345637-71-0|2-(5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetic acid| Ambeed

Structure of 345637-71-0

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Quality Control of [ 345637-71-0 ] Purity: 95% SDS Specification

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Product Details of [ 345637-71-0 ]

CAS No. :	345637-71-0
Formula :	C₇H₇F₃N₂O₂
M.W :	208.14
SMILES Code :	O=C(O)CN1N=C(C(F)(F)F)C=C1C
MDL No. :	MFCD00297315
InChI Key :	RBHQAIFXLJIFFM-UHFFFAOYSA-N
Pubchem ID :	596118

Safety of [ 345637-71-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 345637-71-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	5
Fraction Csp3	0.43
Num. rotatable bonds	3
Num. H-bond acceptors	6.0
Num. H-bond donors	1.0
Molar Refractivity	40.04
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	55.12 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.18
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.25
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.45
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	0.83
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.12
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.37

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.98
Solubility	2.16 mg/ml ; 0.0104 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.01
Solubility	2.05 mg/ml ; 0.00987 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-1.47
Solubility	7.07 mg/ml ; 0.034 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.68 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.07

Application In Synthesis of [ 345637-71-0 ]

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

Downstream synthetic route of [ 345637-71-0 ]

[ 345637-71-0 ] Synthesis Path-Downstream 1~35

1
[ 105-36-2 ]
[ 10010-93-2 ]
[ 345637-71-0 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 2. Preparation of N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1-phenylpropyl]-4-thiazolecarboxamide (Compound 117) Step A: Preparation of 5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-acetic acid. A mixture of 3-methyl-5-trifluoromethylpyrazole (10.0 g, 66.7 mmol), ethyl bromoacetate (11.1 mL, 100 mmol) and potassium carbonate (18.4 g, 133 mmol) in 80 mL of N,N-dimethylformamide was stirred at ambient temperature overnight. The orange mixture was filtered, diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give 15.7 g of the pyrazole ester. The ester, in 100 mL of tetrahydrofuran, was treated with 11 mL of a 50 % aqueous NaOH solution in 90 mL of water and stirred at ambient temperature overnight. The tetrahydrofuran was removed under reduced pressure and the aqueous solution was washed with ether and acidified with conc. HCl to pH 1 to give a precipitate. The precipitate was filtered, washed with water and dried to give 12.1 g of the title compound as a white solid. 1H NMR (Acetone-d6) delta 2.35 (s, 3H), 5.07 (s, 2H), 6.45 (s, 1H).

References: [1]Patent: WO2007/14290,2007,A2 .Location in patent: Page/Page column 55-56.

2
[ 345637-71-0 ]
[ 922515-98-8 ]
N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1-phenylpropyl]-4-thiazolecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;	iV-Methyl-N-[(l/?)-l-phenylpropyl]-2-(4-piperidinyl)-4-thiazolecarboxamide (i.e. the product of Example 1, Step E) (150 mg, 0.44 mmol) was dissolved in 3 mL of dry dichloromethane. To this solution was added triethylamine (30 muL, 0.22 mmol), 5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-acetic acid (83 mg, 0.4 mmol), l-(3-dimethylaminopropyl)- <n="74"/>3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) and a catalytic amount of 4- (dimethylamino)pyridine (~1 mg). The reaction mixture was shaken overnight at ambient temperature, concentrated under reduced pressure and passed through a silica gel column (2 g) using 1:1 hexanes/ethyl acetate as eluant. The dichloromethane/hexanes/ethyl acetate solution was concentrated under reduced pressure, and the residue was purified by preparative reverse phase High Pressure Liquid Chromatography (HPLC) using a solvent gradient going from 100 % water to 100 % acetonitrile to give 85 mg of the title product, a compound of the present invention, as an oil.1H NMR (CDCl3) delta 0.9-1.1 (br m, 3H), 1.7-1.9 (m, 2H), 1.9-2.2 (m, 4H), 2.31 (s, 3H), 2.7- 3.0 (m, 4H), 3.2-3.4 (m, 2H), 3.9-4.6 (br m, 2H), 4.96 (br s, 2H), 5.6-6.0 (m, IH), 6.3 (s, IH) 7.20-7.45 (m, 5H), 7.8 (s, IH).
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine;dmap; In dichloromethane; at 20℃;	Step B: Preparation of N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1-phenylpropyl]-4-thiazolecarboxamide N-Methyl-N-[(1R)-1-phenylpropyl]-2-(4-piperidinyl)-4-thiazolecarboxamide (i.e. the product of Example 1, Step E) (150 mg, 0.44 mmol) was dissolved in 3 mL of dry dichloromethane. To this solution was added triethylamine (30 mL, 0.22 mmol), 5-methyl-3- (trifluoromethyl)-1H-pyrazol-1-acetic acid (83 mg, 0.4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol) and a catalytic amount of 4-(dimethylamino)pyridine (~1 mg). The reaction mixture was shaken overnight at ambient temperature, concentrated under reduced pressure and passed through a silica gel column (2 g) using 1:1 hexanes/ethyl acetate as eluant. The dichloromethane/hexanes/ethyl acetate solution was concentrated under reduced pressure, and the residue was purified by preparative reverse phase High Pressure Liquid Chromatography (HPLC) using a solvent gradient going from 100 % water to 100 % acetonitrile to give 85 mg of the title product, a compound of the present invention as an oil. 1H NuMR (CDCl3) delta 0.9-1.1 (br m, 3H), 1.7-1.9 (m, 2H), 1.9-2.2 (m, 4H), 2.31 (s, 3H), 2.7- 3.0 (m, 4H), 3.2-3.4 (m, 2H), 3.9-4.6 (br m, 2H), 4.96 (br s, 2H), 5.6-6.0 (m, IH), 6.3 (s, IH) 7.20-7.45 (m, 5H), 7.8 (s, IH).

References: [1]Patent: WO2008/91594,2008,A2 .Location in patent: Page/Page column 72-73.
[2]Patent: WO2007/14290,2007,A2 .Location in patent: Page/Page column 56.

3
[ 345637-71-0 ]
[ 922516-43-6 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 3h;	Step F: Preparation of 5-methyl-3-(trifluoromethyl)-lH-pyrazole-l-acetyl chloride; 5-Methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]acetic acid (7.58 g, 36.4 mmol) (i.e. the product of Example 1, Step E) was dissolved in dichloromethane (100 mL). N^/V-dimethyl- formamide (1 drop) was added to the reaction mixture, which was then cooled to 0 C.Oxalyl chloride (3.5 mL, 40 mmol) was added drop wise to the stirred reaction mixture, which was then allowed to warm to room temperature for 3 h. The resulting mixture was concentrated under reduced pressure and placed under high vacuum to give 7.93 g of the title compound as a tan solid. This compound was of sufficient purity to use in subsequent reactions.1H NMR (CDCl3) delta 2.31 (s, 3H), 5.27 (s, 2H), 6.38 (s, IH).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 3h;	5-Methyl-3-(trifluoromethyl)-lH-pyrazol-l-yl]acetic acid (7.58 g, 36.4 mmol) (i.e. the product of Example 2, Step A) was dissolved in 100 mL of dichloromethane. To the reaction mixture, 1 drop of lambdaf.lambdaf-dimethylformamide was added and the reaction mixture was cooled to 0 C. The reaction mixture was treated with oxalyl chloride (3.5 mL, 40 mmol) dropwise and allowed to warm to room temperature and stirred for 3 h. The resulting mixture was evaporated in vacuo and placed under high vacuum to give 7.93 g of the corresponding acid chloride, 5-methyl-3-(trifluoromethyl)-lH-pyrazole-l -acetyl chloride, as a tan solid. The acid chloride was dissolved in 50 mL of dichloromethane and a solution of ethyl 2-(4-piperidinyl)-4-thiazolecarboxylate monohydrochloride (10.38 g, 33.1 mmol) (i.e. the product of Example 19, Step A) and triethylamine (23 mL, 165 mmol) in 200 mL of dichloromethane was added at 0 C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into water and extracted with dichloromethane. The extract was washed with 1 M aqueous hydrochloric acid, water, saturated aqueous solution of sodium bicarbonate, and brine. The filtered mixture was dried (MgSC>4) and evaporated in vacuo to give 13.0 g of the title compound as an oil. 1H NMR (CDCl3) delta 1.4 (t, 3H), 1.78 (m, 2H), 2.2 (m, 2H), 2.32 (s, 3H), 2.80 (m, 1 H), 3.25 (m, IH), 3.36 (m, IH), 4.07 (m, IH), 4.42 (q, 2H), 4.62 (m, IH), 4.98 (m, 2H), 6.34 (s, IH), 8.09 (s, IH).
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃;Product distribution / selectivity;	Method A 2-[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (I-53) At 0 C., oxalyl chloride (134 mg) and a drop of N,N-dimethylformamide are added to a solution of <strong>[345637-71-0][5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid</strong> (185 mg) in dichloromethane. The reaction mixture is stirred at room temperature for 3 h. Solvent and excess reagent are removed under reduced pressure. The solid residue is then once more dissolved in dichloromethane and, at 0 C., added dropwise to a solution of 4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 250 mg) and triethylamine (410 mg) in dichloromethane. Concentrated ammonium chloride solution is then added to the reaction solution, and the aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over anhydrous sodium sulphate and concentrated. This gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (122 mg). 1H NMR (DMSO-d6): delta 7.28-7.26 (m, 2H), 7.22-7.21 (m, 2H), 7.19-7.15 (m, 2H), 6.51 (s, 1H), 5.33 (d, 1H), 5.25 (d, 1H), 4.36 (d, 1H), 3.95 (d, 1H), 3.35-3.20 (m, 2H), 2.96 (s, 4H), 2.82 (t, 1H), 2.21 (s, 3H), 2.09 (d, 1H), 2.07 (d, 1H), 1.78 (m, 1H), 1.53 (m, 1H) ppm MS (ESI): 463 ([M+H]+)

