine (0.278 mL, 2 mmol). After being stirred at room temperature for 10 min., a mixture of <strong>[54221-93-1]2,6-dimethylisonicotinic acid</strong> (182 mg, 1.2 mmol), EDCI (191.7 mg, 1 mmol) and HOBt (135 mg, 1 mmol) in 4 ml of DMF was added and the reaction mixture was then stirred at room temperature overnight. The resulting solution was purified by HPLC, and then the product was re-crystallized from ethanol/water, after dry to give the title compound as an off white solid (237 mg) in 57% yield. M.p.: 240-241 C. 1H NMR (400 MHz, DMSO-d6) δ 1.45 (s, 6H), 2.45 (s, 6H), 4.37 (s, 2H), 6.61 (d, J=8.0 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 7.28 (s, 2H), 7.46 (t, J=8.0 Hz, 1H), 7.81 (s, 1H), 8.35 (s, 1H), 8.50 (s, 1H), 10.99 (s, 1H). MS 418 (MH+).

Reference： [1]Patent: US2014/235624,2014,A1 .Location in patent: Paragraph 0129; 0130

30
[ 54221-93-1 ]
(2,6-dimethylpyridin-4-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanone [ No CAS ]

Reference： [1]Patent: US2015/105366,2015,A1
[2]Patent: WO2015/57205,2015,A1
[3]Patent: US2015/111870,2015,A1

31
[ 54221-93-1 ]
[ 6638-79-5 ]
N-methoxy-N,2,6-trimethylisonicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%		Oxalyl chloride (1.46mL, 17.3 mmol) was added to a suspension of 2,6- dimethylisonicotinic acid (2.38g, 15.7 mmol) in DCM (100 mL, anhydrous) and DMF (1.3 mmol) at r.t.. The mixture was stirred at r.t. for 1 h to give a colorless solution which was cooled to 0 C. N,O-Dimethylhydroxylamine hydrochloride (1.46mL, 17.3 mmol) and pyridine (3.82 mL, 47.2 mmol) were added sequentially and the mixture was stirred at r.t. for 18 h, then partitioned between EtOAc and sat. aq. NaHC03. Column chromatography with hexanes:EtOAc 1 : 1 gave 282 as an oil (1.50 g, 49%). 1H MR (CDC13) δ 7.15 (s, 2H), 3.56 (s, 3H), 3.35 (s, 3H), 2.57 (s, 6H). Found: [M+H]=195.1
49%		General procedure: Oxalyl chloride (1.85 mL, 21.88 mmol) was added to a suspensionof 6-methylpicolinic acid (2.50 g, 18.23 mmol) in DCM (75 mL,anhydrous) and DMF (1.3 mmol) at 20 C. The mixture was stirred at20 C for 1 h to give a colorless solution which was cooled to 0 C. N,ODimethylhydroxylaminehydrochloride (1.95 g, 20.1 mmol) andpyridine (3.25 mL, 40.11 mmol) were added sequentially and themixture was stirred at 20 C for 18 h, then partitioned between EtOAcand sat. aq. NaHCO3. Column chromatography with hexanes:EtOAc 1:1gave N-methoxy-N,6-dimethylpicolinamide as an oil (2.68 g, 82%).
		To <strong>[54221-93-1]2,6-dimethylisonicotinic acid</strong> (1.00 g, 6.61 mmol) in DCM (8.3 mL), CDI (1.18 g, 7.27 mmol) was added and the mixture was stirred for 45 minutes after which N,O-dimethylhydroxylamine hydrochloride (0.71 g, 7.3 mmol) was added and the mixture was stirred for 20 hours. The reaction mixture was quenched with 0.3 M aqueous solution of NaOH and partitioned between water and DCM. The aqueous layer was extracted with DCM, washed with aqueous saturated solution of NaCl, dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-100% EtOAc-DCM) to provide the title compound.

