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[ CAS No. 135900-33-3 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 135900-33-3

Chemical Structure| 135900-33-3

Chemical Structure| 135900-33-3

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Quality Control of [ 135900-33-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 135900-33-3 ]

Product Details of [ 135900-33-3 ]

CAS No. :	135900-33-3	MDL No. :	MFCD07374879
Formula :	C₆H₅F₃N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HYBWXJYCVPLEPI-UHFFFAOYSA-N
M.W :	178.11	Pubchem ID :	45790047
Synonyms :

Calculated chemistry of [ 135900-33-3 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	35.32
TPSA :	48.14 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) :	-6.19 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.23
Log Po/w (XLOGP3) :	1.69
Log Po/w (WLOGP) :	2.83
Log Po/w (MLOGP) :	0.45
Log Po/w (SILICOS-IT) :	1.22
Consensus Log Po/w :	1.48

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.25
Solubility :	1.01 mg/ml ; 0.00566 mol/l
Class :	Soluble
Log S (Ali) :	-2.32
Solubility :	0.861 mg/ml ; 0.00483 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.29
Solubility :	0.911 mg/ml ; 0.00512 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.93

Safety of [ 135900-33-3 ]

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

Application In Synthesis of [ 135900-33-3 ]

* 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 [ 135900-33-3 ]
Downstream synthetic route of [ 135900-33-3 ]

[ 135900-33-3 ] Synthesis Path-Upstream 1~5

1
[ 1221172-05-9 ]
[ 135900-33-3 ]

Yield	Reaction Conditions	Operation in experiment
89.4%	With palladium 10% on activated carbon; ammonium formate In methanol at 55℃; for 16 h;	[00537] A mixture of 81(2.00 g, 9.43 mmols, 1.0 eq), Pd/C (10percent, 1.0 g), HCOONH4 (1.2 g, 18.9 mmols, 2.0 eq.) in MeOH (20 mL) was heated to 55 °C for 16 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated. The residue was partitioned between ethyl acetate (100 mL) and NaOH (4percent in water, 30 mL). The organic layer were washed with brine, dried over Na2SO4, filtered, and concentrated to afford the desired product 82 (1.50 g, 8.38 mmols, 89.4percent) as a yellow oil.
85%	With ammonium formate In methanol at 55℃; for 16 h;	3-Amino-6-trifluoromethoxypyridine (52); At 25 ⁰C, palladium (10percent on charcoal, 700 mg) was added with stirring to a solution of 3-amino-2-chloro-6-trifluoromethoxypyridine (51, 1.3 g, 6.1 mmol, 1 eq) and ammonium formate (770 mg, 12.1 mmol, 2 eq) in methanol (20 mL). The reaction mixture was stirred for 16 h at 55 ⁰C before being filtrated under suction and the filtrate evaporated. The residue was partitioned between ethyl acetate (2^χ 30 mL) and an aqueous solution of sodium hydroxide (4percent, 30 mL). The combined organic layers were dried over sodium sulfate before being evaporated to afford pure 3-amino-6- trifluoromethoxypyridine (52, 920 mg, 5.2 mmol, 85percent) as colorless crystals; m.p. 31-33⁰C.¹H NMR (CDCl₃, 300 MHz): δ = 7.66 (d, J= 2.9 Hz, 1 H), 6.97 (dd, J= 8.6, 2.9 Hz, 1 H), 6.76 (d, J = 8.6, 1 H), 3.55 (bs, 2 H). - ¹⁹F NMR (CDCl₃, 282 MHz): δ = -57.7 - ¹³C NMR (CDCl₃, 75 MHz): δ = 148.8, 141.6, 133.9, 125.8, 120.3 (q, J = 257 Hz), 114.3. - C₆H₅F₃N₂O (178): calcd. (percent) C 40.46, H 2.83, N 15.73; found C 40.00, H 2.92, N 15.37.

