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[ CAS No. 80194-68-9 ]

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3d Animation Molecule Structure of 80194-68-9

Chemical Structure| 80194-68-9

Chemical Structure| 80194-68-9

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Quality Control of [ 80194-68-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 80194-68-9 ]

Product Details of [ 80194-68-9 ]

CAS No. :	80194-68-9	MDL No. :	MFCD00277482
Formula :	C₇H₃ClF₃NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HXRMCZBDTDCCOP-UHFFFAOYSA-N
M.W :	225.55	Pubchem ID :	2821908
Synonyms :

Calculated chemistry of [ 80194-68-9 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	6.0
Num. H-bond donors :	1.0
Molar Refractivity :	41.21
TPSA :	50.19 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.1 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.17
Log Po/w (XLOGP3) :	2.22
Log Po/w (WLOGP) :	3.6
Log Po/w (MLOGP) :	0.56
Log Po/w (SILICOS-IT) :	2.45
Consensus Log Po/w :	2.0

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.82
Solubility :	0.34 mg/ml ; 0.00151 mol/l
Class :	Soluble
Log S (Ali) :	-2.91
Solubility :	0.278 mg/ml ; 0.00123 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.91
Solubility :	0.278 mg/ml ; 0.00123 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.87

Safety of [ 80194-68-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 80194-68-9 ]

* 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.

Upstream synthesis route of [ 80194-68-9 ]
Downstream synthetic route of [ 80194-68-9 ]

[ 80194-68-9 ] Synthesis Path-Upstream 1~2

1
[ 80194-70-3 ]
[ 80194-68-9 ]

Reference： [1] Patent: US4367336, 1983, A,

2
[ 75806-84-7 ]
[ 80194-68-9 ]

Reference： [1] Patent: US4367336, 1983, A,

[ 80194-68-9 ] Synthesis Path-Downstream 1~68

1
[ 80194-68-9 ]
[ 79-37-8 ]
[ 80194-72-5 ]

Yield	Reaction Conditions	Operation in experiment
	In hexane; N,N-dimethyl-formamide;	P.2.1.4. Preparation of <strong>[80194-68-9]3-chloro-5-trifluoromethylpyridine-2-carboxylic acid</strong> chloride 16.9 g (75 mmol) of <strong>[80194-68-9]3-chloro-5-trifluoromethylpyridine-2-carboxylic acid</strong> are suspended in 75 ml of hexane. After the addition of 2 drops of DMF 7 ml (80 mmol) of oxalyl chloride in 25 ml of hexane are added dropwise. The whole is then stirred for 4 hours at 50 C. until the evolution of gas has ceased. The reaction solution is filtered and concentrated by evaporation on a rotary evaporator. 18 g (98%) of the title compound of formula STR31 are isolated in the form of a yellow oil (Compound No. 3.073).

Reference： [1]Patent: US4995902,1991,A

2
3-chloro-5-trifluoromethylpyridine-2-carboxylic acid ethyl ester [ No CAS ]
[ 80194-68-9 ]

Yield	Reaction Conditions	Operation in experiment
90%	With lithium hydroxide monohydrate; water; In tetrahydrofuran; at 20℃; for 3h;Inert atmosphere;	[00231] Step B: A mixture of ethyl 3-chloro-5-(trifluoromethyl)picolinate (500 mg, 2.0 mmol) and LiOH H20 (1.24 g, 29.6 mmol) in THF/H20 (12/4 mL) was stirred at room temperature for 3 hours. The mixture was concentrated, then dissolved in DCM, filtered and the filtrate was concentrated to give 3-chloro-5-(trifluoromethyl)picolinic acid (400 mg, 90% yield). 1H NMR ((CD3)2SO, 400 MHz) delta 8.96 (s, 1H), 8.61 (s, 1H).
	With sodium hydroxide;	P.2.1.3. Preparation of 3-chloro-5-trifluoromethylpyridine-2-carboxylic acid 76 g (0.3 mol) of 3-chloro-5-trifluoromethylpyridine-2-carboxylic acid ethyl ester are stirred for 6 hours with 165 ml (0.33 mol) of 2N NaOH. The resulting solution is washed twice with methylene chloride. The aqueous solution is then adjusted to pH 1 with 37% hydrochloric acid and the product is filtered off with suction and dried at room temperature in vacuo. 65 g (96%) of the title compound of formula STR30 are isolated in the form of white crystals having a melting point of 135 C. (decomp.) (Compound No. 3.039).
	With sodium hydroxide; In ethanol; water;	Example H3 3-Chloro-5-trifluoromethyl-2-pyridinecarboxylic acid 423 g of ethyl 3-chloro-5-trifluoromethyl-2-pyridinecarboxylate (Example H2) is initially introduced into a mixture of 800 ml of water and 160 ml of ethanol. 800 ml of a 2N sodium hydroxide solution are added dropwise at a temperature below 35 C. After 3 hours, the mixture is washed twice with methylene chloride and then rendered acid with an excess of concentrated hydrochloric acid, while cooling in an ice-bath. The slurry formed is filtered and the solid is washed with water and dried in vacuo. 318 g of the desired product are obtained as a white solid of melting point 135 C. (decomposition).

With sodium hydroxide; In ethanol; water;

Example P3 3-Chloro-5-trifluoromethyl-2-pyridinecarboxylic Acid 423 g of 3-chloro-5-trifluoromethyl-2-pyridinecarboxylic acid ethyl ester (Example P2) is placed in a mixture of 800 ml of water and 160 ml of ethanol. 800 ml of a 2N sodium hydroxide solution are added dropwise at below 35 C. After 3 hours, the mixture is washed twice with dichloromethane and then rendered acidic with excess concentrated hydrochloric acid while cooling with an ice-bath. The resulting slurry is filtered, washed with water and dried in vacuo. 318 g of the desired product are obtained in the form of a white solid having a melting point of 135 C. (decomposition).

Reference： [1]Patent: WO2013/148851,2013,A1 .Location in patent: Paragraph 00231
[2]Patent: US4995902,1991,A
[3]Patent: US6204221,2001,B1
[4]Patent: US6274536,2001,B1

3
[ 75806-84-7 ]
[ 80194-68-9 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In diethyl ether; hexane; nitrogen; water;	Preparation Example 1 Ten grams of 2-bromo-3-chloro-5-trifluoromethylpyridine was dissolved in 100 ml of dry diethyl ether in a nitrogen stream, and the resulting solution was cooled to -78 C. To the solution thus cooled was gradually dropwise added 30 ml of a 15% solution of n-butyl lithium in hexane, and the resulting mixture was stirred at that temperature for 30 minutes. Thereafter, an excessive amount of pulverized dry ice was gradually introduced into the solution. The temperature of the solution was returned to room temperature, and the solution was stirred at that temperature for an additional 1 hour. After the reaction was completed, 100 ml of water was added to thereby subject to the extraction. An aqueous layer thus formed was isolated and made acidic by adding thereto concentrated hydrochloric acid to form an oily product. The thus formed oily product was extracted with 300 ml of methylene chloride. After drying an organic layer over anhydrous sodium sulfate, the solvent was evaporated off under reduced pressure to obtain 5.1 g of 3-chloro-5-trifluoromethylpyridine-2-carboxylic acid.

Reference： [1]Patent: US4367336,1983,A

4
[ 80194-68-9 ]
[ 80194-72-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; toluene; at 0 - 20℃; for 2h;	3-Chloro-5-(trifluoromethyl)picolinic acid (72.3 mg, 320 mupiiotaomicron) was suspended in dichloromethane (5 mL), the suspension was cooled to 0-5C (ice bath) and oxalyl chloride (56.9 mg, 39.3 mu, 448 muiotaetaomicron) as well as dimethylformamide (0.308 M in toluene, 51.9 mu, 16 muiotaetaomicron) were added. The mixture was stirred for 2 h at room temperature. Then, it was concentrated in vacuo (40C, 5 mbar) and dried azeotropically by two cycles of addition of toluene (3 mL) followed by concentration in vacuo to afford 3-chloro-5-(trifluoromethyl)picolinoyl chloride as yellow oil (78 mg, quant.). After that, tert-butyl ((3aS,4R,8R)-4-(5-amino-2-fluorophenyl)-4,7,7- trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[l,5-a] [l,4]thiazin-6-yl)carbamate (Int- 16ABp, 80 mg, 188 muiotaetaomicron) was dissolved in dichloromethane (5 mL), the solution cooled to 10C and N,N-diisopropylethylamine (36.5 mg, 49.4 mu, 283 muiotaetaomicron) was added, followed by a solution of 3-chloro-5-(trifluoromethyl)picolinoyl chloride (vide supra, 62 mg, 256 muiotaetaomicron) in dichloro- methane (4 mL). The reaction mixture was stirred for 15 min at 10C. Then, methanol (2 mL) was added, the mixture was stirred for 5 min at room temperature and concentrated in vacuo. The crude was purified by column chromatography (silica gel, 12 g, eluting with ethyl acetate / n-heptane, gradient 25:75 to 100:0) to yield, after drying in vacuo (40C, 5 mbar), the title compound as an off-white solid (100 mg, 84% yield). HPLC (method LCMS_fglm) tR = 1.35 min. MS (ES+) m/z 632.5 [M+H] .
	With thionyl chloride; In toluene;	Example H5 3-Chloro-5-trifluoromethyl-2-pyridinecarbonyl chloride 89.3 g of 3-chloro-5-trifluoromethyl-2-pyridinecarboxylic acid (Example H3) are slowly heated to reflux temperature together with 60 ml of thionyl chloride and the mixture is then subsequently stirred at this temperature for 4 hours. Thereafter, it is cooled to 25 C. and concentrated to dryness in vacuo. Toluene is added twice more and the mixture is concentrated again to dryness. 94.0 g of the desired product are obtained as a yellow residue. 1H-NMR (CDCl3): 8.91 ppm (d, 1H); 8.13 ppm (d, 1H).
	With thionyl chloride; In toluene;	Example P5 3-Chloro-5-trifluoromethyl-2-pyridinecarboxylic Acid Chloride 89.3 g of 3-chloro-5-trifluoromethyl-2-pyridinecarboxylic acid (Example P3) are slowly heated to reflux with 60 ml of thionyl chloride and the mixture is then stirred at that temperature for 4 hours, after which it is cooled to 25 C. and concentrated to dryness in vacuo. Twice, toluene is added and the mixture is again concentrated to dryness. 94.0 g of the desired product are obtained in the form of a yellow residue. 1H-NMR (CDCl3): 8.91 ppm (d, 1H); 8.13 ppm (d, 1H).