	With 1,1'-carbonyldiimidazole; In dichloromethane; for 20h;	Intermediate 29: step a N-methoxy-N-2,6-trimethylisonicotinamide To 2,6-dimethylisonicotinie acid (1 ,00 g, 6.61 mmol) in DCM (8.3 niL), CDI (1.18 g, 7.27 mmol) was added and the mixture was stirred for 45 minutes after which N,0~ dimethylhydroxylamine hydrochloride (0.71 g, 7.3 mmol) was added and the mixture was stirred for 20 hours. The reaction mixture was quenched with 0.3 M aqueous solution of NaOH and partitioned between water and DCM. The aqueous layer was extracted with DCM, washed with aqueous saturated solution of NaCl, dried (MgS04) and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-100% EtOAc-DCM) to provide the title compound.
		To a solution of <strong>[54221-93-1]2,6-dimethylisonicotinic acid</strong> (1.00 g, 6.61 mmol) in DCM (8.3 mL), CDI (1.18 g, 7.27 mmol) was added and the mixture was stirred for 45 minutes after which N,O-dimethylhydroxylamine hydrochloride (0.71 g, 7.3 mmol) was added and the mixture was stirred for 20 hours. The reaction mixture was quenched with 0.3 M aqueous solution of NaOH and partitioned between water and DCM. The aqueous layer was extracted with DCM, washed with aqueous saturated solution of NaCl, dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-100% EtOAc-DCM) to provide the title compound.

Reference： [1]Patent: WO2017/155909,2017,A1 .Location in patent: Paragraph 0242
[2]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1283 - 1291
[3]Patent: US2015/105366,2015,A1 .Location in patent: Paragraph 0344; 0345
[4]Patent: WO2015/57205,2015,A1 .Location in patent: Page/Page column 99; 100
[5]Patent: US2015/111870,2015,A1 .Location in patent: Paragraph 0581; 0582

32
[ 54221-93-1 ]
[ 673500-72-6 ]
C₄₂H₆₁NO₁₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;Inert atmosphere;	Toa 2-dram vial, equipped with magnetic stir bar under an atmosphere of argon, were added dimer alcohol 4 (10 mg, 0.017 mmol, 1.0 eq), anhydrous dichloromethane (400 mL), N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (3.8 mg 0.02mmol, 1.2 eq), and DMAP (1.6 mg,0.013 mmol, 0.8 eq). The mixture was stirred for 10 min, then <strong>[54221-93-1]2,6-dimethylisonicotinic acid</strong> (3.0 mg, 0.02 mmol, 1.2 eq) was added and the reaction mixture was stirred at rt overnight or until complete consumption of 4 as indicated by analytical TLC. The reaction was quenched with water and extracted with dichloromethane (3 x 5 mL). The organic layers were combined and washed with brine, dried over Na2SO4, vacuum filtered, and concentrated under reduced pressure. The crude residue was purified directly on silica gel; gradient elution (0-30% EtOAc in hexanes) afforded the desired product as a colorless, amorphous solid. 11.3 mg, 93% yield;

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 245 - 248

33
[ 54221-93-1 ]
(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-4-yl) (1-methyl-1H-1,2,3-triazol-5-yl)methanol [ No CAS ]

Reference： [1]Patent: WO2015/57205,2015,A1

34
[ 54221-93-1 ]
(R)-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-4-yl) (1-methyl-1H-1,2,3-triazol-5-yl)methanol [ No CAS ]
(S)-(4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(2,6-dimethylpyridin-4-yl)(1-methyl-1H-1,2,3-triazol-5-yl)methanol [ No CAS ]

Reference： [1]Patent: WO2015/57205,2015,A1

35
[ 54221-93-1 ]
C₂₀H₂₂F₂N₆O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%		2,6-Dimethylpyridine-4-carboxylic acid (1.84 g, 12.2 mmol) was stirred in DCM (100 mL), DIPEA (6.31 g, 48.8 mmol) and HBTU (4.63 g, 12.2 mmol) were added, stirring was continued for 0.5 h at RT. Intermediate 9b (3.26 g, 12.2 mmol) was added to the solution and stirring was continued for 5 h at RT. NaOH IN solution was added and stirred for 5 min. The organic layer was separated, dried over MgS04, filtered and evaporated. The product was purified by column chromatography (silica gel, eluent: 1% MeOH in DCM, 2%, 4%). The pure fractions were evaporated and the product was crystallized from DIPE, filtered off and dried, yielding compound 1 (3.85 g, 79%).

Reference： [1]Patent: WO2017/76900,2017,A1 .Location in patent: Page/Page column 24-25

36
C₁₂H₁₅F₂N₅*ClH [ No CAS ]
[ 54221-93-1 ]
C₂₀H₂₂F₂N₆O*2ClH [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		2,6-Dimethylpyridine-4-carboxylic acid (1.84 g, 12.2 mmol) was stirred in DCM (100 mL), DIPEA (6.31 g, 48.8 mmol) and HBTU (4.63 g, 12.2 mmol) were added, stirring was continued for 0.5 h at RT. Intermediate 9b (3.26 g, 12.2 mmol) was added to the solution and stirring was continued for 5 h at RT. NaOH IN solution was added and stirred for 5 min. The organic layer was separated, dried over MgS04, filtered and evaporated. The product was purified by column chromatography (silica gel, eluent: 1% MeOH in DCM, 2%, 4%). The pure fractions were evaporated and the product was crystallized from DIPE, filtered off and dried, yielding compound 1 (3.85 g, 79%).

