Name: 99585-12-3|Methyl 4-chloro-2-methylbenzoate|98%
Brand: Ambeed
SKU: A609463
Price: 20.0 USD
Availability: InStock
Rating: 92 (32 reviews)

Yield	Reaction Conditions	Operation in experiment
	at 45℃; Hydrolysis;

2
[ 7499-07-2 ]
[ 18107-18-1 ]
[ 99585-12-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	In methanol; hexane; dichloromethane at 20℃;	62.A Example 62 2- {4- [3- (5-Chloro-1-oxo-1, 3-dihydro-isoindol-2-ylmethyl)-5-fluoro-phenoxy]-2-methyl- phenoxy}-2-methyl-propionic acid Step A 4-chloro-2-methylbenzoic acid methyl ester; 4-Chloro-2-methylbenzoic acid (3.4 g, 20.0 mmol) is dissolved in a solution of methanol (25 ml) and dichloromethane (200 ml) and tetramethylsilyl diazomethane (15 mL, 30.0 mmol, 2M in hexane) is added dropwise keeping the temperature near rt with some cooling. Reaction is stirred overnight at rt under nitrogen. Water is added, the organic layer is separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure providing the title compound with no purification (3.3 g, 90 %). GC/MS : M- 184 ;'HNMR (400 MHz, CDCl3).

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2005/54176, 2005, A1 Location in patent: Page/Page column 136

3
[ 99585-12-3 ]
[ 145908-29-8 ]

Yield	Reaction Conditions	Operation in experiment
45.8%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane;Heating / reflux;	Compound C (10.86 g, 58.8 mmol, 1.0 eq.) was dissolved in carbon tetrachloride (100 mL), and N-bromosuccinimide (15.7 g, 88.2 mmol., 1.5 eq.) was added followed by benzoylperoxide (0.05 g). The mixture was refluxed overnight. The reaction mixture was then filtered, and the solids were washed with dichloromethane. The combined organic filtrate was concentrated and dried to give compound D (7.1 g, 45.8%). The structure was confirmed by 1H NMR.
45.8%	With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane;Heating / reflux;	Compound C (10.86 g, 58.8 mmol, 1.0 eq.) was dissolved in carbon tetrachloride (100 mL), and N-bromosuccinimide (15.7 g, 88.2 mmol., 1.5 eq.) was added followed by benzoylperoxide (0.05 g). The mixture was refluxed overnight. The reaction mixture was then filtered, and the solids were washed with dichloromethane. The combined organic filtrate was concentrated and dried to give compound D (7.1 g, 45.8%). The structure was confirmed by 1H NMR.
45%	With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane;Heating / reflux;	Step B 2-Bromomethyl-4-chloro-benzoic acid methyl ester; The compound from Step A (1.0 g, 5.4 mmol), N-bromosuccinimide (1.1 g, 6.0 mmol), and benzoylperoxide (catalytic amount) are refluxed overnight in carbon tetrachloride (10 mL) under nitrogen. Upon cooling the solid is removed by filtration and the filtrate is concentrated under reduced pressure. Ether is added, and the mixture is washed with water and brine, and then dried over sodium sulfate, and concentrated under reduced pressure. The remaining solid is triturated with hexane and collected by filtration providing the title compound (0.65 g, 45 %). GC/MS: M-'*'263/264 ; HNMR (400 MHz, CDCl3).

