[ CAS No. 618-89-3 ] {[proInfo.proName]}

Name: 618-89-3|Methyl 3-bromobenzoate|97%
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Quality Control of [ 618-89-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 618-89-3 ]

Product Details of [ 618-89-3 ]

CAS No. :	618-89-3	MDL No. :	MFCD00017777
Formula :	C₈H₇BrO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KMFJVYMFCAIRAN-UHFFFAOYSA-N
M.W :	215.04	Pubchem ID :	12070
Synonyms :

Calculated chemistry of [ 618-89-3 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	45.42
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.55 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.34
Log Po/w (XLOGP3) :	2.91
Log Po/w (WLOGP) :	2.24
Log Po/w (MLOGP) :	2.67
Log Po/w (SILICOS-IT) :	2.36
Consensus Log Po/w :	2.5

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.28
Solubility :	0.113 mg/ml ; 0.000527 mol/l
Class :	Soluble
Log S (Ali) :	-3.12
Solubility :	0.162 mg/ml ; 0.000753 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.33
Solubility :	0.0999 mg/ml ; 0.000465 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.42

Safety of [ 618-89-3 ]

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 [ 618-89-3 ]

* 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 [ 618-89-3 ]
Downstream synthetic route of [ 618-89-3 ]

[ 618-89-3 ] Synthesis Path-Upstream 1~14

1
[ 618-89-3 ]
[ 618-91-7 ]
[ 1751-97-9 ]

Reference： [1] Bulletin of the Chemical Society of Japan, 1980, vol. 53, # 12, p. 3691 - 3695

2
[ 618-89-3 ]
[ 39115-96-3 ]

Reference： [1] Journal of the Chilean Chemical Society, 2012, vol. 57, # 4, p. 1492 - 1496
[2] Patent: WO2009/54923, 2009, A2, . Location in patent: Page/Page column 29; 30; 31
[3] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2010, vol. 65, # 2, p. 178 - 184
[4] Monatshefte fur Chemie, 2010, vol. 141, # 4, p. 479 - 484
[5] Medicinal Chemistry, 2012, vol. 8, # 6, p. 1190 - 1197,8
[6] Medicinal Chemistry, 2012, vol. 8, # 6, p. 1190 - 1197
[7] Zeitschrift fur Naturforschung - Section B Journal of Chemical Sciences, 2015, vol. 70, # 8, p. 609 - 616
[8] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 12, p. 3943 - 3949
[9] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 12, p. 4180 - 4184
[10] Chemical Biology and Drug Design, 2013, vol. 82, # 5, p. 546 - 556
[11] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 1, p. 192 - 194
[12] Chemical Communications, 2015, vol. 51, # 76, p. 14365 - 14368
[13] Journal of Molecular Structure, 2016, vol. 1117, p. 8 - 16
[14] Letters in Drug Design and Discovery, 2016, vol. 13, # 9, p. 968 - 981
[15] Chemical Biology and Drug Design, 2017, vol. 89, # 1, p. 47 - 60

3
[ 928664-98-6 ]
[ 618-89-3 ]
[ 68432-92-8 ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium fluoride; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂ In dimethyl sulfoxide at 130℃; for 18 h; Inert atmosphere; Sealed tube	Step 1: To a vial with a stir bar was added methyl 3-bromobenzoate (1.0 equiv.) 4-isoxazoleboronic acid (1.2 equiv.), PdCl₂(dppf).CH₂Cl₂adduct (0.1 equiv.), 1M KF (2.0) and DMSO (0.10 M). The reaction mixture was degassed with bubbling nitrogen and the vial capped and heated at 130° C. for 18 hr. LCMS analysis indicated the formation of the desired product (MH⁺-176, Rt—0.62 min). The reaction mixture was diluted with a saturated solution of NH₄Cl and extracted with EtOAc (2×). The combined organics were washed with water and brine, dried over MgSO₄, filtered and concentrated. The crude material was purified via flash chromatography over silica gel eluting with heptanes and 0-100percent ethyl acetate gradient. Isolated methyl 3-(cyanomethyl)benzoate in 69percent yield. LCMS (m/z) (M+H)=176.1, Rt=0.62). ¹H NMR (400 MHz, ) δ ppm 3.92 (s, 3H), 3.99 (s, 2H), 7.49-7.55 (m, 1H), 7.62 (d, J=7.83 Hz, 1H), 7.99 (d, J=7.83 Hz, 1H), 8.04 (s, 1H).

Reference： [1] Patent: US2014/275003, 2014, A1, . Location in patent: Paragraph 0182

4
[ 618-89-3 ]
[ 68432-92-8 ]

Reference： [1] Patent: CN106928092, 2017, A,

5
[ 618-89-3 ]
[ 15852-73-0 ]

Reference： [1] Catalysis Science and Technology, 2017, vol. 7, # 6, p. 1297 - 1304
[2] Organic Letters, 2016, vol. 18, # 15, p. 3894 - 3897

6
[ 618-89-3 ]
[ 75-16-1 ]
[ 30951-66-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: at 6 - 20℃; for 3.66667 h; Stage #2: With hydrogenchloride In tetrahydrofuran; diethyl ether; water at 0℃;	EXAMPLE 76; Preparation of N- [ (lS, 2R)-3- { [l- (3-bromophenyl)-l- methylethyl] amino}-1- (3, 5-difluorobenzyl)-2-hydroxypropyl] acetamide; 32 Scheme 8 O Br MeMgBr g NaN3 Br '°H Bu OMe OH Nh THF TFA THF 4 \| kOH SOH 4 reflux H 19 H HOH H N, 1) TFA-0 zon F F 0 HCI 2) Ac-Im F 31 3) HCI 30 30 F 31 F NaOH HOH H Bu F 32 Step 1; Preparation of 2- (3-bromophenyl)-2-propanol 27; To 75 mmol of methylmagnesium bromide in 25 mL of ether stirring at 6 °C is added, dropwise over 10 min, a solution of methyl-3-bromobenzoate (4.3 g, 20 mmol) in 25 mL of dry THF. The mixture is then allowed to warm to ambient temperature and stirred for 3.5 h, then cooled to 0°C and quenched by dropwise addition of aqueous 10percent HC1. The acidified mixture is extracted twice with ethyl acetate, and the combined organic phases are washed with 1 N NaHC03 and with brine. The solution is dried over Na2SO4, concentrated, and chromatographed over silica gel, eluting with 15percent ethyl acetate in heptane, to afford 4.00 g (18.6 mmol, 93percent) of 2- (3-bromophenyl)-2- propanol 27 as a pale yellow oil
14.9 g	at -78 - 20℃; for 2 h;	To a solution of methyl 3-bromobenzoate (15.0 g, 69.8 mmol) in THF (140 mL) at -78 °C was added dropwise a solution of MeMgBr/diethyl ether [3.0M] (58 mL). The reaction mixture was warmed up to room temperature and stirred for 2 h. The solution was poured to an aqueous saturated solution of ammonium chloride and the organic material was extracted with EtOAc. The organic layer was dried over Na₂S0₄, filtered and concentrated to afford the corresponding alcohol (14.9 g) which was used without further purification.
14.9 g	at -78 - 20℃; for 2 h;	To a solution of methyl 3-bromobenzoate (15.0 g, 69.8 mmol) in THF (140 mL) at −78° C. was added dropwise a solution of MeMgBr/diethyl ether [3.0M] (58 mL). The reaction mixture was warmed up to room temperature and stirred for 2 h. The solution was poured to an aqueous saturated solution of ammonium chloride and the organic material was extracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered and concentrated to afford the corresponding alcohol (14.9 g) which was used without further purification.

Reference： [1] Patent: WO2005/95326, 2005, A2, . Location in patent: Page/Page column 189-190
[2] Journal of Organic Chemistry, 1960, vol. 25, # 10, p. 1691 - 1693
[3] Patent: WO2005/70932, 2005, A2, . Location in patent: Page/Page column 51
[4] Patent: WO2015/89067, 2015, A1, . Location in patent: Page/Page column 122
[5] Patent: US9126993, 2015, B2, . Location in patent: Page/Page column 50

7
[ 618-89-3 ]
[ 74-88-4 ]
[ 30951-66-7 ]

Yield	Reaction Conditions	Operation in experiment
4.98 g	Stage #1: With magnesium In diethyl etherReflux Stage #2: for 3 h; Reflux	A solution of methylmagnesium iodide is prepared from 5.79 ml of methyl iodide and 2.2 g of magnesium turnings in refluxing ether. A solution of 5 g of methyl 3- bromobenzoate in 110 ml of ether is then added dropwise and the mixture is refluxed for 3 hours. The reaction mixture is poured onto ice/saturated NH₄C1, the phases are separated by settling, the organic phase is washed with 10percent aHC03 solution and with saturated NaCl solution, and dried over MgS0₄, and the solvent is evaporated off under vacuum. 4.98 g of the expected compound are obtained.

Reference： [1] Patent: WO2013/87643, 2013, A1, . Location in patent: Page/Page column 15

8
[ 618-89-3 ]
[ 10602-06-9 ]

Reference： [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 6, p. 1475 - 1486
[2] Journal of Organic Chemistry, 1985, vol. 50, # 10, p. 1763 - 1765
[3] Journal of Organic Chemistry, 1981, vol. 46, # 11, p. 2280 - 2286
[4] Journal of the American Chemical Society, 2013, vol. 135, # 22, p. 8400 - 8408
[5] Molecules, 2018, vol. 23, # 8,

9
[ 618-89-3 ]
[ 10601-99-7 ]

Reference： [1] Patent: WO2014/168824, 2014, A1,

10
[ 618-89-3 ]
[ 13411-48-8 ]
[ 21860-07-1 ]

Reference： [1] Organic Letters, 2014, vol. 16, # 3, p. 824 - 827

11
[ 618-89-3 ]
[ 21860-07-1 ]

Reference： [1] Patent: WO2008/65508, 2008, A1,

12
[ 618-89-3 ]
[ 52787-19-6 ]

Reference： [1] Patent: CN106928092, 2017, A,

13
[ 618-89-3 ]
[ 99769-19-4 ]

Reference： [1] Organic Letters, 2012, vol. 14, # 18, p. 4814 - 4817,4

14
[ 618-89-3 ]
[ 73183-34-3 ]
[ 269409-73-6 ]

Reference： [1] Synthesis (Germany), 2012, vol. 44, # 14, p. 2173 - 2180

[ 618-89-3 ] Synthesis Path-Downstream 1~88

1
[ 618-89-3 ]
[ 75-16-1 ]
[ 30951-66-7 ]

Yield	Reaction Conditions	Operation in experiment
93%		EXAMPLE 76; Preparation of N- [ (lS, 2R)-3- { [l- (3-bromophenyl)-l- methylethyl] amino}-1- (3, 5-difluorobenzyl)-2-hydroxypropyl] acetamide; 32 Scheme 8 O Br MeMgBr g NaN3 Br 'H Bu OMe OH Nh THF TFA THF 4 \| kOH SOH 4 reflux H 19 H HOH H N, 1) TFA-0 zon F F 0 HCI 2) Ac-Im F 31 3) HCI 30 30 F 31 F NaOH HOH H Bu F 32 Step 1; Preparation of 2- (3-bromophenyl)-2-propanol 27; To 75 mmol of methylmagnesium bromide in 25 mL of ether stirring at 6 C is added, dropwise over 10 min, a solution of methyl-3-bromobenzoate (4.3 g, 20 mmol) in 25 mL of dry THF. The mixture is then allowed to warm to ambient temperature and stirred for 3.5 h, then cooled to 0C and quenched by dropwise addition of aqueous 10% HC1. The acidified mixture is extracted twice with ethyl acetate, and the combined organic phases are washed with 1 N NaHC03 and with brine. The solution is dried over Na2SO4, concentrated, and chromatographed over silica gel, eluting with 15% ethyl acetate in heptane, to afford 4.00 g (18.6 mmol, 93%) of 2- (3-bromophenyl)-2- propanol 27 as a pale yellow oil
		2- (3-Bromo-phenyl)-propan-2-ol :; The 3-bromo-benzoic acid methyl ester (1.0 g, 4.7 mmol) in tetrahydrofuran (10 mL) was brought to-78 C followed by the addition of methyl magnesium bromide (7.7 mL, 10.81 mmol) and warmed to room temperature and stirred for 17 h. The mixture was poured into sat NH4Cl and extracted with ethylacetate. The organic extracts were combined, washed with brine, dried over magnesium sulfate and chromatographed on silica gel using 04% methanol/dichloromethane to afford colorless oil.
14.9 g	In tetrahydrofuran; diethyl ether; at -78 - 20℃; for 2h;	To a solution of methyl 3-bromobenzoate (15.0 g, 69.8 mmol) in THF (140 mL) at -78 C was added dropwise a solution of MeMgBr/diethyl ether [3.0M] (58 mL). The reaction mixture was warmed up to room temperature and stirred for 2 h. The solution was poured to an aqueous saturated solution of ammonium chloride and the organic material was extracted with EtOAc. The organic layer was dried over Na2S04, filtered and concentrated to afford the corresponding alcohol (14.9 g) which was used without further purification.

14.9 g

In tetrahydrofuran; diethyl ether; at -78 - 20℃; for 2h;

To a solution of methyl 3-bromobenzoate (15.0 g, 69.8 mmol) in THF (140 mL) at -78 C. was added dropwise a solution of MeMgBr/diethyl ether [3.0M] (58 mL). The reaction mixture was warmed up to room temperature and stirred for 2 h. The solution was poured to an aqueous saturated solution of ammonium chloride and the organic material was extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to afford the corresponding alcohol (14.9 g) which was used without further purification.

