[ CAS No. 18595-16-9 ] {[proInfo.proName]}

Name: 18595-16-9|Methyl 2-amino-5-methylbenzoate|97%
Brand: Ambeed
SKU: A199903
Price: 5.0 USD
Availability: InStock
Rating: 96 (30 reviews)

,{[proInfo.pro_purity]}

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

DV 2D 3D

3d Animation Molecule Structure of 18595-16-9

Structure of 18595-16-9 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 18595-16-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 18595-16-9 ]

SDS Specification

Alternatived Products of [ 18595-16-9 ]

Product Details of [ 18595-16-9 ]

CAS No. :	18595-16-9	MDL No. :	MFCD00661547
Formula :	C₉H₁₁NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MDHYFUPTSWXVIA-UHFFFAOYSA-N
M.W :	165.19	Pubchem ID :	1201104
Synonyms :

Calculated chemistry of [ 18595-16-9 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	47.09
TPSA :	52.32 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.72 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.97
Log Po/w (XLOGP3) :	2.24
Log Po/w (WLOGP) :	1.37
Log Po/w (MLOGP) :	1.64
Log Po/w (SILICOS-IT) :	1.44
Consensus Log Po/w :	1.73

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.51
Solubility :	0.507 mg/ml ; 0.00307 mol/l
Class :	Soluble
Log S (Ali) :	-2.97
Solubility :	0.175 mg/ml ; 0.00106 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.49
Solubility :	0.531 mg/ml ; 0.00321 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.31

Safety of [ 18595-16-9 ]

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 [ 18595-16-9 ]

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

Upstream synthesis route of [ 18595-16-9 ]
Downstream synthetic route of [ 18595-16-9 ]

[ 18595-16-9 ] Synthesis Path-Upstream 1~11

1
[ 20587-30-8 ]
[ 18595-16-9 ]

Yield	Reaction Conditions	Operation in experiment
60%	With ammonium chloride; zinc In methanol; water at 0 - 20℃; for 12 h;	A solution of methyl 5-methyl-2-nitrobenzoate (8 g, 41.025 mmol) in methanol (80 mL) and water (10 mL) was cooled to 0°C. Zinc powder (13.33 g, 205.128 mmol) was then added, followed by NH₄C1 (17.6 g, 328.2 mmol). The mixture was stirred for 12 h at rt. Progress of the reaction was followed by TLC (20percent ethyl acetate/hexane). After completion of the reaction, the mixture was filtered and the filtrate was evaporated to provide crude residue. The crude reside was basified with saturated NaHC0₃ solution and extracted with DCM (2 x 20 mL). The combined organic layers were dried over Na₂S0₄, filtered and evaporated to give methyl 2-amino-5-methylbenzoate (Yield: 4 g, 60percent).1H NMR (400 MHz, CDC1₃): δ 7.65 (s, 1H), 7.25 (s, 1H), 7.10-7.07 (q, 1H, J=8 Hz), 6.58 (d, 1H), 3.86 (s, 3H), 2.22 (s, 3H).

Reference： [1] Patent: WO2015/38417, 2015, A1, . Location in patent: Paragraph 151; 152
[2] Journal of the Chemical Society, 1930, p. 1513,1516
[3] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420
[4] Patent: EP1475368, 2004, A1, . Location in patent: Page 57

2
[ 67-56-1 ]
[ 2941-78-8 ]
[ 18595-16-9 ]

Yield	Reaction Conditions	Operation in experiment
64%	at 0℃; for 18.5 h; Heating / reflux	EXAMPLE 18; 5-Bromomethyl-2-propionylamino-benzoic acid methyl ester; 2-Amino-5-methyl-benzoic acid (23,58 g, 156 mmol) was dissolved in methanol. The solution was brought to 0°C on an ice-bath and thionyl chloride (46.3 mL, 636 mmol) was added dropwise during 30 minutes. After the addition the reaction mixture was refluxed for 18 hours and was then allowed to reach room temperature. The solvent was evaporated and the remain- der was divided between CH2Cl2 (500 mL) and aqueous saturated NaHC03 (500 mL). The organic layer was washed with an additional 500 mL of aqueous saturated NaHCO3, dried over MgS04 and evaporated to dryness (16.59 g, 64percent). 2-Amino-5-methyl-benzoic acid methyl ester (8.00 g, 48.4 mmol) was dissolved in CHC13 (275 mL) and propionyl chloride (12.6 mL, 145 mmol) was added dropwise during 10 min- utes after which the reaction mixture was left with stirring at room temperature for 72 hours. Aqueous saturated NaHCO3 (400 mL) was carefully added under vigorous stirring and when no more gas evolved the organic layer was separated, dried over MgSO4, filtered and evapo- rated to dryness (10.06 g, 94percent). The radical bromination was performed as described by Patil et al. 1989: 5-Methyl-2- propionylamino-benzoic acid methyl ester (8.85 g, 40 mmol) and 1, 3-dibromo-5, 5-dimethyl hydantoin (DDH) (5,72 g, 20 mmol) in a mixture of CHC13 (500 mL) and CCI4 (500 mL) was heated to reflux. Every 60 minutes 50 mg of dibenzoyl peroxide was added for six hours and then the reaction mixture was left at reflux over night. It was then allowed to reach room tem- perature and the solvents were removed by evaporation. Chromatography using silica gel 60 and heptane/ethyl acetate (18: 2-> 17: 3-> 16: 4) as eluent afforded the pure title compound (6.40 g, 53percent). 1H NMR (CDC13) 8 1.26 (t, 3H), 2.48 (q, 2H), 3.95 (s, 3H), 4.47 (s, 2H), 7.55 (dd, 1H), 8.04 (d, 1H), 8.72 (d, 1H), 11.06 (bs, 1H).
61%	at 0℃; for 16 h; Reflux	Thionyl chloride (2.88 mL, 39.69 mmol) was added drop wise to a solution of 2-amino-5-methyl-benzoic acid (3.0 g, 19.84 mmol) in methanol (10 mL) at 0° C. and refluxed for 16 hr. The reaction mixture was concentrated to dryness and the residue dissolved in chloroform (100 mL). The organic layer was washed with sodium bicarbonate solution (530 mL), water (330 mL), brine (3*30 mL) and dried over anhydrous sodium sulphate. The residue was concentrated under vacuum to yield the crude compound, which was purified by column chromatography over silica gel (100-200 mesh) using 2percent ethyl acetate in pet ether as eluent to afford 2-amino-5-methyl-benzoic acid methyl ester (2.0 g, 61percent) as a pale yellow semi solid.

Reference： [1] Organic and Biomolecular Chemistry, 2017, vol. 15, # 9, p. 2104 - 2118
[2] Chemical Communications, 2011, vol. 47, # 3, p. 1057 - 1059
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 21, p. 8332 - 8338
[4] Patent: WO2005/75410, 2005, A1, . Location in patent: Page/Page column 31-32
[5] Journal of Chemical Research, Miniprint, 1986, # 7, p. 2001 - 2025
[6] Patent: US2011/160231, 2011, A1, . Location in patent: Page/Page column 10
[7] Journal of Heterocyclic Chemistry, 1989, vol. 26, # 5, p. 1501 - 1507
[8] Scientia Pharmaceutica, 2003, vol. 71, # 4, p. 331 - 356
[9] Journal of Heterocyclic Chemistry, 2010, vol. 47, # 2, p. 415 - 420
[10] Journal of Organic Chemistry, 2015, vol. 80, # 21, p. 11175 - 11183
[11] Organic and Biomolecular Chemistry, 2015, vol. 13, # 47, p. 11486 - 11491
[12] Patent: US2015/315198, 2015, A1, . Location in patent: Paragraph 1505; 1506

3
[ 2941-78-8 ]
[ 18595-16-9 ]

Yield	Reaction Conditions	Operation in experiment
74%	With sulfuric acid In methanol; water	REFERENCE EXAMPLE 51 Methyl 2-amino-5-methylbenzoate A mixture of 2-amino-5-methyl benzoic acid (10 g) in methanol (50 ml) containing conc. sulfuric acid (5.5 ml) was heated for 19 hours under reflux. The solvent was distilled off, and the residue was dissolved in water. The solution was neutralized with an aqueous sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was dried and concentrated to afford a pale brown oil (8.1 g, 74percent). ¹ H-NMR(90MHz,CDCl₃) δ: 2.24(3H,s), 3.89(3H,s), 5.55(2H,s), 6.59(1H,d), 7.10(1H,dd), 7.68(1H,d).

