[ CAS No. 358780-14-0 ] {[proInfo.proName]}

Name: 358780-14-0|1-(6-(Trifluoromethyl)pyridin-3-yl)ethanone|97%
Brand: Ambeed
SKU: A161402
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Quality Control of [ 358780-14-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 358780-14-0 ]

SDS Specification

Alternatived Products of [ 358780-14-0 ]

Product Details of [ 358780-14-0 ]

CAS No. :	358780-14-0	MDL No. :	MFCD07375085
Formula :	C₈H₆F₃NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NAUKVLRFGMDIAN-UHFFFAOYSA-N
M.W :	189.13	Pubchem ID :	21880578
Synonyms :

Calculated chemistry of [ 358780-14-0 ] Expand+

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	39.43
TPSA :	29.96 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.42 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.55
Log Po/w (XLOGP3) :	1.46
Log Po/w (WLOGP) :	3.46
Log Po/w (MLOGP) :	1.2
Log Po/w (SILICOS-IT) :	2.68
Consensus Log Po/w :	2.07

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.14
Solubility :	1.36 mg/ml ; 0.00721 mol/l
Class :	Soluble
Log S (Ali) :	-1.7
Solubility :	3.81 mg/ml ; 0.0202 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.25
Solubility :	0.107 mg/ml ; 0.000564 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.54

Safety of [ 358780-14-0 ]

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

Application In Synthesis of [ 358780-14-0 ]

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

Upstream synthesis route of [ 358780-14-0 ]
Downstream synthetic route of [ 358780-14-0 ]

[ 358780-14-0 ] Synthesis Path-Upstream 1~16

1
[ 416852-53-4 ]
[ 75-16-1 ]
[ 358780-14-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	at 0℃; for 1 h;	B) 1-(6-(trifluoromethyl)pyridin-3-yl)ethanoneN-Methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (19.1 g, 81.6 mmol) was dissolved in tetrahydrofuran (410 mL). The system was purged with N₂and then cooled to 0° C. 1.4 M of methylmagnesium bromide in toluene/THF (75:25) (87.4 mL, 122.4 mmol) was added dropwise using an additional funnel. At the end of the addition the mixture was cloudy off-white. The mixture was stirred at 0° C. for 1 hour and carefully quenched by dropwise addition of 1 M aq. HCl (150 mL) and diluted with ethyl ether (300 mL) and EtOAc (100 mL). The organic layer was separated and washed with 0.1 M aq. NaOH (200 mL) and brine (2.x.50 mL), dried (Na₂SO₄), and concentrated to yield a light yellow solid (15.04 g, 98percent).LC-MS: 190.2 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃): δ 9.25 (d, 1H, J=1.6 Hz), 8.42 (dd, 1H, J=8.0, 1.6 Hz), 7.82 (d, 1H, J=8.0 Hz), 2.70 (s, 3H).
98%	Stage #1: at 0℃; Inert atmosphere Stage #2: With hydrogenchloride In tetrahydrofuran; water; toluene Stage #3: With sodium hydroxide In tetrahydrofuran; diethyl ether; water; ethyl acetate; toluene	B) 1 -(6-(trifluoromethyl)pyridin-3-yl)ethanone[00283] N-Methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (19.1 g, 81.6 mmol) was dissolved in tetrahydrofuran (410 mL). The system was purged with N₂ and then cooled to 0 ⁰C. 1.4 M of methylmagnesium bromide in toluene/THF (75:25) (87.4 mL, 122.4 mmol) was added dropwise using an additional funnel. At the end of the addition the mixture was cloudy off- white. The mixture was stirred at 0 ⁰C for 1 hour and carefully quenched by dropwise addition of 1 M aq. HCl (150 mL) <n="50"/>and diluted with ethyl ether (300 mL) and EtOAc (100 mL). The organic layer was separated and washed with 0.1 M aq. NaOH (200 mL) and brine (2 x 50 mL), dried (Na₂SO₄), and concentrated to yield a light yellow solid (15.04 g, 98percent).MS: 190.2 [M+l]⁺;¹H NMR (CDCl₃): 9.25 (d, IH, J = 1.6 Hz), 8.42 (dd, IH, J = 8.0, 1.6 Hz), 7.82 (d, IH, J = 8.0 Hz),2.70 (s, 3H).
98%	for 16 h;	Dissolve N-methoxy-N-methyl-6-(trifluoromethyl)pyridine-3-carboxamide (0.685 g, 2.92 mmol) in THF (20 mL). Add methylmagnesium bromide (3.0 M in EtO₂, 1.950 mL, 5.850 mmol). Stir the mixture for 16 hours. Pour the reaction mixture into a saturated NaHCO₃ aqueous solution (20 mL). Extract with EtOAc (320 mL). Wash the combined organic extracts with water (30 mL) and saturated sodium chloride (230 mL). Dry the organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give the title compound (0.545 g, 98percent) as a light yellow solid. ¹H NMR (400.43 MHz, d₆-DMSO) δ 9.21-9.21 (m, 1H), 8.51-8.49 (m, 1H), 8.03 (d, J=8.2 Hz, 1H), 2.64 (s, 3H).

Reference： [1] Patent: US2008/275037, 2008, A1, . Location in patent: Page/Page column 25
[2] Patent: WO2008/123963, 2008, A1, . Location in patent: Page/Page column 48-49
[3] Patent: US2012/302608, 2012, A1, . Location in patent: Page/Page column 12

2
[ 97674-02-7 ]
[ 436799-32-5 ]
[ 358780-14-0 ]

Yield	Reaction Conditions	Operation in experiment
59.25%	With PdCl₂(PPh₃)2 In toluene at 120℃; for 3 h; Inert atmosphere	Step-2: Synthesis of 1-(6-(trifluoromethyl)pyridin-3-yl)ethanone To a stirred solution of 5-bromo-2-(trifluoromethyl)pyridine (0.07 g, 0.31 mmol) in dry toluene (10 mL), Int-B (0.124 g, 0.34 mmol) was added. Purged reaction mass with nitrogen for 30 min. To resultant reaction mass Dikis (0.01 g, 0.015 mmol) was added and stirred at 120° C. for 3 h. Completion of reaction was monitored by TLC. On completion, quenched with ice water, extracted with ether. The organic layer was washed with water, brine, dried over sodium sulphate, concentrated under reduced pressure obtained crude. Purification of the crude was done via silica gel (100-200 Mesh) column chromatography and desired compound eluted at 15percent ethyl acetate/n-Hexane to obtained 1-(6-(trifluoromethyl)pyridin-3-yl)ethanone (0.035 g, 59.25percent) as off white solid. Mass: 190.08 [M⁺+1]
56%	Stage #1: With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate In water; N,N-dimethyl-formamide at 110℃; for 1.5 h; Inert atmosphere Stage #2: With potassium fluoride In diethyl ether; water; N,N-dimethyl-formamide for 1 h; Inert atmosphere Stage #3: With hydrogenchloride In tetrahydrofuran; water at 20℃; for 0.666667 h;	5-Bromo-2-(trif[uoromethy[)pyridine (10.0 g, 44.3 mmo[), water (40 mL), DMF (120mL), potassium carbonate (12.2 g, 88.5 mmo[),bis(tripheny[phosphine)pa[[adium(II) dich[oride (621 mg, 2 mo[ percent) and tributy[(1ethoxyetheny[)stannane (19.2 g, 53.1 mmo[) were stirred and heated to 110 °Cunder nitrogen for 1.5 h. The reaction mixture was coo[ed down, di[uted withdiethy[ ether (120 mL) and KF (12.8 g in 50 mL of water) was added. The resu[ting reaction mixture was vigorous[y stirred for 1 h before being fi[tered through Ce[ite®. The organic [ayer was then washed with saturated aqueous NaHCO3 fo[[owed by brine and was then dried over MgSO4, fi[tered and concentrated underreduced pressure. The residue was taken up in THF (200 mL) and 2M HC[ (60 mL) and the reaction was stirred at ambient temperature for 40 minutes. The organics were removed under reduced pressure and the aqueous [ayer was extracted with DCM (3 x 50 mL). The organic [ayers were combined, dried over MgSO4, fi[tered and concentrated under reduced pressure. The crude materia[ was purified by BiotageIso[era chromatography (si[ica ge[, e[uting with heptane-EtOAc, 1:0 to 10:1) toafford 4.90 g (56percent yie[d) as a white crysta[[ine so[id.1H NMR (250 MHz, Ch[oroform-d): 6 [ppm] 9.25 (d, J = 1.3 Hz, 1H), 8.41 (dd, J8.2, 1.6 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 2.70 (5, 3H).LCMS (Ana[ytica[ Method A) Rt = 1.15 mm, MS (ESipos): m/z = 190.0 (M+H).

