Name: 128455-62-9|5-Chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde|98%
Brand: Ambeed
SKU: A883399
Price: 7.0 USD
Availability: InStock
Rating: 92 (30 reviews)

1
[ 128455-62-9 ]
[ 128455-63-0 ]

Yield	Reaction Conditions	Operation in experiment
90.3%	With sodium chlorite; sodium dihydrogenphosphate; 2-methyl-but-2-ene In water; <i>tert</i>-butyl alcohol at 20℃; for 14h;	7.1; 43.1 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (Compound I-7B) Add the compound 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (700mg, 3.30mmol) to tert-butanol (20mL) and water (5mL) at room temperature Add 2-methyl-2-butene (1.80 g, 25.7 mmol), sodium chlorite (1.48 g, 16.4 mmol), sodium dihydrogen phosphate (3.10 g, 25.8 mmol), and stir at room temperature for 14 hours. Dilute with water (50mL), extract with ethyl acetate (30mL×3), separate, combine the organic phases, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate to obtain a colorless liquid crude residue, which is separated by a silica gel column Purification (petroleum ether: ethyl acetate (V/V) = 1:1) to obtain a colorless solid 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (compound I-7B) (680 mg, yield 90.3%).
80%	With sodium hydroxide; dihydrogen peroxide In water at 40 - 50℃; for 2h;	5 EXAMPLE 5 EXAMPLE 5 10 g of 5-chloro-1-methyl-3-trifluoromethylpyrazol-4-carboaldehyde was added to an aqueous solution of 5 g of sodium hydroxide (2 equivalents to the amount of the aldehyde) in 50 ml of water.While stirring the resulting solution vigorously, 34.4 g of 35% hydrogen peroxide was added, in eight portions, over 1.5 hours at 40° C. to 50° C. After the completion of the dropping, the solution was stirred for 30 minutes, cooled to 15° C. and adjusted PH to 1 with concentrated hydrochloric acid.The crystals obtained were sufficiently washed with water and dissolved in ether.The ether solution was dried over anhydrous magnesium sulfate and further treated with active carbon.Ether was distilled out under reduced pressure to give 8.6 g of the target compound.Melting point: 197.5-199.5° C. Yield: 80.0%. Applicability in Industry The 4-cyanoacetylpyrazoles of the present invention, represented by Formula (1), are useful as intermediates for producing agricultural chemicals and drugs, for example for producing insecticides and acarcides described in Japanese Patent Laid-open No. Hei 11-269173 and patent application ser. No. 2000-178334. According to the present invention, 4-cyanoacetylpyrazoles useful as intermediates for producing compounds with insecticidal and acaricidal activities can be produced by an industrially advantageous process using easily available starting materials. The present invention does not use at all reaction solvents, such as toluene or ethylene dichloride, heavy metal oxidizing agents or heavy metal catalysts, which known processes have adopted.Use of water as a reaction solvent and only hydrogen peroxide as an oxidizing agent allows an industrially advantageous process to produce substituted pyrazole-4-carboxylic acids.
72.5%	With potassium permanganate; water at 70 - 80℃; for 8h;	1.3 Preparation of 1-methyl-3-trifluoromethyl-5-chloro-4-pyrazole acid intermediates: In a 500 mL three-necked flask, add 0.05 mol of 1-methyl-3-trifluoromethyl-5-chloro-4-pyrazole and 100 mLWater, slowly dropping 0.075 mol KMnO4 200 mL of aqueous solution for oxidation. Drop complete, heating to 70 ~ 80° C for 8 h. After slow cooling, the pH of the reaction solution was adjusted to alkaline with 10% KOH solution, and the insolubility was removed by filtration Acidification of the filtrate with concentrated hydrochloric acid, precipitation of white solid, filtration, washing, drying, in a white solid; yield: 72.5%.

70.2%	With potassium permanganate In water; acetone at 60 - 80℃; for 4h;
63%	With potassium hydroxide; potassium permanganate In water at 60℃; for 1h;
58%	Stage #1: 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde With sodium hydroxide; dihydrogen peroxide In water at 20℃; for 0.266667h; Stage #2: With hydrogenchloride In water	49.1 To awell stirred solution of 5-chloro-l-methyl-3-(trifiuoromethyl)-4-pyrazolecarboxaldehyde (1.01 g, 4.75 mmol) and sodium hydroxide (500 mg, 12.5 mmol) in water (5 mL) was added hydrogen peroxide (3.44 g of a 30 wt. % solution in water) at rt. The reaction mixture was stirred for 16 minutes then pH was adjusted to 1 with cone. HCl causing precipitation of the product. The product was collected via vacuum filtration, washed with water and dissolved in diethyl ether. The organic solution was dried over Na2SO4, filtered and concentrated under vacuum to afford 627 mg (58%) of 5-chloro-l-methyl-3- trifluoromethyl-lH-pyrazole-4-carboxylic acid as a white solid.
	With potassium permanganate
	With potassium permanganate In water at 80℃;

Reference： [1]Current Patent Assignee: HUMANWELL HEALTHCARE (GROUP) CO., LTD.; HUBEI BIO PHARMACEUTICAL INDUSTRIAL TECH INSTITUTE - CN113354585, 2021, A Location in patent: Paragraph 0275; 0280-0285; 1144; 1149-1154
[2]Current Patent Assignee: NIPPON SODA COMPANY LIMITED - US2004/19221, 2004, A1 Location in patent: Page 7
[3]Current Patent Assignee: GUIZHOU UNIVERSITY - CN103951663, 2016, B Location in patent: Paragraph 0091; 0096; 0097
[4]Si, Wei-Jie; Wang, Xiao-Bin; Chen, Min; Wang, Meng-Qi; Lu, Ai-Min; Yang, Chun-Long [New Journal of Chemistry, 2019, vol. 43, # 7, p. 3000 - 3010]
[5]Lee, Len F.; Schleppnik, Francis M.; Schneider, Ronald W.; Campbell, Dwane H. [Journal of Heterocyclic Chemistry, 1990, vol. 27, # 2, p. 243 - 245]
[6]Current Patent Assignee: KALYPSYS, INC. - WO2007/84868, 2007, A2 Location in patent: Page/Page column 39
[7]Location in patent: scheme or table Wu, Lintao; Song, Baoan; Bhadury, Pinaki S.; Yang, Song; Hu, Deyu; Jin, Linhong [Journal of Heterocyclic Chemistry, 2011, vol. 48, # 2, p. 389 - 396]
[8]Chen, Min; Li, Guohua; Lu, Aimin; Qiu, Lingling; Wang, An; Wang, Xiaobin; Xue, Wei; Yang, Chunlong [Journal of Agricultural and Food Chemistry, 2020, vol. 68, # 49, p. 14426 - 14437]

