[ CAS No. 633328-95-7 ] {[proInfo.proName]}

Name: 633328-95-7|5-Bromo-2-chloro-4-methylpyrimidine|97%
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SKU: A316150
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Quality Control of [ 633328-95-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 633328-95-7 ]

CAS No. :	633328-95-7	MDL No. :	MFCD13193654
Formula :	C₅H₄BrClN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IIALSLVGUGOODS-UHFFFAOYSA-N
M.W :	207.46	Pubchem ID :	20600736
Synonyms :

Calculated chemistry of [ 633328-95-7 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.2
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	39.71
TPSA :	25.78 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.96 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.09
Log Po/w (XLOGP3) :	2.26
Log Po/w (WLOGP) :	2.2
Log Po/w (MLOGP) :	1.33
Log Po/w (SILICOS-IT) :	2.7
Consensus Log Po/w :	2.12

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.04
Solubility :	0.188 mg/ml ; 0.000905 mol/l
Class :	Soluble
Log S (Ali) :	-2.44
Solubility :	0.757 mg/ml ; 0.00365 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.51
Solubility :	0.0635 mg/ml ; 0.000306 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.67

Safety of [ 633328-95-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P264-P271-P280-P302+P352-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P403+P233-P405-P501	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 633328-95-7 ]

* 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 [ 633328-95-7 ]
Downstream synthetic route of [ 633328-95-7 ]

[ 633328-95-7 ] Synthesis Path-Upstream 1~2

1
[ 36082-50-5 ]
[ 75-16-1 ]
[ 633328-95-7 ]

Yield	Reaction Conditions	Operation in experiment
60%	With iron(III)-acetylacetonate In tetrahydrofuran; diethyl ether at 0℃; for 25 h;	A mixture of 5-Bromo 2,4-dichloropyrimidine (0.4 g) and lron(lll)acetylacetonate (0.062 g) in Tetrahydrofuran (10 mL) was cooled to 0 °C. Methyl magnessium bromide (3 M solution in Diethylether) (0.76 mL) was added dropwise and the mixture stirred for 2 h. Saturated Aminonium Chloride solution was added and the mixture extracted with Ethyl acetate (2 X 20 mL). The organic extracts were dried over anhydrous Sodium sulphate and evaporated under reduced pressure to get a residue which was purified by Silica gel flash column chromatography eluting with a gradient of Ethyl acetate and n-heptane to afford the desired product (0.220 g, 60 percent) as a white solid. I H NMR (300 MHz, CDCI3) 6 8.52 (5, 1 H), 2.57 (5, 3H).

Reference： [1] Patent: WO2018/108671, 2018, A1, . Location in patent: Page/Page column 169; 170

2
[ 17321-93-6 ]
[ 633328-95-7 ]

Yield	Reaction Conditions	Operation in experiment
45%	With tert.-butylnitrite; N-benzyl-N,N,N-triethylammonium chloride In dichloromethane at 25℃; for 2 h;	Tert-butyl nitrite (16 g, 155 mmol) was added dropwise to a mixture of 5-bromo-4-methyl-2-pyrimidinylamine (5 g, 26.59 mmol), and benzyltriethylammoniumchloride (27 g, 118.54 mmol) in dichloromethane (200 mL). The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was diluted with H₂O (50 mL), neutralized with sat. NaHCO₃and extracted with dichloromethane (300 mL×3). All of the dichloromethane layers were combined, dried over Na₂SO₄, filtered and evaporated. The residue was purified by silica-gel column chromatography (petroleum ether/ethyl acetate=10:1) to give 5-bromo-2-chloro-4-methyl-pyrimidine (2.5 g, 45percent yield) as a white solid. LCMS (ESI) [M+H]⁺=208.9.

Reference： [1] Patent: US2018/282282, 2018, A1, . Location in patent: Paragraph 0613; 0614

[ 633328-95-7 ] Synthesis Path-Downstream 1~63

1
[ 633328-95-7 ]
[ 104706-47-0 ]
[ 1454301-74-6 ]

Yield	Reaction Conditions	Operation in experiment
89.5%	With N-ethyl-N,N-diisopropylamine; In ethanol; at 70℃; for 18h;	STEP A: (i?)-l-(5-bromo- -methylpyrimidin-2-yl)pyrrolidin-3-ol [1131] In a 500 mL pear flask equipped with a magnetic stir bar were mixed (i?)-pyrrolidin- 3-ol hydrochloride (8.94 g, 72.3 mmol), <strong>[633328-95-7]5-bromo-2-chloro-4-methylpyrimidine</strong> (15 g, 72.3 mmol), DIPEA (31.6 mL, 181 mmol), and EtOH (150 mL). The resulting yellow suspension was heated in a sand bath to 70C for 18 hours. At this time about half of the solvent was evaporated. Water (250 mL) was added to the flask while rapidly stirring the solution. An off-white precipitate formed and was filtered off, washed with water (100 mL) and dried to give the title compound (16.7 g, 89.5%).

