Structure of 6967-82-4

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Quality Control of [ 6967-82-4 ] Purity: 97% SDS Specification

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Product Details of [ 6967-82-4 ]

CAS No. :	6967-82-4
Formula :	C₈H₇BrO₂
M.W :	215.04
SMILES Code :	C1=C(C(=CC=C1C)Br)C(O)=O
MDL No. :	MFCD00079722
InChI Key :	ZXMISUUIYPFORW-UHFFFAOYSA-N
Pubchem ID :	228080

Safety of [ 6967-82-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 6967-82-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	46.07
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	37.3 ?2

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.76
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	3.27
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.46
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.67
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.35
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.5

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.57
Solubility	0.0577 mg/ml ; 0.000269 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.73
Solubility	0.0402 mg/ml ; 0.000187 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.02
Solubility	0.207 mg/ml ; 0.000962 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.29 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.33

Application In Synthesis of [ 6967-82-4 ]

* 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 [ 6967-82-4 ]
Downstream synthetic route of [ 6967-82-4 ]

[ 6967-82-4 ] Synthesis Path-Upstream 1~1

1
[ 6967-82-4 ]
[ 1088994-22-2 ]

References: [1] Patent: CN105461699, 2016, A, .

[ 6967-82-4 ] Synthesis Path-Downstream 1~33

1
[ 6967-82-4 ]
[ 100-39-0 ]
[ 790230-08-9 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7688 - 7705.

2
[ 6967-82-4 ]
[ 727985-37-7 ]

Yield	Reaction Conditions	Operation in experiment
79%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃;Inert atmosphere; Reflux;	PREPARATION 143 (2-Bromo-5-methylphenyl)methanol Lithium aluminium hydride (2.83 g, 74.57 mmol) was suspended in 1 10 ml tetrahydrofuran under nitrogen and cooled to 0 C with an ice-bath. A solution of 2- bromo-5-methylbenzoic acid (6.6 g, 30.69 mmol) dissolved in 60 ml tetrahydrofuran was added drop-wise with stirring. The mixture was then stirred at reflux overnight. The mixture was allowed to cool to room temperature and was quenched by the successive addition with stirring of 3 ml water dissolved in 20 ml tetrahydrofuran, 3 ml 1 N sodium hydroxide and 24 ml water. The mixture was stirred at room temperature overnight. The mixture was filtered through Celite, washing the Celite with ethyl acetate. The combined filtrate was evaporated under reduced pressure and the residue was purified using the Isolera Purification system (ether-hexane gradient, 0: 100 rising to 60:40) to give 4.87g (24.3 mmol, 79%) of the title compound as a white solid. Purity 100%. 1 H N MR (400 MHz, CH LOROFORM-d) delta ppm 2.32 (s, 3 H), 4.71 (d, J=5.47 Hz, 2 H), 6.98 (dd, J=8.01 , 1 .76 Hz, 1 H), 7.28 (s, 1 H), 7.41 (d, J=8.21 Hz, 1 H). UPLC/MS (3 min) retention time 1 .48 min. LRMS: m/z : Molecular ion not detected.
	With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 18.5h;	A solution of borane THF complex 1M in THF (13.95 mL, 13.95 mmol) was added dropwise to a solution of <strong>[6967-82-4]2-bromo-5-methylbenzoic acid</strong> (1 g, 4.65 mmol) in THF (20 mL) at 000. The resulting mixture was stirred for 30 mm at 0C then allowed to warm to room temperatureand stirred for 18h. The reaction was quenched with methanol followed by 2M hydrochloric acid. The resulting mixture was stirred for 30 mm and extracted with ethyl acetate (3x25 mL). The combined organic solutions were washed with water (25 mL), brine (25 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to the title compound as a white solid; LC MS Rt 1.13 mm; MS mlz [M-18+H] 183.1, 185.1, Method 2minLowpHvo3.

References: [1]Patent: WO2013/10880,2013,A1 .Location in patent: Page/Page column 151.
[2]Organic and Biomolecular Chemistry,2015,vol. 13,p. 11645 - 11650.
[3]Journal of Medicinal Chemistry,2006,vol. 49,p. 4447 - 4450.
[4]Journal of the American Chemical Society,2011,vol. 133,p. 7916 - 7925.
[5]Patent: WO2015/8230,2015,A1 .Location in patent: Page/Page column 324.
[6]Phosphorus, Sulfur and Silicon and the Related Elements,2015,vol. 190,p. 2142 - 2153.
[7]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 1278 - 1283.

3
[ 6967-82-4 ]
[ 89-56-5 ]

