517920-75-1|(3-Chloro-2-fluorophenyl)hydrazine hydrochloride| Ambeed

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Quality Control of [ 517920-75-1 ] Purity: 97% SDS Specification

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Product Details of [ 517920-75-1 ]

CAS No. :	517920-75-1
Formula :	C₆H₇Cl₂FN₂
M.W :	197.04
SMILES Code :	NNC1=CC=CC(Cl)=C1F.[H]Cl
MDL No. :	MFCD03094280
Boiling Point :	No data available
InChI Key :	TWYLYPMRIHFEQN-UHFFFAOYSA-N
Pubchem ID :	25067375

Safety of [ 517920-75-1 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 517920-75-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	2.0
Molar Refractivity	45.58
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.05 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.69
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.8
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.72
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.42
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.93

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.09
Solubility	0.159 mg/ml ; 0.000805 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.14
Solubility	0.142 mg/ml ; 0.000722 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.97
Solubility	0.209 mg/ml ; 0.00106 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.59 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.81

Application In Synthesis of [ 517920-75-1 ]

* 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.

Downstream synthetic route of [ 517920-75-1 ]

[ 517920-75-1 ] Synthesis Path-Downstream 1~25

1
[ 517920-75-1 ]
[ 41979-39-9 ]
7-Chloro-6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In isopropyl alcohol; at 20 - 80℃; for 15.1667h;	Step B.; A solution of 1-<strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (3.35 g, 17.0 mmol) and 4-piperidone hydrochloride monohydrate (2.6 g, 17.0 mmol) in IPA(50.0 mL) was stirred at 20 C. for 10 min, following by stirring at 80 C. for 15 h. The reaction mixture was filtered to obtain the title compound (3.2g, 12.5 mmol) as a beige solid: MS (ES) 269.0 (M-H).

References: [1]Patent: US2007/27178,2007,A1 .Location in patent: Page/Page column 21.

2
[ 650578-82-8 ]
[ 517920-75-1 ]

Yield	Reaction Conditions	Operation in experiment
		Example 15 7-Chloro-6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride Step A.; A solution of sodium nitrite (12.5 g, 85.9 mmol) and H2O (21.4 mL) was added dropwise at 0 C. to a solution of 3-chloro-2-fluorobenzenamine hydrochloride (2.0 g, 8.45 mmol) in 12N HCl (203.3 mL) and TFA (23.4 mL). The reaction mixture was stirred at 0 C. for 1 h followed by the dropwise addition of a solution of tin(II)chloride (35.8 g, 188.9 mmol) in 12N HCl (51.6 mL) and H2O (6.8 mL) at 0 C. The reaction mixture stirred for 15 h at 20 C. and was filtered and placed under vacuum to give 1-(3-chloro-2-fluorophenyl)hydrazine hydrochloride as a gold solid (23.5 g, 119.0 mmol).

References: [1]Patent: US2007/27178,2007,A1 .Location in patent: Page/Page column 21.

3
[ 517920-75-1 ]
[ 3609-53-8 ]
[ 926634-47-1 ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; zinc(II) chloride; at 105℃; for 48h;	(3-Chloro-2-fluoro-phenyl)-hydrazine hydrochloride (Apollo Scientific, Ltd., 221 mg, 1.12 mmol) and 4-acetyl-benzoic acid methyl ester (200 mg, 1.12 mmol) are treated with anhydrous ZnCl2 (382 mg, 2.81 mmol) and acetic acid (10 mL). The reaction is heated to 105 C. for 48 hours. After cooling to room temperature, the reaction is diluted with ethyl acetate and sequentially washed with H2O (5×) followed by saturated aqueous NaCl. The organics are then dried over Na2SO4 and filtered. After concentration, the crude product is purified by preparative RP LC-MS to give 4-(6-chloro-7-fluoro-1H-indol-2-yl)-benzoic acid methyl ester as an off-white solid: ESMS m/z 304.0 (M+H+).

References: [1]Patent: US2008/194668,2008,A1 .Location in patent: Page/Page column 5-6.