2
[ 122431-37-2 ]
[ 33513-42-7 ]
[ 128455-62-9 ]

Yield	Reaction Conditions	Operation in experiment
79.4%	Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 4 - 5℃; Stage #2: 2-methyl-5-trifluoromethyl-2H-pyrazol-3-ol for 1h; Reflux;	1.b b) Preparation of 5-chloro-l-methyl-3- (trifluoro- methyl ) -lff-pyrazole-4-carbaldehyde [compound having general formula (V) ] 24.3 ml (265.62 mmoles) of phosphorous oxychloride were added dropwise to 7 ml (88.54 mmoles) of N,N- dimethylformamide, maintaining a temperature of about 4-5°C with an ice bath; 7.35g (44.27 mmoles) of 1- methyl-3- (trifluoromethyl) -lJJ-pyrazol-5-ol (IVa) were then added at room temperature. The mixture was heated to reflux temperature for 1 hour . After control in GC-MS and LC-MS, the mixture was carefully poured into water and ice; the aqueous phase was extracted three times with chloroform. The organic phases were combined and washed with a saturated solution of NaHCC>3, water and a saturated solution of NaCl. After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 7.4 g of the desired product were obtained (34.9 mmoles) as a brown solid. Yield 79.4%. LC-MS [M+H] = 213.
79.6%	Stage #1: N,N-dimethyl-formamide With trichlorophosphate at -5 - 20℃; for 1h; Stage #2: 2-methyl-5-trifluoromethyl-2H-pyrazol-3-ol at 55 - 100℃; for 7h;
73.4%	With trichlorophosphate at 0 - 20℃; for 1h; Heating / reflux;	2 (Reference Example 2)Production of 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-carboaldehyde (Reference Example 2) Production of 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-carboaldehyde 360 g (2.31 M) of phosphorus oxychloride was added to 60.0 g (0.76 M) of N,N-dimethylformamide with ice-cooling.. Thereto was added, at room temperature, 64.0 g (0.385 M) of 1-methyl-3-trifluoromethyl-1H-pyrazol-5-ol.. The mixture was heated and refluxed for 1 hour to give rise to a reaction.. After the completion of the reaction, the reaction mixture was poured into water with ice-cooling, and extraction with chloroform was conducted.. The resulting organic layer was washed with an aqueous sodium hydrogencarbonate solution and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate.. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein.. The residue was purified by silica gel column chromatography (eluding solvent: hexane/ethyl acetate mixed solvent) to obtain 60.4 g (yield: 73.4%) of white crystals of 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.1H-NMR [CDCl3/TMS, δ (ppm)]: 9.96 (1H,d), 3.96 (3H,s)

51%	With trichlorophosphate In 1,2-dichloro-ethane at 20 - 80℃; for 4h;	3.2 To a well stirred 00C solution of DMF (8.78 mL, 120 mmol) and 1,2-dichlorocthanc (60 mL) was added phosphorus oxychloride (11.2 mL, 120 mmol) under nitrogen. The resulting suspension was warmed to rt and l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-ol (5.00 g, 30.0 mmol) was added. The mixture was heated to 80 0C for 4 h then cooled to rt. The solution was poured directly into ice-water and extracted with ethyl acetate (2 x 200 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum to afford an oily residue. The material was purified by column chromatography (DCM to 9:1 DCM/MeOH) to afford 3.23 g (51%) of 5-chloro-l-methyl-3- trifluoromethyl-4-pyrazolecarboxaldehyde as a white solid.
40%	With trichlorophosphate at 110℃; for 16h;
	With trichlorophosphate at 80℃; for 12h;

Reference： [1]Current Patent Assignee: INTESA SANPAOLO - WO2016/142918, 2016, A1 Location in patent: Page/Page column 29-30
[2]Si, Wei-Jie; Wang, Xiao-Bin; Chen, Min; Wang, Meng-Qi; Lu, Ai-Min; Yang, Chun-Long [New Journal of Chemistry, 2019, vol. 43, # 7, p. 3000 - 3010]
[3]Current Patent Assignee: KUMIAI CHEMICAL INDUSTRY CO LTD - EP1405853, 2004, A1 Location in patent: Page 83-84
[4]Current Patent Assignee: KALYPSYS, INC. - WO2007/84868, 2007, A2 Location in patent: Page/Page column 26-27
[5]Lee, Len F.; Schleppnik, Francis M.; Schneider, Ronald W.; Campbell, Dwane H. [Journal of Heterocyclic Chemistry, 1990, vol. 27, # 2, p. 243 - 245]
[6]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

3
[ 128455-62-9 ]
[ 735316-45-7 ]
Biogen-34 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde; 2-furan-2-yl-5-piperazin-1-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine With acetic acid In dichloromethane at 20℃; for 0.5h; Stage #2: With sodium tris(acetoxy)borohydride In dichloromethane at 20℃; for 18h;

Reference： [1]Vu, Chi B.; Peng, Bo; Kumaravel, Gnanasambandam; Smits, Glenn; Jin, Xiaowei; Phadke, Deepali; Engber, Thomas; Huang, Carol; Reilly, Jennifer; Tam, Stacy; Grant, Donna; Hetu, Gregg; Chen, Liqing; Zhang, Jianbo; Petter, Russell C. [Journal of Medicinal Chemistry, 2004, vol. 47, # 17, p. 4291 - 4299]

