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[ CAS No. 653-92-9 ] {[proInfo.proName]}

,{[proInfo.pro_purity]}

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Chemical Structure| 653-92-9

Chemical Structure| 653-92-9

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Quality Control of [ 653-92-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 653-92-9 ]

Product Details of [ 653-92-9 ]

CAS No. :	653-92-9	MDL No. :	MFCD06204026
Formula :	C₈H₆BrFO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JENBPOJAZCPSEW-UHFFFAOYSA-N
M.W :	233.03	Pubchem ID :	7210837
Synonyms :

Calculated chemistry of [ 653-92-9 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	45.38
TPSA :	26.3 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) :	-5.88 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.28
Log Po/w (XLOGP3) :	2.6
Log Po/w (WLOGP) :	2.8
Log Po/w (MLOGP) :	3.09
Log Po/w (SILICOS-IT) :	2.79
Consensus Log Po/w :	2.71

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.16
Solubility :	0.161 mg/ml ; 0.000691 mol/l
Class :	Soluble
Log S (Ali) :	-2.8
Solubility :	0.368 mg/ml ; 0.00158 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.61
Solubility :	0.0569 mg/ml ; 0.000244 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 653-92-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 653-92-9 ]

* 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 [ 653-92-9 ]
Downstream synthetic route of [ 653-92-9 ]

[ 653-92-9 ] Synthesis Path-Upstream 1~8

1
[ 1006-41-3 ]
[ 74-88-4 ]
[ 653-92-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 23℃; for 48 h; Inert atmosphere	DBU (1.7 equiv, 1.16 mL, 7.76 mmol) was added to a solution of 2-bromo-4-fluorobenzoicacid (1.0equiv, 1.0 g, 4.57 mmol) and iodomethane (2.0 equiv, 0.57 mL, 9.14 mmol) in CH₃CN(11 mL) at 23 °C. After stirring for 48 h, the reaction was quenched with H₂O(10 mL) and extracted with Et₂O (2 x 10 mL). The combined organicextracts were washed with water (20 mL), brine (20 mL), dried over Na₂SO₄and filtrated. Evaporation of the solvent under reduced pressure followed byflash chromatography (SiO₂, 95/5 hexane/EtOAc) afforded 1.0 g (98percent)of the entitled ester as a colorless oil. Rf = 0.50 (95/5 hexane/EtOAc);¹H NMR (400 MHz, CDCl₃, 25 °C): d 7.88(dd, J = 8.8, 6.0 Hz, 1H), 7.41 (dd, J = 8.3, 2.5 Hz, 1H), 7.08 (ddd, J = 8.8,7.6, 2.5 Hz, 1H), 3.92 (s, 3H) ppm.

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 20, p. 4393 - 4398
[2] Patent: US6407250, 2002, B1,
[3] Patent: US6511999, 2003, B2,
[4] Patent: US2002/128233, 2002, A1,
[5] Patent: US2004/162323, 2004, A1,
[6] Patent: US2005/65200, 2005, A1,
[7] Patent: US6369089, 2002, B1,

2
[ 67-56-1 ]
[ 1006-41-3 ]
[ 653-92-9 ]

Yield	Reaction Conditions	Operation in experiment
88.3%	for 4 h; Reflux	To a solution of 2-bromo-4-fluorobenzoic acid (2.17 g, 10.00 mmol) in methanol (10 mL) was added sulfuric acid (1.63 mL, 30 mmol) , the reaction mixture was refluxed for 4 h.The solvent was removed in vacuo.The mixture was diluted with diethyl ether, and washed water (50 mL * 3) and brine (50 mL * 3), dried over MgSO_4. The solvent was removed under reduced pressure.The residue was purified by flash column chromatography with petroleum ether-ethyl acetate (80/1) as eluant to afford colorless liquid. Yield: 88.3percent.This compound was prepared according to the general procedure reported by Baker.¹³ The spectral data were consistent with that reported in the literature.
86%	at 60℃; for 10 h;	To a mixture of 2-bromo-4-fluorobenzoic acid 1 (2.19 g, 10 mmol) in MeOH (20 mL) was added SOCl₂ (0.5 mL) dropwise at rt. The resulting mixture was stirred at 60°C for 10 h. The mixture was concentrated to give the title compound (2 g, 86percent>) as brown oil. MS (ESI): m/z = 232.8 [M + H]⁺.
37%	at 0℃; for 19 h; Heating / reflux	Intermediate Preparation 21 2-Bromo-4-fluoro-benzoic acid methyl esterTo a solution of thionyl chloride (2.6 mL, 35.7 mmol) in methanol (500 mL) at 0 ⁰C is added 4-fluoro-2-bromo benzoic acid (5.18 g, 23.6 mmol). The mixture is heated to reflux for 19 h. The mixture is concentrated and purified via flash chromatography on silica (120 g) using a gradient of 0 to 80percent ethyl acetate in heptane to provide the title compound (2.06 g, 37percent) as an oil. MS m/z 233.0 (M+l)

Reference： [1] Tetrahedron Letters, 2007, vol. 48, # 23, p. 4123 - 4126
[2] Patent: WO2005/58826, 2005, A1, . Location in patent: Page/Page column 100
[3] Angewandte Chemie - International Edition, 2013, vol. 52, # 28, p. 7177 - 7180
[4] Journal of Organic Chemistry, 2013, vol. 78, # 13, p. 6735 - 6745
[5] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 24, p. 7101 - 7111
[6] Patent: WO2015/48662, 2015, A2, . Location in patent: Page/Page column 124
[7] Synthesis (Germany), 2012, vol. 44, # 14, p. 2173 - 2180
[8] Patent: WO2009/12125, 2009, A1, . Location in patent: Page/Page column 26
[9] Patent: WO2006/25783, 2006, A1, . Location in patent: Page/Page column 98-100
[10] Tetrahedron, 2016, vol. 72, # 24, p. 3454 - 3467
[11] Patent: WO2018/89449, 2018, A1, . Location in patent: Page/Page column 175-179

3
[ 1006-41-3 ]
[ 653-92-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	With thionyl chloride In methanol at 70℃; for 2 h;	To a 250-mL row1d-bottom flask was added a solution of 2-bromo-4-fluorohenzoicacid J 01 a (1 0 g, 45.66 rnmol, 1.0 equiv.) in methanol (l 00 mL) Thionyl chloride (16 2 g,137.29 mmoL 3.0 equiv.) vvas added dropvvise. The resulting mixture vvas stirred at 70°C for2h, and then quenched ,.vith the addition of water/ice. The aqueous mixture was extracted5 v\~th ethyl acetate (lOO mL x 2). The combined organic extracts vvere washed brine (50 rnL x2), concentrated to a crude solid, which was further purified by silica gel columnchromatography eluting with ethyl acetate/petroleum ether (0percent-8°1()). Removal of solventsafforded methy 12-bromo-4-fluorobenzoate 101 b (9.4 g, 88percent) as a colorless solid.

Reference： [1] Patent: WO2018/39386, 2018, A1, . Location in patent: Page/Page column 229; 230

4
[ 1006-41-3 ]
[ 18107-18-1 ]
[ 653-92-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	at 20℃; for 3 h;	A. 2-Bromo-4-fluoro-benzoic acid methyl ester. To a solution of 2-bromo-4-fluoro-benzoic acid (10.95 g, 50 mmol) in toluene/MeOH (3:1; 200 mL) was added trimethylsilyidiazomethane (2 M in hexanes; 36 mL, 71.7 mmol) at RT for 3 h. The mixture was diluted with EtOAc (300 mL) and washed sequentially with satd. aq. NaHCO₃ (50 mL) and brine (50 mL), dried (MgSO₄), and concentrated to provide 11.5 g (99percent) of the crude material which was used in the next step without further purification. ¹H NMR (500 MHz, CDCl₃): 7.86 (dd, J=8.8, 6.0, 1H), 7.39 (dd, J=8.3, 2.5, 2H), 7.08-7.05 (m, 1H), 3.91 (s, 3H).

Reference： [1] Patent: US2006/223810, 2006, A1, . Location in patent: Page/Page column 28

5
[ 496-69-5 ]
[ 79-22-1 ]
[ 653-92-9 ]

Reference： [1] Patent: US4427438, 1984, A,
[2] Patent: US4437877, 1984, A,
[3] Patent: US4431822, 1984, A,

6
[ 653-92-9 ]
[ 544-92-3 ]
[ 127510-96-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: for 1.25 h; Heating / reflux Stage #2: With sodium cyanide In DMF (N,N-dimethyl-formamide); water	(b) Methyl 2-cyano-4-fluorobenzoate; Methyl 2-bromo-4-fluorobenzoate (1.0 g, 4.29 mmol; see step (a) above) was dissolved in dry DMF (5 mL) and degassed with N2-gas for 5 minutes. CuCN (769 mg, 8.58 mmol) was added and mixture was degassed again before the temperature was raised. The reaction mixture was refluxed for 75 minutes. NaCN (aq, 10percent) was added and the mixture was extracted with DCM. The DCM phase was dried through a phase separator and the solvent was removed in vacuo. The crude product was dissolved in toluene and washed once with water. The organic phase was dried over MgS04 and filtered. The solvent was removed in vacuo to give the product (in 94percent yield), which was used without further purification. 'H NMR (500 MHz, CDC13) 5 4.01 (s, 3H), 7.35-7. 42 (m, 1H), 7.52 (dd, 1H), 8.15-8. 23 (m, 1H)

Reference： [1] Patent: WO2005/58826, 2005, A1, . Location in patent: Page/Page column 100

7
[ 653-92-9 ]
[ 127510-96-7 ]

Yield	Reaction Conditions	Operation in experiment
39%	at 140℃; Inert atmosphere	To a 250-mL round-bottom flask purged and maintained under an inert atmosphere ofnitrogen, was added methyl2-bromo-4-fluorobenzoate 101 b (4 g, 17.16 mmol, 1.0 equiv.)andN';N-dimethylformamide (20 mL). Solid CuCN (2.3 g, 25.84 mmol, 1.5 equiv.) wasadded in several batches. The resulting mixture vvas stirred at l40°C overnight. Upon coolingto room temperature, the mixture '.vas quenched with water. The aqueous mixture was15 extracted with ethyl acetate (100 mL x 3), and the combined organic extracts were washedwith t-hO (50 mL x 2) and brine (80 mL x 2) Removal of solvents gave a residue which waspmitl.ed by silica gel column chromatography eluting with ethyl acetate/petroleum ether(lOpercent) to provide methyl2-cyano-4-t1uorobenzoate 101c (1.2g, 39percent) as a white solid
850 mg	at 120℃; for 1.5 h; Inert atmosphere	To a solution of methyl 2-bromo-4-fluorobenzoate (1.2 g, 5.15 mmol) in DMF (5 mL) was added cyanocopper (0.92 g, 10.3 mmol) under N₂. The reaction was stirred at 120 ^°C for 1.5 h under N₂. Then, the reaction was cooled to room temperature.10percent NaCN (10 mL) was added to the reaction. The mixture was extracted with DCM (3 x 30 mL). The layers were separated and the organic phase was washed with saturated aqueous NaCl (3 x 50 mL) .The combined organic layers were dried over Na₂SO₄. After filtration, 850 mg of product was obtained as a white solid.

Reference： [1] Patent: WO2018/39386, 2018, A1, . Location in patent: Page/Page column 229; 230
[2] Patent: WO2018/26371, 2018, A1, . Location in patent: Paragraph 0158; 0260

8
[ 653-92-9 ]
[ 1260666-80-5 ]

Reference： [1] Patent: WO2018/26371, 2018, A1,

[ 653-92-9 ] Synthesis Path-Downstream 1~74

1
[ 591-50-4 ]
[ 653-92-9 ]
[ 724-10-7 ]

Yield	Reaction Conditions	Operation in experiment
	With copper

Reference： [1]Dewar,M.J.S.; Grisdale,P.J. [Journal of Organic Chemistry, 1963, vol. 28, p. 1759 - 1762]

2
[ 13331-19-6 ]
[ 653-92-9 ]
[ 152609-92-2 ]

