[ CAS No. 292621-45-5 ]

Name: 292621-45-5|4-Bromo-2-fluorobenzamide|96%
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Quality Control of [ 292621-45-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 292621-45-5 ]

Product Details of [ 292621-45-5 ]

CAS No. :	292621-45-5	MDL No. :	MFCD03094432
Formula :	C₇H₅BrFNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MJDRFCPNHLHNON-UHFFFAOYSA-N
M.W :	218.02	Pubchem ID :	2773331
Synonyms :

Calculated chemistry of [ 292621-45-5 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	42.19
TPSA :	43.09 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) :	-6.2 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.33
Log Po/w (XLOGP3) :	2.01
Log Po/w (WLOGP) :	2.11
Log Po/w (MLOGP) :	2.38
Log Po/w (SILICOS-IT) :	2.08
Consensus Log Po/w :	1.98

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.8
Solubility :	0.349 mg/ml ; 0.0016 mol/l
Class :	Soluble
Log S (Ali) :	-2.54
Solubility :	0.626 mg/ml ; 0.00287 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.13
Solubility :	0.163 mg/ml ; 0.000748 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.26

Safety of [ 292621-45-5 ]

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 [ 292621-45-5 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 292621-45-5 ]

[ 292621-45-5 ] Synthesis Path-Downstream 1~45

1
[ 18871-66-4 ]
[ 292621-45-5 ]
[ 845306-17-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N,N-dimethylacetamide dimethyl acetal; 4-bromo-2-fluorobenzamide at 120℃; for 2h; Stage #2: With sodium hydroxide; hydroxylamine hydrochloride; acetic acid In 1,4-dioxane; water at 20 - 90℃; for 3.5h; Stage #3: With sodium hydrogencarbonate In water	50 Description 50 5- (4-Bromo-2-fluorophenyl)-3-methyl-1, 2, 4-OXADIAZOLE (D50) 4-Bromo-2-fluorobenzoic acid (5.27g) was heated at reflux in thionyl chloride (50ML) for 4h and then allowed to cool. The mixture was evaporated in vacuo and the residue re- evaporated with DCM (2x) to give the acid chloride as a light brown oil. This was added dropwise to vigorously stirred, ice-cooled concentrated aqueous ammonia (50ml) and when addition was complete the mixture was stirred for 5min and then extracted (3x) with EtOAc. The combined organic extracts were washed with water and brine, dried (NA2SO4) and evaporated to give 4-bromo-2-fluorobenzamide as a white solid (4. 72G). This material and N, N-DIMETHYLACETAMIDE dimethylacetal (17ML) were heated together at 120°C for 2h. The reaction was allowed to cool to rt and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and EtOAc. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated to a gum. This was purified by chromatography (silica gel, eluant hexane/EtOAc) to give the acylamidine intermediate as a gum which solidified in vacuo (4.15g). Hydroxylamine hydrochloride (1. 32G) in 1N NAOH SOLUTION (23. 5MI) was added, followed by dioxane (23. 5MOI) then ACOH (30MOL) The reaction mixture was stirred at rt for 30min then heated at 90°C for 3h. The reaction was allowed to cool to rt and poured into water. The pH was adjusted to-9 by addition of solid NAHC03 AND the precipitated product was collected by filtration, washed on the filter with water and dried at 40°C IN VACUO to give the title compound (D50) as a greyish-brown solid (2. 82G). LCMS electrospray (+ve) 257 and 259 (MH+).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2005/14571, 2005, A1 Location in patent: Page/Page column 30-31

