[ CAS No. 206362-80-3 ] {[proInfo.proName]}

Name: 206362-80-3|4-(Bromomethyl)-1-chloro-2-fluorobenzene|98%
Brand: Ambeed
SKU: A364549
Price: 13.0 USD
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3d Animation Molecule Structure of 206362-80-3

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Quality Control of [ 206362-80-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 206362-80-3 ]

SDS Specification

Alternatived Products of [ 206362-80-3 ]

Product Details of [ 206362-80-3 ]

CAS No. :	206362-80-3	MDL No. :	MFCD04115859
Formula :	C₇H₅BrClF	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CNUYBEIHDWMLSD-UHFFFAOYSA-N
M.W :	223.47	Pubchem ID :	2783136
Synonyms :

Calculated chemistry of [ 206362-80-3 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	44.25
TPSA :	0.0 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.35
Log Po/w (XLOGP3) :	3.66
Log Po/w (WLOGP) :	3.64
Log Po/w (MLOGP) :	4.1
Log Po/w (SILICOS-IT) :	3.89
Consensus Log Po/w :	3.53

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.91
Solubility :	0.0275 mg/ml ; 0.000123 mol/l
Class :	Soluble
Log S (Ali) :	-3.35
Solubility :	0.1 mg/ml ; 0.000448 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.56
Solubility :	0.0062 mg/ml ; 0.0000277 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.74

Safety of [ 206362-80-3 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	3261
Hazard Statements:	H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 206362-80-3 ]

* 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 [ 206362-80-3 ]
Downstream synthetic route of [ 206362-80-3 ]

[ 206362-80-3 ] Synthesis Path-Upstream 1~5

1
[ 202925-10-8 ]
[ 206362-80-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With bromine; triphenylphosphine In ethanol; dichloromethane at 0℃; for 0.5 h;	Step 1: 4-(bromomethyl)-1-chloro-2-fluorobenzene ,To a solution of triphenylphosphine (27.8 g, 0.103 mol) in CH₂Cl₂ (200 mL), bromine (16.5 g, 0.103 mol) was added dropwise at 0°C under stirring. Upon completion of the addition, the resultant was stirred for 10 minutes. (4-Chloro-3-fluorophenyl)methanol (15.8 g, 0.098mol) was then added. The resultnat was stirred for 30 minutes. The reaction was quenched with ethanol, poured into saturated sodium bicarbonate solution, and extracted with CH₂Cl₂. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 4-(bromomethyl)-1-chloro-2-fluorobenzene (18.6 g, 85percent yield). ¹H-NMR (400 MHz, CDCl₃):δ= 7.27 (t, J = 7.9Hz, 1H), 7.10 (dd, J= 7.9 Hz, 2.1 Hz, 1H), 7.04-6.99 (m, 1H), 4.32 (s, 2H).

Reference： [1] Patent: EP2952510, 2015, A1, . Location in patent: Paragraph 0185

2
[ 106-96-7 ]
[ 206362-77-8 ]
[ 206362-80-3 ]

Reference： [1] Journal of Fluorine Chemistry, 1998, vol. 88, # 2, p. 143 - 151

3
[ 106-95-6 ]
[ 206362-77-8 ]
[ 206362-80-3 ]

Reference： [1] Journal of Fluorine Chemistry, 1998, vol. 88, # 2, p. 143 - 151
[2] Journal of Fluorine Chemistry, 1998, vol. 88, # 2, p. 143 - 151

4
[ 206362-80-3 ]
[ 251570-03-3 ]

Yield	Reaction Conditions	Operation in experiment
93%	for 1.5 h; Reflux	To a boiling solution of 4-chloro-3-flurorobenzyl bromide (1Og, 44.8mmol) in absolute ethanol (40 ml) was added a solution of potassium cyanide (2.9g, 44.8mmol) in water (6ml). The mixture was refluxed for 1.5 hours, then most of the ethanol was distilled off under reduced pressure and the cooled residue poured into water. The solution was extracted three times with ether. The combined organic layers were washed with brine, dried and concentrated into dryness to give the titled product (7.8g, 93percent yield)¹H NMR (300 MHz, DMSO-d⁶) 4.09 (s, 2H), 7.25 (ddd, J= 0.8, 2.0, 8.2 Hz, IH), 7.43 (dd, J= 2.0, 10.0 Hz, IH), 7.64 (t, J=8.2 Hz, IH).MS (ESI^") m/z 168 (M-I)
93%	for 1.5 h; Reflux	To a boiling solution of 4-chloro-3-flurorobenzyl bromide (1Og, 44.8mmol) in absolute ethanol (40 ml) was added a solution of potassium cyanide (2.9g, 44.8mmol) in water (6ml). The mixture was refluxed for 1.5 hours, then most of the ethanol was distilled off under reduced pressure and the cooled residue poured into water. The solution was extracted three times with ether. The combined organic layers were washed with brine, dried and concentrated into dryness to give the titled product (7.8g, 93percent yield)¹H NMR (300 MHz, DMS(W⁵) 4.09 (s, 2H), 7.25 (ddd, J= 0.8, 2.0, 8.2 Hz, IH), 7.43 (dd, J= 2.0, 10.0 Hz, IH), 7.64 (t, J =8.2 Hz, IH).MS (ESF) m/z 168 (M-I)
93%	for 1.5 h; Reflux	To a boiling solution of 4-chloro-3-flurorobenzyl bromide (1Og, 44.8mmol) in absolute ethanol (40 ml) was added a solution of potassium cyanide (2.9g, 44.8mmol) in water (6ml). The mixture was refluxed for 1.5 hours, then most of the ethanol was distilled off under reduced pressure and the cooled residue poured into water. The solution was extracted three times with ether. The combined organic layers were washed with brine, dried and concentrated into dryness to give the titled product (7.8g, 93percent yield) ¹H NMR (300 MHz, DMSO-d⁶) 4.09 (s, 2H), 7.25 (ddd, J= 0.8, 2.0, 8.2 Hz, IH), 7.43 (dd, J= 2.0, 10.0 Hz, IH), 7.64 (t, J =8.2 Hz, IH).MS (ESI^") m/z 168 (M-I)