Reference： [1]Patent: WO2017/76900,2017,A1 .Location in patent: Page/Page column 24-25

37
[ 54221-93-1 ]
3-(dimethylamino)-1-(2,6-dimethylpyridin-4-yl)propan-1-one [ No CAS ]

Reference： [1]Patent: WO2017/155909,2017,A1
[2]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1283 - 1291

38
[ 54221-93-1 ]
C₁₂H₁₄N₆ [ No CAS ]
C₂₀H₂₁N₇O [ No CAS ]
C₂₀H₂₁N₇O [ No CAS ]

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 3.5h;	2,6-Dimethylisonicotinic acid (154.845 mg, 1.0 mmol) was stirred DCM (10 mL). DIPEA (0.53 mL, 3.1 mmol) and HBTU (427 mg, 1.1 mmol) were added, stirring was continued for 0.5 hours at RT. Intermediate 38 (273 mg, 1.1 mmol) was dissolved in DCM (5 mL) and this mixture was added to the solution, which was stirred was continued for 3.5 hours at room temperature. The RM was quenched with water, then the two layers were separated and the WL back-extracted with DCM. The OL was dried on MgS04, filtered and evaporated. The product was purified on silica gel, eluent: DCM/MeOH, 100/0 to 97/3 to 94/6 which afforded the two pairs of diastereomers as a mixture. A purification was performed via Prep SFC (Stationary phase: Chiralcel (0461) Diacel OD 20 x 250 mm, Mobile phase: C02, EtOH + 0.4 iPrNH2) which afforded the two trans enantiomers. A purification was performed via Prep HPLC (Stationary phase: RP XBridge Prep C18 ODB- 5μιη,30χ250ιηιη, Mobile phase: 0.25% NH4HCO3 solution in water, CH3CN to give compound 26a (26 mg, yield 6.761%) and 26b (20 mg, yield 5.201%).

Reference： [1]Patent: WO2018/83098,2018,A1 .Location in patent: Page/Page column 69

39
[ 54221-93-1 ]
C₁₂H₁₇N₅*ClH [ No CAS ]
C₂₀H₂₄N₆O [ No CAS ]
C₂₀H₂₄N₆O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
18%; 19%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 16h;	A mixture of 1-12 (0.27 g, 0.001 mol) and <strong>[54221-93-1]2,6-dimethylisonicotinic acid</strong> (0.16 g, 0.001 mol) in DCM (10 mL) was treated with DIPEA (0.69 mL, 0.75 g/mL, 0.004 mol) and HBTU (0.38 g, 0.001 mol). Stirring was continued for 16 h. The RM was diluted with water (5 mL), acidified with 1 M HC1 until pH~3 and the layers were separated and the OL was washed with 1 M NaOH until pH~9, water, then dried over MgS04, filtered and concentrated in vacuo to give an oil (0.8 g). A purification was performed via Prep HPLC (stationary phase: RP XBridge Prep C18 OBD-ΙΟμιη, 50 xl50mm, mobile phase: 0.25% NH4HCO3 solution in water, MeOH) yielding two fractions. A purification was performed using Prep SFC (stationary phase: Chiralpak Diacel AD 20 x 250 mm, mobile phase: C02, EtOH with 0.4% iPrNH2) yielding 4 fractions of which two afforded compounds lb (64 mg, 18%) and la (70 mg, 19%).

Reference： [1]Patent: WO2018/83098,2018,A1 .Location in patent: Page/Page column 63; 64

40
[ 54221-93-1 ]
N'-((2,6-dimethylpyridin-4-yl)carbamoyl)-4-methyl-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide [ No CAS ]

Reference： [1]Patent: WO2019/23147,2019,A1

41
[ 54221-93-1 ]
C₈H₈N₄O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With diphenyl phosphoryl azide; triethylamine; In toluene; at 60℃; for 4h;	To the solution of <strong>[54221-93-1]2,6-dimethylpyridine-4-carboxylic acid</strong> (151 mg, 1.0 mmol) in dried toluene (15 mL). To the solution was added DPPA (825 mg, 3.0 mmol) and TEA (303 mg, 3.0 mmol). The mixture was stirred at 60C for 4 h. The solution was concentrated under vacuum. This gave 900 mg (crude) of the title compound as yellow oil.

