206551-41-9|Methyl 3-bromo-2-fluorobenzoate| Ambeed

Structure of 206551-41-9

*Storage: {[sel_prStorage]}

*Shipping: {[sel_prShipping]}

4.5 *For Research Use Only !

{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]} Purity: {[proInfo.pro_purity]}

Change View

Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 5-7 days

{[ item.pr_size ]}

In Stock

- +

Please Login or Create an Account to: See VIP prices and availability

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 206551-41-9 ] Purity: 98% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support

Product Details of [ 206551-41-9 ]

CAS No. :	206551-41-9
Formula :	C₈H₆BrFO₂
M.W :	233.03
SMILES Code :	COC(=O)C1=CC=CC(Br)=C1F
MDL No. :	MFCD09261255
Boiling Point :	No data available

Safety of [ 206551-41-9 ]

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

Computational Chemistry of [ 206551-41-9 ] Show Less

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 ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	26.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.21
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	2.51
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.8
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	3.09
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.79
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.68

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.1
Solubility	0.183 mg/ml ; 0.000787 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.71
Solubility	0.456 mg/ml ; 0.00196 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.61
Solubility	0.0569 mg/ml ; 0.000244 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.94 cm/s

Druglikeness

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

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.63

Application In Synthesis of [ 206551-41-9 ]

* 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 [ 206551-41-9 ]
Downstream synthetic route of [ 206551-41-9 ]

[ 206551-41-9 ] Synthesis Path-Upstream 1~1

1
[ 206551-41-9 ]
[ 1195768-19-4 ]

References: [1] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 3, p. 358 - 362.

[ 206551-41-9 ] Synthesis Path-Downstream 1~35

1
[ 206551-41-9 ]
[ 796061-07-9 ]
methyl 9-tosyl-9H-carbazole-1-carboxylate [ No CAS ]

References: [1]Organic Letters,2007,vol. 9,p. 4893 - 4896.

2
[ 206551-41-9 ]
[ 478374-74-2 ]

References: [1]Patent: EP1394147,2004,A1 .Location in patent: Page 66.

3
[ 6165-68-0 ]
[ 206551-41-9 ]
[ 110-71-4 ]
[ 374555-00-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine)palladium (0);	REFERENCE EXAMPLE 83 To a mixture of <strong>[206551-41-9]methyl 3-bromo-2-fluorobenzoate</strong> (117 mg), 2-thiopheneboronic acid (83 mg) and 1,2-dimethoxyethane (2 ml) were added a 2M aqueous solution of sodium carbonate (0.83 ml) and tetrakis(triphenylphosphine)palladium(0) (29 mg) at ambient temperature. The mixture was heated for 3 hours at 90° C. After cooling, the reaction mixture was diluted with ethyl acetate (30 ml), and washed with water (20 ml*3) and brine (20 ml). The organic layer was dried over magnesium sulfate and filtered. After evaporation, the residue was chromatographed on a silica gel eluding with a mixture of ethyl acetate and n-hexane to give methyl 2-fluoro-3-(2-thienyl)benzoate (99 mg). Mass: 237 (m/z, (M+H)+) NMR(DMSO-d6, delta): 3.89 (3H, s), 7.1-7.3 (1H, m), 7.39 (1H, t, J=7.8 Hz), 7.6-7.9 (3H, m), 8.0-8.2 (1H, m).

References: [1]Patent: US2003/176454,2003,A1 .

4
[ 161957-56-8 ]
[ 149-73-5 ]
[ 206551-41-9 ]

