Name: 2213-43-6|1-Aminopiperidine|98%
Brand: Ambeed
SKU: A874021
Price: 14.0 USD
Availability: InStock
Rating: 93 (27 reviews)

1
[ 110-89-4 ]
[ 2213-43-6 ]

Yield	Reaction Conditions	Operation in experiment
96.5%	With sodium hydroxide; hydroxylamine-O-sulfonic acid In water at 20℃;
90%	With sodium hydroxide; chloroamine In water at 55 - 60℃; for 0.00833333h;	1; 2 EXAMPLE 1; Continuous Preparation of N-amino piperidine; All the quantities indicated correspond to an operating unit and relate to one litre of injected hypochlorite. One litre of hypochlorite solution prepared by 50% dilution of a high titer hypochlorite solution (100 to 120° chlorometric degrees, i.e. [NaOCl]=2.14 mol.L-1; [NaCl]=0.85 mol.L-1) and one litre of solution having an ammonia concentration of 3.60 mol.L-1 and ammonium chloride concentration of 2.38 mol.L-1 are continuously added to an agitated reactor (R1) at the rate of 5 mL.min-1 each (i.e. 6 g/min of hypochlorite solution with 48 chlorometric degrees and 5.05 g/min of the ammonia mixture NH3+NH4Cl). The temperature inside the reactor is maintained between -8° C. and -11° C. and the pH of the reaction is close to 10. On leaving R1 a monochloramine solution is obtained with a titer of more than 1 mol.L-1 which corresponds to a yield close to 100% with respect to the sodium hypochlorite. On leaving R1 the monochloramine solution obtained above (2 litres) is alkalinised by continuously adding a concentrated solution of sodium hydroxide (0.37 litre at 30% by weight) to the mixer M with double casing maintained at a low temperature between -9° C. and -11° C. Homogenisation is ensured by magnetic driving. Synthesis of N-amino piperidine is conducted in a monophase medium in an agitated tubular reactor (R2) under a stream of argon or nitrogen. The NH2Cl/NaOH mixture obtained (2.37 litres) and the piperidine solution (2.36 litres at 66% by weight) are simultaneously and continuously added (under argon or nitrogen) to reactor R2 at a suitable rate so that the molar ratio of piperidine to monochloramine is around 8 and the sodium hydroxide titer in the reaction medium at the end of the reaction is 0.3 mol.L-1. The reaction temperature is maintained at approximately 55° C. After 30 seconds reaction, the reaction mixture then undergoes degassing to remove the ammonia contained in the solution. The reaction solution is firstly rid of ammonia by stripping (distillation column CD1, around 62 g ammonia are collected at the head of the column) then approximately 4.6 kg of the ammonia-free solution are distilled at 92.2° C. under atmospheric pressure (distillation column CD2) to remove the amine which has not reacted, the piperidine. After this distillation step, piperidine is obtained at the head of the column in the form of an aqueous solution whose composition is approximately 66% amine. (around 2 kg). This solution is then recycled and immediately re-injected into R2 with no additional treatment (FIG. 1: dotted arrow). After separating the piperidine, the reaction solution containing the hydrazine (collected at the foot of column CD2, approx. 2.7 kg) is treated with the addition of solid sodium hydroxide under cooling and a stream of argon to separate the N-aminopiperidine in an organic phase, its titer being almost 70 to 80% hydrazine at 80° C. The weight percentage of the injected anhydrous sodium hydroxide is preferably between 15 and 30% by weight. Therefore the collection is made of said organic phase having a hydrazine content of nearly 92% and an aqueous phase containing the water and salts (NaCl, NaOH). Depending upon the specifications for use, the concentrated hydrazine solution (organic phase) may then be used directly or distilled under reduced pressure (distillation column CD3). After distillation under reduced pressure, N-aminopiperidine is obtained whose purity is greater than 99.5%. The hydrazine yield with respect to consumed piperidine is greater than 92%.; EXAMPLE 2; Batch Preparation of N-amino piperidine; All the quantities indicated correspond to an operating unit and relate to one litre of injected hypochlorite. The method is characterized in that a solution of ammonium hydroxide and ammonium chloride ([NH3]=3.60 mol.L-1; [NH4Cl]=2.38 mol.L-1; 5 mL/min) is caused to react with an aqueous solution of sodium hypochlorite (rate of 5 mL/min) at a temperature of between -15° C. and -7° C. in an alkaline medium in a continuous agitated reactor R1. The reaction fluid derived from R1 (2 litres) has a titer of more than 1 mol.L-1 monochloramine and is added to a mixer M continuously supplied with a 30% solution of sodium hydroxide (rate 1/75 mL/min). A thermostatic casing maintains a fixed-temperature inside-the mixer of -10° C. Synthesis of N-aminopiperidine is conducted using an agitated tubular reactor R2 under a stream of argon. The alkalinised monochloramine (2.35 litres) derived from the chamber of the mixer M and the amino reagent are simultaneously added at the base of the reactor by means of metering pumps. 1.69 litres of anhydrous piperidine are added i.e. 1.455 kg since the density is 0.861. The addition rate of the anhydrous piperidine is 8.47 mL/min and part of the reaction is conducted in a heterogeneous medium at 55° C. The final NaOH concentration on leaving R2 is 0.3 mol.L-1. The present variant is characterized in that, to the homogeneous reaction liquid (4.04 litres), a quantity of sodium hydroxide is added of between 13 and 30% under cooling so that the temperature does not exceed 60° C. Under these conditions, -two phases are obtained, one light (1.8 kg) contains the entirety of the organics i.e. the N-aminopiperidine and excess piperidine with a titer of around 15 and 20% by weight. With this treatment it is possible to remove between 80 and 85% of the water present in the synthesis solutions. Obtaining N-aminopiperidine then requires two successive steps: collecting the piperidine which has not reacted by distilling the organic phase at atmospheric pressure under argon. Initially approximately 1 kg of concentrated amine solution at 66% by weight is obtained (1) at a temperature of 92.2° C. until exhaustion of the water, then approximately 600 g anhydrous piperidine (1') at a temperature of 105° C. (distillation column CD1'). rectifying the solution obtained at the foot of the column, under 115 mm Hg (distillation column CD2'). After distilling under reduced pressure, N-aminopiperidine is obtained that is more than 99.5% pure. The hydrazine yield with respect to consumed piperidine is greater than 90%.
	With chloroamine

	With potassium hydroxide; hydroxylamine-O-sulfonic acid In water for 0.166667h; Heating;
	With dimethylchloroamine; ammonia at 35℃; for 0.833333h;
	Stage #1: piperidine With sodium hydroxide In water at 55 - 65℃; for 0.25h; Industry scale; Stage #2: With hydroxylamine-O-sulfonic acid In water at 40 - 55℃; for 0.25 - 3.75h;	[0008] In one embodiment of the invention, hydroxylamine-O-sulfonic acid(HOS) is freshly prepared in water. Five portions of HOS (each portion of 28.6 kg, i.e., 252 mol/portion) for a total amount of about 143 kg (260 mol) in water (57 kg per portion, total amount of 285 kg). EPO [0009] A reactor is charged with sodium hydroxide (88 kg, 2210 mol) and water(48 kg, 2650 mol) and then heated to a temperature of 65+/-5 0C to dissolve the sodium hydroxide completely. The sodium hydroxide solution then is cooled to a temperature of 55+/-50C and piperidine (327 kg, 3850 mol) is added. The solution is stirred at a temperature of 55 + 5 0C for 15 min to ensure complete dissolution and then cooled to a temperature of about 40+/-5°C.[0010] The five separate portions of the aqueous hydroxylamine-O-sulfonic acid, described above, is added into the reaction mixture at a temperature of 55+/-5°C over a period of 180+/-60 min. After the addition of the last portion of HOS, the mixture is stirred at 55+/-5°C for an additional time period of 15+/-5 min.[0011] At this point additional sodium hydroxide in an amount of 87 kg (2175 mol) is added and the mixture is stirred at 55+/-5 0C for an additional time period of 30+/-10 min. The contents of the reactor then is emptied and the liquid is pumped back into the reactor at a temperature of 55+/-5°C.[0012] Thereafter, four additional charges of sodium hydroxide are made over time in an amount respectively of 43, 21, 21, 21 kg. The reaction mixture is maintained at a temperature of about 55+/-5°C as these portions of sodium hydroxide are separately added. Before each additional portion of sodium hydroxide is added, the previous addition of sodium hydroxide should be totally dissolved. This may require about 5 to 10 min of stirring before the next portion is added. Once all of the sodium hydroxide has been added and thoroughly mixed, the organic and aqueous phases are allowed to separate. The lower aqueous phase is removed and can be discarded.[0013] Another (fifth) charge of sodium hydroxide (21 kg) then is added at a temperature of about 55+/-5°C and stirred for about 20 min. Any undissolved sodium hydroxide is filtered off at 55+/-5°C and the phases are allowed once again to separate. As before, the lower water phase is removed and discarded. EPO [0014] The recovered organic phase then is cooled to a temperature of about 0 to70C and stirred slowly for a time period of 4+/-1 hours. Any precipitates that form are filtered off and the liquid containing the desired 1-aminopiperidine is recovered. [0015] In accordance with another embodiment of the invention, a freshly prepared portion of Hydroxylamine-0-sulfonic acid, 113 kg, is subdivided into three portions of about 38 kg each (i.e., 0.33 kmol/portion). Each portion is individually added to a previously prepared concentrated aqueous alkaline solution of piperidine (piperidine 272 kg (3.20 kmol), sodium hydroxide 128 kg (3.20 kmol) and water 36 kg (1.99 kmol)). The alkaline piperidine solution is maintained at a temperature of about 55 +/- 5 0C during the HOS addition. After the addition of all three portions is completed, the mixture is stirred at a temperature of about 55 +/- 5 0C for about 15 +/- 5 minutes.[0016] After completing the reaction, the reactor is emptied and the liquid is pumped back into the reactor at a temperature of about 50 + 5 °C. The aqueous and organic phases are separated at 50 + 5 QC and the lower aqueous phase is removed. The upper organic phase contains the desired 1-aminoρiperidine product and is kept at 50 +/- 5 °C for processing. The lower water phase is discarded.[0017] Sodium hydroxide 48 kg (1.20 kmol) is added to the organic phase at a temperature of 50 +/- 5 0C and stirred for 20 min. Any undissolved sodium hydroxyde is filtered off at 50 +/- 5 0C, and the aqueous and organic phases which form are separated at 50 +/- 5 0C. Again, the lower aqueous phase is removed.[0018] Another portion of sodium hydroxide 22 kg (0.55 kmol) is added to the organic phase at a temperature of about 50 +/- 5 0C and stirred for 20 min. Any undissolved sodium hydroxyde is filtered off at a temperature of 50 +/- 5 0C, and the phases are allowed to separate at a temperature of 50 +/- 5 0C. Once again, the lower aqueous phase is removed and discarded. EPO [0019] At this point, the organic phase is cooled to a temperature of about 5 +20C and stirred slowly. During this time, solid impurities and sodium hydroxide precipitates form and they are filtered off at a temperature of 5+ 2 0C. The remaining organic liquid phase contains the desired N-Aminopiperidine in unreacted piperidine and is recovered as the product.
	With chloroamine; sodium hydroxide In water at 25℃;
	Multi-step reaction with 2 steps 1: sodium nitrite; hydrogenchloride / water; tetrahydrofuran / 4 h / 0 - 25 °C 2: zinc; acetic acid / water / 5 h / 0 °C
	With sodium hydroxide; sulfoperamic acid
	Multi-step reaction with 2 steps 1: sodium nitrite; hydrogenchloride / water; tetrahydrofuran / 4 h / 25 °C 2: zinc; acetic acid / water / 5 h / 0 °C

Reference： [1]Location in patent: scheme or table Labarthe; Bougrine; Pasquet; Delalu [Kinetics and Catalysis, 2012, vol. 53, # 1, p. 25 - 35]
[2]Current Patent Assignee: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; UNIVERSITY OF LYON; SAFRAN - US2007/249829, 2007, A1 Location in patent: Page/Page column 4-5
[3]Forster [Journal of the Chemical Society, 1915, vol. 107, p. 267] Omietanski et al. [Journal of the American Chemical Society, 1956, vol. 78, p. 3874,3875]
[4]Brehme, Rainer [Chemische Berichte, 1990, vol. 123, # 10, p. 2039 - 2046]
[5]Stephan, Juliette; Berthet, Jacques; Goutelle, Veronique; Pasquet, Veronique; Delalu, Henri [Journal of Chemical Research, 2005, # 12, p. 808 - 812]
[6]Current Patent Assignee: PERMIRA HOLDINGS LIMITED - WO2006/115456, 2006, A1 Location in patent: Page/Page column 2-4
[7]Darwich; Elkhatib; Pasquet; Delalu [Kinetics and Catalysis, 2013, vol. 54, # 6, p. 649 - 655]
[8]Wu, Yachuang; Ding, Xiudong; Ding, Liang; Zhang, Yongsheng; Cui, Lei; Sun, Lu; Li, Wei; Wang, Di; Zhao, Yanfang [European Journal of Medicinal Chemistry, 2018, vol. 158, p. 247 - 258]
[9]Current Patent Assignee: FRITZ SOMMER DR; OTTO FRITZ SCHULZ DR - DE338609, 1921, C [Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 13, p. 205][Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 13, p. 205]
[10]Wu, Yachuang; Ding, Xiudong; Yang, Yifeng; Li, Yingxiu; Qi, Yinliang; Hu, Feng; Qin, Mingze; Liu, Yajing; Sun, Lu; Zhao, Yanfang [European Journal of Medicinal Chemistry, 2020, vol. 185]

2
[ 100-75-4 ]
[ 2213-43-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	With zinc powder In glacial acetic acid
92%	With carbon dioxide; water monomer; ammonia hydrochloride; zinc powder at 35℃; for 1.5h; Autoclave; Green chemistry;	Synthesis of N-amino aza-aliphatic cyclic compounds 2a-c, 5a,b, 7a,b, and 9 General procedure: A solution ofN-nitroso aza-aliphatic cyclic compound 1a-c, 4a,b, 6a,b, or 8 (1.0 mol) in H2O (250 ml) was placed into a 1-l autoclave equipped with a CO2 ventilation device, a gas flow meter, and a barometer. NH4Cl (5.35 g, 0.1 mol) was added to the solution and the system was charged with CO2 at a flow rate 30 l/h. After stirring for 20 min, the mixture was heated to 35°C and zinc powder (163 g, 2.5 mol) was added in portions (16.3 g every 6 min). The pressure in the closed system was maintained at 0.2 MPa and temperature at 35°C. After addition of all zinc (about 1 h), the reaction mixture was stirred at 35°C for 0.5 h and then analyzed by GC. The resulting ZnCO3 was filtered off and washed with H2O (150 ml). The filtrate was transferred to a 1-l three neck round-bottom flask, H2O was removed under reduced pressure, and vacuum distillation at 60-135 °C (internal temperature) was performed to afford products 2a-c, 5a,b, 7a,b, and 9.
71%	With titanium(III) trichloride In water monomer for 1h; Ambient temperature;

	With tetrahydrofuran; lithium aluminium hydride
	With lithium aluminium hydride; diethyl ether
	With titanium(III) trichloride; water monomer In ethanol at 20℃; for 1h; Inert atmosphere;
	With glacial acetic acid; zinc powder In water monomer at 0℃; for 5h;	4 5.1.5.2 General procedure for the preparation of intermediates 8a-e General procedure: To a well-stirred solution of an appropriate intermediate (7a-e) (0.10mol) in a mixed solution of AcOH (100mL) and H2O (100mL) was added zinc powder (26.2g,0.40mol) at 0°C, followed by stirring for 6-8hat the same temperature. After completion of the reaction as indicated by TLC, the resulted mixture was filtered and the filtrate was concentrated under reduced pressure. Then ethyl acetate (100mL) was added and the misture was stirred for 0.5hat the room temperature. The mixture was filtered, and the filtrate was concentrated under reduced presusre to yield the corresponding intermediates 8a-e.
	With glacial acetic acid; zinc powder In water monomer at 0℃; for 5h;
	With glacial acetic acid; zinc powder In methanol at 20℃; for 2h; Inert atmosphere;	N-Nitrosamine Reduction by Zn. General procedure: Following a modified and reported procedure,33 zinc powder and N-nitrosamine were mixed in methanol/acetic acid mixture (v/v 8:1), and stirred for 2 h at room temperature for reduction under nitrogen protection. After reaction, the zinc powder was removed by filtration or centrifugation.

Reference： [1]Auelbekov, S. A.; Mirzaabdullaev, A. B.; Aslanova, D. Kh.; Kurchakov, S.; Achilova, G. Sh. [Pharmaceutical Chemistry Journal, 1985, vol. 19, # 7, p. 479 - 481][Khimiko-Farmatsevticheskii Zhurnal, 1985, vol. 19, # 7, p. 829 - 832]
[2]Yang, Weiqing; Lu, Xiang; Zhou, Tingting; Cao, Yongjing; Zhang, Yuanyuan; Ma, Menglin [Chemistry of Heterocyclic Compounds, 2018, vol. 54, # 8, p. 780 - 783][Khim. Geterotsikl. Soedin., 2018, vol. 54, # 8, p. 780 - 783,4]
[3]Lunn, George; Sansone, Eric B.; Keefer, Larry K. [Journal of Organic Chemistry, 1984, vol. 49, # 19, p. 3470 - 3473]
[4]Hanna; Schueler [Journal of the American Chemical Society, 1952, vol. 74, p. 3693]
[5]Zimmer et al. [Journal of the American Chemical Society, 1955, vol. 77, p. 790]
[6]Zhang, Yan; Tang, Qiang; Luo, Meiming [Organic and Biomolecular Chemistry, 2011, vol. 9, # 13, p. 4977 - 4982]
[7]Wu, Yachuang; Ding, Xiudong; Ding, Liang; Zhang, Yongsheng; Cui, Lei; Sun, Lu; Li, Wei; Wang, Di; Zhao, Yanfang [European Journal of Medicinal Chemistry, 2018, vol. 158, p. 247 - 258]
[8]Wu, Yachuang; Ding, Xiudong; Yang, Yifeng; Li, Yingxiu; Qi, Yinliang; Hu, Feng; Qin, Mingze; Liu, Yajing; Sun, Lu; Zhao, Yanfang [European Journal of Medicinal Chemistry, 2020, vol. 185]
[9]Wang, Qi; Liu, Zhijian; Liu, Yong; Chen, Hao [Journal of the American Society for Mass Spectrometry, 2022, vol. 33, # 5, p. 875 - 884]

3
[ 39565-00-9 ]
[ 2213-43-6 ]
1-[1-(5-nitro-[2]thienyl)-ethylLiDenamino]-piperidine [ No CAS ]

Reference： [1]Gazzetta Chimica Italiana,1953,vol. 83,p. 609,610, 614

4
[ 2213-43-6 ]
[ 123-11-5 ]
[ 14492-08-1 ]

Yield	Reaction Conditions	Operation in experiment
96%	With magnesium sulfate In dichloromethane at 20℃;
	With acetic acid
	With potassium hydroxide In ethanol for 2h; Heating; pH 8-9; Yield given;

at 25℃; for 2.5h;

Reference： [1]Vega, Juan A.; Alonso, José Manuel; Méndez, Gabriela; Ciordia, Myriam; Delgado, Francisca; Trabanco, Andrés A. [Organic Letters, 2017, vol. 19, # 4, p. 938 - 941]
[2]Weinhagen [Journal of the Chemical Society, 1918, vol. 113, p. 586]
[3]Brehme, Rainer [Chemische Berichte, 1990, vol. 123, # 10, p. 2039 - 2046]
[4]Breuil-Desvergnes, Valérie; Goré, Jacques [Tetrahedron, 2001, vol. 57, # 10, p. 1939 - 1950]

5
[ 106-88-7 ]
[ 524-95-8 ]
[ 2213-43-6 ]
[ 21862-34-0 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1969,vol. 721,p. 231 - 233

6
[ 590-92-1 ]
[ 2213-43-6 ]
bis(1-aminopiperidinium) 2-oxo-1-aza-5-azoniaspiro<4,5>decane tribromide [ No CAS ]

Reference： [1]Australian Journal of Chemistry,1980,vol. 33,p. 1365 - 1372

7
[ 2213-43-6 ]
[ 10318-18-0 ]
[ 13553-79-2 ]
[ 72676-34-7 ]

Reference： [1]European Journal of Medicinal Chemistry,1981,vol. 16,p. 301 - 306

8
[ 2213-43-6 ]
[ 10111-08-7 ]
[ 125142-73-6 ]

Reference： [1]European Journal of Medicinal Chemistry,1989,vol. 24,p. 313 - 316

9
[ 3056-18-6 ]
[ 2213-43-6 ]
[ 203384-12-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1997,vol. 7,p. 3085 - 3090

10
[ 2213-43-6 ]
[ 292638-85-8 ]
[ 71365-42-9 ]

Yield	Reaction Conditions	Operation in experiment
43%	In methanol at 20℃;	1.1 To a solution of 1-aminopiperidine (100 g, 1.00 mol) in dry methanol at 0 0C, methyl acrylate (99.0 ml, 1.10 mol) was added dropwise. The resulting mixture-was stirred at room temperature overnight. After evaporation of the solvent, heptane was added to the residue, and the white solid (impurity) removed by filtration. The filtrate was concentrated to dryness to afford 80.0 g (43%) of the title compound as a yellow oil.
43%	In methanol at 20℃;	1.1 Step 1 3-(Piperidin-1-ylamino)-propionic acid methyl ester To a solution of 1-aminopiperidine (100 g, 1.00 mol) in dry methanol at 0° C., methyl acrylate (99.0 ml, 1.10 mol) was added dropwise. The resulting mixture was stirred at room temperature overnight. After evaporation of the solvent, heptane was added to the residue, and the white solid (impurity) removed by filtration. The filtrate was concentrated to dryness to afford 80.0 g (43%) of the title compound as a yellow oil.
43%	In methanol at 0 - 20℃;	1.1 Example 14-[l-(2,4-dichlorophenv0-3-methyl-4-oxo-5-piperidin-l-yl-4,,5,6,7-tetrahvdro-lH- pyrrolo[3,2-c]pyridin-2-yl\| phenyl propane-1-sulfonate Step 1 3-(Piperidin-l-ylamino)-propionic acid methyl ester; To a solution of 1 -aminopiperidine (100 g, 1.00 mol) in dry methanol at 00C, methyl acrylate (99.0 ml, 1.10 mol) was added dropwise. The resulting mixture was stirred at room temperature overnight. After evaporation of the solvent, heptane was added to the residue, and the white solid (impurity) removed by filtration. The filtrate was concentrated to dryness to afford 80.0 g (43%) of the title compound as a yellow oil. Alternatively this reaction was performed at 5O0C using toluene as the solvent with a 0.7 molar excess of 1- aminopiperidine. Excess 1-aminopiperidine was removed from the residue by co- distillation with xylene, then toluene and then hexane.