Reference： [1]Patent: WO2005/95326,2005,A2 .Location in patent: Page/Page column 189-190
[2]Journal of Organic Chemistry,1960,vol. 25,p. 1691 - 1693
[3]Patent: WO2005/70932,2005,A2 .Location in patent: Page/Page column 51
[4]Patent: WO2015/89067,2015,A1 .Location in patent: Page/Page column 122
[5]Patent: US9126993,2015,B2 .Location in patent: Page/Page column 50

2
[ 618-89-3 ]
[ 544-92-3 ]
[ 13531-48-1 ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1983,vol. 48,p. 1765 - 1773

3
[ 618-89-3 ]
[ 118062-05-8 ]
[ 125110-18-1 ]

Yield	Reaction Conditions	Operation in experiment
58%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; toluene; at 100℃;	(The following reaction is done in an N2 atmosphere.) To a solution of <strong>[118062-05-8]2,3,4-Trimethoxyphenylboronic acid</strong> (32) (1.40g, 6.60mmol) in toluene (15.0mL) is added EtOH (2.0mL), Pd(PPh3)4 (208mg, 0.18mmol) and Na2CO3·10H2O (4.81g, 16.80mmol) in water (5.2mL). The resulting mixture is carefully degassed (5 times alternating vacuum and flushing with N2). A solution of Methyl-3-bromobenzoate (9) (1.29g, 6.00mmol) in toluene (9.0mL) is added by syringe, the resulting mixture is again carefully degassed and stirred overnight at 100C. Partition the mixture between brine/EtOAc (1+1), separate layers, extract the aqu. layer with EtOAc (3x), wash the combined organic layer with brine, dry with Na2SO4 and remove solvent. Purify crude product by preparative radial chromatography (silica gel, EtOAc/CyH 1+5) to obtain 2',3',4'-Trimethoxy-biphenyl-3-carboxylic acid methyl ester (33) as a yellowish oil (1.07g, 58%). 1H NMR (400MHz, CDCl3): 3.66 (s, 3 H); 3.89 (s, 3 H); 3.92 (s, 6 H); 6.74 (d, 1 H, J= 8.6Hz); 7.03 (d, 1 H, J = 8.6Hz); 7.44 (t, 1 H, J = 7.8Hz); 7.70 (d, 1 H, J = 7.6Hz); 7.97 (d, 1 H, J = 7.8Hz); 8.15 (br.s 1 H).

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 1101 - 1115
[2]Patent: EP1764093,2007,A1 .Location in patent: Page/Page column 22
[3]Australian Journal of Chemistry,1992,vol. 45,p. 1967 - 1982

4
[ 618-89-3 ]
[ 151-50-8 ]
[ 13531-48-1 ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1983,vol. 48,p. 1765 - 1773

5
[ 618-89-3 ]
[ 93-58-3 ]

Yield	Reaction Conditions	Operation in experiment
84%Chromat.	With 1,2,3,4-tetrakis(carbazol-9-yl)-5,6-dicyanobenzene; triethylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; for 1h;Inert atmosphere; Irradiation;	General procedure: To a 10 mL photocatalytic reactor containing a solution of an aryl halide (0.5 mmol, 1equiv) and 5CzBN (0.01 mmol, 0.02 equiv) in dry NMP (3 mL) was added Et3N (0.8 mmol, 1.6 equiv) under nitrogen atmosphere. The solution was stirred under their radiation of 5 W blue LED for the indicated time until complete consumption of starting material as monitored by GC-MS analysis at rt. The yields were calculated from GC measurements using internal standards.
68%Chromat.	With 1,2-dimethoxyethane; hydrogen; C51H53ClOP3Ru(1+)*ClO4(1-); at 120℃; under 60006.0 Torr; for 36h;Autoclave;	General procedure: Under an atmosphere of nitrogen, a stainless steel 100 mL autoclave,equipped with a magnetic stir bar, was charged with Ru-Cat. (0.5 - 5.0mol) and the solvent to be used (5 mL). A solution of the substrates (0.5mmol) in the solvent (5 mL) was then added via a syringe. The autoclavewas purged by three cycles of pressurization/ venting with N2 (1 - 5 bar),and then pressurized with the desired pressure (40 ~ 80 bar). Theautoclave was heated to the desired temperature (100 ~ 160 C) and thecontents stirred. After the pre-determined reaction time, the autoclavewas cooled to room temperature and the pressure slowly released. Thereaction mixture was filtered through a plug of silica gel and thenanalyzed by GC and GC-MS. The mixture was concentrated underreduced pressure. The residue was purified by column chromatographyon silica gel (EtOAc in petroleum ether) to afford the correspondingreduced product.

Reference： [1]Journal of Organic Chemistry,1989,vol. 54,p. 5308 - 5313
[2]Journal of Organic Chemistry,2007,vol. 72,p. 5631 - 5636
[3]Science,2014,vol. 346,p. 725 - 728
[4]Chemistry of Materials,2017,vol. 29,p. 5225 - 5231
[5]European Journal of Organic Chemistry,2018,vol. 2018,p. 34 - 40
[6]Chinese Chemical Letters,2020,vol. 31,p. 1899 - 1902
[7]Molecular catalysis,2021,vol. 516

6
[ 618-89-3 ]
[ 1751-97-9 ]

Yield	Reaction Conditions	Operation in experiment
73%	With bis(bipyridine)nickel(II) bromide; ethylene dibromide; sodium iodide; In N,N-dimethyl-formamide; at 20℃; for 2.5h;Electrochemical reaction; Inert atmosphere;	General procedure: DMF (40 mL), NaI (375 mg, 2.5 mmol), and 1,2-dibromoethane (100μL, 1.16 mmol) were added to an undivided electrochemical cell, fitted with an iron/nickel (64/36) anode, and surrounded by a nickel foam as the cathode (surface: 40 cm2, porosity: 500 μm, Goodfellow).The mixture was electrolyzed under argon at a constant current intensityof 0.2 A at r.t. for 15 min. The current was then stopped, then NiBr2bpy (187 mg, 0.5 mmol) and aryl or heteroaryl halide (5 mmol),were sequentially added. The solution was electrolyzed at 0.2 A untilthe starting aryl or heteroaryl halide had been totally consumed (2-5h). Sat. aq EDTA-Na2 solution (50 mL) was added, and the resultingsolution was extracted either with EtOAc (for aryl halides) or withCH2Cl2 (for heteroaryl halides) (3 × 50 mL). The combined organic layerswere washed with brine (50 mL), dried (MgSO4), filtered, and concentratedunder vacuum. The crude product was purified by flashchromatography (silica gel, 70-200 μm).

Reference： [1]Bulletin of the Chemical Society of Japan,1984,vol. 57,p. 1887 - 1890
[2]Tetrahedron Letters,2011,vol. 52,p. 4405 - 4407
[3]Bulletin of the Chemical Society of Japan,1990,vol. 63,p. 80 - 87
[4]Synlett,2009,p. 85 - 88
[5]Synthesis,2018,vol. 50,p. 146 - 154
[6]Tetrahedron Letters,2000,vol. 41,p. 10319 - 10321
[7]Chinese Journal of Chemistry,2021,vol. 39,p. 1573 - 1579
[8]Australian Journal of Chemistry,1997,vol. 50,p. 1159 - 1182
[9]Bulletin of the Chemical Society of Japan,1980,vol. 53,p. 3691 - 3695

7
[ 75-63-8 ]
[ 618-89-3 ]
[ 2557-13-3 ]

Reference： [1]Journal of Organometallic Chemistry,1995,vol. 489,p. 137 - 144

8
[ 618-89-3 ]
[ 380430-68-2 ]
3'-tert-Butoxycarbonylamino-biphenyl-3-carboxylic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 1595 - 1600

9
[ 618-89-3 ]
[ 557-21-1 ]
[ 13531-48-1 ]

Reference： [1]Tetrahedron Letters,2005,vol. 46,p. 1815 - 1818

10
[ 618-89-3 ]
[ 105-53-3 ]
2-(3-methoxycarbonylphenyl)malonic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With di-tert-butyl(neopentyl)phosphine; sodium hydride; bis(dibenzylideneacetone)-palladium(0); In toluene; mineral oil; at 70℃; for 24h;	General procedure: Reactions were conducted using standard dry box techniques and all solvents were distilled over Reactions were conducted using standard dry box techniques and all solvents were distilled oversodium. Method A: To a screw capped vial was added Pd(dba)2 (0.010 mmol), DTBNpP(0.020mmol), and NaH (1.2 mmol). The vial was sealed with a septa screw cap and removed from the glove box. To the vial was added toluene (1.0 mL), aryl bromide (1.0 mmol), and diethyl malonate (1.2 mmol). The reaction mixture was stirred at 70 C for 24 hours and the conversion of the aryl bromide was then measured by GC. The crude reaction mixture was filtered through a plug of Celite and then concentrated in vacuo. The concentrate was thenpurified by column chromatography on silica gel.

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 3447 - 3450
[2]Organic Letters,2005,vol. 7,p. 4693 - 4695

11
[ 618-89-3 ]
[ 13331-27-6 ]
[ 149506-24-1 ]

Yield	Reaction Conditions	Operation in experiment
26%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; toluene; at 20 - 80℃; for 5h;Inert atmosphere;	[000408] Synthesis of methyl 3’-nitro-[l, 1’-biphenylj-3-carboxylate (515): To a stirred solution of <strong>[618-89-3]methyl 3-bromobenzoate</strong> 514 (2.5 g, 14.99 mmol) and (3-nitrophenyl) boronic acid 382 (3.8 g, 17.99 mmol) in toluene (20 mL) under inert atmosphere were added sodium carbonate (3.17 g, 29.99 mmol in 20 mL of H20) at RT and purged under argon atmosphere for 20 mm. To this was added Pd(PPh3)4 (693 mg, 0.59 mmol) and heated to 80 C for 5 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with EtOAc (200 mL). The organic extract was dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 10% EtOAc/ hexanes to afford compound 515 (1 g, 26%) as yellow liquid. TLC: 15% EtOAc/ hexanes (R 0.5); 1H NMR (400 MHz, DMSO-d6): ö 8.48-8.46 (m, 1H), 8.30-8.25 (m, 2H), 8.22-8.18 (m, 1H), 8.11-8.07 (m, 1H), 8.04 (dt,J 7.8, 1.3 Hz, 1H),7.80 (t, J= 8.0 Hz, 1H), 7.69 (t, J= 7.8 Hz, 1H), 3.91 (s, 3H).
	With palladium 10% on activated carbon; sodium carbonate; In methanol;Reflux;	[0089] A mixture of (3-nitrophenyl)boronic acid and <strong>[618-89-3]methyl 3-bromobenzoate</strong> was placed into a reaction vessel with 10% palladium on carbon (Pd/C) and sodium carbonate (Na2C03) in methanol (MeOH). The reaction mixture was held at reflux until the starting materials had been converted into methyl 3'-nitro-[l1,1]-biphenyl]-3-carboxylate. The methyl 3'-nitro-[1,1]biphenyl]-3-carboxylate was maintained in the reaction vessel, used without purification, isopropyl acetate was added to the reaction vessel and the mixture subsequently reacted with 10% Pd/C in a hydrogen atmosphere to yield methyl 3'-amino-[1,1]-biphenyl]- 3-carboxylate.

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2758 - 2771
[2]Patent: WO2015/138895,2015,A1 .Location in patent: Paragraph 000408
[3]Journal of Organic Chemistry,2015,vol. 80,p. 2937 - 2941
[4]Patent: WO2017/70689,2017,A2 .Location in patent: Paragraph 0075;0089

12
[ 201230-82-2 ]
[ 618-89-3 ]
[ 6638-79-5 ]
N-methoxy-N-methyl-isophthalamic acid methyl ester [ No CAS ]

Reference： [1]Organic Letters,2006,vol. 8,p. 4843 - 4846
[2]Journal of Organic Chemistry,2008,vol. 73,p. 7102 - 7107

13
[ 618-89-3 ]
[ 17997-47-6 ]
[ 98061-20-2 ]

Reference： [1]Tetrahedron,2006,vol. 62,p. 11483 - 11498

14
[ 618-89-3 ]
[ 108-95-2 ]
[ 50789-43-0 ]

Yield	Reaction Conditions	Operation in experiment
73%	With thio-xanthene-9-one; (2,2'-bipyridine)nickel(II) dibromide; N-tert-butylisopropylamine; In acetonitrile; for 72h;Inert atmosphere; Irradiation; Green chemistry;	Methyl 3-bromobenzoate (0.2 mmol), phenol (0.6 mmol), TXO (20 mol %), Ni(bpy)Br2 (10 mol %), t-BuNH(i-Pr) (0.4 mmol) and MeCN (3 mL) was added to a dry reaction tube with a magnetic stir bar, then the reaction tube was replaced with N2 3 times, and the reaction was stirred for 72 hours under 45 W CFL irradiation. After the reaction, 5 mL of water was added, then extracted with 3×5 mL of ethyl acetate, the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated by rotary evaporation, and separated by silica gel column chromatography to obtain The target product (73% yield).

