[ CAS No. 344-19-4 ] {[proInfo.proName]}

Name: 344-19-4|2,6-Dichloro-4-fluoroaniline|98%
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SKU: A735512
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Quality Control of [ 344-19-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 344-19-4 ]

SDS Specification

Alternatived Products of [ 344-19-4 ]

Product Details of [ 344-19-4 ]

CAS No. :	344-19-4	MDL No. :	MFCD00142845
Formula :	C₆H₄Cl₂FN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YAUYKCFMKMZTEX-UHFFFAOYSA-N
M.W :	180.01	Pubchem ID :	2774008
Synonyms :

Calculated chemistry of [ 344-19-4 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	40.82
TPSA :	26.02 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.15 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.9
Log Po/w (XLOGP3) :	3.16
Log Po/w (WLOGP) :	3.14
Log Po/w (MLOGP) :	3.1
Log Po/w (SILICOS-IT) :	2.84
Consensus Log Po/w :	2.83

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.39
Solubility :	0.0732 mg/ml ; 0.000407 mol/l
Class :	Soluble
Log S (Ali) :	-3.38
Solubility :	0.0756 mg/ml ; 0.00042 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.55
Solubility :	0.051 mg/ml ; 0.000283 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.52

Safety of [ 344-19-4 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P501-P261-P270-P271-P264-P280-P337+P313-P305+P351+P338-P361+P364-P332+P313-P301+P310+P330-P302+P352+P312-P304+P340+P311-P403+P233-P405	UN#:	2811
Hazard Statements:	H301+H311+H331-H315-H319	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 344-19-4 ]

* 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 [ 344-19-4 ]
Downstream synthetic route of [ 344-19-4 ]

[ 344-19-4 ] Synthesis Path-Upstream 1~4

1
[ 371-40-4 ]
[ 344-19-4 ]

Reference： [1] Acta Chimica Academiae Scientiarum Hungaricae, 1957, vol. 10, p. 227,229
[2] Chemical Communications, 2013, vol. 49, # 94, p. 11044 - 11046

2
[ 106-49-0 ]
[ 344-19-4 ]

Reference： [1] Chemical Communications, 2013, vol. 49, # 94, p. 11044 - 11046

3
[ 2106-02-7 ]
[ 344-19-4 ]

Reference： [1] Chemical Communications, 2013, vol. 49, # 94, p. 11044 - 11046

4
[ 392-16-5 ]
[ 344-19-4 ]

Reference： [1] Acta Chimica Academiae Scientiarum Hungaricae, 1957, vol. 10, p. 227,229

[ 344-19-4 ] Synthesis Path-Downstream 1~67

1
[ 392-16-5 ]
[ 344-19-4 ]

Reference： [1]Acta Chimica Academiae Scientiarum Hungaricae,1957,vol. 10,p. 227,229

2
[ 344-19-4 ]
[ 108-24-7 ]
[ 392-16-5 ]

Reference： [1]Acta Chimica Academiae Scientiarum Hungaricae,1957,vol. 10,p. 227,229

3
[ 371-40-4 ]
[ 344-19-4 ]

Reference： [1]Acta Chimica Academiae Scientiarum Hungaricae,1957,vol. 10,p. 227,229
[2]Chemical Communications,2013,vol. 49,p. 11044 - 11046

4
[ 344-19-4 ]
[ 100754-92-5 ]
[ 127792-44-3 ]

Reference： [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 2358 - 2368

5
[ 344-19-4 ]
[ 127792-50-1 ]
[ 127792-42-1 ]

