[ CAS No. 176548-70-2 ]

Name: 176548-70-2|3-Bromo-5-fluorobenzoic acid|98%
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Quality Control of [ 176548-70-2 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 176548-70-2 ]

CAS No. :	176548-70-2	MDL No. :	MFCD01569540
Formula :	C₇H₄BrFO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KLSLJMGWUPAQGZ-UHFFFAOYSA-N
M.W :	219.01	Pubchem ID :	2773339
Synonyms :

Calculated chemistry of [ 176548-70-2 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	41.06
TPSA :	37.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.96 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.54
Log Po/w (XLOGP3) :	2.36
Log Po/w (WLOGP) :	2.71
Log Po/w (MLOGP) :	2.79
Log Po/w (SILICOS-IT) :	2.32
Consensus Log Po/w :	2.34

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-3.02
Solubility :	0.208 mg/ml ; 0.00095 mol/l
Class :	Soluble
Log S (Ali) :	-2.78
Solubility :	0.361 mg/ml ; 0.00165 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.91
Solubility :	0.269 mg/ml ; 0.00123 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.4

Safety of [ 176548-70-2 ]

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 [ 176548-70-2 ]

* 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 [ 176548-70-2 ]
Downstream synthetic route of [ 176548-70-2 ]

[ 176548-70-2 ] Synthesis Path-Upstream 1~13

1
[ 176548-70-2 ]
[ 179898-34-1 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 11, p. 3243 - 3247

2
[ 179898-34-1 ]
[ 176548-70-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	for 2 h; Reflux	A mixture of 3-bromo-5-fluorobenzonitrile (2.8 g, 13.8 mmol) and aqueous sodium hydroxide (5 M, 28 mL) was heated to reflux for 2 h. After cooling to room temperature, pH was adjusted to 1 by the addition of concentrated hydrochloric acid. The formed precipitate was collected by filtration, the solid was washed with cold water and dried to afford the title compound (2.8 g, 94percent). ¹H NMR (400 MHz, CD₃OD) d ppm 6.31 (dt, J=8.08, 2.02 Hz, 1 H), 6.37 - 6.43 (m, 1 H), 6.68 (s, 1 H).

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6974 - 6979,6

3
[ 124-38-9 ]
[ 1435-51-4 ]
[ 176548-70-2 ]

Reference： [1] European Journal of Organic Chemistry, 2005, # 24, p. 5242 - 5247
[2] Patent: US6586633, 2003, B1,

4
[ 872545-52-3 ]
[ 176548-70-2 ]

Reference： [1] European Journal of Organic Chemistry, 2005, # 24, p. 5242 - 5247

5
[ 1073-06-9 ]
[ 176548-70-2 ]

Reference： [1] European Journal of Organic Chemistry, 2005, # 24, p. 5242 - 5247

6
[ 1435-51-4 ]
[ 176548-70-2 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6974 - 6979,6

7
[ 176548-70-2 ]
[ 18107-18-1 ]
[ 334792-52-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	Stage #1: for 1 h; Stage #2: With acetic acid In methanol; diethyl ether; dichloromethane	To a solution of 3-bromo-5-fluorobenzoic acid (2 g, 9.13 mmol) in DCM/ MeOH (20 ml/ 5 ml) is added trimethylsilyldiazomethane (2M solution in ether; 1 eq, 9.13 mmol) and the mixture is stirred for 1 h. Acetic acid was added dropwise until the yellow colour disappeared. The solvents are then removed in vacuo. The residue is dissolved in DCM and washed with K₂CO₃. The organic phase is dried (MgSO₄) and concentrated in vacuo to give the title compound (1.5 g, 71 percent) LC/MS: 91percent MH⁺, m/z not ionised, Rt = 1.55 mins.
21%	at 20℃; for 0.5 h;	Commercially available 3-bromo-5-fmorobenzoic acid (1.Og, 4.57 mmol) was dissolved in methylene chloride (20 mL) trimethylsilyl diazomethane (2M solution in hexane) (5 mL, 10 mmol) was added and the reaction mixture was stirred for 30 min. at room temperature. The reaction mixture was concentrated and purified by silica gel chromatography (hexane/methylene chloride 2:1) to yield A101.1 (229mg, 21percent).

Reference： [1] Patent: EP1655283, 2006, A1, . Location in patent: Page/Page column 16-17
[2] Patent: WO2006/122137, 2006, A1, . Location in patent: Page/Page column 124-125

8
[ 176548-70-2 ]
[ 144-55-8 ]
[ 334792-52-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sulfuric acid In methanol; diethyl ether	Intermediate 25: Methyl 3-bromo-5-fluorobenzoate Methanol (30 ml) was added to 3-bromo-5-fluorobenzoic acid (3.1 g, 14 mmol) to prepare a solution. Concentrated sulfuric acid (3.0 ml) was added to the solution, and the mixture was heated under reflux for 1.5 hr. The temperature of the reaction mixture was returned to room temperature, and the reaction mixture was slowly poured into 400 ml of a saturated aqueous sodium hydrogencarbonate solution, followed by extraction twice with 250 ml of diethyl ether. The combined organic layers were dried over anhydrous magnesium sulfate and were concentrated under the reduced pressure to give the title compound (2.6 g, 80percent). Physicochemical properties of intermediate 25

Reference： [1] Patent: EP1229024, 2002, A1,

9
[ 176548-70-2 ]
[ 67-56-1 ]
[ 334792-52-8 ]

Yield	Reaction Conditions	Operation in experiment
10 g	at 0 - 60℃; for 2 h;	Step 1: Preparation of methyl 3-bromo-5-fluoro-benzoate To a solution of 3-bromo-5-fluorobenzoic acid (10.0 g, 45.7 mmol) in MeOH (100 mL) was added SOCl₂ (6.6 mL, 91.3 mmol) at 0 ^oC. The reaction mixture was heated to 60 ^oC and stirred for 2 hrs. The reaction mixture was concentrated in vacuo and the residue was diluted with DCM (250 mL). The resulting mixture was washed with a saturated aqueous solution of NaHCO₃ (100 mL), H₂O (100 mL) and brine (100 mL) successively, then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography to afford methyl 3-bromo-5-fluoro-benzoate (10.0 g) as colorless oil.

Reference： [1] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 5, p. 508 - 513
[2] Patent: WO2016/177655, 2016, A1, . Location in patent: Page/Page column 235; 236

10
[ 176548-70-2 ]
[ 334792-52-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 22, p. 6974 - 6979,6

11
[ 176548-70-2 ]
[ 216755-57-6 ]

Reference： [1] Patent: US2011/34450, 2011, A1,
[2] Patent: US2012/172448, 2012, A1,
[3] Patent: WO2016/54728, 2016, A1,
[4] Patent: WO2016/74068, 2016, A1,
[5] Patent: CN104447730, 2017, B,

12
[ 176548-70-2 ]
[ 105515-20-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: With methyllithium In diethyl ether at -78 - -10℃; Stage #2: With ammonium chloride In diethyl ether	1-(3-Bromo-5-fluorophenyl)-ethanone Methyllithium (1.3 M in diethyl ether, 35 mL) was added dropwise to 3-bromo-5-fluorobenzoic acid (5 g) in diethyl ether at -78° C. keeping the temperature below -60° C. The reaction was then left to warm to -10° C. and was stirred for 1 h before being carefully quenched with saturated ammonium chloride (100 mL) until pH=3. The product was extracted with diethyl ether (2*100 mL), dried over sodium sulfate and the solvent removed by evaporation to yield 1-(3-bromo-5-fluorophenyl)ethanone as an off-white solid (4.67 g, 94percent). ¹H NMR (CDCl₃): 2.59 (3H, s, ArCOCH₃), 7.44 (1H, dd, Ar), 7.59 (1H, dd, Ar), 7.87 (1H, s, Ar).