	With thionyl chloride; In N,N-dimethyl-formamide; for 3h;Reflux;	(1 ) To 1.0 g of <strong>[80194-68-9]3-chloro-5-(trifluoromethyl)picolinic acid</strong>, 1.0 ml of thionyl chloride and 0.1 ml of N,N-dimethylformamide were added, followed by heating and refluxing for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. A mixture of the obtained residue and 1 ml of tetrahydrofuran was dropwise added to a mixture of 0.52 g of isopropylamine and 10 ml of tetrahydrofuran under cooling with ice, followed by stirring for 1 hour under cooling with ice. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and washed with a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to washing with hexane to obtain 1.05 g of 3-chloro-N- isopropyl-5-(trifluoromethyl)picolinamide as colorless needle crystals. Its NMR spectrum data are as follows. 1 H NMR (400MHz, CDCI3): delta ppm = 1.27(6H, d, J=6.4Hz), 4.19-4.28(1 H, m), 7.49(1 H, broad singlet), 8.03(1 H, d, J=1.2Hz), 8.67(1 H, d, J=1.2Hz)
	With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 110℃; for 5h;	Preparation Example 29(1) (0660) To a mixture of <strong>[80194-68-9]3-chloro-5-(trifluoromethyl)pyridine-2-carboxylic acid</strong> 30 g and toluene 130 mL were added successively thionyl chloride 25 mL and DMF 1. 6 mL under room temperature. The reaction mixtures were stirred at 110 C. for 5 hours. The reaction mixtures were allowed to stand to room temperature, and then concentrated under reduced pressure to give oily materials.
	With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 2.16667h;	(1) Add 1 g (1 mmol) of 3-chloro-5-trifluoromethylpicolinic acid and 5 ml of a solvent to a 50 ml single-neck round bottom flask,Add a few drops of the DMF mixture and stir for 10 min.Slowly add a mixture of 0.675 g (1.2 mmol) of oxalyl chloride and DCM. After the dropwise addition, stir at room temperature for 3 h and stop the reaction.The system was spin-dried to obtain intermediate 2;

Reference： [1]Patent: WO2017/25491,2017,A1 .Location in patent: Page/Page column 56; 57
[2]Patent: US6204221,2001,B1
[3]Patent: US6274536,2001,B1
[4]Patent: WO2010/55896,2010,A2 .Location in patent: Page/Page column 18
[5]Patent: US2017/305896,2017,A1 .Location in patent: Paragraph 0660
[6]Patent: CN110526863,2019,A .Location in patent: Paragraph 0034-0036; 0042-0052; 0058-0068; 0073-0089

5
[ 80194-68-9 ]
[ 916160-19-5 ]
3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid (4-cyclopropylmethanesulfonyl-1-cyclopropylmethyl-cyclohexylmethyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 3-[(ethylimino)methylene]-amino}-N,N,N-trimethyl-1-propanaminium iodide; benzotriazol-1-ol; In dichloromethane; for 20h;	To a stirred solution of C-(4-cyclopropylmethanesulfonyl1-1-cyclopropylmethyl-cyclohexyl)-methylamine (64 mg; 0.224 mmol) in DCM (1 ml) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (100 mg; 0.336 mmol), 1-hydroxybenzotriazole hydrate (5 mg; 0.0336 mmol), and 3-chloro-5-trifluoromethyl)pyridine-2-carboxylic acid (65 mg; 0.288 mmol). The mixture was stirred for 20 hours. Water (5 ml) and DCM (5 ml) were added and the mixture was stirred vigorously for 5 minutes then passed through a PTFE separation frit. The organic phase was collected and evaporated in vacuo. The residue was dissolved in MeOH and passed through a Si-carbonate cartridge, eluding with MeOH. The filtrate was evaporated in vacuo to give an oil. The crude product was purified by prep. TLC eluted with 50% EtOAc in hexane to give a colourless oil. The oil was crystallized from EtOAC using hexane to give a white solid (57 mg). 1H NMR (400 MHz, CDCl3): delta 8.72 (1H, s), 8.07 (1H, s), 7.80 (1H, t, J 6.5), 3.60 (2H, d, J 6.6), 2.94-2.88 (3H, m), 2.09-2.05 (2H, m), 2.00-1.86 (4H, m), 1.41-1.35 (2H, m), 1.26-1.16 (3H, m), 0.78-0.70 (3H, m), 0.56-0.52 (2H, m), 0.44-0.40 (2H, m), 0.09-0.07 (2H, m). MS (m/e)=493.

Reference： [1]Patent: US2006/276655,2006,A1 .Location in patent: Page/Page column 20-21

6
[ 80194-68-9 ]
[ 1346146-78-8 ]
[ 1346146-79-9 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;	A solution of the carboxylic acid (0.3 mmol) in N,N-dimethylformamide (5 ml) was cooled to 0 C. Consecutively, 1 -hydro xybenzotriazole hydrate (52 mg, 0.38 mmol), 0-(benzotriazol-l- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (143 mg, 0.38 mmol), (R)-3-(5-amino- 2-fluoro-phenyl)-3-methyl-[l,4]oxazepan-5-one hydrochloride (intermediate C13A) (74 mg, 0.27 mmol), and N-ethyldiisopropylamine (124 mg, 0.94 mmol) were added, and the mixture was stirred at 0 C for 10 minutes, then left at room temperature for 16 hours. For the workup, the reaction mixture was evaporated to dryness and the residue directly purified by chromatography on a Silicycle-Si-amine column using a gradient of heptane and ethyl acetate as the eluent.Intermediate C14AStarting from 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid and (R)-3-(5-amino-2- fluoro-phenyl)-3-methyl-[l,4]oxazepan-5-one hydrochloride, the 3-chloro-5-trifluoromethyl- pyridine-2-carboxylic acid [4-fluoro-3-((R)-3-methyl-5-oxo-[ 1 ,4]oxazepan-3-yl)-phenyl] -amide was obtained as a light yellow foam. MS (ISP): m/z = 446.1 [M+H]+.
	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 0 - 20℃; for 16h;	Synthesis of Intermediate Amide Derivatives C14a (R7=COR10) General Procedure A solution of the carboxylic acid (0.3 mmol) in N,N-dimethylformamide (5 ml) was cooled to 0 C. Consecutively, 1-hydroxybenzotriazole hydrate (52 mg, 0.38 mmol), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (143 mg, 0.38 mmol), (R)-3-(5-amino-2-fluoro-phenyl)-3-methyl-[1,4]oxazepan-5-one hydrochloride (intermediate C13A) (74 mg, 0.27 mmol), and N-ethyldiisopropylamine (124 mg, 0.94 mmol) were added, and the mixture was stirred at 0 C. for 10 minutes, then left at room temperature for 16 hours. For the workup, the reaction mixture was evaporated to dryness and the residue directly purified by chromatography on a Silicycle-Si-amine column using a gradient of heptane and ethyl acetate as the eluent. Intermediate C14A Starting from 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid and (R)-3-(5-amino-2-fluoro-phenyl)-3-methyl-[1,4]oxazepan-5-one hydrochloride, the 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [4-fluoro-3-((R)-3-methyl-5-oxo-[1,4]oxazepan-3-yl)-phenyl]-amide was obtained as a light yellow foam. MS (ISP): m/z=446.1 [M+H]+.

