Name: 162758-35-2|5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylic acid|95%
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[ 162758-35-2 ]
[ 168273-05-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With thionyl chloride; In toluene; for 3h;Heating / reflux;	To a suspension of <strong>[162758-35-2]5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid</strong> (3.82 g, 10 mmol) in toluene (75 ml) was added thionyl chloride (3.64 ml, 50 mmol) and the mixture was refluxed for 3 hours and then cooled to the room temperature. The solvent was evaporated off under the reduced pressure. The residue was redissolved in toluene (30 ml) and the solvent was evaporated off again (procedure repeated twice) to yield the carboxyl chloride (3.94 g, 98% yield).
97%	With thionyl chloride; In toluene; for 3.5h;Heating / reflux;	Example 5 5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride A solution of <strong>[162758-35-2]5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid</strong> (1.50 g, 3.94 mmol) in dry toluene (80 mL) was treated with thionyl chloride (0.6 mL, 8.22 mmol) under nitrogen, and heated at reflux for 3.5 hours. The solvent was removed under reduced pressure to afford the title compound (1.52 g, 97%).
90%	With thionyl chloride; In toluene; for 3h;Heating / reflux;	A solution of the acid 5c (80 mg, 0.21 mmol) and thionyl chloride (0.88 mL, 1.2 mmol) in toluene (5 mL) was reflux for 3 h. Solvent was evaporated under reduced pressure, and gave the crude carboxylic chloride (56 mg, 90%) as a light solid.