Yield	Reaction Conditions	Operation in experiment
		Under nitrogen, 2 mmol of the halogen-substituted benzoic acid indicated in Table 6 was stirred with a solution of 3 mmol Na2CO3 at 50-75 C. until all of the halogen-substituted benzoic acid was dissolved. Subsequently, 0.02 mmol CuSO4 and 0.04 mmol rac-trans-N,N'-dimethylcyclohexane-1,2-diamine (Ligand F) dissolved in 1 mL deionized water were added and the reaction mixture was heated at 80-100 C. for 4 h. After cooling to ambient temperature the reaction mixtures were carefully acidified with 35% aqueous HCl.In isolation method A, the products were extracted from the aqueous layer twice with ethyl acetate, the ethyl acetate fractions were combined and the crude reaction product was isolated by evaporation of ethyl acetate under vacuum. In isolation method B, the products were isolated by filtration, washed with water and dried under vacuum. The crude reaction product was analyzed by 1H NMR (d6-dmso). The results are summarized in Table 6. TABLE 6 Examples 8~23 Starting material Halogenated Benzoic Acid Isolation CONV SEL Example Benzoic Acid Product T ( C.) Method (%) (%) 8 2,5-dibromo- 2-hydroxy-5- 80 B >99 >99 bromo- 9 2-bromo-5-nitro- 2-hydroxy-5- 80 B >99 >99 nitro- 10 2-bromo-5-nitro- 2-hydroxy-5- 100 A >99 >99 nitro- 11 2-bromo-5-methyl- 2-hydroxy-5- 80 B >99 >99 methyl- 12 2-bromo-5-methyl- 2-hydroxy-5- 100 A >99 >99 methyl- 13 4-bromo- 4-hydroxy- 100 A >99 >99 14 4-chloro- 4-hydroxy- 80 B >99 >99 15 2,4-dichloro- 2-hydroxy-4- 100 A 70 >99 chloro- 16 2,5-dichloro- 2,5-dihydroxy- 80 B 93 >99 17 2-chloro-5-nitro- 2-hydroxy-5- 100 A 74 >99 nitro- 18 2-chloro-3,5-dinitro- 2-hydroxy-3,5- 100 A >99 >99 dinitro- 19 2-chloro-3,5-dinitro- 2-hydroxy-3,5- 80 B >99 >99 dinitro- 20 2-chloro-5-methyl- 2-hydroxy-5- 100 A >99 >99 methyl- 21 2-bromo-5- 2-hydroxy-5- 100 A >99 >99 methoxy- methoxy- 22 2-bromo-5- 2-hydroxy-5- 80 B >99 >99 methoxy- methoxy- 23 2-chloro-5-bromo- 2-hydroxy-5- 80 B 73 >99 bromo-

References: [1]Patent: US7335791,2008,B1 .Location in patent: Page/Page column 20-21.

4
[ 6967-82-4 ]
1,3-dihydro-5-methyl-1-hydroxy-2,1-benzoxaborole [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 4447 - 4450.

5
[ 6967-82-4 ]
[ 905710-68-1 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 4447 - 4450.

6
[ 6967-82-4 ]
C₁₀H₁₅BO₄ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 4447 - 4450.

7
[ 6967-82-4 ]
4-methyl-biphenyl-2,2'-dicarboxylic acid 2'-methyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7688 - 7705.

8
[ 6967-82-4 ]
[ 916904-28-4 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7688 - 7705.

9
[ 6967-82-4 ]
[ 239462-54-5 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7688 - 7705.

10
[ 6967-82-4 ]
[ 916904-33-1 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7688 - 7705.

11
[ 6967-82-4 ]
4-isobutylcarbamoyl-4'-methyl-biphenyl-2,2'-dicarboxylic acid 2-methyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7688 - 7705.

12
[ 6967-82-4 ]
2'-(3-carbamoyl-phenylcarbamoyl)-4'-methyl-biphenyl-2-carboxylic acid methyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7688 - 7705.

13
[ 6967-82-4 ]
2'-(3-carbamoyl-phenylcarbamoyl)-4'-methyl-biphenyl-2-carboxylic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7688 - 7705.

14
[ 6967-82-4 ]
[ 790230-09-0 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7688 - 7705.

15
[ 6967-82-4 ]
[ 790230-10-3 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7688 - 7705.

16
[ 6967-82-4 ]
4-isobutylcarbamoyl-4'-methyl-biphenyl-2,2'-dicarboxylic acid 2'-benzyl ester [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7688 - 7705.

17
[ 6967-82-4 ]
[ 790230-34-1 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7688 - 7705.

18
[ 6967-82-4 ]
2'-(3-carbamoyl-phenylcarbamoyl)-4-isobutylcarbamoyl-4'-methyl-biphenyl-2-carboxylic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7688 - 7705.