Reference： [1] Patent: US2017/291894, 2017, A1, . Location in patent: Paragraph 0448-0450
[2] Patent: WO2016/91776, 2016, A1, . Location in patent: Page/Page column 379; 380

3
[ 917-64-6 ]
[ 416852-53-4 ]
[ 358780-14-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	at 0℃; for 2 h;	[00376] N-Methoxy-N-methyl-6-(trifluoromethyl)nicotinamide ( 12 g, 51 mmol) in dry THF ( 500 mL) was cooled to 0 °C and kept for 10 min. To this cooled solution methylmagnesium iodide (18.8 mL, 3M solution in THF) was added and stirred at the same temperature for 2 h. The reaction mixture was then quenched with the addition of saturated NH₄C1 solution and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine. The organic phase was dried using Na₂SO₄ and evaporated to give l-(6-(trifluoromethyl)pyridin-3-yl)ethan-l- one as a pale yellow solid (9.61 g, 99percent). 1HNMR (400 MHz, CDCI3): δ9.23 (s, 1H), 8.40 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 7.3 Hz, 1H), 2.68 (s, 3H). The crude product was used for the next step without further purification.

Reference： [1] Patent: WO2015/191630, 2015, A1, . Location in patent: Paragraph 00376

4
[ 358780-13-9 ]
[ 108-59-8 ]
[ 358780-14-0 ]

Yield	Reaction Conditions	Operation in experiment
79%	Stage #1: With triethylamine; magnesium chloride In toluene for 2.5 h; light cooling Stage #2: for 2 h; Cooling	i) l-(6-Trifluoromethyl-pyridin-3-yl)-ethanone. Magnesium chloride 3.18 g (33.4 mmol) was suspended in 160 ml toluene. After the addition of triethylamine 16.63 ml (119.3 mmol) and malonic acid dimethyl ester 6.58 ml (57.3 mmol) the reaction mixture was stirred for 2.5 hours under light cooling. 6-Trifluoromethyl-nicotinoyl chloride was dissolved in 15 ml toluene and added dropwise under cooling to the reaction mixture. After stirring for 2 hours the mixture was acidified with cone, hydrochloric acid (15 ml). A white precipitate was formed which was dissolved by the addition of water. The water was separated and extracted one time with ethyl acetate and one time with dichloromethane. The combined organic layers were evaporated and the residue was dissolved in 52 ml dimethyl sulfoxide (DMSO) and 2 ml water. The obtained solution was stirred at155 ⁰C for 2.5 hours. After cooling and the addition of 100 ml ice water it was stirred for 15 minutes. The product was isolated by suction and washed with ice water (3 x 15 ml). The solid was dried at 40⁰C to give 7.11 g (79percent) of the title compound as white solid. MS: 189.90 (ESI+)¹H-NMR (400 MHz, [D6]DMSO): δ = 2.69 (s, 3H, CH₃), 8.08 (d, IH, 5-H-pyridine), 8.56 (d, IH, 4-H-pyridine), 9.26 (s, IH, 2-H-pyridine)

Reference： [1] Patent: WO2008/34579, 2008, A1, . Location in patent: Page/Page column 24-25

5
[ 75-16-1 ]
[ 216431-85-5 ]
[ 358780-14-0 ]

Yield	Reaction Conditions	Operation in experiment
0.500 g	Stage #1: at 0 - 26℃; for 3 h; Stage #2: With hydrogenchloride In tetrahydrofuran; diethyl ether; water at 60℃; for 2 h;	To a solution of 6-(trifluoromethyl)nicotinonitrile (2.0 g, 0.0 ii mmol) in diethyl ether (30 mL) was added methyl magnesium bromide solution (3M in THF) (5.6 ml) at 0°C. The reaction mixture was stirred at RT for 3 h. Concentrated HC1 was added to the reaction mixture and was heated at 60 °C for 2 h. The reaction mixture was concentrated and neutrallised with sat NaHCO3 and extracted with EtOAc. The organic layers were concentrated to afford 0.500 g of the title product.

Reference： [1] Patent: US2006/89370, 2006, A1, . Location in patent: Page/Page column 34
[2] Patent: WO2015/59618, 2015, A1, . Location in patent: Page/Page column 45

6
[ 944900-15-6 ]
[ 358780-14-0 ]

Reference： [1] Patent: WO2017/198812, 2017, A2, . Location in patent: Page/Page column 12

7
[ 2976-86-5 ]
[ 59938-06-6 ]
[ 358780-14-0 ]

Reference： [1] Patent: WO2017/198812, 2017, A2, . Location in patent: Page/Page column 11; 12

8
[ 127-19-5 ]
[ 436799-32-5 ]
[ 358780-14-0 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 17, p. 4999 - 5003

9
[ 75-07-0 ]
[ 436799-32-5 ]
[ 358780-14-0 ]

Reference： [1] Journal of the American Chemical Society, 2017, vol. 139, # 33, p. 11353 - 11356

10
[ 917-64-6 ]
[ 216431-85-5 ]
[ 358780-14-0 ]

Reference： [1] Advanced Synthesis and Catalysis, 2017, vol. 359, # 2, p. 279 - 291

11
[ 139042-59-4 ]
[ 358780-14-0 ]

Reference： [1] RSC Advances, 2016, vol. 6, # 79, p. 75465 - 75469

12
[ 231291-22-8 ]
[ 358780-14-0 ]

Reference： [1] Patent: US2012/302608, 2012, A1,
[2] Patent: WO2015/191630, 2015, A1,

13
[ 358780-13-9 ]
[ 358780-14-0 ]

Reference： [1] Patent: WO2008/123963, 2008, A1,

14
[ 624-28-2 ]
[ 358780-14-0 ]

Reference： [1] Patent: US2017/291894, 2017, A1,

15
[ 116548-05-1 ]
[ 358780-14-0 ]

Reference： [1] Patent: WO2017/198812, 2017, A2,

16
[ 358780-14-0 ]
[ 1228631-54-6 ]

Reference： [1] Patent: WO2017/198812, 2017, A2, . Location in patent: Page/Page column 13

[ 358780-14-0 ] Synthesis Path-Downstream 1~106

1
[ 358780-13-9 ]
[ 358780-14-0 ]

Reference： [1]Patent: WO2008/123963,2008,A1

2
[ 358780-14-0 ]
[ 4637-24-5 ]
[ 1015078-44-0 ]

Yield	Reaction Conditions	Operation in experiment
74%	at 100℃; for 12h;	ii) 3-Dimethylamino-l-(6-trifluoromethyl-pyridin-3-yl)-propenone. l-(6-Trifiuoromethyl-pyridin-3-yl)-ethanone 7.0 g (37.01 mmol) and dimethoxymethyl-dimethyl-amine 14.75 ml (111.03 mmol) were mixed and stirred under argon at 1000C for 12 hours. After evaporation the residue was purified by chromatography on silica gel (ethyl acetate) to yield 6.65 g (74%) of the title compound as an orange powder. MS: 245.1 (ESI+), 1H-NMR (400 MHz, [D6]DMSO): delta = 2.97 (s, 3H, CH3), 3.19 (s, 3H, CH3), 5.91 (d,IH, CO-CH), 7.82 (d, IH, CH-N), 7.96 (d, IH, 5-H-pyridine), 8.47 (d, IH, 4-H- pyridine), 9.20 (s, IH, 2-H-pyridine)

Reference： [1]Patent: WO2008/34579,2008,A1 .Location in patent: Page/Page column 25

3
[ 75-16-1 ]
[ 216431-85-5 ]
[ 358780-14-0 ]

Yield	Reaction Conditions	Operation in experiment
		A 3 M solution of MeMgBr in Et2O (7.2 mmol) was added to a stirred solution of <strong>[216431-85-5]6-(trifluoromethyl)nicotinonitrile</strong> (0.82 g, 4.8 mmol) in ether (16 mL) dropwise over a 30 minute period. The reaction was stirred for 2 hours then the mixture was quenched with aqueous 1N HCl and extracted with Et2O. The organics were combined and washed with brine and dried over anhydrous MgSO4. The solvent was removed in vacuo yielding 530 mg of a brown solid.
0.500 g		To a solution of <strong>[216431-85-5]6-(trifluoromethyl)nicotinonitrile</strong> (2.0 g, 0.0 ii mmol) in diethyl ether (30 mL) was added methyl magnesium bromide solution (3M in THF) (5.6 ml) at 0C. The reaction mixture was stirred at RT for 3 h. Concentrated HC1 was added to the reaction mixture and was heated at 60 C for 2 h. The reaction mixture was concentrated and neutrallised with sat NaHCO3 and extracted with EtOAc. The organic layers were concentrated to afford 0.500 g of the title product.