	With thionyl chloride; In toluene; for 3h;Heating / reflux;Product distribution / selectivity;	EXAMPLE 1; Preparation of Form III of rimonabant ; Thionyl chloride (2.84ml, 0.039mole) was added slowly to a suspension of <strong>[162758-35-2]5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid</strong> (6) (5g, 0.0139mole) in toluene (50ml) and the mixture was refluxed for 3h and evaporated under vacuum. The resultant acid chloride was dissolved in dichloromethane (45ml) and the solution was slowly added to a solution of 1-aminopiperidine (1.6ml, 0.0 1 6mole) and triethylamine (2ml) in dichloromethane (60ml) at 0-5C. The reaction mixture was stirred at ambient temperature and the completion of the reaction was monitored by TLC. When the reaction was complete, as indicated by the near absence of the starting material, ice-cold water was added, the reaction mixture was stirred at ambient temperature for 15 min and the layers were separated. The organic layer was washed with water and brine solution. The solvent was evaporated under vacuum, methanol (25ml) was added and then the solvent (~10ml) was removed under vacuum. The residue was stirred for 1 hr at 15-20C. The product was filtered, washed with chilled methanol (5ml) and dried at 40-45C to get title product as crystalline Form-III (4g, 62%).; EXAMPLE 2 Preparation of Form III of rimonabant a. Preparation of rimonabant (1) (Form-I) Thionyl chloride (3.72g, 0.031mole) was added slowly to a suspension of <strong>[162758-35-2]5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid</strong> (6) (4g, 0.01 1mole) in toluene (40ml) and the mixture was refluxed for 3 h. The solvent was evaporated off under vacuum. The resultant acid chloride was dissolved in dichloromethane (35ml) and the solution was slowly added to a solution of 1-aminopiperidine (1.22ml, 0.012mole) and triethylamine (1.55ml) in dichloromethane (44ml) at 0-5C. The reaction mixture was stirred at ambient temperature and the completion of the reaction was monitored by TLC. When the reaction was complete, as indicated by the near absence of the starting material, ice-cold water was added, the reaction mixture was stirred at ambient temperature for 15 min and the layers were separated. Organic layer was washed with water and brine solution. The solvent was evaporated under vacuum, added hexanes (20ml) and stirred for 1 hr at ambient temperature. The product was filtered off, washed with hexanes (10ml) and dried at 40-45C to get title product as crystalline Form-I (3g, 58%).
	With thionyl chloride;Product distribution / selectivity;	Scheme 1 shows how the condensation of a propiophenone with diethyl oxalate in the presence of a base such as lithium hexamethydilsilazide should afford, after acidification with hydrochloric acid solution, the diketoester (step a). Heating this ester with an aryl hydrazine in a solvent such as ethanol should produce the pyrazole ester along with the uncyclized imine (step b). These materials may be separated due to their solubility differences, or heated together in ethanolic hydroxide solution to cause further conversion of the imine to the pyrazole along with concomitant saponification of the ester to the carboxylic acid (step c). Subsequent conversion of the carboxylic acid to the acid chloride using thionyl chloride followed by treatment with ethyl N-aminonipecotate should afford the hydrazide ester (step d). Hydrolysis of the ester with lithium hydroxide and acidification with dilute hydrochloric acid solution should yield the hydrazide carboxylic acid (step e). Treatment of this acid with thionyl chloride followed by ammonia should afford the carboxamide (step f).
	Product distribution / selectivity;	Scheme 3 depicts the conversion of the carboxylic acid from Scheme 1 to its acid chloride using thionyl chloride or oxalyl chloride in dichloroethane at ambient to elevated temperatures followed by treatment with an amine such as alanine ethyl ester (A=methyl, n=0) in the presence of triethylamine to afford the amide ester (step a). Hydrolysis of the ester with lithium hydroxide in aqueous THF solution and acidification with dilute hydrochloric acid solution should yield the amide carboxylic acid (step b). This acid can be further treated with Boc anhydride (Boc2O) in THF in the presence of pyridine, followed by a solution of ammonia in THF at 0 degrees to ambient temperature to yield the carboxamido compound (step c).
	With thionyl chloride; In 1,2-dichloro-ethane; at 60℃; for 2h;	Preparation 2.2 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbohydrazide A) 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride 2.9 ml of thionyl chloride are added to a suspension of 5 g of the compound obtained in Preparation 1.2 in 50 ml of 1,2-dichloroethane, the mixture is then heated at 60 C. for 2 hours and the reaction mixture is concentrated under vacuum. 5.25 g of the expected compound are obtained, which compound is used as is.
	With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 25 - 85℃; for 3h;	Step-I:;Toluene (700 ml) and dimethylformamide (4 ml) are added to 5-(4- chlorophenyl)-1 -(2,4-dichlorophenyl-4-methyl-pyrazole-3-carboxylic acid (100 gm, obtained in step-d of reference example) under stirring at 25 - 300C, the solution of thionyl chloride (33 ml) in toluene (100 ml) is slowly added for 30 - 45 minutes at 25 - 300C and then the contents are stirred for 3 hours at 80 - 850C. Distilled the reaction mass under vacuum at below 700C, to the residue added toluene (200 ml) and again distilled to give 5-(4-chlorophenyl)-1-(2,4- dichlorophenyl^-methyl-pyrazole-S-carboxylic acid chloride. The residue is cooled to 300C and dissolved in methylene chloride (700 ml) and kept aside.
	With thionyl chloride; In toluene; for 3h;Heating / reflux;	3.8 ml dichlorosulfoxide was added to a suspension of 6.7g of the intermediate (4) in 70 ml toluene, the mixture was refluxed for 3 hours, evaporated in vacuum to dryness. The residue was dissolved in 70 ml toluene, and evaporated in vacuum to dryness, such evaporation was repeated for three times to give 6.2 g of yellow solid intermediate (5).
	With thionyl chloride; In toluene; at 25 - 30℃; for 4 - 5h;Heating / reflux;Product distribution / selectivity;	Thionyl chloride (93.4g, 0.78 mol) was added to a suspension of 5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid ( 150 g, 0.39 mol) in toluene (750 ml) at 25-28C. The reaction mass was stirred for 5 hours at reflux temperature and then toluene and thionyl chloride were evaporated to under vacuum. The resulting residue was taken up in toluene (75 ml) and the solvent was again evaporated under vacuum. The acid chloride so obtained was dissolved in methylene chloride (750 ml), the mixture was cooled to 10-150C and was added to a stirred mixture of a solution of 1-aminopiperidine (59.39 g, 0.59 mol) in methylene chloride (700 ml) and anhydrous powdered potassium carbonate (108.46 g, 0.78mol) at 10-15C. The reaction mixture was stirred at 25-30C and progress of the reaction was monitored by high performance liquid chromatography. After completion of the reaction, the reaction mass was filtered and the filtrate was successively washed with demineralized water (450ml) and 20% brine solution (450ml) and dried over anhydrous sodium sulphate. The organic layer was evaporated under vacuum to give residue. The resulting residue was taken up in methanol (75 ml) and the solvent was again evaporated under vacuum to give the solid product which was slurried in methanol (450 ml) and stirred for 20 minutes at 0-5C, filtered, washed with chilled methanol (150ml) and dried. The isolated solid was suspended in isopropyl ether (750 ml) and then heated to reflux temperature (60-65 C) and maintained the same temperature for 3 hours. The mass was cooled to 10-15C, filtered and washed with isopropyl ether (3 x,100 ml). The product was dried under vacuum at 45-50C for 4 hours to give 125 g of rimonabant having purity of 99.86% by high performance liquid chromatography; Example 7: Preparation of RimonabantThionyl chloride (12.38 g, 0.1 mol) was added to a suspension of 5-(4-chlorophenyi)-l-(2,4- dichlorophenyl)-4-methyl-l/J-pyrazole-3-carboxylic acid (20 g, 0.053 mol) in toluene (100 ml) at 25-28C. The reaction mass was stirred for 4 hours at reflux temperature and then toluene and thionyl chloride were recovered under vacuum. The resulting residue was taken up in toluene (20 ml) and the solvent was again evaporated under vacuum. The acid chloride so obtained was dissolved in methylene chloride (100 ml), the mixture was cooled to 5-15 C and was added to a stirred mixture of a solution of 1-aminopiperidine (7.85 g, 0.078 mol) in methylene chloride (100 <n="18"/>ml) and anhydrous powdered potassium carbonate (14.5 g, 0.1 mol) at 5-15C. After completion of the reaction, the reaction mass was filtered and the filtrate was successively washed with demineralized water and 20% brine solution. The organic layer was charcolized and then evaporated under vacuum to give the crude product. The crude rinionabant was refluxed in isopropyl ether (100 ml) for two hours. The product was filtered and dried to give 18 g of off white rimonabant having purity of 99.57 % by high performance liquid chromatography; Example 8; Preparation of RinionabantThionyl chloride (67Og) was added to a suspension of 5-(4-chloropb.enyl)-l-(2,4- dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid (1.0 Kg,) in toluene (5.0 It) at 25-280C. The reaction mass was stirred for 5 hours at reflux temperature and then toluene and thionyl chloride were evaporated to under vacuum. The resulting residue was taken up in toluene (1000 ml) and the solvent was again evaporated under vacuum. The acid chloride so obtained was dissolved in methylene chloride (5.0 It), the mixture was cooled to 10-150C and was added to a stirred mixture of a solution of 1-aminopiperidine (408g) in methylene chloride (5.0 It) and anhydrous powdered potassium carbonate (72Og) at 10-150C. The reaction mixture was stirred at 25-3O0C and progress of the reaction was monitored by high performance liquid chromatography. After completion of the reaction, the reaction mass was filtered and the filtrate was successively washed with demineralized water and 20% brine solution and dried over anhydrous sodium sulphate. The organic layer was evaporated under vacuum to give title compound having purity 93.5%; bis impurity 3.5 %; Example 12: Preparation of rimonabant form-HI Step 1: Preparation of RimonabantTo a suspension of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylic acid (4Og, O.lmol) in 200 ml of toluene, was added thionyl chloride (24.79g, 0.2mol) at 30+/-5C. The reaction mass was stirred for 4 hours at reflux temperature and then evaporated to dryness under vacuum to give the expected acid chloride. The acid chloride was dissolved in <n="20"/>methylene chloride (200 ml) and treated with a solution of 1-aminopiperidine (12.16g, 0.12mol) in methylene chloride (700 ml) in presence of triethyl amine (13.29g, 0.13mol ) at 5- 10 C and progress of the reaction was monitored by high performance liquid chromatography. After completion of the reaction, the react...
	With oxalyl dichloride;N,N-dimethyl-formamide; In toluene; at 0 - 20℃;Product distribution / selectivity;	Example 36; Synthesis of 2-[5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazol-3-yl]-1,5,5-trimethyl-1,5-dihydro-imidazol-4-one (6)To a solution of 4a (1.0 g, 2.62 mmol) in toluene (30 mL) at 0 C. were sequentially added DMF (0.2 mL) and oxalyl chloride (1.48 g, 11.66 mmol) dropwise. The resulting mixture was allowed to warm to room temperature and stirred for 1 h, then transferred slowly to a mixture of 5a (0.50 g, 4.30 mmol) and triethylamine (0.42 g, 4.16 mmol) in THF (30 mL) at 0 C. After the mixture was warmed and stirred at room temperature for 15 h, the reaction was quenched with water and extracted with ethyl acetate (2×30 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude residue (1.22 g), which without purification, underwent intramolecular cyclization by treatment with sodium methoxide (270 mg, 5.00 mmol) in methanol (30 mL) at 60 C. for 4 h. After the reaction was complete, the reaction mixture was concentrated and poured into ice water and the resulting mixture was extracted with ethyl acetate (2×30 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel with hexanes/ethyl acetate (1:1) to afford the desired product 6 (0.67 g, 55%) as a white solid. 1H NMR (400 MHz, CDCl3) delta 7.41 (d, 1H), 7.25 (d, 2H), 7.22 (dd, 1H), 7.12 (d, 1H), 7.01 (d, 2H), 3.42 (s, 3H), 2.35 (s, 3H), 1.37 (s, 6H); ESMS m/z: 461.0 (M+1).
	With thionyl chloride; In toluene; for 3h;Reflux;	3.8 ml dichlorosulfoxide was added to a suspension of 6.7 g of the intermediate (4) in 70 ml toluene, the mixture was refluxed for 3 hours, evaporated in vacuum to dryness. The residue was dissolved in 70 ml toluene, and evaporated in vacuum to dryness, such evaporation was repeated for three times to give 6.2 g of yellow solid intermediate (5).
	With thionyl chloride; for 2h;Reflux;	A solution of <strong>[162758-35-2]5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid</strong> (18.0 g, 47.16 mmol) in SOCl2 (60 mL) was refluxed for 2 h. All the volatilities were evaporated and dried under vacuum and the residual mass (crude acid chloride) was dissolved in DCM (25 mL) and the solution was added drop wise at 0 C to a solution of triethyl amine (10.9 mL, 94.4 mmol) and methyl 2-amino-2-methylpropanoate hydrochloride (8 g, 47.20 mmol) in DCM (100 mL). The reaction mixture was stirred at room temperature for 16 h and then quenched with aq. sodium bicarbonate solution. The organic layer was separated and the aqueous layer was further extracted with additional DCM (200 mL). The combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Concentration and chromatographic purification over silica gel (100-200 mesh) afforded the title compound (21.5 g, 95% yield). 1H NMR (400 MHz, CDCl3): delta 7.42 (d, J = 1.0 Hz, 1H), 7.33 (s, 1H), 7.30-7.27 (m, 2H), 7.28 (d, J = 8.3 Hz, 2H), 7.04 (d, J = 8.3 Hz, 2H), 3.78 (s, 3H), 2.34 (s, 3H), 1.65 (s, 6H); ESMS: m/z 480 (M + 1).
	With thionyl chloride; In toluene; for 3h;Reflux;	Under anhydrous atmosphere, compound 6 (0.13g, 0.35mmol) was solved in dry Toluene (9mL) and SOCl2 (1mL) was added. The mixture was heated under reflux for 3 hours and then was allowed to reach room temperature and evaporated to dryness.On the other hand, under argon atmosphere, in a microwave vial amine 9 (0.06g, 0.35mmol) was solved in dry Toluene (1mL). Over this mixture, a solution of the freshly prepared acid chloride in dry Toluene (1mL) was added; and the final mixture reaction was heated in a microwave for 50 minutes at 150ºC. Then the reaction mixture was evaporated to dryness and purified by silica gel column chromatography (hexane/ethyl acetate 6:1) to obtain compound 1 (0.08g, 43%).
	With thionyl chloride; In toluene; at 110℃; for 2.5h;	General procedure: A solution of the crude 1,5-diaryl pyrazole acid (0.7mmol) was suspended in Toluene (25mL) and SOCl2 (2.8mmol) and it was heated to 110C for 2.5h. The excess of SOCl2 was removed by co-distillation with PhMe (3×25mL) and the residue was dissolved in 10mL of CHCl3. A solution of 1-aminopiperidine (3.1mmol) and DIPEA (3.1mmol) in 10mL of CHCl3 was added dropwise at 0C. The reaction was stirred with an anhydrous trap from 0C to room temperature for 4h. The solution was successively washed with a solution of citric acid 0.02M (3×10mL), NaHCO3 pH 10 (3×10mL) and a saturated solution of NaCl (10mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude carbohydrazides. Purification was carried out by column chromatography (CHCl3 to CHCl3-MeOH, 95:5) which afforded the carbohydrazides 1-13 as solids.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 4h;	To the solution of <strong>[162758-35-2]rimonabant acid</strong> 3(usually 1.91 g, 5 mmol) in CH2Cl2 (40 mL) was added oxalyl chloride (4 mL), and one drop of DMF. The resulting mixture was stirred at r.t. for 4hrs before being concentrated in vacuo. The residue was dissolved in 10 mL of CH2Cl2, and was added to a solution of 2a-d (0.55 mmol) and 4-dimethylaminopyridine (0.671g, 0.55 mmol) in 40 mL of CH2Cl2. The resulting mixture was stirred at r.t. for 20 hrs, and then quenched with water. The organic phases were washed with brine, dried over sodium sulfate, and concentrated in vacuo. Purification of the crude product by column chromatography (petroleum ether/ethyl acetate= 10/1~ 2/1) afforded compounds4a-d.
	With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 0 - 100℃; for 4h;	To a stirred solution of compound 2 (382 mg; 1.0 mmol) in toluene (10 ml) one drop of dimethyl formamide was added. The reaction mixture was cooled to 0 C and added thionyl chloride (140 mg:1 .2mmol) in 2ml toluene drop-wise for the period of 2 minutes at the same temperature. The reaction mixture was allowed to attain room temperature and heated at 100 C for 4 h. Excess of thionyl chloride and toluene was distilled off under reduced pressure. In another flask under nitrogen atmosphere was introduced 1- amino piperidine (100 mg; 1.0 mmol) and triethyl amine (101 mg; 1.0 mmol) in 5.0 ml dichloromethane. The flask was cooled to 0 C. To this was added a cooled solutionof acid chloride drop-wise at the same temperature. The resulting reaction mixture was allowed to attain room temperature and then it was stirred for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water (10 ml) and organic layer was separated, washed with water (2 x 5 ml) and brine solution(5m1), dried over Na2SO4(anhydrous) and concentrated in vacuo. The residue was purified by column chromatography over silica gel (ethyl acetate/petroleumether 1:9(v/v)) afforded pure product.
	With thionyl chloride; In toluene; at 110℃; for 2.5h;	General procedure: To a stirred solution of 0.5 mmol of the corresponding 1,5-diarylpyrazole-3-carboxylic acid (19-31) in 15 mL of toluene, 0.2 mL of SOCl2 was slowly added. The mixture was heated to refluxfor ca. 2.5 h. Then, the excess of solvent and SOCl2 was removed in vacuo and the residue was dissolved in 10 mL of CHCl3. To this stirred mixture at 0 C, a solution of 0.55 mmol of t-butyl carbazate and 0.55 mmol of diisopropylethylamine (DIPEA) was added dropwise. After the consumption of the acyl chloride, the chloroformic solution was subsequently washed with citric acid 0.5 M and saturated aqueous NaHCO3. The combined organic extracts were filtered, dried over Na2SO4 and evaporated, which afforded the desired N-Boc carbohydrazides in an acceptable purity. The unpurified N-Boc carbohydrazides were stirred with 1mL of TFA at room temperature for 2.5 h. Once the deprotection was completed, the remnant TFA was co-distilled with 20 mL of CHCl3 (this procedure was repeated two more times). Finally, to the resulting oil 20 mL of CHCl3 were added and 0.55 mmol of vanillin and catalytic acetic acid were aggregated. The solution was stirred for ca. 4 h at room temperature and then evaporated. The solid was purified by column chromatography on silica gel (CHCl3 to CHCl3-MeOH 9:1) to afford the desired carbohydrazydes 1-13.
		To a stirred solution of 2 (382 mg;1.0 mmol) in toluene (10 ml), one drop of dimethyl formamidewas added. The reaction mixture was cooled to 0C and thionyl chloride (140 mg: 1.2 mmol) in 2 mltoluene was added dropwise for the period of 2 min at thesame temperature. The reaction mixture was allowed toattain room temperature and heated at 100C for 4 h.Excess of thionyl chloride and toluene was distilled offunder reduced pressure.
	With thionyl chloride; In toluene; for 3h;Heating / reflux;	A solution of 3.3 g of KOH in 70 ml of water is added t? a solution of 9.6 g of Ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-pyrazole-3- carboxylate in 70 ml of methanol. The mixture is refluxed for 3 hours, poured into 200 ml of iced water and the reaction mixture is acidified to pH=l upon addition of a 10% solution of HCl. The precipitate formed is filtered off, washed with water and dried under vacuum to give 8.8 g of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methyl-pyrazole-3-carboxylic acid. 5 ml of thionyl chloride are added to a suspension of 8.8 g of the above acid in 90 ml of toluene, the mixture is refluxed for 3 hours and then evaporated to dryness under vaccum. The residue is taken up in 90 ml of toluene and the solvent is evaporated off again to give 8.0 g of 5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid chloride. A solution of 8.0 g of this acid chloride in 80 ml of dichloromethane is added dropwise to a solution of 2.8 ml of 1-aminopiperidine and 3.6 ml of triethylamine in 100 ml of dichloromethane, cooled to 0C. The reaction mixture is stirred for 3 hours while allowing the temperature to rise to room temperature and then poured into 200 ml of iced water. The mixture is extracted with dichloromethane, washed with water and then a saturated solution of NaCl, dried over MgSO4 and evaporated under vaccum. The residue is purified by chromatography on silica gel using AcOEt/toluene (10/90; v/v) as the eluent. Crystallization in isopropyl ether gives 5.9 g of Rimonabant.
	With thionyl chloride; In toluene; at 30 - 110℃; for 4h;	EXAMPLE 2; PREPARATION OF 5-(4-CHLOROPHENYL)-1 -(2,4-DICHLOROPHENYL)-4- METHYLPYRAZOLE-3-CARBOXYLIC ACID CHLORIDE (FORMULA VIb)17 g of 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-pyrazole-3- carboxylic acid of Formula Vl and 525 ml of toluene were charged into a clean and dry round bottom flask followed by the addition of 15.9 ml of thionyl chloride at 30 0C. The reaction solution was heated to 110 0C and maintained for 4 hours. The solvent was then distilled off completely at 110 0C under a vacuum of 700 mm Hg. 700 ml of toluene was added to the residue and was distilled completely at 110 C under a vacuum of 700 mm Hg, followed by addition of an additional 700 ml of toluene and distilling completely at 110 0C to afford 16.8 g of the title compound.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h;Inert atmosphere;	To a suspension of carboxylic acid in CH2Cl2 (0.1 M) at rt. was added (COCl)2(3 eq) and a catalytic amount of DMF (1 drop). The mixture was then stirred for 1 h and concentratedin vacuo. The resultant crude acid chloride was dissolved in CH2Cl2 then DIPEA (6 eq) and the amine(1.5 eq) were added. The mixture was stirred at rt. for a further 16 h, washed with H2O three times,dried over Mg2SO4, filtered, and concentrated in vacuo. The resultant crude oil was then purified byflash chromatography to give the amide product.