Reference： [1]Patent: WO2019/23147,2019,A1 .Location in patent: Page/Page column 552

42
[ 54221-93-1 ]
N-(tert-butyldimethylsilyl)-N’-((2,6-dimethylpyridin-4-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-3-methylthiophene-2-sulfonimidamide [ No CAS ]

Reference： [1]Patent: WO2019/23147,2019,A1

43
[ 54221-93-1 ]
C₃₀H₃₄BrN₃O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1283 - 1291

44
[ 54221-93-1 ]
C₃₀H₃₃BrFN₃O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1283 - 1291

45
[ 54221-93-1 ]
C₃₁H₃₃FN₄O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1283 - 1291

46
[ 54221-93-1 ]
1-(7-bromo-3-methoxynaphthalen-2-yl)-1-(2,3-dimethoxyphenyl)-4-(dimethylamino)-2-(2,6-dimethylpyridin-4-yl)butan-2-ol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1283 - 1291

47
[ 54221-93-1 ]
C₃₂H₃₆N₄O₄ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 1283 - 1291

48
[ 1122-43-6 ]
[ 54221-93-1 ]

Reference： [1]Organic Letters,2019,vol. 21,p. 2464 - 2467

49
[ 186581-53-3 ]
[ 54221-93-1 ]
[ 142896-15-9 ]

Reference： [1]Organic Letters,2019,vol. 21,p. 2464 - 2467

50
[ 124-38-9 ]
C₇H₈FNO₃S [ No CAS ]
[ 54221-93-1 ]

Reference： [1]Organic Letters,2019,vol. 21,p. 2464 - 2467

51
[ 54221-93-1 ]
tert-butyl 4-(2-((4-fluorophenyl)amino)-7-(trans-4-hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-1-carboxylate [ No CAS ]
(2,6-dimethylpyridin-4-yl)(4-(2-((4-fluorophenyl)amino)-7-(trans-4-hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)piperidin-1-yl)methanone hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%		fe/7-Butyl 4-(2-((4-fluorophenyl)amino)-7-(/ra//.v-4-hydroxycyclohexyl)-7//- pyrrolo[2,3-d]pyrimidin-5-yl)piperidine-l-carboxylate (149 mg, 0.29 mmol) was dissolved in 4M HC1 in dioxane (10 mL, 40 mmol). The reaction mixture was stirred at room temperature for 2h (white solid precipitated out). The solvent was removed and the crude material was dissolved in DMF (5 mL). To this solution was added <strong>[54221-93-1]2,6-dimethylisonicotinic acid</strong> (40 mg, 0.26 mmol), HATU (222 mg, 0.58 mmol) and DIPEA (740 mg, 1 mL, 5.73 mmol). The reaction mixture was stirred at room temperature for lh, concentrated, and purified by prep- HPLC (0-100% MeCN in water + 0.1% trifluoroacetic acid) to afford the title compound as a TFA salt, which was treated with a 4.0 N HC1 solution in dioxane to yield a HC1 salt of the title compound (2,6-dimethylpyridin-4-yl)(4-(2-((4-fluorophenyl)amino)-7-(/ra^-4- hydroxycyclohexyl)-777-pyrrolo[2,3-i/]pyrimidin-5-yl)piperidin-l-yl)methanone as a yellow solid (74 mg, 58% for two steps). NMR (400 MHz, CD3OD) 8.84 (s, 1H), 7.78 (s, 2H), 7.64-7.55 (m, 2H), 7.45 (s, 1H), 7.25-7.16 (m, 2H), 4.77^1.71 (m, 1H), 4.50-4.42 (m, 1H), 3.71-3.58 (m, 2H), 3.41-3.33 (m, 1H), 3.24-3.02 (m, 2H), 2.80 (s, 6H), 2.20-1.97 (m, 8H), 1.85-1.73 (m, 2H), 1.53-1.41 (m, 2H); MS (ESI) for [M+H]+ (CsiHseFNeCh*): calcd. m/z 543.29; found m/z 543.30; LC-MS: >95% purity.