4
[ 517920-75-1 ]
[ 134653-70-6 ]
[ 1422386-21-7 ]

Yield	Reaction Conditions	Operation in experiment
28%	With triethylamine; In ethanol; at 20℃; for 0.166667h;	[00375] Intermediate 25 A. Ethyl 1 -(3 -chloro-2-fluorophenyl)-5 -methyl- lH-pyrazole- 4-carboxylate: (Reference: Herold, P. et al, Tetrahedron, 56:6497-6499 (2000)) A solution of ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.517 g, 2.79 mmol), <strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (0.500 g, 2.54 mmol) in EtOH (2.54 mL) and TEA (0.707 mL, 5.08 mmol) was stirred at rt. After 10 min, the reaction mixture was concentrated and purified by silica gel chromatography. The desired product, ethyl 1 -(3 -chloro-2-fluorophenyl)-5 -methyl- lH-pyrazole -4-carboxylate (200 mg, 28%), was obtained as an off white solid. MS(ESI) m/z: 283.1 (M+H)+.
28%	With triethylamine; In ethanol; at 20℃; for 0.166667h;	Intermediate 15A. Ethyl l-(3-chloro-2-fluorophenyl)-5-methyl-lH-pyrazole-4- carboxylate: (Reference: Herold, P. et al, Tetrahedron, 56:6497-6499 (2000)) A solution of ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (0.517 g, 2.79 mmol), <strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (0.500 g, 2.54 mmol) in EtOH (2.54 mL) and TEA (0.707 mL, 5.08 mmol) was stirred at room temperature t. After 10 min, the reaction mixture was concentrated and purified by silica gel chromatography. The desired product, ethyl l-(3-chloro-2-fluorophenyl)-5-methyl-lH-pyrazole-4-carboxylate (200 mg, 28%), was obtained as an off-white solid. MS (ESI) m/z: 283.1 (M+H)+.
28%	With triethylamine; In ethanol; at 20℃; for 0.166667h;	A solution of ethyl 2-((dimethylamino) methylene)-3-oxobutanoate (0.5 17 g, 2.79mmol), <strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (0.500 g, 2.54 mmol) inEtOH (2.54 ml) and TEA (0.707 ml, 5.08 mmol) was stirred at rt. After 10 mm, thereaction mixture was concentrated and purified by normal phase chromatography. Thedesired product, ethyl 1 -(3 -chloro-2-fluorophenyl)-5-methyl- 1 H-pyrazole-4-carboxyl ate(200 mg, 28%), was obtained as an off white solid. MS (ESI) m/z: 283.1 (M+H)t

References: [1]Journal of Medicinal Chemistry,2020,vol. 63,p. 784 - 803.
[2]Patent: WO2013/22818,2013,A1 .Location in patent: Paragraph 00375.
[3]Patent: WO2014/160668,2014,A1 .Location in patent: Page/Page column 119.
[4]Patent: WO2016/205482,2016,A1 .Location in patent: Page/Page column 133.

5
[ 517920-75-1 ]
[ 108-24-7 ]
[ 1422386-49-9 ]

Yield	Reaction Conditions	Operation in experiment
		[00390] Intermediate 33A. N'-(3-Chloro-2-fluorophenyl)acetohydrazide: To a solution of (3-chloro-2-fluorophenyl)hydrazine, HC1 (450 mg, 2.284 mmol) in ether (10 mL) and THF (1 mL) at 0 C was added sodium hydroxide (0.228 mL, 2.284 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated, diluted with EtOAc and washed with brine. The crude product was then dried under vacuum and taken to the next step. To a solution of the above obtained oil in ether (10 mL) at 0 C was added dropwise a solution of acetic anhydride (0.215 mL, 2.284 mmol) in ether (5 mL) and stirred at 0 C for 30 min. The reaction mixture was concentrated, diluted with ethyl acetate and washed with brine. The organic layer was dried over MgSC^ and concentrated to yield the crude product. The crude product was then taken to the next step without further purification. MS(ESI) m/z: 203.1 (M+H)+.
		Intermediate 45 A. N'-(3-Chloro-2-fluorophenyl)acetohydrazide: To a solution of (3-chloro-2-fluorophenyl)hydrazine, HC1 (450 mg, 2.284 mmol) in ether (10 mL) and THF (1 mL) at 0 C was added sodium hydroxide (0.228 mL, 2.284 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated, diluted with EtOAc and washed with brine. The crude product was then dried under vacuum and taken to the next step. To a solution of the above obtained oil in ether (10 mL) at 0 C was added dropwise a solution of acetic anhydride (0.215 mL, 2.284 mmol) in ether (5 mL) and stirred at 0 C for 30 min. The reaction mixture was concentrated, diluted with ethyl acetate and washed with brine. The organic layer was dried over MgS04 and concentrated to yield the crude product. The crude product was then taken to the next step without further purification. MS(ESI) m/z: 203.1 (M+H)+.

