[ CAS No. 74-69-1 ] {[proInfo.proName]}

Name: 74-69-1|2-Methyl-4-pyrimidinamine|95%
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2D 3D

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Quality Control of [ 74-69-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 74-69-1 ]

Product Details of [ 74-69-1 ]

CAS No. :	74-69-1	MDL No. :	MFCD00626295
Formula :	C₅H₇N₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GKVDLTTVBNOGNJ-UHFFFAOYSA-N
M.W :	109.13	Pubchem ID :	295763
Synonyms :

Calculated chemistry of [ 74-69-1 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.2
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	31.4
TPSA :	51.8 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.78 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.13
Log Po/w (XLOGP3) :	0.26
Log Po/w (WLOGP) :	0.38
Log Po/w (MLOGP) :	-0.31
Log Po/w (SILICOS-IT) :	0.69
Consensus Log Po/w :	0.43

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.24
Solubility :	6.35 mg/ml ; 0.0582 mol/l
Class :	Very soluble
Log S (Ali) :	-0.91
Solubility :	13.5 mg/ml ; 0.123 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.62
Solubility :	2.64 mg/ml ; 0.0242 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.45

Safety of [ 74-69-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 74-69-1 ]

* 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 [ 74-69-1 ]
Downstream synthetic route of [ 74-69-1 ]

[ 74-69-1 ] Synthesis Path-Upstream 1~10

1
[ 1445-45-0 ]
[ 60838-50-8 ]
[ 74-69-1 ]

Yield	Reaction Conditions	Operation in experiment
72%	With ammonia In methanol at 130℃; for 8 h;	Example 4; Synthesis of 2-methyl-4-aminopyrimidine; In a pressure-resistant vessel made of stainless steel having an inner volume of 10 ml were charged 1.0 g (12 mmol) of 3-methoxyacrylonitrile, 3.9 g (32 mmol) of methyl orthoacetate and 4.0 g (56 mmol) of 24percent by weight ammonia-methanol solution, and the mixture was reacted under stirring at 130° C. for 8 hours. After completion of the reaction, 20 ml of hexane was added to the reaction mixture, and the mixture was stirred and then filtered to obtain 0.94 g (Isolation yield: 72percent) of 2-methyl-4-aminopyrimidine as yellow crystals. Physical properties of the 2-methyl-4-aminopyrimidine were as follows. ¹H-NMR (DMSO-d₆, δ (ppm)); 2.29 (3H, s), 6.22 (1H, dd, J=5.9, 0.5 Hz), 6.69 (2H, brs), 7.94 (1H, d, J=5.9 Hz) CI-MS (m/e); 109 (M+1)

Reference： [1] Patent: US2008/45712, 2008, A1, . Location in patent: Page/Page column 3-4

2
[ 1749-68-4 ]
[ 74-69-1 ]

Reference： [1] Journal of Organic Chemistry, 1952, vol. 17, p. 1320,1322
[2] Collection of Czechoslovak Chemical Communications, 1949, vol. 14, p. 223,228
[3] Chemische Berichte, 1942, vol. 75, p. 760

3
[ 4994-86-9 ]
[ 74-69-1 ]

Reference： [1] Chemische Berichte, 1904, vol. 37, p. 3641

4
[ 1780-26-3 ]
[ 74-69-1 ]

Reference： [1] Journal of Organic Chemistry, 1952, vol. 17, p. 1320,1322

5
[ 40497-30-1 ]
[ 74-69-1 ]

Reference： [1] Journal of Organic Chemistry, 1952, vol. 17, p. 1320,1322

6
[ 5053-43-0 ]
[ 74-69-1 ]

Reference： [1] Journal of Heterocyclic Chemistry, 1987, vol. 24, p. 1377 - 1380

7
[ 767-16-8 ]
[ 74-69-1 ]

Reference： [1] Chemische Berichte, 1942, vol. 75, p. 760

8
[ 698-29-3 ]
[ 74-69-1 ]

Reference： [1] Yakugaku Zasshi, 1950, vol. 70, p. 283,284[2] Chem.Abstr., 1951, p. 2894

9
[ 769-52-8 ]
[ 74-69-1 ]

Reference： [1] Yakugaku Zasshi, 1950, vol. 70, p. 283,284[2] Chem.Abstr., 1951, p. 2894