Reference： [1] Patent: US2009/209529, 2009, A1, . Location in patent: Page/Page column 35

13
[ 176548-70-2 ]
[ 216755-56-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: With borane-THF In tetrahydrofuran at 0 - 20℃; Stage #2: With methanol In tetrahydrofuran at 0℃;	(3-Bromo-5-fluorophenyl)methanol. 3-Bromo-5-fluorobenzoic acid (1.0 g, 4.52 mmol) was suspended in tetrahydrofuran (8 mL) and cooled to 0° C. To this solution was added borane tetrahydrofuran complex (1 M in tetrahydrofuran, 9 mL, 9.0 mmol) cautiously over 15 min. The reaction mixture was allowed to warm to room temperature overnight. The mixture was cooled to 0° C., treated with excess methanol, diluted with ethyl acetate, washed with 1 N sodium hydroxide (2.x.), then brine (2.x.), dried over sodium sulfate, and concentrated to afford 0.88 g (95percent) as a white powder. ¹H-NMR (CDCl_3,500 MHz) 7.29 (s, 1H), 7.16 (d, J=7.9 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H), 4.66 (s, 2H).
95%	With borane-THF In tetrahydrofuran at 0 - 20℃;	To a solution of 3-bromo-5-fluorobenzoic acid (4.38 g, 20.0 mmol) Of tetrahydrofuran(20 mL)A solution of 1M borane tetrahydrofuran complex in tetrahydrofuran (30 mL,30. Ommol).Continue stirring at 0 ° C for 1.5 hours,Then stirred at room temperature overnight. Methanol was slowly added to it at room temperature until no gas had escaped to quench. The solvent was evaporated under reduced pressureThe crude product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 10/1), A pale yellow liquid (3.9 g, 95percent)
67%	With borane-THF In tetrahydrofuran at 0 - 20℃; for 23.3667 h; Inert atmosphere	[00127] A solution of 3-bromo-5-fluorobenzoic acid (2.74 g, 12.5 mmol) in tetrahydrofuran (6 mL), at 0°C under nitrogen, was treated with borane-tetrahydrofuran complex (1M, 15 mL, 15 mmol) in small portions over 12 mm, and the reaction was then stirred at 0°C for 70 minutes, and at room temperature for 22 h. The reaction was quenched by addition of methanol (10 mL), and the methanolic mixture was stirred at room temperature for 3 h, and then evaporated in vacuo, with co-evaporation from methanol, then from ethyl acetate, to give the crude product. The material was dissolved in ethyl acetate (200 mL), and the solution was washed with 0.5M aqueous sodium hydroxide (200 mL), and with saturated aqueous sodium chloride (100 mL); then dried over sodium sulfate; filtered and evaporated in vacuo to give 3-bromo-5-fluorobenzyl alcohol (1.79 g, 67percent). 1H NMR (400 MHz, CDCI3): ö 7.29 (s, IH), 7.15 (ddd, JHF = 8.2 Hz, JHH = 2.2, 1.8 Hz, 1H), 7.00-7.02 and 7.02-7.04 (dm, JHF = 9.2 Hz, JHH = unresolved, 1H), 4.66 (s, 2H), 2.04 (br s, 1 H); 19F NMR (377 MHz, CDCI3): -111.05 (dd, JHF = 9.3, 8.0 Hz, 1 F); 13C NMR (101 MHz, CDCI3):162.87 (d, JCF 250.6 Hz), 145.42 (d, JCF = 6.9 Hz), 125.45 (d, JCF = 3.1 Hz), 122.69 (d, JCF = 9.2 Hz), 118.01 (d, JCF = 24.6 Hz), 112.51 (d, JCF = 21.5 Hz), 63.60 (d, JCF = 2.3 Hz).

67%

With borane-THF In tetrahydrofuran at 0 - 20℃; for 23.4 h; Inert atmosphere

A solution of 3-bromo-5-fluorobenzoic acid (2.74 g, 12.5 mmol) in tetrahydrofuran (6 mL), at 0°C under nitrogen, was treated with borane-tetrahydrofuran complex (1 M, 15 mL, 15 mmol) in small portions over 12 min, and the reaction was then stirred at 0°C for 70 minutes, and at room temperature for 22 h. The reaction was quenched by addition of methanol (10 mL), and the methanolic mixture was stirred at room temperature for 3 h, and then evaporated in vacuo, with co-evaporation from methanol, then from ethyl acetate, to give the crude product. The material was dissolved in ethyl acetate (200 mL), and the solution was washed with 0.5M aqueous sodium hydroxide (200 mL), and with saturated aqueous sodium chloride (100 mL); then dried over sodium sulfate; filtered and evaporated in vacuo to give 3-bromo-5- fluorobenzyl alcohol (1.79 g, 67percent). ¹H NMR (400 MHz, CDCI₃): δ 7.29 (s, 1 H), 7.15 (ddd, JHF = 8.2 Hz, JHH = 2.2, 1.8 Hz, 1 H), 7.00-7.02 and 7.02-7.04 (dm, JHF = 9.2 Hz, JHH = unresolved, 1 H), 4.66 (s, 2H), 2.04 (br s, 1 H); ¹⁹F NMR (377 MHz, CDCI₃): δ -111.05 (dd, JHF = 9.3, 8.0 Hz, 1 F); ¹³C NMR (101 MHz, CDCI3): δ 162.87 (d, J_CF = 250.6 Hz), 145.42 (d, JCF = 6.9 Hz), 125.45 (d, JCF = 3.1 Hz), 122.69 (d, J_CF = 9.2 Hz), 118.01 (d, J_CF = 24.6 Hz), 112.51 (d, J_CF = 21.5 Hz),

Reference： [1] Patent: US2007/249607, 2007, A1, . Location in patent: Page/Page column 81
[2] Patent: CN104447730, 2017, B, . Location in patent: Paragraph 0146-0147
[3] Patent: WO2016/54728, 2016, A1, . Location in patent: Paragraph 00127
[4] Patent: WO2016/74068, 2016, A1, . Location in patent: Paragraph 00121
[5] Patent: WO2006/79791, 2006, A1, . Location in patent: Page/Page column 44
[6] Patent: US6586633, 2003, B1,
[7] Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 6, p. 1864 - 1868
[8] Patent: US2011/34450, 2011, A1, . Location in patent: Page/Page column 96
[9] Patent: US2012/172448, 2012, A1, . Location in patent: Page/Page column 19
[10] Patent: US9242996, 2016, B2, . Location in patent: Page/Page column 271; 272

[ 176548-70-2 ] Synthesis Path-Downstream 1~68

1
[ 124-38-9 ]
[ 1435-51-4 ]
[ 176548-70-2 ]

Yield	Reaction Conditions	Operation in experiment
55.4%	With iodine; magnesium;	Referential Example 15 Production of 3-Bromo-5-fluorobenzoic Acid Magnesium turnings (1.97 g) and iodine (catalytic amount) were added to ether (150 ml), and 1,3-dibromo-5-fluorobenzene (19.6 g) in ether (20 ml) was added dropwise under nitrogen atmosphere at such a rate that gentle reflux occurred. The mixture was refluxed for 3 hours, and left to cool. Crushed dry ice was added thereto, and the mixture was stirred for 1 hour. The reaction mixture was poured into water, and acidified with hydrochloric acid. The mixture was extracted with ether (200 ml), and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform?chloroform:methanol=100:1), to thereby yield 9.37 g of the target compound (yield: 55.4%). 1H-NMR (CDCl3, ppm); 7.51 (1H, dt, J=7.83 Hz, 2.30 Hz), 7.74 (1H, d dd, J=8.91 Hz, 2.30 Hz, 1.35 Hz), 8.06 (1H, brs).