Reference： [1]Patent: WO2013/130855,2013,A1 .Location in patent: Paragraph 1130; 1131

2
[ 633328-95-7 ]
[ 1454299-21-8 ]

Reference： [1]Patent: WO2013/130855,2013,A1

3
[ 633328-95-7 ]
(1R,5S)-3-(4-methyl-5-(6-(trifluoromethyl)-1H-indazol-4-yl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [ No CAS ]

Reference： [1]Patent: WO2013/130855,2013,A1

4
[ 633328-95-7 ]
[ 1454301-78-0 ]

Reference： [1]Patent: WO2013/130855,2013,A1

5
[ 633328-95-7 ]
[ 22255-16-9 ]
[ 1454301-76-8 ]

Yield	Reaction Conditions	Operation in experiment
64.3%	With triethylamine; In ethanol; at 75℃; for 18h;	STEP A: (1R,5S)-3-(5-bromo-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid [0631] A 100 mL round-bottom flask was charged with 5-bromo-2-chloro-4- methylpyrimidine (3.09 g, 14.87 mmol), (li?,55)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.08 g, 16.36 mmol), and Et3N (6.22 mL, 44.6 mmol) in EtOH (70 mL) to give a yellow solution. The reaction mixture was stirred at 75C for 18 hours and then partitioned between IN HC1 (40 mL) and ethyl acetate (40 mL). The organic and aqueous layers were separated, and the aqueous layer was back-extracted with ethyl acetate (75 mL). The organic layers were combined, washed with brine (40 mL), dried over Na2S04, filtered, and concentrated to give the title compound as a tan solid which was used without further purification (2.85 g,
660 mg	With triethylamine; In ethanol; at 75℃; for 72h;	STEP A: (li?,55)-3-(5-bromo-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane- 2-carboxylic acid [1141] In a 40 mL vial were mixed <strong>[633328-95-7]5-bromo-2-chloro-4-methylpyrimidine</strong> (438 mg, 2.109 mmol), (li?,55)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (295mg, 2.320 mmol), and Et3N (0.882 mL, 6.33 mmol) in EtOH (90 mL). The resulting yellow solution was stirred at 75C for 3 days. The reaction mixture was subsequently partitioned between IN HCl (40 mL) and EtOAc (40 mL). The phases were separated and the aqueous layer was back-extracted with EtOAc (75 mL). The organic layers were combined, washed with brine (40 mL), dried over Na2S04, filtered, and concentrated to give the title compound as a white solid, which was used without further purification (660 mg).

Reference： [1]Patent: WO2014/39831,2014,A1 .Location in patent: Paragraph 0630-0631
[2]Patent: WO2013/130855,2013,A1 .Location in patent: Paragraph 1140; 1141

6
[ 1124369-40-9 ]
[ 633328-95-7 ]
[ 1578255-99-8 ]

Yield	Reaction Conditions	Operation in experiment
38.7%	With triethylamine; In N,N-dimethyl-formamide; at 70℃; for 72h;Sealed tube;	STEP A: (S)-1-(5-Bromo-4-methylpyrimidin-2-yl)pyrrolidine-3-carboxylic acid [0550] 5-Bromo-2-chloro-4-methylpyrimidine (300 mg, 1.446 mmol), (5)-pyrrolidine-3- carboxylic acid hydrochloride (219 mg, 1.446 mmol), Et3N (0.605 mL, 4.34 mmol) and DMF (2 mL) were mixed in an 8 mL tube equipped with a magnetic stir bar to give an orange solution. The tube was sealed and the mixture was heated to 70C for 72 hours. The reaction was partitioned between water (20 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was back-extracted with EtOAc (20 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated to yield the title compound as a tan solid which was used without further purification (160 mg, 38.7%). MS [M+H]+ calc'd for CioHi2BrN302, 286.02; found 286.0.