Reference： [1] Patent: WO2010/31, 2010, A1, . Location in patent: Page/Page column 55
[2] Patent: WO2010/32, 2010, A1, . Location in patent: Page/Page column 54
[3] Patent: WO2010/30, 2010, A1, . Location in patent: Page/Page column 47-48

5
[ 151-50-8 ]
[ 206362-80-3 ]
[ 251570-03-3 ]

Yield	Reaction Conditions	Operation in experiment
61.2%	for 1 h;	Example 26; (4-(4-chloro-3-fluorophenvπpiperidin-4-yl)(4-((5RJR)-7-hydroxy-5-methyl-6.7-dihvdro-5H- cvclopenta[dlpyrimidin-4-yDpiperazin- 1 -vPmethanone; Step 1:; KCN (1.25 g, 19.2 mmol) was added to a solution of 4-(bromomethyl)-l- chloro-2-fluorobenzene (3.90 g, 17.5 mmol) in DMSO (60 mL). Several milliliters of H₂O were added to help dissolve the KCN. After 1 hour, the reaction mixture was diluted with H₂O and extracted with EtOAc. The extracts were dried (Na₂SO₄), filtered, and concentrated. The crude product was flashed on silica (Biotage 4OM, 9:1 to 4:1 hex:EtOAc) to give 2-(4-chloro-3- fluorophenyl)acetonitrile (1.81 g, 61.2percent yield) as a yellow crystalline solid.

Reference： [1] Patent: WO2008/6040, 2008, A1, . Location in patent: Page/Page column 114

[ 206362-80-3 ] Synthesis Path-Downstream 1~67

1
[ 106-95-6 ]
[ 206362-77-8 ]
[ 206362-80-3 ]
5-Bromomethyl-2-chloro-3-fluoro-cyclohexa-1,3-diene [ No CAS ]
5-Bromomethyl-3-chloro-2-fluoro-cyclohexa-1,3-diene [ No CAS ]

Reference： [1]Journal of Fluorine Chemistry,1998,vol. 88,p. 143 - 151
[2]Journal of Fluorine Chemistry,1998,vol. 88,p. 143 - 151

2
[ 106-96-7 ]
[ 206362-77-8 ]
[ 206362-80-3 ]

Reference： [1]Journal of Fluorine Chemistry,1998,vol. 88,p. 143 - 151

3
[ 151-50-8 ]
[ 206362-80-3 ]
[ 251570-03-3 ]

Yield	Reaction Conditions	Operation in experiment
61.2%	In water; dimethyl sulfoxide; for 1h;	Example 26; (4-(4-chloro-3-fluorophenv?piperidin-4-yl)(4-((5RJR)-7-hydroxy-5-methyl-6.7-dihvdro-5H- cvclopenta[dlpyrimidin-4-yDpiperazin- 1 -vPmethanone; Step 1:; KCN (1.25 g, 19.2 mmol) was added to a solution of 4-(bromomethyl)-l- chloro-2-fluorobenzene (3.90 g, 17.5 mmol) in DMSO (60 mL). Several milliliters of H2O were added to help dissolve the KCN. After 1 hour, the reaction mixture was diluted with H2O and extracted with EtOAc. The extracts were dried (Na2SO4), filtered, and concentrated. The crude product was flashed on silica (Biotage 4OM, 9:1 to 4:1 hex:EtOAc) to give 2-(4-chloro-3- fluorophenyl)acetonitrile (1.81 g, 61.2% yield) as a yellow crystalline solid.

Reference： [1]Patent: WO2008/6040,2008,A1 .Location in patent: Page/Page column 114

5
[ 879893-59-1 ]
[ 206362-80-3 ]
1-(4-chloro-3-fluorobenzyl)-5-(benzo[d]thiazol-2-yl)pyridin-2(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With sodium iodide; In acetonitrile; at 90℃; for 14h;Product distribution / selectivity;	Step 2 : l-(4-Chloro-3-fluorobenzyl)-5-(betizo[d]thiazol-2-yl)pyridin-2(lH)-one; According to Scheme 4, Step 1: A mixture of 2-(6-methoxypyridin-3- yl)benzo[

Reference： [1]Patent: WO2006/30032,2006,A1 .Location in patent: Page/Page column 86; 162

6
potassium cyanide [ No CAS ]
[ 206362-80-3 ]
[ 251570-03-3 ]