Reference： [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 2358 - 2368

7
[ 344-19-4 ]
(2,6-dichloro-4-fluorophenyl)hydrazine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%		Preparation 10 2,6 Dichloro-4-fluoro-phenylhydrazine hydrochlorideTo a 0 0C solution of 2,6 Dichloro-4-fluorophenylamine (3.0 g, 16.6 mmol) in 12 M HCl (30 mL) and TFA (20 mL) is added slowly and dropwise NaNO2 (20 mmol, 1.37 mL) in water (6 mL). The reaction is stirred at 0 0C for 1 h. A solution of SnCl2 (5.74 g, 25.6 mmol) in 12 M HCl (16 mL) is added over 15 minutes. The ice bath is removed and <n="24"/>the reaction is stirred for 18 h. The reaction is filtered and the solid is washed with isopropyl alcohol. The solid is dried to yield the title compound (3.0 g, 96 %). LC-ES/MS m/e 194.0 (M+ 1)
		Step 1: (2,6-dichloro-4-fluorophenyl)hydrazine hydrochloride To a - 5 C solution (internal temperature, wet ice/acetone bath) of <strong>[344-19-4]2,6-dichloro-4-fluoroaniline</strong> (3.0 g, 17 mmol) in 37 % hydrochloric acid (30 mL) and trifluoroacetic acid (20 mL) was added dropwise an aqueous solution of sodium nitrite (1.4 g, 20 mmol, 6 mL water). The reaction was stirred for 90 minutes, then a solution of stannous chloride dihydrate (5.6 g, 25 mmol) in 37 % hydrochloric acid (16 mL) was added over 15 minutes, keeping the internal temperature ? 2 C. The mixture was stirred overnight at room temperature. The mixture was filtered and the collected solid was washed with isopropyl alcohol and dried under house vacuum to provide the title compound. LCMS-ESI+ (m/z): [M+H]+ calcd for C6H6Cl2FN2: 195.0; found: 194.9.

Reference： [1]Patent: WO2007/140183,2007,A1 .Location in patent: Page/Page column 22-23
[2]Patent: EP3257847,2017,A1 .Location in patent: Paragraph 0191; 0192

8
[ 344-19-4 ]
[ 88972-04-7 ]

Yield	Reaction Conditions	Operation in experiment
71%		PREPARATION CXXXVI; 2,6-dichloro-4-fluorobenzenesulphonyl chloride; A solution of 4.75 g (25 mM) of <strong>[344-19-4]2,6-dichloro-4-fluoroaniline</strong> in 50 ml of dichloromethane are added, at -15 C., to 4.75 ml of boron trifluoride etherate. 5 ml of tetrahydrofuran are added to dissolve the precipitate formed, then, slowly, 3.6 ml of t-butyl nitrite in solution in 25 ml of dichloromethane are added. The reaction mixture is agitated 10 minutes at -15 C. and then 20 minutes at +5 C. 200 ml of pentane are added, and agitation is maintained at 0 C. for 30 min and the precipitate is filtered off. After drying, 7.2 g of the diazonium salt are obtained. This salt is dissolved in 30 ml of acetonitrile and is added, at 10 C., to a mixture of a solution of sulphur dioxide in 90 ml of acetic acid to which 1.4 g of anhydrous copper (II) chloride and 23 ml of concentrated hydrochloric acid have been added. The reaction mixture is agitated 30 min at ambient temperature and then concentrated under reduced pressure. The residue from evaporation is taken up into 60 ml of dichloromethane and the insoluble salts are removed by filtration. The filtrate is concentrated under reduced pressure to give 4.71 g of the product sought after as orange crystals (yield=71%). M.Pt.=57 C.

Reference： [1]Patent: US2006/178360,2006,A1 .Location in patent: Page/Page column 24

9
tin(II)chloride dihydrate [ No CAS ]
[ 344-19-4 ]
2,6-DICHLORO-4-FLUOROPHENYLHYDRAZINE [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; sodium nitrite; In hydrogenchloride; water;	PREPARATION OF 2,6-DICHLORO-4-FLUOROPHENYLHYDRAZINE (INTERMEDIATE NO. 2) 9.0 g (0.05 mol) of <strong>[344-19-4]2,6-dichloro-4-fluoroaniline</strong> was added to 50 ml of concentrated hydrochloric acid, and a solution of 3.8 g (0.055 mol) of sodium nitrite in 25 ml of water was dropwise added thereto at a temperature of from 0 to 5 C. After completion of the dropwise addition, the mixture was stirred at the same temperature for further 1 hour. Insolubles were removed by filtration, and the filtrate was dropwise added at a temperature of from 0 to 10 C. to a solution of 33.8 g (0.15 mol) of stannous chloride dihydrate in 50 ml of concentrated hydrochloric acid. After completion of the dropwise addition, the mixture was stirred at the same temperature for further 2 hours. The precipitated hydrochloride was collected by filtration, and 50 ml of water was added thereto. The mixture was made alkaline with an addition of 20% sodium hydroxide, and the precipitated solid was extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue thereby obtained was washed with cold n-hexane to obtain 6.9 g (yield: 70.4%) of the desired compound as white feather-like crystals. Melting point: 117-119 C.