19
[ 6967-82-4 ]
[ 409110-31-2 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2h;	To a suspension of <strong>[6967-82-4]2-bromo-5-methyl benzoic acid</strong> (1.0 g, 0.00465 mole) in dry dichloromethane (10 mL ) was added oxalylchloride (1.22 mL, 0.013 mole) dropwise at 00C followed by 1-2 drops of N,N-dimethyl formamide. The reaction mixture was then stirred for 2 hours at room temperature and the solvents were evaporated and the product dried under vacuum to yield 2-bromo-5-methylbenzoyl chloride which was used for the next step. To a precooled solution of 2-bromo-5-methyl benzoyl chloride in toluene (5mL) was slowly added a pre-cooled solution of triethylphosphite (1.05 mL, 0.00604 mole) in toluene. The reaction EPO <DP n="85"/>was then left at room temperature for overnight. The solvents were then evaporated on a rotovap. The resultant product was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate (NaHCO3, 25 mL), and then dried over magnesium sulfate (MgSO4). Filtration and solvent evaporation provided l .lg of product. Flash chromatography on silica gel using 0%-5% ethyl acetate/dichloromethane followed by drying of the product under high vacuum afforded 0.900 g of (2-bromo-5-methylbenzoyl)phosphonic acid diethyl ester.
	With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; at 20℃; for 0.75h;Inert atmosphere;	General procedure: To a 100-mL round-bottom flask, flame-dried and cooled under argon containing 40 mL THF was added 2-bromobenzoic acid (1.98 g, 8.25 mmol), followed by 2-3 drops of DMF. Oxalyl chloride (1.02 mL, 11.8 mmol) was then slowly added over 15 min, causing bubbling and the formation of a bright yellow solution. The reaction was stirred for 30 min. To this was added cyclopropylamine (0.8 mL, 11.8 mmol). After 10 min, triethylamine (3.40 mL, 24.6 mmol) was added slowly, forming a faint yellow precipitate. The reaction was stirred overnight (16 h) at ambient temperature. It was then quenched with 10% HCl (50 mL), dissolving the white precipitate, and then transferred to a 250-mL separatory funnel. The layers were separated, and the aqueous layer was extracted with dichloromethane (3×'s, 50 mL each). The combined organics were then washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the desired product as an off-white solid. It was used crude in the subsequent methylation step.
	With thionyl chloride; for 2h;Reflux; Inert atmosphere;	Formylbenzamide 81. A solution of <strong>[6967-82-4]2-bromo-5-methylbenzoic acid</strong> (156 mg, 0.73 mmol, 1.0 equiv) in SOCI2 (5 mL) was stirred at reflux for 2 h. The reaction mixture was concentrated under N2 and the residue was coevaporated with toluene (2 5 mL) to remove all traces of SOCI2. The crude product was dissolved in CH2CI2 (5 mL) and the reaction mixture was cooled to 0 C. A solution of diethylamine (97 mg, 0.14 mL, 1.31 mmol, 1.8 equiv) in CH2CI2 (0.2 mL) was added dropwise, the ice bath was removed and the reaction mixture was stirred at ambient temperature for 2 h. The reaction was quenched with IN aq. HCl (1.5 mL), and the resulting mixture was extracted with CH2CI2 (2 5 mL). The combined organic layers were washed with brine (5 mL), dried over MgS04 and concentrated. Flash column chromatography (silica gel, hexanes:EtOAc 3 : 1 to 2: 1) yielded benzamide 80 as a yellowish solid (194 mg, 0.72 mmol, 98% yield). To a stirred solution of z-PrMgBr (0.85 mL, 1.0 M in THF, 0.85 mmol, 1.2 equiv) in THF (1.0 mL) at 0 C was added -BuLi (0.68 mL, 2.50 M in hexanes, 1.70 mmol, 2.4 equiv). The resulting yellow solution was cooled to -78 C and a solution of bromide 80 (234 mg, 0.72 mmol, 1.0 equiv) in THF (1.0 mL) was added dropwise. After stirring for 1 h at -78 C, DMF (0.23 mL, 2.88 mmol, 4.0 equiv) was added. After stirring for 3 h at -78 C, saturated aq. NH4CI (5 mL) was added and the resulting mixture was allowed to reach ambient temperature. The mixture was extracted with EtOAc (10 mL), the organic layer was dried over MgSO t, concentrated, and purified by column chromatography (silica gel, hexanes:EtOAc = 1 :1) to provide aldehyde 81 (156 mg, 0.71 mmol, 99% yield) as a white powder. 81 : R = 0.42 (silica gel, hexanes:EtOAc 1:2); FontWeight="Bold" FontSize="10" H NMR (500 MHz, CDCI3): delta = 10.01 (s, 1 H), 7.77 (s, 1 H), 7.45 (d, J = 7.7 Hz, 1 H), 7.28 (d, J = 7.7 Hz, 1 H), 3.42 (m, 2 H), 3.13 (m, 2 H), 2.46 (s, 3 H), 1.32 (t, J = 7.1 Hz, 3 H), 1.08 (t, J = 7.2 Hz, 3 H) ppm; HRMS (ESI-TOF): calcd for C15H22 O/ [M+H+]: 280.1543, found 280.1540.

	With thionyl chloride; In N,N-dimethyl-formamide; toluene; at 0 - 80℃; for 2.25h;	General procedure: 2-bromobenzoic acid derivatives (8 mmol), toluene (40 mL) were added to a 100 mL round-bottom flask. After cooled to 0 oC, DMF (0.1 eq., 0.8 mmol) was added to the mixture. SOCl2 (1.2 eq., 9.6 mmol) was slowly added to the flask with more than 10 min. After performed at 0 oC for 5 min, the reaction was warmed to 23 oC for 10 min. At last the mixture was performed at 80 oC for 2 h. After evaporated the solvent and dried by vacuum pump, the crude product of 2,4-dibromobenzoyl chloride derivatives were provided as a oil. After 2,4-dibromobenzoyl chloride derivative (6 mmol) was added to it, the tube evacuated and recharged with N2 for 3 times. Before the mixture was cooled to -78 oC, THF (20 mL) was added to the tube. MeMgCl (6 mmol) was dropwised to the mixture. The reaction was performed for 1h at -78 oC, 2 h at 0 oC, 5 to 10 h at rt. 20 mL water was added to the tube and the mixture was extracted with Et2O (30 mL x 3),dried by anhydrous Na2SO4. Evaporation of the solvent followed by purification on silica gel provided 1-(2-bromophenyl)ethanone derivative, yield 60-70%.
	With thionyl chloride; for 2h;Reflux;	General procedure: Substituted N'-acetyl-2-bromobenzohydrazides(1a-w) were synthesizedaccording to the procedures reported in theliteratures.[1,2]Thionyl chloride (10 mL) was added tosubstituted 2-bromobenzoic acid (5 mol) in a 50 mL round bottom flask, and the reaction mixturewas refluxed for 2 h. The excess amount of thionyl chloride was removed by distillation. Theresulted acid chloride was dissolved in MeOH (20 mL), and then 40% hydrazine hydrate (3 mL)was added. The mixture was refluxed for 2 h and then cooled to room temperature, and the resulting precipitate was collected, washed with distilled water and recrystallized fromethanol.Subsequently,another acylchloride (2 mmol) was added to a solution of substituted 2-bromobenzohydrazide (1 mmol) and pyridine (2 mmol) in NMP (6 mL), the mixture was stirred for12 h, and the resulting solution was poured into ice water. The solid product was filtered andcrystallized from EtOH to get pure 1a-w.
	With thionyl chloride; N,N-dimethyl-formamide; for 2h;Reflux;	General procedure: 1 drop of DMF was added to a suspension of 2-bromobenzoic acid (2g, 9.95mmol) in 5ml SOCl2, the mixture was heated under reflux for 2h, then concentrated and diluted with DCM 20ml, concentrated again and re-diluted with DCM 20ml and concentrated. The residue was dissolved in 20ml DCM, added dropwise to a solution of 4-methoxy-2-methylaniline (1.4g, 9.95mmol) and triethylamine (3.43ml, 24.9mmol) in 10ml DCM, and then stirred for 2h. The mixture was concentrated to give brown solid, which was treated with EtOH/H2O (10ml/20ml) to give off-white solid 2.5g, yield: 78.4%.