Yield	Reaction Conditions	Operation in experiment
1.45 g (15%)	With potassium tert-butylate;copper(I) iodide; In pyridine; diethyl ether;	A. Preparation of 4-fluoro-2-(3-hydroxy-2-propylphenoxy)benzoic acid methyl ester. To a solution of 2-propylresorcinol (10.0 g, 65.7 mmol) in pyridine (120 mL) was added potassium tert-butoxide (7.00 g, 62.5 mmol) at room temperature with stirring. To this was added a mixture of <strong>[653-92-9]methyl 2-bromo-4-fluorobenzoate</strong> (7.60 g, 32.6 mmol) and copper(I) iodide (12.5 g, 65.7 mmol) in pyridine (120 mL). The resulting mixture was gently refluxed for 4 hours. The reaction was cooled to room temperature and stirred for 18 hours. The mixture was concentrated in vacuo and the resulting material dissolved in ethyl ether. The solution was washed once with 5N aqueous hydrochloric acid. The aqueous layer was extracted once with fresh ethyl ether and the combined organic layers were washed twice with 5N aqueous ammonium hydroxide. The organic layer was washed once with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography of the resulting residue provided 1.45 g (15%) of the desired intermediate product as a light tan solid: mp 92-94 C.; NMR (CDCl3) 7.95 (m, 1H), 7.04 (t, J=9.5 Hz, 1H), 6.79 (t, J=9 Hz, 1H), 6.65 (d, J=9.5 Hz, 1H), 6.50 (m, 2H), 5.25 (bs, 1H, --OH), 3.88 (s, 3H), 2.60 (t, J=8.7 Hz, 2H), 1.55 (hextet, J=7.8 Hz, 2H), 0.92 (t, J=7.8 Hz, 3H); MS-FD m/e 305 (p+1, 40), 304 (p, 100); IR. Analysis for C17 H17 O4 F: Calc: C, 67.10; H, 5.63; Found: C, 67.32; H, 5.78.
1.45 g (15%)	With potassium tert-butylate;copper(I) iodide; In pyridine; diethyl ether;	A. Preparation of 4-fluoro-2-(3-hydroxy-2 -propyl-phenoxy)benzoic acid methyl ester. To a solution of 2-propylresorcinol (10.0 g, 65.7 mmol) in pyridine (120 mL) was added potassium tert-butoxide (7.00 g, 62.5 mmol) at room temperature with stirring. To this was added a mixture of <strong>[653-92-9]methyl 2-bromo-4-fluorobenzoate</strong> (7.60 g, 32.6 mmol) and copper(I) iodide (12.5 g, 65.7 mmol) in pyridine (120 mL). The resulting mixture was gently refluxed for 4 hours. The reaction was cooled to room temperature and stirred for 18 hours. The mixture was concentrated in vacuo and the resulting material dissolved in ethyl ether. The solution was washed once with 5N aqueous hydrochloric acid. The aqueous layer was extracted once with fresh ethyl ether and the combined organic layers were washed twice with 5N aqueous ammonium hydroxide. The organic layer was washed once with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography of the resulting residue provided 1.45 g (15%) of the desired intermediate product as a light tan solid: mp 92-94 C.; NMR (CDCl3) 7.95 (m, 1H), 7.04 (t, J=9.5 Hz, 1H), 6.79 (t, J=9 Hz, 1H), 6.65 (d, J=9.5 Hz, 1H), 6.50 (m, 2H), 5.25 (bs, 1H, --OH), 3.88 (s, 3H), 2.60 (t, J=8.7 Hz, 2H), 1.55 (hextet, J=7.8 Hz, 2H), 0.92 (t, J=7.8 Hz, 3H; MS-FD m/e 305 (p+1, 40), 304 (p, 100); IR. Analysis for C17 H17 O4 F: Calc: C, 67.10; H, 5.63; Found: C, 67.32; H, 5.78.
1.45 g (15%)	With potassium tert-butylate;copper(I) iodide; In pyridine; diethyl ether;	A. Preparation of 4-fluoro-2-(3-hydroxy-2-propyl-phenoxy)benzoic acid methyl ester To a solution of 2-propylresorcinol (10.0 g, 65.7 mmol) in pyridine (120 mL) was added potassium tert-butoxide (7.00 g, 62.5 mmol) at room temperature with stirring. To this was added a mixture of <strong>[653-92-9]methyl 2-bromo-4-fluorobenzoate</strong> (7.60 g, 32.6 mmol) and copper(I) iodide (12.5 g, 65.7 mmol) in pyridine (120 mL). The resulting mixture was gently refluxed for 4 hours. The reaction was cooled to room temperature and stirred for 18 hours. The mixture was concentrated in vacuo and the resulting material dissolved in ethyl ether. The solution was washed once with 5N aqueous hydrochloric acid. The aqueous layer was extracted once with fresh ethyl ether and the combined organic layers were washed twice with 5N aqueous ammonium hydroxide. The organic layer was washed once with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography of the resulting residue provided 1.45 g (15%) of the desired intermediate product as a light tan solid: mp 92-94 C.; NMR (CDCl3) 7.95 (m, 1H), 7.04 (t, J=9.5 Hz, 1H), 6.79 (t, J=9 Hz, 1H), 6.65 (d, J=9.5 Hz, 1H), 6.50 (m, 2H), 5.25 (bs, 1H, -OH), 3.88 (s, 3H), 2.60 (t, J=8.7 Hz, 2H), 1.55 (hextet, J=7.8 Hz, 2H), 0.92 (t, J=7.8 Hz, 3H); MS-FD m/e 305 (p+1, 40), 304 (p, 100); IR. Analysis for C17H17O4F: Calc: C, 67.10; H, 5.63; Found: C, 67.32; H, 5.78.

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 4411 - 4432
[2]Patent: US5462954,1995,A
[3]Patent: US5543428,1996,A
[4]Patent: US6235785,2001,B1

3
[ 123-07-9 ]
[ 653-92-9 ]
2-bromo-4-(ethylphenoxy)-benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 160℃; for 16h;	1) Synthesis of 2-bromo-4-(ethylphenoxy)-benzoic acid methyl ester To a solution of <strong>[653-92-9]2-bromo-4-fluoro-benzoic acid methyl ester</strong> (488 mg, 2.09 mmol) in anhydrous DMF (15 ml), 4-ethylphenol (256 mg, 2.09 mmol) and potassium carbonate (289 mg, 2.09 mmol) were added at room temperature, followed by stirring under a nitrogen atmosphere for 16 hours at 160C. The reaction mixture was cooled and, after addition of saturated aqueous ammonium chloride, was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (developing solution = ethyl acetate:n-hexane (1:20)) to give the titled compound (455 mg, 65%). 1H-NMR (CDCl3) delta: 1.26 (3H, t, J=7.6Hz), 2.67 (2H, q, J=7.6Hz), 3.90 (3H, s), 6.88-6.93 (1H, m), 6.94-7.01 (2H, m), 7.19-7.26 (3H, m), 7.83 (1H, d, J=8.7Hz)

Reference： [1]Patent: EP1852439,2007,A1 .Location in patent: Page/Page column 26-27

4
[ 653-92-9 ]
[ 506-59-2 ]
[ 67-68-5 ]
[ 1012867-44-5 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate;	a) 2-Bromo-4-dimethylamino-benzoic acid methyl ester (7a) To a stirred solution of 5,24 g (22.5 mmol) 2-Bromo-4-fluoro-benzoic acid methyl ester (Rarechemicals) and 60.0 ml dimethylsulphoxid are added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture is stirred for 11h at 70C in an autoclave and is concentrated with high vacuum rotation evaporator at 65C. The residue is diluted with dichloromethane, washed twice with water. The combined water phases are extracted with dichloromethane. The combined dichloromethane phases are washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude is purified by column chromatography and the desired product 7a is obtained in 70 % yield (4,08 g, 15.8 mmol). MS-ESI: 258/560 (M+ +1, 88/83).

Reference： [1]Patent: EP1897885,2008,A1

5
[ 653-92-9 ]
[ 506-59-2 ]
[ 1012867-44-5 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium carbonate; In dimethyl sulfoxide; at 70℃; for 11h;Autoclave;	Example 7a) 2-Bromo-4-dimethylamino-benzoic acid methyl ester (7a)To a stirred solution of 5,24 g (22.5 mmol) 2-Bromo-4-fluoro-benzoic acid methyl ester (Rarechemicals) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 11 h at 7O0C in an autoclave and was concentrated with high vacuum rotation evaporator at 650C. The residue was diluted with dichloromethane, <n="101"/>washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 7a was obtained in 70 % yield (4,08 g, 15.8 mmol).MS-ESI: 258/560 (M+ +1 , 88/83).Elementary analysis: C 46.53% H 4.69% N 5.43% Determined: C 46,60% H 4.71% N 5.42%

Reference： [1]Patent: WO2008/28688,2008,A2 .Location in patent: Page/Page column 99-100

6
[ 67-56-1 ]
[ 1006-41-3 ]
[ 653-92-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sulfuryl dichloride; at 0 - 80℃; for 12h;	To a solution of 2-bromo-4-fluoro-benzoic acid (100 g, 456.60 mmol, 1 eq) in methanol (800 mL) was added sulfurous dichloride (108.64 g, 913.21 mmol, 2 eq) at 0C. The mixture was stirred at 80 C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water 500 mL and extracted with ethyl acetate (200 mL x 2). The combined organic phase was washed with saturated sodium bicarbonate (200 mL) and saturated brine (200 mL x 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuum to give methyl 2-bromo-4-fluoro-benzoate (102 g, 437.70 mmol, 95% yield) as a brown oil.
94%	With hydrogenchloride;	Preparation 4; r2- .-4-fluorophenyl] methanol (a) Methyl 2-bromo-4-fluorobenzoate; 2-Bromo-4-fluorobenzoic acid (1.0 g, 4.6 mmol) was dissolved in methanol (3 mL) before methanol saturated with HC1 (10 mL) was added. The reaction mixture was stirred overnight and then concentrated. The excess of HC1 was removed by co-evaporation from methanol to give the sub-title compound (in 94% yield), which was used in the next step without further purification. 1H NMR (500 MHz, CDC13) 6 3.92 (s, 3H), 7.04-7. 12 (m, 1H), 7.38-. 7.44 (m, 1H), 7.83-7. 91 (m, 1H)
94%	With thionyl chloride; at 0 - 5℃; for 4h;Reflux;	Add methanol (182 ml) to a 500 ml reaction flask.Stir,The ice water bath is cooled to 0-5 C.Thionyl chloride (17.6 ml) was slowly added dropwise.After the addition is completed, the ice water bath is removed.Add 2-bromo-4-fluorobenzoic acid (14.00 g),The reaction was refluxed for 4 h. Cool down to room temperature,The solvent was removed by concentration to give ethyl 2-bromo-4-fluorobenzoate (14 g, 94%).

93%	With hydrogenchloride; In water; for 16h;Reflux;	To a solution of 2-bromo-4-fluorobenzoic acid (1000 mg, 4.57 mmol) in MeOH (10 ml_) was added concentrated aqueous HCI solution (100 pL) and the mixture was stirred under reflux conditions for 16 h. After removing the organic solvent under reduced pressure, saturated aqueous NaHC03 solution was added and the aqueous layer was extracted three times with CHCI3. The combined organic layer was washed with saturated aqueous NaCI solution and was dried over Na2S04. The organic solvent was removed under reduced pressure to afford 6 (987 mg, 93 %) as yellow oil.HPLC (254 nm, System A): tR = 19.45 min; HPLC (254 nm, System B): tR = 18.57 min
88.3%	With sulfuric acid; for 4h;Reflux;	To a solution of 2-bromo-4-fluorobenzoic acid (2.17 g, 10.00 mmol) in methanol (10 mL) was added sulfuric acid (1.63 mL, 30 mmol) , the reaction mixture was refluxed for 4 h.The solvent was removed in vacuo.The mixture was diluted with diethyl ether, and washed water (50 mL * 3) and brine (50 mL * 3), dried over MgSO4. The solvent was removed under reduced pressure.The residue was purified by flash column chromatography with petroleum ether-ethyl acetate (80/1) as eluant to afford colorless liquid. Yield: 88.3%.This compound was prepared according to the general procedure reported by Baker.13 The spectral data were consistent with that reported in the literature.
> 86%	With thionyl chloride; at 60℃; for 10h;	To a mixture of 2-bromo-4-fluorobenzoic acid 1 (2.19 g, 10 mmol) in MeOH (20 mL) was added SOCl2 (0.5 mL) dropwise at rt. The resulting mixture was stirred at 60C for 10 h. The mixture was concentrated to give the title compound (2 g, 86%>) as brown oil. MS (ESI): m/z = 232.8 [M + H]+.
37%	With thionyl chloride; at 0℃; for 19h;Heating / reflux;	Intermediate Preparation 21 2-Bromo-4-fluoro-benzoic acid methyl esterTo a solution of thionyl chloride (2.6 mL, 35.7 mmol) in methanol (500 mL) at 0 0C is added 4-fluoro-2-bromo benzoic acid (5.18 g, 23.6 mmol). The mixture is heated to reflux for 19 h. The mixture is concentrated and purified via flash chromatography on silica (120 g) using a gradient of 0 to 80% ethyl acetate in heptane to provide the title compound (2.06 g, 37%) as an oil. MS m/z 233.0 (M+l)
		Example 364'-Chloro-5-fluoro-3'-[[(tricyclo[3.3.1.13'7]dec-l-ylmethyl)amino]carbonyl]-[l,l'-biphenyl]-2-carboxyIic acidClTo a stirred solution of 2-bromo-4-fluoro-benzoic acid (500 mg) in dichloromethane (5mL) at 0C under nitrogen was added N, N-dimemylformamide (1 drop) and oxalylchloride (0.4 mL). The reaction mixture was allowed to warm to room temperature over 2hours, concentrated in vacua and then redissolved in dichloromethane (5 mL). Methanol (1mL) was added dropwise and the mixture was stirred at room temperature for 2 hoursbefore being concentrated in vacuo to give a colourless oil which was dissolved intetrahydrofuran (3 mL) /water(3 mL). [[(Tricyclo[3.3.1.13>7]dec-l-ylmethyl)amino]carbonyl]phenyl]-boronic acid (Example 2 (a)) (500 mg), potassiumcarbonate (400 mg) and te?rato(triphenylphosphine)palladium(0) (80 mg) were added andthe mixture was stirred at 65 C under a nitrogen atmosphere for 8 hours. The productswere filtered through diatomaceous earth, washing with methanol (3x10 mL), and werethen concentrated in vacuo. Dichloromethane (20 mL) and 2M aqueous hydrochloric acid(10 mL) were added, the layers were separated and the aqueous fraction was extracted withdichloromethane (2x10 mL). The combined organic layers were washed with saturatedaqueous sodium chloride (10 mL), dried (MgSO4), filtered and concentrated. The residuewas dissolved in tetrahydrofuran (3 mL) and a solution of sodium hydroxide (250 mg) inwater (3 mL) was added. The mixture was stirred at room temperature for 24 hours,adjusted to pH 5 with 2M aqueous hydrochloric acid and concentrated in vacuo.Purification by chromatography (SiO2, dichloromethane methanol 98:2 as eluant) gave thetitle compound as a colourless solid (90 mg).MS: APCI(-ve) 440 (M-H4).m.p. 120-124C.'HNMR (400 MHz, d6-DMSO) 8 13.01 (1H, s), 8.36 (1H, t), 7.87 (1H, dd), 7.52 (1H, d),7.42-7.37 (2H, m), 7.34 (1H, ddd), 7.27 (1H, dd), 2.95 (2H, d), 1.94 (3H, s), 1.71-1.56 (6H,m), 1.55-1.50 (6H,m).
	With sulfuric acid; for 24h;Reflux;	General procedure: 4.2.1. General procedures I for the synthesis of starting materials 1 a-n. Compounds 1a-g, i-n were synthesized according to general procedures I. Compound 1h was commercially available. Method A:16, 17 A two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar was charged withthe 2-bromobenzoic acid (20 mmol) and freshly distilled methanol(25 mL). The solution was heated in a hot water bath, conc. H2SO4(8 mmol) was added slowly and the reaction mixture was refluxed for 24 h. After cooling to room temperature around half of theamount of the solvent was removed in vacuo and the residue was partitioned between water (50 mL) and diethyl ether (70 mL). The organic layer was separated and washed with saturated NaHCO3(250 mL), water (50 mL) and brine (50 mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure.The crude product thus obtained was purified by flash chromatographyon silica gel to afford the alkyl-2-halobenzoate.In a two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar the alkyl 2-halobenzoate(22.5 mmol) was dissolved in freshly distilled dry THF (30 mL) under argon. The solution was cooled to 0 C using an ice bath and NaH (60% in mineral oil, 15 mmol) was added portion wise. After stirring for 15 min a solution of the alkyl acetate (15 mmol) in dry THF (30 mL) was added dropwise to the reaction mixture at 0 C.The mixture was warmed up, stirred at room temperature for 2 h and heated under reflux for 24 h. After cooling to room temperature around half of the amount of the solvent was removed in vacuo and the reaction mixture was diluted with toluene (50 mL). The resulting mixture was washed with 2N HCl (50 mL), saturated NH4Cl (50 mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure. The crude product was purifiedby flash column chromatography on silica gel to afford the alkyl 3-(20-halophenyl)-3-oxo-propanoate 1.
	With thionyl chloride; at 20 - 80℃; for 2h;	To a mixture of 2-bromo-4-fluorobenzoic acid (10 g, 59.47 mmol, 1.00 equiv) in MeOH (100 ml) was added SOCI2 (10.9 g, 91.60 mmol, 1.50 equiv) dropwise at 20C. The reaction mixture was stirred at 80C for 2 h, then concentrated to yield methyl 2-bromo-4-fluorobenzoate as a yellow oil.