Reference： [1]Patent: WO2011/138293,2011,A1 .Location in patent: Page/Page column 128; 129
[2]Patent: US2011/312937,2011,A1 .Location in patent: Page/Page column 59

7
[ 80194-68-9 ]
[ 5188-07-8 ]
[ 1245784-28-4 ]

Yield	Reaction Conditions	Operation in experiment
51%		Example 2. Procedure for the synthesis of 3-(methylsulfonyl)-5-(trifluoromethyl)picolinic acid (7); 3-Chloro-5-(trifluoromethyl)picolinic acid (6) (2.1 1 g, 10.0 mmol), K2C03 (1.38 g, 10.0 mmol), and NaSMe (1.20 g, 25.0 mmol) were stirred in DMF (15 mL) at 110 C for 16 h. The reaction was concentrated in vacuo and the residue dissolved in MeOH (80 mL) and H20 (80 mL). Oxone monopersulfate (30 g, 49 mmol) was added, and the reaction stirred at room temperature for 16 hours. The solid was removed by filtration, and the filtrate basified with 10% NaOH for 30 minutes. The MeOH was removed in vacuo, and the aqueous portion acidified to pH 1 with 6 N HC1, extracted with EtOAc (3 x 80 mL), dried (Na2S04), and concentrated in vacuo. The residue was recrystallized (with 1 eq. DMF) from EtOAc/hexanes to give 3- (methylsulfonyl)-5-(trifluoromethyl)picolinic acid (7) containing one DMF molecule (1.70 g, 51%); NMR (300 MHz, CD3OD) delta 2.88 (s, 3H, DMF), 3.01 (s, 3H, DMF), 3.45 (s, 3H), 8.00 (s, 1H, DMF), 8.73 (s, 1H), 9.22 (s, 1H).

Reference： [1]Patent: WO2012/61926,2012,A1 .Location in patent: Page/Page column 33-34

8
[ 80194-68-9 ]
[ 1421950-51-7 ]
[ 1421950-54-0 ]

Reference： [1]Patent: WO2013/18928,2013,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: EP2952097,2015,A1
[4]Patent: US2015/359219,2015,A1
[5]Patent: EP2952100,2015,A1

9
[ 80194-68-9 ]
[ 1421951-50-9 ]

Reference： [1]Patent: WO2013/18928,2013,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: EP2952097,2015,A1
[4]Patent: US2015/359219,2015,A1
[5]Patent: EP2952100,2015,A1

10
[ 80194-68-9 ]
[ 1421949-97-4 ]

Reference： [1]Patent: WO2013/18928,2013,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: EP2952097,2015,A1
[4]Patent: US2015/359219,2015,A1
[5]Patent: EP2952100,2015,A1

11
[ 80194-68-9 ]
[ 1421949-98-5 ]

Reference： [1]Patent: WO2013/18928,2013,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: EP2952097,2015,A1
[4]Patent: US2015/359219,2015,A1
[5]Patent: EP2955179,2015,A1
[6]Patent: EP2952100,2015,A1

12
[ 80194-68-9 ]
N<SUP>2</SUP>-methyl-5-(trifluoromethyl)pyridine-2,3-diamine [ No CAS ]
[ 1421952-81-9 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;	Production Example 4(1) A mixture of N2-methyl-5-trifluoromethylpyridin-2 , 3- diamine (0.70 g) , 3-chloro-5-trifluoromethylpyridin-2- carboxylic acid (0.53 g) , WSC (0.82 g) , HOBt (42 mg) and pyridine (4.5 ml) was stirred at 60C for 4 hours. To the cooled reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give an intermediate compound (M20-3).
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;	0621) A mixture of N2-methyl-5-trifluoromethylpyridine-2,3-diamine 0.70 g, <strong>[80194-68-9]3-chloro-5-trifluoromethylpyridine-2-carboxylic acid</strong> 0.53 g, EDC hydrochloride 0.82 g, HOBt 42 mg, and pyridine 4.5 mL was stirred at 60C for 4 hr. To the reaction mixture allowed to cool was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give Intermediate compound (M20-3). Intermediate compound (M20-3)
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;	Production example 4 (1)[0661] A mixture of N2-methyl-5-trifluoromethylpyridine-2,3-diamine 0.70 g, 3-chloro-5-trifluoromethylpyridine-2-carboxylicacid 0.53 g, EDC hydrochloride 0.82 g, HOBt 42 mg, and pyridine 4.5 mL was stirred at 60C for 4 hr. To thereaction mixture allowed to cool was added water, and the resulting mixture was extracted with ethyl acetate. The organiclayer was washed with water, and dried over anhydrous magnesium sulfate, and then concentrated under reducedpressure to give Intermediate compound (M20-3).

	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;	A mixture of N2-methyl-5-trifluoromethylpyridine-2,3-diamine 0.70 g, <strong>[80194-68-9]3-chloro-5-trifluoromethylpyridine-2-carboxylic acid</strong> 0.53 g, EDC hydrochloride 0.82 g, HOBt 42 mg, and pyridine 4.5 mL was stirred at 60 C. for 4 hr. To the reaction mixture allowed to cool was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give Intermediate compound (M20-3).
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;	[0420] A mixture of 0.70 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine (synthesized by a method described inWO2010-125985), 0.53 g of <strong>[80194-68-9]3-chloro-5-trifluoromethylpyridine-2-carboxylic acid</strong>, 0. 82 g of EDCI hydrochloride, 42 mgof HOBt and 4.5 ml of pyridine was stirred at 60C for 4 hours. Water was added to the cooled reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washed with water, and then dried over anhydrousmagnesium sulfate and concentrated under reduced pressure to obtain 3-chloro-N-(2-methylamino-5-trifluoromethylpyridin-3-yl)-5-trifluoromethyl picolinamide. 3-Chloro-N-(2-methylamino-5-trifluoromethylpyridin-3-yl)-5-trifluoromethyl picolinamide
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;	A mixture of N2-methyl-5-trifluoromethylpyridine-2,3-diamine 0.70 g, <strong>[80194-68-9]3-chloro-5-trifluoromethylpyridine-2-carboxylic acid</strong> 0.53 g, EDC hydrochloride 0.82 g, HOBt 42 mg, and pyridine 4.5 mL was stirred at 60C for 4 hr. To the reaction mixture allowed to cool was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give Intermediate compound (M20-3). Intermediate compound (M20-3).
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;	Production example 4 (1) (0649) A mixture of N2-methyl-5-trifluoromethylpyridine-2,3-diamine 0.70 g, <strong>[80194-68-9]3-chloro-5-trifluoromethylpyridine-2-carboxylic acid</strong> 0.53 g, EDC hydrochloride 0.82 g, HOBt 42 mg, and pyridine 4.5 mL was stirred at 60C for 4 hr. To the reaction mixture allowed to cool was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give Intermediate compound (M20-3).

Reference： [1]Patent: WO2013/18928,2013,A1 .Location in patent: Paragraph 0317
[2]Patent: EP2952099,2015,A1 .Location in patent: Paragraph 0621
[3]Patent: EP2952097,2015,A1 .Location in patent: Paragraph 0661; 0662
[4]Patent: US2015/359219,2015,A1 .Location in patent: Paragraph 1040
[5]Patent: EP2955179,2015,A1 .Location in patent: Page/Page column 0420
[6]Patent: EP2952098,2015,A1 .Location in patent: Paragraph 0617
[7]Patent: EP2952100,2015,A1 .Location in patent: Paragraph 0649; 0650

13
[ 80194-68-9 ]
[ 89571-66-4 ]
C₁₅H₈ClF₆NOS [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;	[ 0325] Production Example 10(1) A mixture of 3-amino-5-trifluoromethylpyridin-2-thiol (0.45 g) , <strong>[80194-68-9]3-chloro-5-trifluoromethylpyridin-2-carboxylic acid</strong> (0.55 g) , WSC (0.67 g) , HOBt (31 mg) and pyridine (4.5 ml) was stirred at 60C for 4 hours. To the cooled reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give intermediate compound (M20-9) .