Reference： [1] Patent: WO2016/144792, 2016, A1, . Location in patent: Paragraph 00537
[2] Patent: WO2010/40461, 2010, A1, . Location in patent: Page/Page column 49
[3] European Journal of Organic Chemistry, 2010, # 31, p. 6043 - 6066

2
[ 1221171-70-5 ]
[ 135900-33-3 ]

Reference： [1] Patent: WO2016/144792, 2016, A1,

3
[ 1221172-02-6 ]
[ 135900-33-3 ]

Reference： [1] Patent: WO2016/144792, 2016, A1,

4
[ 1221172-06-0 ]
[ 135900-33-3 ]

Reference： [1] Patent: WO2016/144792, 2016, A1,

5
[ 1221172-07-1 ]
[ 135900-33-3 ]

Reference： [1] Patent: WO2016/144792, 2016, A1,

[ 135900-33-3 ] Synthesis Path-Downstream 1~20

1
[ 75-77-4 ]
[ 135900-33-3 ]
3-bis(trimethylsilyl)amino-6-trifluoromethoxypyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%		3-2?is(trimethylsUyl)amino-6-trifluoromethoxypyridine (53); At -78 0C, butyllithium (1.56 M, 7.2 mL, 11.2 mmol, 2 eq) was added dropwise to a solution of <strong>[135900-33-3]3-amino-6-trifluoromethoxypyridine</strong> (52, 1.0 g, 5.6 mmol) in THF (12 mL) followed after 1 min by chlorotrimethylsilane (1.4 mL, 11.2 mmol, 2 eq). The reaction mixture was allowed to reach 25 0C for 2 h before being filtrated onto a pad of celite.The solvent was removed and the crude oil was distilled under vacuum (101-103 0C / 1 mbar) to afford pure 3-6zs(trimethylsilyl)amino-6-trifluoromethoxypyridine (53, 1.5 g, 4.6 mmol, 83%) as a colorless oil.1H NMR (CDCl3, 300 MHz): delta = 7.80 (d, J= 2.7 Hz, 1 H), 7.21 (dd, J= 8.5, 2.7 Hz, 1 H), 6.81 (d, J = 8.5, 1 H), 0.00 (s, 18 H). - 13C NMR (CDCl3, 75 MHz): delta = 150.7,146.3, 141.5, 139.1, 118.3 (q, J= 260 Hz), 110.8, 0.02.

Reference： [1]Patent: WO2010/40461,2010,A1 .Location in patent: Page/Page column 50

2
[ 1221172-05-9 ]
[ 135900-33-3 ]

Yield	Reaction Conditions	Operation in experiment
89.4%	With palladium 10% on activated carbon; ammonium formate; In methanol; at 55℃; for 16h;	[00537] A mixture of 81(2.00 g, 9.43 mmols, 1.0 eq), Pd/C (10%, 1.0 g), HCOONH4 (1.2 g, 18.9 mmols, 2.0 eq.) in MeOH (20 mL) was heated to 55 C for 16 hours. The reaction mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated. The residue was partitioned between ethyl acetate (100 mL) and NaOH (4% in water, 30 mL). The organic layer were washed with brine, dried over Na2SO4, filtered, and concentrated to afford the desired product 82 (1.50 g, 8.38 mmols, 89.4%) as a yellow oil.
85%	With ammonium formate;palladium 10% on activated carbon; In methanol; at 55℃; for 16h;	3-Amino-6-trifluoromethoxypyridine (52); At 25 0C, palladium (10% on charcoal, 700 mg) was added with stirring to a solution of 3-amino-2-chloro-6-trifluoromethoxypyridine (51, 1.3 g, 6.1 mmol, 1 eq) and ammonium formate (770 mg, 12.1 mmol, 2 eq) in methanol (20 mL). The reaction mixture was stirred for 16 h at 55 0C before being filtrated under suction and the filtrate evaporated. The residue was partitioned between ethyl acetate (2chi 30 mL) and an aqueous solution of sodium hydroxide (4%, 30 mL). The combined organic layers were dried over sodium sulfate before being evaporated to afford pure 3-amino-6- trifluoromethoxypyridine (52, 920 mg, 5.2 mmol, 85%) as colorless crystals; m.p. 31-330C.1H NMR (CDCl3, 300 MHz): delta = 7.66 (d, J= 2.9 Hz, 1 H), 6.97 (dd, J= 8.6, 2.9 Hz, 1 H), 6.76 (d, J = 8.6, 1 H), 3.55 (bs, 2 H). - 19F NMR (CDCl3, 282 MHz): delta = -57.7 - 13C NMR (CDCl3, 75 MHz): delta = 148.8, 141.6, 133.9, 125.8, 120.3 (q, J = 257 Hz), 114.3. - C6H5F3N2O (178): calcd. (%) C 40.46, H 2.83, N 15.73; found C 40.00, H 2.92, N 15.37.