Reference： [1]Patent: WO2020/51564,2020,A1 .Location in patent: Paragraph 1777; 1778
[2]Tetrahedron Letters,2007,vol. 48,p. 4123 - 4126
[3]Patent: WO2005/58826,2005,A1 .Location in patent: Page/Page column 100
[4]Angewandte Chemie - International Edition,2013,vol. 52,p. 7177 - 7180
[5]Patent: CN108794397,2018,A .Location in patent: Paragraph 0039; 0040
[6]Patent: WO2019/110521,2019,A1 .Location in patent: Page/Page column 34; 35
[7]Journal of Organic Chemistry,2013,vol. 78,p. 6735 - 6745
[8]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 7101 - 7111
[9]Patent: WO2015/48662,2015,A2 .Location in patent: Page/Page column 124
[10]Synthesis,2012,vol. 44,p. 2173 - 2180
[11]Patent: WO2009/12125,2009,A1 .Location in patent: Page/Page column 26
[12]Patent: WO2006/25783,2006,A1 .Location in patent: Page/Page column 98-100
[13]Tetrahedron,2016,vol. 72,p. 3454 - 3467
[14]Patent: WO2018/89449,2018,A1 .Location in patent: Page/Page column 175-179
[15]Chemistry - A European Journal,2020

7
[ 653-92-9 ]
[ 2714-91-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Cu 2: aq. NaOH
	Multi-step reaction with 2 steps 1: tetrakis-(triphenylphosphine)-palladium; potassium carbonate / tetrahydrofuran; lithium hydroxide monohydrate / 80 °C / Inert atmosphere 2: sodium hydroxide; lithium hydroxide monohydrate / methanol / 50 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: potassium carbonate; palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride / lithium hydroxide monohydrate; 1,4-dioxane / 16 h / 100 °C / Inert atmosphere 2: methanol; lithium hydroxide monohydrate; sodium hydroxide / tetrahydrofuran / 16 h / 20 °C

Reference： [1]Dewar,M.J.S.; Grisdale,P.J. [Journal of Organic Chemistry, 1963, vol. 28, p. 1759 - 1762]
[2]Hayakawa, Kazuki; Ikai, Kana; Ogiwara, Yohei; Sakai, Norio; Sakurai, Yuka [Bulletin of the Chemical Society of Japan, 2021, vol. 94, # 7, p. 1882 - 1893]
[3]Current Patent Assignee: JIANGXI JEMINCARE GROUP CO LTD; SHANGHAI JEMINCARE PHARMACEUTICAL CO LTD; JIANGXI JIANGMAN TRUSTED GROUP LTD; SHANGHAI LUBRIGHT MEDICINE TECH - WO2022/135335, 2022, A1

8
[ 653-92-9 ]
[ 337533-96-7 ]
[ 705277-81-2 ]

Yield	Reaction Conditions	Operation in experiment
89%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 20h;	[167] To a dried 25 mL flask was introduced 3-TELT-BUTYL-1-(2-METHYLPHENYL)-1H-PYRAZOL- 5-amine (intermediate C, 110 mg, 0.48 MMOL), <strong>[653-92-9]methyl 2-bromo-4-fluorobenzoate</strong> (93.1 mg, 0.40 MMOL), PD2 (dba) 3 (18.3 mg, 0.02 MMOL), BINAP (24.9 mg, 0.04 MMOL), and Cs2CO3 (182 mg, 0.56 MMOL). The flask was degassed followed by the addition of toluene (1 mL), and the mixture was heated to 110C for 20 h. The mixture was then cooled to rt, and diluted with ethyl acetate. The solid was filtered off, and the solvent was removed under reduced pressure. The residue was redissolved in methanol/THF (4: 1, v/v) and filtered through a Cl-silica plug. HPLC purification using gradient elution from 30% to 90% ACETONITRILE in water afforded 136.2 mg (89%) of the title COMPOUND. 1H NMR (300 MHz, CD2CI2) 8 9.42 (s, 1 H), 7.85 (dd, 1 H), 7.21-7. 30 (m, 4 H), 6.86 (dd, 1 H), 6.44 (dt, 1 H), 6.11 (s, 1 H), 3.70 (s, 3 H), 2.04 (s, 3 H), 1.30 (s, 9 H). ES-MS M/Z 381.9 (MH+) ; HPLC RT (min) 4.50.

Reference： [1]Patent: WO2004/50650,2004,A1 .Location in patent: Page 82

9
[ 653-92-9 ]
[ 544-92-3 ]
[ 127510-96-7 ]

Yield	Reaction Conditions	Operation in experiment
94%		(b) Methyl 2-cyano-4-fluorobenzoate; Methyl 2-bromo-4-fluorobenzoate (1.0 g, 4.29 mmol; see step (a) above) was dissolved in dry DMF (5 mL) and degassed with N2-gas for 5 minutes. CuCN (769 mg, 8.58 mmol) was added and mixture was degassed again before the temperature was raised. The reaction mixture was refluxed for 75 minutes. NaCN (aq, 10%) was added and the mixture was extracted with DCM. The DCM phase was dried through a phase separator and the solvent was removed in vacuo. The crude product was dissolved in toluene and washed once with water. The organic phase was dried over MgS04 and filtered. The solvent was removed in vacuo to give the product (in 94% yield), which was used without further purification. 'H NMR (500 MHz, CDC13) 5 4.01 (s, 3H), 7.35-7. 42 (m, 1H), 7.52 (dd, 1H), 8.15-8. 23 (m, 1H)

Reference： [1]Patent: WO2005/58826,2005,A1 .Location in patent: Page/Page column 100

10
[ 1006-41-3 ]
[ 74-88-4 ]
[ 653-92-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 23℃; for 48h;Inert atmosphere;	DBU (1.7 equiv, 1.16 mL, 7.76 mmol) was added to a solution of 2-bromo-4-fluorobenzoicacid (1.0equiv, 1.0 g, 4.57 mmol) and iodomethane (2.0 equiv, 0.57 mL, 9.14 mmol) in CH3CN(11 mL) at 23 C. After stirring for 48 h, the reaction was quenched with H2O(10 mL) and extracted with Et2O (2 x 10 mL). The combined organicextracts were washed with water (20 mL), brine (20 mL), dried over Na2SO4and filtrated. Evaporation of the solvent under reduced pressure followed byflash chromatography (SiO2, 95/5 hexane/EtOAc) afforded 1.0 g (98%)of the entitled ester as a colorless oil. Rf = 0.50 (95/5 hexane/EtOAc);1H NMR (400 MHz, CDCl3, 25 C): d 7.88(dd, J = 8.8, 6.0 Hz, 1H), 7.41 (dd, J = 8.3, 2.5 Hz, 1H), 7.08 (ddd, J = 8.8,7.6, 2.5 Hz, 1H), 3.92 (s, 3H) ppm.
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetone;	EXAMPLE 2 2-Bromo-4-fluorobenzoic acid, methylester A solution of 2-bromo-4-fluorobenzoic acid (5 g, 22.8 mmol), DBU (5.21 g, 34.2 mmol), and methyl iodide (6.48 g, 45.7 mmol) in acetone (23 mL) was stirred at room temperature for 2 h. The reaction was concentrated in vacuo and the residue partitioned between EtOAc and 1 M HCl. The organic portion was washed with saturated aqueous NaHCO3, brine and then was dried (MgSO4), filtered and evaporated to give the ester of Example 2 (5.18 g) which was used directly in the next step.
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetone;	EXAMPLE 2 2-Bromo-4-fluorobenzoic acid, methylester. A solution of 2-bromo-4-fluorobenzoic acid (5 g, 22.8 mmol), DBU (5.21 g, 34.2 mmol), and methyl iodide (6.48 g, 45.7 mmol) in acetone (23 mL) was stirred at room temperature for 2 h. The reaction was concentrated in vacuo and the residue partitioned between EtOAc and 1 M HCl. The organic portion was washed with saturated aqueous NaHCO3, brine and then was dried (MgSO4), filtered and evaporated to give the ester of Example 2 (5.18 g) which was used directly in the next step.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 4393 - 4398
[2]Patent: US6407250,2002,B1
[3]Patent: US2004/162323,2004,A1

11
[ 878206-29-2 ]
[ 653-92-9 ]
C₂₆H₂₇ClFNO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; at 65℃; for 8h;	Example 364'-Chloro-5-fluoro-3'-[[(tricyclo[3.3.1.13'7]dec-l-ylmethyl)amino]carbonyl]-[l,l'-biphenyl]-2-carboxyIic acidClTo a stirred solution of 2-bromo-4-fluoro-benzoic acid (500 mg) in dichloromethane (5mL) at 0C under nitrogen was added N, N-dimemylformamide (1 drop) and oxalylchloride (0.4 mL). The reaction mixture was allowed to warm to room temperature over 2hours, concentrated in vacua and then redissolved in dichloromethane (5 mL). Methanol (1mL) was added dropwise and the mixture was stirred at room temperature for 2 hoursbefore being concentrated in vacuo to give a colourless oil which was dissolved intetrahydrofuran (3 mL) /water(3 mL). [[(Tricyclo[3.3.1.13>7]dec-l-ylmethyl)amino]carbonyl]phenyl]-boronic acid (Example 2 (a)) (500 mg), potassiumcarbonate (400 mg) and te?rato(triphenylphosphine)palladium(0) (80 mg) were added andthe mixture was stirred at 65 C under a nitrogen atmosphere for 8 hours. The productswere filtered through diatomaceous earth, washing with methanol (3x10 mL), and werethen concentrated in vacuo. Dichloromethane (20 mL) and 2M aqueous hydrochloric acid(10 mL) were added, the layers were separated and the aqueous fraction was extracted withdichloromethane (2x10 mL). The combined organic layers were washed with saturatedaqueous sodium chloride (10 mL), dried (MgSO4), filtered and concentrated. The residuewas dissolved in tetrahydrofuran (3 mL) and a solution of sodium hydroxide (250 mg) inwater (3 mL) was added. The mixture was stirred at room temperature for 24 hours,adjusted to pH 5 with 2M aqueous hydrochloric acid and concentrated in vacuo.Purification by chromatography (SiO2, dichloromethane methanol 98:2 as eluant) gave thetitle compound as a colourless solid (90 mg).MS: APCI(-ve) 440 (M-H4).m.p. 120-124C.'HNMR (400 MHz, d6-DMSO) 8 13.01 (1H, s), 8.36 (1H, t), 7.87 (1H, dd), 7.52 (1H, d),7.42-7.37 (2H, m), 7.34 (1H, ddd), 7.27 (1H, dd), 2.95 (2H, d), 1.94 (3H, s), 1.71-1.56 (6H,m), 1.55-1.50 (6H,m).