Reference： [1]European Journal of Organic Chemistry,2005,p. 5242 - 5247
[2]Patent: US6586633,2003,B1

2
[ 176548-70-2 ]
[ 3644-18-6 ]
[ 1000067-93-5 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 20℃;	40 mg (0.18 mmol) of <strong>[176548-70-2]3-bromo-5-fluoro benzoic acid</strong> was dissolved in 2 niL DMF and 29 mg (0.22 mmol) of l-[2-(Dimethylamino)ethyl]piperazine, 88 mg (0.27 mmol) TBTU and 22 mg (0.22 mmol) of TEA were added. The mixture was stirred at room temperature overnight, then concentrated and purified with preparative HPLC giving 2-[4-(3-bromo-5-fluorobenzoyl)piperazin-l-yl]- N,N-dimethylethanamine as a yellow gum in an amount of 85 mg.21 mg (0.062 mmol) of 2-[4-(3-bromo-5-fluorobenzoyl)piperazin-l-yl]-N,N- dimethylethanamine, 22 mg (0.1 mmol) of bis(neopentyl glycolato) diboron, 30 mg (0.30 mmol) of KOAc and 4 mg of PdCl2 were heated at 125C for 900 s in microwave. To the same microwave tube were then 15 mg (0.06 mmol) of 2-(6- chloropyrazin-2-yl)-5-fluoro-lH-indole, 4 mg (0.12 mmol) of NaHCtheta3 and 4 mg of Pd(tetrakis) added. The mixture was heated at 1200C for 700 s then filtrated through celite. Finally purification using preparative HPLC giving the product as a light brown gum in an amount of 0.9 mg (yield 3%).HPLC (system A) 94 %, RT 1.874 min (10-97 % MeCN over 3 min) HPLC (system B) 98 %, RT 1.748 min (10-97 % MeCN over 3 min) MS (ESI+) for C2TH28F2N6O m/z 491(M+H+)

Reference： [1]Patent: WO2007/147874,2007,A1 .Location in patent: Page/Page column 65-66

3
[ 176548-70-2 ]
[ 64021-83-6 ]
[ 1000067-94-6 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 20℃;	40 mg (0.18 mmol) of <strong>[176548-70-2]3-bromo-5-fluoro benzoic acid</strong> was dissolved in 2 rnL DMF and 21 mg (0.22 mmol) of N,N'-Dimethyl-3-aminopyrrolidine, 88 mg <n="68"/>(0.27 mmol) TBTU and 22 mg (0.22 mmol) of TEA were added. The mixture was stirred at room temperature overnight, then concentrated and purified with preparative HPLC giving 3-bromo-5-fluoro-N-methyl-N-(l- methylpyrrolidin-3-yl)benzamide as a yellow gum in an amount of 81 mg.20 mg (0.063 mmol) of 4-bromo-3-fluoro-N-methyl-N-(l-methylpyrrolidin-3- yl)benzamide, 22 mg (0.1 mmol) of bis(neopentyl glycolato) diboron, 30 mg (0.30 mmol) of KOAc and 4 mg of PdCl2 were heated at 125C for 900 s in microwave. To the same microwave tube were then 15 mg (0.06 mmol) of 2-(6- chloropyrazin-2-yl)-5-fluoro-lH-indole, 4 mg (0.12 mmol) of NaHCO3 and 4 mg of Pd(tetrakis) added. The mixture was heated at 1200C for 700 s then filtrated through celite. Finally purification using preparative HPLC giving the product as a brown gum in an amount of 2.2 mg (yield 8%).HPLC (system A) 95 %, RT 1.997 min (10-97 % MeCN over 3 min) HPLC (system B) 97 %, RT 1.885 min (10-97 % MeCN over 3 min) MS (ESI+) for C25H23F2N5O m/z 448(M+H+)

Reference： [1]Patent: WO2007/147874,2007,A1 .Location in patent: Page/Page column 66-67

4
[ 872545-52-3 ]
[ 176548-70-2 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 5242 - 5247

5
[ 1073-06-9 ]
[ 176548-70-2 ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 5242 - 5247

6
[ 176548-70-2 ]
[ 64-17-5 ]
[ 353743-43-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sulfuric acid; at 20℃; for 16h;Reflux;	Step 1: To a solution of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (2.00 g, 9.13 mmol) in absolute EtOH (20 mL) was added conc. H2504 (2 mL) at 20-25 C. The resulting reaction mixture was heated under reflux for 16 hours. The mixture was concentrated and the residue was diluted with EtOAc (100 mL). Then the mixture was washed with saturated aqueous NaHCO3 (50 mL), brine (50 mL), dried over anhydrous Na2504 and concentrated to give ethyl 3-bromo-5-fluorobenzoate (2.10 g, yield: 91%) as a yellow oil.
84%	With sulfuric acid;Reflux;	Reference Example 61; Ethyl 3-bromo-5-fluorobenzoate; An ethanol (40 mL) solution of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (2.00 g, 9.13 mmol) and concentrated sulfuric acid(2.0 ml) was heated to reflux over night. Water was poured into the reaction solution, and the product was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off at reduced pressure to give 1.89 g of the titled compound (yield: 84%) in the form of an oily substance. 1H-NMR (CDCl3 ) delta: 1.40 (3H, t, J = 7.2 Hz), 4.39 (2H, q, J = 7.2 Hz), 7.40 - 7.47 (1H, m), 7.64 - 7.70 (1H, m), 7.96 - 8.00 (1H, m).
84%	With sulfuric acid; at 85℃;	A mixture of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (2 g, 9.13 mmol, 1.00 equiv), ethanol (40 mL), and sulfuric acid (3 mL) was stirred overnight at 85C in an oil bath. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in the title compound (1.9 g, 84%) as a light brown solid.

	sulfuric acid; at 90℃; for 17h;Heating / reflux;	<strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> ethyl ester Sulphuric acid (5 drops) was added to <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (1. 194g, 5. 45mmol) in ethanol (10ml) and refluxed with stirring at 90 C for 17 hours. Reaction mixture partitioned between diethyl ether and water, washed with sodium hydrogen carbonate, dried (MgSO4) and evaporated to dryness. 'H NMR (CDC13) b : 1.40 (3H, t, J=7. 2Hz), 4.39 (2H, q, J=7. 1Hz), 7.42-7. 45 (1 H, m), 7.66- 7.69 (1 H, m), 7.98 (1 H, s).
	With sulfuric acid; for 17h;Heating / reflux;	Sulphuric acid (0.5 mL) was added to a stirring solution of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (473 mgs, 2.16 MMOL) in ethanol (10 mL) and refluxed for 17 hours. The reaction mixture was cooled to room temperature and diluted with diethyl ether and water. The ether layer was washed with 5% sodium hydrogen carbonate solution, dried over magnesium sulphate and evaporated to dryness to give the title compound as a brown oil. (506 mg). 1H NMR (CDCl3) delta: 1.40 (3H, t, J=7Hz), 4.39 (2H, q, J=7Hz), 7.43 (1H, td, J=2Hz, J=8Hz), 7.67 (1H, dd, J=2Hz, J=8Hz), 7.98 (1H, s).