2
[ 151982-51-3 ]
[ 292621-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; In water; at 0℃; for 0.0833333h;	Description 50 5- (4-Bromo-2-fluorophenyl)-3-methyl-1, 2, 4-OXADIAZOLE (D50) 4-Bromo-2-fluorobenzoic acid (5.27g) was heated at reflux in thionyl chloride (50ML) for 4h and then allowed to cool. The mixture was evaporated in vacuo and the residue re- evaporated with DCM (2x) to give the acid chloride as a light brown oil. This was added dropwise to vigorously stirred, ice-cooled concentrated aqueous ammonia (50ml) and when addition was complete the mixture was stirred for 5min and then extracted (3x) with EtOAc. The combined organic extracts were washed with water and brine, dried (NA2SO4) and evaporated to give 4-bromo-2-fluorobenzamide as a white solid (4. 72G). This material and N, N-DIMETHYLACETAMIDE dimethylacetal (17ML) were heated together at 120C for 2h. The reaction was allowed to cool to rt and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and EtOAc. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated to a gum. This was purified by chromatography (silica gel, eluant hexane/EtOAc) to give the acylamidine intermediate as a gum which solidified in vacuo (4.15g). Hydroxylamine hydrochloride (1. 32G) in 1N NAOH SOLUTION (23. 5MI) was added, followed by dioxane (23. 5MOI) then ACOH (30MOL) The reaction mixture was stirred at rt for 30min then heated at 90C for 3h. The reaction was allowed to cool to rt and poured into water. The pH was adjusted to-9 by addition of solid NAHC03 AND the precipitated product was collected by filtration, washed on the filter with water and dried at 40C IN VACUO to give the title compound (D50) as a greyish-brown solid (2. 82G). LCMS electrospray (+ve) 257 and 259 (MH+).
	With ammonia; at 0℃; for 0.0833333h;	5-(4-Bromo-2-fluorophenyl)-3-methyl-1 ,2,4-oxadiazole (D32); 4-Bromo-2-fluorobenzoic acid (5.27g) was heated at reflux in thionyl chloride (50ml) for 4h and then allowed to cool. The mixture was evaporated in vacuo and the residue re- evaporated with DCM (2x) to give the acid chloride as a light brown oil. This was added dropwise to vigorously stirred, ice-cooled concentrated aqueous ammonia (50ml) and when addition was complete the mixture was stirred for 5min and then extracted (3x) with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated to give 4-bromo-2-fluorobenzamide as a white solid (4.72g). This material and /V,Lambda/-dimethylacetamide dimethyl acetal (17ml) were heated together at 1200C for 2h. The reaction was allowed to cool to rt and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and EtOAc. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated to a gum. This was purified by chromatography (silica gel, eluant hexane/EtOAc) to give the acylamidine intermediate as a gum which solidified in vacuo (4.15g). Hydroxylamine hydrochloride (1.32g) in 1 N NaOH solution (23.5ml) was added, followed by dioxane (23.5ml) then AcOH (30ml). The reaction mixture was stirred at rt for 30min then heated at 900C for 3h. The reaction was allowed to cool to rt and poured into water. The pH was adjusted to ~9 by addition of solid NaHCO3 and the precipitated product was collected by filtration, washed on the filter with water and dried at 4O0C in vacuo to give the title compound (D32) as a greyish-brown solid (2.82g). LCMS electrospray (+ve) 257 and 259 (MH+).
	With ammonia; In water; at 0℃; for 0.0833333h;	Description 16; 5-(4-Bromo-2-fluorophenyl)-3-methyl-1 ,2,4-oxadiazole (D16); 4-Bromo-2-fluorobenzoic acid (5.27g) was heated at reflux in thionyl chloride (50ml) for 4h and then allowed to cool. The mixture was evaporated in vacuo and the residue re- evaporated with dichloromethane (2x) to give the acid chloride as a light brown oil. This was added dropwise to vigorously stirred, ice-cooled concentrated aqueous ammonia (50ml) and when addition was complete the mixture was stirred for 5min and then extracted with ethyl acetate (3x). The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated to give 4-bromo-2-fluorobenzamide as a white solid (4.72g). This material and Lambda/,Lambda/-dimethylacetamide dimethylacetal (17ml) were heated together at 1200C for 2h. The reaction was allowed to cool to rt and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated to a gum. This was purified by chromatography (silica gel, eluant hexane/ethyl acetate) to give the acylamidine intermediate as a gum which solidified in vacuo (4.15g). Hydroxylamine hydrochloride (1.32g) in 1 N sodium hydroxide solution (23.5ml) was added, followed by dioxane (23.5ml) then acetic acid (30ml). The reaction mixture was stirred at rt for 30min then heated at 900C for 3h. The reaction was allowed to cool to rt and poured into water. The pH was adjusted to ~9 by addition of solid NaHCO3 and the precipitated product was collected by filtration, washed on the filter with water and dried at 400C in vacuo to give the title compound (D16) as a greyish-brown solid (2.82g). LCMS electrospray (+ve) 257 and 259 (MH+).