	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; for 0.25h;Reflux;Product distribution / selectivity;	Step B: Preparation of 4-(4-formyl-2-thiazolyl)-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (also known as 2-[1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarboxaldehyde) To a solution of <strong>[345637-71-0]5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid</strong> (0.8 g, 3.8 mmol) in dichloromethane (10 mL) was added oxalyl chloride (2.4 g, 19.2 mmol) and two drops of N,N-dimethylformamide, resulting in slight exothermicity. The reaction mixture was then heated at reflux for 15 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in tetrahydrofuran (10 mL) and treated with a solution of 2-(4-piperidinyl)-4-thiazolecarboxaldehyde monohydrochloride (i.e. the product of Example 2, Step A) (1.1 g, 5.1 mmol) in tetrahydrofuran (10 mL), followed by dropwise addition of triethylamine (1.2 g, 11.9 mmol). The reaction mixture was stirred overnight at room temperature and then partitioned between 1 N aqueous hydrochloric acid and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate (2*30 mL). The combined organic layers were washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure to give 0.8 g of the title compound as a yellow oil. 1H NMR (CDCl3): delta 1.79-1.90 (m, 2H), 2.18-2.29 (m, 2H), 2.33 (s, 3H), 2.87-2.94 (m, 1H), 3.28-3.40 (m, 2H), 4.05-4.15 (m, 1H), 4.56-4.64 (m, 1H), 4.99-5.02 (m, 2H), 6.35 (s, 1H), 8.12 (s, 1H), 10.01 (s, 1H).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 45℃; for 2h;	To a stirred solution of (5-methyl-3-trifluoromethyl-pyrazol-l-yl)acetic acid (0.0885 g, 0.4255 mmol) in dichloromethane (10 mL) was added oxalylchloride (0.108 g, 0.851 mmol) and drop a of DMF. The reaction mixture was stirred at 45 C for 2 h, and then concentrated under reduced pressure to provide the title compound as a white solid (0.096 g)..H NMR (CDCI3): delta 6.38 (s, 1H), 5.27 (s, 2H), 2.31 (s, 3H).
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; for 24h;Product distribution / selectivity;	Step 21-[4-(4-Acetyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (XXII-1)Oxalyl chloride (1.74 g) and a drop of N,N-dimethylformamide were added to a solution of <strong>[345637-71-0][5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid</strong> (1.00 g) in dichloromethane (10 ml). The reaction mixture was then stirred for 24 hours. Excess oxalyl chloride was then removed under reduced pressure, and the residue was redissolved in dichloromethane (10 ml). With cooling on an ice bath, the solution was then added to a suspension of 1-[2-(piperidin-4-yl)-1,3-thiazol-4-yl]ethanone hydrochloride (1.13 g) in dichloromethane (10 ml) and N,N-diisopropylethylamine (1.77 g). The reaction mixture was then allowed to warm to room temperature and stirred for another 2 hours. Saturated aqueous ammonium chloride solution (5 ml) was then added to the reaction mixture. The aqueous phase was separated off and extracted with dichloromethane. All organic phases were combined and dried with anhydrous sodium sulphate. The solid was then filtered off and the solvent was removed under reduced pressure. Purification by column chromatography (silica gel, ethyl acetate:hexane 0%-100% elution gradient) gave 1-[4-(4-acetyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (1.00 g).logP (pH2.7): 2.251H NMR (DMSO-d6, 400 MHz): deltappm. 1.65 (bs, 1H), 1.80 (bs, 1H), 2.18-2.11 (m, 2H), 2.23 (s, 3H), 2.55 (s, 3H), 2.90 (bs, 1H), 3.28 (bs, 1H), 3.39 (m, 1H), 4.00 (bs, 1H), 4.33 (bs, 1H), 5.22 (bs, 2H), 6.45 (s, 1H), 8.36 (s, 1H)MS (ESI): 401 ([M+H]+)
5.64 g	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 16h;	Step A: Preparation of 5-methyl-3-(trifluoromethyl)-lH-pyrazole-l -acetyl chloride A mixture of 5-methyl-3-(trifluoromethyl)-lH-pyrazole-l -acetic acid (5.2 g, 25 mmol) in dichloromethane (70 mL) and N,N-dimethylformamide (2 drops) was cooled to 0 C and oxalyl chloride (4.76 g, 37.5 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 h, and then concentrated under reduced pressure to give the title compound as a slightly yellowish solid (5.64 g). H NMR (CDC13): delta 6.38 (s, 1H), 5.27 (s, 2H), 2.31 (s, 3H).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; for 0.25h;Heating / reflux;Product distribution / selectivity;	To a solution of 5-methyl-3-(trifluoromethyl)-lH-pyrazole-l -acetic acid (0.8 g, 3.8 mmol) in dichloromethane (10 mL) was added oxalyl chloride (2.4 g, 19.2 mmol) and two drops of iV.TV-dimethylformamide, resulting in slight exothermicity. The reaction mixture was then heated at reflux for 15 minutes. The reaction mixture was concentrated in vacuo, and the residue was suspended in tetrahydrofuran (10 mL) and treated with a solution of 2-(4-piperidinyl)-4-thiazolecarboxaldehyde' monohydrochloride (i.e. the product of Example 2, Step A) (1.1 g, 5.1 mmol) in tetrahydrofuran (10 mL), followed by dropwise addition of triethylamine (1.2 g, 11.9 mmol). The reaction mixture was stirred overnight at room temperature and then partitioned between 1 N aqueous hydrochloric acid and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate (2 x 30 mL). The combined organic layers were washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine. The organic layer was dried (MgSC^) and evaporated under reduced pressure to give 0.8 g of the title compound as a yellow oil. <n="79"/>IH NMR (CDCl3) delta 1.79-1.90 (m, 2H)5 2.18-2.29 (m, 2H), 2.33 (s, 3H), 2.87-2.94 (m, IH)5 3.28-3.40 (m, 2H), 4.05-4.15 (m, IH), 4.56-4.64 (m, IH), 4.99-5.02 (m, 2H), 6.35 (s, IH), 8.12 (s, IH)5 IO-Ol (s, IH).; To a solution of 5-methyl-3-(trifluoromethyl)-li'-pyrazole-l -acetic acid (0.5 g,2.4 mmol) in dichloromethane (4 mL) was added oxalyl chloride (0.3 mL, 3.6 mmol) and one drop of N,LambdaT-dimethylformamide, resulting in slight exothermicity. The reaction mixture was then heated at reflux for 15 minutes. The reaction mixture was evaporated, and the resulting residue was suspended in dichloromethane (4 mL) and treated with a solution of 4-(4-ethenyl-2-thiazolyl)piperidine (i.e. the product of Example 4, Step B) (302 mg,1.5 mmol) in dichloromethane (2 mL), followed by addition of triethylamine (0.32 mL, 2.3 mmol). The reaction mixture was stirred overnight at room temperature, then concentrated, and purified by column chromatography on silica gel using 30-40 % ethyl acetate in hexanes as eluant to give 414 mg of the title compound as a white solid. IH NMR (CDCl3) 6 1.78 (m, 2H), 2.18 (m, 2H), 2.32 (s, 3H), 2.90 (br t, IH), 3.30 (m, 2H),4.03 (d, IH), 4.55 (d, IH), 5.00 (m, 2H), 5.35 (d, IH), 6.02 (d, IH), 6.33 (s, IH), 6.68 (dd,IH)5 7.01 (s, IH).
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 3h;	Step B: Preparation of ethyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarboxylate. 5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (7.58 g, 36.4 mmol) (i.e. the product of Example 2, Step A) was dissolved in 100 mL of dichloromethane. To the reaction mixture, 1 drop of N,N-dimethylformamide was added and the reaction mixture was cooled to 0 0C. The reaction mixture was treated with oxalyl chloride (3.5 mL, 40 mmol) dropwise and allowed to warm to room temperature and stirred for 3 h. The resulting mixture was evaporated in vacuo and placed under high vacuum to give 7.93 g of the corresponding acid chloride, 5-methyl-3-(trifluoromethyl)-lH-pyrazole-l-acetyl chloride, as a tan solid. The acid chloride was dissolved in 50 mL of dichloromethane and a solution of ethyl 2-(4-piperidinyl)-4-thiazolecarboxylate monohydrochloride (10.38 g, 33.1 mmol) (i.e. the product of Example 19, Step A) and triethylamine (23 mL, 165 mmol) in 200 mL of dichloromethane was added at 0 0C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was poured into water and extracted with dichloromethane. The extract was washed with 1 M aqueous hydrochloric acid, water, saturated aqueous solution of sodium bicarbonate, and brine. The filtered mixture was dried (MgSC^) and evaporated in vacuo to give 13.0 g of the title compound as an oil. EPO <DP n="85"/>1H NMR (CDCl3) delta 1.4 (t, 3H), 1.78 (m, 2H), 2.2 (m, 2H), 2.32 (s, 3H), 2.80 (m, 1 H), 3.25 (m, IH), 3.36 (m, IH), 4.07 (m, IH), 4.42 (q, 2H), 4.62 (m, IH), 4.98 (m, 2H), 6.34 (s, IH),8.09 (s, IH).