References: [1]Russian Journal of General Chemistry,2020,vol. 90,p. 311 - 313.
[2]Patent: WO2006/55525,2006,A2 .Location in patent: Page/Page column 83.
[3]Tetrahedron,2013,vol. 69,p. 4479 - 4487.
[4]Organic Letters,2013,vol. 15,p. 5986 - 5989.
[5]Journal of the American Chemical Society,2014,vol. 136,p. 4841 - 4844.
[6]Patent: WO2015/23879,2015,A1 .Location in patent: Page/Page column 111; 112.
[7]Chinese Chemical Letters,2015,vol. 26,p. 1231 - 1235.
[8]RSC Advances,2018,vol. 8,p. 13879 - 13890.
[9]Synlett,2018,vol. 29,p. 1395 - 1399.
[10]Chinese Journal of Chemistry,2018,vol. 36,p. 743 - 748.
[11]Journal of the American Chemical Society,2018,vol. 140,p. 13945 - 13951.
[12]European Journal of Medicinal Chemistry,2019,vol. 162,p. 407 - 422.
[13]Organic Letters,2019,vol. 21,p. 3696 - 3700.

20
[ 79-37-8 ]
[ 6967-82-4 ]
[ 90971-88-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	In methanol; dichloromethane; N,N-dimethyl-formamide;	Example 86 6-(2-BROMO-5-METHYL-PHENYL)-N-(4-CHLORO-PHENYL)-[1,3,5]TRIAZINE-2,4-DIAMINE To a suspension of <strong>[6967-82-4]2-bromo-5-methyl-benzoic acid</strong> (3.0 g, 14 mmol) in dichloromethane (100 ml) was added a solution of oxalyl chloride in dichloromethane (2 M, 8 ml, 16 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 30 minutes, methanol (15 ml) was added. After stirring for 3 hours, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (200 ml) and saturated aqueous potassium carbonate solution (100 ml). The organic layer was concentrated under reduced pressure to provide methyl 2-bromo-5-methyl-benzoate (3.2 g, 99% yield).

References: [1]Patent: US2003/153570,2003,A1 .

21
[ 6967-82-4 ]
[ 25487-66-5 ]
[ 378242-13-8 ]

Yield	Reaction Conditions	Operation in experiment
37%	With sodium carbonate; In 1,2-dimethoxyethane; water;	4-Methyl-[1,1'-biphenyl]-2,3'-dicarboxylic acid To a solution of <strong>[6967-82-4]2-bromo-5-methylbenzoic acid</strong> (5.00 g, 23.3 mmol) in DME (100 mL) were added 3-carboxyphenylboronic acid (3.86 g; 23.3 mmol), a solution of Na2CO3 (9.90 g, 93 mmol) in H2O and tetrakis(triphenylphosphine)palladium. The mixture was stirred at 90 C. for 4 days. The mixture was allowed to cool to room temperature, diluted with EtOAc (50 mL), and washed with a saturated NaHCO3 solution. The aqueous layer was separated, acidified with 10 % HCl, and extracted with EtOAc (3*20 mL). The combined extracts were dried over MgSO4 and concentrated. The crude material was purified by column chromatography (9:1 hexanes/EtOAc 1% acetic acid) to afford 4-methyl-[1,1'-biphenyl]-2,3'-dicarboxylic acid (2.20 g, 37%) as a solid: H NMR (DMSO-d6) delta2.40 (s, 3H), 7.30 (m, 1H), 7.42 (m, 1H), 7.52-7.57 (m, 2H), 7.60 (s, 1H), 7.85 (s, 1H), 7.91-7.92 (m, 1H).
37%	With sodium carbonate; In 1,2-dimethoxyethane; water;	4-Methyl-[1,1'-biphenyl]-2,3'-dicarboxylic acid To a solution of <strong>[6967-82-4]2-bromo-5-methylbenzoic acid</strong> (5.00 g, 23.3 mmol) in DME (100 mL) were added 3-carboxyphenylboronic acid (3.86 g; 23.3 mmol), a solution of Na2CO3 (9.90 g, 93 mmol) in H2O and tetrakis(triphenylphosphine)palladium. The mixture was stirred at 90 C. for 4 days. The mixture was allowed to cool to rt, diluted with EtOAc (50 mL), and washed with a saturated NaHCO3 solution. The aqueous layer was separated, acidified with 10% HCl, and extracted with EtOAc (3*20 mL). The combined extracts were dried over MgSO4 and concentrated. The crude material was purified by column chromatography (9:1 hexanes/EtOAc 1% acetic acid) to afford 4-methyl-[1,1'-biphenyl]-2,3'-dicarboxylic acid (2.20 g, 37%) as a solid: 1H NMR (DMSO-d6) delta2.40 (s, 3H), 7.30 (m, 1H), 7.42 (m, 1H), 7.52-7.57 (m, 2H), 7.60 (s, 1H), 7.85 (s, 1H), 7.91-7.92 (m, 1H).

References: [1]Patent: US2003/36534,2003,A1 .
[2]Patent: US2003/100607,2003,A1 .

22
[ 6967-82-4 ]
[ 90971-88-3 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; chloro-trimethyl-silane;	i 2-Bromo-5-methylbenzoic acid, methyl ester A solution of <strong>[6967-82-4]2-bromo-5-methylbenzoic acid</strong> (10 g) in trimethylsilyl chloride (30 ml) and methanol (100 ml) was stirred at room temperature overnight and evaporated. The residue was partitioned between ethyl acetate and sodium bicarbonate solution, dried (MgSO4) and evaporated. Yield 10.1 g. 1H NMR delta (CDCl3) 7.60(d,1H), 7.52(d,1H), 7.13(dd,1H), 3.92(s,3H), 2.33(s,3H).