Reference： [1]Patent: WO2005/14571,2005,A1 .Location in patent: Page/Page column 30-31
[2]Patent: WO2006/40192,2006,A1 .Location in patent: Page/Page column 33
[3]Patent: WO2006/29906,2006,A1 .Location in patent: Page/Page column 18-19

3
[ 105942-08-3 ]
[ 292621-45-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	With aluminum oxide; methanesulfonate at 120℃; for 0.5h;	Charge a flask with acidic alumina (Al2O3) (3.03 g, 29.718 mmol) and methanesulfonic acid (10 mL). Heat the resulting solution to 12O0C, and add 4-bromo-2-fluorobenzonitrile (2.00 g, 9.999 mmol) in one portion. Stir the resulting mixture for 30 minutes, then cool the reaction to room temperature and pour it into water (50 mL). Extract the aqueous mixture with dichloromethane (3 x 30 mL). Combine the organic extracts; dry(Na2SO4); remove the solids by filtration; and concentrate the filtrate in vacuo, affording 2.14 g (98%) 4-bromo-2-fluoro-benzamide as a white solid. 1HNMR (DMSO-U5) δ 7.706 (d, 2H, J = 21.1 Hz), 7.598 (dd, IH, J= 1.9, 10.1 Hz), 7.557 (dd, IH, J= 8.0, 8.0 Hz), 7.446 (ddd, IH, J= 0.4, 1.9, 8.1 Hz).
88%	With sodium perborate In 1,4-dioxane; water for 2h; Heating / reflux;	4 4-Bromo-2-fluoro-cyanobenzne (2.Og, 10 mmol) and sodium perborate (3.0g, 20 mmol) were dissolved in dioxane (40ml), water (40ml) and heated at reflux for 1 hour. An extra 2.0 g of sodium perborate was added and the reaction was refluxed for 1 hour. The reaction was cooled, extracted with DCM (2 x 100 ml), dried and the solvent was removed in vacuo to yield a white solid. Ether was added to dissolve any remaining starting material and the solid was stirred for 10 minutes and filtered to give the title compound (1.7g, 88%). NMR (400.132 MHz) 7.74 (brs, IH), 7.68 (brs, IH), 7.64 (d, IH), 7.61 (t, IH), 7.50 (d, IH).
88%	Stage #1: 4-bromo-6-fluorobenzonitrile With sulfuric acid; trifluoroacetic acid at 20 - 50℃; for 25h; Stage #2: With water at 0℃; for 1.5h;	6.1 A solution of 4-bromo-2-fluorobenzonitrile (1.00 g, 5.00 mmol), trifluoroacetic acid (3.5 mL, 45 mmol), and sulfuric acid (3.5 mL, 66 mmol) was stirred at ambient temperature for 4 hours, at 30 °C for 15 hours, and at 50 °C for 6 hours. After cooling to 0 °C, water (20 mL) was added, and the resulting suspension was stirred at 0 °C for 1.5 hours. The solids were collected by vacuum filtration, rinsed with excess water, and dried to afford 4-bromo-2-fluorobenzamide (0.956 g, 88%) as an off-white solid which was carried on without further purification.

87%	With sulfuric acid; trifluoroacetic acid at 40℃; for 16h;	A A solution of 4-bromo-2- fluorobenzonitrile (10.0 g, 50.0 mmol) in a 70 mL mixture of TFA (56.0 mL, 727 mmol)- sulfuric acid (14.0 mL, 263 mmol) (4:1 V/V) was stirred at 40 0C for 16 h. The reaction was poured while still warm over ice water. The product precipitated and the solid was filtered and dried to give 4-bromo-2-fTuorobenzamide (9.53 g, 43.7 mmol, 87 % yield) as a white solid. MS (ESI) m/z 218.1 [M]+, 220.1 [M+2]+.
73%	In Petroleum ether	300.1 Step 1: Step 1: 4-Bromo-2-fluorobenzamide A mixture of 4-bromo-2-fluorobenzonitrile (50.0 g, 249 mmol) and aluminum oxide (76.5 g, 750 mmol) in methanesulfonic acid (650 mL) was stirred at 120° C. for 1 h. The resultant mixture was quenched with water and extracted with DCM. The organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue was purified via flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate in petroleum ether) to yield 40 g (73%) of the title compound as a gray solid. LCMS (ESI): [M+H]+=218/220.
1284 mg	With dihydrogen peroxide; potassium carbonate In water; dimethyl sulfoxide at 20℃; Cooling with ice;	78.1 To a solution of Compound 1 (3.00 g) and potassium carbonate (311 mg) in dimethylsulfoxide (45 mL) wasadded an aqueous 30% hydrogen peroxide solution (1.7 mL) under ice cooling, and the mixture was stirred at roomtemperature overnight. To this was added an additional aqueous 30% hydrogen peroxide solution (0.5 mL), and themixture was further stirred at room temperature for 4 days. Water was slowly added dropwise, and the obtained crystalswere collected by filtration, washed with diethyl ether and subsequently vacuum-dried to obtain Compound 2 (1284 mg)as a colorless solid.MS (m/z): 218/220 [M+H]+
	With Rhodococcus rhodochrous ATCC BAA 870 cobalt nitrile hydratase In aq. buffer at 30℃; Enzymatic reaction;	Composition of the reaction mixture General procedure: 1800 μL (90%) Tris buffer (50 mM, pH 7.6) and 200 μL(10%) of methanol or acetone. In a 2 mL Eppendorf, NHase (10 mg) was added followed by Trisbuffer. Nitrile substrate (10 mg dissolved in 200 μL methanol or acetone) was added to the 2 mLEppendorf tube. (If an amine group was present on the nitrile substrate a Tris buffer of pH 9 wasused). The reaction mixture was incubated at 30 °C on an ESCO Provocell microplateshaker/incubator (Esco Technologies, Halfway House, South Africa) (199 rpm). The reaction wasallowed to proceed for 24 h, 48 h or 5 d, depending on conversion, as monitored by TLC analysis.Ethyl acetate and water were added to the reaction mixture, and after separation, the organic layerwas concentrated under reduced pressure, and the resulting mixture was then purified by silica gelcolumn chromatography eluting with 20% to 90% ethyl acetate/ hexane.