Reference： [1]Angewandte Chemie - International Edition,2006,vol. 45,p. 4321 - 4326
[2]Organic Letters,2021,vol. 23,p. 8327 - 8332
[3]Patent: CN113717038,2021,A .Location in patent: Paragraph 0037-0039

15
[ 618-89-3 ]
[ 63503-60-6 ]
[ 168618-92-6 ]

Yield	Reaction Conditions	Operation in experiment
89%		General procedure: A solution of sodium carbonate (0.55mmol) in water (1.75mL) and EtOH (1.25mL) was prepared and degassed. In a 10mL vial Tetrakis (triphenylphosphine) palladium (0.055mmol) was added to a solution of 4a-e (0.275mmol) in DME (5mL) in a 10mL vial. Argon was bubbled into the DME solution with stirring for 10min. The boronic acid (1.650mmol) was added to the vial followed by the addition of the sodium carbonate mixture. The vial was sealed under argon and heated to 80C while stiring for 12h. The mixture was diluted in water and extracted with ethyl acetate. The extracts were washed with brine and dried over magnesium sulfate. The mixture was concentrated in vacuo to give the product as an oil. The product was purified in by column chromatography and characterized by 1H and 13C NMR.

Reference： [1]Bioorganic and medicinal chemistry,2020,vol. 28
[2]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3258 - 3261

16
[ 1722-10-7 ]
[ 618-89-3 ]
methyl 3-(6-methoxypyridazin-3-yl)benzoate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 5631 - 5636
[2]Electrochimica Acta,2010,vol. 55,p. 4495 - 4500

17
[ 618-89-3 ]
[ 10602-06-9 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 1475 - 1486
[2]Journal of Organic Chemistry,1985,vol. 50,p. 1763 - 1765
[3]Journal of Organic Chemistry,1981,vol. 46,p. 2280 - 2286
[4]Journal of the American Chemical Society,2013,vol. 135,p. 8400 - 8408
[5]Molecules,2018,vol. 23
[6]Journal of Medicinal Chemistry,2018,vol. 61,p. 9756 - 9783

18
[ 618-89-3 ]
[ 153599-45-2 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 1508 - 1518
[2]Patent: EP3190113,2017,A1
[3]Patent: TWI558709,2016,B

19
[ 618-89-3 ]
[ 158619-46-6 ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 217 - 223

20
[ 618-89-3 ]
[ 206761-84-4 ]

Reference： [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1954,vol. 74,p. 1065,1067
Chem.Abstr.,1955,p. 11592

21
[ 93138-55-7 ]
[ 618-89-3 ]
N-(3-Methoxycarbonylbenzyl)-3-(piperidinomethyl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium hydride; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 50℃; for 3.5h;	1-(3-Aminobenzyl)piperidine (0.52 g) obtained by the known process (WO99/32100) was dissolved in tetrahydrofuran (4.0 mL) and N,N-dimethylformamide (1.0 mL), and methyl 3-(bromomethyl)benzoate (0.63 g) and a 60% dispersion (0.013 g) of sodium hydride in mineral oil were added thereto, followed by stirring at 50 C. for 3.5 hours. The mixture was allowed to stand for cooling to room temperature, and then a saturated aqueous sodium bicarbonate solution and water were added thereto, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel preparative thin layer chromatography (chloroform:methanol=5:1) to give Compound X (0.67 g, 72%) as a pale yellow oily substance. [0583] 1H NMR (270 MHz, CDCl3) δ8.03 (1H, m), 7.91 (1H, m), 7.56 (1H, m), 7.38 (1H, t), 7.08 (1H, t), 6.71 (1H, m), 6.65 (1H, brd), 6.51 (1H, brdd), 4.48 (1H, brs), 4.37 (2H, brs), 3.89 (3H, s), 3.49 (2H, brs), 2.45 (4H, m), 1.61 (4H, m), 1.43 (2H, m).

Reference： [1]Patent: US2003/225288,2003,A1 .Location in patent: Page 31

22
[ 618-89-3 ]
[ 62-53-3 ]
[ 6025-56-5 ]

Yield	Reaction Conditions	Operation in experiment
82%	With caesium carbonate; DavePhos;tris-(dibenzylideneacetone)dipalladium(0); In toluene; at 100℃; for 20h;	Methyl 3-bromobenzoate (1000 mg, 4.65 [MMOL),] Pd2 (dba) 3 (53 mg, 0.058 mmol), [CS2CO3] (2120 mg, 1.4 mmol) [AND N-[2'-(DICYCLOHEXYLPHOSPHINO)-1, 1'-BIPHENYL-2-YL]-] [N,] N-dimethylamine (27mg, 0.07 mmol) were placed in a 100ml one-necked round bottom flask. The system was evacuated and filled with argon several times. Then aniline (519 mg, 5.58 mmol) was added, followed by the addition of toluene (50 ml). The solution was heated at [100C] for 20h, the solvent was removed in vacuo and residue was purified by silica gel chromatography [(ETOAC/HEPATANE] [1/3)] to get 180 mg (18%) of methyl ester as a yellow solid, which was hydrolyzed by [LIOH] (50 mg) ) in THF (4 [ML)] and water (1 [ML)] to afford 140 mg (82%) of 3-Anilinobenzoic acid as a white [SOLID. 1H] NMR (400 MHz, DMSO-d6) 8 8.02 (s, 1 H), 7.65 (s, 1 H), 7.33 (d, J = 7.5 Hz, 1 H), 7.19 (t, J= 8.3 Hz, 2 H), 7.10 (d, J= 7.7 Hz, 1H), 7.03 (d, J= 7.6 Hz, 2 H), 6.96 [(M,] [1] H), 6.76 (t, J= 7.3 Hz, [1] [H)

Reference： [1]Patent: WO2004/18414,2004,A2 .Location in patent: Page 76
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1464 - 1468
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 2311 - 2323

23
[ 108-22-5 ]
[ 618-89-3 ]
[ 74998-19-9 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation 65: methyl [3-(2-oxopropyl)phenyl]acetate Tributyltin methoxide (80.3ml, 279mmol), <strong>[618-89-3]methyl 3-bromobenzoate</strong> (53.5g, 249mmol), isopropenyl acetate (39.4ml, 358mmol), palladium(II)acetate (2.6g, 11.6mmol) and tri-o -tolylphosphine (7.1 g, 23.2mmol) were stirred together in toluene (350ml) at 100C under nitrogen for 18 hours. After cooling, the reaction was treated with 4M aqueous potassium fluoride solution (560ml) and stirred for 2 hours. The resulting mixture was diluted with further toluene (200ml) and filtered through celite, washing the filter pad with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and reduced in vacuo. The residue was purified by flash column chromatography on silica gel eluding with ethylacetate:pentane (10:90, changing to 20:80, by volume) to give the title compound (45.3g) as an orange oil. 1H NMR (400MHz, CDCl3): δ = 7.95-7.93 (1H, d), 7.87 (1H, s), 7.43-7.37 (2H, m), 3.91 (3H, s), 3.75 (2H, s), 2.18 (3H, s) ppm. LRMS (electrospray): m/z [M+Na]+ 215, [M-H]- 191.
		Tributyltin methoxide (80.3 mL, 279 mmol), <strong>[618-89-3]methyl 3-bromobenzoate</strong> (53.5 g, 249 mmol), isopropenyl acetate (39.4 ml, 358 mmol), palladium (11) acetate (2.6 g, 11.6 mmol) and tri-ortho-tolylphosphine (7.1 g, 23.2 mmol) were stirred together in toluene (350 mL) at 100 C under nitrogen for 18 hours. After cooling, the reaction was treated with potassium fluoride solution (4M, 560 ml) and stirred for 2 hours. The resulting mixture was diluted with further toluene (200 mL) and filtered through Celite No., washing the filter pad with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and reduced in vacuo. The residue was purified by chromatography eluting with ethylacetate : pentane 10 : 90 to 20: 80 to give the title compound (45.3 g) as an orange oil- 'H NMR-(400MHz, CDCI3) ã : 2.18 (3H, s), 3.75 (2H, s), 3.91 (3H, s), 7.43-7. 37 (2H, m), 7.87 (1H, s), 7.95-7. 93 (1H, d); LRMS ESI m/z 215 [M+Na] +, 191 [M- H]-.
		Tributyltin methoxide (80.3 ml, 279 mmol), <strong>[618-89-3]methyl 3-bromobenzoate</strong> (53.5 g, 249 mmol), isopropenyl acetate (39.4 ml, 358 mmol), palladium(II)acetate (2.6 g, 11.6 mmol) and tri-o-tolylphosphine (7.1 g, 23.2 mmol) were stirred together in toluene (350 ml) at 100 C. under nitrogen for 18 hours. After cooling, the reaction was treated with 4M aqueous potassium fluoride solution (560 ml) and stirred for 2 hours. The resulting mixture was diluted with further toluene (200 ml) and filtered through celite, washing the filter pad with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and reduced in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethylacetate:pentane (10:90, changing to 20:80, by volume) to give the title compound (45.3 g) as an orange oil. 1H NMR (400 MHz, CDCl3): δ=7.95-7.93 (1H, d), 7.87 (1H, s), 7.43-7.37 (2H, m), 3.91 (3H, s), 3.75 (2H, s), 2.18 (3H, s) ppm. LRMS (electrospray): m/z [M+Na]+215, [M-H]-191.

Tributyltin methoxide (80.3ml, 279mmol), <strong>[618-89-3]methyl 3-bromobenzoate</strong> (53.5g, 249mmol), isopropenyl acetate (39.4ml, 358mmol), palladium(ll)acetate (2.6g, 11.6mmol) and tri-o-tolylphosphine (7.1g, 23.2mmol) were stirred together in toluene (350ml) at 100C under nitrogen for 18 hours. After cooling, the reaction was treated with 4M aqueous potassium fluoride solution (560ml) and stirred for 2 hours. The resulting mixture was diluted with further toluene (200ml) and filtered through Celite, washing the filter pad with ethyl acetate. The organic phase was separated, dried (sodium sulfate) and reduced invacua. The residue was purified by flash column chromatography on silica gel eluting with ethylacetate:pentane (10:90, changing to 20:80, by volume) to give the title compound (45.3g) as an orange oil.1H NMR (400MHz, CDCI3): 8 = 7.95-7.93 (1H, d), 7.87 (1H, s), 7.43-7.37 (2H, m), 3.91 (3H, s), 3.75 (2H, s), 2.18 (3H, s) ppm.LRMS (electrospray): m/z [M+Na]+ 215, [M-H]' 191.

Reference： [1]Patent: EP1577291,2005,A1 .Location in patent: Page/Page column 83
[2]Patent: WO2005/92840,2005,A1 .Location in patent: Page/Page column 102
[3]Patent: US2005/222128,2005,A1 .Location in patent: Page/Page column 40
[4]Patent: WO2004/108676,2004,A1 .Location in patent: Page 159-160

24
[ 431052-64-1 ]
[ 618-89-3 ]
[ 780800-90-0 ]

Yield	Reaction Conditions	Operation in experiment
17%		EXAMPLE 36 COMPOUND 36: 3-(2-[(4-Amino-butyl)-(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-pyridin-3-yl)-benzoic acid methyl ester (HBr salt) A stirred solution of 3-Tributylstannanyl-pyridine-2-carbaldehyde (256 mg, 0.65 mmol) and <strong>[618-89-3]methyl 3-bromobenzoate</strong> (128 mg, 0.59 mmol) in DMF (2.1 mL) was degassed with Ar for 5 minutes, after which PdCl2(PPh3)2 (25 mg, 0.036 mmol) and CuO (34 mg, 0.43 mmol) was added and the mixture heated to 110 C. overnight. The reaction was cooled to room temperature, and diluted with saturated aqueous NaHCO3 (15 mL) and EtOAc (40 mL). The organic phase was separated, washed with brine (3*15 mL), dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash chromatography on silica gel (Hexanes/EtOAc, 60:40) gave 3-(2-Formyl-pyridin-3-yl)-benzoic acid methyl ester (25 mg, 17%) as a white solid. 1H NMR (CDCl3) δ 3.92 (s, 3H), 7.47-7.56 (m, 2H), 7.58 (d, 1H, J=4.9 Hz), 8.03 (s, 1H), 8.07-8.20 (m, 1H), 8.86 (dd, 1H, J=4.9, 1.8 Hz), 10.08 (s, 1H).

Reference： [1]Patent: US2004/209921,2004,A1 .Location in patent: Page 25

25
[ 201230-82-2 ]
[ 618-89-3 ]
[ 1877-71-0 ]

Yield	Reaction Conditions	Operation in experiment
82%	With methanol; triethylamine;palladium diacetate; 1,3-bis-(diphenylphosphino)propane; at 100℃; under 25858.1 Torr; for 15h;	The following were introduced into a vessel: [10.] Og (40.3 mmol) of <strong>[618-89-3]methyl 3-bromobenzoate</strong>, 2.5g (mmol) of 1, 3-bis (diphenylphosphino) propane ("DPPP"), 14 mL of triethylamine, 0.905 g of palladium acetate, and 140 ml of methanol. The vessel was sealed and pressurized with carbon monoxide to a pressure of 500 psi. The vessel was heated to [100 C] for 15 hours. The mixture was then cooled and concentrated on a rotary evaporator before partitioning between EtOAc and 2M HC1. The layers were separated, and the aqueous layer was extracted with EtOAc [(LX).] The organic extracts were combined and washed with saturated aqueous [NACL] solution and dried [(MGSO4).] Concentration provided a solid, which is slurred in hexane and filtered. The material is dried in a vacuum oven at- 10mmHg at [70 C] ; yield 5.9g [(82%).] NMR: [DMSO'H 8] (ppm) 3.54 (3H, s); 7. [18-7.] 21 [(1H,] m); 7. [34- 7.] 40 [(1H,] m); 7. 46- 7.49 (1H m); 7. [87- 7.] 89 [(1H,] m).