43%	In methanol at 0 - 20℃;	1.A Step A 3-(Piperidin-l-ylamino)propionic acid methyl esterTo a solution of 1-aniinopiperidine (100 g, 1.00 mol) in dry methanol at 0 0C, methyl acrylate (99.0 ml, 1.10 mol) was added dropwise. The resulting mixture was stirred at room temperature overnight. After evaporation of the solvent, heptane was added to the residue, and the white solid (impurity) removed by filtration. The filtrate was concentrated to dryness to afford 80.0 g (43%) of the title compound as a yellow oil.
	In methanol at 0 - 20℃; for 16h;

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/39740, 2007, A2 Location in patent: Page/Page column 23
[2]Current Patent Assignee: ASTRAZENECA PLC - US2008/262026, 2008, A1 Location in patent: Page/Page column 11
[3]Current Patent Assignee: ASTRAZENECA PLC - WO2008/120000, 2008, A1 Location in patent: Page/Page column 8; 32
[4]Current Patent Assignee: ASTRAZENECA PLC - WO2008/96151, 2008, A1 Location in patent: Page/Page column 34
[5]Smith, Roger A.; Fathi, Zahra; Brown, Su-Ellen; Choi, Soongyu; Fan, Jianmei; Jenkins, Susan; Kluender, Harold C.E.; Konkar, Anish; Lavoie, Rico; Mays, Ronald; Natoli, Jennifer; O'Connor, Stephen J.; Ortiz, Astrid A.; Podlogar, Brent; Taing, Christy; Tomlinson, Susan; Tritto, Theresa; Zhang, Zhonghua [Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 3, p. 673 - 678]

11
[ 951330-76-0 ]
[ 2213-43-6 ]
(8E)-1-(2,4-dichloro-phenyl)-8-(4-fluoro-benzylidene)-3-(piperidin-1-ylcarbamoyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.6%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃;	1 Compound Ih (0.1 g, 0.19 mmol) was taken up in D3VIF (5 niL) in a 50 niL round bottom flask, then EDCI (54 mg, 0.28 mmol) and HOBt (31 mg, 0.23 mmol) were added in one portion and the mixture was stirred for 0.5 hr. Piperidin-l-ylamine Compound Ii (50 mg, 0.5 mmol), Et3N (0.1 mL, 0.7 mmol) and a catalytic amount of DMAP (5 mg) were added. The mixture was stirred overnight at room temperature and diluted with EtOAc, then washed with IN HCl (5 x 0 mL) and brine. The organic layer was dried over sodium sulfate, then filtered, concentrated and purified on silica gel column with 40% EtOAc/Hexane to give Compound 2 (0.1 g, 86.6%). MS 614 (MH+)

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2007/112402, 2007, A1 Location in patent: Page/Page column 43; 46

12
[ 909871-48-3 ]
[ 2213-43-6 ]
[ 909872-24-8 ]

Yield	Reaction Conditions	Operation in experiment
86.4%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In N,N-dimethyl-formamide at 20℃; for 24h;	2.14.1 The First Step: Preparation of 2,4-bis-benzyloxy-5-isopropyl-N-piperidin-1-yl-benzamide (F67-02) 2,4-bis-benzyloxy-5-isopropylbenzoic acid (F67-01: 188 mg, 0.5 mmol), dimethylformamide (2 mL) and 1-hydroxy-1,2,3-benzotriazole (72 mg, 0.55 mmol) were placed in a test tube and then 1-amino-piperidine (0.059 mL, 0.55 mmol) was added. A mixed solution of dimethylformamide (1 mL), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (105 mg, 0.55 mmol) and triethylamine (0.15 mL, 1.1 mmol) was slowly added to the reaction mixture at 0°C while stirring. Further, the reaction mixture was allowed to come to room temperature and stirred for 24 hours. After completing the reaction, the reaction mixture was extracted with ethyl acetate, and the extract was washed 4 times with saturated sodium chloride, dried with sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol) followed by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (F67-02: 198 mg, 86.4%). LC/MS (Method 5): m/z(ESI, POS): 459[M+H]+; retention time: 7.44 minutes.

Reference： [1]Current Patent Assignee: NIPPON KAYAKU CO LTD - EP1857446, 2007, A1 Location in patent: Page/Page column 57

13
[ 1003004-79-2 ]
[ 2213-43-6 ]
1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-5-(selenophen-2-yl)-1H-pyrazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine In dichloromethane at 0 - 20℃; for 3h;	1 The carboxylic chloride dissolved in dichloromethane (5 mL) was added dropwise to a mixture of 1-aminopiperidine (42.7 μL, 0.39 mmol) and triethylamine (56.5 μL, 0.39 mmol) in 5 mL of dichloromethane at 0° C. After stirring at room temperature for 3 hours, the reaction was quenched with water. The aqueous layer was separated and extracted with dichloromethane (2×10 mL). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product, which was purified by flash column chromatography on silica gel with n-hexane/ethyl acetate (2:1) to give compound 1 as a white solid (86 mg, 75%). 1H-NMR (CDCl3, ppm): 7.96 (d, 1H), 7.56 (s, 1H), 7.46 (s, 2H), 7.21-7.12 (m, 3H), 6.80 (d, 1H), 4.43-4.36 (m, 1H), 2.10-2.01 (m, 2H), 1.74-1.47 (m, 6H). ES-MS (M+1): 469.0.

Reference： [1]Current Patent Assignee: NATIONAL HEALTH RESEARCH INSTITUTES - US2008/21031, 2008, A1 Location in patent: Page/Page column 12; 13

14
[ 2213-43-6 ]
[ 168273-05-0 ]
[ 158681-13-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-Aminopiperidine; 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride With sodium hydroxide In dichloromethane; water at 10 - 25℃; for 2 - 3.5h; Stage #2: With hydrogenchloride In water; acetone at 20 - 25℃; for 0.5h;	II Step-li:; 1-Aminopiperidine (33 gm), 30% NaOH solution (333 ml) and tetra-n- butylammonium bromide (5 gm) are added to methylene chloride (1115 ml) under stirring at 25 - 300C, the contents are cooled to 100C and then the solution resulted in the step-l is slowly added for 1 hour to 1 hour 30 minutes at 10 - 150C. The reaction mass temperature is raised to 250C, stirred for 1 - 2 hours and separated the layers. The resulting organic layer is washed with 10% NaCI solution (300 ml) and then subjected to carbon treatment at 25 - 300C. The celite bed is washed with methylene chloride (200 ml), the resulting organic layer is dried on Na2SO4, distilled under vacuum at 400C and then co-distilled with acetone (100 ml). The residue is dissolved in acetone (725 ml), pH of the mass is adjusted to 2.0 with cone. HCI (25 ml) and then stirred for 30 minutes at 20 - 250C. Filtered the solid, washed with 50 ml of acetone and then dried to give 120 gm of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin- 1-yl)-pyrazole-3-carboxamide hydrochloride (rimonabant hydrochloride, HPLC purity: 99.7%).
33 g	Stage #1: 1-Aminopiperidine; 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl chloride With triethylamine In dichloromethane at 10 - 20℃; for 1h; Stage #2: With hydrogenchloride
	Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 3 h / 0 - 20 °C 2: hydrogenchloride / diethyl ether / pH 1

With TEA In dichloromethane at 0 - 20℃; for 0.5h;

Reference： [1]Current Patent Assignee: HETERO DRUGS LIMITED - WO2008/32330, 2008, A2 Location in patent: Page/Page column 7
[2]Location in patent: experimental part Fang, Zheng; Yang, Zhao; Xu, Jia-Feng; Guo, Kai; Wei, Ping [Organic Preparations and Procedures International, 2012, vol. 44, # 2, p. 164 - 168]
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2008/130630, 2008, A2
[4]Rodríguez-Soacha, Diego A.; Fender, Julia; Ramírez, Yesid A.; Collado, Juan Antonio; Muñoz, Eduardo; Maitra, Rangan; Sotriffer, Christoph; Lorenz, Kristina; Decker, Michael [ACS Chemical Neuroscience, 2021, vol. 12, # 9, p. 1632 - 1647]

15
[ 2213-43-6 ]
[ 5044-52-0 ]
triphenyl[2-(piperidinoamino)ethyl]phosphonium bromide [ No CAS ]
triphenyl[2-(piperidinoamino)vinyl]phosphonium bromide [ No CAS ]

Reference： [1]Russian Journal of General Chemistry,2006,vol. 76,p. 1393 - 1396

16
[ 2213-43-6 ]
[ 131818-17-2 ]
C₁₆H₂₅N₃O₂ [ No CAS ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 8409 - 8412

17
[ 2213-43-6 ]
[ 125971-96-2 ]
C₃₁H₃₂FN₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With toluene-4-sulfonic acid In cyclohexane for 5h; Heating;

Reference： [1]Sagyam, Rajeshwar Reddy; Vurimidi, Himabindu; Padi, Pratap Reddy; Ghanta, Mahesh Reddy [Journal of Heterocyclic Chemistry, 2007, vol. 44, # 4, p. 923 - 926]

18
[ 35265-83-9 ]
[ 2213-43-6 ]
[ 221043-56-7 ]

Yield	Reaction Conditions	Operation in experiment
59.4%	In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; N,N-dimethyl-formamide;	Reference Example 35 2-Chloro-7-methyl-4-piperidinoaminothieno[3,2-d] pyrimidine In DMF (N,N-dimethylformamide) was dissolved 700 mg (3.4 mmol) of 2,4-dichloro-7-methylthieno[3,2-d] pyrimidine, and then a solution of 751 mg (7.5 mmol) of 1-aminopiperidine was added dropwise to the resulting solution under ice cooling over 5 minutes. The reaction solution was stirred at 0C. for one hour and then allowed to resume room temperature, followed by stirring for further one hour. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml*3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane= 1/8) to give 573 mg (yield: 59.4%) of the title compound. NMR (delta, CDCl3): 1.20-1.28 (1H, m), 1.76-1.91 (5H, m), 2.41 (3H, s), 2.44-2.49 (2H, m), 3.17-3.20 (2H, m), 6.46 (1H, s), 7.46 (1H, s)

Reference： [1]Patent: US2001/6969,2001,A1
[2]Patent: US6339089,2002,B2 .Location in patent: Referential example 35

19
[ 811441-30-2 ]
[ 2213-43-6 ]
[ 811441-31-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine In dichloromethane at 20℃; for 60h;	19.D Step D 3-(azidomethyl)-5,6-bis(4-chlorophenyl)-N-piperidin-l-vlpvrazine-2-carboxarnide A mixture of 1-aminopiperidine (687.1 mg, 5.03 mmol), TEA (1.36 ml, 9.75 mmol) andDCM (10 ml) was added to 3-(azidomethyl)-5,6-bis(4-chlorophenyl)pyrazine-2-carbonylchloride (1.0 g, 2.44 mmol) dissolved in DCM (10 ml). The reaction mixture was stirred atrt for 2.5 days whereafter the organic phase was extracted twice with water before thesolvent was removed under reduced pressure. The residue was purified by flashchromatography (SiO2, DCM:ethyl acetate, 0 % to 7 % ethyl acetate) to yield the titlecompound (1005 mg, 85 %) as a pale yellow powder.1E NMR (400 MHz, CDC13) 5 8.54 (1H, s), 7.41 (8H, m), 5.12 (2H, s), 2.90 (4H, s), 1.78(4H,m), 1.47(2H,s).MS m/z 482, 484,486 (M+H)+.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2004/111034, 2004, A1 Location in patent: Page 51

20
[ 109812-64-8 ]
[ 2213-43-6 ]
1-[(2-methyl-1, 5-diphenyl-1H-pyrrole-3-yl)carbonyl]piperidine [ No CAS ]
2-methyl-1, 5-diphenyl-N-piperidin-1-yl-1H-pyrrole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 7% 2: 31%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In DMF (N,N-dimethyl-formamide); dichloromethane at 0 - 20℃;	10a; 10b The crude 2-methyl-1, 5-DIPHENYL-LH-PYRROLE-3-CARBOXYLIC acid (236 mg, 0.85 mmol) from Preparation C (a) and 4-dimethylaminopyridine (47 mg, 0.38 mmol) were dissolved in CH2C12 (5 ML) and DMF (0.142 mL) and 1-AMINOPIPERIDINE (0.218 ML, 2.18 mmol) was added. The solution was cooled to 0°C. A slurry of l-ethyl-3- (3-dimethylaminopropyl)- carbodiimide hydrochloride (360 MG, 01.88 mmol) IN CH2CL2 (2. 4 ML) and DMF (0.189 mL) was added dropwise. The mixture was allowed to attain room temperature, and was stirred overnight. The mixture was diluted with CH2CL2, washed with NAZHCOS (sat, AQ) and the phases were separated. The organic phase was concentrated and the residue was purified by semipreparative HPLC to give 10a (20 MG, 7%), and 10b (91 mg, 31%). 10A HAD : 1H-NMR (CD30D) 6 7.41 (M, 3H), 7.20-7. 04 (m, 7H), 6.68 (s, 1H), 2.84 (brs, 4H), 2.32 (s, 3H), 1.74 (m, 4H), 1. 46 (brs, 2H). MS m/z 360 (M+H) +. 10B HAD : 1H-NMR (CDSOD) 8 7.41 (M, 3H), 7.20-7. 04 (M, 7H), 6.37 (s, 1H), 3.70 (t, 4H), 2.32 (s, 3H), 1.74 (M, 2H), 1.65 (brs, 4H). MS INIZ 345 (M+H) +.
1: 7% 2: 31%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃;	10a; 10b The crude 2-methyl-1, 5-diphenyl-lH-pyrrole-3-carboxylic acid (236 mg, 0.85 mmol) from Preparation C (a) and 4-DIMETHYLAMINOPYRIDINE (47 mg, 0.38 mmol) were dissolved in CH2C12 (5 ML) and DMF (0.142 mL) and 1-AMINOPIPERIDINE (0.218 ML, 2.18 mmol) was added. The solution was cooled to 0 C. A slurry of 1-ethyl-3- (3-dimethylaminopropyl)- carbodiimide hydrochloride (360 mg, 01. 88 mmol) in CHZCLZ (2.4 mL) and DMF (0.189 mL) was added dropwise. The mixture was allowed to attain room temperature, and was stirred overnight. The mixture was diluted with CH2C12, washed with Na2HCO3 (sat, AQ) and the phases were separated. The organic phase was concentrated and the residue was purified by semipreparative HPLC to give 10a (20 mg, 7%), and 10B (91 mg, 31%). 10a had : IH-NMR (CD30D) 6 7.41 (m, 3H), 7.20-7. 04 (M, 7H), 6.68 (s, 1H), 2.84 (brs, 4H), 2.32 (s, 3H), 1.74 (M, 4H), 1. 46 (brs, 2H). MS INTO 360 (M+H) +. 10b HAD: 1H-NMR (CD3OD) No. 7.41 (M, 3H), 7. 20-7. 04 (M, 7H), 6.37 (S, 1H), 3.70 (T, 4H), 2.32 (s, 3H), 1.74 (M, 2H), 1.65 (brs, 4H). MS MLZ 345 (M+H) +.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2004/58249, 2004, A1 Location in patent: Page/Page column 21-22
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2004/69227, 2004, A1 Location in patent: Page/Page column 39

21
[ 861151-23-7 ]
[ 2213-43-6 ]
1-(4-chloro-phenyl)-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid piperidine-1-ylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃; for 16h;	1.D Part D: To a stirred suspension of 1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxylic acid (1.50 gram, 5 mmol) in anhydrous acetonitrile (40 ml) is successively added N-diisopropylethylamine (DIPEA) (1.92 ml, 11 mmol), O-benzotriazol-1-yl-N,N, N',N'-tetramethyluronium hexafluorophosphate (HBTU) (2.08 g, 5.5 mmol) and 1-aminopiperidine (0.59 ml, 5.5 mmol) and the resulting mixture is reacted at room temperature for 16 hours in a N2 atmosphere. The mixture is concentrated and added to a mixture of ethyl acetate and aqueous NaHCO3. The Ethyl acetate layer is collected, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is recrystallized from acetonitrile to give N-(piperidin-1-yl)-1-(4-chlorophenyl)-5-phenyl-4,5-dihydro-(1H)-pyrazole-3-carboxamide (compound 1), 1.34 gram, 70% yield). Melting point: 189-192° C. I

Reference： [1]Current Patent Assignee: ABBVIE INC - US2005/171179, 2005, A1 Location in patent: Page/Page column 7

22
[ 16321-99-6 ]
[ 2213-43-6 ]
[ 151666-19-2 ]

Yield	Reaction Conditions	Operation in experiment
71%	With triethylamine In 1,4-dioxane	9 2-Fluoro-N-(1-piperidinyl)adenosine EXAMPLE 9 (METHOD C) 2-Fluoro-N-(1-piperidinyl)adenosine 9-(2',3',5'-Tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloro-(9H)-purine (6.0 g, 14 mmol) (prepared as described by Robins, M. J. and Uznanski, B., in Nucleic Acid Chemistry (Townsend, L. B. and Tipson, R. S., eds.,) John Wiley and Sons, Inc., 1986, 3, 144) was dissolved in dioxan (100 ml). 1-Aminopiperidine (1.83 ml, 16.95 mmol) was added followed by triethylamine (2.33 ml, 18.5 mmol) and the solution was stirred for 190 hours at room temperature. The reaction mixture was filtered, evaporated and the resultant residue was purified by column chromatography on silica gel eluding with ethyl acetate/cyclohexane (3/1) to afford 2',3',5'-tri-O-acetyl-2-amino-N-(1-piperidinyl)adenosine (4.88 g, 71%) as a foam which solidified on coevaporation with methanol: m.p. 77°-79° C. 1 H NMR (400 MHz, Me2 SO-d6) δ2.04 (6H, s, 2' and 3'-O-acetyl-CH3), 2.13 (3H, s, 5'-O-acetyl-CH3), 4.30 (2H, m, H-5'a and H-4'), 4.40 (1H, dd, H-5'b) 6.03 (1H, d, H-1').

Reference： [1]Current Patent Assignee: NOVO NORDISK A/S - US5432164, 1995, A

23
[ 895582-45-3 ]
[ 2213-43-6 ]
1-(2,4-dichlorophenyl)-4-hvdroxymethyl-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	Stage #1: 1-(2,4-dichlorophenyl)-4-hydroxymethyl-5-(4-methoxyphenyl)-1H-pyrazole-3-carboxylic acid ethyl ester; 1-Aminopiperidine With aluminum (III) chloride In 1,2-dichloro-ethane at 0 - 20℃; Stage #2: With water	1.D l-(2,4-DichlorophenylV4-hvdroxymethyl-5-('4-methoxyphenvD-lH-pyrazole-3- carboxylic acid piperidin-1-ylamide To a magnetically stirred suspension of aluminium chloride (1.64 g, 12.3 mmol) in 1,2- dichloroethane (25 ml) was added 1-aminopiperidine (2.66 ml, 24.6 mmol) at 0 0C. The suspension was allowed to warm to room temperature and a solution of l-(2,4-dichloro- phenyl)-4-hydroxymethyl-5-(4-methoxyphenyl)-l/i'-ρyrazole-3-carboxylic acid ethyl ester (2.59 g, 6.15 mmol) in 1,2-dichloroethane (25 ml) was added. The reaction mixture was stirred at room temperature overnight, then water was added carefully and the product extracted with DCM (x3). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Flash chromatography (Ηexane : EtOAc 50 : 50 - EtOAc) afforded 2.17 g (74%) of the title compound as a colorless solid. Step E: 4-Bromomethyl-l-(2,4-dichlorophenyl')-5-('4-hvdroxyphenvD-5-lH-pyrazole-3- carboxylic acid piperidin-1-ylamide

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2006/67443, 2006, A1 Location in patent: Page/Page column 35

24
[ 895582-60-2 ]
[ 2213-43-6 ]
1-(2,4-dichloro-phenyl)-4-hydroxymethyl-5-(4-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With aluminum (III) chloride In 1,2-dichloro-ethane at 0 - 60℃; for 1h;	5.F To a suspension OfAlCl3 (1.59 g, 11.9 mmol) in 1,2-dichloroethane (20 ml) at 0 0C was added 1-aminopiperidine (2.38 g, 23.8 mmol). The reaction mixture allowed to reach room temperature and a solution of l-(2,4-dichlorophenyl)-4~hydroxymethyl-5-(4- hydroxyphenyl)-lH"-pyrazole-3-carboxylic acid methyl ester (1.17 g, 2.98 mmol) in 1,2- dichloroethane (20 ml) added. The reaction mixture was heated 1 hour at 60 0C, cooled to room temperature, poured into ice-water, and extracted with DCM (x3). The combined organic extracts were washed with water , dried (Na2SO4), filtered and concentrated. Flash chromatography (EtOAc) produced 1.00 g (73%) of the title compound as a pale yellow solid.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2006/67443, 2006, A1 Location in patent: Page/Page column 43