Reference： [1]Patent: US4925864,1990,A

10
[ 1378039-78-1 ]
[ 344-19-4 ]
[ 1378040-07-3 ]

Yield	Reaction Conditions	Operation in experiment
	With titanium tetrachloride; triethylamine; In dichloromethane; at 0 - 20℃; for 5h;	Method 2:Example 43 :2-(2,6-Dichloro-4-fluorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)- amineStep 1 : [l-(4-Azido-5-fluoropyridin-3-yl)-meth-(£)-ylidene]-(2,6-dichloro-4-fluorophenyl)-amineTo a cooled (0 C) solution of 4-azido-5-fluoro-pyridine-3-carbaldehyde (2.44 g, 14.7 mmol), 2,6-dichloro-4- fluorophenylamine (2.65 g, 14.7 mmol) and triethylamine (6.1 mL, 44 mmol) in DCM (50 mL) was added titanium tetrachloride (1M in DCM, 8.8 mL, 8.8 mmol) dropwise. The reaction mixture was stirred at 0 C for 1 hour, warmed to room temperature, and stirred for a further 4 hours. The mixture was concentrated under reduced pressure. The residue was dissolved in toluene and filtered through Celite. The filtrate was concentrated under to dryness under reduced pressure to afford the title compound that was used without further purification.

Reference： [1]Patent: WO2012/66061,2012,A1 .Location in patent: Page/Page column 150-151

11
[ 1378039-22-5 ]
[ 344-19-4 ]
[ 1378039-63-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With titanium tetrachloride; triethylamine; In dichloromethane; at 0 - 20℃; for 2.5h;Inert atmosphere;	Method 2: Example 27: [2-(2,6-Dichloro-4-fluorophenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl]-(6-methylpyrimidin-4-yl)amine Step 1 : l-(4-Azidopyridin-3-yl)meth-(E)-ylidene]-(2,6-dichloro-4-fluorophenyl)amine Titanium tetrachloride (1M, 4.0 mL, 4.15 mmol) was added to a cooled (0 C) mixture of 4-azidopyridine-3- carbaldehyde (1.0 g, 6.75 mmol), <strong>[344-19-4]2,6-dichloro-4-fluorophenylamine</strong> (1.22 g, 6.75 mmol) and triethylamine (2.8 mL, 20.3 mmol) in DCM (24 mL), under nitrogen. The reaction was stirred for 30 minutes at 0 C, warmed to room temperature, stirred for an additional 2 h, and concentrated under reduced pressure. The residue was dissolved in toluene and filtered though a pad of Celite. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as a yellow solid (2.09 g, quant.). This crude material was employed in the next step without further purification or analysis.

Reference： [1]Patent: WO2012/66061,2012,A1 .Location in patent: Page/Page column 118-119

12
[ 344-19-4 ]
[ 5188-07-8 ]
[ 1443249-09-9 ]

Yield	Reaction Conditions	Operation in experiment
34%		Aniline 1 (12 g, 67 mmol) was taken up in concentrated HCI (13 mL) and water (51 mL) at 0 C. After stirring for 15 min, a solution of NaN02 (4.85 g, 70.3 mmol) in water (10 mL) was added drop-wise at 0C and the mixture was stirred for 45 min. A solution of MeSNa (35 g, 100 mmol) and Na2C03 (10.6 g, 100 mmol) in water (100 mL) was then added to the above solution drop- wise at 50 C. After addition, the mixture was stirred for 1 hour, then extracted with EtOAc and the combined organic layers were dried (MgSC ), filtered and the filtrate concentrated in vacuo to give the crude product. Flash chromatography using neat 60-90 petrol ether afforded thi- oether 2 (4.7 g, 34%). H NMR (CDCI3, 400MHz): delta 7.17 (d, 2H), 2.41 (s, 3H).
34%		<strong>[344-19-4]2,6-dichloro-4-fluoro-aniline</strong> (12 g, 67 mmol) was taken up in concentrated H0I (13 mL)and water (Si mL) at 0 00 After stirring for iS mm, a solution of NaNO2 (4.85 g, 70.3 mmol) in 147water (10 mL) was added drop-wise at 0 00 and the mixture was stirred for 45 mm. A solution of MeSNa (35 g, 100 mmol) and Na2CO3 (10.6 g, 100 mmol) in water (100 mL) was then added to the above solution drop-wise at 50 00. After addition, the mixture was stirred for 1 hour, then extracted with Et0Ac and the combined organic layers were dried (MgS04), filtered and thefiltrate concentrated in vacuo to give the crude product. Flash chromatography using neat 60-90 petrol ether afforded 1 ,3-d ichloro-5-fluoro-2-methylsulfanyl-benzene (4.7 g, 34%).1H NMR (ODd3, 400MHz): 57.17 (d, 2H), 2.41 (s, 3H).