4
[ 128455-62-9 ]
2-furan-2-yl-N⁵-(octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine [ No CAS ]
(7RS,9aSR)-N⁵-[2-(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)octahydropyrido[1,2-a]pyrazin-7-ylmethyl]-2-furan-2-yl[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃;

Reference： [1]Peng, Hairuo; Kumaravel, Gnanasambandam; Yao, Gang; Sha, Li; Wang, Joy; Van Vlijmen, Herman; Bohnert, Tonika; Huang, Carol; Vu, Chi B.; Ensinger, Carol L.; Chang, Hexi; Engber, Thomas M.; Whalley, Eric T.; Petter, Russell C. [Journal of Medicinal Chemistry, 2004, vol. 47, # 25, p. 6218 - 6229]

5
[ 6258-63-5 ]
[ 128455-62-9 ]
1-methyl-5-(thiophen-2-ylmethylsulfanyl)-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dimethyl sulfoxide at 40℃; for 12h;

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

6
[ 38212-33-8 ]
[ 128455-62-9 ]
5-[4-(4-chloro-phenyl)-piperazin-1-yl]-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In N,N-dimethyl-formamide at 100℃; for 12h;

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

7
[ 39718-00-8 ]
[ 128455-62-9 ]
[ 321533-90-8 ]

Yield	Reaction Conditions	Operation in experiment
96%	With triethylamine In 1,2-dichloro-ethane at 20 - 80℃; for 14h;	3.3 To a well stirred solution of 5-chloro-l-methyl-3-trifluoromethyl-4-pyrazolecarboxaldehyde (3.20 g, 15.1 mmol) and 2-chlorobenzenemethanethiol (3.58 g, 22.6 mmol) in 1,2-dichloroethane (64 mL) was added triethylamine (4.20 mL, 30.1 mmol) at rt under nitrogen. The reaction mixture was heated to 80 0C for 14 h then cooled to rt. The reaction mixture as concentrated under vacuum to an oil and purified by column chromatography (hexanes to 1:1 hexanes/EtOAc) to afford 4.82 g (96%) of 5-(2- chloroben2ylsulfanyl)-l-methyl-3-trifluoromethyl-lH-pyrazole-4-carboxaldehyde as a white solid.
	With triethylamine In dimethyl sulfoxide at 40℃; for 12h;

Reference： [1]Current Patent Assignee: KALYPSYS, INC. - WO2007/84868, 2007, A2 Location in patent: Page/Page column 27
[2]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

8
[ 49543-63-7 ]
[ 128455-62-9 ]
5-(4-tert-butyl-benzylsulfanyl)-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dimethyl sulfoxide at 40℃; for 12h;

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

9
[ 128455-62-9 ]
[ 6258-60-2 ]
5-(4-methoxy-benzylsulfanyl)-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dimethyl sulfoxide at 40℃; for 12h;

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

10
[ 128455-62-9 ]
[ 108-98-5 ]
1-methyl-5-phenylsulfanyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dimethyl sulfoxide at 40℃; for 12h;

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

11
[ 128455-62-9 ]
[ 100-53-8 ]
[ 929634-62-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dimethyl sulfoxide at 40℃; for 12h;

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

12
[ 128455-62-9 ]
[ 106-54-7 ]
5-(4-chloro-phenylsulfanyl)-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dimethyl sulfoxide at 40℃; for 12h;

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

13
[ 128455-62-9 ]
[ 6258-66-8 ]
5-(4-chloro-benzylsulfanyl)-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dimethyl sulfoxide at 40℃; for 12h;

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

14
[ 128455-62-9 ]
5-(1-methyl-5-phenylsulfanyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylene)-2-thioxo-thiazolidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Et₃N / dimethylsulfoxide / 12 h / 40 °C 2: β-alanine; acetic acid / 12 h / 110 °C

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

15
[ 128455-62-9 ]
5-[1-methyl-5-(thiophen-2-ylmethylsulfanyl)-3-trifluoromethyl-1H-pyrazol-4-ylmethylene]-2-thioxo-thiazolidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Et₃N / dimethylsulfoxide / 12 h / 40 °C 2: β-alanine; acetic acid / 12 h / 110 °C

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

16
[ 128455-62-9 ]
5-(5-benzylsulfanyl-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylene)-2-thioxo-thiazolidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Et₃N / dimethylsulfoxide / 12 h / 40 °C 2: β-alanine; acetic acid / 12 h / 110 °C

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

17
[ 128455-62-9 ]
5-[5-(4-chloro-phenylsulfanyl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylene]-2-thioxo-thiazolidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Et₃N / dimethylsulfoxide / 12 h / 40 °C 2: β-alanine; acetic acid / 12 h / 110 °C

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

18
[ 128455-62-9 ]
5-[5-(2-chloro-benzylsulfanyl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylene]-2-thioxo-thiazolidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Et₃N / dimethylsulfoxide / 12 h / 40 °C 2: β-alanine; acetic acid / 12 h / 110 °C

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

19
[ 128455-62-9 ]
5-[5-(4-chloro-benzylsulfanyl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylene]-2-thioxo-thiazolidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Et₃N / dimethylsulfoxide / 12 h / 40 °C 2: β-alanine; acetic acid / 12 h / 110 °C

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

20
[ 128455-62-9 ]
5-[5-(4-methoxy-benzylsulfanyl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylene]-2-thioxo-thiazolidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Et₃N / dimethylsulfoxide / 12 h / 40 °C 2: β-alanine; acetic acid / 12 h / 110 °C

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

21
[ 128455-62-9 ]
5-[5-(4-tert-butyl-benzylsulfanyl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylene]-2-thioxo-thiazolidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Et₃N / dimethylsulfoxide / 12 h / 40 °C 2: β-alanine; acetic acid / 12 h / 110 °C

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

22
[ 128455-62-9 ]
5-{5-[4-(4-chloro-phenyl)-piperazin-1-yl]-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylene}-2-thioxo-thiazolidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Et₃N / dimethylformamide / 12 h / 100 °C 2: β-alanine; acetic acid / 12 h / 110 °C

Reference： [1]Gilbert, Adam M.; Bursavich, Matthew G.; Lombardi, Sabrina; Georgiadis, Katy E.; Reifenberg, Erica; Flannery, Carl R.; Morris, Elisabeth A. [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 5, p. 1189 - 1192]

23
[ 128455-62-9 ]
[ 282523-11-9 ]

Yield	Reaction Conditions	Operation in experiment
82.2%	With sodium tetrahydroborate In methanol at 0 - 20℃; for 2h;	3 (Reference Example 3)production of (5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol (Reference Example 3) production of (5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol A solution of 10.0 g (47.0 mmoles) of 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 100 ml of methanol was cooled to 0°C. Thereto was gradually added 2.1 g (56.5 mmoles) of sodium borohydride.. The mixture was stirred at room temperature for 2 hours to give rise to a reaction.. After the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted.. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate.. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein, to obtain 8.3 g (yield: 82.2%) of (5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol.