Yield	Reaction Conditions	Operation in experiment
93%	In ethanol; water; for 1.5h;Reflux;	To a boiling solution of 4-chloro-3-flurorobenzyl bromide (1Og, 44.8mmol) in absolute ethanol (40 ml) was added a solution of potassium cyanide (2.9g, 44.8mmol) in water (6ml). The mixture was refluxed for 1.5 hours, then most of the ethanol was distilled off under reduced pressure and the cooled residue poured into water. The solution was extracted three times with ether. The combined organic layers were washed with brine, dried and concentrated into dryness to give the titled product (7.8g, 93% yield)1H NMR (300 MHz, DMSO-d6) 4.09 (s, 2H), 7.25 (ddd, J= 0.8, 2.0, 8.2 Hz, IH), 7.43 (dd, J= 2.0, 10.0 Hz, IH), 7.64 (t, J=8.2 Hz, IH).MS (ESI") m/z 168 (M-I)
93%	In ethanol; water; for 1.5h;Reflux;	To a boiling solution of 4-chloro-3-flurorobenzyl bromide (1Og, 44.8mmol) in absolute ethanol (40 ml) was added a solution of potassium cyanide (2.9g, 44.8mmol) in water (6ml). The mixture was refluxed for 1.5 hours, then most of the ethanol was distilled off under reduced pressure and the cooled residue poured into water. The solution was extracted three times with ether. The combined organic layers were washed with brine, dried and concentrated into dryness to give the titled product (7.8g, 93% yield)1H NMR (300 MHz, DMS(W5) 4.09 (s, 2H), 7.25 (ddd, J= 0.8, 2.0, 8.2 Hz, IH), 7.43 (dd, J= 2.0, 10.0 Hz, IH), 7.64 (t, J =8.2 Hz, IH).MS (ESF) m/z 168 (M-I)
93%	In ethanol; water; for 1.5h;Reflux;	To a boiling solution of 4-chloro-3-flurorobenzyl bromide (1Og, 44.8mmol) in absolute ethanol (40 ml) was added a solution of potassium cyanide (2.9g, 44.8mmol) in water (6ml). The mixture was refluxed for 1.5 hours, then most of the ethanol was distilled off under reduced pressure and the cooled residue poured into water. The solution was extracted three times with ether. The combined organic layers were washed with brine, dried and concentrated into dryness to give the titled product (7.8g, 93% yield) 1H NMR (300 MHz, DMSO-d6) 4.09 (s, 2H), 7.25 (ddd, J= 0.8, 2.0, 8.2 Hz, IH), 7.43 (dd, J= 2.0, 10.0 Hz, IH), 7.64 (t, J =8.2 Hz, IH).MS (ESI") m/z 168 (M-I)

Reference： [1]Patent: WO2010/31,2010,A1 .Location in patent: Page/Page column 55
[2]Patent: WO2010/32,2010,A1 .Location in patent: Page/Page column 54
[3]Patent: WO2010/30,2010,A1 .Location in patent: Page/Page column 47-48

7
[ 947590-65-0 ]
[ 206362-80-3 ]
C₂₁H₂₀ClFN₂O₃S [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 1465 - 1472

8
[ 73260-12-5 ]
[ 206362-80-3 ]
[ 1240660-23-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 5510 - 5518

9
[ 24922-01-8 ]
[ 206362-80-3 ]
[ 1335027-58-1 ]

Yield	Reaction Conditions	Operation in experiment
79%	With N-ethyl-N,N-diisopropylamine; lithium chloride; In tetrahydrofuran; at 80℃; for 18h;	Method XEthyl 2- [(4-chlor o-3-fluoro-phenyl)methyl] -3-cyclobutyl-3-oxo-propanoateN-Ethyl-N-isopropylpropan-2-amine (2.047 mL, 11.75 mmol) was added to lithium chloride (0.249 g, 5.88 mmol), ethyl 3-cyclobutyl-3-oxopropanoate (lg, 5.88 mmol) and 4- (bromomethyl)-l-chloro-2-fluorobenzene (1.313 g, 5.88 mmol) in THF (12 mL) at 20 C under air. The resulting mixture was stirred at 80 C for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (20 mL)andsaturated brine (20 mL). The organic layer was dried over MgS04, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford the title compound (1.450 g, 79 %) as a colourless oil. 1H NMR (400.13 MHz, CDC13) delta 1.15-1.25 (3H, m), 1.73-1.78 (1H, m), 1.92-2.00 (2H, m), 2.02-2.10 (2H, m), 2.23-2.33 (1H, m), 3.05-3.17 (2H, m), 3.37-3.41 (1H, m), 3.69 (1H, t), 4.06-4.16 (2H, m), 6.89-6.91 (1H, m), 6.96-6.99 (1H, m), 7.29 (1H, d); m/z (ES) (M- H) = 311.

Reference： [1]Patent: WO2011/114148,2011,A1 .Location in patent: Page/Page column 85

10
[ 1428794-58-4 ]
[ 206362-80-3 ]
[ 1428794-65-3 ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 70℃; for 19h;	An ice cold solution of methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1 H- pyrrolo[2,3-c]pyridin-5-yl)acetate (21 mg, 0.055 mmol) in Nu,Nu-Dimethylformamide (DMF) (500 muIota) was treated with K2COs (37.9 mg, 0.275 mmol), DIEA (47.9 muIota, 0.275 mmol), and 4-chloro-3- fluorobenzyl bromide (61.4 mg, 0.275 mmol), stirred at rt for 1 hr, and then heated to 70C for 18 hours. The reaction was diluted with water, extracted with EtOAc, washed with Brine, dried with Na2S04, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/hexane) gave methyl 2-(tert-butoxy)-2-(1-(4-chloro-3-fluorobenzyl)-6-methyl-7-oxo-4-(p- tolyl)-6,7-dihydro-1 H-pyrrolo[2,3-c]pyridin-5-yl)acetate (26.2 mg, 0.050 mmol, 91 % yield) as clear oil. The ester intermediate was dissolved in Methanol (500 muIota) and Tetrahydrofuran (THF) (500 muIota), treated with 2M LiOH (150 muIota, 0.3 mmol), and stirred at 60C for 2.5 hours. The reaction was concentrated and purified with reverse phase HPLC (20-100% MeCN/H2O-0.1 % TFA, 12 min) to give title compound (1 1.6 mg, 0.022 mmol, 40.9 % yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.99 (s, 9 H), 2.43 (s, 3 H), 3.65 (s, 3 H), 5.46 (s, 1 H), 5.79 (d, J=2.3 Hz, 2 H), 6.06 (d, J=2.8 Hz, 1 H), 6.94 - 7.07 (m, 3 H), 7.24 - 7.31 (m, 2 H), 7.30 - 7.38 (m, 2 H), 7.49 - 7.56 (m, 1 H); LCMS (m/z) ES+= 51 1 (M+1 ).