Reference： [1]Patent: US2006/89370,2006,A1 .Location in patent: Page/Page column 34
[2]Patent: WO2015/59618,2015,A1 .Location in patent: Page/Page column 45

Yield	Reaction Conditions	Operation in experiment
		Yield: 6.1 g of 1-[6-(trifluoromethyl)-3-pyridinyl]ethanone (interm. 5)

5
[ 416852-53-4 ]
[ 75-16-1 ]
[ 358780-14-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	In tetrahydrofuran; toluene; at 0℃; for 1h;	B) 1-(6-(trifluoromethyl)pyridin-3-yl)ethanoneN-Methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (19.1 g, 81.6 mmol) was dissolved in tetrahydrofuran (410 mL). The system was purged with N2 and then cooled to 0 C. 1.4 M of methylmagnesium bromide in toluene/THF (75:25) (87.4 mL, 122.4 mmol) was added dropwise using an additional funnel. At the end of the addition the mixture was cloudy off-white. The mixture was stirred at 0 C. for 1 hour and carefully quenched by dropwise addition of 1 M aq. HCl (150 mL) and diluted with ethyl ether (300 mL) and EtOAc (100 mL). The organic layer was separated and washed with 0.1 M aq. NaOH (200 mL) and brine (2×50 mL), dried (Na2SO4), and concentrated to yield a light yellow solid (15.04 g, 98%).LC-MS: 190.2 [M+1]+; 1H NMR (400 MHz, CDCl3): delta 9.25 (d, 1H, J=1.6 Hz), 8.42 (dd, 1H, J=8.0, 1.6 Hz), 7.82 (d, 1H, J=8.0 Hz), 2.70 (s, 3H).
98%		B) 1 -(6-(trifluoromethyl)pyridin-3-yl)ethanone[00283] N-Methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (19.1 g, 81.6 mmol) was dissolved in tetrahydrofuran (410 mL). The system was purged with N2 and then cooled to 0 0C. 1.4 M of methylmagnesium bromide in toluene/THF (75:25) (87.4 mL, 122.4 mmol) was added dropwise using an additional funnel. At the end of the addition the mixture was cloudy off- white. The mixture was stirred at 0 0C for 1 hour and carefully quenched by dropwise addition of 1 M aq. HCl (150 mL) <n="50"/>and diluted with ethyl ether (300 mL) and EtOAc (100 mL). The organic layer was separated and washed with 0.1 M aq. NaOH (200 mL) and brine (2 x 50 mL), dried (Na2SO4), and concentrated to yield a light yellow solid (15.04 g, 98%).MS: 190.2 [M+l]+;1H NMR (CDCl3): 9.25 (d, IH, J = 1.6 Hz), 8.42 (dd, IH, J = 8.0, 1.6 Hz), 7.82 (d, IH, J = 8.0 Hz),2.70 (s, 3H).
98%	In tetrahydrofuran; diethyl ether; for 16h;	Dissolve N-methoxy-N-methyl-6-(trifluoromethyl)pyridine-3-carboxamide (0.685 g, 2.92 mmol) in THF (20 mL). Add methylmagnesium bromide (3.0 M in EtO2, 1.950 mL, 5.850 mmol). Stir the mixture for 16 hours. Pour the reaction mixture into a saturated NaHCO3 aqueous solution (20 mL). Extract with EtOAc (320 mL). Wash the combined organic extracts with water (30 mL) and saturated sodium chloride (230 mL). Dry the organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure to give the title compound (0.545 g, 98%) as a light yellow solid. 1H NMR (400.43 MHz, d6-DMSO) delta 9.21-9.21 (m, 1H), 8.51-8.49 (m, 1H), 8.03 (d, J=8.2 Hz, 1H), 2.64 (s, 3H).

Reference： [1]Patent: US2008/275037,2008,A1 .Location in patent: Page/Page column 25
[2]Patent: WO2008/123963,2008,A1 .Location in patent: Page/Page column 48-49
[3]Patent: US2012/302608,2012,A1 .Location in patent: Page/Page column 12

6
[ 358780-14-0 ]
[ 196929-78-9 ]
[ 1071435-65-8 ]
[ 1071435-64-7 ]