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2007/87488, 2007, A2 Location in patent: Page/Page column 24
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2006/64251, 2006, A1 Location in patent: Page/Page column 61
[3]Current Patent Assignee: PFIZER INC - WO2011/29027, 2011, A1 Location in patent: Page/Page column 51
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2010/62571, 2010, A1 Location in patent: Page/Page column 129
[5]Current Patent Assignee: ROCHE HOLDING AG - US2018/65983, 2018, A1
[6]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - EP2862856, 2015, A1 Location in patent: Paragraph 0883; 0884
[7]Mashweu, Adelaide R.; Chhiba‐Govindjee, Varsha P.; Bode, Moira L.; Brady, Dean [Molecules, 2020, vol. 25, # 1]

4
[ 18871-66-4 ]
[ 292621-45-5 ]
[ 845306-18-5 ]

Yield	Reaction Conditions	Operation in experiment
	at 120℃; for 2h;	32 5-(4-Bromo-2-fluorophenyl)-3-methyl-1 ,2,4-oxadiazole (D32); 4-Bromo-2-fluorobenzoic acid (5.27g) was heated at reflux in thionyl chloride (50ml) for 4h and then allowed to cool. The mixture was evaporated in vacuo and the residue re- evaporated with DCM (2x) to give the acid chloride as a light brown oil. This was added dropwise to vigorously stirred, ice-cooled concentrated aqueous ammonia (50ml) and when addition was complete the mixture was stirred for 5min and then extracted (3x) with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated to give 4-bromo-2-fluorobenzamide as a white solid (4.72g). This material and /V,Λ/-dimethylacetamide dimethyl acetal (17ml) were heated together at 1200C for 2h. The reaction was allowed to cool to rt and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and EtOAc. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated to a gum. This was purified by chromatography (silica gel, eluant hexane/EtOAc) to give the acylamidine intermediate as a gum which solidified in vacuo (4.15g). Hydroxylamine hydrochloride (1.32g) in 1 N NaOH solution (23.5ml) was added, followed by dioxane (23.5ml) then AcOH (30ml). The reaction mixture was stirred at rt for 30min then heated at 900C for 3h. The reaction was allowed to cool to rt and poured into water. The pH was adjusted to ~9 by addition of solid NaHCO3 and the precipitated product was collected by filtration, washed on the filter with water and dried at 4O0C in vacuo to give the title compound (D32) as a greyish-brown solid (2.82g). LCMS electrospray (+ve) 257 and 259 (MH+).
	at 120℃; for 2h;	16 Description 16; 5-(4-Bromo-2-fluorophenyl)-3-methyl-1 ,2,4-oxadiazole (D16); 4-Bromo-2-fluorobenzoic acid (5.27g) was heated at reflux in thionyl chloride (50ml) for 4h and then allowed to cool. The mixture was evaporated in vacuo and the residue re- evaporated with dichloromethane (2x) to give the acid chloride as a light brown oil. This was added dropwise to vigorously stirred, ice-cooled concentrated aqueous ammonia (50ml) and when addition was complete the mixture was stirred for 5min and then extracted with ethyl acetate (3x). The combined organic extracts were washed with water and brine, dried (Na2SO4) and evaporated to give 4-bromo-2-fluorobenzamide as a white solid (4.72g). This material and Λ/,Λ/-dimethylacetamide dimethylacetal (17ml) were heated together at 1200C for 2h. The reaction was allowed to cool to rt and the liquid evaporated in vacuo to give a brown gum which was partitioned between saturated aqueous sodium hydrogen carbonate and ethyl acetate. The organic extract was washed with water and brine, dried (Na2SO4) and evaporated to a gum. This was purified by chromatography (silica gel, eluant hexane/ethyl acetate) to give the acylamidine intermediate as a gum which solidified in vacuo (4.15g). Hydroxylamine hydrochloride (1.32g) in 1 N sodium hydroxide solution (23.5ml) was added, followed by dioxane (23.5ml) then acetic acid (30ml). The reaction mixture was stirred at rt for 30min then heated at 900C for 3h. The reaction was allowed to cool to rt and poured into water. The pH was adjusted to ~9 by addition of solid NaHCO3 and the precipitated product was collected by filtration, washed on the filter with water and dried at 400C in vacuo to give the title compound (D16) as a greyish-brown solid (2.82g). LCMS electrospray (+ve) 257 and 259 (MH+).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/40192, 2006, A1 Location in patent: Page/Page column 33
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2006/29906, 2006, A1 Location in patent: Page/Page column 18-19