Reference： [1]Patent: WO2014/39831,2014,A1 .Location in patent: Paragraph 0549-0550

7
[ 633328-95-7 ]
(S)-1-(5-(7-fluoropyrazolo[4,3-b]indol-4(1H)-yl)-4-methylpyrimidin-2-yl)pyrrolidin-3-ol trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2014/39831,2014,A1

8
[ 633328-95-7 ]
[ 1578254-85-9 ]

Reference： [1]Patent: WO2014/39831,2014,A1

9
[ 633328-95-7 ]
[ 1578255-36-3 ]

Reference： [1]Patent: WO2014/39831,2014,A1

10
[ 633328-95-7 ]
((3S)-1-(5-(7-fluoropyrazolo[4,3-b]indol-4(1H)-yl)-4-methylpyrimidin-2-yl)pyrrolidin-3-yl)(3-hydroxyazetidin-1-yl)methanone trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2014/39831,2014,A1

11
[ 633328-95-7 ]
[ 1578256-00-4 ]

Reference： [1]Patent: WO2014/39831,2014,A1

12
[ 633328-95-7 ]
[ 1578256-01-5 ]

Reference： [1]Patent: WO2014/39831,2014,A1

13
[ 633328-95-7 ]
[ 1578256-74-2 ]
[ 1578256-75-3 ]

Reference： [1]Patent: WO2014/39831,2014,A1

14
[ 633328-95-7 ]
[ 1578256-76-4 ]

Reference： [1]Patent: WO2014/39831,2014,A1

15
[ 633328-95-7 ]
(1R,5S)-3-(5-(7-fluoropyrazolo[4,3-b]indol-4(1H)-yl)-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide [ No CAS ]

Reference： [1]Patent: WO2014/39831,2014,A1

16
[ 290328-57-3 ]
[ 633328-95-7 ]
7-fluoro-4-(4-methyl-2-((S)-3-(methylsulfonyl)pyrrolidin-1-yl)pyrimidin-5-yl)-1,4-dihydropyrazolo[4,3-b]indole trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2014/39831,2014,A1

17
[ 290328-57-3 ]
[ 633328-95-7 ]
[ 1578256-82-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine; In ethanol; at 75℃; for 72h;	STEP A: (S)-5-Bromo-4-methyl-2-(3-(methylsulfonyl)pyrrolidin-1-yl)pyrimidine [0638] A 40 mL vial was charged with 5-bromo-2-chloro-4-methylpyrimidine (348 mg, 1.675 mmol), (5)-3-(methylsulfonyl)pyrrolidine (250 mg, 1.675 mmol), and Et3N (0.701 mL, 5.03 mmol) in EtOH (90 mL). The resulting yellow solution was stirred at 75C for 3 days. The reaction mixture was partitioned between water (40 mL) and ethyl acetate (40 mL). The organic and aqueous layers were separated, and the aqueous layer was back-extracted with ethyl acetate (75 mL). The organic layers were combined, washed with brine (40 mL), dried over Na2S04, filtered, and concentrated to give the title compound as a white solid, which was used without further purification (430 mg, 80%).

Reference： [1]Patent: WO2014/39831,2014,A1 .Location in patent: Paragraph 0637-0638

18
[ 633328-95-7 ]
[ 122536-94-1 ]
[ 1578253-13-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In ethanol; at 75℃; for 18h;	PREPARATION xl : (S)-1-(5-Bromo-4-methylpyrimidin-2-yl)pyrrolidin-3-ol [0148] 5-Bromo-2-chloro-4-methylpyrimidine (200 mg, 0.964 mmol), (5)-pyrrolidin-3-ol hydrochloride (0.596 g, 4.82 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.504 mL, 2.89 mmol), and ethanol (6 mL) were combined in a 40 mL vial to give a yellow solution. The reaction mixture was stirred at 75C for 18 hours. The mixture was subsequently diluted with EtOAc (75 mL), washed with water (30 mL), dried over Na2S04, and concentrated to give the title compound as an off-white solid which was used without further purification (1.25 g, 100%).

Reference： [1]Patent: WO2014/39831,2014,A1 .Location in patent: Paragraph 0147-0148

19
[ 633328-95-7 ]
(R)-piperidin-3-ol hydrochloride [ No CAS ]
[ 1578253-30-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N,N-dimethyl-formamide; at 150℃; for 1h;Sealed tube; Microwave irradiation;	PREPARATION xl4: (R)-1-(5-Bromo-4-methylpyrimidin-2-yl)piperidin-3-ol [0192] 5-Bromo-2-chloro-4-methylpyrimidine (100 mg, 0.482 mmol), (i?)-piperidin-3-ol hydrochloride (86 mg, 0.627 mmol), Et3N (0.202 mL, 1.446 mmol) and DMF (2 mL) were mixed in an 8 mL tube equipped with a magnetic stir bar to give an orange solution. The tube was sealed and the mixture was heated in a microwave to 150C for 60 minutes. The reaction mixture was subsequently partitioned between water (20 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was back-extracted with EtOAc (20 mL). The combined organic layers were concentrated to give the title compound as a tan syrup, which was used without further purification.