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[ 158941-22-1 ]
[ 162758-35-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium hydroxide; In methanol; water; for 5h;Inert atmosphere; Reflux;	To a suspension of ester S1 (1.36 g, 3.31 mmol) in MeOH (30 mL) at rt. was addedaq. 2 M KOH (12 mL). The resultant mixture was heated at reflux for 5 h, then cooledto rt. and acidified with aq. 1 M HCl until a precipitate formed. The precipitate wasthen filtered, washed with cold H2O, and dried in vacuo to give the product as a whitesolid (1.21 g, 96 %). MP: 210-213C; deltaH (400 MHz; CDCl3) 7.32 (d, J = 2.0, 1H), 7.31 (m, 4H), 7.08(dt, J = 8.5, 2.2, 2H), 2.35 (s, 3H); deltaC (100 MHz; CDCl3) 165.2, 143.6, 142.2, 136.4, 135.8, 135.4,133.0, 131.0, 130.7, 130.4, 129.2, 128.0, 126.9, 119.7, 9.7. Spectroscopic and physical data were ingood agreement with those previously reported.2
94%		Example 17; Synthesis of 5-(4-chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (4a)To a solution of the ester 3a (1.0 g, 2.44 mmol) in methanol (25 mL) was added potassium hydroxide (1.0 g, 17.86 mmol) in one portion. The resulting mixture was heated at 60 C. for 4 h. The reaction mixture was then poured into ice water, and the pH of the mixture was adjusted to acidic with addition of 10% hydrochloric acid. The precipitate formed was collected by filtration, washed with water, and dried under vacuum to give carboxylic acid 4a (0.88 g, 94%) as a white solid.
92%	With water; In tetrahydrofuran; methanol; water; for 3h;Reflux;	To a stirred solution of the compound of example 20 (5.0 g, 12.20 mmol) in 120 mL of THF:methanol:water (7:2:1) was added LiOH.H20 (2.69 g, 64.1 mmol) and ref luxed for 3 h. The mixture was allowed to cool to room temperature, and solvent was removed to give a sticky solid. To the solid was added water and acidified using 1 N HCI (pH = 2), filtered, washed with water, diethyl ether and dried under vacuum toobtain the title compound.Yield: 92 %; 1H NMR (300 MHz, DMSO-c13): 2.22 (5, 3H, pyrazole-CH3), 7.22 (brd, J=8.1 Hz, 2H, Ar-I-n, 7.46 (brd, J= 8.1 Hz, 2H, Ar-I-n, 7.57 (d, J= 8.4 Hz, 1H, Ar-I-n, 7.36(d, J = 8.4 Hz, 1 H, Ar-I-n, 7.78 (m, 1 H, Ar-I-n, 12.95 (brs, 1 H, exchangeable in D20,COOl-I); MS: m/z382.9 [M + H].

36.7%	With methanol; potassium hydroxide; at 25℃; for 1h;	100ml of methanol and 8.1g of potassium hydroxide were added to the solution. The mixture was allowed to react at 25 C for 1 hour, poured into water at 60 ± 5 C, cooled to room temperature and allowed to stand. The aqueous layer was washed with a small amount of toluene and then added dropwise Concentrated hydrochloric acid to pH = 1.5, precipitation of a large number of solid, filter, filter cake washed with water to neutral, dry to get the crude product 36.7g, 80% acetic acid recrystallization of light yellow solid (Compound 7) 28.1g, yield 36.7% ( Based on compound 2).
		Steo-d:; Benzyl trimethylammonium chloride (25 gm) is added to the solution of NaOH (147.2 gm) in water (250 ml) under stirring at 25 - 300C and then the organic layer resulted in step-c is added at 25 - 300C (pH should be between: 9 - 10). The reaction mass is heated to 700C, stirred for 3 hours 30 minutes at 68 - 700C and then cooled to 100C. To the reaction mass added the solution of cone. HCI (475 ml) in water (1583 mi) for 30 minutes at 10 - 150C (pH = 1.0) and stirred for 1 hour at 10 - 150C. Filtered the solid, washed with 300 ml of toluene followed by 500 ml of water and then dried to give 380 gm of 5-(4- chlorophenyl)-1-(2,4-dichlorophenyl-4-methyl-pyrazole-3-carboxylic acid.
4.1 g	With water; potassium hydroxide; In methanol; for 3h;Reflux;	To a solution of hexamethyldisilazane (HMDS) (92.6 mL, 443 mmol) in diethyl ether (2 L) was added 15% n-butyllithium in hexane (200 mL, 443 mmol) at -20 C and stirred for 30 min. The reaction mixture was cooled to -78 C and to it was added 4-chloropropiophenone (50 g, 295 mmol) in ether (500 mL) and stirred for 45 min at -78 C. The cooling bath was removed and the reaction mixture was allowed to warm up to -20 C and stirred until the reaction mixture turned into a clear solution. The reaction mixture was cooled again to -78 C and diethyl oxalate (80.4 mL, 591 mmol) was added to it. The reaction mixture was slowly warmed up to room temperature over 4 h and stirred for additional 16 h. The yellow colored solid was filtrated and washed with ether and dried under vacuum to give 57 g of lithium salt of 4-(4-chloro-phenyl)-3-methyl-2,4-dioxo-butyric acid ethyl ester. This solid was added to a solution of 2,4-dichlorophenylhydrazine hydrochloride (44.5 g, 208 mmol) in ethanol (1.2 L) and stirred at room temperature for 16 h. The precipitated solid was filtered, washed with ethanol and dried under vacuum. This solid was dissolved in acetic acid (1 L) and refluxed for 16 h. The reaction mixture was cooled and slowly poured into cold water. The separated solid was filtered, washed with water and dried to give 24 g of the pyrazole ester which was dissolved in methanol (50 mL). To this solution was added a solution of potassium hydroxide (1.6 g, 28.4 mmol) in water (10 mL) and the mixture was refluxed for 3 h. The solvent was evaporated under vacuum and the residue was poured into crushed ice and acidified with 6N HCl (pH ~2). The separated solid was filtered, washed with water and dried under vacuum to give the desired compound (4.1 g) as a solid. 1H NMR (200 MHz, CDCl3): delta 7.39-7.26 (m, 5H), 7.09-7.05 (m, 2H), 2.33 (s, 3H); ESMS (m/z): 381 (M + 1).
	With potassium hydroxide; In ethanol; at 50℃; for 12h;	General procedure: A mixture of the lithium salt of the corresponding ethyl 3-methyl-2,4-dioxo-4-phenylbutanoate (13.8mmol) and substituted phenylhydrazine (15.6mmol) were suspended in 50mL of EtOH and H2SO4 was added dropwise in an ice bath. The mixture was heated to reflux and stirred until the starting material was completely consumed. The resulting solution was cooled to room temperature and the excess of ethanol was removed in vacuo. 20mL of water was added and the suspension was neutralized with NaHCO3 and then extracted with CHCl3 (3×20mL). The organic layer was successively dried over Na2SO4, filtered and concentrated in vacuo. The residue containing the ester product was then dissolved in 20mL of EtOH and KOH (23mmol) was added. The mixture was allowed to react 12h at 50C. The resulting suspension was concentrated in vacuo and dissolved in 30mL of water and later washed with hexane (3×15mL). The aqueous layer was acidified with concentrated HCl until the pure carboxylic acids precipitated.
	With potassium hydroxide; In ethanol; at 50℃; for 12h;	General procedure: A mixture of the lithium salt of the corresponding ethyl 3-methyl-2,4-dioxo-4-phenylbutanoate (13.8 mmol) and substituted phenylhydrazine (15.6 mmol) was suspended in 50 mL of EtOH and H2SO4 was added dropwise in an ice bath. The mixture was heated to reflux and stirred until the starting material was completely consumed. The resulting solution was cooled to room temperature and the excess of ethanol was removed in vacuo. 20 mL of water were added and the suspension was neutralized with NaHCO3 and then extracted with CHCl3 (3 20 mL). The organic layer was successively dried over Na2SO4, filtered and concentrated in vacuo.The residue containing the ester product was then dissolved in 20 mL of EtOH and KOH (23 mmol) was added. The mixture was allowed to react 12 h at 50 C. The resulting suspension was concentrated in vacuo and dissolved in 30 mL of water and later washed with hexane (3 15 mL). The aqueous layer was acidified with concentrated HCl until the pure carboxylic acids precipitated.
	With potassium hydroxide; water; In methanol; for 3h;Heating / reflux;	A solution of 3.3 g of KOH in 70 ml of water is added t? a solution of 9.6 g of Ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-pyrazole-3- carboxylate in 70 ml of methanol. The mixture is refluxed for 3 hours, poured into 200 ml of iced water and the reaction mixture is acidified to pH=l upon addition of a 10% solution of HCl. The precipitate formed is filtered off, washed with water and dried under vacuum to give 8.8 g of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methyl-pyrazole-3-carboxylic acid. 5 ml of thionyl chloride are added to a suspension of 8.8 g of the above acid in 90 ml of toluene, the mixture is refluxed for 3 hours and then evaporated to dryness under vaccum. The residue is taken up in 90 ml of toluene and the solvent is evaporated off again to give 8.0 g of 5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-pyrazole-3-carboxylic acid chloride. A solution of 8.0 g of this acid chloride in 80 ml of dichloromethane is added dropwise to a solution of 2.8 ml of 1-aminopiperidine and 3.6 ml of triethylamine in 100 ml of dichloromethane, cooled to 0C. The reaction mixture is stirred for 3 hours while allowing the temperature to rise to room temperature and then poured into 200 ml of iced water. The mixture is extracted with dichloromethane, washed with water and then a saturated solution of NaCl, dried over MgSO4 and evaporated under vaccum. The residue is purified by chromatography on silica gel using AcOEt/toluene (10/90; v/v) as the eluent. Crystallization in isopropyl ether gives 5.9 g of Rimonabant.
		24.5 g of the above crude compound and 500 ml of water were taken into a clean and dry round bottom flask and stirred for 10 minutes. pH of the reaction mass was adjusted to 12 by the addition of 5 g of sodium hydroxide followed by washing the solution with 2*150 ml of petroleum ether. Organic and aqueous phases were separated followed by adjusting the pH of the aqueous layer to about 2, by addition of 4.6 ml of 12 N hydrochloric acid. The resultant suspension was stirred for 10 minutes followed by filtration of the separated solid. The solid was washed with 3 liters of water. The solid obtained was dried at 35 0C under a vacuum of 700 mm Hg for 2 hours to afford 17.5 g of the title compound.
		42 g of the above obtained crude form of the title compound and 420 ml of methanol were charged into a clean and dry round bottom flask and stirred for 10 minutes. 14.4 g of potassium hydroxide dissolved in 294 ml water was added followed by heating to 90 0C and stirring for 3 hours. The reaction mass was cooled to 28 0C. The reaction mass was then added to 2840 ml of ice water and the mixture was stirred for 20 minutes. pH of the reaction mass was then adjusted to 2 by addition of 4.6 ml of 12N hydrochloric acid. The resultant suspension was stirred for 30 minutes followed by filtration of the separated solid and washing the solid with 3 liters of water. The solid obtained was dried at 35 0C under a vacuum of 700 mm Hg for 2 hours to afford 17.5 g of the title compound.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 1151 - 1154
[2]Tetrahedron Letters,2012,vol. 53,p. 4743 - 4746
[3]Archiv der Pharmazie,2013,vol. 346,p. 171 - 179
[4]RSC Advances,2014,vol. 4,p. 20164 - 20176
[5]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29
[6]Journal of Enzyme Inhibition and Medicinal Chemistry,2011,vol. 26,p. 222 - 230
[7]Journal of Medicinal Chemistry,2009,vol. 52,p. 4496 - 4510
[8]Patent: US2010/113546,2010,A1 .Location in patent: Page/Page column 15
[9]Patent: WO2015/162452,2015,A1 .Location in patent: Page/Page column 70
[10]Patent: WO2020/103856,2020,A1 .Location in patent: Paragraph 0176; 0178
[11]Medicinal Chemistry Research,1995,vol. 5,p. 54 - 62
[12]Patent: CN105566224,2016,A .Location in patent: Paragraph 0013
[13]Australian Journal of Chemistry,2008,vol. 61,p. 484 - 499
[14]Journal of the Chemical Society. Chemical communications,1995,p. 1549 - 1550
[15]Patent: WO2008/32330,2008,A2 .Location in patent: Page/Page column 6
[16]Tetrahedron Letters,2008,vol. 49,p. 2789 - 2791
[17]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 3080 - 3092
[18]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 562 - 568
[19]Synlett,2012,vol. 23,p. 2965 - 2968
[20]European Journal of Medicinal Chemistry,2013,vol. 69,p. 10 - 21
[21]European Journal of Medicinal Chemistry,2015,vol. 100,p. 106 - 118
[22]Patent: WO2008/130630,2008,A2 .Location in patent: Page/Page column 12-13
[23]Patent: WO2007/121466,2007,A2 .Location in patent: Page/Page column 18
[24]Patent: WO2007/121466,2007,A2 .Location in patent: Page/Page column 22