Reference： [1]Patent: WO2016/144792,2016,A1 .Location in patent: Paragraph 00537
[2]Patent: WO2010/40461,2010,A1 .Location in patent: Page/Page column 49
[3]European Journal of Organic Chemistry,2010,p. 6043 - 6066

3
[ 16885-99-7 ]
[ 79-37-8 ]
[ 135900-33-3 ]
2-(1-isopropyl-1H-indol-3-yl)-2-oxo-N-(6-(trifluoromethyl)-pyridin-3-yl)acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 9309 - 9333

4
[ 79-37-8 ]
[ 1158209-64-3 ]
[ 135900-33-3 ]
2-(1-(2-methoxyethyl)-1H-indol-3-yl)-2-oxo-N-(6-(trifluoromethyl)pyridin-3-yl)acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 9309 - 9333

5
[ 1221171-70-5 ]
[ 135900-33-3 ]

Reference： [1]Patent: WO2016/144792,2016,A1

6
[ 1221172-02-6 ]
[ 135900-33-3 ]

Reference： [1]Patent: WO2016/144792,2016,A1

7
[ 1221172-06-0 ]
[ 135900-33-3 ]

Reference： [1]Patent: WO2016/144792,2016,A1

8
[ 1221172-07-1 ]
[ 135900-33-3 ]

Reference： [1]Patent: WO2016/144792,2016,A1

9
[ 135900-33-3 ]
7-bromo-6-fluoroquinoline [ No CAS ]
[ 13939-06-5 ]
6-fluoro-N-(6-(trifluoromethoxy)pyridin-3-yl)quinoline-7-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16%	With palladium diacetate; sodium carbonate; tri tert-butylphosphoniumtetrafluoroborate; In acetonitrile; at 90℃; for 2.16667h;Inert atmosphere;	[0294] A stirred solution of 7-bromo-6-fluoroquinoline Int-6 (Example 123) (100 mg, 0.442 mmol), <strong>[135900-33-3]6-(trifluoromethoxy)pyridin-3-amine</strong> (157 mg, 0.884 mmol, 2.0 eq) and Na2CC>3 (112 mg, 0.884 mmol) in dry acetonitrile (2 mL) was degassed with Argon gas in a microwave vessel for 15 min. Then Mo(CO)6 (117 mg, 0.442 mmol, 1.0 eq), T3u3PHBF4 (15.3 mg, 0.05 mmol 0.12 eq) and Pd(OAc)2 (10 mg, 0.044 mmol, 0.1 eq) were added to this mixture, and degassing was continued for additional 10 min. The reaction mixture was irradiated in microwave at 90 C for 2 hrs. The progress of the reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography using 50% EtOAc in petroleum ether as eluent to give 25 mg (16% yield) of the desired compound 129 as a pale-yellow solid. 99.2 % HPLC purity at 215 nm. 1H NMR (400 MHz, CDC13): delta 9.03- 9.02 (dd, J = 4.0 Hz, 1.6 Hz, 1H), 8.97-8.99 (d, J = 7.6 Hz, 1H), 8.59 (s, 1H), 8.55 (s, 1H), 8.47-8.49 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 8.45-8.46 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 7.61-7.64 (d, J = 12.8 Hz, 1H), 7.56-7.52 (dd, J = 8.4 Hz, 4.0 Hz, 1H), 7.12-7.10 (d, J = 8.0 Hz, 1H). 99.7% purity by LCMS; MS (ESI) m/z =352.14 [M+H]+.