10
[ 4994-86-9 ]
[ 7664-41-7 ]
[ 74-69-1 ]

Reference： [1] Chemische Berichte, 1904, vol. 37, p. 3641

[ 74-69-1 ] Synthesis Path-Downstream 1~74

1
[ 4994-86-9 ]
[ 74-69-1 ]

Reference： [1]Chemische Berichte,1904,vol. 37,p. 3641

2
[ 74-69-1 ]
[ 98-74-8 ]
[ 855230-90-9 ]

Reference： [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1950,vol. 70,p. 283,284
Chem.Abstr.,1951,p. 2894

3
[ 74-69-1 ]
[ 74-88-4 ]
4-amino-1,2-dimethyl-pyrimidinium; iodide [ No CAS ]

Reference： [1]Journal of the Chemical Society,1955,p. 1850,1852

4
[ 1749-68-4 ]
[ 74-69-1 ]

Reference： [1]Journal of Organic Chemistry,1952,vol. 17,p. 1320,1322

5
[ 769-52-8 ]
[ 74-69-1 ]

Reference： [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1950,vol. 70,p. 283,284
Chem.Abstr.,1951,p. 2894

6
[ 5053-43-0 ]
[ 74-69-1 ]

Reference： [1]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1377 - 1380

7
[ 74-69-1 ]
[ 638-07-3 ]
[ 141368-29-8 ]

Reference： [1]Il Farmaco,1991,vol. 46,p. 1099 - 1110

Yield	Reaction Conditions	Operation in experiment
44%		EXAMPLE 143 2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide A mixture of acetamidine hydrochloride (2.00 g, 21.2 mmol) in a 0.5M solution of sodium methoxide in methanol (42.3 mL, 21.2 mmol) was stirred at 25 C. for 30 min. After this time, the sodium chloride was collected by filtration, and the filtrate was concentrated in vacuo. The resulting residue was diluted with 3-ethoxyacrylonitrile (2.18 ml, 21.2 mmol), and the reaction mixture was heated at 160 C. for 3 h. After this time, ethanol evolution stopped, and the melt began to crystallize. The red-brown solution was cooled to 25 C. A small amount of methanol was added, and the solid was filtered. The solid was then washed with methanol to afford 4-amino-2-methylpyrimidine (1.03 g, 44%) as an off-white solid: mp >200 C.; EI-HRMS m/e calcd for C5H7N3 (M+) 109.0640, found 109.0640.

10
[ 4994-86-9 ]
[ 7664-41-7 ]
[ 74-69-1 ]

Reference： [1]Chemische Berichte,1904,vol. 37,p. 3641

11
[ 74-69-1 ]
[ 201230-82-2 ]
(S)-2-{2-[7-Chloro-3-(3,5-dimethyl-phenyl)-6-iodo-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
2-{2-[7-chloro-3-(3,5-dimethyl-phenyl)-6-(2-methyl-pyrimidin-4-ylcarbamoyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid <i>tert</i>-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 443 - 447

12
[ 1445-45-0 ]
[ 60838-50-8 ]
[ 74-69-1 ]

Yield	Reaction Conditions	Operation in experiment
72%	With ammonia; In methanol; at 130℃; for 8h;	Example 4; Synthesis of 2-methyl-4-aminopyrimidine; In a pressure-resistant vessel made of stainless steel having an inner volume of 10 ml were charged 1.0 g (12 mmol) of 3-methoxyacrylonitrile, 3.9 g (32 mmol) of methyl orthoacetate and 4.0 g (56 mmol) of 24% by weight ammonia-methanol solution, and the mixture was reacted under stirring at 130 C. for 8 hours. After completion of the reaction, 20 ml of hexane was added to the reaction mixture, and the mixture was stirred and then filtered to obtain 0.94 g (Isolation yield: 72%) of 2-methyl-4-aminopyrimidine as yellow crystals. Physical properties of the 2-methyl-4-aminopyrimidine were as follows. 1H-NMR (DMSO-d6, delta (ppm)); 2.29 (3H, s), 6.22 (1H, dd, J=5.9, 0.5 Hz), 6.69 (2H, brs), 7.94 (1H, d, J=5.9 Hz) CI-MS (m/e); 109 (M+1)