Reference： [1]Patent: WO2006/25783,2006,A1 .Location in patent: Page/Page column 98-100

12
[ 496-69-5 ]
[ 79-22-1 ]
[ 653-92-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In water;	EXAMPLE 8 Production of the nitrophenol (VII: X=Br): 2-Bromo-4-fluorophenol (28 g) was added to a solution of sodium hydroxide (7 g) in water (100 ml), and methyl chloroformate was dropwise added thereto at a temperature of below 10 C. Precipitated crystals were collected by filteration and washed with water to give methyl (2-bromo-4-fluorophenyl)formate (41 g). M.P., 80.7 C.
	With sodium hydroxide; In water;	EXAMPLE 11 To a solution of 2-bromo-4-fluorophenol (28 g) in a solution of sodium hydroxide (7 g) in water (100 ml), methyl chloroformate was dropwise added thereto at a temperature below 10 C. The produced crystals were collected by filtration and washed with water to give methyl 2-bromo-4-fluorophenylformate (41 g). M.P., 80.7 C.
	With sodium hydroxide; In water;	EXAMPLE 11 Production of the nitrophenol (V: X=Br): 2-Bromo-4-fluorophenol (28 g) was added to a solution of sodium hydroxide (7 g) in water (100 ml), and methyl chloroformate was dropwise added thereto at a temperature of below 10 C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-bromo-4-fluorophenyl)formate (41 g). M.P., 80.7 C.

Reference： [1]Patent: US4427438,1984,A
[2]Patent: US4437877,1984,A
[3]Patent: US4431822,1984,A

13
[ 653-92-9 ]
2-bromo-4-fluoro-5-nitrobenzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With sulfuric acid; nitric acid; at 0 - 20℃; for 18.5h;	B. 2-Bromo4-fluoro-5-nitro-benzoic acid methyl ester. To conc. fuming H2SO4 (8 mL) at 0 C. was added conc. fuming HNO3 (8 mL) and the mixture allowed to stand for 5 min. To a solution of <strong>[653-92-9]2-bromo-4-fluoro-benzoic acid methyl ester</strong> (9.32 g, 40 mmol) at 0 C., the mixture of acids was added dropwise over 30 min. The mixture was allowed to warm to RT and was stirred for 18 h. The mixture was poured into ice water, diluted with EtOAc, and treated with 6 N NaOH. The aqueous layer was extracted with EtOAc (3*300 mL). The combined organic layers were washed with brine (200 mL), dried (MgSO4), and concentrated. The crude material was purified on SiO2 (0-25% EtOAc/hexanes) to provide 4.9 g (43%) of the title compound. 1H NMR (500 MHz, CDCl3): 8.61 (d, J=8.0, 1H), 7.66 (d, J=10.0, 1H), 3.91 (s, 3H).
	With conc. nitric acid; In sulfuric acid;	The thus obtained methyl (2-bromo-4-fluorophenyl)formate was suspended in conc. sulfuric acid (13 ml). To the suspension, a mixture of conc. sulfuric acid (13 ml) and conc. nitric acid (13 ml) was added at about 30 C. The mixture was stirred for 30 minutes and poured onto ice. Precipitated crystals were thoroughly washed with water, whereby yellow crystals of methyl (2-bromo-4-fluoro-5-nitrophenyl)formate (38.3 g) were obtained. M.P., 63.5-64.5 C.

Reference： [1]Patent: US2006/223810,2006,A1 .Location in patent: Page/Page column 28
[2]Patent: US4431822,1984,A

14
[ 13331-19-6 ]
[ 653-92-9 ]
[ 865-47-4 ]
[ 152609-92-2 ]

Yield	Reaction Conditions	Operation in experiment
1.45 g (15%)	copper(I) iodide; In pyridine; diethyl ether;	A. Preparation of 4-fluoro-2-(3-hydroxy-2-propylphenoxy)benzoic acid methyl ester. To a solution of 2-propylresorcinol (10.0 g, 65.7 mmol) in pyridine (120 mL) was added potassium tert -butoxide (7.00 g, 62.5 mmol) at room temperature with stirring. To this was added a mixture of <strong>[653-92-9]methyl 2-bromo-4-fluorobenzoate</strong> (7.60 g, 32.6 mmol) and copper(I) iodide (12.5 g, 65.7 mmol) in pyridine (120 mL). The resulting mixture was gently refluxed for 4 hours. The reaction was cooled to room temperature and stirred for 18 hours. The mixture was concentrated in vacuoand the resulting material dissolved in ethyl ether. The solution was washed once with 5N aqueous hydrochloric acid. The aqueous layer was extracted once with fresh ethyl ether and the combined organic layers were washed twice with 5N aqueous ammonium hydroxide. The organic layer was washed once with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo.Silica gel chromatography of the resulting residue provided 1.45 g (15%) of the desired intermediate product as a light tan solid: mp 92-94C; NMR (CDCl3) 7.95 (m, 1H), 7.04 (t, J = 9.5 Hz, 1H), 6.79 (t, J = 9 Hz, 1H), 6.65 (d, J = 9.5 Hz, 1H), 6.50 (m, 2H), 5.25 (bs, 1H, -OH), 3.88 (s, 3H), 2.60 (t, J = 8.7 Hz, 2H), 1.55 (hextet, J = 7.8 Hz, 2H), 0.92 (t, J = 7.8 Hz, 3H); MS-FD m/e 305 (p + 1, 40), 304 (p, 100); IR.

Reference： [1]Patent: EP743064,1996,A1

15
[ 1006-41-3 ]
[ 18107-18-1 ]
[ 653-92-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	In methanol; hexanes; toluene; at 20℃; for 3h;	A. 2-Bromo-4-fluoro-benzoic acid methyl ester. To a solution of 2-bromo-4-fluoro-benzoic acid (10.95 g, 50 mmol) in toluene/MeOH (3:1; 200 mL) was added trimethylsilyidiazomethane (2 M in hexanes; 36 mL, 71.7 mmol) at RT for 3 h. The mixture was diluted with EtOAc (300 mL) and washed sequentially with satd. aq. NaHCO3 (50 mL) and brine (50 mL), dried (MgSO4), and concentrated to provide 11.5 g (99%) of the crude material which was used in the next step without further purification. 1H NMR (500 MHz, CDCl3): 7.86 (dd, J=8.8, 6.0, 1H), 7.39 (dd, J=8.3, 2.5, 2H), 7.08-7.05 (m, 1H), 3.91 (s, 3H).

Reference： [1]Patent: US2006/223810,2006,A1 .Location in patent: Page/Page column 28

16
[ 88-12-0 ]
[ 653-92-9 ]
5-(2-bromo-4-fluorophenyl)-3,4-dihydro-2H-pyrrole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%		Treat a solution of l-vinylpyrrolidin-2-one (2 g, 8.58 mmol) in dry THF (30 mL) with lithium diisopropylamide (LDA) (13 mL, 31.45 mmol) at -20 0C under N2 atmosphere and stir at the same temperature for 30 min. Then add methyl 2-bromo-4- fluorobenzoate (2 g, 8.58 mmol) and stir it over the weekend. Add an HCl (12 N, 9 mL) solution and water (12 mL). Remove the THF and add HCl (12 N, 12 mL) and water (15 mL). Heat it to 100 0C for 15 h. Cool the mixture to RT and add a 5 % NaOH solution. Extract the solution with ether, dry over magnesium sulfate, and remove the solvent. Purify the residue by column chromatography (hexane to ethyl acetate) to give the title compound (0.42 g, 27 %). MS (ES) m/z 244 [M+l]+.

Reference： [1]Patent: WO2008/144223,2008,A2 .Location in patent: Page/Page column 19

17
[ 201230-82-2 ]
[ 653-92-9 ]
[ 100-46-9 ]
[ 351996-10-6 ]

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 7102 - 7107

18
[ 5382-16-1 ]
[ 653-92-9 ]
[ 1103500-40-8 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate; In acetonitrile; at 90℃; for 17h;	Intermediate Preparation 22; 2-Bromo-4-(4-hydroxy-piperidin-l-yl)-benzoic acid methyl ester; A mixture of <strong>[653-92-9]2-bromo-4-fluoro-benzoic acid methyl ester</strong> (2.06 g, 8.84 mmol), A- hydroxy piperidine (1.86 g, 18.4 mmol), and potassium carbonate (1.33 g, 9.62 mmol) in acetonitrile (25 mL) is heated to 90 0C for 17 h. The mixture is concentrated and partitioned between ethyl acetate and water. The solvent layers are separated and the aqueous layer is extracted with ethyl acetate (3x). The combined ethyl acetate layers are dried (MgSO4), filtered, and concentrated under reduced pressure. The residue is purified on silica (120 g) using a gradient of 0% to 90% ethyl acetate in heptane to provide the title compound (2.10 g, 76%) LC-ES/MS m/z 314.0 (M+ 1)

Reference： [1]Patent: WO2009/12125,2009,A1 .Location in patent: Page/Page column 27

19
[ 653-92-9 ]
[ 62-53-3 ]
[ 1228780-34-4 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 90℃; for 24h;	EXAMPLE 15A methyl 4-fluoro-2-(phenylamino)benzoate; Methyl 2-bromo-4-fluorobenzoate (1.00 g), aniline (0.47 mL), palladium(II) acetate (0.048 g), 2,2'-bis(diphenylphosphino)-l,r-binaphthyl (0.214 g) and Cs2CO3 (2.08 g) in toluene (12 mL) were stirred at 9O0C for 24 hours. The reaction was concentrated and chromatographed on silica gel with 5-50% ethyl acetate/hexanes.

Reference： [1]Patent: WO2010/65865,2010,A2 .Location in patent: Page/Page column 236-237

20
[ 653-92-9 ]
[ 108-95-2 ]
[ 448-20-4 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;copper(I) trifluoromethanesolfonate toluene complex; In ethyl acetate; toluene; at 110℃; for 24h;	EXAMPLE 1C methyl 4-fluoro-2-phenoxybenzoate; Methyl 2-bromo-4-fluorobenzoate (1 g), phenol (0.565 g), cesium carbonate (1.96 g), copper(I) triflate toluene complex (0.087 g), and ethyl acetate (0.034 mL) in toluene (12 mL) was stirred at HO0C for 24 hours. The reaction was cooled and chromatographed on silica gel with 5% ethyl acetate/hexanes.
	With caesium carbonate;copper(I) triflate; In ethyl acetate; toluene; at 110℃; for 24h;	Example 9A methyl 4-fluoro-2-phenoxybenzoate Methyl 2-bromo-4-fluorobenzoate (1 g), phenol (0.565 g), cesium carbonate (1.96 g), copper(I) triflate toluene complex (0.087 g), and ethyl acetate (0.034 mL) in toluene (12 mL) was stirred at 110 C. for 24 hours. The reaction was cooled and chromatographed on silica gel with 5% ethyl acetate/hexanes.

Reference： [1]Patent: WO2010/65865,2010,A2 .Location in patent: Page/Page column 226
[2]Patent: US2010/184750,2010,A1 .Location in patent: Page/Page column 49

21
[ 6783-05-7 ]
[ 653-92-9 ]
[ 1228780-27-5 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 13A methyl 4-fluoro-2-phenethylbenzoate; Methyl 2-bromo-4-fluorobenzoate (1.00 g), (E)-styrylboronic acid (0.89 g), tetrakis(triphenylphosphine)palladium(0) (0.50 g), and K3PO4 (2.28 g) were stirred in dioxane (17 rnL) at 9O0C for 24 hours. The reaction mixture chromatographed on silica gel with 1-5% ethyl acetate/hexanes. The product in methanol (10 ml) was added to 20 wt% of fresh dry 5% Pd-C and stirred 4 days with H2 in a pressure bottle. The mixture was filtered through a nylon membrane and concentrated.

Reference： [1]Patent: WO2010/65865,2010,A2 .Location in patent: Page/Page column 235

22
(-)-1-[(4chlorophenyl)-phenylmethyl]piperazine [ No CAS ]
[ 653-92-9 ]
[ 1228781-20-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 125℃; for 24h;	Methyl 2-bromo-4-fluorobenzoate (3 g), EXAMPLE 1B (4.43 g), and K2CO3 (3.56 g) were stirred in DMSO (35 mL) at 125 C. for 24 hours. The mixture was cooled, taken up in ethyl acetate (500 mL), washed with water and brine, dried over Na2SO4, filtered and concentrated. The concentrate was chromatographed on silica gel with 5-25% ethyl acetate/hexanes.