Reference： [1]Patent: WO2014/39831,2014,A1 .Location in patent: Paragraph 0191-0192

20
[ 5382-16-1 ]
[ 633328-95-7 ]
[ 1578253-31-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In ethanol; at 75℃; for 18h;	PREPARATION xl5: 1-(5-Bromo-4-methylpyrimidin-2-yl)piperidin-4-ol [0194] 5-Bromo-2-chloro-4-methylpyrimidine (100 mg, 0.482 mmol), piperidin-4-ol (48.8 mg, 0.482 mmol), Et3N (0.202 mL, 1.446 mmol) and EtOH (2 mL) were mixed in a 4 mL vial equipped with a magnetic stir bar to give an orange solution. The reaction mixture was stirred for 18 hours at 75C and was subsequently partitioned between water (20 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was back-extracted with EtOAc (20 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated to give crude title compound as a white solid (150 mg).

Reference： [1]Patent: WO2014/39831,2014,A1 .Location in patent: Paragraph 0193-0194

21
[ 633328-95-7 ]
[ 33208-98-9 ]
[ 1578253-39-0 ]

Yield	Reaction Conditions	Operation in experiment
97%	With triethylamine; In N,N-dimethyl-formamide; at 70℃; for 72h;Sealed tube;	REPARATION x22: (S)-1-(5-Bromo-4-methylpyrimidin-2-yl)-N-methylpyrrolidine-2-carboxamide [0208] 5-Bromo-2-chloro-4-methylpyrimidine (100 mg, 0.482 mmol), (S)-N- methylpyrrolidine-2-carboxamide hydrochloride (79 mg, 0.482 mmol), Et3N (0.202 mL, 1.446 mmol) and DMF (2 mL) were mixed in an 8 mL tube equipped with a magnetic stir bar to give an orange solution. The tube was sealed and the mixture was heated to 70C for 72 hours. The reaction mixture was subsequently partitioned between water (20 mL) and EtOAc (20 mL), the layers separated, and the aqueous layer back-extracted with EtOAc (20 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated to give the title compound as a tan solid, which was used without further purification (140 mg, 97%).

Reference： [1]Patent: WO2014/39831,2014,A1 .Location in patent: Paragraph 0207-0208

22
[ 633328-95-7 ]
[ 1273577-42-6 ]
[ 1578253-45-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In ethanol; at 110℃; for 18h;	PREPARATION x28: (R)-1-(5-Bromo-4-methylpyrimidin-2-yl)pyrrolidine-3-carboxamide [0220] A mixture of <strong>[633328-95-7]5-bromo-2-chloro-4-methylpyrimidine</strong> (100 mg, 0.482 mmol), (R)- pyrrolidine-3-carboxamide, HCl (109 mg, 0.723 mmol) and N-ethyl-N-isopropylpropan-2- amine (0.252 mL, 1.446 mmol) in EtOH (3 mL) was stirred at 1 10C for 18 hours. The reaction mixture was subsequently diluted with EtOAc, washed with water and with brine, was dried over MgS04, and was concentrated to yield the title compound, which was used without further purification (0.137 g, 100%).

Reference： [1]Patent: WO2014/39831,2014,A1 .Location in patent: Paragraph 0219-0220

23
[ 633328-95-7 ]
[ 740768-99-4 ]
[ 1578253-59-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In ethanol; at 75℃;	General procedure: PREPARATION x43: 1-(5-Bromo-4-methylpyrimidin-2-yl)piperidin-4-ol [0250] A mixture of <strong>[633328-95-7]5-bromo-2-chloro-4-methylpyrimidine</strong> (100 mg, 0.482 mmol), piperidin-4-ol (58.5 mg, 0.578 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.252 mL, 1.446 mmol) in EtOH (6 mL) was heated at 75C overnight. The mixture was subsequently diluted with EtOAc, washed with water and brine, dried over Na2S04, and concentrated to give the title compound as a brown oil, which was used without further purification (131 mg, 100%). PREPARATION x44: l-(5-Bromo-4-methylpyrimidin-2-yl)azetidine-3- carboxamide [0252] The title compound was prepared by a method similar to PREPARATION x43, using azetidine-3-carboxamide in place of piperidin-4-ol.