Reference： [1]Patent: US2008/45712,2008,A1 .Location in patent: Page/Page column 3-4

13
[ 74-69-1 ]
[ 943653-41-6 ]
(R)-4-(4-(2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)-N-(2-methylpyrimidin-4-yl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,4-diaza-bicyclo[2.2.2]octane; In acetonitrile; at 20℃; for 19h;	General Procedure 7: Method B A solution of 4-(4-((R)-2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)benzene-1-sulfonyl chloride (1 equivalent), DABCO (5 equivalents), and amine (1 equivalent) in acetonitrile (0.3-0.5 M) was stirred under an N2 atmosphere at RT for 19 h. Purification via reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) gave the desired product. ; (R)-4-(4-(2-(6-Chloro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)-N-(2-methylpyrimidin-4-yl) Synthesized according to general procedure 7: method B. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=555.3; tR=2.49 min.

Reference： [1]Patent: US2008/27067,2008,A1 .Location in patent: Page/Page column 268; 269-270

14
[ 74-69-1 ]
[ 141368-30-1 ]

Reference： [1]Il Farmaco,1991,vol. 46,p. 1099 - 1110

15
[ 767-16-8 ]
[ 74-69-1 ]

Reference： [1]Chemische Berichte,1942,vol. 75,p. 760

16
[ 74-69-1 ]
[ 24903-63-7 ]

Reference： [1]Journal of the Chemical Society,1955,p. 1850,1852

17
[ 74-69-1 ]
[ 599-84-8 ]

Reference： [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1950,vol. 70,p. 283,284
Chem.Abstr.,1951,p. 2894

18
[ 74-69-1 ]
[ 53135-36-7 ]

Reference： [1]Journal of the Chemical Society,1955,p. 1850,1852

19
[ 1780-26-3 ]
[ 74-69-1 ]

Reference： [1]Journal of Organic Chemistry,1952,vol. 17,p. 1320,1322

20
[ 40497-30-1 ]
[ 74-69-1 ]

Reference： [1]Journal of Organic Chemistry,1952,vol. 17,p. 1320,1322

21
[ 698-29-3 ]
[ 74-69-1 ]

Reference： [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1950,vol. 70,p. 283,284
Chem.Abstr.,1951,p. 2894

22
[ 74-69-1 ]
[ 80563-86-6 ]
3-chloro-2-methyl-N-(2-methyl-pyrimidin-4-yl)-benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 50 - 60℃; for 48h;	Example 1; 3-Chloro-2-methyl-N-(2-methyl-pyrimidin-4-yl)-benzenesulfonamide; <strong>[74-69-1]2-Methyl-pyrimidin-4-ylamine</strong> (91 mg, Gabriel, Chem. Ber. 37, 1904, 3641) and 3-chloro-2-methyl-benzenesulfonyl chloride (179 mg) were dissolved in pyridine (5 mL) and the resulting mixture was allowed to stir at 50 to 60 C. for 48 hours. The mixture was then evaporated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 1M CuSO4 solution twice, dried over Na2SO4, filterd and evaporated. The residue was purified by flash chromatography (CH2Cl2MeOH/NH3 90:10:0.5) to give the desired product 3-chloro-2-methyl-N-(2-methyl-pyrimidin-4-yl)-benzenesulfonamide as a yellow powder (22 mg). MS (ESI-): 297.1 ([M-H]-).

Reference： [1]Patent: US2005/288308,2005,A1 .Location in patent: Page/Page column 8

23
[ 74-69-1 ]
[ 300355-26-4 ]
[ 56602-33-6 ]
[ 588942-68-1 ]

Yield	Reaction Conditions	Operation in experiment
18%	With triethylamine; In dichloromethane;	EXAMPLE 159 3-Cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamide A mixture of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 14, 250 mg, 0.732 mmol), triethylamine (0.306 mL, 2.19 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (487 mg, 1.10 mmol), and <strong>[74-69-1]4-amino-2-methylpyrimidine</strong> (120 mg, 1.10 mmol) in methylene chloride (5 mL) was stirred at 25 C. for 24 h. The reaction mixture was then diluted with water (25 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (25 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/3 hexanes/ethyl acetate) afforded impure 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamide. Re-purification by flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 then 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamide (59 mg, 18%) as a white foam: mp 96-99 C. (foam to gel); EI-HRMS m/e calcd for C20H24N4O5S (M+) 432.1467, found 432.1470.