Reference： [1]Patent: WO2004/14366,2004,A1 .Location in patent: Page/Page column 107-108

26
[ 618-89-3 ]
[ 81290-20-2 ]
[ 655-26-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	With tetrabutyl ammonium fluoride; In toluene; at -78 - 20℃;	In a dry round bottom flask, 3-bromo-benzoic acid methyl ester (2 g, 9.3 mmol, Aldrich Chemical Company) and trimethyl(trifluoromethyl)silane (1.72 mL, 11.6 mmol, Aldrich Chemical Company) were dissolved in dry toluene (50 mL). Upon cooling the solution TO-78 C, TBAF (232 UL, 0.23 mmol) was added and the reaction was allowed to warm up slowly to rt overnight. After stirring for 20 hr, 2N HCl (50 mL) and EtOAc (100 mL) were added, the layers were separated, and the aqueous layer was extracted with another portion of EtOAc. The combined organic fractions were dried (MgS04), concentrated in vacuo, and resulting crude oil was purified using Si02 flash chromatography (elution: 5-20% EtOAc in hexanes) to give 1.5 g (65%) the title compound as a light yellow OIL. 1H-NMR (CDC13 ; 400 MHz) δ 8. 18 (br s, 1H), 7. 98-8. 00 (m, 1H), 7.82-7. 85 (m, 1H), 7.42-7. 46 (m, 1H). 19F-NMR (CDC13 ; 400 M HZ) δ -72. 06 (s).
	With hydrogenchloride; tetrabutyl ammonium fluoride; In ethyl acetate; toluene;	a 1-(3-Bromo-phenyl)-2,2,2-trifluoro-ethanone In a dry round bottom flask, 3-bromo-benzoic acid methyl ester (2 g, 9.3 mmol, Aldrich Chemical Company) and trimethyl(trifluoromethyl)silane (1.72 mL, 11.6 mmol, Aldrich Chemical Company) were dissolved in dry toluene (50 mL). Upon cooling the solution to -78 C., TBAF (232 μL, 0.23 mmol) was added and the reaction was allowed to warm up slowly to rt overnight. After stirring for 20 hr, 2N HCl (50 mL) and EtOAc (100 mL) were added, the layers were separated, and the aqueous layer was extracted with another portion of EtOAc. The combined organic fractions were dried (MgSO4), concentrated in vacuo, and resulting crude oil was purified using SiO2 flash chromatography (elution: 5-20% EtOAc in hexanes) to give 1.5 g (65%) the title compound as a light yellow oil. 1H-NMR (CDCl3; 400 MHz) δ 8.18 (br s, 1H), 7.98-8.00 (m, 1H), 7.82-7.85 (m, 1H), 7.42-7.46 (m, 1H).

Reference： [1]Patent: WO2003/99805,2003,A1 .Location in patent: Page 118
[2]Patent: US2004/9995,2004,A1

27
[ 618-89-3 ]
[ 104013-60-7 ]
3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 100℃; for 18h;	Combine 1 - [4-(3 -amino-benzyloxy)-2-hydroxy-3 -propyl-phenyl] -ethanone (500 mg, 1.67 mmol), 3-bromo-benzoic acid methyl ester (326 mg, 1.52 mmol) and cesium carbonate (693 mg, 2.13 mmol) in toluene (25 mL) and stir. Purge reaction vessel with argon. Add BINAP [rac-2,2'-Bis(diphenyl-phosphino)-l,l'-binaphthyl] (142 mg, 0.228 mmol), and palladium acetate (34 mg, 0.152 mmol). Purge reaction vessel with argon. Heat to 100 0C. After 18 hours, cool to ambient temperature. Add 10% aqueous citric acid, and extract with ethyl acetate. Combine the organic layers, dry with sodium sulfate, filter and concentrate to dryness. Purify the resulting residue by flash chromatography eluting with ethyl acetate :hexanes to yield the title compound as a white solid (280 mg, 43%): 1H NMR (DMSO-^6) δ 0.81 (t, 3H), 1.46 (sextet, 2H), 2.57 (m, 5H), 3.82 (s, 3H), 5.23 (s, 2H), 6.71 (d, IH), 6.95 (d, IH), 7.01 (d, IH), 7.19 (m, IH), 7.28-7.41 (m, 4H), 7.65 (m, IH), 7.81 (d, IH), 8.49 (bs, IH), 12.84 (s, IH).

Reference： [1]Patent: WO2006/57860,2006,A1 .Location in patent: Page/Page column 124

28
[ 618-89-3 ]
[ 78782-27-1 ]
[ 25692-41-5 ]

Yield	Reaction Conditions	Operation in experiment
82%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water;	74A: 3-Styryl-benzoic acid methyl ester; Methyl 3-bromobenzoate (458 mg, 2 mmol), 1-styreneboronic acid pinacoyl ester (484 mg, 2.1 mmol), Na2CO3 (222 mg, 2.1 mmol), tetrakis(triphenylphosphino)palladium (116 mg, 0.1 mmol), water (4 mL) and 1,2-dimethoxyethane (6 mL) were stirred with reflux conditions for one hour, under nitrogen. The reaction mixture was diluted with water andwas extracted three times with EtOAc. The organic layers were combined, washed with water and then brine, dried over MgSO4 and concentrated. The product was purified by trituration with Et2O. White crystals were obtained (393 nig, 82 %). NMR 1U (ppm, CDC13): 8.19 (t, / = 1.6 Hz, 1H), 7.91 (dt, / = 7.7 Hz, / = 1.3 Hz, 1H), 7.67 (d, J3 = 7.8 Hz, 1H), 7.52 (d, J3 = 7.3 Hz, 2H), 7.42 (t, J3 = 7.9 Hz, 1H), 7.36 (t, J3 = 7.4 Hz, 2H), 7.30-7.26 (m, 1H), 7.19 (d, J3 = 16.3 Hz, 1H), 7.11 (d, / = 16.4 Hz, 1H), 3.06 (s, 3H).
82%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 1h;Heating / reflux;	74A: 3-Styryl-benzoic acid methyl ester; Methyl 3-bromobenzoate (458 mg, 2 mmol), 1-styreneboronic acid pinacoyl ester (484 mg, 2.1 mmol), Na2CO3 (222 mg, 2.1 mmol), tetrakis(triphenylphosphino)palladium (116 mg, 0.1 mmol), water (4 mL) and 1,2-dimethoxyethane (6 mL) were stirred with reflux conditions for one hour, under nitrogen. The reaction mixture was diluted with water and was extracted three times with EtOAc. The organic layers were combined, washed with water and then brine, dried over MgSO4 and concentrated. The product was purified by trituration with Et2O. White crystals were obtained (393 mg, 82%). NMR 1H (ppm, CDCl3): 8.19 (t, J4=1.6 Hz, 1H), 7.91 (dt, J3=7.7 Hz, J4=1.3 Hz, 1H), 7.67 (d, J3=7.8 Hz, 1H), 7.52 (d, J3=7.3 Hz, 2H), 7.42 (t, J3=7.9 Hz, 1H), 7.36 (t, J3=7.4 Hz, 2H), 7.30-7.26 (m, 1H), 7.19 (d, J3=16.3 Hz, 1H), 7.11 (d, J3=16.4 Hz, 1H), 3.06 (s, 3H).

Reference： [1]Patent: WO2006/2474,2006,A1 .Location in patent: Page/Page column 183-184
[2]Patent: US2008/153802,2008,A1 .Location in patent: Page/Page column 90

29
[ 72287-26-4 ]
[ 474111-60-9 ]
[ 618-89-3 ]
argon [ No CAS ]
[ 497-19-8 ]
[ 474111-79-0 ]

Yield	Reaction Conditions	Operation in experiment
3.83 g (77%)	In water; ethyl acetate; toluene;	EXAMPLE 85 Preparation of Methyl 3-[(2R)-2-({(tert-butoxycarbonyl)[(2R)-2-[tert-butyl(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]amino}methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate Argon was bubbled through a solution of the compound of Example 81 (5 g, 8 mmol) in toluene (100 mL) for 10 minutes. Then, [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) (460 mg, 0.56 mmol) and methyl 3-bromobenzoate (2.6 g, 12 mmol) were added in a single portion. The resulting reaction mixture was degassed with argon for an additional 5 minutes before aqueous Na2CO3 (2M, 40 mL, 80 mmol) was added and the solution was heated at 85° C. overnight. The product mixture was allowed to cool to room temperature, water was added and the biphasic mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, concentrated and purified with a Biotage column, gradient 10-30percent ethyl acetate/hexanes to obtain 3.83 g (77percent) of the title compound. MH+=633.5

Reference： [1]Patent: US2003/78260,2003,A1

30
dimethylformamide [DMF] [ No CAS ]
2,2-Dimethyl-7-methoxy-4-tributylstannyl-2,3-dihydrobenzofuran [ No CAS ]
[ 618-89-3 ]
2,2-Dimethyl-7-methoxy-4-[3-(methoxycarbonyl)phenyl]-2,3-dihydrobenzofuran [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.5%	With sodium carbonate;palladium diacetate; In water; N,N-dimethyl-formamide;	EXAMPLE 146 2,2-Dimethyl-7-methoxy-4-[3-(methoxycarbonyl)phenyl]-2,3-dihydrobenzofuran (Compound 146) A solution (30 ml) of Compound 144a obtained in Step A of Example 144 in DMF was added to a mixture of <strong>[618-89-3]methyl 3-bromobenzoate</strong> (1.67 g), palladium acetate (0.18 g), sodium carbonate (2.10 g), and dimethylformamide (DMF) (70 ml), followed by stirring at 80 C. for one hour. A small amount of water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and a saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/20) to give Compound 146 (1.69 g, 69.5%) as pale-yellow crystals. Melting point: 89-91 C. NMR(DMSO-d6, δ, ppm): 1.42(s, 6H), 3.12(s, 2H), 3.80 (s, 3H), 3.88(s, 3H), 6.90(d, J=8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 7.58(dd, J=7.4 Hz, 1H), 7.76(dd, 7.76(dd, J=7.9 Hz, 1.5 Hz, 1H), 7.91(d, J=7.4 Hz, 1H), 7.99(d, J=1.5 Hz, 1H) IR(KBr, cm-1): 1716

Reference： [1]Patent: US2002/128290,2002,A1

31
[ 618-89-3 ]
[ 17933-03-8 ]
[ 158619-46-6 ]
[ 128460-74-2 ]

Yield	Reaction Conditions	Operation in experiment
97%		G. 3-Methyl-3'-tert-butoxycarbonylbiphenyl (19). The coupling of 3-methylphenylboronic acid with 3-bromobenzoic acid methyl ester gave a 3-methyl-3'-methoxycarbonylbiphenyl (79% yield), which was then hydrolyzed to yield a 3-methyl-3'-carboxybiphenyl (97% yield).

Reference： [1]Patent: US5965539,1999,A

32
[ 618-89-3 ]
[ 17933-03-8 ]
[ 158619-46-6 ]
[ 172542-51-7 ]
[ 172542-49-3 ]
[ 161721-66-0 ]

Yield	Reaction Conditions	Operation in experiment
		Compound 19 was made from <strong>[158619-46-6]3-methyl-3'-carboxybiphenyl</strong> (itself formed from aryl--aryl coupling of methyl 3-bromobenzoate with 3-methylphenylboronic acid followed by a saponification) via the same method as compound 16. Bromination of 19 followed by reaction with sodium azide gave 20 which as catalytically hydrogenated to give the corresponding amine.
		Compound 19 was made from <strong>[158619-46-6]3-methyl-3'-carboxybiphenyl</strong> (itself formed from aryl-aryl coupling of methyl 3-bromobenzoate with 3-methylphenylboronic acid followed by a saponification) via the same method as compound 16. Bromination of 19 followed by reaction with sodium azide gave 20 which as catalytically hydrogenated to give the corresponding amine.

Reference： [1]Patent: US5965539,1999,A
[2]Patent: US6011175,2000,A

33
[ 585-76-2 ]
[ 618-89-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sulfuric acid; In methanol; dichloromethane; ethyl acetate;	Part A: 3-Bromobenzoic acid (1.1 g, 5.47 mmol) was dissolved in methanol (20 ml) in a 50 ml flask. Concentrated sulfuric acid (2 drops) was added and the mixture was refluxed under nitrogen for ten hours then concentrated under reduced pressure. The residue was mixed with dichloromethane (20 ml) and saturated sodium bicarbonate solution (10 ml). The organic material was separated, dried (MgSO4) and concentrated under reduced pressure. The residue was flushed through silica gel with hexane/ethyl acetate (3:1), and concentrated which provided methyl 3-bromobenzoate (1.0 g, 85%).