3
[ 169544-41-6 ]
[ 13123-92-7 ]
[ 162758-35-2 ]

Yield	Reaction Conditions	Operation in experiment
96%		Example 4 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-Carboxylic acid 2,4-dichlorophenylhydrazine free-base (4.61 g, 18.2 mmol) was added in one portion to a mechanically stirred solution of 4-(4-chlorophenyl)-3-methyl-2,4-dioxo-butyric acid ethyl ester (4.89 g, 18.2 mmol) in 100 mL of absolute ethanol under dry nitrogen. The reaction was heated at reflux for 2.5 hours, cooled to ambient temperature, treated with solid sodium hydroxide (1.088 g, 27.2 mmol), and heated under nitrogen at reflux for 2 hours. Water (140 mL) was added and the ethanol was removed in vacuo. The residual basic solution was extracted with ether. The aqueous phase was acidified to pH 1 with 50% aqueous hydrochloric acid and extracted with ether. The combined organic layers of the acid extract were dried over sodium sulfate and evaporated in vacuo to afford the title compound (6.68 g, 96%). 1H-NMR (300 MHz, CD3OD): delta 7.58-7.46 (m, 3H), 7.38 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.8 Hz, 2H), 2.30 (s, 3H); LC-MS: m/z=381, 383 [M+H]+, 403, 405 [M+Na]+

Reference： [1]Patent: US2007/287734,2007,A1 .Location in patent: Page/Page column 28
[2]Journal of labelled compounds and radiopharmaceuticals,2002,vol. 45,p. 59 - 70

4
[ 2213-43-6 ]
[ 162758-35-2 ]
[ 168273-06-1 ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: rimonabant acid With benzotriazol-1-ol In dichloromethane for 0.166667h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 25℃; Stage #3: 1-Aminopiperidine Further stages;
68%	With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 72h;
	Stage #1: rimonabant acid With thionyl chloride In methyl cyclohexane at 83℃; for 3h; Heating / reflux; Stage #2: With triethylamine In tetrahydrofuran; methyl cyclohexane at 12 - 20℃; for 0.25h; Stage #3: 1-Aminopiperidine With triethylamine In tetrahydrofuran; methyl cyclohexane at 12 - 20℃;	7 A solution of 72.2 g of thionyl chloride in 60 ml of methylcyclohexane is added, after heating to 83° C.+/-3° C., under a nitrogen atmosphere, to a suspension of 190.80 g of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxylic acid in 940 ml of methylcyclohexane. [0126] The mixture is stirred for 2 hours at 83° C.+/-3° C. and then the temperature of the reaction medium is raised over 1 hour up to the reflux temperature of the methylcyclohexane while removing the excess of thionyl chloride by distillation. The reaction medium is cooled to room temperature and a solution of 7 ml of triethylamine in 382 ml of tetrahydrofuran is added. [0127] The solution obtained is added over 15 minutes at 12° C.+/-3° C. to a medium composed of 50.08 g of triethylamine, 55.10 g of 1-aminopiperidine and 460 ml of methylcyclohexane. The temperature is allowed to rise to 20° C.+/-5° C. and then the organic phase is successively washed at 70° C.+/-3° C. with deionized water and acetic acid at 4% in water. The washes of the organic phase at 70° C.+/-3° C. are completed with a 1.5% NaOH solution and then with deionized water and the tetrahydrofuran and the water are carried away by azeotropic distillation at atmospheric pressure. The heating is then interrupted and when the temperature is 85° C., the crystallization of the expected products is initiated by adding 4 g of substance of form II. The mixture is thus stirred for 1 hour at 85° C.+/-3° C. and then cooled to 10° C.+/-3° C. over 5 hours and maintained for 2 hours at 10° C. The crystals formed are filtered, washed with methylcyclohexane, and dried under vacuum at 60° C. [0128] In this trial, 217 g of form II of rimonabant were obtained.

	With 1,1'-carbonyldiimidazole In tetrahydrofuran at 65 - 70℃; for 2.33333h;	11 EXAMPLE 11; PREPARATION OF N-PIPERIDONO-5-(4-CHLOROPHENYL)-1 (2,4- DICHLOROPHENYLM-METHYL-PYRAZOLE-S-CARBOXAMIDE (FORMULA I) 10.0 g of 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4-methyl-pyrazole-3- carboxylic acid of Formula Vl, 6.3 g 1 ,1 '-carbonyldiimidazole, and 100 ml of THF were taken into a clean and dry round bottom flask and stirred for 20 minutes. 2.88 g of N-aminopipehdine was added and the reaction mass was heated to 70 0C. The reaction mass was maintained at 65 to 70 0C for 2 hours. Reaction completion was checked using thin layer chromatography. After completion of the reaction, the solvent was distilled completely under a vacuum of 300 mm Hg at a temperature of 50 0C to afford a residue. The residue was dissolved in 100 ml of diisopropyl ether and washed twice with water and then with 50 ml of saturated vacuum salt solution. The organic layer was dried over sodium sulfate and filtered. The solvent was distilled completely under a vacuum of 300 mm/Hg at 50 0C. The residue obtained was dissolved in 30 ml of diisiopropyl ether. The solution was then cooled to 25 0C and further cooled to 0 0C. The separated solid was filtered and washed with 10 ml of n-heptane. The wet compound was dried at 60 0C for 5 hours to afford 9.0 g of a crude form of the title compound of Formula I.
	With boric acid In toluene at 29 - 112℃; for 12.83h;	12 EXAMPLE 12; PREPARATION OF N-PIPERIDONO-5-(4-CHLOROPHENYL)-1 (2.4-DICHLOROPHENYLM-METHYL-PYRAZOLE-S-CARBOXAMIDE (FORMULA I) 150 ml of toluene and 5 g of 5-(4-chlorophenyl)-1 -(2,4-dichlorophenyl)-4- methyl-pyrazole-3-carboxylic acid of Formula Vl were taken into a round bottom flask and stirred at 29 0C for 10 minutes. 0.08 g of boric acid was added and stirred for another 10 minutes. The reaction mass was then heated to 40 0C and a solution of 1.31 g of 1 -aminopiperidine in 15 ml toluene was added. The reaction mass was maintained at 40 0C for 30 minutes and then further heated to 112 0C. The reaction mass was maintained at 111 0C for 12 hours. The reaction mass was then cooled to 29 0C and 100 ml of n-heptane was added to it and stirred for 15 minutes. The formed solid was filtered and washed with 50 ml of n-heptane. The wet solid was dried at 50 0C for 8 hours to yield 3.6 g of the title compound.

Reference： [1]Kotagiri, Vijay Kumar; Suthrapu, Sashikanth; Reddy, Jambula Mukunda; Rao, Chitneni Prasad; Bollugoddu, Vijaybhaskar; Bhattacharya, Apurba; Bandichhor, Rakeshwar [Organic Process Research and Development, 2007, vol. 11, # 5, p. 910 - 912]
[2]Moloney, Gerard P.; Angus, James A.; Robertson, Alan D.; Stoermer, Martin J.; Robinson, Michael; Lay, Lucy; Wright, Christine E.; McRae, Ken; Christopoulos, Arthur [Australian Journal of Chemistry, 2008, vol. 61, # 7, p. 484 - 499]
[3]Current Patent Assignee: SANOFI - US2005/43356, 2005, A1 Location in patent: Page/Page column 6
[4]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2007/121466, 2007, A2 Location in patent: Page/Page column 24-25
[5]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2007/121466, 2007, A2 Location in patent: Page/Page column 25

5
[ 162758-35-2 ]
[ 614726-85-1 ]

Yield	Reaction Conditions	Operation in experiment
		6. Preparations of the Compounds of Formula (XIV) Preparation 6.1 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N'-hydroxy-4-methyl-1H-pyrazole-3-carboximidamide A) 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide A mixture of 10 g of the compound from Preparation 1.2 and 5 ml of SOCl2 in 100 ml of 1,2-dichloroethane is heated at 60 C. for 1 hour and then the reaction mixture is concentrated under vacuum. The acid chloride thus obtained is taken up in 100 ml of DCM, this solution is added dropwise to 40 ml of a 2M solution of ammonia in MeOH cooled beforehand to -10 C. and the mixture is left stirring overnight while allowing the temperature to rise to AT. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water and dried over MgSO4, the solvent is evaporated under vacuum down to a volume of 50 ml, and the precipitate formed is filtered off and washed with isopropyl ether. 9 g of the expected compound are obtained.

Reference： [1]Organic and Biomolecular Chemistry,2008,vol. 6,p. 3399 - 3407
[2]Patent: WO2020/103856,2020,A1 .Location in patent: Paragraph 0210
[3]Patent: US2008/39510,2008,A1 .Location in patent: Page/Page column 23

6
[ 3538-65-6 ]
[ 162758-35-2 ]
[ 1016557-47-3 ]

Yield	Reaction Conditions	Operation in experiment
77%		Step 1: N-butanoyl-N'-[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl]-hydrazine Added to a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid (0.40 g, 1.05 mmol), N-butanoyl-hydrazine (0.11 g, 1.05 mmol) and EDCI (0.24 g, 1.26 mmol) dissolved in DCM (11 ml), was DMAP (0.15 g, 1.26 mmol) in one portion at room temperature. The reaction mixture was stirred at room temperature for 6 hrs, and then treated with 10% aq. HCl. The organic layer was collected, and evaporated under a vacuum. The crude mixture was further purified by preparative HPLC, to obtain 0.38 g (0.81 mmol, 77%) of the title compound as yellow solid. 1H NMR (400 MHz, CDCl3) delta 7.40 (br s, 1H), 7.31-7.27 (m, 4H), 7.08-7.03 (m, 2H), 2.33 (s, 3H), 2.31 (t, J=7.8 Hz, 2H), 1.72 (m, 2H), 0.97 (t, J=7.3 Hz, 3H).