Reference： [1]Patent: WO2014/39831,2014,A1 .Location in patent: Paragraph 0249-0252

24
[ 633328-95-7 ]
5-bromo-4-methyl-pyrimidine-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2015/86506,2015,A1
[2]Patent: US2018/282282,2018,A1

25
[ 633328-95-7 ]
ethyl 5-bromo-4-methylpyrimidine-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/86506,2015,A1

26
[ 633328-95-7 ]
2-(5-bromo-4-methylpyrimidin-2-yl)propan-2-ol [ No CAS ]

Reference： [1]Patent: WO2015/86506,2015,A1

27
[ 773837-37-9 ]
[ 633328-95-7 ]
[ 114969-80-1 ]

Yield	Reaction Conditions	Operation in experiment
73%	With 1,4-diaza-bicyclo[2.2.2]octane; In water; dimethyl sulfoxide;	A mixture of <strong>[633328-95-7]5-bromo-2-chloro-4-methylpyrimidine</strong> (2.5 g, 12.08 mmol), sodium cyanide (600 mg, 12.24 mmol), and DABCO (500 mg, 4.46 mmol) in dimethyl sulfoxide (40 mL) and water (40 mL) was stirred overnight. The reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (80 mL×3). The ethyl acetate layers were combined, washed with brine (50 mL×2), dried over Na2SO4, filtered and concentrated. The residue was purified with silica-gel column chromatography (petroleum ether/ethyl acetate=10:1) to give 5-bromo-4-methyl-pyrimidine-2-carbonitrile (1.75 g, 73% yield) as a light yellow solid. LCMS (ESI) [M+H]+=199.9
67%	With 1,4-diaza-bicyclo[2.2.2]octane; In water; dimethyl sulfoxide; at 20℃; for 12h;	To a solution of sodium cyanide (6.18 g, 126.2 mmol) and DABCO (2.17 g, 19.41mmol) in DMSO:H20 (1:1, 200 mL) was added <strong>[633328-95-7]5-bromo-2-chloro-4-methylpyrimidine</strong>(20 g, 97.08 mmol in DMSO). The reaction mixture was stirred at room temperature for12 h, then diluted with water and extracted with ethyl acetate. The organic layer wasseparated and dried over sodium sulphate, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, using 20% ethyl acetate in hexanes as eluent, to afford the title compound (19 g, 67%) as a colourless oil. H (500 MHz, CDC13) 8.80 (s, 1H), 2.62-2.80 (m, 3H).

Reference： [1]Patent: US2018/282282,2018,A1 .Location in patent: Paragraph 0615; 0616
[2]Patent: WO2015/86506,2015,A1 .Location in patent: Page/Page column 181

28
[ 633328-95-7 ]
(S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one monohydrochloride [ No CAS ]
3-[(1S)-1-[(5-bromo-4-methylpyrimidin-2-yl)amino]ethyl]-6-chloro-1,2-dihydroquinolin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 110℃; for 12h;	A mixture of <strong>[633328-95-7]5-bromo-2-chloro-4-methylpyrimidine</strong> (440 mg, 2.122 mmol) and (S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one hydrochloride (500 mg, 1.930 mmol) was dissolved in DMSO (3 mL) and DIEA (5.79 mmol, 748 mg, 1 mL) and the solution was stirred at 110 C. for 12 hours. Once LCMS indicated most of the starting material was consumed, the mixture was cooled to room temperature and stirred for 2 days. The solution was then diluted with water and extracted with DCM (2*). The extracts were dried (Na2SO4), filtered, and evaporated under reduced pressure. The crude material was purified by silica gel chromatography on a Biotage chromatography system (eluted with 0-80% EtOAc/Hexanes) on 50 g column to afford (S)-3-(1-((5-bromo-4-methylpyrimidin-2-yl)amino)ethyl)-6-chloroquinolin-2(1H)-one (635 mg, 84% yield). 1H NMR (300 MHz, DMSO-d6): delta ppm 11.94 (s, 1H), 8.13-8.29 (m, 1H), 7.66-7.88 (m, 2H), 7.46 (dd, J=8.79, 2.35 Hz, 1H), 7.20-7.32 (m, 1H), 5.08 (br s, 1H), 2.17-2.37 (m, 3H), 1.25-1.46 (m, 3H). LCMS (Method 1): Rt 2.59 min, m/z 395.84 [M+H]+.