Reference： [1]Patent: WO2013/43553,2013,A1 .Location in patent: Page/Page column 31

11
[ 50424-51-6 ]
[ 206362-80-3 ]
[ 1447534-00-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 0℃; for 4.5h;	(2R,11aS)-2-Hydroxy-2,3-dihydro-1H-benzo[e]pyrrole[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione 3 (0.4g, 1.71mmol) and K2CO3 (0.473g, 3.43mmol) in DMF at 0C for 30min was added substituted alkyl bromides 4a-w (2.06mmol) to the reaction and stirred for 4h under inert conditions. After completion (by TLC), the reaction mixture was filtered through Buchner funnel and washed with EtOAc. The product was extracted with EtOAc (3×30mL) and cold water (20mL). Combined organic phase was dried over Na2SO4 and evaporated under vacuum. The crude residue thus obtained was further purified by silica gel column chromatography eluted with mixture of ethyl acetate and hexane.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 4485 - 4493

12
[ 603-35-0 ]
[ 206362-80-3 ]
[ 174701-71-4 ]

Yield	Reaction Conditions	Operation in experiment
	In diethyl ether; at 20 - 25℃;	Intermediate 24: tert-Butyl 4-(4-chloro-3-fluorobenzylidene)piperidine-l- carboxylate A suspension of triphenylphosphine (2.347 g, 8.95 mmol) and 4-(bromomethyl)-l-chloro- 2-fluorobenzene (2 g, 8.95 mmol) in ether (25 mL ) was stirred at room temperature overnight. The suspension was concentrated to give (4-chloro-3- fluorobenzyl)triphenylphosphonium bromide (quantitative) as a white solid that was used crude. Butyl lithium (1.6 M in hexanes) (6.03 mL , 9.65 mmol) was added slowly to a suspension of (4-chloro-3-fluorobenzyl)triphenylphosphonium bromide (4.26 g, 8.77 mmol) in THF (40 mL ) under inert atmosphere at 0 C. The resulting suspension was stirred at 0 C for 15 minutes, then warmed to room temperature for 2 hours. ie/ -Butyl 4- oxopiperidine- l-carboxylate (1.922 g, 9.65 mmol) as a solution in THF (5 mL) was added and the suspension was stirred at room temperature overnight. Petroleum ether was added, the precipitate (0=PPh3) was filtered and the filtrate concentrated. The crude product was purified by silica chromatography eluted with 0-100% DCM / petroleum ether to give tert- butyl 4-(4-chloro-3-fluorobenzylidene)piperidine- l-carboxylate (2.03 g, 6.23 mmol, 71% yield) as a colourless oil that solidified on standing. 1H NMR (400 MHz, DMSO- d6) delta ppm 1.42 (s, 9H) 2.28-2.30 (m, 2H) 2.39-2.40 (m, 2H) 3.27-3.34 (m, 2H) 3.36-3.47 (m, 2H) 6.35 (s, 1H) 7.06-7.13 (m, 1H) 7.25-7.28 (m, 1H) 7.51-7.55 (m, 1H)
	In diethyl ether; at 20℃;	Intermediate 3: fert-Butyl 4-(4-chloro-3-fluorobenzylidene)piperidine-l-carboxylateA suspension of triphenylphosphine (2.347 g, 8.95 mmol) and 4-(bromomethyl)-l-chloro-2-fluorobenzene (2 g, 8.95 mmol) in ether (25 mL ) was stirred at room temperature overnight. The suspension was concentrated to give (4-chloro-3-fluorobenzyl)-triphenylphosphonium bromide (quantitative) as a white solid that was used crude.Butyl lithium (1.6 M in hexanes) (6.03 mL , 9.65 mmol) was added slowly to a suspension of (4-chloro-3-fluorobenzyl)triphenylphosphonium bromide (4.26 g, 8.77 mmol) in THF (40 mL ) under inert atmosphere at 0 C. The resulting suspension was stirred at 0 C for 15 minutes, then warmed to room temperature for two hours. ie/ -Butyl 4-oxopiperidine-l-carboxylate (1.922 g, 9.65 mmol) as a solution in THF (5 mL) was added and the suspension was stirred at room temperature overnight. Petroleum ether was added, the precipitate (0=PPh3) was filtered and the filtrate concentrated. The crude product was purified by silica chromatography eluted with 0-100% DCM / petroleum ether to give tert-butyl 4-(4-chloro-3-fluorobenzylidene)piperidine- l-carboxylate (2.03 g, 6.23 mmol, 71% yield) as a colourless oil that solidified on standing.1H NMR (400 MHz, DMSO- d6) delta ppm 1.42 (s, 9H) 2.28-2.30 (m, 2H) 2.39-2.40 (m, 2H) 3.27-3.34 (m, 2H) 3.36-3.47 (m, 2H) 6.35 (s, 1H) 7.06-7.13 (m, 1H) 7.25-7.28 (m, 1H) 7.51-7.55 (m, 1H)
	In diethyl ether; at 20 - 25℃;	A suspension of triphenyiphosphine (2.347 g, 8.95 mmol) and 4-(bromomethyl)-1-chloro- 2-fluorobenzene (2 g, 8.95 mmol) in ether (25 mL) was stirred at room temperature overnight. The suspension was concentrated to give (4-chloro-3-fluorobenzyl)-triphenyiphosphonium bromide (quantitative) as a white solid that was used crude.Butyl lithium (1.6 M in hexanes) (6.03 mL, 9.65 mmol) was added slowly to a suspensionof (4-chloro-3-fluorobenzyl)triphenylphosphonium bromide (4.26 g, 8.77 mmol) in THF(40 mL) under inert atmosphere at 0 C. The resulting suspension was stirred at 0 C for15 minutes, then warmed to room temperature for two hours. tert-Butyl 4-oxopiperidine-1-carboxylate (1.922 g, 9.65 mmol) as a solution in THF (5 mL) was added and the suspension was stirred at room temperature overnight. Petroleum ether was added, the precipitate (O=PPh3) was filtered and the filtrate concentrated. The crude product was purified by silica chromatography eluted with 0-100% DCM / petroleum ether to give tertbutyl 4-(4-chloro-3 -fluorobenzylidene)piperidine- 1 -carboxylate (2.03 g, 6.23 mmol, 71%yield) as a colourless oil that solidified on standing.?H NMR (400 MHz, DMSO- d6) ppm 1.42 (s, 9H) 2.28-2.30 (m, 2H) 2.39-2.40 (m, 2H)3.27-3.34 (m, 2H) 3.36-3.47 (m, 2H) 6.35 (s, 1H) 7.06-7.13 (m, 1H) 7.25-7.28 (m, 1H)7.5 1-7.55 (m, 1H)

