[ CAS No. 56181-39-6 ] {[proInfo.proName]}

Name: 56181-39-6|5-Bromo-4-chloropyrimidine|95%
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SKU: A180868
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Quality Control of [ 56181-39-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 56181-39-6 ]

Product Details of [ 56181-39-6 ]

CAS No. :	56181-39-6	MDL No. :	MFCD09750158
Formula :	C₄H₂BrClN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WTVLUSWQWGHYIS-UHFFFAOYSA-N
M.W :	193.43	Pubchem ID :	12270078
Synonyms :

Calculated chemistry of [ 56181-39-6 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	34.74
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) :	-6.17 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.68
Log Po/w (XLOGP3) :	1.85
Log Po/w (WLOGP) :	1.89
Log Po/w (MLOGP) :	0.99
Log Po/w (SILICOS-IT) :	2.38
Consensus Log Po/w :	1.76

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.76
Solubility :	0.336 mg/ml ; 0.00174 mol/l
Class :	Soluble
Log S (Ali) :	-2.01
Solubility :	1.88 mg/ml ; 0.00972 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.12
Solubility :	0.145 mg/ml ; 0.000752 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.53

Safety of [ 56181-39-6 ]

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 [ 56181-39-6 ]

* 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 [ 56181-39-6 ]
Downstream synthetic route of [ 56181-39-6 ]

[ 56181-39-6 ] Synthesis Path-Upstream 1~6

1
[ 56181-39-6 ]
[ 1439-10-7 ]

Reference： [1] Journal of the Chemical Society, 1955, p. 3478,3481

2
[ 19808-30-1 ]
[ 56181-39-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	for 3 h; Reflux	To a mixture of 5-bromopyrimidin-4-ol (1-111) (40 g, 0.22 mol) in POCI3 (300 mL) was added in a dropwise manner DIPEA (29 g, 0.22 mol) at room temperature. Then the resulting mixture was heated to reflux for 3 hr. TLC (petroleum ether/EtOAc 1 :1) showed the reaction was complete. Excess POCI3 was removed through distillation under reduced pressure. The residue was poured into ice-water (300 mL) slowly with stirring. The mixture was extracted with EtOAc (2 x 300 mL), the combined organic layers were washed with water (300 mL), brine (300 mL), dried over Na2S04 and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether/EtOAc from 20:1 to 10:1) to give 5-bromo-4-chloropyrimidine (1-112) (25 g, 60percent) as a yellow oil.
43%	at 100℃;	EXAMPLE 12: 5-bromo-4-chloropyrimidine15 A stirred solution of 5-bromopyrimidin-4-ol (650mg, 3.73mmol) in POCI₃ (in excess) was heated at 100°C overnight. The reaction mixture was cooled and concentrated under reduced pressure. Crude product was dissolved in ethyl acetate and this mixture was slowly poured into saturated sodium bicarbonate solution. The ethyl acetate layer was separated and washed with brine solution, and dried over anhydrous sodium sulphate and concentrated to get the desired product 15 as yellow solid, 300mg (Yield- 43percent). The product was confirmed by ¹HNMR and MS spectrum analysis. 1H NMR (400 MHz, CDC1₃) δ: 8.86 (s, 1H), 8.82 (s, 1H); MS- 192 (M+l).

Reference： [1] Patent: WO2016/97918, 2016, A1, . Location in patent: Page/Page column 88
[2] Patent: WO2012/135631, 2012, A1, . Location in patent: Page/Page column 21-22
[3] Patent: WO2010/88518, 2010, A2, . Location in patent: Page/Page column 86-87
[4] Organic Process Research and Development, 2000, vol. 4, # 4, p. 275 - 285

3
[ 19808-30-1 ]
[ 56181-39-6 ]

Reference： [1] Journal of the Chemical Society, 1955, p. 3478,3481
[2] European Journal of Organic Chemistry, 2012, # 34, p. 6777 - 6784

4
[ 19808-30-1 ]
[ 10025-87-3 ]
[ 56181-39-6 ]

Reference： [1] Helvetica Chimica Acta, 1922, vol. 5, p. 278

5
[ 56181-39-6 ]
[ 124-41-4 ]
[ 4319-85-1 ]

Yield	Reaction Conditions	Operation in experiment
79%	at 60℃; for 15 h;	Compound (VII-36) (9.90 g, 41.2 mmol) was dissolved in methanol (140 mL), 28percent sodium methoxide methanolsolution (24 mL, 120 mmol) was added and the mixture was stirred at 60°C for 15 hr. The reaction mixture was allowedto cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturatedbrine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure to givecompound (VII-37) (yield 7.72 g, 79percent) as a pale-yellow solid

Reference： [1] Patent: EP3351533, 2018, A1, . Location in patent: Paragraph 0510; 0511

6
[ 67-56-1 ]
[ 56181-39-6 ]
[ 4319-85-1 ]

Yield	Reaction Conditions	Operation in experiment
79%	at 60℃; for 15 h;	The compound (VII-36) (9.90 g, 41.2 mmol) was dissolved in methanol (140 mL), 28percent sodium methoxide methanol solution (24 mL, 120 mmol) was added and the mixture was stirred at 60 ° C. for 15 hours. The reaction solution was allowed to cool, water was added,And extracted with ethyl acetate.The organic layer was washed with saturated brine,After drying with anhydrous sodium sulfate, filtration was carried out.The solvent was distilled off under reduced pressure to obtain compound (VII-37)(Yield 7.72 g, Yield 79percent)As a pale yellow solid.

Reference： [1] Patent: JP2018/145180, 2018, A, . Location in patent: Paragraph 0478; 0479; 0480

[ 56181-39-6 ] Synthesis Path-Downstream 1~53

1
[ 19808-30-1 ]
[ 56181-39-6 ]

Reference： [1]Journal of the Chemical Society,1955,p. 3478,3481
[2]European Journal of Organic Chemistry,2012,p. 6777 - 6784

2
[ 56181-39-6 ]
[ 1439-10-7 ]

Reference： [1]Journal of the Chemical Society,1955,p. 3478,3481

3
[ 56181-39-6 ]
(5-bromo-pyrimidin-4-yl)-hydrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine; In ethanol; at 20℃;	Step 4: 5-Bromo-4-hydrazinylpyrimidine[0363] A 100-mL round-bottomed flask was charged with a solution of 5- bromo-4-chloropyrimidine (8 g, 25.00 mmol, 1.00 equiv, 60%) in ethanol (50 mL). To this solution was added hydrazine (10 mL, 99%) drop wise with stirring. The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by TLC (MeOH: DCM = 1: 10). The solids were collected by filtration affording 5-bromo-4-hydrazinylpyrimidine as yellow solid (0.83 g, 18%).