Reference： [1]Patent: WO2019/222524,2019,A1 .Location in patent: Page/Page column 82; 84

52
[ 54221-93-1 ]
tert-butyl 3-(2-((4-fluorophenyl)amino)-7-(trans-4-hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrrolidine-1-carboxylate [ No CAS ]
(2,6-dimethylpyridin-4-yl)(3-(2-((4-fluorophenyl)amino)-7-(trans-4-hydroxycyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrrolidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 23℃; for 8h;Inert atmosphere;	To a solution of tert- butyl 3-(2-((4-fluorophenyl)amino)-7-( ra.s-4- hydroxycyclohexyl)-77/-pyrrolo[2,3- (0519) 0.043 mmol) in DMF (50 mL) was added <strong>[54221-93-1]2,6-dimethylisonicotinic acid</strong> (8.4 mg, 0.056 mmol), 2-( l//-[ l ,2,3]triazolo[4,5-/>]pyridin- 1 -yl )- 1 , 1 ,3,3-tetramethylisouronium (0520) hexafluorophosphate (V) (32 mg, 0.085 mmol) and DIPEA (28 mg, 37 pL, 0.21 mmol). The reaction mixture was stirred under nitrogen atmosphere at rt for 8 h, quenched with water, and extracted with ethyl acetate (3X). The combined organic layers were washed with brine, dried (NaiSCL), and concentrated. The residue was purified by column chromatography with pre-packed silica gel disposable column to provide the desired product (2,6-dimethylpyridin- 4-yl)(3-(2-((4-fluorophenyl)amino)-7-(/ra/?.s-4-hydroxycyclohexyl)-7//-pyrrolo[2,3-

Reference： [1]Patent: WO2019/222524,2019,A1 .Location in patent: Page/Page column 84-86

53
[ 54221-93-1 ]
C₂₁H₂₈FN₅O [ No CAS ]
(2,6-dimethylpyridin-4-yl)(4-(2-((4-fluorophenyl)amino)-4-((trans-4-hydroxycyclohexyl)amino)pyrimidin-5-yl)piperidin-1-yl)methanone hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%		To a solution of /ra//.s-4-((2-((4-fuorophenyl)amino)-5-(4-(pyrrolidin- l - ylmethyl)phenyl) pyrimidin-4-yl)amino)cyclohexan-l-ol (45 mg, 0.106 mmol) and 2,6- dimethylisonicotinic acid (0.019 g, 0.127 mmol) in DMF (0.5 ml) was added HATLT (0.081 g, 0.213 mmol) and DIPEA (0.074 g, 0.1 mL, 0.572 mmol). The reaction mixture was ultrasonicated for 15 min, then was purified by HPLC (0-50% MeCN/water + 0. l%TFA) to yield a TFA salt of the desired product, which was treated with a 4.0 M HC1 aqueous solution and concentrated to yield the HC1 salt of the desire product (2,6-dimethylpyridin-4-yl)(4-(2- ((4-fluorophenyl)amino)-4-((trans-4-hydroxycyclohexyl)amino)pyrimidin-5-yl)piperidin-l- yl)methanone (43 mg, 64%) as an off-white solid. NMR (400 MHz, CD3OD) d 7.73 (s, 2H), 7.55-7.46 (m, 3H), 7.18 (t, J= 8.7 Hz, 2H), 4.76 (d, J= 13.5 Hz, 1H), 4.09-4.01 (m, 1H), 3.65-3.52 (m, 2H), 3.39-3.33 (m, 1H), 3.06-2.90 (m, 2H), 2.78 (s, 6H), 2.05-1.90 (m, 5H), 1.84-1.75 (m, 1H), 1.68-1.50 (m, 4H), 1.36-1.25 (m, 2H). MS (ESI) for [M+H]+ (C29H36FN602+): calcd. m/z 519.28; found m/z 519.30.; LC-MS: >95% purity.

Reference： [1]Patent: WO2019/222538,2019,A1 .Location in patent: Page/Page column 96-98

54
[ 54221-93-1 ]
methyl 2,6-dimethylpiperidine-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2020/23393,2020,A1

55
[ 54221-93-1 ]
O₁-tert-butyl O₄-methyl 2,6-dimethylpiperidine-1,4-dicarboxylate [ No CAS ]

Reference： [1]Patent: WO2020/23393,2020,A1

56
[ 54221-93-1 ]
tert-butyl 4-(hydroxymethyl)-2,6-dimethylpiperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2020/23393,2020,A1

57
[ 54221-93-1 ]
[ 637739-99-2 ]
(2,6-dimethylpyridin-4-yl)(1-(hydroxymethyl)-2-azabicyclo[2.1.1]hexan-2-yl)methanone [ No CAS ]