Reference： [1]Patent: US2010/160322,2010,A1 .Location in patent: Page/Page column 86

23
[ 6783-05-7 ]
[ 653-92-9 ]
methyl 4-fluoro-2-(2-phenylethenyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 90℃; for 24h;	EXAMPLE 18AMETHYL 4-FLUORO-2-PHENETHYLBENZOATEMethyl 2-bromo-4-fluorobenzoate (1.00 g), (E)-styrylboronic acid (0.89 g), tetrakis(triphenylphosphine)palladium(0) (0.50 g), and K3PO4 (2.28 g) were stirred in dioxane (17 mL) at 90 C. for 24 hours. The reaction mixture was chromatographed on silica gel with 1-5% ethyl acetate/hexanes. The product in methanol (10 ml) was added to 20 wt % of fresh dry 5% Pd-C and stirred 4 days with H2 in a pressure bottle. The mixture was filtered through a nylon membrane and concentrated.

Reference： [1]Patent: US2010/184750,2010,A1 .Location in patent: Page/Page column 51

24
[ 259209-20-6 ]
[ 653-92-9 ]
[ 1238197-08-4 ]

Reference： [1]Journal of Combinatorial Chemistry,2010,vol. 12,p. 664 - 669

25
[ 653-92-9 ]
[ 89466-08-0 ]
[ 1238196-74-1 ]

Reference： [1]Journal of Combinatorial Chemistry,2010,vol. 12,p. 664 - 669

26
[ 851666-27-8 ]
[ 653-92-9 ]
[ 1359681-76-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 100℃; for 0.25h;Inert atmosphere; Microwave irradiation;	General procedure: Method A: A sealed tube was charged with compound 4a,b (0.93 mmol), 5a-e (0.93 mmol), 5 mol % of Pd(OAc)2, 10 mol % of Xantphos, 2 equiv of Cs2CO3 (1.86 mmol) and 10 mL of 1,4-dioxane. The mixture was degassed and backfilled with argon, the reaction vessel was sealed with a Teflon tap and heated at 100 C for 12 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in chloroform, washed with 10% citric acid solution, brine solution, dried over anhydrous Na2SO4 and concentrated. The crude compound was purified by flash column chromatography using 3-5% of MeOH/CHCl3 as an eluent to give the title cyclized compound.Method B: To a thick-well borosilicate glass vial (5 mL) was added compound 4a,b (0.23 mmol), compound 5a-e (0.23 mmol), 5 mol % of Pd(OAc)2, 10 mol % of Xantphos, 2 equiv Cs2CO3 (0.46 mmol) and 1,4-dioxane (2 mL). The mixture was degassed and the reaction vial was sealed and placed in the CEM-DISCOVER microwave reactor and irradiated at 100 C for 15 min. After cooled to rt, the product was isolated as above described in method A.

Reference： [1]Tetrahedron,2012,vol. 68,p. 2001 - 2006

27
[ 653-92-9 ]
[ 68-12-2 ]
4-fluoro-2-formylbenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of methyl R-16 (5 g, 21.46 mmol) in anhydrous THF (40 mL) is cooled to -30 C and isopropyl magnesium chloride (2M in THF, 16.1 mL, 32.18 mmol) is added. The reaction is stirred at -30 C for 3 hours, DMF (16.6 mL, 0.215 mol) is added and the mixture is warmed to room temperature and stirred for 2 hours. The reaction mixture is concentrated in vacuo and the residue diluted with 0.5M aqueous HC1 (100 mL). The product is extracted into CH2CI2 and the combined organics are washed with brine and then dried with Na2S04, filtered and concentrated in vacuo. The residue is purified by flash chromatography (S1O2, 30% EtOAc in heptane) to give R-17 (1.56 g)

Reference： [1]Patent: WO2012/58254,2012,A1 .Location in patent: Page/Page column 47-48

28
[ 653-92-9 ]
[ 73183-34-3 ]
[ 1400976-17-1 ]

Yield	Reaction Conditions	Operation in experiment
1 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 2h;Inert atmosphere;	A mixture of methyl 2-bromo441uorobenzoate (compound 14a, 1 g, 4.29 mmoi),4,4,4,4?,5,5 ,5?,5?octamethyl-2,2?-bi(1 ,3,2-dioxaborolane) (1.63 g, 6.44 mmol), PdCi2(DPPF)(350 mg, 429 imol) and potassium acetate (632 mg, 6.44 mmol) in dioxane (30 mL) was heated to 90 C and stirred for 2 hours under nitrogen. The crude reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 40 g, 0% to 10% EtOAc inpetroleum ether) to give compound 14b as colorless oil (1 g), LCMS (M+H): 281.

Reference： [1]Synthesis,2012,vol. 44,p. 2173 - 2180
[2]Patent: EP3686201,2020,A1 .Location in patent: Paragraph 0335-0336
[3]Patent: WO2018/11162,2018,A1 .Location in patent: Page/Page column 41

29
[ 288-13-1 ]
[ 653-92-9 ]
[ 1398756-48-3 ]

Reference： [1]Journal of the American Chemical Society,2012,vol. 134,p. 15572 - 15580

30
[ 653-92-9 ]
[ 5720-05-8 ]
[ 1095549-74-8 ]

Yield	Reaction Conditions	Operation in experiment
82.6%	With palladium diacetate; potassium carbonate; triphenylphosphine; for 5h;Inert atmosphere; Reflux;	To a solution of 5a (2.00 g, 8.58 mmol), Palladium acetate (0.008 g, 0.04 mmol), PPh3 (0.47 g, 1.69 mmol) and p-tolylboronic acid (10 mL) was added 6 mL of 2 M K2CO3. The mixture was refluxed under nitrogen for 5 h, then diluted with ethyl acetate, and washed with water (50 mL * 3) and brine (50 mL * 3).The organic layer was dried over MgSO4. The solvent was removed under reduced pressure.The residue was purified by flash column chromatography with petroleum ether-ethyl acetate (100/1) as eluant. The product was obtained as a yellow oil. Yield: 82.6%. 1H NMR (CDCl3, 400 MHz) delta: 7.53(1H, dd, J1 = 8.4 Hz, J2 = 2.8 Hz, Ph-H), 7.35(1H,dd, J1 = 8.4 Hz, J2 = 5.6 Hz, Ph-H), 7.25-7.16(5H, m, Ph-H), 3.69(3H, s, Ph-COOCH3)2.41(3H, s, Ph-CH3). ESI-MS (m/z): 245.2 [M+1]+.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 7101 - 7111

31
[ 653-92-9 ]
[ 1692-15-5 ]
[ 1214374-65-8 ]

Yield	Reaction Conditions	Operation in experiment
0.89 g	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 120℃; for 1h;Microwave irradiation;	A mixture of <strong>[653-92-9]methyl 2-bromo-4-fluorobenzoate</strong> (1.5 g), pyridine-4-boronic acid (0.95 g), sodium carbonate (1.0 g), tetrakis(triphenylphosphine)palladium(0) (0.22 g), water (1.5 mL) and DME (9.0 mL) was stirred at 120 C. for 1 hr under microwave irradiation. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.89 g).[0600]MS (APCI+): [M+H]+ 232.1

Reference： [1]Patent: US2013/90341,2013,A1 .Location in patent: Page/Page column 0599-0600

32
[ 653-92-9 ]
[ 5570-18-3 ]
[ 1379820-77-5 ]

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 3712 - 3714

33
[ 653-92-9 ]
[ 140-75-0 ]
[ 1445137-09-6 ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 6735 - 6745

34
[ 110-91-8 ]
[ 653-92-9 ]
[ 1092352-96-9 ]

Reference： [1]Chemical Communications,2014,vol. 50,p. 9914 - 9916
[2]Journal of Organic Chemistry,2013,vol. 78,p. 6735 - 6745
[3]Chemistry - A European Journal,2019,vol. 25,p. 976 - 980

35
[ 93-98-1 ]
[ 653-92-9 ]
[ 1453167-83-3 ]

Reference： [1]Synthesis,2013,vol. 45,p. 1955 - 1964

36
[ 653-92-9 ]
[ 106-96-7 ]
methyl 4-fluoro-2-(propa-1,2-dien-1-yl)benzoate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 7177 - 7180

37
[ 653-92-9 ]
potassium isopropenyltrifluoroborane [ No CAS ]
methyl 4-fluoro-2-(prop-1-en-2-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine; In isopropyl alcohol; for 21h;Reflux;	Step 1 : Triethylamine (13 mL, 9.44 g, 93.3 mmol), potassium isopropenyltrifluoroborate (18.0 g, 121 .6 mmol) and PdCl2(dppf).CH2Cl2 (1.38 g, 1.70 mmol) were added to a solution of compound 479 (21.8 g, 93.6 mmol) in n-propanol (640 mL) and the mixture was heated at reflux for 17 hours. TLC analysis (10% 2-butanone in heptane) showed starting material remaining and PdCl2(dppf).CH2Cl2 (0.69 g, 0.84 mmol) was added and heating continued for a further 4 hours. After cooling to room temperature the mixture was concentrated to -100 mL in vacuo and diluted with EtOAc (400 mL) before being washed with 1 M HCI (250 mL) and brine (250 mL). The combined aqueous washings were extracted with EtOAc (100 mL) and this was washed with brine (75 mL). The combined organic layers were dried (MgS04) and concentrated in vacuo to give a dark brown oil. Purification by column chromatography (1500 mL silica, 4% EtOAc in heptane) gave the desired product (8.63 g, 47%) as a colorless liquid, contaminated with methyl 4-fluorobenzoate (<10%), and a mixture of the desired product and starting material (5.05 g) also contaminated with methyl 4-fluorobenzoate. Further purification by column chromatography (500 mL silica, 4% EtOAc in heptane) gave a further 1.60 g (9%) of the desired product contaminated with methyl 4-fluorobenzoate (<10%). The product was further purified by Kugelrohr distillation, discarding the forerun (70C, 4 mmHg), and then increasing the temperature to 95C to collect the compound 480 (95% recovery) containing <5% methyl 4- fluorobenzoate. 1 H NMR (400 MHz, CDCI3) delta 7.84 (dd, J = 8.7, 5.9 Hz, 1 H) 6.99 (ddd, J = 8.6, 8.0, 2.6 Hz, 1 H) 6.93 (dd, J = 9.4, 2.6 Hz, 1 H) 5.12 (p, J = 1.6 Hz, 1 H) 4.85 (dq, J = 1.8, 0.9 Hz, 1 H) 3.85 (s, 3H) 2.07 (t, J = 1 .2 Hz, 3H). LCMS m/z 195 [M+H]+.

Reference： [1]Patent: WO2013/132376,2013,A1 .Location in patent: Page/Page column 345

38
[ 653-92-9 ]
[ 5176-28-3 ]
9-fluoro-13,14-cis-dihydrobenzo[c]phenanthridin-6-one [ No CAS ]

Reference： [1]RSC Advances,2013,vol. 3,p. 17271 - 17280

39
tert-butyl 5,8-dihydro-5,8-epiminonaphtho[2,3-d][1,3]dioxole-10-carboxylate [ No CAS ]
[ 653-92-9 ]
9-fluoro-13,14-cis-dihydrobenzodioxolebenzo[c]phenanthridin-6-one [ No CAS ]

Reference： [1]RSC Advances,2013,vol. 3,p. 17271 - 17280

40
[ 653-92-9 ]
[ 935657-73-1 ]

Reference： [1]Chemical Communications,2014,vol. 50,p. 9914 - 9916

41
[ 50-00-0 ]
[ 653-92-9 ]
[ 100-63-0 ]
6-fluoro-2-phenylphthalazin-1(2H)-one [ No CAS ]

Reference： [1]Organic Letters,2014,vol. 16,p. 5324 - 5327

42
[ 653-92-9 ]
[ 57260-71-6 ]
2-bromo-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 5h;	To a solution of <strong>[653-92-9]methyl 2-bromo-4-fluorobenzoate</strong> 2 (1.8 g, 7.72 mmol) in DMSO (30 mL) was added tert-butyl piperazine-l-carboxylate 3 (1.726 g, 9.27 mmol) and K2C03 (4.26 g, 30.9 mmol). The mixture was stirred at 120C for 5 h. When finished, the mixture was extracted with ethyl acetate (2 x 50 mL), and washed with water (50 mL) and brine (2 x 50 mL). The organic layer was dried over Na2S04, filtered and concentrated to get a residue which was purified by silica gel column chromatography eluting with 10: 1 PE/EA to get the title compound (1.1 g, 36%) as a yellow oil. MS (ESI): m/z = 328.7 [M - 55]+.