Yield	Reaction Conditions	Operation in experiment
73.5%		C) (R)-2-methyl-N-((R)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)propane-2-sulfinamide and (R)-2-methyl-N-((S)-1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)propane-2-sulfmamideTo a solution of <strong>[358780-14-0]1-(6-(trifluoromethyl)pyridin-3-yl)ethanone</strong> (15.0 g, 79.3 mmol) in tetrahydrofuran (450 mL) under N2 was added tetraethoxytitanium (28.8 mL, 132 mmol). Solid (R)-(+x)-2-methylpropane-2-sulfinamide (8.01 g, 66.1 mmol) was then added and the reaction was heated under reflux overnight. The resulting imine solution was cooled to -45 to -50 C. and cannulated into flask containing sodium tetrahydroborate (12.5 g, 330 mmol) and tetrahydrofuran (100 mL) that was cooled to -45 to -50 C. The resulting cloudy orange solution was stirred at -40 C. for 4 h and then slowly warmed to rt and stirred at rt for 2 days. After cooling to 0 C., the reaction mixture was carefully quenched by dropwise addition of MeOH (100 mL) followed by dropwise addition of water (40 mL). The mixture was stirred for about 20 minutes, and then rotovapped to dryness. EtOAc (500 mL) was added and the mixture was stirred for about 1 hr, and then brine (50 mL) was added portionwise. The mixture was filtered through Celite and the filter cake was washed with EtOAc (3×100 mL). The filtrate was washed with saturated aq. NaHCO3, water, and brine, dried (Na2SO4), concentrated to yield a light yellow waxy solid (22.40 g, 96%). 1H NMR of the crude product indicates about 93:7 ratio of two diastereomers. The product was recrystallized from EtOAc (150 mL) and washed with cold EtOAc (3×20 mL) to yield a white crystalline solid (12.22 g, 52.5%) as the (R,R)-isomer. The mother liquor was concentrated and purified by silica gel column chromatography to yield additional (R,R)-isomer (5 g, 21%) and the (R,S)-isomer (1.1 g) which was recrystallized from methylcyclohexane to yield an off white solid. 1H NMR (CDCl3 and DMSO-d6) of each recrystallized fraction (R, R and R, S) indicated less than 1% of the other isomer and good purities in all cases.(R,R)-isomer: LC-MS: 295.4 [M+1]+;1H NMR (400 MHz, CDCl3): delta 8.73 (d, 1H, J=1.6 Hz), 7.90 (dd, 1H, J=8.0, 2.4 Hz), 7.69 (d, 1H, J=8.0 Hz), 4.68 (m, 1H), 3.53 (d, 1H, J=3.6 Hz), 1.59 (d, 3H, J=6.8 Hz), 1.25 (s, 9H). 1H NMR (d6-DMSO): 8.80 (d, 1H, J=1.6 Hz), 8.11 (dd, 1H, J=8.0, 2.0 Hz), 7.90 (d, 1H, J=8.0 Hz), 5.94 (d, 1H, J=7.6 Hz), 4.57 (p, 1H, J=7.2 Hz), 1.46 (d, 3H, J=7.2 Hz), 1.13 (s, 9H).(R,S)-isomer: 1H NMR (400 MHz, CDCl3): 8.73 (d, 1H, J=1.6 Hz), 7.84 (dd, 1H, J=8.0, 1.6 Hz), 7.67 (d, 1H, J=8.0 Hz), 4.72 (m, 1H), 3.42 (d, 1H, J=2.4 Hz), 1.60 (d, 3H, J=6.8 Hz), 1.23 (s, 9H).1H NMR (d6-DMSO): 8.77 (d, 1H, J=1.6 Hz), 8.06 (dd, 1H, J=8.0, 2.0 Hz), 7.90 (d, 1H, J=8.0 Hz), 5.67 (d, 1H, J=6.0 Hz), 4.62 (p, 1H, J=6.4 Hz), 1.52 (d, 3H, J=6.8 Hz), 1.12 (s, 9H).
		C) (R)-2-methyl-N-((R)-l -(6-(trifluoromethyl)pyridin-3-yl)ethyl)propane-2-sulfinamide and (R)-2- methyl-N-((S)- 1 -(6-(trifluoromethyl)pyridin-3 -yl)ethyl)propane-2-sulfinamide[00284] To a solution of l-(6-(trifluoromethyl)pyridin-3-yl)ethanone (15.0 g, 79.3 mmol) in tetrahydrofuran (450 mL) under N2 was added tetraethoxytitanium (28.8 mL, 132 mmol). Solid (R)-(+)-2-methylpropane-2-sulfinamide (8.01 g, 66.1 mmol) was then added and the reaction was heated under reflux overnight. The resulting imine solution was cooled to -45 to -50 0C and cannulated into flask containing sodium tetrahydroborate (12.5 g, 330 mmol) and tetrahydrofuran (100 mL) that was cooled to -45 to -50 0C. The resulting cloudy orange solution was stirred at -40 0C for 4h and then slowly warmed to rt and stirred at rt for 2 days. After cooling to 0 0C, the reaction mixture was carefully quenched by dropwise addition of MeOH (100 mL) followed by dropwise addition of water(40 mL). The mixture was stirred for about 20 minutes, and then rotovapped to dryness. EtOAc (500 mL) was added and the mixture was stirred for about 1 hr, and then brine (50 mL) was added portionwise. The mixture was filtered through Celite and the filter cake was washed with EtOAc (3 x100 mL). The filtrate was washed with saturated aq. NaHCO3, water, and brine, dried (Na2SO4), concentrated to yield a light yellow waxy solid (22.40 g, 96%). 1H NMR of the crude product indicates about 93:7 ratio of two diastereomers. The product was recrystallized from EtOAc (150 mL) and washed with cold EtOAc (3 x 20 mL) to yield a white crystaline solid (12.22 g, 52.5%) as the(R,R)-isomer. The mother liquor was concentrated and purified by silica gel column chromatography to give additional (R,R)-somer (5 g, 21%) and the (R,5)-isomer (1.1 g) which was recrystallized from methylcyclohexane to yield an off white solid. 1H NMR (CDC13 and DMSO-d6) of each recrystallized fraction (R, R and R, S) indicated less than 1% of the other isomer and good purities in all cases.(R,R)-isomer: MS: 295.4 [M+l]+;1H NMR (400 MHz, CDCl3): 8.73 (d, IH, J = 1.6 Hz), 7.90 (dd, IH, J = 8.0, 2.4 Hz), 7.69 (d, IH, J =8.0 Hz), 4.68 (m, IH), 3.53 (d, IH, J = 3.6 Hz), 1.59 (d, 3H, J = 6.8 Hz), 1.25 (s, 9H). 1H NMR (d6-DMSO): 8.80 (d, IH, J = 1.6 Hz), 8.11 (dd, IH, J = 8.0, 2.0 Hz), 7.90 (d, IH, J = 8.0 Hz), 5.94 (d, IH,J = 7.6 Hz), 4.57 (p, IH, J = 7.2 Hz), 1.46 (d, 3H, J = 7.2 Hz), 1.13 (s, 9H).(R,S)-isomer: 1H NMR (400 MHz, CDCl3): 8.73 (d, IH, J = 1.6 Hz), 7.84 (dd, IH, J = 8.0, 1.6 Hz),7.67 (d, IH, J = 8.0 Hz), 4.72 (m, IH), 3.42 (d, IH, J = 2.4 Hz), 1.60 (d, 3H, J = 6.8 Hz), 1.23 (s, 9H). <n="51"/>1H NMR (d6-DMSO): 8.77 (d, IH, J = 1.6 Hz), 8.06 (dd, IH, J = 8.0, 2.0 Hz), 7.90 (d, IH, J = 8.0 Hz), 5.67 (d, IH, J = 6.0 Hz), 4.62 (p, IH, J = 6.4 Hz), 1.52 (d, 3H, J = 6.8 Hz), 1.12 (s, 9H).

Reference： [1]Patent: US2008/275037,2008,A1 .Location in patent: Page/Page column 25; 26
[2]Patent: WO2008/123963,2008,A1 .Location in patent: Page/Page column 49-50

7
[ 358780-14-0 ]
[ 2181-42-2 ]
[ 1147939-55-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 32 Preparation of 2-(t?fluoromethyl)-5-(2-methyloxiran-2-yl)pyridme[0397] The title compound was prepared by following general procedure 3 DMSO was added to NaH (1 equiv ) and heated to 65 0C for 1 h THF was added at the same temperature and heated for another 10 mm After 10 mm , the reaction mixture was cooled to 00C T?methylsulfomum iodide (1 equiv ) was added and stirred for 10 mm after which the solution of l-(6-(t?fluoromethyl)py?dm-3-yl)ethanone (1 equiv ) in THF was added dropwise After complete addition, the reaction mixture was stirred at RT for 2 h The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4 x 5OmL), dried over Na2SO4 and concentrated at 25 0C to obtain the product
		Example 36 A [0460] DMSO was added to NaH (1 equiv) and heated to 65 0C for 1 h. THF was added at same temperature and heated for another 10 min. After 10 min, reaction mixture was cooled to 0 0C. Trimethylsulfonium iodide (1 equiv) was added and stirred for 10 min after which the solution of l-(6-(trifluoromethyl)pyridin-3-yl)ethanone (1 equiv) in THF was added dropwise. After complete addition, reaction mixture was stirred at RT for 2 h. Product was detected by LCMS. Reaction mixture was poured in ice water. Product was extracted with diethyl ether (4x50 mL), dried over sodium sulfate and concentrated under vacuum at 25 0C to get the product.

Reference： [1]Patent: WO2010/51503,2010,A1 .Location in patent: Page/Page column 257
[2]Patent: WO2010/51501,2010,A1 .Location in patent: Page/Page column 253-254

8
[ 358780-14-0 ]
[ 17223-45-9 ]
[ 1147864-81-0 ]

Yield	Reaction Conditions	Operation in experiment
		Sodium hydride (1-3 equiv.) is added to a solution of 8-chloro-2,3,4,5-tetrahydro-2- methyl-lH-pyrido[4,3-b]indole (1.0 equiv.) in DMF, and heated to 120 0C for 1 h with stirring. The reaction mixture is cooled to 0 0C and 5-acetyl-2-(trifluoromethyl)pyridine (2-7.5 equiv.) is added dropwise over 5 min. The temperature is raised to 120 0C and stirred for 2 h. The reaction mixture is cooled to RT and partitioned between EtOAc and water. The organic layer is separated and the aqueous layer extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and concentrated under vacuum to provide the crude product. The product is purified by flash column chromatography over silica gel (230-400 mesh, deactivated with 1% triethylamine/hexane) using a gradient of 5 to 15% MeOH/EtOAc to yield the free base. The pure compound is converted to its oxalate salt. The analytical sample is prepared by dissolving free base in THF and treatment with 1 equiv. of oxalic acid dihydrate.

Reference： [1]Patent: WO2010/51501,2010,A1 .Location in patent: Page/Page column 262

9
[ 867-13-0 ]
[ 358780-14-0 ]
[ 1100756-76-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 4999 - 5003

10
[ 127-19-5 ]
[ 436799-32-5 ]
[ 358780-14-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 4999 - 5003

11
[ 358780-13-9 ]
[ 108-59-8 ]
[ 358780-14-0 ]

Yield	Reaction Conditions	Operation in experiment
79%		i) l-(6-Trifluoromethyl-pyridin-3-yl)-ethanone. Magnesium chloride 3.18 g (33.4 mmol) was suspended in 160 ml toluene. After the addition of triethylamine 16.63 ml (119.3 mmol) and malonic acid dimethyl ester 6.58 ml (57.3 mmol) the reaction mixture was stirred for 2.5 hours under light cooling. 6-Trifluoromethyl-nicotinoyl chloride was dissolved in 15 ml toluene and added dropwise under cooling to the reaction mixture. After stirring for 2 hours the mixture was acidified with cone, hydrochloric acid (15 ml). A white precipitate was formed which was dissolved by the addition of water. The water was separated and extracted one time with ethyl acetate and one time with dichloromethane. The combined organic layers were evaporated and the residue was dissolved in 52 ml dimethyl sulfoxide (DMSO) and 2 ml water. The obtained solution was stirred at155 0C for 2.5 hours. After cooling and the addition of 100 ml ice water it was stirred for 15 minutes. The product was isolated by suction and washed with ice water (3 x 15 ml). The solid was dried at 400C to give 7.11 g (79%) of the title compound as white solid. MS: 189.90 (ESI+)1H-NMR (400 MHz, [D6]DMSO): delta = 2.69 (s, 3H, CH3), 8.08 (d, IH, 5-H-pyridine), 8.56 (d, IH, 4-H-pyridine), 9.26 (s, IH, 2-H-pyridine)