	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In acetic acid tert-butyl ester; at 90℃;	(Step 2) A solution of N-bromosuccinimide (6.33 g), 2,2'-azobis(isobutyronitrile) (0.27 g) and methyl 4-chloro-2-methylbenzoate obtained in Step 1 (5.05 g) in t-butyl acetate (80 ml) was stirred overnight at 90 C. The mixture was allowed to cool to room temperature, poured into aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:hexane=0:1-3:17) to give methyl 4-chloro-2-bromomethylbenzoate (6.05 g) as a white solid. 1H NMR (300 MHz, CDCl3) delta ppm 3.94 (3H, s) 4.91 (2H, s) 7.35 (1H, dd, J=8.4, 2.2 Hz) 7.47 (1H, d, J=2.1 Hz), 7.93 (1H, d, J=8.3 Hz).
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); at 90℃;	Methyl 4-chloro-2-methylbenzoate (25.7 g, 139 mmol) was placed in a flask with t-butyl acetate (400 mL). NBS (32.2 g, 181 mmol) was added followed by AIBN (1.14 g, 6.96 mmol) and the mixture was stirred at 90C overnight. The mixture was partitioned between EtOAcand water. The organic phase was washed with water and brine, dried over Mg504, filtered and the solvent was removed in vacuo. The product was purified by chromatography on silica eluting with 19:1 iso-hexane: EtOAc. The resulting material was triturated in a minimal volume of ice cold iso-hexane and filtered to afford the title compound;1H NMR (400 MHz, DMSO-d6) O 7.90 (1H, d), 7.78 (1H, d), 7.57 (1H, d of d), 5.01 (2H, 5),3.89(3H,s).
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 80℃; for 20h;Inert atmosphere;	Into a 1000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of N2, was placed CC14 (600 ml), methyl 4-chloro-2-methylbenzoate (60 g, (0418) 325mmol), BS (87 g, 487mmol) and BPO (3.15 g, 13.00mmol). The mixture was heated to 80 C for 20 hours . The resulting solution was cooled to room temperature. The mixture was concentrated under vacuum and then purified by HPLC to give methyl 2-(bromomethyl)-4- chlorobenzoate. 1H NMR (300 MHz, CDC13) delta 7.92 (d, J= 8.4 Hz, 1H), 7.47 (d, J= 2.2 Hz, 1H), 7.35 (dd, J= 8.5, 2.2 Hz, 1H), 4.91 (s, 2H), 3.94 (s, 3H).
	With N-Bromosuccinimide; dibenzoyl peroxide; In 1,2-dichloro-ethane; at 80℃; for 12h;	General procedure: A mixture of methyl 3-bromo-2-methylbenzoate (500 mg, 3.3 mmol), NBS (770.4 mg, 4.3 mmol), and di-benzoyl peroxide (BPO, 80.7 mg, 0.3 mmol) in 1,2-dichloroethane (10 mL) was heated at 80 C for 12 h. The reaction mixture was cooled to room temperature, and the precipitated solid was removed by filtration and washed with ethers (10 mL). The filtrate was concentrated in vacuo and the residue was partitioned between 2 N NaHCO3 (15 mL) and ethers (15 mL). The organic layer was separated, dried over NaSO4, filtered and concentrated to give a crude product (683.2 mg, 89.6%), which was used in the next step reaction without further purification.

Reference： [1]Patent: US2005/143348,2005,A1 .Location in patent: Page/Page column 45; 49; 55
[2]Patent: US2005/239838,2005,A1 .Location in patent: Page/Page column 41
[3]Patent: WO2005/54176,2005,A1 .Location in patent: Page/Page column 136
[4]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1628 - 1631
[5]Patent: US2009/270393,2009,A1 .Location in patent: Page/Page column 43-44
[6]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 360 - 365
[7]Patent: WO2015/8230,2015,A1 .Location in patent: Page/Page column 318
[8]Patent: WO2019/94312,2019,A1 .Location in patent: Page/Page column 50; 61
[9]European Journal of Medicinal Chemistry,2019,vol. 180,p. 509 - 523

4
[ 67-56-1 ]
[ 7499-07-2 ]
[ 99585-12-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride at 0 - 20℃; for 65.5h;
94.4%	With thionyl chloride for 5h; Heating / reflux;	1.2; 2; 7 Compound B (10.62 g, 62.3 mmol, 1.0 eq.) was dissolved in methanol (200 mL) and thionyl chloride (11.3 mL, 155.25 mmol, 2.5 eq.) was added slowly. The reaction solution was refluxed for 5 h, the solvent was removed, and the oil was taken up in methylene chloride (200 mL). The organic layer was washed with H2O (3×100 mL), dried over MgSO4, filtered, concentrated, and dried to give compound C (10.86 g, 94.4%). The structure was confirmed by 1H-NMR.
94.4%	With thionyl chloride for 5h; Heating / reflux;	1.2 Compound B (10.62 g, 62.3 mmol, 1.0 eq.) was dissolved in methanol (200 mL) and thionyl chloride (11.3 mL, 155.25 mmol, 2.5 eq.) was added slowly. The reaction solution was refluxed for 5 h, the solvent was removed, and the oil was taken up in methylene chloride (200 mL). The organic layer was washed with H2O (3×100 mL), dried over MgSO4, filtered, concentrated, and dried to give compound C (10.86 g, 94.4%). The structure was confirmed by 1H-NMR.