Reference： [1]Patent: US6610846,2003,B1

24
[ 74-69-1 ]
[ 300355-72-0 ]
[ 79-37-8 ]
[ 588941-78-0 ]

Yield	Reaction Conditions	Operation in experiment
6%	With triethylamine; In dichloromethane; N,N-dimethyl-formamide;	EXAMPLE 152 2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 75, 200 mg, 0.622 mmol) in methylene chloride (5 mL) was treated with N,N-dimethylformamide (2 drops) and then cooled to 0 C. The reaction mixture was then treated with oxalyl chloride (0.081 mL, 0.933 mmol). The resulting reaction mixture was allowed to warm to 25 C. where it was stirred for 1 h. The reaction mixture was then concentrated in vacuo. The resulting yellow gel was diluted with methylene chloride (2 mL) and then slowly added to a mixture of <strong>[74-69-1]4-amino-2-methylpyrimidine</strong> (102 mg, 0.933 mmol) and triethylamine (0.173 mL, 1.24 mmol) in N,N-dimethylformamide (3 mL). The resulting reaction mixture was stirred at 25 C. for 24 h. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40S, Silica, 19/1 methylene chloride/methanol) to afford 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide (15 mg, 6%) as a white foam: mp 89-94 C. (foam to gel); EI-HRMS m/e calcd for C21H24N4O3S (M+) 412.1569, found 412.1568.

Reference： [1]Patent: US6610846,2003,B1

25
[ 74-69-1 ]
[ 300356-11-0 ]
[ 79-37-8 ]
[ 588941-11-1 ]

Yield	Reaction Conditions	Operation in experiment
25%	With pyridine; In dichloromethane; N,N-dimethyl-formamide;	A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.61 mmol) in methylene chloride (2 mL) was treated with N,N-dimethylformamide (1 drop) and then cooled to 0 C. The reaction mixture was then treated dropwise with a 2M solution of oxalyl chloride in methylene chloride (0.45 mL, 0.91 mmol) and stirred at 0 C. for 30 min. The resulting reaction mixture was then treated with a solution of <strong>[74-69-1]4-amino-2-methylpyrimidine</strong> (98.9 mg, 0.91 mmol) and pyridine (0.25 mL, 3.03 mmol) in N,N-dimethylformamide (5 mL). The resulting reaction mixture was allowed to warm to 25 C. where it was stirred for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3*15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 55/45 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide (64 mg, 25%) as a colorless oil: EI-HRMS m/e calcd for C20H24ClN3O3S (M+) 421.1227, found 421.1230.

Reference： [1]Patent: US6610846,2003,B1

26
[ 74-69-1 ]
[ 100960-55-2 ]
[ 934486-92-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1302 - 1306

27
[ 74-69-1 ]
[ 74630-73-2 ]
C₁₇H₁₃N₅S [ No CAS ]
[ 1068569-82-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4723 - 4726

28
[ 74-69-1 ]
[ 1187324-91-9 ]
[ 1187324-68-0 ]

Yield	Reaction Conditions	Operation in experiment
		Compound 25: 1-(3-Chloro-4-fluorophenyl)-5-methyl-/V-(2-methyl-4-pyrimidinyl)-1 H- 1 ,2,3-triazole-4-carboxamide; To a solution of <strong>[74-69-1]2-methyl-4-pyrimidinamine</strong> (0.060 g, 0.549 mmol) in dry 1 ,4-dioxane (1 ml) was added dropwise trimethylaluminium (0.268 ml, 0.536 mmol) (2M solution in toluene). The solution was stirred at room temperature for 30 min. Then a solution of ethyl 1 -(3-chloro-4-fluorophenyl)-5-methyl-1 H-1 ,2,3-triazole-4-carboxylate (0.038 g, 0.134 mmol) (Intermediate 5) in dry 1 ,4-dioxane (1 ml) was added at room temperature and the reaction was heated to 100 0C for 1.5 hours. The reaction was cooled to room temperature, quenched cautiously with water (0.06 ml), and stirred at room temperature for 10 min. Then, sodium sulphate (0.25 g) was added to bind the water and the mixture was stirred vigorously for 5 min. Dichloromethane was added and the mixture was stirred for additional 10 min at room temperature. The solution was filtered and the solid was washed with dichloromethane. The combined filtrate and washings were evaporated to a residue which was purified by MDAP to afford <n="45"/>the title compound (16.8%); MH+=347; 1HNMR (DMSO, 250 MHz): 2.57 (3H s), 2.59(3H, s), 7.76 (2H m), 8.0 (1 H d), 8.09 (1 H m), 8.65 (1 H d), 10.21 (1 H s).