References: [1]Patent: US6200981,2001,B1 .

23
[ 67-56-1 ]
[ 6967-82-4 ]
[ 90971-88-3 ]

Yield	Reaction Conditions	Operation in experiment
99%		To a suspension of compound 4 (2.15 g, 10 mmol) in dry DCM (40 mL) and DMF (0.2 mL) at 0 C was slowly added oxalyl chloride (1.3 mL, 15 mmol). After being stirred for 1 h at room temperature, the reaction mixture was treated with MeOH (20 mL) and then stirred for 3 h. The resulting solution was neutralized with saturated aqueous Na2CO3 (100 mL) and extracted with DCM (70 mL×2). The combined organic layer was washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel, eluting with petroleum ether/ethyl acetate (30:1), to afford compound 5 (2.27 g) as colorless oil in 99% isolated yield. 1H NMR (CDCl3, 400 MHz) delta 2.30 (s, 3H), 3.90 (s, 3H), 7.10 (dd, J=2.4, 8.4 Hz, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) delta 20.7, 52.4, 118.2, 131.7, 131.9, 133.5, 134.1, 137.3, 166.8.
96.1%	With sulfuric acid; for 16h;Reflux;	The <strong>[6967-82-4]2-bromo-5-methyl benzoic acid</strong> (10.75g, 50mmol) is added to 500 ml round bottom flask, with methanol (100 ml) to dissolve fully, and then slowly adding concentrated sulfuric acid (1.5 ml, 25mmol), reaction solution gradually heated up to reflow, reaction 16 hours. Stop reaction, to be reacted after cooling to room temperature, solvent evaporating under reduced pressure, the residue is dissolved in dichloromethane (200 ml) is dissolved, and with water (200 ml) and saturated salt water (100 ml) washing, separating the organic layer, drying with anhydrous sodium sulfate. Filtering, the filtrate concentrated under reduced pressure, the resulting residue is purified by silica gel column chromatography separation ((v/v)=200/1 petroleum ether/ethyl acetate) to obtain the title compound as a yellow oily matter (11.00g, 96.1%).
92%	With acetyl chloride; at 0 - 20℃;	Acetyl chloride (1.66 ml, 23.3 mmol) was added to a stirred solution of 2-bromo-5- methylbenzoic acid (2.00 g, 9.30 mmol) in MeOH (50 ml) at 0C. The reaction was then stirred at r.t. over night. More acetyl chloride (1 ml, 14.0 mmol) was added and the reaction was stirred for 24 hours. The solvent was removed in vacuo and the crude material was dissolved in Et02 (-100 ml) and washed with 0.5 M NaOH. The organic phase was dried over MgS04and removed in vacuo. Yield: 1.97 g (92%). ? NMR (400 MHz, DMSO~i 6): delta 2.33 (s, 3H), 3.94 (s, 3H), 7.13 (d, 1H), 7.52 (d, 1H), 7.60 (s, 1H) The ester from above (800 mg, 3.49 mmol) in dry 1,4 dioxane (15 ml) was added to bis(pinacolato)diboron (976 mg, 3.84 mmol) and AcOK (1.27 g, 12.9 mmol). The stirred mixture was flushed with argon and l,l'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (25.6 mg, 0.035 mmol) was added. The reaction was heated in a sealed flask at 100C for 3 hours then cooled and diluted with Et20. The organic phase was washed with water and brine, dried over MgSC>4 and removed in vacuo. The crude material was diluted with iso-hexane and purified by flash chromatography (20% EtOAc in iso-hexane, 200 ml silica). Yield: 697 mg (72%) as a colourless oil. 1H NMR (400 MHz, DMSO~i 6): delta 1.42 (s, 12H), 2.38 (s, 3H), 3.91 (s, 3H), 7.31- 7.35 (m, 1H), 7.38-7.43 (m, 1H), 7.76 (s, 1H). Argon was flushed through a stirred solution of intermediate D (120 mg, 0.217 mmol) and the pinacolester from above (150 mg, 0.543 mmol) in a mixture of toluene (3 ml) and MeOH (3 ml). K2C03 (150 mg, 0.543 mmol) and PEPPSI-iPr (19.8 mg, 0.027 mmol) were added and the reaction heated at 60C for 2 hours in a sealed flask. The solvents were removed in vacuo and the crude material was added dioxane (2 ml), water (2 ml) and 5 M NaOH (1 ml). The reaction was stirred at 80 C for 30 min. The mixture was cooled and concentrated. Some water and 1 M NH4HCO3 (until pH~10) were added and the mixture was purified by prep-HPLC (5-40% MeCN, in 50 mM NH3/NH4HCO3 buffer). The combined pure fractions were concentrated to dryness. The compound was dissolved in water (20 ml) and some 2 M HC1 was added. The solid was collected and washed several times with water and dried. Yield: 25 mg (18%); yellow solid. 1H NMR (400 MHz, DMSO-i/6): delta 2.37 (s, 6 H), 3.74 (s, 4 H), 7.10 (s, 2 H), 7.29 (s, 2 H), 7.36 - 7.44 (m, 4 H), 7.47 - 7.49 (m, 2 H). HPLC: Rt =1.82 mm, 100% (254 nm, 10-40% MeCN in 10 mM buffer, XBndge) and Rt =1.35 mm, 97% (400 nm, 10-90% MeCN in 10 mM buffer, XBndge). LC-MS: m/z = 650 (M + 18).