References: [1]Patent: WO2013/22818,2013,A1 .Location in patent: Paragraph 00390.
[2]Patent: WO2014/160668,2014,A1 .Location in patent: Page/Page column 137-138.

6
[ 517920-75-1 ]
[ 42466-67-1 ]
[ 1422385-89-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium acetate; In water; acetic acid; at 20 - 100℃;	[00319] Intermediate 2 A. Ethyl 5-amino-l-(3-chloro-2-fluorophenyl)-lH-pyrazole-4- carboxylate: To a mixture of <strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (0.67 g, 3.40 mmol), (E)-ethyl 2-cyano-3-ethoxyacrylate (0.633 g, 3.72 mmol) and sodium acetate (0.586 g, 7.12 mmol) at rt was added AcOH and H20 to form a slurry. The reaction mixture was continued to stir at rt for 0.25 h and then heated at 100 C for overnight. After overnight stirring, the reaction mixture was quenched with H20 (200 mL) and a yellowish brown solid separated. The solids were filtered and washed thoroughly with H20. Re-dissolved the residue in DCM, dried and evaporated to a brown solid as the desired product (0.76 g, 78%). MS(ESI) m/z: 284.2 (M+H)+. 1H NMR (400 MHz, CDCls) delta 7.76 (s, 1H), 7.51 - 7.29 (m, 2H), 7.27 - 7.03 (m, 1H), 5.30 - 5.06 (m, 2H), 4.24 (q, J = 7.2 Hz, 2H), 1.38 - 1.04 (m, 3H) ppm.

References: [1]Patent: WO2013/22818,2013,A1 .Location in patent: Paragraph 00319.
[2]Journal of Medicinal Chemistry,2020,vol. 63,p. 784 - 803.

7
[ 517920-75-1 ]
[ 100-52-7 ]
[ 1422386-76-2 ]

Yield	Reaction Conditions	Operation in experiment
27%	With sodium hydroxide; In methanol; at 20℃; for 2.5h;	[00405] Intermediate 40 A. (E)-l-Benzylidene-2-(3-chloro-2-fluorophenyl)hydrazine: Using a modified procedure described by Deprez-Poulain. (Deprez-Poulain, R. et al, European Journal of Medicinal Chemistry, 46:3867 (2011).) To a clear, orange brown solution of (3-chloro-2-fluorophenyl)hydrazine, HC1 (3 g, 15.23 mmol) in methanol (60.9 ml) was added benzaldehyde (1.543 mL, 15.23 mmol) followed by the slow addition of 1.0 M NaOH (15.23 mL, 15.23 mmol). The resulting dark brown solution was stirred at rt. Over time, a precipitate formed. After 2.5 h, the reaction was stopped and the solid was collected by filtration. The solid was washed with water, air-dried, and dried under vacuum overnight to give Intermediate 40A (1.01 g, 27%) as an off- white solid. MS(ESI) m/z: 249.0 (M+H)+.

References: [1]Patent: WO2013/22818,2013,A1 .Location in patent: Paragraph 00405.