25
5-(5-chlorothiophen-2-yl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazol-3-carbonyl chloride [ No CAS ]
[ 2213-43-6 ]
5-(5-Chloro-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3-carboxylic acid piperidin-1-ylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	With triethylamine In dichloromethane at 0 - 20℃;	1 Crude 5-(5-chlorothiophen-2-yl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazol-3- carboxylic acid (0.25 g, 0.66 mmol) was dissolved several times in 5 ml_ of anhydrous toluene and the solvate was removed in vacuo. The acid was dissolved in 3 ml_ of anhydrous toluene under nitrogen atmosphere, and thionylchloride (0.8 ml_, 4.86 mmol, 16 equiv) and anhydrous dimethylformamide (55 μl_) were added. The reaction mixture was heated at reflux and monitored by IR (NaCI, film). After 2 h reaction mixture was left to cool to room temperature and the solvents were evaporated to dryness under high vacuum. The desired product 5-(5-chlorothiophen- 2-yl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazol-3-carbonyl chloride (0.19 g, 74%) was obtained as a dark oil and used for the next step without further purification.IR (NaCI, film) υ: 802, 1106, 1213, 1477, 1735 cm'1Triethylamine (0.4 mL, 6 equiv.) was added drop wise to a solution of N- aminopiperidine (71 μl_, 0.66 mmol, 1.3 equiv.) in anhydrous dichloromethane (3.5ml_). The mixture was cooled in an ice bath and a solution of 5-(5-chlorothiophen- 2-yl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazol-3-carbonyl chloride (0.19 g, 0.48 mmol, 1 equiv.) in anhydrous DCM (3.5 mL) was added. After 15 min the ice bath was removed and the reaction was left stirring at room temperature overnight. The solution was poured in a separating funnel and washed once with water, with a saturated aqueous solution of NaHCU3 and again with water, dried over Na2SO4 and evaporated to dryness to give 0.22 g of the crude product. EPO Purification by column chromatography (SiO2 with 2.5% v/v of Et3N1 30:1 ratio SiO2: product, packed with 5% ethylacetate/hexane and eluted with a gradient of 5% ethylacetate/hexane to 20% ethylacetate/hexane) provided racemic Λ/-(piperidin-1- yl)-5-(5-chlorothiophen-2-yl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3- carboxamide (35 mg, 16% yield, 81 % pure by HPLC) as a dark oil.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (m, 2 H) 1.76 (dt, J=11.23, 5.71 Hz, 4 H) 2.84 (m, 4 H) 3.45 (dd, J=18.17, 4.69 Hz, 1 H) 3.61 (dd, J=18.17, 11.14 Hz, 1 H) 5.93 (dd, J=11.14, 4.69 Hz, 1 H) 6.57 (m, 2 H) 7.06 - 7.19 (m, 2 H) 7.32 (d, J=2.15 Hz, 1 H) 7.40 (m, 1 H)13C NMR (100 MHz, CDCI3): δ 23.4 (CH2), 25.3 (CH2), 40.5 (CH2), 57.3 (CH2), 63.7 (CH), 125.7 (CH), 125.8 (CH), 126.1 (CH), 127.1 (C), 127.8 (CH), 130.1 (CH), 131.1 (C), 139.6 (C), 139.9 (C), 146.1 (C), 158.9 (CO).IR (NaCI, film) υ 1476, 1663, 2833, 2938 cϖf1MS (M+H)+: 457
16%	With triethylamine In dichloromethane at 0 - 20℃;	1 Triethylamine (0.4 mL, 6 equiv.) was added drop wise to a solution of N-aminopiperidine (71 µL, 0.66 mmol, 1.3 equiv.) in anhydrous dichloromethane (3.5mL). The mixture was cooled in an ice bath and a solution of 5-(5-chlorothiophen-2-yl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazol-3-carbonyl chloride (0.19 g, 0.48 mmol, 1 equiv.) in anhydrous DCM (3.5 mL) was added. After 15 min the ice bath was removed and the reaction was left stirring at room temperature overnight. The solution was poured in a separating funnel and washed once with water, with a saturated aqueous solution of NaHCO3 and again with water, dried over Na2SO4 and evaporated to dryness to give 0.22 g of the crude product. Purification by column chromatography (SiO2 with 2.5% v/v of Et3N, 30:1 ratio SiO2: product, packed with 5% ethylacetate/hexane and eluted with a gradient of 5% ethylacetate/hexane to 20% ethylacetate/hexane) provided racemic N-(piperidin-1-yl)-5-(5-chlorothiophen-2-yl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide (35 mg, 16% yield, 81% pure by HPLC) as a dark oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (m, 2 H) 1.76 (dt, J=11.23, 5.71 Hz, 4 H) 2.84 (m, 4 H) 3.45 (dd, J=18.17, 4.69 Hz, 1 H) 3.61 (dd, J=18.17, 11.14 Hz, 1 H) 5.93 (dd, J=11.14, 4.69 Hz, 1 H) 6.57 (m, 2 H) 7.06 - 7.19 (m, 2 H) 7.32 (d, J=2.15 Hz, 1 H) 7.40 (m, 1 H) 13C NMR (100 MHz, CDCl3): δ 23.4 (CH2), 25.3 (CH2), 40.5 (CH2), 57.3 (CH2), 63.7 (CH), 125.7 (CH), 125.8 (CH), 126.1 (CH), 127.1 (C), 127.8 (CH), 130.1 (CH), 131.1 (C), 139.6 (C), 139.9 (C), 146.1 (C), 158.9 (CO). IR (NaCl, film) υ 1476, 1663, 2833, 2938 cm-1 MS (M+H)+: 457
16%	In dichloromethane at 0 - 20℃;	A3.A3.1 Preparation of 5-(5-Chloro-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3-carboxylic acid piperidin-1-ylamide Crude 5-(5-chlorothiophen-2-yl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazol-3-carboxylic acid (0.25 g, 0.66 mmol) was dissolved several times in 5 mL of anhydrous toluene and the solvate was removed in vacuo. The acid was dissolved in 3 mL of anhydrous toluene under nitrogen atmosphere, and thionylchloride (0.8 mL, 4.86 mmol, 16 equiv) and anhydrous dimethylformamide (55 µL) were added. The reaction mixture was heated at reflux and monitored by IR (NaCl, film). After 2 h reaction mixture was left to cool to room temperature and the solvents were evaporated to dryness under high vacuum. The desired product 5-(5-chlorothiophen-2-yl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazol-3-carbonyl chloride (0.19 g, 74%) was obtained as a dark oil and used for the next step without further purification. IR (NaCl, film) u: 802, 1106, 1213, 1477, 1735 cm-1 Triethylamine (0.4 mL, 6 equiv.) was added drop wise to a solution of N-aminopiperidine (71 µL, 0.66 mmol, 1.3 equiv.) in anhydrous dichloromethane (3.5mL). The mixture was cooled in an ice bath and a solution of 5-(5-chlorothiophen-2-yl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazol-3-carbonyl chloride (0.19 g, 0.48 mmol, 1 equiv.) in anhydrous DCM (3.5 mL) was added. After 15 min the ice bath was removed and the reaction was left stirring at room temperature overnight. The solution was poured in a separating funnel and washed once with water, with a saturated aqueous solution of NaHCO3 and again with water, dried over Na2SO4 and evaporated to dryness to give 0.22 g of the crude product. Purification by column chromatography (SiO2 with 2.5% v/v of Et3N, 30:1 ratio SiO2: product, packed with 5% ethylacetate/hexane and eluted with a gradient of 5% ethylacetate/hexane to 20% ethylacetate/hexane) provided racemic N-(piperidin-1-yl)-5-(5-chlorothiophen-2-yl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide (35 mg, 16% yield, 81% pure by HPLC) as a dark oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (m, 2 H) 1.76 (dt, J=11.23, 5.71 Hz, 4 H) 2.84 (m, 4 H) 3.45 (dd, J=18.17, 4.69 Hz, 1 H) 3.61 (dd, J=18.17, 11.14 Hz, 1 H) 5.93 (dd, J=11.14, 4.69 Hz, 1 H) 6.57 (m, 2 H) 7.06 - 7.19 (m, 2 H) 7.32 (d, J=2.15 Hz, 1 H) 7.40 (m, 1 H) 13C NMR (100 MHz, CDCl3): δ 23.4 (CH2), 25.3 (CH2), 40.5 (CH2), 57.3 (CH2), 63.7 (CH), 125.7 (CH), 125.8 (CH), 126.1 (CH), 127.1 (C), 127.8 (CH), 130.1 (CH), 131.1 (C), 139.6 (C), 139.9 (C), 146.1 (C), 158.9 (CO). IR (NaCl, film) u 1476, 1663, 2833, 2938 cm-1 MS (M+H)+: 457

16%

With triethylamine In dichloromethane at 0 - 20℃;

A3.1 Triethylamine (0.4 mL, 6 equiv.) was added drop wise to a solution of N-aminopiperidine (71 µL, 0.66 mmol, 1.3 equiv.) in anhydrous dichloromethane (3.5mL). The mixture was cooled in an ice bath and a solution of 5-(5-chlorothiophen-2-yl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazol-3-carbonyl chloride (0.19 g, 0.48 mmol, 1 equiv.) in anhydrous DCM (3.5 mL) was added. After 15 min the ice bath was removed and the reaction was left stirring at room temperature overnight. The solution was poured in a separating funnel and washed once with water, with a saturated aqueous solution of NaHCO3 and again with water, dried over Na2SO4 and evaporated to dryness to give 0.22 g of the crude product. Purification by column chromatography (SiO2 with 2.5% v/v of Et3N, 30:1 ratio SiO2: product, packed with 5% ethylacetate/hexane and eluted with a gradient of 5% ethylacetate/hexane to 20% ethylacetate/hexane) provided racemic N-(piperidin-1-yl)-5-(5-chlorothiophen-2-yl)-1-(2,4-dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide (35 mg, 16% yield, 81% pure by HPLC) as a dark oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (m, 2 H) 1.76 (dt, J=11.23, 5.71 Hz, 4 H) 2.84 (m, 4 H) 3.45 (dd, J=18.17, 4.69 Hz, 1 H) 3.61 (dd, J=18.17, 11.14 Hz, 1 H) 5.93 (dd, J=11.14, 4.69 Hz, 1 H) 6.57 (m, 2 H) 7.06 - 7.19 (m, 2 H) 7.32 (d, J=2.15 Hz, 1 H) 7.40 (m, 1H) 13C NMR (100 MHz, CDCl3): δ 23.4 (CH2), 25.3 (CH2), 40.5 (CH2), 57.3 (CH2), 63.7 (CH), 125.7 (CH), 125.8 (CH), 126.1 (CH), 127.1 (C), 127.8 (CH), 130.1 (CH), 131.1 (C), 139.6 (C), 139.9 (C), 146.1 (C), 158.9 (CO). IR (NaCl, film) u 1476, 1663, 2833, 2938 cm-1 MS (M+H)+: 457

Reference： [1]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - WO2007/9690, 2007, A1 Location in patent: Page/Page column 128-129; 132-133
[2]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - EP1743894, 2007, A1 Location in patent: Page/Page column 52
[3]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - EP1946777, 2008, A1 Location in patent: Page/Page column 100
[4]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - EP1946778, 2008, A1 Location in patent: Page/Page column 99-100

26
C₁₄H₈BrCl₃N₂OS [ No CAS ]
[ 2213-43-6 ]
5-(4-bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With N-ethyl-N,N-diisopropylamine In dichloromethane; toluene at 5 - 25℃;	23 5-(5-Bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-3- carboxylic acid (0.290 g, 0.69 mmol) was dissolved in toluene (8 ml_) and partially distilled at atmospheric pressure to eliminate water traces. The resulting solution was cooled to 75 0C - 85 0C. Dimethylformamide was added (2 drops) and thionylchloride (0.060 ml_, 0.83 mmol) was added drop by drop. The solution was stirred until the complete formation of the acid chloride (monitoring by IR). The mixture was cooled to 20 0C - 25 0C which was added drop wise under nitrogen atmosphere to a solution of 1-aminopiperidine (0.090 mL, 0.82 mmol), dichloromethane (5 mL) and N1N- diisopropylethylamine (0.281 mL, 1.64 mmol) while keeping the temperature of the mixture between 5-10 0C. The mixture was warmed to 20 0C - 25 0C and stirred overnight. The organic layer was washed with water (3 x 5 mL), with a saturated aqueous solution of NaHCO3 (3 x 25 mL) and again with water (3 x 5 mL). The final EPO organic extract was dried with Na2SO4, filtered and concentrated in vacuo to afford a beige solid (263 mg, 77 % yield).The solid was dissolved in 3 mL of ethyl acetate and 2.8 N HCI in ethanol was added (3 mL, 1.2 eq). The mixture was stirred at room temperature for 30 min and a beige solid appeared. The solid was filtered and washed several times with ethyl acetate to obtain a white solid (170 mg, 47 % yield).1H NMR (300 MHz, DMSO-cfe) δ ppm 1.42 (m, 2 H) 1.72 (m, 4 H) 3.15 (m, 4 H) 3.25 (dd, J=18.02, 5.13 Hz, 1 H) 3.68 (dd, J=18.02, 11.50 Hz, 1 H) 6.08 (dd, J=11.50, 5.13 Hz, 1 H) 6.95 (d, J=1.17 Hz, 1 H) 7.34 (m, 1 H) 7.46 (m, 2 H) 7.58 (d, J=2.20 Hz, 1 H) 10.68 (s, 1 H)MS (M+H)+: 501
	With N-ethyl-N,N-diisopropylamine In dichloromethane; toluene at 5 - 25℃;	23 5-(5-Bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (0.290 g, 0.69 mmol) was dissolved in toluene (8 mL) and partially distilled at atmospheric pressure to eliminate water traces. The resulting solution was cooled to 75°C - 85 °C. Dimethylformamide was added (2 drops) and thionylchloride (0.060 mL, 0.83 mmol) was added drop by drop. The solution was stirred until the complete formation of the acid chloride (monitoring by IR). The mixture was cooled to 20 °C - 25 °C which was added drop wise under nitrogen atmosphere to a solution of 1-aminopiperidine (0.090 mL, 0.82 mmol), dichloromethane (5 mL) and N,N-diisopropylethylamine (0.281 mL, 1.64 mmol) while keeping the temperature of the mixture between 5-10 °C. The mixture was warmed to 20 °C - 25 °C and stirred overnight. The organic layer was washed with water (3 x 5 mL), with a saturated aqueous solution of NaHCO3 (3 x 25 mL) and again with water (3 x 5 mL). The final organic extract was dried with Na2SO4, filtered and concentrated in vacuo to afford a beige solid (263 mg, 77 % yield). The solid was dissolved in 3 mL of ethyl acetate and 2.8 N HCl in ethanol was added (3 mL, 1.2 eq). The mixture was stirred at room temperature for 30 min and a beige solid appeared. The solid was filtered and washed several times with ethyl acetate to obtain a white solid (170 mg, 47 % yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.42 (m, 2 H) 1.72 (m, 4 H) 3.15 (m, 4 H) 3.25 (dd, J=18.02, 5.13 Hz, 1 H) 3.68 (dd, J=18.02, 11.50 Hz, 1 H) 6.08 (dd, J=11.50, 5.13 Hz, 1 H) 6.95 (d, J=1.17 Hz, 1 H) 7.34 (m, 1 H) 7.46 (m, 2 H) 7.58 (d, J=2.20 Hz, 1 H) 10.68 (s, 1 H) MS (M+H)+: 501
	With N-ethyl-N,N-diisopropylamine In dichloromethane; toluene at 5 - 25℃;	A3.23 5-(5-Bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (0.290 g, 0.69 mmol) was dissolved in toluene (8 mL) and partially distilled at atmospheric pressure to eliminate water traces. The resulting solution was cooled to 75 °C - 85 °C. Dimethylformamide was added (2 drops) and thionylchloride (0.060 mL, 0.83 mmol) was added drop by drop. The solution was stirred until the complete formation of the acid chloride (monitoring by IR). The mixture was cooled to 20 °C - 25 °C which was added drop wise under nitrogen atmosphere to a solution of 1-aminopiperidine (0.090 mL, 0.82 mmol), dichloromethane (5 mL) and N,N-diisopropylethylamine (0.281 mL, 1.64 mmol) while keeping the temperature of the mixture between 5-10 °C. The mixture was warmed to 20 °C - 25 °C and stirred overnight. The organic layer was washed with water (3 x 5 mL), with a saturated aqueous solution of NaHCO3 (3 x 25 mL) and again with water (3 x 5 mL). The final organic extract was dried with Na2SO4, filtered and concentrated in vacuo to afford a beige solid (263 mg, 77 % yield). The solid was dissolved in 3 mL of ethyl acetate and 2.8 N HCl in ethanol was added (3 mL, 1.2 eq). The mixture was stirred at room temperature for 30 min and a beige solid appeared. The solid was filtered and washed several times with ethyl acetate to obtain a white solid (170 mg, 47 % yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.42 (m, 2 H) 1.72 (m, 4 H) 3.15 (m, 4 H) 3.25 (dd, J=18.02, 5.13 Hz, 1 H) 3.68 (dd, J=18.02, 11.50 Hz, 1 H) 6.08 (dd, J=11.50, 5.13 Hz, 1 H) 6.95 (d, J=1.17 Hz, 1 H) 7.34 (m, 1 H) 7.46 (m, 2 H) 7.58 (d, J=2.20 Hz, 1 H) 10.68 (s, 1 H) MS (M+H)+: 501

Reference： [1]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - WO2007/9690, 2007, A1 Location in patent: Page/Page column 131-132
[2]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - EP1743894, 2007, A1 Location in patent: Page/Page column 53-54
[3]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - EP1946778, 2008, A1 Location in patent: Page/Page column 101-102

27
C₁₆H₁₀Cl₄N₂O [ No CAS ]
[ 2213-43-6 ]
[ 918870-60-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In toluene at 10 - 20℃;	Preparation of (R)-N-piperidinyl-5-(4chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide (A) 9.94 g (26.89 mmol) of (R)-5-(4-chlorophenyl)-1(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid were dissolved in 95 ml of toluene, followed by the addition of 2.35 ml (32.3 mmoles) of thionyl chloride and 4 drops of DMF. Under anhydrous nitrogen atmosphere the mixture was heated to a temperature of 75-80° C. under vigorous stirring for two hours and then allowed to cool to room temperature. Said acid chloride solution was then added dropwise to a solution of 3.47 ml (31.2 mmol) of N-Aminopiperidine, 15 ml (107.6 mmol) of triethylamine and 38 ml of anhydrous toluene, which was cooled to 0-5° C., thereby keeping the temperature below 10° C. during the addition. The reaction mixture was stirred at room temperature overnight, whereupon a suspension was obtained. Water and Toluene were added to said suspension until dissolution was complete and the phases were separated. The aqueous phase was extracted with toluene, the combined organic phases washed with an NaOH solution (10%) and water, dried over sodium sulfate, filtered off and evaporated to dryness to yield 13.41 g of light yellow oil, which failed to crystallise. The oil was purified via column chromatography over silica gel (eluent; petrol ether ethylacetate 90:10 to 60:40) to give 10.5 g (83.5%) of (R)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide in form of an amorphous solid of light yellow colour (melting point 75-78° C.). 1H-NMR (DMSO-d6) δ ppm: 9.25 (s, 1H), 7.5 (d, J=8.8 Hz, 1H), 7.4 (d, J=2.3 Hz, 1H), 7.3-7.25 (2d, J=8.8 and 8.5 Hz, 3H), 7.1 (d, J=8.5 Hz, 2H), 5.8 (dd, J=5.7 and 11.8 Hz, 1H), 3.65 (dd, J=11.8 and 18.1 Hz, 1H), 3.0 (dd, J=5.7 and 18.1 Hz, 1H), 2.75 (m, 4H), 1.5 (m, 4H), 1.2 (m, 2H).
100 % ee	With triethylamine In toluene at 0 - 20℃;	1 Preparation of (R)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide (Compound A); 9.94 g (26.89 mmol) of (R)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid were dissolved in 95 ml of toluene, followed by the addition of 2.35 ml (32.3 mmoles) of thionyl chloride and 4 drops of DMF. Under anhydrous nitrogen atmosphere the mixture was heated to a temperature of 75-80° C under vigorous stirring for two hours and then allowed to cool to room temperature. Said acid chloride solution was then added dropwise to a solution of 3.47 ml (31.2 mmol) of N-Aminopiperidine, 15 ml (107.6 mmol) of triethylamine and 38 ml of anhydrous toluene, which was cooled to 0-5 °C, thereby keeping the temperature below 10 °C during the addition. The reaction mixture was stirred at room temperature overnight, whereupon a suspension was obtained. Water and Toluene were added to said suspension until dissolution was complete and the phases were separated. The aqueous phase was extracted with toluene, the combined organic phases washed with an NaOH solution (10 %) and water, dried over sodium sulfate, filtered off and evaporated to dryness to yield 13.41 g of light yellow oil, which failed to crystallise. The oil was purified via column chromatography over silica gel (eluent: petrol ether ethylacetate 90: 10 to 60: 40) to give 10.5 g (83.5 %) of (R)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide in form of an amorphous solid of light yellow colour (melting point 75-78 °C). 1H-NMR (DMSO-d6) δ ppm : 9,25 (s, 1 H), 7,5 (d, J=8,8Hz, 1H), 7,4 (d, J=2,3Hz, 1 H), 7,3-7,25 (2d, J=8,8 and 8,5Hz, 3H), 7,1 (d, J=8,5Hz, 2H), 5,8 (dd, J=5,7 and 11,8 Hz, 1H), 3,65 (dd, J=11,8 and 18,1Hz, 1H), 3,0 (dd, J=5,7 and 18,1Hz, 1H), 2,75 (m, 4H), 1,5 (m, 4H), 1,2 (m, 2H). Analysis of the enantiomer via chiral HPLC: ee = 100 % Chemical purity determined by HPLC: 98,5% [α]D (c=1, 23°C, MeOH) = - 293,5
	With triethylamine In toluene at 0 - 20℃;	A2.A2.1 Preparation of (R)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1 H-pyrazole-3-carboxamide Preparation of (R)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1 H-pyrazole-3-carboxamide 9.94 g (26.89 mmol) of (R)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid were dissolved in 95 ml of toluene, followed by the addition of 2.35 ml (32.3 mmoles) of thionyl chloride and 4 drops of DMF. Under anhydrous nitrogen atmosphere the mixture was heated to a temperature of 75-80° C under vigorous stirring for two hours and then allowed to cool to room temperature. Said acid chloride solution was then added dropwise to a solution of 3.47 ml (31.2 mmol) of N-Aminopiperidine, 15 ml (107.6 mmol) of triethylamine and 38 ml of anhydrous toluene, which was cooled to 0-5 °C, thereby keeping the temperature below 10 °C during the addition. The reaction mixture was stirred at room temperature overnight, whereupon a suspension was obtained. Water and Toluene were added to said suspension until dissolution was complete and the phases were separated. The aqueous phase was extracted with toluene, the combined organic phases washed with an NaOH solution (10 %) and water, dried over sodium sulfate, filtered off and evaporated to dryness to yield 13.41 g of light yellow oil, which failed to crystallise. The oil was purified via column chromatography over silica gel (eluent: petrol ether ethylacetate 90: 10 to 60: 40) to give 10.5 g (83.5 %) of -(R)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5 dihydro-1 H-pyrazole-3-carboxamide in form of an amorphous solid of light yellow colour (melting point 75-78 °C).