Reference： [1]Patent: WO2013/179024,2013,A1 .Location in patent: Page/Page column 59-60
[2]Patent: WO2014/202999,2014,A1 .Location in patent: Page/Page column 35
[3]Patent: WO2016/75457,2016,A1 .Location in patent: Page/Page column 31

13
[ 206362-80-3 ]
tert-butyl 4-(4-chloro-3-fluorobenzylidene)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2013/179024,2013,A1
[2]Patent: WO2014/202999,2014,A1
[3]Patent: WO2016/75457,2016,A1

14
[ 206362-80-3 ]
[ 849766-53-6 ]

Reference： [1]Patent: WO2013/179024,2013,A1
[2]Patent: WO2014/202999,2014,A1
[3]Patent: WO2016/75457,2016,A1

15
[ 1616371-96-0 ]
[ 206362-80-3 ]
[ 1616371-97-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl acetamide; at 25℃; for 72h;	Step 3: To 4-[(1 R)-1 -cyclobutylethyl]amino}-6-(3-methylphenyl)-5H- pyrrolo[3,2-d]pyrimidine-2-carbonitrile (60 mg, 0.18 mmol) dissolved in N,N- dimethylacetamide (0.25 mL) were added potassium carbonate (50 mg, 0.36 mmol) and <strong>[206362-80-3]4-chloro-3-fluorobenzyl bromide</strong> (44.5 mg, 0.2 mmol). The reaction mixture was stirred at room temperature for 3 days. The reaction was diluted with ethyl acetate and washed with water. The water layer was extracted with ethyl acetate (2x), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-70% ethyl acetate/hexanes, linear gradient) to afford 5-(4-chloro-3-fluorobenzyl)-4-[(1 f?)-1 -cyclobutylethyl]amino}-6-(3-methylphenyl)- 5H-pyrrolo[3,2-d]pyrimidine-2-carbonitrile. MS ESI calc'd. for C27H25CIFN5 [M + H]+ 474, found 474.

Reference： [1]Patent: WO2014/100071,2014,A2 .Location in patent: Page/Page column 95

16
[ 18552-90-4 ]
[ 206362-80-3 ]
[ 1621222-31-8 ]
[ 1621227-20-0 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl acetamide; at 20℃; for 2h;	Step 1: 2-Iodo-6-chloropurine (2.5 g, 8.91 mmol) in N,N-dimethylacetamide (12 mL) was treated with <strong>[206362-80-3]4-chloro-3-fluorobenzyl bromide</strong> (2.1 g, 9.4 mmol). Cesium carbonate (3.05 g, 9.4 mmol) was added and the mixture was stirred at room temperature for 2 hours. Thereaction was quenched with water and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a 25:75 mixture of 6-chloro-7-(4-chloro-3-fluorobenzyl)-2- iodo-7H-purine: 6-chloro-9-(4-chloro-3 -fluorobenzyl)-2-iodo-9H-purine. The residue was purified by silica gel chromatography (0-80% ethyl acetate/hexanes, linear gradient) toafford 6-chloro-7-(4-chloro-3-fluorobenzyl)-2-iodo-7H-purine. MS ESI calc?d. for C12H6Cl2Fll?4 [M+H]+423, found 423.

Reference： [1]Patent: WO2014/120748,2014,A1 .Location in patent: Page/Page column 160

17
[ 206362-80-3 ]
[ 1621222-32-9 ]

Reference： [1]Patent: WO2014/120748,2014,A1

18
[ 206362-80-3 ]
[ 1621222-33-0 ]

Reference： [1]Patent: WO2014/120748,2014,A1

19
C₁₈H₁₇N₃O₂ [ No CAS ]
[ 206362-80-3 ]
C₂₅H₂₁ClFN₃O₂ [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 6831 - 6836

20
[ 1453851-89-2 ]
[ 206362-80-3 ]
1-(4-chloro-3-fluorobenzyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 1976 - 1991

21
[ 206362-80-3 ]
C₁₄H₁₀ClFO₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6148 - 6156

22
[ 206362-80-3 ]
2-(2-methyl-5-nitro-1H-imidazol-1-yl)-ethyl 2-((4-chloro-3-fluorobenzyl)oxy)benzoate [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6148 - 6156

23
[ 206362-80-3 ]
[ 119-36-8 ]
C₁₅H₁₂ClFO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetone; at 60℃;	General procedure: Compounds 3a-3w were synthesized by the following procedure.Methyl salicylate (4 mmol), 2a-2w (4 m mol) and K2CO3 (8 mmol) were added in acetone. The reaction was stirred at 60 C for 6-8 h to gain 3a-3w.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6148 - 6156

24
[ 202925-10-8 ]
[ 206362-80-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With bromine; triphenylphosphine; In ethanol; dichloromethane; at 0℃; for 0.5h;	Step 1: 4-(bromomethyl)-1-chloro-2-fluorobenzene ,To a solution of triphenylphosphine (27.8 g, 0.103 mol) in CH2Cl2 (200 mL), bromine (16.5 g, 0.103 mol) was added dropwise at 0C under stirring. Upon completion of the addition, the resultant was stirred for 10 minutes. (4-Chloro-3-fluorophenyl)methanol (15.8 g, 0.098mol) was then added. The resultnat was stirred for 30 minutes. The reaction was quenched with ethanol, poured into saturated sodium bicarbonate solution, and extracted with CH2Cl2. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to give 4-(bromomethyl)-1-chloro-2-fluorobenzene (18.6 g, 85% yield). 1H-NMR (400 MHz, CDCl3):delta= 7.27 (t, J = 7.9Hz, 1H), 7.10 (dd, J= 7.9 Hz, 2.1 Hz, 1H), 7.04-6.99 (m, 1H), 4.32 (s, 2H).