5
[ 292621-45-5 ]
[ 73183-34-3 ]
[ 957346-57-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium acetate In 1,4-dioxane at 90℃; for 0.35h; Microwave irradiation;	E.1 E.1 2-Fluoro-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)benzamide[0360] Pd(dppf)Cl2 (21 mg, 0.028 mmol, 0.03 eq), potassium acetate (277 mg, 1.03 mmol, 2.82 mmol, 3 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (263 mg, 1.1 eq), and 4-bromo-2- fluorobenzamide (205 mg, 0.94 mmol, 1.0 eq) are suspended in anhydrous dioxane (2 mL) in a 5-mL microwave vial and the mixture is purged with nitrogen for 1 min. The resulting slurry is heated for 20 min at 90 0C in a microwave (Biotage Initiator, Absorption high). DCM (2 mL) is added to the dark brown reaction mixture and the resulting suspension is filtered. The precipitate collected on the frit is washed with DCM (2 x 5 mL) and the solid residue remaining in the microwave tube is washed with DCM (2 x 2 mL). The DCM washes and filtrates are combined. Celite (1.5 g) is added to the organic extracts and the solvent is evaporated on a rotary evaporator to provide a free-flowing powder. The Celite/compound mixture was loaded onto a prepacked silica column (10 g of silica) and the column eluted with 1 :1 hexane/ethyl acetate to provide the crude 2-fluoro-4-(4,4,5, 5-tetramethyl-l, 3,2- dioxaborolan-2-yl)benzamide (307 mg, 124% recovery). The product was used in the next step without further purification. LCMS Purity: 78% by UV 254 nm detection); LCMS-ESI (m/z): calcd for Ci3H17BFNO3, 265.1; [M+H]+ found, 266.1.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In 1,4-dioxane

Reference： [1]Current Patent Assignee: GALAPAGOS - WO2008/65198, 2008, A1 Location in patent: Page/Page column 82-83
[2]Currie, Kevin S.; Kropf, Jeffrey E.; Lee, Tony; Blomgren, Peter; Xu, Jianjun; Zhao, Zhongdong; Gallion, Steve; Whitney, J. Andrew; Maclin, Deborah; Lansdon, Eric B.; Maciejewski, Patricia; Rossi, Ann Marie; Rong, Hong; Macaluso, Jennifer; Barbosa, James; Di Paolo, Julie A.; Mitchell, Scott A. [Journal of Medicinal Chemistry, 2014, vol. 57, # 9, p. 3856 - 3873]

6
[ 602306-61-6 ]
[ 292621-45-5 ]
C₁₈H₁₉FN₆O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane

Reference： [1]Location in patent: scheme or table Jones, Clifford D.; Andrews, David M.; Barker, Andrew J.; Blades, Kevin; Byth, Kate F.; Finlay, M. Raymond V.; Geh, Catherine; Green, Clive P.; Johannsen, Marie; Walker, Mike; Weir, Hazel M. [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 24, p. 6486 - 6489]

7
[ 893420-22-9 ]
[ 292621-45-5 ]
C₁₈H₁₈F₂N₆O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane

8
[ 112704-79-7 ]
[ 292621-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia
	With 4-methyl-morpholine
	Stage #1: 2-fluoro-4-bromobenzoic acid With 1,1'-carbonyldiimidazole In dichloromethane at 0℃; Stage #2: With ammonium hydroxide In dichloromethane at 0℃;	4.1 Example 4Synthesis of 1-r2-f4-(3-Fluoro-4-ri-(2-methoxy-ethvn-1 H-M .2.41triazol-3-vn- phenyl)-3,6-dihvdro-2H-pyridin-1-yl)-2-oxo-ethvϖ-3-methoxy-pyrrolidine-3- carboxylic acid r3-(6-isopropoxy-pyridin-3-yl)-1 H-indazol-5-yll-amide Svnthesis of (S)-1-r2-(4-(3-fluoro-4-ri-(2-methoxy-ethyl)-1 H-λ .2,41triazol-3-yll- phenyl}-3,6-dihvdro-2^-pyridin-1-yl)-2-oxo-ethvn-3-methoxy-pyrrolidine-3- carboxylic acid r3-(6-isopropoxy-pyridin-3-yl)-1 H-indazol-S-yli-amideStep 1 : Preparation of 4-bromo-2-f luoro-benzamide At 0 0C, 1 ,1'-carbonyldiimidazole (8.8 g, 54.3 mmol) was added in portions to a stirred mixture of 4-bromo-2-fluorobenzoic acid (6 g, 27.3 mmol) in dichloromethane (100 ml). After 20 minutes, a clear solution was obtained. Ammonium hydroxide (28%, 30 ml) was added and the mixture was stirred overnight. Aqueous layer was isolated, extracted with dichloromethane twice. Combined organic extracts were washed with water, 1 N HCI twice, water, brine and dried (MgSO4). Solvent was removed under vacuum, and the solid was washed with hexane to afford 4-bromo-2- fluoro-benzamide 2BL (5.56 g).

Reference： [1]Location in patent: body text Jones, Clifford D.; Andrews, David M.; Barker, Andrew J.; Blades, Kevin; Byth, Kate F.; Finlay, M. Raymond V.; Geh, Catherine; Green, Clive P.; Johannsen, Marie; Walker, Mike; Weir, Hazel M. [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 24, p. 6486 - 6489]
[2]Currie, Kevin S.; Kropf, Jeffrey E.; Lee, Tony; Blomgren, Peter; Xu, Jianjun; Zhao, Zhongdong; Gallion, Steve; Whitney, J. Andrew; Maclin, Deborah; Lansdon, Eric B.; Maciejewski, Patricia; Rossi, Ann Marie; Rong, Hong; Macaluso, Jennifer; Barbosa, James; Di Paolo, Julie A.; Mitchell, Scott A. [Journal of Medicinal Chemistry, 2014, vol. 57, # 9, p. 3856 - 3873]
[3]Current Patent Assignee: MERCK & CO INC - WO2009/105500, 2009, A1 Location in patent: Page/Page column 228-229

9
[ 292621-45-5 ]
[ 17950-40-2 ]
C₉H₉BrFNO*F₆P^(1-)*H⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In 1,2-dichloro-ethane for 1h; Reflux;	4.2 Step 2: Preparation of compound 3BL A mixture of compound 2BL (4.66 g, 21.48 mmol), Et3OPF6 (6.4 g, 25.77 mmol) in dichloroethane (86 ml) was refluxed for 1 hr. Solvent was removed under reduced pressure. The crude was cooled to 0 0C, triturated with ether and filtered to give the desired product 3BL (7.5 g).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2009/105500, 2009, A1 Location in patent: Page/Page column 229

10
[ 292621-45-5 ]
[ 107-11-9 ]
[ 1221408-00-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl acetamide at 130℃;

Reference： [1]Location in patent: scheme or table Ahmad, Saleem; Ngu, Khehyong; Miller, Keith J.; Wu, Ginger; Hung, Chen-pin; Malmstrom, Sarah; Zhang, Ge; O'Tanyi, Eva; Keim, William J.; Cullen, Mary Jane; Rohrbach, Kenneth W.; Thomas, Michael; Ung, Thao; Qu, Qinling; Gan, Jinping; Narayanan, Rangaraj; Pelleymounter, Mary Ann; Robl, Jeffrey A. [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 1128 - 1133]