	With triethylamine In toluene at 0 - 20℃;	A2.1 9.94 g (26.89 mmol) of (R)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid were dissolved in 95 ml of toluene, followed by the addition of 2.35 ml (32.3 mmoles) of thionyl chloride and 4 drops of DMF. Under anhydrous nitrogen atmosphere the mixture was heated to a temperature of 75-80° C under vigorous stirring for two hours and then allowed to cool to room temperature. Said acid chloride solution was then added dropwise to a solution of 3.47 ml (31.2 mmol) of N-Aminopiperidine, 15 ml (107.6 mmol) of triethylamine and 38 ml of anhydrous toluene, which was cooled to 0-5 °C, thereby keeping the temperature below 10 °C during the addition. The reaction mixture was stirred at room temperature overnight, whereupon a suspension was obtained. Water and Toluene were added to said suspension until dissolution was complete and the phases were separated. The aqueous phase was extracted with toluene, the combined organic phases washed with an NaOH solution (10 %) and water, dried over sodium sulfate, filtered off and evaporated to dryness to yield 13.41 g of light yellow oil, which failed to crystallise. The oil was purified via column chromatography over silica gel (eluent: petrol ether ethylacetate 90:10 to 60: 40) to give 10.5 g (83.5 %) of (R)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1 H-pyrazole-3-carboxamide in form of an amorphous solid of light yellow colour (melting point 75-78 °C). 1H-NMR (DMSO-d6) δ ppm : 9,25 (s, 1H), 7,5 (d, J=8,8Hz, 1H), 7,4 (d, J=2,3Hz, 1H), 7,3-7,25 (2d, J=8,8 and 8,5Hz, 3H), 7,1 (d, J=8,5Hz, 2H), 5,8 (dd, J=5,7 and 11,8 Hz, 1H), 3,65 (dd, J=11,8 and 18,1 Hz, 1H), 3,0 (dd, J=5,7 and 18,1 Hz, 1 H), 2,75 (m, 4H), 1,5 (m, 4H), 1,2 (m, 2H). Analysis of the enantiomer via chiral HPLC: ee = 100 % Chemical purity determined by HPLC: 98,5% [α]D (c=1, 23°C, MeOH) = - 293,5
100 % ee	With triethylamine In toluene at 0 - 20℃;	1 Preparation of (R)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4.,5-dihydro-1H-pyrazole-3-carboxamide (Compound A); 9.94 g (26.89 mmol) of (R)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid were dissolved in 95 ml of toluene, followed by the addition of 2.35 ml (32.3 mmoles) of thionyl chloride and 4 drops of DMF. Under anhydrous nitrogen atmosphere the mixture was heated to a temperature of 75-80° C under vigorous stirring for two hours and then allowed to cool to room temperature. Said acid chloride solution was then added dropwise to a solution of 3.47 ml (31.2 mmol) of N-Aminopiperidine, 15 ml (107.6 mmol) of triethylamine and 38 ml of anhydrous toluene, which was cooled to 0-5 °C, thereby keeping the temperature below 10 °C during the addition. The reaction mixture was stirred at room temperature overnight, whereupon a suspension was obtained. Water and Toluene were added to said suspension until dissolution was complete and the phases were separated. The aqueous phase was extracted with toluene, the combined organic phases washed with an NaOH solution (10 %) and water, dried over sodium sulfate, filtered off and evaporated to dryness to yield 13.41 g of light yellow oil, which failed to crystallise. The oil was purified via column chromatography over silica gel (eluent: petrol ether ethylacetate 90:10 to 60: 40) to give 10.5 g (83.5 %) of (R)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide in form of an amorphous solid of light yellow colour (melting point 75-78 °C). 1H-NMR (DMSO-d6) δ ppm : 9,25 (s, 1H), 7,5 (d, J=8,8Hz, 1H), 7,4 (d, J=2,3Hz, 1H), 7,3-7,25 (2d, J=8,8 and 8,5Hz, 3H), 7,1 (d, J=8,5Hz, 2H), 5,8 (dd, J=5,7 and 11,8 Hz, 1H), 3,65 (dd, J=11,8 and 18,1Hz, 1H), 3,0 (dd, J=5,7 and 18,1Hz, 1H), 2,75 (m, 4H), 1,5 (m, 4H), 1,2 (m, 2H). Analysis of the enantiomer via chiral HPLC: ee = 100 % Chemical purity determined by HPLC: 98,5% [α]D (c=1, 23°C, MeOH) = - 293,5

Reference： [1]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - US2007/15810, 2007, A1 Location in patent: Page/Page column 28
[2]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - EP1944296, 2008, A1 Location in patent: Page/Page column 28-29
[3]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - EP1946777, 2008, A1 Location in patent: Page/Page column 97
[4]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - EP1946778, 2008, A1 Location in patent: Page/Page column 97
[5]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - EP1944295, 2008, A1 Location in patent: Page/Page column 23

28
1-(4-benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid chloride [ No CAS ]
[ 2213-43-6 ]
[ 866598-40-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine In dichloromethane at 0 - 20℃; for 2h;	A.4 Step 4.1 -(4-Benzyloxyphenyl)-2-f2,4-dichlorophenyl)-5-methyl- lH-imidazole-4-carboxylic acid piperidin- 1 -ylamide A solution of l-(4-benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl-lH-imidazole-4- 0 carboxylic acid, from Step 3 (3.38 g, 7.5 mmol) in 60 ml CH2Cl2 was added 3 drops of DMF followed by oxalyl chloride (1.3 ml, 14.9 mmol). The mixture was refluxed for 2 hours, cooled to room temperature and evaporated to dryness. The residue was dissolved EPO in 50 ml CH2Cl2 and cooled to O0C. Triethylamine (2.1 ml, 14.9 mmol) was added followed by 1-aminopiperidine (0.9 ml, 8.2 mmol) and the mixture was stirred at room temperature for 2 hours. Water (300 ml) was added, the mixture extracted with CH2Cl2 (3x100 ml), dried (Na2SO4), filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 1:2, EtOAc) afforded 2.94 g (74%) of the title compound as a white solid. 1H NMR (CDCl3): δ 7.5-7.2 (8H, m), 7.1-6.9 (4H, m), 5.1 (2H, s), 3.0-2.7 (4H, m), 2.5 (3H, s), 1.9-1.7 (4H, m), 1.6-1.4 (2H, m). MS m/z 558 (M+Na). HPLC: 96.5%.
74%	With triethylamine In dichloromethane at 0 - 20℃; for 2h;	6.1 Step 1.1 -(4-Benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl- lH-imidazole-4-carboxylic acid 5 piperidin-1-ylamideA solution of l-(4-benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl-lH-imidazole-4- carboxylic acid, from Ex 1, Step 3 (3.38 g, 7.5 mmol) in 60 ml CH2Cl2 was added 3 drops of DMF followed by oxalyl chloride (1.3 ml, 14.9 mmol). The mixture was refluxed for 2 hours, cooled to room temperature and evaporated to dryness. The residue was dissolved in o 50 ml CH2Cl2 and cooled to O0C. Triethylamine (2.1 ml, 14.9 mmol) was added followed by 1-aminopiperidine (0.9 ml, 8.2 mmol) and the mixture was stirred at room temperature for 2 hours. Water (300 ml) was added, the mixture extracted with CH2Cl2 (3x100 ml), EPO dried (Na2SO4), filtered and concentrated. Flash chromatography (silica, hexane:EtOAc 1:2, EtOAc) afforded 2.94 g (74%) of the title compound as a white solid. 1H NMR (CDCl3): δ 7.5-7.2 (8H, m), 7.1-6.9 (4H, m), 5.1 (2H, s), 3.0-2.7 (4H, m), 2.5 (3H, s), 1.9-1.7 (4H, m), 1.6-1.4 (2H, m). MS m/z 558 (M+Na). HPLC: 96.5%.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/31720, 2007, A1 Location in patent: Page/Page column 35-36
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2007/31721, 2007, A1 Location in patent: Page/Page column 37-38

29
[ 2213-43-6 ]
6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-piperidinocarbamoyl)-pyrazolo[1,5-a]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	Stage #1: 3-carboxy-6-(2-chlorophenyl)-7-(4-chlorophenyl)-pyrazolo[1,5-a]pyrimidine With thionyl chloride In toluene at 20℃; for 2h; Stage #2: 1-Aminopiperidine With triethylamine In dichloromethane at 20℃; for 0.166667h;	1 Example 1; 'To a suspension of 3-carboxyl-6-(2-chlorophenyl)-7-(4-chlorophenyl)- pyrazolo[l,5-a]pyrimidine (200 mg, compound obtained in Reference Example 1) in toluene (1.5 mL) was added thionyl chloride (114 μL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the resultant crude product was dissolved in methylene chloride (1.5 mL). To a solution was added triethylamine (217 μL) and 1-aminopiperidine (56 μL) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: chloroform/methanol = 100/0 to 19/5 and hexane/ethyl acetate = 67/3 to 2/3) to obtain 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-piperidinocarbamoyl)- pyrazolo[l,5-a]pyrimidine (162 mg; yield: 67 %) as a powder. MS(APCI)m/z; 466/468[M+H]+

Reference： [1]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - WO2007/46548, 2007, A1 Location in patent: Page/Page column 45

30
5-(5-bromothiophen-2-yl)-1-(2,4-dichlorophenyl)-4-ethyl-1H-pyrazole-3-carbonyl chloride [ No CAS ]
[ 2213-43-6 ]
5-(5-bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-ethyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine In dichloromethane at 20℃; for 2h;	1 A solution of Compound 1g (0.1 g, 0.215 mmol) in CH2Cl2 (2 mL) at room temperature was added to a solution of piperidin-1-ylamine Compound 1h (43 mg, 0.43 mmol) and triethylamine (0.09 mL, 0.65 mmol) in CH2Cl2 (8 mL). The resulting suspension was stirred at room temperature for 2 hrs, then concentrated and purified on silica gel column with 30% EtOAc/Hexane to give Compound 35 (85 mg, 75%). MS 527 (MH+).

Reference： [1]Current Patent Assignee: TUPPERWARE BRANDS CORP; JOHNSON & JOHNSON INC - US2007/117858, 2007, A1 Location in patent: Page/Page column 28

31
[ 947309-63-9 ]
[ 2213-43-6 ]
3-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-4,5,6,7-tetrahydro-2H-indazole-7-carboxylic acidpiperidin-1-ylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With dmap; 1,1'-carbonyldiimidazole In dichloromethane at 0℃; for 20h;	1 Piperidin-1-ylamine Compound Ig (0.010 g, 0.10 mmol), EDCI (0.015 g, 0.10 mmol) and DMAP (0.012 g, 0.10 mmol) were added to a solution of Compound If (0.042 g, 0.10 mmol) in CH2Cl2 (10 mL) at 00C under a N2 atmosphere. The mixture was stirred for 20 hours and allowed to warm to ambient temperature. The reaction mixture was concentrated in vacuo to yield a crude precipitate. The precipitate was purified by flash chromatography (25 % EtOAc in Hexane) to provide Compound 33 (0.038 g, 75 %) as a white solid. MS m/z 505, 507 (M+H+)

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2007/95513, 2007, A1 Location in patent: Page/Page column 54

32
[ 1170062-04-0 ]
[ 2213-43-6 ]
[ 1034890-97-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 5-(4-cyclopropylphenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid With oxalyl dichloride In dichloromethane at 20℃; for 2h; Stage #2: 1-Aminopiperidine With triethylamine In dichloromethane at 0 - 20℃; for 14 - 16h;	1.e e.:5-(4-cyclopropylphenyl)- 1 -(2,4-dichlorophenyl)-4-methyl-iV-piperidin- 1 - yl- 1 -H-p yrazole-3 - carboxamide; To a stirred suspension of 5-(4-cyclopropylphenyl)-l-(2,4-dichlorophenyl)-4-methyl-l-H- pyrazole-3-carboxylic acid (8.9 g, 0.021 mol) and DMF (0.36 ml) in dichloromethane (278 ml) oxalyl chloride (3.8 ml, 0.043 mol) was added dropwise with cooling. The mixture was stirred for 2 h at room temperature then evaporated in vacuo and dissolved in dichloromethane (80 ml). The so obtained solution was added dropwise to a stirred mixture of N-amino-piperidine (3.4 ml, 0.032 mol) and triethyl amine (4.5 ml, 0.032 mol) in dichloromethane (150 ml) at 0-5°C. The resulting mixture was allowed to warm to ambient temperature and stirred for 14-16 h then evaporated in vacuo. The residue was purified by column chromatography using dichloromethane/ethyl acetate as eluent. Yield: 8.6 g (80%)

Reference： [1]Current Patent Assignee: angolul : Chemical Works of Gedeon Richter Plc. Gedeon Richter Plc. - WO2008/75118, 2008, A1 Location in patent: Page/Page column 15

33
[ 1034926-18-5 ]
[ 2213-43-6 ]
[ 1034925-91-1 ]

Yield	Reaction Conditions	Operation in experiment
37%	With caesium carbonate In toluene at 20 - 110℃;	1.107.b The product of step (a) (130 mg, 0.34 mmol) was dissolved in dry toluene (12 mL) under N2 atmosphere. To the stirring solution were added Pd(OAc)2 (7.5 mg, 0.034 mmol), BINAP (23 mg, 0.037 mmol) and cesium carbonate (144 mg, 0.442 mmol) and the reaction mixture was stirred at rt for 20 min. 1-Aminopiperidine (51 mg, 0.51 mmol) was added and the mixture was stirred at rt for 10 min. Stirring was continued at 110 C under N2 atmosphere for 6 hours, cooled and allowed to proceed overnight at rt. The mixture was filtered through a small pad of silica gel on a sinter glass, eluted with additional amount of 30 mL toluene and then 50 mL EtOAc. 250 mg of yellowish crude oil obtained which was further purified using Combiflash (PE - THF) affording the clean desired product as a yellow oil (51 mg, 37% yield).1H NMR: (CDCl3) δ 8.05 (d, IH, CH); 7.26 (d, IH5 CH); 7.04 (d, IH, CH); 5.22 (bs, IH5 NH); 4.65 (s, IH5 NH); 2.72 (bs, 4H, CH2N); 1.74 (quint, 4H, CH2N); 1.11 (m, IH, CH); 1.10 (s, 6H5 CH3); 0.98 (m, IH, CH); 0.28 (m, 4H, CH2).MS: m/z 406.10 (MH+).

Reference： [1]Current Patent Assignee: PHARMOS CORPORATION - WO2008/75353, 2008, A1 Location in patent: Page/Page column 104-105

34
[ 918870-57-2 ]
[ 2213-43-6 ]
[ 918870-60-7 ]

Yield	Reaction Conditions	Operation in experiment
83.5%	Stage #1: (R)-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazol-3-carboxylic acid With thionyl chloride In toluene at 75 - 80℃; for 2h; Stage #2: 1-Aminopiperidine With triethylamine In toluene at 0 - 20℃;	1 9.94 g (26.89 mmol) of (R)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid were dissolved in 95 ml of toluene, followed by the addition of 2.35 ml (32.3 mmoles) of thionyl chloride and 4 drops of DMF. Under anhydrous nitrogen atmosphere the mixture was heated to a temperature of 75-80° C under vigorous stirring for two hours and then allowed to cool to room temperature. Said acid chloride solution was then added dropwise to a solution of 3.47 ml (31.2 mmol) of N-Aminopiperidine, 15 ml (107.6 mmol) of triethylamine and 38 ml of anhydrous toluene, which was cooled to 0-5 °C, thereby keeping the temperature below 10 °C during the addition. The reaction mixture was stirred at room temperature overnight, whereupon a suspension was obtained. Water and Toluene were added to said suspension until dissolution was complete and the phases were separated. The aqueous phase was extracted with toluene, the combined organic phases washed with an NaOH solution (10 %) and water, dried over sodium sulfate, filtered off and evaporated to dryness to yield 13.41 g of light yellow oil, which failed to crystallise. The oil was purified via column chromatography over silica gel (eluent: petrol ether ethylacetate 90: 10 to 60: 40) to give 10.5 g (83.5 %) of (R)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide in form of an amorphous solid of light yellow colour (melting point 75-78 °C). 1H-NMR (DMSO-d6) δ ppm : 9,25 (s, 1H), 7,5 (d, J=8,8Hz, 1H), 7,4 (d, J=2,3Hz, 1H), 7,3-7,25 (2d, J=8,8 and 8,5Hz, 3H), 7,1 (d, J=8,5Hz, 2H), 5,8 (dd, J=5,7 and 11,8 Hz, 1H), 3,65 (dd, J=11,8 and 18,1Hz, 1H), 3,0 (dd, J=5,7 and 18,1Hz, 1H), 2,75 (m, 4H), 1,5 (m, 4H), 1,2 (m, 2H). Analysis of the enantiomer via chiral HPLC: ee = 100 % Chemical purity determined by HPLC: 98,5% [α]D (c=1, 23°C, MeOH) = - 293,5
10.5 g (83.5 %)	With thionyl chloride; triethylamine In water; N,N-dimethyl-formamide; toluene	1 Preparation of (R)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide (Compound A) Preparation of (R)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1H-pyrazole-3-carboxamide (Compound A) 9.94 g (26.89 mmol) of (R)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid were dissolved in 95 ml of toluene, followed by the addition of 2.35 ml (32.3 mmoles) of thionyl chloride and 4 drops of DMF. Under anhydrous nitrogen atmosphere the mixture was heated to a temperature of 75-80° C under vigorous stirring for two hours and then allowed to cool to room temperature. Said acid chloride solution was then added dropwise to a solution of 3.47 ml (31.2 mmol) of N-Aminopiperidine, 15 ml (107.6 mmol) of triethylamine and 38 ml of anhydrous toluene, which was cooled to 0-5 °C, thereby keeping the temperature below 10 °C during the addition. The reaction mixture was stirred at room temperature overnight, whereupon a suspension was obtained. Water and Toluene were added to said suspension until dissolution was complete and the phases were separated. The aqueous phase was extracted with toluene, the combined organic phases washed with an NaOH solution (10 %) and water, dried over sodium sulfate, filtered off and evaporated to dryness to yield 13.41 g of light yellow oil, which failed to crystallise. The oil was purified via column chromatography over silica gel (eluent: petrol ether ethylacetate 90: 10 to 60: 40) to give 10.5 g (83.5 %) of (R)-N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-1 H-pyrazole-3-carboxamide in form of an amorphous solid of light yellow colour (melting point 75-78 °C). 1H-NMR (DMSO-d6) δ ppm: 9,25 (s, 1H), 7,5 (d, J=8,8Hz, 1H), 7,4 (d, J=2,3Hz, 1H), 7,3-7,25 (2d, J=8,8 and 8,5Hz, 3H), 7,1 (d, J=8,5Hz, 2H), 5,8 (dd, J=5,7 and 11,8 Hz, 1H), 3,65 (dd, J=11,8 and 18,1Hz, 1H), 3,0 (dd, J=5,7 and 18,1Hz, 1H), 2,75 (m, 4H), 1,5 (m, 4H), 1,2 (m, 2H). Analysis of the enantiomer via chiral HPLC: ee = 100 % Chemical purity determined by HPLC: 98,5% [α]D (c=1, 23°C, MeOH) = - 293,5

Reference： [1]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - EP1944293, 2008, A1 Location in patent: Page/Page column 28-29
[2]Current Patent Assignee: Corporacion Quimico Farmaceutica Esteve SA - EP1944294, 2008, A1

35
[ 1040879-55-7 ]
[ 2213-43-6 ]
[ 1040879-51-3 ]

Yield	Reaction Conditions	Operation in experiment
68%	With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 0 - 20℃; for 16h;	2.1.F To mixture of the acid derivative obtained above (0.5g, 1.42 mmol, 1 equiv.) DMAP (0.174 g, 1.42 mmol, 1 equiv.) and dry dichloromethane (10 mL) in a round bottomed flask was added EDCI (0.654 g, 3.42 mmol, 2.4 equiv.) under nitrogen atmosphere, followed by 1 -aminopiperidine (0.174g, 0.18 mL, 1.56 mmol, 1.1 equiv.) at 0 0C to 50C. The reaction mixture was brought to the room temperature and stirred for 16h. Then the reaction mixture was diluted with dichloromethane. The organic layer washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography using (0.7:99.3) methanol xhloroform as eluent to furnish the desired product (0.420 g, 0.967 mmol,68%).IH NMR: (DMSO-d6, 400 MHz) δ 8.73 (bs, IH); 7.92-7.96 (m, 2H); 7.56 (t, J = 8.4Hz, IH); 3.58-3.54 (m, 2H); 2.82-2.75 (m, 2H); 2.61-2.52 (m, 3H); 2.24-2.20 (m, IH); 1.88 - 1.83 (m, 2H); 1.67-1.65 (m, 2H); 1.53-1.25 (m, 8H); 1.06 - 1.03 (m, IH).

Reference： [1]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - WO2008/87654, 2008, A2 Location in patent: Page/Page column 50-51

36
[ 1040878-00-9 ]
[ 2213-43-6 ]
[ 1040877-90-4 ]

Yield	Reaction Conditions	Operation in experiment
65.4%	With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 0 - 20℃; for 16h;	1.1.G To a mixture of the acid (5 g, 17.66 mmol, 1 equiv., obtained above) and DMAP (2.15 g, 17.66 mmol, 1 equiv.), dry dichloromethane (50 mL) in a round bottomed flask was added EDCI (6.76g, 35.3 mmol, 2 equiv.) under nitrogen atmosphere, followed by 1-aminopiperidine (1.94 g, 19.42 mmol, 1.1 equiv.) at 0 0C to 5 0C. The reaction mixture was brought to the room temperature and stirred for 16h. The completion of the reaction was checked by TLC. Then the reaction mixture was diluted with dichloromethane. The organic layer washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The compound was purified by column chromatography using (0.7:99.3) methanol xhloro form as eluent to furnish the desired product (4.2g, 65.4%).IH NMR (CDCl3, 300MHz) δ 7.71-7.77 (m, 2H), 7.50-7.62 (m, 3H), 3.45-3.50 (m,IH), 2.92-3.20 (m, 3H), 2.7-2.77 (m, 2H), 2.01-2.43 (m, 4H), 2.45-2.55 (m, I H), 1.62-1.76 (m, 7H), 1.25-1.41 (m, 2H), 1.05-1.15 (m, IH).