References: [1]Patent: WO2008/91580,2008,A2 .Location in patent: Page/Page column 53.
[2]Patent: WO2008/91594,2008,A2 .Location in patent: Page/Page column 100.
[3]Patent: US2010/137245,2010,A1 .Location in patent: Page/Page column 37.
[4]Patent: US2010/240619,2010,A1 .Location in patent: Page/Page column 59.
[5]Patent: WO2011/85170,2011,A1 .Location in patent: Page/Page column 100.
[6]Patent: US2011/312999,2011,A1 .Location in patent: Page/Page column 35.
[7]Patent: WO2014/179144,2014,A1 .Location in patent: Page/Page column 61.
[8]Patent: WO2008/13622,2008,A2 .Location in patent: Page/Page column 77-78; 80.
[9]Patent: WO2007/14290,2007,A2 .Location in patent: Page/Page column 83.

4
[ 345637-71-0 ]
[ 1003639-38-0 ]
4-[4-[4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 16h;	Step B: Preparation of 4-[4-[4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine To a solution of 1,1-dimethylethyl 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperidinecarboxylate (i.e. the product of Example 1, Step A) (0.815 g, 1.97 mmol) in dichloromethane (50 mL) was added a solution of hydrogen chloride in diethyl ether (2 M, 10 mL, 20 mmol). The reaction mixture was stirred at room temperature for 1 h to give a gummy precipitate. Methanol was added to dissolve the precipitate, and the reaction mixture was stirred for an additional 1 h. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic layer was dried (MgSO4) and concentrated to give the free amine as a clear oil (0.31 g), which solidified on standing. A mixture of the resulting free amine (0.31 g, 1.0 mmol), <strong>[345637-71-0]5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid</strong> (0.208 g, 1.0 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25 g, 1.3 mmol), triethylamine (150 muL, 1.08 mmol) and a catalytic amount of 1-hydroxy-benzotriazole hydrate (~1 mg) in dichloromethane (5 mL) was swirled to form a vortex and held at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (10 mL), and washed with 1 N aqueous hydrochloric acid and saturated aqueous sodium bicarbonate solution. The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 0.47 g of the title product as a white foam. 1H NMR (CDCl3): delta 1.8 (m, 2H), 2.2 (m, 2H), 2.32 (s, 3H), 2.9 (m, 1H), 3.3 (m, 2H), 3.42 (m, 1H), 3.85 (m, 1H), 4.05 (m, 1H), 4.55 (m, 1H), 4.98 (m, 2H), 5.75 (m, 1H), 6.33 (s, 1H), 7.25-7.42 (m, 5H), 7.63 (s, 1H).
0.47 g	With benzotriazol-1-ol; triethylamine; In dichloromethane; at 20℃; for 16h;	A mixture of the resulting free amine (0.31 g, 1.0 mmol), <strong>[345637-71-0]5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid</strong> (19, 0.208 g, 1.0 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25 g, 1.3 mmol), triethylamine (150 muL, 1.08 mmol) and a catalytic amount of 1-hydroxy-benzotriazole hydrate (?1 mg) in dichloromethane (5 mL) was swirled to form a vortex and held at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (10 mL), and washed with 1 N aqueous hydrochloric acid and saturated aqueous sodium bicarbonate solution. The organic layer was dried (MgSO4) and concentrated under reduced pressure to give 4-[4-[4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperindine (13, 0.47 g, 0.93 mmol, 93%) as a white foam. A sample crystallized from ethanol melted at 109-113 C. 1H NMR (CDCl3) delta 1.8 (m, 2H), 2.2 (m, 2H), 2.32 (s, 3H), 2.9 (m, 1H), 3.3 (m, 2H), 3.42 (m, 1H), 3.85 (m, 1H) 4.05 (m, 1H), 4.55 (m, 1H), 4.98 (m, 2H), 5.75 (m, 1H), 6.33 (s, 1H), 7.25-7.42 (m, 5H), 7.63 (s, 1H).
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine;benzotriazol-1-ol; In dichloromethane; at 20℃; for 16h;	To a solution of 1,1-dimethylethyl 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)- 2-thiazolyl]-l -piperidinecarboxylate (i.e. the product of Example 1, Step A) (0.815 g,1.97 mmol) in dichloromethane (50 mL) was added a solution of hydrogen chloride in diethyl ether (2 M, 10 mL, 20 mmol). The reaction mixture was stirred at room temperature <n="77"/>for 1 h to give a gummy precipitate. Methanol was added to dissolve the precipitate, and the reaction mixture was stirred for an additional 1 h. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, and the organic layer was dried (MgSC^) and concentrated to give the free amine as a clear oil (0.31 g), which solidified on standing. A mixture of the resulting free amine (0.31 g, 1.0 mmol), 5-methyl-3-(trifluoromethyl)-li-pyrazole-l -acetic acid (0.208 g, 1.0 mmol), l-[3-(dimemylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25 g, 1.3 mmol), triethylamine (150 muL, 1.08 mmol) and a catalytic amount of 1-hydroxy- benzotriazole hydrate (~1 mg) in dichloromethane (5 mL) was swirled to form a vortex and held at room temperature for 16 h. The reaction mixture was diluted with dichloromethane (10 mL), and washed with 1 N aqueous hydrochloric acid and saturated aqueous sodium bicarbonate solution. The organic layer was dried (MgSC>4) and concentrated under reduced pressure to give 0.47 g of the title product, a compound of present invention, as a white foam. 1H NMR (CDCl3) delta 1.8 (m, 2H), 2.2 (m, 2H), .2.32 (s, 3H), 2.9 (m, IH), 3.3 (m, 2H), 3.42 (m, IH), 3.85 (m, IH) 4.05 (m, IH)5 4.55 (m, IH)5 4.98 (m, 2H), 5.75 (m, IH), 6.33 (s, IH), 7.25-7.42 (m, 5H), 7.63 (s, IH).

References: [1]Patent: US2010/240619,2010,A1 .Location in patent: Page/Page column 58.
[2]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 354 - 361.
[3]Patent: WO2008/13622,2008,A2 .Location in patent: Page/Page column 75-76.

5
[ 345637-71-0 ]
[ 1003320-11-3 ]
1-[4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperazinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 24h;	Step F: Preparation of 1-[4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1-piperazinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone To a solution of 1-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]piperazine hydrochloride (i.e. the product of Example 7, Step E) (200 mg, 0.57 mmol) and <strong>[345637-71-0]5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid</strong> (0.120 g, 0.57 mmol) in dichloromethane (10 mL) at room temperature was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.110 g, 0.57 mmol), triethylamine (0.086 g, 0.85 mmol) and 1-hydroxy-benzotriazole hydrate (0.020 g, 0.14 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with dichloromethane (30 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by column chromatography using 3% methanol in chloroform as eluant to give 180 mg of the title product as a white solid. 1H NMR (CDCl3): delta 2.32 (s, 3H), 3.29 (m, 1H), 3.52 (m, 2H), 3.61 (m, 2H), 3.79-3.72 (m, 5H), 4.98 (m, 2H), 5.69 (m,1H), 6.33 (s, 1H), 6.93 (s, 1H), 7.38-7.28 (m, 5H). Mass spectrum at 505.5 (M+1).
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 24h;	To a solution of l-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]piperazine hydrochloride (i.e. the product of Example 7, Step E) (200 mg, 0.57 mmol) and 5-methyl-3- (trifluoromethyl)-l.H-pyrazole-l -acetic acid (0.120 g, 0.57 mmol) in dichloromethane (10 mL) at room temperature was added l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.110 g, 0.57 mmol), triethylamine (0.086 g, 0.85 mmol) and 1-hydroxy- benzotriazole hydrate (0.020 g, 0.14 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with dichloromethane (30 mL), and washed with water (20 mL) and brine (20 mL). The organic layer was dried (Na2SO.;) and concentrated under reduced pressure. The crude residue was purified by column chromatography using 3 % methanol in chloroform as eluant to give 180 mg of the title product, a compound of the present invention as a white solid.1Eta NMR (CDCl3) delta 2.32 (s, 3Eta), 3.29 (m, IH), 3.52 (m, 2H), 3.61 (m, 2H), 3.79-3.72 (m,5H), 4.98 (m, 2H), 5.69 (m,lH), 6.33 (s, IH), 6.93 (s, IH), 7.38-7.28 (m, 5H). Mass spectrum at 505.5 (M+l).