Reference： [1]Patent: EP2952510,2015,A1 .Location in patent: Paragraph 0185

25
[ 206362-80-3 ]
1-(4-chloro-3-fluorobenzyl)-1H-pyrazole-2-oxide [ No CAS ]

Reference： [1]Patent: EP2952510,2015,A1

26
[ 206362-80-3 ]
5-bromo-1-(4-chloro-3-fluorobenzyl)-1H-pyrazole-2-oxide [ No CAS ]

Reference： [1]Patent: EP2952510,2015,A1

27
[ 206362-80-3 ]
5-bromo-1-(4-chloro-3-fluorobenzyl)-1H-pyrazole [ No CAS ]

Reference： [1]Patent: EP2952510,2015,A1

28
[ 206362-80-3 ]
1-(4-chloro-3-fluorobenzyl)-5-((trimethylsilyl)ethynyl)-1H-pyrazole [ No CAS ]

Reference： [1]Patent: EP2952510,2015,A1

29
[ 206362-80-3 ]
1-(4-chloro-3-fluorobenzyl)-5-ethynyl-1H-pyrazole [ No CAS ]

Reference： [1]Patent: EP2952510,2015,A1

30
[ 206362-80-3 ]
2-chloro-4-((1-(4-chloro-3-fluorobenzyl)-1H-pyrazol-5-yl)ethynyl)pyridine [ No CAS ]

Reference： [1]Patent: EP2952510,2015,A1

31
[ 118-10-5 ]
[ 206362-80-3 ]
C₂₆H₂₇ClFN₂O⁽¹⁺⁾*Br^(1-) [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 11818 - 11848

32
[ 118-10-5 ]
[ 206362-80-3 ]
N,N′-(3-chloro-4-fluorobenzyl)cinchonidinium dibromide [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 11818 - 11848

33
[ 288-13-1 ]
[ 206362-80-3 ]
1-(4-chloro-3-fluorobenzyl)-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	Step 2: 1-(4-chloro-3-fluorobenzyl)-1H-pyrazole 4-(Bromomethyl)-1-chloro-2-fluorobenzene (16.0 G, 72 mmol), pyrazole (5.35 g, 79 mmol), and K2CO3 (20.0 g, 145mmol) were added into dry DMF. The resultant was stirred at room temperature overnight. The solvent was spin evaporated, the residue was dissolved by adding ethyl acetate and purified by silica gel column chromatography to give 1-(4-chloro-3-fluorobenzyl)-1H-pyrazole (13.7 g, 91% yield). MS m/z [ESI]: 211.0 [M+1].

Reference： [1]Patent: EP2952510,2015,A1 .Location in patent: Paragraph 0186

34
[ 26621-44-3 ]
[ 206362-80-3 ]
1-(4-chloro-3-fluorobenzyl)-3-nitro-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutylammomium bromide; potassium carbonate; In acetone; at 20℃; for 4h;	Prepared according to general procedure 4 with K2CO3 (3.18 g, 23.0 mmol), 4-fluoro-3,5-dimethylbenzyl bromide (1.00 g, 4.61 mmol), 5-nitro-1 H-pyrazole (521 mg, 4.61 mmol), and BmNBr (303 mg, 0.921 mmol) in acetone (45 mL). The reaction is complete after 30 h at rt. Purification of the crude by automated FC (Buchi, EtOAc / heptane 1 :99? 5:95? 10:90? 15:85? 25:75 ? 35:65, 20 g silicagel, flow 20 mL/min) yields the title compound. LC-MS: tR = 0.90 min (conditions 3). General procedure 4 for the N-alkylation of 5-nitro-1H-pyrazole. K2CO3 or NaH is added to a sol. of 5-nitro-1 H- pyrazole in acetone or DMF or THF. The mixture is stirred for 15-30 min. The desired electrophile and Bu4NBr are added. The mixture is stirred efficiently at rt until the reaction is complete. The mixture is optionally filtered (if K2CO3 is used) or quenched with water (if NaH is used), and the filtrate is evaporated under reduced pressure. The residue is partitioned between water and EtOAc. The org. layer is dried over MgS04, filtered, and the solvents are removed under reduced pressure. Purification of the crude by automated FC or by HPLC yields the desired product.

Reference： [1]Patent: WO2015/186056,2015,A1 .Location in patent: Page/Page column 52

35
[ 206362-80-3 ]
1-(4-chloro-3-fluorobenzyl)-1H-pyrazol-3-amine [ No CAS ]

Reference： [1]Patent: WO2015/186056,2015,A1

36
[ 123770-62-7 ]
[ 206362-80-3 ]
5-(4-chloro-3-fluorobenzyloxymethyl)isoxazole-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Reference Production Example 218 (0861) Ethyl 5-hydroxymethylisoxazole-3-carboxylate (1.71 g, 10.0 mmol) was dissolved in N,N-dimethylformamide (50 mL), and <strong>[206362-80-3]4-chloro-3-fluorobenzyl bromide</strong> (2.79 g, 12.5 mmol) was added to the resulting solution. Sodium hydride (60% oil-based) (0.40 g, 10.0 mmol) was slowly added thereto under cooling with ice water bath, and the mixture was stirred at room temperature for 1 hour. Then, dilute hydrochloric acid was added thereto, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in ethanol (20 mL), and an aqueous solution obtained by dissolving potassium hydroxide (2.81 g, 50 mmol) in water (10 mL) was added thereto at room temperature, and then the mixture was stirred at 80C for 3 hours. Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure. Tert-butyl methyl ether was added to the concentrate, and the aqueous layer was fractionated. Dilute hydrochloric acid was added to the resulting aqueous layer, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with saturated saline water, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 1.06 g of 5-(4-chloro-3-fluorobenzyloxymethyl)isoxazole-3-carboxylic acid represented by the following formula. The product was subjected to a next reaction without purification.

