[ CAS No. 214759-21-4 ] {[proInfo.proName]}

Name: 214759-21-4|(2,4,6-Trifluorophenyl)methanamine|95%
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SKU: A303259
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Quality Control of [ 214759-21-4 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 214759-21-4 ]

Product Details of [ 214759-21-4 ]

CAS No. :	214759-21-4	MDL No. :	MFCD00236317
Formula :	C₇H₆F₃N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RCHOKTKXVKKNBC-UHFFFAOYSA-N
M.W :	161.12	Pubchem ID :	2777046
Synonyms :

Calculated chemistry of [ 214759-21-4 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	33.99
TPSA :	26.02 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) :	-6.52 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.82
Log Po/w (XLOGP3) :	1.08
Log Po/w (WLOGP) :	2.67
Log Po/w (MLOGP) :	2.84
Log Po/w (SILICOS-IT) :	2.7
Consensus Log Po/w :	2.22

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.86
Solubility :	2.24 mg/ml ; 0.0139 mol/l
Class :	Very soluble
Log S (Ali) :	-1.22
Solubility :	9.75 mg/ml ; 0.0605 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-3.27
Solubility :	0.0865 mg/ml ; 0.000537 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.1

Safety of [ 214759-21-4 ]

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

Application In Synthesis of [ 214759-21-4 ]

* 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 [ 214759-21-4 ]
Downstream synthetic route of [ 214759-21-4 ]

[ 214759-21-4 ] Synthesis Path-Upstream 1~5

1
[ 96606-37-0 ]
[ 214759-21-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With ammonia; hydrogen In methanol at 90℃; for 8 h; Autoclave	50 g of 2,4,6-trifluorobenzonitrile was charged into a 1000 ml autoclave,2.5 grams of Raney-Ni, 75 grams of 25percent ammonia,500 g of methanol,The control temperature is 90 , the mixing speed is 350r / min,Hydrogen hydrogenation,Hydrogenation pressure 1Mpa, hydrogen time 8 hours reaction end,Filtration of the catalyst Raney-Ni, distillation of the methanol in the filtrate, distillation of the end of the addition of dichloromethane extraction, extraction of the first pressure of the solvent, and then vacuum distillation of the product, the product 43.6 grams, 2,4,6-trifluorobenzene The amine content was 99percent and the yield was 85percent based on 2,4,6-trifluorobenzonitrile.
39.3%	at 10 - 15℃; for 5 h; Autoclave	50 g of 2,4,6-trifluoro-3,5-dichlorobenzonitrile was added to a 500 ml autoclave.200 g of ethyl acetate, 67 g of triethylamine, 6 g of 10percent wet palladium on carbon, sealed autoclave,First, replace the gas with nitrogen three times, then replace the gas with hydrogen for 5 times, control the internal pressure of the reactor with hydrogen to 1.0~1.2 MPa, at 60~65 ° (hydrogenation reaction for 8 hours, sample analysis, disappearance of the raw materials. Filtration of the reaction solution,The filtrate was concentrated under reduced pressure to give crude 2,4,6-trifluorobenzonitrile.The obtained crude 2,4,6-trifluorobenzonitrile was transferred into a 500 ml autoclave, and 300 g of propionic acid was added.7.5 g of 5percent dry palladium carbon, sealed autoclave, first replace the gas with nitrogen for 3 times, then replace the gas with hydrogen for 5 times, control the internal pressure of the autoclave with hydrogen to 1.3~1.5 MPa, and hydrogenate at 10~15 °C for 5 hours. Sampling analysis,The raw materials disappeared. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure.Adjust the pH to alkaline with 20percent potassium carbonate solution, let stand, and separate the organic phase.After rectification, 14.0 g of a colorless transparent liquid was obtained, which was 2,4,6-trifluorobenzylamine, the yield was 39.3percent, and the purity was 98.5 percent.
6 g	at 90℃; for 16 h;	3,5-Dichloro-2,4,6-trifluorobenzonitrile (15.0, 66.4 mmol),Diisopropylethylamine (25.7g,199.2mmol) and 0.75g 10percent Pd/C,450 mL of ethyl acetate was put into a 1000 mL autoclave.Replace it with nitrogen three times.Through hydrogen pressure to 0.5Mpa,Warming to 90 °C, reaction 12h.Sampling analysisThe raw material disappearsRemove insolubles,Vacuum recovery of solvent,Intermediate 2,4,6-trifluorobenzonitrile was obtained.The intermediate-trifluorobenzonitrile was dissolved in 250 mL acetic acid,1.5g 10percentPd/C, nitrogen replaced three times,With hydrogen pressure to 1.0Mpa,Warming to 90°C,Reaction 16h. Sampling analysisRaw material disappears, insolubleThe product was distilled under reduced pressure to recover the solvent.Add 150 mL of dichloromethane to the residue.Cool the mixture to 0-5 °C with an ice bath.Adjust the pH to about 10 with liquid caustic.Separate the organic phase.Dry organically with anhydrous sodium sulfatefilter,After atmospheric distillation to recover the solvent,Distillation under reduced pressure gave 2,4,6-trifluorobenzylamine (6.0 g, 56.1percent yield over two steps) with an HPLC content of 99.3percent.

Reference： [1] Patent: CN106349083, 2017, A, . Location in patent: Paragraph 0025; 0026
[2] Patent: CN108586267, 2018, A, . Location in patent: Paragraph 0096-0102
[3] Patent: CN107778183, 2018, A, . Location in patent: Paragraph 0051; 0052; 0054; 0056; 0058; 0072; 0074; 0076

2
[ 31881-89-7 ]
[ 214759-21-4 ]

Yield	Reaction Conditions	Operation in experiment
89.8%	Stage #1: at 30 - 35℃; for 5 h; Autoclave Stage #2: With Johnson & Matthey type 440; magnesium oxide In methanol at 20 - 25℃; for 6 h; Autoclave	In a 500 ml autoclave, 45 g of 2,4,6-trifluoro-3,5-dichlorobenzonitrile, 315 g of n-butyric acid, 4.5 g of 10percent wet palladium carbon, and a closed autoclave were used. Replace the gas three times, then replace the gas with hydrogen for 5 times, and control the internal pressure of the autoclave with 0.3 to 0.4 MPa.Hydrogenation reaction at 30~35" € for 5 hours.The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to remove n-butyric acid, and 180 g of water was added thereto, and stirred at room temperature.Adjust the pH to alkaline with sodium hydroxide solid, let stand, separate the organic phase, and set aside. The above organic phase was added to a 500 ml autoclave, and 225 g of methanol, 12 g of magnesium oxide, and 4.5 g of 5percent dry palladium carbon were added, and the autoclave was sealed, and the gas was first replaced with nitrogen three times, and then the gas was replaced with hydrogen. 5 times, the internal pressure of the autoclave was controlled by hydrogen to 0.2 to 0.3 MPa at 20 to 25 ° (hydrogenation reaction for 6 hours. The reaction liquid was filtered, and the filtrate was concentrated under reduced pressure. The concentrated liquid was rectified to obtain 28.8 g of a colorless transparent liquid. ,4,6-trifluorobenzylamine,The yield was 89.8percent, and the purity was 99.7percent.

Reference： [1] Patent: CN108586267, 2018, A, . Location in patent: Paragraph 0087-0094; 0102-0103
[2] Patent: CN108586267, 2018, A,

3
[ 20925-85-3 ]
[ 214759-21-4 ]

Reference： [1] Patent: CN107778183, 2018, A,
[2] Patent: CN108586267, 2018, A,
[3] Patent: CN108586267, 2018, A,
[4] Patent: CN108586267, 2018, A,

4
[ 372-38-3 ]
[ 214759-21-4 ]

Reference： [1] Patent: CN104610068, 2016, B,

5
[ 58551-83-0 ]
[ 214759-21-4 ]

Reference： [1] Patent: CN104610068, 2016, B,

[ 214759-21-4 ] Synthesis Path-Downstream 1~88

1
[ 1171823-26-9 ]
[ 214759-21-4 ]
[ 1304701-53-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 760 - 763

2
[ 214759-21-4 ]
[ 1304699-85-1 ]
[ 1304701-74-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 760 - 763

3
[ 871002-41-4 ]
[ 214759-21-4 ]
C₂₉H₂₆F₆N₄O₅ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 2594 - 2597

4
[ 321432-82-0 ]
[ 214759-21-4 ]
[ 1393999-78-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; for 72h;Reflux; Inert atmosphere;	A mixture of 4-chloro-5-methoxy-2-(pyridin-2-yl)pyrimidine (4) (100 mg), 4-fluoro-2-(trifluoromethyl)benzylamine (57 muL) and potassium carbonate (38 mg) in acetonitrile (2 mL) was refluxed for 3 days. The reaction mixture was cooled to room temperature, diluted with water and extracted with CHCl3. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (CHCl3: MeOH = 90:10). The obtained pale brown oil was dissolved in 1,4-dioxane (10 ml). A 4N HCl/AcOEt solution (1 ml) was added at room temperature and the mixture was diluted with diisopropyl ether. A precipitated solid was collected and dried in vacuo to afford N-(2-Fluorobenzyl)-5-methoxy-2-(pyridin-2-yl)pyrimidin-4-amine HCl salt (20) (106 mg, 61% yield) as a pale brown solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 5681 - 5684

5
[ 321432-82-0 ]
[ 214759-21-4 ]
5-methoxy-2-(pyridin-2-yl)-N-(2,4,6-trifluorobenzyl)pyrimidin-4-amine dihydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 5681 - 5684

6
[ 214759-21-4 ]
C₂₄H₃₁N₅O₄S₂ [ No CAS ]
C₃₀H₃₃F₃N₆O₃S [ No CAS ]

Reference： [1]Bioorganic and medicinal chemistry letters,2012,vol. 22,p. 6967 - 6973,7

7
[ 214759-21-4 ]
2-(4-((4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetic acid [ No CAS ]

Reference： [1]Patent: WO2013/174895,2013,A1

8
[ 214759-21-4 ]
N-(1-cyanoethyl)-2-(4-((4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetamide [ No CAS ]

Reference： [1]Patent: WO2013/174895,2013,A1

9
[ 214759-21-4 ]
N-ethyl-2-(4-((4-((2,4,6-trifluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)acetamide [ No CAS ]

Reference： [1]Patent: WO2013/174895,2013,A1

10
[ 3934-20-1 ]
[ 214759-21-4 ]
2-chloro-N-(2,4,6-trifluorobenzyl)pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 0 - 20℃;	<strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (5 g, 31 mmol) was added dropwise to a stirred suspension of 2,4- dichloropyrimidine (4.6 g, 31 mmol) and DIPEA (5.4 mL, 62 mmol) in IPA (100 mL) at 0C then the reaction mixture was warmed to room temperature and stirred overnight. The precipitate was collected and washed with diethyl ether to afford the first crop of 2-chloro-N- (2,4,6-trifluorobenzyl)pyrimidin-4-amine IV- 1. The filtrate was concentrated and purified by column chromatography (0-30% v/v ethyl acetate / petrol) to afford a second crop (total yield 5.3 g, 62%). LC-MS (Method F), RT = 2.27 min. (ES+) 274

Reference： [1]Patent: WO2013/174895,2013,A1 .Location in patent: Page/Page column 67; 68

11
[ 214759-21-4 ]
[ 1156722-48-3 ]
[ 1534390-53-8 ]

Yield	Reaction Conditions	Operation in experiment
98 mg	In acetonitrile; at 100 - 180℃; for 3h;Microwave irradiation;	Step 1 : Preparation of N-(3,4-dimethoxyphenyl)-2-[(2,4,6- trifluorobenzyl)amino]pyridine-3-sulfonamide A solution of (IntCI) (82 mg, 0.25 mmol) and <strong>[214759-21-4]2,4,6-trifluorobenzyl amine</strong> (120 mg, 0.75 mmol) in acetonitrile (1.5 mL) was heated at 100C in a Biotage Initiator microwave reactor for 1 h. Further <strong>[214759-21-4]2,4,6-trifluorobenzyl amine</strong> (120 mg, 0.75 mmol) was added and the mixture heated at 180C in a Biotage Initiator microwave reactor for 2 h. After concentration in vacuo purification by gradient column chromatography eluting with 15-60% EtOAc in iso-hexane yielded the title compound (98 mg, 0.22 mmol). LCMS (Method B): m/z 454 (M+H)+ (ES+), at 1.22 min.