Reference： [1]Patent: WO2008/34579,2008,A1 .Location in patent: Page/Page column 24-25

12
[ 231291-22-8 ]
[ 358780-14-0 ]

Reference： [1]Patent: US2012/302608,2012,A1
[2]Patent: WO2015/191630,2015,A1

13
[ 358780-14-0 ]
[ 1071435-61-4 ]

Reference： [1]Advanced Synthesis and Catalysis,2017,vol. 359,p. 279 - 291
[2]Patent: WO2008/123963,2008,A1

14
[ 358780-14-0 ]
[ 1071435-62-5 ]

Reference： [1]Advanced Synthesis and Catalysis,2017,vol. 359,p. 279 - 291
[2]Patent: WO2008/123963,2008,A1

15
[ 358780-14-0 ]
[ 1071436-22-0 ]

Reference： [1]Patent: WO2008/123963,2008,A1

16
[ 358780-14-0 ]
[ 1071436-23-1 ]

Reference： [1]Patent: WO2008/123963,2008,A1

17
[ 917-64-6 ]
[ 416852-53-4 ]
[ 358780-14-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	In tetrahydrofuran; at 0℃; for 2h;	[00376] N-Methoxy-N-methyl-6-(trifluoromethyl)nicotinamide ( 12 g, 51 mmol) in dry THF ( 500 mL) was cooled to 0 C and kept for 10 min. To this cooled solution methylmagnesium iodide (18.8 mL, 3M solution in THF) was added and stirred at the same temperature for 2 h. The reaction mixture was then quenched with the addition of saturated NH4C1 solution and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine. The organic phase was dried using Na2SO4 and evaporated to give l-(6-(trifluoromethyl)pyridin-3-yl)ethan-l- one as a pale yellow solid (9.61 g, 99%). 1HNMR (400 MHz, CDCI3): delta9.23 (s, 1H), 8.40 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 7.3 Hz, 1H), 2.68 (s, 3H). The crude product was used for the next step without further purification.

Reference： [1]Patent: WO2015/191630,2015,A1 .Location in patent: Paragraph 00376

18
[ 358780-14-0 ]
[ 1068103-84-3 ]

Reference： [1]Patent: WO2015/191630,2015,A1

19
[ 358780-14-0 ]
[ 1068104-49-3 ]

Reference： [1]Patent: WO2015/191630,2015,A1

20
[ 358780-14-0 ]
3'-(4-(trifluoromethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-yl)biphenyl-3-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2015/191630,2015,A1

21
[ 358780-14-0 ]
2-(3-((4-fluorophenyl)ethynyl)phenyl)-4-(trifluoromethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine [ No CAS ]

Reference： [1]Patent: WO2015/191630,2015,A1

22
[ 358780-14-0 ]
[ 383-63-1 ]
4,4,4-trifluoro-1-(6-(trifluoromethyl)pyridin-3-yl)butane-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		[00377] To a stirred solution of l-(6-(trifluoromethyl)pyridin-3-yl)ethan-l-one (7.5 g, 39.68 mmol) in diethyl ether (500 mL), was added NaH (1.19 g, 49.60 mmol) while the temperature was kept between 0 - 5 C. After stirring at that temperature for 30 min, ethyl trifluoroacetate (5.89 mL, 49.60 mmol) was added to the reaction mixture. The reaction mixture was poured into ice water and acidified with 2N HC1. The organic layer was separated and aqueous layer extracted with ethyl acetate (3 x 20 mL). The combined organic layer was washed with water and brine. The organic phase was dried using Na2SO4 and evaporated to give 4,4,4-trifluoro-l-(6- (trifluoromethyl)pyridin-3-yl)butane-l,3-dione as a pale yellow liquid (as enol form, 9.3 g, 82%). 1H NMR (400 MHz, CDC13): delta 9.62 (s, 1H), 8.45 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 7.3 Hz, 1H), 6.61 (s, 1H).

Reference： [1]Patent: WO2015/191630,2015,A1 .Location in patent: Paragraph 00377

23
[ 358780-14-0 ]
[ 1379332-23-6 ]

Yield	Reaction Conditions	Operation in experiment
86.66%	With hydrogen bromide; bromine; acetic acid; In diethyl ether; at 0℃; for 0.5h;	To a stirred solution of <strong>[358780-14-0]1-(6-(trifluoromethyl)pyridin-3-yl)ethanone</strong> (0.035 g, 0.18 mmol) in ether (2 mL) was added HBr-AcOH (0.5 mL). To resultant reaction mass Br2 (diluted in 0.5 mL HBr-AcOH) (0.027 g, 0.17 mmol) was added at 0 C. and stirred for 30 min. Allow temp to increase gradually to RT. Completion of reaction was monitored by TLC. On completion, quenched with ice water, extracted with ether. The organic layer was washed with aqueous-bicarbonate, brine, dried over sodium sulphate, concentrated under reduced pressure obtained 2-bromo-<strong>[358780-14-0]1-(6-(trifluoromethyl)pyridin-3-yl)ethanone</strong> (0.26 g, 86.66%) as semisolid brownish gummy mass. (0453) Mass: 268.2 [M++1]
	With hydrogen bromide; bromine; acetic acid; In chloroform; at 0 - 20℃; for 2h;	Bromo ketone 4[0116] Bromo ketone 4: To l-(6-(trifluoromethyl)pyridin-3-yl)ethanone (3 g, 15.86 mmol) in CHC13(Volume: 50 ml) was added a solution of bromine (0.300 ml, 5.82 mmol) in 5 mL chloroform, slowly at 0 C. Add HBr (1.740 ml, 10.57 mmol) in AcOH and slowly warm to RT and stir for 2 h. The solvent was evaporated and the crude product used in the next step without further purification.

Reference： [1]Patent: US2017/291894,2017,A1 .Location in patent: Paragraph 0451-0453
[2]Patent: WO2016/106331,2016,A1 .Location in patent: Paragraph 0116

24
[ 358780-14-0 ]
[ 343338-28-3 ]
2-methyl-N-{(1R)-1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-2-propanesulfinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		To a stirred so[ution of Intermediate XLI (5.44 g, 28.8 mmo[) and titanium(IV)ethoxide (18.6 mL, 57.5 mmo[) in diethy[ ether (120 mL) was added (S)-2-t-buty[su[finamide (3.85 g, 31.6 mmo[) and the resu[ting so[ution was stirred at ref[ux under nitrogen for 3 h. The reaction mixture was coo[ed to room temperature and then to -78 C and [ithium tri-s-buty[borohydride (1M in THF, 34.5 m[, 34.5 mmo[) was added dropwise. The reaction was stirred at -78 C for 30minutes. The reaction was quenched by addition of brine (20 mL) and was a[[owed to warm up to room temperature prior to fi[tration through a p[ug of Ce[ite(washing with ethy[ acetate). The fi[trate was washed with brine (40 mL) and the aqueous [ayer was extracted once with ethy[ acetate (40 mL). The organic [ayers were combined, dried over MgSO4, fi[tered and concentrated under reduced pressure. The residue was triturated with Et20, and the so[ids co[[ected by vacuumfi[tration to afford 5.15 g (61% yie[d) of the tit[e compound as a white so[id.1H NMR (500 MHz, Ch[oroform-d): 6 [ppm] 8.71 (d, J = 1.6, 1H), 7.83 (dd, J = 8.1,2.0, 1H), 7.66 (d, J = 8.1, 1H), 4.70 (qd, J = 6.7, 2.6, 1H), 3.44- 3.39 (m, 1H), 1.58(d, J = 6.8, 3H), 1.21 (5, 9H).LCMS (Ana[ytica[ Method A) Rt = 1.13 mm, MS (ESipos): m/z = 295.05 (M+H).