Reference： [1]Patent: US2008/81812,2008,A1 .Location in patent: Page/Page column 38-39
[2]Journal of Medicinal Chemistry,2008,vol. 51,p. 7216 - 7233

7
[ 162758-35-2 ]
[ 168273-06-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 94 percent / SOCl₂ / toluene / 6 h / Heating 2: 11.5 g / triethylamine / CH₂Cl₂ / 2 h / 20 °C
	Multi-step reaction with 2 steps 1: DMF / CH₂Cl₂ / 3 h / 20 °C 2: 66 percent / triethylamine / CH₂Cl₂ / 1.5 h / 20 °C
	Multi-step reaction with 2 steps 1: thionyl chloride / toluene / 2.5 h / 110 °C 2: N-ethyl-N,N-diisopropylamine / chloroform / 4 h / 0 - 20 °C

	Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide / toluene / 0 °C / Inert atmosphere 1.2: 4 h / 100 °C / Inert atmosphere 2.1: triethylamine / dichloromethane / 0 - 20 °C / Inert atmosphere
	Multi-step reaction with 2 steps 1: thionyl chloride / toluene / 3 h / Heating / reflux 2: triethylamine / dichloromethane / 3 h / 0 - 20 °C
	Multi-step reaction with 2 steps 1: thionyl chloride / toluene / 4 h / 30 - 110 °C 2: triethylamine / dichloromethane / 0.5 h / -15 - 15 °C
	Multi-step reaction with 2 steps 1: dicyclohexyl-carbodiimide / dichloromethane / 1.17 h / 0 - 30 °C 2: potassium carbonate / dichloromethane / 0.5 h / 30 °C

Reference： [1]Seltzman, Herbert H.; Carroll, F. Ivy; Burgess, Jason P.; Wyrick, Christopher D.; Burch, David F. [Journal of labelled compounds and radiopharmaceuticals, 2002, vol. 45, # 1, p. 59 - 70]
[2]Dutta, Aloke K.; Sard, Howard; Ryan, William; Razdan, Raj K.; Compton, David R.; Martin, Billy R. [Medicinal Chemistry Research, 1995, vol. 5, # 1, p. 54 - 62]
[3]Hernández-Vázquez, Eduardo; Aguayo-Ortiz, Rodrigo; Ramírez-Espinosa, Juan José; Estrada-Soto, Samuel; Hernández-Luis, Francisco [European Journal of Medicinal Chemistry, 2013, vol. 69, p. 10 - 21]
[4]Gajbhiye; More; Patil, Manoj D.; Ummanni; Kotapalli; Yogeeswari; Sriram; Masand [Medicinal Chemistry Research, 2015, vol. 24, # 7, p. 2960 - 2971]
[5]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/130630, 2008, A2
[6]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2007/121466, 2007, A2
[7]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2007/121466, 2007, A2

8
[ 1668-10-6 ]
[ 162758-35-2 ]
[ 949522-87-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	To a mixture of glycinamide hydrochloric acid (166 mg, 1.5 mmol), HOBt (243 mg, 1.8 mmol), NMM (1.82 g, 18 mmol) and <strong>[162758-35-2]5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid</strong> (572 mg, 1.5 mmol) in DMF (15 mL) was added EDCI (345 mg, 1.8 mmol). The reaction mixture was subsequently stirred at room temperature overnight and then the solvent was evaporated off under the reduced pressure. The residue was redissolved in DCM (30 ml) and then washed successively with water, dried over MgSO4 and evaporated under vacuum to provide 550 mg (1.26 mmol, 84% yield) of N-carbamoylmethyl amide (19) as an intermediate.

Reference： [1]Patent: US2008/262066,2008,A1 .Location in patent: Page/Page column 26
[2]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 3080 - 3092

9
[ 2213-43-6 ]
[ 158941-22-1 ]
[ 162758-35-2 ]
[ 168273-06-1 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran at 80℃; for 2 - 4h;	17 Example 17; Comparison of the reactivity of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH- pyrazole-3-cyrboxylate (III, R = Et) with N-aminopiperidine without and in the presence of MgCl2; A mixture of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylate (III, R = Et) (1 g, 2.5 mmol), dry MgCl2 (1.16 g) and the corresponding solvent (20 ml) was stirred (700-900 rpm) in a nitrogen atmosphere at the room temperature for 10 minutes. Dry tetrahydrofuran (Experiment 1), dried over sodium (water content 0.07 %), dry15 acetonitrile Aldrich (cat. no. 271004, water content < 0.005 %) (Experiment 3) and N- aminopiperidine Aldrich (cat. no. A75900) (Experiment 5) were used as the solvents. Then, N- aminopiperidine (1 ml) was added in a single dose and the mixture was stirred at the temperature of the reaction mixture of 80 °C. Under identical conditions experiments without the use of the catalyst (Experiments 2, 4 and 6) were carried out in parallel. After 2 and 420 hours 100 μl of the samples were drawn from the reaction flasks; each drawn sample was diluted with 3 ml of acetonitrile and 2 ml of water in a vial, the solution was degassed by sonication and an ηPLC analysis was performed. Table 1 summarizes the results of these experiments.25 Table 1 - ηPLC evaluation of reaction mixtures after 2 and 4 hours
	In acetonitrile at 80℃; for 2 - 4h;	17; 18 Example 17; Comparison of the reactivity of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH- pyrazole-3-cyrboxylate (III, R = Et) with N-aminopiperidine without and in the presence of MgCl2; A mixture of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylate (III, R = Et) (1 g, 2.5 mmol), dry MgCl2 (1.16 g) and the corresponding solvent (20 ml) was stirred (700-900 rpm) in a nitrogen atmosphere at the room temperature for 10 minutes. Dry tetrahydrofuran (Experiment 1), dried over sodium (water content 0.07 %), dry15 acetonitrile Aldrich (cat. no. 271004, water content < 0.005 %) (Experiment 3) and N- aminopiperidine Aldrich (cat. no. A75900) (Experiment 5) were used as the solvents. Then, N- aminopiperidine (1 ml) was added in a single dose and the mixture was stirred at the temperature of the reaction mixture of 80 °C. Under identical conditions experiments without the use of the catalyst (Experiments 2, 4 and 6) were carried out in parallel. After 2 and 420 hours 100 μl of the samples were drawn from the reaction flasks; each drawn sample was diluted with 3 ml of acetonitrile and 2 ml of water in a vial, the solution was degassed by sonication and an ηPLC analysis was performed. Table 1 summarizes the results of these experiments.25 Table 1 - ηPLC evaluation of reaction mixtures after 2 and 4 hours; Example 18; 5 Comparison of the reactivity of esters of 5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methyl- lH-pyrazole-3-carboxylic acid (III, R = Me, Et, Ph) with s jV-aminopiperidine without and in the presence OfMgCl2; A mixture of the respective ester of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-10 pyrazole-3-carboxylic acid of formula III (2.5 mmol), dry MgCl2 (1.16 g) and acetonitrile (20 ml; acetonitrile Aldrich, cat. no. 271004, water content < 0.005 % of weight) was stirred (700- 900 rpm) in a nitrogen atmosphere at the room temperature for 10 minutes. Then, N- aminopiperidine (1 ml) was added in a single dose and the mixture was stirred at the temperature of the reaction mixture of 80 °C. Under identical conditions experiments without15 the use of the catalyst (Experiments 2, 4 and 6) were carried out in parallel. After 2 and 4 hours 100 μl of the samples were drawn from the reaction flasks; each drawn sample was diluted with 3 ml of acetonitrile and 2 ml of water in a vial, the solution was degassed by sonication and an ηPLC analysis was performed. Table 2 summarizes the results of these experiments.20Table 2 - ηPLC evaluation of the reaction mixtures after 2 and 4 hours
	at 80℃; for 2 - 4h;	17 Example 17; Comparison of the reactivity of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH- pyrazole-3-cyrboxylate (III, R = Et) with N-aminopiperidine without and in the presence of MgCl2; A mixture of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylate (III, R = Et) (1 g, 2.5 mmol), dry MgCl2 (1.16 g) and the corresponding solvent (20 ml) was stirred (700-900 rpm) in a nitrogen atmosphere at the room temperature for 10 minutes. Dry tetrahydrofuran (Experiment 1), dried over sodium (water content 0.07 %), dry15 acetonitrile Aldrich (cat. no. 271004, water content < 0.005 %) (Experiment 3) and N- aminopiperidine Aldrich (cat. no. A75900) (Experiment 5) were used as the solvents. Then, N- aminopiperidine (1 ml) was added in a single dose and the mixture was stirred at the temperature of the reaction mixture of 80 °C. Under identical conditions experiments without the use of the catalyst (Experiments 2, 4 and 6) were carried out in parallel. After 2 and 420 hours 100 μl of the samples were drawn from the reaction flasks; each drawn sample was diluted with 3 ml of acetonitrile and 2 ml of water in a vial, the solution was degassed by sonication and an ηPLC analysis was performed. Table 1 summarizes the results of these experiments.25 Table 1 - ηPLC evaluation of reaction mixtures after 2 and 4 hours

	In acetonitrile at 80℃; for 2 - 4h;	17; 18 Example 17; Comparison of the reactivity of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH- pyrazole-3-cyrboxylate (III, R = Et) with N-aminopiperidine without and in the presence of MgCl2; A mixture of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylate (III, R = Et) (1 g, 2.5 mmol), dry MgCl2 (1.16 g) and the corresponding solvent (20 ml) was stirred (700-900 rpm) in a nitrogen atmosphere at the room temperature for 10 minutes. Dry tetrahydrofuran (Experiment 1), dried over sodium (water content 0.07 %), dry15 acetonitrile Aldrich (cat. no. 271004, water content < 0.005 %) (Experiment 3) and N- aminopiperidine Aldrich (cat. no. A75900) (Experiment 5) were used as the solvents. Then, N- aminopiperidine (1 ml) was added in a single dose and the mixture was stirred at the temperature of the reaction mixture of 80 °C. Under identical conditions experiments without the use of the catalyst (Experiments 2, 4 and 6) were carried out in parallel. After 2 and 420 hours 100 μl of the samples were drawn from the reaction flasks; each drawn sample was diluted with 3 ml of acetonitrile and 2 ml of water in a vial, the solution was degassed by sonication and an ηPLC analysis was performed. Table 1 summarizes the results of these experiments.25 Table 1 - ηPLC evaluation of reaction mixtures after 2 and 4 hours; Example 18; 5 Comparison of the reactivity of esters of 5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methyl- lH-pyrazole-3-carboxylic acid (III, R = Me, Et, Ph) with s jV-aminopiperidine without and in the presence OfMgCl2; A mixture of the respective ester of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-10 pyrazole-3-carboxylic acid of formula III (2.5 mmol), dry MgCl2 (1.16 g) and acetonitrile (20 ml; acetonitrile Aldrich, cat. no. 271004, water content < 0.005 % of weight) was stirred (700- 900 rpm) in a nitrogen atmosphere at the room temperature for 10 minutes. Then, N- aminopiperidine (1 ml) was added in a single dose and the mixture was stirred at the temperature of the reaction mixture of 80 °C. Under identical conditions experiments without15 the use of the catalyst (Experiments 2, 4 and 6) were carried out in parallel. After 2 and 4 hours 100 μl of the samples were drawn from the reaction flasks; each drawn sample was diluted with 3 ml of acetonitrile and 2 ml of water in a vial, the solution was degassed by sonication and an ηPLC analysis was performed. Table 2 summarizes the results of these experiments.20Table 2 - ηPLC evaluation of the reaction mixtures after 2 and 4 hours
	In tetrahydrofuran at 80℃; for 2 - 4h;	17 Example 17; Comparison of the reactivity of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH- pyrazole-3-cyrboxylate (III, R = Et) with N-aminopiperidine without and in the presence of MgCl2; A mixture of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylate (III, R = Et) (1 g, 2.5 mmol), dry MgCl2 (1.16 g) and the corresponding solvent (20 ml) was stirred (700-900 rpm) in a nitrogen atmosphere at the room temperature for 10 minutes. Dry tetrahydrofuran (Experiment 1), dried over sodium (water content 0.07 %), dry15 acetonitrile Aldrich (cat. no. 271004, water content < 0.005 %) (Experiment 3) and N- aminopiperidine Aldrich (cat. no. A75900) (Experiment 5) were used as the solvents. Then, N- aminopiperidine (1 ml) was added in a single dose and the mixture was stirred at the temperature of the reaction mixture of 80 °C. Under identical conditions experiments without the use of the catalyst (Experiments 2, 4 and 6) were carried out in parallel. After 2 and 420 hours 100 μl of the samples were drawn from the reaction flasks; each drawn sample was diluted with 3 ml of acetonitrile and 2 ml of water in a vial, the solution was degassed by sonication and an ηPLC analysis was performed. Table 1 summarizes the results of these experiments.25 Table 1 - ηPLC evaluation of reaction mixtures after 2 and 4 hours
	at 80℃; for 2 - 4h;	17 Example 17; Comparison of the reactivity of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH- pyrazole-3-cyrboxylate (III, R = Et) with N-aminopiperidine without and in the presence of MgCl2; A mixture of ethyl 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylate (III, R = Et) (1 g, 2.5 mmol), dry MgCl2 (1.16 g) and the corresponding solvent (20 ml) was stirred (700-900 rpm) in a nitrogen atmosphere at the room temperature for 10 minutes. Dry tetrahydrofuran (Experiment 1), dried over sodium (water content 0.07 %), dry15 acetonitrile Aldrich (cat. no. 271004, water content < 0.005 %) (Experiment 3) and N- aminopiperidine Aldrich (cat. no. A75900) (Experiment 5) were used as the solvents. Then, N- aminopiperidine (1 ml) was added in a single dose and the mixture was stirred at the temperature of the reaction mixture of 80 °C. Under identical conditions experiments without the use of the catalyst (Experiments 2, 4 and 6) were carried out in parallel. After 2 and 420 hours 100 μl of the samples were drawn from the reaction flasks; each drawn sample was diluted with 3 ml of acetonitrile and 2 ml of water in a vial, the solution was degassed by sonication and an ηPLC analysis was performed. Table 1 summarizes the results of these experiments.25 Table 1 - ηPLC evaluation of reaction mixtures after 2 and 4 hours