11
[ 292621-45-5 ]
[ 4637-24-5 ]
C₁₀H₁₀BrFN₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 85℃; for 2h; Inert atmosphere;	B 4-Bromo-2- fluorobenzamide (9.53 g, 43.7 mmol) and N,N-dimethylformamide dimethylacetal (75.0 mL) were combined in a 500 mL round bottom flask and purged with nitrogen. The reaction was heated to reflux at 85 0C for 2 h. The resulting mixture was concentrated under reduced pressure and dried under vacuum to afford a yellow oil. The oil was suspended in concentrated acetic acid (75.0 mL) and cooled to 0 0C. Hydrazine hydrate (21.88 g, 437 mmol) was added dropwise and the mixture was allowed to stir at rt for 5 h. The reaction was poured warm onto cold ice and extracted with dichloromethane (3x200 mL). Organic volatiles were removed under reduced pressure to afford 3-(4-bromo-2- fluorophenyl)-4H-l,2,4-triazole (7.20 g, 29.7 mmol, 68.1 % yield) as a white solid. MS (ESI) m/z 241.9 [M]+, 243.9 [M+2]+.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2010/62571, 2010, A1 Location in patent: Page/Page column 129-130

12
[ 7664-41-7 ]
[ 112704-79-7 ]
[ 292621-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-fluoro-4-bromobenzoic acid With Chloro-oxo-acetic acid In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; Stage #2: ammonia In tetrahydrofuran; water at 0 - 20℃;	6a To a stirred solution of 4-bromo-2-fluorobenzoic acid (1.5 g, 6.84 mmol) in DCM(15 mL) was added dropwise oxalyl chloride (3.45 g, 27.39 mmol) at 0 °C. After addition was complete, 2-3 drops of DMF were added at 0 0C and the reaction mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dry THF (20 mL). To this solution was added aq. ammonia (50 mL) at 0 °C. The reaction mixture was warmed to and stirred at room temperature for 30 min. The solvent was removed under reduced pressure and the residue was azeotroped with toluene to obtain 1.3 g of product. 1H NMR (CDCl3, Freebase): δ (ppm) 8.0 (t, IH), 7.40 (d, IH), 7.30 (d, IH), 6.60 (bs, IH), 5.9 (bs, IH).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2010/99238, 2010, A1 Location in patent: Page/Page column 33

13
[ 292621-45-5 ]
[ 62-57-7 ]
[ 1242137-20-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In water; N,N-dimethyl-formamide at 95 - 100℃; for 48h;	6b 4-Bromo-2-fluorobenzamide (0.5 g, 2.29 mmol), 2 aminoisobutyric acid (0.354 g,3.54 mmol), CuI (87 mg, 0.458 mmol), and K2CO3 (0.790 g, 5.72 mmol) were mixed in DMF (5 mL). H2O (0.5 mL) and TEA (11 mg, 0.1 mmol) were added followed by 2-acetyl cyclohexanone (60 mg, 0.428 mmol). The reaction mixture was heated to 95-100 °C for 48 h. The reaction mixture was diluted with H2O (20 mL) and the aqueous layer was washed with ethyl acetate (20 mL). The aqueous layer was acidified with IM citric acid to pH 4 and the product was extracted with ethyl acetate (20 mL x 3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the product. 1H NMR (DMSO, Freebase): δ (ppm) 7.55-7.45 (t, IH), 7.20 (bs, IH), 7.05 (bs, IH), 6.80 (bs, IH), 6.35-6.30 (d, IH), 6.18-6.10 (d, IH), 1.42 (s, 6H).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2010/99238, 2010, A1 Location in patent: Page/Page column 33

14
[ 292621-45-5 ]
[ 4637-24-5 ]
[ 1269646-51-6 ]

Yield	Reaction Conditions	Operation in experiment
96%	at 100℃; for 3.5h;	6.2 A suspension of 4-bromo-2-fluorobenzamide (0.929 g, 4.26 mmol) in l,l-dimethoxy-N,N-dimethylmethanamine (1.66 mL, 11.7 mmol) in a round bottom flask topped with a short path distillation head was heated to 100-100 °C. The resulting solution was allowed to stir at this temperature for 3.5 hours, during which time the MeOH that was formed was collected from the distillation condenser. Heptane (5 mL) was added dropwise and the resulting suspension was cooled to 0-5 °C. The solids were collected by vacuum filtration, rinsed with excess heptane, and dried to afford (E)-4-bromo-N- ((dimethylamino)methylene)-2-fluorobenzamide (1.111 g, 96%) as an off-white solid which was carried on without further purification.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/29027, 2011, A1 Location in patent: Page/Page column 51

15
[ 292621-45-5 ]
[ 1228014-45-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 3.5 h / 100 °C 2: hydrazine; acetic acid / 2 h / 95 - 100 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/29027, 2011, A1