Reference： [1]Current Patent Assignee: KUMIAI CHEMICAL INDUSTRY CO LTD - EP1405853, 2004, A1 Location in patent: Page 84

24
[ 128455-62-9 ]
[ 447401-88-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium fluoride In dimethyl sulfoxide at 120 - 130℃; for 5h; Inert atmosphere;	1.c c) Preparation of 5-fluoro-1-methyl-3- (trifluoromethyl) -lff-pyrazole-4-carbaldehyde [compound having general formula (VI), R' = F] 4.8 g (82.55 mmoles) of KF were added at room temperature to a solution under nitrogen of 7 g (33.02 mmoles) of 5-chloro-l-methyl-3- (trifluoromethyl) -1H- pyrazole-4-carbaldehyde (V) in 80 ml of dimethylsulfoxide . The mixture was heated to 120-130°C for 5 hours. After control in GC-MS and LC-MS, the mixture was poured into water; the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined and washed with water and with a saturated solution of NaCl . After anhydrification on sodium sulfate, filtration and evaporation of the solvent at reduced pressure, 5.3 g of the desired product were obtained (27.04 mmoles) as a brown oil. Yield 82%. LC-MS [M+H] = 197.
66%	With potassium fluoride In dimethyl sulfoxide at 120 - 140℃; for 5h;	21 (Reference Example 21)Production of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde (Reference Example 21) Production of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde 42.0 g (711.9 mmoles) of potassium fluoride was added into a solution of 60.4 g (282.7 mmoles) of 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 700 ml of dimethyl sulfoxide.. The mixture was stirred at 120 to 140°C for 5 hours to give rise to a reaction.. After confirmation of the completion of the reaction, the reaction mixture was poured into water and extraction with ethyl acetate was conducted.. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate.. The resulting solution was subjected to reduced pressure distillation to remove the solvent contained therein.. The residue was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate mixed solvent) to obtain 36.8 g (yield: 66.0%) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-.
66%	With potassium fluoride In dimethyl sulfoxide at 120 - 140℃; for 5h;	25 Production of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde 42.0 g (711.9 mmoles) of potassium fluoride was added to a solution of 60.4 g (282.7 mmoles) of 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved- in 700 ml of dimethyl sulfoxide. The mixture was stirred at 120 to 140°C for 5 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 36.8 g (yield: 66.0%) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.

66%

With potassium fluoride In dimethyl sulfoxide at 120 - 140℃; for 5h;

25 REFERENCE EXAMPLE 25 Production of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde; 42.0 g (711.9 mmoles) of potassium fluoride was added to a solution of 60.4 g (282.7 mmoles) of 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 700 ml of dimethyl sulfoxide. The mixture was stirred at 120 to 140° C. for 5 hours to give rise to a reaction. After confirmation of the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with water and an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 36.8 g (yield: 66.0%) of 5-fluoro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde.

Reference： [1]Current Patent Assignee: INTESA SANPAOLO - WO2016/142918, 2016, A1 Location in patent: Page/Page column 30-31
[2]Current Patent Assignee: KUMIAI CHEMICAL INDUSTRY CO LTD - EP1405853, 2004, A1 Location in patent: Page 88
[3]Current Patent Assignee: IHARA CHEMICAL INDUSTRY CO LTD - EP1364946, 2003, A1 Location in patent: Page/Page column 195-196
[4]Current Patent Assignee: KUMIAI CHEMICAL INDUSTRY CO LTD - US2005/256004, 2005, A1 Location in patent: Page/Page column 31

25
[ 824937-95-3 ]
[ 128455-62-9 ]
6-[4-(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-piperazin-1-yl]-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%	With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃;	18 Example 18; 6- [4- (5-CHLORO-1-METHYL-3-TRIFLUOROMETHYL-1H-PYRAZOL-4-YLMETHYL)-PIPERAZIN-1- YLJ-2-FURAN-2-YL- [1, 2,4] triazolo [1, 5-A] PYRAZIN-8-YLAMINE To a solution of 2-furan-2-yl-6-piperazin-1-yl- [1, 2,4] triazolo [1, 5-A] PYRAZIN-8- ylamine in methylene chloride (see Example 16 above) was added 5-CHLORO-1-METHYL- 3-(trifluoromethyl) pyrazole-4-carboxaldehyde (45 mg, 0.21 mmol), sodium triacetoxyborohydride (65 mg, 0.31 mmol) and acetic acid (12 U. L, 0.2 mmol). The reaction was stirred at room temperature overnight. After the solvent was removed, the residue was subjected to flash chromatography (ethyl ACETATE/HEXANES = 40: 60) to afford 6- [4- (5-CHLORO-1-METHYL-3-TRIFLUOROMETHYL-1 H-PYRAZOL-4-YLMETHYL)-PIPERAZIN-L- YL]-2-FURAN-2-YL- [1, 2,4] triazolo [1, 5-a] PYRAZIN-8-YLAMINE as a white solid (9 mg, 13 %). 1H NMR (300 MHz, CDC13) 82. 62- 2. 70 (m, 4 H), 3. 27- 3. 39 (m, 4 H), 3.54 (s, 2H), 3.92 (s, 3H), 5.54 (s, 2H), 6.56 (dd, J = 1. 8,3. 3 Hz, 1 H), 7.08 (d, J= 3.3 Hz, 1 H), 7.27 (s, 1 H), 7.58 (d, J = 1.8 Hz, 1H). MS: m/z 482.14 [M+H]+.