Reference： [1]Journal of the Chemical Society,1955,p. 3478,3481
[2]Patent: WO2010/88518,2010,A2 .Location in patent: Page/Page column 87

4
[ 56181-39-6 ]
[ 1121-24-0 ]
[ 93577-95-8 ]

Reference： [1]Journal of Heterocyclic Chemistry,1984,vol. 21,p. 995 - 1000

6
5-bromo-4-oxy-pyrimidine [ No CAS ]
[ 56181-39-6 ]

Reference： [1]Helvetica Chimica Acta,1922,vol. 5,p. 278

7
[ 19808-30-1 ]
[ 10025-87-3 ]
[ 56181-39-6 ]

Reference： [1]Helvetica Chimica Acta,1922,vol. 5,p. 278

8
5-(tributylstannanyl)nicotinic acid ethyl ester [ No CAS ]
[ 56181-39-6 ]
[ 405939-98-2 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 1886 - 1900

9
[ 19808-30-1 ]
[ 56181-39-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	With N-ethyl-N,N-diisopropylamine; trichlorophosphate; for 3h;Reflux;	To a mixture of 5-bromopyrimidin-4-ol (1-111) (40 g, 0.22 mol) in POCI3 (300 mL) was added in a dropwise manner DIPEA (29 g, 0.22 mol) at room temperature. Then the resulting mixture was heated to reflux for 3 hr. TLC (petroleum ether/EtOAc 1 :1) showed the reaction was complete. Excess POCI3 was removed through distillation under reduced pressure. The residue was poured into ice-water (300 mL) slowly with stirring. The mixture was extracted with EtOAc (2 x 300 mL), the combined organic layers were washed with water (300 mL), brine (300 mL), dried over Na2S04 and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether/EtOAc from 20:1 to 10:1) to give 5-bromo-4-chloropyrimidine (1-112) (25 g, 60%) as a yellow oil.
43%	With trichlorophosphate; at 100℃;	EXAMPLE 12: 5-bromo-4-chloropyrimidine15 A stirred solution of 5-bromopyrimidin-4-ol (650mg, 3.73mmol) in POCI3 (in excess) was heated at 100C overnight. The reaction mixture was cooled and concentrated under reduced pressure. Crude product was dissolved in ethyl acetate and this mixture was slowly poured into saturated sodium bicarbonate solution. The ethyl acetate layer was separated and washed with brine solution, and dried over anhydrous sodium sulphate and concentrated to get the desired product 15 as yellow solid, 300mg (Yield- 43%). The product was confirmed by 1HNMR and MS spectrum analysis. 1H NMR (400 MHz, CDC13) delta: 8.86 (s, 1H), 8.82 (s, 1H); MS- 192 (M+l).
	With N,N-dimethyl-aniline; trichlorophosphate; at 130℃;	Step 3: 5-Bromo-4-chloropyrimidine[0362] Into a 500-mL round-bottomed flask was charged with 5- bromopyrimidin-4-ol (22 g, 63.22 mmol, 1.00 equiv, 50 %), N,N- dimethylbenzenamine (4 mL), POCI3 (266.8 g). The resulting solution was stirred at 1300C in an oil bath overnight. The mixture was cooled down to room temperature and diluted with ether (1 L). The pH was adjusted to 9 with sodium bicarbonate/water. The resulting mixture was extracted with ether (4x1 L). Combined organic layers were washed with brine (2x1 L), dried over anhydrous sodium sulfate, filtered and concentrated under vacuum affording 5-bromo-4- chloropyrimidine as black liquid (15 g, 124%).

Reference： [1]Patent: WO2016/97918,2016,A1 .Location in patent: Page/Page column 88
[2]Patent: WO2012/135631,2012,A1 .Location in patent: Page/Page column 21-22
[3]Patent: WO2010/88518,2010,A2 .Location in patent: Page/Page column 86-87
[4]Organic Process Research and Development,2000,vol. 4,p. 275 - 285

10
[ 56181-39-6 ]
[ 2365-48-2 ]
[ 1352794-95-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium carbonate; In N,N-dimethyl-formamide; at 150℃; for 0.333333h;microwave irradiation;	[00301] Step A: methyl 2-(5-bromopyrimidin-4-ylthio)acetateA mixture of <strong>[56181-39-6]4-chloro-5-bromopyrimidine</strong> (0.193g, l .Ommol), methyl 2- mercaptoacetate (0.116g, l . lmmol) and sodium carbonate (0.159g, 1.5mmol) in DMF (0.7mL) was heated under microwave irradiation to 150C for 20 minutes. The mixture was washed with water, extracted with ethyl acetate and purified by chromatography to yield methyl 2-(5-bromopyrimidin-4-ylthio)acetate (0.22g, 84%).

Reference： [1]Patent: WO2011/159839,2011,A2 .Location in patent: Page/Page column 105

11
[ 56181-39-6 ]
[ 1352794-90-1 ]
[ 1352794-96-7 ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 12h;	[00307] Step A: 4-(5-Bromopyrimidin-4-yl)-l-naphthonitrileA mixture of <strong>[56181-39-6]4-chloro-5-bromopyrimidine</strong> (193mg, lmmol), 4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l-naphthonitrile (279mg, lmmol) palladium tetrakis triphenylphoshine (0.023g, 0.02mmol) and aqueous sodium carbonate solution (2M, 1.5mL, 3mmol) in dioxane (3mL) was heated to 80C for 12 hours. The reaction mixture cooled to room temperature, washed with water, extracted with ethyl acetate and purified by chromatography to yield 4-(5-bromopyrimidin-4-yl)-l-naphthonitrile (214mg, 69%).

Reference： [1]Patent: WO2011/159839,2011,A2 .Location in patent: Page/Page column 109

12
[ 41838-46-4 ]
[ 56181-39-6 ]
[ 1289021-14-2 ]

Yield	Reaction Conditions	Operation in experiment
40%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80℃;	EXAMPLE 13: 5-bromo-N-(l-methylpiperidin-4-yl)pyridine-4-amine17To a stirred solution of <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (300mg, 1.562mmol) in DMF, DIPEA (400mg, 3.124mmol) was added followed by l-methylpiperidine-4-amine (0.193ml, 1.562mmol) and the reaction mixture was heated at 80 C overnight. TLC showed absence SM, and then reaction mixture was concentrated. The crude product was purified by flash column chromatography over 230-400 mesh silica gel and using a mixture of 30% EtO Ac/petroleum ether to afford the desired product 17, 180mg (Yield: 40 %) as yellow solid. The product was confirmed by 1FiNMR and MS spectrum analysis. 1H NMR (400 MHz, CDC13) delta: 8.4 (s, 1H), 8.35 (s, 1H), 6.81 (d, 1H), 4.95 (m, 1H), 2.78 (d, 2H), 2.17 (s, 3H), 1.95 (t, 2H), 1.6-1.8 (m, 4H); MS- 270 (M+l).