Yield	Reaction Conditions	Operation in experiment
	With toluene-4-sulfonic acid; In methanol;	EXAMPLE 120 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2-fluoro-benzonitrile A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in dry methanol (5 mL) under nitrogen was treated with trimethylorthoformate (0.22 mL, 2 mmol) and p-toluenesulfonic acid (catalytic amount), and then heated under reflux. After 16 h, the mixture was evaporated and the residue partitioned between water and Et2O. the organic layer was washed with sat. sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84percent): 1H-NMR (CDCl3) delta7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.10 (dt, 1H, J=8.0, 1.0 Hz), 3.94 (s, 3H): MS (EI) 232 (M+).
	With toluene-4-sulfonic acid; In methanol;	EXAMPLE 68 2-fluoro-3-(1',2'-Dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol-5'-yl)benzaldehyde oxime A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in dry methanol (5 ml) under nitrogen was treated with trimethylorthoformate (0.22 ml, 2 mmol) and p-toluenesulfonic acid (catalytic amount), and then heated under reflux. After 16 h, the mixture was evaporated and the residue partitioned between water and Et2O. The organic layer was washed with sat. sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84percent): 1H NMR (CDCl3) delta7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.10 (dt, 1H, J=8.0, 1.0 Hz) and 3.94 (s, 3H): MS (EI) 232 (M+).
	With toluene-4-sulfonic acid; In methanol;	EXAMPLE 120 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-2fluoro-benzonitrile A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in dry methanol (5 mL) under nitrogen was treated with trimethylorthoformate (0.22 mL, 2 mmol) and p-toluenesulfonic acid (catalytic amount), and then heated under reflux. After 16 h, the mixture was evaporated and the residue partitioned between water and Et2O. the organic layer was washed with sat. sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84percent): 1H-NMR (CDCl3) delta7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.10 (dt, 1H, J=8.0, 1.0 Hz), 3.94 (s, 3H): MS (EI) 232 (M+).

With toluene-4-sulfonic acid; In methanol;

EXAMPLE 68 2-Fluoro-3-(1',2'-dihydro-2'-oxospiro[cyclohexane-1,3'-[3H]indol]-5-yl) A solution of 3-bromo-2-fluorobenzoic acid (0.219 g, 1 mmol) in dry methanol 5 ml) under nitrogen was treated with trimethylorthoformate (0.22 ml, 2 mmol) and p-toluenesulfonic acid (catalytic amount), and then heated under reflux. After 16 h, the mixture was evaporated and the residue partitioned between water and Et2O. The organic layer was washed with sat. sodium hydrogen carbonate solution, water, brine, dried (MgSO4) and evaporated to give methyl 3-bromo-2-fluorobenzoate (0.195 g, 0.84 mmol, 84percent): 1H NMR (CDCl3) delta 7.90-7.85 (m, 1H), 7.71-7.65 (m, 1H), 7.10 (dt, 1H, J=8.0, 1.0 Hz) and 3.94 (s, 3H): MS (EI) 232 (M+).

References: [1]Patent: US2002/49204,2002,A1 .
[2]Patent: US6391907,2002,B1 .
[3]Patent: US6444668,2002,B1 .
[4]Patent: US6462032,2002,B1 .

5
[ 206551-41-9 ]
[ 1129-26-6 ]
3-Bromo-2[-(4-methoxybenzenesulfonyl)amino]-benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.037 g (19%)	In N,N-dimethyl-formamide;	EXAMPLE 198 3-Bromo-2[-(4-methoxybenzenesulfonyl)amino]-benzoic acid methyl ester To 0.096 g (0.5 mmol) of 4-methoxyphenylsulphonamide in 3 mL of DMF was added in one portion 0.020 g (0.50 mmol) of 60percent sodium hydride and the reaction was stirre at 25° C. for 15 min. Then, 0.135 g (0.58 mmol) of <strong>[206551-41-9]methyl 3-bromo-2-fluorobenzylate</strong> was added to the solution in one portion and the resulting mixture was heated at 90° C. (bath temperature) for 18 h. The reaction was cooled to room temperature, acidified with 1N HCl and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica eluding with 30percent-50percent ethyl acetate/hexane to provide 0.037 g (19percent) of the desired product. 1 H-NMR(CDCl3): 8 ppm (s, 1H, NH), 6.8-7.8 ppm (m, 7H, Ar), 3.9 ppm (s, 1H, OMe), 3.7 ppm (s, 1H, OMe).
0.037g (19%)	In N,N-dimethyl-formamide;	Example 198 3-Bromo-2[-(4-methoxybenzenesulfonyl)amino]-benzoic acid methyl ester To 0.096g (0.5 mmol) of 4-methoxyphenylsulphonamide in 3mL of DMF was added in one portion 0.020g (0.50 mmol) of 60percent sodium hydride and the reaction was stirred at 25-C for 15 min. Then, 0.135g (0.58 mmol) of <strong>[206551-41-9]methyl 3-bromo-2-fluorobenzylate</strong> was added to the solution in one portion and the resulting mixture was heated at 90 °C (bath temperature) for 18h. The reaction was cooled to room temperature, acidified with 1N HCl and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica eluding with 30percent-50percent ethyl acetate/hexane to provide 0.037g (19percent) of the desired product. 1H-NMR(CDCl3): 8 ppm (s, 1H, NH), 6.8-7.8 ppm (m, 7H, Ar), 3.9 ppm (s, 1H, OMe), 3.7 ppm (s, 1H, OMe).