Reference： [1]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - WO2008/87654, 2008, A2 Location in patent: Page/Page column 27-28

37
[ 2213-43-6 ]
[ 100-52-7 ]
[ 17328-08-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: 1-Aminopiperidine; benzaldehyde In methanol at 20℃; for 12h; Stage #2: With sodium cyanoborohydride; acetic acid In methanol at 20℃; for 2h; Further stages.;
91%	Stage #1: 1-Aminopiperidine; benzaldehyde In methanol at 20℃; Inert atmosphere; Stage #2: With sodium cyanoborohydride; acetic acid In methanol for 2h; Inert atmosphere;	Benzyl-piperidin-1-yl-amine (15) Benzaldehyde (2.44 g, 23.02 mmol) and 1-Aminopiperidine (2.00 g, 20.00 mmol) were stirred at room temperature in anhydrous MeOH (150 mL) overnight. Acetic acid (30 mL, 525 mmol) and NaCNBH3 (6.30 g, 100 mmol) were added, and stirring was continued for 2 h. Most of the solvent was removed under vacuum. Then a pH value around 8 was adjusted by adding NaHCO3 (saturated aqueous solution, 40 mL) and NaOH (aqueous solution, 10 mL), and the mixture was extracted with CH2Cl2 (3 × 40 mL). The combined organic extracts were dried over Na2SO4, and the solvent was evaporated under vacuum. After purification by flash chromatography (50% EtOAc/cyclohexane), 15 was obtained as a colorless oil (3.44 g, 91%). 1H NMR (500 MHz, CDCl3) δ 7.36-7.23 (m, 5H), 3.97 (s, 2H), 2.67 (br s, 4H), 1.66-1.62 (m, 4H), 1.57-1.52 (m, 2H). 13C NMR (50 MHz, CDCl3) δ 138.9, 128.3, 128.0, 126.7, 57.3, 52.6, 25.8, 23.7.

Reference： [1]Waibel, Michael; Hasserodt, Jens [Journal of Organic Chemistry, 2008, vol. 73, # 16, p. 6119 - 6126]
[2]Gros, Guillaume; Martinez, Lorena; Gimenez, Anna Servat; Adler, Paula; Maurin, Philippe; Wolkowicz, Roland; Falson, Pierre; Hasserodt, Jens [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 17, p. 5407 - 5413]

38
[ 7154-73-6 ]
[ 27578-60-5 ]
[ 140-31-8 ]
[ 2038-03-1 ]
[ 25560-00-3 ]
[ 123-00-2 ]
[ 5036-48-6 ]
[ 7663-77-6 ]
[ 34035-03-5 ]
[ 1761-71-3 ]
[ 6864-37-5 ]
[ 2213-43-6 ]
[ 63234-71-9 ]
[ 5906-35-4 ]
[ 59983-39-0 ]
[ 1664-40-0 ]
[ 6530-09-2 ]
[ 108-00-9 ]
[ 109-55-7 ]
[ 51387-90-7 ]
[ 102-83-0 ]
[ 849908-66-3 ]
C₁₅H₁₇ClN₂O [ No CAS ]
[ 849908-70-9 ]
[ 940358-24-7 ]
C₁₆H₁₉ClN₂O [ No CAS ]
C₁₉H₁₉ClN₂O [ No CAS ]
[ 849908-71-0 ]
C₁₇H₂₁ClN₂O₂ [ No CAS ]
[ 849908-67-4 ]
C₁₇H₂₁ClN₂O [ No CAS ]
[ 880815-24-7 ]
C₁₇H₂₂ClN₃O [ No CAS ]
C₁₈H₂₁ClN₂O [ No CAS ]
[ 849908-65-2 ]
[ 932172-19-5 ]
[ 875001-79-9 ]
[ 849908-68-5 ]
[ 849908-69-6 ]
[ 849908-81-2 ]
[ 849908-75-4 ]

Yield	Reaction Conditions	Operation in experiment
	With polymer-bound trimethyl ammonium cyanoborohydride; acetic acid; In 1,2-dichloro-ethane; at 20℃; for 24 - 36h;Combinatorial reaction / High throughput screening (HTS);	All sixty diamines were separated in four groups based on their steric and electronic characteristics, Figures 1-4. Each diamine was measured in the amount of 0.05 g (approximately 0.3 mmol) and pooled together with the others in the group. Obtained diamine mixtures were dissolved in 5 ml of 1,2-dichloroethane and used for the syntheses. Each well of the 96-well filterplates was loaded with 0.2 ml of 1: 10 mixture of acetic acid: DCE, 0.03 ml of the diamine mixture in DCE (group 1, group 2, group 3, or group 4) to assure 0.04 mmol of the diamines per well, and shaken for 5 min at room temperature. Appropriate carbonyl compounds from the master plate (0.1 ml of 1.2 M solution) were added into corresponding wells of the reaction plates followed by the addition of (polystyrylmethyl) trimethylammonium cyanoborohydride, (0.020 g, 0.08 mmol per well). The reaction plates were sealed and placed on a shaker. The reaction was allowed to proceed 24-36 hours at room temperature. At the end, the reaction mixtures were filtered using a filtration manifold, and products were collected into four (one per group) collection plates. Solvents were evaporated in SpeedVac and formed residues were analyzed by mass spectrometry prior to biological screening. Mono and double alkylated products were observed in 1: 0.5 to 1: 2 ratios by mass spectral analysis.

Reference： [1]Patent: WO2005/34857,2005,A2 .Location in patent: Page/Page column 15; 22

39
[ 1121-60-4 ]
[ 2213-43-6 ]
[ 1021443-59-3 ]

Yield	Reaction Conditions	Operation in experiment
96%	In methanol at 20℃; for 24h;
94%	In dichloromethane at 20℃; for 24h;	2.2.1 N-cyclopentyl-1-(pyridin-2-yl)methanimine (L₁) General procedure: Although L1 and L2 [21] have been synthesized previously, here we report a similar procedure as described in the literature with complementary spectroscopic data [40,77-79]. Cyclopentylamine (1.70g, 0.020mol) in dichloromethane (20.0mL) was added to 2-picolylcarbaldehyde (2.14g, 0.020mol) in dichloromethane (20.0mL). After 24h of stirring at room temperature, water was removed from the reaction solution. The dichloromethane solution was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was vacuum distilled and dried to give a brown oil (3.41g, 98.0%).

Reference： [1]Location in patent: experimental part Mino, Takashi; Kajiwara, Kenji; Shirae, Yoshiaki; Sakamoto, Masami; Fujita, Tsutomu [Synlett, 2008, # 17, p. 2711 - 2715]
[2]Kim, Sunghoon; Kim, Eunhee; Lee, Ha-Jin; Lee, Hyosun [Polyhedron, 2014, vol. 69, p. 149 - 155]

40
[ 5735-99-9 ]
[ 2213-43-6 ]
[ 1021151-18-7 ]

Yield	Reaction Conditions	Operation in experiment
68%	With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h;	2.1 0.28g (1.1mmol) of 3,3-ethylene glycosyldodecanoyl acid obtained in Reference Example 1 and 0.10g (1mmol) of 1-aminopiperidine were dissolved in 10mL of dichloromethane. 0.13g (1.1mmol) of dimethylaminopyridine, 0.15g (1.2mmol) of diisopropylethylamine, and 0.21g (1.1mmol) of 1-ethyl-3-dimethylaminopropyl carbodiimide were added to the solution, and the mixture was stirred at room temperature for 12 hours. The reaction liquid was concentrated under reduced pressure, and the residue was subjected to extraction with ethyl acetate. The obtained organic layer was washed with diluted hydrochloric acid and saturated saline, dried with magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (developing solvent: ethyl acetate/methanol=4/6) to obtain N-(piperidine-1-yl)-3,3-ethyleneglycosyldodecanoyl amide denoted by the following formula. [Show Image] Quantity Yield: 0.23g (0.68mmol) Percent Yield: 68% 1H-NMR (CDCl3, 500MHz); 0.88ppm (t, 3H), 1.28ppm (m, 12H), 1.55ppm (m, 6H), 1.75ppm (m, 2H), 2.48ppm (dm, d=400Hz, 2H), 2.56ppm (m, 2H), 2.67ppm (dm, d=400Hz, 2H), 3.48ppm (s, 2H), 4.01ppm (m, 4H), 7.08ppm (br, 1H).

Reference： [1]Current Patent Assignee: OTSUKA HOLDINGS CO LTD; THE UNIVERSITY OF TOKYO - EP2077109, 2009, A1 Location in patent: Page/Page column 16

41
5-(5-Chloro-thiophen-2-yl)-1-(2',4'-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic acid [ No CAS ]
[ 2213-43-6 ]
5-(5-chlorothiophen-2-yl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.17%	Stage #1: 5-(5-Chloro-thiophen-2-yl)-1-(2',4'-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 0.5h; Stage #2: 1-Aminopiperidine In dichloromethane at 20℃; for 0.5h;	3.1a; 3.1b To a sunspension of the acid obtained in the Example 2.1 (0.64 mmol, 1 eq) in dichloromethane (1.3 ml), HOBt (1-hydroxybenzotriazole, 0.77 mmol, 1.2 eq) and EDC (1-(3-diamino propyl)-3-ethylcarbodiimide hydrochloride, 0.77 mmol, 1.2 eq) were added. The solution was maintained under stirring at room temperature for 30 min, then used as such to prepare the compounds described hereinafter in the Examples 3.1b-3.1g, without isolating the amide which was formed. Example 3.1b Preparation of N-piperidinyl-5-(5-Cyloro-thiophen-2-yl)-1-(2',4'-dichloro-phenyl)-4-methyl-1H-pyrazol-3-carboxamide The solution contianing the ester-amide adduct prepared in the Example 3.1a was added, by quick dripping, to a solution of 1-aminopiperidine (1.28 mmol, 2 eq) in dichloromethane (2 ml). The reaction mixture was stirred at room temperature for 30 min. After having removed the solvent, the obtained product was treated with oil ether and purified by flash chromatography (oil ether/ethyl acetate 8/2) obtaining 0.16 g (yield 55.17%) of carboxamide in the form of a white solid. Rf 0.25 (oil ether/ethyl acetate 8/2); m.p.: 125-126° C.; IR (nujol) (λ=cm-1) 1662 (C=O); 3213 (NH); 1H-NMR (CDCl3) δ 1.38-1.50 (m, 2H); 1.69-1.80 (m, 4H); 2.45 (s, 3H); 2.85 (t, 4H, J=5.6 Hz); 6.65 (d, 1H, J=4.0 Hz); 6.81 (d, 1H, J=4.0 Hz); 7.30-7.36 (m, 2H, NH exchanges with D2O); 7.49-7.51 (m, 1H); 7.61 (s, 1H); 13C-NMR (CDCl3) δ 9.56 (CH3); 23.33 (CH2); 25.40 (2CH2); 57.08 (2CH2); 119.44 (C); 126.39 (CH); 127.79 (C); 127.97 (CH); 128.17 (CH); 130.22 (C); 130.32 (CH); 130.75 (CH); 130.84 (C); 133.73 (C); 135.62 (C); 136.54 (C); 144.28 (C) 159.70 (CO); Anal. calc. for C20H19Cl3N4OS: C, 51.13; H, 4.08; Cl, 22.64; N, 11.93. Found: C, 51.24; H, 4.09; Cl, 22.58; N, 11.90.
	With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane

Reference： [1]Current Patent Assignee: NEUROSCIENZE PHARMANESS S.C.A.R.L. - US2005/261281, 2005, A1 Location in patent: Page/Page column 12
[2]Location in patent: scheme or table Srivastava, Brijesh Kumar; Soni, Rina; Patel, Jayendra Z.; Joharapurkar, Amit; Sadhwani, Nisha; Kshirsagar, Samadhan; Mishra, Bhupendra; Takale, Vijay; Gupta, Sunil; Pandya, Purvi; Kapadnis, Prashant; Solanki, Manish; Patel, Harilal; Mitra, Prasenjit; Jain, Mukul R.; Patel, Pankaj R. [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 9, p. 2546 - 2550]

42
[ 721399-96-8 ]
[ 2213-43-6 ]
5-(4-chloro-phenyl)-4-(2,4-dichloro-phenyl)-thiazole-2-carboxylic acid piperidin-1-ylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	Stage #1: 5-(4-chloro-phenyl)-4-(2,4-dichloro-phenyl)-thiazole-2-carboxylic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 0.25h; Stage #2: 1-Aminopiperidine In dichloromethane at 20℃;	3 5- (4-CHLOROPHENYL)-4- (2, 4-DICHLOROPHENYL) thiazole-2-carboxylic acid or 4- (4-CHLOROPHENYL)- 5- (2, 4-dichlorophenyl) thiazole-2-carboxylic acid (51 mg, 0.13 mmol) from Preparation C step (a) and 4-dimethylaminopyridine (2 mg, 0.013 mmol) were dissolved in DCM (9 ML) and DMF (0.5 ml). The solution was cooled to 0°C. A slurry of 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (32 mg, 0.16 mmol) in DCM (0.5 ml) was added dropwise. After 15 minutes N-AMINOPIPERIDINE (16 Y1, 0.15 mmol) in DCM (0.5 ml) was added dropwise. The mixture was allowed to attain room temperature, and was stirred overnight. The mixture was diluted with DCM, washed with NAHCO3 (aq), dried (MGSO4) and evaporated under reduced pressure. The residue was chromatographed (SIO2, toluene: ethyl acetate 9: 1) to give the title compound (20 mg, 31 %). 1H-NMR (500 MHz) 8 8.21 (d, 1H), 7.64 (d, 2H), 7.55 (d, 1H), 7.41 (dd, 1H), 7.38 (d, 2H), 2.96 (br, 4H), 1.77 (br, 4H), 1.46 (br, 2H). MS M/Z 466,468, 470 (M+H) +.
31%	Stage #1: 5-(4-chloro-phenyl)-4-(2,4-dichloro-phenyl)-thiazole-2-carboxylic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 0.25h; Stage #2: 1-Aminopiperidine In dichloromethane at 20℃;	3 5- (4-CHLOROPHENYL)-4- (2, 4-dichlorophenyl) THIAZOLE-2-CARBOXYLIC acid or 4- (4-CHLOROPHENYL)- 5- (2, 4-dichlorophenyl) THIAZOLE-2-CARBOXYLIC acid (51 mg, 0.13 mmol) from Preparation C step (a) and 4-DIMETHYLAMINOPYRIDINE (2 MG, 0. 013 MMOL) were dissolved in DCM (9 ml) and DMF (0.5 ml). The solution was cooled to 0 C. A slurry of 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (32 mg, 0.16 mmol) in DCM (0.5 ml) was added dropwise. After 15 minutes N-aminopiperidine (16 pl, 0.15 mmol) in DCM (0.5 ml) was added dropwise. The mixture was allowed to attain room temperature, and was stirred overnight. The mixture was diluted with DCM, washed with NAHCO3 (aq), dried (MGS04) and evaporated under reduced pressure. The residue was chromatographed (SIO2, toluene: ethyl acetate 9: 1) to give the title compound (20 mg, 31 %). 1H-NMR (500 MHz) 8 8.21 (d, 1H), 7.64 (d, 2H), 7.55 (d, 1H), 7.41 (dd, 1H), 7.38 (d, 2H), 2.96 (br, 4H), 1.77 (br, 4H), 1.46 (br, 2H). MS N/Z 466,468, 470 (M+H) +.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2004/58255, 2004, A1 Location in patent: Page/Page column 18-19
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2004/69226, 2004, A1 Location in patent: Page/Page column 36

43
[ 605670-45-9 ]
[ 2213-43-6 ]
4-(4-chloro-phenyl)-5-(2,4-dichloro-phenyl)-thiazole-2-carboxylic acid piperidin-1-ylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%	Stage #1: 4-(4-chloro-phenyl)-5-(2,4-dichloro-phenyl)-thiazole-2-carboxylic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 0.25h; Stage #2: 1-Aminopiperidine In dichloromethane at 20℃;	3 5- (4-CHLOROPHENYL)-4- (2, 4-DICHLOROPHENYL) thiazole-2-carboxylic acid or 4- (4-CHLOROPHENYL)- 5- (2, 4-dichlorophenyl) thiazole-2-carboxylic acid (51 mg, 0.13 mmol) from Preparation C step (a) and 4-dimethylaminopyridine (2 mg, 0.013 mmol) were dissolved in DCM (9 ML) and DMF (0.5 ml). The solution was cooled to 0°C. A slurry of 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (32 mg, 0.16 mmol) in DCM (0.5 ml) was added dropwise. After 15 minutes N-AMINOPIPERIDINE (16 Y1, 0.15 mmol) in DCM (0.5 ml) was added dropwise. The mixture was allowed to attain room temperature, and was stirred overnight. The mixture was diluted with DCM, washed with NAHCO3 (aq), dried (MGSO4) and evaporated under reduced pressure. The residue was chromatographed (SIO2, toluene: ethyl acetate 9: 1) to give the title compound (20 mg, 31 %). 1H-NMR (500 MHz) 8 8.21 (d, 1H), 7.64 (d, 2H), 7.55 (d, 1H), 7.41 (dd, 1H), 7.38 (d, 2H), 2.96 (br, 4H), 1.77 (br, 4H), 1.46 (br, 2H). MS M/Z 466,468, 470 (M+H) +.
31%	Stage #1: 4-(4-chloro-phenyl)-5-(2,4-dichloro-phenyl)-thiazole-2-carboxylic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 0.25h; Stage #2: 1-Aminopiperidine In dichloromethane at 20℃;	3 5- (4-CHLOROPHENYL)-4- (2, 4-dichlorophenyl) THIAZOLE-2-CARBOXYLIC acid or 4- (4-CHLOROPHENYL)- 5- (2, 4-dichlorophenyl) THIAZOLE-2-CARBOXYLIC acid (51 mg, 0.13 mmol) from Preparation C step (a) and 4-DIMETHYLAMINOPYRIDINE (2 MG, 0. 013 MMOL) were dissolved in DCM (9 ml) and DMF (0.5 ml). The solution was cooled to 0 C. A slurry of 1-ethyl-3- (3- dimethylaminopropyl) carbodiimide hydrochloride (32 mg, 0.16 mmol) in DCM (0.5 ml) was added dropwise. After 15 minutes N-aminopiperidine (16 pl, 0.15 mmol) in DCM (0.5 ml) was added dropwise. The mixture was allowed to attain room temperature, and was stirred overnight. The mixture was diluted with DCM, washed with NAHCO3 (aq), dried (MGS04) and evaporated under reduced pressure. The residue was chromatographed (SIO2, toluene: ethyl acetate 9: 1) to give the title compound (20 mg, 31 %). 1H-NMR (500 MHz) 8 8.21 (d, 1H), 7.64 (d, 2H), 7.55 (d, 1H), 7.41 (dd, 1H), 7.38 (d, 2H), 2.96 (br, 4H), 1.77 (br, 4H), 1.46 (br, 2H). MS N/Z 466,468, 470 (M+H) +.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2004/58255, 2004, A1 Location in patent: Page/Page column 18-19
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2004/69226, 2004, A1 Location in patent: Page/Page column 36

44
[ 866598-57-4 ]
[ 2213-43-6 ]
[ 866598-40-5 ]

Yield	Reaction Conditions	Operation in experiment
74%	Stage #1: 1-(4-(benzyloxy)phenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 2h; Heating / reflux; Stage #2: 1-Aminopiperidine With triethylamine In dichloromethane at 0 - 20℃; for 2h;	1.4 A solution of 1-(4-benzyloxyphenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4- carboxylic acid, from Ex 1, Step 3 (3.38 g, 7.5 mmol) in 60 ml CHUCK was added 3 drops of DMF followed by oxalyl chloride (1.3 ml, 14.9 mmol). The mixture was refluxed for 2 hours, cooled to room temperature and evaporated to dryness. The residue was dissolved in 50 ml CH2C12 and cooled to 0°C. Triethylamine (2.1 ml, 14.9 mmol) was added followed by 1-aminopiperidine (0.9 ml, 8.2 mmol) and the mixture was stirred at room temperature for 2 hours. Water (300 ml) was added, the mixture extracted with CH2C12 (3x100 ml), dried (Na2SO4), filtered and concentrated. Flash chromatography (silica, hexane: EtOAc 1: 2, EtOAc) afforded 2. 94 g (74%) of the title compound as a white solid. 'H NMR (CDC13): 8 7.5-7. 2 (8H, m), 7.1-6. 9 (4H, m), 5.1 (2H, s), 3.0-2. 7 (4H, m), 2.5 (3H, s), 1.9-1. 7 (4H, m), 1.6-1. 4 (2H, m). MS m/z 558 (M+Na). HPLC: 96.5%.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC; LINDSTEDT ASLSTERMARK - WO2005/95354, 2005, A1 Location in patent: Page/Page column 34; 43

45
[ 1152179-07-1 ]
[ 2213-43-6 ]
[ 1229003-12-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: 1-[4-(4-acetyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone; 1-Aminopiperidine at 80℃; for 2h; Stage #2: With ammonium chloride In water	2-[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[N-(piperidin-1-yl)ethanimidoyl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (I-17); At 80° C., piperidine-1-amine (104 mg) is added to a solution of 1-[4-(4-acetyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (46 mg). The reaction mixture is stirred at this temperature for a further 2 hours. Aqueous ammonium chloride solution (10 ml) is then added to the reaction mixture. After phase separation, the aqueous phase is extracted three times with methyl tert-butyl ether (20 ml). All the organic phases are dried over Na2SO4. The mixture is then filtered and concentrated under reduced pressure. This gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[N-(piperidin-1-yl)ethanimidoyl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (55 mg, 99%), (log P(pH2.7)=3.69).1H NMR (DMSO-d6, 400 MHz): δppm: 1.50-1.43 (m, 2H), 1.85-1.60 (m, 6H), 2.15-2.06 (m, 2H), 2.22 (s, 3H), 2.32 (s, 3H), 2.71 (m, 4H), 2.90 (m, 1H), 3.30 (bs, 1H), 3.33 (m, 1H), 4.00 (bs, 1H), 4.35 (bs, 1H), 5.25-5.15 (m, 2H), 6.45 (s, 1H), 7.74 (s, 1H)MS (ESI): 483 ([M+H]+)

Reference： [1]Current Patent Assignee: BAYER AG - US2010/190828, 2010, A1 Location in patent: Page/Page column 29

46
[ 1240402-60-1 ]
[ 2213-43-6 ]
[ 1240401-47-1 ]