References: [1]Patent: US2010/240619,2010,A1 .Location in patent: Page/Page column 62.
[2]Patent: WO2008/13622,2008,A2 .Location in patent: Page/Page column 83.

6
[ 345637-71-0 ]
[ 1003320-32-8 ]
[ 1003318-70-4 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 24h;	Step D: Preparation of 1-[4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-3,6-dihydro-1(2H)-pyridinyl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone To a solution of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-1,2,3,6-tetrahydropyridine hydrochloride (i.e. the product of Example 13, Step C) (0.250 g, 0.720 mmol) and <strong>[345637-71-0]5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid</strong> (0.150 g, 0.720 mmol) in dichloromethane (10 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.138 g, 0.720 mmol), 1-hydroxybenzotriazole (0.024 g, 0.177 mmol), and triethylamine (0.145 g, 1.44 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with dichloromethane (30 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was separated, washed with water, dried (Na2SO4), and concentrated under reduced pressure and purified by medium-pressure liquid chromatography using 3% methanol in chloroform as eluant to give 200 mg of the title product as a white solid. 1H NMR (CDCl3): delta 2.3 (s, 3H), 2.71-2.75 (m, 2H), 3.42-3.46 (m, 1H), 3.74-3.88 (m, 3H), 4.24-4.27 (m, 2H), 5.02 (s, 2H), 5.71-5.76 (m, 1H), 6.32 (s, 1H), 6.57 (s, 1H), 7.3-7.38 (m, 5H), 7.64 (s, 1H).
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 24h;	To a solution of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-l,2,3,6- tetrahydropyridine hydrochloride (i.e. the product of Example 13, Step C) (0.250 g, 0.720 mmol) and 5-methyl-3-(trifluoromethyl)-lH-pyrazole-l-acetic acid (0.150 g, 0.720 mmol) in dichloromethane (10 mL) was added N- (3-dimethylamuiopropyl)-Lambda^-ethylcarbodiimide (0.138 g, 0.720 mmol), 1-hydroxybenzotriazole (0.024 g, 0.177 mmol), and triethylamine (0.145 g, 1.44 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with dichloromethane (30 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was separated, washed with water, dried (Na2SC>4), and concentrated under reduced pressure and purified by medium-pressure liquid chromatography using 3 % methanol in chloroform as eluant to give 200 mg of the title product, a compound of the present invention, as a white solid. *Eta NMR (CDCl3) 52.3 (s, 3Eta), 2.71-2.75 (m, 2H), 3.42-3.46 (m, IH), 3.74-3.88 (m, 3H), 4.24-4.27 (m, 2H)5 5.02 (s, 2H), 5.71-5.76 (m, IH), 6.32 (s, IH), 6.57 (s, IH), 7.3-7.38 (m, 5H), 7.64 (s, IH).

References: [1]Patent: US2010/240619,2010,A1 .Location in patent: Page/Page column 67.
[2]Patent: WO2008/13622,2008,A2 .Location in patent: Page/Page column 96.

7
[ 299405-24-6 ]
[ 345637-71-0 ]

Yield	Reaction Conditions	Operation in experiment
		Step E: Preparation of 5-methyl-3-(trifluoromethyl)-lH-pyrazol-l-acetic acid; A mixture of 3-methyl-5-trifluoromethylpyrazole (10.0 g, 66.7 mmol), ethyl bromoacetate (11.1 mL, 100 mmol) and potassium carbonate (18.4 g, 133 mmol) inlambdafN-dimethylformamide (80 mL) was stirred at ambient temperature overnight. The orange mixture was filtered, diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give 15.7 g of the pyrazole ester. The ester dissolved in tetrahydrofuran (100 mL) was treated with 11 mL of a 50 % aqueous NaOH solution in 90 mL of water, and the mixture was stirred at ambient temperature overnight.The tetrahydrofuran solvent was removed from the mixture by evaporation under reduced pressure. The aqueous solution remaining was washed with ether and then acidified with concentrated hydrochloric acid to lower the pH to 1, resulting formation of a precipitate.The precipitate was collected under filtration, washed with water and dried to give 12.1 g of the title compound as a white solid.1H NMR (Acetone-
		A mixture of 3-methyl-5-trifluoromethylpyrazole (10.0 g, 66.7 mmol), ethyl bromoacetate (11.1 mL, 100 mmol) and potassium carbonate (18.4 g, 133 mmol) in 80 mL of lambdaf lambdaf-dimethylformamide was stirred at ambient temperature overnight. The orange mixture was filtered, diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated under reduced pressure to give 15.7 g of the pyrazole ester. The ester, in 100 mL of tetrahydrofuran, was treated with 11 mL of a 50 % aqueous NaOH solution in 90 mL of water and stirred at ambient temperature overnight. The tetrahydrofuran was removed under reduced pressure and the aqueous solution was washed with ether and acidified with cone. HCl to peta 1 to give a precipitate. The precipitate was filtered, washed with water and dried to give 12.1 g of the title compound as a white solid. 1H NMR (Acetone-d6) 5 2.35 (s, 3H), 5.07 (s, 2H), 6.45 (s, IH).

References: [1]Patent: WO2008/91580,2008,A2 .Location in patent: Page/Page column 53.
[2]Patent: WO2008/91594,2008,A2 .Location in patent: Page/Page column 72.

8
[ 345637-71-0 ]
[ 922516-60-7 ]
[ 922516-59-4 ]

Yield	Reaction Conditions	Operation in experiment
		Trifluoroacetic acid (3 mL) was added to 1,1-dimethylethyl 4-[4-(ethoxycarbonyl)- 2H-l,2,3-triazol-2-yl]-l-piperidinecarboxylate (0.41 g, 1.3 mmol) (i.e. the product of Example 32, Step A). The reaction mixture was stirred for 45 minutes. The reaction mixture was then concentrated in vacuo. The resulting mixture was treated with saturated aqueous sodium bicarbonate and the aqueous layer was extracted three times with dichloromethane. The solvent was removed with a rotary evaporator to afford 0.23 g of ethyl 4-piperidinyl-2H-l,2,3-triazole-4-carboxylate as an oil. This compound was of sufficient purity to use in subsequent reactions.To a slurry of 5-methyl-3-(trifluoromethyl)-lH-pyrazole-l-acetic acid (0.23 g, 1.1 mmol) in dichloromethane (5 mL) was added oxalyl chloride (0.20 mL, 1.4 mmol) and one drop of N,N-dimethylformamide. After 45 minutes the reaction mixture was concentrated in vacuo and the resulting residue was dissolved in dichloromethane (10 mL). The reaction mixture was then added to a solution of ethyl 4-piperidinyl-2H-l,2,3-triazole-4-carboxylate (0.23 g) and triethylamine (0.20 mL, 1.4 mmol) in dichloromethane (10 mL) at 0 C. The reaction mixture was stirred at room temperature overnight. The organic layer was washed with saturated aqueous sodium bicarbonate, dried (Na2SO4) and the solvent was removed with a rotary evaporator. The residue was purified by medium pressure liquid chromatography (MPLC) using 35 to 60 % ethyl acetate in hexanes as eluant to afford 0.35 g of the title compound as a white solid.1H NMR (CDCl3) delta 1.41 (t, 3H), 2.23 (m, 4H), 2.33 (s, 3H), 3.09 (m, IH), 3.40 (m, IH), 4.10 (m, IH), 4.43 (q, 2H), 4.45 (m, IH), 4.80 (m, IH), 5.00 (m, 2H), 6.34 (s, IH), 8.06 (s, IH)
		Step B: Preparation of ethyl 2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-2H-1,2,3-triazole-4-carboxylate. Trifluoroacetic acid (3 mL) was added to 1,1-dimethylethyl 4-[4-(ethoxycarbonyl)-2H-1,2,3-triazol-2-yl]-1-piperidinecarboxylate (0.41 g, 1.3 mmol) (i.e. the product of Example 32, Step A). The reaction mixture was stirred for 45 minutes. The reaction mixture was then concentrated in vacuo. The resulting mixture was treated with saturated aqueous sodium bicarbonate and the aqueous layer was extracted three times with dichloromethane. The solvent was removed with a rotary evaporator to afford 0.23 g of ethyl 4-piperidinyl-2H-1,2,3-triazole-4-carboxylate as an oil. This compound was of sufficient purity to use in subsequent reactions.To a slurry of <strong>[345637-71-0]5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid</strong> (0.23 g, 1.1 mmol) in dichloromethane (5 mL) was added oxalyl chloride (0.20 mL, 1.4 mmol) and one drop of N,N-dimethylformamide. After 45 minutes the reaction mixture was concentrated in vacuo and the resulting residue was dissolved in dichloromethane (10 mL). The reaction mixture was then added to a solution of ethyl 4-piperidinyl-2H-1,2,3-triazole-4-carboxylate (0.23 g) and triethylamine (0.20 mL, 1.4 mmol) in dichloromethane (10 mL) at 0 0C. The reaction mixture was stirred at room temperature overnight. The organic layer was washed with saturated aqueous sodium bicarbonate, dried (Na2SO4) and the solvent was removed with a rotary evaporator. The residue was purified by medium pressure liquid chromatography (MPLC) using 35 to 60 % ethyl acetate in hexanes as eluant to afford 0.35 g of the title compound as a white solid.1H NMR (CDCl3) 6 1.41 (t, 3H), 2.23 (m, 4H), 2.33 (s, 3H), 3.09 (m, IH), 3.40 (m, IH), 4.10 (m, IH), 4.43 (q, 2H), 4.45 (m, IH), 4.80 (m, IH), 5.00 (m, 2H), 6.34 (s, IH), 8.06 (s, IH).