92%	With acetyl chloride; at 0 - 20℃;	Acetyl chloride (1.66 ml, 23.3 mmol) was added to a stirred solution of 2-bromo-5- methylbenzoic acid (2.00 g, 9.30 mmol) in MeOH (50 ml) at 0C. The reaction was then stirred at r.t. over night. More acetyl chloride (1 ml, 14.0 mmol) was added and the reaction was stirred for 24 hours. The solvent was removed in vacuo and the crude material was dissolved in Et02 (-100 ml) and washed with 0.5 M NaOH. The organic phase was dried over MgS04 and removed in vacuo. Yield: 1.97 g (92%). 1H NMR (400 MHz, DMSO-i?): delta 2.33 (s, 3H), 3.94 (s, 3H), 7.13 (d, 1H), 7.52 (d, 1H), 7.60 (s, 1H)
92%		Step 1: Preparation of methyl 2-bromo-5-methylbenzoate To a solution of <strong>[6967-82-4]2-bromo-5-methylbenzoic acid</strong> (215 mg, 1.0 mmol) in DCM (4 mL) and DMF (1 drop) at 0 C. was slowly added oxalyl chloride (0.13 mL, 1.5 mmol). The reaction mixture was stirred at rt for 1 h and to it was added additional oxalyl chloride (0.13 mL, 1.5 mmol). The reaction mixture was stirred for 1 h, added with MeOH (2 mL) and stirred for 6 h. The mixture was treated with Na2CO3 to pH of 9 and extracted with DCM (2*10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (15:1) to give methyl 2-bromo-5-methylbenzoate (210 mg; yield 92%) as colorless oil. 1H NMR (400 MHz, CDCl3): delta 7.60 (d, J=1.6 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.15 (q, J=3.2 Hz, 1H), 3.92 (s, 3H), 2.33 (s, 3H) ppm.
60%	With dimethyl sulfate; sodium hydroxide; for 0.5h;Reflux;	Dimethyl sulfate (2.2 mL, 21.1 mmol)was slowly dropped under stirring into a solution of <strong>[6967-82-4]2-bromo-5-methylbenzoic acid</strong> (3.78 g,17.6 mmol) in 22mLmethanolic NaOH. Themixturewas refluxed for 30min.After cooling,waterwas added and the solutionwas 3×extracted with diethyl ether. The combined extractswere washed twice with 5% aq NaHCO3 solution then with satd. NaCl solution and finallywith H2O. After drying over Na2SO4, the solvent was removed and the residue was purifiedby CC (Kieselgel, CH2Cl2). Yield: 2.4 g (10.5 mmol, 60%) light-yellow liquid. IR: nu =2952, 1736 (C O), 1435, 1300, 1252, 1205, 1030. 1H NMR (in agreement with lit.11): delta= 2.33 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 7.13 (dd, 1H, J = 2.0 Hz/8.0 Hz, 4-H), 7.52 (d,1H, J = 8.0 Hz, 3-H), 7.59 (d, 1 H, J = 2.0 Hz, 6-H). 13C NMR (in agreement with lit.11):delta = 20.74 (OCH3), 52.40 (ArCH3), 118.23 (Cq, ar), 131.81, 131.87, 133.42, 134.06 (CHar),137.25 (Cq,ar), 166.29 (C O). MS: m/z (%) = 230 (37) [M]+, 228 (38) [M]+, 199(94) [M- OCH3]+, 197 (100) [M - OMe]+, 171 (23) [M - CO2CH3]+, 169 (25) [M - CO2CH3]+,91 (14) [C7H7]+, 90 (48), 89 (34), 63 (15). C9H9BrO2 (229.08): calcd. C 47.19, H 3.96, Br34.88, found C 47.01, H 3.97, Br 34.85.
	With sulfuric acid; In water; for 16h;Heating / reflux;	Example 16; Synthesis of <strong>[6967-82-4]2-bromo-5-methyl-benzoic acid</strong> methyl ester (Method 16.) 1 mL H2SO4 is added to <strong>[6967-82-4]2-bromo-5-methyl-benzoic acid</strong> (7.5 g, 70 mmol) in 75 mL methanol. The reaction mixture is refluxed 16 hours and cooled to room temperature. 100 mL saturated NaHCO3 (aq) is added. Methanol is removed in vacuo. The resulting mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give the title compound.
	With sulfuric acid; for 3h;Reflux;	Example 205] (1250) (1251) To the solution of 108 mg of <strong>[6967-82-4]2-bromo-5-methylbenzoic acid</strong> in 10 mL of methanol, 0.5 mL of concentrated sulfuric acid was added, and the resultant was heated at reflux for three hours. The reaction mixture was cooled to room temperature, and a saturated aqueous sodium bicarbonate solution and ethyl acetate were then added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give methyl 2-bromo-5-methylbenzoate. (1252) To the obtained methyl 2-bromo-5-methylbenzoate, 110 mg of 1-benzyl-1H-indol-5-amine, 10 mg of tris(dibenzylideneacetone)dipalladium(0), 18 mg of 4,5'-bis(diphenylphosphino)-9,9'-dimethylxanthene, 342 mg of cesium carbonate and 4 mL of toluene were added, and the resultant was stirred at 190C for one hour and 30 minutes using microwave equipment. After cooling the reaction mixture to room temperature, the insoluble matter was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (gradient elution with hexane:ethyl acetate = 100:0-75:25) to give methyl 2-((1-benzyl-1H-indol-5-yl)amino)-5-methylbenzoate as a yellow oil. MS (ESI, m/z): 371 (M+H)+.
5.5 g	In water; at 70℃; for 24h;	In a 250 mL single-mouth flask, 5.00 g (23.26 mmol) of Compound 1 and 6.64 g (28.99 mmol) of Compound 2 were added, 150 mL of methanol was added, and the water separator was installed and refluxed at 70 for 24 hours to stop the reaction. After spin-drying the solvent, the reaction was washed with water several times and extracted with ethyl acetate. The ethyl acetate layer was purified by rotary column chromatography to obtain 5.5 g of compound 2 as an oil