Reference： [1]Patent: EP2952096,2015,A1 .Location in patent: Paragraph 0861

37
[ 206362-80-3 ]
4-(4-chloro-3-fluorobenzyl)piperidine hydrochloride salt [ No CAS ]

Reference： [1]Patent: WO2016/75457,2016,A1

38
[ 206362-80-3 ]
4-(4-chloro-3-fluorobenzyl)-1-((3-cyclopropyl-5-methyl-1H-pyrazol-4-yl)sulfonyl)piperidine [ No CAS ]

Reference： [1]Patent: WO2016/75457,2016,A1

39
[ 206362-80-3 ]
[ 1066-54-2 ]
C₁₂H₁₄ClFSi [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2017,vol. 15,p. 7770 - 7782

40
[ 206362-80-3 ]
C₉H₆ClF [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2017,vol. 15,p. 7770 - 7782

41
[ 1489-97-0 ]
[ 206362-80-3 ]
ethyl 8-(4-chloro-3-fluorobenzyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		To a solution of diisopropylamine (5.16 ml, 36.2 mmol) in THF (78 ml) in an ice bath was added n-BuLi (1.6 M, 21.88 ml, 35.0 mmol), and the reaction mixture was stirred at 0 C for 20 min. This solution was colled to -78 C, and ethyl l,4-dioxaspiro[4.5]decane-8-carboxylate (5 g, 23.34 mmol) was added, and the reaction mixture was warmed up to RT over 30 min. The solution was cooled to -78 C, and 4-(bromomethyl)-l-chloro-2-fluorobenzene (3.69 ml, 27.3 mmol) was added. The reaction mixture was stirred at -78 C for 1 h, and then warmed up to rt over a period of 15 min. After 10 min RT, water was added and the aqueous layer was extracted with ethyl acetate (x3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered, and the filltrate was evaporated in vacuo to give the crude product. 100 mgs of this crude product was spurified by preparative TLC on silica gel (0.50 mm thickness) eluting with 20% ethyl acetate/hexanes to give ethyl 8-(4-chloro-3-fluorobenzyl)-l,4-dioxaspiro[4.5]decane-8- carboxylate (6.8 g, 19.06 mmol, 82 % yield) as a colorless oil. NMR (500MHz, CHLOROFORM-d) delta 7.29 - 7.26 (m, 1H), 6.86 (dd, J=10.0, 1.9 Hz, 1H), 6.79 (dd, J=8.2, 1.8 Hz, 1H), 4.11 (q, J=7.1 Hz, 2H), 3.94 (s, 4H), 2.80 (s, 2H), 2.17 - 2.07 (m, 2H), 1.74 - 1.51 (m, 7H), 1.21 (t, J=7.1 Hz, 3H).

Reference： [1]Patent: WO2018/81384,2018,A1 .Location in patent: Page/Page column 79

42
6-(2-(methylthio) pyrimidin-4-yl)isoindolin-1-one [ No CAS ]
[ 206362-80-3 ]
2-(4-chloro-3-fluorobenzyl)-6-(2-(methylthio)pyrimidin-4-yl)isoindolin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%		General procedure: A mixture of 9 (3.90 mmol) and 1, 4-dioxane (50 mL) was added NaH (4.70 mmol). The mixture was stirred for 1h at room temperature before appropriate arylmethyl bromide (5.85 mmol) added, then the mixture was stirred at 70 oC for 12 h. The solvent was evaporated under reduced pressure and the residue was purification by column chromatography on silica gel to give the derivatives. 2.5.1. 2-(4-chloro-3-fluorobenzyl)-6-(2-(methylthio) pyrimidin-4-yl) isoindolin-1-one (10a) Yield 55%. m.p. 143~144 oC. 1H NMR (300 MHz, CDCl3) delta (ppm): 8.63 (d, J = 5.20 Hz, 1H, ArH), 8.57 (s, 1H, ArH), 8.43 (dd, J = 8.00, 1.60 Hz, 1H, ArH), 7.58 (d, J = 8.00 Hz, 1H, ArH), 7.49 (d, J = 5.30 Hz, 1H, ArH), 7.41 (t, J = 7.80 Hz, 1H, ArH), 7.12 (ddd, J = 9.50, 8.90, 1.60 Hz, 2H, ArH), 4.83 (s, 2H, CH2), 4.40 (s, 2H, CH2), 2.70 (s, 3H, SCH3).
54.8%		Compound XIV (1 g, 3.9 mmol) was dissolved in 1,4-dioxane (50 mL).Add 60% sodium hydride (188 mg, 4.7 mmol) and stir at room temperature for 1 h.<strong>[206362-80-3]4-chloro-3-fluorobenzyl bromide</strong> (1.3 g, 5.85 mmol) was added, and the mixture was stirred at 70 C for about 12 h, and the reaction of the material XIV was completely determined by TLC (petroleum ether: ethyl acetate = 2:1). Residue by column chromatography (eluent: stoneThe oily ether: ethyl acetate = 6:1) was isolated to give 555 mg of white solid, yield: 54.8%,