References: [1]Patent: US5929097,1999,A .
[2]Patent: EP938471,2001,B1 .

6
[ 206551-41-9 ]
[ 82702-31-6 ]
[ 77771-03-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium borohydrid;aluminium trichloride; In diethylene glycol dimethyl ether;	EXAMPLE 3 STR11 4-Fluoro-3-bromo-benzyl alcohol from <strong>[206551-41-9]fluorobromobenzoic acid methyl ester</strong>: First 3.8 g (0.1 mole) of sodium borohydride and then 4.5 g (0.033 mole) of aluminum chloride were added in portions to a solution of 23.3 g (0.1 mole) of 4-fluoro-3-bromobenzoic acid methyl ester in 50 ml of diglyme at 5° C. The mixture was subsequently stirred, without cooling, until the exothermic reaction had ended (a rise in temperature up to about 50° C.) and the reaction was then allowed to go to completion in the course of 1 hour at 100° C. The reaction solution was then poured onto a mixture of 125 ml of icewater and 12 ml of concentrated hydrochloric acid and the benzyl alcohol which had separated out was separated off and distilled in vacuo. 18.7 g (91percent of theory) of 4-fluoro-3-bromobenzyl alcohol were obtained in this manner as a colorless oil with a boiling point of 65° to 70° C. (0.1 mbar).

References: [1]Patent: US4386035,1983,A .

7
[ 1007-16-5 ]
[ 74-88-4 ]
[ 206551-41-9 ]

Yield	Reaction Conditions	Operation in experiment
89.5%	With potassium carbonate; In tert-butyl methyl ether; N,N-dimethyl-formamide; at 20℃; for 16h;	To a 100 mL round bottom flask was added 3-bromo-2-fluorobenzoic acid (5.00 g, 22.8 mmol, Oakwood), potassium carbonate (3.17 g, 22.9 mmol), and DMF (30 mL).Iodomethane, 2 M in MTBE (11.6 ml, 23.2 mmol) was added and the reaction mixture was stirred at RT for 16 hours. The reaction was filtered and the filtrate concentrated was in vacuo. The resulting brown crude residue was taken up with EtOAc and again filtered and concentrated to give methyl 3-bromo-2-fluorobenzoate (4.76 g, 20.4 mmol, 89.5percent yield), as a brown syrup that was used in the Step 2 without further purification.

References: [1]Patent: WO2007/61930,2007,A1 .Location in patent: Page/Page column 63.

8
[ 67-56-1 ]
[ 161957-56-8 ]
[ 206551-41-9 ]

Yield	Reaction Conditions	Operation in experiment
	sulfuric acid; for 1h;Inert atmosphere; Reflux;	To a 100 mL round bottom flask was added 3-bromo-2-fluorobenzoiotac acid (10 4 g, 10 47 5 mmol), MeOH (100 mL, 2472 mmol) and sulfuric acid (6 mL, 113 mmol) The reaction mixture was refluxed for 1 hr After cooling to rt, the MeOH was removed under reduced pressure and the acidic residue was poured into cold water and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc The organic layers were combined, washed with brine, dried over sodium sulfate and 15 concentrated under reduced pressure to afford 10 02 g of methyl 3-bromo-2- fluorobenzoate 1H-NMR (400 MHz, DMSO-ds) delta 7 95 (ddd, J = 8 1 , 6 4, and 1 7 Hz, 1 H), 7 82 - 7 87 (m, 1 H), 7 26 (t, J =7 9 Hz, 1 H), and 3 86 (s, 3 H)
	With sulfuric acid; for 1h;Inert atmosphere; Reflux;	To a 100 mL round bottom flask was added 3-bromo-2-fluorobenzoic acid (10.4 g, 47.5 mmol), MeOH (100 mL, 2472 mmol) and sulfuric acid (6 mL, 1 13 mmol). The reaction mixture was refluxed for 1 hr. After cooling to rt, the MeOH was removed under reduced pressure and the acidic residue was poured into cold water and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO and concentrated under reduced pressure to afford methyl 3-bromo-2-fluorobenzoate. 10.02 g. 1H-NMR (400 MHz, DMSO-de) delta 7.95 (ddd, J = 8.1 , 6.4, and 1 .7 Hz, 1 H), 7.82 - 7.87 (m, 1 H), 7.26 (t, J =7.9 Hz, 1 H), and 3.86 (s, 3 H).
	With sulfuric acid; at 20℃; for 18h;	3-Bromo-2-fluorobenzoic acid was transformed to intermediate 4 using the same procedure reported in example intermediate 2 to afford the corresponding amine as pale yellow oil.