Reference： [1]Patent: WO2012/135631,2012,A1 .Location in patent: Page/Page column 22

13
[ 56181-39-6 ]
[ 683-60-3 ]
[ 1427688-88-7 ]

Reference： [1]European Journal of Organic Chemistry,2012,p. 6777 - 6784

14
[ 56181-39-6 ]
[ 1350643-72-9 ]
[ 1425045-78-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; for 2h;Reflux;	Example 241:[1222] The amine 1 (4.00 g, 13.39 mmol) and <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> were suspended in 1-butanol (65 mL) and charged with Hunig's Base (2.338 ml, 13.39 mmol). The mixture was heated to reflux for 2 h. The reaction was cooled to room temperature, diluted with toluene (50 mL) and concentrated. The residue was suspended in toluene (50 mL) and heated to reflux until all solids dissolved to form a solution. The solution was then cooled to 0 C. The resulting solid was filtered and washed with cold toluene to give the bromide 421

Reference： [1]Patent: US2013/53362,2013,A1 .Location in patent: Paragraph 1221; 1222

15
[ 56181-39-6 ]
[ 17356-08-0 ]
C₅H₅BrN₄S*ClH [ No CAS ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 275 - 285

16
[ 56181-39-6 ]
[ 5188-07-8 ]
[ 14001-68-4 ]

Reference： [1]Organic Process Research and Development,2000,vol. 4,p. 275 - 285

17
[ 56181-39-6 ]
[ 137076-22-3 ]
tert-butyl 4-[(4-chloropyrimidin-5-yl)(hydroxy)methyl]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		To a - 30 C solution of <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (1-112) (13 g, 0.07 mol) in anhydrous THF (130 ml_) was added in a dropwise manner a solution of /'-PrMgCI (50 ml_, 0.1 mol, 2M in THF). Then the resulting mixture was stirred at - 30 C for 30 min. A solution of tert-butyl 4-formylpiperidine-1 -carboxylate (15 g, 0.07 mol) in THF (20 ml_) was added to the above solution at - 30 C. After the addition, the mixture was allowed to room temperature, and stirred for a further 4 hr. TLC (petroleum ether/EtOAc 3:1 ) showed the reaction was complete. Saturated aq. NH4CI (200 ml_) was added to quench the reaction at 0 C. The mixture was extracted with EtOAc (2 x 200 ml_). The organic layers were dried over Na2S04 and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether/EtOAc from 10:1 to 3:1 ) to give tert-butyl 4-[(4-chloropyrimidin-5-yl)(hydroxy)methyl]piperidine-1 -carboxylate (1-113) (13.7 g, 60%) as a pale white solid .1H NMR (400 MHz, CDCI3) delta ppm 8.91 (s, 1 H), 8.83 (s, 1 H), 4.85 - 4.93 (m, 1 H), 4.14 (br. s., 2 H), 2.55 - 2.62 (m, 3 H), 1 .83 - 1 .92 (m, 1 H), 1 .41 - 1 .46 (m, 15 H).

Reference： [1]Patent: WO2016/97918,2016,A1 .Location in patent: Page/Page column 89

18
[ 56181-39-6 ]
[ 100-51-6 ]
[ 1232361-96-4 ]

Yield	Reaction Conditions	Operation in experiment
80%		Benzyl alcohol (1.02 ml, 9.82 mmol,2.00 eq) was dissolved in 12 ml of dimethyl formamide (DMF) (12 ml), and sodium hydride (248 mg, 9.82 mmol, 2.00 eq) was added. After 5 minutes <strong>[56181-39-6]5-bromo-4-chloro-pyrimidine</strong> (950 mg, 4.91 mmol, 1.00 eq) was added as a solution in DMF (4 ml). The reaction was stirred overnight and then quenched with a saturated solution of ammonium chloride. The mixture was diluted with ethyl acetate and washed with water (2). The aqueous washes were back extracted with ethyl acetate, and the combined organics were dried (MgSO4),filtered, and concentrated in vacuo. Purification using 0%-20% hexanes/ethyl acetate afforded 1.04 g (80%) of the title compound as a clear oil: ES-MS[M + 1]+: 265.0.

Reference： [1]Drug Metabolism and Disposition,2017,vol. 45,p. 1245 - 1259

19
[ 56181-39-6 ]
2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester hemioxylate [ No CAS ]
tert-butyl 6-(5-bromopyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 15h;Reflux;	Step 4. tert-butyl 6-(5-bromopyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0755) A suspension of <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (1.67 g, 8.65 mmol), tert-butyl 2,6- diazaspiro[3.3]heptane-2-carboxylate hemioxalate salt (2 g, 4.12 mmol) and iPr2NEt (1.80 mL, 10.3 mmol) in iPrOH (10 mL) was heated at reflux for 15 h. Saturated NH4Cl aqueous solution (10 mL) and EtOAc (20 mL) were added to the reaction for the workup. The EtOAc layer was separated and the aqueous layer was extracted again with EtOAc. The EtOAc layers were combined, washed with water, then brine, and dried using Na2SO4. Evaporation of the EtOAc gave tert-butyl 6-(5-bromopyrimidin-4-yl)-2,6- diazaspiro[3.3]heptane-2-carboxylate as an off-white foamy solid (2 grams, 70%) that was nearly pure by LCMS analysis and used directly for the next step without further purification. LCMS method A: tR = 1.330 min; [M + H]+ = 355.41 and 357.

Reference： [1]Patent: WO2017/214367,2017,A1 .Location in patent: Page/Page column 150-151

20
[ 56181-39-6 ]
[ 124-41-4 ]
[ 4319-85-1 ]

Yield	Reaction Conditions	Operation in experiment
79%	In methanol; at 60℃; for 15h;	Compound (VII-36) (9.90 g, 41.2 mmol) was dissolved in methanol (140 mL), 28% sodium methoxide methanolsolution (24 mL, 120 mmol) was added and the mixture was stirred at 60C for 15 hr. The reaction mixture was allowedto cool, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturatedbrine, dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure to givecompound (VII-37) (yield 7.72 g, 79%) as a pale-yellow solid

Reference： [1]Patent: EP3351533,2018,A1 .Location in patent: Paragraph 0510; 0511

21
[ 56181-39-6 ]
[ 455-14-1 ]
C₁₁H₇BrF₃N₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With p-toluenesulfonic acid monohydrate; In 1-methyl-pyrrolidin-2-one; at 60℃; for 2h;	Compound (III-11) (120 mg, 0.620 mmol) and compound (IIb-2) (150 mg, 0.931 mmol) were dissolved in NMP (2.0 mL), And p-toluenesulfonic acid monohydrate(118 mg, 0.620 mmol) was added,Followed by stirring at 60 C. for 2 hours. The reaction solution was allowed to cool,Water was added and extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate,It was filtered. After distilling off the solvent under reduced pressure,The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate)Compound (IV-122)(Yield 100 mg, Yield 51%)Was obtained.
51%	With toluene-4-sulfonic acid; In 1-methyl-pyrrolidin-2-one; at 60℃; for 2h;	Compound (III-11) (120 mg, 0.620 mmol) and compound (IIb-2) (150 mg, 0.931 mmol) were dissolved in NMP(2.0 mL), p-toluenesulfonic acid monohydrate (118 mg, 0.620 mmol) was added and the mixture was stirred at 60C for2 hr. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate) to give compound (IV-122)(yield 100 mg, 51%)

Reference： [1]Patent: JP2018/145180,2018,A .Location in patent: Paragraph 0772; 0773; 0774
[2]Patent: EP3351533,2018,A1 .Location in patent: Paragraph 0848; 0849

22
[ 67-56-1 ]
[ 56181-39-6 ]
[ 4319-85-1 ]

Yield	Reaction Conditions	Operation in experiment
79%	With sodium methylate; at 60℃; for 15h;	The compound (VII-36) (9.90 g, 41.2 mmol) was dissolved in methanol (140 mL), 28% sodium methoxide methanol solution (24 mL, 120 mmol) was added and the mixture was stirred at 60 C. for 15 hours. The reaction solution was allowed to cool, water was added,And extracted with ethyl acetate.The organic layer was washed with saturated brine,After drying with anhydrous sodium sulfate, filtration was carried out.The solvent was distilled off under reduced pressure to obtain compound (VII-37)(Yield 7.72 g, Yield 79%)As a pale yellow solid.