Reference： [1]Patent: WO2009/115486,2009,A1 .Location in patent: Page/Page column 43-44

29
[ 74-69-1 ]
[ 1187324-94-2 ]
[ 1187324-70-4 ]

Yield	Reaction Conditions	Operation in experiment
		Compound 27: 1-(3,4-Dimethylphenyl)-5-methyl-lambda/-(2-methyl-4-pyrimidinyl)-1 H-1 ,2,3- triazole-4-carboxamide; To a solution of <strong>[74-69-1]2-methyl-4-pyrimidinamine</strong> (0.047 g, 0.427 mmol) in dry 1 ,4-dioxane (1 ml) was added dropwise trimethylaluminium (0.208 ml, 0.417 mmol) (2M solution in toluene). The solution was stirred at room temperature for 30 min. Batches A and <n="46"/>B of impure ethyl 1-(3,4-dimethylphenyl)-5-methyl-1 H-1 ,2,3-triazole-4-carboxylate (0.013 g) (Intermediate 6) were dissolved in dry 1 ,4-dioxane (1 ml). This solution was added at room temperature to the reaction mixture and the mixture was heated to 1000C overnight. The reaction was cooled to room temperature, quenched cautiously with water (0.06 ml), and stirred at room temperature for 10 min. Then, sodium sulphate (0.25 g) was added to bind the water and the mixture was stirred vigorously for 5 min. Dichloromethane was added and the mixture was stirred for an additional 10 min at room temperature. The solution was filtered and the solid was washed with dichloromethane. Evaporation of the solvent gave a crude residue which was purified by MDAP to afford the title compound (3.6 mg); MH+=323; 1HNMR (CDCI3, 250 MHz): 2.37 (6H s), 2.65 (3H, s), 2.67 (3H s), 7.22 (2H m), 7.33 (1 H d), 8.09 (1 H d), 8.57 (1 H d), 9.67 (1 H s).

Reference： [1]Patent: WO2009/115486,2009,A1 .Location in patent: Page/Page column 44-45

30
[ 74-69-1 ]
[ 79-04-9 ]
[ 1196093-66-9 ]

Yield	Reaction Conditions	Operation in experiment
7.5%	In 1,2-dichloro-ethane; at 80℃;Microwave irradiation;	a) 2-Chloro-N-(2-methyl-pyrimidin-4-yl)-acetamide 2-Methyl-pyrimidin-4-yl amine (545 mg) was suspended in DCE (5 mL) and chloroacetylchloride (0.4 mL) was added dropwise. The reaction was heated in a microwave at 80 C. for 5 mins. The reaction mixture was cooled to give a solid that was filtered, washed with dichloromethane then suspended in dichloromethane and sat. NaHCO3 (aq) was added. The organic phase was collected and the aqueous layer extracted with dichloromethane (*2). The combined organic layer was dried over sodium sulphate and concentrated. The crude product was purified by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to give the sub-titled compound as a yellow solid (70 mg, 7.5%). 1H NMR (400 MHz, DMSO-D6): delta 11.16 (s, 1H), 8.58 (d, 1H), 7.84 (d, 1H), 4.37 (s, 2H), 2.53 (s, 3H).
7.5%		Example 58: (R)-l-[(2-Methyl-pyrimidin-4-ylcarbamoyl)-methyl]-3-(l-phenyl- cycloheptanecarbonyloxy)-l-azonia-bicyclo[2.2.2]octane chloridea) 2-Chloro-N-(2-methyl-pyrimidin-4-yl)-acetarnideH,ISLCl <n="113"/>2-Methyl-pyrimidin-4-yl amine (545 mg) was suspended in DCE (5 niL) and chloroacetylchloride (0.4 mL) was added dropwise. The reaction was heated in a microwave at 8O0C for 5mins. The reaction mixture was cooled to give a solid that wa ftered, washed with dichloromethane then suspended in dichloromethane and sat. NaHCO3 (aq) was added. The organic phase was collected and the aqueous layer ext? with dichloromethane (x2). The combined organic layer was dried over sodium sulphc and concentrated. The crude product was purified by silica gel chromatography elutinj with 0-10%MeOH/dichloromethane to give the sub-titled compound as a yellow solid mg, 7.5 %).1H NMR (400 MHz, DMSO-D6): delta 1 1.16 (s, IH), 8.58 (d, IH), 7.84 (d, IH), 4.37 (s, 2.53 (s, 3H).