Reference： [1] Patent: US5128356, 1992, A,

4
[ 2941-78-8 ]
[ 18107-18-1 ]
[ 18595-16-9 ]

Reference： [1] Patent: US2006/35908, 2006, A1, . Location in patent: Page/Page column 62

5
[ 2941-78-8 ]
[ 80-11-5 ]
[ 18595-16-9 ]

Reference： [1] Heterocycles, 2006, vol. 67, # 1, p. 161 - 173

6
[ 67-56-1 ]
[ 134-20-3 ]
[ 18595-16-9 ]

Reference： [1] Angewandte Chemie - International Edition, 2014, vol. 53, # 31, p. 8211 - 8215[2] Angew. Chem., 2014, vol. 126, # 31, p. 8350 - 8354

7
[ 3113-72-2 ]
[ 18595-16-9 ]

Reference： [1] Patent: WO2015/38417, 2015, A1,
[2] Patent: EP1475368, 2004, A1,

8
[ 186581-53-3 ]
[ 2941-78-8 ]
[ 18595-16-9 ]

Reference： [1] Journal of Organic Chemistry, 2010, vol. 75, # 20, p. 7033 - 7036

9
[ 67-56-1 ]
[ 4692-99-3 ]
[ 18595-16-9 ]

Reference： [1] Journal fuer Praktische Chemie (Leipzig), 1886, vol. <2>33, p. 58

10
[ 18595-16-9 ]
[ 2967-93-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420

11
[ 18595-16-9 ]
[ 90971-88-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420

[ 18595-16-9 ] Synthesis Path-Downstream 1~74

1
[ 67-56-1 ]
[ 4692-99-3 ]
[ 18595-16-9 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1886,vol. <2>33,p. 58

2
[ 18595-16-9 ]
[ 151-50-8 ]
[ 127510-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; water; copper(II) sulfate Diazotization_.Erhitzen des Reaktionsgemisches;

Reference： [1]Hayashi [Journal of the Chemical Society, 1930, p. 1513,1516]

3
[ 20587-30-8 ]
[ 18595-16-9 ]

Yield	Reaction Conditions	Operation in experiment
60%	With ammonium chloride; zinc; In methanol; water; at 0 - 20℃; for 12.0h;	A solution of <strong>[20587-30-8]methyl 5-methyl-2-nitrobenzoate</strong> (8 g, 41.025 mmol) in methanol (80 mL) and water (10 mL) was cooled to 0C. Zinc powder (13.33 g, 205.128 mmol) was then added, followed by NH4C1 (17.6 g, 328.2 mmol). The mixture was stirred for 12 h at rt. Progress of the reaction was followed by TLC (20% ethyl acetate/hexane). After completion of the reaction, the mixture was filtered and the filtrate was evaporated to provide crude residue. The crude reside was basified with saturated NaHC03 solution and extracted with DCM (2 x 20 mL). The combined organic layers were dried over Na2S04, filtered and evaporated to give methyl 2-amino-5-methylbenzoate (Yield: 4 g, 60%).1H NMR (400 MHz, CDC13): delta 7.65 (s, 1H), 7.25 (s, 1H), 7.10-7.07 (q, 1H, J=8 Hz), 6.58 (d, 1H), 3.86 (s, 3H), 2.22 (s, 3H).
	With hydrogen;5% palladium-on-charcoal; In ethyl acetate; for 8.0h;	A mixture of which under argon gas 5% palladium carbon (1.55g) has been added to the compound (5.85g) prepared in Reference example 13, which ethyl acetate (150ml) had been added, was stirred for 8 hours under hydrate gas. The reactive mixture filtered with celite was concentrated. A title compound (4.89g) having the following physical properties values was obtained. TLC:Rf 0.44 (n-hexane: ethyl acetate =6:1); NMR (CDCl3):delta 7.66 (dd, J = 1.8 Hz, 0.6 Hz, 1H), 7.10 (m, 1H), 6.59 (d, J = 8.7 Hz, 1H), 5.56 (bs, 1H), 3.86 (s, 3H), 2.23 (s, 3H)

Reference： [1]Dalton Transactions,2019,vol. 48,p. 6071 - 6082
[2]Patent: WO2015/38417,2015,A1 .Location in patent: Paragraph 151; 152
[3]Journal of the Chemical Society,1930,p. 1513,1516
[4]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4416 - 4420
[5]Patent: EP1475368,2004,A1 .Location in patent: Page 57

4
[ 67-56-1 ]
[ 2941-78-8 ]
[ 18595-16-9 ]

Yield	Reaction Conditions	Operation in experiment
64%	With thionyl chloride; at 0℃; for 18.5h;Heating / reflux;	EXAMPLE 18; 5-Bromomethyl-2-propionylamino-benzoic acid methyl ester; 2-Amino-5-methyl-benzoic acid (23,58 g, 156 mmol) was dissolved in methanol. The solution was brought to 0C on an ice-bath and thionyl chloride (46.3 mL, 636 mmol) was added dropwise during 30 minutes. After the addition the reaction mixture was refluxed for 18 hours and was then allowed to reach room temperature. The solvent was evaporated and the remain- der was divided between CH2Cl2 (500 mL) and aqueous saturated NaHC03 (500 mL). The organic layer was washed with an additional 500 mL of aqueous saturated NaHCO3, dried over MgS04 and evaporated to dryness (16.59 g, 64%). 2-Amino-5-methyl-benzoic acid methyl ester (8.00 g, 48.4 mmol) was dissolved in CHC13 (275 mL) and propionyl chloride (12.6 mL, 145 mmol) was added dropwise during 10 min- utes after which the reaction mixture was left with stirring at room temperature for 72 hours. Aqueous saturated NaHCO3 (400 mL) was carefully added under vigorous stirring and when no more gas evolved the organic layer was separated, dried over MgSO4, filtered and evapo- rated to dryness (10.06 g, 94%). The radical bromination was performed as described by Patil et al. 1989: 5-Methyl-2- propionylamino-benzoic acid methyl ester (8.85 g, 40 mmol) and 1, 3-dibromo-5, 5-dimethyl hydantoin (DDH) (5,72 g, 20 mmol) in a mixture of CHC13 (500 mL) and CCI4 (500 mL) was heated to reflux. Every 60 minutes 50 mg of dibenzoyl peroxide was added for six hours and then the reaction mixture was left at reflux over night. It was then allowed to reach room tem- perature and the solvents were removed by evaporation. Chromatography using silica gel 60 and heptane/ethyl acetate (18: 2-> 17: 3-> 16: 4) as eluent afforded the pure title compound (6.40 g, 53%). 1H NMR (CDC13) 8 1.26 (t, 3H), 2.48 (q, 2H), 3.95 (s, 3H), 4.47 (s, 2H), 7.55 (dd, 1H), 8.04 (d, 1H), 8.72 (d, 1H), 11.06 (bs, 1H).
61%	With thionyl chloride; at 0℃; for 16h;Reflux;	Thionyl chloride (2.88 mL, 39.69 mmol) was added drop wise to a solution of 2-amino-5-methyl-benzoic acid (3.0 g, 19.84 mmol) in methanol (10 mL) at 0 C. and refluxed for 16 hr. The reaction mixture was concentrated to dryness and the residue dissolved in chloroform (100 mL). The organic layer was washed with sodium bicarbonate solution (530 mL), water (330 mL), brine (3*30 mL) and dried over anhydrous sodium sulphate. The residue was concentrated under vacuum to yield the crude compound, which was purified by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate in pet ether as eluent to afford 2-amino-5-methyl-benzoic acid methyl ester (2.0 g, 61%) as a pale yellow semi solid.
	With thionyl chloride; at 0 - 70℃;	methyl 2-amino-5-methylbenzoateInto a 250-mL 3-necked round-bottom flask, was placed a mixture of 2-amino-5-methylbenzoic acid (5.00 g, 33.08 mmol, 1.00 equiv) and methanol (50 mL) with stirring at 0 C., to which was added sulfurous dichloride (39.00 g, 327.81 mmol, 10.00 equiv) dropwise. The resulted solution was stirred overnight at 70 C. The cooled reaction solution was extracted with 3×50 mL of dichloromethane. The organic layers were combined and concentrated under vacuum. This resulted in 5.00 g (crude) of methyl 2-amino-5-methylbenzoate as off-white solid. MS (ESI) m/z 166 [M+H]+