76.2%	With sulfuric acid Reflux; Inert atmosphere;
	With thionyl chloride for 4h; Heating;
	With sulfuric acid at 10 - 70℃;	32.1 Example 32; methyl2-[(3-carbamoyl-5-chloro-2-iminopyridin-1(2H)-yl)methyl]-4-chlorobenzoate hydrobromide; (Step 1); To a solution of 4-chloro-2-methylbenzoic acid (5.0 g) in methanol (40 ml) was added concentrated sulfuric acid at room temperature. The mixture was stirred at 70° C. for 3 hr, neutralized with 1N sodium hydroxide, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate:hexane=1:19→3:7) to give methyl 4-chloro-2-methylbenzoate (5.05 g) as an oil. 1H NMR (300 MHz, CDCl3) δ ppm 2.58 (3H, s) 3.88 (3H, s) 7.14-7.30 (2H, m) 7.83-7.92 (1H, m).
	With sulfuric acid Reflux;
	With sulfuric acid Reflux;	1: Methyl 4-chloro-2-methylbenzoate 4-Chloro-2-methylbenzoic acid (25 g, 147 mmol) was placed in a flask with dry MeOH (250 mL). Concentrated sulfuric acid (15.62 mL, 293 mmol) was added slowly to the suspensionand the mixture was heated at reflux overnight. The solvent was removed in vacuo and the mixture was partitioned between EtOAc and 1M NaOH. The organic phase was washed with water and brine, dried over MgSO4, filtered and the solvent was removed in vacuo to give the title compound as a light golden oil;1H NMR (400 MHz, DMSO-d6) O 7.82 (1H, d), 7.46 (1H, d), 7.39 (1H, d of d), 3.82 (3H,s),2.50(3H,s).
	With sulfuric acid at 75℃; for 6h; Inert atmosphere;	10.1 Step 1 Into a 1000-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of N2, was placed 4-chloro-2-methylbenzoic acid (60 g, 352 mmol), MeOH (600 ml) and sulfuric acid (37.5 ml, 703mmol). The mixture was heated to 75 °C for 6 hours. The resulting solution was quenched by adding 2L of water and then extracted with 2 x 500 mL of EtOAc. The organic layers were combined. The resulting mixture was washed with 2 x 300mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give methyl 4-chloro-2- methylbenzoate. 1H NMR (300 MHz, CDC13) δ 7.86 (d, J= 8.3 Hz, 1H), 7.29 - 7.14 (m, 2H), 3.89 (s, 3H), 2.59 (s, 3H).

Reference： [1]Kurata, Haruto; Kusumi, Kensuke; Otsuki, Kazuhiro; Suzuki, Ryo; Kurono, Masakuni; Komiya, Takaki; Hagiya, Hiroshi; Mizuno, Hirotaka; Shioya, Hiroki; Ono, Takeji; Takada, Yuka; Maeda, Tatsuo; Matsunaga, Norikazu; Kondo, Tetsu; Tominaga, Sachiko; Nunoya, Ken-Ici; Kiyoshi, Hidekazu; Komeno, Masaharu; Nakade, Shinji; Habashita, Hiromu [Journal of Medicinal Chemistry, 2017, vol. 60, # 23, p. 9508 - 9530]
[2]Current Patent Assignee: ELI LILLY & CO - US2005/143348, 2005, A1 Location in patent: Page/Page column 44-45; 49; 55
[3]Current Patent Assignee: ELI LILLY & CO - US2005/239838, 2005, A1 Location in patent: Page/Page column 40
[4]Aswathanarayanappa, Chandrashekar; Bheemappa, Eswarappa; Bodke, Yadav D.; Krishnegowda, Peethambar S.; Venkata, Srinivas P.; Ningegowda, Raghu [Archiv der Pharmazie, 2013, vol. 346, # 12, p. 922 - 930]
[5]Lee, Hyu Ji; Lim, Soo Jeong; Oh, Seung Jun; Moon, Dae Hyuk; Kim, Dong Jin; Tae, Jinsung; Yoo, Kyung Ho [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 5, p. 1628 - 1631]
[6]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2009/270393, 2009, A1 Location in patent: Page/Page column 43
[7]Nencini, Arianna; Castaldo, Cristiana; Comery, Thomas A.; Dunlop, John; Genesio, Eva; Ghiron, Chiara; Haydar, Simon; Maccari, Laura; Micco, Iolanda; Turlizzi, Elisa; Zanaletti, Riccardo; Zhang, Jean [European Journal of Medicinal Chemistry, 2014, vol. 78, p. 401 - 418]
[8]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2015/8230, 2015, A1 Location in patent: Page/Page column 318
[9]Current Patent Assignee: MERCK & CO INC - WO2019/94312, 2019, A1 Location in patent: Page/Page column 50; 60; 61

5
[ 99585-12-3 ]
[ 925-90-6 ]
[ 190367-33-0 ]