Yield	Reaction Conditions	Operation in experiment
82%	Stage #1: 1-Aminopiperidine With trimethylaluminum In 1,4-dioxane; toluene at 20℃; for 1h; Stage #2: 3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester In 1,4-dioxane; toluene at 85 - 90℃; for 4h;	11 3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid piperidin-1-yl-amide Example 11 3-(5-Methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid piperidin-1-yl-amide A solution of trimethylaluminium (2 M in toluene, 0.6 mL, 1.3 mmol) was added dropwise (exothermic) to a solution of 1-aminopiperidine (127 mg, 1.3 mmol) in dioxane (3 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.32 mmol) in dioxane (2 mL) was added. The resulting mixture was then heated at 85-90° C. for 4 h and then cooled to room temperature, stirred overnight, and then poured into Seignette's salt and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, dichloromethane:methanol=9:1 to 4:1) afforded the title compound (100 mg, 82%) which was obtained as a white solid. MS: m/e=383.3 [M+H]+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2010/210651, 2010, A1 Location in patent: Page/Page column 18

47
[ 1240998-70-2 ]
[ 2213-43-6 ]
[ 1240996-80-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: 1-(2,4-dichlorophenyl)-6-methyl-1H-benzofuro[3,2-0c]pyrazole-3-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h; Stage #2: 1-Aminopiperidine In dichloromethane at 20℃; for 22h;	3.20 Example 3.20 Preparation of N-piperidinyl-1-(2,4-dichlorophenyl)-6-methyl-1H-benzofuro[3,2-c]pyrazole-3-carboxamide To the solution in methylene chloride (2 ml), of the acid obtained in ex. 2.9 (0.09 g; 0.25 mmol) HOBt (0.04 g; 0.30 mmol) and EDC (0.06 g, 0.30 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour, then a solution of aminopiperidine (0.50 mmol) in 3 ml of CH2Cl2, was added. The resulting mixture was stirred at room temperature for 22 hours, then the solvent was removed under reduced pressure. The oily residue was purified by flash chromatography (oil ether/ethyl ether 6/4 v/v on silica gel). 0.09 g (81% yield) of a white solid corresponding to N-piperidinyl-1-(2,4-dichlorophenyl)-6-methyl-1H-benzofuro[3,2-c]pyrazole-3-carboxamide were recovered. Rf=0.10 (oil ether/ethyl ether 6/4 on silica gel); m.p.: 155-1570° C.; IR (nujol) (λ=cm-1) 3434 (NH), 1648 (C=O); 1H-NMR (CDCl3); δ 0.86 (m, 2H), 1.25-1.98 (m, 4H), 2.49 (s, 3H) 2.92 (m, 4H), 7.09 (d, J=7.6 Hz, 1H), 7.29 (m, 2H), 7.47 (m, 2H), 7.62 (m, 2H); 13C-NMR (CDCl3) δ 21.9, 23.2, 25.2, 57.0, 113.9, 119.0, 124.4, 125.4, 128.2, 128.8, 129.2, 130.3, 130.5, 130.6, 136.0, 136.2, 137.8, 157.5, 162.9; API-ESI calc. for 443.33, found 443.10.
81%	Stage #1: 1-(2,4-dichlorophenyl)-6-methyl-1H-benzofuro[3,2-0c]pyrazole-3-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h; Stage #2: 1-Aminopiperidine In dichloromethane at 20℃; for 22h;	3.20 To the solution in methylene chloride (2 ml) of the acid obtained in ex. 2.9 (0.09 g; 0.25 mmol) HOBt (0.04 g; 0.30 mmol) and EDC (0.06 g, 0.30 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour, then a solution of aminopiperidine (0.50 mmol) in 3 ml of CH2Cl2, was added. The resulting mixture was stirred at room temperature for 22 hours, then the solvent was removed under reduced pressure. The oily residue was purified by flash chromatography (oil ether/ethyl ether 6/4 v/v on silica gel). 0.09 g (81% yield) of a white solid corresponding to N-piperidinyl-1-(2,4-dichlorophenyl)-6-methyl-1H-benzofuro[3,2-c] pyrazole-3-carboxamide were recovered. Rf=0.10 (oil ether/ethyl ether 6/4 on silica gel); m.p.: 155-157°C; IR (nujol) (λ = cm-1) 3434 (NH), 1648 (C=O); 1H-NMR (CDCl3) δ 0.86 (m, 2H), 1.25-1.98 (m, 4H), 2.49 (s, 3H) 2.92 (m, 4H), 7.09 (d, J=7.6 Hz, 1H), 7.29 (m, 2 H), 7.47 (m, 2H), 7.62 (m, 2H); 13C-NMR (CDCl3) δ 21.9, 23.2, 25.2, 57.0, 113.9, 119.0, 124.4, 125.4, 128.2, 128.8, 129.2, 130.3, 130.5, 135.6, 136.0, 136.2, 137.8, 157.5, 162.9; API-ESI calc. for 443.33, found 443.10
81%	Stage #1: 1-(2,4-dichlorophenyl)-6-methyl-1H-benzofuro[3,2-0c]pyrazole-3-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h; Stage #2: 1-Aminopiperidine In dichloromethane at 20℃; for 22h;	3.20 To the solution in methylene chloride (2 ml) of the acid obtained in ex. 2.9 (0.09 g; 0.25 mmol) HOBt (0.04 g; 0.30 mmol) and EDC (0.06 g, 0.30 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour, then a solution of aminopiperidine (0.50 mmol) in 3 ml of CH2Cl2, was added. The resulting mixture was stirred at room temperature for 22 hours, then the solvent was removed under reduced pressure. The oily residue was purified by flash chromatography (oil ether/ethyl ether 6/4 v/v on silica gel). 0.09 g (81% yield) of a white solid corresponding to N-piperidinyl-1-(2,4-dichlorophenyl)-6-methyl-1H-benzofuro[3,2-c] pyrazole-3-carboxamide were recovered. Rf=0.10 (oil ether/ethyl ether 6/4 on silica gel); m.p.: 155-157°C; IR (nujol) (λ = cm-1) 3434 (NH), 1648 (C=O); 1H-NMR (CDCl3) δ 0.86 (m, 2H), 1.25-1.98 (m, 4H), 2.49 (s, 3H) 2.92 (m, 4H), 7.09 (d, J=7.6 Hz, 1H), 7.29 (m, 2 H), 7.47 (m, 2H), 7.62 (m, 2H); 13C-NMR (CDCl3) δ 21.9, 23.2, 25.2, 57.0, 113.9, 119.0, 124.4, 125.4, 128.2, 128.8, 129.2, 130.3, 130.5, 135.6, 136.0, 136.2, 137.8, 157.5, 162.9; API-ESI calc. for 443.33, found 443.10

81%

Stage #1: 1-(2,4-dichlorophenyl)-6-methyl-1H-benzofuro[3,2-0c]pyrazole-3-carboxylic acid With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In dichloromethane at 20℃; for 1h; Stage #2: 1-Aminopiperidine In dichloromethane at 20℃; for 22h;

6.3 General procedure I: preparation of carbohydrazides 15-17 and carboxamides 18-24 General procedure: A mixture of the benzofuro[3,2-c]pyrazole-3-carboxylic acid 29 (1.0 eq, 0.25 mmol), 1-hydroxybenzotriazole (HOBt) (1.2 eq, 0.30 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (1.2 eq, 0.30 mmol) in dichloromethane (2.0 mL) was stirred at room temperature for 1 h. A solution of the appropriate amine or hydrazine (2.0 eq, 0.50 mmol) in dichloromethane (3.0 mL) was added drop-wise. The resulting mixture was stirred at room temperature for 22 h. The solvent was removed under vacuum and the residue was purified by flash-chromatography to afford the desired compound.

Reference： [1]Current Patent Assignee: NEUROSCIENZE PHARMANESS S.C.A.R.L. - US2010/216785, 2010, A1 Location in patent: Page/Page column 42
[2]Current Patent Assignee: NEUROSCIENZE PHARMANESS S.C.A.R.L. - EP2223914, 2010, A1 Location in patent: Page/Page column 51; 52
[3]Current Patent Assignee: NEUROSCIENZE PHARMANESS S.C.A.R.L. - EP2223913, 2010, A1 Location in patent: Page/Page column 56; 57
[4]Pinna, Giovanni; Loriga, Giovanni; Lazzari, Paolo; Ruiu, Stefania; Falzoi, Matteo; Frau, Simona; Pau, Amedeo; Murineddu, Gabriele; Asproni, Battistina; Pinna, Gerard A. [European Journal of Medicinal Chemistry, 2014, vol. 82, p. 281 - 292]

48
5-(2-bromophenyl)-5,6-diazatetracyclo[7.3.1.1^3,11.0^4,8]tetradeca-4⁽⁸⁾,6-diene-7-carboxylic acid [ No CAS ]
[ 2213-43-6 ]
N⁽⁷⁾-piperidino-5-(2-bromophenyl)-5,6-diazatetracyclo[7.3.1.1^3,11.0^4,8]tetradeca-4⁽⁸⁾,6-diene-7-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	Stage #1: 5-(2-bromophenyl)-5,6-diazatetracyclo[7.3.1.1^3,11.0^4,8]tetradeca-4⁽⁸⁾,6-diene-7-carboxylic acid With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: 1-Aminopiperidine In N,N-dimethyl-formamide at 20℃; for 1h;	101 A solution of intermediate 1 (300 mg, 0.78 mmol) in DMF (3 ml), was treated with BOP reagent (319 mg, 0.72 mmol) and Et3N (0.10 ml, 0.99 mmol) at room temperature for 15 minutes after which period, N-aminopiperidine (80 μl, 0.90 mmol) was added to the mixture and stirred at room temperature for 1 h. The mixture was poured into water and the precipitate formed was collected by filtration, dried and purified by flash chromatography to get pure title compound (270 mg, 74 %). M.P.: 244 °C. 1H-NMR (δ ppm, CDCl3, 300 MHz): 7.72 (d, J = 7.6, 1H); 7.65 (br. s, 1H); 7.50-7.30 (m, 3H; 3.97 (br. s, 1H); 2.85 (br. s, 4H); 2.51 (br. s, 1H); 2.16 (br. s, 2H); 2.10-1.50 (m, 14H); 1.40(br. s, 2H). IR (cm-1, KBr): 3311 (w), 2913 (s), 2844 (m), 2793 (m), 1687 (s), 1570 (w), 1522 (s), 1489 (m), 1479 (m), 1440 (m), 1352 (m), 1227 (m), 1214 (m). MS (m/z) 469.4 ([M+H]+).

Reference： [1]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2006/129178, 2006, A1 Location in patent: Page/Page column 94

49
[ 2162-74-5 ]
[ 2213-43-6 ]
[ 1255649-91-2 ]

Reference： [1]Organometallics,2010,vol. 29,p. 5946 - 5952

50
[ 574-96-9 ]
[ 2213-43-6 ]
[ 1290140-27-0 ]

Yield	Reaction Conditions	Operation in experiment
25%	In methanol; ethanol; at 20℃;	General procedure: To a solution of the amine (2.90 mmol) in ethanol (10 mL) was slowly added a solution of the corresponding aldehyde (2.90 mmol) in a small volume of methanol. The mixture was stirred at room temperature giving rise to a precipitate within a few minutes. When the mixture did not precipitate spontaneously, it was evaporated in vacuum and gave a solid on standing or on cooling. The resulting product was collected by filtration, washed successively with cold water, ethanol, and diethyl ether, and recrystallized from ethanol or methanol.

Reference： [1]Tetrahedron,2011,vol. 67,p. 2025 - 2034

51
[ 5428-43-3 ]
[ 2213-43-6 ]
C₁₉H₂₃N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine In acetone for 8h;

Reference： [1]Location in patent: experimental part Nikalje, Anna Pratima G.; Ghodke, Mangesh; Girbane, Amol [Archiv der Pharmazie, 2012, vol. 345, # 1, p. 57 - 64]

52
[ 1416564-42-5 ]
[ 2213-43-6 ]
[ 1416564-37-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 18.5h; Inert atmosphere;	1 5.2 General procedure for the amidation reaction General procedure: To a solution of the appropriate acid derivative (1 mmol) in dryDMF (5 mL) O-benzotriazol-1-yl-N,N,N',N'-tetramethyluroniumhexafluorophosphate (HBTU, 2 mmol) was added followed by 1-hydroxybenzotriazole (HOBt, 1 mmol), diisopropylethylamine (DIPEA, 1.5 mmol) and the appropriate amine (1.2 mmol). The mixture was stirred under N2 atmosphere at room temperature for 30 min and DIPEA (1.5 mmol) was added again. The reaction mixture was stirred at room temperature for 18 h, poured into water and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous Na2SO4 and evaporated to dryness. The crude product, unless otherwise indicated, was recrystallized from EtOH.

Reference： [1]Pasquini, Serena; De Rosa, Maria; Ligresti, Alessia; Mugnaini, Claudia; Brizzi, Antonella; Caradonna, Nicola P.; Cascio, Maria Grazia; Bolognini, Daniele; Pertwee, Roger G.; Di Marzo, Vincenzo; Corelli, Federico [European Journal of Medicinal Chemistry, 2012, vol. 58, p. 30 - 43]

53
[ 1248340-80-8 ]
[ 2213-43-6 ]
[ 1422250-97-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; XPhos In toluene at 80℃; for 1.5h;	4.2.3. Procedure for the palladium-catalyzed amination reaction of 7-halobenzo[b]furans (5b,c,d,e,f,g,j): synthesis of 1-(5-methyl-2-phenylbenzo[b]furan-7-yl)piperidine (10b). General procedure: A solution of 2-phenyl-5-methyl-7-bromobenzo[b]furan 5d (0.100 g, 0.34 mmol), Pd2(dba)3 (0.0078 g, 0.0085 mmol), X-Phos (0.0162 g, 0.034 mmol), NaOBu-t (0.065 g, 0.68 mmol), and piperidine (0.337 mL, 3.4 mmol) in toluene (1 mL) was stirred at 80 °C for 24 h. After cooling, the reaction mixturewas dried under reduced pressure and the residue was purified by flash chromatography (SiO2, 50 g; n-hexane/ethyl acetate 85:15 v/v) to give 10b (0.133 g, 99%) as a yellow solid.

Reference： [1]Arcadi, Antonio; Blesi, Federico; Cacchi, Sandro; Fabrizi, Giancarlo; Goggiamani, Antonella; Marinelli, Fabio [Tetrahedron, 2013, vol. 69, # 7, p. 1857 - 1871]

54
[ 1422250-61-0 ]
[ 2213-43-6 ]
[ 1422251-01-1 ]

Yield	Reaction Conditions	Operation in experiment
91%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; sodium t-butanolate; XPhos In toluene at 80℃; for 2h;	4.2.3. Procedure for the palladium-catalyzed amination reaction of 7-halobenzo[b]furans (5b,c,d,e,f,g,j): synthesis of 1-(5-methyl-2-phenylbenzo[b]furan-7-yl)piperidine (10b). General procedure: A solution of 2-phenyl-5-methyl-7-bromobenzo[b]furan 5d (0.100 g, 0.34 mmol), Pd2(dba)3 (0.0078 g, 0.0085 mmol), X-Phos (0.0162 g, 0.034 mmol), NaOBu-t (0.065 g, 0.68 mmol), and piperidine (0.337 mL, 3.4 mmol) in toluene (1 mL) was stirred at 80 °C for 24 h. After cooling, the reaction mixturewas dried under reduced pressure and the residue was purified by flash chromatography (SiO2, 50 g; n-hexane/ethyl acetate 85:15 v/v) to give 10b (0.133 g, 99%) as a yellow solid.

Reference： [1]Arcadi, Antonio; Blesi, Federico; Cacchi, Sandro; Fabrizi, Giancarlo; Goggiamani, Antonella; Marinelli, Fabio [Tetrahedron, 2013, vol. 69, # 7, p. 1857 - 1871]

55
[ 917081-44-8 ]
[ 2213-43-6 ]
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-(hydroxymethyl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With aluminum (III) chloride In 1,2-dichloro-ethane at 0 - 20℃; for 16h; Inert atmosphere;	3 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-(hydroxymethyl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (Compound 117) To a magnetically stirred solution of 116 (1.21 g, 2.84 mmol) and aluminum trichloride (1.52 g, 11.36 mmol) in dichloride ethane (20 mL) was added 1-amino piperidine (1.14 g, 11.36 mmol) slowly under argon at 0° C. The resulting mixture was allowed to warm up to room temperature for 16 h, and then quenched with ice water and the aqueous phase was extracted with CH2Cl2 (2*20 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude residue, which was subjected to purification by flash chromatography on silica gel with n-hexane/ethyl acetate (1:1) to afford compound 117 (1.27 g, 93%) as a white solid: 1H NMR (CDCl3) δ 7.78 (brs, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.33-7.20 (m, 4H), 7.08-7.03 (m, 2H), 5.16 (t, J=6.9 Hz, 1H), 4.60 (d, J=6.9 Hz, 2H), 2.88-2.80 (m, 4H), 1.78 (quintet, J=5.4 Hz, 4H), 1.50-1.40 (m, 2H); ESMS m/z: 479.0 (M+1).

Reference： [1]Current Patent Assignee: NATIONAL HEALTH RESEARCH INSTITUTES - US2013/85126, 2013, A1 Location in patent: Paragraph 0162; 0165

56
[ 1429242-11-4 ]
[ 2213-43-6 ]
[ 1429242-12-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	With aluminum (III) chloride In 1,2-dichloro-ethane at 0 - 20℃; for 16h; Inert atmosphere;	1 5-(5-Bromothiophen-2-yl)-1-(2,4-dichlorophenyl)-4-(hydroxymethyl)-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (Compound 7) To a magnetically stirred solution of 6 (4.40 g, 9.24 mmol) and aluminum trichloride (2.46 g, 18.48 mmol) in dichloride ethane (88 mL) was added 1-aminopiperidine (3.70 g, 36.96 mmol) slowly under argon at 0° C. The resulting mixture was allowed to warm up to room temperature and stirred for 16 h, then quenched with ice water. The aqueous phase was extracted with CH2Cl2 (2*40 mL). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude residue, which was purified by flash chromatography eluting with n-hexane/ethyl acetate (1:1) to afford Compound 7 (4.75 g, 97%) as a white solid: 1H NMR (CDCl3) δ 7.73 (s, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.35 (dd, J=8.4, 2.4 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 6.95 (d, J=4.0 Hz, 1H), 6.69 (d, J=4.0 Hz, 1H), 5.17 (t, J=7.2 Hz, 1H), 4.67 (d, J=7.2 Hz, 2H), 2.83 (brs, 4H), 1.78-1.73 (m, 4H), 1.42 (brs, 2H); 13C NMR (CDCl3) δ 160.0, 144.7, 136.9, 136.6, 135.0, 133.6, 130.7, 130.3, 130.2, 128.6, 128.1, 124.0, 115.8, 57.1, 54.7, 25.3, 23.2; ESMS m/z: 529.1 (M+1).
97%	With aluminum (III) chloride at 0 - 20℃; for 16h; Inert atmosphere;

Reference： [1]Current Patent Assignee: NATIONAL HEALTH RESEARCH INSTITUTES - US2013/85126, 2013, A1 Location in patent: Paragraph 0033; 0039
[2]Chang, Chun-Ping; Wu, Chien-Huang; Song, Jen-Shin; Chou, Ming-Chen; Wong, Ying-Chieh; Lin, Yinchiu; Yeh, Teng-Kuang; Sadani, Amit A.; Ou, Ming-Hung; Chen, Kun-Hung; Chen, Pei-Hsuan; Kuo, Po-Chu; Tseng, Chen-Tso; Chang, Kuei-Hua; Tseng, Shi-Liang; Chao, Yu-Sheng; Hung, Ming-Shiu; Shia, Kak-Shan [Journal of Medicinal Chemistry, 2013, vol. 56, # 24, p. 9920 - 9933]

57
[ 17355-75-8 ]
[ 2213-43-6 ]
[ 1428261-50-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: 1-Aminopiperidine With trimethylaluminum In n-heptane; dichloromethane at 20℃; for 1h; Inert atmosphere; Stage #2: ethyl 1,5-diphenyl-1H-pyrazole-3-carboxylate In n-heptane; dichloromethane Reflux; Stage #3: With hydrogenchloride In n-heptane; dichloromethane; water at 40℃; for 0.5h;	4.1.7. General procedure for the synthesis of 8a-8h General procedure: To a solution of the corresponding amine (5 equiv) in dry DCM was added a solution of Al(Me)3 in heptane (2 M, 5 equiv) under N2 atmosphere. The mixture was stirred at rt for 1 h. Then, a solution of alkyl carboxylate (1 equiv) in dry DCM was added dropwise. The mixture was refluxed for 14-48 h, and then was carefully poured onto 1 N HCl. The biphasic solution was heated to 40 °C for 30 min and cooled to rt. The organic layer was separated, dried over MgSO4 and evaporated. The residue was purified by flash chromatography (eluent n-hexane/EtOAc, 9:1 for pyrazoles and 1:1 for triazoles), except 8b which was recrystallized from hexane.

Reference： [1]Alvarado, Mario; Decara, Juan; Luque, María Jesús; Hernandez-Folgado, Laura; Gómez-Cañas, María; Gómez-Ruiz, María; Fernández-Ruiz, Javier; Elguero, José; Jagerovic, Nadine; Serrano, Antonia; Goya, Pilar; De Fonseca, Fernando Rodríguez [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 7, p. 1708 - 1716]

58
[ 741287-00-3 ]
[ 2213-43-6 ]
[ 1428261-53-3 ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: 1-Aminopiperidine With trimethylaluminum In n-heptane; dichloromethane at 20℃; for 1h; Inert atmosphere; Stage #2: ethyl 1,5-diphenyl-4-methyl-1H-pyrazole-3-carboxylate In n-heptane; dichloromethane Reflux; Stage #3: With hydrogenchloride In n-heptane; dichloromethane; water at 40℃; for 0.5h;	4.1.7. General procedure for the synthesis of 8a-8h General procedure: To a solution of the corresponding amine (5 equiv) in dry DCM was added a solution of Al(Me)3 in heptane (2 M, 5 equiv) under N2 atmosphere. The mixture was stirred at rt for 1 h. Then, a solution of alkyl carboxylate (1 equiv) in dry DCM was added dropwise. The mixture was refluxed for 14-48 h, and then was carefully poured onto 1 N HCl. The biphasic solution was heated to 40 °C for 30 min and cooled to rt. The organic layer was separated, dried over MgSO4 and evaporated. The residue was purified by flash chromatography (eluent n-hexane/EtOAc, 9:1 for pyrazoles and 1:1 for triazoles), except 8b which was recrystallized from hexane.