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2004/92177, 2004, A1 Location in patent: Page 40-41

26
[ 128455-62-9 ]
(7RS,9aSR)-N₅-[2-(5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazine-5,7-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: trans-7-[(7-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-ylamino)-methyl]-octahydro-pyrido[1,2-a]pyrazine-2-carboxylic acid tert-butyl ester With trifluoroacetic acid In dichloromethane at 20℃; for 2h; Stage #2: 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde With sodium tris(acetoxy)borohydride; acetic acid In dichloromethane at 20℃;	7.c (C) (7RS, 9AS N5-[2-(5-CHLORO-L-METHYL-3-TRIFLUOROMETHYL-LEX-PYRAZOL-4- ylmethyl)-octahydro-pyrido[1,2-a]pyrazin-7-ylmethyl]-2-furan-2-yl- [1, 2, 4] triazolo [1, 5-A] [1, 3, 5] triazine-5, 7-diamine To a solution OF TRANS-7- [ (7-AMINO-2-FURAN-2-YL- [1, 2, 4] TRIAZOLO [1, 5- a] [1, 3, 5] triazin-5-ylamino)-methyl]-octahydro-pyrido [1, 2-a] pyrazine-2-carboxylic acid tert-butyl ester (1 eq., see subpart (b) above) in methylene chloride was added trifluoroacetic acid to reach a final concentration of 10% TFA. The mixture was stirred at room temperature for 2 hours, after which the solvent was removed under reduced pressure, and the residue was dissolved in methylene chloride. To this solution was added 5-CHLORO-1-METHYL-3-TRIFLUOROMETHYL-1H-PYRAZOLE-4-CARBALDEHYDE (1 eq.), sodium triacetoxyborohydride (1. 5 eq.), and acetic acid (1. 5 eq.). The reaction was stirred at room temperature for overnight. The solvent was then removed, and the residue was purified by preparative HPLC using aqueous CH3CN (buffered with 0. 1 % TFA) to afford (7RS, 9ASR)-N5- [2- (5-CHLORO-L-METHYL-3-TRIFLUOROMETHYL-LH-PYRAZOL- 4-ylmethyl)-octahydro-pyrido [1, 2-a] PYRAZIN-7-YLMETHYL]-2-FURAN-2-YL- [1, 2, 4] triazolo [1, 5-A] [1, 3, 5] triazine-5, 7-DIAMINE. LH NMR (400 MHz, DMSO-D6) No. 7. 70 (d, J= 5. 0 Hz, 1 H), 7. 12 (d, J= 3. 6 Hz, 1 H), 6. 62 (m, 1 H), 4. 51 (s, 3 H), 4. 50 (s, 2 H), 3. 39- 3. 53 (m, 4 H), 3. 00- 3. 12 (m, 4 H), 2. 80- 2.86 (m, 1 H), 2. 37- 2. 43 (m, 1 H), 2. 21-2. 27 (m, 2H), 1. 94-1. 97 (m, 2 H), 1. 53-1. 58 (m, 1 H), 1. 30-1. 44 (m, 1 H). MS m/z = 568 (M+ + H).

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - WO2004/92173, 2004, A2 Location in patent: Page 28

27
[ 356759-12-1 ]
[ 128455-62-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; trichlorophosphate In N,N-dimethyl-formamide	1 Synthesis of 1-methyl-3-trifluoromethyl-5-chloropyrazole-4-carboxylic acid 1) 21.35 g of phosphorus oxychloride was dropwise added to 4.72 g of DMF at 10° C. or lower. After the temperature of the reaction solution was returned to room temperature, the reaction mixture was stirred for 1 hour, and 10.71 g of 1-methyl-3-trifluoromethyl-5-pyrazolone was added thereto. The resulting mixture was heated up to 110° C., and stirred for 7 hours. After having been left to be at 70° C. the reaction mixture was poured into ice water. After pH of the mixture was made to be about 4 with an aqueous solution of sodium hydroxide added thereto, and precipitated crystals were taken out through filtration and dried to obtain 10.55 g of 1-methyl-3-trifluoromethyl-5-chloropyrazole-4-carbaldehyde.

Reference： [1]Current Patent Assignee: NISSAN CHEMICAL CORPORATION - US6063734, 2000, A

28
[ 7748-36-9 ]
[ 128455-62-9 ]
[ 878204-38-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 0.416667h;	I1 Oxetane-3-ol (6.12 g, 82.7 mmol) was added dropwise to potassium tert-butoxide (1M in THF) (69.6 ml, 69.6 mmol) at room temperature. 5-Chloro-l-methyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehyde (9.86 g, 46.4 mmol) was dissolved in THF (40 ml) and added slowly to the solution. After 25 minutes the mixture was concentrated and the residue partitioned between ethyl acetate and water. The two phases were separated and the aqueous phase was extracted several times with ethyl acetate. The combined organic phases were washed with brine; dried over magnesium sulfate and concentrated to yield the product as brown oil (11.6 g) which was used in the next step without further purification.

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2006/24820, 2006, A1 Location in patent: Page/Page column 109

29
[ 128455-62-9 ]
[ 811-51-8 ]
[ 915137-34-7 ]

Yield	Reaction Conditions	Operation in experiment
51%	In N,N-dimethyl-formamide at 20℃;	I12 Sodium ethylthiolate (1.05 g, 12.5 mmol) was stirred in dry DMF (50 ml). After 10 minutes 5-chloro-l-methyl-3-trifluoromethyl-lH-pyrazole-4-carbaldehyde (2.12 g, 10 mmol) was added in dry DMF (5 ml). The mixture was stirred at room temperature overnight. More sodium ethylthiolate was added (700 mg, 8.3 mmol) and the reaction mixture stirred at room temperature for 24 hours. The reaction mixture was diluted with water and extracted with diethyl ether (2x). The combined organic extracts were washed (4x) with water, brine, and dried over sodium sulfate and concentrated. The residue was purified by chromatography over silica gel (eluent 0-50% ethyl acetate in hexane) to give the product as a mobile oil (1.228 g, 51 % yield).1H-NMR (400 MHz, CDCl3): 1.25 (t, 3H, CH3), 3.0 (q, 2H, CH2), 4.05 (s, 3H, CH3),10.05 (s, IH, CH).