Reference： [1]Patent: US2016/83365,2016,A1 .Location in patent: Paragraph 0773; 0774
[2]Journal of Medicinal Chemistry,2019,vol. 62,p. 6575 - 6596

29
[ 633328-95-7 ]
(S)-3-(1-aminoethyl)-6-chloroquinolin-2(1H)-one monohydrochloride [ No CAS ]
2-[(1S)-1-(6-chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino}-4-methylpyrimidine-5-carbonitrile [ No CAS ]

Reference： [1]Patent: US2016/83365,2016,A1

30
[ 633328-95-7 ]
[ 67-63-0 ]
5-bromo-2-isopropoxy-4-methylpyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%		5-Bromo-2-isopropoxy-4-methylpyrimidine (B10.1) (0382) To a solution of <strong>[633328-95-7]5-bromo-2-chloro-4-methylpyrimidine</strong> (3.0 g, 14.5 mmol) in THF (30 mL) was added NaH (1.74 g, 44 mmol), it was stirred at rt for 0.5 h. Then propan-2-ol (2.6 g, 44 mmol) was added, the mixture was stirred at rt for 3 h. The mixture was concentrated, the residue was diluted with water (20 mL), extracted with EA (20×3 mL). The organic layer was dried and concentrated, the crude product was purified by flash chromatography (silica gel; EA:PE=1:4) to give the title compound (2.8 g, 83%)) as a gray solid. LC-MS: [M+H]+=231.0; 232.9.
83%		To a solution of 5-bromo- 2-chloro-4-methylpyrimidine (3.0 g, 14.5 mmol) in THF (30 mL)was added NaH (1.74 g,44 mmol), it was stirred at rt for 0.5 h. Then propan-2-ol (2.6 g, 44 mmol) was added, the mixture was stirred at rt for 3 h. The mixture was concentrated, the residue was diluted with water (20 mL), extracted with EA (20 x 3 mL). The organic layer was dried and concentrated, the crude product was purified by flash chromatography (silica gel; EA:PE1 :4) to give the title compound (2.8 g, 83%)) as a gray solid. LC-MS: [M+H] =231.0; 232.9.
53.9%		A fifth exemplary Intermediate D, Intermediate D-5, may be used to synthesize compounds of formula I, wherein R1 is heteroaryl substituted with two R4 substituents. To a solution of isopropanol (869 mg, 14.5 mmol, 1.11 mL, 3.00 equiv) in THF (10.0 mL) was added portionwise NaH (578 mg, 14.5 mmol, 60.0 % purity, 3.00 equiv) at 0 C. The mixture was stirred at 0 C for 0.5 h. Subsequent to the addition of <strong>[633328-95-7]5-bromo-2-chloro-4-methyl-pyrimidine</strong> (1.00 g, 4.82 mmol, 1.00 equiv) the mixture was allowed to stir at 25 C for 3 h. The mixture was poured into water (20.00 mL) and the aqueous phase was extracted with ethyl acetate (20.0 mL x 3). The combined organic phase was washed with brine (20.0 mL c 3), dried over anhydrous Na2S04, filtered and concentrated to provide 5-bromo-2-isopropoxy-4-methyl- pyrimidine (600 mg, 2.60 mmol, 53.9 % yield) as a yellow oil.

350 mg

Sodium hydride (550 mg, 60% purity, 13.75 mmol) was added batchwise into a solution of 2-propanol (1.75 g, 29.12 mmol) in tetrahydrofuran (50 mL) at 0 C. The resulting solution was stirred for 30 minutes at room temperature. 5-Bromo-2-chloro-4-methylpyrimidine (1.0 g, 4.82 mmol) was added at 0 C. The resulting solution was stirred for 16 hours at room temperature. The mixture was diluted with brine. The resulting solution was extracted with ethyl acetate, dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether/dichloromethane (2/1) to afford 5-bromo-2-isopropoxy-4-methyl-pyrimidine (350 mg, 1.51 mmol) as light yellow oil. LCMS (ESI) [M+H]+=231

Reference： [1]Patent: US2016/176882,2016,A1 .Location in patent: Paragraph 0381; 0382
[2]Patent: WO2017/221100,2017,A1 .Location in patent: Paragraph 00185
[3]Patent: WO2019/152419,2019,A1 .Location in patent: Paragraph 0300
[4]Patent: US2018/282282,2018,A1 .Location in patent: Paragraph 1705; 1706

31
[ 633328-95-7 ]
2-(2-chlorophenyl)-N-[3-[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide [ No CAS ]
N-[4-(2-chloro-4-methylpyrimidin-5-yl)-3-[(dimethylamino)methylidene]sulfamoyl}phenyl]-2-(2-chlorophenyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%	With potassium fluoride; bis(tri-t-butylphosphine)palladium(0); at 80℃; for 2h;Inert atmosphere;	To the solution containing the boronic ester intermediate 2-(2-chlorophenyl)-N-[3- [(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]acetamide (400 mg, 792 pmol), <strong>[633328-95-7]5-bromo-2-chloro-4-methylpyrimidine</strong> (362 mg,1.74 mmol) and potassium fluoride (101 mg, 1.74 mmol) were added under argon atmosphere. The solution was purged with argon for 5 minutes and bis(tri-tertbutylphosphine)palladium(0) (CAS 53199-31-8) (22.3 mg, 43.6 pmol) was added. The solution was purged again with argon and the reaction was heated at 80C for 2h. Afterwards the mixture was filtered over Celite, the solvent was removed under reduced pressure and the crude was purified by chromatography on silica gel (Biotage, hexane I ethyl acetate) to yield 124 mg (28% yield).LC-MS (Method B): R1 = 1.12 mm; MS (ESIneg): mlz = 504 [M-H]