Reference： [1]Patent: JP2018/145180,2018,A .Location in patent: Paragraph 0478; 0479; 0480

23
[ 56181-39-6 ]
6-methoxy-1-[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole-5-amine [ No CAS ]
1-((2-(trimethylsilyl)ethoxy)methyl)-5-((5-bromopyrimidin-4-yl)amino)-6-methoxyindazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With caesium carbonate; In N,N-dimethyl-formamide; at 150℃; for 1h;Inert atmosphere; Microwave irradiation;	The compound 1-((2-(trimethylsilyl)ethoxy)methyl)-5-amino-6-methoxyindazole 57a (200 mg,0.68 mmol), <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (164 mg, 0.9 mmol), cesium carbonate (445 mg, 1.4 mmol) and N,N-dimethylformamide (5 mL) was mixed and reacted under microwave at 150 C for 1 hour. This mixture was diluted with dichloromethane (20 mL) with saturated brineWash with water (50 mL x 2). Dry the organic phase with anhydrous sodium sulfate, remove the desiccant by filtration, and decompose the mixture under reduced pressure to obtain a crude product.Fast column chromatography (dichloromethane:methanol = 20:1) gave the desired product 1-((2-(trimethylsilyl)ethoxy)methyl)-5-(5-Bromopyrimidin-4-yl)amino)-6-methoxyindazole 57b (102.0 mg, 0.23 mmol, yellow oily).34%.

Reference： [1]Patent: CN109020957,2018,A .Location in patent: Paragraph 0241

24
[ 56181-39-6 ]
[ 14002-80-3 ]
methyl 3-((5-bromopyrimidin-4-yl)oxy)-2,2-dimethylpropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%		To a 100 mL round-bottomed flask containing sodium hydride (60 wt %, 0.155 g, 3.88 mmol) was added to DMF (8 mL) to give a white suspension. Methyl 3-hydroxy -2,2- dimethylpropanoate (0.342 g, 2.58 mmol) was added dropwise. After stirring for 1 hour at room temperature, a solution of <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (0.500 g, 2.58 mmol) in DMF (2 mL) was added. The mixture was stirred at room temperature overnight. The reaction was quenched with saturated aq NH4Cl and extracted with EtOAc. The organic phase was washed with brine, dried over MgSCft, filtered, and concentrated. The residue was purified via automated flash silica column chromatography (40 g column) eluting with a gradient of 20- 50% EtOAc in heptanes. The fractions containing the desired product were evaporated to give the title compound as a brown syrup (0.362 g, 48%). ESI-MS [M+H]+ calc?d for CioHi3BrN203, 289.02, 291.02; found 291.0.

Reference： [1]Patent: WO2019/169153,2019,A1 .Location in patent: Paragraph 0225

25
[ 56181-39-6 ]
(S)-2-amino-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl) (2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)(2-(2,2,2-trifluoroethoxy)ethyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 70℃; for 3h;	To a mixture of (S)-2-amino-4-((4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl) (2-(2,2,2-trifluoroethoxy)ethyl)amino) butanoic acid (140 mg, 259 mumol) in THF (4 mL) and H2O (1 mL) was added <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (55 mg, 285 mumol) and NaHCO3 (109 mg, 1.29 mmol) and the resulting mixture was heated to 70 C. for 3 h, cooled to rt, and then concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z=589.1 (M+H)+.

Reference： [1]Patent: US2019/276449,2019,A1 .Location in patent: Paragraph 1505

26
[ 56181-39-6 ]
(S)-2-amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid trifluoroacetate [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl) amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 70℃; for 2h;	To a solution of (S)-2-amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid trifluoroacetate (150 mg, 0.3 mmol) in 4:1 THF/H2O (3 mL) was added <strong>[56181-39-6]5-bromo-4-chloro-pyrimidine</strong> (69 mg, 0.4 mmol) and NaHCO3 (137 mg, 1.63 mmol) and then was stirred at 70 C. for 2 h and then cooled to rt and concentrated in vacuo. The crude residue was used without further purification.

Reference： [1]Patent: US2019/276449,2019,A1 .Location in patent: Paragraph 0682; 0687

27
[ 56181-39-6 ]
(S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-(((R)-2-methoxypropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 70℃; for 2h;	To a solution of (S)-2-amino-4-(((R)-2-methoxypropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid hydrochloride (100 mg, 241 mumol) and <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (51 mg, 265 mumol) in 4:1 THF/H2O (2.5 mL) was added NaHCO3 (101 mg, 1.20 mmol) and the resulting mixture was stirred at 70 C. for 2 h. The mixture was cooled to rt and then adjusted to pH=6 by aq. 1 M HCl and then concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z=535.3 (M+H)+.

Reference： [1]Patent: US2019/276449,2019,A1 .Location in patent: Paragraph 0778

28
[ 56181-39-6 ]
(S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 70℃; for 1h;	To a solution of (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid hydrochloride (250 mg, 577 mumol) and <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (134 mg, 693 mumol) in THF (2 mL) and H2O (0.5 mL) was added NaHCO3 (243 mg, 2.89 mmol) and the resulting mixture was stirred at 70 C. for 1 h and then allowed to cool to rt and then adjusted to pH=6 by the addition of 1 M aq. HCl and concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z=554.2 (M+H)+.

Reference： [1]Patent: US2019/276449,2019,A1 .Location in patent: Paragraph 0856

29
[ 56181-39-6 ]
(S)-2-amino-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2,2-difluoroethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 70℃; for 1h;	To a solution of (S)-2-amino-4-((2,2-difluoroethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid (150 mg, 405 mumol) and <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (94 mg, 486 mumol) in THF (1.2 mL) and H2O (0.3 mL) was added NaHCO3 (170 mg, 2.02 mmol) and the resulting mixture was stirred at 70 C. for 1 h and then allowed to cool to rt and then adjusted to pH=6 by the addition of 1 M aq. HCl and concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z=527.2 (M+H)+

Reference： [1]Patent: US2019/276449,2019,A1 .Location in patent: Paragraph 0840

30
[ 56181-39-6 ]
(S)-2-amino-4-((2-phenoxyethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 70℃; for 2h;	To a (S)-2-amino-4-((2-phenoxyethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid hydrochloride (150 mg, 324 mumol) in 4:1 THF/H2O (2 mL) was added <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (69 mg, 356 mumol) and NaHCO3 (136, 1.62 mmol) and the resulting mixture was stirred at 70 C. for 2 h. The reaction mixture was cooled to rt and then concentrated in vacuo to give a (S)-2-((5-bromopyrimidin-4-yl) amino)-4-((2-phenoxyethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid intermediate, which was used without further purification. Of the butanoic acid intermediate, 189 mg, 324 mumol, was mixed with phenylboronic acid (43 mg, 356 mumol) in 3:1 dioxane/H2O (3 mL), to which was added K2CO3 (90 mg, 649 mumol) then Pd(dppf)Cl2 (24 mg, 32 mumol) and the resulting mixture was heated to 100 C. for 2 h. The reaction mixture was cooled to rt and then concentrated in vacuo. The crude residue was purified by reverse phase prep-HPLC to give the title compound. LCMS (ESI+): m/z=581.3 (M+H). H NMR (400 MHz, Methanol-d4) delta ppm 8.42 (s, 1H) 7.94 (s, 1H) 7.45-7.51 (m, 2H) 7.38-7.45 (m, 3H) 7.20-7.30 (m, 3H) 6.83-7.00 (m, 3H) 6.42 (d, J=7.34 Hz, 1H) 4.52 (dd, J=6.79, 4.22 Hz, 1H) 4.19 (t, J=5.14 Hz, 2H) 3.33-3.41 (m, 3H) 3.20-3.30 (m, 2H) 2.88-3.11 (m, 3H) 2.70 (t, J=6.17 Hz, 2H) 2.57 (brt, J=6.97 Hz, 2H) 2.22-2.32 (m, 1H) 2.12-2.20 (m, 1H) 1.86 (q, J=5.90 Hz, 2H) 1.55-1.72 (m, 4H).