Reference： [1]Patent: US2011/172237,2011,A1 .Location in patent: Page/Page column 43
[2]Patent: WO2009/138707,2009,A1 .Location in patent: Page/Page column 111-112

31
[ 74-69-1 ]
[ 1196091-83-4 ]

Reference： [1]Patent: US2011/172237,2011,A1
[2]Patent: WO2009/138707,2009,A1

32
[ 74-69-1 ]
[ 1448541-31-8 ]
[ 1448541-18-1 ]

Yield	Reaction Conditions	Operation in experiment
38%		Example 2: Preparation of N-(2-methylpyrimidin-4-yl)-2-[3-[[2-(trifluoromethyl)-4-pyridyl] oxy]phenyl]acetamide To a solution of <strong>[74-69-1]2-methyl-4-pyrimidinamine</strong> (200 mg, 1.83 mmol) in benzene (20 mL) was slowly added trimethylaluminium (132 mg, 1.83 mmol); keeping the temperature below 30C, the solution was left to stir for 1 h. To this mixture was then added a solution of methyl 2-[3-[[2- (trifluoromethyl)-4-pyridyl]oxy]phenyl]acetate (570 mg, 1.83 mmol) in benzene (4 mL). The reaction was heated to reflux for 3 h then stirred at room temperature overnight. The reaction was quenched with the addition of 2N HCI and was brought to pH 10 with an aqueous solution of NaOH (10%). The product was extracted with dichloromethane (DCM) and the combine organic layers were dried over Na2S04 and concentrated. The residue was purified by flash silica gel column chromatography (1 : 1 to 1 :2 to 0: 100 heptane:ethyl acetate) to afford a 38% (269 g, 0.69 mmol) yield of the desired amide product.
38%		Example 2: Preparation of N-(2-methylpyrimidin-4-yl)-2-[3-[[2-(trifluoromethyl)-4- pyridyl]oxy]phenyl]acetamide (IV-10) To a solution of <strong>[74-69-1]2-methyl-4-pyrimidinamine</strong> (200 mg, 1.83 mmol) in benzene (20 ml.) was slowly added trimethylaluminum (132 mg, 1 .83 mmol); keeping the temperature below 30C, the solution was left to stir for 1 h. To this mixture was then added a solution of methyl 2-[3-[[2- (trifluoromethyl)-4-pyridyl]oxy]phenyl]acetate (570 mg, 1.83 mmol) in benzene (4 ml_). The reaction was heated to reflux for 3 h then stirred at room temperature overnight. The reaction was quenched with the addition of 2N HCI and was brought to pH 10 with an aqueous solution of NaOH (10%). The product was extracted with dichloromethane and the combine organic layers were dried over Na2S04 and concentrated. The residue was purified by flash silica gel column chromatography (1 :1 to 1 :2 to 0:100 heptane:ethyl acetate) to afford a 38% (269 g, 0.69 mmol) yield of the desired amide product.

Reference： [1]Patent: WO2013/113782,2013,A1 .Location in patent: Page/Page column 47-48
[2]Patent: WO2013/113781,2013,A1 .Location in patent: Page/Page column 46

33
[ 74-69-1 ]
[ 1453851-69-8 ]
[ 1453853-24-1 ]

Yield	Reaction Conditions	Operation in experiment
32%	In iso-butanol; at 110℃; for 18h;Sealed tube;	[003611 Step A: 2-Methylpyrimidin-4-amine (0.41 g, 3.7 mmol) and (S)-1-(2-(tert- butyldimethylsilyloxy)- 1 -(4-chloro-3 -fluorophenyl)ethyl)-4-(2-(methylsulfonyl)pyrimidin-4- yl)pyridin-2( 1 H)-one (0.10 g, 0.19 mmol) were placed in sec-BuOH (1 mL), heated to 110C in a sealed tube for 18 hours, then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by column chromatography (500:5 DCMJMeOH to remove impurity, then 500:15 for product) to give (8)-i -(2-(tert-butyldimethylsilyloxy)- 1 -(4-chloro-3 - fluorophenyl)ethyl)-4-(2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)pyridin-2( 1 11)-one (0.034 g, 32% yield).