Reference： [1]Patent: WO2018/85348,2018,A1 .Location in patent: Paragraph 0294

10
[ 135900-33-3 ]
6-chloroquinoline-7-carboxylic acid [ No CAS ]
6-chloro-N-(6-(trifluoromethoxy)pyridin-3-yl)quinoline-7-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;	[0293] Compound Int-5 (Example 122) (90 mg, 0.43 mmol, 1.0 eq) and 6- (trifluoromethoxy)pyridin-3-amine (84 mg, 0.47 mmol, 1.1 eq) were dissolved in DMF (3 mL), and the resulting mixture was cooled down to 0 C. Then HATU (181 mg, 0.47 mmol, 1.1 eq) and DIPEA (0.16 mL, 0.868 mmol, 2.0 eq) were added to the reaction mixture at 0 C. The reaction mixture was allowed to warm up to room temperature, and stirred at room temperature for 3 hrs. The progress of the reaction was monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water. The formed solid was filtered, washed and dried in vacuo to give 40 mg of the desired compound 128 as an off-white solid in 25% yield. 1H NMR (400 MHz, DMSO-de): delta 11.12 (s, 1H), 9.03-9.02 (dd, J = 4.4 Hz, 2.0 Hz, 1H), 8.68-8.69 (d, J = 2.4 Hz, 1H), 8.46-8.44 (d, J = 7.6 Hz, 1H), 8.39-8.36 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 8.30-8.31 (m, 2H), 7.70- 7.67 (dd, J = 8.4 Hz, 4.0 Hz, 1H), 7.39-7.37 (d, J = 8.8 Hz, 1H). 99.45% purity by LCMS; m/z =368.11 [M+H]+.

Reference： [1]Patent: WO2018/85348,2018,A1 .Location in patent: Paragraph 0293

11
[ 135900-33-3 ]
6-methylquinoline-7-carboxylic acid [ No CAS ]
6-methyl-N-(6-(trifluoromethoxy)pyridin-3-yl)quinoline-7-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 4h;	[0292] Compound Int-8 (100 mg, 0.53 mmol, 1.0 eq) and 6-(trifluoromethoxy)pyridin- 3-amine (190 mg, 1.06 mmol, 2.0 eq) were dissolved in DMF (3.0 mL) and the reaction mixture was cooled down to 0 C. HATU (221 mg, 0.58 mmol, 1.1 eq) and DIPEA (136 mg, 1.06 mmol, 2.0 eq) were added to the reaction mixture at 0 C. The reaction mixture was allowed to warm up to room temperature, and stirred at room temperature for 4 hrs. The progress of the reaction was monitored by LCMS and TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water. The formed solid was filtered, washed and dried under vacuum to give 40 mg of the desired compound 127 as a pale-yellow solid in 21% yield. 97.88% purity as determined by HPLC at 215 nm. 1H NMR (400 MHz, DMSO-d6): delta 10.97 (s, 1H), 8.94 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.40 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 7.60 (dd, J = 8.4 Hz, 4.4 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 2.57 (s, 3H). ESI m/z =348.27 [M+H]+.

Reference： [1]Patent: WO2018/85348,2018,A1 .Location in patent: Paragraph 0292

12
[ 135900-33-3 ]
8-chloroquinoline-7-carboxylic acid [ No CAS ]
8-chloro-N-(6-(trifluoromethoxy)pyridin-3-yl)quinoline-7-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%		0383] To a solution of 8-chloroquinoline-7-carboxylic acid Int-56 (Example 166) (0.139 g, 0.674 mmol) in DMF (5 mL) was added DIPEA (0.49 mL 2.808 mmol), followed by HATU (0.42 g, 1.123 mmol) at 0 C, and the reaction mixture was stirred at 0 C for 15 min. Then 6- (trifluoromethoxy)pyridin-3 -amine (0.1 g, 0.561 mmol) was added to reaction mixture at 0 C. The reaction mixture was stirred at r.t. for 16 hrs. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with Ethyl Acetate (2x50 mL). Combined organic layers were washed with water (2x30 mL), brine (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resultant crude product was purified by column chromatography (100-200 silica gel) using 50% Ethyl Acetate in Hexane as eluent to afford 50 mg (24% yield) of 8-chloro-N-(6-(trifluoromethoxy)pyridin-3-yl)quinoline-7-carboxamide 169 as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): delta 11.08 (s, 1H), 9.12 (dd, J = 4.4, 1.6 Hz, 1H), 8.68 (d, J = 2.4 Hz, 1H), 8.55 (J = 8.4, 1.6 Hz, 1H), 8.37 (dd, J = 8.8, 2.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.75 (dd, J= 8.4, 4.0 Hz, 1H), 7.38 (d, J= 8.8 Hz, 1H); MS (ESI) m/z 368.24 [M+H]+.