Reference： [1]Patent: US5622937,1997,A
[2]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 192 - 194
[3]Journal of Molecular Structure,2016,vol. 1117,p. 8 - 16
[4]Chemistry and biodiversity,2022

34
[ 893420-22-9 ]
[ 618-89-3 ]
[ 934280-95-2 ]

Yield	Reaction Conditions	Operation in experiment
62%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 90 - 100℃;	5-Fluoro-4-(l-isopropyl-2-methyl-lH'-imidazol-5-yl)pyrimidin-2-amuie (obtained from Example l(b)) (99 mg, 0.42 mmol), <strong>[618-89-3]methyl 3-bromobenzoate</strong> (97 mg, 0.45 mmol) and Cs2CO3 (230 mg, 0.71 mmol) were mixed in anhydrous 1,4-dioxane and the mixture was flushed with argon for 10 minutes before Pd2(dba)3 (23 mg, 0.025 mmol) and X-Phos (24 mg, 0.050 mmol) were added. The mixture was flushed with argon, then heated in a sealed tube at +90-100 C until the reaction was complete. The reaction mixture was diluted with CH2Cl2, filtered and evaporated. The residue was taken up in CH2Cl2 and the organic phase was washed with H2O. Residual water was removed from the organic phase by treatment with Na2SO4. The crude of the base product was purified using preparative HPLC to give s the title compound (97 mg, 62%) as a solid.1HNMR (400 MHz, DMSO-J6) δ ppm 9.73 (s, 1 H) 8.57 (d, 1 H) 8.19 (t, 1 H) 8.04 - 7.95 (m, 1 H) 7.59 - 7.52 (m, 1 H) 7.43 (t, 1 H) 7.37 (d, 1 H) 5.44 - 5.31 (m, 1 H) 3.84 (s, 3 H) 2.51 (s, 3 H) 1.42 (d, 3 H) 1.40 (d, 3 H); MS (ESI) m/z 370 (M+l).
62%	With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 90 - 100℃;	Example 18(a)Methyl 3-[5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-yl]amino}benzoate 5-Fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (obtained from Example 1(b)) (99 mg, 0.42 mmol), <strong>[618-89-3]methyl 3-bromobenzoate</strong> (97 mg, 0.45 mmol) and Cs2CO3 (230 mg, 0.71 mmol) were mixed in anhydrous 1,4-dioxane and the mixture was flushed with argon for 10 minutes before Pd2(dba)3 (23 mg, 0.025 mmol) and X-Phos (24 mg, 0.050 mmol) were added. The mixture was flushed with argon, then heated in a sealed tube at +90-100 C. until the reaction was complete. The reaction mixture was diluted with CH2Cl2, filtered and evaporated. The residue was taken up in CH2Cl2 and the organic phase was washed with H2O. Residual water was removed from the organic phase by treatment with Na2SO4. The crude of the base product was purified using preparative HPLC to give the title compound (97 mg, 62%) as a solid.1H NMR (400 MHz, DMSO-d6) δ ppm 9.73 (s, 1H) 8.57 (d, 1H) 8.19 (t, 1H) 8.04-7.95 (m, 1H) 7.59-7.52 (m, 1H) 7.43 (t, 1H) 7.37 (d, 1H) 5.44-5.31 (m, 1H) 3.84 (s, 3H) 2.51 (s, 3H) 1.42 (d, 3H) 1.40 (d, 3H); MS (ESI) m/z 370 (M+1).

Reference： [1]Patent: WO2007/40436,2007,A1 .Location in patent: Page/Page column 43-44
[2]Patent: US2008/214560,2008,A1 .Location in patent: Page/Page column 18

35
[ 618-89-3 ]
[ 57260-71-6 ]
[ 179003-10-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 100℃; for 12h;Inert atmosphere;	A mixture of 86 (3.00 g, 14.0 mmol), /V-Boc-piperazine (2.73 g, 14.7 mmol), Pd(OAc)2(313 mg, 1.40 mmol), Cs2C03(9.09 g, 27.9 mmol) and BINAP (869 mg, 1.40 mmol) in toluene (20 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 100 C for 12 h under N2atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give 87 (3.80 g, 85%) as a pale yellow solid.1H N R (400 MHz, CDCI3) 7.60 (s, 1 H), 7.55 (d, J = 7.6 Hz, 1 H),7.33 (t, J - 8.0 Hz, 1 H), 7.13 (d, J - 2.4 Hz, 1 H), 3.91 (s, 3H), 3.60 (t, J = 4.4 Hz, 4H), 3.19 (t, J = 4.8 Hz, 4H), 1 .49 (s, 9H). To a solution of 87 (1 .00 g, 3.12 mmol) in THF (20 mL) was added LiAIH4(1 18 mg,3.12 mmol). The mixture was stirred at 0 C for 1 h. The reaction mixture was quenched by sodium potassium tartrate (0.5 mL) at 15 C, and then filtered and concentrated under reduced pressure to give 88 (700 mg, 77%) as a pale yellow oil.1H NMR (400 MHz, CDCI3) 7.28-7.25 (m, 1 H), 6.96 (s, 1 H), 6.89-6.84 (m, 2H), 4.66 (s, 2H), 3.58 (t, J = 4.8 Hz, 4H), 3.15 (t, J = 4.8 Hz, 4H), 1.49 (s, 9H). To a solution of 88 (293 mg, 1.00 mmol) and Et3N (304 mg, 3.00 mmol) in DCM (10 mL) was added MsCI (229 mg, 2.00 mmol). The mixture was stirred at 0 C for 2 h. The reaction mixture was quenched by addition H20 (20 mL) at 15 C, and then extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give crude 89 (200 mg, yellow solid) which was used in the next step without further purification. MS (ESI): mass calcd. for C17H26N205S 370.16, m/z found 371.2 [M+H]+. A mixture of 89 (300 mg, 810 umol), 6-003 (236 mg, 0.810 mmol) and K2C03(336 mg, 2.43 mmol) in DMF (5 mL) was stirred at 60 C for 1 h under N2atmosphere. The reaction mixture was quenched by H20 (10 mL) at 15 C, and then extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2S04, filtered and concentrated under reduced pressure to give crude 90 (400 mg, pale yellow oil) which was used in the next step without further purification. MS (ESI): mass calcd. for C3oH4oBN307565.30, m/z found 566.3 [M+H]+. To a solution of 90 (400 mg, 0.707 mmol) in EtOAc (10 mL) was added HCI/EtOAc (6 M, 1.18 mL). The mixture was stirred at 15 C for 1 h. After concentrated under reduced pressure, the reaction mixture was purified by prep. HPLC (column: Luna C18 100 x 30 mm; liquid phase: [A-HCI/H2O=0.040% v/v; B-ACN] B%: 13%-43%, 12 min]) to give 6-126 (102 mg, 28%) as a white solid.1H NMR (400 MHz, DMSO-d6) 9.17 (s, 2H), 8.58 (d, J = 7.2 Hz, 1 H),7.34 (d, J = 7.2 Hz, 1 H), 7.28-7.22 (m, 2H), 7.01 (s, 1 H), 6.95 (d, J = 8.0 Hz, 1 H), 6.88 (d, J = 7.2 Hz, 1 H), 5.13 (s, 2H), 4.97 (s, 2H), 4.34 (t, J = 7.2 Hz, 1 H), 3.36 (d, J = 5.2 Hz, 4H), 3.17 (d, J = 2.8 Hz, 4H), 2.44 (s, 3H), 2.20-2.11 (m, 6.8 Hz, 1 H), 0.958-0.942 (m, 6 H); ESI-MS m/z 466 [M+H]+; HPLC purity: 97.27% (220 nm), 96.92% (254 nm)
30%	With palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 100℃; for 0.25h;Inert atmosphere;	A mixture of tert-butyl piperazine-1-carboxylate (1.0 eq), 17 (1.0 eq.), BINAP (5% mol) and sodium tert-butoxide (3.0 eq) were placed in two neck round bottom flask. Then anhydrous toluene was added to the mixture. The mixture was degassed and back-filled with dry nitrogen gas before suspension of palladium (II) acetate (5%mol) in dry toluene was added. The mixture reaction was stirred at 100 oC for 15min, cooled to room temperature, quenched by water. Normal extraction and purification was applied to get white solid, yield 30%.1H NMR (300MHz, CDCl3) δ 7.59 (s, 1H), 7.54 (d, J = 7.68 Hz, 1H), 7.33 (t, J = 8.04 Hz, 1H), 7.10 (d, J = 8.25 Hz, 1H), 3.91 (s, 3H), 3.59 (t, J = 4.95 Hz, 4H), 3.18 (t, J = 5.31 Hz, 4H), 1.49 (s, 9H).
23%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; for 18h;Inert atmosphere; Reflux;	To a 250 mL round-bottom flask containing 40 mL of 1,4-dioxane, raw material 2-23 (<strong>[618-89-3]methyl m-bromobenzoate</strong>) (2.15 g, 10 mmol), BINAP (622 mg, 1 mmol), palladium acetate (45 mg, 0.2 mmol), cesium carbonate (6.5 g, 20 mmol), Boc-piperazine 2-24 (1.86 g, 10 mmol) were added in sequence, and reacted under argon atmosphere and reflux at 100 C for 18 hours, until TLC (PE: EA = 10: 1) detection showed the reaction was completed. Filtration was carried out with diatomite to remove solid(s). The filtrate was evaporated under reduced pressure and subjected to column chromatography (PE: EA = 10: 1) to give 720 mg of a light yellow oily product, yield: 23%.

With sodium t-butanolate;palladium diacetate; johnphos; In toluene; at 50℃;

To a mixture containing piperazine-1-carboxyltc acid tert-butyl ester (400 mg, 2.16 mmol), 3-bromo-benzoic acid methyl ester (547 mg, 2.56 mmol), Pd(AcO) (32 mg, 0.14 mmol), 2-(di-f-butylphosphino)biphenyl (80 mg, 0.28 mmol) and sodium t- butoxide (400 mg, 4 mmol) in toluene (20 mL) was degassed with Ar. The reaction mixture was heated at 50 C for overnight. At the end of reaction, ethyl acetate was added and the mixture was filter through celite. After removal of solvent, TFA was added to the residue. The reaction mixture was stirred at ambient temperature for 1 hour. The excess TFA was removed under vacuum and the residue was purified <n="183"/>using prep-HPLC to give desired product (250 mg, 37 % yield for two steps) as TFA salt.

Reference： [1]Patent: WO2017/195069,2017,A1 .Location in patent: Page/Page column 89
[2]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 1035 - 1049
[3]Patent: EP3722299,2020,A1 .Location in patent: Paragraph 0075-0076
[4]Journal of Medicinal Chemistry,2021,vol. 64,p. 9010 - 9041
[5]Patent: WO2007/97937,2007,A1 .Location in patent: Page/Page column 181-182

36
[ 42397-28-4 ]
[ 618-89-3 ]
[ 959706-81-1 ]

Reference： [1]Angewandte Chemie - International Edition,2007,vol. 46,p. 7236 - 7239

37
[ 34713-70-7 ]
[ 618-89-3 ]
[ 959706-74-2 ]

Reference： [1]Angewandte Chemie - International Edition,2007,vol. 46,p. 7236 - 7239

38
[ 618-89-3 ]
[ 128622-13-9 ]
methyl 3-[7-tert-butyldimethylsilyloxy-1-formylheptyl]benzoate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2007,vol. 46,p. 7236 - 7239

39
[ 618-89-3 ]
[ 66-25-1 ]
[ 959706-81-1 ]

Reference： [1]Angewandte Chemie - International Edition,2007,vol. 46,p. 7236 - 7239

40
[ 618-89-3 ]
[ 1035869-05-6 ]

Yield	Reaction Conditions	Operation in experiment
37.22%	With Lawessons reagent; In toluene; at 140℃; for 4h;Microwave irradiation;	To a solution of <strong>[618-89-3]methyl 3-bromobenzoate</strong> (10 g, 46.50 mmol) in toluene (10 mL) was added 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4dithiadiphosphetane (20.69 g, 51.15 mmol). The mixture was stirred in a microwave reactor at 140 C for 4 h. After cooling to rt the solvent was removed under reduced pressure and the crude residue was purified by column chromatography to give O-methyl 3-bromobenzenecarbothioate (4 g, 37.22% yield). 1H NMR (400 MHz, METHANOL-d4) d ppm 8.29 (t, J = 1.76, 1 H) 8.08 - 8.16 (m, 1 H) 7.70 - 7.77 (m, 1 H) 7.34 (t, J = 7.94, 1 H) 4.27 - 4.33 (m, 3 H).

Reference： [1]Tetrahedron Letters,2008,vol. 49,p. 3682 - 3686
[2]Patent: WO2020/180770,2020,A1 .Location in patent: Paragraph 00578

41
[ 618-89-3 ]
[ 98-80-6 ]
[ 35714-17-1 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium phosphate;bis-triphenylphosphine-palladium(II) chloride; In water; N,N-dimethyl-formamide; at 80℃; for 1h;	I. Methyl 3-benzylbenzoate; [00306] A solution of 3-bromomethylbenzoate (500 mg, 2.18 mmol), phenylboronic acid (290 mg, 2.40 mmol), PdCl2(PPh3)2 (46 mg, 0.07 mmol) and K3PO4 (1.16 g, 5.45 mmol) in DMF (10 mL) and water (2 mL) was heated at 8O0C for 1 hr and then cooled to room temperature and diluted with EtOAc. The reaction mixture was washed with water (3 times) and saturated NaCl, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with 1 :19 EtOAc:hexanes to give a colorless oil (353 mg, 72%).