References: [1]Tetrahedron,2014,vol. 70,p. 2383 - 2388.
[2]Patent: CN105461699,2016,A .Location in patent: Paragraph 0739; 0740; 0741; 0742; 0743.
[3]Patent: WO2013/9259,2013,A1 .Location in patent: Page/Page column 90; 91.
[4]Patent: WO2013/36196,2013,A1 .Location in patent: Page/Page column 95.
[5]Patent: US2013/131016,2013,A1 .Location in patent: Paragraph 0199.
[6]Chemistry - A European Journal,2015,vol. 21,p. 7030 - 7034.
[7]Phosphorus, Sulfur and Silicon and the Related Elements,2015,vol. 190,p. 2142 - 2153.
[8]Patent: US2006/287386,2006,A1 .Location in patent: Page/Page column 18.
[9]Patent: EP2915804,2015,A1 .Location in patent: Paragraph 1250-1252.
[10]Patent: CN107915733,2018,A .Location in patent: Paragraph 0024; 0025; 0026.

24
[ 99-04-7 ]
C₈H₆Br₂O₂ [ No CAS ]
[ 6967-82-4 ]

References: [1]Angewandte Chemie - International Edition,2008,vol. 47,p. 5215 - 5219.

25
[ 5350-93-6 ]
[ 6967-82-4 ]
[ 1119088-90-2 ]

Yield	Reaction Conditions	Operation in experiment
46%	With copper(I) oxide; copper; potassium carbonate; In 1,2-dimethoxyethane; at 130℃; for 16h;	Intermediate 13; 2-(6-Chloropyridin-3-ylamino)-5-methylbenzoic acid A mixture of 6-ch.oropyridin-3-amine (11.67 mmol, 1.5 g) and 2-bromn-5-methylbenzoic acid (23.34 mmol, 5.02 g), Cu (1.17 mmol, 0.1 g), Cu2O (0.58 mmol, 0.1 g) and K2CO3 (23.34 mmol, 3.2 g) in 1 ,2-dimethoxyethane (15 ml) was heated at 13O0C for 16 hours, under argon atmosphere. Water was added and the mixture was filtered through celite. HCI 2N aqueous solution was added until pH 6 and the solid formed was filtered off. The crude was purified by chromatography eluting with DCM/MeOH mixtures affording 1.40 g (yield 46%).1H NMR (DMSO-de) delta ppm: 2.24 (s, 3H), 7.16-7.19 (d, 1 H), 7.25-7.27 (d, 1 H), 7.38- 7.41 (d, 1 H), 7.67-7.73 (m, 2H), 8.28 (s, 1 H), 9.45 (bs, 1 H).ESI/MS (m/e, %): 263 [(M+1)+, 100].

References: [1]Patent: WO2009/21696,2009,A1 .Location in patent: Page/Page column 49.

26
[ 1119088-10-6 ]
[ 6967-82-4 ]
[ 1119085-63-0 ]

Yield	Reaction Conditions	Operation in experiment
57%	With copper(I) oxide; copper; potassium carbonate; In 1,2-dimethoxyethane; at 130℃;	Example 29; 5-Methyl-2-(6-phenyl-5-(trifluoromethyl)pyridin-3-ylamino)benzoic acidIn a schlenck tube, a mixture of <strong>[6967-82-4]2-bromo-5-methylbenzoic acid</strong> (0.57 mmol, 0.120 g), Intermediate 1 (1.12 mmol, 0.265 g), potassium carbonate (1.12 mmol, 0.153 g), Cu2O (0.06 mmol, 0.008 g) and Cu (0.06 mmol, 0.004 g) in DME (2 ml) was heated at 13O0C overnight, under argon atmosphere. The solvent was evaporated and the crude mixture was purified over SiO2 eluting with CH2CI2/ MeOH mixtures affording 0.12O g (57% of yield) of the expected compound.ESI/MS (m/e, %): 373 [(M+1)+, 100]

References: [1]Patent: WO2009/21696,2009,A1 .Location in patent: Page/Page column 93.

27
[ 6967-82-4 ]
[ 6638-79-5 ]
[ 1048108-06-0 ]

Yield	Reaction Conditions	Operation in experiment
55%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 60h;	To a solution of <strong>[6967-82-4]2-bromo-5-methylbenzoic acid</strong> (1000.0 mg, 4.65 mmol) in DMF (100 mL) were added N,O-dimethylhydroxylamine hydrochloride (454 mg, 4.65 mmol), EDC (891 mg, 4.65 mmol), and HOBT (628 mg, 4.65 mmol). The reaction mixture was stirred at rt for 2.5 days. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography to give 2-bromo-N-methoxy-N,5-dimethylbenzamide (656 mg, 55%) as a colorless oil. LC-MS (M+H)+=258.21.

References: [1]Patent: US2008/194535,2008,A1 .Location in patent: Page/Page column 31.
[2]Chinese Journal of Chemistry,2018,vol. 36,p. 743 - 748.

28
1,1-dimethylethyl (endo)-3-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]
[ 6967-82-4 ]
1,1-dimethylethyl endo-3-[([(2-bromo-5-methylphenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 1: 1,1-Dimethylethyl (3-endo)-[([(2-bromo-5-methylphenyl)amino]carbonyl}oxy)methyl]-8-azabicyclo[3.2.1]octane-8-carboxylate; A solution of <strong>[6967-82-4]2-bromo-5-methylbenzoic acid</strong> (430 mg) in chloroform (10 ml) was treated with diphenylphosphoryl azide (450 mul) and triethylamine (450 mul). The resulting reaction mixture was heated at 60 C. for 10 minutes then treated with a solution of 1,1-dimethylethyl-(3-endo)-(hydroxymethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (470 mg) in chloroform (2 ml). The reaction mixture was heated at reflux for 6 hours. The cooled solution was loaded onto a SPE cartridge (Si, 10 g). Elution with chloroform, followed by evaporation of the solvent gives the title compound (920 mg). LC/MS ESI RT 3.93 mins MH+ 453.