Reference： [1]Patent: WO2017/191000,2017,A1 .Location in patent: Page/Page column 417; 418

32
[ 633328-95-7 ]
5-Bromo-4-methyl-2-(methylsulfonyl)pyrimidine [ No CAS ]

Reference： [1]Patent: WO2017/221092,2017,A1

33
[ 633328-95-7 ]
5-bromo-2-isobutyl-4-methylpyrimidine [ No CAS ]

Reference： [1]Patent: WO2017/221092,2017,A1

34
[ 633328-95-7 ]
[ 5188-07-8 ]
5-bromo-4-methyl-2-(methylthio)pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.5%	In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;	Sodium methanethiolate (1.04 g, 11.6 mmol) was added in portions into a solution of B14.1 (2.0 g, 9.66 mmol) in DMF (20 mL) at 0 oC. After addition, the mixture was stirred at rt for 16 h, then poured into water (100 mL) and extracted with EtOAc (50 mL × 3). The organic layer was washed with water (50 mL), brine (50 mL) and dried over Na2SO4, then concentrated under vacuum to give the title compound (2.0 g, 94.5 %) as a yellow oil. LC-MS: [MH]+ = 218.8.

Reference： [1]Patent: WO2017/221092,2017,A1 .Location in patent: Paragraph 00196

35
[ 36082-50-5 ]
[ 75-16-1 ]
[ 633328-95-7 ]

Yield	Reaction Conditions	Operation in experiment
60%	With iron(III)-acetylacetonate; In tetrahydrofuran; diethyl ether; at 0℃; for 25h;	A mixture of 5-Bromo 2,4-dichloropyrimidine (0.4 g) and lron(lll)acetylacetonate (0.062 g) in Tetrahydrofuran (10 mL) was cooled to 0 C. Methyl magnessium bromide (3 M solution in Diethylether) (0.76 mL) was added dropwise and the mixture stirred for 2 h. Saturated Aminonium Chloride solution was added and the mixture extracted with Ethyl acetate (2 X 20 mL). The organic extracts were dried over anhydrous Sodium sulphate and evaporated under reduced pressure to get a residue which was purified by Silica gel flash column chromatography eluting with a gradient of Ethyl acetate and n-heptane to afford the desired product (0.220 g, 60 %) as a white solid. I H NMR (300 MHz, CDCI3) 6 8.52 (5, 1 H), 2.57 (5, 3H).

Reference： [1]Patent: WO2018/108671,2018,A1 .Location in patent: Page/Page column 169; 170

36
[ 633328-95-7 ]
1-(2-isopropylphenyl)-3-[(E)-[(E)-2-methyl-3-[4-methyl-2-[N-methyl-4-(trifluoromethoxy)anilino]pyrimidin-5-yl]prop-2-enylidene]amino]thiourea [ No CAS ]

Reference： [1]Patent: WO2018/108671,2018,A1

37
[ 633328-95-7 ]
5-bromo-N,4-dimethyl-N-[4-(trifluoromethoxy)phenyl]pyrimidin-2-amine [ No CAS ]

Reference： [1]Patent: WO2018/108671,2018,A1

38
[ 633328-95-7 ]
(E)-2-methyl-3-[4-methyl-2-[N-methyl-4-(trifluoromethoxy)anilino]pyrimidin-5-yl]prop-2-enal [ No CAS ]

Reference： [1]Patent: WO2018/108671,2018,A1

39
[ 633328-95-7 ]
(2Z)-3-(2-isopropylphenyl)-2-[(E)-[(E)-2-methyl-3-[4-methyl-2-[N-methyl- 4-(trifluoromethoxy)anilino] pyrim idin-5-yl]prop-2-enylidene]hydrazono]thiazolidin-4-one [ No CAS ]

Reference： [1]Patent: WO2018/108671,2018,A1

40
[ 633328-95-7 ]
1-(2-isopropylphenyl)-3-[(E)-[2-methyl-3-[4-methyl-2-[N-methyl-4- (trifluoromethoxy)anilino]pyrimidin-5-yl]propylidene]amino]thiourea [ No CAS ]