Reference： [1]Patent: WO2014/186704,2014,A2 .Location in patent: Paragraph 00317
[2]Patent: EP2253618,2010,A1 .Location in patent: Page/Page column 48
[3]Patent: WO2015/52264,2015,A1 .Location in patent: Paragraph 01499; 01500
[4]Patent: WO2003/84917,2003,A1 .Location in patent: Page/Page column 102-103
[5]Patent: WO2004/39753,2004,A2 .Location in patent: Page 60

7
[ 176548-70-2 ]
[ 191337-05-0 ]
3-bromo-N-{4-((7-chloroquinolin-4-yl)amino)cyclohexyl}-5-fluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane;	A mixture of 23A cis-N,N'-bis(7-chloroquinolin-4-yl)cyclohexane-1,4-diamine (500 mg, 3.6 mmol), <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (600 mg, 5.4 mmol), 1-hydroxybenzotriazole (245 mg, 3.6 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(348 mg, 3.6 mmol) in 30 mL dichloromethane was stirred for 3 hours. The reaction was incomplete. <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (160 mg, 0.9 mmol), 1-hydroxybenzotriazole (61 mg, 0.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (87 mg, 0.9 mmol) was added and the solution was allowed to stir overnight. The solution was then washed with 1N NaOH, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (10% methanol in dichloromethane) to provide 700 mg of pure compound, an 81% yield. MS (ESI(+)Q1MS m/z 477 (M+2H)+; 1H NMR (300 MHz, MeOH) delta ppm 8.36-8.42 (m, 3H), 7.95 (t, 1 H), 7.69-7.79 (m, 3H), 7.45 (dd, 1H), 6.83 (d, 1H), 6.54 (d, 1H), 3.95 (m, 1H), 3.68 (m, 1H), 1.66-1.98 (m, 8H).

Reference： [1]Patent: US2003/229119,2003,A1 .Location in patent: Page 60

8
[ 176548-70-2 ]
[ 216755-56-5 ]

Yield	Reaction Conditions	Operation in experiment
95%		(3-Bromo-5-fluorophenyl)methanol. <strong>[176548-70-2]3-Bromo-5-fluorobenzoic acid</strong> (1.0 g, 4.52 mmol) was suspended in tetrahydrofuran (8 mL) and cooled to 0 C. To this solution was added borane tetrahydrofuran complex (1 M in tetrahydrofuran, 9 mL, 9.0 mmol) cautiously over 15 min. The reaction mixture was allowed to warm to room temperature overnight. The mixture was cooled to 0 C., treated with excess methanol, diluted with ethyl acetate, washed with 1 N sodium hydroxide (2×), then brine (2×), dried over sodium sulfate, and concentrated to afford 0.88 g (95%) as a white powder. 1H-NMR (CDCl3, 500 MHz) 7.29 (s, 1H), 7.16 (d, J=7.9 Hz, 1H), 7.03 (d, J=9.2 Hz, 1H), 4.66 (s, 2H).
95%	With borane-THF; In tetrahydrofuran; at 0 - 20℃;	To a solution of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (4.38 g, 20.0 mmol) Of tetrahydrofuran(20 mL)A solution of 1M borane tetrahydrofuran complex in tetrahydrofuran (30 mL,30. Ommol).Continue stirring at 0 C for 1.5 hours,Then stirred at room temperature overnight. Methanol was slowly added to it at room temperature until no gas had escaped to quench. The solvent was evaporated under reduced pressureThe crude product was purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 10/1), A pale yellow liquid (3.9 g, 95%)
67%	With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 23.3667h;Inert atmosphere;	[00127] A solution of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (2.74 g, 12.5 mmol) in tetrahydrofuran (6 mL), at 0C under nitrogen, was treated with borane-tetrahydrofuran complex (1M, 15 mL, 15 mmol) in small portions over 12 mm, and the reaction was then stirred at 0C for 70 minutes, and at room temperature for 22 h. The reaction was quenched by addition of methanol (10 mL), and the methanolic mixture was stirred at room temperature for 3 h, and then evaporated in vacuo, with co-evaporation from methanol, then from ethyl acetate, to give the crude product. The material was dissolved in ethyl acetate (200 mL), and the solution was washed with 0.5M aqueous sodium hydroxide (200 mL), and with saturated aqueous sodium chloride (100 mL); then dried over sodium sulfate; filtered and evaporated in vacuo to give 3-bromo-5-fluorobenzyl alcohol (1.79 g, 67%). 1H NMR (400 MHz, CDCI3): oe 7.29 (s, IH), 7.15 (ddd, JHF = 8.2 Hz, JHH = 2.2, 1.8 Hz, 1H), 7.00-7.02 and 7.02-7.04 (dm, JHF = 9.2 Hz, JHH = unresolved, 1H), 4.66 (s, 2H), 2.04 (br s, 1 H); 19F NMR (377 MHz, CDCI3): -111.05 (dd, JHF = 9.3, 8.0 Hz, 1 F); 13C NMR (101 MHz, CDCI3):162.87 (d, JCF 250.6 Hz), 145.42 (d, JCF = 6.9 Hz), 125.45 (d, JCF = 3.1 Hz), 122.69 (d, JCF = 9.2 Hz), 118.01 (d, JCF = 24.6 Hz), 112.51 (d, JCF = 21.5 Hz), 63.60 (d, JCF = 2.3 Hz).