16
[ 292621-45-5 ]
[ 1269646-54-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: 3.5 h / 100 °C 2.1: hydrazine; acetic acid / 2 h / 95 - 100 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 3.2: 2 h / 0 - 20 °C 3.3: 92.5 h / 20 - 90 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: 3.5 h / 100 °C 2.1: hydrazine; acetic acid / 2 h / 95 - 100 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 3.2: 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/29027, 2011, A1
[2]Current Patent Assignee: PFIZER INC - WO2011/29027, 2011, A1

17
[ 292621-45-5 ]
[ 1269646-54-9 ]
[ 1269646-55-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: 3.5 h / 100 °C 2.1: hydrazine; acetic acid / 2 h / 95 - 100 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 3.2: 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/29027, 2011, A1

18
[ 292621-45-5 ]
[ 1269643-46-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: 3.5 h / 100 °C 2.1: hydrazine; acetic acid / 2 h / 95 - 100 °C 3.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C 3.2: 2 h / 0 - 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC - WO2011/29027, 2011, A1

19
[ 292621-45-5 ]
C₂₃H₂₇FN₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: copper(l) iodide; potassium phosphate; 1,10-Phenanthroline / 1,4-dioxane / 120 °C / Sealed tube 2: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene / toluene
	Multi-step reaction with 2 steps 1: copper(l) iodide; 1,10-Phenanthroline; potassium phosphate / 1,4-dioxane / 120 °C / Inert atmosphere; Sealed tube 2: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; sodium t-butanolate / toluene / Inert atmosphere; Reflux

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2015/197503, 2015, A1
[2]Pinard, Emmanuel; Green, Luke; Reutlinger, Michael; Weetall, Marla; Naryshkin, Nikolai A.; Baird, John; Chen, Karen S.; Paushkin, Sergey V.; Metzger, Friedrich; Ratni, Hasane [Journal of Medicinal Chemistry, 2017, vol. 60, # 10, p. 4444 - 4457]

20
[ 292621-45-5 ]
[ 1159811-97-8 ]
4-bromo-2-fluoro-N-(2-methylimidazo[1,2-a]pyrazin-6-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	With potassium phosphate; copper(l) iodide; 1,10-Phenanthroline; In 1,4-dioxane; at 120℃;Sealed tube;	In a sealed tube, 4-bromo-2-fluorobenzamide (150 mg, 0.688 mmol), 6-bromo-2- methylimidazo[l,2-a]pyrazine (146 mg, 0.688 mmol), copper (I) iodide (13.1 mg, 0.068 mmol, 0.1 eq.), K3PO4 (307 mg, 1.44 mmol, 2.1 eq.) and 1,10-phenantroline (14.9 mg, 0.138 mmol, 0.2 eq.) in dioxane (5 mL) was heated at 120C overnight. The reaction mixture was filtered on celite, concentrated under vacuo, and purification on column chromatography (S1O2, CH2C12 / MeOH 99/1 to 98/2) afforded 24 mg (10%) of 4-bromo-2-fluoro-N-(2-methylimidazo[l,2- a]pyrazin-6-yl)benzamide. MS (m/e): 349.1 (M+H+, Br).

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 4444 - 4457
[2]Patent: WO2015/197503,2015,A1 .Location in patent: Page/Page column 52

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide	IV-7 3-bromo-4-methylbenzamide General procedure: To a slurry of 3-bromo-4-methylbenzoic acid (2.53 g, 85% purity; 10 mmol) in CH2Cl2(20 mL) at 0° C., under N2, was added oxalyl chloride (0.91 mL; 10.5 mmol), followed by dropwise addition of DMF (0.04 mL; 0.5 mmol). The mixture was stirred 5 min at 0° C., 15 min at rt, and then heated at reflux under N2for 1 h. The mixture was cooled, and poured into NH4OH (30 mL; ca. 30% NH3). Precipitated solids were collected by filtration and purified by flash chromatography (EtOAc/hexanes), affording the title compound as a colorless solid.

22
[ 292621-45-5 ]
(Z)-4-bromo-N-((dimethylamino)methylene)-2-fluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%		300.2 Step 2: Step 2: (Z)-4-Bromo-N-((dimethylamino)methylene)-2-fluorobenzamide A mixture of 4-bromo-2-fluorobenzamide (20.0 g, 91.7 mmol) in dimethoxy-N,N-dimethylmethanamine (150 mL) was stirred at 100° C. for 3 h. The resulting mixture was cooled to room temperature and diluted with hexane. The solid was collected by filtration to yield 23 g (92%) of the title compound as an off-white solid. LCMS (ESI): [M+H]+=273/275.