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2008/64615, 2008, A2 Location in patent: Page/Page column 15-16
[2]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2008/64615, 2008, A2 Location in patent: Page/Page column 15-16
[3]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2008/64615, 2008, A2 Location in patent: Page/Page column 15-16
[4]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2008/64615, 2008, A2 Location in patent: Page/Page column 15-16
[5]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2008/64615, 2008, A2 Location in patent: Page/Page column 15-16
[6]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2008/64615, 2008, A2 Location in patent: Page/Page column 15-16

10
[ 168272-78-4 ]
[ 2213-43-6 ]
[ 162758-35-2 ]
[ 168273-06-1 ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile at 80℃; for 2 - 4h;	18 Example 18; 5 Comparison of the reactivity of esters of 5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-4-methyl- lH-pyrazole-3-carboxylic acid (III, R = Me, Et, Ph) with s jV-aminopiperidine without and in the presence OfMgCl2; A mixture of the respective ester of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-10 pyrazole-3-carboxylic acid of formula III (2.5 mmol), dry MgCl2 (1.16 g) and acetonitrile (20 ml; acetonitrile Aldrich, cat. no. 271004, water content < 0.005 % of weight) was stirred (700- 900 rpm) in a nitrogen atmosphere at the room temperature for 10 minutes. Then, N- aminopiperidine (1 ml) was added in a single dose and the mixture was stirred at the temperature of the reaction mixture of 80 °C. Under identical conditions experiments without15 the use of the catalyst (Experiments 2, 4 and 6) were carried out in parallel. After 2 and 4 hours 100 μl of the samples were drawn from the reaction flasks; each drawn sample was diluted with 3 ml of acetonitrile and 2 ml of water in a vial, the solution was degassed by sonication and an ηPLC analysis was performed. Table 2 summarizes the results of these experiments.20Table 2 - ηPLC evaluation of the reaction mixtures after 2 and 4 hours

Reference： [1]Current Patent Assignee: ADVENT INTERNATIONAL CORPORATION - WO2008/64615, 2008, A2 Location in patent: Page/Page column 16

11
[ 192702-54-8 ]
[ 1193-72-2 ]
[ 162758-35-2 ]

Yield	Reaction Conditions	Operation in experiment
		529 mg (2 mmol) Ethyl 5-(4-chlorophenyl)-4-methyl-pyrazole-3-carboxylate, 452 mg (2 mmol) 2,4- dichloro-1-bromobenzene, 384 mg (4 mmol) NaOt-Bu, 23.0 mg Bis(dibenzylideneacetone)palladium(0) (2 mol%) and 31.5 mg 2-(N,N-dimethylamino)-2'-(dicyclohexylphosphino)biphenyl (4 mol%) are heated in 12 ml degassed toluene, free of water for 15 h to 120 C until the starting aryl bromide has been completely comsumed as judged by GC analysis. The reaction mixture is then cooled to room temperature, diluted with ether and filtered through celite. Water is added to the filtrate and the phases are separated. The aqueous phase is acidified by addition of HCl until pH = 1.5. The resulting mixture is stirred, the precipitate formed is filtered off and dried under vacuum.
		529 mg (2 mmol) Ethyl 5-(4-chlorophenyl)-4-methyl-pyrazole-3-carboxylate, 452 mg (2 mmol) 2,4- dichloro-1-bromobenzene, 384 mg (4 mmol) NaOt-Bu, 23.0 mg Bis(dibenzylideneacetone)palladium(0) (2 mol%) and 30.4 mg 2-Dicyclohexylphosphino-2'-methoxy-l,l'-biphenyl (4 mol%) are heated in 12 ml degassed toluene, free of water for 15 h to 120 C until the starting aryl bromide has been completely comsumed as judged by GC analysis. The reaction mixture is then cooled to room temperature, diluted with ether and filtered through celite. Water is added to the filtrate and the phases are separated. The aqueous phase is acidified by addition of HCl until pH = 1.5. The resulting mixture is stirred, the precipitate formed is filtered off and dried under vacuum.

Reference： [1]Patent: WO2008/101860,2008,A1 .Location in patent: Page/Page column 7
[2]Patent: WO2008/101860,2008,A1 .Location in patent: Page/Page column 7

12
[ 1520-70-3 ]
[ 162758-35-2 ]
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(ethylsulfonyl)-4-methyl-1H-pyrazole-3-carboxamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 3080 - 3092

13
[ 1524-40-9 ]
[ 162758-35-2 ]
[ 1159836-09-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 3080 - 3092

14
[ 402-46-0 ]
[ 162758-35-2 ]
[ 1159836-06-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 3080 - 3092

15
[ 42826-42-6 ]
[ 162758-35-2 ]
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-N'-(2,2-dimethylpropanoyl)-4-methyl-1H-pyrazole-3-carbohydrazide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 7216 - 7233

16
[ 2443-62-1 ]
[ 162758-35-2 ]
[ 1020796-92-2 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 20℃; Inert atmosphere;

Reference： [1]Location in patent: scheme or table Suk, Ho Lee; Hee, Jeong Seo; Lee, Sung-Han; Myung, Eun Jung; Park, Ji-Hyun; Park, Hyun-Ju; Yoo, Jakyung; Yun, Hoseop; Na, Jooran; Suk, Youn Kang; Song, Kwang-Seop; Kim, Min-Ah; Chang, Chong-Hwan; Kim, Jeongmin; Lee, Jinhwa [Journal of Medicinal Chemistry, 2008, vol. 51, # 22, p. 7216 - 7233]

17
[ 3619-17-8 ]
[ 162758-35-2 ]
[ 1020796-44-4 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 20℃; Inert atmosphere;

Reference： [1]Location in patent: scheme or table Suk, Ho Lee; Hee, Jeong Seo; Lee, Sung-Han; Myung, Eun Jung; Park, Ji-Hyun; Park, Hyun-Ju; Yoo, Jakyung; Yun, Hoseop; Na, Jooran; Suk, Youn Kang; Song, Kwang-Seop; Kim, Min-Ah; Chang, Chong-Hwan; Kim, Jeongmin; Lee, Jinhwa [Journal of Medicinal Chemistry, 2008, vol. 51, # 22, p. 7216 - 7233]

18
[ 929-75-9 ]
[ 162758-35-2 ]
[ 1250437-02-5 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 7048 - 7060

19
[ 6105-75-5 ]
[ 162758-35-2 ]
[ 1265633-81-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃;	General procedure for amide formation To a mixture of pyrazole acid (1 mmol), EDC.HCl (1.2 mmol) and HOBt (1.2 mmol) in dry dichloromethane (10 mL) was added a mixture of amine (1 mmol) and triethyl amine (1.5 mmol) in dichloromethane (5 mL) at 0 °C. The mixture was stirred at room temperature till the completion of reaction (judged by TLC). The reaction mixture was diluted with additional DCM (20 mL). The organic layer was washed with water, brine and dried (Na2SO4). Concentration and purification over silica gel (100-200 mesh) afforded the desired compound.

Reference： [1]Sasmal, Pradip K.; Reddy, D. Srinivasa; Talwar, Rashmi; Venkatesham; Balasubrahmanyam; Kannan; Srinivas; Kumar, K. Shiva; Devi, B. Neelima; Jadhav, Vikram P.; Khan, Sanjoy K.; Mohan, Priya; Chaudhury, Hira; Bhuniya, Debnath; Iqbal, Javed; Chakrabarti, Ranjan [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 1, p. 562 - 568]

20
1-aminocyclobutane-1-carbonitrile [ No CAS ]
[ 162758-35-2 ]
[ 1265634-40-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃;	To a mixture of pyrazole acid (1 mmol), EDC.HCl (1.2 mmol) and HOBt (1.2 mmol) in dry dichloromethane (10 mL) was added a mixture of amine (1 mmol) and triethyl amine (1.5 mmol) in dichloromethane (5 mL) at 0 C. The mixture was stirred at room temperature till the completion of reaction (judged by TLC). The reaction mixture was diluted with additional DCM (20 mL). The organic layer was washed with water, brine and dried (Na2SO4). Concentration and purification over silica gel (100-200 mesh) afforded the desired compound.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 10h;	General procedure: To a mixture of carboxylic acid (1 mmol), EDC·HCl (1.2 mmol) and HOBt (1.2 mmol) in dry dichloromethane (10 mL) was added a mixture of amine (1 mmol) and triethyl amine (1.5 mmol) in dichloromethane (5 mL) at 0 C. The mixture was stirred at room temperature till the completion of reaction (judged by TLC). The reaction mixture was diluted with additional DCM (20 mL). The organic layer was washed with water, brine and dried (Na2SO4). Concentration and purification over silica gel (100-200 mesh) afforded the desired compound.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 562 - 568
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4913 - 4918

21
[ 6105-74-4 ]
[ 162758-35-2 ]
[ 1265633-80-4 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃;	General procedure for amide formation To a mixture of pyrazole acid (1 mmol), EDC.HCl (1.2 mmol) and HOBt (1.2 mmol) in dry dichloromethane (10 mL) was added a mixture of amine (1 mmol) and triethyl amine (1.5 mmol) in dichloromethane (5 mL) at 0 °C. The mixture was stirred at room temperature till the completion of reaction (judged by TLC). The reaction mixture was diluted with additional DCM (20 mL). The organic layer was washed with water, brine and dried (Na2SO4). Concentration and purification over silica gel (100-200 mesh) afforded the desired compound.

Reference： [1]Sasmal, Pradip K.; Reddy, D. Srinivasa; Talwar, Rashmi; Venkatesham; Balasubrahmanyam; Kannan; Srinivas; Kumar, K. Shiva; Devi, B. Neelima; Jadhav, Vikram P.; Khan, Sanjoy K.; Mohan, Priya; Chaudhury, Hira; Bhuniya, Debnath; Iqbal, Javed; Chakrabarti, Ranjan [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 1, p. 562 - 568]

22
[ 1265634-34-1 ]
[ 162758-35-2 ]
[ 1265634-35-2 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃;	General procedure for amide formation To a mixture of pyrazole acid (1 mmol), EDC.HCl (1.2 mmol) and HOBt (1.2 mmol) in dry dichloromethane (10 mL) was added a mixture of amine (1 mmol) and triethyl amine (1.5 mmol) in dichloromethane (5 mL) at 0 °C. The mixture was stirred at room temperature till the completion of reaction (judged by TLC). The reaction mixture was diluted with additional DCM (20 mL). The organic layer was washed with water, brine and dried (Na2SO4). Concentration and purification over silica gel (100-200 mesh) afforded the desired compound.