Reference： [1]Patent: US2019/276449,2019,A1 .Location in patent: Paragraph 1064

31
[ 56181-39-6 ]
(S)-2-amino-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-((3,3-difluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 60℃; for 17h;	To a solution of (S)-2-amino-4-((3,3-difluoropropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid (140 mg, 344 mumol) in THF (4 mL) and H2O (1 mL) was added <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (73 mg, 378 mumol) and NaHCO3 (144 mg, 1.72 mmol) and the resulting mixture was heated to 60 C. for 17 h and then cooled to rt and then concentrated in vacuo. The crude residue was used without further purification. LCMS (ESI+): m/z=540.9 (M+H)+.

Reference： [1]Patent: US2019/276449,2019,A1 .Location in patent: Paragraph 1008

32
[ 56181-39-6 ]
(S)-2-amino-4-((3-fluoropropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-((3-fluoropropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 60℃; for 17h;	To a solution of (S)-2-amino-4-((3-fluoropropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid (140 mg, 344 mumol) in THF (4 mL) and H2O (1 mL) was added <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (73 mg, 378 mumol) and NaHCO3 (144 mg, 1.72 mmol) and the resulting mixture was stirred for 17 h at 60 C. and then cooled to rt and concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z=523.2 (M+H)+

Reference： [1]Patent: US2019/276449,2019,A1 .Location in patent: Paragraph 1025

33
[ 56181-39-6 ]
(S)-2-amino-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-(dimethylamino)-2-oxoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 70℃; for 2h;	To a mixture of (S)-2-amino-4-((2-(dimethylamino)-2-oxoethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid (150 mg, 383 mumol) and <strong>[56181-39-6]5-bromo-4-chloro-pyrimidine</strong> (89 mg, 460 mol) in THF (2 mL) and H2O (0.5 mL) was added NaHCO3 (161 mg, 1.92 mmol) and the resulting mixture was stirred at 70 C. for 2 h and then allowed to cool to rt and then concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z=548.4 (M+H)+.

Reference： [1]Patent: US2019/276449,2019,A1 .Location in patent: Paragraph 1152

34
[ 56181-39-6 ]
(S)-2-amino-4-((3,3-difluorocyclobutyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-((3,3-difluorocyclobutyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 70℃; for 1h;	To a mixture of (S)-2-amino-4-((3,3-difluorocyclobutyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid (140 mg, 247 mumol) in THF (4 mL) and H2O (1 mL) was added <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (53 mg, 272 mumol) and NaHCO3 (104 mg, 1.24 mmol) and the resulting mixture was heated to 70 C. for 1 h, cooled to rt, and then concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z=553.0 (M+H)+.

Reference： [1]Patent: US2019/276449,2019,A1 .Location in patent: Paragraph 0936

35
[ 56181-39-6 ]
(S)-2-amino-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 70℃; for 2h;	To a mixture of (S)-2-amino-4-((2-(4-fluorophenoxy)ethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid hydrochloride (150 mg, 312 mumol) in 4:1 THF/H2O (3 mL) was added <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (66 mg, 343 mumol) and NaHCO3 (79 mg, 936 mumol) and the resulting mixture was heated to 70 C. for 2 h and then cooled to rt and concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z=614.9 (M+H)+.

Reference： [1]Patent: US2019/276449,2019,A1 .Location in patent: Paragraph 1466

36
[ 56181-39-6 ]
(S)-2-amino-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 70℃; for 1h;	To a mixture of (S)-2-amino-4-((2-ethoxyethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid hydrochloride (150 mg, 361 mumol) in 4:1 THF/H2O (3 mL) was added <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (77 mg, 398 mumol) and NaHCO3 (152 mg, 1.81 mmol) and the resulting mixture was heated to 70 C. for 1 h, cooled to rt, and then concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z=535.0 (M+H)+

Reference： [1]Patent: US2019/276449,2019,A1 .Location in patent: Paragraph 1091

37
[ 56181-39-6 ]
(S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-aminobutanoic acid [ No CAS ]
(S)-4-((2-acetamidoethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-2-((5-bromopyrimidin-4-yl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran-d8; water; at 70℃; for 1h;	To a mixture of (S)-4-((2-acetamidoethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino)-2-aminobutanoic acid (200 mg, 511 mumol) and <strong>[56181-39-6]5-bromo-4-chloropyrimidine</strong> (109 mg, 562 mumol) in THF (2 mL) and H2O (0.5 mL) was added NaHCO3 (215 mg, 2.55 mmol) and the resulting mixture was heated to 70 C. for 1 h and then cooled to rt and then concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z=548.3 (M+H)+.

Reference： [1]Patent: US2019/276449,2019,A1 .Location in patent: Paragraph 1121

38
[ 56181-39-6 ]
(S)-2-amino-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-(2,2-difluoroethoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 70℃; for 2h;	To a mixture of <strong>[56181-39-6]5-bromo-4-chloro-pyrimidine</strong> (77 mg, 398 mumol) and (S)-2-amino-4-((2-(2,2-difluoroethoxy)ethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid (150 mg, 362 mumol) in THF (2 mL) H2O (0.5 mL) was added NaHCO3 (152 mg, 1.81 mmol) and the resulting mixture was heated to 70 C. for 2 h, cooled to rt, and then concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z=571.3 (M+H)+.

Reference： [1]Patent: US2019/276449,2019,A1 .Location in patent: Paragraph 1477

39
[ 56181-39-6 ]
(S)-2-amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl) amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In tetrahydrofuran; water at 70℃; for 2h;	2.6 Step 6: (S)-2-((5-bromopyrimidin-4-yl) amino)-4-(cyclopropyl(4-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid. To a solution of (S)-2-amino- 4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid trifluoroacetate (150 mg, 0.3 mmol) in 4:1 THF/H2O (3 mL) was added 5-bromo-4-chloro- pyrimidine (69 mg, 0.4 mmol) and NaHCO3 (137 mg, 1.63 mmol) and then was stirred at 70° C for 2 h and then cooled to rt and concentrated in vacuo. The crude residue was used without further purification

Reference： [1]Current Patent Assignee: PLIANT THERAPEUTICS INC - WO2020/210404, 2020, A1 Location in patent: Paragraph 00381; 00386

40
[ 41838-46-4 ]
[ 56181-39-6 ]
C₁₀H₁₅BrN₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%	With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80℃;	13 EXAMPLE 13: 5-bromo-N-(l-methylpiperidin-4-yl)pyridine-4-amine17To a stirred solution of 5-bromo-4-chloropyrimidine (300mg, 1.562mmol) in DMF, DIPEA (400mg, 3.124mmol) was added followed by l-methylpiperidine-4-amine (0.193ml, 1.562mmol) and the reaction mixture was heated at 80 °C overnight. TLC showed absence SM, and then reaction mixture was concentrated. The crude product was purified by flash column chromatography over 230-400 mesh silica gel and using a mixture of 30% EtO Ac/petroleum ether to afford the desired product 17, 180mg (Yield: 40 %) as yellow solid. The product was confirmed by 1FiNMR and MS spectrum analysis. 1H NMR (400 MHz, CDC13) δ: 8.4 (s, 1H), 8.35 (s, 1H), 6.81 (d, 1H), 4.95 (m, 1H), 2.78 (d, 2H), 2.17 (s, 3H), 1.95 (t, 2H), 1.6-1.8 (m, 4H); MS- 270 (M+l).