With sulfuric acid; for 1h;Reflux;

Intermediate 15: N-{3-[(2-Chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide; Step A: Methyl 3-bromo-2-fluorobenzoate; To a 100 mL round bottom flask was added 3-bromo-2-fluorobenzoic acid (10.4 g, 47.5 mmol), MeOH (100 mL, 2472 mmol) and sulfuric acid (6 mL, 113 mmol). The reaction mixture was refluxed for 1 hr. After cooling to rt, the MeOH was removed under reduced pressure and the acidic residue was poured into cold water and EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried over NaSO4 and concentrated under reduced pressure to afford 10.02 g of methyl 3-bromo-2-fluorobenzoate. 1H-NMR (400 MHz, DMSO-d6) delta 7.95 (ddd, J=8.1, 6.4, and 1.7 Hz, 1H), 7.82-7.87 (m, 1H), 7.26 (t, J=7.9 Hz, 1H), and 3.86 (s, 3H).

References: [1]Patent: WO2010/104899,2010,A1 .Location in patent: Page/Page column 162.
[2]Patent: WO2011/59610,2011,A1 .Location in patent: Page/Page column 86.
[3]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 358 - 362.
[4]Patent: US9126993,2015,B2 .Location in patent: Page/Page column 51.
[5]Patent: US2009/298815,2009,A1 .Location in patent: Page/Page column 52-53.

9
[ 206551-41-9 ]
[ 4248-19-5 ]
[ 1042055-86-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 90℃;Inert atmosphere; Sealed flask;	In a 500 mL flask was placed 1 ,1-diotamethylethyl carbamate (6 03 g, 51 5 mmol), <strong>[206551-41-9]methyl 3-bromo-2-fluorobenzoate</strong> (10 g, 42 9 mmol), Pd2(dba)3 CHCI3 (0 89 g, 0 86 mmol), xantphos (1 49 g, 2 57 mmol) and cesium carbonate (16 8 g, 51 5 mmol) The flask was sealed with a rubber septum, placed under high vac, and toluene (200 mL) was added Three cycles of high vac/N2 were performed and the reaction 25 mixture was stirred at 90 C overnight The reaction was filtered through a pad of celite with EtOAc washing and concentrated To the residue was added DCM (200 mL) followed by TFA (50 mL, 649 mmol), and the mixture was stirred at rt for 1 h The volatiles were removed under reduced pressure and the residue was taken up in EtOAc and washed with saturated NaHCO3 and brine The organic layer was dried over sodium sulfate and stripped onto silica and column chromatographed on silica with 5% to 50% EtOAc Hexane to give 5 53 g (76%) of the title compound of Step B 1H-NMR (400 MHz, DMSO-d6) delta 6 92 - 7 01 (m, 3 H), 5 37 (s, 2 H), and 3 81 (s, 3 H) MS (ESI) 170 [M+H]+
	With caesium carbonate;tris(dibenzylideneacetone)dipalladium(0) chloroform complex; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 90℃;Inert atmosphere;	Step B: Methyl 3-amino-2-fluorobenzoate; In a 500 mL flask was placed 1,1-dimethylethyl carbamate (6.03 g, 51.5 mmol), <strong>[206551-41-9]methyl 3-bromo-2-fluorobenzoate</strong> (10 g, 42.9 mmol), Pd2(dba)3.CHCl3 (0.89 g, 0.86 mmol), xantphos (1.49 g, 2.57 mmol) and cesium carbonate (16.8 g, 51.5 mmol). The flask was sealed with a rubber septum, placed under high vacuum, and toluene (200 mL) was added. Three cycles of high vacuum/N2 were performed and the reaction mixture was stirred at 90 C. overnight. The reaction was filtered through a pad of celite with EtOAc washing and concentrated. To the residue was added DCM (200 mL) followed by TFA (50 mL, 649 mmol), and the mixture was stirred at rt for 1 h. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried over NaSO4, stripped onto silica and column chromatographed on silica with 5% to 50% EtOAc:Hexane to give 5.53 g (76%) of the title compound of Step B. 1H-NMR (400 MHz, DMSO-d6) delta 6.92-7.01 (m, 3H), 5.37 (s, 2H), and 3.81 (s, 3H). MS (ESI): 170 [M+H]+.