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2006/123088, 2006, A2 Location in patent: Page/Page column 72

30
[ 75-89-8 ]
[ 128455-62-9 ]
[ 915137-25-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium <i>tert</i>-butylate In tetrahydrofuran at 10 - 20℃; for 2h;	2.I9 Example 19: Preparation of l-methyl-5-(2,2,2-trifluoro-ethoxyV3-trifluoromethyl-lH- pyrazole-4-carbaldehyde2,2,2-Trifluoroethanol (12.1 ml, 0.17 mol) was added dropwise to a solution of potassium terf-butoxide (IM in THF) (170ml, 0.17mol) in dry tetrahydrofuran (80 ml) at 1O0C. Then S-chloro-l-methyl-S-trifluoromethyl-lH-pyrazole^-carbaldehyde (30 g, 0.14 mol) (prepared according to WO 04/014138) in tetrahydrofuran (40 ml) was added dropwise at 10-150C over 1 hour. At the end of the addition, the mixture was stirred at room temperature for one hour, then water (200 ml) and ethyl acetate (200 ml) were added. The phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give l-methyl-5-(2,2,2-trifluoro-ethoxy)-3-trifiuoro~methyl- lH-pyrazole-4-carbaldehyde (35.9 g, 92% yield). 1H-NMR (400 MHz, CDCl3): 3.8 (s, 3H, Me), 4.9-5.0 (q, 2H, CH2), 9.85 (s, IH, CH) ppm.
92%	With potassium <i>tert</i>-butylate In tetrahydrofuran at 10 - 20℃; for 2h;	I1 2,2,2-Trifluoroethanol (12.1 ml, 0.17 mol) was added dropwise to a solution of potassium tert-butoxide (IM in THF) (170ml, 0.17mol) in dry THF (80 ml) at 1O0C. EPO Then 5-chloro-l-methyl-3-trifluoromethyl-lH-pyrazole-4-carbaldehyde (30 g, 0.14 mol) (prepared according to WO 04/014138) in THF (40 ml) was added dropwise at 10-150C over 1 hour. At the end of the addition, the mixture was stirred at room temperature for one hour, then water (200 ml) and ethyl acetate (200 ml) were added. The phases were separated and the aqueous phase extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give the product (35.9 g, 92% yield).1H-NMR (400 MHz, CDCl3): 3.8 (s, 3H, CH3), 4.9-5.0 (q, 2H, CH2), 9.85 (s, IH, CHO).

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2007/71900, 2007, A1 Location in patent: Page/Page column 76
[2]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2006/123088, 2006, A2 Location in patent: Page/Page column 65-66

31
[ 866546-07-8 ]
[ 128455-62-9 ]
[ 1048018-17-2 ]

Yield	Reaction Conditions	Operation in experiment
73%		Reference Example 1915-(5-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehydeTo a solution of <strong>[866546-07-8]5-chloro-1H-pyrrolo[2,3-b]pyridine</strong> (1.22 g) in N,N-dimethylformamide (25 mL), which was cooled at 0 C. in an ice bath, was added 60% sodium hydride (in oil, 340 mg) with stirring, and the mixture was stirred at 0 C. for 20 min. 5-Chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (1.51 g) was added to this reaction mixture at 0 C., and the reaction mixture was stirred at 100 C. for 3.5 hr. After the reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The filtrate was concentrated, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 80:20, v/v) to give the title compound (1.71 g, yield 73%) as colorless crystals.1H-NMR (300 MHz, CDCl3) delta:3.81 (s, 3H), 6.76 (d, J=3.6 Hz, 1H), 7.36 (d, J=3.6 Hz, 1H), 8.00 (d, J=2.3 Hz, 1H), 8.27 (d, J=2.3 Hz, 1H), 9.87 (s, 1H).

Reference： [1]Patent: US2008/194617,2008,A1 .Location in patent: Page/Page column 82

32
trans-3-methyl-1-[5-(trifluoromethyl)-pyridin-2-yl]-4-piperidinol [ No CAS ]
[ 128455-62-9 ]
trans-3-methyl-4-[4-formyl-1-methyl-3-(trifluoromethyl)pyrazol-5-yloxy]-1-[5-(trifluoromethyl)-2-pyridyl]-piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: trans-3-methyl-1-[5-(trifluoromethyl)-pyridin-2-yl]-4-piperidinol With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde In N,N-dimethyl-formamide at 100℃; for 15h;	8 Production Example 8 Production of trans-3-methyl-4-[4-formyl-1-methyl-3-(trifluoromethyl)pyrazol-5-yloxy]-1-[5-(trifluoromethyl)-2-pyridyl]-piperidine (Compound No. 1a-222) [Show Image] A solution of 0.50 g of trans-3-methyl-1-[5-(trifluoromethyl)-2-pyridyl]-piperidin-4-ol (3-4) in 5 ml of anhydrous DMF was added dropwise to 0.08 g of 60% sodium hydride. The mixture was stirred at room temperature for 30 minutes. Thereto was added a solution of 0.41 g of 5-chloro-l-methyl-3-(trifluoromethyl)pyrazol-4-carbaldehyde (2-3) in 5 ml of anhydrous DMF. The mixture was stirred at 100°C for 15 hours. The reaction mixture was poured into 100 ml of water, and the mixture was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5:1) to produce 0.30 g of Compound (1a-222).