Reference： [1]Patent: WO2018/85348,2018,A1 .Location in patent: Paragraph 0383

13
[ 1078-30-4 ]
[ 135900-33-3 ]
N-(6-(trifluoromethoxy)pyridin-3-yl)quinoline-7-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 4h;	[0289] Quinoline-7-carboxylic acid (70 mg, 0.404 mmol, 1.0 eq) and 6- (trifluoromethoxy)-pyridin-3-amine (79 mg, 0.44 mmol, 1.1 eq) were dissolved in 1 mL of DMF and the resulting mixture was cooled down to 0 C. HATU (168 mg, 0.44 mmol, 1.1 eq) and DIPEA (0.144 mL, 0.808 mmol, 2.0 eq) were added at 0 C, and then the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 4 hrs. The progress of the reaction was monitored by LCMS and TLC. Upon completion, the reaction mixture was poured into ice-cold water. The formed solid was filtered, washed and dried in vacuo to give 20 mg of the desired compound 126 as a pale-yellow solid in 15% yield. 1H NMR (400 MHz, CDC13): delta 9.03-9.02 (dd, J = 2.8 Hz, 1.6 Hz, 1H), 8.57 (s, 1H), 8.48 (s, 1H), 8.46-8.45 (d, J = 2.8 Hz, 1H), 8.26 (s, 1H), 8.24 (brs, 1H), 8.09-8.12 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 8.0-7.97 (d, J = 8.8 Hz, 1H), 7.56-7.52 (dd, J = 8.4 Hz, 4.4 Hz, 1H), 7.12-7.10 (d, J = 8.8 Hz, 1H). 99.15% purity by LCMS; m/z =334.19 [M+H]+.

Reference： [1]Patent: WO2018/85348,2018,A1 .Location in patent: Paragraph 0289

14
[ 135900-33-3 ]
4-[2-(4-chloro-3-fluorophenoxy)acetamido]bicyclo[2.2.2]octane-1-carboxylic acid [ No CAS ]
4-[2-(4-chloro-3-fluorophenoxy)acetamido]-N-[6-(trifluoromethoxy)pyridin-3-yl]bicyclo[2.2.2]octane-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; ((3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V); In N,N-dimethyl-formamide; at 20℃; for 0.5h;	General procedure: N,N-Dimethylformamide (2 mL), triethylamine (0.079 mL, 0.57 mmol) and 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-]pyridinium 3-oxid hexafluorophosphate (79 mg, 0.208 mmol, HATU) were added to a mixture of the product of Example 18A (59.4 mg, 0.189 mmol) and (5-(difluoromethoxy)pyridin-2-yl)methanamine (Enamine, 33 mg, 0.189 mmol) in sequential order. The reaction mixture was then stirred at ambient temperature for 30 minutes. The resulting solution was filtered through a glass microfiber frit and purified by preparative HPLC [YMC TriArt CI 8 Hybrid 5 mupiiota column, 50 x 100 mm, flow rate 90 mL/minute, 5-100% gradient of acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to give the title compound (56 mg, 0.119 mmol, 63% yield). JH NMR (501 MHz, DMSO-de) delta ppm 8.73 (s, 1H), 8.44 (t, J = 6.1 Hz, 1H), 8.40 (d, J = 2.8 Hz, 1H), 7.64 (dd, J = 8.6, 2.9 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.29 (dd, J = 8.6, 0.7 Hz, 1H), 7.27 (t, J = 73.5 Hz, 1H), 7.08 (dd, J = 11.4, 2.9 Hz, 1H), 6.86 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4.47 (s, 2H), 4.33 (d, J = 6.1 Hz, 2H), 2.22 (s, 6H); MS (ESI+) m/z 470 (M+H)+.