67%	With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 23.4h;Inert atmosphere;	A solution of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (2.74 g, 12.5 mmol) in tetrahydrofuran (6 mL), at 0C under nitrogen, was treated with borane-tetrahydrofuran complex (1 M, 15 mL, 15 mmol) in small portions over 12 min, and the reaction was then stirred at 0C for 70 minutes, and at room temperature for 22 h. The reaction was quenched by addition of methanol (10 mL), and the methanolic mixture was stirred at room temperature for 3 h, and then evaporated in vacuo, with co-evaporation from methanol, then from ethyl acetate, to give the crude product. The material was dissolved in ethyl acetate (200 mL), and the solution was washed with 0.5M aqueous sodium hydroxide (200 mL), and with saturated aqueous sodium chloride (100 mL); then dried over sodium sulfate; filtered and evaporated in vacuo to give 3-bromo-5- fluorobenzyl alcohol (1.79 g, 67%). 1H NMR (400 MHz, CDCI3): delta 7.29 (s, 1 H), 7.15 (ddd, JHF = 8.2 Hz, JHH = 2.2, 1.8 Hz, 1 H), 7.00-7.02 and 7.02-7.04 (dm, JHF = 9.2 Hz, JHH = unresolved, 1 H), 4.66 (s, 2H), 2.04 (br s, 1 H); 19F NMR (377 MHz, CDCI3): delta -111.05 (dd, JHF = 9.3, 8.0 Hz, 1 F); 13C NMR (101 MHz, CDCI3): delta 162.87 (d, JCF = 250.6 Hz), 145.42 (d, JCF = 6.9 Hz), 125.45 (d, JCF = 3.1 Hz), 122.69 (d, JCF = 9.2 Hz), 118.01 (d, JCF = 24.6 Hz), 112.51 (d, JCF = 21.5 Hz),
	With borane; In tetrahydrofuran; at 0 - 25℃; for 12.5h;	Method 42; (3-Bromo-5-fluorophenyl)methanol ?>A solution of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (1.14 g, 5.21 mmol) in THF (10 ml) was treated with BH3 (1.0 M in THF, 8.0 ml, 8.0 mmol, 1.5 equiv) dropwise under Ar at 0 C. The mixture was stirred at 0 0C for 30 min then allowed to warm to 25 0C and stirred for 12 h. The reaction was quenched with 10% HCl and extracted with EtOAc. The organic layer was washed with 10% NaOH and then dried with NaCl(Sat) and Na2SO4(S). The solvents were removed under reduced pressure and the resulting product was used without further purification, m/z 284.
	With sodium borohydrid; In diethylene glycol dimethyl ether;	Referential Example 16 Production of 3-Bromo-5-fluorobenzyl Alcohol Sodium borohydride (1.68 g) was added to diethylene glycol dimethyl ether (40 ml). While the mixture was stirred at room temperature, <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (9.72 g) was added portionwise (six portions). After the crystals were completely dissolved, trifluoroborane ether complex (8.40 g) in diethylene glycol dimethyl ether (10 ml) was added dropwise thereto. The mixture was stirred for 5 hours, and poured into ice/water. The mixture was extracted with ether (200 ml), and washed with water, followed by drying over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1?5:1), to thereby yield a mixture of the target compound and diethylene glycol dimethyl ether. The thus-obtained mixture was analyzed by NMR to determine the content of diethylene glycol dimethyl ether. The content and the yield of the target compound as determined by NMR were 7.70 g and 84.6%, respectively. 1H-NMR (CDCl3, ppm); 1.87 (1H, t, J=5.94 Hz), 4.69 (2H, d, J=5.94 Hz), 7.04 (1H, brd), 7.16 (1H, dt, J=7.83 Hz, 1.89 Hz), 7.31 (1H, brs).
		General Procedure 1: Preparation of Benzyl Alcohols from Benzoic AcidsAt RT, 1.3 eq. of triethylamine and then 1.2 eq. of methyl chloroformate were added to a 0.5 M solution of the benzoic acid in question in toluene, and the mixture was stirred at RT overnight. The resulting suspension was then filtered through Celite and the residue was washed with toluene. The filtrate was concentrated, and the residue of the filtrate was dissolved in THF (1.5 ml/mmol) and then added dropwise to a suspension, cooled to -78 C., of 1.2 eq. of lithium aluminum hydride in THF (1 ml/mmol). After 1.5 h at -78 C., the reaction mixture was warmed to RT, and stirring was continued overnight. The resulting suspension was poured into 5% strength aqueous sodium hydroxide solution (5 ml/mmol), and the mixture was filtered through Celite and the filter cake was washed with ethyl acetate. The filtrate was extracted repeatedly with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure.
		General Procedure 1: Preparation of Benzyl Alcohols from Benzoic Acids; At RT, 1.3 eq. of triethylamine and then 1.2 eq. of methyl chloroformate were added to a 0.5 M solution of the benzoic acid in question in toluene. The mixture was stirred at RT overnight. The suspension formed was then filtered through Celite and the residue was washed with toluene. The filtrate was concentrated, and the filtrate residue was dissolved in THF (1.5 ml/mmol) and then added dropwise to a suspension, cooled to -78 C., of 1.2 eq. of lithium aluminium hydride in THF (1 ml/mmol). After 1.5 h at -78 C., the reaction mixture was warmed to RT, and stirring was continued overnight. The suspension formed was poured into 5% strength aqueous sodium hydroxide solution (5 ml/mmol), the mixture was filtered through Celite and the residue was washed with ethyl acetate. The filtrate was extracted repeatedly with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure.
	With borane-THF; In tetrahydrofuran; at 0 - 20℃;	Step 1. (3-bromo-5-fluorophenyl)methanol To a suspension of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (4.51 g, 20.59 mmol) in THF (41.2 mL) at 0 C., BH3.THF (41.2 mL, 41.2 mmol) was added dropwise over 30 min, the reaction mixture was then allowed to return to room temperature and stirred at room temperature overnight. Methanol (40 mL) was added slowly and stirred at room temperature for 1 h. THF and Methanol was removed in vacuo. The residue was then extracted by EtOAc, and washed with sat.NaHCO3, The organic was dried and concentrated. The crude product was used in next step reaction without purification. LCMS (m/z): 187.2 (MH+-18), 0.66 min. 1H NMR (400 MHz, CDCl3) delta ppm 7.32 (s, 1H), 7.19-7.14 (m, 1H), 7.05 (tdd, J=0.7, 1.5, 9.1 Hz, 1H), 4.70 (br. s., 2H), 1.78 (br. s., 1H).
966 mg	With borane-THF; In tetrahydrofuran;Cooling with ice;	(1) Borane-tetrahydrofuran complex (0.98 mol/L tetrahydrofuran solution, 9.3 mL) was added to a solution of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (1.0 g) in tetrahydrofuran (23 mL) under ice cooling, the ice bath was removed, and the mixture was stirred overnight. Water was added to the reaction solution under ice cooling, the mixture was extracted with chloroform, and the organic layer was separated by a phase separator. The obtained organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform/methanol = 99:1 to 47:3) to give (3-bromo-5-fluorophenyl)methanol (966 mg) as a colorless oily substance.

Reference： [1]Patent: US2007/249607,2007,A1 .Location in patent: Page/Page column 81
[2]Patent: CN104447730,2017,B .Location in patent: Paragraph 0146-0147
[3]Patent: WO2016/54728,2016,A1 .Location in patent: Paragraph 00127
[4]Patent: WO2016/74068,2016,A1 .Location in patent: Paragraph 00121
[5]Patent: WO2006/79791,2006,A1 .Location in patent: Page/Page column 44
[6]Patent: US6586633,2003,B1
[7]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1864 - 1868
[8]Patent: US2011/34450,2011,A1 .Location in patent: Page/Page column 96
[9]Patent: US2012/172448,2012,A1 .Location in patent: Page/Page column 19
[10]Patent: US9242996,2016,B2 .Location in patent: Page/Page column 271; 272
[11]Patent: EP3418276,2018,A1 .Location in patent: Paragraph 0691; 0692

9
[ 176548-70-2 ]
[ 18107-18-1 ]
[ 334792-52-8 ]

Yield	Reaction Conditions	Operation in experiment
71%		To a solution of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (2 g, 9.13 mmol) in DCM/ MeOH (20 ml/ 5 ml) is added trimethylsilyldiazomethane (2M solution in ether; 1 eq, 9.13 mmol) and the mixture is stirred for 1 h. Acetic acid was added dropwise until the yellow colour disappeared. The solvents are then removed in vacuo. The residue is dissolved in DCM and washed with K2CO3. The organic phase is dried (MgSO4) and concentrated in vacuo to give the title compound (1.5 g, 71 %) LC/MS: 91% MH+, m/z not ionised, Rt = 1.55 mins.
21%	In hexane; dichloromethane; at 20℃; for 0.5h;	Commercially available 3-bromo-5-fmorobenzoic acid (1.Og, 4.57 mmol) was dissolved in methylene chloride (20 mL) trimethylsilyl diazomethane (2M solution in hexane) (5 mL, 10 mmol) was added and the reaction mixture was stirred for 30 min. at room temperature. The reaction mixture was concentrated and purified by silica gel chromatography (hexane/methylene chloride 2:1) to yield A101.1 (229mg, 21%).