Reference： [1]Patent: WO2013/18928,2013,A1 .Location in patent: Paragraph 0325

14
[ 80194-68-9 ]
[ 1383840-72-9 ]
[ 1421952-92-2 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 5h;	Production Example 17(1) A mixture of N2-methyl-5-pentafluoroethyl-pyridin-2 , 3- diamine (590 mg) , 3-chloro-5-trifluoromethyl-pyridin-2- carboxylic acid (560 mg) , WSC (520 mg) , HOBt (35 mg) , and pyridine (5 ml) was stirred at room temperature for 5 hours To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give intermediate compound (M20-17) .
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 5h;	Production example 17(1) (0664) A mixture of N2-methyl-5-pentafluoroethyl-pyridine-2,3-diamine 590 mg, 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid 560 mg, EDC hydrochloride 520 mg, HOBt 35 mg, pyridine 5 mL was stirred at RT for 5 hr. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure to give Intermediate compound (M20-17). Intermediate compound (M20-17) (0665)
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 5h;	Production example 17(1)[0705] A mixture of N2-methyl-5-pentafluoroethyl-pyridine-2,3-diamine 590 mg, 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid 560 mg, EDC hydrochloride 520 mg, HOBt 35 mg, pyridine 5 mL was stirred at RT for 5 hr. To the reactionmixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried oversodium sulfate, and then concentrated under reduced pressure to give Intermediate compound (M20-17).Intermediate compound (M20-17

	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 5h;	A mixture of N2-methyl-5-pentafluoroethyl-pyridine-2,3-diamine 590 mg, 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid 560 mg, EDC hydrochloride 520 mg, HOBt 35 mg, pyridine 5 mL was stirred at RT for 5 hr. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure to give Intermediate compound (M20-17).
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 5h;	A mixture of N2-methyl-5-pentafluoroethyl-pyridine-2,3-diamine 590 mg, 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid 560 mg, EDC hydrochloride 520 mg, HOBt 35 mg, pyridine 5 mL was stirred at RT for 5 hr. To the reactionmixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried oversodium sulfate, and then concentrated under reduced pressure to give Intermediate compound (M20-17).
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 5h;	Production example 17(1) (0691) A mixture of N2-methyl-5-pentafluoroethyl-pyridine-2,3-diamine 590 mg, 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid 560 mg, EDC hydrochloride 520 mg, HOBt 35 mg, pyridine 5 mL was stirred at RT for 5 hr. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure to give Intermediate compound (M20-17). Intermediate compound (M20-17)

Reference： [1]Patent: WO2013/18928,2013,A1 .Location in patent: Paragraph 0336
[2]Patent: EP2952099,2015,A1 .Location in patent: Paragraph 0664; 0665
[3]Patent: EP2952097,2015,A1 .Location in patent: Paragraph 0705; 0706
[4]Patent: US2015/359219,2015,A1 .Location in patent: Paragraph 1104
[5]Patent: EP2952098,2015,A1 .Location in patent: Paragraph 0660; 0661
[6]Patent: EP2952100,2015,A1 .Location in patent: Paragraph 0691; 0692

15
[ 80194-68-9 ]
[ 1383840-72-9 ]
[ 1421951-58-7 ]

Reference： [1]Patent: WO2013/18928,2013,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: EP2952097,2015,A1
[4]Patent: US2015/359219,2015,A1
[5]Patent: EP2952100,2015,A1

16
[ 80194-68-9 ]
[ 1425841-72-0 ]
3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((R)-5,5-difluoro-2-[(4-methoxy-phenyl)-(3-methoxy-phenyl)-phenyl-methyl]-amino}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29.2%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 18h;Inert atmosphere;	c) 3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((R)-5,5-difluoro-2-[(4- methoxy-phenyl)-(3-methoxy-phenyl)-phenyl-methyl]-amino}-4-methyl-5,6-dihydro-4H- [1 ,3]oxazin-4-yl)-5-fluoro-pyridin-2-yl]-amide [(R)-4-(6-amino-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1 ,3]oxazin-2-yl]-[bis- (4-methoxy-phenyl)-phenyl-methyl]-amine (250 mg, 0.444 mmol), 3-chloro-5-(trifluoromethyl)- picolinic acid (120 mg, 0.533 mmol) and HOAt (109 mg, 0.800 mmol) were dissolved in DMF (4.44 ml) under argon. EDCxHCI (128 mg, 0.667 mmol) was added and the reaction mixture was stirred at rt for 18 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude product was chromatographed over silica gel (Redisep column 12 g, cyclohexane/ethyl acetate) to give the title compound: 100 mg (29.2 % yield). LC-MS: RtH2 = 1.43 min; (96 % purity; ESI+-MS: m/z 770 [(M+H)+,1 CI]; 772); 1H-NMR (400 MHz, DMSO-d6): delta 1 1.22 (s, 1 H), 9.08 (s, 1 H), 8.72 (s, 1 H), 8.16 (dd, 1 H), 7.71 (dd, 1 H), 7.30 - 7.24 (m, 2 H), 7.23 - 7.10 (m, 7 H), 6.81 - 6.74 (m, 5 H), 4.33-4.23 (m, 1 H), 4.08-4.00 (m, 1 H), 3.70 (s, 6 H), 1.06 (br. s, 3 H).

Reference： [1]Patent: WO2013/27188,2013,A1 .Location in patent: Page/Page column 70; 71; 72

17
[ 80194-68-9 ]
[ 1425841-84-4 ]
[ 1425841-87-7 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h;	d) ((R)-4-{6-[(3-Chloro-5-trifluoromethyl-pyridine-2-carbonyl)-amino]-3-fluoro-pyridin-2-yl}- 5,5-difluoro-4-methyl-5,6-dihydro-4H-[1 ,3]oxazin-2-yl)-carbamic acid tert-butyl ester To a solution of [(R)-4-(6-amino-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H- [1 ,3]oxazin-2-yl]-carbamic acid tert-butyl ester (134 mg, 0.372 mmol) in DMF (1.3 ml) was added 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid (101 mg, 0.446 mmol) and HOAt (91 mg, 0.669 mmol). The mixture was cooled to 0 C, EDC*HCI (107 mg, 0.558) was added and the mixture stirred for 1 h while allowing to warm to rt. To the reaction mixture was added TBME and water, the layers were separated and the aq. layer extracted with TBME. The combined organic layers were washed with sat. aq. NaHC03, sat. aq. NaCI, dried with MgS04 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane / EtOAc 6:1 to 5: 1 ) to provide the title compound as colorless solid. HPLC: RtH7= 2.920 min; ESIMS [M+H]+ = 568.0/570,0; 1H-NMR (600 MHz, DMSO-c/6): delta 1 1.25 (s, 1 H), 9.65 (s, 1 H), 9.08 (br. s, 1 H), 8.72 (br. s, 1 H), 8.23 (d, 1 H), 7.83 (t, 1 H), 4.57 - 4.41 (m, 2H), 1.72 (s, 3H), 1.40 (s, 9H).

Reference： [1]Patent: WO2013/27188,2013,A1 .Location in patent: Page/Page column 70; 74

18
[ 80194-68-9 ]
(2'R,4S,4a'R₉a'S)-7'-isopropyl-1',2',3',4',4a',9a'-hexahydro-5H-spiro[1,3-oxazole-4,9'-xanthene]-2,2'-diamine [ No CAS ]
N,N'-((4S,4a'R,9a'S)-7'-isopropyl-1',2',3',4',4a',9a'-hexahydro-5H-spiro[1,3-oxazole-4,9'-xanthene]-2,2'-diyl)bis(3-chloro-5-(trifluoromethyl)picolinamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
200 mg	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 20℃;Inert atmosphere;	[00232] Step C: EDCI (184 mg, 0.96 mmol), HOBT (130 mg, 0.96 mmol) and DIPEA (206 mg, 1.6 mmol) were added at 0C to a mixture of (45',4a'^,9a,5)-7'-isopropyl- l',2',3',4',4a',9a'-hexahydro-5H-spiro[oxazole-4,9'-xanthene]-2,2,-diamine (100 mg, 0.32 mmol) and <strong>[80194-68-9]3-chloro-5-(trifluoromethyl)picolinic acid</strong> (136 mg, 0.79 mmol) in DCM (8 mL). The mixture was stirred at room temperature overnight. Saturated NaHC03 was added, and the mixture was extracted with EtOAc. The organic layer was concentrated to give N,iV- ((45,4a'i?,9a*S)-7'-isopropyl-l',2,,3',4,,4a,,9a,-hexahydro-5H-spiro[oxazole-4,9,-xanthene]-2,2'- diyl)bis(3-chloro-5-(trifluoromethyl)picolinamide) (200 mg crude).

Reference： [1]Patent: WO2013/148851,2013,A1 .Location in patent: Paragraph 00232

19
[ 80194-68-9 ]
(2'R,4S,4a'R₉a'S)-7'-isopropyl-1',2',3',4',4a',9a'-hexahydro-5H-spiro[1,3-oxazole-4,9'-xanthene]-2,2'-diamine [ No CAS ]
N-((2'R,4S,4a'R,9a'S)-2-amino-7'-isopropyl-1',2',3',4',4a',9a'-hexahydro-5H-spiro[1,3-oxazole-4,9'-xanthen]-2'-yl)-3-chloro-5-(trifluoromethyl)picolinamide [ No CAS ]
N-((2'R,4S,4a'R,9a'S)-2-amino-7'-isopropyl-1',2',3',4',4a',9a'-hexahydro-5H-spiro[1,3-oxazole-4,9'-xanthen]-2'-yl)-3-methoxy-5-(trifluoromethyl)picolinamide [ No CAS ]

Reference： [1]Patent: WO2013/148851,2013,A1

20
[ 80194-68-9 ]
2-amino-4-trifluoromethylthiophenol [ No CAS ]
[ 1616681-85-6 ]