Reference： [1]Patent: WO2013/83859,2013,A2 .Location in patent: Page/Page column 115
[2]Patent: WO2015/7564,2015,A1 .Location in patent: Page/Page column 146; 147

13
[ 344-19-4 ]
[ 1443249-10-2 ]

Reference： [1]Patent: WO2013/83859,2013,A2
[2]Patent: WO2015/7564,2015,A1

14
[ 344-19-4 ]
[ 1443249-11-3 ]

Reference： [1]Patent: WO2013/83859,2013,A2
[2]Patent: WO2015/7564,2015,A1

15
[ 344-19-4 ]
[ 1443249-12-4 ]

Reference： [1]Patent: WO2013/83859,2013,A2

16
[ 344-19-4 ]
[ 1443249-01-1 ]

Reference： [1]Patent: WO2013/83859,2013,A2

17
[ 344-19-4 ]
[ 1443249-02-2 ]

Reference： [1]Patent: WO2013/83859,2013,A2

18
[ 344-19-4 ]
[ 1443248-95-0 ]

Reference： [1]Patent: WO2013/83859,2013,A2

19
N-(2,6-dichloro-4-fluorophenyl)pyrimidine-2-sulfonamide [ No CAS ]
[ 344-19-4 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 11044 - 11046

20
N-(2-chloro-4-fluorophenyl)pyrimidine-2-sulfonamide [ No CAS ]
[ 344-19-4 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 11044 - 11046

21
N-(4-fluorophenyl)pyrimidine-2-sulfonamide [ No CAS ]
[ 344-19-4 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 11044 - 11046

22
N-(p-tolyl)pyrimidine-2-sulfonamide [ No CAS ]
[ 344-19-4 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 11044 - 11046

23
[ 106-49-0 ]
[ 344-19-4 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 11044 - 11046

24
[ 2106-02-7 ]
[ 344-19-4 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 11044 - 11046

25
[ 1131736-53-2 ]
[ 344-19-4 ]
[ 1581260-55-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1466 - 1471

26
C₁₁H₆ClN₃O [ No CAS ]
[ 344-19-4 ]
[ 1581260-63-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1466 - 1471

27
[ 344-19-4 ]
1,3-dichloro-5-fluoro-2-nitrobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%		Procedure adapted from Guan, Z. et ah , Organometallics, 2011, (30), 2432-2452. To a solution of <strong>[344-19-4]2,6-dichloro-4-fluorobenzenamine</strong> (1.8 g, 10 mmol) in dichloromethane (36 mL) was added 3-chloroperoxybenzoic acid (6.88 g, 40 mmol). The mixture was heated to reflux and stirred for 5 h. The reaction mixture was cooled to 0 C in an ice bath and then filtered. The filtrate was then washed with 1 N potassium hydroxide (2 x 50 mL), the organic layer was concentrated in vacuum to afford a brown solid, which was dissolved in 18 mL of glacial acetic acid. To this solution was added a 30% H202 solution (9 mL) and concentrated nitric acid (1.8 mL). The mixture was heated to reflux and stirred for 3 h, then poured into 50 mL of ice water and left to stand overnight at 4 C. The suspension was filtered and the solid washed with water, dissolved in ethyl acetate (50 mL) and dried (Na2S04) and concentrated. The crude was purified by silica gel column chromatography to afford the title compound as a white solid (, 517 mg, 26%): mp 78-80 C; ]H NMR (400 MHz, CDC13) delta 7.24 (dd, J = 7.7, 1.0 Hz, 2H); EIMS m/z 209.