Reference： [1]Organic and Biomolecular Chemistry,2017,vol. 15,p. 2104 - 2118
[2]Chemical Communications,2011,vol. 47,p. 1057 - 1059
[3]Journal of Medicinal Chemistry,2013,vol. 56,p. 8332 - 8338
[4]Patent: WO2005/75410,2005,A1 .Location in patent: Page/Page column 31-32
[5]Journal of Chemical Research, Miniprint,1986,p. 2001 - 2025
[6]Patent: US2011/160231,2011,A1 .Location in patent: Page/Page column 10
[7]Journal of Heterocyclic Chemistry,1989,vol. 26,p. 1501 - 1507
[8]Scientia Pharmaceutica,2003,vol. 71,p. 331 - 356
[9]Journal of Heterocyclic Chemistry,2010,vol. 47,p. 415 - 420
[10]Journal of Organic Chemistry,2015,vol. 80,p. 11175 - 11183
[11]Organic and Biomolecular Chemistry,2015,vol. 13,p. 11486 - 11491
[12]Patent: US2015/315198,2015,A1 .Location in patent: Paragraph 1505; 1506
[13]Journal of Medicinal Chemistry,2020

5
[ 358-23-6 ]
[ 18595-16-9 ]
[ 125665-64-7 ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,2004,vol. 68,p. 425 - 427
[2]Journal of Fluorine Chemistry,2007,vol. 128,p. 1174 - 1181
[3]Journal of Medicinal Chemistry,1990,vol. 33,p. 1312 - 1329

6
[ 18595-16-9 ]
[ 1488-42-2 ]
[ 100038-87-7 ]

Reference： [1]Synthesis,1985,p. 220 - 222
[2]Journal of Medicinal Chemistry,1986,vol. 29,p. 472 - 477

7
[ 18595-16-9 ]
methyl 5-methyl-2-azidobenzoate [ No CAS ]

Reference： [1]Journal of Heterocyclic Chemistry,2010,vol. 47,p. 415 - 420
[2]Tetrahedron,1991,vol. 47,p. 2277 - 2290
[3]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1767 - 1770

8
[ 18595-16-9 ]
[ 638-29-9 ]
[ 136285-53-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrogenchloride; sodium carbonate; triethylamine; In dichloromethane; water;	REFERENCE EXAMPLE 52 Methyl 5-methyl-2-valerylaminobenzoate To a solution of <strong>[18595-16-9]methyl 2-amino-5-methylbenzoate</strong> (8.1 g) and triethylamine (6.0 g) in methylene chloride (50 ml) was added dropwise, while stirring under ice-cooling, valeryl chloride (6.5 g). The reaction was allowed to stir for two hours, then the reaction mixture was washed with an aqueous solution of sodium carbonate, dilute hydrochloric acid and water, followed by drying. The solvent was evaporated to dryness to give a pale brown oil (12.8 g, 99%). 1 H-NMR(90MHz,CDCl3) delta: 0.95(3H,t), 1.2-1.9(4H,m), 2.33(3H,s), 2.43(2H,t), 3.93(3H,s), 7.34(1H,dd), 7.82(1H,d), 8.62(1H,d).

Reference： [1]Patent: US5128356,1992,A
[2]Journal of Medicinal Chemistry,1993,vol. 36,p. 1772 - 1784

9
[ 18595-16-9 ]
[ 79-30-1 ]
[ 141541-70-0 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1992,vol. 40,p. 675 - 682

10
[ 18595-16-9 ]
[ 98-59-9 ]
[ 34161-82-5 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; at 0 - 20℃;	A mixture of which tosyl chloride (7.022g) has been added to pyridine (15ml) solution of the compound (4.69g) prepared in Reference example 14 during storage in ice was stirred at room temperature over night. The crystal extracted from the reactive mixture dissolved to water/2N hydrochloric acid was removed by filtration followed to be washed in clear water. A title compound (8.84g) having the following physical properties values was obtained. TLC:Rf 0.41 (n-hexane: ethyl acetate =4:1); NMR (CDCl3):delta 10.38 (s, 1H), 7.72-7.69 (m, 3H), 7.60 (d, J = 8.1 Hz, 1H, 7.28-7.19 (m, 3H), 3.85 (s, 3H), 2.36 (s, 3H), 2.27 (s, 3H)

Reference： [1]Journal of Heterocyclic Chemistry,1989,vol. 26,p. 1501 - 1507
[2]Journal of the Chemical Society. Perkin transactions I,1991,p. 1565 - 1569
[3]Patent: EP1475368,2004,A1 .Location in patent: Page 57

11
[ 18595-16-9 ]
[ 107-14-2 ]
[ 18731-18-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; ammonia; In 1,4-dioxane;	19) 1. 91.4 g of <strong>[18595-16-9]methyl 2-amino-5-methylbenzoate</strong> and 23.4 ml of chloroacetonitrile are dissolved in 1.01 of absolute dioxan and the solution is cooled to 10 C. Subsequently, a weak stream of dry hydrogen chloride is introduced for 8 h. at 5 to 15 C. After 4 h., a further 23.4 ml of chloroacetonitrile are added thereto. The mixture is stirred at room temperature for a further 18 h. The suspension is subsequently evaporated in a vacuum. The crystalline residue is suspended with 2.51 of ice/water, adjusted to pH 8 to 9 with about 100 ml of 25% ammonia, stirred at 5 C. for 1 h. and then filtered. The crystals are washed with water and dried in a vacuum. There are obtained 114.1 g of 2-chloromethyl-6-methyl-3H-quinazolin-4-one of m.p. 263-265 C.

Reference： [1]Heterocycles,1994,vol. 39,p. 693 - 722
[2]Patent: US5387585,1995,A

12
[ 18595-16-9 ]
<i>N</i>-(2-methoxycarbonyl-4-methyl-phenyl)-diazenium; chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium nitrite; In water; at 0 - 5℃; for 0.166667h;	General procedure: Appropriate amine 1 (0.02 mol) was dissolved in concentrated hydrochloric acid (5 ml) and ice (15 g) was added. When the mixture was cooled to 0 C, saturated sodium nitrite(1.73 g; 0.025 mol) aqueous solution was added keeping the temperature below 5 C. After 10 min, resinous sediment (in case it was formed) should be filtered. Filtrated solution of the diazonium salt was added dropwise into quinone (2.5 g; 0.024 mol), AcONa · 3H2O (6.84 g; 0.045 mol), water (150 ml) suspension keeping the temperature at 15-20 C. The reaction mixture was left stirring for 2 h. The formed solid product was filtered and recrystallized from ethanol or ethanol/DMF solution.