References: [1]Patent: WO2008/91594,2008,A2 .Location in patent: Page/Page column 113.
[2]Patent: WO2007/14290,2007,A2 .Location in patent: Page/Page column 96.

9
[ 345637-71-0 ]
C₁₈H₂₃N₃OS [ No CAS ]
N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1-phenylethyl]-4-thiazolecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 400 mg (0.77 mmol) of 1,1-dimethylethyl 4-[4-[[methyl[(l/?)-l- phenylethyl]amino]carbonyl]-2-thiazolyl]-l-piperidinecarboxylate (i.e. the product of Example 5, Step A) in 10 mL of a 1:1 mixture of methanol and dichloromethane was treated with 10 mL of 2 N hydrochloric acid in ether and stirred at room temperature for 4 h. The reaction mixture was concentrated on rotary evaporator, and the residue was three times treated with 10 mL of methanol followed by concentration to leave the crude piperidine hydrochloride. The reaction mixture was then dissolved in 10 mL of acetonitrile, and 1.O mL of triethylamine was added. Meanwhile, a solution of 310 mg (1.49 mmol) of 5-methyl-3-(trifluoromethyl)-lH-pyrazole-l -acetic acid in 10 mL of acetonitrile was treated with 1.0 mL of a solution of 1-propanephosphonic acid cyclic anhydride (50 % in ethyl acetate), stirred at room temperature for 15 minutes, then combined with the above amine solution. The reaction mixture was stirred at room temperature overnight, diluted with 50 mL of ethyl acetate, washed with 1 N aqueous hydrochloric acid, 1 N aqueous sodium hydroxide and brine, dried with MgSC^, filtered and concentrated under reduced pressure. Purification by Medium Pressure Liquid Chromatography (MPLC) on silica gel using ethyl acetate/methanol as eluant provided 330 mg of the title product, a compound of the present invention, as a white solid. <n="78"/>1H NMR (CDCl3) delta 1.60-1.80 (m, 5 H), 2.18 (m, 2 H), 2.30 (s, 3H), 2.80 (m, 5 H), 3.27 (m, 2 H), 4.00 (m, IH), 4.95 (s, 2 H), 5.79 and 6.14 (m, total IH), 6.35 (s, IH), 7.37 (m, 5H), 7.84 (s, IH).

References: [1]Patent: WO2008/91594,2008,A2 .Location in patent: Page/Page column 76-77.

10
[ 345637-71-0 ]
C₁₉H₂₅N₃O₂*ClH [ No CAS ]
N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1-phenylpropyl]-4-oxazolecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 3h;	1,1-Dimethylethyl 4-[4-[[methyl[(l/?)-l-phenylpropyl]amino]carbonyl]-2-oxazolyl]-l- piperidinecarboxylate (i.e. the product of Example 7, Step E) (209 mg, 0.49 mmol) was dissolved in 3 mL of a mixture of dichloromethane and methanol (1:1), and 1.23 mL (4.9 mmol) of 1 N HCl in dioxane was added. The reaction mixture was stirred at room temperature for 3 h. The solvents were evaporated under reduced pressure, and the residue was dissolved in 5 mL methanol and concentrated under reduced pressure (this procedure was repeated 3 times) to give the amine hydrochloride. To a solution of 5-methyl-3- (trifluoromethyl)-lH-pyrazole-l-acetic acid (89.5 mg, 0.43 mmol) and triethylamine (87 mg, <n="83"/>0.86 mmol) in 2 mL of dry acetonitrile was added a suspension of O-benzotriazol-1-yl- N,N,N',//'-tetramethyluronium hexafluorophosphate (178.25 mg. 0.47 mmol) in 2 mL acetonitrile and then a mixture of 140 mg (0.43 mmol) of the amine hydrochloride in 2 mL acetonitrile. The resulting mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 25-75 % of ethyl acetate in hexanes to give 84 mg of the title product, a compound of the present invention, as an oil.1H NMR (CDCl3) delta 0.90-1.04 (m, 3H), 1.71-1.89 (m, 2H), 1.90-2.19 (m, 4H), 2.28-2.35 (m, 3H), 2.72 (s, 2H), 3.00-3.2 (m, 3H), 3.30-3.36 (t, IH), 3.87-4.35 (m, 2H), 4.98 (s, 2H), 5.92- 6.12 (m, IH), 6.3 (s, IH), 7.25-7.4 (m, 5H), 8.08-8.15 (br s, IH).

References: [1]Patent: WO2008/91594,2008,A2 .Location in patent: Page/Page column 81-82.

11
[ 345637-71-0 ]
C₂₀H₂₅N₃O₂*ClH [ No CAS ]
N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-oxazolecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1,1-Dimethylethyl 4-[4-[[methyl[(lNo.)-l,2,3,4-tetrahydro-l-naphthalenyl]amino]- carbonyl]-2-oxazolyl]-l-piperidinecarboxylate (i.e. the product of Example 8, Step A) (317 mg, 0.72 mmol) was dissolved in 3 mL of a mixture of dichloromethane and methanol (1:1), and 1.8 mL (7.2 mmol) of 1 N HCl in dioxane was added. The reaction mixture was stirred at room temperature for 3 h. The solvents were evaporated under reduced pressure, and the residue was dissolved in 5 mL methanol and evaporated (this sequence was repeated 3 times) giving the amine hydrochloride. A mixture of 5-methyl-3-trifluoromethylpyrazol-l- ylacetic acid (179 mg, 0.86 mmol), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide <n="84"/>hydrochloride (191.7 mg, 1.00 mmol), and 1-methylmorpholine (354 mg, 3.5 mmol) in 3 mL of dry dichloromethane was stirred 15 minutes at room temperature, and a solution of the amine hydrochloride in 2 mL of dry dichloromethane was added. The resulting mixture was stirred at room temperature for 16 h and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 75 % ethyl acetate in hexanes as eluant to give 79 mg of the title product, a compound of the present invention, as an oil. 1H NMR (CDCl3) delta 1.70-2.00 (m, 5H), 2.01-2.32 (m, 6H), 2.72-3.2 (m, 7H), 3.28-3.40 (m, IH), 3.85-4.4 (m, 2H), 4.96-5.00 (m, 2H), 5.97-6.1 (m, IH), 6.29-6.31 (m, IH), 7.1-7.2 (m, 4H), 8.13-8.18 (m, IH)

References: [1]Patent: WO2008/91594,2008,A2 .Location in patent: Page/Page column 82-83.

12
[ 345637-71-0 ]
3-[2-(piperidin-4-yl)-1,3-thiazol-4-yl]ethynyl}-pyridine hydrochloride [ No CAS ]
[ 1220711-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; at 20℃;	2-[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(pyridin-3-ylethynyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (I-51) tert-Butyl 4-[4-(pyridin-3-ylethynyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (IV-7, 469 mg) is deprotected analogously to Example II-2 giving 3-[2-(piperidin-4-yl)-1,3-thiazol-4-yl]ethynyl}-pyridine hydrochloride (407 mg). This is immediately reacted at room temperature with <strong>[345637-71-0][5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid</strong> (277 mg) in the presence of 4-dimethylaminopyridine (16 mg) and 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (268 mg) in dichloromethane (5 ml). Stirring at room temperature overnight, concentration and chromatographic purification gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-{4-[4-(pyridin-3-ylethynyl)-1,3-thiazol-2-yl]piperidin-1-yl}ethanone (65 mg). 1H NMR (CD3CN): delta 8.74 (dd, 1H), 8.59 (dd, 1H), 7.99 (s, 1H), 7.96 (m, 1H), 7.45 (dd, 1H), 6.45 (s, 1H), 5.22 (bs, 2H), 4.35 (bs, 1H), 4.00 (bs, 1H), 3.40-3.20 (m, 3H), 2.22 (s, 3H), 2.17-2.10 (m, 2H), 1.90-1.55 (m, 2H) ppm MS (ESI): 460 ([M+H]+)

References: [1]Patent: US2010/137245,2010,A1 .Location in patent: Page/Page column 40.