Reference： [1]Patent: WO2016/91776,2016,A1 .Location in patent: Page/Page column 380; 381

25
[ 97674-02-7 ]
[ 436799-32-5 ]
[ 358780-14-0 ]

Yield	Reaction Conditions	Operation in experiment
59.25%	With dichlorobis(triphenylphosphine)palladium(II); In toluene; at 120℃; for 3h;Inert atmosphere;	Step-2: Synthesis of 1-(6-(trifluoromethyl)pyridin-3-yl)ethanone To a stirred solution of 5-bromo-2-(trifluoromethyl)pyridine (0.07 g, 0.31 mmol) in dry toluene (10 mL), Int-B (0.124 g, 0.34 mmol) was added. Purged reaction mass with nitrogen for 30 min. To resultant reaction mass Dikis (0.01 g, 0.015 mmol) was added and stirred at 120 C. for 3 h. Completion of reaction was monitored by TLC. On completion, quenched with ice water, extracted with ether. The organic layer was washed with water, brine, dried over sodium sulphate, concentrated under reduced pressure obtained crude. Purification of the crude was done via silica gel (100-200 Mesh) column chromatography and desired compound eluted at 15% ethyl acetate/n-Hexane to obtained 1-(6-(trifluoromethyl)pyridin-3-yl)ethanone (0.035 g, 59.25%) as off white solid. Mass: 190.08 [M++1]
56%		5-Bromo-2-(trif[uoromethy[)pyridine (10.0 g, 44.3 mmo[), water (40 mL), DMF (120mL), potassium carbonate (12.2 g, 88.5 mmo[),bis(tripheny[phosphine)pa[[adium(II) dich[oride (621 mg, 2 mo[ %) and tributy[(1ethoxyetheny[)stannane (19.2 g, 53.1 mmo[) were stirred and heated to 110 Cunder nitrogen for 1.5 h. The reaction mixture was coo[ed down, di[uted withdiethy[ ether (120 mL) and KF (12.8 g in 50 mL of water) was added. The resu[ting reaction mixture was vigorous[y stirred for 1 h before being fi[tered through Ce[ite. The organic [ayer was then washed with saturated aqueous NaHCO3 fo[[owed by brine and was then dried over MgSO4, fi[tered and concentrated underreduced pressure. The residue was taken up in THF (200 mL) and 2M HC[ (60 mL) and the reaction was stirred at ambient temperature for 40 minutes. The organics were removed under reduced pressure and the aqueous [ayer was extracted with DCM (3 x 50 mL). The organic [ayers were combined, dried over MgSO4, fi[tered and concentrated under reduced pressure. The crude materia[ was purified by BiotageIso[era chromatography (si[ica ge[, e[uting with heptane-EtOAc, 1:0 to 10:1) toafford 4.90 g (56% yie[d) as a white crysta[[ine so[id.1H NMR (250 MHz, Ch[oroform-d): 6 [ppm] 9.25 (d, J = 1.3 Hz, 1H), 8.41 (dd, J8.2, 1.6 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 2.70 (5, 3H).LCMS (Ana[ytica[ Method A) Rt = 1.15 mm, MS (ESipos): m/z = 190.0 (M+H).

Reference： [1]Patent: US2017/291894,2017,A1 .Location in patent: Paragraph 0448-0450
[2]Patent: WO2016/91776,2016,A1 .Location in patent: Page/Page column 379; 380

26
[(2,2'-bipyridine)₂Cu][O₂CCF₂Cl] [ No CAS ]
[ 139042-59-4 ]
[ 358780-14-0 ]

Reference： [1]RSC Advances,2016,vol. 6,p. 75465 - 75469

27
[ 917-64-6 ]
[ 216431-85-5 ]
[ 358780-14-0 ]

Reference： [1]Advanced Synthesis and Catalysis,2017,vol. 359,p. 279 - 291

28
[ 358780-14-0 ]
(±)-1-[(6-trifluoromethyl)pyridine-3-yl]ethan-1-amine [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2017,vol. 359,p. 279 - 291

29
[ 358780-14-0 ]
C₁₁H₁₃F₃N₂O₂ [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2017,vol. 359,p. 279 - 291

30
[ 358780-14-0 ]
C₁₀H₁₁F₃N₂O [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2017,vol. 359,p. 279 - 291

31
[ 358780-14-0 ]
6-chloro-3-ethylsulfanyl-2-[1-methyl-5-[6-(trifluoromethyl)-3-pyridyl]pyrazol-3-yl]pyridine [ No CAS ]
6-chloro-3-ethylsulfanyl-2-[2-methyl-5-[6-(trifluoromethyl)-3-pyridyl]pyrazol-3-yl]pyridine [ No CAS ]

Reference： [1]Patent: WO2017/50751,2017,A1

32
[ 358780-14-0 ]
6-chloro-3-ethylsulfonyl-2-[1-methyl-5-[6-(trifluoromethyl)-3-pyridyl]pyrazol-3-yl]pyridine [ No CAS ]

Reference： [1]Patent: WO2017/50751,2017,A1

33
[ 358780-14-0 ]
3-ethylsulfonyl-2-[1-methyl-5-[6-(trifluoromethyl)-3-pyridyl]pyrazol-3-yl]pyridine [ No CAS ]

Reference： [1]Patent: WO2017/50751,2017,A1

34
[ 358780-14-0 ]
3-ethylsulfonyl-2-[1-methyl-5-[6-(trifluoromethyl)-3-pyridyl]pyrazol-3-yl]-6-(1,2,4-triazol-1-yl)pyridine [ No CAS ]

Reference： [1]Patent: WO2017/50751,2017,A1

35
[ 358780-14-0 ]
methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate [ No CAS ]
1-(6-chloro-3-ethylsulfanyl-2-pyridyl)-3-[6-(trifluoromethyl)-3-pyridyl]propane-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 1 : Preparation of 1 -(6-chloro-3-ethylsulfanyl-2-pyridyl)-3-[6-(trifluoromethyl)-3-pyridyl]propane- 1 .3- dione (compound W2) To a solution of 1 -[6-(trifluoromethyl)-3-pyridyl]ethanone (4.03 g, 21 .3 mmol ) at 0-5C in tetrahydrofuran (1 10 ml) under argon was added a 1 M [bis(trimethylsilyl)amino]lithium solution in tetrahydrofuran (LiHMDS, 42.6 ml, 42.6 mmol) dropwise. The mixture was stirred one hour at 5-10C, then warmed to room temperature for one hour. Methyl 6-chloro-3-ethylsulfanyl-pyridine-2-carboxylate (4.94 g, 21 .3 mmol) was added as a solid in 5 portions to the previous solution at 0-5C, and stirring continued for one hour whilst warming to room temperature. Upon completion of the reaction, the mixture was concentrated in vacuo and the solid residue added to a vigorously stirred ice-cooled solution of acetic acid and water (100 ml, 1 :1 , v/v). The yellow suspension was stirred for 15 minutes, filtered and washed with cold water. The solid was dissolved into dichloromethane, the solution dried over sodium sulfate, filtered and concentrated in vacuo to dryness to afford 1 -(6-chloro-3-ethylsulfanyl-2-pyridyl)-3- [6-(trifluoromethyl)-3-pyridyl]propane-1 ,3-dione (compound W2) as a solid (4.3 g), mp 123-125C. This material was used in the next step without further purification. LCMS (method 4): 389/391 (M+H)+; retention time: 1 .25 min. H-NMR (CDCI3, ppm) 1 .43 (t, J=7.34 Hz, 3H), 2.98 (q, J=7.34 Hz, 2H), 7.42 (d, J=8.80 Hz, 1 H), 7.54 (s, 1 H), 7.70 (d, J=8.80 Hz, 1 H), 7.80 (d, J=8.25 Hz, 1 H), 8.42 (dd, J=8.25, 1 .8 Hz, 1 H), 9.28 (d, J=1 .8 Hz, 1 H), 15.25 (br s, 1 H). [major tautomer, keto-enol form]

Reference： [1]Patent: WO2017/50751,2017,A1 .Location in patent: Page/Page column 89

36
[ 75-07-0 ]
[ 436799-32-5 ]
[ 358780-14-0 ]

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 11353 - 11356

37
[ 624-28-2 ]
[ 358780-14-0 ]

Reference： [1]Patent: US2017/291894,2017,A1

38
[ 358780-14-0 ]
2-chloro-6-(6-(trifluoromethyl)pyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazole [ No CAS ]

Reference： [1]Patent: US2017/291894,2017,A1

39
[ 358780-14-0 ]
2-((S)-1-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)ethoxy)-6-(6-(trifluoromethyl)pyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazole [ No CAS ]

Reference： [1]Patent: US2017/291894,2017,A1

40
[ 944900-15-6 ]
[ 358780-14-0 ]

Yield	Reaction Conditions	Operation in experiment
	With palladium on activated charcoal; hydrogen; triethylamine; In methanol; at 20℃;Cooling with ice;	0.044 mol l-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)ethanone and 50 mL MeOH are charged into a stirred three-necked flask, cooled with ice and 0.088 mol triethylamine are added. 1 g Pd/C is added. The system is flushed with hydrogen, and a hydrogen balloon is attached to the stoppered flask. The reaction is allowed to stirr at room temperature overnight. The mixture is filtered, evaporated, the residue dissolved in ethyl acetate and washed with water. After drying over Na2S04, the crude l-[6-(Trifluoromethyl)-3-pyridinyl]ethanone is obtained.