Reference： [1]Patent: WO2014/6402,2014,A1 .Location in patent: Page/Page column 122

12
[ 214759-21-4 ]
[ 1534390-23-2 ]
C₂₄H₂₆F₃N₅O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 120℃; for 12h;	2-[6-Methoxy-5-(methylamino)pyridin-2-yl]-4-(2,4,6-trifluorobenzyl)-2H- pyrido[2,3-e][1 ,2,4]thiadiazin-3(4H)-one 1 ,1 -dioxide (172) The title compound (266 mg, 0.55 mmol) was prepared in three steps from te/f-butyl (6-[(2-chloropyridin-3-yl)sulfonyl]amino}-2-methoxypyridin-3-yl)methylcarbamate (lntC8) (755 mg, 1.76 mmol), <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (1.13 g, 7.01 mmol) and A/,A/-diisopropylethylamine (0.46 mL, 2.64 mmol) in MeCN (10 mL) at 120C for 12 hours; followed by 1 , 1 '-carbonyldiimidazole (832 mg, 5.13 mmol) and triethylamine (358 uL, 2.57 mmol) using the methods of (95); followed by TFA (2 mL) in DCM (3 mL) at rt using the method of (179), step 2. LCMS (Method B): m/z 480.1 (M+H)+ (ES+), at 4.62 min, 100% 1H NMR: (400 MHz, DMSO) delta: 2.70 (d, J=5.0, 3H), 3.78 (s, 3H), 5.53 (s, 2H), 5.77 (d, J=5.0, 1 H), 6.73 (d, J=8.2, 1 H), 6.87 (d, J=7.8, 1 H), 7.14 (t, J=8.9, 2H), 7.46 (dd, J=7.8, 5.0, 1 H), 8.17-8.42 (m, 1 H), 8.60-8.79 (m, 1 H)

Reference： [1]Patent: WO2014/6402,2014,A1 .Location in patent: Page/Page column 125-126

13
[ 214759-21-4 ]
[ 1616340-91-0 ]
[ 1656286-93-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 2h;	Step 7 A 100-mL round bottom flask was charged with reactant 41-G (0.14 g, 0.37 mmol ), <strong>[214759-21-4](2,4,6-trifluorophenyl)methanamine</strong> (0.12 g, 0.73 mmol), N,N- diisopropylethyiamme (DIPEA) (0.24 g, 1.84 mmol) and HATU (0.28 g, 0.74 mmol) were dissolved in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL) and washed with saturated Na C03 (2x), saturated NH4CI (2x) and dried over Na2S04. After concentration, the crude was purified by column chromatography on silica gel with hexane-EtOAc to afford compound 41-H. LCMS-ESf (m/z): [M+H]+ calculated for ( i J I ,oF A .()-: 524.5; found: 524.5

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 96; 98

14
[ 214759-21-4 ]
[ 1616342-45-0 ]
[ 1616340-94-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In acetonitrile; for 1.5h;	Step 3 Intermediate 42-A (0.225 g, 0.702 mmol) and (2,4,6- trifluorophenyl)methanamine (0.125 g, 0.773 mmol) were suspended in acetonitrile (4 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.183 mmol, 1.05 mmol). To this suspension was added (dimethyiammo)- V,A/-dimethyi(3H-[l ,2,3]triazolo[4,5- &]pyridm~3-yiox.y)methammimum hexafluorophosphate (HATU, 0.294 g, 0.774 mmol). After 1.5 hours, the crude reaction mixture was taken on to the next step. LfJMS-ESlT (m/z): [M+H calculated for ( ,l l.,, i :0< : 464.14; found: 464.2.
	With 4-methyl-morpholine; chloroformic acid ethyl ester; In dichloromethane; at 0℃;Flow reactor;	A solution of l-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-l,4- dihydropyridine-3 -carboxylic acid (V) in acetic acid / Dimethyl carbonate (lOg, 0.032 moles) and methane sulfonic acid (0.30g, 0.003 moles) were introduced in micro channel reactor. After residence time of 9 mins at l30C, the reaction mixture containing 5-methoxy-6-(m ethoxy carbonyl)-4-oxo- 1 -(2-oxoethyl)- 1 ,4- dihydropyridine-3 -carboxylic acid (IVa) was further introduced into a second Tube Flow reactor and cyclised with solution of (lR,3S)-3-aminocyclopentanol (3.85g,0.038 moles) in Dimethyl carbonate at l00C at a residence time of 6 mins followed by quenching with Aq HC1 solution. The organic layer containing (2R,5 S, l3aR )-8-methoxy -7 ,9-dioxo-2,3,4,5, 7,9, 13, l3a-octahydro-2,5- methanopyrido[ 1 ',2':4,5]pyrazino[2, l-b ][l ,3]oxazepine-l0-carboxilic acid (III c) was separated and introduced into a third Tube Flow Reactor with a solution of N- Methyl Morpholine (4.8lg,0.048 moles) and a solution of (2,4,6-trifluorophenyl) methanamine (6. l2g, 0.038 moles) in MDC solvent and reacted in presence of Ethyl chloroformate (4.82g,0.044 moles) at 0C . After a residence time of 2 mins yields (2R,5 S, 13 aR )-8-m ethoxy -7 ,9-dioxo-N -(2,4,6-trifluorobenzyl)- 2, 3, 4, 5, 7,9, 13, l3a-octahydro-2,5-ethanopyrido[r,2':4,5]pyrazino[2, l-b][l,3]oxazepine-l0- carboxamide( lie) which was isolated in IPA after acid base workup. (0326) HPLC purity : 95.0% (0327) Yield : 80%.
		Charged (2R,5S,l3aR) -8-methoxy-7,9-dioxo-2,3,4,5,7,9,l3,l3a-octahydro-2,5- methano pyrido[l',2':4,5]pyrazino[2, l-b][l,3]oxazepine-l0-carboxylicacid, (60gm, 0.1874 moles) in methylene chloride (390 ml) at 25-30C under nitrogen. Cooled the reaction mixture to -15 to -l0C. N-methylmorpholine (20.7gm, 0.2047moles) was added to the reaction mixture at -15 to -l0C. Isobutylchloroformate (28gm, 0.205moles) in methylene chloride (60ml) was added for 1 hr to the cold reaction mass. (2,4,6- trifluorophenyl) methanamine (33gm, 0.204 moles) in methylene chloride (60 ml) was added to the above reaction mixture for 45 minutes at-20 to -l5C. Raised the temperature to 25-30C and stirred for 2.30 hrs. After completion of reaction, the reaction mass was washed with sodiumbicarbonate (l20ml), 1N HC1 (l20ml) water (l20ml) and concentrated. The Concentrated mass diluted with IPA (60 ml) and stirred for 20 minutes n-heptane was added to the reaction mass for 30 minutes at 25-30C and stirred for 3 hours to crystallize the product. The product was filtered and dried to yield the title compound.Yield-90%; Purity by HPLC (by chromatography): 94.16%

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 100-101
[2]Patent: WO2019/159199,2019,A1 .Location in patent: Page/Page column 43; 44; 45
[3]Patent: WO2020/3151,2020,A1 .Location in patent: Page/Page column 20

15
[ 214759-21-4 ]
[ 1616341-15-1 ]
[ 1616341-16-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	Step 7 A suspension of the crude residue 57-G (189 mg), 2,4,6- <strong>[214759-21-4]trifluorobenzylamine</strong> (95 mg, 0.59 mmol) and HATU (276 mg, 0.73 mmol) in dichloromethane (3 ml) was stirred at room temperature as N,N-diisopropylethylamine (DIPEA) (0.59 ml, 3,4 mmol) was added. After 1 h he mixture was diluted with water, extracted into EtOAc (3x). The combined organic phases were dried (Na2S04) and concentrated to 57-H. LCMS-ESI* (m/z): [M+H]+ calculated for C28H22F5N3O4: 559,48; found: 560.24,

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 127; 129

16
[ 214759-21-4 ]
C₃₇H₃₈N₂O₆Si [ No CAS ]
[ 1616341-24-2 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 2h;	Step 6 A mixture of 59-F (680 mg, 1.03 mmol) in MeOH (10 ml) and THE (10 ml) was stirred at room temperature as IM KOH (5.42 ml) was added. After 30 min the reaction mixture was neutralized with IN HC1, extracted into EtOAc (2x) and the combined organic extracts were dried (Na2SQ4) and concentrated. LC S-ESI4 (m/z): [M+H]+ calculated for ( I N .O,.Si : 634.79; found: 635.466. A suspension of the cmde residue (650 mg), <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (214 mg, 1.33 mmol) and HATU (623 mg, 1.64 mmol) in dichloromethane (6 mi) was stirred at room temperature as Nu,Nu-diisopropylethylamine (DIPEA) (1 .34 ml, 7.68 mmol) was added. After 2 h, the mixture was diluted with water, extracted into EtOAc (3x) nad the combined organic phases were dried (Na?S04), concentrated and the residue was purified by silica column chromatography (50-75% EtOAc/hexanes) to afford 59~G. LCMS-ESI+ (m/z): j · H \| calculated for ' n :..;.>X ^Si : 777.9; found: 778,566.

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 132; 134; 135

17
[ 214759-21-4 ]
[ 1616342-35-8 ]
[ 1616341-39-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h;	Step 7 A 100-mL round bottom flask was charged with 81-H (0.56 g, 1 .4 mmol) in THF (5 mL) and MeOH (5 mL). 1 N OH (4 mL) was added to the reaction mixture. Then the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1 N HCl (4 mL), After concentration, the residue was co-evaporated with toluene (3 x). Half of the crude acid, 2,4,6- trifluobenzylamme (0.2 g, 1.3 mmol), N,N-diisopropylethylamine (DIPEA) (0,41 g, 3 , 1 mmol) and HATU (0.48 g, 1 .25 mmol) were dissolved in D F (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc ( 100 mL) and washed with saturated NaHC03 (2x), saturated M I iota( (2x) and dried over Na2S04. After concentration, the crude was purified by column chromatography on silica gel with hexane-EtOAc to afford 81-1. LCMS-ESI4' (m/z) [M+H] 4 found: 542,

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 154; 156

18
[ 214759-21-4 ]
[ 1616342-36-9 ]
[ 1616341-46-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 2h;	Step 7 A 1.00-mL round bottom flask was charged with 82-H (0.2 g, 0.49 mmol ) in THF (5 mL) and MeOH (5 mL). 1 N OH (1.5 mL) was added to the reaction mixture. Then the reaction mixture was stirred at room temperature for I hour. The reaction mixture was acidified by adding 1 N HCl (1.5 mL). After concentration, the residue was co-evaporated with toluene (3 x). The crude acid, 2,4,6-trifluobenzylamine (0.15 g, 0.95 mmol), N.N-diisopropylethyiamiiie (DIPEA) (0.31 g, 2.4 mmol) and HATU (0.36 g, 0.95 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (100 mL) and washed with saturated aHC03 (2x), saturated NH4C1 (2x) and dried over Na2S04. After concentration, the crude was purified by column chromatography on silica gei with hexane-EtOAc to afford 82-1. LCMS-ESF (m/z): [M+H]4 found: 542.

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 158; 160

19
[ 214759-21-4 ]
[ 1616342-37-0 ]
[ 1616341-54-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 2h;	Step 8 A 100-mL round bottom flask was charged with 83- (0.2 g, 0.47 mmol) in THF (5 mL) and MeOH (5 mL). 1 N KOH (1.4 mL) was added to the reaction mixture. Then the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1 N HCl (1.4 mL). After concentration, the residue was co-evaporated with toluene (3 x). The crude acid, 2,4,6~trifiuobenzylamme (0.14 g, 0.91 mmol), Nu,Nu-diisopropylemylarmne (DIPEA) (0.29 g, 2.2 mmol) and HATU (0.35 g, 0.91 rnmol) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (100 mL) and washed with saturated NaHC03 (2x), saturated NH4CI (2x) and dried over 'Na2S04. After concentration, the crude was purified by column chromatography on si lica gel with hexane-EtOAc to afford 83-J. LCMS-ESI+ (m/z): [M+Hf found: 560.

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 162; 164; 165

20
[ 214759-21-4 ]
[ 1616342-38-1 ]
[ 1616341-63-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 2h;	Step 9 A IGO-mL round bottom flask was charged with 84-J (0.4 g, 0.98 mmol) in THF (5 mL) and MeOH (5 mL). 1 N OH (3.0 mL) was added to the reaction mixture. Then the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1 N HCl (3.0 mL), After concentration, the residue was co-evaporated with toluene (3 x). The crude acid, 2,4,6-trifIuobenzylamine (0.32 g, 1.96 mmol), , -diisopropylethyamine (DI PEA) (0.63 g, 4.9 mmol) and HATU (0.74 g, 1.9 mmol ) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (100 mL) and washed with saturated NaHC0 (2x), saturated NH Cl (2x) and dried over Na2S04. After concentration, the crude was purified by column chromatography on silica gel with hexane-EtOAc to afford 84-K. LCMS~ESI+ (m/z): [M+H]+ found: 538.

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 166; 169

21
[ 214759-21-4 ]
[ 1616341-71-9 ]
[ 1616341-70-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 0.5h;	Step 9 A mixture of 85- J (214 mg, 0.507 mmol) in THF (4 mL) and MeOH (4 mL) was stirred at room temperature as 1 N KOH (1 .1 mL) was added. After 30 min, the reaction mixture was concentrated to ~1 mL, acidified with 1 N HQ (~1.2 raL), and diluted with brine before extraction with CH2Ci2 (20 mL x 2). The combined extracts were dried (Na2S04) and concentrated to obtain the crude acid. LCMS-ESI+ (m/z): [M +H]+ calculated for C22H23N2O5 : 395.2; found: 395.3. A mixture of the crude acid (199 mg, 0.505 mmol), <strong>[214759-21-4]2,4,6-trifluorobenzyl amine</strong> (130 mg, 0.807 mmol), and HATU (304 mg, 0.800 mmol) in CH2Ci2 (6 mL) was stirred at room temperature as N.N-diisopropylethyiamine (DIPEA) (0.62 mL, 3.559 mmol) was added. After 30 mm, the reaction mixture was concentrated and the residue was dissolved in EtOAc, washed with saturated aqueous NH4C1 (x 2), saturated aqueous NaHC03 (x 2), and brine. After the aqueous fractions were extracted with EtOAc, two organic fractions were combined, dried (Na2S04) and concentrated. The residue was purified by flash using EtOAc-20%MeOH/EA as eluents to obtain 85- . -NMR (400 MHz, CDCI3) delta 10.40 (t, J = 5.7 Hz, IH), 8.42 (s, 1 H), 7.68 - 7.54 (m, 2H), 7.33 (ddd, J = 7.7, 6.3, 1.5 Hz, 2H), 7.30 - 7.26 (m, IH), 6.74 - 6.60 (m, 2H), 5.37 (d, J = 10.0 Hz, IH), 5.17 (d, J = 10.0 Hz, IH), 4.76 - 4.57 (m, 2H), 4.46 (dd, J = 6.0, 4.3 Hz, I H), 4.34 (t, J = 12.4 Hz, IH), 4.07 (dd, J = 12.4, 3.6 Hz, I H), 3.91 (dt, J = 12.4, 3.9 Hz, I H), 2.52 - 2.44 (m, I H), 2.32 (dd, J = 1 1 .8, 6.2 Hz, IH), 1 .92 (dt, J = 10.7, 5.4 Hz, I H), 1 .83 - 1.70 (m, 3 H i. 1 .67 (d, J = 1 1 .7 Hz, I H), 1 .52 (dddt, J - 25.5, 17.0, 1 1 .8, 5.3 Hz, 2H). "F-NMR (376 MHz, CDCI3) delta -109.15 (dq, J ==: 15.0, 7.5, 7.1 Hz, I F), - 1 1 1.85 (t, J = 6.8 Hz, 2F). LCMS-ES (m/z): [M +Hf calculated for C29H27F3N3O4: 538.2; found: 538.3.