Reference： [1]Current Patent Assignee: ARRIEN PHARMACEUTICALS LLC - WO2012/135631, 2012, A1 Location in patent: Page/Page column 22

41
[ 56181-39-6 ]
4,5-dibromopyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trimethylsilyl bromide In acetonitrile for 5h; Reflux;	1-3 Preparation of compound III: Compound II (87.50g, 452.36mmol, 1eq.), trimethylsilyl bromide (346.3g, 2.26mol, 5.00eq.) were mixed in acetonitrile (800mL), heated to reflux and stirred for 5h, GC detected the disappearance of raw materials ( HP-5 column, General-12min, Tf=3.66min), the reaction solution was concentrated under reduced pressure to remove acetonitrile. Then add 200 mL of acetonitrile to the residue, and concentrate under reduced pressure to remove the remaining TMSBr in the system. After repeating this operation twice, 110.1 g of crude compound III is obtained as a brown solid, which is directly put into the next reaction.

Reference： [1]Current Patent Assignee: PHARMABLOCK SCIENCES (NANJING), INC. - CN113087669, 2021, A Location in patent: Paragraph 0035-0038; 0041-0044; 0047-0050

42
[ 462-08-8 ]
[ 56181-39-6 ]
5-bromo-N-(3-pyridyl)pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.5h;	5-bromo-N-(3-pyridyl)pyrimidin-4-amine A solution of 1 M potassium bis(trimethylsilyl)amide in THF (1.24 mL, 1.24 mmol) was added to a solution of 3-aminopyridine (127 mg, 1.33 mmol) in THF (4.5 mL) at -78 °C. The reaction was stirred for 5 min before the addition of a solution of 5-bromo-4-chloropyrimidine (220 mg, 1.08 mmol) in THF (0.5 mL). The reaction was stirred for a further 1.5 h at -78 °C, then quenched by the slow addition of sat. aq. NH4CI (20 mL) and DCM (10 mL) at 0 °C. The layers were separated, and the aq. layer extracted with DCM (2 x 15 mL). The organic layers were passed through a phase separator, concentrated in vacuo and purified by column chromatography on silica (gradient elution with 0% to 100% EtOAc in isohexanes; 0-20% MeOH in EtOAc) to give the title compound (94.2 mg, 35% Yield). 1H NMR (300 MHz, Chloroform-d) d 8.75 (d, J = 2.7 Hz, 1H), 8.62 (s, 1H), 8.52 (s, 1H), 8.41 (dd, J = 4.7, 1.6 Hz, 1H), 8.25 - 8.18 (m, 1H), 7.37 - 7.26 (m, 2H).

Reference： [1]Current Patent Assignee: UCB - WO2021/130259, 2021, A1 Location in patent: Page/Page column 82

43
[ 56181-39-6 ]
[ 2516-47-4 ]
5-bromo-N-(cyclopropylmethyl)pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine In acetonitrile at 120℃; for 1h; Microwave irradiation;	5-bromo-N-(cvclopropylmethyl)pyrimidin-4-amine Cyclopropylmethylamine (0.12 mL, 1.4 mmol) and DIPEA (0.22 mL, 1.3 mmol) were added to a solution of 5-bromo-4-chloropyrimidine (104 mg, 0.509 mmol) in MeCN (2.5 mL). The reaction was stirred at 120 °C in the microwave for 1 h, concentrated in vacuo and purified by column chromatography on silica (gradient elution with 0% to 100% EtOAc in isohexanes) to give the title compound (116 mg, quantitative). LCMS [M+H]+ 228.2 / 230.2, RT 0.93 min (Method 6).

Reference： [1]Current Patent Assignee: UCB - WO2021/130259, 2021, A1 Location in patent: Page/Page column 82

44
[ 56181-39-6 ]
[ 1311138-07-4 ]
5-bromo-N-[6-(3-methoxy-4-methyl-phenoxy)-3-pyridyl]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.2%	With toluene-4-sulfonic acid In 1-methyl-pyrrolidin-2-one at 80℃; for 2h; Inert atmosphere;	43.a Step a) 5-bromo-N-[6-(3-methoxy-4-methyl-phenoxy)-3-pyridyl]pyrimidin-4-amine To a mixture of 6-(3-methoxy-4-methylphenoxy)pyridin-3-amine (A.3) (1.00 g, 4.34 mmol) and 4-chloro-5-bromopyrimidine (840 mg, 4.34 mmol) in NMP (4.00 mL) was added TsOH·H2O (826 mg, 4.34 mmol). The mixture was stirred at 80°C for 2 h. The reaction mixture was filtered, water was added (20.0 mL) and the mixture was extracted with ethyl acetate (20.0 mL x 3). The combined organic layers were washed with brine (30.0 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (eluting with Petroleum ether/Ethyl acetate = 100 to 0% gradient) and concentrated under vacuum to give the title compound (1.50 g, 3.87 mmol, 89.2% yield) was obtained as a yellow solid. MS (ESI): m/z = 387.0 [M+H]+

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - EP3901152, 2021, A1 Location in patent: Paragraph 0146; 0218

45
[ 56181-39-6 ]
[ 57260-71-6 ]
tert-butyl 4-(5-bromopyrimidin-4-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate In N,N-dimethyl-formamide at 130℃; for 16h; Inert atmosphere;	1 Synthesis of tert-butyl 4-(5-bromopyrimidin-4-yl)piperazine-1-carboxylate [00165] To a solution of tert-butyl piperazine-1-carboxylate (2.00 g, 10.74 mmol) and 5-bromo-4-chloropyrimidine (2.08 g, 10.75 mmol) in DMF (30 mL) was added potassium carbonate (1.48 g, 10.71 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 16 h at 130°C. After cooling down to room temperature, the resulting mixture was filtered. The collected filtered cake was washed with ethyl acetate (3 x 30 mL). The combined washings and filtrate were concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography with the following conditions: column, C18 silica gel; Mobile Phase A: water (plus 10 mM NH4HCO3); Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 60% B - 80% B in 20 min; Detector: UV 254/220 nm. The fractions containing the desired product were collected and concentrated under reduced pressure to afford tert-butyl 4-(5-bromopyrimidin-4-yl)piperazine-1-carboxylate as a yellow solid. [00166] Yield 3.20 g (87%). 1H NMR (400 MHz, DMSO) d 8.63 (s, 1H), 8.57 (s, 1H),3.60 (t, J = 5.2 Hz,4H),3.46 (t, J = 5.2 Hz,4H), 1.43 (s, 9H). m/z: [ESI+] 343,345 (M+H)+.