Reference： [1]Patent: WO2017/198812,2017,A2 .Location in patent: Page/Page column 12

41
[ 2976-86-5 ]
[ 59938-06-6 ]
[ 358780-14-0 ]

Yield	Reaction Conditions	Operation in experiment
		420 mmoles of 1 -amino- l-penten-3-one are added to ice cooledtriethylamine (420 mmoles) over a period of about 20 min under vigorous stirring. ETFBO is then added dropwise under ice cooling and over a period of about 30 min whereby the temperature of the reaction mixture is kept under 10C. The reaction mixture is then further stirred at room temperature for 20 h. A concentrated HC1 solution (2N) is added to the solution until a pH of 3 is obtained. After extraction of the solution with ethyl acetate, the organic phase is washed with water and dried over sodium sulfate. After removing the volatile compounds on a rotary evaporator, the crude product can be obtained

Reference： [1]Patent: WO2017/198812,2017,A2 .Location in patent: Page/Page column 11; 12

42
[ 358780-14-0 ]
[ 1228631-54-6 ]

Yield	Reaction Conditions	Operation in experiment
	With methanol; sodium tetrahydroborate; at 0℃; for 0.5h;	In methanol (30.0 mL), 10.3 mmol l-[6-(Trifluoromethyl)-3- pyridinyl]ethanone is dissolved. Sodium borohydride (584 mg, 15.4 mmol) is added and the mixture is stirred at 0C for 30 minutes. The solvent is evaporated under reduced pressure and water is added. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate is performed. After filtration, the solvent in the filtrate is evaporated under reduced pressure.

Reference： [1]Patent: WO2017/198812,2017,A2 .Location in patent: Page/Page column 13

43
[ 358780-14-0 ]
[ 1030632-95-1 ]

Reference： [1]Patent: WO2017/198812,2017,A2

44
[ 358780-14-0 ]
(±)5-(1-(methylthio)ethyl)-2-trifluoromethyl pyridine [ No CAS ]

Reference： [1]Patent: WO2017/198812,2017,A2
[2]Patent: WO2017/198812,2017,A2

45
[ 358780-14-0 ]
1-(6-(trifluoromethyl)pyridin-3-yl)ethanethione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With Lawessons reagent; In 1,4-dioxane; at 40 - 50℃; for 5h;	l-[6-(Trifluoromethyl)-3-pyridinyl]ethanone ( 30.0 mmol) is dissolved in anhydrous 1,4-dioxane (50 mL), and Lawesson's reagent (6.10 g, 15.0 mmol) is added. The reaction mixture is stirred at 40-50 C for 5 h. The mixture is cooled to room temperatur, and filtered over a plug of silica gel, rinsing with dioxane. The solvent is removed from the combined organic phases under reduced pressure.

Reference： [1]Patent: WO2017/198812,2017,A2 .Location in patent: Page/Page column 15

46
[ 358780-14-0 ]
1-(6-(trifluoromethyl)pyridin-3-yl)ethanethiol [ No CAS ]

Reference： [1]Patent: WO2017/198812,2017,A2

47
[ 116548-05-1 ]
[ 358780-14-0 ]

Reference： [1]Patent: WO2017/198812,2017,A2

48
[ 358780-14-0 ]
[ 609-09-6 ]
diethyl 2-hydroxy-2-[2-oxo-2-[6-(trifluoromethyl)-3-pyridyl]ethyl]propanedioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at 130℃; for 37h;	Into a 100-mL round-bottom flask, was placed <strong>[358780-14-0]1-[6-(trifluoromethyl)pyridin-3-yl]ethanone</strong> (10 g, 52.87 mmol) and 1,3-diethyl 2-oxopropanedioate (15.65 g, 89.9 mmol). The resulting solutionwas stirred for 24 h at 130C followed by the addition of more 1 ,3-diethyl 2-oxopropanedioate (13.81 g, 79.30 mmol) and heating for another 13 h at 130C. The resulting mixture was cooled down to rt and poured into pentane. The precipitate was filtered off, washed with pentane and water yielding 22.6 g (crude) of diethyl hydroxy{2-oxo-2-[6-(trifluoromethyl)pyridin-3- yl]ethyl}malonate which was used without further purification.
	at 130℃; for 37h;	Into a 100-mL round-bottom flask, was placed <strong>[358780-14-0]1-[6-(trifluoromethyl)-3-pyridyl]ethanone</strong> (10 g, 52.87 mmol) and 1 ,3-diethyl 2-oxopropanedioate (15.65 g, 89.9 mmol). The resulting solution was stirred for 24 h at 130C followed by the addition of more 1 ,3-diethyl 2-oxopropanedioate (13.81 g, 79.30 mmol) and heating for another 13 h at 130C. The resulting mixture was cooled down to rt and poured into pentane. The precipitate was filtered of, washed with pentane and water yielding 22.6 g (crude) of diethyl 2-hydroxy-2-[2-oxo-2-[6-(trifluoromethyl)-3- pyridyl]ethyl]propanedioate which was used without further purification in the next step.
	at 130℃; for 37h;	Into a 100-mL round-bottom flask, was placed <strong>[358780-14-0]1-[6-(trifluoromethyl)-3-pyridyl]ethanone</strong> (10 g, 52.87 mmol) and 1 ,3-diethyl 2-oxopropanedioate (15.65 g, 89.9 mmol). The resulting solution was stirred for 24 h at 130C followed by the addition of more 1 ,3-diethyl 2-oxopropanedioate (13.81 g, 79.30 mmol) and heating for another 13 h at 130C. The resulting mixture was cooled down to rt and poured into pentane. The precipitate was filtered off, washed with pentane and water yielding 22.6 g (crude) of diethyl 2-hydroxy-2-[2-oxo-2-[6-(trifluoromethyl)-3- pyridyl]ethyl]propanedioate which was used without further purification.

Reference： [1]Patent: WO2018/146010,2018,A1 .Location in patent: Page/Page column 138
[2]Patent: WO2019/101642,2019,A1 .Location in patent: Page/Page column 63-64
[3]Patent: WO2019/101643,2019,A1 .Location in patent: Page/Page column 50

49
[ 358780-14-0 ]
ethyl 3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/146010,2018,A1
[2]Patent: WO2019/101642,2019,A1
[3]Patent: WO2019/101643,2019,A1

50
[ 358780-14-0 ]
ethyl 2-(5-fluoropyridin-3-yl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/146010,2018,A1

51
[ 358780-14-0 ]
2-(5-fluoropyridin-3-yl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/146010,2018,A1

52
[ 358780-14-0 ]
2-(5-fluoropyridin-3-yl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/146010,2018,A1

53
[ 358780-14-0 ]
2-(5-fluoropyridin-3-yl)-N-[(1S,2R)-2-hydroxycyclopentyl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/146010,2018,A1

54
[ 358780-14-0 ]
N-[(1S)-1-cyclopropyl-2-hydroxyethyl]-2-(5-fluoropyridin-3-yl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/146010,2018,A1

55
[ 358780-14-0 ]
2-(5-fluoropyridin-3-yl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/146010,2018,A1

56
[ 358780-14-0 ]
N-[(1S)-1-cyano-2-hydroxyethyl]-2-(5-fluoropyridin-3-yl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/146010,2018,A1

57
[ 358780-14-0 ]
2-(5-fluoropyridin-3-yl)-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/146010,2018,A1

58
[ 358780-14-0 ]
1,5-anhydro-2,4-dideoxy-2-[({2-(5-fluoropyridin-3-yl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-yl}carbonyl)amino]-D-erythropentitol [ No CAS ]

Reference： [1]Patent: WO2018/146010,2018,A1

59
[ 358780-14-0 ]
2-(5-fluoropyridin-3-yl)-N-(2-hydroxy2-methylpropyl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/146010,2018,A1