Reference： [1]Patent: WO2013/130976,2013,A1 .Location in patent: Paragraph 00361

34
[ 74-69-1 ]
[ 1529805-47-7 ]
5-bromo-N-(2-methylpyrimidin-4-yl)phthalamic acid tert-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 177 - 180

35
[ 74-69-1 ]
[ 78164-32-6 ]
[ 1620997-28-5 ]

Yield	Reaction Conditions	Operation in experiment
77%	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 0 - 20℃; for 18h;	To a solution of intermediate Tl (100 mg, 0.331 mmol) and 2-methylpyrimidin-4- amine (36 mg, 0.331 mmol) in DCM (3.0 mL) were added HATU (188 mg, 0.496 mmol) and DIPEA (0.18 mL, 0.993 mmol) at 0 C. The reaction mixture was stirred at room temperature for 18 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (50 mL), extracted with EtOAc (50 mL) and dried over anhydrous Na2S04. The crude product was purified by column chromatography to afford the title compound (100 mg, 77%) as a white solid. 1H NMR (DMSO-d6, 400 MHz) delta: 14.07 (IH, br), 11.61 (IH, s), 8.63-8.62 (IH, d, J= 6.0Hz), 8.36 (IH, s), 8.30 (IH, s), 7.95 (IH, s), 2.49 (3H, s). LCMS Method A: tR = 0.55 min, m/z = 393.9 [M+H]+

Reference： [1]Patent: WO2014/114779,2014,A1 .Location in patent: Page/Page column 78

36
[ 74-69-1 ]
[ 1620998-38-0 ]
[ 1620998-23-3 ]

Reference： [1]Patent: WO2014/114779,2014,A1 .Location in patent: Page/Page column 40-41; 45

37
[ 74-69-1 ]
[ 22918-01-0 ]
N-(4-chloropyridin-2-yl)-2-methylpyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium tert-butylate; In tetrahydrofuran; toluene; at 110℃; for 16h;Inert atmosphere;	[00119] t-BuOK (1.00 M in THF, 84 mL, 84 mmol) was added to a stirring mixture of 2-bromo-4 chloropyridine (14.0 g, 72.7 mmol), <strong>[74-69-1]2-methylpyrimidin-4-amine</strong> (6.1 g, 55.9 mmol), Pd(dppf)C12 (0.82 g, 1.12 mmol), and dppf (2.48 g, 4.47 mmol) in toluene (204 mL). The reaction mixture was allowed to stir at 110 C for 16 h under a nitrogen atmosphere, then was allowed to cool to rt and concentrated. The crude compound was purified by column chromatography to provide N-(4-chloropyridin-2-yl)-2- methylpyrimidin-4-amine (10 g, 8 1%). LCMS (FA): m/z = 221.0 (M+H).
81%	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium tert-butylate; In tetrahydrofuran; toluene; at 110℃; for 16h;Inert atmosphere;	[00196] t-BuOK (i.00 M in THF, 84 niL, 84 mmol) was added to a stirring mixture of 2-bromo-4 chioropyridine (i4.0 g, 72.7 mmol), <strong>[74-69-1]2-methylpyrimidin-4-amine</strong> (6.i g, 55.9 mmol), Pd(dppf)C12 (0.82 g, i.i2 mmol), and dppf (2.48 g, 4.47 mmol) in toluene (204 niL). The reaction mixture was allowed to stir at i iO C for i6 h under a nitrogen atmosphere then was allowed to cool toil and then concentrated. The crude compound was purified by column chromatography to provide N-(4-chloropyridin-2-yl)-<strong>[74-69-1]2-methylpyrimidin-4-amine</strong> (iO g, 8i% yield). LCMS (FA): m/z 22i.0 (M+n).
81%	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium tert-butylate; In tetrahydrofuran; toluene; at 110℃; for 16h;Inert atmosphere;	Step 1: N-(4-chloropyridin-2-yl)-<strong>[74-69-1]2-methylpyrimidin-4-amine</strong> t-BuOK (1.00 M in THF, 84 mL, 84 mmol) was added to a stirring mixture of 2-bromo-4 chloropyridine (14.0 g, 72.7 mmol), <strong>[74-69-1]2-methylpyrimidin-4-amine</strong> (6.1 g, 55.9 mmol), Pd(dppf)Cl2 (0.82 g, 1.12 mmol), and dppf (2.48 g, 4.47 mmol) in toluene (204 mL). The reaction mixture was allowed to stir at 110 C. for 16 h under a nitrogen atmosphere then was allowed to cool to rt and then concentrated. The crude compound was purified by column chromatography to provide N-(4-chloropyridin-2-yl)-<strong>[74-69-1]2-methylpyrimidin-4-amine</strong> (10 g, 81% yield). LCMS (FA): m/z=221.0 (M+H).