Reference： [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1999,vol. 38,p. 1139 - 1142
[2]Synthetic Communications,2017,vol. 47,p. 2399 - 2405

13
[ 18595-16-9 ]
[ 34535-42-7 ]
9-methylquinolino[2',3':3,4]pyrrolo[2,1-b]quinazolin-11(13H)-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2004,vol. 12,p. 6287 - 6299
[2]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2051 - 2054

14
[ 64119-42-2 ]
[ 18595-16-9 ]
5-cyano-6-(2-methoxycarbonyl-4-methyl-phenylamino)-2-methyl-nicotinic acid ethyl ester [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,2004,vol. 40,p. 510 - 515

15
[ 4641-57-0 ]
[ 18595-16-9 ]
methyl 5-methyl-2-(1-phenylpyrrolidin-2-ylideneamino)benzoate [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 1736 - 1740

16
[ 7661-32-7 ]
[ 18595-16-9 ]
methyl 2-[1-(4-bromophenyl)pyrrolidin-2-ylideneamino]-5-methylbenzoate [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2005,p. 1736 - 1740

17
[ 18595-16-9 ]
[ 28461-49-6 ]

Reference： [1]Heterocycles,2006,vol. 67,p. 161 - 173
[2]Scientia Pharmaceutica,2003,vol. 71,p. 331 - 356

18
methyl 5-methyl-2-azidobenzoate [ No CAS ]
[ 18595-16-9 ]

Reference： [1]Tetrahedron Letters,2006,vol. 47,p. 4253 - 4257
[2]Synlett,2008,p. 1297 - 1300

19
[ 2941-78-8 ]
[ 80-11-5 ]
[ 18595-16-9 ]

Reference： [1]Heterocycles,2006,vol. 67,p. 161 - 173

20
[ 18595-16-9 ]
[ 195823-25-7 ]

Reference： [1]Synlett,2006,p. 610 - 614
[2]Synlett,2006,p. 610 - 614
[3]Synlett,2006,p. 610 - 614

21
[ 18595-16-9 ]
[ 79-03-8 ]
[ 862671-79-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	In chloroform; at 20℃; for 72.1667h;	EXAMPLE 18; 5-Bromomethyl-2-propionylamino-benzoic acid methyl ester; 2-Amino-5-methyl-benzoic acid (23,58 g, 156 mmol) was dissolved in methanol. The solution was brought to 0C on an ice-bath and thionyl chloride (46.3 mL, 636 mmol) was added dropwise during 30 minutes. After the addition the reaction mixture was refluxed for 18 hours and was then allowed to reach room temperature. The solvent was evaporated and the remain- der was divided between CH2Cl2 (500 mL) and aqueous saturated NaHC03 (500 mL). The organic layer was washed with an additional 500 mL of aqueous saturated NaHCO3, dried over MgS04 and evaporated to dryness (16.59 g, 64%). 2-Amino-5-methyl-benzoic acid methyl ester (8.00 g, 48.4 mmol) was dissolved in CHC13 (275 mL) and propionyl chloride (12.6 mL, 145 mmol) was added dropwise during 10 min- utes after which the reaction mixture was left with stirring at room temperature for 72 hours. Aqueous saturated NaHCO3 (400 mL) was carefully added under vigorous stirring and when no more gas evolved the organic layer was separated, dried over MgSO4, filtered and evapo- rated to dryness (10.06 g, 94%). The radical bromination was performed as described by Patil et al. 1989: 5-Methyl-2- propionylamino-benzoic acid methyl ester (8.85 g, 40 mmol) and 1, 3-dibromo-5, 5-dimethyl hydantoin (DDH) (5,72 g, 20 mmol) in a mixture of CHC13 (500 mL) and CCI4 (500 mL) was heated to reflux. Every 60 minutes 50 mg of dibenzoyl peroxide was added for six hours and then the reaction mixture was left at reflux over night. It was then allowed to reach room tem- perature and the solvents were removed by evaporation. Chromatography using silica gel 60 and heptane/ethyl acetate (18: 2-> 17: 3-> 16: 4) as eluent afforded the pure title compound (6.40 g, 53%). 1H NMR (CDC13) 8 1.26 (t, 3H), 2.48 (q, 2H), 3.95 (s, 3H), 4.47 (s, 2H), 7.55 (dd, 1H), 8.04 (d, 1H), 8.72 (d, 1H), 11.06 (bs, 1H).

Reference： [1]Patent: WO2005/75410,2005,A1 .Location in patent: Page/Page column 31-32

22
[ 18595-16-9 ]
[ 122-01-0 ]
[ 1057250-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 3h;	Step 1: To a solution of 2-amino-5-methyl benzoic acid (1.0 mmol) dissolved in 10% MeOH in toluene (2.5 mL) is added dropwise trimethylsilyl-diazomethane (2.0 M in hexanes, 0.75 mL). The reaction mixture is stirred at room temperature for 1 hour and the solvent is removed under reduced pressure. The resulting methyl ester is dissolved in dichloromethane (3.0 mL) and then 4-chlorobenzoyl chloride (1.0 equivalent) and DIEA (1.0 equivalent) is added sequentially. The reaction mixture is stirred for 3 hours and the solvent is evaporated. The yellow residue is diluted with EtOAc, washed with 1 M NaHSO4, brine, dried, filtered and concentrated under reduced pressure to provide 2-(4-chloro-benzoylamino)-5-methyl-benzoic acid methyl ester (compound 11.1) which is used without purification in the next step.

Reference： [1]Patent: US2006/35908,2006,A1 .Location in patent: Page/Page column 62

23
[ 2941-78-8 ]
[ 18107-18-1 ]
[ 18595-16-9 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; hexane; toluene; at 20℃; for 1h;	Step 1: To a solution of 2-amino-5-methyl benzoic acid (1.0 mmol) dissolved in 10% MeOH in toluene (2.5 mL) is added dropwise trimethylsilyl-diazomethane (2.0 M in hexanes, 0.75 mL). The reaction mixture is stirred at room temperature for 1 hour and the solvent is removed under reduced pressure. The resulting methyl ester is dissolved in dichloromethane (3.0 mL) and then 4-chlorobenzoyl chloride (1.0 equivalent) and DIEA (1.0 equivalent) is added sequentially. The reaction mixture is stirred for 3 hours and the solvent is evaporated. The yellow residue is diluted with EtOAc, washed with 1 M NaHSO4, brine, dried, filtered and concentrated under reduced pressure to provide 2-(4-chloro-benzoylamino)-5-methyl-benzoic acid methyl ester (compound 11.1) which is used without purification in the next step.

Reference： [1]Patent: US2006/35908,2006,A1 .Location in patent: Page/Page column 62

24
[ 75-44-5 ]
[ 18595-16-9 ]
[ 351435-64-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; toluene;	EXAMPLE 4 Preparation of 2-phenylthio-6-methyl-4H-3,1-benzoxazin-4-one <strong>[18595-16-9]2-Amino-5-methylbenzoic acid methyl ester</strong> (122 mg, 0.79 mmol) and triethylamine (0.28 ml, 1.96 mmol) were dissolved in THF (10 ml). A 20% solution of phosgene in toluene (0.74 ml, 1.6 mmol) was added, causing immediate formation of a white precipitate.

Reference： [1]Patent: US2003/176429,2003,A1

25
3-[4-(4-Chloro-phenyl)-3,6-dihyro-2H-pyridin-1-]-propylamine [ No CAS ]
[ 32315-10-9 ]
[ 18595-16-9 ]
3-{3-[4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridinyl-1-yl]-propyl}-6-1H-quinazoline-2,4-dione [ No CAS ]
[ 329789-96-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	With triethylamine; In methanol; dichloromethane; ethyl acetate; toluene;	Example 7 Preparation of 11, 3-{3-[4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridinyl-1-yl]-propyl}-6-methyl-1H-quinazoline-2,4-dione 2-Amino-5-methylbenzoic acid, methyl ester (0.250 g, 1.51 mmol) and triethylamine (0.48 mL, 3.47 mmol) in methylene chloride (8 mL) were cooled in an ice bath. Triphosgene (0.149 g, 0.503 mmol) was added and the resulting mixture was stirred for 1 h at 0 C. to form the isocyanate intermediate. 3-[4-(4-Chloro-phenyl)-3,6-dihyro-2H-pyridin-1-]-propylamine (0.379 g, 1.51 mmol) was added in one portion and the mixture was stirred for 15 h at room temperature. The mixture was concentrated, added toluene (30 mL) and refluxed for 24 h. The mixture was diluted with sat. sodium bicarbonate and extracted with 3 times ethyl acetate (200 mL). Pooled ethyl acetate was washed with brine (200 mL), dried over magnesium sulfate and concentrated to give a white solid. Flash chromatography using 5% methanol/chloroform as eluent gave 3-{3-[4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridinyl-1-yl]-propyl}-6-1H-quinazoline-2,4-dione (0.49 g, 79%) as a white solid. The maleate salt had the following properties: M.p. 199-201 C.; 1H NMR DMSO-d6 delta 11.39 (s, 1H), 9.45 (brd s, 1H), 7.71 (s,1H), 7.45 (dd, J=8.1, 22.0 Hz, 4H), 7.07 (d, J=9.5 Hz, 1H), 6.20 (brd s, 1H), 5.99 (s, 2H), 3.96 (t, J=6.9 Hz, 2H), 3.82-3.60 (m, 2H), 3.40-3.00 (m, 2H), 2.69 (brd s, 2H), 2.30 (s, 2H), 2.08-1.95 (m, 2H); 13C NMR DMSO-d6 delta 167.64, 162.67, 150.70, 137.78, 137.46, 136.59, 136.01, 133.45, 133.01, 132.22,. 129.15, 128.88, 127.22, 127.06, 126.97, 115.68, 115.43, 114.10, 53.44, 37.83, 26.48, 23.27, 20.66; IR (KBr) 3052, 2959, 2300, 1719, 1659, 1629, 1578, 1516, 1459, 1374, 1354, 1283, 1196, 1097, 1072, 1011, 984, 957, 946, 883, 873, 827, 811, 800, 776, 729, 720, 699, 678, 648, 625, 584, 556, 546, 530, 464, 431, 406; Analysis calculated for C23H24CIN3O2.C4H4O4: C, 61.66; H, 5.37; N, 7.99. Found: C, 61.64; H, 5.57; N, 7.98.

Reference： [1]Patent: US6521630,2003,B1

26
[ 2941-78-8 ]
[ 18595-16-9 ]

Yield	Reaction Conditions	Operation in experiment
74%	With sulfuric acid; In methanol; water;	REFERENCE EXAMPLE 51 Methyl 2-amino-5-methylbenzoate A mixture of 2-amino-5-methyl benzoic acid (10 g) in methanol (50 ml) containing conc. sulfuric acid (5.5 ml) was heated for 19 hours under reflux. The solvent was distilled off, and the residue was dissolved in water. The solution was neutralized with an aqueous sodium hydroxide, followed by extraction with ethyl acetate. The organic layer was dried and concentrated to afford a pale brown oil (8.1 g, 74%). 1 H-NMR(90MHz,CDCl3) delta: 2.24(3H,s), 3.89(3H,s), 5.55(2H,s), 6.59(1H,d), 7.10(1H,dd), 7.68(1H,d).

Reference： [1]Patent: US5128356,1992,A

27
[ 18595-16-9 ]
methyl 2-amino-6-methylbenzothiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; In ice-water; glacial acetic acid-are; acetic acid;	(a) Methyl 2-amino-6-methylbenzothiazole-4-carboxylate (5a) 50 g (0.303 mol) of <strong>[18595-16-9]methyl 2-amino-5-methylbenzoate</strong> are dissolved in 300 ml of glacial acetic acid, and 120.6 g (1.24 mol) of potassium thiocyanate--dissolved in 200 ml of glacial acetic acid--are added. At 10 C., 17.42 ml (0.335 mol) of bromine are added dropwise, and the mixture is then stirred without cooling for 2 hours. The suspension is tipped into 3 l of ice-water, while stirring, and the precipitated product is filtered off with suction and washed with dilute sodium carbonate solution and water. The filter cake is suspended in H2 O and the suspension is stirred at 100 C. overnight. After cooling, the product is filtered off with suction, washed with H2 O and dried at 40 C. in vacuo. Yield: 60 g (89%). C10 H10 N2 O2 S (222.2). NMR (DMSO): =2.35 (s, 3H), 3.8 (s, 3H), 7.5 (s, 1H), 7.71 (s, 1H), 7.81 (s, 2H) ppm.

Reference： [1]Patent: US4748163,1988,A

28
[ 18595-16-9 ]
[ 103440-52-4 ]

Yield	Reaction Conditions	Operation in experiment
75%	With copper(l) iodide; diiodomethane; isopentyl nitrite; In tetrahydrofuran; at 70℃; for 1.5h;	Example 28; 2-Butoxy-7,8-dihydro-9-(3-methoxycarbonyl-4-{N-[3-(methoxycarbonylmethy)benzyl]-N-methylaminomethylpropargyl}benzyl)-8-oxoadenine; [Show Image] Step (i); 4-Iodo-3-methoxycarbonyltoluene; [Show Image] To 4-amino-3-methoxycarbonyltoluene 1.36g (8.2mmol) in THF (20ml) were added cupper iodide 1.56g (8.2mmol), diiodomethane 3.32ml (41.2mmol) and isoamyl nitrite 3.32ml (41.2mmol), and the mixture was stirred at 70C for 1.5 hours. After filtration and concentration, the residue was purified by silica gel column chromatography to give the titled compound 1.7g (6.2mmol) as an yellow oil. Yield 75% 1H NMR (CDCl3) delta 7.86 (1H, d, J = 8.2 Hz), 7.63 (1H, s), 6.99 (1H, d, J = 8.2 Hz), 3.94 (3H, s), 2.34 (3H, s).
		General procedure: To concentrated aqueous HCl (12 M, 15 mL) was added methyl 2-amino-5-(4-fluorophenyl)benzoate (1.50 g, 6.12 mmol) at 0 C, and the suspension was stirred for 15 minat the same temperature. To the mixture was added ice (6 g) at 0 C, and after stirring for 10min at the same temperature, to the resulting suspension was added a solution of NaNO2 (848mg, 12.2 mmol, 1.99 equiv) dissolved in H2O (10 mL) at 0 C. After stirring for 10 min at thesame temperature, to this mixture was added a solution of KI (4.47 g, 26.9 mmol, 4.40 equiv) dissolved in H2O (20 mL) at 0 C. After gradually warming to room temperature, to themixture was added saturated aqueous sodium thiosulfate (50 mL) and extracted with EtOAc(50 mL × 3). The combined organic extract was washed with brine (50 mL), dried (Na2SO4),and after filtration, the filtrate was concentrated under reduced pressure. The residue waspurified by flash column chromatography (silica-gel 30 g, n-hexane/EtOAc = 30/1) to givemethyl 5-(4-fluorophenyl)-2-iodobenzoate (5c) (1.85 g, 5.19 mmol, 84.8%) as a colorless oil.

Reference： [1]Patent: EP1939202,2008,A1 .Location in patent: Page/Page column 54-55
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4416 - 4420
[3]Chemistry Letters,2017,vol. 46,p. 858 - 861

29
[ 22462-26-6 ]
[ 18595-16-9 ]
[ 1107664-06-1 ]

Reference： [1]Tetrahedron,2009,vol. 65,p. 563 - 578

30
[ 18595-16-9 ]
[ 292638-85-8 ]
[ 890646-70-5 ]

Reference： [1]Tetrahedron Letters,2009,vol. 50,p. 6112 - 6115

31
[ 18595-16-9 ]
[ 80-62-6 ]
[ 890646-76-1 ]

Reference： [1]Tetrahedron Letters,2009,vol. 50,p. 6112 - 6115

32
[ 18595-16-9 ]
[ 16220-95-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; copper(l) chloride; sodium nitrite In water at 0 - 5℃;

Reference： [1]Location in patent: scheme or table Chang, Dong-Jo; Yoon, Eun-Young; Lee, Geon-Bong; Kim, Soon-Ok; Kim, Wan-Joo; Kim, Young-Myeong; Jung, Jong-Wha; An, Hongchan; Suh, Young-Ger [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 15, p. 4416 - 4420]

33
[ 18595-16-9 ]
[ 2967-93-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4416 - 4420

34
[ 18595-16-9 ]
[ 90971-88-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 4416 - 4420

35
[ 18595-16-9 ]
copper(l) cyanide [ No CAS ]
[ 127510-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium nitrite In water at 0 - 5℃;

36
[ 30425-47-9 ]
[ 18595-16-9 ]
[ 1263220-14-9 ]

Reference： [1]Chemical Communications,2011,vol. 47,p. 1057 - 1059

37
3-(N,N-diethylsulfamoyl)benzoyl chloride [ No CAS ]
[ 18595-16-9 ]
[ 1448009-47-9 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 6146 - 6155

38
[ 18595-16-9 ]
[ 292638-85-8 ]
[ 1623803-95-1 ]

Reference： [1]Chemistry - A European Journal,2014,vol. 20,p. 6603 - 6607

39
[ 13691-26-4 ]
[ 18595-16-9 ]
methyl 2-[(2E)-1-(4-nitrophenyl)pyrrolidin-2-ylidene]amino}-5-methylbenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	Stage #1: 2-amino-5-methylbenzoic acid methyl ester With trichlorophosphate In dichloromethane for 3h; Stage #2: 1-(4-nitrophenyl)pyrrolidin-2-one In dichloromethane at 50℃; for 18h; Inert atmosphere; Reflux;

Reference： [1]Kepiro, Miklos; Varkuti, Boglarka H.; Vegner, Laszlo; Voeroes, Gergely; Hegyi, Gyoergy; Varga, Mate; Malnasi-Csizmadia, Andras [Angewandte Chemie - International Edition, 2014, vol. 53, # 31, p. 8211 - 8215][Angew. Chem., 2014, vol. 126, # 31, p. 8350 - 8354]

40
[ 18595-16-9 ]
[ 124-63-0 ]
methyl 5-methyl-2-(methylsulfonamido)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With pyridine; In dichloromethane; at 0 - 20℃; for 12h;	A solution of <strong>[18595-16-9]methyl 2-amino-5-methylbenzoate</strong> (2.76 g, 16.727 mmol) in DCM (30 mL) and pyridine (6.6 mL, 83.636 mmol) was cooled to 0C. Methane sulfonyl chloride (2.88 g, 1.95 mL, 25.09 mmol) was then added to the mixture drop-wise. The mixture was stirred for 5 h at rt. Progress of the reaction was followed by TLC (25% ethyl acetate/hexane). After completion of the reaction, the mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with saturated NH4C1 solution (50 mL), followed brine (20 mL). The mixture was then dried over Na2S04, filtered and evaporated to provide crude product. The resulting residue was purified by Biotage Isolera using 15% ethyl acetate/hexane to provide methyl 5-methyl-2-(methylsulfonamido)benzoate (Yield: 3.36 g, 84%).1H NMR (400 MHz, CDC13): delta 10.20 (s, 1H), 7.83 (s, 1H), 7.63-7.61 (d, 1H, J=8 Hz), 7.37-7.34 (d, 1H, J=12 Hz), 3.92 (s, 3H), 3.0 (s, 3H), 2.33 (s, 3H)

Reference： [1]Patent: WO2015/38417,2015,A1 .Location in patent: Paragraph 152

41
[ 1943-83-5 ]
[ 18595-16-9 ]
7-methyl-2H,3H,5H-[1,3]oxazolo[3,2-b]isoquinolin-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With triethylamine; In 1,2-dichloro-ethane; at 100℃;	7-methyl-2H,3H,5H-[1,3]oxazolo[3,2-b]isoquinolin-5-oneInto a 100-mL round-bottom flask, was placed a mixture of <strong>[18595-16-9]methyl 2-amino-5-methylbenzoate</strong> (4.00 g, 24.21 mmol, 1.00 equiv)(Example 625), ClCH2CH2Cl (30 mL) and 1-chloro-2-isocyanatoethane (3.82 g, 36.20 mmol, 1.50 equiv), to which was added triethylamine (3.67 g, 36.27 mmol, 1.50 equiv) with stirring. The resulted solution was stirred overnight at 100 C. The cooled reaction mixture was concentrated under vacuum and diluted with 50 mL of H2O. The resulted solution was extracted with 3×50 mL of dichloromethane. The organic layers were combined and concentrated under vacuum. The residue was purified by silica gel column chromategraphy eluted with dichloromethane and tetrahydrofuran (10:1). This resulted in 2.50 g (51%) of 7-methyl-2H,3H,5H-[1,3]oxazolo[3,2-b]isoquinolin-5-one as off-white solid. MS (ESI) m/z 203 [M+H]+

Reference： [1]Patent: US2015/315198,2015,A1 .Location in patent: Paragraph 1507; 1508

42
[ 547739-67-3 ]
[ 18595-16-9 ]
C₁₇H₁₆ClNO₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-amino-5-methylbenzoic acid methyl ester With sodium hydride In tetrahydrofuran for 0.333333h; Stage #2: 3-chlorosulfonyl-4-methylbenzoic acid chloride In tetrahydrofuran at 20℃;

Reference： [1]Patrone, James D.; Pelz, Nicholas F.; Bates, Brittney S.; Souza-Fagundes, Elaine M.; Vangamudi, Bhavatarini; Camper, Demarco V.; Kuznetsov, Alexey G.; Browning, Carrie F.; Feldkamp, Michael D.; Frank, Andreas O.; Gilston, Benjamin A.; Olejniczak, Edward T.; Rossanese, Olivia W.; Waterson, Alex G.; Chazin, Walter J.; Fesik, Stephen W. [ChemMedChem, 2016, vol. 11, # 8, p. 893 - 899]

43
[ 5535-48-8 ]
[ 18595-16-9 ]
C₁₇H₁₉NO₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; bis[2-(diphenylphosphino)phenyl] ether; copper(l) chloride; In toluene; at 22℃; for 5h;Inert atmosphere; Sealed tube;	General procedure: CuCl (1.50 mg, 0.0150 mmol), DPEPhos (8.10 mg, 0.0150 mmol) and KOt-Bu (1.70 mg,0.0150 mmol) were added to a 8 mL vial charged with a magnetic bar. The vial was sealedwith a cap (phenolic open top cap with gray PTFE/silicone) and purged by N2 gas for 5 min.Toluene (0.8 mL) and methyl 2-aminobenzoate (1a) (46.6 L, 0.360 mmol) were added to themixture, which was allowed for 10 min. And then a solution of phenyl vinyl sulfone (2) (50.5mg, 0.300 mmol) in toluene (0.7 mL) was added to the reaction solution. After stirring atroom temperature for 5 h, THF (5 mL) was added and the reaction was allowed to cool to 0C (ice bath). After addition of KOt-Bu (101 mg, 0.900 mmol), the resulting solution wasallowed to stir for further 1 h at 0 C. After that time, the reaction was quenched with asaturated aqueous solution of NH4Cl (1 mL) and NaHCO3 (2 mL) and washed with EtOAc (7x 3 mL). The organic layers were combined, dried over MgSO4, filtered, and concentrated invacuo. The crude product was purified by silica gel column chromatography (CH2Cl2/EtOAc,8:1) to afford the desired product 4a (76.8 mg, 0.267 mmol, 89% yield) as a yellow solid.

Reference： [1]Chemistry Letters,2016,vol. 45,p. 1356 - 1358

44
[ 942-24-5 ]
[ 18595-16-9 ]
methyl 5,12-dihydro-2-methyl-12-oxoindolo[2,1-b]-quinazoline-6-carboxylate [ No CAS ]

Reference： [1]Organic Letters,2016,vol. 18,p. 6504 - 6507
[2]Helvetica Chimica Acta,2018,vol. 101

45
[ 776-41-0 ]
[ 18595-16-9 ]
ethyl 5,12-dihydro-2-methyl-12-oxoindolo[2,1-b]-quinazoline-6-carboxylate [ No CAS ]

Reference： [1]Organic Letters,2016,vol. 18,p. 6504 - 6507
[2]Helvetica Chimica Acta,2018,vol. 101

46
[ 4641-57-0 ]
[ 18595-16-9 ]
methyl 5-methyl-2-((1-phenylpyrrolidin-2-ylidene)amino)benzoate [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2017,vol. 15,p. 2104 - 2118

47
[ 18595-16-9 ]
1-(3-(allyloxy)phenyl)pyrrolidin-2-one [ No CAS ]
methyl 2-((1-(3-(allyloxy)phenyl)pyrrolidin-2-ylidene)amino)-5-methyl benzoate [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2017,vol. 15,p. 2104 - 2118

48
[ 939999-23-2 ]
[ 18595-16-9 ]
methyl 2-((1-(3-cyanophenyl)pyrrolidin-2-ylidene)amino)-5-methylbenzoate [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2017,vol. 15,p. 2104 - 2118

49
[ 38348-86-6 ]
[ 18595-16-9 ]
methyl 5-methyl-2-((1-(naphthalen-2-yl)pyrrolidin-2-ylidene)amino)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%		General procedure: The preparation of amidines was adopted from Verhasselt et al.[19].A flame-dried bulb of 250 mL, kept under a nitrogen atmosphere,was loaded with 120 mL of dry dichloromethane and pyrrolidinone(43.9 mmol, 1 equiv). Next, 8.18 mL of POCl3 (87.7 mmol,2 equiv) was added and the resulting mixture was stirred at roomtemperature for 24 h. Afterwards, a solution of <strong>[18595-16-9]methyl 2-amino-5-methylbenzoate</strong> (22) (7.61 g, 46.0 mmol, 1.05 equiv) in drydichloromethane (45 mL) was added via cannula and the reactionmixture was heated to 35 C for 24 h. Then, the reaction mixturewas cooled to 0 C, basified with 3 M aqueous NaOH until the pHequaled 10 and subsequently extracted with ethyl acetate (450 mLand 150 mL). The combined organic layers were washed with300 mL of brine, dried over magnesium sulfate and evaporated invacuo.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 136,p. 85 - 103

50
[ 18595-16-9 ]
1-(4-allyloxyphenyl)pyrrolidin-2-one [ No CAS ]
methyl 2-((1-(4-allyloxyphenyl)pyrrolidin-2-ylidene)amino)-5-methylbenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		General procedure: The preparation of amidines was adopted from Verhasselt et al.[19].A flame-dried bulb of 250 mL, kept under a nitrogen atmosphere,was loaded with 120 mL of dry dichloromethane and pyrrolidinone(43.9 mmol, 1 equiv). Next, 8.18 mL of POCl3 (87.7 mmol,2 equiv) was added and the resulting mixture was stirred at roomtemperature for 24 h. Afterwards, a solution of <strong>[18595-16-9]methyl 2-amino-5-methylbenzoate</strong> (22) (7.61 g, 46.0 mmol, 1.05 equiv) in drydichloromethane (45 mL) was added via cannula and the reactionmixture was heated to 35 C for 24 h. Then, the reaction mixturewas cooled to 0 C, basified with 3 M aqueous NaOH until the pHequaled 10 and subsequently extracted with ethyl acetate (450 mLand 150 mL). The combined organic layers were washed with300 mL of brine, dried over magnesium sulfate and evaporated invacuo.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 136,p. 85 - 103

51
[ 13691-26-4 ]
[ 18595-16-9 ]
C₁₉H₁₉N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%		General procedure: The preparation of amidines was adopted from Verhasselt et al.[19].A flame-dried bulb of 250 mL, kept under a nitrogen atmosphere,was loaded with 120 mL of dry dichloromethane and pyrrolidinone(43.9 mmol, 1 equiv). Next, 8.18 mL of POCl3 (87.7 mmol,2 equiv) was added and the resulting mixture was stirred at roomtemperature for 24 h. Afterwards, a solution of <strong>[18595-16-9]methyl 2-amino-5-methylbenzoate</strong> (22) (7.61 g, 46.0 mmol, 1.05 equiv) in drydichloromethane (45 mL) was added via cannula and the reactionmixture was heated to 35 C for 24 h. Then, the reaction mixturewas cooled to 0 C, basified with 3 M aqueous NaOH until the pHequaled 10 and subsequently extracted with ethyl acetate (450 mLand 150 mL). The combined organic layers were washed with300 mL of brine, dried over magnesium sulfate and evaporated invacuo.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 136,p. 85 - 103

52
[ 18595-16-9 ]
1-(1-allylindolin-6-yl)pyrrolidin-2-one [ No CAS ]
methyl 2-((1-(1-allylindolin-6-yl)pyrrolidin-2-ylidene)amino)-5-methylbenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42%		General procedure: The preparation of amidines was adopted from Verhasselt et al.[19].A flame-dried bulb of 250 mL, kept under a nitrogen atmosphere,was loaded with 120 mL of dry dichloromethane and pyrrolidinone(43.9 mmol, 1 equiv). Next, 8.18 mL of POCl3 (87.7 mmol,2 equiv) was added and the resulting mixture was stirred at roomtemperature for 24 h. Afterwards, a solution of <strong>[18595-16-9]methyl 2-amino-5-methylbenzoate</strong> (22) (7.61 g, 46.0 mmol, 1.05 equiv) in drydichloromethane (45 mL) was added via cannula and the reactionmixture was heated to 35 C for 24 h. Then, the reaction mixturewas cooled to 0 C, basified with 3 M aqueous NaOH until the pHequaled 10 and subsequently extracted with ethyl acetate (450 mLand 150 mL). The combined organic layers were washed with300 mL of brine, dried over magnesium sulfate and evaporated invacuo.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 136,p. 85 - 103

53
[ 35660-91-4 ]
[ 18595-16-9 ]
methyl 5-methyl-2-((4-oxo-4-phenylbutan-2-yl)amino)benzoate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2018,vol. 83,p. 2694 - 2705

54
[ 18595-16-9 ]
(±)-5-(allyloxymethyl)-1-phenylpyrrolidin-2-one [ No CAS ]
(±)-methyl 2-((5-(allyloxymethyl)-1-phenylpyrrolidin-2-ylidene)amino)-5-methylbenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%		General procedure: A flame-dried bulb of 250 mL, kept under a nitrogen atmosphere, was loaded with 120 mL of dry dichloromethane and amide (43.9 mmol, 1 equiv). Next, 8.18 mL of POCl3 (87.7 mmol, 2 equiv) was added and the resulting mixture was stirred at room temperature for 24 hours. Afterwards, a solution of amine (46.0 mmol, 1.05 equiv) in dry dichloromethane (45 mL) was added via cannula and the reaction mixture was heated to 35 C for 1-4 days. Then, the reaction mixture was cooled to 0 C, basified with 3-M aqueous NaOH until the pH equaled 10 and subsequently extracted with ethyl acetate (450 mL and 150 mL). The combined organic layers were washed with 300 mL of brine, dried over magnesium sulfate and evaporated in vacuo.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2261 - 2264

55
[ 18595-16-9 ]
(±)-allyl 5-oxo-1-phenylpyrrolidine-2-carboxylate [ No CAS ]
(±)-allyl 5-((2-(methoxycarbonyl)-4-methylphenyl)imino)-1-phenylpyrrolidine-2-carbo-xylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%		General procedure: A flame-dried bulb of 250 mL, kept under a nitrogen atmosphere, was loaded with 120 mL of dry dichloromethane and amide (43.9 mmol, 1 equiv). Next, 8.18 mL of POCl3 (87.7 mmol, 2 equiv) was added and the resulting mixture was stirred at room temperature for 24 hours. Afterwards, a solution of amine (46.0 mmol, 1.05 equiv) in dry dichloromethane (45 mL) was added via cannula and the reaction mixture was heated to 35 C for 1-4 days. Then, the reaction mixture was cooled to 0 C, basified with 3-M aqueous NaOH until the pH equaled 10 and subsequently extracted with ethyl acetate (450 mL and 150 mL). The combined organic layers were washed with 300 mL of brine, dried over magnesium sulfate and evaporated in vacuo.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 2261 - 2264

56
[ 55-22-1 ]
[ 18595-16-9 ]
C₁₅H₁₄N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
Ca. 27%		1.0018 g (8.1374 mmol) of pyridine-4-carboxylic acid was dissolvedin10mL of thionyl chloride and stirred under reflux for 3 h.Then the 1.3420 g (8.1240 mmol) of <strong>[18595-16-9]methyl-2-amino-5-methylbenzoate</strong> dissolved in (30 mL) chloroform was added intothe reaction mixture and heated with stirring under reflux for 6 h.1.4070 g, (2.2280 mmol, yield ca.: 27%, Anal. Calc.C15H15Cl1N2O3 (H2O)0.5 [%]: C, 57.06; H, 5.11; N, 8.87; Found: C,57.24; H, 4.69; N, 8.96) of yellow powder precipitated from themixture and then it was filtered and washed with diethyl ether. Theyellow water-free crystals have grown after recrystallization inEtOH and few days of deposition on air. 1H NMR (600 MHz, CDCl3) delta 12.12 (s, 1H), 8.84 (d, 2H), 8.77 (d, J 8.5 Hz, 1H), 7.90 (d, J 1.9 Hz,1H), 7.87 (d, J 5.9 Hz, 2H), 7.43 (dd, J 8.6, 2.1 Hz, 1H), 3.97 (s, 3H),2.36 (s, 3H). 13C NMR (151 MHz, CDCl3) delta 169.35, 163.51, 150.97,142.13, 138.95, 135.82, 133.15, 131.32, 121.16, 120.61, 115.38, 52.70,20.91. FT-IR (KBr, cm-1): 3434 n(O-H KBr), 3231 n(N-H), 3177, 3113,3032, 2959, 2924, 2849 n(C-H), 1694, 1672 n(C]O), 1607-1435n(ringC]C), 1317-1082 n(C-O) and (C-N) overlapped, 842, 746, 673d(C-H ringC]C)oop.

Reference： [1]Journal of Molecular Structure,2019,vol. 1178,p. 669 - 681

57
[ 98-98-6 ]
[ 18595-16-9 ]
C₁₅H₁₄N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
Ca. 29%		Pyridine-2-carboxylic acid (1.0075 g, 8.1837 mmol) was dissolvedin thionyl chloride (15 mL) with stirring under reflux for 3 h.After evaporation under vacuum an excess of thionyl chloride the<strong>[18595-16-9]methyl-2-amino-5-methylbenzoate</strong> 1.3421 g (8.1246 mmol) wasadded in 35 mL of chloroform into the precipitated acid chloride.The reaction mixture was stirred and refluxed than for 3 h. Afterevaporation of chloroform under vacuum a beige powderprecipitated:(2,1067 g, 2.3861 mmol, yield ca.: 29%, Anal. Calc.C15H14N2O3 (H2O)1.33 [%]: C, 61.22; H, 5.71, N, 9.52; Found: C,61.36; H, 4.92; N, 9.47). The water free beige crystals were obtainedafter recrystallization from 2-propanol. 1H NMR (600 MHz,Acetone) delta 12.80 (s, 1H), 8.83 (d, J 8.5 Hz, 4H), 8.75-8.70 (m, 4H),8.21 (dt, J 7.7, 0.9 Hz, 4H), 8.02 (td, J 7.7, 1.7 Hz, 4H), 7.86 (d,J 2.0 Hz, 4H), 7.61 (ddd, J 7.5, 4.7, 1.2 Hz, 4H), 7.44 (dd, J 8.3,2.5 Hz, 4H), 3.93 (s, 12H), 2.32 (s, 13H). 13C NMR (151 MHz, Acetone)delta 168.36, 163.61, 151.25, 149.49, 139.17, 138.66, 135.66, 133.27,132.00, 127.63, 123.22, 121.20, 117.22, 52.70, 20.63. FT-IR (KBr,cm-1): 3447 n(O-H KBr), 3238 n(N-H), 3095, 3063, 3017, 2952,2922, 2850 n(C-H), 1696, 1675 n(C]O), 1586-1431 n(ringC]C),1296-1088 n(C-O) and (C-N) overlapped, 820, 789, 743, 695d(C-H ringC]C)oop.

Reference： [1]Journal of Molecular Structure,2019,vol. 1178,p. 669 - 681

58
[ 18595-16-9 ]
2-(methoxycarbonyl)-4-methylbenzenediazonium tetrafluoroborate [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2018,vol. 83,p. 14138 - 14145

59
[ 18595-16-9 ]
[ 459-44-9 ]
[ 75-05-8 ]
2,6-dimethyl-3-(p-tolyl)quinazolin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	at 80℃; for 2h;Sealed tube;	General procedure: A mixture of diazonium salt (100mg, 1 eq) and methyl anthranilate (1.1 eq) dissolved in dry nitrile (2mL) was placed in a sealed tube. Reaction mixture was heated to 80C with stirring for 2h. Upon cooling, the reaction mixture was diluted with CH2Cl2 (20mL) followed by an aqueous basic workup with aq. NaHCO3 (5mL). The crude product was purified by column chromatography with the eluent of ethyl acetate/hexane (20%-40% EtOAc:Hexane) to afford the pure product.

Reference： [1]Tetrahedron,2019,vol. 75,p. 791 - 796

60
[ 67-56-1 ]
[ 608-05-9 ]
[ 18595-16-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	With tert.-butylhydroperoxide; caesium carbonate; at 20 - 30℃; for 4h;Sealed tube;	General procedure: A sealed tube was charged with isatin 1 (1a 147 mg, 1.0 mmol), TBHP (70%, 257 mg, 2.0 mmol), and Cs2CO3 (652 mg, 2.0 mmol) at room temperature, and then solvent CH3OH (4 mL) was added. The resulting mixture was stirred at 30 C in a sealed vessel under air after 4 h, then added 50 mL water to the mixture, extracted with CH3COOC2H5 3 times (3 50 mL). The extract was washed with 30%NaCl solution (V/V), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (Petroleum ether/Ethyl acetate =10:1) to yield the desired product 4a as a yellow liquid (93% yield).

Reference： [1]Tetrahedron,2019,vol. 75,p. 1497 - 1503

61
[ 103440-52-4 ]
[ 18595-16-9 ]
C₂₇H₂₇NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.2%	With copper; potassium carbonate; at 180℃; for 48h;Inert atmosphere;	Add 1.65 g (10 mmol) to a 250 mL round bottom flask.<strong>[18595-16-9]2-Amino-5-methylbenzoic acid methyl ester</strong>, 6.07 g (22 mmol)Methyl 2-iodo-5-methylbenzoate, 3.32 g (24 mmol) potassium carbonate,0.26 g (4 mmol) of activated copper powder and 100 mL of o-dichlorobenzene,Degas the reaction system and then protect it with argon.The mixture was heated to 180 C with stirring and the reaction was continued for 72 h. After the reaction is complete,The system was cooled to room temperature, suction filtered under reduced pressure and the residue was washed with dichloromethane.After the filtrate is dried,With dichloromethane:The petroleum ether = 4:1 (volume ratio) eluent was separated and purified on a silica gel column.Obtained a yellow solid 3.38g,The yield was 73.2%.

Reference： [1]Patent: CN109456326,2019,A .Location in patent: Paragraph 0112; 0113; 0114

62
[ 18595-16-9 ]
[ 538-75-0 ]
3-cyclohexyl-2-(cyclohexylamino)-6-methylquinazolin-4(3H)-one [ No CAS ]