Reference： [1]Patent: WO2015/48662,2015,A2 .Location in patent: Page/Page column 124

43
[ 653-92-9 ]
[ 24850-33-7 ]
methyl 2-allyl-4-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With tetrakis(triphenylphosphine) palladium(0); lithium chloride; In 1,4-dioxane; at 110℃; for 10h;Inert atmosphere;	General procedure: A solution containing allyl tributyltin(1.5 mmol), the triflate or bromide (1.0 mmol), Pd(PPh3)4(5.0 mmol%) and LiCl (3.0 mmol) in dioxane (5.0 mL) was heated at 100 C for 10h. The reaction was quenched with satd. aqueous KF solution and extracted with Et2O(x3). The combined organic extracts were washed with brine, dried overanhydrous MgSO4 and filtrated. The solvent was concentrated underreduced pressure, and the residue was purified by flash chromatography as indicated.
39.6%	With bis-triphenylphosphine-palladium(II) chloride; lithium chloride; In N,N-dimethyl-formamide; acetonitrile; at 90℃; for 16h;Inert atmosphere;	A mixture of <strong>[653-92-9]methyl 2-bromo-4-fluorobenzoate</strong> (1 g, 4.29 mmol), allyltributylstannane (1.464 mL, 4.72 mmol), lithium chloride (0.364 g, 8.58 mmol) in DMF (1 mL), acetonitrile (10 mL) was added bis(triphenylphosphine)palladium(ii) dichloride (0.151 g, 0.215 mmol). It was then degassed for 2 min, then filled with N2. After heating at 90 C. for 16 h, it was quenched with NH4Cl, extracted with EtOAc. The organic layer was washed with KF solution, dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 10% EtOAc/hexane to isolate methyl 2-allyl-4-fluorobenzoate (330 mg, 1.699 mmol, 39.6% yield) as an white solid. 1H NMR (400 MHz, CDCl3) delta 7.96 (dd, J=8.6, 6.1 Hz, 1H), 7.09-6.87 (m, 2H), 6.01 (ddt, J=16.9, 10.3, 6.6 Hz, 1H), 5.19-4.96 (m, 2H), 3.90 (s, 3H), 3.80 (d, J=6.6 Hz, 2H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 4393 - 4398
[2]Angewandte Chemie - International Edition,2019,vol. 58,p. 18159 - 18164
Angew. Chem.,2020,vol. 131,p. 18327 - 18332,6
[3]Patent: US2015/232481,2015,A1 .Location in patent: Paragraph 0404

44
[ 653-92-9 ]
[ 6258-60-2 ]
methyl 4-fluoro-2-((4-methoxybenzyl)thio)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; at 20 - 120℃; for 16h;Inert atmosphere;	[000106] To a stirred solution of <strong>[653-92-9]methyl 2-bromo-4-fluorobenzoate</strong> 36 (2 g, 8.58 mmol) in 1,4- dioxane (50 mL) under inert atmosphere were added (4-methoxyphenyl) methanethiol 8 (1.58 g, 10.25 mmol), cesium carbonate (4.18 g, 12.80 mmol) at RT and purged under argon atmosphere for 30 mm. To this was added Pd(dppf)2C12 (306 mg, 0.42 mmol); heated to 120 C and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 250 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 7% EtOAc/ hexanes to afford compound 37 (1.6 g, 61%) as an off-white solid. TLC: 10% EtOAc/ hexanes(R 0.4); 1H NMR (CDC13, 400 MHz): oe 8.01 (dd, J 8.7, 6.2 Hz, 1H), 7.34 (d, J 7.9 Hz, 2H), 7.04 (dd, J= 10.3, 2.4 Hz, 1H), 6.88-6.80 (m, 3H), 4.09 (s, 2H), 3.88 (s, 3H), 3.80 (s, 3H).

Reference： [1]Patent: WO2015/138895,2015,A1 .Location in patent: Paragraph 000106

45
[ 3724-55-8 ]
[ 653-92-9 ]
6-fluoro-2-(methoxycarbonyl)-1-hydroxynaphthalene [ No CAS ]

Reference： [1]Organic Process Research and Development,2015,vol. 19,p. 2022 - 2024

46
[ 6165-69-1 ]
[ 653-92-9 ]
methyl 4-fluoro-2-(thiophen-3-yl)benzoate [ No CAS ]

Reference： [1]Journal of Polymer Science, Part A: Polymer Chemistry,2016,vol. 54,p. 889 - 899

47
[ 700-36-7 ]
[ 653-92-9 ]
methyl 5,5'-difluoro-2'-nitrobiphenyl-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
279.8 mg	With tris-(dibenzylideneacetone)dipalladium(0); copper; In dimethyl sulfoxide; at 100℃; for 2h;	Example 38a Methyl 5,5'-difluoro-2'-nitrobiphenyl-2-carboxylate To <strong>[700-36-7]2-bromo-4-fluoro-1-nitrobenzene</strong> (185.16 mg, 0.842 mmol) was added Pd2dba3 (23.12 mg, 0.025 mmol) and copper powder (271 mg, 4.26 mmol). Dimethylsulfoxide (2.3 ml) and methyl 2-bromo-4-fluorobenzoate (0.122 ml, 0.842 mmol) were added and the mixture was stirred vigorously at 100 C. for 2 h. The mixture was cooled to room temperature, diluted with ethyl acetate (20 ml), and filtered. The filtrate was washed with water and dried (anhydrous Na2SO4) and concentrated to give a yellow oil (279.8 mg). This oil was utilized without purification for the preparation of Example 38b.
279.8 mg	With tris-(dibenzylideneacetone)dipalladium(0); copper; In dimethyl sulfoxide; at 100℃; for 2h;	<strong>[700-36-7]2-bromo-4-fluoro-1-nitrobenzene</strong>(185.16mg, 0.842mmol) to was added Pd 2 dba 3 (23.12mg, 0.025mmol) and copperpowder a (271mg, 4.26mmol). Dimethyl sulfoxide (2.3 ml) and methyl2-bromo-4-fluorobenzoate (0.122ml, 0.842mmol) was added and the mixture wasstirred vigorously for 2 hours at 100 C. The mixture was cooled to roomtemperature, diluted with ethyl acetate (20 ml), and filtered. The filtrate waswashed with water, dried (anhydrous Na 2 SO 4), and concentrated to give ayellow oil (279.8mg). It was used in the preparation of Example 38b withoutpurification this oil.

Reference： [1]Patent: US9309279,2016,B2 .Location in patent: Page/Page column 61; 62
[2]Patent: JP5902123,2016,B2 .Location in patent: Paragraph 0294

48
[ 5308-25-8 ]
[ 653-92-9 ]
methyl 2-bromo-4-(4-ethylpiperazin-1-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	In N,N-dimethyl-formamide; at 20℃; for 2h;	General procedure: A mixture ofdifferent fluoro substituted 2-nitrobenzoate (1.5 mmol) and various amines (7.5 mmol) in DMF (3 mL) was stirred atroom temperature for 2 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine. After dried by sodium sulfate and concentration, the residue was purified by chromatography on silica gel to give as yellowish solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 2594 - 2599

49
[ 79-20-9 ]
[ 653-92-9 ]
methyl 3-(2-bromo-4-fluorophenyl)-3-oxopropanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%		General procedure: Method A:16,17 A two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar was charged with the 2-bromobenzoic acid (20mmol) and freshly distilled methanol (25mL). The solution was heated in a hot water bath, conc. H2SO4 (8mmol) was added slowly and the reaction mixture was refluxed for 24h. After cooling to room temperature around half of the amount of the solvent was removed in vacuo and the residue was partitioned between water (50mL) and diethyl ether (70mL). The organic layer was separated and washed with saturated NaHCO3 (2×50mL), water (50mL) and brine (50mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure. The crude product thus obtained was purified by flash chromatography on silica gel to afford the alkyl-2-halobenzoate. (0023) In a two-necked round-bottomed flask equipped with a reflux condenser and a magnetic stir bar the alkyl 2-halobenzoate (22.5mmol) was dissolved in freshly distilled dry THF (30mL) under argon. The solution was cooled to 0C using an ice bath and NaH (60% in mineral oil, 15mmol) was added portionwise. After stirring for 15min a solution of the alkyl acetate (15mmol) in dry THF (30mL) was added dropwise to the reaction mixture at 0C. The mixture was warmed up, stirred at room temperature for 2h and heated under reflux for 24h. After cooling to room temperature around half of the amount of the solvent was removed in vacuo and the reaction mixture was diluted with toluene (50mL). The resulting mixture was washed with 2N HCl (50mL), saturated NH4Cl (50mL), dried over anhydrous MgSO4 and the volatiles were removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford the alkyl 3-(2?-halophenyl)-3-oxo-propanoate 1.

Reference： [1]Tetrahedron,2016,vol. 72,p. 3454 - 3467

50
[ 653-92-9 ]
[ 83947-58-4 ]
methyl (E)-4-fluoro-2-(prop-1-en-1-yl)benzoate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2016,vol. 138,p. 13858 - 13861

51
[ 653-92-9 ]
[ 126726-62-3 ]
methyl 4-fluoro-2-(prop-1-en-2-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; at 50℃; for 3h;Inert atmosphere;	Step 1 : methyl 4-fluoro-2-(prop-1-en-2-yl)benzoate A solution containing methyl 2-bromo-6-fluorobenzoate (1.00g, 4.29 mmol) and 4,4,5,5- tetramethyl-2-(prop-1-en-2-yl)-1 ,3,2-dioxaborolane (1.210 mL, 6.44 mmol) was degassed by bubbling N2 through the solution for 10 min. PdCI2(dppf)-CH2CI2 (0.175 g, 0.215 mmol) was added followed by Na2C03 (12.87 mL, 12.87 mmol). The resulting mixture was stirred at 50 C for 3 h. The mixture was diluted with EtOAc and water. The mixture was washed with brine (2x). Aqueous washes were back extracted using EtOAc (2x). The combined organic phase was dried over MgS04, filtered, and concentrated. Purification by Si (0-100% EtOAc/Hex) afforded the title compound as a clear oil. (625 mg, 75 % yield). MS (m/z) 194.9 (M+H)+

Reference： [1]Patent: WO2017/6296,2017,A1 .Location in patent: Page/Page column 149-150

52
[ 653-92-9 ]
[ 536-74-3 ]
[ 1359988-53-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With copper(l) iodide; sodium hydroxide; In acetonitrile; at 100℃; for 24h;Sealed tube; Inert atmosphere;	General procedure: A sealed tube of 25 mL equipped with a magnetic stir bar was charged with alkynes (0.20 mmol), 2-bromobenzoic esters (0.22 mmol), CuI (0.02 mmol, 10 mol%), NaOH (0.4 mmol, 2 equiv) and CH3CN (1.0 mL). The reaction mixture was stirred at 100 C for 24 h. The reaction was monitored by GC or GC-MS. After completion of the reaction, the reaction mixture was cooled to room temperature, then washed with saturated NH4Cl aqueous solution (5.0 mL), and extracted with CHCl3 (3 * 5.0 mL). The combined organic phases were dried over Na2SO4 (anhydrous), concentrated in vacuum. The crude product was purified by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1/20-1/10) on silica gel to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 2433 - 2437

53
[ 629-05-0 ]
[ 653-92-9 ]
6-fluoro-3-hexyl-1H-isochromen-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With copper(l) iodide; sodium hydroxide; In acetonitrile; at 100℃; for 24h;Sealed tube; Inert atmosphere;	General procedure: A sealed tube of 25 mL equipped with a magnetic stir bar was charged with alkynes (0.20 mmol), 2-bromobenzoic esters (0.22 mmol), CuI (0.02 mmol, 10 mol%), NaOH (0.4 mmol, 2 equiv) and CH3CN (1.0 mL). The reaction mixture was stirred at 100 C for 24 h. The reaction was monitored by GC or GC-MS. After completion of the reaction, the reaction mixture was cooled to room temperature, then washed with saturated NH4Cl aqueous solution (5.0 mL), and extracted with CHCl3 (3 * 5.0 mL). The combined organic phases were dried over Na2SO4 (anhydrous), concentrated in vacuum. The crude product was purified by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1/20-1/10) on silica gel to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 2433 - 2437

54
[ 917-92-0 ]
[ 653-92-9 ]
3-(tert-butyl)-6-fluoro-1H-isochromen-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With copper(l) iodide; sodium hydroxide; In acetonitrile; at 100℃; for 24h;Sealed tube; Inert atmosphere;	General procedure: A sealed tube of 25 mL equipped with a magnetic stir bar was charged with alkynes (0.20 mmol), 2-bromobenzoic esters (0.22 mmol), CuI (0.02 mmol, 10 mol%), NaOH (0.4 mmol, 2 equiv) and CH3CN (1.0 mL). The reaction mixture was stirred at 100 C for 24 h. The reaction was monitored by GC or GC-MS. After completion of the reaction, the reaction mixture was cooled to room temperature, then washed with saturated NH4Cl aqueous solution (5.0 mL), and extracted with CHCl3 (3 * 5.0 mL). The combined organic phases were dried over Na2SO4 (anhydrous), concentrated in vacuum. The crude product was purified by flash column chromatography (eluent: ethyl acetate/petroleum ether = 1/20-1/10) on silica gel to afford the desired product.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 2433 - 2437

55
[ 653-92-9 ]
[ 98-86-2 ]
[ 1359988-53-6 ]

Reference： [1]Journal of Organic Chemistry,2017,vol. 82,p. 8296 - 8303

56
[ 653-92-9 ]
[ 108-95-2 ]
methyl 2-bromo-4-phenoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 16h;	Dry DMF (40 ml) was added to a 250 ml reaction flask, and phenol (3.88 g), potassium carbonate (5.70 g), and <strong>[653-92-9]methyl 2-bromo-4-fluorobenzoate</strong> (8.00 g) were added under stirring. The temperature was raised at 70 C for 16 h, and the temperature was lowered to room temperature. Water (40 ml) was added, and the mixture was washed with EtOAc (EtOAc)The organic layer was dried over anhydrous sodium sulfate and evaporated to afford Compound (I) (10 g, 94%).It can also be used directly in the next step.
58.3%		To a solution of phenol (0.207 g, 2.200 mmol) in dry DMF (10 mL) was added 60% sodium hydride (0.096 g, 2.400 mmol) and the resulting mixture was stirred at RT under N2 for 30 min. To the resulting clear solution was added methyl 2-bromo-4- fluorobenzoate (0.476 g, 2.000 mmol) all at once and stirring was continued at RT for 18 h. The reaction mixture was quenched with saturated aqueous NH4CI (2 mL) and then it was poured into ice 0 and extracted with EtOAc (x2). The combined organic phase was dried (Na2SO4) and evaporated to give a colourless oil. This oil was purified by flash chromatography (ISCO/ 0-30% EtOAc-hexane) to give methyl 2-bromo-4- phenoxybenzoate (0.358 g, 58.3% yield) as a colourless oil which was used as such in the next step. LC-MS (Method J): 1.391 min, [M + H]+ = 307.0; 1H NMR (400 MHz, DMSO-d6) delta ppm 7.83 (d, /= 8.6 Hz, 1H), 7.46 (dd, /= 7.4, 8.6 Hz, 2H), 7.26 (m, 2H), 7.15 (dd, /= 1.2, 9.0 Hz, 2H), 7.02 (dd, /= 2.3, 8.6 Hz, 1H), 3.81 (s, 3H).