Reference： [1]Current Patent Assignee: OAT AGRIO CO., LTD. - EP2050745, 2009, A1 Location in patent: Page/Page column 31

33
[ 1965-09-9 ]
[ 128455-62-9 ]
[ 769171-48-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4,4'-dihydroxydiphenyl ether With sodium hydride In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 0.166667h; Stage #2: 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde In DMF (N,N-dimethyl-formamide) at 70℃; for 2.16667h;	26 Reference Production Example 26; 570 mg of 4, 4'-dihydroxybiphenylether was dissolved to 5 ml of N, N-dimethylformaide, 170 mg of sodium hydride (60% in oil) was added to the solution under ice-cooling, and then the mixture was stirred at room temperature for ten minutues. After that, to the said mixture was added 5 ml of N, N-dimethylformamide solution of 570 mg of 5-chloro-1-methyl-3-trifluoromethyl-lH-pyrazol-4-carbaldehy de'shown by the formula: over ten minutes at 70 °C, and then the mixture was stirred at 70 °C for two hours. After that, water and 10 % hydrochloric acid were added to the reaction mixture which was cooled to room temperature, and extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 440 mg of the compound shown by the formula (xxvi). 1H-NMR (CDCl3, TMS) 5 (ppm) : 9.66 (lH, s), 6.79-6. 93 (8H, m), 4.95 (1H, s), 3.81 (3H, s)
	Stage #1: 4,4'-dihydroxydiphenyl ether With sodium hydride In DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 0.166667h; Stage #2: 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde In DMF (N,N-dimethyl-formamide) at 70℃; for 2.16667h;	5 Reference Production Example 5; 570 mg of 4,4'-dihydroxydiphenyl ether was dissolved in 5 ml of N,N-dimethylformamide, 170 mg of sodium hydride (60% oil suspension) was added thereto under ice-cooling, the mixture was stirred at room temperature for ten minutes. Afterward, 570 mg of 5-chloro-1-methyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde in 5 ml of N,N-dimethylformamide was added dropwise at 70°C under stirring over ten minutes, stirred at 70°C for two hours. The reaction mixture was cooled to room temperature, water and 10% hydrochloric acid were added thereto, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 440 mg of the compound of formula (vii).

Reference： [1]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - WO2005/75433, 2005, A1 Location in patent: Page/Page column 176-177
[2]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - EP1607390, 2005, A1 Location in patent: Page/Page column 62

34
[ 128455-62-9 ]
[ 75-33-2 ]
[ 878204-78-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: 2-propanethiol With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde In N,N-dimethyl-formamide at 20℃; for 16h; Stage #3: With ammonium chloride In water; N,N-dimethyl-formamide	I46 Potassium carbonate (1.68 g, 12 mmol) was suspended in DMF (50 ml) and iso-propylthiol (1 ml, 11 mmol) added. The suspension was stirred at room temperature for15 minutes before a solution of 5-chloro-l-methyl-3-trifluoromethyl-lH-pyrazole-4-carbaldehyde (2.12 g, lOmmol) in DMF (5 ml) was added. The reaction was stirred atroom temperature for 16 hours. The reaction was partitioned between aqueousammonium chloride solution and diethyl ether and the two phases were separated. Theorganic phase was washed with water and brine, dried over sodium sulfate andconcentrated to give the product (2.584 g, 100% yield) which was used without furtherpurification. .H NMR (400 MHz, CDC13): 1.29 (3H, s, Me), 1.31 (3H, s, Me), 3.52 (1H,heptet, CH), 4.02 (3H, s, Me), 10.03 (1H, s, CH).

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2006/24820, 2006, A1 Location in patent: Page/Page column 139

35
[ 98437-24-2 ]
[ 128455-62-9 ]
[ 1251914-07-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium phosphate; chloro(2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-1,1‘-biphenyl)[2-(2’-amino-1,1‘-biphenyl’)]palladium(II) In tetrahydrofuran; water at 40℃; for 2h; Inert atmosphere;

Reference： [1]Kinzel, Tom; Zhang, Yong; Buchwald, Stephen L. [Journal of the American Chemical Society, 2010, vol. 132, # 40, p. 14073 - 14075]

36
[ 128455-62-9 ]
[ 128564-57-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium permanganate 2: thionyl chloride
	Multi-step reaction with 2 steps 1: potassium permanganate; water / 8 h / 70 - 80 °C 2: thionyl chloride / Reflux
	Multi-step reaction with 2 steps 1: potassium permanganate / water; acetone / 4 h / 60 - 80 °C 2: thionyl chloride / 6 h / Reflux

Reference： [1]Wu, Lintao; Song, Baoan; Bhadury, Pinaki S.; Yang, Song; Hu, Deyu; Jin, Linhong [Journal of Heterocyclic Chemistry, 2011, vol. 48, # 2, p. 389 - 396]
[2]Current Patent Assignee: GUIZHOU UNIVERSITY - CN103951663, 2016, B
[3]Si, Wei-Jie; Wang, Xiao-Bin; Chen, Min; Wang, Meng-Qi; Lu, Ai-Min; Yang, Chun-Long [New Journal of Chemistry, 2019, vol. 43, # 7, p. 3000 - 3010]

37
[ 1481-02-3 ]
[ 33513-42-7 ]
[ 128455-62-9 ]

Yield	Reaction Conditions	Operation in experiment
78.1%	Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0 - 20℃; for 1h; Stage #2: 2,4-dihydro-2-methyl-5-trifluoromethyl-3H-pyrazol-3-one at 50 - 90℃; for 10h;
45.7%	Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.333333h; Stage #2: 2,4-dihydro-2-methyl-5-trifluoromethyl-3H-pyrazol-3-one at 80 - 90℃; for 5h;	1.2 (2) Preparation of 1-methyl-3-trifluoromethyl-5-chloro-4-pyrazolealdehyde intermediate: To a 250 mL three-necked flask, 0.35 mol of DMF was added. At 0 ° C, 0.83 mol POCl was slowly added dropwiseAfter stirring for 20 min, 0.10 mol of 1-methyl-3-trifluoromethyl-5-pyrazolone was slowly added and the temperature was raised to 80 to 90° C reaction 5h, slowly cooled into 200 mL of ice water, standing 2 h, filtration, washing, drying, in yellow solid Yield: 45.7%.
	With trichlorophosphate

With trichlorophosphate Reflux;