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 170; 174; 175

22
[ 214759-21-4 ]
[ 1616341-81-1 ]
[ 1616341-79-7 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 0.5h;	Step 10 A mixture of 86- J (83 rag, 0.196 mmol) in THF (2 mL) and EtOH (2 mL) was stirred at room temperature as 1 N OH (0.4 mL) was added. After 30 mitt, the reaction mixture was diluted with water and washed with CH2Cl2. After the aqueous fraction was acidified with 1 N HCI 0,45 mL), the product was extracted with CI ··('·· (x 2). The combined extracts were dried (Na2S04) and concentrated to obtain the crude acid. LCMS-ESF (m/z): [M +H]+ calculated for C22H23N2O5: 395.2; found: 395.2. A mixture of the crude acid (69 mg, 0.175 mmol), <strong>[214759-21-4]2,4,6-trifluorobenzyl amine</strong> (42 mg, 0.261 mmol), and HA.TU (106 mg, 0.279 mmol) in CH2Ci2 (3 ml.) was stirred at room temperature as Nu,Nu-diisopropyiethylamine (DIPEA) (0.25 mL, 1.435 mmol ) was added. After 30 min, the reaction mixture was concentrated and the residue was dissolved in EtOAc, washed with saturated aqueous NH4CI (x 2), saturated aqueous NaHC03 (x 2), and brine. After the aqueous fractions were extracted with EtOAc, two organic fractions were combined, dried (Na2S04) and concentrated. The residue was purified by flash chromatography using EtOAc-20%MeOH/EtOAc as eluents to obtain 86-K. 1H- MR (400 MHz, CDC1) delta 10.40 (t, J - 5.7 Hz, IH), 8.40 (s, IH), 7.66 - 7.51 (m, 2H), 7.36 - 7.29 (m, 2H), 7.29 - 7.23 (m, IH), 6.71 - 6.61 (m, 2H), 5.36 (d, J = 10.0 Hz, IH), 5.18 (d, J = 10.0 Hz, IH), 4.73 - 4.58 (m, 2H), 4.53 (s, IH), 4.22 - 4.11 (m, IH), 4.03 (dd, J = 12.4, 3.1 Hz, IH), 3.81 (dt, J = 12.3, 3.1 Hz, IH), 2.68 - 2.59 (m, IH), 2.29 (dddd, J = 11.4, 7.1, 4.7, 2.4 Hz, IH), 1.94 (ddd, J = 13.5, 11.2, 4.6 Hz, IH), 1.88 - 1.67 (m, 2H), 1.06 (d, J = 7.0 Hz, 3H), 1.03-1.09 (m, IH). i9F- MR (376 MHz, CDCI3) 8 -109.14 (ddd, J = 15.2, 8.7, 6.2 Hz, IF), -111.86 (t, J = 7.0 Hz, 2F). LCMS-ESf (mz): [M H\| calculated for Omicron,Iota -.Lambda,Omicron,: 538.2; found: 538.1.

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 177; 182

23
[ 214759-21-4 ]
C₂₂H₂₂N₂O₅ [ No CAS ]
C₂₉H₂₆F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 2h;	Example 101 Preparation of Compound 101 (1 R,4R, 12aS)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifliiorobeTizyl)- 1 ,2,3,4,6,8, 12, 12a- octahydro- 1 ,4-ethanodipyrido[ 1 ,2-a: 1 ',2'-d]pyrazine-9-carboxamide A 100-mL rbf was charged with 101-A (0.3 g, 0.72 mmol) in THF (2 mL) and MeOH (2 mL). 1 N KOI I (2.1 mL) was added to the reaction mixture. Then the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1 N HC1 (2, 1 mL). After concentration, the residue was co- evaporated with toluene (3 x). The cmde acid (0.72 mmol), 2, 4, 6-trifluobenzylamine (0.23 g, 1.44 mmol), N,N-diisopropyiethylamme (D1PEA) (0.47 g, 3.6 mmol) and HATU (0.55 g, 1.44 mmol) were dissolved in DCM (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL) and washed with saturated 'NaHC03 (2x), saturated M I (2x) and dried over Na2S04. After concentration, the cmde was purified by column chromatography on silica gel with hexane-EtOAc to afford 101-B. LCMS-ESI+ (m/z): [M+H found: 538. A 50-mL rbf was charged with 101-B (0.36 g, 0.67 mmol) in TFA (5 mL). The reaction mixture was stirred at room temperature for 30 minutes. After concentration, the crude was purified by column chromatography on si lica gel with EtOAc-MeOH to afford compound 101. 1H-NMR (400 MHz, Chioroform-d) delta 12.1 1 (s, 1 H), 10.40 (t, J = 5.8 Hz, 1H), 8.28 (s, 1H), 6.91 - 6.39 (m, 2H), 4.62 (ddd, J = 25.0, 6.5, 2.8 Hz, 1 i h 4.21 (t, J - 12.2 Hz, }.4.09 (dd, J - 12.5, 3.0 Hz, ill).3.93 (dd, J 12.2, 3.1 Hz, 1H), 2.35 - 1.39 (m, 9H).19F NMR (376 MHz, Chloroform-d) delta -112.3 (t, J = 7.7 Hz), -114.78 (q, .1 = 8.5 Hz). LCMS-ESI+ (ni/z): found: 448.

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 203-204

24
[ 214759-21-4 ]
C₂₂H₂₂N₂O₅ [ No CAS ]
C₂₉H₂₆F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 2h;	A 100-mL rbf was charged with 102-G (0.3 g, 0.72 mmol) in THF (2 mL) and MeOH (2 mL). 1 N OH (2.1 mL) was added to the reaction mixture. Then the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1 N HC1 (2, 1 mL). After concentration, the residue was co- evaporated with toluene (3x). The crude acid (0.72 mmol), 2, 4, 6-trifiuobenzylamine (0.23 g, 1.44 mmol), N,N-diisopropyiethylamme (DIPEA) (0.47 g, 3.6 mmol) and HATU (0.55 g, 1.44 mmol) were dissolved in DC (20 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL) and washed with saturated NaHC03 (2x), saturated NH4CI (2x) and dried over Na2S04. After concentration, the crude was purified by column chromatography on silica gel with hexane-EtOAc to afford 102-H. LCMS-ESI* (m/z): [M+H]+ found: 538.

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 206; 208

25
[ 214759-21-4 ]
C₃₇H₃₈N₂O₆Si [ No CAS ]
[ 1616341-08-2 ]

Yield	Reaction Conditions	Operation in experiment
88.2%	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; for 1.5h;	Step 7 The mixture of 56-G (890 mg, 1.34 mmol) in MeOH (14 ml) and THF (14 ml) was stirred at room temperature as 1M OH (7.09 ml) was added. After 30 min the reaction mixture was neutralized with IN HQ, extracted into EtOAc (2x) and the combined organic extracts were dried (Na2S04) and concentrated. A suspension of the cmde residue (850 mg), <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (248 mg, 1.54 mmol ) and HATU (662 mg, 1.74 mmol) in dichioromethane (5 ml) was stirred at room temperature as Nu,Nu-diisopropylethylamine (DIPEA) (1 .63 ml, 9.37 mmol) was added. After 1 h, additional 2,4,6-difluorobenzylamine (32 mg, 0.2 mmol), HATU (153 mg, 0.4 mmol) and Nu,Nu-diisopropylethylamine (DIPEA) (0.12 ml, 0.67 mmol) were added. After 30 minutes the mixture was diluted with water, extracted into EtOAc (3x) the combined organic phases were dried (Na2S04), concentrated and the residue was purified by silica column chromatography (50-75% EtOAc/hexanes) to afford 56- I f (919 mg, 88.23%). LCMS-ESI+ (m/z): i VI · 1 1 1 calculated for C - i - i S:: 777.9; found: 778.409. Step 8 A solution of 56-H (915 mg, 1.18 mmol) in THF (5 ml) was stirred in an ice bath as 1.0 M tetrabutyl ammonium fluoride in THF (1 , 18 ml) was added dropwise. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under vacuum and the residue was diluted with EtOAc, washed with water, dried ( a2S04), concentrated and the residue was purified by si lica column chromatography (50-75% EtOAc hexanes then 5% MeOH/EtOAc). The resulting material (248 mg, 0.46 mmol) was dissolved in dichioromethane (2 ml) cooled to -78C as diethylaminosulfur trifluoride (0.07 mL, 0.55 mmol) was added dropwise and the reaction was warmed to room temperature and stirred for 1 h. The reaction was cooled in an ice bath and quenched with saturated NaHC03, two phases were separated, and the separated aqueous fraction was extracted with CH2C12. The two organic fractions were combined dried (Na2S04), and concentrated. The residue was purified by silica column chromatography (1% MeOH/EtOAc) to afford 56-J (75 mg) (LCMS-ESF (ni/z): [M+H]+ calculated for C28H23F4N3O4 : 541.49; found: 542.320) and 56-1 (30 mg) (LC S-ESI+ ijn/z): [M+H]+ calculated for ( '..xI -W^O i : 521 .49; found: 522.05). Compound 56-J (75 mg, 139 mmol) was dissolved in TFA (1 iriL), stirred at room temperature for 10 minutes, and the solution was concentrated. The residue was purified by reverse phase HPLC (Gemini, 15 to 43% ACN/H20 + 0.1 % TFA) to afford compound 56. ^-NMR (400 MHz, DMSO- 6) delta 10.67 (s, I H), 7.80 (s, IH), 7.17 (t, J = 8.6 Hz, 2H), 5.45 - 5.18 (m, IH), 4.70 - 4.39 (m, 3H), 4.23 (d, J i 1 .5 Hz, I H), 4.1 1 - 3.85 (m, 2H), 2.85 (dd, J = 4.2, 2.0 Hz, H), 2.34 - 2.13 (m, I H), 1.81 (s, IH), 1.55 - 1.33 (m, 2H). "F-NMR (376 MHz, DMSO-ifc) delta -74.20 (m), - 106.95 - -1 16.45 (m), -190.65 - -194.54 (m).

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 122; 125

26
[ 214759-21-4 ]
C₂₀H₁₈N₂O₅ [ No CAS ]
C₂₇H₂₂F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 2h;	Step 3 A mixture of 96-C (112 mg, 0.28 mmol), 1 M aqueous potassium hydroxide (1 mL), 4 mL methanol, and 4 mL THF was stirred at room temperature for 3 hours, at which point the mixture was diluted with dichloromethane, acidified by addition of 1M aqueous hydrogen chloride, and the organic phase extracted to dichloromethane. The combined organics were dried, filtered, and concentrated from toluene. After drying under vacuum, the residue was suspended in 1.5 mL DCM and trifluorobenzyiamine (62 mg, 0.38 mmol), HA.TU (220 mg, 0.58 mmol), and N,N~ diisopropyiethyl amine (DIPEA) (0.15 mL, 0.86 mmol) were added. This reaction mixture wras stirred at room temperature for 2 hours to afford 96-D which was carried forward as crude.

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 191; 192

27
[ 214759-21-4 ]
[ 1616340-76-1 ]
[ 1616340-97-6 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In acetonitrile; at 20℃; for 2h;	Example 45 Preparation of Compound 45 ( 13aS)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3 ,4,5 ,7,9,13, 13a-octahydro- 2,5-methanopyrido[ 1 ',2':4,5]pyrazino[2, 1 -b] [ 1 ,3]oxazepine-l 0-carboxamide Step 1 Compound 15-B (38 rag, 0, 12 mmol) was taken up in 1 mL acetonitrile and treated with 2,4, 6-trifluorobenzy famine (34 mg, 0.21 mmol), HATU (50 mg, 0.13 mmol), N,N-dii.sopropylethylamine (DIPEA) (23 mg, 0, 1 8 mmol), and stirred at room temperature for 2 hours, after which LCMS analysis revealed complete consumption of compound 15-B and formation of intermediate 45-A. The reaction mixture was carried onto the next step.

Reference： [1]Patent: WO2014/100323,2014,A1 .Location in patent: Page/Page column 104-105

28
[ 214759-21-4 ]
[ 1624255-71-5 ]
[ 1624256-31-0 ]

Reference： [1]ChemMedChem,2014,vol. 9,p. 1704 - 1724

29
[ 214759-21-4 ]
C₂₂H₂₀N₂O₅ [ No CAS ]
C₂₉H₂₄F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	Step 9; A mixture of 12- J (752 mg, 1.841 mmol) in THF (4 mL) and MeOH (4 mL) was stirred at room temperature as IN KOH (3.75 mL) was added. After 1 hour, the reaction mixture was acidified with 3N HCl (ImL), and diluted with brine before extraction with EtOAc. The combined extracts was dried (MgS04) and concentrated.To the mixture of the above crude reactant (158mg, 0.403 mmol) in DCM (4mL) were added <strong>[214759-21-4]2,4,6-trifluorobenzyl amine</strong> (85 mg, 0.52 mmol), and HATU (230 mg, 0.604 mmol) at room temperature followed by DIPEA (0.3 mL, 1.6 mmol). After about 60 min, the reaction mixture was diluted with DCM, washed with saturated NaHCC>3, dried (MgS04), and concentrated. The residue was purified by CombiFlash on silica gel using 0- 20%MeOH/EtOAc to provide compound 12-H.

Reference： [1]Patent: WO2015/6731,2015,A1 .Location in patent: Page/Page column 83

30
[ 214759-21-4 ]
C₁₆H₁₆N₂O₅ [ No CAS ]
C₂₃H₂₀F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1.5h;	Step 1; A mixture of compound 8-H (84 mg, 0.254 mmol) in THF (2 mL) and MeOH (2 mL) was stirred at room temperature as 1 N KOH (1 mL) was added. After 30 min, the reaction mixture was concentrated to ~ 2 mL, acidified with 1 N HC1 (~1.1 mL), concentrated to ~2 mL, and diluted with brine before extraction with CH2CI2 (thrice). The combined extracts was dried (Na2S04) and the solution was used for the next reaction.To the crude acid solution were added <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (57 mg, 0.354 mmol), and HATU (157 mg, 0.413 mmol) at room temperature followed by DIEA (0.31 mL, 1.780 mmol). After -30 min, additional DIEA (0.31 mL, 1.78 mmol) was added. After 1 hour, the reaction mixture was washed with saturated NH4CI and water. After the aqueous fractions were extracted with CH2C12, the two organic fractions were combined, dried (Na2S04) and concentrated. The residue was purified by CombiFlash (24 g column) using ethyl acetate - 20%MeOH/ethyl acetate as eluents to obtain compound 9- A. 1H NMR (400 MHz, Chloroform-d) delta 10.37 (t, J = 5.7 Hz, 1H), 8.36 (s, 1H), 6.74 - 6.57 (m, 2H), 5.03 (s, 1H), 4.64 (qd, J = 14.5, 5.7 Hz, 2H), 4.11 - 4.06 (m, 1H), 4.04 (s, 3H), 3.83 (t, J = 12.0 Hz, 1H), 3.76 (dd, J = 12.2, 2.8 Hz, 1H), 2.74 (d, J = 1.8 Hz, 1H), 1.33 (dd, J = 13.7, 2.8 Hz, 2H), 1.19 - 1.08 (m, 2H), 0.60 (dt, J = 6.6, 3.1 Hz, 1H), 0.40 (q, J = 7.2 Hz, 1H). 19F NMR (376 MHz, Chloroform-d) delta -108.39 - -109.90 (m, IF), -1 1 1.99 (t, J = 6.9 Hz, 2F). LCMS-ESI+ (m/z): [M+H]+ calculated for C23H21F3N3O4: 460.15; found: 460.3.