Reference： [1]Patent: CN108794397,2018,A .Location in patent: Paragraph 0041; 0042
[2]Patent: WO2018/5591,2018,A1 .Location in patent: Page/Page column 331

57
[ 653-92-9 ]
[ 1260666-80-5 ]

Reference： [1]Patent: WO2018/26371,2018,A1

58
[ 653-92-9 ]
copper(l) cyanide [ No CAS ]
[ 127510-96-7 ]

Yield	Reaction Conditions	Operation in experiment
39%	In N,N-dimethyl-formamide; at 140.0℃;Inert atmosphere;	To a 250-mL round-bottom flask purged and maintained under an inert atmosphere ofnitrogen, was added methyl2-bromo-4-fluorobenzoate 101 b (4 g, 17.16 mmol, 1.0 equiv.)andN';N-dimethylformamide (20 mL). Solid CuCN (2.3 g, 25.84 mmol, 1.5 equiv.) wasadded in several batches. The resulting mixture vvas stirred at l40C overnight. Upon coolingto room temperature, the mixture '.vas quenched with water. The aqueous mixture was15 extracted with ethyl acetate (100 mL x 3), and the combined organic extracts were washedwith t-hO (50 mL x 2) and brine (80 mL x 2) Removal of solvents gave a residue which waspmitl.ed by silica gel column chromatography eluting with ethyl acetate/petroleum ether(lO%) to provide methyl2-cyano-4-t1uorobenzoate 101c (1.2g, 39%) as a white solid
850 mg	In N,N-dimethyl-formamide; at 120.0℃; for 1.5h;Inert atmosphere;	To a solution of methyl 2-bromo-4-fluorobenzoate (1.2 g, 5.15 mmol) in DMF (5 mL) was added cyanocopper (0.92 g, 10.3 mmol) under N2. The reaction was stirred at 120 C for 1.5 h under N2. Then, the reaction was cooled to room temperature.10% NaCN (10 mL) was added to the reaction. The mixture was extracted with DCM (3 x 30 mL). The layers were separated and the organic phase was washed with saturated aqueous NaCl (3 x 50 mL) .The combined organic layers were dried over Na2SO4. After filtration, 850 mg of product was obtained as a white solid.

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 229; 230
[2]Patent: WO2018/26371,2018,A1 .Location in patent: Paragraph 0158; 0260

59
[ 1006-41-3 ]
[ 653-92-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	With thionyl chloride; In methanol; at 70℃; for 2h;	To a 250-mL row1d-bottom flask was added a solution of 2-bromo-4-fluorohenzoicacid J 01 a (1 0 g, 45.66 rnmol, 1.0 equiv.) in methanol (l 00 mL) Thionyl chloride (16 2 g,137.29 mmoL 3.0 equiv.) vvas added dropvvise. The resulting mixture vvas stirred at 70C for2h, and then quenched ,.vith the addition of water/ice. The aqueous mixture was extracted5 v~th ethyl acetate (lOO mL x 2). The combined organic extracts vvere washed brine (50 rnL x2), concentrated to a crude solid, which was further purified by silica gel columnchromatography eluting with ethyl acetate/petroleum ether (0%-81()). Removal of solventsafforded methy 12-bromo-4-fluorobenzoate 101 b (9.4 g, 88%) as a colorless solid.

Reference： [1]Patent: WO2018/39386,2018,A1 .Location in patent: Page/Page column 229; 230

60
[ 97-94-9 ]
[ 653-92-9 ]
methyl 2-ethyl-4-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In tetrahydrofuran; at 80℃;	To a mixture of <strong>[653-92-9]methyl 2-bromo-4-fluorobenzoate</strong> (10.1 g, 43.34 mmol, 1.00 equiv) in THF (100 ml) with Cs2C03 (42 g, 128.91 mmol, 3.00 equiv) and Pd(dppf)CI2 (3.5 g, 4.78 mmol, 0.1 1 equiv) was added Et3B (1 M in tetrahydrofuran) (65 ml, 65 mmol, 1.50 equiv). The reaction mixture was stirred overnight at 80C. Water was added and the mixture was extracted with EA thrice. The combined extracts were washed with water, saturated brine and dried over anhydrous Na2S04, then concentrated and purified by chromatography on silica gel (1 :30 EA/PE) to yield methyl 2-ethyl-4- fluorobenzoate as a yellow oil.

Reference： [1]Patent: WO2018/89449,2018,A1 .Location in patent: Page/Page column 175-179

61
[ 653-92-9 ]
[ 1560648-02-3 ]
C₁₈H₁₃FO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In tetrahydrofuran; water; at 80.0℃; for 12.0h;Inert atmosphere;	Add M2a (75.6 mg, 0.28 mmol) in a 25 mL Shrek bottleAnd methyl 2-bromo-4-fluorobenzoate (46.6 mg, 0.2 mmol),Tetrakis(triphenylphosphine)palladium (23.1 mg, 0.02 mmol),Anhydrous sodium carbonate (102 mg, 0.96 mmol), 5 mL of tetrahydrofuran and 2 mL of water.Stir at 80 C for 12 h under nitrogen protection (TLC monitoring),After the reaction is completed, it is then washed with brine, water, extracted with EA, and concentrated.Column chromatography separation. Yield: 99%.

Reference： [1]Patent: CN108623554,2018,A .Location in patent: Paragraph 0049; 0053-0055

62
[ 4433-63-0 ]
[ 653-92-9 ]
methyl 2-ethyl-4-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.6%	With potassium phosphate; palladium diacetate; In water; toluene; at 100℃; for 3h;Inert atmosphere;	Under a nitrogen atmosphere, a solution of compound 46 (11 g, 47.30 mmol) in 210 mL of toluene was added to 12 mL of water, K3PO4 (20 g, 94.59 mmol) and <strong>[4433-63-0]ethylboronic acid</strong> (7 g, 94.59 mmol), followed by the addition of Pd(OAc)2 (149 mg, 0.66 mmol). The mixture was heated to 100C, reacted for 3 hours, and then cooled to room temperature. After filteration, the filter cake was washed with ethyl acetate, and the organic phase was collected and purified by column to obtain a total of 8.3 g of the title compound 47 with a yield of 96.6%.

Reference： [1]Patent: EP3415518,2018,A1 .Location in patent: Paragraph 0081; 0082

63
[ 653-92-9 ]
[ 1066-54-2 ]
methyl 4-fluoro-2-[(trimethylsilyl)ethynyl]benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; at 90℃; for 2h;Inert atmosphere;	Under a nitrogen atmosphere, a solution of compound 35 (5 g, 21.46 mmol), PdCl2(PPh3)2 (452 mg, 0.64 mmol), and CuI (41 mg, 0.21 mmol) in 40 mL of triethylamine (TEA) was added dropwise to ethynyltrimethylsilane (2.52 g, 25.75 mmol) and heated to 90C for 2 hours. After cooling to room temperature, 50 mL of ethyl acetate was added. After filtration, the filtrate was collected and purified by column to give a totle of 5.3 g of the title compound 36 with a yield of 97%. 1H NMR (400 MHz, CDCl3)(delta/ppm)7.97-7.90 (m, 1H), 7.28-7.25 (m, 1H), 7.08-7.04 (m, 1H), 3.92 (s, 3H), 0.28 (s, 9H).

Reference： [1]Patent: EP3415518,2018,A1 .Location in patent: Paragraph 0068; 0072

64
[ 67-56-1 ]
[ 59142-68-6 ]
[ 653-92-9 ]

Reference： [1]Chemistry - A European Journal,2019,vol. 25,p. 976 - 980

65
[ 1228780-72-0 ]
[ 653-92-9 ]
[ 1228780-55-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 100℃; for 12h;	Into a 250-mL round-bottom flask, was placed a solution of Example 1-i, i.e, 1- [[2-(4-chlorophenyl)-4,4-dimethylcyclohex- i-en-i -ylj methyljpiperazine (15.09 g, 47.32 mmol, 1.00 equiv) in DMA (150 mL), DIEA (12.9 g, 99.81 mmol, 2.00 equiv), methyl 2-bromo-4-fluorobenzoate (11.6 g, 49.78 mmol, 1.00 equiv). The resulting solution was stirred for 12 h at 100 degree. The reaction mixture was cooled to room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3xiOO mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3xiOO mL of brine. The mixture was dried over anhydrous sodium sulfate, then filtered and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0:1-1:5). This resulted in 7 g (crude) of methyl 2-bromo-4-(4-[[2- (4-chlorophenyl)-4,4-dimethylcyclohex- i-en-i -ylj methyljpiperazin- 1 -yl)benzoate as yellow oil. LC-MS: (ES, m/z): M+i=533, 531.

Reference： [1]Patent: WO2019/40550,2019,A1 .Location in patent: Page/Page column 67

66
[ 6165-68-0 ]
[ 653-92-9 ]
methyl 4-fluoro-2-(thiophen-2-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 90℃; for 16h;Sealed tube;	General procedure: To a solution of (2) in 1 ,4-dioxane (4 mL) were added 1 '1 [bis(diphenylphosphino) ferrocene] dichloropalladium(ll) (0.2 eq), Na2C03 (8 eq) and one of the following regents heteroarylboronic acid or heteroaryiboronic acid pinacol ester or heteroarylboronic MIDA ester (2 eq) in a microwave tube. After addition of H20 (1 mL), the tube was sealed and the reaction mixture was stirred at 90C for 16 h. The mixture was allowed to cool to room temperature, was filtered through celite and MgS04 and the filter was repeatedly washed with ethyl acetate. After removing the solvent under reduced pressure, the crude residue was dissolved in saturated aqueous Na2C03 solution. The aqueous layer was extracted three times with CHCI3 and the combined organic layers were washed with saturated, aqueous NaCI solution and dried over Na2S04). The organic solvent was removed under reduced pressure and the residue was purified by preparative HPLC to obtain the appropriate target compound

Reference： [1]Patent: WO2019/110521,2019,A1 .Location in patent: Page/Page column 28; 35

67
[ 653-92-9 ]
[ 41201-58-5 ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 18159 - 18164
Angew. Chem.,2020,vol. 131,p. 18327 - 18332,6

68
[ 653-92-9 ]
[ 925-90-6 ]
methyl 2-ethyl-4-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%		Methyl 2-ethyl-4-fluorobenzoate was prepared according to the general method disclosed in WO 2017/048950. (1363) Zinc bromide (8 g, 35.5 mmol) was dissolved in THF (88 mL) in a 250 mL round bottom flask under nitrogen. Ethylmagnesium bromide (3 M in ether, 11.78 mL, 35.3 mmol) was added dropwise over 10 minutes. A thick slurry formed as the Grignard reagent was added, but the reaction mixture thinned after approximately 1/2 of the reagent was added. The reaction mixture was cooled in a dry ice bath to form a very thick slurry. Pd(dppf) ([1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium(II)) (1.293 g, 1.767 mmol) and <strong>[653-92-9]methyl 2-bromo-4-fluorobenzoate</strong> (4.12 g, 17.67 mmol) were added to the top of the slurry. The cooling bath was removed. As the temperature increased, the reaction was mixed by hand to homogenize it until the stir bar began to stir. The reaction mixture was stirred at room temperature overnight. TLC analysis in 2:1 hexanes:ethyl acetate showed starting material with about 50 % conversion to a higher Rf product. The reaction mixture was heated at reflux for 3 hours. Starting material was shown to be consumed by TLC. The reaction mixture was cooled on an ice bath and 100 mL of saturated ammonium chloride was added. The mixture was partitioned between ethyl acetate and water. The organic portion was concentrated and chromatographed with ethyl acetate and hexanes on an 80 g silica gel column to afford methyl 2-ethyl-4- fluorobenzoate (2.7 g, 14.82 mmol, 84 % yield). 1H NMR (400 MHz, chloroform-d) d 7.93 (dd, J=8.8, 6.1 Hz, 1H), 7.00 (dd, J=9.9, 2.6 Hz, 1H), 6.94 (td, J=8.3, 2.7 Hz, 1H), 3.91 (s, 3H), 3.03 (q, J=7.3 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H).