Reference： [1]Patent: EP1655283,2006,A1 .Location in patent: Page/Page column 16-17
[2]Patent: WO2006/122137,2006,A1 .Location in patent: Page/Page column 124-125

10
[ 176548-70-2 ]
[ 334792-52-8 ]
tetrakis(triphenylphoshine)palladium ⁽⁰⁾ [ No CAS ]
Pyridine-3-boronic acid-1,3-propanediol ester [ No CAS ]
[ 453565-94-1 ]
[ 453565-93-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide; potassium carbonate; In N-methyl-acetamide; methanol; thionyl chloride; dichloromethane; ethyl acetate; toluene;	3-Fluoro-5-(3-pyridyl)benzoic Acid A solution of <strong>[176548-70-2]3-Bromo-5-fluorobenzoic acid</strong> (2.00 g, 9.13 mmol) in thionyl chloride (16 ml) and dimethylformamide (0.4 ml) was stirred at 80 C. for 1 h. The reaction mixture was concentrated in-vacuo and the residue was dissolved in methanol (15 ml) and left stirring at room temperature overnight. The reaction mixture was concentrated in-vacuo, and the residue was dissolved in ethyl acetate (50 ml). Organic phase was sequentially washed with water (50 ml), saturated sodium bicarbonate (50 ml, aqueous), water (50 ml) and brine (50 ml), dried (sodium sulfate), filtered and concentrated in-vacuo to provide the title compound (1.97 g, 92%) as yellow oil. To the solution of Methyl-3-bromo-5-fluorobenzoate (1.97 g, 8.44 mmol) in toluene (40 ml) added Pyridine-3-boronic acid-1,3-propanediol ester (1.79 g, 7.63 mmol), potassium carbonate (11.66 g, 84.4 mmol) and tetrakis(triphenylphoshine)palladium (0) (0.49, 0.42 mmol), sequentially. The resulting brownish yellow reaction mixture was heated at 120 C. under argon overnight. The reaction mixture was cooled to room temperature, filtered through a pad of celite and concentrated in-vacuo. The residue was purified on silica gel using 1% methanol in dichloromethane to isolate the title compound (0.92 g, 47%) as a yellow solid. In a 100 ml round bottom flask equipped with stir bar added Methyl-3-fluoro-5-(3-pyridyl)benzoate (0.92 g, 3.93 mmol), methanol (10 ml) and sodium hydroxide (5.89 ml, 5.89 mmol, 1N aqueous). Stirred the resulting mixture at 50 C. for 2 h. The reaction mixture was cooled to room temperature, concentrated in-vacuo and the residue was dissolved in methanol (20 ml). To this mixture added hydrochloric acid (1N diethyl ether) dropwise and stirred at room temperature for 10 min. The reaction mixture was concentrated in-vacuo and the residue was triturated with diethyl ether to provide the crude hydrochloride salt of title compound (1.00 g) as an off white solid.

Reference： [1]Patent: US2003/55085,2003,A1

11
[ 176548-70-2 ]
[ 79-37-8 ]
[ 327056-58-6 ]
[ 453566-50-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N-methyl-acetamide; dichloromethane; ethyl acetate; N,N-dimethyl-formamide;	3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-(1H-imidazol-4-yl)phenyl) -1,2,4-oxadiazole A mixture of <strong>[176548-70-2]3-Bromo-5-fluorobenzoic acid</strong> (0.41 g, 1.87 mmol) in dichloromethane (5 mL) was treated with oxalyl chloride (2.8 ml, 5.60 mmol, 2M dichloromethane) and 3 drops of N,N-dimethylformamide. The mixture was stirred 4 hours at room temperature. The solvent and excess reagent were removed in-vacuo. The residue was treated with 5-Fluoro-2-pyridylamidoxime (0.29 g, 1.87 mmol) and triethylamine (0.78 ml, 5.60 mmol) in dichloromethane (5 mL). The mixture was then heated in dimethylformamide (5 mL) at 120 C., overnight. Standard work up followed by purification on silica gel using 20% ethyl acetate in hexanes afforded 3-(5-Fluoro-2-pyridyl)-5-(3-bromo-5-fluorophenyl)-1,2,4-oxadiazole (150 mg).

Reference： [1]Patent: US2003/55085,2003,A1

12
[ 176548-70-2 ]
[ 1772-01-6 ]
[ 453566-48-8 ]

Yield	Reaction Conditions	Operation in experiment
168.3 mg (38%)	In pyridine; water;	3-(2-Pyridyl)-5-(3-fluoro-5-bromophenyl)-1,2,4-oxadiazole Using the general procedure for the preparation of acid chlorides, 3-fluoro-5-bromobenzoyl chloride was prepared from 3-fluoro-5-bromobenzoic acid (300 mg, 1.369 mmol). The acid chloride was treated with pyrid-2-ylamidoxime (187.7 mg, 1.369 mmol) in pyridine (2 mL) and the mixture heated in sealed tube at 130 C. for 16 hours. After cooling, the reaction was treated with water and the solid collected by filtration. Recrystallization from ethanol afforded 168.3 mg (38%) of 3-(2-pyridyl)-5-(3-fluoro,5-bromophenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), delta (ppm): 8.82 (d, 1H), 8.25 (s, 1H), 8.21 (d, 1H), 7.92 (td, 2H), 7.50 (m, 2H).

Reference： [1]Patent: US2003/55085,2003,A1

13
[ 176548-70-2 ]
[ 327056-58-6 ]
[ 453566-50-2 ]

Yield	Reaction Conditions	Operation in experiment
218 mg (45%)	In N-methyl-acetamide; water;	3-(5-Fluoro-2-pyridyl)-5-(3-fluoro-5-bromophenyl)-1,2,4-oxadiazole Using the general procedure for the preparation of acid chlorides, 3-fluoro-5-bromobenzoyl chloride was prepared 3-fluoro-5-bromobenzoic acid (350 mg, 1.598 mmol). The acid chloride was treated 5-fluoropyrid-2-ylamidoxime (223 mg, 1.438 mmol) in dimethylformamide (5 mL) and the mixture heated in sealed tube at 130 C. for 16 hours. After cooling, the reaction was treated with water and the solid collected by filtration. Recrystallization from ethanol afforded 218 mg (45%) of 3-(5-fluoro-2-pyridyl)-5-(3-fluoro-5-bromophenyl)-1,2,4-oxadiazole: 1H-NMR (CDCl3), delta (ppm): 8.70 (d, 1H), 8.28 (s, 1H), 8.27 (dd, 1H), 7.93 (td, 1H), 7.61 (td, 1H), 7.53 (td, 1H).

Reference： [1]Patent: US2003/55085,2003,A1

14
[ 176548-70-2 ]
[ 144-55-8 ]
[ 334792-52-8 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sulfuric acid; In methanol; diethyl ether;	Intermediate 25: Methyl 3-bromo-5-fluorobenzoate Methanol (30 ml) was added to <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (3.1 g, 14 mmol) to prepare a solution. Concentrated sulfuric acid (3.0 ml) was added to the solution, and the mixture was heated under reflux for 1.5 hr. The temperature of the reaction mixture was returned to room temperature, and the reaction mixture was slowly poured into 400 ml of a saturated aqueous sodium hydrogencarbonate solution, followed by extraction twice with 250 ml of diethyl ether. The combined organic layers were dried over anhydrous magnesium sulfate and were concentrated under the reduced pressure to give the title compound (2.6 g, 80%). Physicochemical properties of intermediate 25

Reference： [1]Patent: EP1229024,2002,A1

15
[ 176548-70-2 ]
[ 411235-57-9 ]
[ 896161-19-6 ]

Yield	Reaction Conditions	Operation in experiment
37%		Method 31; S-Cvclopropyl-S-fluorobenzoic acid; To a solution of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (0.500 g, 4.56 mmol) and cyclopropylboronic acid (0.590 g, 6.84 mmol) in toluene (15 ml) and water (0.75 ml) was added K3PO4 (3.86 g, 18.24 mmol) and Pd(PPh3)4 (1.05 g, 0.912 mmol). The reaction mixture was heated to 100 C for 12 hours, cooled to room temperature, and quenched with 10% aqueous NaOH (100 ml). The reaction mixture was washed with EtOAc (100 ml) and the resulting aqueous layer isolated and brought to a pH of ~2 by the careful addition of 3N HCl. The resulting precipitate was filtered, washed with water (100 ml), and dried under vacuum for 24 hours to give 0.31 g (37%) off-white solid; m/z: 181.
	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 100℃; for 12h;	Method 56; S-Cyclopropyl-S-fluorobenzoic acid; 3-Bromo-5-Fluorobenzoic acid (1.00 g, 4.57 mmol), cyclopropylboronic acid (1.18 g, 13.71 mmol, 3.0 equiv) and K3PO4 (7.76 g, 36.56 mmol, 8.0 equiv) in toluene-H2O (25:1, 31 ml) were treated with Pd(Ph3P)4 (1.05 g, 0.912 mmol, 20 mol%). The reaction mixture was heated to 100 C for 12 h. The reaction was quenched with 10% NaOH and extracted with EtOAc. The aqueous layer was acidified with 10% HCl and extracted with EtOAc. The organics were dried with NaCl(sat) and Na2SO4(S) and removed under reduced pressure; m/z 181.