Reference： [1]Patent: WO2008/79371,2008,A1 .Location in patent: Page/Page column 108

42
[ 1040745-70-7 ]
[ 618-89-3 ]
[ 1041642-15-2 ]

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 9257 - 9259

43
[ 618-89-3 ]
[ 39115-96-3 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine; In methanol; water; at 50 - 55℃; for 3.33333h;	To a 100 L round bottom flask under nitrogen was added DABCO (2.81 kg, 25.06 mol) and MeOH (35 L). 3-bromobenzoyl chloride 1 (5.0 kg, 22.78 mol) was charged over 30 min at 20 - 25 0C and an ice water bath was used to control the temperature. <n="33"/>The mixture was stirred at room temperature for 10 - 20 minutes. Hydrazine (64%, 8.8 L, 182 mol) was added over 20 minutes, and the reaction mixture was heated at 50 to 55 0C for 3 hours. Water (35 L) was added to crystallize the batch at room temperature over 1 hour. The resulting slurry was stirred at room temperature for 1 -2 hours and filtered. The wet cake was washed with water (3 x 15 L), and dried at room temperature under a vacuum/N2 sweep to afford hydrazide 3 as white solid. HPLC retention time of hydrazide 3 = 6.75 minutes, on Waters Symmetry C- 18 column, 5 micron, 4.6 x 250 mm; 20 0C, UV detection at 215 nm; gradient flow 1.0 mL/min; A = water with 0.1% H3PO4; B = acetonitrile; gradient elution: 0 minutes: 95% A/5% B; 5 minutes: 55% A/45% B; 10 minutes: 25% A/75% B; 13 minutes: 10% A/90% B; and 26 minutes: 10% A/90% B. IH NMR (DMSO-d6): 69.88 (IH, s), 7.98 (IH, m), 7.81 (IH, m), 7.70 (IH, m), 7.41 (IH, m), 4.52 (2H, s).
	With hydrazine hydrate; In methanol; for 5h;Reflux;	General procedure: Compounds 6a-t were synthesized from substituted benzoic acid via six steps according to the literature method as described. Various substituted benzoic acids 1a-t were treated with SOCl2 to give compounds 2a-t, which were reacted with CH3OH and EtN3 in CH2Cl2 at 0 to afford compounds 3a-t. Compounds 4a-t were prepared by the reaction of compounds 3a-t, hydrazine hydrate in CH3OH under reflux condition about 5h. Subsequently, compounds 5a-t were obtained by reaction of compounds 4a-t with CS2 and KOH in CH3OH. Compounds 6a-t were obtained by the cyclization reaction of compounds 5a-t in the presence of HCl at 0-5C.
	With hydrazine hydrate; In ethanol; for 9h;Reflux;	General procedure: Substituted benzoic acid (1.0 mmol) was dissolved in thionylchloride and refluxed for 2 h, then the solvent was removed underreduced pressure to obtain the white solid. The white solid in methanol was added concentrated sulfuric acid (1 mL) and themixture was refluxed for 4 h, the solvent was removed to obtaincrude solid. The crude solid was extracted with ethyl acetate andwater. The solvents were evaporated to afford the pure product.Finally, the pure product was dissolved in ethanol, and the hydrazinehydrate was added. The mixture was refluxed for 9 h, and thesolvent was removed

	With hydrazine hydrate; In methanol; for 8h;Reflux;	General procedure: To a solution of methyl ester of aromatic carboxylic acid 2 (0.1 mol) in methanol (30 mL), hydrazine hydrate (0.2 mol) was added drop wise with stirring. The resulting mixture was allowed to reflux for 8 h. After the completion of the reaction as monitored by TLC, the excess methanol was distilled off under reduced pressure. The resulting acid hydrazide 3 was washed with cold water, dried and recrystallized from ethanol.
	With hydrazine hydrate; In methanol; at 65℃; for 4h;	General procedure: To a solution of esters (2a~2t, 1.0 equiv.), furan-2-carbonyl chloride (7a, 1.0 equiv.) orthiophene-2-carbonyl chloride (7b, 1.0 equiv.) in MeOH (2 mL/1 mmol) was added hydrazine hydrate(1 mL/1 mmol), then the mixture was allowed to reach 65 C and stirred for 4 h. After completion(monitored by TLC), the organic solvent was removed and extracted three times with ethyl acetate,the combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to givethe corresponding hydrazides (3a~3t, 8a, or 8b) in high yields, which were taken up for the next stepwithout any purification.

Reference： [1]Journal of the Chilean Chemical Society,2012,vol. 57,p. 1492 - 1496
[2]Patent: WO2009/54923,2009,A2 .Location in patent: Page/Page column 29; 30; 31
[3]Zeitschrift fur Naturforschung, B: Chemical Sciences,2010,vol. 65,p. 178 - 184
[4]Monatshefte fur Chemie,2010,vol. 141,p. 479 - 484
[5]Medicinal Chemistry,2012,vol. 8,p. 1190 - 1197,8
[6]Bulletin of the Korean Chemical Society,2012,vol. 33,p. 3943 - 3949
[7]Chemical Biology and Drug Design,2013,vol. 82,p. 546 - 556
[8]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 192 - 194
[9]Chemical Communications,2015,vol. 51,p. 14365 - 14368
[10]Journal of Molecular Structure,2016,vol. 1117,p. 8 - 16
[11]Letters in drug design and discovery,2016,vol. 13,p. 968 - 981
[12]Chemical Biology and Drug Design,2017,vol. 89,p. 47 - 60
[13]Molecules,2020,vol. 25
[14]Biomolecules,2019,vol. 9
[15]Bioorganic and medicinal chemistry letters,2020

44
[ 3438-61-7 ]
[ 618-89-3 ]
[ 1173285-70-5 ]

Reference： [1]Tetrahedron Letters,2009,vol. 50,p. 3952 - 3954

45
[ 37441-50-2 ]
[ 618-89-3 ]
[ 1207356-79-3 ]

Reference： [1]Tetrahedron Letters,2010,vol. 51,p. 360 - 362

46
[ 618-89-3 ]
[ 68432-92-8 ]

Reference： [1]Patent: CN106928092,2017,A

47
[ 618-89-3 ]
[ 1569-16-0 ]
[ 1256347-57-5 ]

Reference： [1]Organic Letters,2010,vol. 12,p. 5359 - 5361

48
[ 872-36-6 ]
[ 618-89-3 ]
[ 1313497-03-8 ]

Yield	Reaction Conditions	Operation in experiment
55%	With palladium diacetate; caesium carbonate; triphenylphosphine; In N,N-dimethyl-formamide; at 120℃; for 1h;Inert atmosphere;	General procedure: A stirred mixture of bromobenzene (471 mg, 3.0 mmol), <strong>[872-36-6]vinylene carbonate</strong> (86 mg, 1.0 mmol), Pd(OAc)2 (22 mg, 10 mol %), PPh3 (52 mg, 20 mol %), and Cs2CO3 (715 mg, 2.2 mmol) in DMF (1.5 mL) was heated to 120 C for 30 min under nitrogen atmosphere. After aqueous extractive workup and column chromatographic purification process (hexanes/EtOAc, 20:1) benzil was obtained as a pale yellow solid, 170 mg (81% based on <strong>[872-36-6]vinylene carbonate</strong>), along with biphenyl (65 mg, 28% based on bromobenzene) as a white solid.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 3463 - 3466

49
[ 618-89-3 ]
potassium ferrocyanide [ No CAS ]
[ 13531-48-1 ]

Reference： [1]Chemistry - A European Journal,2012,vol. 18,p. 2978 - 2986

50
[ 618-89-3 ]
[ 121-01-7 ]
[ 1359968-17-4 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 2311 - 2323

51
[ 618-89-3 ]
[ 121-01-7 ]
[ 1359967-55-7 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 2311 - 2323

52
[ 335255-43-1 ]
[ 279240-83-4 ]
[ 1663-39-4 ]
[ 618-89-3 ]
triacetoxylpalladium [ No CAS ]
[ 1228793-90-5 ]
[ 1228793-91-6 ]
[ 1228793-92-7 ]
[ 12125-02-9 ]
[ 6163-58-2 ]
[ 98116-12-2 ]
[ 1228793-77-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; LiOH; DIPEA; sodium hydrogencarbonate; benzotriazol-1-ol; triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In tetrahydrofuran; methanol; dichloromethane; water; ethyl acetate; trifluoroacetic acid;	Synthesis of (E)-3-(3-(2-amino-5-(thiophen-2-yl)phenylamino)-3-oxoprop-1-enyl)benzamide (BRD-3636) A mixture of methyl 3-bromobenzoate (10.8 g, 50.2 mmol, 1.0 eq), t-butyl acrylate (8.05 g, 62.8 mmol, 1.25 eq), triethylamine (10.16 g, 100 mmol, 2.0 eq), triacetoxylpalladium (0.14 g, 0.50 mmol, 0.01 eq) and tri-o-tolylphosphine (0.61 g, 2.0 mmol, 0.04 eq) was heated at 100 C. for 2 h under nitrogen atmosphere. The reaction mixture was diluted with water. The product was extracted with ethyl acetate. The organic phase was adjusted to pH~3 with a 1M aqueous solution of HCl. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow solid (11 g, 84% yield). A mixture (E)-methyl 3-(3-tert-butoxy-3-oxoprop-1-enyl)benzoate (12.0 g, 45.7 mmol) in TFA (100 mL) was stirred at room temperature for 20 h. The solvent was removed under reduced pressure. The residue obtained was washed with ethyl acetate to give a white solid (8.5 g, 90% yield). A mixture of (E)-3-(3-(methoxycarbonyl)phenyl)acrylic acid (5.56 g, 27 mmol, 1.5 eq), <strong>[335255-43-1]tert-butyl 2-amino-4-(thiophen-2-yl)phenylcarbamate</strong> (5.22 g, 17.98 mmol, 1.0 eq), HATU (10.30, 42.7 mmol, 2.37 eq) and DIPEA (6.96 g, 98 mmol, 5.45 eq) in THF (80 ml) was stirred at room temperature for 20 h. The reaction was then concentrated. The residue was diluted with ethyl acetate and washed with water, then brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography (silica gel, 50% PE/CH2Cl2) to afford a yellow solid (6.0 g, 64.9% yield). To a solution of (E)-methyl 3-(3-(2-(tert-butoxycarbonylamino)-5-(thiophen-2-yl)phenylamino)-3-oxoprop-1-enyl)benzoate (5.5 g, 11.49 mmol, 1.0 eq) in THF (60 mL) was added a solution of LiOH (0.69 g, 28.7 mmol, 2.5 eq) in water (60 mL). The reaction was stirred at room temperature for 20 h. The reaction was extracted with ethyl acetate. The aqueous layer was separated and acidified with a 1N aqueous solution of HCl to pH~2. The precipitate formed was filtered and rinsed subsequently with water (200 mL), then methanol (100 mL) to afford a white solid (4.2 g, 79% yield). A mixture of ammonia hydrochloride (0.02 g, 0.43 mmol, 2.0 eq), (E)-3-(3-(2-(tert-butoxycarbonylamino)-5-(thiophen-2-yl)phenylamino)-3-oxoprop-1-enyl)benzoic acid (0.10 g, 0.21 mmol, 1.0 eq), HATU (0.08 g, 0.32 mmol, 1.5 eq), HOBt (0.043 g, 0.32 mmol, 1.5 eq) and DIPEA (0.11 g, 0.86 mmol, 4.0 eq) in THF (10 mL) was stirred at room temperature for 20 h. The reaction was then concentrated. The residue was diluted with ethyl acetate and washed with water, then brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography (silica gel, 10% MeOH/CH2Cl2) to afford the desired product (0.08 g, 80% yield). A solution of (E)-tert-butyl 2-(3-(3-carbamoylphenyl)acrylamido)-4-(thiophen-2-yl)phenylcarbamate (0.08 g, 0.17 mmol, 1.0 eq) in CH2Cl2 was treated with trifluoroacetic acid (1 mL). The solution was stirred at room temperature for 1 h. The reaction was then concentrated. The residue was dissolved in ethyl acetate (20 mL). The solution was washed with a saturated aqueous solution of sodium bicarbonate (10 mL), then water (10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The product was washed with ether (2 mL) to give the target compound (0.05 g, 73% yield). ESI+ MS: m/z (rel intensity) 364 (92.63, M+H), 1H NMR (500 MHz, d6-DMSO): delta 9.48 (s, 1H), 8.18 (s, 1H), 8.09 (s, 1H), 7.90 (d, J=8 Hz, 1H), 7.80-7.70 (m, 2H), 7.62 (d, J=16 Hz, 1H), 7.54 (t, J=8 Hz, 1H), 7.49 (s, 1H), 7.36 (d, J=5 Hz, 1H), 7.29-7.19 (m, 2H), 7.10-6.59 (m, 2H), 6.79 (d, J=8 Hz, 1H), 5.24 (s, 2H).