Reference： [1]Patent: WO2020/6018,2020,A1 .Location in patent: Page/Page column 340; 341

69
[ 653-92-9 ]
1-((4′-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1′-biphenyl]-2-yl)methyl) piperazine dihydrochloride [ No CAS ]
[ 1228780-55-9 ]

Reference： [1]Patent: WO2020/41406,2020,A1 .Location in patent: Page/Page column 193

70
1-(1,1-dimethylethoxycarbonyl)piperazine hydrochloride [ No CAS ]
[ 653-92-9 ]
tert-butyl 4-(3-bromo-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 130℃; for 36h;	To a solution of methyl 2-bromo-4-fluoro-benzoate (90 g, 386.21 mmol, 1 eq) in dimethylsulfoxide (500 mL) was added tert-butyl piperazine-1-carboxylate (111.82 g, 502.07 mmol, 1.3 eq, hydrochloric salt) and N,N-diisopropylethylamine (199.66 g, 1.54 mol, 269 mL, 4 eq). The mixture was heated to 130 C and stirred at 130 C for 36 hours. The mixture was poured into 1.0 L water, and extracted with ethyl acetate (500 mL x 2). The organic layer was washed with water (1000 mL), 0.5 M hydrochloric acid (500 mL), saturated brine (500 mL) and then dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was triturated with (petroleum ether : ethyl acetate =5:1, 300 mL), the solid was filtered and dried in vacuum. tert-butyl 4-(3-bromo-4-methoxycarbonyl-phenyl)piperazine-1-carboxylate (93 g, 232.92 mmol, 60% yield) was obtained as an off-white solid. LC/MS (ESI) m/z: 422.1 [M+23] +; 1H-NMR (400MHz, DMSO-d6) d 7.73 (d, J=8.8 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 6.98 (dd, J=8.8, 2.4 Hz, 1H), 3.77 (s, 3H), 3.45-3.42 (m, 4H), 3.34-3.31 (m, 4H), 1.42 (s, 9H).

Reference： [1]Patent: WO2020/51564,2020,A1 .Location in patent: Paragraph 1779; 1780

71
[ 653-92-9 ]
[ 98-80-6 ]
[ 724-10-7 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrakis-(triphenylphosphine)-palladium; potassium carbonate In tetrahydrofuran; lithium hydroxide monohydrate at 80℃; Inert atmosphere;	General Procedure for the Preparation of 2-Phenylbenzoic Acids (Precursors to 1g or 1h) General procedure: Based on a modified literature procedure,25 a round bottom flask was charged with methyl 2-bromobenzoate (10mmol), phenylboronic acid (1.3 g, 11mmol), Pd(PPh3)4 (60 mg, 0.05mmol), K2CO3 (3.9 g, 2.8 mmol) in THF (12.5 mL) and H2O (12.5 mL) under nitrogen atmosphere. The mixture was stirred at 80 °C overnight. The resulting reaction mixture was cooled to room temperature before H2O was added, and the mixture was extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4, and the filtrate was evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (hexane/EtOAc) to give the corresponding methyl 2-phenylbenzoate as a colorless liquid. Next, to a solution of the methyl 2-phenylbenzoate (7mmol) in MeOH (28 mL), 1M NaOH in H2O (28 mL) was added slowly. The resultant mixture was stirred at 50 °C overnight. The mixture was then acidified using an aqueous solution of HCl (1 M) and extracted with CH2Cl2. The combined organic layer was dried over anhydrous Na2SO4, and the filtrate was evaporated under reduced pressure. The crude material was purified by recrystallization from hexane/EtOAc to afford the desired 2-phenylas a white solid.
	With palladium (II) [1,1'-bis(diphenylphosphanyl)ferrocene] dichloride; potassium carbonate In 1,4-dioxane; lithium hydroxide monohydrate at 100℃; for 16h; Inert atmosphere;	18 Reference Example 18: Preparation of Intermediate I-18 At room temperature, methyl 2-bromo-4-fluorobenzoate (500 mg, 2.14 mmol), phenylboronic acid (288 mg, 2.36 mmol), 1,1'-bisdiphenylphosphinoferrocene palladium dichloride ( 156 mg, 0.21 mmol) and potassium carbonate (886 mg, 6.42 mmol) were mixed in 1,4-dioxane/water (10 mL/1 mL), and the reaction solution was stirred at 100 °C for 16 hours under nitrogen protection. The reaction system was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (30 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product. The crude product was isolated and purified by silica gel chromatography to give intermediate I-18.

Reference： [1]Hayakawa, Kazuki; Ikai, Kana; Ogiwara, Yohei; Sakai, Norio; Sakurai, Yuka [Bulletin of the Chemical Society of Japan, 2021, vol. 94, # 7, p. 1882 - 1893]
[2]Current Patent Assignee: SHANGHAI LUBRIGHT MEDICINE TECH; JIANGXI JIANGMAN TRUSTED GROUP LTD; SHANGHAI JEMINCARE PHARMACEUTICAL CO LTD; JIANGXI JEMINCARE GROUP CO LTD - WO2022/135335, 2022, A1 Location in patent: Page/Page column 13

72
[ 653-92-9 ]
[ 1421312-35-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: potassium carbonate / dimethyl sulfoxide / 110 °C / Inert atmosphere; Large scale 2.1: potassium hydroxide / water / 1.5 h / 80 °C / Inert atmosphere; Large scale 3.1: 1,1'-carbonyldiimidazole / acetonitrile / 4 h / 20 °C / Inert atmosphere; Large scale 3.2: 6 h / Inert atmosphere; Large scale 4.1: palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 120 °C / Inert atmosphere; Large scale 5.1: hydrogenchloride / water; ethanol / 12 h / 60 °C / Large scale 6.1: sodium hydroxide / ethanol / 80 °C
	Multi-step reaction with 6 steps 1.1: potassium carbonate / dimethyl sulfoxide / 110 °C / Inert atmosphere; Large scale 2.1: potassium hydroxide / water / 1.5 h / 80 °C / Inert atmosphere; Large scale 3.1: 1,1'-carbonyldiimidazole / acetonitrile / 4 h / 20 °C / Inert atmosphere; Large scale 3.2: 6 h / Inert atmosphere; Large scale 4.1: palladium diacetate; bis[2-(diphenylphosphino)phenyl] ether; N-ethyl-N,N-diisopropylamine / tetrahydrofuran; ethylene glycol / 18 h / 90 °C / Inert atmosphere 5.1: hydrogenchloride / water; ethanol / 12 h / 60 °C / Large scale 6.1: sodium hydroxide / ethanol / 80 °C
	Multi-step reaction with 6 steps 1.1: potassium carbonate / dimethyl sulfoxide / 110 °C / Inert atmosphere; Large scale 2.1: potassium hydroxide / water / 1.5 h / 80 °C / Inert atmosphere; Large scale 3.1: 1,1'-carbonyldiimidazole / acetonitrile / 4 h / 20 °C / Inert atmosphere; Large scale 3.2: 6 h / Inert atmosphere; Large scale 4.1: palladium diacetate; N-ethyl-N,N-diisopropylamine; 1,4-di(diphenylphosphino)-butane / tetrahydrofuran; ethylene glycol / 18 h / 90 °C / Inert atmosphere 5.1: hydrogenchloride / water; ethanol / 12 h / 60 °C / Large scale 6.1: sodium hydroxide / ethanol / 80 °C

Reference： [1]Píša, Ondřej; Rádl, Stanislav; Čerňa, Igor; Šembera, Filip [Organic Process Research and Development, 2022, vol. 26, # 3, p. 915 - 924]
[2]Píša, Ondřej; Rádl, Stanislav; Čerňa, Igor; Šembera, Filip [Organic Process Research and Development, 2022, vol. 26, # 3, p. 915 - 924]
[3]Píša, Ondřej; Rádl, Stanislav; Čerňa, Igor; Šembera, Filip [Organic Process Research and Development, 2022, vol. 26, # 3, p. 915 - 924]

73
[ 653-92-9 ]
[ 188646-83-5 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
79%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 120℃; for 2h;	A Step A: methyl 2-bromo-4-[4-(dimethoxymethyl)-1-piperidyl]benzoate To a solution of 4-(dimethoxymethyl)piperidine (44.41 g, 278.9 mmol) and methyl 2-bromo-4- fluoro-benzoate (50.0 g, 214.6 mmol) in dimethyl sulfoxide (500 mL) was added N,N- diisopropylethylamine (55.46 g, 429.1 mmol). The reaction was stirred at 120 °C for 2 h. The mixture was diluted with water (1500 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic fractions were washed with saturated aqueous sodium chloride (3 x 1000 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was triturated with 1:20 ethyl acetate:petroleum ether (200 mL) to afford methyl 2-bromo-4-[4-(dimethoxymethyl)-1- piperidyl]benzoate (64 g, 79%) as a light yellow solid.
79%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 120℃; for 2h;	A Step A: methyl 2-bromo-4-[4-(dimethoxymethyl)-1-piperidyl]benzoate To a solution of 4-(dimethoxymethyl)piperidine (44.41 g, 278.9 mmol) and methyl 2-bromo-4- fluoro-benzoate (50.0 g, 214.6 mmol) in dimethyl sulfoxide (500 mL) was added N,N- diisopropylethylamine (55.46 g, 429.1 mmol). The reaction was stirred at 120 °C for 2 h. The mixture was diluted with water (1500 mL) and extracted with ethyl acetate (3 x 500 mL). The combined organic fractions were washed with saturated aqueous sodium chloride (3 x 1000 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was triturated with 1:20 ethyl acetate:petroleum ether (200 mL) to afford methyl 2-bromo-4-[4-(dimethoxymethyl)-1- piperidyl]benzoate (64 g, 79%) as a light yellow solid.

Reference： [1]Current Patent Assignee: ARVINAS - WO2022/47145, 2022, A1 Location in patent: Paragraph 00286
[2]Current Patent Assignee: ARVINAS - WO2022/47145, 2022, A1 Location in patent: Paragraph 00286

74
[ 653-92-9 ]
[ 1392211-51-6 ]
[ 2794948-32-4 ]

Yield	Reaction Conditions	Operation in experiment
46.5%	With Cs₂CO₃ In N,N-dimethyl-formamide at 80℃; for 8h;	18; 4-8; 12-25; 27-29; 31-35 Synthesis of methyl 2-bromo-4-{2-oxo-7-azaspiro[3.5]nonan-7-yl}benzoate: Into a 500 mL 3- necked round-botom flask were added 7-azaspiro[3.5]nonan-2-one hydrochloride (7.3 g, 41.6 mmol, 1.0 eq), DMF (100 mL), CS2CO3 (33.8 g, 103.9 mmol, 2.5 eq) and methyl 2-bromo-4-fluorobenzoate (10.5 g, 45.1 mmol, 1 .1 eq) at 25°C. The resulting mixture was stirred for 8 hours at 80°C. The mixture was allowed to cool down to 25°C. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with Ethyl acetate (3x200 mL). The combined organic layers were washed with brine (1 x300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was purified by a flash column (silica gel, ethyl acetate/petroleum ether=1 :2) to afford methyl 2-bromo-4-{2-oxo-7- azaspiro[3.5]nonan-7-yl}benzoate (6.8 g, 46.5%) as light yellow solid. LC-MS (ES, m/z) M+1 : 352/354. 1HNMR (300 MHz, DMSO-cfc) 5 7.73 (d, J=8.9 Hz, 1 H), 7.19 (d, J=2.5 Hz, 1 H), 6.99 (ddt, J=9.0, 2.6, 1.3 Hz, 1 H), 3.77 (s, 3H), 3.40-3.33 (m, 4H), 2.85 (s, 4H), 1.78-1.71 (m, 4H).
46.5%	With Cs₂CO₃ In N,N-dimethyl-formamide at 80℃; for 8h;	18; 4-8; 12-25; 27-29; 31-35 Synthesis of methyl 2-bromo-4-{2-oxo-7-azaspiro[3.5]nonan-7-yl}benzoate: Into a 500 mL 3- necked round-botom flask were added 7-azaspiro[3.5]nonan-2-one hydrochloride (7.3 g, 41.6 mmol, 1.0 eq), DMF (100 mL), CS2CO3 (33.8 g, 103.9 mmol, 2.5 eq) and methyl 2-bromo-4-fluorobenzoate (10.5 g, 45.1 mmol, 1 .1 eq) at 25°C. The resulting mixture was stirred for 8 hours at 80°C. The mixture was allowed to cool down to 25°C. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with Ethyl acetate (3x200 mL). The combined organic layers were washed with brine (1 x300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude residue was purified by a flash column (silica gel, ethyl acetate/petroleum ether=1 :2) to afford methyl 2-bromo-4-{2-oxo-7- azaspiro[3.5]nonan-7-yl}benzoate (6.8 g, 46.5%) as light yellow solid. LC-MS (ES, m/z) M+1 : 352/354. 1HNMR (300 MHz, DMSO-cfc) 5 7.73 (d, J=8.9 Hz, 1 H), 7.19 (d, J=2.5 Hz, 1 H), 6.99 (ddt, J=9.0, 2.6, 1.3 Hz, 1 H), 3.77 (s, 3H), 3.40-3.33 (m, 4H), 2.85 (s, 4H), 1.78-1.71 (m, 4H).

Reference： [1]Current Patent Assignee: GUANGZHOU LUPENG PHARMACEUTICAL COMPANY LTD; NEWAVE PHARMACEUTICAL INC - WO2022/140224, 2022, A1 Location in patent: Page/Page column 203-204; 237; 239; 241; 245; 248-249; 252-253; ...
[2]Current Patent Assignee: GUANGZHOU LUPENG PHARMACEUTICAL COMPANY LTD; NEWAVE PHARMACEUTICAL INC - WO2022/140224, 2022, A1 Location in patent: Page/Page column 203-204; 237; 239; 241; 245; 248-249; 252-253; ...

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

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