8
[ 517920-75-1 ]
[ 1357191-82-2 ]
[ 1357191-83-3 ]

Yield	Reaction Conditions	Operation in experiment
97 mg	With trifluoroacetic acid; In ethanol; at 35℃;Cooling with ice;	To a solution of 3- [3- (dimethylamino) prop-2-enoyl] -1- [2- fluoro-4- (lH-pyrazol-l-yl) phenyl] -5-methoxypyridazin-4 (IH) -one (200 mg) in trifluoroacetic acid/ethanol (5/95, 8 mL) was added (3-chloro-2-fluorophenyl) hydrazine hydrochloride (98.8 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (97 mg) . 1H NMR (300 MHz, DMSO-d6) delta 3.80 (3H, s) , 6.57-6.71 (1H, m) , 7.12-7.22 (1H, m) , 7.23-7.32 (1H, m) , 7.38-7.49 (2H, m) , 7.55- 7.69 (1H, m) , 7.72-7.81 (1H, m) , 7.81-8.01 (3H, m) , 8.50 (1H, d, J = 1.9 Hz), 8.67 (1H, d, J = 2.6 Hz).

References: [1]Patent: WO2013/27845,2013,A1 .Location in patent: Paragraph 0388.

9
[ 517920-75-1 ]
[ 144918-37-6 ]
[ 1422385-89-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium acetate; acetic acid; In water; at 20 - 100℃;	Intermediate 13A. Ethyl 5-amino-l-(3-chloro-2-fluorophenyl)-lH-pyrazole-4- carboxylate: To a mixture of <strong>[517920-75-1](3-chloro-2-fluorophenyl)hydrazine hydrochloride</strong> (0.67 g, 3.40 mmol), (E)-ethyl 2-cyano-3-ethoxyacrylate (0.633 g, 3.72 mmol) and sodium acetate (0.586 g, 7.12 mmol) at room temperature was added AcOH and 0 to form a slurry. The reaction mixture was continued to stir at room temperature for 0.25 h and then heated at 100 C overnight. After overnight stirring, the reaction mixture was quenched with H20 (200 mL) and a yellowish brown solid separated. The solids were filtered and washed thoroughly with H20. Re-dissolved the residue in DCM, dried and evaporated to a brown solid as the desired product (0.76 g, 78%). MS (ESI) m/z: 284.2 (M+H)+. NMR (400 MHz, CDC13) delta 7.76 (s, 1H), 7.51 - 7.29 (m, 2H), 7.27 - 7.03 (m, 1H), 5.30 - 5.06 (m, 2H), 4.24 (q, J = 7.2 Hz, 2H), 1.38 - 1.04 (m, 3H) ppm.

References: [1]Patent: WO2014/160668,2014,A1 .Location in patent: Page/Page column 118.

10
[ 517920-75-1 ]
[ 1359980-64-5 ]
[ 1359982-39-0 ]

Yield	Reaction Conditions	Operation in experiment
44%	In tert-butyl alcohol; at 90℃; for 24h;Inert atmosphere;	To a stirred solution of compound A-S (5.25 g, 22.05 mmol) in t-BuOH (200 mL) under inert atmosphere was added (3-chloro-2-fluorophenyl) hydrazine hydrochloride (6.5 g, 33.08 mmol) at RT. The reaction mixture was heated to 90 oC and stirred for 24 h. The reaction progress was monitored by TLC; after reaction completion, the reaction mixture was diluted with ice cold water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were dried over Na2504, filtered and concentrated under reduced pressure to obtain crude material. The crude material was purified through silica gel flash column chromatography using 3% EtOAc/ hexanes to afford mt-A (3.5 g, 44%) as an off-white solid. 1H NMR (400 MHz, CDC13): 8.52 (br s, 1H), 7.77 (s, 1H), 7.73 (d, J= 8.0 Hz, 1H), 7.25-7.17 (m, 2H), 7.12-7.05 (m, 2H), 4.32 (q, 2H), 2.53 (s, 3H), 1.34 (t,J6.8Hz,3H).

References: [1]Patent: WO2015/48301,2015,A1 .Location in patent: Paragraph 00405.