Reference： [1]Patent: US2012/101147,2012,A1

53
[ 618-89-3 ]
[ 73183-34-3 ]
[ 480425-35-2 ]

Yield	Reaction Conditions	Operation in experiment
83%	With meso-tetra(p-tolyl)porphinato-palladium(II); potassium acetate; In 1,4-dioxane; at 110℃; for 7h;	General procedure: Aryl/heteroaryl bromide 1 (1 mmol), B2pin2(2), B2npg2(4) orBpin (6, 1.2 mmol), and dioxane (5 mL) are taken into a 25 mLround-bottomed flask. KOAc (2 mmol) was added and stirredthe resultant mixture at room temperature for 5 min, PdII-TpTP(0.15 mol%) was added, and the contents were refluxed on preheatedoil bath at 110 C under constant stirring in open-air.The reaction progress was ensured by TLC. After completion ofthe reaction, the mixture was cooled, dilute with water (20 mL)and extracted with tertbutylmethyl ether (3 × 10 mL). The combinedn-hexane layers were concentrated, and the crudeproduct obtained was purified by column chromatography (CC)on silica gel using a mixture of ethyl acetate and hexane (1:30)as eluent.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; for 2h;Reflux; Inert atmosphere;	General procedure: A mixture of substituted 3-(or 4-) bromobenzamides or 3-bromobenzoate or N-(3-(or 4-)bromophenyl)acetamide 3, (0.5 mmol), bis(pinacolato)diboron (0.14 g, 0.55 mmol), potassium acetate (0.15 g, 1.5 mmol), PdCl2(dppf) (0.03 g, 0.04 mmol) and 1,4-dioxane (10 mL) was refluxed for 2 h under nitrogen atmosphere. The solvent was evaporated under reduced pressure to afford a dark brown residue. To the residue was added intermediate 2 (0.4 mmol), sodium carbonate (0.16 g, 1.5 mmol), PdCl2(dppf) (0.03 g, 0.04 mmol), 1,2-dimethoxyethane (8 mL) and water (2 mL) and the mixture was refluxed for 2 h under nitrogen atmosphere. The mixture was evaporated under reduced pressure and purified by silica gel column chromatography using chloroform/methanol = 30: 1 as the eluent to afford the compounds T1-T6, T9-T10, T12 and T14-T21 as an off-white or a white solid.

Reference： [1]Journal of Organic Chemistry,2014,vol. 79,p. 888 - 900
[2]Synthesis,2012,vol. 44,p. 2173 - 2180
[3]Synlett,2018,vol. 29,p. 1055 - 1060
[4]Chemistry - An Asian Journal,2017,vol. 12,p. 3110 - 3113
[5]Organic Letters,2016,vol. 18,p. 5248 - 5251
[6]Journal of the American Chemical Society,2020,vol. 142,p. 2087 - 2092
[7]European Journal of Medicinal Chemistry,2015,vol. 96,p. 382 - 395

54
[ 618-89-3 ]
[ 73183-34-3 ]
[ 269409-73-6 ]

Reference： [1]Synthesis,2012,vol. 44,p. 2173 - 2180

55
[ 109-09-1 ]
[ 618-89-3 ]
[ 98061-20-2 ]

Reference： [1]Journal of Organic Chemistry,2012,vol. 77,p. 8678 - 8688

56
[ 618-89-3 ]
[ 63744-25-2 ]
[ 98-80-6 ]
[ 1412909-03-5 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 6012 - 6015

57
[ 618-89-3 ]
[ 74-88-4 ]
[ 30951-66-7 ]

Yield	Reaction Conditions	Operation in experiment
4.98 g		A solution of methylmagnesium iodide is prepared from 5.79 ml of methyl iodide and 2.2 g of magnesium turnings in refluxing ether. A solution of 5 g of methyl 3- bromobenzoate in 110 ml of ether is then added dropwise and the mixture is refluxed for 3 hours. The reaction mixture is poured onto ice/saturated NH4C1, the phases are separated by settling, the organic phase is washed with 10% aHC03 solution and with saturated NaCl solution, and dried over MgS04, and the solvent is evaporated off under vacuum. 4.98 g of the expected compound are obtained.

Reference： [1]Patent: WO2013/87643,2013,A1 .Location in patent: Page/Page column 15

58
[ 618-89-3 ]
[ 103-67-3 ]
[ 349405-39-6 ]

Yield	Reaction Conditions	Operation in experiment
75%	With [m-(1,4-diazabicyclo[2.2.2]octanekN1:kN4)]hexamethyldialuminum; In tetrahydrofuran; at 130℃; for 0.13333299999999998h;Inert atmosphere; Microwave irradiation;	General procedure: 4.2 General procedures: A. Microwave. Neat samples of amine (1.00 mmol) and carboxylic derivative (methyl ester or acid, 1.00 mmol) and DABAL-Me3 (202 mg, 0.8 equiv) were placed in a 5 mL microwave vial and dry THF added (1 mL) under a blanket of argon. For coupling partners containing acidic hydrogens additional DABAL-Me3 (total of 410 mg, 1.6 equiv) was used. The vial was promptly capped and placed in a CEM Discover microwave reactor. After irradiation (290 W, 130 C, 8 min) and programmed cool down (ca. 20 min). The reactions were quenched by cautious addition of HCl (2 M, 4 mL) or aqueous solutions of Rochelle salt (saturated potassium sodium tartrate, 4 mL) (CARE: methane liberated). Extraction with dichloromethane, drying (MgSO4) and evaporation frequently provided the pure products directly. If purification was required column chromatography 3:2 to 2:3 hexane:EtOAc was used for amides lacking highly polar functional groups (CH2Cl2 with 2 % v/v MeOH was used for amides bearing pendant amines, alcohols and other polar functional groups).

Reference： [1]Tetrahedron,2013,vol. 69,p. 9890 - 9897

59
[ 618-89-3 ]
[ 288-36-8 ]
methyl 3-(2H-1,2,3-triazole-2-yl)benzoate [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2013,vol. 11,p. 7830 - 7833

60
[ 1001-26-9 ]
[ 618-89-3 ]
[ 1491168-33-2 ]

Yield	Reaction Conditions	Operation in experiment
71%	With bis(tri-t-butylphosphine)palladium(0); dicyclohexylmethylamine; lithium chloride; In 1,4-dioxane; at 110℃; for 16h;Inert atmosphere;	General procedure: A flask containing LiCl (980 mg,23.1 mmol), 2-bromo-4-fluoroanisole (1.0 mL, 7.7 mmol), DCMA (1.8 mL,8.4 mmol) and <strong>[1001-26-9]ethyl 3-ethoxyacrylate</strong> (3.3 mL, 23 mmol) in 1,4-dioxane(20 mL) was degassed by passing a stream of nitrogen through the mixturefor 10 min. Bis(tri-t-butylphosphine) palladium(0) (166 mg, 0.32 mmol) wasadded, and reaction mixture was heated at reflux under nitrogen for 16 h. Thebrown mixture was then cooled and partitioned between ethyl acetate andwater. The layers were separated, and the organic layer was washedsequentially with aqueous NH4Cl and brine, followed by drying over Na2SO4.The mixture was filtered, and the filtrate was concentrated under reducedpressure to give an oil which was purified by flash chromatography on silica(40 g, 10?50percent ethyl acetate in heptane) to afford 22c as an orange oil (1.93 g,92percent) as an inseparable mixture of E- and Z-isomers: 1H NMR (CDCl3, 500 MHz)alkene protons d: 5.21, 5.33 ppm (1:1 ratio); LCMS (ES): 269.2 (MH). HRMSCalcd for C14H17FO: 269.1184. Found: 269.1196.

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 7065 - 7068

61
[ 1001-26-9 ]
[ 618-89-3 ]
3-(3-methoxycarbonylphenyl)-3-oxopropanoic Acid Ethyl Ester [ No CAS ]

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 7065 - 7068

62
[ 618-89-3 ]
[ 13411-48-8 ]
[ 21860-07-1 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 824 - 827

63
[ 253-66-7 ]
[ 618-89-3 ]
[ 1562366-98-6 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 1232 - 1235

64
[ 618-89-3 ]
[ 75-05-8 ]
[ 70591-86-5 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium hydride; In tetrahydrofuran; at 75℃; for 4h;	Acetonitrile (21.86 mL, 419 mmol) was added to a stirred suspension of 60% NaH (7.25 g, 181 mmol) in THF (150 mL). Then, methyl 3-bromobenzoate (30 g, 140 mmol) was added and the mixture was heated at 75C for 4 h. After cooling to room temperature, water followed by 1N HCl (200 mL) was added and the mixture was extracted with ethyl acetate (500 mL), washed with sat .NaHCO3 solution (200 mL), dried (Na2SO4), filtered andconcentrated to afford 3-(3-bromophenyl)-3-oxopropanenitrile (29 g, 129 mmol, 93% yield) as light yellow solid. 1H NMR (500 MHz, CDCl3) 8.09 (t, J1.7 Hz, 1H),7.90 - 7.86 (m, 1H), 7.83 (ddd, J=8.0, 2.0, 1.1 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 4.08(s, 2H).
93%		Intermediate 1 3-(3-bromophenyl)-3-oxopropanenitrile Acetonitrile (21.86 mL, 419 mmol) was added to a stirred suspension of 60% NaH (7.25 g, 181 mmol) in THF (150 mL). Then, methyl 3-bromobenzoate (30 g, 140 mmol) was added and the mixture was heated at 75C for 4 h. After cooling to room temperature, water followed by IN HC1 (200 mL) was added and the mixture was extracted with ethyl acetate (500 mL) , washed with sat .NaHC03 solution (200 mL), dried (Na2S04), filtered and (0090) concentrated to afford 3-(3-bromophenyl)-3-oxopropanenitrile (29 g, 129 mmol, 93 % yield) as light yellow solid. 1H NMR (500 MHz, CDC13) delta 8.09 (t, J=1.7 Hz, 1H), 7.90 - 7.86 (m, 1H), 7.83 (ddd, J=8.0, 2.0, 1.1 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 4.08 (s, 2H).
93%	With sodium hydride; In tetrahydrofuran; at 75℃; for 4h;	Acetonitrile (21.86 mL, 419 mmol) was added to a stirred suspension of 60% NaH (7.25 g, 181 mmol) in THF (150 mL). Then, methyl 3-bromobenzoate (30 g, 140 mmol) was added and the mixture was heated at 75C for 4 h. After cooling to room temperature, water followed by 1N HCl (200 mL) was added and the mixture was extracted with ethyl acetate (500 mL) , washed with sat .NaHCO3 solution (200 mL), dried (Na2SO4), filtered and concentrated to afford 3-(3-bromophenyl)-3-oxopropanenitrile (29 g, 129 mmol, 93 % yield) as light yellow solid. 1H NMR (500 MHz, CDC13) delta 8.09 (t, J=1.7 Hz, 1H), 7.90 - 7.86 (m, 1H), 7.83 (ddd, J=8.0, 2.0, 1.1 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 4.08 (s, 2H).

93%	With sodium hydride; In tetrahydrofuran; at 75℃; for 4h;	3-(3-bromophenyl)-3-oxopropanenitrile: Acetonitrile (21.86 mL, 419 mmol) was added to a stirred suspension of 60% NaH (7.25 g, 181 mmol) in THF (150 mL). Then, methyl 3-bromobenzoate (30 g, 140 mmol) was added and the mixture was heated at 75C for 4 h. After cooling to room temperature, water followed by iN HC1 (200 mL) was added and the mixture was extracted with ethyl acetate (500 mL), washed with sat .NaHCO3 solution (200 mL), dried (Na2SO4), filtered andconcentrated to afford 3-(3-bromophenyl)-3-oxopropanenitrile (29 g, 129 mmol, 93% yield) as light yellow solid. ?H NMR (500 MHz, CDC13) oe 8.09 (t, J1 .7 Hz, 1H),7.90 - 7.86 (m, 1H), 7.83 (ddd, J8.0, 2.0, 1.1 Hz, 1H), 7.45 (t, J7.9 Hz, 1H), 4.08(s, 2H).
	With sodium hydride; In tetrahydrofuran; at 0 - 77℃; for 2h;Inert atmosphere;	1003271 To a mixture of acetonitrile (7.78 g, 190 mmol, 9.97 mL) and anhydrous tetrahydrofuran (300 mL) was added sodium hydride (6.05 g, 15 lmmol) portion-wise at rt under nitrogen atmosphere. Then methyl 3-bromobenzoate (25.0 g, 116 mmol) was added to the mixture and the resulting mixture was heated to 77 C and stirred for 2 hours. On completion, the reaction was cooled to rt and hydrochloric acid solution (1 N, 400 mL) was added to the reaction. The aqueous was extracted with ethyl acetate (4 X 250 mL). The organic layer was washed with sodium bicarbonate (1.0 L), dried over sodium sulfate, and concentrated in vacuo to give the title compound. ?H NMR (400MHz, CDC13) = 8.07 (br. s., 1H), 7.94 - 7.76 (m, 2H), 7.44 (t, J=7.6 Hz, 1H), 4.10 (s, 2H).

Reference： [1]Patent: WO2014/28384,2014,A1 .Location in patent: Page/Page column 24; 25
[2]Patent: WO2015/123182,2015,A1 .Location in patent: Page/Page column 18; 19
[3]Patent: WO2015/126743,2015,A1 .Location in patent: Page/Page column 21
[4]Patent: WO2015/126376,2015,A1 .Location in patent: Page/Page column 23; 24
[5]Patent: WO2017/156179,2017,A1 .Location in patent: Paragraph 00323; 00326; 00327

65
[ 618-89-3 ]
[ 455-68-5 ]

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 3792 - 3795

66
[ 928664-98-6 ]
[ 618-89-3 ]
[ 68432-92-8 ]

Yield	Reaction Conditions	Operation in experiment
69%	With potassium fluoride; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 130℃; for 18h;Inert atmosphere; Sealed tube;	Step 1: To a vial with a stir bar was added methyl 3-bromobenzoate (1.0 equiv.) 4-isoxazoleboronic acid (1.2 equiv.), PdCl2(dppf).CH2Cl2 adduct (0.1 equiv.), 1M KF (2.0) and DMSO (0.10 M). The reaction mixture was degassed with bubbling nitrogen and the vial capped and heated at 130 C. for 18 hr. LCMS analysis indicated the formation of the desired product (MH+-176, Rt-0.62 min). The reaction mixture was diluted with a saturated solution of NH4Cl and extracted with EtOAc (2×). The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated. The crude material was purified via flash chromatography over silica gel eluting with heptanes and 0-100% ethyl acetate gradient. Isolated methyl 3-(cyanomethyl)benzoate in 69% yield. LCMS (m/z) (M+H)=176.1, Rt=0.62). 1H NMR (400 MHz, ) delta ppm 3.92 (s, 3H), 3.99 (s, 2H), 7.49-7.55 (m, 1H), 7.62 (d, J=7.83 Hz, 1H), 7.99 (d, J=7.83 Hz, 1H), 8.04 (s, 1H).