Reference： [1]Current Patent Assignee: ANIMA BIOTECH - WO2021/216665, 2021, A1 Location in patent: Paragraph 00165-00166

46
[ 56181-39-6 ]
(S)-2-amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid trifluoroacetate [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl) amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In tetrahydrofuran; water at 70℃; for 2h;	6 [0290] Step 6: (S)-2-((5-bromopyrimidin-4-yl) amino)-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid. To a solution of (S)-2-amino-4-(cyclopropyl(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid trifluoroacetate (150 mg, 0.3 mmol) in 4:1 THF/H2O (3 mL) was added 5-bromo-4-chloro-pyrimidine (69 mg, 0.4 mmol) and NaHCO3 (137 mg, 1.63 mmol) and then was stirred at 70°C for 2 h and then cooled to rt and concentrated in vacuo. The crude residue was used without further purification.

Reference： [1]Current Patent Assignee: PLIANT THERAPEUTICS INC - WO2021/225912, 2021, A1 Location in patent: Paragraph 0285; 0290

47
[ 56181-39-6 ]
(S)-2-amino-4-(((R)-2-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-(((R)-2-methoxypropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In tetrahydrofuran; water at 70℃; for 2h;	1 [0381] Step 1: (S)-2-((5-bromopyrimidin-4-yl) amino)-4-(((R)-2-methoxypropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid: To a solution of (S)-2-amino-4-(((R)-2-methoxypropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid hydrochloride (100 mg, 241 μmol) and 5-bromo-4-chloropyrimidine (51 mg, 265 μmol) in 4:1 THF/H2O (2.5 mL) was added NaHCO3 (101 mg, 1.20 mmol) and the resulting mixture was stirred at 70°C for 2 h. The mixture was cooled to rt and then adjusted to pH = 6 by aq.1 M HCl and then concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z = 535.3 (M+H)+.

Reference： [1]Current Patent Assignee: PLIANT THERAPEUTICS INC - WO2021/225912, 2021, A1 Location in patent: Paragraph 0381; 0428

48
[ 56181-39-6 ]
(S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-(((S)-2-fluoro-3-methoxypropyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In tetrahydrofuran; water at 70℃; for 1h;	1 [0458] Step 1: (S)-2-((5-bromopyrimidin-4-yl) amino)-4-(((S)-2-fluoro-3-methoxypropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid: To a solution of (S)-2-amino-4-(((S)-2-fluoro-3-methoxypropyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid hydrochloride (250 mg, 577 μmol) and 5-bromo-4-chloropyrimidine (134 mg, 693 μmol) in THF (2 mL) and H2O (0.5 mL) was added NaHCO3 (243 mg, 2.89 mmol) and the resulting mixture was stirred at 70°C for 1 h and then allowed to cool to rt and then adjusted to pH = 6 by the addition of 1 M aq. HCl and concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z = 554.2 (M+H)+.

Reference： [1]Current Patent Assignee: PLIANT THERAPEUTICS INC - WO2021/225912, 2021, A1 Location in patent: Paragraph 0458

49
[ 56181-39-6 ]
(S)-2-amino-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-phenoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In tetrahydrofuran; water at 70℃; for 2h;	[0654] Compound 302: (S)-4-((2-phenoxyethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino)-2-((5-phenylpyrimidin-4-yl) amino) butanoic acid: To a (S)-2-amino-4-((2-phenoxyethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid hydrochloride(150 mg, 324 μmol) in 4:1 THF/H2O (2 mL) was added 5-bromo-4-chloropyrimidine (69 mg, 356 μmol) and NaHCO3 (136, 1.62 mmol) and the resulting mixture was stirred at 70°C for 2 h. The reaction mixture was cooled to rt and then concentrated in vacuo to give a (S)-2-((5-bromopyrimidin-4-yl) amino)-4-((2-phenoxyethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid intermediate, which was used without further purification. Of the butanoic acid intermediate, 189 mg, 324 μmol, was mixed with phenylboronic acid (43 mg, 356 μmol) in 3:1 dioxane/H2O (3 mL), to which was added K2CO3 (90 mg, 649 μmol) then Pd(dppf)Cl2 (24 mg, 32 μmol) and the resulting mixture was heated to 100°C for 2 h. The reaction mixture was cooled to rt and then concentrated in vacuo. The crude residue was purified by reverse phase prep-HPLC to give the title compound. LCMS (ESI+): m/z = 581.3 (M+H)+.1H NMR (400 MHz, Methanol-d4) ppm 8.42 (s, 1H) 7.94 (s, 1H) 7.45 - 7.51 (m, 2 H) 7.38 - 7.45 (m, 3 H) 7.20 - 7.30 (m, 3 H) 6.83 - 7.00 (m, 3 H) 6.42 (d, J=7.34 Hz, 1H) 4.52 (dd, J=6.79, 4.22 Hz, 1H) 4.19 (t, J=5.14 Hz, 2 H) 3.33 - 3.41 (m, 3 H) 3.20 - 3.30 (m, 2 H) 2.88 - 3.11 (m, 3 H) 2.70 (t, J=6.17 Hz, 2 H) 2.57 (br t, J=6.97 Hz, 2 H) 2.22 - 2.32 (m, 1H) 2.12 - 2.20 (m, 1H) 1.86 (q, J=5.90 Hz, 2 H) 1.55 - 1.72 (m, 4 H).

Reference： [1]Current Patent Assignee: PLIANT THERAPEUTICS INC - WO2021/225912, 2021, A1 Location in patent: Paragraph 0654

50
[ 56181-39-6 ]
(S)-2-amino-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-(4-fluorophenoxy)ethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In tetrahydrofuran; water at 70℃; for 2h;	1 [0785] Step 1: (S)-2-((5-bromopyrimidin-4-yl) amino)-4-((2-(4-fluorophenoxy)ethyl) (4- (5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid: To a mixture of (S)- 2-amino-4-((2-(4-fluorophenoxy)ethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid hydrochloride (150 mg, 312 μmol) in 4:1 THF/H2O (3 mL) was added 5-bromo-4-chloropyrimidine (66 mg, 343 μmol) and NaHCO3 (79 mg, 936 μmol) and the resulting mixture was heated to 70°C for 2 h and then cooled to rt and concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z = 614.9 (M+H)+.

Reference： [1]Current Patent Assignee: PLIANT THERAPEUTICS INC - WO2021/225912, 2021, A1 Location in patent: Paragraph 0785

51
[ 56181-39-6 ]
(S)-2-amino-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid hydrochloride [ No CAS ]
(S)-2-((5-bromopyrimidin-4-yl)amino)-4-((2-ethoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In tetrahydrofuran; water at 70℃; for 1h;	1 [0675] Step 1: (S)-2-((5-bromopyrimidin-4-yl) amino)-4-((2-ethoxyethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid: To a mixture of (S)-2-amino-4-((2-ethoxyethyl) (4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl) butyl)amino) butanoic acid hydrochloride (150 mg, 361 μmol) in 4:1 THF/H2O (3 mL) was added 5-bromo-4-chloropyrimidine (77 mg, 398 μmol) and NaHCO3 (152 mg, 1.81 mmol) and the resulting mixture was heated to 70°C for 1 h, cooled to rt, and then concentrated in vacuo to give the title compound that was used without further purification. LCMS (ESI+): m/z = 535.0 (M+H)+.