Reference： [1]Patent: WO2014/126580,2014,A1 .Location in patent: Page/Page column 101; 102

28
[ 344-19-4 ]
1,3-dichloro-2-nitro-5-phenoxybenzene [ No CAS ]

Reference： [1]Patent: WO2014/126580,2014,A1

29
[ 344-19-4 ]
2,6-dichloro-4-phenoxyaniline [ No CAS ]

Reference： [1]Patent: WO2014/126580,2014,A1

30
[ 344-19-4 ]
2,4-dichloro-3-ethylsulfinyl-6-fluoro-N-(1-methyltetrazol-5-yl)benzamide [ No CAS ]

Reference： [1]Patent: WO2014/184016,2014,A1

31
[ 344-19-4 ]
2,4-dichloro-3-ethylsulfonyl-6-fluoro-N-(1-methyltetrazol-5-yl)benzamide [ No CAS ]

Reference： [1]Patent: WO2014/184016,2014,A1

32
[ 344-19-4 ]
2,4-dichloro-3-ethylsulfanyl-6-fluorobenzoic acid [ No CAS ]

Reference： [1]Patent: WO2014/184016,2014,A1

33
[ 344-19-4 ]
2,4-dichloro-3-ethylsulfanyl-6-fluorobenzoyl chloride [ No CAS ]

Reference： [1]Patent: WO2014/184016,2014,A1

34
[ 344-19-4 ]
2,4-dichloro-3-ethylsulfanyl-6-fluoro-N-(1-methyltetrazol-5-yl)benzamide [ No CAS ]

Reference： [1]Patent: WO2014/184016,2014,A1

35
[ 110-81-6 ]
[ 344-19-4 ]
1,3-dichloro-2-ethylsulfanyl-5-fluorobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With tert.-butylnitrite; copper; at 80℃; for 2h;	Cu-powder (5.3 g) was added with stirring to <strong>[344-19-4]2,6-dichloro-4-fluoro-aniline</strong> (100 g, 0.56 mol) dissolved in diethyldisulfide (400 mL) and the mixture was heated at 80 C. Tert-butyl nitrite (86g, 1 .5 equiv.) was added slowly over a period of 1 hour (exothermic reaction) and stirring was continued for an additional hour at 80 C.Work-up: Excess diethyl disulfide was evaporated in vacuo and the residual crude was treated with diluted aqueous hydrochloric acid. The aqueous phase was extracted with toluene. Thr organic phase was washed sequentially with hydrochloric acid and water, dried over mag35 nesium sulfate. Evaporation of the solvent gave 1 ,3-dichloro-2-ethylsulfanyl-5-fluoro-benzene asa brownish oil (111 g, 0.50 mol, 89%) which was used without further purification in the next step.1H NMR (CDCI3, 400 MHz): D = 7.2 (d, 2 H), 2.9 (q, 2 H), 1.2 (t, 3H).

Reference： [1]Patent: WO2014/184016,2014,A1 .Location in patent: Page/Page column 149

36
[ 344-19-4 ]
2,4-dichloro-6-fluoro-3-methylsulfanyl-N-(4-methyl-1,2,4-triazol-3-yl)benzamide [ No CAS ]

Reference： [1]Patent: WO2015/7564,2015,A1

37
[ 344-19-4 ]
2,4-dichloro-6-fluoro-3-methylsulfonyl-N-(4-methyl-1,2,4-triazol-3-yl)benzamide [ No CAS ]

Reference： [1]Patent: WO2015/7564,2015,A1

38
[ 344-19-4 ]
2,4-dichloro-N-(4-ethyl-1,2,4-triazol-3-yl)-6-fluoro-3 methyl-sulfanyl-benzamide [ No CAS ]

Reference： [1]Patent: WO2015/7564,2015,A1

39
[ 344-19-4 ]
2,4-dichloro-N-(4-ethyl-1,2,4-triazol-3-yl)-6-fluoro-3-methyl-sulfonyl-benzamide [ No CAS ]