Yield	Reaction Conditions	Operation in experiment
1.94 g	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃; for 1h;	Production Example 4(1)A mixture of 2-amino-4- (trifluoromethylsulfanyl)phenol (1.0 g), 3 -chloro-5-trifluoromethylpicolinic acid (1.08 g), EDCI hydrochloride (1.10 g) and chloroform (10 ml) was stirred at room temperature for one hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturatedaqueous sodium bicarbonate solution, water and a saturated brine, dried on anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3-chloro-5--- trifluoromethyl-N- [2-hydroxy-5-(trifluoromethylsulfanyl)phenyllpicolinamide (hereinafterreferred to as ?the intermediate compound M10-40?) (1.94 g)The intermediate compound M10-40:CIHIS N -F3C NLOHO?H-NMR(CDC13) 5: 8.78(1H,d), 8.15(1H,d), 8.09(1H,d),7.37(lH,dd), 7.04(1H,d).
1.94 g	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃; for 1h;	Production example 71 (1) A mixture of 2-amino-4-(trifluoromethylsulfanyl)phenol 1.0 g, 3-chloro-5-trifluoromethylpicolinic acid 1.08 g, EDC hydrochloride 1.10 g, and chloroform 10 mL was stirred at RT for 1 hr. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 3-chloro-5-trifluoromethyl-N-[2-hydroxy-5-(trifluoromethylsulfanyl)phenyl]picolinamide 1.94 g. 3-chloro-5-trifluoromethyl-N-[2-hydroxy-5-(trifluoromethylsulfanyl)phenyl]picolinamide 1H-NMR(CDCl3)delta: 8.78(1H, d), 8.15(1H, d), 8.09(1H, d), 7.37(1H, dd), 7.04(1H, d).
1.94 g	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃; for 1h;	Production example 71 (1) A mixture of 2-amino-4-(trifluoromethylsulfanyl)phenol 1.0 g, 3-chloro-5-trifluoromethylpicolinic acid 1.08 g, EDC hydrochloride 1.10 g, and chloroform 10 mL was stirred at RT for 1 hr. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 3-chloro-5-trifluoromethyl-N-[2-hydroxy-5-(trifluoromethylsulfanyl)phenyl]picolinamide 1.94 g. 1H-NMR(CDCl3)delta: 8.78(1H, d), 8.15(1H, d), 8.09(1H, d), 7.37(1H, dd), 7.04(1H, d).

1.94 g	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃; for 1h;	A mixture of 2-amino-4-(trifluoromethylsulfanyl)phenol 1.0 g, 3-chloro-5-trifluoromethylpicolinic acid 1.08 g, EDC hydrochloride 1.10 g, and chloroform 10 mL was stirred at RT for 1 hr. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 3-chloro-5-trifluoromethyl-N-[2-hydroxy-5-(trifluoromethylsulfanyl)phenyl]picolinamide 1.94 g. 3-chloro-5-trifluoromethyl-N-[2-hydroxy-5-(trifluoromethylsulfanyl)phenyl]picolinamide (1356) (1357) 1H-NMR (CDCl3) delta: 8.78 (1H, d), 8.15 (1H, d), 8.09 (1H, d), 7.37 (1H, dd), 7.04 (1H, d).
1.94 g	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃; for 1h;	A mixture of 2-amino-4-(trifluoromethylsulfanyl)phenol 1.0 g, 3-chloro-5-trifluoromethylpicolinic acid 1.08 g, EDC hydrochloride 1.10 g, and chloroform 10 mL was stirred at RT for 1 hr. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 3-chloro-5-trifluoromethyl-N-[2-hydroxy-5-(trifluoromethylsulfanyl)phenyl]picolinamide 1.94 g. 3-chloro-5-trifluoromethyl-N-[2-hydroxy-5-(trifluoromethylsulfanyl)phenyl]picolinamide 1H-NMR(CDCl3)delta: 8.78(1H, d), 8.15(1H, d), 8.09(1H, d), 7.37(1H, dd), 7.04(1H, d).
1.94 g	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In chloroform; at 20℃; for 1h;	Production example 71 (1) A mixture of 2-amino-4-(trifluoromethylsulfanyl)phenol 1.0 g, 3-chloro-5-trifluoromethylpicolinic acid 1.08 g, EDC hydrochloride 1.10 g, and chloroform 10 mL was stirred at RT for 1 hr. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water, and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 3-chloro-5-trifluoromethyl-N-[2-hydroxy-5-(trifluoromethylsulfanyl)phenyl]picolinamide 1.94 g. 3-chloro-5-trifluoromethyl-N-[2-hydroxy-5-(trifluoromethylsulfanyl)phenyl]picolinamide 1H-NMR(CDCl3)delta: 8.78(1H, d), 8.15(1H, d), 8.09(1H, d), 7.37(1H, dd), 7.04(1H, d).

Reference： [1]Patent: WO2014/104407,2014,A1 .Location in patent: Page/Page column 91
[2]Patent: EP2952099,2015,A1 .Location in patent: Paragraph 0831
[3]Patent: EP2952097,2015,A1 .Location in patent: Paragraph 0868; 0869
[4]Patent: US2015/359219,2015,A1 .Location in patent: Paragraph 1355-1357
[5]Patent: EP2952098,2015,A1 .Location in patent: Paragraph 0826; 0827
[6]Patent: EP2952100,2015,A1 .Location in patent: Paragraph 0863; 0864

21
[ 80194-68-9 ]
[ 1616679-35-6 ]

Reference： [1]Patent: WO2014/104407,2014,A1
[2]Patent: EP2952097,2015,A1
[3]Patent: US2015/359219,2015,A1
[4]Patent: EP2952100,2015,A1

22
[ 80194-68-9 ]
[ 1616678-38-6 ]

Reference： [1]Patent: WO2014/104407,2014,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: EP2952097,2015,A1
[4]Patent: US2015/359219,2015,A1
[5]Patent: EP2952100,2015,A1

23
[ 80194-68-9 ]
[ 1616678-39-7 ]

Reference： [1]Patent: WO2014/104407,2014,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: EP2952097,2015,A1
[4]Patent: US2015/359219,2015,A1
[5]Patent: EP2952098,2015,A1
[6]Patent: EP2952100,2015,A1

24
[ 80194-68-9 ]
[ 1616678-40-0 ]

Reference： [1]Patent: WO2014/104407,2014,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: EP2952097,2015,A1
[4]Patent: US2015/359219,2015,A1
[5]Patent: EP2952098,2015,A1
[6]Patent: EP2952100,2015,A1

25
[ 80194-68-9 ]
[ 1616678-41-1 ]

Reference： [1]Patent: WO2014/104407,2014,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: EP2952097,2015,A1
[4]Patent: US2015/359219,2015,A1
[5]Patent: EP2952098,2015,A1
[6]Patent: EP2952100,2015,A1

26
[ 80194-68-9 ]
[ 1616678-42-2 ]

Reference： [1]Patent: WO2014/104407,2014,A1
[2]Patent: EP2952099,2015,A1
[3]Patent: EP2952097,2015,A1
[4]Patent: US2015/359219,2015,A1
[5]Patent: EP2952098,2015,A1
[6]Patent: EP2952100,2015,A1

27
[ 80194-68-9 ]
[ 1624603-50-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 44 Synthesis of N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-3-chloro-5-(trifluoromethyl)picolinamide The title compound was synthesized by procedures and steps analogous to those described in Method F, Example 32 above, but using <strong>[80194-68-9]3-chloro-5-(trifluoromethyl)-2-pyridine carboxylic acid</strong> (Bionet Research). MS m/z=516.8 [M+H]+. Calculated for C19H13ClF8N4O2: 516.06 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 2.23 (t, J=13.23 Hz, 1H) 2.75 (dd, J=13.67, 2.56 Hz, 1H) 4.14-4.28 (m, 1H) 4.38-4.83 (m, 2H) 7.15 (dd, J=11.55, 8.92 Hz, 1H) 7.48 (dd, J=6.87, 2.78 Hz, 1H) 8.08-8.20 (m, 2H) 8.79 (d, J=1.02 Hz, 1H) 9.82 (s, 1H).

Reference： [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column

28
[ 80194-68-9 ]
[ 338758-69-3 ]

Yield	Reaction Conditions	Operation in experiment
		Synthesis of 3-chloro-5-(trifluoromethyl)picolinamide The title compound was synthesized according to Method AA starting from <strong>[80194-68-9]3-chloro-5-(trifluoromethyl)picolinic acid</strong> (Ark Pharm). MS m/z=224.9 [M+H]+. Calculated for C7H4ClF3N2O: 224

Reference： [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column
[2]Patent: CN110526863,2019,A

29
[ 80194-68-9 ]
[ 1624603-83-3 ]

Reference： [1]Patent: US2014/249104,2014,A1

30
[ 80194-68-9 ]
[ 1624604-86-9 ]

Yield	Reaction Conditions	Operation in experiment
		Example 187 N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4,5-difluorophenyl)-3-chloro-5-(trifluoromethyl)picolinamide The title compound was synthesized by procedures and steps analogous to those described in Method Z, Example 186 above, but using <strong>[80194-68-9]3-chloro-5-(trifluoromethyl)-2-pyridine carboxylic acid</strong> (Bionet Research). MS m/z=517.1 [M+H]+. Calculated for C19H13ClF8N4O2: 516.77 1H NMR (300 MHz, CHLOROFORM-d) delta=9.82 (br. s., 1H), 8.77 (s, 1H), 8.22-8.08 (m, 2H), 7.10-7.00 (m, 1H), 4.37 (br. s., 2H), 4.04 (dd, J=5.3, 9.7 Hz, 1H), 2.86-2.70 (m, 1H), 1.91 (t, J=13.2 Hz, 1H), 1.64 (s, 3H)