References: [1]Patent: WO2010/104899,2010,A1 .Location in patent: Page/Page column 162-163.
[2]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 358 - 362.
[3]Patent: US2009/298815,2009,A1 .Location in patent: Page/Page column 53.

10
[ 206551-41-9 ]
[ 114995-47-0 ]
[ 333793-52-5 ]

Yield	Reaction Conditions	Operation in experiment
60.9%		To a solution of N-(4fluorophenyl)-2,2-dimethylpropionamide (195 mg) in tetrahydrofuran (2 ml) was added a solution of n-butyl lithium in n-hexane (1.54M, 1.5 ml) dropwise at 0° C. under nitrogen atmosphere, and the mixture was stirred for 2 hours at 0° C. To the reaction mixture was added triisopropyl borate (0.692 ml) at -40° C., and the mixture was stirred for 30 minutes at ambient temperature.. To the mixture was added 1N-hydrochloric acid (3 ml), and the mixture was diluted with ethyl acetate and water.. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure.. To the residue were added <strong>[206551-41-9]methyl 3-bromo-2-fluorobenzoate</strong> (117 mg), tetrakis(triphenylphosphine)palladium (29 mg), an aqueous solution of sodium carbonate (2M, 2 ml) and 1,2-dimethoxyethane (5 ml).. The resulting mixture was stirred under nitrogen atmosphere for 48 hours at 75° C., and diluted with ethyl acetate and water.. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure.. The residue was purified with a silica gel column chromatography eluding with 20percent ethyl acetate/n-hexane to give 2'-(2,2-dimethylpropionamido)-2,5'-difluoro-biphenyl-3-carboxylic acid methyl ester (106 mg, 60.9percent). APCI-mass m/z: 348 (M+1) NMR (DMSO-d6, delta); 0.96 (9H, s), 3.85 (3H, s), 7.2-7.4 (4H, m), 7.52 (1H, dt, J=2.0 Hz, 7.1 Hz), 7.86 (1H, dt, J=1.9 Hz, 7.3 Hz), 8.92 (1H, s).

References: [1]Patent: US6770667,2004,B1 .Location in patent: Page column 20.

11
[ 206551-41-9 ]
[ 17997-47-6 ]
[ 76-05-1 ]
methyl 2-fluoro-3-(pyridine-2-yl)benzoate trifluoroacetate [ No CAS ]
[ 939024-44-9 ]

Yield	Reaction Conditions	Operation in experiment
17%; 23%		In a 150 mL round bottom flask was combined methyl 3-brorno-2-fluorobenzoate (1.47 g,6.3 mmol), DMF (10 mL), silver oxide (0.79 g, 6.4 mmol), 2-(tributylstannyl)pyridine (2.40 ml, 7.2 mmol), and dichlorobis(triphenylphosphine)-palladium (II) (0.23 g, 0.33 mmol) and the mixture was stirred at 100 0C fo about 72 h. Monitoring the reaction by LC-MS revealed two products, the ester and the hydrolyzed product. The reaction was cooled, filtered through a pad of celite and the celite was washed with EtOAc. The filtrate was concentrated in vacuo and taken up in a small amount of DMF. The solution was purified by reverse-phase preparative HPLC on a Phenomenex Luna column (10 micron, <n="66"/>A-1050-WO-PCT - 64 -C18, 100 A, 150 x 50 mm) eluting at 45 ml/min with an linear gradient of 10percent(v/v) to 100percent MeCN (0.1percent v/v TFA) in water (0.1percent TFA) over 10 minutes to give 2-fluoro-3- (pyridine-2-yl)benzoic acid (0.24 g, 0.72 mmol, 23percent yield) as a light red-colored TFA salt and methyl 2-fluoro-3-(pyridine-2-yl)benzoate (0.19 g, 0.55 mmol, 17percent yield) as a golden syrup-colored TFA salt.