Reference： [1]Patent: WO2015/7564,2015,A1

40
[ 344-19-4 ]
[ 106-95-6 ]
1,3-dichloro-5-fluoro-2-(prop-2-en-1-yl)benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With tert.-butylnitrite; In acetonitrile; at 20℃; for 1.83333h;	A.9.1. Synthesis of 1 ,3-dichloro-5-fluoro-2-(prop-2-en-1 -yl)benzene a23. To a solution of allyl bromide (21 .6 mL, 249.9 mmol) in degassed ACN (80 mL) was added fert-butyl nitrite (3.99 mL, 33.22 mmol). A solution of <strong>[344-19-4]2,6-dichloro-4-fluoroaniline</strong> (3 g, 16.66 mmol) in ACN (5 mL) was added dropwise within 20 min. The reaction mixture was stirred at rt for 90 min. and concentrated under vacuum. The residue was taken up EtOAc and washed with water. The organic layer was dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by column chromatography using 1 % EtOAc in hexanes as eluent to afford 1 .4 g of 1 ,3-dichloro-5-fluoro-2-(prop-2-en-1 -yl)benzene a23. Yield: 41 % LCMS: 205 (M+H)+. 1H NMR (400 MHz, DMSO-d6) delta 7.54 (d, J = 8.4 Hz, 2H), 5.91 -5.82 (m, 1 H), 5.07 (d, J = 9.9 Hz, 1 H), 4.91 (m, 1 H), 3.59 (d, J = 5.2 Hz, 2H).

Reference： [1]Patent: WO2016/55479,2016,A1 .Location in patent: Page/Page column 73

41
[ 344-19-4 ]
(2,6-dichloro-4-fluorophenyl)acetic acid [ No CAS ]

Reference： [1]Patent: WO2016/55479,2016,A1

42
[ 344-19-4 ]
C₁₂H₁₈ClN₃OS [ No CAS ]
N-(2',6'-dichloro-4'-fluorophenyl)-5-isopropyl-2-(4"-methylpiperazin-1-yl)thiazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
231.5 mg	With pyridine; In dichloromethane; at 20℃; for 12h;Inert atmosphere;	General procedure: 1 molar equivalent of the carboxylic acid obtained in the hydrolysis reaction (general procedure B) was introduced into a 25 mL round-bottom flask fitted with a condenser. The system was purged with an argon stream and 4 mL of SOCl2 (excess) were added. The reaction mixture was refluxed for 1 h, after which it was concentrated under reduced pressure and the crude acyl chloride was dissolved in dichloromethane. In parallel, 1.33 eq. of the corresponding aniline were dissolved in a 1:1 mixture of dichloromethane:pyridine (0.2 M). The resulting solution was added to the reaction mixture, which was then stirred for 12 h at rt. The solvents were removed under reduced pressure and the resulting crude mixture was purified by column chromatography on silica gel.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 3938 - 3944

43
[ 344-19-4 ]
ethyl 4-cyclopropyl-1-(2,6-dichloro-4-fluorophenyl)-1H-pyrazole-5-carboxylate [ No CAS ]

Reference： [1]Patent: EP3257847,2017,A1

44
[ 344-19-4 ]
(4-cyclopropyl-1-(2,6-dichloro-4-fluorophenyl)-1H-pyrazol-5-yl)methanol [ No CAS ]

Reference： [1]Patent: EP3257847,2017,A1

45
[ 344-19-4 ]
5-(chloromethyl)-4-cyclopropyl-1-(2,6-dichloro-4-fluorophenyl)-1H-pyrazole [ No CAS ]

Reference： [1]Patent: EP3257847,2017,A1

46
[ 344-19-4 ]
[ 1885-14-9 ]
C₁₃H₈Cl₂FNO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 0 - 20℃;	General procedure: The appropriate aromatic amine (1mmol) was dissolved under Ar in dry 47 CH2Cl2 (3mL), cooled in an ice bath and treated with a solution of 12 phenyl chloroformiate (190muL, 1.5mmol) and 48 pyridine (200muL, 2.5mmol) in dry CH2Cl2 (1mL). The mixture was then stirred for 2hat room temperature and then worked up. The residue was subjected to column chromatography on silica gel (elution with hexane-EtOAc 9:1) to afford the corresponding 13 urethane.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 150,p. 817 - 828

47
[ 344-19-4 ]
(S)-1-(2,6-dichloro-4-fluorophenyl)-3-(1,2,3,10-tetramethoxy-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl)urea [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 150,p. 817 - 828

48
[ 344-19-4 ]
ethyl 7-chloro-1-(2,6-dichloro-4-fluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate [ No CAS ]

Reference： [1]Patent: US2018/297994,2018,A1

49
[ 344-19-4 ]
7-chloro-1-(2,6-dichloro-4-fluorophenyl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid [ No CAS ]