Reference： [1]Patent: WO2015/6731,2015,A1 .Location in patent: Page/Page column 71; 72

31
[ 214759-21-4 ]
C₂₃H₂₀F₃N₃O₅ [ No CAS ]

Reference： [1]Patent: WO2015/6731,2015,A1

32
[ 214759-21-4 ]
C₂₂H₁₈F₃N₃O₅ [ No CAS ]

Reference： [1]Patent: WO2015/6731,2015,A1

33
[ 214759-21-4 ]
[ 1335210-23-5 ]
C₂₀H₂₁F₃N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 0℃; for 1.5h;	Step 1; A suspension of compound 11-A (965 mg, 3.061 mmol), 2,4,6- trifiuorobenzylamine (493 mg, 3.06 mmol), and HATU (1402 mg, 3.688 mmol) in CH2C12 (15 mL) was stirred in 0 C as DIEA (2 mL, 11.48 mmol) was added.After 1.5 hours at 0 C, the reaction mixture was diluted with ethyl acetate, and washed with water (twice). After the aqueous fractions were extracted with ethyl acetate, the organic fractions were combined, dried (Na2S04), and concentrated. The residue was purified by CombiFlash (40 g column) using hexanes-ethyl acetate as eluents to obtain compound 11-B. 1H NMR (400 MHz, Chloroform-d) delta 10.30 (t, J = 5.9 Hz, 1H), 8.40 (s, 1H), 6.79 - 6.51 (m, 2H), 4.65 (d, J = 5.6 Hz, 2H), 4.48 (t, J = 4.8 Hz, 1H), 4.01 (d, J = 4.8 Hz, 2H), 3.97 (s, 3H), 3.94 (s, 3H), 3.38 (s, 6H). 19F NMR (376 MHz, Chloroform-d) delta - 109.07 - -109.35 (m, IF), -1 1 1.93 (t, J = 6.9 Hz, 2F). LCMS-ESI+ (m/z): [M+H]+ calculated for C20H22F3N2O7: 459.14; found: 459.2.

Reference： [1]Patent: WO2015/6731,2015,A1 .Location in patent: Page/Page column 75; 76

34
[ 214759-21-4 ]
C₂₁H₂₀N₂O₅ [ No CAS ]
C₂₈H₂₄F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	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 20℃; for 52h;	A mixture of compound 3-G (165 mg, 0.404 mmol) in THF (2.5 mL) and MeOH (2.5 mL) was stirred at room temperature as 1 N KOH (2.13 mL) was added. After 30 minutes at room temperature, the reaction mixture was concentrated and diluted with water, acidified with 1 N HCl, and extracted with ethyl acetate (x 2). The extracts were combined, dried (Na2SO4), and concentrated to provide the crude acid. LCMS-ESI+ (m/z): [M+H]+ calculated for C21H21N2O5: 381.15; found: 381.13. A mixture of the crude acid from the previous step (150 mg, 0.394 mmol), <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (76 mg, 0.47 mmol), and HATU (188 mg, 0.49 mmol) in DMF (3 mL) was stirred at room temperature as DIPEA (0.48 mL, 2.76 mmol) was added. After 2 hours, additional <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (32 mg, 0.20 mmol), HATU (105 mg, 0.28 mmol), and DIPEA (0.14 mL, 0.79 mmol) were added and the resulting mixture was stirred at room temperature. After 2 days, additional <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (32 mg, 0.20 mmol), HATU (105 mg, 0.28 mmol), and DIPEA (0.14 mL, 0.79 mmol) were added and the resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with water, extracted with ethyl acetate (x 3), and combined extracts were dried (Na2SO4), and concentrated to provide crude compound 15-A. LCMS-ESI+ (m/z): [M+H]+ calculated for C28H25F3N3O4: 524.18; found: 524.15.

Reference： [1]Patent: WO2015/6733,2015,A1 .Location in patent: Page/Page column 80; 81; 82

35
[ 214759-21-4 ]
C₂₂H₂₂N₂O₅ [ No CAS ]
C₂₉H₂₆F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	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 dichloromethane; at 20℃; for 0.5h;	A mixture of compound 4-B (70 mg, 0.166 mmol) in THF (2 mL) and MeOH (2 mL) was stirred at room temperature as 1 N KOH (0.35 mL) was added. After 2.25 hours, the reaction mixture was concentrated, acidified with 1 N HCl (~0.4 mL), and diluted with brine before extraction with CH2Cl2 (thrice). The combined extracts was dried (Na2SO4) and concentrated. The residual crude acid was used for the next reaction. A mixture of the crude acid, <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (41 mg, 0.254 mmol), and HATU (97 mg, 0.255 mmol) in CH2Cl2 (3 mL) was stirred at room temperature as DIPEA (0.20 mL, 1.148 mmol) was added. After ~30 min, the reaction mixture was diluted with ethyl acetate, and washed with saturated NH4Cl, water, saturated NaHCO3, and brine. After the aqueous fractions were extracted with ethyl acetate, two organic fractions were combined, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate - 20%MeOH/ethyl acetate as eluents to obtain compound 5-A. 1H NMR (400 MHz, Chloroform-d) delta 10.40 (t, J = 5.7 Hz, 1H), 8.35 (s, 1H), 7.64 - 7.53 (m, 2H), 7.35 - 7.23 (m, 3H), 6.74 - 6.57 (m, 2H), 5.41 (d, J = 10.0 Hz, 1H), 5.19 (d, J = 10.0 Hz, 1H), 4.76 - 4.54 (m, 2H), 4.03 (d, J = 2.5 Hz, 2H), 3.76 - 3.63 (m, 1H), 3.50 (d, J = 12.3 Hz, 1H), 2.64 (dq, J = 5.0, 2.4 Hz, 1H), 1.87 - 1.76 (m, 2H), 1.76 - 1.30 (m, 6H).19F NMR (376 MHz, Chloroform-d) delta -109.10 (tt, J = 8.8, 6.3 Hz, 1F), -111.87 (t, J = 7.0 Hz, 2F). LCMS-ESI+ (m/z): [M+H]+ calculated for C29H27F3N3O4: 538.20; found: 538.3.

Reference： [1]Patent: WO2015/6733,2015,A1 .Location in patent: Page/Page column 60; 61; 62

36
[ 214759-21-4 ]
C₂₂H₂₂N₂O₅ [ No CAS ]
C₂₉H₂₆F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	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 dichloromethane; at 20℃; for 1h;	A mixture of compound 6-C (266 mg, 0.674 mmol), <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (150 mg, 0.931 mmol), and HATU (390 mg, 1.026 mmol) in CH2Cl2 (10 mL) was stirred at room temperature as DIPEA (0.82 mL, 4.708 mmol) was added. After 1 hour, the reaction mixture was diluted with ethyl acetate, and washed with saturated NH4Cl, water, saturated NaHCO3, and water. After the aqueous fractions wereextracted with ethyl acetate, two organic fractions were combined, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate - 20%MeOH/ethyl acetate as eluents to obtain compound 7- A. 1H NMR (400 MHz, Chloroform-d) delta 10.40 (t, J = 5.9 Hz, 1H), 8.34 (s, 1H), 7.65 - 7.51 (m, 2H), 7.38 - 7.20 (m, 3H), 6.74 - 6.58 (m, 2H), 5.41 (d, J = 10.0 Hz, 1H), 5.18 (d, J = 10.0 Hz, 1H), 4.66 (qd, J = 14.5, 5.8 Hz, 2H), 4.03 (s, 2H), 3.71 (dd, J = 12.4, 5.5 Hz, 1H), 3.50 (d, J = 12.3 Hz, 1H), 2.64 (dt, J = 6.0, 3.2 Hz, 1H), 1.88 - 1.77 (m, 2H), 1.77 - 1.51 (m, 3H), 1.40 (m, 3H). 19F NMR (376 MHz, Chloroform-d) delta -109.12 (ddd, J = 15.2, 8.9, 6.4 Hz, 1F), -111.87 (t, J = 7.0 Hz, 2F). LCMS-ESI+ (m/z): [M+H]+ calculated for C29H27F3N3O4: 538.20; found: 538.3.

Reference： [1]Patent: WO2015/6733,2015,A1 .Location in patent: Page/Page column 65; 66

37
[ 214759-21-4 ]
C₂₃H₂₄N₂O₅ [ No CAS ]
C₃₀H₂₈F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	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 dichloromethane; at 20℃; for 0.5h;	A mixture of compound 9-G (188 mg, 0.460 mmol), <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (99 mg, 0.614 mmol), and HATU (270 mg, 0.710 mmol) in CH2Cl2 (5 mL) was stirred at room temperature as DIPEA (0.595 mL, 3.414 mmol) was added. After 30 min, the reaction mixture was diluted with ethyl acetate, and washed with saturated NH4Cl (x 2), water), saturated NaHCO3 (x 2), and brine. After the aqueous fractions were extracted with ethyl acetate, the two organic fractions were combined, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel using ethyl acetate - 20%MeOH/ethyl acetate as eluents to obtain compound 9-H. 1H NMR (400 MHz, Chloroform-d) delta 10.48 - 10.31 (m, 1H), 8.36 (s, 1H), 7.57 (dt, J = 6.1 , 1.5 Hz, 2H), 7.37 - 7.21 (m, 3H), 6.74 - 6.57 (m, 2H), 5.40 (d, J = 10.0 Hz, 1H), 5.18 (d, J = 10.0 Hz, 1H), 4.69 (dd, J = 14.5, 5.7 Hz, 1H), 4.61 (dd, J = 14.5, 5.5 Hz, 1H), 4.04 (s, 2H), 3.43 (d, J = 12.2 Hz, 1H), 3.36 (d, J = 12.2 Hz, 1H), 1.73 - 1.52 (m, 4H), 1.52 - 1.27 (m, 4H), 1.17 (s, 3H). 19F NMR (377 MHz, Chloroform-d) delta -72.06 (s 1F), -109.08 , -111.85 (s, 2F). LCMS-ESI+ (m/z): [M+H]+ calculated for C30H29F3N3O4: 552.21; found: 552.3.

Reference： [1]Patent: WO2015/6733,2015,A1 .Location in patent: Page/Page column 68; 69; 72

38
[ 214759-21-4 ]
C₂₁H₂₀N₂O₅ [ No CAS ]
C₂₈H₂₄F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	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 dichloromethane; for 1h;	To 10-C (0.0601 g, 0.158 mmol) and 2,4,6-trifiuorobenzylamine (0.0463 g, 0.287 mmol, 1.8 equiv.) in CH2Cl2 (5 mL) was added DIPEA (0.20 mL, 1.10 mmol, 7 equiv.) and HATU (0.0953 g, 0.237 mmol, 1.5 equiv.). After 60 minutes, the reaction was diluted with CH2Cl2 (10 mL), and washed with sat. NH4Cl (10mL) and water (10 mL). The combined aqueous layers were extracted with CH2Cl2 (2 x 20 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography on silica gel (0-10% MeOH:EtOAc) afforded 13-A (0.1064 g , 97%). 1H NMR (400 MHz, DMSO-d6) delta 10.45 (t, J = 5.8 Hz, 1H), 8.53 (s, 1H), 7.61 - 7.45 (m, 2H), 7.38 - 7.27 (m, 3H), 7.27 - 7.16 (m, 2H), 5.12 (d, J = 10.3 Hz, 1H), 5.01 (d, J = 10.3 Hz, 1H), 4.79 (d, J = 13.2 Hz, 1H), 4.62 - 4.50 (m, 3H), 3.62 (pd, J = 6.5, 3.8 Hz, 1H), 3.26 (d, J = 10.9 Hz, 1H), 3.14 (qd, J = 7.3, 4.2 Hz, 1H), 1.83 (d, J = 9.3 Hz, 2H), 1.71 - 1.59 (m, 2H), 1.42 (p, J = 10.1, 9.4 Hz, 2H). 19F NMR (376 MHz, DMSO-d6) delta -109.21 - -109.34 (m), -112.38 (t, J = 7.3 Hz). LCMS-ESI+ (m/z): [M+H]+ calculated for C28H25F3N3O4: 524.18; found: 524.28.

Reference： [1]Patent: WO2015/6733,2015,A1 .Location in patent: Page/Page column 77; 78

39
[ 214759-21-4 ]
C₂₁H₂₀N₂O₅ [ No CAS ]
C₂₈H₂₄F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	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 dichloromethane; for 1h;	To compound 11-C (0.0850 g, 0.223 mmol) and <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (0.0701 g, 0.435 mmol, 2 equiv.) in CH2Cl2 (5 mL) was added DIPEA (0.28 mL, 1.56 mmol, 7 equiv.) and HATU (0.1277 g, 0.335 mmol, 1.5 equiv.). After 60 minutes, the reaction was diluted with CH2Cl2 (10 mL), and washed with sat. NH4Cl (10mL) and water (10 mL). The combined aqueous layers were extracted with CH2Cl2 (2 x 20 mL). The combined organics were dried over Na2SO4, concentrated in vacuo and purified by column chromatography on silica gel (0-10% MeOH:EtOAc) to obtain compound 12-A. 1H NMR (400 MHz, DMSO-d6) delta - 10.45 (t, J = 5.8 Hz, 1H), 8.53 (s, 1H), 8.18 (s, OH), 7.63 - 7.45 (m, 2H), 7.39 - 7.27 (m, 3H), 7.21 (dd, J = 9.2, 8.1 Hz, 2H), 5.12 (d, J = 10.3 Hz, 1H), 5.01 (d, J = 10.3 Hz, 1H), 4.79 (d, J = 13.2 Hz, 1H), 4.57 (dd, J = 8.7, 3.7 Hz, 2H), 3.62 (pd, J = 6.6, 3.9 Hz, 1H), 3.29 - 3.22 (m, 1H), 3.14 (qd, J = 7.3, 4.2 Hz, 1H), 2.63 (s, 1H), 1.83 (d, J = 9.3 Hz, 2H), 1.71 - 1.58 (m, 2H), 1.43 (q, J = 11.1 Hz, 2H). 19F NMR (376 MHz, DMSO-d6) delta -109.28 (tt, J = 9.3, 6.4 Hz), -112.37 (t, J = 7.2 Hz). LCMS-ESI+ (m/z): [M+H]+ calculated for C28H25F3N3O4: 524.18; found: 524.14.