13
[ 345637-71-0 ]
[ 1229003-43-3 ]
[ 1152179-07-1 ]

Yield	Reaction Conditions	Operation in experiment
52%		Preparation of Starting Materials of the Formula (IVb): 1-[4-(4-Acetyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (IV-1); Oxalyl chloride (1.74 g) and a drop of N,N-dimethylformamide are added to a solution of <strong>[345637-71-0][5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid</strong> (1.00 g) in dichloromethane (10 ml). The reaction mixture is then stirred for 24 hours. Excess oxalyl chloride is then removed under reduced pressure, and the residue is once more dissolved in dichloromethane (10 ml). With ice-bath cooling, the solution is then added to a suspension of 1-[2-(piperidin-4-yl)-1,3-thiazol-4-yl]ethanone hydrochloride (1.13 g) in dichloromethane (10 ml) and N,N-diisopropylethylamine (1.77 g). The reaction mixture is then allowed to warm to room temperature and stirred for a further 2 hours. Saturated aqueous ammonium chloride solution (5 ml) is then added to the reaction mixture. The aqueous phase is separated off and extracted with dichloromethane. All the organic phases are combined and dried using anhydrous sodium sulphate. The solid is then filtered off, and the solvent is removed under reduced pressure. Purification by column chromatography (silica gel, ethyl acetate:hexane 0%-100% elution gradient) gives 1-[4-(4-acetyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (1.00 g, 52%) (log P(pH2.7)=2.25).1H NMR (DMSO-d6, 400 MHz): deltappm: 1.65 (bs, 1H), 1.80 (bs, 1H), 2.18-2.11 (m, 2H), 2.23 (s, 3H), 2.55 (s, 3H), 2.90 (bs, 1H), 3.28 (bs, 1H), 3.39 (m, 1H), 4.00 (bs, 1H), 4.33 (bs, 1H), 5.22 (bs, 2H), 6.45 (s, 1H), 8.36 (s, 1H)MS (ESI): 401 ([M+H]+)

References: [1]Patent: US2010/190828,2010,A1 .Location in patent: Page/Page column 28.

14
[ 345637-71-0 ]
[ 782493-96-3 ]
[ 922516-62-9 ]

Yield	Reaction Conditions	Operation in experiment
		Step B: Preparation of ethyl 1-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-1H-pyrazole-4-carboxylate. By a procedure analogous to that of Example 32 Step B, 1,1-dimethylethyl 4-[4-(ethoxycarbonyl)-1H-pyrazol-1-yl]-1-piperidinecarboxylate (0.38 g, 1.2 mmol) (i.e. the product of Example 33, Step A) was deprotected with trifluoroacetic acid (4 mL) to afford the corresponding amine (0.18 g). This amine was reacted with the acid chloride formed from <strong>[345637-71-0]5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid</strong> (0.18 g, 0.88 mmol) and oxalyl chloride (0.10 mL, 1.15 mmol) in the presence of triethylamine (0.16 mL, 1.15 mmol) to afford 0.24 g of the title compound as a white solid.1H NMR (CDCl3) 6 1.35 (t, 3H), 1.95 (m, 2H), 2.24 (m, 2H), 2.34 (s, 3H), 2.90 (m, IH), 3.32 (m, IH), 4.13 (m, IH), 4.30 (q, 2H), 4.37 (m, IH), 4.63 (m, IH), 4.99 (s, 2H), 6.34 (s, IH), 7.91 (s, IH), 7.92 (s, IH).

References: [1]Patent: WO2007/14290,2007,A2 .Location in patent: Page/Page column 97.

15
[ 345637-71-0 ]
[ 922516-10-7 ]
N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1-phenylpropyl]-4-oxazolecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step F: Preparation of N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl3acetyl]-4-piperidinyl]-N-[(1R)-1-phenylpropyl]-4-oxazolecarboxamide. 1,1-Dimethylethyl 4-[4-[[methyl[(1R)-1-phenylpropyl]amino]carbonyl]-2-oxazolyl]-1-piperidinecarboxylate (i.e. the product of Example 7, Step E) (209 mg, 0.49 mmol) was dissolved in 3 mL of a mixture of dichloromethane and methanol (1:1), and 1.23 mL (4.9 mmol) of 1 N HCl in dioxane was added. The reaction mixture was stirred at room temperature for 3 h. The solvents were evaporated under reduced pressure, and the residue was dissolved in 5 mL methanol and concentrated under reduced pressure (this procedure was repeated 3 times) to give the amine hydrochloride. To a solution of 5-methyl-3-(trifluoromethyl)-(1H)-pyrazole-1-acetic acid (89.5 mg, 0.43 mmol) and triethylamine (87 mg, 0.86 mmol) in 2 mL of dry acetonitrile was added a suspension of 0-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (178.25 mg. 0.47 mmol) in 2 mL acetonitrile and then a mixture of 140 mg (0.43 mmol) of the amine hydrochloride in 2 mL acetonitrile. The resulting mixture was stirred at room temperature for 3 h and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 25-75 % of ethyl acetate in hexanes to give 84 mg of the title product, a compound of the present invention as an oil.1H NMR (CDCl3) delta 0.90-1.04 (m, 3H), 1.71-1.89 (m, 2H), 1.90-2.19 (m, 4H), 2.28-2.35 (m, 3H), 2.72 (s, 2H), 3.00-3.2 (m, 3H), 3.30-3.36 (t, IH), 3.87-4.35 (m, 2H), 4.98 (s, 2H), 5.92- 6.12 (m, IH), 6.3 (s, IH), 7.25-7.4 (m, 5H), 8.08-8.15 (br s, IH).

References: [1]Patent: WO2007/14290,2007,A2 .Location in patent: Page/Page column 65.

16
[ 345637-71-0 ]
[ 922516-11-8 ]
N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-oxazolecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step B: Preparation of N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4- oxazolecarboxamide. 1,1-Dimethylethyl 4-[4-[[methyl[(1R)-1,2,3,4-tetrahydro-1-naphthalenyljamino]-carbonyl]-2-oxazolyl]-1-piperidinecarboxylate (i.e. the product of Example 8, Step A) (317 mg, 0.72 mmo) was dissolved in 3 mL of a mixture of dichloromethane and methanol (1:1), and 1.8 mL (7.2 mmol) of 1 N HCl in dioxane was added. The reaction mixture was stirred at room temperature for 3 h. The solvents were evaporated under reduced pressure, and the residue was dissolved in 5 mL methanol and evaporated (this sequence was repeated 3 times) giving the amine hydrochloride. A mixture of 5-methyl-3-trifluoromethylpyrazol-1-ylacetic acid (179 mg, 0.86 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (191.7 mg, 1.00 mmo), and 1-methylmorpholme (354 mg, 3.5 mmol) in 3 mL of dry dichloromethane was stirred 15 minutes at room temperature, and a solution of the amine hydrochloride in 2 mL of dry dichloromethane was added. The resulting mixture was stirred at room temperature for 16 h and concentrated under reduced pressure. The residue was purified by silica gel chromatography using 75 % ethyl acetate in hexanes as eluant to give 79 mg of the title product, a compound of the present invention as an oil. 1H NMR (CDCl3) 5 1.70-2.00 (m, 5H), 2.01-2.32 (m, 6H), 2.72-3.2 (m, 7H), 3.28-3.40 (m, IH), 3.85-4.4 (m, 2H), 4.96-5.00 (m, 2H), 5.97-6.1 (m, IH), 6.29-6.31 (m, IH), 7.1-7.2 (m, 4H), 8.13-8.18 (m, IH).

References: [1]Patent: WO2007/14290,2007,A2 .Location in patent: Page/Page column 66.