Reference： [1]Patent: US2018/297994,2018,A1

50
[ 157373-27-8 ]
[ 344-19-4 ]
C₁₉H₁₆Cl₃FN₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 4h;	To a solution of 6.07 g (19.1 mmol) of ethyl 2-[(2,6-dichloropyridin-3-yl)carbonyl]-3-ethoxyacrylate (CAS 157373-27-8) and 4.81 g (26.7 mmol) of <strong>[344-19-4]2,6-dichloro-4-fluoroaniline</strong> in 30 ml DCM were added 23.3 ml (134 mmol) of DIPEA, and the mixture was stirred at RT for 4 h. Subsequently, 2.64 g (19.1 mmol) of potassium carbonate were added and the mixture was heated under reflux overnight. The mixture was diluted with 200 ml of DCM and washed twice with 75 ml of 1 M aqueous hydrochloric acid. The organic phase was dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. The suspension obtained was stirred with 40 ml of tert-butyl methyl ether, and the precipitate was filtered off with suction, washed with 10 ml of tert-butyl methyl ether and dried under high vacuum. 3.81 g (45% of theory, 94% purity) of the title compound were obtained. LC-MS (Method 1): Rt=1.04 min; MS (ESIpos) m/z 415 [M+H]+. 1H NMR (400 MHz, DMSO-d6): delta [ppm]=8.88 (s, 1H), 8.65 (d, 1H), 7.92 (d, 2H), 7.69 (d, 1H), 4.25 (q, 2H), 1.28 (t, 3H).

Reference： [1]Patent: US2018/297994,2018,A1 .Location in patent: Paragraph 1210-1214

51
[ 344-19-4 ]
C₅H₅⁽²⁾H₆NO [ No CAS ]
[ 73183-34-3 ]
C₁₇H₁₈⁽²⁾H₆BFN₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The compound 2 (850 mg, 7.93 mmol) was dissolved in toluene (10 mL), and the compound 4-bromo-2,6-difluoroaniline (825 mg, 3.97 mmol) was added, and phosphorus oxychloride (1.13 mL, 12.1 mmol) was added in one portion. TEA (1.64 mL, 11.9 mmol) was heated to reflux for 5 h. After cooling to room temperature, it was diluted with EA (30 mL) and filtered and evaporatedThe brown liquid (917 mg, 3.03 mmol) was taken in THF (15 mL).Heat to reflux overnight. Cool to room temperature,The reaction mixture was concentrated, EA (5 mL) and brine (5 mL)The organic phases were combined and washed with saturated brine.Dry over anhydrous sodium sulfate and EtOAc (EtOAc)EtOAc. The above pale yellow solid was placed in a single-necked flask, followed by the addition of bis-boronic acid pinacol ester (904 mg, 3.56 mmol).Tricyclohexylphosphine (113 mg, 0.04 mmol),Palladium acetate (59 mg, 0.26 mol),Potassium acetate (699 mg, 7.12 mmol) was replaced with nitrogen three times, and anhydrous DMSO (11 mL) was added under a nitrogen atmosphere, and the mixture was stirred and stirred at 90 C for 45 minutes. The reaction was cooled to room temperature, poured into 50 mL of water and extracted with EA-PE (v/v, 1/1, 10mL*2).

Reference： [1]Patent: CN110066272,2019,A .Location in patent: Paragraph 0109-0012; 0117-0118

52
[ 344-19-4 ]
C₁₁H₄Cl₂F₄N₂O [ No CAS ]
1-(2-chloro-4-fluorophenyl)-N-(2,6-dichloro-4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In dichloromethane;Reflux;	General procedure: A solution of 2,4,6-trisubstitutedphenylamine (10, 0.8 mmol) in pyridine (10 mL) was added to the flask containingt he crude acyl chloride 8 (0.8 mmol) which was prepared from the procedure described above, and the mixture was refluxed for 3-5 h. After cooling down, the mixture was poured into water (50 mL) and extracted with ethyl acetate (3× 15 mL). The extracts were combined and washed with hydrochloric acid (2 × 10 mL) and brine, successively. The organic phase was dried over anhydrous Na2SO4. After solvent removal, the residue was further purified by recrystallization from ethanol to afford the title compound 12(a-c) as a solid.

Reference： [1]Chinese Chemical Letters,2020,vol. 31,p. 739 - 745

53
[ 344-19-4 ]
C₂₉H₂₁ClN₄ [ No CAS ]
C₃₅H₂₄Cl₂FN₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Pd2dba3 (34.2 mg, 37.3 pmol), Xantphos (53.9 mg, 93.3 pmol) and CS2CO3 (456 mg, 1.40 mmol) were added to a mixture of 1-170 (430 mg, 0.93 mmol) in DMF (12 mL) in a sealed tube while N2 was bubbling. After 10 min, <strong>[344-19-4]2,6-dichloro-4-fluoroaniline</strong> [344- 19-4] (218 mg, 1.21 mmol) was added and the reaction mixture was stirred at room temperature for 10 min, and at 100 C for 20 h. The mixture was filtered over Celite and the filtrate was concentrated in vacuo. The crude mixture was purified by flash column chromatography (silica, heptane/EtOAc, gradient from 100:0 to 0:100) to afford 1-171 (400 mg, 64%, 90% purity).

Reference： [1]Patent: WO2019/243535,2019,A1 .Location in patent: Page/Page column 88

54
[ 344-19-4 ]
[ 76513-69-4 ]
[ 4522-35-4 ]
[ 60290-21-3 ]
C₂₂H₂₄Cl₂FN₅OSi [ No CAS ]
C₂₂H₂₄Cl₂FN₅OSi [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		NaH (60% dispersion in mineral oil, 143 mg, 3.57 mmol) was added to a stirred solution of 3-iodo-lH-pyrazole [4522-35-4] (659 mg, 4.00 mmol) in DMF (20 mL) at 0 C under N2 atmosphere. The mixture was stirred at room temperature for 30 min. 2- (Trimethylsilyl)ethoxymethyl chloride [76513-69-4] (0.66 mL, 3.74 mmol) was added at 0 C and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried (MgS04), filtered and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in heptane, gradient from 0/100 to 10/90). The desired fractions were collected and concentrated in vacuo to afford a mixture of 1-188 and 1-189 (965 mg, 86%).; Cul (28.3 mg, 0.15 mmol), N,N?-dimethylcyclo hexane- 1, 2-diamine (46.9 uL, 0.30 mmol) and K2C03 (411 mg, 2.98 mmol) were added to a solution of 1-188 and 1-189 (965 mg, 2.98 mmol) in l,4-dioxane (10 mL) in a sealed tube while nitrogen was bubbling. After 10 min, 4-chloro-lH-pyrrolo[3,2-c]pyridine [60290-21-3] (227 mg, 1.49 mmol) was added. The reaction mixture was stirred at room temperature for 10 min, and at 100 C for 20 h. The mixture was diluted with water and extracted with EtOAc. The combined organic extarcts were dried (MgS04), filtered and the solvents were evaporated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in heptane, gradient from 0/100 to 15/85). The desired fractions were collected and concentrated in vacuo to afford a mixture of 1-190 and I- 191 (270 mg, 51%).; Pd2dba3 (39.1 mg, 42.6 pmol), XantPhos (61.7 mg, 0.11 mmol) and CS2CO3 (521 mg, 1.60 mmol) were added to a solution of 1-190 and 1-191 (372 mg mg, 1.07 mmol) in anhydrous DMF (12 mL) in a sealed tube while nitrogen was bubbling. After 10 min, 2,6-dichloro-4-fluoroaniline [344-19-4] (249 mg, 1.39 mmol) was added. The reaction mixture was stirred at room temperature for 10 min, and at 100 C for 20 h. The mixture was filtered over a pad of Celite and the filtrate was concentrated in vacuo. The crude product was purified by flash column chromatography (silica; EtOAc in heptane, gradient from 0/100 to 100/0).). The desired fractions were collected and concentrated in vacuo to afford a mixture of I- 192 and 1-193 (376 mg, 71 %).

Reference： [1]Patent: WO2019/243535,2019,A1 .Location in patent: Page/Page column 93-94

55
[ 344-19-4 ]
[ 60290-21-3 ]
C₁₉H₁₆Cl₂FN₅O [ No CAS ]

Reference： [1]Patent: WO2019/243535,2019,A1

56
[ 344-19-4 ]
C₁₀H₃BrCl₃FN₂O [ No CAS ]