References: [1]Patent: US2008/249127,2008,A1 .Location in patent: Page/Page column 10.

29
aqueous potassium carbonate [ No CAS ]
[ 6967-82-4 ]
[ 90971-88-3 ]
(4-methoxy-2-(trifluoromethyl)phenyl)boronic acid [ No CAS ]
[ 1186482-29-0 ]

Yield	Reaction Conditions	Operation in experiment
	Pd(PPh3)4; In methanol; toluene;	Example 102 4'-Methoxy-4-methyl-2'-trifluoromethyl-biphenyl-2-carboxylic acid methyl ester A solution of <strong>[6967-82-4]2-bromo-5-methyl-benzoic acid</strong> (0.8 g, 3.7 mmol) in MeOH (15 mL) was treated with TMS-diazomethane (2 M in hexanes) until TLC showed consumption of starting material. Approximately 4 mL (2 equiv) of the TMS-diazomethane was required. The solvents were removed to give crude <strong>[6967-82-4]2-bromo-5-methyl-benzoic acid</strong> methyl ester as a white solid used without further purification. A vial was charged with <strong>[6967-82-4]2-bromo-5-methyl-benzoic acid</strong> methyl ester (250 mg, 1.1 mmol), 4-methoxy-2-trifluoromethylbenzeneboronic acid (330 mg, 1.5 mmol), Pd(PPh3)4 (50 mg, 0.048 mmol), aqueous potassium carbonate (0.5 mL, 2 N, 1.0 mmol), and toluene (1.0 mL) under Ar. The reaction was heated to 95 C. for 2 h, and was then partitioned between ether and water. The organic layer was washed with brine, dried over sodium sulfate, and concentrated onto celite. The product was isolated using silica gel chromatography using EtOAc in hexanes (0-20%) to give 4'-methoxy-4-methyl-2'-trifluoromethyl-biphenyl-2-carboxylic acid methyl ester as a colorless oil (270 mg).

References: [1]Patent: US2009/226398,2009,A1 .

30
[ 273376-39-9 ]
[ 6967-82-4 ]
[ 861133-95-1 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 1: 1,1-DimethgammaIethyl (3-gHrfo)-[([(2-bromo-5- methylphenvI)amino1carbonylloxy)methvIl-8-azabicyclo[3.2.?octane-8- carboxylate; A solution of <strong>[6967-82-4]2-bromo-5-methylbenzoic acid</strong> (430 mg) in chloroform (10 ml) was treated with diphenylphosphoryl azide (450 Dl) and triethylamine (450 Dl). The resulting reaction mixture was heated at 6O0C for 10 minutes then treated with a solution of 1,1-dimethylethyl -(3-en

References: [1]Patent: WO2006/5057,2006,A2 .Location in patent: Page/Page column 20.

31
2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1R*,2S*,5S*)-3-aza-bicyclo[3.1.0]hex-2-ylmethyl]-amide [ No CAS ]
[ 6967-82-4 ]
2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1R*,2S*,5S*)-3-(2-bromo-4-methyl-benzoyl)-3-aza-bicyclo[3.1.0]hex-2-ylmethyl]-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 0.666667h;	To a solution of the respective carboxylic acid (1.37 mmol, 1.00 eq) and DIPEA (2.06 mmol, 1.50 eq) in DMF (2.0 mL) is added TBTU (1.47 mmol, 1.05 eq). The obtained mixture is treated with a solution of the respective (1R,2S,5S)-3-aza-bicyclo[3.1.0]-hexane derivative (1.37 mmol, 1.00 eq) and DIPEA (2.06 mmol, 1.50 eq) in DMF (2.0 mL). After 40 min sat. water and TBME are added, the layers are separated and the organic layer is washed with water, hydrochloric acid (0.5 M), aq. NaOH solution (0.5 M) and brine. After drying over Na2SO4 and removal of solvents in vacuo the desired amides are obtained which are used without further purification.2,3-Dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1R,2S,5S)-3-(2-bromo-4-methyl-benzoyl)-3-aza-bicyclo[3.1.0]hex-2-ylmethyl]-amide prepared by reaction of 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid [(1R,2S,5S*)-3-aza-bicyclo[3.1.0]hex-2-ylmethyl]-amide with 2-bromo-4-methyl-benzoic acid. LC-MS: tR=0.89 min; [M+H]+=471.1.

References: [1]Patent: US2010/16401,2010,A1 .Location in patent: Page/Page column 53.

32
[ 6967-82-4 ]
[ 108-24-7 ]
[ 1255719-53-9 ]

References: [1]Tetrahedron Letters,2010,vol. 51,p. 5588 - 5591.

33
[ 6967-82-4 ]
[ 1310071-28-3 ]

References: [1]Chemical Communications,2011,vol. 47,p. 5596 - 5598.

Historical Records

Technical Information

? Alkyl Halide Occurrence ? Arndt-Eistert Homologation ? General Reactivity ? Grignard Reaction ? Hiyama Cross-Coupling Reaction ? Hunsdiecker-Borodin Reaction ? Kinetics of Alkyl Halides ? Kumada Cross-Coupling Reaction ? Passerini Reaction ? Preparation of Amines ? Preparation of Carboxylic Acids ? Reactions of Alkyl Halides with Reducing Metals ? Reactions of Amines ? Reactions of Benzene and Substituted Benzenes ? Reactions of Carboxylic Acids ? Reactions of Dihalides ? Schmidt Reaction ? Specialized Acylation Reagents-Ketenes ? Stille Coupling ? Substitution and Elimination Reactions of Alkyl Halides ? Suzuki Coupling ? Ugi Reaction

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[ 6967-82-4 ]

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Carboxylic Acids

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

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

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