Reference： [1]Patent: WO2007/71955,2007,A1 .Location in patent: Page/Page column 55
[2]Patent: WO2007/71963,2007,A2 .Location in patent: Page/Page column 56

16
[ 176548-70-2 ]
[ 887266-90-2 ]

Yield	Reaction Conditions	Operation in experiment
97.1%	With thionyl chloride; at 80℃; for 3h;	10287] Compound 1 (16 g, 73.4 mmol) was dissolved in50C12 (160 mE) and heated to 80 C. for 3 hour. The mixturewas concentrated in vacuo to give compound 2 as brown oil(16.8 g, 97.1%).
	With thionyl chloride;N,N-dimethyl-formamide; In dichlorodimethane; at 0 - 5℃; for 1h;Heating / reflux;	Prepared as described in the general procedure A using 3-bromo, 5-fluoro benzoic acid (4.00 g, 17.5 mmol).Yield g, %, mp 0C; 1HNMR (400 MHz, CDCl3) delta 2.58 (s, 3H), 7.02-7.04 (d, J = 8.0 Hz, IH), 7.45-7.48 (m, IH), 7.73-7.80 (m, 2H), 8.08-8.11 (dt, J = 1.2, 11.2 Hz, IH), 8.31- 8.33 (d, J = 8.0 Hz, IH); 13CNMR (101 MHz, CDCl3) delta 2; IR (Neat, cm"1); GC-MS (EI) m/z 309 (M+); Anal. (C20H18N2O2.HBr.H2O) C, H, N.
	With thionyl chloride; for 2h;Reflux;	General procedure: 3,5-dibromobenzoic acid (5g, 17.8 mmol) was suspended in 25 mL of thionyl chloride, an refluxed for 2h. After cooling to room temperature the excess thionyl chloride was removed under reduce pressure and the residue was cautiously poured into 100 mL of ice cold NH4OH 28%, and stirred at room temperature for 3h. Filtration of the precipitate provide after drying in vacuum the amide intermediate in quantitative yield. The amide was suspended in 25 mL of thionyl chloride, and refluxed for 18h before removing the excess thionyl chloride under reduce pressure. The residue was dissolved in 50 mL of AcOEt, and washed with a saturated solution of NaHCO3 (3 X 50 mL), dry over Na2SO4, and concentrated on a rotary evaporator. Purification of the residue by column chromatography yielded 2.71g (58 %) 9a as a yellow solid.1H NMR (CDCl3), d = 8.07 (t, 1H, J=2.0 Hz, CHAr); 8.40 (t, 1H, J=2.0 Hz, CHAr); 8.52 (t, 1H, J=2.0 Hz, CHAr). 13C NMR (CDCl3), d = 115.7 (1C, Cq); 115.8 (1C, Cq); 124.3 (1C, Cq); 126.2 (1C, CHAr); 131.3 (1C, CHAr); 140.7 (1C, Cq).

	With thionyl chloride; for 2h;Reflux;	A solution of <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (commercially available) (10.0 g, 45.7 mmol) in thionyl chloride (80 mL) was heated at reflux for 2 hours. Thionyl chloride was removed under reduced pressure and the residue was added to solution of N,O-dimethylhydroxylamine hydrochloride (5.32 g, 54.8 mmol) and Et3N (10.1 g, 0.1 mol) in DCM (300 mL) dropwise at 0 C. After the reaction mixture was stirred at r.t. overnight, it was washed with water (3*100 mL), brine, dried over anhydrous Na2SO4 and concentrated. The colorless oil was used in next step without further purification (11.0 g, yield: 95%).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1.66667h;	Synthesis of 3-Bromo-5-fl uoro-benzoyl chloride lOg of <strong>[176548-70-2]3-bromo-5-fluoro-benzoic acid</strong> are suspended in 1 OOml of DCM, O,5m1 DMF and 4.5m1 oxalyl chloride (1,15 Eq) are added and the resulting mixture is stirred for 100 minutes at RT. The solvent is removed by vacuo and the benzoic acid chloride isisolated by distillation.
	With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 1.66667h;	10 g of <strong>[176548-70-2]3-bromo-5-fluoro-benzoic acid</strong> are suspended in 100 ml of DCM, 0.5 ml DMF and 4.5 ml oxalyl chloride (1.15 Eq) are added and the resulting mixture is stirred for 100 minutes at RT. The solvent is removed by vacuo and the benzoic acid chloride is isolated by distillation.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1.66667h;	10g of <strong>[176548-70-2]3-bromo-5-fluoro-benzoic acid</strong> are suspended in 100ml of DCM, 0,5ml DMF and 4.5ml oxalyl chloride (1 ,15 Eq) are added and the resulting mixture is stirred for 100 minutes at RT. The solvent is removed by vacuo and the benzoic acid chloride is isolated by distillation.
	With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 1.66667h;	10 g of <strong>[176548-70-2]3-bromo-5-fluoro-benzoic acid</strong> are suspended in 100 ml of DCM, 0.5 ml DMF and 4.5 ml oxalyl chloride (1.15 Eq) are added and the resulting mixture is stirred for 100 minutes at RT. The solvent is removed by vacuo and the benzoic acid chloride is isolated by distillation.
	With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; dichloromethane; at 20℃; for 1.5h;	<strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (32.0 g, 1 .0 equiv) was stirred in a mixture of DCM (288 mL, 9 vol) and THF (32 mL, 1 vol) until the majority of the solid dissolved. DMF (0.57 mL, 5 mol%) was added, and the flask placed in an ambient temperature water bath. Oxalyl chloride (13.7 mL, 1.10 equiv) was added over 1 h via syringe pump; 30 minute after the end of addition the reaction was complete by HPLC (sample quenched into MeOH to form methyl ester prior to analysis). The resulting thin slurry was aged overnight, concentrated to 100 mL volume, diluted with THF (160 mL, 5 vol) and again concentrated to 100 mL. The resulting thin slurry of acid chloride was diluted to 160 mL total volume with THF. A solution of LiOtBu in THF (20 wt%, 67.3 g, 77 mL, 1.15 equiv) was diluted with THF (243 mL), then this solution was cooled to an internal temperature of - 9 C with an ice/salt bath. To this was added the slurry containing acid chloride over 55 mm, while the internal temperature remained below -3 C . The reaction was complete 15 mm following the end of addition. The solution was aged overnight as it warmed to ambient temperature, diluted with heptane (320 mL, 10 vol), and washed with water (160 mL, 5 vol). The aqueous layer was removed to the insoluble rag at the interlace, then the organic layer was filtered through a pad of solka-floc. The pad was rinsed with heptane (10 mL), then the combined organic layer was washed 2xwith water (2 x 80 mL, 2.5 vol). The resulting organic layer was distilled under reduced pressure to a 100 mL final volume, diluted with heptane (160 mL, 5 vol), and concentrated again to 100 mLtotal volume. The solution of tert-butyl 3-bromo-5-fluorobenzoate was used directly in the next step.NMR 1H (400MHz; CDCI3): 7.89-7.88 (1H, m), 7.60-7.57 (1H, m), 7.40-7.37 (1H, m), 1.57 (9H, 5).