81%	With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium tert-butylate; In tetrahydrofuran; toluene; at 110℃; for 16h;Inert atmosphere;	Step 1: N-(4-chloropyridin-2-yl)-<strong>[74-69-1]2-methylpyrimidin-4-amine</strong> t-BuOK (1.00 M in THF, 84 mL, 84 mmol) was added to a stirring mixture of 2-bromo-4-chloropyridine (14.0 g, 72.7 mmol), <strong>[74-69-1]2-methylpyrimidin-4-amine</strong> (6.1 g, 55.9 mmol), Pd(dppf)Cl2 (0.82 g, 1.12 mmol), and dppf (2.48 g, 4.47 mmol) in toluene (204 mL). The reaction mixture was allowed to stir at 110 C. for 16 h under a nitrogen atmosphere, then was allowed to cool to rt and concentrated. The crude compound was purified by column chromatography to provide N-(4-chloropyridin-2-yl)-<strong>[74-69-1]2-methylpyrimidin-4-amine</strong> (10 g, 81%). LCMS (FA): m/z=221.0 (M+H).
36%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium tert-butylate; In tetrahydrofuran; toluene; at 110℃;	2-Bromo-4-chloro-pyridine (250 mg, 1 .25 mmol), <strong>[74-69-1]2-methylpyrimidin-4-amine</strong> (107 mg, 0.9 mmol), Pd012(dppf) (14 mg, 0.015 mmol) and dppf (43 mg, 0.07mmol)were taken up in Toluene. 1M KOtBu (167 mg, 1.4 mmol) in THE was added and the resulting mixture stirred at 11000 overnight. Work up and purification on a silica gel column chromatography gave the product as a solid (100 mg, 36%). MS ES+ m/z221 [M+H].

Reference： [1]Patent: WO2015/108881,2015,A1 .Location in patent: Paragraph 00119
[2]Patent: WO2015/108861,2015,A1 .Location in patent: Paragraph 00196
[3]Patent: US2015/225422,2015,A1 .Location in patent: Paragraph 0260-0261
[4]Patent: US2016/333007,2016,A1 .Location in patent: Paragraph 0233
[5]Patent: WO2019/38389,2019,A1 .Location in patent: Page/Page column 44

38
[ 74-69-1 ]
2-methyl-N-[4-(7-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)pyridin-2-yl]pyrimidin-4-amine [ No CAS ]

Reference： [1]Patent: WO2015/108881,2015,A1
[2]Patent: US2016/333007,2016,A1

39
[ 74-69-1 ]
2-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-4-amine [ No CAS ]

Reference： [1]Patent: WO2015/108881,2015,A1
[2]Patent: WO2015/108861,2015,A1
[3]Patent: US2015/225422,2015,A1
[4]Patent: US2016/333007,2016,A1

40
[ 74-69-1 ]
{6-methyl-2’-[(2-methylpyrimidin-4-yl)amino]-3,4’-bipyridin-5-yl}(pyrrolidin-1-yl)methanone [ No CAS ]

Reference： [1]Patent: WO2015/108861,2015,A1

41
[ 74-69-1 ]
N-(6-{2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl}pyrazolo[1,5-a]pyridin-4-yl)acetamide [ No CAS ]