Reference： [1]Current Patent Assignee: PLIANT THERAPEUTICS INC - WO2021/225912, 2021, A1 Location in patent: Paragraph 0675

52
[ 56181-39-6 ]
[ 182163-96-8 ]
5-bromo-4-(3,4,5-trimethoxyphenyl)pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In ethanol; water monomer; toluene at 70℃; for 5h; Inert atmosphere;	4.1.1. The synthesis of intermediate 8 4-Chloro-5-bromo-pyrimidine (7, 5.00 g, 25.8 mmol), (3,4,5-trimethoxyphenyl) boric acid (6.30 g, 14.9 mmol) and potassiumcarbonate (7.14 g, 51.6 mmol) were dissolved in 75 mL of mixedsolvents (Toluene: Ethanol: Water 3 : 1: 1), then tetrakis(-triphenylphosphine)palladium (3.00 g, 2.58 mmol) was addedquickly. The flask was evacuated and backfilled with nitrogen forthree times. The resulting mixture was stirred at 70 C for 5 h andfollowed by TLC until completion. The mixture was filtered, and thefiltrate was collected and concentrated. The crude residue waspurified by silica gel chromatography to provide the title product 8.5-bromo-4-(3,4,5-trimethoxyphenyl)pyrimidine (8). White solid,yield 36%, m.p. 121.5e123.6 C. 1H NMR (400 MHz, DMSO-d6) d 9.22(s, 1H), 9.12 (s, 1H), 7.13 (s, 2H), 3.85 (s, 6H), 3.76 (s, 3H). 13C NMR(100 MHz, CDCl3) d 163.7, 160.4, 156.8, 153.0, 140.1, 131.8, 118.8,107.1, 60.9, 56.3. ESI-MS: m/z 325.0, 327.0 [MH]. C13H13BrN2O3(324.0, 326.0).
36%	With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In ethanol; water monomer; toluene at 70℃; for 5h; Inert atmosphere;	4.1.1. The synthesis of intermediate 8 4-Chloro-5-bromo-pyrimidine (7, 5.00 g, 25.8 mmol), (3,4,5-trimethoxyphenyl) boric acid (6.30 g, 14.9 mmol) and potassiumcarbonate (7.14 g, 51.6 mmol) were dissolved in 75 mL of mixedsolvents (Toluene: Ethanol: Water 3 : 1: 1), then tetrakis(-triphenylphosphine)palladium (3.00 g, 2.58 mmol) was addedquickly. The flask was evacuated and backfilled with nitrogen forthree times. The resulting mixture was stirred at 70 C for 5 h andfollowed by TLC until completion. The mixture was filtered, and thefiltrate was collected and concentrated. The crude residue waspurified by silica gel chromatography to provide the title product 8.5-bromo-4-(3,4,5-trimethoxyphenyl)pyrimidine (8). White solid,yield 36%, m.p. 121.5e123.6 C. 1H NMR (400 MHz, DMSO-d6) d 9.22(s, 1H), 9.12 (s, 1H), 7.13 (s, 2H), 3.85 (s, 6H), 3.76 (s, 3H). 13C NMR(100 MHz, CDCl3) d 163.7, 160.4, 156.8, 153.0, 140.1, 131.8, 118.8,107.1, 60.9, 56.3. ESI-MS: m/z 325.0, 327.0 [MH]. C13H13BrN2O3(324.0, 326.0).

Reference： [1]Huo, Zhipeng; Liang, Yongxi; Liu, Kunlin; Sun, Xun; Zhang, Xi [European Journal of Medicinal Chemistry, 2022, vol. 235]
[2]Huo, Zhipeng; Liang, Yongxi; Liu, Kunlin; Sun, Xun; Zhang, Xi [European Journal of Medicinal Chemistry, 2022, vol. 235]

53
[ 56181-39-6 ]
[ 1310048-95-3 ]
4-chloro-5-[(3-fluorophenyl)methyl]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate	90.a.E E) E) 4-chloro-5-[(3-fluorophenyl)methyl]pyrimidine To a mixture of 5-bromo-4-chloro-pyrimidine (300 mg), 2-[(3-fluorophenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (785 mg), dioxane (10 mL) and water (0.5 mL) were added Pd(dppf)Cl2 (113 mg) and potassium carbonate (472 mg) at room temperature. The mixture was stirred under nitrogen atmosphere at 85° C. for 12 hr. The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was purified by preparative TLC (petroleum ether/ethyl acetate=3/1) to give the title compound (140 mg). MS: [M+H]+ 223.6.
140 mg	With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; water monomer at 85℃; for 12h; Inert atmosphere;	90.a.E E) 4-chloro-5-[(3-fluorophenyl)methyl]pyrimidine To a mixture of 5-bromo-4-chloro-pyrimidine (300 mg), 2-[(3-fluorophenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (785 mg), dioxane (10 mL) and water (0.5 mL) were added Pd(dppf)Cl2 (113 mg) and potassium carbonate (472 mg) at room temperature. The mixture was stirred under nitrogen atmosphere at 85° C. for 12 hr. The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was purified by preparative TLC (petroleum ether/ethyl acetate=3/1) to give the title compound (140 mg). MS: [M+H]+ 223.6.
140 mg	With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; water monomer at 85℃; for 12h; Inert atmosphere;	90.a.E E) 4-chloro-5-[(3-fluorophenyl)methyl]pyrimidine To a mixture of 5-bromo-4-chloro-pyrimidine (300 mg), 2-[(3-fluorophenyl)methyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (785 mg), dioxane (10 mL) and water (0.5 mL) were added Pd(dppf)Cl2 (113 mg) and potassium carbonate (472 mg) at room temperature. The mixture was stirred under nitrogen atmosphere at 85° C. for 12 hr. The reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was purified by preparative TLC (petroleum ether/ethyl acetate=3/1) to give the title compound (140 mg). MS: [M+H]+ 223.6.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED; AXCELEAD DRUG DISCOVERY PARTNERS - US2022/98180, 2022, A1
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED; AXCELEAD DRUG DISCOVERY PARTNERS - US2022/98180, 2022, A1 Location in patent: Paragraph 0663; 0671-0672
[3]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED; AXCELEAD DRUG DISCOVERY PARTNERS - US2022/98180, 2022, A1 Location in patent: Paragraph 0663; 0671-0672

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P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 56181-39-6 ] {[proInfo.proName]}

Quality Control of [ 56181-39-6 ]

Related Doc. of [ 56181-39-6 ]

Product Details of [ 56181-39-6 ]

Calculated chemistry of [ 56181-39-6 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 56181-39-6 ]

Application In Synthesis of [ 56181-39-6 ]

[ 56181-39-6 ] Synthesis Path-Upstream 1~6

[ 56181-39-6 ] Synthesis Path-Downstream 1~53

Related Functional Groups of [ 56181-39-6 ]

Bromides

Chlorides

Related Parent Nucleus of [ 56181-39-6 ]

Pyrimidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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[ 56181-39-6 ]

Related Parent Nucleus of
[ 56181-39-6 ]