Reference： [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column

31
[ 80194-68-9 ]
[ 74784-70-6 ]
3-chloro-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.35 g	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 2h;	Production Example 1 (1) [0694] A mixture of 0.81 g of 2-amino-5-trifluoromethylpyridine, 1.13 g of 3-chloro-5-trifluoromethylpicolinic acid, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at 60C for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 1.35 g of 3-chloro-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl )picolinamide. 3-Chloro-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl )picolinamide 1H-NMR (CDCl3) delta: 10.51 (1H, brs), 8.83 (1H, brs), 8.64 (1H, brs), 8.56 (1H, d), 8.17 (1H, d), 8.02 (1H, dd)

Reference： [1]Patent: EP2881386,2015,A1 .Location in patent: Paragraph 0694

32
[ 80194-68-9 ]
3-ethylsulfonyl-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide [ No CAS ]
3-ethylsulfinyl-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide [ No CAS ]

Reference： [1]Patent: EP2881386,2015,A1

33
[ 80194-68-9 ]
3-ethylsulfanyl-5-trifluoromethyl-N-(5-trifluoromethylpyridin-2-yl)picolinamide [ No CAS ]

Reference： [1]Patent: EP2881386,2015,A1

34
[ 80194-68-9 ]
[ 1421950-91-5 ]

Reference： [1]Patent: EP2952099,2015,A1
[2]Patent: EP2952097,2015,A1
[3]Patent: US2015/359219,2015,A1
[4]Patent: EP2952100,2015,A1

35
[ 80194-68-9 ]
[ 1421950-92-6 ]

Reference： [1]Patent: EP2952099,2015,A1
[2]Patent: EP2952097,2015,A1
[3]Patent: US2015/359219,2015,A1
[4]Patent: EP2952100,2015,A1

36
[ 80194-68-9 ]
[ 1421951-01-0 ]

Reference： [1]Patent: EP2952099,2015,A1
[2]Patent: EP2952097,2015,A1
[3]Patent: US2015/359219,2015,A1
[4]Patent: EP2952098,2015,A1
[5]Patent: EP2952100,2015,A1

37
[ 80194-68-9 ]
[ 89571-66-4 ]
[ 1421951-54-3 ]

Reference： [1]Patent: EP2952099,2015,A1
[2]Patent: EP2952097,2015,A1
[3]Patent: US2015/359219,2015,A1
[4]Patent: EP2952098,2015,A1
[5]Patent: EP2952100,2015,A1

38
[ 80194-68-9 ]
[ 89571-66-4 ]
2-(3-chloro-5-trifluoromethylpyridin-2-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In 1-methyl-pyrrolidin-2-one; at 60℃; for 4h;	Production example 10 (1) (0638) A mixture of 3-amino-5-trifluoromethylpyridine-2-thiol 0.45 g, <strong>[80194-68-9]3-chloro-5-trifluoromethylpyridine-2-carboxylic acid</strong> 0.55 g, EDC hydrochloride 0.67 g, HOBt 31 mg, and pyridine 4.5 mL was stirred at 60C for 4 hr. The reaction mixture was allowed to cool, and to the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give Intermediate compound (M20-9). Intermediate compound (M20-9)
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;	Production example 10 (1)[0680] A mixture of 3-amino-5-trifluoromethylpyridine-2-thiol 0.45 g, <strong>[80194-68-9]3-chloro-5-trifluoromethylpyridine-2-carboxylic acid</strong>0.55 g, EDC hydrochloride 0.67 g, HOBt 31 mg, and pyridine 4.5 mL was stirred at 60C for 4 hr. The reaction mixturewas allowed to cool, and to the reaction mixture was added water, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, and then concentratedunder reduced pressure to give Intermediate compound (M20-9).
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;	A mixture of 3-amino-5-trifluoromethylpyridine-2-thiol 0.45 g, <strong>[80194-68-9]3-chloro-5-trifluoromethylpyridine-2-carboxylic acid</strong> 0.55 g, EDC hydrochloride 0.67 g, HOBt 31 mg, and pyridine 4.5 mL was stirred at 60 C. for 4 hr. The reaction mixture was allowed to cool, and to the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give Intermediate compound (M20-9).

	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;	A mixture of 3-amino-5-trifluoromethylpyridine-2-thiol 0.45 g, <strong>[80194-68-9]3-chloro-5-trifluoromethylpyridine-2-carboxylic acid</strong>0.55 g, EDC hydrochloride 0.67 g, HOBt 31 mg, and pyridine 4.5 mL was stirred at 60C for 4 hr. The reaction mixturewas allowed to cool, and to the reaction mixture was added water, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, and then concentratedunder reduced pressure to give Intermediate compound (M20-9).
	With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 60℃; for 4h;	Production example 10 (1) (0667) A mixture of 3-amino-5-trifluoromethylpyridine-2-thiol 0.45 g, <strong>[80194-68-9]3-chloro-5-trifluoromethylpyridine-2-carboxylic acid</strong> 0.55 g, EDC hydrochloride 0.67 g, HOBt 31 mg, and pyridine 4.5 mL was stirred at 60C for 4 hr. The reaction mixture was allowed to cool, and to the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give Intermediate compound (M20-9).

Reference： [1]Patent: EP2952099,2015,A1 .Location in patent: Paragraph 0638; 0639
[2]Patent: EP2952097,2015,A1 .Location in patent: Paragraph 0680; 0681
[3]Patent: US2015/359219,2015,A1 .Location in patent: Paragraph 1069
[4]Patent: EP2952098,2015,A1 .Location in patent: Paragraph 0634; 0635
[5]Patent: EP2952100,2015,A1 .Location in patent: Paragraph 0667; 0668

39
[ 80194-68-9 ]
methyl 3-ethylsulfonyl-5-(trifluoromethyl)pyridine-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/116338,2016,A1

40
[ 80194-68-9 ]
methyl 3-ethylsulfonyl-1-oxido-5-(trifluoromethyl)pyridin-1-ium-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/116338,2016,A1

41
[ 80194-68-9 ]
methyl 6-chloro-3-ethylsulfonyl-5-(trifluoromethyl)pyridine-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/116338,2016,A1

42
[ 80194-68-9 ]
methyl 3-ethylsulfonyl-5-(trifluoromethyl)-6-[4-(trifl uoromethyl)phenyl]pyridine-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/116338,2016,A1

43
[ 80194-68-9 ]
3-ethylsulfonyl-5-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]pyridine-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2016/116338,2016,A1

44
[ 80194-68-9 ]
3-ethylsulfonyl-N-[5-(methylamino)-2-(trifluoromethyl)-4-pyridyl]-5-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]pyridine-2-carboxamide [ No CAS ]
N-[4-amino-6-(trifluoromethyl)-3-pyridyl]-3-ethylsulfonyl-N-methyl-5-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]pyrid ine-2-carboxamide [ No CAS ]

Reference： [1]Patent: WO2016/116338,2016,A1

45
[ 80194-68-9 ]
2-[3-ethylsulfonyl-5-(trifluoromethyl)-6-[4-(trifluoromethyl)phenyl]-2-pyridyl]-3-methyl-6-(trifluoromethyl)imidazo[4,5-c]pyridine [ No CAS ]

Reference： [1]Patent: WO2016/116338,2016,A1

46
[ 80194-68-9 ]
[ 811-51-8 ]
methyl 3-ethylsulfanyl-5-(trifluoromethyl)pyridine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 20℃;	A solution of methyl <strong>[80194-68-9]3-chloro-5-(trifluoromethyl)pyridine-2-carboxylate</strong> (30 g, 125 mmol, GAS Registry Number [655235-65-7]) was dissolved in DMF (630 mL), Sodium ethanethiolate (12.87 g, 138 mmol) was added in portions keeping the temperature below 20 CC. The reaction mixture was allowed to stirovernight after which LCMS analysis showed reaction completion. The mixture was diluted with water, extracted with AcOEt (3 times), and the combined organic phases washed successively with saturated aqueous NH4CI and brine, dried over Mg504 and concentrated in vacuo. The crude title compoundwas used for the next step without further purification.LCMS (method 1); Rt= 0.96mm, [M+H] 266. 1H NMR (400 MHz, CHLOROFORM-d)o ppm: 1.43 (t,J=7.5 Hz, 3 H); 3.00 (q, J=7.5 Hz, 2 H); 4.04 (s, 3 H); 7.87 (d, J=1 .1 Hz, 1 H); 8.66 (d, J1 .1 Hz, 1 H)

Reference： [1]Patent: WO2016/116338,2016,A1 .Location in patent: Page/Page column 71; 72

47
[ 80194-68-9 ]
N<SUP>3</SUP>-methyl-6-(trifluoromethyl)pyridine-3,4-diamine [ No CAS ]
2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 115℃; for 7h;	Preparation of 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridine (IX-01) 950 mg (4.97 mmol) of N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (II-01), 1.12 g (4.97 mmol) of <strong>[80194-68-9]3-chloro-5-(trifluoromethyl)pyridine-2-carboxylic acid</strong> and 953 mg (4.97 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) are stirred in 10 ml of pyridine at 115 C. for 7 h. The reaction mixture is freed of solvent under reduced pressure, then water is added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate, concentrated again and purified by column chromatography purification by means of preparative HPLC with a water/acetonitrile gradient as eluent. (log P (neutral): 2.96; MH+: 381; 1H NMR (400 MHz, D6-DMSO) delta ppm: 4.00 (s, 3H), 8.35 (s, 1H), 8.86 (s, 1H), 9.22 (s, 1H), 9.30 (s, 1H).