Reference： [1]Alvarado, Mario; Decara, Juan; Luque, María Jesús; Hernandez-Folgado, Laura; Gómez-Cañas, María; Gómez-Ruiz, María; Fernández-Ruiz, Javier; Elguero, José; Jagerovic, Nadine; Serrano, Antonia; Goya, Pilar; De Fonseca, Fernando Rodríguez [Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 7, p. 1708 - 1716]

59
[ 2213-43-6 ]
[ 3282-30-2 ]
[ 925126-09-6 ]

Yield	Reaction Conditions	Operation in experiment
51.3%	With triethylamine In diethyl ether at 20℃; for 17h; Inert atmosphere;	5 4.5. Preparation of N-(1-piperidinyl)pivalamide (L⁴H) A 100 mL Schlenk flask was charged with 1-aminopiperidine (2.156 mL, 19.97 mmol), triethylamine (2.782 mL, 19.97 mmol), and diethyl ether (300 mL). Pivaloyl chloride (1.889 mL, 10.25 mmol) was slowly added to the stirred solution at 0 °C. The resultant white solution was stirred at ambient temperature for 17 h. The solution was filtered through a coarse glass funnel to afford a colorless solution. Volatile components were subsequently removed and the resultant white powder was collected and sublimed at 111 °C/0.05 Torr to afford L4H as colorless crystals (1.889 g, 51.3%): mp 141-143 °C; IR 1651 (νCO, s); 1H NMR (CDCl3, 23 °C, δ) 6.30 (br s, 1H, NH), 2.71 (t, 4H, N(CH3)2), 1.67 (p, 4H, CH2), 1.37 (p, 2H, CH2,), 1.16 (s, 9H, (CH3)3); 13C{1H}(CDCl3, 23 °C, ppm) 175.27 (s, C=O), 56.70 (s, CH2), 38.06 (s, C(CH3)3), 27.48 (s, C(CH3)3), 25.37 (s, CH2), 23.29 (s, CH2).4.5.

Reference： [1]Karunarathne, Mahesh C.; Knisley, Thomas J.; Tunstull, Gabriel S.; Heeg, Mary Jane; Winter, Charles H. [Polyhedron, 2013, vol. 52, p. 820 - 830]

60
[ 1358040-29-5 ]
[ 2213-43-6 ]
[ 1358039-14-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 16h; Inert atmosphere;	4.1.4 (9-Pentyl-9H-carbazol-3-yl)(piperidin-1-yl)methanone (4) General procedure: Method A: amide coupling: Carboxylic acid 3 (300mg, 1.07mmol), piperidine (215mg, 2.53mmol), DIPEA (363μL, 2.14mmol), and DMAP (156mg, 1.28mmol) were added to DCM (30mL) under nitrogen. The obtained solution was cooled down on an ice-water bath. EDC (350mg, 1.83mmol) was added to the solution, and the reaction mixture was stirred for 16 h while warming at room temperature. The solvent was removed in vacuo, and the obtained residue was extracted with EtOAc (100mL). The organic layer was washed consecutively with 5% citric acid solution (50mL×3), concentrated sodium bicarbonate (50mL×3), brine (50mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified on silica gel using heptanes/ EtOAc in different proportions to afford the title compound as a light yellow gum (345mg, 93%).

Reference： [1]Petrov, Ravil R.; Knight, Lindsay; Chen, Shao-Rui; Wager-Miller, Jim; McDaniel, Steven W.; Diaz, Fanny; Barth, Francis; Pan, Hui-Lin; Mackie, Ken; Cavasotto, Claudio N.; Diaz, Philippe [European Journal of Medicinal Chemistry, 2013, vol. 69, p. 881 - 907]

61
[ 2943-75-1 ]
[ 2213-43-6 ]
[ 1620205-86-8 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 4056 - 4058

62
[ 75-15-0 ]
[ 2213-43-6 ]
[ 29053-42-7 ]

Yield	Reaction Conditions	Operation in experiment
93.5%	With sodium hydroxide In water; ethyl acetate at 0 - 20℃; for 3h;	4.1.1 Sodium piperidin-1-yl-carbamodithioate (3) To the ice cooled mixture of N-amino piperidine (1, 5.0 g, 50 mmol), ethyl acetate (50.0 mL) was added aq. NaOH (1.2 g, 75 mmol, 30%) drop wise followed by carbon disulfide and stirred at rt for 3 h. The reaction mixture was brought to room temperature and stirring continued for another 3 h. The separated solid was collected through filtration, washed several times with ethyl acetate and dried in desiccator to give the title compound 3 (1.86 g, 93.5%) as white solid; mp 85-87 °C; IR (KBr) ν (cm-1) 3012, 2840, 1644, 1480, 1439, 1385, 1313; 1H NMR (400 MHz, CDCl3) δ 2.88 (4H, bs), 1.71 (4H, s), 1.48 (2H, bs); Elemental analysis calculated (%) for C6H11N2NaS2; C, 36.34; H, 5.59; N, 14.13; Found C, 36.44; H,5.79; N, 14.03.

Reference： [1]Bala, Veenu; Jangir, Santosh; Kumar, Vikas; Mandalapu, Dhanaraju; Gupta, Sonal; Kumar, Lalit; Kushwaha, Bhavana; Chhonker, Yashpal S.; Krishna, Atul; Maikhuri, Jagdamba P.; Shukla, Praveen K.; Bhatta, Rabi S.; Gupta, Gopal; Sharma, Vishnu L. [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 24, p. 5782 - 5786]

63
[ 533-67-5 ]
[ 2213-43-6 ]
(2R,3S)-5-(piperidin-1-ylimino)pentane-1,2,3-triol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	In methanol for 1h; Reflux;	(2R,3S)-5-(piperidin-1-ylimino)pentane-1,2,3-triol (20) In a 100 ml flask, N-aminopiperidine (800 mg, 8 mmol) was dissolved in 15 ml of methanol. 2-deoxy-D-ribose (670 mg, 5 mmol) was added and the mixture was stirred at the methanol reflux. After 1 h of stirring the reaction was complete according to the TLC. Volatiles were removed under reduced pressure and the residuewas purified by column chromatography (eluent: ethanol-benzene-triethylamine 29:10:1). Process yielded slightly yellow liquid (1055 mg, 4.88 mmol, 98%).

Reference： [1]Ilisson, Mihkel; Tomson, Kristjan; Selyutina, Anastasia; Türk, Silver; Mäeorg, Uno [Synthetic Communications, 2015, vol. 45, # 11, p. 1367 - 1373]

64
[ 5328-37-0 ]
[ 2213-43-6 ]
(2S,3R,4S)-5-(piperidin-1-ylimino)pentane-1,2,3,4-tetrol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	In methanol; for 3.5h;Reflux;	In a 100 ml flask, N-aminopiperidine (800 mg, 8 mmol) was dissolved in 15 ml of methanol. <strong>[5328-37-0]L-<strong>[5328-37-0]arabinose</strong></strong> (750mg, 5 mmol) was added and the mixture was stirred at the methanol reflux. After 3.5 h of stirring the reaction was complete according to the TLC. Volatiles were removed under reduced pressure and the residue was recrystallized in MTBE-ethanol 1:1 mixture. Process yielded white crystals (984 mg, 4.24 mmol, 85%) which were dried further in vacuum.

Reference： [1]Synthetic Communications,2015,vol. 45,p. 1367 - 1373

65
[ 2213-43-6 ]
[ 10030-85-0 ]
(2S,3S,4S,5S)-1-(piperidin-1-ylimino)hexane-2,3,4,5-tetrol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	In methanol; for 3.75h;Reflux;	In a 100 ml flask, N-aminopiperidine (800 mg, 8 mmol) was dissolved in 15 ml of methanol. <strong>[10030-85-0]L-<strong>[10030-85-0]rhamnose monohydrate</strong></strong> (910 mg, 5 mmol) was added and the mixture was stirred at the methanol reflux. After 3.75 h of stirring the reaction was complete according to the TLC. Volatiles were removed under reduced pressure andthe residue was recrystallized in MTBE-ethanol 3:1 mixture. Process yielded white crystals (1021 mg, 4.15mmol, 83%) which were dried further in vacuum.

Reference： [1]Synthetic Communications,2015,vol. 45,p. 1367 - 1373

66
[ 1271-48-3 ]
[ 2213-43-6 ]
C₂₂H₃₀FeN₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With magnesium sulfate; In dichloromethane; at 20℃;Schlenk technique; Inert atmosphere;	General procedure: General procedure: in a Schlenk tube, under argon,were added 115 mg (0,47 mmol) of 1,10-ferrocenedicarboxaldehyde,625 mg (5,19 mmol) of anhydrous magnesiumsulphate MgSO4 and 10 ml of anhydrousdichloromethane. To the red suspension was then added12 equiv of the specific hydrazine using a syringe. Thereaction mixture was then stirred at room temperatureovernight. The crude material was purified by flashchromatography on silica gel. 2d: reaction with 626 mL of 1-aminopiperidine to yield189 mg of 2d (yield = 98%). 1H (300 MHz, CDCl3): 7.37 (s,2H, CH), 4.52 (t, J = 1.9 Hz, 4H, Cp), 4.23 (t, J = 1.9 Hz, 4H,Cp), 3.02 (m, 8H, CH2), 1.75 (m, 8H, CH2), 1.52 (m, 4H, CH2).13C (300 MHz, CDCl3): 135.8 (s, CH), 83.2 (s, quat. Cp), 70.0(s, subst. Cp), 67.6 (s, subst. Cp), 52.7 (s, CH2), 25.3 (s, CH2),24.2 (s, CH2). HR MS (ESI+): 407.1892 (100%, 407.1898 forC22H31FeN4: M + 1).

Reference： [1]Comptes Rendus Chimie,2015,vol. 18,p. 801 - 807

67
[ 22996-21-0 ]
[ 2213-43-6 ]
C₁₃H₁₇N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In toluene at 90℃; for 2h; Sealed tube;	General procedure for preparation of N-substituted-2H-indazol-2-amine derivatives 8 General procedure: To a solution of 2-nitrobenzaldehyde (0.5 mmol) in 4 mL of anhydrous toluene was added phenyl hydrazine (0.55 mmol) at room temperature in a sealed tube. The reaction mixture was heated at 90 °C for 2 hours and then cooled down to room temperature to add tri(N-butyl)phosphine (375 L, 1.5 mmol). The reaction mixture was further heated at 90 °C for 18 hours. After completion of the reaction (monitored by LC/MS), the reaction mixture was cooled down to room temperature, CH2Cl2 (15 mL) and water (15 mL) were added. The phases were separated and the organic layer was washed two times with water (10 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography (hexane/EtOAc 9:1) to provide the N-substituted-2H-indazol-2-amine derivative 8.

Reference： [1]Schoene, Jens; Bel Abed, Hassen; Christmann, Mathias; Nazaré, Marc [Tetrahedron Letters, 2017, vol. 58, # 16, p. 1633 - 1635]

68
[ 2213-43-6 ]
[ 148625-35-8 ]
methyl 2-(piperidin-1-yl)indazole-5-carboxylate [ No CAS ]

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1633 - 1635

69
[ 2213-43-6 ]
[ 148625-35-8 ]
C₁₄H₁₇N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; at 90℃; for 2h;Sealed tube;	General procedure: To a solution of 2-nitrobenzaldehyde (0.5 mmol) in 4 mL of anhydrous toluene was added phenyl hydrazine (0.55 mmol) at room temperature in a sealed tube. The reaction mixture was heated at 90 °C for 2 hours and then cooled down to room temperature to add tri(N-butyl)phosphine (375 L, 1.5 mmol). The reaction mixture was further heated at 90 °C for 18 hours. After completion of the reaction (monitored by LC/MS), the reaction mixture was cooled down to room temperature, CH2Cl2 (15 mL) and water (15 mL) were added. The phases were separated and the organic layer was washed two times with water (10 mL). The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure and purified by flash chromatography (hexane/EtOAc 9:1) to provide the N-substituted-2H-indazol-2-amine derivative 8.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 1633 - 1635

70
[ 337526-61-1 ]
[ 2213-43-6 ]
8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,2-diaza-benzo[<i>e</i>]azulene-3-carboxylic acid piperidin-1-ylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: 8-chloro-1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 1h; Stage #2: 1-Aminopiperidine In dichloromethane at 20℃; for 22h;	6.1.2. General procedure A: preparation of carbohydrazides 9a-cand carboxamides 9d-i A mixture of the appropriate carboxylic acid 7a-b or 8a-b (1.0eq, 0.25 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (1.2 eq,0.30 mmol) and N-(3-dimethylaminopropyl)-N0-ethylcarbodiimidehydrochloride (EDC) (1.2 eq, 0.30 mmol) in dichloromethane(2.0 ml) was stirred at room temperature for 1 h. A solution of therequisite hydrazine or amine (2.0 eq, 0.50 mmol) in dichloromethane(3.0 ml) was added drop-wise. The resulting mixture wasstirred at room temperature for 22 h. The solvent was removedunder vacuum and the residue was purified by flashchromatographyto afford the desired compound. When the startinghydrazines or amines were used as hydrochloride salt, triethylamine(TEA) (2.0 eq, 0.50 mmol) was added to the mixture. 6.1.2.1. N-Piperidin-1-yl-8-chloro-1-(20,40-dichlorophenyl)-1,4,5,6-tetrahydrobenzo [6,7]cyclohepta [1,2-c]pyrazole-3-carboxamide (9a)[12]. General procedure A was used to convert 7a and N-aminopiperidineinto the title product. White solid; yield: 79%; mp199e200 C (acetone), (202 C [12]); Rf 0.40 (diethyl ether/petroleumether, 6:4); IR 3200, 1650; ESI-MS (m/z): 513.1 (MNa); 1HNMR (CDCl3) d 1.40e1.48 (m, 2H), 1.72e1.80 (m, 4H), 2.19e2.30 (m,2H), 2.66 (t, 2H, J 6.6 Hz), 2.83e2.90 (m, 4H), 2.90e3.48 (m, 2H),6.56 (d, 1H, J 8.3 Hz), 7.00 (dd, 1H, J 2.2 and 8.3 Hz), 7.30 (d, 1H,J 2.2 Hz), 7.40 (dd, 1H, J 2.2 and 8.3 Hz); 7.42e7.48 (m, 2H), 7.66(bs, 1H); 13C NMR (CDCl3) d 20.2, 23.4, 25.5, 31.4, 32.6, 57.1, 122.7,126.2, 127.7, 128.0, 128.2, 129.9, 130.4, 130.5, 132.5, 134.2, 135.9,136.0, 142.2, 143.6, 143.8, 160.0. Anal. C24H23Cl3N4O (C, H, Cl, N).

Reference： [1]Lazzari, Paolo; Distinto, Rita; Manca, Ilaria; Baillie, Gemma; Murineddu, Gabriele; Pira, Marilena; Falzoi, Matteo; Sani, Monica; Morales, Paula; Ross, Ruth; Zanda, Matteo; Jagerovic, Nadine; Pinna, Gérard Aimè [European Journal of Medicinal Chemistry, 2016, vol. 121, p. 194 - 208]

71
[ 2213-43-6 ]
[ 175137-21-0 ]
C₁₂H₁₆N₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	In isopropyl alcohol; at 75℃; for 3h;	4-chloro-7-methylthieno [3,2-d] pyrimidine (Maybridge) (200 mg, 1.1 mmol) was dissolved in isopropanol (5 mL), 1-aminopiperidine (0.50 mL, 4.6 mmol) was added and It was heated for 3 hours. After standing to cool, water (30 mL) was added and the precipitated solid was collected by filtration. After drying, the resulting solid was suspended and washed with isopropyl ether to obtain N 2914 X 5 (128 mg, 0.515 mmol, yield 47%) as a colorless solid

Reference： [1]Patent: JP2018/95564,2018,A .Location in patent: Paragraph 0091-0093

72
[ 843647-60-9 ]
[ 2213-43-6 ]
N-{3-[2-fluoro-4'-(piperidine-4-yliminomethyl)-biphenyl-4-yl]-2-oxo-1,3-oxazolidin-5-(S)-ylmethyl}-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: (S)-N-[3-(2-fluoro-4'-formylbiphenyl-4-yl)-2-oxo-1,3-oxazolidine-5-ylmethyl]acetamide With acetic acid In ethanol at 78℃; for 0.5h; Stage #2: 1-Aminopiperidine In ethanol at 78℃;	10 5.1.7 N-{3-{2-fluoro-4'-[(4-methylpiperazin-1-yl)iminomethyl]-biphenyl-4-yl}-2-oxo-1,3-oxazolidine-5-(S)-ylmeth yl}-acetamide(9a) General procedure: To a well-stirred solution of intermediate 5 (2g, 5.6mmol) in C2H5OH(60mL) was added a drop of AcOH. The resulted mixture was refluxed for 0.5h. Then intermediates 8a (2.95g) was added, followed by stirring for 10hat the same temperature. After cooled to room temperature, The resulting solid was collected by filtration and dried to give the target compounds 9a as a light yellow solid in 82% yield.

Reference： [1]Wu, Yachuang; Ding, Xiudong; Ding, Liang; Zhang, Yongsheng; Cui, Lei; Sun, Lu; Li, Wei; Wang, Di; Zhao, Yanfang [European Journal of Medicinal Chemistry, 2018, vol. 158, p. 247 - 258]

73
4-(5-(2-nitrobenzyl)-4-oxo-2,3,4,5-tetrahydrobenzo-1,5-thiazepin-2-yl)benzoic acid [ No CAS ]
[ 2213-43-6 ]
 N-(1-piperidinyl)-4-(5-(2-nitrobenzyl)-4-oxo-2,3,4,5-tetrahydrobenzo-1,5-thiazepin-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane at 0 - 20℃;	47 4.1.39. General procedure for the synthesis of 5-(2-nitrobenzyl)-2-(4-substituted)- dihydrobenzo-1,5-thiazepin-4(5H)-one 6a-6u General procedure: To a mixture of 5a (435mg, 1mmol), HATU (760mg, 2mmol), HOAt (272mg, 2mmol), substituted amine (1.2mmol) and DCM (10mL) at 0°C was added DIPEA (0.52mL, 3mmol), and the reaction mixture was then slowly warm to room temperature and stirred overnight. The reaction was quenched by water and the mixture was extracted with ethyl acetate, washed with water and brine, dried over Na2SO4 and then subjected to flash chromatography

Reference： [1]Gao, Yang; Zhang, Peng; Cui, Anfeng; Ye, De-Yong; Xiang, Meng; Chu, Yong [Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 20, p. 5479 - 5493]

74
[ 2213-43-6 ]
[ 762-21-0 ]
diethyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-2,3-dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With copper diacetate In 5,5-dimethyl-1,3-cyclohexadiene at 140℃; for 16h;	Diethyl 5,6-dihydropyrazolo[5,1-a]isoquinoline-1,2-dicarboxylate (3) General procedure: In a RB flask, a solution of 3,4-dihydroisoquinolin-2(1H)-amine 1a (1.57 g, 5 mmol), diethyl acetylenedicarboxylate 2a (0.94 g, 5.5 mmol) in xylene (25 mL) was treated with Cu(OAc)2 (0.91 g, 5 mmol) and the reaction mixture is heated to 140 °C for 8 h. Then the reaction mixture was cooled to room temperature and all the volatiles were evaporated under reduced pressure. The crude compound thus obtained was purified by silica gel flash column chromatography to afford diethyl 5,6-dihydropyrazolo[5,1-a]isoquinoline-1,2-dicarboxylate 3 (1.43 g, 91%) as brown viscous liquid.

Reference： [1]Regalla, Venkata Reddy; Addada, RamaKrishnam Raju; Chatterjee, Anindita [Tetrahedron Letters, 2018, vol. 59, # 47, p. 4161 - 4164]

75
[ 7515-15-3 ]
[ 2213-43-6 ]
methyl 2-(4-nitrophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With copper diacetate In 5,5-dimethyl-1,3-cyclohexadiene at 140℃; for 16h;	Diethyl 5,6-dihydropyrazolo[5,1-a]isoquinoline-1,2-dicarboxylate (3) General procedure: In a RB flask, a solution of 3,4-dihydroisoquinolin-2(1H)-amine 1a (1.57 g, 5 mmol), diethyl acetylenedicarboxylate 2a (0.94 g, 5.5 mmol) in xylene (25 mL) was treated with Cu(OAc)2 (0.91 g, 5 mmol) and the reaction mixture is heated to 140 °C for 8 h. Then the reaction mixture was cooled to room temperature and all the volatiles were evaporated under reduced pressure. The crude compound thus obtained was purified by silica gel flash column chromatography to afford diethyl 5,6-dihydropyrazolo[5,1-a]isoquinoline-1,2-dicarboxylate 3 (1.43 g, 91%) as brown viscous liquid.

Reference： [1]Regalla, Venkata Reddy; Addada, RamaKrishnam Raju; Chatterjee, Anindita [Tetrahedron Letters, 2018, vol. 59, # 47, p. 4161 - 4164]

76
[ 95725-65-8 ]
[ 2213-43-6 ]
2-(5-isopropyl-2-methylphenoxy)-N-(piperidin-1-yl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine In acetonitrile at 60℃;	4.5. Synthesis of 2-(5-isopropyl-2-methylphenoxy)-N-Racetamide (5a-w) General procedure: Compound 4 (1.0 mmol) and Et3N (1.1 mmol) were dispersed in dry acetonitrile (5 ml). And then, appropriate amine(1.0 mmol) was added to the mixture. The mixture wasstirred at 60° C for overnight. The solvent was evaporated and the residue was washed with water. The resulting crude product was purified by column chromatography (Hexane:Ethylacetate).