Reference： [1]Patent: WO2015/6733,2015,A1 .Location in patent: Page/Page column 76; 77

40
[ 214759-21-4 ]
C₂₁H₂₀N₂O₅ [ No CAS ]
C₂₁H₁₈F₃N₃O₄ [ No CAS ]

Reference： [1]Patent: WO2015/6733,2015,A1

41
[ 214759-21-4 ]
C₁₅H₁₇NO₆ [ No CAS ]
C₂₂H₂₁F₃N₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; at 20 - 25℃; for 16h;	To a solution of compound Int-15a (12 mg, 0.03 9 mmol) in 0.5 mL of DMF, was added <strong>[214759-21-4](2,4,6-trifluorophenyl)methanamine</strong> (9.44 mg, 0.059 mmol), 4-methylmorpholine (15.80 mg,0.156 mmol), and HATU (22.27 mg, 0.059 mmol) sequentially. The reaction was allowed to stir at room temperature for 16 h. The reaction solution was purified using Gilson reverse phase HPLC (0-100% 0.05% TFA in ACN / 0.05% TFA in water) to provide compound Int-15b as a light yellow film. C22H21F3N205: 450.14; Found: 451.01 (M+1).

Reference： [1]Patent: WO2015/48363,2015,A1 .Location in patent: Page/Page column 49; 50

42
[ 214759-21-4 ]
[ 1534390-20-9 ]
N-(5,6-dimethoxypyridin-3-yl)-2-[(2,4,6-trifluorobenzyl)-amino]pyridine-3-sulfonamide [ No CAS ]

Reference： [1]MedChemComm,2015,vol. 6,p. 947 - 955

43
[ 214759-21-4 ]
[ 1534390-19-6 ]
C₁₉H₁₇F₃N₄O₄S [ No CAS ]

Reference： [1]MedChemComm,2015,vol. 6,p. 947 - 955

44
[ 214759-21-4 ]
C₁₅H₁₉NO₅ [ No CAS ]
4-((trans-2-hydroxycyclohexyl)oxy)-2-(2,4,6-trifluorobenzyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one [ No CAS ]
4-((trans-2-hydroxycyclohexyl)oxy)-2-(2,4,6-trifluorobenzyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixed solution of ethyl 2-((trans-2-hydroxycyclohexyl)oxy)-4-vinylnicotinate (1.0 g) obtained in Reference Example 116, sodium periodate (3.7 g) and osmium oxide (immobilized catalyst I) (0.44 g) in acetonitrile (15 mL)-acetone (15 mL)-water (15 mL) was stirred at room temperature overnight. The insoluble material was filtered off, and the filtrate was diluted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue (0.21 g) was dissolved in THF (3 mL), <strong>[214759-21-4](2,4,6-trifluorophenyl)methanamine</strong> (0.12 g) and anhydrous magnesium sulfate (0.18 g) were added, and the mixture was stirred under an argon atmosphere at room temperature for 20 min. The insoluble material was filtered off, and the filtrate was concentrated. To a solution of the residue in acetic acid (3 mL) was added sodium triacetoxyhydroborate (0.23 g), and the mixture was stirred under an argon atmosphere at room temperature overnight. The reaction mixture was neutralized with saturated sodium hydrogen carbonate solution, and diluted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by NH silica gel chromatography (hexane-ethyl acetate) and chiral HPLC (column: CHIRALPAK IA (trade name), 50 mmID×500 mmL, manufactured by Dicel Corporation, mobile phase: hexane/ethanol = 650/350), and solidified with ethyl acetate-diisopropyl ether to give the title compound. retention time: tR1 (Example 315, yield 0.056 g) MS: [M+H]+ 393.2 1H NMR (300 MHz, DMSO-d6) delta 1.20-1.45 (4H, m), 1.65 (2H, brs), 1.85-2.04 (2H, m), 3.55-3.67 (1H, m), 4.36 (2H, s), 4.61-4.71 (2H, m), 4.73 (1H, d, J = 4.5 Hz), 5.09 (1H, td, J = 8.4, 4.1 Hz), 7.13 (1H, d, J = 5.3 Hz), 7.16-7.28 (2H, m), 8.24 (1H, d, J = 5.3 Hz). retention time: tR2 (Example 316, yield 0.052 g) MS: [M+H]+ 393.1 1H NMR (300 MHz, DMSO-d6) delta 1.22-1.46 (4H, m), 1.64 (2H, brs), 1.83-2.05 (2H, m), 3.55-3.67 (1H, m), 4.36 (2H, s), 4.60-4.71 (2H, m), 4.73 (1H, d, J = 4.5 Hz), 5.09 (1H, td, J = 8.3, 4.0 Hz), 7.13 (1H, d, J = 5.3 Hz), 7.17-7.29 (2H, m), 8.18-8.28 (1H, m), 8.24 (1H, d, J = 5.1 Hz).

Reference： [1]Patent: EP2921480,2015,A1 .Location in patent: Paragraph 1288; 1289

45
[ 214759-21-4 ]
[ 86823-81-6 ]
7-methoxy-2-(2,4,6-trifluorobenzyl)isoindolin-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In ethanol; at 10 - 35℃;	A solution of ethyl 2-(bromomethyl)-6-methoxybenzoate (2.0 g), <strong>[214759-21-4](2,4,6-trifluorophenyl)methanamine</strong> (1.2 g) and potassium carbonate (2.0 g) in ethanol (20 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water and ethyl acetate, and the organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was crudely purified by NH silica gel chromatography (hexane-ethyl acetate). To the crudely purified product was added 25% hydrobromic acid (acetic acid solution) (44 mL), and the mixture was stirred under a nitrogen atmosphere at 120C overnight. The reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate solution, and ethyl acetate was added. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by NH silica gel chromatography (hexane-ethyl acetate) to give the title compound (0.51 g). 1H NMR (300 MHz, DMSO-d6) delta 4.28 (2H, s), 4.70 (2H, s), 6.79 (1H, d, J = 8.1 Hz), 6.93 (1H, d, J = 7.4 Hz), 7.13-7.28 (2H, m), 7.32-7.43 (1H, m), 9.34 (1H, brs).

Reference： [1]Patent: EP2921480,2015,A1 .Location in patent: Paragraph 0587; 0588

46
[ 214759-21-4 ]
1,5-anhydro-2-deoxy-3-O-(3-oxo-2-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-isoindol-4-yl)-threo-pentitol [ No CAS ]
1,5-anhydro-2-deoxy-3-O-(3-oxo-2-(2,4,6-trifluorobenzyl)-2,3-dihydro-1H-isoindol-4-yl)-threo-pentitol [ No CAS ]

Reference： [1]Patent: EP2921480,2015,A1

47
[ 214759-21-4 ]
7-hydroxy-2-(2,4,6-trifluorobenzyl)isoindolin-1-one [ No CAS ]

Reference： [1]Patent: EP2921480,2015,A1

48
[ 214759-21-4 ]
ethyl 4-formyl-2-(((2R,3R)-3-hydroxybutan-2-yl)oxy)nicotinate [ No CAS ]
4-(((2R,3R)-3-hydroxybutan-2-yl)oxy)-2-(2,4,6-trifluorobenzyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.10 g		A solution of ethyl 4-formyl-2-(((2R,3R)-3-hydroxybutan-2-yl)oxy)nicotinate (0.16 g) obtained in Reference Example 297, <strong>[214759-21-4](2,4,6-trifluorophenyl)methanamine</strong> (0.13 g) and magnesium sulfate (0.072 g) in THF (0.5 mL) was stirred at room temperature for 30 min. To the reaction mixture were added acetic acid (1.5 mL) and sodium triacetoxyhydroborate (0.25 g), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with saturated sodium hydrogen carbonate solution, and diluted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by NH silica gel chromatography (hexane-ethyl acetate) to give the title compound (0.10 g). MS: [M+H]+ 367.0 1H NMR (300 MHz, DMSO-d6) delta1.11 (3H, d, J = 6.2 Hz), 1.21 (3H, d, J = 6.2 Hz), 3.78-3.89 (1H, m), 4.36 (2H, s), 4.61-4.75 (3H, m), 5.18-5.30 (1H, m), 7.14 (1H, d, J = 5.3 Hz), 7.18-7.28 (2H, m), 8.24 (1H, d, J = 5.1 Hz).

Reference： [1]Patent: EP2921480,2015,A1 .Location in patent: Paragraph 1500; 1501

49
[ 214759-21-4 ]
C₂₁H₂₂N₂O₅ [ No CAS ]
C₂₈H₂₆F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	10413] A 50-mE 1-neck round bottom flask was charged with reactant 1-D (crude from step 2, 0.27 mmol), 2,4,6- trifluorophenyl methanamine (0.084 g, 0.52 mmol), DIPEA (0.169 g, 1.3 mmol) and HATU (0.20 g, 0.52 mmol) in DCM (10 ml). The reaction mixture was stirred at room temperature for 1 hout The reaction mixture was concentrated down, re-dissolved in EtOAc (50 mE), washed with saturated NaHCO3 twice, saturated NH4C1 and dried over Na2SO4. Afier concentration, the crude was purified by column chromatography on silica gel with hexane-EtOAc to obtain 1-E. ECMS-ESI (mlz): [M+H]. found: 526.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0410; 0413

50
[ 214759-21-4 ]
C₂₁H₂₂N₂O₅ [ No CAS ]
C₂₈H₂₆F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	10418] A 50-mE 1-neck round bottom flask was charged with reactant 2-D (crude from step 2, 0.54 mmol), 2,4,6- trifluorophenyl methanamine (0.168 g, 1.04 mmol), DIPEA (0.34 g, 2.6 mmol) and HATU (0.40 g, 1.04 mmol) in DCM (20 ml). The reaction mixture was stirred at room temperature for 1 hout The reaction mixture was concentrated down, re-dissolved in EtOAc (50 mE), washed with saturated NaHCO3 twice, saturated NH4C1 and dried over Na2504. Afier concentration, the crude was purified by column chromatography on silica gel with hexane-EtOAc to obtain 2-E. ECMS-ESI (mlz): [M+H]. found: 526.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0415; 0418

51
[ 214759-21-4 ]
C₂₁H₂₂N₂O₅ [ No CAS ]
C₂₈H₂₆F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	10423] A 50-mE 1-neck round bottom flask was charged with reactant 3-D (crude from step 2, 0.27 mmol), 2,4,6- trifluorophenyl methanamine (0.084 g, 0.52 mmol), DIPEA (0.169 g, 1.3 mmol) and HATU (0.20 g, 0.52 mmol) in DCM (10 ml). The reaction mixture was stirred at room temperature for 1 hout The reaction mixture was concentrated down, re-dissolved in EtOAc (50 mE), washed with sat NaHCO3 twice, sat NH4C1 and dried over Na2504. After concentration, the crude was purified by column chromatography on silica gel with hexane-EtOAc to obtain 3-E. ECMS-ESI (mlz):[M+H]. found: 526.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0420; 0423

52
[ 214759-21-4 ]
C₂₂H₂₄N₂O₅ [ No CAS ]
C₂₉H₂₈F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	10432] A 50-mE 1-neck round bottom flask was charged with reactant 5-13 (crude from step 2, 1.0 mmol), 2,4,6-trif- luorophenyl methanamine (0.33 g, 2.0 mmol), DIPEA (0.65 g, 5.0 mmol) and HATU (0.77 g, 2.Ommol)inDCM(lOml). The reaction mixture was stirred at room temperature forhour. The reaction mixture was concentrated down, re-dissolved in EtOAc (50 mE), washed with saturated NaHCO3 twice, saturated NH4C1 and dried over Na2504. After concentration, the crude was purified by column chromatography on silica gel with hexane-EtOAc to obtain 5-C. ECMS-ESI (mlz): [M+H]. found: 540.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0430; 0432

53
[ 214759-21-4 ]
C₁₄H₁₆N₂O₅ [ No CAS ]
C₂₁H₂₀F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	10437] A 50-mE 1-neck round bottom flask was charged with reactant 6-D (crude from step 2, 0.27 mmol), 2,4,6- trifluorophenyl methanamine (0.088 g, 0.55 mmol), DIPEA (0.177 g, 1.4 mmol) and HATU (0.21 g, 0.55 mmol) in DCM (10 ml). The reaction mixture was stirred at room temperature for 1 hout The reaction mixture was concentrated down, re-dissolved in EtOAc (50 mE), washed with saturated NaHCO3 twice, saturated NH4C1 and dried over Na2SO4. After concentration, the crude was purified by column chromatography on silica gel with hexane-EtOAc to obtain 6-E. ECMS-ESI (mlz): [M+H]. found: 436.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0434; 0437

54
[ 214759-21-4 ]
C₁₆H₁₇F₃N₂O₅ [ No CAS ]
C₂₃H₂₁F₆N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	10441] A 50-mE 1-neck round bottom flask was charged with reactant 7-B (crude from step 1, 0.33 mmol), 2,4,6- trifluorophenyl methanamine (0.13 g, 0.82 mmol), DIPEA (0.53 g, 4.0 mmol) and HATU (0.37 g, 0.98 mmol) in DCM (5 ml). The reaction mixture was stirred at room temperature for 1 hout The reaction mixture was concentrated down, redissolved in EtOAc (50 mE), washed with saturated NaHCO3 twice, saturated NH4C1 and dried over Na2504. After concentration, the crude was purified by column chromatography on silica gel with hexane-EtOAc to obtain 7-C. ECMS-ESI (mlz): [M+H]. found: 518.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0439; 0441