Reference： [1]Patent: US2014/275003,2014,A1 .Location in patent: Paragraph 0182

67
[ 618-89-3 ]
[ 10601-99-7 ]

Reference： [1]Patent: WO2014/168824,2014,A1

68
[ 618-89-3 ]
[ 197223-39-5 ]
methyl 3',5'-di-t-butylbiphenyl-3-carboxylate [ No CAS ]

Reference： [1]Chemical Communications,2015,vol. 51,p. 1926 - 1929

69
[ 618-89-3 ]
[ 2993-24-0 ]
3-[(4-(pentafluorosulfanyl)phenyl)amino]benzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 110℃; for 18h;Inert atmosphere; Schlenk technique;	General procedure: A flame-dried and argon-flushed Schlenk tube was charged with methyl bromobenzoate (65 mg, 0.3 mmol), pentafluorosulfanyl aniline (79 mg, 0.36 mmol), Cs2CO3 (137 mg, 0.42 mmol), BINAP (15 mg, 8 mol%), Pd(OAc)2 (3.4 mg, 5 mol%) and absolute toluene (3 mL). The reaction mixture was stirred at 110 C for 18 h. Ethyl acetate (5 mL) was added, and the mixture was washed with 1 N HCl solution (2 x 10 mL) and brine (10 mL). The organic phase was dried over anhydrous magnesium sulfate and the crude product was purified by column chromatography (acetone/n-pentane 1:20).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 4437 - 4440

70
[ 618-89-3 ]
[ 776-34-1 ]
[ 1378871-28-3 ]

Yield	Reaction Conditions	Operation in experiment
22%	With palladium diacetate; caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In toluene; at 25 - 120℃; for 48h;	(3-((4-nitronaphthalen-1-yl)amino)benzoic acid methyl ester 4-Nitro-1-naphthylamine (1.2 equiv), Cs2CO3 (1.4 equiv), BINAP (0.08 equiv), and Pd(OAc)2 (0.05 equiv) were added to a solution of methyl 3-bromobenzoate (1 equiv) in toluene (0.1 M) at 25 C. The reaction mixture was allowed to stir at 120 C. for 48 h. Once the reaction appeared to be complete by consumption of the bromide (or triflate) by TLC analysis, the mixture was allowed to cool to 25 C., diluted with EtOAc, washed with 2 M aq HCl (2*), brine, and dried over sodium sulfate. The solution was concentrated, loaded on silica gel, and purified by silica gel chromatography to give the methyl ester of compound 13 as an orange solid (22% yield). 1H NMR (CDCl3, 500 MHz): delta=8.94 (d, J=8.8 Hz, 1H), 8.35 (d, J=8.7 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 7.86 (d, J=7.2 Hz, 1H), 7.78 (t, J=7.8 Hz, 1H), 7.64 (t, J=7.7 Hz, 1H), 7.45-7.54 (m, 2H), 7.15 (d, J=8.7 Hz, 1H), 6.75 (s, 1H), 3.94 (s, 3H). 13C NMR (CDCl3, 125 MHz): delta=166.7, 146.3, 141.0, 138.9, 132.2, 130.2, 130.1, 127.8, 127.7, 127.0, 126.3, 125.7, 125.0, 124.6, 123.1, 120.9, 107.3, 52.6. HRMS (ES) Calcd. for C18H14N2O4: 321.0875 (M-H-). found 321.0872 (M-H-).

Reference： [1]Patent: US9271961,2016,B2 .Location in patent: Page/Page column 70; 71

71
[ 618-89-3 ]
[ 1195-66-0 ]
[ 480425-35-2 ]

Reference： [1]Chemical Communications,2016,vol. 52,p. 7009 - 7012

72
[ 78593-40-5 ]
[ 618-89-3 ]
methyl 3-(quinolin-3-ylethynyl)benzoate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 4202 - 4209

73
[ 618-89-3 ]
[ 75-86-5 ]
[ 13531-48-1 ]

Reference： [1]Organic Process Research and Development,2016,vol. 20,p. 1540 - 1545

74
[ 905966-40-7 ]
[ 618-89-3 ]
[ 55676-76-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium phosphate tribasic hydrate; NiIICl(1-naphthyl)(tricyclohexylphosphine)2; tricyclohexylphosphine; In tetrahydrofuran; at 23℃; for 24h;Inert atmosphere; Glovebox; Sealed tube;	General procedure: Cross-Coupling of ortho-, meta-, and para-Substituted, Electron-Rich and Electron-Deficient Aryl Halides and Aryl Mesylates with Aryl Neopentylglycolboronates Catalyzed by NiIICl(1-naph-thyl)(PCy3)2/PCy3 in Anhydrous THF at 23 C; General Procedure 2In an oven-dried test tube charged with a Teflon coated stirring barwere added aryl halide or aryl mesylate (0.3 mmol), aryl neopentyl-glycolboronates (0.315 mmol), K3PO4(H2O)3.2 (191.00 ± 1.00 mg, 0.9mmol), and NiIICl(1-naphthyl)(PCy3)2 (11.73 ± 0.0510 mg, 0.015mmol, 5% catalyst loading). The test tube was brought into a N2 filledglove box (moisture level <2 ppm) through three degassing cycles andPCy3 (8.4 mg, 0.03 mmol, 10% loading) ligand was added. Distilled sol-vent (1 mL) was added inside the glove box and the test tube wassealed by a rubber septum and left stirring at 23 C. A sample was tak-en by syringe and transferred outside the glove box. The sample wasdiluted by distilled THF (0.2 mL) and filtered through a short columnof Al2O3. The filtrate was concentrated and the GC analysis was car-ried out. The reaction mixture was diluted with CH2Cl2 (2 mL), filteredthrough a layer of Al2O3, and washed with CH2Cl2 (3 1 mL). The fil-trate was collected and concentrated under vacuum. The crude prod-uct was purified by column chromatography on silica gel with EtO-Ac/hexane mixture as eluent. The reductive elimination side-productwas also isolated and characterized.

Reference： [1]Synthesis,2016,vol. 48,p. 2795 - 2807

75
[ 618-89-3 ]
[ 766-55-2 ]
methyl 3-(imidazo[1,2-b]pyridazin-3-yl)benzoate [ No CAS ]

Reference： [1]Chemistry - An Asian Journal,2016,vol. 11,p. 2443 - 2452

76
[ 568577-88-8 ]
[ 618-89-3 ]
methyl 4'-(morpholin-4-yl)biphenyl-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 80℃;	To a solution of methyl 3-bromobenzoate (31; 500 mg, 2.33 mmol) in DME (5.0 mL)/water (2.0 mL) were added 15 (700 mg, 2.42 mmol), Na2CO3 (739 mg, 6.98 mmol), and Pd(PPh3)4(80 mg, 0.069 mmol). The mixture was stirred at 80 C overnight. After being cooled to room temperature, the mixture was concentrated in vacuo. The residue was diluted with saturated NaHCO3 aqueous solution and extracted with CHCl3. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (CHCl3/MeOH) to afford methyl 4'-(morpholin-4-yl)biphenyl-3-carboxylate (531 mg, 77%). To a solution of methyl 4'-(morpholin-4-yl)biphenyl-3-carboxylate (531 mg, 1.79 mmol) in EtOH (10 mL) was added 1M NaOH aqueous solution (5.00 mL, 5.00 mmol). The mixture was stirred at 60 C for 3 h. After being cooled to room temperature, the mixture was neutralized with 1M HCl aqueous solution. The resulting precipitate was filtered to give the product (470 mg, 93%) as a solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 187 - 201

77
[ 225931-80-6 ]
[ 618-89-3 ]
[ 1160861-53-9 ]
C₃₉H₅₆BrO₄PPd [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2017,vol. 56,p. 3177 - 3181
Angew. Chem.,2017,vol. 129,p. 3225 - 3229,5

78
[ 557-21-1 ]
[ 618-89-3 ]
[ 13531-48-1 ]

Reference： [1]Journal of Organic Chemistry,2017,vol. 82,p. 7040 - 7044

79
[ 75-21-8 ]
[ 618-89-3 ]
[ 153599-45-2 ]

Yield	Reaction Conditions	Operation in experiment
89%		2.1) raw materials and dosage:Methyl bromobenzoate 107g,13g of magnesium powder, 150g of tetrahydrofuran, 1g of iodine,Ethylene oxide 26g;2.2) Operation steps:Under nitrogen protection, 13 g of magnesium powder, 50 g of tetrahydrofuran,7g m-bromobenzoate,1g iodine,70 under the conditions of reaction,After initiating the reaction, remove the heat,To the system dropwise the remaining methyl m-bromobenzoate in tetrahydrofuran solution;Dropping is completed, continue to react 2h,After the reaction was completed, the reaction solution was cooled to 0 C in an ice bath,Into the system into the 26g of ethylene oxide,Ice bath reaction 3h,Reaction at room temperature for 3h,After the reaction was completed, most of the solvent was recovered under reduced pressure,To the reaction system was added 150 ml of 20% hydrochloric acid,After stirring at room temperature overnight,200 ml of ethyl acetate,Washed until neutral, dried over anhydrous sodium sulfate, filtered,The filtrate was added 150 ml of petroleum ether was recrystallized to give a white solid 80g, a yield of 89%;

Reference： [1]Patent: CN106928092,2017,A .Location in patent: Paragraph 0005; 0012

80
potassium hexacyanoferrate(II) trihydrate [ No CAS ]
[ 618-89-3 ]
[ 13531-48-1 ]

Reference： [1]Journal of Organic Chemistry,2018,vol. 83,p. 4922 - 4931

81
[ 618-89-3 ]
[ 21860-07-1 ]

Reference： [1]Patent: WO2008/65508,2008,A1

82
[ 3430-16-8 ]
[ 618-89-3 ]
2,5-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole [ No CAS ]
5-(3-methoxycarbonylphenyl)-2-(5-methylpyrid-3-yl)pyrrole [ No CAS ]

Reference： [1]Chemistry - A European Journal,2018,vol. 24,p. 16176 - 16182

83
[ 33279-01-5 ]
[ 618-89-3 ]
methyl 3-(1-cyano-2-oxobutyl)benzoate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2018,vol. 83,p. 15380 - 15405

84
[ 618-89-3 ]
[ 6307-87-5 ]

Reference： [1]Chemistry - A European Journal,2019,vol. 25,p. 8018 - 8023

85
[ 618-89-3 ]
[ 62-53-3 ]
[ 63710-33-8 ]

Reference： [1]Journal of the American Chemical Society,2019,vol. 141,p. 11161 - 11172

86
[ 618-89-3 ]
[ 476004-81-6 ]
[ 1059628-81-7 ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,4-dioxane; at 100℃; for 16h;	To a stirred solution of <strong>[476004-81-6]2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole</strong> 1 (200 mg, 0.93 mmol) and methyl 3-bromobenzoate 2 (271 mg, 1.12 mmol) in l,4-dioxane (3 mL) was added a solution of sodium carbonate (296 mg, 2.79 mmol) in water (1 mL) at RT and purged with argon for 5 min. Then Pd(dppf)Cl2.CH2Cl2 (76 mg, 0.09 mmol) was added at RT. The reaction mixture was heated to 100 C and stirred for 16 h. The progress of the reaction was monitored by TLC, after the completion, the reaction mixture was cooled to RT, filtered through a pad of celite and the celite bed was washed with EtOAc (20 mL). The filtrate was concentrated under reduced pressure to obtain the crude. The crude material was purified by silica gel column chromatography (eluent: 10% EtOAc/-hexanes) to afford compound 3 (185 mg, 0.74 mmol, 79%) as pale yellow liquid. NMR (400 MHz, CDCb): d 8.47 (br s, 1H), 8.33 (t, J= 1.6 Hz, 1H), 7.98 (dt, J= 7.7, 1.3 Hz, 1H), 7.89-7.86 (m, 1H), 7.66-7.62 (m, 1H), 7.52 (t, J= 7.8 Hz, 1H), 7.44-7.40 (m, 1H), 7.24-7.20 (m, 1H), 7.16-7.11 (m, 1H), 6.91 (dd, J= 2.1, 0.9 Hz, 1H), 3.97 (s, 3H). LC-MS: m/z 252.1 [M+H]+ at 4.24 RT (73.82% purity).

Reference： [1]Patent: WO2019/213148,2019,A1 .Location in patent: Page/Page column 97; 98

87
[ 618-89-3 ]
[ 4385-77-7 ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 10272 - 10293

88
[ 618-89-3 ]
[ 19158-51-1 ]
[ 13531-48-1 ]

Reference： [1]Chemical Communications,2020,vol. 56,p. 4240 - 4243

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P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
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H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
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Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
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H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 618-89-3 ] {[proInfo.proName]}

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[ 618-89-3 ] Synthesis Path-Upstream 1~14

[ 618-89-3 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 618-89-3 ]

Aryls

Bromides

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[ 618-89-3 ]