Reference： [1]Zengin Kurt, Belma; Durdagi, Serdar; Celebi, Gulsen; Ekhteiari Salmas, Ramin; Sonmez, Fatih [Journal of Biomolecular Structure and Dynamics, 2020, vol. 38, # 3, p. 841 - 859]

77
2-methoxy-7,7,9,12a-tetramethyl-5,6,6a,7,12,12a-hexahydronaphtho[1,2-g]quinazoline-3-carboxylic acid [ No CAS ]
[ 2213-43-6 ]
2-methoxy-7,7,9,12a-tetramethyl-N-(piperidin-1-yl)-5,6,6a,7,12,12a-hexahydronaphtho[1,2-g]quinazoline-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With triethylamine; HATU In dichloromethane at 20℃; for 6h;	5.16. (12aS)-2-methoxy-N,7,7,9,12a-pentamethyl-5,6,6a,7,12,12ahexahydronaphtho[1,2-g]quinazoline-3-carboxamide (29) General procedure: To a solution of compound 27 (55 mg, 0.15 mmol) in CH2Cl2(10 mL) was added HATU (76 mg, 0.20 mmol), methylamine hydrochloride(14 mg, 0.20 mmol) and TEA (60 mg, 0.60 mmol) atroom temperature. Then the reaction mixture was stirred for 6 h.After that the reaction mixture was poured into water and extractedwith CH2Cl2 (10mL 3). The organic layer was washed withbrine, dried over anhydrous Na2SO4, and concentrated under vacuum.The residue was purified by silica gel chromatography (petroleumether/EtOAc, 2/1, v/v) to afford compound 29 (52 mg, 92%)

Reference： [1]Bai, Jie; Xie, Jia; Xing, Yajing; Wang, Li-Ting; Xie, Jiuqing; Yang, Fan; Liu, Ting; Liu, Mingyao; Tang, Jie; Yi, Zhengfang; Qiu, Wen-Wei [European Journal of Medicinal Chemistry, 2019, vol. 176, p. 21 - 40]

78
[ 201230-82-2 ]
[ 63444-51-9 ]
[ 2213-43-6 ]
C₁₉H₂₄N₂O [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 10928 - 10931
Angew. Chem.,2019,vol. 131,p. 11044 - 11047,4

79
[ 201230-82-2 ]
[ 2213-43-6 ]
[ 73286-71-2 ]
C₁₅H₂₇N₃O₂ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 10928 - 10931
Angew. Chem.,2019,vol. 131,p. 11044 - 11047,4

80
[ 201230-82-2 ]
[ 2213-43-6 ]
[ 73286-71-2 ]
C₁₅H₂₇N₃O₂ [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2019,vol. 58,p. 10928 - 10931
Angew. Chem.,2019,vol. 131,p. 11044 - 11047,4

81
[ 98-01-1 ]
[ 2213-43-6 ]
(E)-1-(furan-2-yl)-N-(piperidin-1-yl)methanimine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.48%	With magnesium sulfate In dichloromethane at 20℃;	67.1 To a mixture of furan-2-carbaldehyde (1 .00 g, 10.407 mmol, 1 .00 equiv) and piperidin-1 -amine (1 .04 g, 10.407 mmol, 1 .00 equiv) in DCM (25.00 mL) was added MgSC (2.51 g, 20.815 mmol, 2.00 equiv). The resulting mixture was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with MeOH in DCM from 0% to 10% to afford the desired product (E)-1 -(furan-2-yl)-N-(piperidin-1 - yl)methanimine (1 .70 g, 9.551 mmol, 82.48%) as a brown solid. LCMS (ESI) m/z: [M+H]+ = 179.

Reference： [1]Current Patent Assignee: FOGHORN THERAPEUTICS INC - WO2019/152440, 2019, A1 Location in patent: Page/Page column 157-158

82
[ 86-57-7 ]
[ 2213-43-6 ]
N-Naphthyl-N',N'-pentamethylen-hydrazin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium phosphate tribasic trihydrate; 2-(2,6-diethyl-4-methylphenyl)-5-(2,4,6-triisopropylphenyl)imidazo[1,5-a]pyridin-2-ium chloride; palladium(II) acetylacetonate In 1,4-dioxane at 130℃; for 24h; Sealed tube; Inert atmosphere;	16 Example 16 In a nitrogen atmosphere,103.9 mg of the above nitroaromatic hydrocarbon was added to the dried sealed tube.90.1 mg of N-aminopiperidine, 9.2 mg of Pd(acac)2,20.0 mg of imidazolium salt L3, 480 mg of tripotassium phosphate trihydrate,3 mL of dioxane, then tighten the sealing cap and react at 130 ° C for 24 h.After the reaction, it was filtered through celite, concentrated, and passed through a silica gel column.The product was obtained in 117.5 mg.The yield was 86%.
86%	With bis(acetylacetonato)palladium(II); potassium phosphate tribasic trihydrate; 2-(2,6-diethyl-4-methylphenyl)-5-(2,4,6-triisopropylphenyl)imidazo[1,5-a]pyridin-2-ium chloride In 1,4-dioxane at 130℃; for 24h; Inert atmosphere;

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY - CN110105230, 2019, A Location in patent: Paragraph 0116-0120
[2]Chen, Kai; Chen, Wanzhi; Chen, Wei; Liu, Miaochang; Wu, Huayue [ACS Catalysis, 2019, p. 8110 - 8115]

83
(S)-N-(3-(2-fluoro-3'-fluoro-4'-formylbiphenyl-4-yl)-2-oxo-1,3-oxazolidine-5-ylmethyl)acetamide [ No CAS ]
[ 2213-43-6 ]
(S)-N-(3-(2-fluoro-3'-fluoro-4’-(piperidin-1-yliminomethyl)biphenyl-4-yl)-2-oxo-1,3-oxazolidine-5-ylmethyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With acetic acid In ethanol at 78℃; for 2h;	5.1.4.1. (S)eN-(3-(2-fluoro-30-hydroxy-4’-((4-methylpiperazin-1-yl)iminomethyl)biphenyl-4-yl)-2-oxo-1,3- oxazolidie-5-ylmethyl)acetamide(6a-1). General procedure: To a well-stirred solution of intermediate 5a (2.0 g,5.29 mmol) in ethanol (10 mL) was added 1-amino-4-methylpiperazine 9a (0.61 g, 5.29 mmol) and a drop of acetic acid,and the mixturewas stirred at 78 C for 2 h. The mixturewas cooledto room temperature and the resulting solid was collected byfiltration and purified by column chromatography to give the targetcompounds 6a-1 as a yellow solid in 75% yield. M.p: 228-230 C;

Reference： [1]Wu, Yachuang; Ding, Xiudong; Yang, Yifeng; Li, Yingxiu; Qi, Yinliang; Hu, Feng; Qin, Mingze; Liu, Yajing; Sun, Lu; Zhao, Yanfang [European Journal of Medicinal Chemistry, 2020, vol. 185]

84
[ 1607803-45-1 ]
[ 2213-43-6 ]
(E)-8-hydroxy-3-methyl-7-((piperidin-1-ylimino)methyl)-1,2,3,4-tetrahydro-5H-chromeno[3,4-c]pyridin-5-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With magnesium sulfate In dichloromethane at 20℃; for 0.5h; Inert atmosphere;	12.f f. Synthesis of 9: (£)-8-hyd roxy-3-methyl-7-((piperidin- l-ylimino)methyl)- 1 ,2,3,4-tetrahyd ro-5H- chromeno [3,4-c] pyridin-5-one (9). A mixture of 3 [Ranatunga, et al., 2014, J. Med. Chem. 57:4289] (25 mg, 0.10 mmol), 1- aminopiperidine (14 mg, 0.13 mmol) and anhydrous magnesium sulfate (60 mg, 0.50 mmol) in DCM (5 mL) was stirred for 30 min at room temperature. The reaction was diluted with DCM and water and the organic layer was washed with brine and dried over anhydrous MgSC>4. Purification by silica gel flash chromatography (0 to 10% MeOH/CHCU) gave 9 as a pale yellow solid (26 mg, 79%). 1H NMR (400 MHz, DMSO-r) d 12.73 (s, 1H), 8.07 (s, 1H), 7.49 (d, J= 8.8 Hz, 1H), 6.85 (d, J= 8.8 Hz, 1H), 3.20 (s, 2H), 3.17 (t, J= 5.7 Hz, 4H), 2.85 (t, J= 5.8 Hz, 2H), 2.63 (t, J= 5.7 Hz, 2H), 2.36 (s, 3H), 1.69 (p, J= 5.6 Hz, 4H), 1.51 (td, J= 6.5, 3.5 Hz, 2H); HRMS (ESI-TOF) m/z [M + H]+ cald for C19H24N3O3 342.1822, found 342.1813.

Reference： [1]Current Patent Assignee: STATE UNIVERSITY SYSTEM OF FLORIDA - WO2019/195135, 2019, A1 Location in patent: Page/Page column 65; 84-85

85
[ 1607803-37-1 ]
[ 2213-43-6 ]
allyl (E)-8-hydroxy-5-oxo-7-((piperidin-1-ylimino)methyl)-1,5-dihydro-2H-chromeno[3,4-c]pyridine-3(4H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With magnesium sulfate In dichloromethane at 20℃; for 3h; Inert atmosphere;	12.c Allyl (iel-S-hydroxy-S-oxo-T-iipipendin-l-yliminolmethyll-l^-dihydiO-l//- chromeno [3,4 -c] pyridine-3(4//)-carboxylate (S2). A mixture of 1 [Tang, et al, 2014, J. Clin. Inv. 124:2585] (50 mg, 0.15 mmol), 1- aminopiperidine (21 mg, 0.21 mmol) and anhydrous magnesium sulfate (60 mg, 0.50 mmol) in DCM (5 mL) was stirred for 3 h at room temperature. The reaction was diluted with DCM and water and the organic layer was washed with brine and dried over anhydrous MgS04. urification by silica gel flash chromatography (30% EtO Ac/hexanes) gave S2 as a pale yellow solid (50 mg, 80%). 1H NMR (500 MHz, CDCh) d 12.91 (s, 1H), 8.14 (s, 1H), 7.27 (d, J= 10.5 Hz, 1H), 6.81 (d, .7= 8.8 Hz, 1H), 5.94 (ddt, .7= 16.4, 10.9, 5.6 Hz, 1H), 5.31 (dd, .7= 17.2, 1.8 Hz, 1H), 5.21 (d, J= 10.5 Hz, 1H), 4.63 (d, .7= 5.7 Hz, 2H), 4.42 (s, 2H), 3.76 (t, J= 5.8 Hz, 2H), 3.18 (t, J= 5.7 Hz, 4H), 2.82 (s, 2H), 1.77 (t, J= 5.9 Hz, 4H), 1.64 - 1.44 (m, 2H); HRMS (ESI-TOF) m/z [M + H]+ cald for C22H26N3O5 412.1867, found 412.1876.

Reference： [1]Current Patent Assignee: STATE UNIVERSITY SYSTEM OF FLORIDA - WO2019/195135, 2019, A1 Location in patent: Page/Page column 65; 82

86
[ 2213-43-6 ]
C₁₉H₂₀F₃N₃O₄ [ No CAS ]
C₂₄H₃₀F₃N₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In acetonitrile at 20℃; for 0.5h; Inert atmosphere;	1 To acetonitrile (1.5 mL) containing compound 1b (theoretical mass: 13 mg, 0.03 mmol)Add compound 1c (4mg, 0.04mmol),N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl) urea hexafluorophosphate (19mg, 0.05mmol) and diisopropylethylamine (13mg , 0.09mmol). The reaction mixture was stirred at room temperature for 30 minutes under the protection of nitrogen. After the reaction is completed, the reaction solution is concentrated under reduced pressure to obtain a crude product.The obtained crude product was separated and purified by preparative thin-layer chromatography (dichloromethane:methanol=20:1) to obtain compound 1d (12mg, yield 71%) as a colorless oil.

Reference： [1]Current Patent Assignee: HANGZHOU INNOGATE PHARMA CO LTD - CN113200981, 2021, A Location in patent: Paragraph 0080-0081; 0084

87
[ 869192-36-9 ]
[ 2213-43-6 ]
1-(2,4-dichlorophenyl)-4-methyl-3-(piperidin-1-ylcarbamoyl)-1H-pyrazol-5-yl trifluoromethanesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%		2.A A) A) 1-(2,4-dichlorophenyl)-4-methyl-3-(piperidin-1-ylcarbamoyl)-1H-pyrazol-5-yl trifluoromethanesulfonate To magnetically stirred suspension of AlCl3 (9.8 g, 3 eq) in anhydrous dichloroethane (30 ml) at 0° C. was added 1-aminopiperidine (8.6 g, 3.5 eq) under argon atmosphere, and the resulting mixture was stirred at 0-5° C. for 25 min. Ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-3-carboxylate (11 g) in dichloroethane (250 ml) was added, and the reaction mixture was slowly brought to room temperature over 30 minutes, and stirred at this temperature for 5 h. Reaction was quenched by adding 10% HCl (50 ml), and the biphasic mixture was stirred for 2 h. Organic layer was separate, and the aqueous layer was extracted with dichloromethane (350 ml). Combined organic layers were washed with water (280 ml), and brine (1*80 ml), dried over anhydrous MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel to give 9.5 g (77% yield) of product as a white solid.
77%		2.A A) A) 1-(2,4-dichlorophenyl)-4-methyl-3-(piperidin-1-ylcarbamoyl)-1H-pyrazol-5-yl trifluoromethanesulfonate To magnetically stirred suspension of AlCl3 (9.8 g, 3 eq) in anhydrous dichloroethane (30 ml) at 0° C. was added 1-aminopiperidine (8.6 g, 3.5 eq) under argon atmosphere, and the resulting mixture was stirred at 0-5° C. for 25 min. Ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-3-carboxylate (11 g) in dichloroethane (250 ml) was added, and the reaction mixture was slowly brought to room temperature over 30 minutes, and stirred at this temperature for 5 h. Reaction was quenched by adding 10% HCl (50 ml), and the biphasic mixture was stirred for 2 h. Organic layer was separate, and the aqueous layer was extracted with dichloromethane (350 ml). Combined organic layers were washed with water (280 ml), and brine (1*80 ml), dried over anhydrous MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel to give 9.5 g (77% yield) of product as a white solid.
77%	Stage #1: 1-Aminopiperidine With aluminum (III) chloride In 1,2-dichloro-ethane at 0 - 5℃; for 0.416667h; Inert atmosphere; Stage #2: Ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(((trifluoromethyl)sulphonyl)oxy)-1H-pyrazole-3-carboxylate In 1,2-dichloro-ethane at 20℃; for 5.5h; Inert atmosphere;	2.A A) 1-(2,4-dichlorophenyl)-4-methyl-3-(piperidin-1-ylcarbamoyl)-1H-pyrazol-5-yl trifluoromethanesulfonate To magnetically stirred suspension of AlCl3 (9.8 g, 3 eq) in anhydrous dichloroethane (30 ml) at 0° C. was added 1-aminopiperidine (8.6 g, 3.5 eq) under argon atmosphere, and the resulting mixture was stirred at 0-5° C. for 25 min. Ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-3-carboxylate (11 g) in dichloroethane (250 ml) was added, and the reaction mixture was slowly brought to room temperature over 30 minutes, and stirred at this temperature for 5 h. Reaction was quenched by adding 10% HCl (50 ml), and the biphasic mixture was stirred for 2 h. Organic layer was separate, and the aqueous layer was extracted with dichloromethane (3×50 ml). Combined organic layers were washed with water (2×80 ml), and brine (1×80 ml), dried over anhydrous MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel to give 9.5 g (77% yield) of product as a white solid.

77%

Stage #1: 1-Aminopiperidine With aluminum (III) chloride In 1,2-dichloro-ethane at 0 - 5℃; for 0.416667h; Inert atmosphere; Stage #2: Ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(((trifluoromethyl)sulphonyl)oxy)-1H-pyrazole-3-carboxylate In 1,2-dichloro-ethane at 20℃; for 5.5h; Inert atmosphere;

2.A A) 1-(2,4-dichlorophenyl)-4-methyl-3-(piperidin-1-ylcarbamoyl)-1H-pyrazol-5-yl trifluoromethanesulfonate To magnetically stirred suspension of AlCl3 (9.8 g, 3 eq) in anhydrous dichloroethane (30 ml) at 0° C. was added 1-aminopiperidine (8.6 g, 3.5 eq) under argon atmosphere, and the resulting mixture was stirred at 0-5° C. for 25 min. Ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-3-carboxylate (11 g) in dichloroethane (250 ml) was added, and the reaction mixture was slowly brought to room temperature over 30 minutes, and stirred at this temperature for 5 h. Reaction was quenched by adding 10% HCl (50 ml), and the biphasic mixture was stirred for 2 h. Organic layer was separate, and the aqueous layer was extracted with dichloromethane (3×50 ml). Combined organic layers were washed with water (2×80 ml), and brine (1×80 ml), dried over anhydrous MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel to give 9.5 g (77% yield) of product as a white solid.

Reference： [1]Current Patent Assignee: MAKSCIENTIFIC - US2022/24910, 2022, A1
[2]Current Patent Assignee: MAKSCIENTIFIC - US2022/24910, 2022, A1
[3]Current Patent Assignee: MAKSCIENTIFIC - US2022/24910, 2022, A1 Location in patent: Paragraph 0132; 0143
[4]Current Patent Assignee: MAKSCIENTIFIC - US2022/24910, 2022, A1 Location in patent: Paragraph 0132; 0143

88
[ 2213-43-6 ]
Ethyl 1-(2,4-dichlorophenyl)-4-ethyl-5-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-3-carboxylate [ No CAS ]
1-(2,4-Dichlorophenyl)-4-ethyl-3-(piperidin-1-ylcarbamoyl)-1H-pyrazol-5-yl trifluoromethanesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: 1-Aminopiperidine With Aluminum Chloride In 1,2-dichloro-ethane at 0 - 5℃; for 0.416667h; Inert atmosphere; Stage #2: Ethyl 1-(2,4-dichlorophenyl)-4-ethyl-5-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-3-carboxylate In 1,2-dichloro-ethane at 20℃; for 5.5h; Inert atmosphere;	1-(2,4-Dichlorophenyl)-4-ethyl-3-(piperidin-1-ylcarbamoyl)-1H-pyrazol-5-yl trifluoromethanesulfonate To magnetically stirred suspension of AlCl3 (9.8 g, 3 eq) in anhydrous dichloroethane (30 ml) at 0° C. was added 1-aminopiperidine (8.6 g, 3.5 eq) under argon atmosphere, and the resulting mixture was stirred at 0-5° C. for 25 min. Ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-3-carboxylate (11 g) in dichloroethane (250 ml) was added, and the reaction mixture was slowly brought to room temperature over 30 minutes, and stirred at this temperature for 5 h. Reaction was quenched by adding 10% HCl (50 ml), and the biphasic mixture was stirred for 2 h. Organic layer was separate, and the aqueous layer was extracted with dichloromethane (3×50 ml). Combined organic layers were washed with water (2×80 ml), and brine (1×80 ml), dried over anhydrous MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel to give 9.5 g (77% yield) of product as a white solid.
77%	Stage #1: 1-Aminopiperidine With Aluminum Chloride In 1,2-dichloro-ethane at 0 - 5℃; for 0.416667h; Inert atmosphere; Stage #2: Ethyl 1-(2,4-dichlorophenyl)-4-ethyl-5-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-3-carboxylate In 1,2-dichloro-ethane at 20℃; for 5.5h; Inert atmosphere;	1-(2,4-Dichlorophenyl)-4-ethyl-3-(piperidin-1-ylcarbamoyl)-1H-pyrazol-5-yl trifluoromethanesulfonate To magnetically stirred suspension of AlCl3 (9.8 g, 3 eq) in anhydrous dichloroethane (30 ml) at 0° C. was added 1-aminopiperidine (8.6 g, 3.5 eq) under argon atmosphere, and the resulting mixture was stirred at 0-5° C. for 25 min. Ethyl 1-(2,4-dichlorophenyl)-4-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazole-3-carboxylate (11 g) in dichloroethane (250 ml) was added, and the reaction mixture was slowly brought to room temperature over 30 minutes, and stirred at this temperature for 5 h. Reaction was quenched by adding 10% HCl (50 ml), and the biphasic mixture was stirred for 2 h. Organic layer was separate, and the aqueous layer was extracted with dichloromethane (3×50 ml). Combined organic layers were washed with water (2×80 ml), and brine (1×80 ml), dried over anhydrous MgSO4, filtered and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel to give 9.5 g (77% yield) of product as a white solid.

Reference： [1]Current Patent Assignee: MAKSCIENTIFIC - US2022/33393, 2022, A1 Location in patent: Paragraph 0542
[2]Current Patent Assignee: MAKSCIENTIFIC - US2022/33393, 2022, A1 Location in patent: Paragraph 0542

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
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CAS No. :	2213-43-6	MDL No. :	MFCD00006489
Formula :	C₅H₁₂N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LWMPFIOTEAXAGV-UHFFFAOYSA-N
M.W :	100.16	Pubchem ID :	16658
Synonyms :

Num. heavy atoms :	7
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	33.55
TPSA :	29.26 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.11 cm/s

[ CAS No. 2213-43-6 ] {[proInfo.proName]}

Quality Control of [ 2213-43-6 ]

Related Doc. of [ 2213-43-6 ]

Product Details of [ 2213-43-6 ]

Calculated chemistry of [ 2213-43-6 ]

Physicochemical Properties

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Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

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Application In Synthesis of [ 2213-43-6 ]

[ 2213-43-6 ] Synthesis Path-Downstream 1~88

Related Functional Groups of
[ 2213-43-6 ]

Amines

Hydrazines

Related Parent Nucleus of
[ 2213-43-6 ]

Piperidines

Precautionary Statements-General

Prevention

Response

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Log Po/w (iLOGP) :	1.54
Log Po/w (XLOGP3) :	-0.28
Log Po/w (WLOGP) :	-0.03
Log Po/w (MLOGP) :	0.65
Log Po/w (SILICOS-IT) :	0.34
Consensus Log Po/w :	0.44

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

Log S (ESOL) :	-0.28
Solubility :	52.0 mg/ml ; 0.519 mol/l
Class :	Very soluble
Log S (Ali) :	0.12
Solubility :	134.0 mg/ml ; 1.33 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-0.17
Solubility :	68.3 mg/ml ; 0.682 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.06

Signal Word:	Danger	Class:	8,3
Precautionary Statements:	P240-P241-P242-P210-P271-P243-P264-P270-P280-P303+P361+P353-P304+P340-P363-P305+P351+P338-P310-P330-P331-P370+P378-P403+P233-P501	UN#:	2920
Hazard Statements:	H226-H314-H302+H312+H332	Packing Group:	Ⅱ
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
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P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
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P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
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P240	Ground/bond container and receiving equipment.
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P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 2213-43-6 ] {[proInfo.proName]}

Quality Control of [ 2213-43-6 ]

Related Doc. of [ 2213-43-6 ]

Product Details of [ 2213-43-6 ]

Calculated chemistry of [ 2213-43-6 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 2213-43-6 ]

Application In Synthesis of [ 2213-43-6 ]

[ 2213-43-6 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 2213-43-6 ]

Amines

Hydrazines

Related Parent Nucleus of [ 2213-43-6 ]

Piperidines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 2213-43-6 ]

Related Parent Nucleus of
[ 2213-43-6 ]