55
[ 214759-21-4 ]
C₁₅H₁₅F₃N₂O₆ [ No CAS ]
C₂₂H₁₉F₆N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	10454] A 50-mE 1-neck round bottom flask was charged with reactant 8-K (crude from step 1, 0.16 mmol), 2,4,6- trifluorophenyl methanamine (0.064 g, 0.4 mmol), DIPEA (0.26 g, 2.0 mmol) and HATU (0.18 g, 0.48 mmol) in DCM (5 ml). The reaction mixture was stirred at room temperature for 1 hout The reaction mixture was concentrated down, redissolved in EtOAc (50 mE), washed with saturated NaHCO3 (twice), washed with saturated NH4C1 and dried over Na2504. Afier concentration, the crude was purified by column chromatography on silica gel with hexane-EtOAc to obtain 8-E. ECMS-ESI (mlz): [M+H]. found: 520.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0444; 0454

56
[ 214759-21-4 ]
C₂₁H₂₀F₂N₂O₆ [ No CAS ]
C₂₈H₂₄F₅N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	10465] A 50-mE 1-neck round bottom flask was charged with reactant 9-J (crude from step 1, 0.18 mmol), 2,4,6- trifluorophenyl methanamine (0.033 g, 0.2 mmol), DIPEA (0.25 g, 1.9 mmol) and HATU (0.18 g, 0.48 mmol) in DCM (3 ml). The reaction mixture was stirred at room temperature for 1 hout The reaction mixture was concentrated down, redissolved in EtOAc (50 mE), washed with saturated NaHCO3 twice, washed with saturated NH4C1 and dried over Na2 SO4. After concentration, the crude was purified by column chromatography on silica gel with hexane-EtOAc to obtain 9-K. ECMS-ESI (mlz): [M+H]. found: 578.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0456; 0465

57
[ 214759-21-4 ]
C₁₄H₁₆N₂O₆ [ No CAS ]
C₂₁H₂₀F₃N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	10469] A 50-mE 1-neck round bottom flask was charged with reactant 10-B (crude from step 1, 0.27 mmol), 2,4,6- trifluorophenyl methanamine (0.043 g, 0.27 mmol), DIPEA (0.33 g, 2.5 mmol) and HATU (0.18 g, 0.49 mmol) in DCM (3 ml). The reaction mixture was stirred at room temperature for 1 hout The reaction mixture was concentrated down, redissolved in EtOAc (50 mE), washed with saturated NaHCO3 twice, washed with saturated NH4C1 and dried over Na2 SO4. After concentration, the crude was purified by column chromatography on silica gel with hexane-EtOAc to obtain 10-C. ECMS-ESI (mlz): [M+H]. found: 452.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0467; 0469

58
[ 214759-21-4 ]
C₁₄H₁₆N₂O₆ [ No CAS ]
C₂₀H₁₈F₃N₃O₅ [ No CAS ]

Reference： [1]Patent: US2016/176870,2016,A1

59
[ 214759-21-4 ]
C₁₅H₁₈N₂O₆ [ No CAS ]
C₂₂H₂₂F₃N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	10476] A 50-mE 1-neck round bottom flask was charged with reactant 12-B (0.075 g, 0.23 mmol), 2,4,6-trifluorophe- nyl methanamine (0.04 1 g, 0.26 mmol), DIPEA (0.33 g, 2.5 mmol) and HATU (0.18 g, 0.49 mmol) in DCM (3 ml). The reaction mixture was stirred at room temperature for 1 hout The reaction mixture was concentrated down, re-dissolved in EtOAc (50 mE), washed with saturated NaHCO3 twice, saturated NH4C1 and dried over Na2504. After concentration, the crude was purified by column chromatography on silica gel with hexane-EtOAc to obtain 12-C. ECMS-ESI (mlz):[M+H]. found: 466.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0474; 0476

60
[ 214759-21-4 ]
C₂₁H₂₂N₂O₆ [ No CAS ]
C₂₈H₂₆F₃N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	10486] A 50-mE 1-neck round bottom flask was charged with reactant 14-F (0.048,0.12 mmol), 2,4,6-trifluorophenyl methanamine (0.033 g, 0.2 mmol), DIPEA (0.25 g, 1.9 mmol) and HATU (0.18 g, 0.48 mmol) in DCM (3 ml). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated down, re-dissolved in EtOAc (50 mE), washed with saturated NaHCO3 twice, washed with saturated NH4C1 and dried over Na2504. After concentration, the crude was purified by colunm chromatography on silica gel with hexane-EtOAc to obtain 1 4-G. ECMS-ESI (mlz): [M+H]. found: 542.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0481; 0486

61
[ 214759-21-4 ]
C₁₅H₁₈N₂O₆ [ No CAS ]
C₂₂H₂₂F₃N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 0.5h;	10574] A mixture of the crude acid, 2,4,6-trifluorobenzy- lamine (833 mg, 0.515 mmol), and HA11J (327 mg, 0.860 mmol) in dichloromethane (4 mE) was stirred at room temperature as DIPEA (0.55 mE, 3.158 mmol) was added. After 30 mm, the reaction mixture was diluted with ethyl acetate, washed with saturated NH4C1 (x2), water (xl), saturated NaHCO3 (x2), and brine (xl). Afier the aqueous fractions were extracted with ethyl acetate (xl), two organic fractions were combined, dried (Na2504) and concentrated. The residue was purified by preparative HPEC and the product containing fractions were pooled and concentrated to remove MeCN. The remained aqueous mixture was neutralized with sodium bicarbonate, diluted with brine, and the product was extracted with dichloromethane (x3). Afier the extracts were washed with water (xl), the organic fractions were combined, dried (Na2504), and concentrated to get compound 33-B 10575] ?H NMR (400 MHz, Chloroform-d) oe 10.51-10.17(m, 1H), 8.44 (s, 1H), 6.66 (t, J=8.1 Hz, 2H), 4.74-4.54 (m,2H), 4.33 (dt, J=8.2, 3.6 Hz, 1H), 4.11 (dt, J=15.3, 7.6 Hz,1H), 4.03 (s, 3H), 4.01 (m, 1H), 3.84 (dq, J=8.2, 5.0, 3.8 Hz,2H), 3.67 (dtd, J=1 1.9, 8.9,7.7,4.1 Hz, 2H), 3.37 (dq, J=14.2,7.1 Hz, 1H), 2.37 (dtd, J=13.3, 9.0, 4.0 Hz, 1H), 2.05 (dd,J=8.0, 3.9 Hz, 1H), 1.23 (t, J=7. 1 Hz, 3H). ?9F 1 9F NMR (376MHz, Chloroform-d) oe -108.99 (p, J=7.5 Hz, iF), -111.82--112.20 (m, 2F). ECMS-ESI (mlz): [M+H] calculated forC22H23F3N305: 466.16. found: 466.24..

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0572; 0574; 0575

62
[ 214759-21-4 ]
C₁₄H₁₇NO₈ [ No CAS ]
C₂₁H₂₁F₃N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In acetonitrile; at 20℃; for 1h;	10513] The crude carboxylic acid intermediate (2.1 g, 6.41 mmol) and <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (1.14 g, 7.06 mmol) were dissolved in acetonitrile (15 mE) and treated with N-ethyl-N-isopropylpropan-2-amine (1.24 g, 9.6 mmol) and HATU (2.68 g, 7.05 mmol). Afier stirring for 1 h at room temperature, the reaction mixture was diluted with ethyl acetate (100 mE) and washed with 0.5 M HC1 andwatet After drying over sodium sulfate, the solution was filtered and concentrated. Flash chromatography (0-40% ethyl acetate:dichloromethane) afforded the desired amide 21-F: ECMSESI (mlz): [M+H] calculated for C2,H22F3N207: 471.14. found: 471.1.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0507; 0513

63
[ 214759-21-4 ]
C₂₀H₂₀N₂O₅ [ No CAS ]
C₂₇H₂₄F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; dichloromethane; at 20℃; for 0.5h;	10732] Intermediate 60-D (1.33 mmol) and (2,4,6-trifluo- rophenyl)methanamine (429 mg, 2.66 mmol) were suspended in dichioromethane (70 mE) and treated with diisopropylethylamine (1 ml, 6.2 mmol) at room temperature. To this suspension was added (dimethylamino)-N,N-dimethyl (3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (HATIJ, 0.76 g, 2.0 mmol). After 0.5 h, the reaction mixture was diluted with dichloromethane, washed with 3% EiC1 aq, saturated NH4C1 and 0.5N HC1. The organic layer was dried (Na2504), concentrated. Purification by flash chromatography gave the desired amide.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0727; 0732

64
[ 214759-21-4 ]
C₁₅H₁₅F₃N₂O₆ [ No CAS ]
C₂₂H₁₉F₆N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 0.5h;	10570] A mixture of the crude acid, 2,4,6-trifluorobenzy- lamine (153 mg, 0.950 mmol), and HATU (626 mg, 1.647 mmol) in dichioromethane (7 mE) was stirred at room temperature as DIPEA (1 mE, 5.741 mmol) was added. After 30 mm, the reaction mixture was diluted with ethyl acetate, washed with saturated NH4C1 (x2), water (xl), saturated NaHCO3 (x2), water (xl), and brine (xl). Afier the aqueous fractions were extracted with ethyl acetate (xl), two organic fractions were combined, dried (Na2504), and concentrated. The residue was purified by colunm chromatography on silica gel (40 g column) using Hexane-ethyl acetate-20% MeOH in ethyl acetate as eluents to get compound 32-F. ?H NMR (400 MHz, Chloroform-d) oe 10.29 (t, J=5.3 Hz, 1H), 8.44 (s, 1H), 6.77-6.50 (m, 2H), 5.15 (dq, J=18.4, 9.5 Hz, 1H), 4.72-4.56 (m, 2H), 4.33 (d, J=14.4 Hz, 2H), 4.09-3.98 (m, 2H), 4.02 (s, 3H), 3.79 (dq, J=16.3, 8.3 Hz, 1H), 3.72-3.65 (m, 1H), 3.65-3.59 (m, 1H), 2.28-2.09 (m, 1H), 2.02-1.92 (m, 1H). ?9F NMR (376 MHz, Chloroform-d) oe -69.87 (t, J=8.8 Hz, 3F),-108.85 (p, J=7.5 Hz, iF), -112.05 (t, J=6.9 Hz, 2F). ECMSESI (mlz): [M+H] calculated for C22H20F5N305: 520.13. found: 520.34.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0562; 0570

65
[ 214759-21-4 ]
C₁₉H₁₈N₂O₆ [ No CAS ]
C₂₆H₂₂F₃N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	10518] A 50-mE 1-neck round bottom flask was charged with reactant 22-C (0.10 g, 0.25 mmol) in THF (5 mE) and MeOH (5 mE). 1 N KOH in water (1.0 mE) was added to the reaction solution. The reaction mixture was stirred at room temperature for 1 hout Afier acidification with 1 N HC1, the solution was concentrated to remove the solvent completely and the crude acid was used for next step without further purification. The crude acid (0.25 mmol), 2,4,6-trifluorophe-nyl methanamine (0.08 g, 0.5 mmol), DIPEA (0.169 g, 1.3 mmol) and HATU (0.20 g, 0.52 mmol) in DCM (10 ml) were stirred at room temperature for 1 hout The reaction mixture was concentrated down, re-dissolved in EtOAc (50 mE), washed with saturated NaHCO3 (2x), saturated NH4C1 and dried over Na2SO4. Afier concentration, the crude was purified by colunm chromatography on silica gel with hexaneEtOAc to obtain 22-D. ECMS-ESI (mlz): [M+H]. found:514.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0516; 0518

66
[ 214759-21-4 ]
C₁₉H₁₈N₂O₅ [ No CAS ]
C₂₆H₂₂F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 0.5h;	10547] A mixture of the reactant 28-C (50 mg, 0.131 mmol) in THF (1 mE) and ethanol (1 mE) was stirred at room temperature and 1 N KOH (0.26 mE) was added. After 30 mm, the reaction mixture was diluted with water and washed with ether (xl). Afier the aqueous fraction was acidified with 1 N HC1 (0.3-0.4 mE), the product was extracted with dichloromethane (x3). The combined extracts were dried (Na2504), and concentrated and dried in vacuum to get the crude acid. A mixture of the crude acid, <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (28 mg, 0.174 mmol), and HATU (76 mg, 0.200 mmol) in dichloromethane (5 mE) was stirred at room temperature as DIPEA (0.2 mE, 1.148 mmol) was added. After 30 mm, the reaction mixture was diluted with ethyl acetate, washed with saturated NH4C1 (x2), water (xl), saturated NaHCO3 (x2), and brine (xl). Afier the aqueous fractions were extracted with ethyl acetate (xl), two organic fractions were combined, dried (Na2504) and concentrated. The residue was purified by column chromatography on silica gel (12 g column) using ethyl acetate as eluent to get compound 28-D. ?H NMR (400 MHz, Chloroform-d) oe 10.40 (s, 1H), 8.48 (s, 1H), 7.59-7.53 (m, 2H), 7.32 (dddd, J=12.2, 7.0, 4.5, 2.3 Hz, 3H), 6.74-6.60 (m, 2H), 6.43 (s, 1H), 5.37 (d, J=10.2 Hz, 1H), 5.20 (d, J=10.1 Hz, 1H), 4.75-4.58 (m, 2H), 4.35 (s, 1H), 4.07 (t, J=4.1 Hz, 1H),2.31 (s, 1H), 2.11-1.77 (m, 5H). ?9F NMR (376 MHz, Chlo56 roform-d) oe -109.05 (s, iF), -111.85 (s, 2F). ECMS-ESI (m/z): [M+H] calculated for C25H23F3N304: 498.16. found:498.10.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0545; 0547