Reference： [1]Sasmal, Pradip K.; Reddy, D. Srinivasa; Talwar, Rashmi; Venkatesham; Balasubrahmanyam; Kannan; Srinivas; Kumar, K. Shiva; Devi, B. Neelima; Jadhav, Vikram P.; Khan, Sanjoy K.; Mohan, Priya; Chaudhury, Hira; Bhuniya, Debnath; Iqbal, Javed; Chakrabarti, Ranjan [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 1, p. 562 - 568]

23
[ 42514-50-1 ]
[ 162758-35-2 ]
[ 1265633-93-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃;	To a mixture of pyrazole acid (1 mmol), EDC.HCl (1.2 mmol) and HOBt (1.2 mmol) in dry dichloromethane (10 mL) was added a mixture of amine (1 mmol) and triethyl amine (1.5 mmol) in dichloromethane (5 mL) at 0 C. The mixture was stirred at room temperature till the completion of reaction (judged by TLC). The reaction mixture was diluted with additional DCM (20 mL). The organic layer was washed with water, brine and dried (Na2SO4). Concentration and purification over silica gel (100-200 mesh) afforded the desired compound.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 562 - 568

24
1-aminocyclopropanecarbonitrile [ No CAS ]
[ 162758-35-2 ]
[ 1265634-38-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃;	To a mixture of pyrazole acid (1 mmol), EDC.HCl (1.2 mmol) and HOBt (1.2 mmol) in dry dichloromethane (10 mL) was added a mixture of amine (1 mmol) and triethyl amine (1.5 mmol) in dichloromethane (5 mL) at 0 C. The mixture was stirred at room temperature till the completion of reaction (judged by TLC). The reaction mixture was diluted with additional DCM (20 mL). The organic layer was washed with water, brine and dried (Na2SO4). Concentration and purification over silica gel (100-200 mesh) afforded the desired compound.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 10h;	General procedure: To a mixture of carboxylic acid (1 mmol), EDC·HCl (1.2 mmol) and HOBt (1.2 mmol) in dry dichloromethane (10 mL) was added a mixture of amine (1 mmol) and triethyl amine (1.5 mmol) in dichloromethane (5 mL) at 0 C. The mixture was stirred at room temperature till the completion of reaction (judged by TLC). The reaction mixture was diluted with additional DCM (20 mL). The organic layer was washed with water, brine and dried (Na2SO4). Concentration and purification over silica gel (100-200 mesh) afforded the desired compound.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 562 - 568
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4913 - 4918

25
[ 29726-60-1 ]
[ 162758-35-2 ]
[ 1265633-65-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃;	To a mixture of pyrazole acid (1 mmol), EDC.HCl (1.2 mmol) and HOBt (1.2 mmol) in dry dichloromethane (10 mL) was added a mixture of amine (1 mmol) and triethyl amine (1.5 mmol) in dichloromethane (5 mL) at 0 C. The mixture was stirred at room temperature till the completion of reaction (judged by TLC). The reaction mixture was diluted with additional DCM (20 mL). The organic layer was washed with water, brine and dried (Na2SO4). Concentration and purification over silica gel (100-200 mesh) afforded the desired compound.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 562 - 568

26
[ 4475-95-0 ]
[ 162758-35-2 ]
[ 1265634-41-0 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃;	To a mixture of pyrazole acid (1 mmol), EDC.HCl (1.2 mmol) and HOBt (1.2 mmol) in dry dichloromethane (10 mL) was added a mixture of amine (1 mmol) and triethyl amine (1.5 mmol) in dichloromethane (5 mL) at 0 C. The mixture was stirred at room temperature till the completion of reaction (judged by TLC). The reaction mixture was diluted with additional DCM (20 mL). The organic layer was washed with water, brine and dried (Na2SO4). Concentration and purification over silica gel (100-200 mesh) afforded the desired compound.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 10h;	General procedure: To a mixture of carboxylic acid (1 mmol), EDC·HCl (1.2 mmol) and HOBt (1.2 mmol) in dry dichloromethane (10 mL) was added a mixture of amine (1 mmol) and triethyl amine (1.5 mmol) in dichloromethane (5 mL) at 0 C. The mixture was stirred at room temperature till the completion of reaction (judged by TLC). The reaction mixture was diluted with additional DCM (20 mL). The organic layer was washed with water, brine and dried (Na2SO4). Concentration and purification over silica gel (100-200 mesh) afforded the desired compound.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 562 - 568
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4913 - 4918

27
[ 162758-35-2 ]
[ 19355-69-2 ]
[ 1265634-36-3 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃;	To a mixture of pyrazole acid (1 mmol), EDC.HCl (1.2 mmol) and HOBt (1.2 mmol) in dry dichloromethane (10 mL) was added a mixture of amine (1 mmol) and triethyl amine (1.5 mmol) in dichloromethane (5 mL) at 0 C. The mixture was stirred at room temperature till the completion of reaction (judged by TLC). The reaction mixture was diluted with additional DCM (20 mL). The organic layer was washed with water, brine and dried (Na2SO4). Concentration and purification over silica gel (100-200 mesh) afforded the desired compound.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 10h;	General procedure: To a mixture of carboxylic acid (1 mmol), EDC·HCl (1.2 mmol) and HOBt (1.2 mmol) in dry dichloromethane (10 mL) was added a mixture of amine (1 mmol) and triethyl amine (1.5 mmol) in dichloromethane (5 mL) at 0 C. The mixture was stirred at room temperature till the completion of reaction (judged by TLC). The reaction mixture was diluted with additional DCM (20 mL). The organic layer was washed with water, brine and dried (Na2SO4). Concentration and purification over silica gel (100-200 mesh) afforded the desired compound.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 562 - 568
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 4913 - 4918

28
[ 105-83-9 ]
[ 162758-35-2 ]
[ 1338604-44-6 ]

Yield	Reaction Conditions	Operation in experiment
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; In tetrahydrofuran; at 20℃; for 16h;	N-{3-[(3-ammopropyl)(methyl)amino]propyl}-5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methyl-lH-pyrazole-3-carboxamide: H NMR (300 MHz, CHLOROFORM- ) d ppm 1.53 - 1.69 (m, 2 H) 1.77 (t, J=6.62 Hz, 2 H) 2.15 - 2.23 (m, 3 H) 2.34 - 2.50 (m, 7 H) 2.66 - 2.75 (m, 2 H) 3.45 - 3.53 (m, 2 H) 7.03 - 7.09 (m, 2 H) 7.23 - 7.35 (m, 3 H) 7.43 (dd, J=2.05, 0.54 Hz, 1 H) 7.75 (t, J=5.37 Hz, 1 H).; Benzotriazole-l-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (leq) was added to a solution of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- carboxylic acid (1 eq), and diamine (5 eq) in tetrahydrofuran (THF). The reaction mixture was stirred for 16 h. Ethyl acetate was added and the solution was washed with 2 N sodium hydroxide and brine. The organic layer was dried with magnesium sulfate. The solution was then filtered and concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% CMA 80/efhyl acetate to yield pure amino- lH-pyrazole-3- carboxamides.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5711 - 5714
[2]Patent: WO2012/174362,2012,A1 .Location in patent: Page/Page column 40

29
[ 2549-93-1 ]
[ 162758-35-2 ]
[ 1338604-32-2 ]

Yield	Reaction Conditions	Operation in experiment
	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate In tetrahydrofuran at 20℃;

Reference： [1]Location in patent: scheme or table Fulp, Alan; Bortoff, Katherine; Zhang, Yanan; Seltzman, Herbert; Snyder, Rodney; Maitra, Rangan [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 19, p. 5711 - 5714]

30
[ 84100-54-9 ]
[ 162758-35-2 ]
[ 1365037-14-4 ]

Yield	Reaction Conditions	Operation in experiment
46%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In tetrahydrofuran; for 16h;	l-[5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazol-3-yl]carbonyl}-4- (ethylamino)piperidine-4-carboxamide 5-(4-Chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid (1 eq,20 mg, 0.052 mmol), triethylamine (3 eq, 0.02 mL, 0.157 mmol), 4-(ethylamino)-4- piperidinecarboxamide (1 eq, 9 mg, 0.052 mmol), and benzotriazole-l -yl-oxytris(dimethyl- amino)phosphonium hexafluorophosphate (BOP) (leq, 23 mg, 0.052 mmol) was stirred in tetrahydrofuran (5 mL) for 16h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% CMA 80/ethyl acetate and precipitated from ethyl acetate with hexane to yield pure l-[5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl- 1 H-pyrazol-3 -yl] carbonyl} -4-(ethylamino)piperidine-4-carboxamide (13 mg, 46%). 1H NMR (300 MHz, CHLOROFORM-^ d ppm 1.10 (t, J=6.97 Hz, 3 H) 1.61 - 1.80 (m, 2 H) 2.08 - 2.26 (m, 5 H) 2.45 - 2.63 (m, 2 H) 3.68 (td, J=8.85, 4.43 Hz, 2 H) 3.96 - 4.19 (m, 2 H) 5.40 (br. s., 1 H) 7.07 (d, J=8.29 Hz, 2 H) 7.12 - 7.19 (m, 1 H) 7.20 - 7.36 (m, 3 H) 7.44 (d, J=1.98 Hz, 1 H).

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 2820 - 2834
[2]Patent: WO2012/174362,2012,A1 .Location in patent: Page/Page column 43-44

31
[ 87120-72-7 ]
[ 162758-35-2 ]
[ 1365037-83-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In tetrahydrofuran; for 16h;	tert-butyl 4-[5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3- amido] piperidine-l-carboxylateBerizotriazole-l-yl-oxytris(dimethylamino)phosphonium-hexafluorophosphate (BOP) (leq, 490 mg, 1.11 mmol) was added to a solution of 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methyl-lH-pyrazole-3-carboxylic acid (leq, 422 mg, 1.11 mmol), tert-butyl 4-amino-l- piperidinecarboxylate (leq, 222 mg, 1.11 mmol), and triethylamine (3 eq., 0.46 mL, 3.32 mmol) in tetrahydrofuran (5 mL). The reaction mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0- 100% ethyl acetate/hexane to yield pure tert-butyl 4-[5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4- methyl-lH-pyrazole-3-amido]piperidine-l-carboxylate (548 mg, 88%). 1H NMR (300 MHz, CHLOROFORM- ) d ppm 1.33 - 1.51 (m, 9 H) 1.93 - 2.10 (m, 2 H) 2.37 (s, 3 H) 2.91 (t, J=11.82 Hz, 2 H) 3.89 - 4.23 (m, 2 H) 6.84 (d, J=8.19 Hz, 1 H) 7.00 - 7.12 (m, 2 H) 7.19 - 7.36 (m, 4 H) 7.43 (d, J=1.32 Hz, 1 H).

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 2820 - 2834
[2]Patent: WO2012/174362,2012,A1 .Location in patent: Page/Page column 48

32
[ 162758-35-2 ]
4-tert-butoxycarbonylamino-4-phenylpiperidine [ No CAS ]
[ 1365037-17-7 ]

Yield	Reaction Conditions	Operation in experiment
87%	With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine; In tetrahydrofuran; for 16h;	tert-Butyl N-(l-[5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazol-3- yl]carbonyl}-4-phenylpiperidin-4-yl)carbamate5-(4-Chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid (1 eq., 201 mg, 0.53 mmol), triethylamine (3 eq, 0.22 mL, 0.157 mmol), tert-butyl N-(4-phenyl piperidin- 4-yl) carbamate (1 eq, 146 mg, 0.53 mmol), and Benzotriazole-l-yl-oxytris(dimethyl- amino)phosphonium hexafluorophosphate (BOP) (leq, 233 mg, 0.53 mmol) was stirred in tetrahydrofuran (10 mL) for 16h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure tert-butyl N-(l-[5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazol-3- yl]carbonyl}-4-phenylpiperidin-4-yl)carbamate (295 mg, 87%). 1H NMR (300 MHz, CHLOROFORM- ) d ppm 1.37 (br. s., 9 H) 2.11 (dd, J=12.67, 4.00 Hz, 2 H) 2.21 (s, 3 H) 2.24 - 2.34 (m, 1 H) 2.34 - 2.56 (m, 1 H) 3.26 (t, J=12.01 Hz, 1 H) 3.56 (t, J=12.39 Hz, 1 H) 4.32 (d, J-13.75 Hz, 1 H) 4.64 (d, J-13.56 Hz, 1 H) 4.96 (br. s., 1 H) 7.08 (d, J-8.38 Hz, 2 H) 7.13 - 7.49 (m, 10 H).