17
[ 345637-71-0 ]
[ 922516-01-6 ]
N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1-phenylethyl]-4-thiazolecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step B: Preparation of N-methyl-2-[1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-N-[(1R)-1-phenylethyl]-4-thiazolecarboxamide. A solution of 400 mg (0.77 mmol) of 1,1-dimethylethyl 4-[4-[[methyl[(1R)-1-phenylethyl]amino]carbonyl]-2-thiazolyl]-1-piperidinecarboxylate (i.e. the product of Example 5, Step A) in 10 mL of a 1:1 mixture of methanol and dichloromethane was treated with 10 mL of 2 N hydrochloric acid in ether and stirred at room temperature for 4 h. The reaction mixture was concentrated on rotary evaporator, and the residue was three times treated with 10 mL of methanol followed by concentration to leave the crude piperidine hydrochloride. The reaction mixture was then dissolved in 10 mL of acetonitrile, and 1.O mL of triethylamine was added. Meanwhile, a solution of 310 mg (1.49 mmol) of <strong>[345637-71-0]5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid</strong> in 10 mL of acetonitrile was treated with 1.0 mL of a solution of 1-propanephosphonic acid cyclic anhydride (50 % in ethyl acetate), stirred at room temperature for 15 minutes, then combined with the above amine solution. The reaction mixture was stirred at room temperature overnight, diluted with 50 mL of ethyl acetate, washed with 1 N aqueous hydrochloric acid, 1 N aqueous sodium hydroxide and brine, dried with MgSO4, filtered and concentrated under reduced pressure. Purification by Medium Pressure Liquid Chromatography (MPLC) on silica gel using ethyl acetate/methanol as eluant provided 330 mg of the title product, a compound of the present invention as a white solid.1HNMR (CDCl3) delta 1.60-1.80 (m, 5 H), 2.18 (m, 2 H), 2.30 (s, 3H), 2.80 (m, 5 H), 3.27 (m, 2 H), 4.00 (m, IH), 4.95 (s, 2 H), 5.79 and 6.14 (m, total IH), 6.35 (s, IH), 7.37 (m, 5H), 7.84 (s, IH).

References: [1]Patent: WO2007/14290,2007,A2 .Location in patent: Page/Page column 59.

18
[ 345637-71-0 ]
[ 922516-44-7 ]

References: [1]Patent: WO2011/18401,2011,A1 .
[2]Patent: WO2012/69633,2012,A1 .
[3]Patent: US2012/142700,2012,A1 .
[4]Patent: WO2013/56911,2013,A1 .
[5]Patent: WO2007/14290,2007,A2 .

19
[ 345637-71-0 ]
[ 1263874-51-6 ]

References: [1]Patent: WO2011/18401,2011,A1 .
[2]Patent: US2012/142700,2012,A1 .

20
[ 345637-71-0 ]
[ 1263874-85-6 ]

References: [1]Patent: WO2011/18401,2011,A1 .
[2]Patent: WO2012/69633,2012,A1 .
[3]Patent: US2012/142700,2012,A1 .

21
[ 345637-71-0 ]
[ 1263874-86-7 ]

References: [1]Patent: WO2011/18401,2011,A1 .
[2]Patent: WO2012/69633,2012,A1 .
[3]Patent: US2012/142700,2012,A1 .

22
[ 345637-71-0 ]
[ 1263874-53-8 ]

References: [1]Patent: WO2011/18401,2011,A1 .
[2]Patent: US2012/142700,2012,A1 .

23
[ 345637-71-0 ]
[ 1263874-50-5 ]

References: [1]Patent: WO2011/18401,2011,A1 .
[2]Patent: US2012/142700,2012,A1 .

24
[ 345637-71-0 ]
[ 1263874-52-7 ]

References: [1]Patent: WO2011/18401,2011,A1 .
[2]Patent: US2012/142700,2012,A1 .

25
[ 345637-71-0 ]
[ 922516-41-4 ]
[ 922516-42-5 ]

Yield	Reaction Conditions	Operation in experiment
88%		Example 1 : This example illustrates the preparation of 1 ,2,3,4-tetrahydro-naphthalene-1- carboxylic acid (2-{1 -[2-(5-methyl-3-trifluoromethyl-pyrazol-1 -yl)-acetyl]-piperidin-4-yl}- thiazol-4-yl)-amide (Compound No. 1.g.01 1 ) a) Preparation of 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}- thiazole-4-carboxylic acid ethyl esterTo a solution of <strong>[345637-71-0](5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid</strong> (9.1 g, 36.1 mmol) in DMF (100 ml.) is added diisopropylethylamine (45 ml_, 216 mmol), followed by O- (benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (15.5 g, 39.7 mmol). After stirring 15 min at RT, 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester hydrochloride (10 g, 36.1 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (300 ml_), washed with saturated aqueous sodium bicarbonate solution (300 ml_), 1 M HCI solution (300 ml_), and brine (100 ml_). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture is purified by column chromatography on silica gel (dichloromethane/methanol 10:1 ) to give 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1- yO-acetylJ-piperidin^-ylHhiazole^-carboxylic acid ethyl ester (13.6 g, 88 %). 1H-NMR (400 MHz, CDCI3): delta = 1.40 (t, 3H), 1.70-1.85 (m, 2H), 2.16-2.30 (m, 2H), 2.32 (s, 3H), 2.79-2.89 (m, 1 H), 3.22-3.43 (m, 1 H), 4.03-4.12 (m, 1 H), 4.42 (q, 3H), 4.54-4.69 (m, 1 H), 4.93-5.08 (2d, 2H (diastereotopic)), 6.35 (s, 1 H), 8.10 (br, 1 H). MS: m/z = 209 (M+1 ).
88%		To a solution of <strong>[345637-71-0](5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid</strong> (9.1 g, 36.1 mmol) in DMF (100 mL) is added diisopropylethylamine (45 mL, 216 mmol), followed by O- (benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (15.5 g, 39.7 mmol). After stirring 15 min at RT, 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester hydrochloride (10 g, 36.1 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (300 mL), washed with saturated aqueous sodium bicarbonate solution (300 mL), 1 M HCI solution (300 mL), and brine (100 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture is purified by column chromatography on silica gel (dichloromethane/methanol 10: 1) to give 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)- acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester (13.6 g, 88 %). 1 H-NMR (400 - -MHz, CDCI3): delta = 1.40 (t, 3H), 1.70-1.85 (m, 2H), 2.16-2.30 (m, 2H), 2.32 (s, 3H), 2.79-2.89 (m, 1 H), 3.22-3.43 (m, 1 H), 4.03-4.12 (m, 1 H), 4.42 (q, 3H), 4.54-4.69 (m, 1 H), 4.93-5.08 (2d, 2H (diastereotopic)), 6.35 (s, 1 H), 8.10 (br, 1 H). MS: m/z = 209 (M+1).
88%		a) Preparation of 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazole- 4-carboxylic acid ethyl esterTo a solution of <strong>[345637-71-0](5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid</strong> (9.1 g, 36.1 mmol) in DMF (100 ml_) is added diisopropylethylamine (45 ml_, 216 mmol), followed by 0-(benzotriazol- 1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (15.5 g, 39.7 mmol). After stirring 15 min at RT, 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester hydrochloride (10 g, 36.1 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (300 ml_), washed with saturated aqueous sodium bicarbonate solution (300 ml_), 1 M HCI solution (300 ml_), and brine (100 ml_). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture is purified by column chromatography on silica gel (dichloromethane/methanol 10: 1 ) to give 2-{1 -[2-(5-methyl-3-trif luoromethyl-pyrazol-1 -yl)-acetyl]-piperidin-4-yl}-thiazole-4- carboxylic acid ethyl ester (13.6 g, 88 %). 1 H-NMR (400 MHz, CDCI3): delta = 1.40 (t, 3H), 1.70-1.85 (m, 2H), 2.16-2.30 (m, 2H), 2.32 (s, 3H), 2.79-2.89 (m, 1 H), 3.22-3.43 (m, 1 H), 4.03-4.12 (m, 1 H), 4.42 (q, 3H), 4.54-4.69 (m, 1 H), 4.93-5.08 (2d, 2H (diastereotopic)), 6.35 (s, 1 H), 8.10 (br, 1 H). MS: m/z = 209 (M+1).

88%		a) Preparation of 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester To a solution of <strong>[345637-71-0](5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid</strong> (9.1 g, 36.1 mmol) in DMF (100 mL) is added diisopropylethylamine (45 mL, 216 mmol), followed by O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (15.5 g, 39.7 mmol). After stirring 15 min at RT, 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester hydrochloride (10 g, 36.1 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (300 mL), washed with saturated aqueous sodium bicarbonate solution (300 mL), 1M HCl solution (300 mL), and brine (100 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture is purified by column chromatography on silica gel (dichloromethane/methanol 10:1) to give 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester (13.6 g, 88%). 1H-NMR (400 MHz, CDCl3): delta=1.40 (t, 3H), 1.70-1.85 (m, 2H), 2.16-2.30 (m, 2H), 2.32 (s, 3H), 2.79-2.89 (m, 1H), 3.22-3.43 (m, 1H), 4.03-4.12 (m, 1H), 4.42 (q, 3H), 4.54-4.69 (m, 1H), 4.93-5.08 (2d, 2H (diastereotopic)), 6.35 (s, 1H), 8.10 (br, 1H). MS: m/z=209 (M+1).
		a) Preparation of 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}- thiazole-4-carboxylic acid ethyl ester To a solution of <strong>[345637-71-0](5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid</strong> (9.1 g, 36.1 mmol) in DMF (100 mL) is added diisopropylethylamine (45 mL, 216 mmol), followed by O- (benzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (15.5 g, 39.7 mmol). After stirring 15 min at RT, 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester hydrochloride (10 g, 36.1 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (300 mL), washed with saturated aqueous sodium bicarbonate solution (300 mL), 1 M HCI solution (300 mL), and brine (100 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture is purified by column chromatography on silica gel (dichloromethane/methanol 10:1 ) to give 2-{1 -[2-(5-methyl-3-trifluoromethyl-pyrazol-1 - yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester. 1H-NMR (400 MHz, CDCI3): delta = 1.40 (t, 3H), 1 .70-1.85 (m, 2H), 2.16-2.30 (m, 2H), 2.32 (s, 3H), 2.79-2.89 (m, 1 H), 3.22- 3.43 (m, 1 H), 4.03-4.12 (m, 1 H), 4.42 (q, 3H), 4.54-4.69 (m, 1 H), 4.93-5.08 (2d, 2H (diastereotopic)), 6.35 (s, 1 H), 8.10 (br, 1 H). MS: m/z = 209 (M+1 ).