Reference： [1]Patent: WO2018/108671,2018,A1

41
[ 633328-95-7 ]
2-methyl-3-[4-methyl-2-[N-methyl-4-(trifluoromethoxy)anilino]pyrimidin-5-yl]propanal [ No CAS ]

Reference： [1]Patent: WO2018/108671,2018,A1

42
[ 633328-95-7 ]
(2Z)-3-(2-isopropylphenyl)-2-[(E)-[2-methyl-3-[4-methyl-2-[N-methyl-4-(trifluoromethoxy)anilino]pyrimidin-5-yl]propylidene]hydrazono]thiazolidin-4-one [ No CAS ]

Reference： [1]Patent: WO2018/108671,2018,A1

43
[ 461-82-5 ]
[ 633328-95-7 ]
5-bromo-4-methyl-N-[4-(trifluoromethoxy)phenyl]pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With hydrogenchloride; water; In isopropyl alcohol; at 100℃; for 4h;	A mixture of <strong>[633328-95-7]5-bromo-2-chloro-4-methyl-pyrimidine</strong> (2 g), 4-Trifluoromethoxyaniline (2.04 g), concentrated Hydrochloric acid solution (0.2 mL) in in 2-propanol (20 mL) was heated at 100 00 for 4 h. The mixture was subsequently cooled to room temperature, poured into ice and basified with a saturated solution Sodium bicarbonate solution and precipitated solids were filtered. The filteredsolid was subjected to Silica gel flash column chromatography eluting with a gradient of Ethyl acetate and n-Heptane to afford the desired product (1 .75 g, 52 %) as an off-white solid. LCMS:Rt: 2.20 min; MS: mz = 346.1 (M-1); IH NMR (300 MHz, CDCI3) 68.32(s, IH), 7.88 (5, IH), 7.63-7.51 (m, 2H), 7.19 -7.07 (m, 2H), 2.50 (5, 3H).

Reference： [1]Patent: WO2018/108671,2018,A1 .Location in patent: Paragraph 169; 170

44
[ 39093-93-1 ]
[ 633328-95-7 ]
4-(5-bromo-4-methylpyrimidin-2-yl)-1-thiomorpholine-1,1-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 48h;	Step 1: DIPEA (804 pL, 4.70 mmol) was added to 5-bromo-2-chloro-4- methylpyrimidine (650 mg, 3.13 mmol) dissolved in CH3CN (20 mL). Then, thiomorpholine-1 ,1-dioxide (508 mg, 3.76 mmol) was added to the mixture. The mixture reaction was heated at 75C for 48h. Solvent was removed under reduced pressure. H20 and AcOEt were added to the residue. The organic layer was separated, dried over Mg504, filtered and the solution was concentrated to dryness to afford 4-(5-bromo-4-methylpyrimid in-2-yl)-1 - thiomorpholine-1 ,1-dione Ex.30a (732 mg, 76%) as yellow solid. The compound was used as such in the next step.

Reference： [1]Patent: WO2018/138359,2018,A1 .Location in patent: Page/Page column 41; 53; 54

45
[ 633328-95-7 ]
methyl 2-[2-(1,1-dioxo-1-thiomorpholin-4-yl)-4-methylpyrimidin-5-yl]-3-oxobutanoate [ No CAS ]

Reference： [1]Patent: WO2018/138359,2018,A1

46
[ 17321-93-6 ]
[ 633328-95-7 ]

Yield	Reaction Conditions	Operation in experiment
45%	With tert.-butylnitrite; N-benzyl-N,N,N-triethylammonium chloride; In dichloromethane; at 25℃; for 2h;	Tert-butyl nitrite (16 g, 155 mmol) was added dropwise to a mixture of 5-bromo-4-methyl-2-pyrimidinylamine (5 g, 26.59 mmol), and benzyltriethylammoniumchloride (27 g, 118.54 mmol) in dichloromethane (200 mL). The reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was diluted with H2O (50 mL), neutralized with sat. NaHCO3 and extracted with dichloromethane (300 mL×3). All of the dichloromethane layers were combined, dried over Na2SO4, filtered and evaporated. The residue was purified by silica-gel column chromatography (petroleum ether/ethyl acetate=10:1) to give 5-bromo-2-chloro-4-methyl-pyrimidine (2.5 g, 45percent yield) as a white solid. LCMS (ESI) [M+H]+=208.9.

Reference： [1]Patent: US2018/282282,2018,A1 .Location in patent: Paragraph 0613; 0614

47
[ 633328-95-7 ]
5-bromo-N,N,4-trimethyl-pyrimidine-2-carboxamide [ No CAS ]