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 164,p. 334 - 341
[2]Patent: CN109608444,2019,A .Location in patent: Paragraph 0075; 0076; 0077; 0078

43
[ 206362-80-3 ]
N-(2-amino-2-oxoethyl)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-N-[(4-chloro-3-fluorophenyl)methyl]bicyclo[2.2.2]octane-1-carboxamide [ No CAS ]

Reference： [1]Patent: WO2019/90074,2019,A1

44
[ 1668-10-6 ]
[ 206362-80-3 ]
2-((4-chloro-3-fluorobenzyl)amino)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 85℃; for 18h;Sealed tube;	A 20 mL vial was charged with dimethyl sulfoxide (5 mL), <strong>[206362-80-3]4-chloro-3-fluorobenzyl bromide</strong> (500 mg, 2.24 mmol, Enamine), glycinamide hydrochloride (200 mg, 1.81 mmol, Enamine) and Hunig's base (2.0 mL). The vial was sealed and stirred at 85 C for 18 hours. The reaction mixture was cooled to ambient temperature and methanol (3 mL) was added. The resulting solution was filtered through a glass microfiber frit and purified by preparative HPLC [Waters XBridge C18 5 mupiiota OBD column, 50 x 100 mm, flow rate 90 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (80 mg, 0.37 mmol, 20 % yield). JH NMR (400 MHz, DMSO-<) delta ppm 7.47 (t, J = 8.0 Hz, 1H), 7.37 (dd, J = 10.6, 1.9 Hz, 1H), 7.26 (br s, 1H), 7.16 (ddd, J = 8.2, 1.9, 0.8 Hz, 1H), 6.99 (br s, 1H), 3.64 (s, 2H), 2.98 (s, 2H), 2.62 (br s, 1H); MS (APCI+) m/z 217 (M+H)+.

Reference： [1]Patent: WO2019/90074,2019,A1 .Location in patent: Page/Page column 234

45
tert-butyl (5S)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate [ No CAS ]
[ 206362-80-3 ]
tert-butyl (5S)-2-(4-chloro-3-fluorobenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With caesium carbonate; In acetonitrile;	tert-Butyl (5S)-2-(4-chloro-3-fluorobenzyl)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate tert-Butyl (5S)-3-oxo-2,3,5,6,7,8-hexahydro[1,2,4]triazolo[4,3-a]pyridine-5-carboxylate (300 mg, 1.25 mmol) was initially charged in acetonitrile (5.0 ml). Caesium carbonate (449 mg, 1.38 mmol) and <strong>[206362-80-3]4-(bromomethyl)-1-chloro-2-fluorobenzene</strong> (294 mg, 1.32 mmol) were subsequently added. After stirring overnight, the reaction mixture was admixed at room temperature with water and ethyl acetate. The organic phase was removed and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered, and the filtrate was concentrated. The residue was purified via preparative HPLC (Chromatorex C18, 10 mum, 125 mm*30 mm; eluent: acetonitrile/water gradient). The product-containing fractions were concentrated under reduced pressure, and 363 mg (76% of theory) of the title compound were obtained. LC-MS (Method 8): Rt=3.17 min; MS (ESIpos): m/z=382 [M+H]+

Reference： [1]Patent: US2019/160048,2019,A1 .Location in patent: Paragraph 1810-1812

46
[ 87199-16-4 ]
[ 206362-80-3 ]
2-(3-(4-chloro-3-fluorobenzyl)benzylidene)malononitrile [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1148 - 1153

47
[ 87199-16-4 ]
[ 206362-80-3 ]
C₁₄H₁₀ClFO [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 1148 - 1153

48
[ 827614-64-2 ]
[ 206362-80-3 ]
5-(3-chloro-4-fluorobenzyl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere;	To a solution of 4-(bromomethyl)-2-chloro-1 -fluorobenzene (1 .12 g, 5 mmol), 5-(4,4,5,5-tetramethyl-1 ,3-dioxolan-2-yl)pyridin-2-amine (1 .34 g, 6 mmol) and potassium carbonate (1 .38 g, 10 mmol) in 1 ,4-dioxane (30 ml_) and water (10 ml_) was added [1 ,1 '-b/s(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.366 g, 0.5 mmol) under nitrogen. The reaction mixture was stirred at 100 C for 2 h. The reaction mixture was concentrated, and water (50 ml_) was added. The aqueous phase was extracted with ethyl acetate (80 ml_ x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether/ethyl acetate from 1 /1 - 0/1 ) to give 5-(3-chloro-4-fluorobenzyl)pyridin-2-amine (870 mg, 74%) as a yellow solid. LCMS (ESI) m/z: 237.1 [M+H]+.

Reference： [1]Patent: WO2019/183587,2019,A1 .Location in patent: Page/Page column 169

49
[ 827614-64-2 ]
[ 206362-80-3 ]
5-(4-chloro-3-fluorobenzyl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In water; acetonitrile; at 80℃;Inert atmosphere;	General procedure: A mixture of 1 -(bromomethyl)-3-fluorobenzene (0.400 g, 2.12 mmol), 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridin-2-amine (0.467 g, 2.12 mmol), [1 ,1 '-b/s(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.154 g, 0.21 mmol) and potassium carbonate (0.586 g, 4.24 mmol) in acetonitrile (40 mL) and water (1 0 mL) under nitrogen atmosphere was heated 80 C for 3 h. The mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate =1 /1 ) to give 5-(3-fluorobenzyl)pyridin-2-amine (0.256 g, 1 .27 mmol, 60%) as a yellow solid.

Reference： [1]Patent: WO2019/183587,2019,A1 .Location in patent: Page/Page column 106-107; 111

50
[ 206362-80-3 ]
N-(5-(3-chloro-4-fluorobenzyl)pyridin-2-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide [ No CAS ]