References: [1]Patent: WO2007/61930,2007,A1 .Location in patent: Page/Page column 63-64.

12
[ 206551-41-9 ]
[ 1389287-37-9 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4502 - 4505.

13
[ 206551-41-9 ]
[ 1389287-38-0 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4502 - 4505.

14
[ 206551-41-9 ]
[ 89415-43-0 ]
[ 177942-40-4 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4502 - 4505.

15
[ 161957-56-8 ]
[ 74-88-4 ]
[ 206551-41-9 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 50℃; for 24h;	To a solution of 3-bromo-2-fluorobenzoic acid (10 g, 0.045 mol) in N,N-dimethylformamide (50 mL) was added iodomethane (5 mL) dropwise. The reaction was heated to 50° C. for 24 hours. After the reaction was cooled and diluted with water (500 mL), ethyl acetate (200 mL) was added. The organic phase was separated, dried over MgSO4, filtered, and concentrated to provide the title compound

References: [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4502 - 4505.
[2]Patent: US2012/220572,2012,A1 .Location in patent: Page/Page column 85.
[3]Organic Letters,2017,vol. 19,p. 1112 - 1115.

16
[ 206551-41-9 ]
[ 89415-43-0 ]
[ 1389287-35-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 85℃; for 10h;	To a solution of Example 223A (3.1 g, 13 mmol) in dimethoxyethane (25 mL) was added (4-aminophenyl)boronic acid (2.77 g, 16 mmol) and Na2CO3 (3.38 g, 31.2 mmol) in water (6 mL) followed by 1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride:dichloromethane:complex (652 mg, 0.8 mmol). The mixture was heated to 85° C. for 10 hours. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water followed by brine then dried over magnesium sulfate. After filtration and concentration, the crude product was purified by flash chromatography (1percent-100percent ethyl acetate/hexane) to provide the title compound.

References: [1]Patent: US2012/220572,2012,A1 .Location in patent: Page/Page column 85.

17
[ 206551-41-9 ]
[ 89415-43-0 ]
[ 1389287-37-9 ]

References: [1]Patent: US2012/220572,2012,A1 .

18
[ 206551-41-9 ]
[ 918523-76-9 ]

References: [1]Patent: WO2011/59610,2011,A1 .

19
[ 206551-41-9 ]
[ 1195768-18-3 ]

Yield	Reaction Conditions	Operation in experiment
76%		In a 500 mL flask was placed 1 ,1 -dimethylethyl carbamate (6.03 g, 51 .5 mmol), <strong>[206551-41-9]methyl 3-bromo-2-fluorobenzoate</strong> (10 g, 42.9 mmol), Pd2(dba)3»CHCI(0.89 g, 0.86 mmol), xantphos (1 .49 g, 2.57 mmol) and cesium carbonate (16.8 g, 51 .5 mmol). The flask was sealed with a rubber septum, placed under high vacuum, and toluene (200 mL) was added. Three cycles of high vacuum/N2 were performed and the reaction mixture was stirred at 90C overnight. The reaction was filtered through a pad of celite with EtOAc washing and concentrated. To the residue was added DCM (200 ml_) followed by TFA (50 ml_, 649 mmol), and the mixture was stirred at rt for 1 h. The volatiles were removed under reduced pressure and the residue was taken up in EtOAc and washed with saturated NaHCO3 and brine. The organic layer was dried over NaSO4, loaded onto silica and columnchromatographed on silica with 5% to 50% EtOAc:hexane to give the title compound. 5.53 g (76% yield). 1 H-NMR (400 MHz, DMSO-d6) delta 6.92 - 7.01 (m, 3 H), 5.37 (s, 2 H), and 3.81 (s, 3 H). MS (ESI): 170 [M+H]+.

References: [1]Patent: WO2011/59610,2011,A1 .Location in patent: Page/Page column 86-87.
[2]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 358 - 362.
[3]Patent: US2009/298815,2009,A1 .

20
[ 206551-41-9 ]
[ 1195768-27-4 ]