Reference： [1]Patent: US2015/274652,2015,A1 .Location in patent: Paragraph 0286; 0287
[2]Patent: WO2008/92072,2008,A2 .Location in patent: Page/Page column 9-10
[3]Journal of Medicinal Chemistry,2009,vol. 52,p. 3563 - 3575
[4]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3243 - 3247
[5]Bioorganic and medicinal chemistry letters,2012,vol. 22,p. 6974 - 6979,6
[6]Patent: US2013/324516,2013,A1 .Location in patent: Paragraph 0411; 0412
[7]Patent: WO2014/154727,2014,A1 .Location in patent: Page/Page column 75; 76
[8]Patent: US2014/296239,2014,A1 .Location in patent: Paragraph 0166; 0167
[9]Patent: WO2014/154726,2014,A1 .Location in patent: Page/Page column 80
[10]Patent: US2014/296296,2014,A1 .Location in patent: Paragraph 0191; 0192
[11]Patent: WO2018/178691,2018,A1 .Location in patent: Page/Page column 246; 247

Yield	Reaction Conditions	Operation in experiment
		Oakwood Products, Inc., 1741 Old Dunbar Road, West Columbia, S.C. 29172, USA. TCI America, 9211 N. Harborgate Street, Portland, Oreg. 97203, USA ... 4-bromo-2,6-difluorobenzoic acid; 2-bromo-3-fluorobenzoic acid; 2-bromo-5-fluorobenzoic acid; 3-bromo-2-fluorobenzoic acid; 3-bromo-5-fluorobenzoic acid; 4-bromo-2-fluorobenzoic acid; 5-bromo-2-fluorobenzoic acid; 2-bromo-5-iodobenzoic acid; ...

18
[ 176548-70-2 ]
[ 105515-20-6 ]

Yield	Reaction Conditions	Operation in experiment
94%		1-(3-Bromo-5-fluorophenyl)-ethanone Methyllithium (1.3 M in diethyl ether, 35 mL) was added dropwise to <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (5 g) in diethyl ether at -78 C. keeping the temperature below -60 C. The reaction was then left to warm to -10 C. and was stirred for 1 h before being carefully quenched with saturated ammonium chloride (100 mL) until pH=3. The product was extracted with diethyl ether (2*100 mL), dried over sodium sulfate and the solvent removed by evaporation to yield 1-(3-bromo-5-fluorophenyl)ethanone as an off-white solid (4.67 g, 94%). 1H NMR (CDCl3): 2.59 (3H, s, ArCOCH3), 7.44 (1H, dd, Ar), 7.59 (1H, dd, Ar), 7.87 (1H, s, Ar).

Reference： [1]Patent: US2009/209529,2009,A1 .Location in patent: Page/Page column 35

19
[ 176548-70-2 ]
[ 216755-57-6 ]

Reference： [1]Patent: US2011/34450,2011,A1
[2]Patent: WO2016/54728,2016,A1
[3]Patent: WO2016/74068,2016,A1
[4]Patent: CN104447730,2017,B

20
[ 176548-70-2 ]
[ 1192039-98-7 ]

Reference： [1]Patent: US2011/34450,2011,A1
[2]Patent: US2012/172448,2012,A1

21
[ 176548-70-2 ]
[ 1192040-04-2 ]

Reference： [1]Patent: US2011/34450,2011,A1
[2]Patent: US2012/172448,2012,A1

22
[ 176548-70-2 ]
[ 1192040-10-0 ]

Reference： [1]Patent: US2011/34450,2011,A1
[2]Patent: US2012/172448,2012,A1

23
[ 176548-70-2 ]
[ 864063-09-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3243 - 3247

24
[ 176548-70-2 ]
3-(2-(6-methylpyridin-2-yl)ethynyl)-5-fluorobenzonitrile hydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3243 - 3247

25
[ 176548-70-2 ]
3-(2-(5-methylpyridin-2-yl)ethynyl)-5-fluorobenzonitrile hydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3243 - 3247

26
[ 176548-70-2 ]
[ 1224431-15-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3243 - 3247

27
[ 176548-70-2 ]
3-(2-(2-methylthiazol-4-yl)ethynyl)-5-fluorobenzonitrile hydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3243 - 3247

28
[ 176548-70-2 ]
[ 1312923-99-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3243 - 3247

29
[ 176548-70-2 ]
[ 933585-20-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3243 - 3247

30
[ 176548-70-2 ]
[ 179898-34-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 3243 - 3247

31
[ 176548-70-2 ]
[ 123-75-1 ]
[ 1264616-18-3 ]

Reference： [1]Organic Process Research and Development,2011,vol. 15,p. 438 - 442

32
[ 176548-70-2 ]
[ 1379545-29-5 ]
[ 1379541-44-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 150℃; for 0.166667h;Microwave irradiation;	Step 2: 3'-([4-Bromo-1-(2,2-dimethylpropyl)-1H-benzotriazol-5-yl]oxy}methyl)-5-fluorobiphenyl-3-carboxylic acid (Example 3-2)[3-([4-Bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-yl]oxy}methyl)phenyl]boronic acid (3-1) (400 mg, 0.957 mmol, 1.0 equiv.), <strong>[176548-70-2]3-bromo-5-fluorobenzoic acid</strong> (12) (800 mg, 3.65 mmol, 3.8 equiv.) and dichloro[1,1'-bis (diphenylphosphino) ferrocene]palladium II dichloromethane adduct (78 mg, 0.096 mmol, 0.1 equiv.) were dissolved in anhydrous degassed 1,4-dioxane (8 mL), then treated with a 1 M aqueous solution of cesium carbonate (5.2 mL, 5.3 mmol, 5.5 equiv.). The reaction mixture was irradiated in microwavereactor at 150 C. for 10 minutes. The mixture was concentrated in vacuo and purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA present) to afford Example 3-2. 1H NMR delta (CDCl3): 8.15 (s, 1H), 7.77 (s, 2H), 7.58-7.52 (m, 4H), 7.41 (d, 1H, J=8.5 Hz), 7.29 (d, 1H, J=9.0 Hz), 5.32 (s, 2H), 4.38 (s, 2H), 1.04 (s, 9H) ppm. LRMS m/z (M+H) 512.0 and 514.0 (intensity ratio 1:1) found, 512.1 and 514.1 required.

Reference： [1]Patent: US2012/135977,2012,A1 .Location in patent: Page/Page column 18

33
[ 179898-34-1 ]
[ 176548-70-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With water; sodium hydroxide; for 2h;Reflux;	A mixture of 3-bromo-5-fluorobenzonitrile (2.8 g, 13.8 mmol) and aqueous sodium hydroxide (5 M, 28 mL) was heated to reflux for 2 h. After cooling to room temperature, pH was adjusted to 1 by the addition of concentrated hydrochloric acid. The formed precipitate was collected by filtration, the solid was washed with cold water and dried to afford the title compound (2.8 g, 94%). 1H NMR (400 MHz, CD3OD) d ppm 6.31 (dt, J=8.08, 2.02 Hz, 1 H), 6.37 - 6.43 (m, 1 H), 6.68 (s, 1 H).