60
[ 358780-14-0 ]
ethyl 3-oxo-2-(1,2-thiazol-4-yl)-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/146010,2018,A1
[2]Patent: WO2019/101642,2019,A1

61
[ 358780-14-0 ]
3-oxo-2-(1,2-thiazol-4-yl)-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2018/146010,2018,A1
[2]Patent: WO2019/101642,2019,A1

62
[ 358780-14-0 ]
[ 1015078-43-9 ]

Reference： [1]Patent: WO2008/34579,2008,A1

63
[ 358780-14-0 ]
6-methyl-5-(3-methyl-4-(4-([1,2,3]triazol-1-yl)-but-1-enyl)-phenoxymethyl)-6'-trifluoromethyl-[2,3']bipyridine [ No CAS ]

Reference： [1]Patent: WO2008/34579,2008,A1

64
[ 358780-14-0 ]
6-methyl-5-(4-(4-([1,2,3]triazol-1-yl)butyl)phenoxymethyl)-6'-trifluoromethyl-[2,3']bipyridine [ No CAS ]

Reference： [1]Patent: WO2008/34579,2008,A1

65
[ 358780-14-0 ]
5-(4-(1-methoxy-4-([1,2,3]triazol-1-yl)butyl)phenoxymethyl)-6-methyl-6'-trifluoromethyl-[2,3']bipyridine [ No CAS ]

Reference： [1]Patent: WO2008/34579,2008,A1

66
[ 358780-14-0 ]
6-methyl-5-(3-methyl-4-(4-([1,2,3]triazol-1-yl)butyl)phenoxymethyl)-6'-trifluoromethyl-[2,3']bipyridine [ No CAS ]

Reference： [1]Patent: WO2008/34579,2008,A1

67
[ 358780-14-0 ]
1-(4-(6-methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)-phenyl)-4-([1,2,3]-triazol-1-yl)-butan-1-ol [ No CAS ]

Reference： [1]Patent: WO2008/34579,2008,A1

68
[ 358780-14-0 ]
1-(4-(6-methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)-phenyl)-4-([1,2,3]-triazol-1-yl)-butan-1-one [ No CAS ]

Reference： [1]Patent: WO2008/34579,2008,A1

69
[ 358780-14-0 ]
5-(4-(1-methoxy-4-([1,2,3]-triazol-1-yl)butyl)-3-methylphenoxymethyl)-6-methyl-6'-trifluoromethyl-[2,3']bipyridine [ No CAS ]

Reference： [1]Patent: WO2008/34579,2008,A1

70
[ 358780-14-0 ]
[ 1015078-29-1 ]

Reference： [1]Patent: WO2008/34579,2008,A1

71
[ 358780-14-0 ]
1-(2-methyl-4-(6-methyl-6'-trifluoromethyl-[2,3']bipyridinyl-5-ylmethoxy)-phenyl)-4-([1,2,3]-triazol-1-yl)-butan-1-ol [ No CAS ]

Reference： [1]Patent: WO2008/34579,2008,A1

72
[ 358780-14-0 ]
[ 1015078-46-2 ]

Reference： [1]Patent: WO2008/34579,2008,A1

73
[ 358780-14-0 ]
[ 1015078-45-1 ]

Reference： [1]Patent: WO2008/34579,2008,A1

74
[ 358780-14-0 ]
tert-butyl 2-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)hydrazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: US2018/354955,2018,A1
[2]Patent: WO2020/123271,2020,A1

75
[ 358780-14-0 ]
5-(1-hydrazinylethyl)-2-(trifluoromethyl)pyridine dihydrochloride [ No CAS ]

Reference： [1]Patent: US2018/354955,2018,A1
[2]Patent: US2018/354955,2018,A1
[3]Patent: WO2020/123271,2020,A1
[4]Patent: WO2020/123271,2020,A1
[5]Patent: WO2020/123272,2020,A1

76
[ 358780-14-0 ]
5-amino-3-((benzyloxy)methyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carbonitrile [ No CAS ]

Reference： [1]Patent: US2018/354955,2018,A1
[2]Patent: US2018/354955,2018,A1
[3]Patent: WO2020/123271,2020,A1
[4]Patent: WO2020/123271,2020,A1
[5]Patent: WO2020/123272,2020,A1

77
[ 358780-14-0 ]
5-amino-3-((benzyloxy)methyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: US2018/354955,2018,A1
[2]Patent: US2018/354955,2018,A1
[3]Patent: WO2020/123271,2020,A1
[4]Patent: WO2020/123271,2020,A1
[5]Patent: WO2020/123272,2020,A1

78
[ 358780-14-0 ]
C₂₂H₁₇F₃N₈O [ No CAS ]
C₂₂H₁₇F₃N₈O [ No CAS ]
C₂₂H₁₇F₃N₈O [ No CAS ]
C₂₂H₁₇F₃N₈O [ No CAS ]

Reference： [1]Patent: US2018/354955,2018,A1
[2]Patent: US2018/354955,2018,A1

79
[ 358780-14-0 ]
(1,2-trans)-2-(3-((benzyloxy)methyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutanecarbonitrile [ No CAS ]

Reference： [1]Patent: US2018/354955,2018,A1
[2]Patent: US2018/354955,2018,A1

80
[ 358780-14-0 ]
(1,2-trans)-2-(3-((benzyloxy)methyl)-4-oxo-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)cyclobutanecarboximidamide [ No CAS ]

Reference： [1]Patent: US2018/354955,2018,A1
[2]Patent: US2018/354955,2018,A1

81
[ 358780-14-0 ]
3-((benzyloxy)methyl)-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(6(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one [ No CAS ]

Reference： [1]Patent: US2018/354955,2018,A1
[2]Patent: US2018/354955,2018,A1

82
[ 358780-14-0 ]
3-(hydroxymethyl)-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one [ No CAS ]

Reference： [1]Patent: US2018/354955,2018,A1
[2]Patent: US2018/354955,2018,A1

83
[ 358780-14-0 ]
4-oxo-6-((1,2-trans)-2-(pyrimidin-2-yl)cyclobutyl)-1-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-3-carbaldehyde [ No CAS ]

Reference： [1]Patent: US2018/354955,2018,A1
[2]Patent: US2018/354955,2018,A1

84
[ 358780-14-0 ]
[ 870-46-2 ]
tert-butyl 2-(1-(6-(trifluoromethyl)pyridin-3-yl)ethyl)hydrazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Acetic acid (1.589 ml,27.8 mmol) was added to a stirred mixture of tert-butylcarbazate (11.53 g, 87 mmol) and 1-(6-(trifluoromethyl) pyridine-3-yl)ethanone (15 g, 79 mmol) in ethanol (375 ml) at ambient temperature and the mixture was stirred at 80 C. for 2 h. The solvent was removed under reduced pressure and acetonitrile (375 ml) and acetic acid (18.16 ml, 317 mmol) were added at ambient temperature followed by sodium cyanoborohydride (9.97 g, 159 mmol). The reaction was heated at 80 C. and after 48 hours at the solvent was removed under vacuum. The crude residue was dissolved in Et20/H20 (150:50 ml) and pH brought to 13 by carefully adding solid KOH. The organic layer was separated, washed with brine (ixiOO mL) dried over Na2504 and concentrated under reduced pressure to afford the title compound. LCMS (ES, mlz): 305 [M+H].

Reference： [1]Patent: US2018/354955,2018,A1 .Location in patent: Paragraph 0452
[2]Patent: WO2020/123272,2020,A1 .Location in patent: Page/Page column 77

85
[ 358780-14-0 ]
[ 870-46-2 ]
tert-butyl 2-(1-(6-(trifluoromethyl)pyridin-3-yl)ethylidene)hydrazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In ethanol; at 80℃; for 2h;	To a solution of 1-(6-(trifluoromethyl) pyridin-3-yl)ethan-1-one (10 g, 53 mmol), tert-butyl hydrazinecarboxylate (7.7 g, 58 mmol) in EtOH (250 mL) was added AcOH (1.1 g, 17 mmol) at room temperature. The reaction solution was stirred at 80 C. for 2 h. The reaction was concentrated under vacuum to afford tert-butyl 2-(1 -(2- chioropyrimidin-5-yl)ethylidene)hydrazinecarboxylate and used directly in the next step.

Reference： [1]Patent: US2018/354955,2018,A1 .Location in patent: Paragraph 0431
[2]Patent: WO2020/123271,2020,A1 .Location in patent: Page/Page column 47

86
[ 358780-14-0 ]
2-(3,5-difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide [ No CAS ]