11
[ 517920-75-1 ]
1-(3-Chloro-2-ethoxyphenyl)-1H-pyrazole-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		analogously to Synthesis Example 3, Step 1, starting with <strong>[517920-75-1]3-chloro-2-fluorophenylhydrazine hydrochloride</strong>: HPLC-MS: log P=1.90; mass (m/z): 212.0 (M+H)+; 1H-NMR (DMSO-D6) 5.22 (br. s, 2H), 5.82 (d, 1H), 7.25-7.30 (m, 1H), 7.36-7.40 (m, 1H), 7.67-7.71 (m, 1H), 7.90-7.10 (m, 1H). 1-(3-Chloro-2-ethoxyphenyl)-1H-pyrazole-3-amine was obtained as a by-product: HPLC-MS: log P=2.13; mass (m/z): 238.0 (M+H)+; 1H-NMR (DMSO-D6) 1.24 (t, 3H), 3.78 (q, 2H), 5.08 (br. s, 2H), 5.78 (d, 1H), 7.17-7.21 (m, 1H), 7.30-7.33 (m, 1H), 7.56-7.59 (m, 1H), 7.97 (d, 1H).

References: [1]Patent: US2015/239847,2015,A1 .

12
[ 517920-75-1 ]
[ 203186-58-7 ]
[ 1422386-21-7 ]

Yield	Reaction Conditions	Operation in experiment
91%	With triethylamine; In ethanol; at 20℃; for 5h;	Ethyl 2- acetyl-3-(dimethylamino)acrylate (4.27 g, 23.07 mmol), <strong>[517920-75-1]3-chloro-2-fluorophenylhydrazine hydrochloride</strong> (4.50 g, 22.83 mmol) of ethanol (23 ml) solution to triethylamine (6.37, 45.68 mmol) and stirred at room temperature for 5 hours. Vacuum concentration and reaction, plus ethanol in residue, filter and the resulting solid ethanol, followed by hexane washing obtained the title compound (2.58 g). In addition, filtrate liquid is evaporated and the residue and at 50 C, after stirring added to hexane, ethanol in addition to residues. Solution at room temperature until releasing chilled, then solid is obtained and filtered in hexane the ethanol, got the title compounds by washing (1.15 g). Got title compounds of compounds obtained by 5.85 g (91%)

References: [1]Patent: JP2015/13821,2015,A .Location in patent: Paragraph 0153-0154.

13
[ 517920-75-1 ]
[ 141-97-9 ]
[ 4637-24-5 ]
[ 1422386-21-7 ]

Yield	Reaction Conditions	Operation in experiment
97%		39a) 1 -(3-chloro-2-fluoro-phenyl)-5-methyl-1 H-pyrazole -4-carboxylic acid ethyl ester A mixture of ethyl acetoacetate (2.01 mmol) and DMF-dimethyl acetal (2.01 mmol) was stirred in a microwave reactor at 130C for 15 min. After cooling, the stirred mixture was diluted with EtOH (5 mL) and treated with 3-chloro-2-fluorophenylhydrazine HCI (0.330 g, 1 .68 mmol), followed by triethylamine (0.23 mL, 1 .68 mmol) and heated at 80C for 3 h. After cooling, the mixture was concentrated to dryness and purified by silica eluting with EtOAc/petrol 10% to give the product (0.462 g, 97%). LC-MS m/z 283 (M + H) +, 1 .44 (ret. time).

References: [1]Patent: WO2017/60854,2017,A1 .Location in patent: Page/Page column 227; 228.

14
[ 517920-75-1 ]
[ 1422386-19-3 ]

References: [1]Patent: WO2017/60854,2017,A1 .
[2]Journal of Medicinal Chemistry,2020,vol. 63,p. 784 - 803.

15
[ 517920-75-1 ]
1-(3-chloro-2-fluoro-phenyl)-5-methyl-1H-pyrazole [ No CAS ]

References: [1]Patent: WO2017/60854,2017,A1 .

16
[ 517920-75-1 ]
5-cyclopropyl-1-{3-[2-fluoro-3-(5-methyl-1H-pyrazol-1-yl)phenyl]phenyl}-1H-pyrazole-4-carboxylic acid [ No CAS ]

References: [1]Patent: WO2017/60854,2017,A1 .

17
[ 517920-75-1 ]
ethyl 1-(3-chloro-2-fluorophenyl)-1H-pyrazole-4-carboxylate [ No CAS ]