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 2820 - 2834
[2]Patent: WO2012/174362,2012,A1 .Location in patent: Page/Page column 45

33
[ 53484-76-7 ]
[ 162758-35-2 ]
[ 1279882-69-7 ]

Yield	Reaction Conditions	Operation in experiment
67%		l-[5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazol-3-yl]carbonyl}-4- phenylpiperidine-4-carboxylic acidA 2 M solution of oxalyl chloride in dichloromethane (3 eq., 0.19 mL, 0.377 mmol) was added to 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-lH-pyrazole-3-carboxylic acid (1 eq., 48 mg, 0.126 mmol) in dichloromethane (5 mL). Next, 2 drops of anhydrous N,N- dimethylformamide was added the reaction was stirred for 2 h. The reaction was concentrated in vacuo. The reaction mixture was dissolved in dichloromethane (5 mL). Triethylamine (3 eq., 0.05 mL, 0.377 mmol) and 4-carboxy-4-phenylpiperidin-l-ium chloride (1.5 eq., 45.7 mg, 0.189 mmol) was added and the reaction was stirred for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-10% methanol/dichloromethane with 1% acetic acid to yield pure l -[5-(4-chlorophenyl)-l-(2,4- dichlorophenyl)-4-methyl-lH-pyrazol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxylic acid (48 mg, 67%). (77) 1H NMR (300 MHz, CHLOROFORM-;/) d ppm 1.87 - 2.09 (m, 2 H) 2.15 (s, 3 H) 2.61 (t, J=16.18 Hz, 2 H) 3.21 (t, 7=12.03 Hz, 1 H) 3.47 (t, 7=11.94 Hz, 1 H) 4.26 (d, 7=13.61 Hz, 1 H) 4.57 (d, 7=13.56 Hz, 1 H) 7.05 (d, 7=8.34 Hz, 2 H) 7.12 - 7.45 (m, 10 H).

Reference： [1]Patent: WO2012/174362,2012,A1 .Location in patent: Page/Page column 42-43

34
[ 98623-16-6 ]
[ 162758-35-2 ]
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid [4-(2-methylsufamoylethyl)-phenyl] amide [ No CAS ]

Reference： [1]Synthetic Communications,2014,vol. 44,p. 32 - 41

35
[ 1470-99-1 ]
[ 162758-35-2 ]
[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-yl]-(octahydroisoindol-2-yl)-methanone [ No CAS ]

Reference： [1]Synthetic Communications,2014,vol. 44,p. 32 - 41

36
N<SUP>1</SUP>-(7-aminoheptyl)-N<SUP>1</SUP>-benzylheptane-1,7-diamine [ No CAS ]
[ 162758-35-2 ]
N,N'-((benzylazanediyl)bis(heptane-7,1-diyl))bis(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		To a solution of <strong>[162758-35-2]rimonabant acid</strong> (3, 411 mg, 1.079 mmol, 2.0 eq) in a mixture of CH2Cl2 (8 mL) and DMF (2 mL) were added EDCI·HCl (258 mg, 1.347 mmol, 2.5 eq.), and HOBt (181 mg, 1.347 mmol, 2.5 eq.). The mixture was stirred at r.t. for 60 min, then N1-(7-aminoheptyl)-N1-benzylheptane-1,7-diamine (180 mg, 0.539 mmol, 1.0 eq.) and N, N-diisopropylethylamine (209 mg, 1.617 mmol, 3 eq.) was added. The resulting mixture was stirred at r.t. for 24 hrs. The reaction mixture was then poured into 40 mL of water, extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with brine (3×20 mL), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (ethyl acetate/petroleum ether =1/1~2/1) to afford compound 18 as a white foam (399 mg, yield 70%). 1H NMR (400 MHz, CDCl3) delta 7.42 (d, J = 4 Hz, 2H), 7.32 - 7.25 (m, 12H), 7.22 - 7.17 (m, 1H), 7.08 - 7.03 (m, 4H), 6.93 (t, J = 8Hz, 2H), 3.51 (s, 2H), 3.39 (q, J =8 Hz, 4H), 2.40 - 2.30 (m, 6H+4H), 1.62 - 1.52 (m, 4H), 1.50 -1.20 (m, 4H+12 H). 13C NMR (101 MHz, CDCl3): delta 162.75 (2 × PyrCONH), 145.30, 143.13, 140.42, 136.14, 136.07, 135.02, 133.16, 130.96 (2 signals overlapped), 130.68, 130.46, 129.01 (2 signals overlapped), 128.96, 128.18, 128.00, 127.44, 126.71, 117.83, 58.77 (1 × NHCH2Ph), 53.94 (2 ×CH2NHBz), 39.17 (2 × PyrCONHCH2), 29.87 (2 × CH2), 29.40 (2 × CH2), 27.47 (2 × CH2), 27.16 (2 × CH2), 27.12 (2 × CH2), 9.56 (2 × CH3). HPLC purity: 98.3% (Method C), tR= 9.81 min. HRMS (ESI): calcd for [M + H] + (C55H58Cl6N7O2) requires m/z 1060.2772, found 1060.2757

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4209 - 4214

37
4,4-dimethyl-1,4-azasilinan-1-amine [ No CAS ]
[ 162758-35-2 ]
5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(4,4-dimethyl-1,4-azasilinan-1-yl)-4-methyl-1H-pyrazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 6h;	To a solution of the compound NDS-100226 (76 mg, 0.20 mmol)in dry dichloromethane, was added N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HC1, 40 mg, 0.26 mmol), Hydroxybenzotriazole (HOBt, 35 mg, 0.26 mmol) and diisopropylethyl amine (0.1 mL, 0.60 mmol) at 0C. Then the amine 3 was added and stirred at RT for 6 h. To the reaction mixture water was added and the organic layer was separated, washed with saturated NaHC03, IN HQ, dried over Na2S04 and concentrated under reduced pressure. This crude mixture was purified by column chromatography to give the title compound NDS-100240 (90 mg) as a white fluffy solid in 89% yield. NMR (400 MHz, CDQ3): delta 7.44 (d, J = 1.8 Hz, 1H), 7.32-7.29 (m, 4H), 7.06 (d, J = 8.3 Hz, 2H), 3.21 (t, J = 6.0 Hz, 411), 2.37 (s, 3H), 0.97 (t, J = 6.3 Hz, 4H), 0.10 (s, 6H) ); 13C NMR (100 MHz, CDC13): 6 159.9, 144.4, 142.9, 135.9 (2C), 134.9, 132.9, 130.8 (2C), 130.5, 130.3, 128.9 (2C), 127.8, 127.2, 1 18.2, 55.4, 13.2, 9.3, -3.5 (2C).

Reference： [1]Patent: WO2014/181357,2014,A1 .Location in patent: Page/Page column 19

38
[ 1012314-40-7 ]
[ 5446-18-4 ]
[ 162758-35-2 ]

Yield	Reaction Conditions	Operation in experiment
65%	With sulfuric acid; In ethanol; water; at 79℃; for 14h;Inert atmosphere;	A mixture oflithium salt of ethyl 4-(4-chlorophenyl)-3-methyl-4-oxydo-2-oxobuten-3-oate (B, 1.0 g, 3.6 mmol), ethanol (25 ml),<strong>[5446-18-4]2,4-dichlorophenyl hydrazine hydrochloride</strong> (0.777 g,3.6 mmol), and 50 % sulfuric acid (10 ml) was refluxed for6 h. After the reaction was complete (TLC), ethanol wasremoved under reduced pressure, and again, a second installmentof 50 % sulfuric acid (20 ml) was added, followedby refluxing for 8 h. The reaction mixture wascooled to room temperature (35C) and was poured ontocrushed ice, stirred for 15 min, filtered and washed withwater (20 ml). The wet solid so obtained was stirred withwater (30 ml), and the pH was adjusted to[10 with 20 %dil. NaOH. This aqueous layer was washed with petroleumether. The aqueous layer was separated, cooled to 0C, andpH was adjusted to 2.0 by concentrated hydrochloric acid.Solid so obtained was filtered, washed with water (100 ml)and dried to afford 2 (Kotagiri et al., 2007), (0.923 mg,65 %), Off white solid, mp 208-209C; 1H NMR (CDCl3, 400 MHz): d 7.44-7.41 (m, 1H), 7.35 (d, J = 1.89 Hz,1H), 7.33-7.28 (m, 3H), 7.09 (d, J = 8.47 Hz, 2H), 2.36 (s,3H); 13C NMR (CDCl3, 100 MHz): d 166.4, 143.3, 136.2,135.6, 135.1, 133.5, 130.8, 130.5, 129.8, 128.9, 127.8,127.7, 126.7, 119.6, 9.6; HRMS-ESI (m/z) Calcd.C17H11O2N2Cl3Na: 402.9778 found: 402.9781.

Reference： [1]Medicinal Chemistry Research,2015,vol. 24,p. 2960 - 2971

39
[ 162758-35-2 ]
[ 765-30-0 ]
[ 1020810-09-6 ]

Yield	Reaction Conditions	Operation in experiment
77%	With bis(isopropyl)ethylamine; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In dichloromethane; at 20℃; for 5h;	To a stirred solution of the compound of example 21 (2.0 g, 5.24 mmol) indichloromethane (20 mL) were added cyclopropylamine (0.406 mL, 5.76 mmol), TBTU(1.85 g, 5.76 mmol) and diisopropyl ethylamine (1 .007 mL, 5.76 mmol) and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was quenched with water, extracted with dichloromethane, washed with water and brine, dried (anhydrous Na2SO4) and concentrated. The crude material obtained was purified by column chromatography (silica gel, 50-60 % ethyl acetate in petroleum ether) to obtain the title compound.Yield: 77 %; 1H NMR (300 MHz, CDCI3): 0.60 - 0.63 (m, 4H, cyclopropyl-CH2), 2.23 (s, 3H, pyrazole-CH3), 2.82 (m, 1H, cyclopropyl-CH), 7.22 (d, J = 8.1 Hz, 2H, Ar-I-n,7.45 (d, J = 8.1 Hz, 2H, Ar-I-n, 7.56 (d, J = 8.4 Hz, 1 H, Ar-I-n, 7.71 - 7.75 (m, 2H, Ar-I-n,8.25 (m, 1 H, exchangeable in D20, -NI-n; MS: 422.1 m/z [M + H].

Reference： [1]Patent: WO2015/162452,2015,A1 .Location in patent: Page/Page column 70; 71

40
4,4-dimethyl-4-silapiperidine [ No CAS ]
[ 162758-35-2 ]
(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)(4,4-dimethyl-1,4-azasilinan-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃; for 6h;Inert atmosphere;	General procedure: To a solution of the carboxylic acid (1 eq) in dry dichloromethane, was added N-(3-Dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (EDC.HCl, 1.2 eq), Hydroxybenzotriazole (1.2 eq) and diisopropylethyl amine (3 eq) at 0C. Then the amine (1.1 eq) was added and stirred at RT for 6h. To the reaction mixture, water was added and the organic layer was separated, washed with saturated NaHCO3, 1N HCl, dried over Na2SO4 and concentrated under reduced pressure. This crude mixture was purified by column chromatography to give the pure compound.