Reference： [1]Patent: US2017/73342,2017,A1 .Location in patent: Paragraph 0518-0520

48
[ 80194-68-9 ]
N<SUP>3</SUP>-methyl-6-(trifluoromethyl)pyridine-3,4-diamine [ No CAS ]
3-chloro-N-[5-(methylamino)-2-(trifluoromethyl)pyridin-4-yl]-5-(trifluoromethyl)pyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 115℃; for 7h;	General procedure: Preparation of 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridine (IX-01) 950 mg (4.97 mmol) of N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (II-01), 1.12 g (4.97 mmol) of <strong>[80194-68-9]3-chloro-5-(trifluoromethyl)pyridine-2-carboxylic acid</strong> and 953 mg (4.97 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) are stirred in 10 ml of pyridine at 115 C. for 7 h. The reaction mixture is freed of solvent under reduced pressure, then water is added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried over sodium sulphate, concentrated again and purified by column chromatography purification by means of preparative HPLC with a water/acetonitrile gradient as eluent. (log P (neutral): 2.96; MH+: 381; 1H NMR (400 MHz, D6-DMSO) delta ppm: 4.00 (s, 3H), 8.35 (s, 1H), 8.86 (s, 1H), 9.22 (s, 1H), 9.30 (s, 1H). By the above method for preparation of 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-3-methyl-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridine (IX-01) from N3-methyl-6-(trifluoromethyl)pyridine-3,4-diamine (II-01) and <strong>[80194-68-9]3-chloro-5-(trifluoromethyl)pyridine-2-carboxylic acid</strong>, it is likewise possible to prepare the compound 3-chloro-N-[5-(methylamino)-2-(trifluoromethyl)pyridin-4-yl]-5-(trifluoromethyl)pyridine-2-carboxamide (VIII-01) as an intermediate for the compound (IX-01). (0522) (log P (neutral): 3.09; MH+: 399; 1H NMR (400 MHz, D6-DMSO) delta ppm: 2.87 (d, 3H), 5.97 (q, 1H), 8.10 (s, 1H), 8.18 (s, 1H), 8.73 (s, 1H), 9.09 (s, 1H), 10.40 (br. S, 1H).

Reference： [1]Patent: US2017/73342,2017,A1 .Location in patent: Paragraph 0521-0522

49
[ 80194-68-9 ]
3-methyl-2-[3-(methylsulphinyl)-5-(trifluoromethyl)pyridin-2-yl]-6-(trifluoro-methyl)-3H-imidazo[4,5-c]pyridine [ No CAS ]

Reference： [1]Patent: US2017/73342,2017,A1

50
[ 80194-68-9 ]
3-methyl-2-[3-(methylsulphonyl)-5-(trifluoromethyl)pyridin-2-yl]-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridine [ No CAS ]

Reference： [1]Patent: US2017/73342,2017,A1

51
[ 80194-68-9 ]
3-methyl-2-[3-(methylsulphanyl)-5-(trifluoromethyl)pyridin-2-yl]-6-(trifluoromethyl)-3H-imidazo[4,5-c]pyridine [ No CAS ]

Reference： [1]Patent: US2017/73342,2017,A1

52
[ 80194-68-9 ]
N-(3-((3aS,4R,8R)-6-amino-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-4-yl)-4-fluorophenyl)-3-chloro-5-(trifluoromethyl)picolinamide [ No CAS ]

Reference： [1]Patent: WO2017/25491,2017,A1

53
[ 80194-68-9 ]
tert-butyl ((3aS,4R,8R)-4-(5-(3-chloro-5-(trifluoromethyl)picolinamido)-2-fluorophenyl)-4,7,7-trimethyl-8-oxido-3,3a,4,7-tetrahydro-2H-isothiazolo[1,5-a][1,4]thiazin-6-yl)carbamate [ No CAS ]

Reference： [1]Patent: WO2017/25491,2017,A1

54
[ 80194-68-9 ]
[ 38330-80-2 ]
C₁₀H₇ClF₃NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29 g		To a mixture of 30 g of 3-chloro-5- (trifluoromethyl) pyridine-2-carboxylic acid and 130 mL of toluene, 25 mL of thionyl chloride and 1.6 mL of DMF were added successively at room temperature. The reaction mixture was stirred at 110 C. for 5 hours. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to obtain an oily substance.32 g of potassium methyl malonate was added to a mixture of 22 g of anhydrous magnesium chloride and 270 mL of THF at room temperature. The reaction mixture was stirred at 50 C. for 1 hour. To the reaction mixture, the whole amount of the oily substance obtained in the above Production Example 28 (1) and 65 mL of triethylamine were successively added under ice cooling. The reaction mixture was warmed to room temperature and stirred at room temperature for 12 hours. 400 mL of 2 N hydrochloric acid was added to the obtained reaction mixture under ice cooling, and the mixture was stirred at room temperature for 2 hours. The resulting reaction mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried with anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was subjected to silica gel chromatography to obtain 29 g of an intermediate (28-2)

Reference： [1]Patent: JP2017/36339,2017,A .Location in patent: Paragraph 0211; 0212

55
[ 80194-68-9 ]
C₁₀H₇ClF₃NO₃ [ No CAS ]

Reference： [1]Patent: US2017/305896,2017,A1

56
ethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-cyanoacetate [ No CAS ]
[ 80194-68-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With dihydrogen peroxide; sodium hydroxide; In water; at 30℃; for 1h;	EMBODIMENT 6: Preparation of 3-chloro-5-(trifluoromethyl)picolinic acid. To a 500 mL three-necked flask equipped with a thermometer was added 29.5 g ethyl 2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-2-cyanoacetate, 15 g sodium hydroxide and 200 g water. The mixture was stirred and heated to 30 C. 30 g hydrogen peroxide (30%) was added dropwise. The reacting was continued for 1 hour. After the reaction was complete, the mixture was cooled down, acidified with hydrochloric acid, filtered by vacuum suction, washed with water, dried to produce 22.5 g 3-chloro-5-(trifluoromethyl)picolinic acid as a solid in 99% yield. 1H-NMR deltappm(CDCl3):14.40(br, 1H), 9.01(s, 1H), 8.65(s, 1H).

