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[ CAS No. 363-51-9 ]

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Chemical Structure| 363-51-9

Chemical Structure| 363-51-9

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Quality Control of [ 363-51-9 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 363-51-9 ]

CAS No. :	363-51-9	MDL No. :	MFCD00040309
Formula :	C₆H₅ClFN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZJLAWMDJTMMTQB-UHFFFAOYSA-N
M.W :	145.56	Pubchem ID :	2734205
Synonyms :

Calculated chemistry of [ 363-51-9 ]

Physicochemical Properties

Num. heavy atoms :	9
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 :	35.81
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) :	-5.56 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.68
Log Po/w (XLOGP3) :	2.29
Log Po/w (WLOGP) :	2.49
Log Po/w (MLOGP) :	2.51
Log Po/w (SILICOS-IT) :	2.21
Consensus Log Po/w :	2.24

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.68
Solubility :	0.305 mg/ml ; 0.0021 mol/l
Class :	Soluble
Log S (Ali) :	-2.47
Solubility :	0.489 mg/ml ; 0.00336 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.91
Solubility :	0.179 mg/ml ; 0.00123 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.39

Safety of [ 363-51-9 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P301+P312-P302+P352-P304+P340-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 363-51-9 ]

* 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 [ 363-51-9 ]
Downstream synthetic route of [ 363-51-9 ]

[ 363-51-9 ] Synthesis Path-Upstream 1~9

1
[ 434-75-3 ]
[ 363-51-9 ]

Reference： [1] Journal of Organic Chemistry, 1955, vol. 20, p. 1577,1589
[2] Patent: US4032639, 1977, A,

2
[ 90493-88-2 ]
[ 363-51-9 ]

Reference： [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1983, vol. 22, # 9, p. 872 - 877

3
[ 2369-21-3 ]
[ 363-51-9 ]

Reference： [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1983, vol. 22, # 9, p. 872 - 877

4
[ 90493-82-6 ]
[ 363-51-9 ]

Reference： [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1983, vol. 22, # 9, p. 872 - 877

5
[ 1493-27-2 ]
[ 363-51-9 ]

Reference： [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1983, vol. 22, # 9, p. 872 - 877

6
[ 363-51-9 ]
[ 64182-61-2 ]

Reference： [1] Journal of Medicinal Chemistry, 2001, vol. 44, # 10, p. 1516 - 1529

7
[ 1234562-75-4 ]
[ 363-51-9 ]
[ 220991-20-8 ]

Reference： [1] Organic Letters, 2010, vol. 12, # 14, p. 3140 - 3143

8
[ 363-51-9 ]
[ 220991-20-8 ]

Reference： [1] Tetrahedron, 2004, vol. 60, # 50, p. 11571 - 11586
[2] Tetrahedron, 2004, vol. 60, # 50, p. 11571 - 11586
[3] Tetrahedron, 2004, vol. 60, # 50, p. 11571 - 11586

9
[ 363-51-9 ]
[ 218796-15-7 ]

Reference： [1] Patent: WO2012/85127, 2012, A1,
[2] Patent: US2012/322803, 2012, A1,
[3] Patent: US2018/98541, 2018, A1,

[ 363-51-9 ] Synthesis Path-Downstream 1~20

1
[ 434-75-3 ]
[ 363-51-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide; sulfuric acid; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; chloroform;	EXAMPLE XVIII 2-Chloro-6-Fluoroaniline To a stirred mixture of 20 g. of <strong>[434-75-3]2-chloro-6-fluorobenzoic acid</strong>, 100 ml. of chloroform and 50 ml. of concentrated sulfuric acid is added slowly 10.2 g. of sodium azide while the temperature is kept at 40-55. Stirring is continued for 2 hours at 40-55 then the mixture is poured into 500 ml. of ice water containing 80 g. of sodium hydroxide. The mixture is extracted with ether and the other extracts are dried over magnesium sulfate. The dry extracts are then treated with hydrogen chloride, and the resultant product as the hydrochloride salt is collected by filtration yielding 12.6 g. of white solid which sublimes at 160-170.

Reference： [1]Journal of Organic Chemistry,1955,vol. 20,p. 1577,1589
[2]Patent: US4032639,1977,A

2
[ 363-51-9 ]
[ 64182-61-2 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1516 - 1529

3
[ 363-51-9 ]
[ 220991-20-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: NaH / dimethylformamide / 1 h / 0 - 4 °C 1.2: 91 percent / dimethylformamide / 20 h / 50 - 55 °C 2.1: HCl gas / ethyl acetate / 2.5 h / -5 - 0 °C 2.2: H₂O / ethyl acetate / 36 h / 20 - 25 °C 3.1: 80 percent / H₂SO₄; EtOH; H₂O / H₂O / 4 h / 66 - 70 °C 4.1: 83 percent / Red-Al / toluene / 1.5 h / 60 - 62 °C 5.1: 82 percent / toluene / 80 - 90 °C 6.1: 80 percent / AlCl₃ / 3 h / 170 °C 7.1: 90 percent / aq. NaOH / ethanol; H₂O / Heating
	Multi-step reaction with 4 steps 1: 90 percent / t-BuONa; t-Bu₃P / Pd(dba)2 / toluene / 14 h / 110 °C 2: 82 percent / toluene / 80 - 90 °C 3: 80 percent / AlCl₃ / 3 h / 170 °C 4: 90 percent / aq. NaOH / ethanol; H₂O / Heating
	Multi-step reaction with 3 steps 1: 76 percent / pTsOH*H₂O / toluene / 18 h / Heating 2: 76 percent / I₂; DBU / xylene / 36 h / 155 °C 3: 90 percent / aq. NaOH / ethanol; H₂O / Heating

Reference： [1]Acemoglu, Murat; Allmendinger, Thomas; Calienni, John; Cercus, Jacques; Loiseleur, Olivier; Sedelmeier, Gottfried H.; Xu, David [Tetrahedron, 2004, vol. 60, # 50, p. 11571 - 11586]
[2]Acemoglu, Murat; Allmendinger, Thomas; Calienni, John; Cercus, Jacques; Loiseleur, Olivier; Sedelmeier, Gottfried H.; Xu, David [Tetrahedron, 2004, vol. 60, # 50, p. 11571 - 11586]
[3]Acemoglu, Murat; Allmendinger, Thomas; Calienni, John; Cercus, Jacques; Loiseleur, Olivier; Sedelmeier, Gottfried H.; Xu, David [Tetrahedron, 2004, vol. 60, # 50, p. 11571 - 11586]

4
[ 363-51-9 ]
[ 96989-50-3 ]
[ 899806-25-8 ]

Yield	Reaction Conditions	Operation in experiment
17%	In tetrahydrofuran at 20℃; for 60h;	5.18 [00311] Synthesis of 6-chloro-2-fluorobenzeneisothiocyanate; [00312] A solution of 2-chloro-6-fluoroaniline (767 mg, 5.29 mmol) in tetrahydrofuran (5 ml) was added drop wise with stirring to a solution of di-2-pyridyl thionocarbonate (2.46 g, 10.58 mmol) in tetrahydrofuran (7 ml) at room temperature. The reaction mixture was stirred for 60 hours at room temperature and then the solvent was evaporated. The resulting residue was purified by chromatography on a normal phase silica gel column with pentane. Fractions containing clean product were combined and the solvent evaporated to give the title compound (167 mg, 17%): 1H NMR (400 MHz, CDCl3) δ 7.19- 7.23 (m, IH), 7.12-7.19 (m, IH), 7.04-7.10 (m, IH).

Reference： [1]Current Patent Assignee: LIGAND PHARMACEUTICALS INC; BRISTOL-MYERS SQUIBB CO - WO2006/76595, 2006, A1 Location in patent: Page/Page column 153

5
[ 1234562-75-4 ]
[ 363-51-9 ]
[ 220991-20-8 ]

Yield	Reaction Conditions	Operation in experiment
41%	With 1-methyl-pyrrolidin-2-one; copper(l) iodide; potassium carbonate at 100℃;

Reference： [1]Mei, Tian-Sheng; Wang, Dong-Hui; Yu, Jin-Quan [Organic Letters, 2010, vol. 12, # 14, p. 3140 - 3143]

6
[ 463-71-8 ]
[ 363-51-9 ]
[ 899806-25-8 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide for 2h; Reflux;	7.B To a solution of 2-chloro-6-fluorobenzenamine (5.0 g, 34 mmol) in chlorobenzene (52 mL) was added carbonothioic dichloride (thiophosgene) (5.1 g, 45 mmol) and DMF (0.27 mL). The reaction mixture was refluxed for 2 h and then concentrated to leave the title compound as a brown oil (6.15 g), which was used in Step C without further purification. ¾ NMR δ 7.18 (m, 2H), 7.07 (m, 1H).
6.15 g	In N,N-dimethyl-formamide; chlorobenzene for 2h; Reflux;	1.B Step B: Preparation of l-Chloro-3-fluoro-2-isothiocyanatobenzene Step B: Preparation of l-Chloro-3-fluoro-2-isothiocyanatobenzene To a solution of 2-chloro-6-fluorobenzenamine (5.0 g, 34 mmol) in chlorobenzene (52 mL) was added carbonothioic dichloride (thiophosgene) (5.1 g, 45 mmol) and DMF (0.27 mL). The reaction mixture was refluxed for 2 h and then concentrated to leave the title compound as a brown oil (6.15 g), which was used in Step C without further purification. H NMR 5 7.18 (m, 2H), 7.07 (m, 1H).
1 g	Stage #1: 2-chloro-6-fluoroaniline With N-ethyl-N,N-diisopropylamine In dichloromethane at 22 - 26℃; for 0.5h; Stage #2: thiophosgene In dichloromethane at 22 - 26℃;	Intermediate- 1 l-Chloro-3-fluoro-2-isothiocyanatobenzene To a solution of 2-chloro-6-fluoro aniline (3.0 g, 19.35 mmol) in DCM (10 mL), N- ethyl di-isopropyl amine (8.0 g, 64.00 mmol) was added. The reaction mass was stirred at RT for 30 minutes. The reaction mass was cooled at 0°C and drop-wise thiophosgene (5.01 g, 43.47 mmol) was added to the reaction mixture. The reaction mass was stirred RT for 3-4 h. After completion of reaction, the reaction mass was diluted with DCM and purified by using column chromatography to afford 1.0 g of desired title product. 1H NMR (DMSO-d6): δ 7.26 (m, 2H), 7.06 (t, J= 9.6Hz, 1H).

31.5 g	In N,N-dimethyl-formamide; chlorobenzene for 2.5h; Reflux;	1.B Step B: Preparation of l-chloro-3-fluoro-2-isothiocyanatobenzene Step B: Preparation of l-chloro-3-fluoro-2-isothiocyanatobenzene A solution of 2-chloro-6-fluorobenzenamine (29.2 g, 0.20 mol) in chlorobenzene (200 mL) was treated with N,N-dimethylformamide (0.10 mL) and then thiophosgene (27.6 g, 0.24 mol) dropwise at room temperature. The reaction mixture was heated to reflux for 2.5 hours and allowed to stir at room temperature for 18 hours. The suspension was filtered through a pad of silica gel and washed with hexane. The filtrate was concentrated under vacuum to give a crude oil which was chromatographed on silica gel with hexane to yield the title compound as a light yellow oil (31.5 g). H NMR (CDC13) δ 7.23-7.19 (m, 1H), 7.18-7.13 (td, 1H), 7.10-7.04 (m, 1H).
	With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;	Intermediate of Example-7k: 1, 3-Dichloro-2-isothiocyanatobenzene (15) General procedure: N, N-Diisopropylethylamine (1.86 g, 18.41 mmol) was added slowly to a stirred solution of 2, 6-dichloroaniline (2 g, 12.34 mmol) in DCM (25 mL) at room temperature and then cooled to 0 oC. Then, thiophosgene (11.4 g, 13.55 mmol) was added dropwise at that temperature and further stirred at room temperature for 3-4 h. After the reaction completion, the reaction mixture was diluted with water and extracted with DCM. The organic portion was dried over Na2SO4, concentrated and purified by flash column using 5% EtOAc in hexane to afford 1, 3-dichloro-2-isothiocyanatobenzene (1.75 g) in 70% yield.
6.15 g	In N,N-dimethyl-formamide; chlorobenzene for 2h; Reflux;	1.B Step B: Preparation of 1 -Chloro-3 -fluoro-2-isothiocyanatobenzene Step B: Preparation of 1 -Chloro-3 -fluoro-2-isothiocyanatobenzeneTo a solution of 2-chloro-6-fluorobenzenamine (5.0 g, 34 mmol) in chlorobenzene(52 mL) was added carbonothioic dichloride (thiophosgene) (5.1 g, 45 mmol) and DMF(0.27 mL). The reaction mixture was refluxed for 2 h and then concentrated to leave the titlecompound as a brown oil (6.15 g), which was used in Step C without further purification.1H NMR ö 7.18 (m, 2H), 7.07 (m, 1H).

Reference： [1]Current Patent Assignee: FMC CORP - WO2012/31061, 2012, A2 Location in patent: Page/Page column 54
[2]Current Patent Assignee: FMC CORP - WO2013/116251, 2013, A2 Location in patent: Page/Page column 30
[3]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2013/153535, 2013, A1 Location in patent: Page/Page column 54
[4]Current Patent Assignee: DUPONT DE NEMOURS INC - WO2014/189753, 2014, A1 Location in patent: Page/Page column 20
[5]Muthukaman, Nagarajan; Tambe, Macchindra; Deshmukh, Sanjay; Pisal, Dnyandeo; Tondlekar, Shital; Shaikh, Mahamadhanif; Sarode, Neelam; Kattige, Vidya G.; Pisat, Monali; Sawant, Pooja; Honnegowda, Srinivasa; Karande, Vikas; Kulkarni, Abhay; Behera, Dayanidhi; Jadhav, Satyawan B.; Sangana, Ramchandra R.; Gudi, Girish S.; Khairatkar-Joshi, Neelima; Gharat, Laxmikant A. [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 23, p. 5131 - 5138]
[6]Current Patent Assignee: DUPONT DE NEMOURS INC - WO2014/130409, 2014, A2 Location in patent: Page/Page column 37

7
[ 363-51-9 ]
[ 218796-15-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: acetic acid / 1 h / 90 °C 2: nitric acid; sulfuric acid / 0 - 20 °C
	Multi-step reaction with 2 steps 1: acetic acid / 2 h / 90 °C 2: sodium nitrate; sulfuric acid / water / 12.5 h / -10 - 24 °C
	Multi-step reaction with 2 steps 1: acetic acid / 2 h / 90 °C 2: sulfuric acid; nitric acid / acetone / 2 h / Cooling with ice

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2012/85127, 2012, A1 Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - US2012/322803, 2012, A1
[2]Current Patent Assignee: CORTEVA INC - US2018/98541, 2018, A1
[3]Current Patent Assignee: INCYTE CORP - US2019/315717, 2019, A1

8
[ 363-51-9 ]
[ 13321-74-9 ]
[ 1432270-44-4 ]

Yield	Reaction Conditions	Operation in experiment
46%	With palladium diacetate; sodium t-butanolate; tri tert-butylphosphoniumtetrafluoroborate; In toluene; at 160℃; for 3h;Inert atmosphere; Microwave irradiation;	General procedure: NaOt-Bu (0.240 g, 2.5 mmol), Pd(OAc)2 (0.006 g, 0.025 mmol) and [HPt-Bu3][BF4] (0.010 g, 0.035 mmol) were suspended in toluene (3 ml) in a 5 ml microwave vial. The appropriate 2-chloroaniline (0.50 mmol) and aryl bromide (0.50 mmol) were then added and the vial sealed. The reaction was then heated in the microwave reactor at 160 C for 3 h, allowed to cool, and then quenched by addition of aqueous HCl (2 M, 3 ml). The organic phase was extracted with CH2Cl2 (2×20 ml), dried (MgSO4), then filtered and the solvent removed under reduced pressure. The crude product mixture was then subjected to column chromatography (SiO2).

Reference： [1]Tetrahedron,2013,vol. 69,p. 4389 - 4394

9
[ 363-51-9 ]
[ 151004-94-3 ]
[ 1567382-34-6 ]

Yield	Reaction Conditions	Operation in experiment
79 mg	With pyridine; trichlorophosphate at 0 - 20℃; for 2h;	4.1 Example 4 (S)-2-[(S)-3-Methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-l ,2,3,4- tetrahydro-isoquinoline-l-carboxylic acid (2-chloro-6-fluoro-phenyl)-amide hydrochloride Step 1 : To the solution of (S)-3,4-dihydro-lH-isoquinoline-l,2-dicarboxylic acid 2- tert-butyl ester (100 mg, 361 μηιο, Eq: 1) and 2-chloro-6-fiuoroaniline (63.0 mg, 433 μηιο, Eq: 1.2) in pyridine (2.00 mL) at 0 °C was added POCL3 (82.9 mg, 50.4 μ, 541 μιηο, Eq: 1.5). Reaction was warmed to RT and stirred for 2 h. The mixture was evaporated and water was added to the residue. The mixture was extracted with EtOAc, the combined organics were washed with water, brine, dried with MgS04 and concentrated in vacuo. The crude material was purified by flash chomatography to give (S)-l-(2-chloro-6-fiuoro- phenylcarbamoyl)-3,4-dihydro-lH-isoquinoline-2-carboxylic acid tert-butyl ester (79 mg) as a white solid.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/26882, 2014, A1 Location in patent: Page/Page column 36

10
[ 363-51-9 ]
[ 1204573-52-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: acetic acid; sulfur dioxide; copper dichloride; hydrogenchloride; sodium nitrite / water / 0.25 h / -5 °C 2: ammonia / water; 1,4-dioxane / 30 h / Cooling

Reference： [1]Francotte, Pierre; Nørholm, Ann-Beth; Deva, Taru; Olsen, Lars; Frydenvang, Karla; Goffin, Eric; Fraikin, Pierre; De Tullio, Pascal; Challal, Sylvie; Thomas, Jean-Yves; Iop, Fabrice; Louis, Caroline; Botez-Pop, Iuliana; Lestage, Pierre; Danober, Laurence; Kastrup, Jette S.; Pirotte, Bernard [Journal of Medicinal Chemistry, 2014, vol. 57, # 22, p. 9539 - 9553]

11
[ 363-51-9 ]
[ 2972-52-3 ]
2,4-dichloro-N-(2-chloro-6-fluorophenyl)pyrimidine-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	In tetrahydrofuran; at 20℃; for 15h;Inert atmosphere;	To a solution of PE1-028-B2 acid chloride (6.36 g, 0.030 mol) obtained in the previous step in THF (40 mL) under inert conditions, 2-chloro-6-fluoroaniline (4.38 g, 0.03 mol) was addedportion wise and the reaction mixture was stirred at r.t. for 15 h. The resulting precipitate was filtered, washed with DCM (15 mL) and the solid obtained was sonicated in HC1 (1M, 100 mL), filtered and washed with water (20 mL), DCM (20 mL) sequentially and dried under high vacuum to obtain the title compound 7c (5.529 g) as a white solid. The first filtrate (i.e., THF and DCM) was concentrated, slurried with DCM (15 mL) and filtered to get a solid. The solidwas again sonicated with HC1 (1M, 30 mL), filtered and washed with water (20 mL), DCM (15 mL) sequentially and dried under high vacuum to obtain another crop of pure product 7c (1.702 g) also as a white solid. The combined yield of 7c (7.23 1 g, 75%), mp 207-211 C. ‘H NMR (400 MHz, DMSO-d6): ö 10.71 (s, 1H), 9.03 (s, 1H), 7.48-7.36 (m, 3H); ‘9F NMR (376 MHz, DMSOd 6): -115.25, -115.28 (m); LC-MS (ESI+) m/z 319.96 (M+H) HRMS (ESI+) m/z calculated forC,,H6C13FN3O (M+H) 319.9555, found 319.9562.

Reference： [1]Patent: WO2015/21149,2015,A1 .Location in patent: Page/Page column 56; 58
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 2746 - 2763

12
[ 363-51-9 ]
[ 1232224-62-2 ]
5-chloro-7-((2-chloro-6-fluorophenyl)amino)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium <i>tert</i>-butylate	13.a (13a) (13a) Synthesis of 5-chloro-7-((2-chloro-6-fluorophenyl)amino)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid ethyl ester Potassium t-butoxide (0.070 g) was added to a mixture of 2-chloro-6-fluoroaniline (CAS No. 363-51-9) (0.090 g) and THF (5 mL) and stirred at room temperature for 15 minutes. 5,7-Dichloropyrazolo[1,5-a]pyrimidine-2-carboxylic acid ethyl ester (CAS No. 1232224-62-2) (0.100 g) was added and stirred with heating at 50° C. for 1 hour. A saturated ammonium chloride aqueous solution was added to separate the organic layer from the aqueous layer. The aqueous layer was extracted with ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system), to obtain the title compound (0.063 g) as a light yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 1.46 (t, J=7 Hz, 3H), 4.30 (q, J=7 Hz, 2H), 5.87 (s, 1H), 7.04 (s, 1H), 7.23-7.27 (m, 1H), 7.40-7.43 (m, 2H), 7.98 (br.s, 1H).

Reference： [1]Current Patent Assignee: EISAI CO LTD - US2018/57499, 2018, A1

13
[ 397308-78-0 ]
[ 363-51-9 ]
N-(2-chloro-6-fluoro-phenyl)-4-hydroxy-2-methylsulfanyl-pyrimidine-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52.8%		A stirred solution of 9 <strong>[397308-78-0]4-hydroxy-2-methylsulfanyl-pyrimidine-5-carboxylic acid</strong> (5.70 g, 30.65 mmol, 1.0 eq) and 237 2-chloro-6-fluoro-aniline (4.50 g, 30.65 mmol, 1.0 eq) in 24 toluene (200 mL) was purged with nitrogen gas for 15 min. To the above solution 91 PCl3 (30 mL) was added. The reaction was heated at 100 C. for 72 h. Progress of reaction was monitored by LCMS. After completion of reaction, solvent was removed under reduced pressure, residue was diluted with a mixture of 238 diethyl ether: 30 MeOH (10:1) (100 mL) stirred for 15 min then filtered off. Solid was suspended in MeOH (20 mL), stirred for 5 min, filtered off and washed with MeOH (10 mL), and then dried under vacuum to obtain of 239 N-(2-chloro-6-fluoro-phenyl)-4-hydroxy-2-methylsulfanyl-pyrimidine-5-carboxamide (5.0 g, 52.8%). (0370) LCMS: 314 [M+1]+

Reference： [1]Patent: US2019/106436,2019,A1 .Location in patent: Paragraph 0368-0370

14
[ 363-51-9 ]
[ 213211-69-9 ]
C₁₄H₁₄FNO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With palladium diacetate; 2-dicyclohexylphosphino-2',6'-dimethylbiphenyl; In toluene; at 100℃; for 3h;	A well-dried 200 mL three-neck eggplant flask2-Ethoxyphenylboronic acid (condenser, with three-way cock, with magnetic stirrer)1.83g (manufactured by Sigma Aldrich Japan)(11.0 mmol),2-Chloro-6-fluoroaniline1.46 g (10 mmol) palladium acetate0.011 g (0.05 mmol),2-Dicyclohexylphosphino-2 ', 6'-dimethylbiphenyl0.041 g (0.1 mmol), potassium phosphate monohydrate 6.9 g (30 mmol) was added, and suspended in 20 mL of toluene.The reaction was carried out at 100 C. for 3 hours.After adding 50 mL of water to this reaction solution and extracting with toluene,The organic layer is dried over MgSO4The solvent was distilled off under reduced pressure to obtain a crude product.Crude product is silica gel column chromatograph(Eluent: hexane / ethyl acetate = 96/4)To give compound 11 2.30 g (99%, pale yellow liquid) was obtained.

Reference： [1]Patent: JP5769444,2015,B2 .Location in patent: Paragraph 0183-0185

15
[ 363-51-9 ]
[ 355836-08-7 ]
C₁₅H₁₆FNO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With palladium diacetate; 2-dicyclohexylphosphino-2',6'-dimethylbiphenyl; In toluene; at 100℃; for 1.5h;	100ml three-neck eggplant flask fully dried1.89 g (10.5 mmol) of Compound 7 (with a condenser, a three-way cock, and a magnetic stirrer)2-Chloro-6-fluoroline1.46 g (10 mmol) (manufactured by Tokyo Chemical Industry Co., Ltd.)0.22 g (0.1 mmol) of palladium acetate,2-Dicyclohexylphosphino-2 ', 6'-dimethylbiphenyl0.082 g (0.2 mmol), potassium phosphate monohydrate6.91 g (30 mmol) was added,Suspend in 18 mL of toluene,The reaction was performed at 100 C. for 1.5 hours.After adding 20 mL of water to this reaction solution and extracting with toluene,The organic layer is dried over MgSO4The solvent was distilled off under reduced pressure to obtain a crude product.The crude product was purified by silica gel column chromatography (eluent;Hexane / ethyl acetate = 95/5)Compound 8 was purified by purification using1.953 g (80%, pale yellow liquid) was obtained.

Reference： [1]Patent: JP5769444,2015,B2 .Location in patent: Paragraph 0174; 0177; 0178

16
[ 363-51-9 ]
[ 2378698-17-8 ]
[ 2225819-06-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-chloro-6-fluoroaniline; 4-[4-ethyl-5-oxo-3-(tetrahydropyran-2-yloxymethyl)-1,2,4-triazol-1-yl]-5-fluoro-2-[(1S)2,2,2-trifluoro-1-methylethoxy]benzoic acid With pyridine; trichlorophosphate In acetonitrile at 0 - 22℃; for 1.16667h; Stage #2: With phosphoric acid In methanol at 60℃; for 2h;	7.B.a; 7.B.b a) To a stirred suspension of (A7) as obtained from example 5 (60.0 g, 126 mmol) in acetonitrile (180 ml.) was added pyridine (35.6 ml_, 440 mmol) and 2-chloro-6-fluoroaniline (27.4 g, 188 mmol, CAS-no. 363-51-9 obtained from Combiblocks, product code OS-7812; alternatively a preparation of 2-chloro-6-fluoroaniline is described in US 4,089,958, example XVIII) at 22°C. The cloudy solution was cooled to 0-5°C and phosphoryl chloride (21.2 g, 138 mmol) was added over a period of 10 min. The reaction mixture was stirred for 1 h resulting in a clear solution. Methanol (360 ml.) and 85% phosphoric acid (12.8 ml_, 189 mmol) were added and the mixture was heated to 60°C for 2 h. (0796) The reaction solvent was partially removed by distillation (95°C bath, 64-72°C internal temperature) to give 420 ml. distillate. The distillation residue was slowly cooled to 22°C and stirred for 16 h. The resulting suspension was cooled to 0-5°C and stirred for additional 2 h. The solid was isolated, washed two times with 2-propanol (30 ml.) and dried in vacuum at 50°C for 16 h to give crude product Compound (I) as a white solid (55g, 106 mmol) in 84% yield. (0797) HPLC (method 1 ): Rt = 2.81 min (> 98% area) (0798) b) The reaction product (30.0 g, 57.6 mmol) was further purified by suspension in anhydrous ethanol (450 ml.) and heating to 60°C. The resulting clear solution was filtered, the filter cake was washed two times with hot anhydrous ethanol (30 ml.) and the filtrate was concentrated by distillation of solvent (270 ml. distillate) at 100°C bath temperature. The solution was cooled to 50°C, seeded (I) (0.3 g), and cooled stepwise to 0-5°C over 4h. The precipitated solid was isolated, washed two times with anhydrous ethanol (15 ml.) and dried in vacuum at 50°C for 16h to give Compound (I) as a white solid (25.7 g, 49.3 mmol) in 86% yield from crude (0799) Compound (I). (0800) HPLC (method 1 ): Rt = 2.81 min (> 99% area) (0801) 1H NMR (400 MHz, DMSO-d6) d ppm 1.29 (t, J=7.15 Hz, 3 H) 1.45 (d, J=6.36 Hz, 3 H) 3.80 (q, J= 7.09 Hz, 2 H) 4.44 - 4.55 (m, 2 H) 5.36 (dt, J=12.78, 6.33 Hz, 1 H) 5.80 (t, J= 5.75 Hz, 1 H) (0802) 7.30 - 7.47 (m, 3 H) 7.50 - 7.66 (m, 2 H) 10.05 (s, 1 H) (0803) LCMS (method 1 ): Rt = 0.90 min; MS (ESIpos): m/z = 521 (M+H)+

Reference： [1]Current Patent Assignee: BAYER AG - WO2019/197239, 2019, A1 Location in patent: Page/Page column 96-97

17
[ 363-51-9 ]
[ 88419-56-1 ]
N-(2-chloro-6-fluorophenyl)-2,4,5-trifluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83.43%	With pyridine In dichloromethane at 25℃; for 16h; Inert atmosphere;	16.B Step B N-(2-Chloro-6-fluorophenyl)-2.4.5-trifluorobenzamide. To a mixture of 2- chloro-6-fluoro-aniline (3.86 g, 26.53 mmol) and pyridine (8.74 g, 110.53 mmol) in DCM (45 mL) was added a solution of 2,4,5-trifluorobenzoyl chloride (4.30 g, 22.11 mmol) in DCM (5 mL). The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched by addition of ThO (70 mL). The mixture was extracted with DCM (60 mL c 2). The combined organic layers were washed with brine (100 mL), dried over NaiSCL, fdtered and concentrated under reduced pressure. The residue was triturated with petroleum ether/ethyl acetate (10: 1,30 mL) to afford the title compound (5.6 g, 18.44 mmol, 83.43% yield) as white solid. MS (ESI): mass calcd. forC13H6CIF4NO, 303.0; m/z found, 304.0 [M+H]+. NMR (400MHz, CDCL) d = 8.06 (ddd, J =12, 8.9, 10.4 Hz, 2H), 7.33 - 7.27 (m, 2H), 7.19 - 7.06 (m, 2H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2020/161663, 2020, A1 Location in patent: Page/Page column 59; 92-93