References: [1]Patent: WO2011/18401,2011,A1 .Location in patent: Page/Page column 29.
[2]Patent: WO2012/69633,2012,A1 .Location in patent: Page/Page column 26-27.
[3]Patent: WO2012/107477,2012,A1 .Location in patent: Page/Page column 30-31.
[4]Patent: US2012/142700,2012,A1 .Location in patent: Page/Page column 15-16.
[5]Patent: WO2013/56911,2013,A1 .Location in patent: Page/Page column 26; 27.

26
[ 345637-71-0 ]
trifluoroacetic acid 4-{4-[(1-naphthylsulphanyl)methyl]-1,3-thiazol-2-yl}piperidine [ No CAS ]
[ 1259322-05-8 ]

Yield	Reaction Conditions	Operation in experiment
		At room temperature, a solution of trifluoroacetic acid solution (30% in dichloromethane, 2 ml) is added dropwise to tert-butyl 4-{4-[(1-naphthylsulphanyl)methyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (269 mg). The reaction mixture is stirred for 30 minutes, and triethylamine (2 ml) is then added to the reaction mixture.Oxalyl chloride (232 mg) and a drop of N,N-dimethylformamide are added to a solution of <strong>[345637-71-0][5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid</strong> (140 mg) in dichloromethane (5 ml). The reaction mixture is then stirred for 30 minutes. Excess oxalyl chloride is then removed under reduced pressure, and the residue is re-dissolved in dichloromethane (1 ml). The solution is then added to the first solution of trifluoroacetic acid 4-{4-[(1-naphthylsulphanyl)methyl]-1,3-thiazol-2-yl}piperidine (1:1) (III-1) in dichloromethane and triethylamine. The reaction mixture is then warmed to room temperature and stirred for another 20 hours. The solvent is then removed under reduced pressure. The residue is purified by column chromatography. This gives 2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[(1-naphthylsulphanyl)methyl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (134 mg, 36%).logP (pH2.7): 4.331H NMR (CD3CN, 400 MHz): deltappm: 1.50-1.80 (m, 2H), 2.15-2.25 (m, 2H), 2.23 (s, 3H), 2.90 (bs, 1H), 3.20 (m, 1H), 3.25 (bs, 1H), 3.90 (bs, 1H), 4.25 (s, 2H), 4.38 (bs, 1H), 5.04 (bs, 2H), 6.37 (s, 1H), 6.87 (s, 1H), 7.41 (dd, 1H), 7.48-7.56 (m, 2H), 7.63 (d, 1H), 7.80 (d, 1H), 7.89 (m, 1H), 8.33 (s, 1H)MS (ESI): 531 ([M+H]+)

References: [1]Patent: US2011/46178,2011,A1 .Location in patent: Page/Page column 29-30.

27
[ 345637-71-0 ]
[ 922516-42-5 ]

References: [1]Patent: WO2007/14290,2007,A2 .

28
[ 345637-71-0 ]
[ 1313705-28-0 ]
[ 1313705-18-8 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 48h;	A mixture of 4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2- thiazolyl]hexahydropyridazine (i.e. the product of Step Eta) (0.29 g, 0.83 mmol), 5-methyl-3- (trifluoromethyl)-lH-pyrazole-l -acetic acid (0.19 g, 0.91 mmol) and N,N- dicyclohexylcarbodiimide (0.19 g, 0.91 mmol) in dichloromethane (5 mL) was stirred at room temperature for 48 h. More dichloromethane was added to the reaction mixture, the mixture was filtered, washing thoroughly with dichloromethane. The filtrate was concentrated under reduced pressure and loaded onto a chromatotron plate (4mm). The plate was eluted with dichloromethane, followed by a gradient of 0.5% to 2% methanol in dichloromethane. Fractions containing product material were further purified by HPLC using an Alltima C18 column (250 x 22 mm), monitored at wavelength 225 nm and eluted with 60% methanol and 0.1% 2,2,2-trifluoroacetic acid in water to provide the title compound (69 mg), a compound of the present invention. in NMR (600 MHz; -40 C, CD3CN): delta 1.95-2.10 (m, 1H), 2.20-2.35 (m, 4H), 2.95-3.15 (m, 2H), 3.40-3.55 (m, 2H), 3.55-3.67 (m, 1H), 3.80-3.95 (m, 1H), 4.50-4.60 (m, 1H), 5.25-5.45 (m, 2H), 6.10-6.20 (m, 1H), 6.50 (s, 1H), 7.05-7.20 (m, 2H), 7.43-7.55 (m, 1H), 7.92 (s, 1H).

References: [1]Patent: WO2011/85170,2011,A1 .Location in patent: Page/Page column 93-94.

29
[ 345637-71-0 ]
[ 1313705-37-1 ]
[ 1313705-20-2 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 20h;	A mixture of 5-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2- thiazolyl]tetrahydro-2H-l,2-oxazine (i.e. the product of Step K) (0.235 g, 0.67 mmol), 5- methyl-3-(trifluoromethyl)-lH-pyrazole-l -acetic acid (0.154 g, 0.74 mmol) and N,N-dicyclohexylcarbodiimide (0.152 g, 0.74 mmol) in dichloromethane was stirred at room temperature for 20 h. The reaction mixture was diluted with more dichloromethane and the urea by-product was removed by filtration. The filtrate was concentrated under reduced pressure to a pale-yellow foam (0.42 g). The resulting foam was dissolved in a minimum amount of dichloromethane and loaded onto a chromatotron plate (2mm) eluting with a gradient of ethyl acetate in dichloromethane to give the title compound, a compound of the present invention, as a colourless foamy solid (0.101 g).in NMR (CDCI3): delta 2.05-2.20 (m, 1H), 2.20-2.35 (m, 4H), 3.403.55 (m, 1H), 3.55-3.70 (m, 2H), 3.75-3.88 (m, 1H), 4.08-4.20 (m, 1H), 4.35-4.45 (m, 1H), 4.45-4.55 (m, 1H), 5.08 (s, 2H), 6.02-6.12 (m, 1H), 6.30 (s, 1H), 6.85-6.98 (m, 2H), 7.25-7.38 (m, 1H), 7.72 (s, 1H).

References: [1]Patent: WO2011/85170,2011,A1 .Location in patent: Page/Page column 98.

30
[ 345637-71-0 ]
[ 1003320-03-3 ]
[ 1003320-04-4 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 5-methyl-3-(trifluoromethyl)-lH-pyrazole-l -acetic acid (0.8 g, 3.8 mmol) in dichloromethane (10 mL) was added oxalyl chloride (2.4 g, 19.2 mmol) and two drops of N,N-dimethylformamide, resulting in slight exotherm. The reaction mixture was then heated at reflux for 15 minutes. The reaction mixture was concentrated in vacuo, the residue was suspended in tetrahydrofuran (10 mL) and treated with a solution of 2-(4- piperidinyl)-4-thiazolecarboxaldehyde monohydrochloride (i.e. the product of Example 8, Step A) (1.1 g, 5.1 mmol) in tetrahydrofuran (10 mL), followed by dropwise addition of triethylamine (1.2 g, 11.9 mmol). The reaction mixture was stirred overnight at room temperature and then partitioned between 1 N aqueous hydrochloric acid and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate (2 x 30 mL). The combined organic layers were washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine. The organic layer was dried (MgS04) and evaporated under reduced pressure to give 0.8 g of the title compound as a yellow oil..H NMR (CDCI3): delta 1.79-1.90 (m, 2H), 2.18-2.29 (m, 2H), 2.33 (s, 3H), 2.87-2.94 (m, 1H), 3.28-3.40 (m, 2H), 4.05-4.15 (m, 1H), 4.56-4.64 (m, 1H), 4.99-5.02 (m, 2H), 6.35 (s, 1H), 8.12 (s, 1H), 10.01 (s, 1H).

References: [1]Patent: WO2011/146182,2011,A1 .Location in patent: Page/Page column 84-85.

31
[ 345637-71-0 ]
[ 1345958-36-2 ]