67
[ 214759-21-4 ]
C₂₀H₂₀N₂O₅ [ No CAS ]
C₂₇H₂₄F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 0.5h;	10551] To a mixture of compound 28-C (129 mg, 0.337 mmol) in THF (3 mE) was added 60% NaH (30 mg, 0.75 mmol) at room temperature. Afier 5 mm, Mel (0.03 mE, 0.482 mmol) was added. Afier stirring at room temperature for 1 h, water was added (.-3 mE) to the mixture. Afier -1 5 mm, 1 N KOH (0.5 mE) was added to complete the hydrolysis. Afier 10 mm, the reaction mixture was diluted with water, and washed with ether (xl). The aqueous fraction was acidified with 1 N HC1 (.-1 mE), and the product was extracted with dichloromethane (x3). After the extracts were washed with water (xl), the extracts were combined, dried (Na2504), and concentrated to get the crude acids 29-B. A mixture of the crude acid 29-B, the <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (75 mg, 0.465 mmol), and HATU (195 mg, 0.5 13 mmol) in dichloromethane (5 mE) was stirred at room temperature as DIPEA (0.55 mE, 3.158 mmol) was added. Afier 30 mm, the reaction mixture was diluted with ethyl acetate, washed with saturated NH4C1 (x2), water (xl), saturated NaHCO3 (x2), and brine (xl). Afier the aqueous fractions were extracted with ethyl acetate (xl), two organic fractions were combined, dried (Na2504), and concentrated. The residue was purified by column chromatography on silica gel (12 g column) using ethyl acetate as eluent to get 126 mg of the partially purified compound 29-C. ECMS-ESI (mlz): [M+H] calculated for C27H25F3N304: 512.18. found: 512.16.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0550; 0551

68
[ 214759-21-4 ]
C₁₄H₁₆N₂O₆ [ No CAS ]
C₂₁H₂₀F₃N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 0.5h;	10556] A mixture of the crude acid, 2,4,6-trifluorobenzy- lamine (96 mg, 0.596 mmol), and HATU (204 mg, 0.537 mmol) in dichloromethane (3 mE) was stirred at room temperature as DIPEA (0.5 mE, 2.87 1 mmol) was added. After 30 mm, the reaction mixture was diluted with ethyl acetate, washed with saturated NH4C1 (x2), water (xl), saturated NaHCO3 (x2), and brine (xl). Afier the aqueous fractions were extracted with ethyl acetate (xl), two organic fractions were combined, dried (Na2504) and concentrated. The residue was purified by colunm chromatography on silica gel (12 g column) using ethyl acetate-20% methanol in ethyl acetate as eluent to get compound 30-D ?H NMR (400 MHz, Chloroform-d) oe 10.37 (d, J=7.3 Hz, 1H), 8.46 (s, 1H), 6.81-6.54 (m, 2H), 4.63 (d, J=5.6 Hz, 2H), 4.34 (d, J=11.1 Hz, 1H), 4.31-4.22 (m, 1H), 4.02 (s, 3H), 4.01-3.92 (m, 1H), 3.86 (d, J=3.2 Hz, 1H), 3.65 (dd, J=13.4, 1.9 Hz, 1H), 3.62-3.55 (m, 1H), 3.22 (s, 3H), 2.23 (qd, J=10.8, 4.5 Hz, 1H), 2.01-1.90(m, 1H). ?9F NMR (377 MHz, Chloroform-d) oe -108.92 (s, iF),-112.01 (s, 2F). ECMS-ESI (mlz): [M+H] calculated for C2,H2,F3N305: 452.14. found: 452.11.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0553; 0556

69
[ 214759-21-4 ]
C₁₄H₁₆N₂O₆ [ No CAS ]
C₂₀H₁₈F₃N₃O₅ [ No CAS ]

Reference： [1]Patent: US2016/176870,2016,A1

70
[ 214759-21-4 ]
C₁₅H₁₅F₃N₂O₆ [ No CAS ]
C₂₂H₁₉F₆N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 0.5h;	10560] A mixture of the crude acid, 2,4,6-trifluorobenzy- lamine (96 mg, 0.596 mmol), and HATU (272 mg, 0.715 mmol) in dichioromethane (3 mE) was stirred at room temperature as DIPEA (0.5 mE, 2.871 mmol) was added. Afier 30 mm, the reaction mixture was diluted with ethyl acetate, washed with saturated NH4C1 (x2), water (xl), saturated NaHCO3 (x2), and brine (xl). Afier the aqueous fractions were extracted with ethyl acetate (xl), two organic fractions were combined, dried (Na2504) and concentrated. The residue was purified by column chromatography on silica gel (12 g column) using ethyl acetate-20% methanol in ethyl acetate as eluent to get compound 31-B, which contained 10-15% ofimpurities. ?H NMR (400 MHz, Chloroform-d) oe 10.30 (s,1H), 8.49 (s, 1H), 6.64 (t, J=8.1 Hz, 2H), 5.16 (dq, J=18.5, 9.5Hz, 1H), 4.71-4.50 (m, 2H), 4.43 (dt, J=11.8, 3.6 Hz, 1H),4.34 (d, J=14.7 Hz, 1H), 4.06 (s, 1H), 4.02 (s, 4H), 3.79 (dq,J=16.3, 8.2 Hz, 1H), 3.69 (d, J=14.3 Hz, 1H), 3.62 (dd,J=11.9, 2.6 Hz, 1H), 2.23-2.07 (m, 1H), 1.97 (dd, J=12.4, 4.0Hz, 1H). ?9F NMR (377 MHz, Chloroform-d) oe -69.91 (t,J=8.8 Hz, 3F), -71.39, -73.29, -108.51 (s, iF), -112.21 (t,J=7.0 Hz, 2F). LCMS-ESI (mlz): [M+H] calculated forC22H20F5N305: 520.13. found: 520.22.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0558; 0560

71
[ 214759-21-4 ]
C₁₅H₁₆F₂N₂O₆ [ No CAS ]
C₂₂H₂₀F₅N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 0.333333h;	10578] To a mixture of compound 32-E (162 mg, 0.525 mmol) and 60% NaH (90 mg, 2.25 mmol) was added DMF (4 mE) at 0C. Afier 20 mi CHF2CH2OTf(.-M.22 mE, 360 mg, 1.681 mmol) was added. Afier stirring at room temperature for .-1 5 mm, the reaction mixture was stirred at 0 C. and added 1 N KOH (1 mE). After 10 mm, the mixture was acidified with concentrated HC1 (0.35 mE), and concentrated to almost dryness to get the crude acid. A mixture of the crude acid, <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (95 mg, 0.590 mmol), and HATU (400 mg, 1.052 mmol) in dichloromethane (5 mE) was stirred at room temperature as DIPEA (0.65 mE, 3.732 mmol) was added. After 20 mm, the reaction mixture was diluted with ethyl acetate, washed with saturated NH4C1 (x2), water (xi, + some brine), saturated NaHCO3 (x2), and brine (xi). After the aqueous fractions were extracted with ethyl acetate (xi), two organic fractions were combined, dried (Na2504), and concentrated. The residue was purified by column chromatography on silica gel (40 g column) using hexane-ethyl acetate-20% MeOH in ethyl acetate as eluents to get compound 34-B. ?H NMR (400 MHz, Chloroform-d) oe 10.30 (t, J=5.9 Hz, 1H), 8.44 (s, 1H), 6.73-6.56 (m, 2H), 6.03 (dddd, J=57.1, 54.5, 6.4, 2.2 Hz, 1H), 4.73-4.50 (m, 3H), 4.42-4.23 (m, 2H), 4.03 (s, 3H), 3.98 (m, 2H), 3.65 (ddt, J=21.7, 14.4, 4.9 Hz, 3H), 2.31-2.15 (m, 1H), 1.99 (dd, J=14.0, 3.8 Hz, 1H). ?9F NMR (376 MHz, Chloroform-d) oe -108.79 (dq, J=14.7, 7.2, 6.5 Hz, iF), -112.08 (t, J=7.0 Hz, 2F), -120.33 (ddt, J=291.1, 54.4, 8.1 Hz, iF), -123.23 (dddd, J=290.8, 57.2, 26.6, 13.6Hz, iF). ECMS-ESI (mlz): [M+H] calculated for C22H2,F5N305: 502.14. found: 502.19.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0577; 0578

72
[ 214759-21-4 ]
C₁₅H₁₅F₃N₂O₆ [ No CAS ]
C₂₂H₁₉F₆N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 0.333333h;	10588] A mixture of the above residue, 2,4,6-trifluoroben- zylamine (182mg, 0.509 mmol), and HATU (343 mg, 0.902 mmol) in dichioromethane (4 mE) was stirred at room temperature as DIPEA (0.55 mE, 3.158 mmol) was added. After 20 mm, the reaction mixture was diluted with ethyl acetate, washed with saturated NH4C1 (x2), water (xl), saturated NaHCO3 (x2), and brine (xl). Afier the aqueous fractions were extracted with ethyl acetate (xl), two organic fractions were combined, dried (Na2504), and concentrated. The residue was purified by preparative HPEC. The product containing fractions were pooled and concentrated to remove acetonitrile, neutralized with saturated NaHCO3, and the organic product was extracted with dichloromethane (x3), combined, dried (Na2504) and concentrated to get compound 35-E. ?H NMR (400 MHz, Chioroform-d) oe 10.29 (d, J=6.8 Hz, 1H), 8.66-8.42 (m, 1H), 6.78-6.53 (m, 2H), 4.85 (dq, J=17.8, 9.1 Hz, 1H), 4.64 (qd, J=14.5, 5.4 Hz, 2H), 4.51-4.41 (m, 1H), 4.35-4.24 (m, 1H), 4.06 (td, J=1 1.0,4.7Hz, 1H), 4.01 (s, 3H),3.77 (td, J=10.3, 4.6 Hz, 1H), 3.63-3.45 (m, 2H), 3.38 (t, J=10.7 Hz, 1H), 2.57 (d, J=12.2 Hz, 1H), 2.06 (qd, J=12.3, 5.3 Hz, 1H). ?9F NMR (376 MHz, Chloroform-d) oe -69.94 (t, J=8.6 Hz, 3F), -109.00 (t, J=8.2 Hz, iF), -111.70--112.47 (m, 2F). ECMS-ESI (mlz): [M+H] calculated for C22H20F5N305: 520.13. found: 520.18.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0580; 0588

73
[ 214759-21-4 ]
C₁₈H₂₂N₂O₇ [ No CAS ]
C₂₅H₂₆F₃N₃O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 0.5h;	j0619] A mixture of the acid, <strong>[214759-21-4]2,4,6-<strong>[214759-21-4]trifluorobenzylamine</strong></strong> (25 mg, 0.155 mmol), and HATU (90 mg, 0.237 mmol) in dichloromethane (3 mE) was stirred at room temperature as DIPEA (0.3 mE, 1.722 mmol) was added. Afier 30 mm, the reaction mixture was diluted with ethyl acetate, washed with saturated NH4C1 (x2), saturated NaHCO3 (x2), and brine (xl). Afier the aqueous fractions were extracted with ethyl acetate (xl), two organic fractions were combined, dried (Na2504) and concentrated.10620] The residue was purified by prep HPEC to get compound 40-F. ?H NMR (400 MHz, Chloroform-d) oe 10.75-10. 48 (m, 1H), 8.58 (s, 1H), 6.80-6.45 (m, 2H), 5.25 (s, 1H), 4.73 (dd, J=14.5, 5.7 Hz, 1H), 4.60 (dd, J=14.7, 5.3 Hz, 1H), 4.36 (d, J=3.3 Hz, 1H), 4.02 (s, 3H), 3.95 (ddd, J=7.0, 5.4, 3.9 Hz, 3H), 3.86 (dq, J=14.2, 7.2 Hz, 1H), 3.75 (dt, J=12.5, 3.8 Hz, 1H), 3.29 (dq, J=14.2, 7.1 Hz, 1H), 2.72 (dd, J=16.2, 3.5 Hz, 1H), 2.30-2.14 (m, 1H), 1.92 (dt, J=13.4, 3.1 Hz, 1H), 1.76-1.64 (m, 1H), 1.55 (t, J=12.9 Hz, 1H), 1.45 (td, J=14.3, 3.5 Hz, 1H), 1.27 (t, J=7.1 Hz, 3H). ?9F NMR (376 MHz, Chioroform-d) oe -76.37 (s, 3F), -108.71 (ddd, J=15.0, 8.8, 6.3 Hz, iF), -111.97 (t, J=6.9 Hz, 2F). ECMS-ESI (mlz): [M+H] calculated for C25H27F3N305: 522.19. found: 522.25.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0608; 0619; 0620

74
[ 214759-21-4 ]
C₁₃H₁₄N₂O₆ [ No CAS ]
C₂₀H₁₈F₃N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; for 0.5h;	10635] The residue from the previous step was taken up in dichloromethane (5 mE) and treated sequentially with (dimethylamino)-N,N-dimethyl(3H-[ 1 ,2,3]triazolo[4,5-b]pyri- din-3-yloxy)methaniminium hexafluorophosphate (HATU, 0.16 g, 0.41 mmol), <strong>[214759-21-4](2,4,6-trifluorophenyl)methanamine</strong> (50 pL, 0.41 mmol), and N,N-diisopropylethylamine (240 pL, 1.34 mmol). The reaction mixture was stirred for 30 minutes and then partitioned between NH4C1Q,q) and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined organics dried over Na2SO4, concentrated and carried to the next step as crude.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0627; 0635

75
[ 214759-21-4 ]
C₁₄H₁₆N₂O₆ [ No CAS ]
C₂₁H₂₀F₃N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; for 0.5h;	10651] The residue from the previous step was taken up in dichloromethane (10 mE) and treated sequentially with (dimethylamino)-N,N-dimethyl(3H-[1 ,2,3]triazolo[4,5-b]pyri- din-3-yloxy)methaniminium hexafluorophosphate (HATU, 300 mg, 0.79 mmol), <strong>[214759-21-4](2,4,6-trifluorophenyl)methanamine</strong> (100 pL, 0.82 mmol), and N,N-diisopropylethylamine (470 pL, 2.63 mmol). The reaction mixture was stirred for 30 minutes and then partitioned between NH4C1(Cq) and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the combined organics dried over Na2504, concentrated, and carried to the next step as crude.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0647; 0651

76
[ 214759-21-4 ]
C₁₄H₁₆N₂O₆ [ No CAS ]
C₂₁H₂₀F₃N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; for 0.75h;	10657] The residue from the previous step was taken up in dichloromethane (5 mE) and treated sequentially with (dimethylamino)-N,N-dimethyl(3H-[1 ,2,3]triazolo[4,5-b]pyri- din-3-yloxy)methaniminium hexafluorophosphate (HATU, 160 mg, 0.42 mmol), <strong>[214759-21-4](2,4,6-trifluorophenyl)methanamine</strong> (100 tE, 0.45 mmol), and N,N-diisopropylethylamine (260 pL, 1.46 mmol). The reaction mixture was stirred for 45 minutes and then partitioned between NH4C1(0q) and ethyl acetate. The aqueous phase was extracted 3 times with ethyl acetate and the combined organics dried over Na2504, concentrated, and carried to the next step as crude.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0653; 0657