Reference： [1]Jiao, Jian; Wang, An; Chen, Min; Wang, Meng-Qi; Yang, Chun-Long [New Journal of Chemistry, 2019, vol. 43, # 16, p. 6350 - 6360]
[2]Current Patent Assignee: GUIZHOU UNIVERSITY - CN103951663, 2016, B Location in patent: Paragraph 0091; 0094; 0095
[3]Location in patent: scheme or table Wu, Lintao; Song, Baoan; Bhadury, Pinaki S.; Yang, Song; Hu, Deyu; Jin, Linhong [Journal of Heterocyclic Chemistry, 2011, vol. 48, # 2, p. 389 - 396]
[4]Chen, Min; Li, Guohua; Lu, Aimin; Qiu, Lingling; Wang, An; Wang, Xiaobin; Xue, Wei; Yang, Chunlong [Journal of Agricultural and Food Chemistry, 2020, vol. 68, # 49, p. 14426 - 14437]

38
[ 271-89-6 ]
[ 128455-62-9 ]
[ 1251914-07-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 1-benzofurane With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; Stage #2: With zinc(II) chloride In tetrahydrofuran; hexane at -78 - 20℃; Inert atmosphere; Stage #3: 5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde With methanesulfonic acid(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II); XPhos In tetrahydrofuran; hexane at 20℃; for 12h; Inert atmosphere;

Reference： [1]Yang, Yang; Oldenhuis, Nathan J.; Buchwald, Stephen L. [Angewandte Chemie - International Edition, 2013, vol. 52, # 2, p. 615 - 619][Angew. Chem., 2013, vol. 125, # 2, p. 643 - 647,5]

39
[ 35691-93-1 ]
[ 128455-62-9 ]
[ 1422280-92-9 ]

Reference： [1]Organic and Biomolecular Chemistry,2013,vol. 11,p. 1171 - 1178

40
[ 615-15-6 ]
[ 128455-62-9 ]
[ 1446741-74-7 ]

Yield	Reaction Conditions	Operation in experiment
31%	With caesium carbonate In N,N-dimethyl-formamide at 120℃; for 20h;

Reference： [1]Kato, Jun-Ya; Ito, Yutaro; Ijuin, Ryosuke; Aoyama, Hiroshi; Yokomatsu, Tsutomu [Organic Letters, 2013, vol. 15, # 14, p. 3794 - 3797]

41
methyl 5-cyclopropyl-2-fluoro-4-(piperidin-4-ylmethoxy)benzoate [ No CAS ]
[ 128455-62-9 ]
methyl 4-((1-((5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; for 16h;	357.1 Step 1. Preparation of methyl 4- ( (1- ( (5-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazol-4-yl) methyl) piperidin-4-yl) methoxy) -5-cyclopropyl-2-fluorobenzoate To a mixture of methyl 5-cyclopropyl-2-fluoro-4- (piperidin-4-ylmethoxy) benzoate (0.12 g, 0.40 mmol) , 5-chloro-1-methyl-3- (trifluoromethyl) -1H-pyrazole-4-carbaldehyde (0.08 g, 0.40 mmol) in dichloroethane (2 mL) was added sodium triacetoxyborohydride (0.25 g, 1.20 mmol) and acetic acid (0.07 g, 1.20 mmol) . After stirring at ambient temperature for 16 hours, the reaction mixture was quenched by addition aqueous ammonium hydroxide solution (28, 3 mL) and extracted with dichloromethane, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the title compound as a colorless gum (0.01 g, 50) . Which was used in next step without further purification: MS (ES+) m/z 506.2, 504.2 (M + 1) .

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG; XENON PHARMACEUTICALS INC - WO2015/78374, 2015, A1 Location in patent: Page/Page column 431; 432

42
[ 1475-91-8 ]
[ 128455-62-9 ]
(1E,4E)-1,5-bis(5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)penta-1,4-dien-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate In ethanol; water at 20℃;

Reference： [1]Wang, Rubing; Chen, Chengsheng; Zhang, Xiaojie; Zhang, Changde; Zhong, Qiu; Chen, Guanglin; Zhang, Qiang; Zheng, Shilong; Wang, Guangdi; Chen, Qiao-Hong [Journal of Medicinal Chemistry, 2015, vol. 58, # 11, p. 4713 - 4726]

43
[ 128455-62-9 ]
(1E,3E,6E,8E)-1,9-bis(5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)nona-1,3,6,8-tetraen-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide / 25 °C 2.1: potassium carbonate / ethanol; water / 0.5 h / 25 °C 2.2: 20 °C

Reference： [1]Zhang, Xiaojie; Wang, Rubing; Perez, German Ruiz; Chen, Guanglin; Zhang, Qiang; Zheng, Shilong; Wang, Guangdi; Chen, Qiao-Hong [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 19, p. 4692 - 4700]

44
[ 128455-62-9 ]
[ 2136-75-6 ]
(E)-3-(5-chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)acrylaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	In N,N-dimethyl-formamide at 25℃;	2 (E)-3-(5-Chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)acrylaldehyde (38) General procedure: The reaction mixture of aldehyde (0.5mmol) and 2-(triphenylphosphoranylidene)acetaldehyde (0.51mmol) in DMF (0.5mL) was stirred for 1-4days and detected with TLC. The reaction mixture was extracted with dichloromethane (10mL×3). The combined organic extracts were rinsed with brine (5mL×3) and dried over anhydrous magnesium sulfate, and the volatile components were evaporated under vacuum to give the crude product, which was subjected to the PTLC purification using hexanes/ethyl acetate (1/1, v/v) as eluent to give the respective product. All intermediates were directly used for the next step reaction after confirming with their 1H NMR data. The 1H NMR data for the sixteen known (E)-3-aryl-2-propenals (33, 34, 36, 37, 39-46, 48, 49, 56, 57) are in consistent with those reported in the literature.

Reference： [1]Zhang, Xiaojie; Wang, Rubing; Perez, German Ruiz; Chen, Guanglin; Zhang, Qiang; Zheng, Shilong; Wang, Guangdi; Chen, Qiao-Hong [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 19, p. 4692 - 4700]

45
[ 128455-62-9 ]
[ 447401-89-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium fluoride / dimethyl sulfoxide / 5 h / 120 - 130 °C / Inert atmosphere 2: sodium tetrahydroborate / tetrahydrofuran / 5 h / 4 - 10 °C / Inert atmosphere