18
[ 107-86-8 ]
[ 363-51-9 ]
N-(2-chloro-6-fluorophenyl)-3-methylbut-2-en-1-imine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With titanium tetrachloride; triethylamine In dichloromethane at 0 - 25℃; for 5h; Inert atmosphere;	3.A Step A. N-(2-Chloro-6-fluorophenyl)-3-methylbut-2-en-1-imine To a solution of 2-chloro-6- fluoroaniline (2.9 g, 20 mmol) and 3-methyl-2-butenal (2 g, 23.9 mmol) in anhydrous dichloromethane (50 mL) at 0 °C was added triethylamine (8.3 mL, 60 mmol), followed by the addition of TiCl4(3 g, 16 mmol) dropwise. The reaction mixture was stirred at 0 °C for 1 h, then warmed to 25 °C and stirred for 4 h. The mixture was filtered through a short pad of Celite, and the filtrate was partitioned between dichloromethane and water. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic extract was dried over MgSO4, filtered, and concentrated to give the crude desired product as a yellow oil (3.3 g, 78%), which was used crude in the next step without further purification.1H NMR (400 MHz, CDCl3) d 8.36 (dd, J = 2.20, 9.66 Hz, 1H), 7.20 (d, J = 7.83 Hz, 1H), 6.94-7.09 (m, 2H), 6.32 (br d, J = 9.66 Hz, 1H), 5.30 (s, 1H), 2.00 (s, 6H)
	With titanium tetrachloride; triethylamine In dichloromethane at 0 - 25℃; for 5h;	11.A Step A N-(2-Chloro-6-fluorophenyl)-3-methylbut-2-en-l-imine. To a solution of 2- chloro-6-fluoroaniline (2.9 g, 20 mmol) and 3-methyl-2-butenal (2 g, 23.9 mmol) in anhydrous dichloromethane (50 mL) at 0 °C was added triethylamine (8.3 mL, 60 mmol), followed by the addition of TiCk (3 g, 16 mmol) dropwise. The reaction mixture was stirred at 0 °C for 1 h, then warmed to 25 °C and stirred for 4 h. The mixture was fdtered through a short pad of Celite, and the fdtrate was partitioned between dichloromethane and water. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic extract was dried over MgSCb and concentrated to give the crude desired product as a yellow oil (3.3 g, 78%), which was used crude in the next step without further purification. NMR (400 MHz, CDCb) d 8.36 (dd, J= 2.20, 9.66 Hz, 1H), 7.20 (d, J= 7.83 Hz, 1H), 6.94-7.09 (m, 2H), 6.32 (br d, J= 9.66 Hz, 1H), 5.30 (s, 1H), 2.00 (s, 6H).

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2020/212897, 2020, A1 Location in patent: Page/Page column 75; 95; 96
[2]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2020/161663, 2020, A1 Location in patent: Page/Page column 81-82

19
[ 363-51-9 ]
[ 929621-33-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: NBS / N,N-dimethyl-formamide / 1 h / Inert atmosphere 2.1: NaNO₂; hydrogenchloride / lithium hydroxide monohydrate; acetonitrile / 1 h / -20 °C / Inert atmosphere 2.2: 2 h / -20 - 25 °C 3.1: isopropylmagnesium chloride lithium chloride / tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 3.2: 1 h / 0 °C

Reference： [1]Current Patent Assignee: YU ELSIE; MERCK & CO INC; FULLER PETER H; METHOT JOEY L; CHEN JOANNA L; CANDITO DAVID A; NAIR ANILKUMAR G; VARA BRANDON A - WO2022/98806, 2022, A1

20
[ 363-51-9 ]
[ 1159512-34-1 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
473 mg	Stage #1: 2-chloro-6-fluorobenzenamine With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 2h; Stage #2: 3-bromo-2-chloro-6-(trifluoromethyl)pyridine In N,N-dimethyl-formamide; mineral oil at 0℃; for 12h;	26.1 Step 1: Synthesis of 3-bromo-N-(2-chloro-6-fluorophenyl)-6-(trifluoromethyl)pyridin-2-amine (Intermediate 26-2) Reactant 26-1 (279.48 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (10 mL), and sodium hydride (60% effective content, 115.20 mg, 2.88 mmol) was added at 0°C.The reaction solution was stirred at 0°C for 2 hours.Intermediate 15-1 (500 mg, 1.92 mmol) was dissolved in N,N-dimethylformamide (5 mL) and added dropwise to the reaction solution. The reaction solution was stirred at 0°C for 12 hours. The reaction solution was quenched by adding water (5 mL) and extracted three times with ethyl acetate (10 mL*3), the organic layer was washed with saturated brine, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:acetic acid) ethyl ester = 10:1) to give the title compound (473 mg).

Reference： [1]Current Patent Assignee: JIANGSU SIMCERE PHARM - WO2022/143864, 2022, A1 Location in patent: Page/Page column 66

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Code	Phrase
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Prevention
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Code	Phrase
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P321
P322
P330	Rinse mouth.
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P378
P380	Evacuate area.
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P401
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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
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H220	Extremely flammable gas
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H240	Heating may cause an explosion
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H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
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H281	Contains refrigerated gas; may cause cryogenic burns or injury
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Health hazards
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H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
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H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
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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
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H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
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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