Reference： [1]Patent: WO2019/90074,2019,A1 .Location in patent: Page/Page column 176; 219

15
[ 135900-33-3 ]
4-((tert-butoxycarbonyl)amino)-2-oxabicyclo [2.2.2] octane-1-carboxylic acid [ No CAS ]
tert-butyl (1-((6-(trifluoromethoxy)pyridin-3-yl)carbamoyl)-2-oxabicyclo[2.2.2]octan-4-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; for 3h;	A mixture of Example 235C (0.095 g, 0.350 mmol), PyBOP ((1H- benzo[(i] [l ,2,3]triazol-l-yl)oxy)tri(pyrrolidin-l-yl)phosphonium hexafluorophosphate(V)) (0.219 g, 0.420 mmol), <strong>[135900-33-3]6-(trifluoromethoxy)pyridin-3-amine</strong> (0.075 g, 0.420 mmol), and triethylamine (0.073 mL, 0.525 mmol) in N,N-dimethylformamide (DMF) (3 mL) was stirred for 3 hours. The reaction mixture was quenched with brine and saturated NaHC(, and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over (1679) MgSO/t, filtered, and concentrated. The residue was purified on a 12 g column using the Biotage Isolera One flash system eluted with heptanes/ethyl acetate (7:3 to 6:4) to provide the title compound (65.1 mg, 43%). MS (ESI+) nt/z 432.3 (M+H)+.

Reference： [1]Patent: WO2019/90074,2019,A1 .Location in patent: Page/Page column 246; 247

16
[ 135900-33-3 ]
2,4-dibromo-6-(trifluoromethoxy)pyridin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With bromine; acetic acid; In ethanol; at 0 - 20℃; for 15h;	A solution of Br2 (0.25 mL, 4.87 mmol) in HO Ac (3 mL) was added dropwise to a stirring solution of <strong>[135900-33-3]6-(trifluoromethoxy)pyridin-3-amine</strong> (400 mg, 2.25 mmol) in EtOH (15 mL) and HO Ac (1.5 mL) at 0C under a nitrogen atmosphere. After addition was complete, the reaction was warmed to room temperature and was allowed to stir for an additional 15 hours. The reaction mixture was concentrated. DCM (30 mL) and saturated aqueous NaHC03 (20 mL) were added to the crude residue. The aqueous layer was extracted with DCM (50 mL x 3). The combined organic layers were dried over Na2S04, filtered and concentrated. The crude residue was purified by column chromatography (0-10% EtOAc in petroleum ether) to give 2,4- dibromo-<strong>[135900-33-3]6-(trifluoromethoxy)pyridin-3-amine</strong> (670 mg, yield: 89%) as light yellow solid. 1H NMR (400 MHz, CDCl3): d = 7.18 (s, 1H), 4.59 (s, 2H).

Reference： [1]Patent: WO2020/18970,2020,A1 .Location in patent: Paragraph 0400

17
[ 135900-33-3 ]
2,4-di(prop-1-en-2-yl)-6-(trifluoromethoxy)pyridin-3-amine [ No CAS ]

Reference： [1]Patent: WO2020/18970,2020,A1

18
[ 135900-33-3 ]
2,4-diisopropyl-6-(trifluoromethoxy)pyridin-3-amine [ No CAS ]

Reference： [1]Patent: WO2020/18970,2020,A1

19
[ 135900-33-3 ]
3-isocyanato-2,4-diisopropyl-6-(trifluoromethoxy)pyridine [ No CAS ]

Reference： [1]Patent: WO2020/18970,2020,A1

20
[ 135900-33-3 ]
N-((2,4-diisopropyl-6-(trifluoromethoxy)pyridin-3-yl)carbamoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide [ No CAS ]

Reference： [1]Patent: WO2020/18970,2020,A1

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