Yield	Reaction Conditions	Operation in experiment
83%	Stage #1: 4-chloro-2-methylbenzoic acid methyl ester; ethylmagnesium bromide With iron(III) acetylacetonate In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; diethyl ether for 0.25h; Stage #2: With hydrogenchloride In tetrahydrofuran; 1-methyl-pyrrolidin-2-one; diethyl ether; water	10.10c Methyl 4-ethyl-2-methylbenzoate 4-Chloro-2-methylbenzoic acid (3 g, 17.6 mmol) was suspended in 12 ml of MeOH with 1 ml of concentrated H2SO4. The mixture was refluxed overnight, MeOH was evaporated and the residue was extracted with EtOAc, dried over MgSO4 filtered and evaporated to give methyl 4-chloro-2-methylbenzoate as a colorless viscous liquid (2.96 g, 92%) that was used in the next step without further purification. The ester (2.96 g, 16 mmol) was, under inert atmosphere, dissolved in THF (100 mL) and NMP (9 mL) and Iron(III) acetylacetonate (318 mg, 0.9 mmol) was added giving a red solution. Then EtMgBr (7 ml of 1M solution in ether) was added dropwise under vigorous stirring. The mixture turned dark brown and then violet and then was stirred for 15 more min. The reaction was diluted with ether and quenched upon the addition of aq. HCl (IM, 10 ml). The crude product was extracted with ether. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The residue was purified on silica gel (30% EtOAc/hexanes) to give methyl 4-ethyl-2-methylbenzoate as an oil (2.37 g, 83%). (1H NMR (500 MHz, CDCl3): δ 1.26 (t, 3H), 2.63 (dd, 2H), 3.9 (s, 3H), 7.1 (b, 2H), 7.85 (d, 1H)).

Reference： [1]Current Patent Assignee: Firmenich International SA - US2006/263411, 2006, A1 Location in patent: Page/Page column 38

6
[ 7499-07-2 ]
[ 99585-12-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With methanol; sulfuric acid Heating / reflux;	10.10c Methyl 4-ethyl-2-methylbenzoate 4-Chloro-2-methylbenzoic acid (3 g, 17.6 mmol) was suspended in 12 ml of MeOH with 1 ml of concentrated H2SO4. The mixture was refluxed overnight, MeOH was evaporated and the residue was extracted with EtOAc, dried over MgSO4 filtered and evaporated to give methyl 4-chloro-2-methylbenzoate as a colorless viscous liquid (2.96 g, 92%) that was used in the next step without further purification. The ester (2.96 g, 16 mmol) was, under inert atmosphere, dissolved in THF (100 mL) and NMP (9 mL) and Iron(III) acetylacetonate (318 mg, 0.9 mmol) was added giving a red solution. Then EtMgBr (7 ml of 1M solution in ether) was added dropwise under vigorous stirring. The mixture turned dark brown and then violet and then was stirred for 15 more min. The reaction was diluted with ether and quenched upon the addition of aq. HCl (IM, 10 ml). The crude product was extracted with ether. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The residue was purified on silica gel (30% EtOAc/hexanes) to give methyl 4-ethyl-2-methylbenzoate as an oil (2.37 g, 83%). (1H NMR (500 MHz, CDCl3): δ 1.26 (t, 3H), 2.63 (dd, 2H), 3.9 (s, 3H), 7.1 (b, 2H), 7.85 (d, 1H)).

Reference： [1]Current Patent Assignee: Firmenich International SA - US2006/263411, 2006, A1 Location in patent: Page/Page column 38

7
[ 99585-12-3 ]
sulfonylated acid [ No CAS ]
methyl 4-chloro-5-chlorosulfonyl-2-methylbenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With chlorosulfonic acid	XX.b Step (b): Step (b): Preparation of methyl 4-chloro-5-chlorosulfonyl-2-methylbenzoate (3) STR31 A mixture of 15.8 g (0.086 mol) of methyl 4-chloro-2-methylbenzoate (2) and 25.8 ml (45.2 g, 0.39 mol) of chlorosulfonic acid was heated to a gentle reflux under nitrogen. After 3 hrs., the mixture was cooled and poured slowly into an ice-water mixture. After stirring for 1 hr., the mixture was filtered and rinsed well with ice cold water. Drying in a vacuum oven (60° C.) gave 17.4 g (0.065 mol, 75% yield) of the sulfonylated acid (off-white crystals). A mixture of 14.5 g of the acid and 2 drops of dimethylformamide in 50 ml of thionyl chloride was heated to reflux under nitrogen. After 11/2 hrs., the solvent was removed under reduced pressure. Methanol (125 ml) was added to residue material and the solution was cooled to 10° C. After 5 hrs., the solid was filtered and airdried, giving 12.8 g of off-white crystals (3); m.p. 94.5° -96° C.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US4585773, 1986, A

8
[ 99585-12-3 ]
[ 1416990-11-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) 2: triethylamine / N,N-dimethyl-formamide

Reference： [1]Ruchelman, Alexander L.; Man, Hon-Wah; Zhang, Weihong; Chen, Roger; Capone, Lori; Kang, Jian; Parton, Anastasia; Corral, Laura; Schafer, Peter H.; Babusis, Darius; Moghaddam, Mehran F.; Tang, Yang; Shirley, Michael A.; Muller, George W. [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 360 - 365]

9
[ 7499-07-2 ]
[ 74-88-4 ]
[ 99585-12-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate

Reference： [1]Ruchelman, Alexander L.; Man, Hon-Wah; Zhang, Weihong; Chen, Roger; Capone, Lori; Kang, Jian; Parton, Anastasia; Corral, Laura; Schafer, Peter H.; Babusis, Darius; Moghaddam, Mehran F.; Tang, Yang; Shirley, Michael A.; Muller, George W. [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 1, p. 360 - 365]

10
[ 67-56-1 ]
[ 40137-29-9 ]
[ 99585-12-3 ]

Reference： [1]RSC Advances,2013,vol. 3,p. 1695 - 1698

11
[ 99585-12-3 ]
5-(4-chloro-2-methylphenyl)-4-[(E)-(2,4-difluorobenzylidene)amino]-4H-1,2,4-triazole-3-thiol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: hydrazine hydrate / ethanol / 8 h / Reflux 2: potassium hydroxide / ethanol / 5 h / 20 °C 3: hydrazine hydrate / 2 h / Reflux 4: sulfuric acid / ethanol / 5 h / Reflux

Reference： [1]Aswathanarayanappa, Chandrashekar; Bheemappa, Eswarappa; Bodke, Yadav D.; Krishnegowda, Peethambar S.; Venkata, Srinivas P.; Ningegowda, Raghu [Archiv der Pharmazie, 2013, vol. 346, # 12, p. 922 - 930]

12
[ 99585-12-3 ]
2-((E)-[3-(4-chloro-2-methylphenyl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]imino}methyl)benzene-1,4-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: hydrazine hydrate / ethanol / 8 h / Reflux 2: potassium hydroxide / ethanol / 5 h / 20 °C 3: hydrazine hydrate / 2 h / Reflux 4: sulfuric acid / ethanol / 5 h / Reflux

Reference： [1]Aswathanarayanappa, Chandrashekar; Bheemappa, Eswarappa; Bodke, Yadav D.; Krishnegowda, Peethambar S.; Venkata, Srinivas P.; Ningegowda, Raghu [Archiv der Pharmazie, 2013, vol. 346, # 12, p. 922 - 930]

13
[ 99585-12-3 ]
5-(4-chloro-2-methylphenyl)-4-[(E)-(2-fluorobenzylidene)amino]-4H-1,2,4-triazole-3-thiol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: hydrazine hydrate / ethanol / 8 h / Reflux 2: potassium hydroxide / ethanol / 5 h / 20 °C 3: hydrazine hydrate / 2 h / Reflux 4: sulfuric acid / ethanol / 5 h / Reflux

Reference： [1]Aswathanarayanappa, Chandrashekar; Bheemappa, Eswarappa; Bodke, Yadav D.; Krishnegowda, Peethambar S.; Venkata, Srinivas P.; Ningegowda, Raghu [Archiv der Pharmazie, 2013, vol. 346, # 12, p. 922 - 930]

14
[ 99585-12-3 ]
5-(4-chloro-2-methylphenyl)-4-[(E)-(3-fluorobenzylidene)amino]-4H-1,2,4-triazole-3-thiol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: hydrazine hydrate / ethanol / 8 h / Reflux 2: potassium hydroxide / ethanol / 5 h / 20 °C 3: hydrazine hydrate / 2 h / Reflux 4: sulfuric acid / ethanol / 5 h / Reflux

Reference： [1]Aswathanarayanappa, Chandrashekar; Bheemappa, Eswarappa; Bodke, Yadav D.; Krishnegowda, Peethambar S.; Venkata, Srinivas P.; Ningegowda, Raghu [Archiv der Pharmazie, 2013, vol. 346, # 12, p. 922 - 930]

15
[ 99585-12-3 ]
4-bromo-2-[(E)-[3-(4-chloro-2-methylphenyl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]imino}methyl]phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: hydrazine hydrate / ethanol / 8 h / Reflux 2: potassium hydroxide / ethanol / 5 h / 20 °C 3: hydrazine hydrate / 2 h / Reflux 4: sulfuric acid / ethanol / 5 h / Reflux

Reference： [1]Aswathanarayanappa, Chandrashekar; Bheemappa, Eswarappa; Bodke, Yadav D.; Krishnegowda, Peethambar S.; Venkata, Srinivas P.; Ningegowda, Raghu [Archiv der Pharmazie, 2013, vol. 346, # 12, p. 922 - 930]

16
[ 99585-12-3 ]
5-(4-chloro-2-methylphenyl)-4-{(E)-[3-fluoro-4-(trifluoromethyl)benzylidene]amino}-4H-1,2,4-triazole-3-thiol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: hydrazine hydrate / ethanol / 8 h / Reflux 2: potassium hydroxide / ethanol / 5 h / 20 °C 3: hydrazine hydrate / 2 h / Reflux 4: sulfuric acid / ethanol / 5 h / Reflux

Reference： [1]Aswathanarayanappa, Chandrashekar; Bheemappa, Eswarappa; Bodke, Yadav D.; Krishnegowda, Peethambar S.; Venkata, Srinivas P.; Ningegowda, Raghu [Archiv der Pharmazie, 2013, vol. 346, # 12, p. 922 - 930]

17
[ 99585-12-3 ]
5-(4-chloro-2-methylphenyl)-4-[(E)-(4-methoxybenzylidene)amino]-4H-1,2,4-triazole-3-thiol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: hydrazine hydrate / ethanol / 8 h / Reflux 2: potassium hydroxide / ethanol / 5 h / 20 °C 3: hydrazine hydrate / 2 h / Reflux 4: sulfuric acid / ethanol / 5 h / Reflux

Reference： [1]Aswathanarayanappa, Chandrashekar; Bheemappa, Eswarappa; Bodke, Yadav D.; Krishnegowda, Peethambar S.; Venkata, Srinivas P.; Ningegowda, Raghu [Archiv der Pharmazie, 2013, vol. 346, # 12, p. 922 - 930]

18
[ 99585-12-3 ]
4-[(E)-benzylideneamino]-5-(4-chloro-2-methylphenyl)-4H-1,2,4-triazole-3-thiol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: hydrazine hydrate / ethanol / 8 h / Reflux 2: potassium hydroxide / ethanol / 5 h / 20 °C 3: hydrazine hydrate / 2 h / Reflux 4: sulfuric acid / ethanol / 5 h / Reflux

Reference： [1]Aswathanarayanappa, Chandrashekar; Bheemappa, Eswarappa; Bodke, Yadav D.; Krishnegowda, Peethambar S.; Venkata, Srinivas P.; Ningegowda, Raghu [Archiv der Pharmazie, 2013, vol. 346, # 12, p. 922 - 930]

19
[ 99585-12-3 ]
4-[(E)-[3-(4-chloro-2-methylphenyl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]imino}methyl]phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: hydrazine hydrate / ethanol / 8 h / Reflux 2: potassium hydroxide / ethanol / 5 h / 20 °C 3: hydrazine hydrate / 2 h / Reflux 4: sulfuric acid / ethanol / 5 h / Reflux

Reference： [1]Aswathanarayanappa, Chandrashekar; Bheemappa, Eswarappa; Bodke, Yadav D.; Krishnegowda, Peethambar S.; Venkata, Srinivas P.; Ningegowda, Raghu [Archiv der Pharmazie, 2013, vol. 346, # 12, p. 922 - 930]

20
[ 99585-12-3 ]
[ 75319-02-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine hydrate In ethanol for 8h; Reflux;
	With hydrazine hydrate In methanol at 80℃; for 4h;	preparation of intermediate 2 General procedure: At the 250 cm3double-mouth bottle, 13.5 mmol of themethyl benzoate derivatives was added to 100 cm3of methanol,added 6.75 cm3of hydrazine hydrate (108 mmol) tothe reaction mixture slowly. After that warming to 80 °Cand reflux for 4 h until the reaction was completed, thenconcentrated under reducing pressure to remove methanol,filtering and drying to get white solid 2.

Reference： [1]Aswathanarayanappa, Chandrashekar; Bheemappa, Eswarappa; Bodke, Yadav D.; Krishnegowda, Peethambar S.; Venkata, Srinivas P.; Ningegowda, Raghu [Archiv der Pharmazie, 2013, vol. 346, # 12, p. 922 - 930]
[2]Li, Yitao; Yao, Wenqiang; Lin, Jian; Gao, Guoliang; Huang, Chang; Wu, Yang [Monatshefte fur Chemie, 2021, vol. 152, # 1, p. 121 - 135]

21
[ 99585-12-3 ]
[ 1003849-06-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: hydrazine hydrate / ethanol / 8 h / Reflux 2: potassium hydroxide / ethanol / 5 h / 20 °C

Reference： [1]Aswathanarayanappa, Chandrashekar; Bheemappa, Eswarappa; Bodke, Yadav D.; Krishnegowda, Peethambar S.; Venkata, Srinivas P.; Ningegowda, Raghu [Archiv der Pharmazie, 2013, vol. 346, # 12, p. 922 - 930]

22
[ 99585-12-3 ]
[ 1003849-08-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: hydrazine hydrate / ethanol / 8 h / Reflux 2: potassium hydroxide / ethanol / 5 h / 20 °C 3: hydrazine hydrate / 2 h / Reflux

Reference： [1]Aswathanarayanappa, Chandrashekar; Bheemappa, Eswarappa; Bodke, Yadav D.; Krishnegowda, Peethambar S.; Venkata, Srinivas P.; Ningegowda, Raghu [Archiv der Pharmazie, 2013, vol. 346, # 12, p. 922 - 930]

23
[ 99585-12-3 ]
[ 75-05-8 ]
[ 1205055-78-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hydride In tetrahydrofuran at 0 - 80℃; for 16h;	1 Int-36: 3-(4-Chloro-2-methylphenyl)-1-methyl-1H-pyrazol-5-amine NaH (60% oil dispersion, 0.87 g, 21.66 mmol) was added to a stirred solution of methyl 4-chloro-2-methylbenzoate (2.0 g, 10.83 mmol) in anhydrous THF (20 mL) at 0°C, followed by dropwise addition of MeCN (2.22 g, 54.2 mmol) at 80°C. The resulting mixture was heated at 80°C for 16 hrs. Then the reaction mixture was diluted with H2O (100 mL), acidified with sat. aq. NH4Cl solution and extracted with EtOAc (3 x 100 mL). Combined organic layers were washed with H2O and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 3-(4-chloro-2-methylphenyl)-3-oxopropanenitrile (2.0 g, 95%) as a yellow solid. 0.45 g of 3-(4-chloro-2-methylphenyl)-3-oxopropanenitrile (0.45 g, 2.32 mmol) was dissolved in 4 mL of MeOH and methyl hydrazine (0.21 g, 4.65 mmol) was added. The resulting mixture was heated at 120°C for 1 hr under microwave. Then MeOH was removed in vacuo and the crude product was purified by reverse phase column chromatography to afford 0.17 g of Int-36 as a yellow solid in 33% yield.
	With n-butyllithium In hexane; toluene; acetonitrile at -78 - 20℃; for 0.333333h; Inert atmosphere;	General procedure: To a solution of dry acetonitrile in toluene (1mmol/mL, 5eq.) cooled down to-78°C under nitrogen, a solution of n-butyllithium in n-hexane (1.6N, 3.5eq) was added dropwise. The mixture was stirred at-78°C for 20min and then a solution of the desired methyl ester (29b-d) in toluene (0.75mmol/mL, 1eq.) was added and the reaction allowed reaching room temperature. Upon reaction completion, after about 20min, the mixture was cooled down to 0°C and HCl 2N was added to pH 2. The organic phase was recovered, dried over Na2SO4 and concentrated under reduced pressure, affording β-ketonitrile (30b-d) which was used without further purification. To a solution of the β-ketonitrile (30b-d) (7.5mmoL), in absolute EtOH (15mL) hydrazine monohydrate (0.44mL, 9.0mmol) was added and the reaction was heated at reflux for 18h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in DCM and washed with water.The organic phase was concentrated under reduced pressure to give a product that, if not enough pure, was purified by SiO2 column.

Reference： [1]Current Patent Assignee: ANTIDOTE IP HOLDINGS - WO2020/231739, 2020, A2 Location in patent: Paragraph 0233
[2]Nencini, Arianna; Castaldo, Cristiana; Comery, Thomas A.; Dunlop, John; Genesio, Eva; Ghiron, Chiara; Haydar, Simon; Maccari, Laura; Micco, Iolanda; Turlizzi, Elisa; Zanaletti, Riccardo; Zhang, Jean [European Journal of Medicinal Chemistry, 2014, vol. 78, p. 401 - 418]

24
[ 99585-12-3 ]
[ 1040720-97-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: n-butyllithium / acetonitrile; toluene; hexane / 0.33 h / -78 - 20 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 18 h / Reflux 3: 1,2-dichloro-ethane / 10 h / 50 °C

Reference： [1]Nencini, Arianna; Castaldo, Cristiana; Comery, Thomas A.; Dunlop, John; Genesio, Eva; Ghiron, Chiara; Haydar, Simon; Maccari, Laura; Micco, Iolanda; Turlizzi, Elisa; Zanaletti, Riccardo; Zhang, Jean [European Journal of Medicinal Chemistry, 2014, vol. 78, p. 401 - 418]

25
[ 99585-12-3 ]
[ 1040721-09-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: n-butyllithium / acetonitrile; toluene; hexane / 0.33 h / -78 - 20 °C / Inert atmosphere 2.1: hydrazine hydrate / ethanol / 18 h / Reflux 3.1: 1,2-dichloro-ethane / 10 h / 50 °C 3.2: 0.17 h

Reference： [1]Nencini, Arianna; Castaldo, Cristiana; Comery, Thomas A.; Dunlop, John; Genesio, Eva; Ghiron, Chiara; Haydar, Simon; Maccari, Laura; Micco, Iolanda; Turlizzi, Elisa; Zanaletti, Riccardo; Zhang, Jean [European Journal of Medicinal Chemistry, 2014, vol. 78, p. 401 - 418]

26
[ 99585-12-3 ]
[ 1608129-76-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: n-butyllithium / acetonitrile; toluene; hexane / 0.33 h / -78 - 20 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 18 h / Reflux 3: potassium hydroxide / water; dichloromethane / 48 h / 20 °C

Reference： [1]Nencini, Arianna; Castaldo, Cristiana; Comery, Thomas A.; Dunlop, John; Genesio, Eva; Ghiron, Chiara; Haydar, Simon; Maccari, Laura; Micco, Iolanda; Turlizzi, Elisa; Zanaletti, Riccardo; Zhang, Jean [European Journal of Medicinal Chemistry, 2014, vol. 78, p. 401 - 418]

27
[ 99585-12-3 ]
[ 1608129-65-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: n-butyllithium / acetonitrile; toluene; hexane / 0.33 h / -78 - 20 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 18 h / Reflux 3: potassium hydroxide / water; dichloromethane / 48 h / 20 °C 4: sodium hydroxide / water; dichloromethane / 48 h / 0 - 20 °C 5: 1,4-dioxane / 6 h / 60 °C

Reference： [1]Nencini, Arianna; Castaldo, Cristiana; Comery, Thomas A.; Dunlop, John; Genesio, Eva; Ghiron, Chiara; Haydar, Simon; Maccari, Laura; Micco, Iolanda; Turlizzi, Elisa; Zanaletti, Riccardo; Zhang, Jean [European Journal of Medicinal Chemistry, 2014, vol. 78, p. 401 - 418]

28
[ 99585-12-3 ]
[ 1608129-80-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: n-butyllithium / acetonitrile; toluene; hexane / 0.33 h / -78 - 20 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 18 h / Reflux 3: potassium hydroxide / water; dichloromethane / 48 h / 20 °C 4: sodium hydroxide / water; dichloromethane / 48 h / 0 - 20 °C

Reference： [1]Nencini, Arianna; Castaldo, Cristiana; Comery, Thomas A.; Dunlop, John; Genesio, Eva; Ghiron, Chiara; Haydar, Simon; Maccari, Laura; Micco, Iolanda; Turlizzi, Elisa; Zanaletti, Riccardo; Zhang, Jean [European Journal of Medicinal Chemistry, 2014, vol. 78, p. 401 - 418]

29
[ 99585-12-3 ]
[ 1040724-41-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: n-butyllithium / acetonitrile; toluene; hexane / 0.33 h / -78 - 20 °C / Inert atmosphere 2: hydrazine hydrate / ethanol / 18 h / Reflux

Reference： [1]Nencini, Arianna; Castaldo, Cristiana; Comery, Thomas A.; Dunlop, John; Genesio, Eva; Ghiron, Chiara; Haydar, Simon; Maccari, Laura; Micco, Iolanda; Turlizzi, Elisa; Zanaletti, Riccardo; Zhang, Jean [European Journal of Medicinal Chemistry, 2014, vol. 78, p. 401 - 418]

30
[ 99585-12-3 ]
4-chloro-2-((5-methyl-2H-tetrazol-2-yl)methyl)benzyl 1H-imidazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) / 90 °C 2: potassium carbonate / N,N-dimethyl-formamide / 20 °C 3: sodium hydroxide / methanol / 20 °C 4: borane-THF / tetrahydrofuran / 2 h / 50 °C 5: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 2 h / 20 °C