77
[ 214759-21-4 ]
C₁₉H₂₆N₂O₉ [ No CAS ]
C₂₆H₃₀F₃N₃O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; for 0.75h;	j0665] To a solution of crude intermediate 46-C (0.09 mmol) in dichioromethane (2 mE) was added sequentially (dimethylamino)-N,N-dimethyl (3H-[ 1 ,2,3]triazolo[4,5-b] pyridin-3-yloxy)methaniminium hexafluorophosphate (HATU, 0.40 g, 0.11 mmol), (2,4,6-trifluorophenyl)metha- namine (40 IL, 0.32 mmol), and N,N-diisopropylethylamine (60 pL, 0.34 mmol). The reaction mixture was stirred for 45 minutes, concentrated onto silica gel, and purified by silica gel chromatography (0-100% EtOAc/hexanes) to afford intermediate 46-D.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0659; 0665

78
[ 214759-21-4 ]
C₁₄H₁₆N₂O₆ [ No CAS ]
C₂₁H₂₀F₃N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	10674] To a slurry of Intermediate 48-B (0.1 g, 0.32 mmol) on CH2C12 (4 mE) was added (2,4,6-trifluorophenyl)metha- namine (0.078 g, 0.48 mmol), HA11J (0.15 g, 0.41 mmol), and N,N-diisopropylethylamine (0.2 mE, 1.15 mmol). The resulting solution was stirred at room temperature for 1 h and then diluted with CH2C12. The solution was then washed with HC1 (aqueous, 1M). The aqueous layer was back-extracted with CH2C12 (2 times) and the combined organic layers were dried over magnesium sulfate and concentrated to dryness. The crude material was then purified by column chromatography (5i02, 2-10% MeOH in CH2C12) to provide Intermediate 48-C.10675] ECMS-ESI (mlz): [M+H] calculated for C2,H20F3N305: 452.14. found: 452.23.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0671; 0674; 0675

79
[ 214759-21-4 ]
C₁₄H₁₆N₂O₆ [ No CAS ]
C₂₀H₁₈F₃N₃O₅ [ No CAS ]

Reference： [1]Patent: US2016/176870,2016,A1

80
[ 214759-21-4 ]
C₂₀H₂₀N₂O₅ [ No CAS ]
C₂₇H₂₄F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	10745] A 50-mE 1-neck round bottom flask was charged with reactant 4-C (0.17 g, 0.43 mmol) in THF (5 mE) and MeOH (5 mE). 1 N KOH in water (1.3 mE) was added to the reaction solution. The reaction mixture was stirred at room temperature for 1 hout Afier acidification with 1 N HC1, the solution was concentrated to remove the solvent completely and the crude acid was used for the next step without further purification. The crude acid (0.27 mmol), 2,4,6-trifluorophe- nyl methanamine (0.084 g, 0.52 mmol), DIPEA (0.169 g, 1.3 mmol) and HATU (0.20 g, 0.52 mmol) in DCM (10 ml) were stirred at room temperature for 1 hout The reaction mixture was concentrated down, re-dissolved in EtOAc (50 mE), washed with saturated NaHCO3 (2x), saturated NH4C1 and dried over Na2504. Afier concentration, the crude was purified by column chromatography on silica gel with hexaneEtOAc to obtain 63-A. ECMS-ESI (mlz): [M+H]. found:512.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0743; 0745

81
[ 214759-21-4 ]
C₂₀H₂₀N₂O₅ [ No CAS ]
C₂₇H₂₄F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	10740] A 50-mE 1-neck round bottom flask was charged with reactant 1-C (0.17 g, 0.43 mmol) in THF (5 mE) and MeOH (5 mE). 1 N KOH in water (1.3 mE) was added to the reaction solution. The reaction mixture was stirred at room temperature for 1 hout Afier acidification with 1 N HC1, the solution was concentrated to remove the solvent completely and the crude acid was used for next step without further purification. The crude acid (0.27 mmol), 2,4,6-trifluorophe- nyl methanamine (0.084 g, 0.52 mmol), DIPEA (0.169 g, 1.3 mmol) and HATU (0.20 g, 0.52 mmol) in DCM (10 ml) were stirred at room temperature for 1 hout The reaction mixture was concentrated down, re-dissolved in EtOAc (50 mE), washed with saturated NaHCO3 (2x), saturated NH4C1 and dried over Na2504. Afier concentration, the crude was purified by column chromatography on silica gel with hexaneEtOAc to obtain 62-A. ECMS-ESI (mlz): [M+H]. found:512.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0738; 0740

82
[ 214759-21-4 ]
C₂₀H₂₀N₂O₅ [ No CAS ]
C₂₇H₂₄F₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃; for 1h;	A 50-mE 1-neck round bottom flask was charged with reactant 2-C (0.17 g, 0.43 mmol) in THF (5 mE) and MeOH (5 mE). 1 N KOH in water (1.3 mE) was added to the reaction solution. The reaction mixture was stirred at room temperature for 1 hout Afier acidification with 1 N HC1, the solution was concentrated to remove the solvent completely and the crude acid was used for the next step without further purification. The crude acid (0.27 mmol), 2,4,6-trifluorophe- nyl methanamine (0.084 g, 0.52 mmol), DIPEA (0.169 g, 1.3 mmol) and HATU (0.20 g, 0.52 mmol) were stirred in DCM (10 ml) at room temperature for 1 hour. The reaction mixture was concentrated down, re-dissolved in EtOAc (50 mE), washed with saturated NaHCO3 (2x), sat NH4C1 and dried over Na2504. After concentration, the crude was purified by colunm chromatography on silica gel with hexane-EtOAc to obtain 61-A. ECMS-ESI+ (mlz): [M+H]+. found: 512.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0734; 0736

83
[ 214759-21-4 ]
C₁₆H₂₀N₂O₆ [ No CAS ]
C₂₃H₂₄F₃N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; for 0.5h;	10602] A mixture of the above residue, 2,4,6-trifluoroben- zylamine (64 mg, 0.397 mmol), and HATU (280 mg, 0.736 mmol) in dichloromethane (3 mE) was stirred at room temperature as DIPEA (0.6 mE, 3.445 mmol) was added. After 30 mm, the reaction mixture was diluted with ethyl acetate, washed with saturated NH4C1 (x2), saturated NaHCO3 (x2), and brine (xl). After the aqueous fractions were extracted with ethyl acetate (xl), two organic fractions were combined, dried (Na2504), and concentrated. The residue was purified by preparative HPEC to get compound 38-A. ?H NMR (400 MHz, Chloroform-d) oe 10.67 (s, 1H), 8.65 (s, 1H), 6.80-6.56 (m, 2H), 4.94-4.80 (m, 1H), 4.79-4.69 (m, 1H), 4.62 (dd, J=15.0, 4.6 Hz, 1H), 4.47 (d, J=3.6 Hz, 1H), 4.04 (s, 3H), 3.92-3.65 (m, 3H), 3.26 (td, J=11.5, 10.9, 6.0 Hz, 2H), 2.77 (d, J=15.6 Hz, 1H), 2.37 (t, J=14.1 Hz, 1H), 1.27 (d, J=6.7 Hz, 6H). ?9F NMR (376 MHz, Chioroform-d) oe -76.30 (s, 3F),-108.39 (ddd, J=15.1, 8.6, 6.1 Hz, iF), -112.00 (t, J=6.9 Hz, 2F). ECMS-ESI (mlz): [M+H] calculated for C23H25F3N305: 480.17. found: 480.23.

Reference： [1]Patent: US2016/176870,2016,A1 .Location in patent: Paragraph 0599; 0602

84
[ 214759-21-4 ]
C₁₆H₂₀N₂O₆ [ No CAS ]
C₂₂H₂₂F₃N₃O₅ [ No CAS ]

Reference： [1]Patent: US2016/176870,2016,A1

85
[ 58551-83-0 ]
[ 214759-21-4 ]

Reference： [1]Patent: CN104610068,2016,B

86
[ 96606-37-0 ]
[ 214759-21-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	With ammonia; hydrogen; In methanol; at 90℃; under 7500.75 Torr; for 8h;Autoclave;	50 g of <strong>[96606-37-0]2,4,6-trifluorobenzonitrile</strong> was charged into a 1000 ml autoclave,2.5 grams of Raney-Ni, 75 grams of 25% ammonia,500 g of methanol,The control temperature is 90 , the mixing speed is 350r / min,Hydrogen hydrogenation,Hydrogenation pressure 1Mpa, hydrogen time 8 hours reaction end,Filtration of the catalyst Raney-Ni, distillation of the methanol in the filtrate, distillation of the end of the addition of dichloromethane extraction, extraction of the first pressure of the solvent, and then vacuum distillation of the product, the product 43.6 grams, 2,4,6-trifluorobenzene The amine content was 99% and the yield was 85% based on <strong>[96606-37-0]2,4,6-trifluorobenzonitrile</strong>.
39.3%	With 5%-palladium/activated carbon; hydrogen; propionic acid; at 10 - 15℃; under 9750.98 - 11251.1 Torr; for 5h;Autoclave;	50 g of 2,4,6-trifluoro-3,5-dichlorobenzonitrile was added to a 500 ml autoclave.200 g of ethyl acetate, 67 g of triethylamine, 6 g of 10% wet palladium on carbon, sealed autoclave,First, replace the gas with nitrogen three times, then replace the gas with hydrogen for 5 times, control the internal pressure of the reactor with hydrogen to 1.0~1.2 MPa, at 60~65 (hydrogenation reaction for 8 hours, sample analysis, disappearance of the raw materials. Filtration of the reaction solution,The filtrate was concentrated under reduced pressure to give crude <strong>[96606-37-0]2,4,6-trifluorobenzonitrile</strong>.The obtained crude <strong>[96606-37-0]2,4,6-trifluorobenzonitrile</strong> was transferred into a 500 ml autoclave, and 300 g of propionic acid was added.7.5 g of 5% dry palladium carbon, sealed autoclave, first replace the gas with nitrogen for 3 times, then replace the gas with hydrogen for 5 times, control the internal pressure of the autoclave with hydrogen to 1.3~1.5 MPa, and hydrogenate at 10~15 C for 5 hours. Sampling analysis,The raw materials disappeared. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure.Adjust the pH to alkaline with 20% potassium carbonate solution, let stand, and separate the organic phase.After rectification, 14.0 g of a colorless transparent liquid was obtained, which was 2,4,6-trifluorobenzylamine, the yield was 39.3%, and the purity was 98.5 %.
6 g	With palladium 10% on activated carbon; hydrogen; acetic acid; at 90℃; under 7500.75 Torr; for 16h;	3,5-Dichloro-<strong>[96606-37-0]2,4,6-trifluorobenzonitrile</strong> (15.0, 66.4 mmol),Diisopropylethylamine (25.7g,199.2mmol) and 0.75g 10% Pd/C,450 mL of ethyl acetate was put into a 1000 mL autoclave.Replace it with nitrogen three times.Through hydrogen pressure to 0.5Mpa,Warming to 90 C, reaction 12h.Sampling analysisThe raw material disappearsRemove insolubles,Vacuum recovery of solvent,Intermediate <strong>[96606-37-0]2,4,6-trifluorobenzonitrile</strong> was obtained.The intermediate-trifluorobenzonitrile was dissolved in 250 mL acetic acid,1.5g 10%Pd/C, nitrogen replaced three times,With hydrogen pressure to 1.0Mpa,Warming to 90C,Reaction 16h. Sampling analysisRaw material disappears, insolubleThe product was distilled under reduced pressure to recover the solvent.Add 150 mL of dichloromethane to the residue.Cool the mixture to 0-5 C with an ice bath.Adjust the pH to about 10 with liquid caustic.Separate the organic phase.Dry organically with anhydrous sodium sulfatefilter,After atmospheric distillation to recover the solvent,Distillation under reduced pressure gave 2,4,6-trifluorobenzylamine (6.0 g, 56.1% yield over two steps) with an HPLC content of 99.3%.

Reference： [1]Patent: CN106349083,2017,A .Location in patent: Paragraph 0025; 0026
[2]Patent: CN108586267,2018,A .Location in patent: Paragraph 0096-0102
[3]Patent: CN107778183,2018,A .Location in patent: Paragraph 0051; 0052; 0054; 0056; 0058; 0072; 0074; 0076

87
[ 214759-21-4 ]
C₁₄H₁₄N₂O₆ [ No CAS ]
[ 1611493-60-7 ]

Yield	Reaction Conditions	Operation in experiment
65 g		50 g of compound (1) was charged along with 500 ml of dimethyl carbonate followed by 52 g of N, N?-Carbonyl Diimidazole. The reaction mass was heated at 40-50C and maintained for 5 hours and then cooled to room temperature. 39.4 g of compound (6) was added to the reaction mass and stirred for 1 hour. 500 ml of water added to the reaction mass and extracted with 500 ml ethyl acetate. Then back extracted with ethyl acetate 500 ml one more time and washed combined organic layer with 50 ml iN HC1. The organic layer was washed with saturated sodium bicarbonate solution 250 ml followed by water 500 ml. The layer was partially concentrated, filtered and then the filtrate was distilled out completely. 150 ml of methanol was added to the residue and heated to 45-50C and maintained for 1 hour. Then cooled to 0-10C, filtered and washed with chilled methanol 50 ml and finally recrystallized from methanol to obtain Bictegravir.Yield-65 gHPLC Purity: > 99.5 %

Reference： [1]Patent: WO2018/229798,2018,A1 .Location in patent: Page/Page column 17; 19

88
[ 214759-21-4 ]
[ 1611493-60-7 ]

Reference： [1]Patent: WO2020/3151,2020,A1

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1-(2-Fluorophenyl)-N-methylmethanamine

Similarity: 0.86

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Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
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
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
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
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
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

[ CAS No. 214759-21-4 ] {[proInfo.proName]}

Quality Control of [ 214759-21-4 ]

Related Doc. of [ 214759-21-4 ]

Product Details of [ 214759-21-4 ]

Calculated chemistry of [ 214759-21-4 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 214759-21-4 ]

Application In Synthesis of [ 214759-21-4 ]

[ 214759-21-4 ] Synthesis Path-Upstream 1~5

[ 214759-21-4 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 214759-21-4 ]

Fluorinated Building Blocks

Aryls

Amines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 214759-21-4 ]