Reference： [1]Patent: US2017/369412,2017,A1 .Location in patent: Paragraph 0036

57
[ 80194-68-9 ]
[ 1387561-59-2 ]
((2R,5R)-5-{6-[(3-chloro-5-trifluoromethylpyridine-2-carbonyl)amino]-3-fluoropyridin-2-yl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
5.2 g	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 48h;	A mixture of [(2R, 5R)-5-(6-amino-3-fluoro-pyridin-2-yl)-2 ,5-dimethyl-2-trifluoromethyl-5 6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (3.3 g, 8.12 mmol), 3-chloro-5-trifluoromethylpicolinic acid (2.2 g, 9.74 mmol), HOAt (1.99 g, 14.62 mmol) and EDC hydrochloride (2.33 g, 12.18 mmol) was stirred in DMF (81 ml) at rt for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude product (12 g) was chromatographedover silicagel (cyclohexane to cyclohexane:ethyl acetate 1:1) to yield 5.2 g of the titlecompound.TLC (silica, cyclohexane:ethyl acetate 3:1): Rf0.47; HPLC: RtH3 = 1.40 mm; ESIMS: 615,616 [(M+H), id]; 1H-NMR (400 MHz, CDCI3): 11.68 (5, 1H), 10.41 (5, 1H), 8.81 (dd, J1.82,0.69 Hz, 1 H), 8.45 (dd, J8.91, 3.14 Hz, 1 H), 8.19 (dd, J1.88, 0.63 Hz, 1 H), 7.59 (dd,J=9.79, 9.16Hz, 1 H), 4.38 (d, J2.13 Hz, 1 H), 4.18 (d, J11.80 Hz, 1 H), 1.75 (5, 3H), 1.62 (5, 3H), 1.60 (5, 9H).
5.2 g	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 48h;	A mixture of [(2R, 5R)-5-(6-amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6- dihydro-2H-[1 ,4]oxazin-3-yl]-carbamic acid tert-butyl ester (3.3 g, 8.12 mmol), 3-chloro-5- trifluoromethylpicolinic acid (2.2 g, 9.74 mmol), HOAt (1.99 g, 14.62 mmol) and EDC hydrochloride (2.33 g, 12.18 mmol) was stirred in DMF (81 ml) at rt for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude product (12 g) was chromatographed over silicagel (cyclohexane to cyclohexane:ethyl acetate 1 : 1) to yield 5.2 g of the title compound. (0364) TLC (silica, cyclohexane:ethyl acetate 3: 1): Rf=0.47; HPLC: RtH3 = 1.40 min; ESIMS: 615, 616 [(M+H)+, 1 CI]; H-NMR (400 MHz, CDCI3): 11.68 (s, 1 H), 10.41 (s, 1 H), 8.81 (dd, J=1.82, 0.69 Hz, 1 H), 8.45 (dd, J=8.91 , 3.14 Hz, 1 H), 8.19 (dd, J=1.88, 0.63 Hz, 1 H), 7.59 (dd, J=9.79, 9.16 (0365) Hz, 1 H), 4.38 (d, J=2.13 Hz, 1 H), 4.18 (d, J=11.80 Hz, 1 H), 1.75 (s, 3H), 1.62 (s, 3H), 1.60 (s, 9H).
5.2 g	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 48h;	A mixture of [(2R, 5f?)-5-(6-amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6- dihydro-2H-[1 ,4]oxazin-3-yl]-carbamic acid tert-butyl ester (3.3 g, 8.12 mmol), 3-chloro-5- trifluoromethylpicolinic acid (2.2 g, 9.74 mmol), HOAt (1 .99 g, 14.62 mmol) and EDC hydrochloride (2.33 g, 12.18 mmol) was stirred in DMF (81 ml) at rt for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude product (12 g) was chromatographed over silicagel (cyclohexane to cyclohexane: ethyl acetate 1 : 1) to yield 5.2 g of the title compound. TLC (silica, cyclohexane: ethyl acetate 3: 1 ): Rf=0.47; HPLC: RtH3 = 1 .40 min; ESIMS: 615, 616 [(M+H)+, 1 CI]; H-NMR (400 MHz, CDCI3): 1 1.68 (s, 1 H), 10.41 (s, 1 H), 8.81 (dd, J=1 .82, 0.69 Hz, 1 H), 8.45 (dd, J=8.91 , 3.14 Hz, 1 H), 8.19 (dd, J=1 .88, 0.63 Hz, 1 H), 7.59 (dd, J=9.79, 9.16 Hz, 1 H), 4.38 (d, J=2.13 Hz, 1 H), 4.18 (d, J=1 1.80 Hz, 1 H), 1 .75 (s, 3H), 1 .62 (s, 3H), 1 .60 (s, 9H).

5.2 g

With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; for 48h;

A mixture of [(2 R, 5R)-5-(6-amino-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6- dihydro-2H-[1 ,4]oxazin-3-yl]-carbamic acid tert-butyl ester (3.3 g, 8.12 mmol), 3-chloro-5- trifluoromethylpicolinic acid (2.2 g, 9.74 mmol), HOAt (1.99 g, 14.62 mmol) and EDC hydrochloride (2.33 g, 12.18 mmol) was stirred in DMF (81 ml) at rt for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulfate, filtered and evaporated. The crude product (12 g) was chromatographed over silicagel (cyclohexane to cyclohexane: ethyl acetate 1 : 1) to yield 5.2 g of the title compound. TLC (silica, cyclohexane:ethyl acetate 3: 1): Rf=0.47; HPLC: RtH3 = 1.40 min; ESIMS: 615, 616 [(M+H)+, 1 Cl]; 1H-NMR (400 MHz, CDCI3): 11.68 (s, 1 H), 10.41 (s, 1 H), 8.81 (dd, J=1.82, 0.69 Hz, 1 H), 8.45 (dd, J=8.91 , 3.14 Hz, 1 H), 8.19 (dd, J=1.88, 0.63 Hz, 1 H), 7.59 (dd, J= 9.79, 9.16 Hz, 1 H), 4.38 (d, J=2.13 Hz, 1 H), 4.18 (d, J=1 1.80 Hz, 1 H), 1.75 (s, 3H), 1.62 (s, 3H), 1.60 (s, 9H).

Reference： [1]Patent: WO2018/15868,2018,A1 .Location in patent: Page/Page column 39
[2]Patent: WO2018/69843,2018,A1 .Location in patent: Page/Page column 36
[3]Patent: WO2018/134760,2018,A1 .Location in patent: Page/Page column 38; 45
[4]Patent: WO2019/142111,2019,A1 .Location in patent: Page/Page column 26; 33

58
[ 80194-68-9 ]
[ 613-94-5 ]
2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-phenyl-1,3,4-oxadiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate; for 10h;Heating;	step 3: Add 0.30 g of 3-chloro-5-(trifluoromethyl)pyridinecarboxylic acid to a three-necked flask.0.18g benzoyl hydrazide, 3ml phosphorus oxychloride, heated and stirred,After 10 hours of reaction, pour the liquid into a beaker containing ice water.Add Na2CO3 to adjust pH = 9-10, suction filtration, drying, and column chromatography to obtain the target compound.

Reference： [1]RSC Advances,2018,vol. 8,p. 6306 - 6314
[2]Patent: CN108218848,2018,A .Location in patent: Paragraph 0157; 0158; 0161

59
[ 80194-68-9 ]
C₈H₉ClN₂O [ No CAS ]
2-(3-chloro-4-methylphenyl)-5-(3-chloro-5-(trifluoromethyl)-pyridin-2-yl)-1,3,4-oxadiazole [ No CAS ]

Reference： [1]RSC Advances,2018,vol. 8,p. 6306 - 6314

60
[ 80194-68-9 ]
[ 85304-05-8 ]
2-(5-chloro-2-methylphenyl)-5-(3-chloro-5-(trifluoromethyl)-pyridin-2-yl)-1,3,4-oxadiazole [ No CAS ]

Reference： [1]RSC Advances,2018,vol. 8,p. 6306 - 6314

61
[ 80194-68-9 ]
[ 13050-47-0 ]
2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-(m-tolyl)-1,3,4-oxadiazole [ No CAS ]

Reference： [1]RSC Advances,2018,vol. 8,p. 6306 - 6314

62
[ 80194-68-9 ]
[ 62899-78-9 ]
2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-(3,5-dichlorophenyl)-1,3,4-oxadiazole [ No CAS ]

Reference： [1]RSC Advances,2018,vol. 8,p. 6306 - 6314

63
[ 80194-68-9 ]
[ 64328-55-8 ]
2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-(4-ethylphenyl)-1,3,4-oxadiazole [ No CAS ]

Reference： [1]RSC Advances,2018,vol. 8,p. 6306 - 6314

64
[ 80194-68-9 ]
[ 85304-03-6 ]
2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-(2,4-dimethylphenyl)-1,3,4-oxadiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trichlorophosphate; for 10h;Heating;	The third step: adding 0.25 g of 3-chloro-5-(trifluoromethyl)pyridinecarboxylic acid, 0.18 g of 2,4-dimethylbenzohydrazide, and 3 ml of phosphorus oxychloride to a three-necked flask, and heating and stirring for 10 hours. After pouring the liquid into a beaker containing ice water, adding Na2CO3 to adjust the pH = 9-10, suction filtration, drying, column chromatography to obtain the target compound.

Reference： [1]RSC Advances,2018,vol. 8,p. 6306 - 6314
[2]Patent: CN108218848,2018,A .Location in patent: Paragraph 0162; 0163; 0166

65
[ 80194-68-9 ]
[ 29418-67-5 ]
2-(2-bromophenyl)-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazole [ No CAS ]

Reference： [1]RSC Advances,2018,vol. 8,p. 6306 - 6314

66
[ 80194-68-9 ]
[ 131634-71-4 ]
2-(5-bromo-2-chlorophenyl)-5-(3-chloro-5-(trifluoromethyl)-pyridin-2-yl)-1,3,4-oxadiazole [ No CAS ]

Reference： [1]RSC Advances,2018,vol. 8,p. 6306 - 6314

67
[ 80194-68-9 ]
[ 39115-95-2 ]
2-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-(4-iodophenyl)-1,3,4-oxadiazole [ No CAS ]

Reference： [1]RSC Advances,2018,vol. 8,p. 6306 - 6314

68
[ 80194-68-9 ]
[ 5933-32-4 ]
2-(4-bromophenyl)-5-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazole [ No CAS ]

Reference： [1]RSC Advances,2018,vol. 8,p. 6306 - 6314

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Precautionary Statements-General
Code	Phrase
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Prevention
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Response
Code	Phrase
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P321
P322
P330	Rinse mouth.
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P332	IF SKIN irritation occurs:
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P337	If eye irritation persists:
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P342	If experiencing respiratory symptoms:
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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
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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.
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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.
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P370 + P378	In case of fire:
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Storage
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P401
P402	Store in a dry place.
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Disposal
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Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
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H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
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H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
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Health hazards
Code	Phrase
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H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
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H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
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H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
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H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
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H341	Suspected of causing genetic defects
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H351	Suspected of causing cancer
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H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere