[ CAS No. 79456-34-1 ] {[proInfo.proName]}

Name: 79456-34-1|5-Bromo-3-(trifluoromethyl)pyridin-2-amine|98%
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SKU: A221840
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Quality Control of [ 79456-34-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 79456-34-1 ]

SDS Specification

Alternatived Products of [ 79456-34-1 ]

Product Details of [ 79456-34-1 ]

CAS No. :	79456-34-1	MDL No. :	MFCD10758088
Formula :	C₆H₄BrF₃N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QUYZBNHTYCLZLW-UHFFFAOYSA-N
M.W :	241.01	Pubchem ID :	20525383
Synonyms :

Calculated chemistry of [ 79456-34-1 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	41.34
TPSA :	38.91 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) :	-6.29 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.64
Log Po/w (XLOGP3) :	2.08
Log Po/w (WLOGP) :	3.61
Log Po/w (MLOGP) :	2.08
Log Po/w (SILICOS-IT) :	2.36
Consensus Log Po/w :	2.35

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.95
Solubility :	0.271 mg/ml ; 0.00113 mol/l
Class :	Soluble
Log S (Ali) :	-2.53
Solubility :	0.717 mg/ml ; 0.00297 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.41
Solubility :	0.0935 mg/ml ; 0.000388 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.9

Safety of [ 79456-34-1 ]

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

Application In Synthesis of [ 79456-34-1 ]

* 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 [ 79456-34-1 ]
Downstream synthetic route of [ 79456-34-1 ]

[ 79456-34-1 ] Synthesis Path-Upstream 1~2

1
[ 183610-70-0 ]
[ 79456-34-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With N-Bromosuccinimide In acetonitrile at 5 - 23℃; for 1 h;	Step 3) 5-Bromo-3-trifluoromethyl-pyridin-2-ylamine CAS-No. [79456-34-11; To a solution of the above 3-trifluoromethyl-pyridin-2-ylamine (16.21 g, 100 mmol) in acetonitrile (300 mL) at 5° C. was added NBS (17.8 g, 100 mmol) and the mixture was stirred at 23° C. for 1 h. Poured into ice and additional sat. NaHCO₃-sol., extracted with EtOAc, washed with brine, dried over Na₂SO₄. Removal of the solvent in vacuum left a yellow solid, which was filtered through a silica gel and cotton wool column with dichloromethane to give the title compound as a yellow solid (23.71 g, 98percent). MS (EI) 240.1 [(M)⁺], 242.0 [(M+2)⁺].
93%	With N-Bromosuccinimide In acetonitrile at 20℃;	Example 46; Preparation of iV-(5-(6-Amino-5-(trifluoromethyl)pyridin-3- yl)thiazolo [5,4-4. Insoluble materials were removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with a 10percent- 30percent mixture of ethyl acetate and hexane. Concentration of appropriate fractions afforded the titled compound 5-Bromo-3- (trifluoromethyl)pyridin-2-amine (46B, 2.91 g, 93percent) as pale yellow crystalline solid. ¹H NMR (300 MHz, CDCl₃): δ 8.26 (d, 1 H, J = 1.9 Hz), 7.79 (d, 1 H, J = 1.9 Hz), 5.00 (br s, 2 H). MS (ES) [M+H] calc'd for C₆H₄BrF₃N₂ 241; found 241.
89.7%	With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 2 h;	Compound BB-21-1 (42.0g, 259mmol) was dissolved in N, N - dimethylformamide (400mL), then was addedN - bromosuccinimide (46.1g, 259mmol).The reaction was stirred at 20 2 hours.The reaction solution was poured into stirred5percent mixture of sodium bisulfite and water (10:1), the precipitate was filtered, washed with water, dissolved in methylene chloride (a 500 mL), dried over sodium sulfatedrying, filtered, and concentrated to give the title compound BB -20-2 (yellow solid, 51.0g, yield: 89.7percent).

88%	With N-Bromosuccinimide In N,N-dimethyl-formamide for 4 h;	2-Amino-3-trifluoromethyl pyridine (5.4 gm, 33.3 mmol) was dissolved in DMF (31 mL) and N-bromosuccinimide (5.9 gm, 33.3 mmol) dissolved in DMF (31 mL) was added <n="198"/>dropwise. The mixture was stirred for 4 hours, concentrated to ~ 20 mL and added dropwise into ice-water (600 mL). The product crashed out, was filtered, washed with water (100 mL) and dried under vacuum to afford 5-bromo-3-trifluoromethyl-pyridin-2-ylamine as a light brown solid (7.12 gm, 88percent). ¹H NMR (d₆-DMSO, 300 MHz) δ 8.22 (s, IH), 7.85 (s, IH), 6.66 (s, 2H); MS (ESI) m/z = 242.9 (MH⁺).
88%	With N-Bromosuccinimide In acetonitrile at 0 - 23℃; for 4 h;	N-bromosuccinimide (20.83g, 117.28 mmol) was portion wise added to a stirred solution of 3-(trifluoro- methyl)pyridin-2-amine (19g, 117.28 mmol) in MeCN (380 mL) at 0°C. The RM was stirred for4h at RT. The RM was quenched with aq. NaHCO3 solution (pH—8) and then filtered. The solid was washed with water (200 mL), and the product was dissolved with EtOAc (300 mL). The organic layer was dried over anhydr. Na2SO4, filtered and solvent was concentrated under reduced pressure to give 5-bromo-3-(trifluoromethyl)pyridin-2-amine (25g, 88percent) as a solid.
85%	With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 2 h;	To a solution of 2-amino-3~trifluoromethylpyridine (100 g, 0.62 mol) in D F (500 mL) was added a solution of NBS (1 10 g, 0,62 mol) in DMF (500 mL) dropwise at room temperature. The solution was stirred at room temperature for 2 hours and then concentrated to 300 mL. The residue was added slowly to the beaker containing a mixture of 5percent aqueous NaHS0₃ and H₂0 (3 L, 1 :10 v/v). The precipitate was filtered, washed with H₂0 (2 x 500 mL) and dried under vacuum to give the title compound (120 g, 85percent) as a light brown solid.
84.6%	With N-Bromosuccinimide In N,N-dimethyl-formamide at 20℃; for 2 h;	Example 1 l-ll-β-Chloro-6-furan-3-yl-8Arifluoromethyl4midazoll,2-a]pyridine-2-carbonyl)-piperidin-4- yl]-pyrrolidin-2-one (Compound 101) Step l 5-Bromo-3-trifluoromethyl-pyridin-2-ylamine[0102] A solution of N-Bromosuccinimide (54.89 g, 308.41 mmol) in DMF (250 niL) was rapidly added dropwise via addition funnel to a stirring solution of 2-Amino-3-(trifluoromethyl) pyridine (50.00 g, 308.41 mmol) in DMF (250 mL) at room temperature. The mixture was stirred for 2 hours, concentrated to a volume of 200 mL and added slowly into a beaker containing a cold stirring mixture of 5percent NaHSO₃ and water (1.5 L, 1 :10 v/v). The precipitate was filtered, washed with water (3 x 500 mL) and dried under vacuum to afford 5-bromo-3- trifluoromethyl-pyridin-2-ylamine (62.89 g, 84.6percent) as a light brown solid. MS 242.9 (M+H⁺).
84.1%	With N-Bromosuccinimide In acetonitrile at 0 - 25℃; for 2 h;	The 3 - (trifluoromethyl) pyridin-2-amine (1.0g, 6 . 17mmol) dissolved in acetonitrile (30 ml) in, then dropped to 0 °C, then the NBS (1.2g, 6 . 74mmol) is slowly added to the system, is omitted, the temperature is increased to 25 °C reaction 2 hours. The concentrated, the residue by silica gel column chromatography (PE:EA=5:1) purification, to obtain the title compound (1.25g, yield 84.1percent).
82%	With bromine In acetic acid at 25 - 30℃;	3-(Trifluoromethyl)-2-pyridinamine (150 g) was added to acetic acid (1500 mL) and stirred the mass for 10 to 15 min. Bromine (47.54 mL) was added to the mixture over a period of 45-60 min at 25-30°C. The reaction mass was maintained under stirring at 25-30°C for 2-3 h. After completion of the reaction, the mass was cooled to 10 to 15°C and diluted with water (2500 mL) subsequently neutralized the mass with solid sodium carbonate (420 g). The reaction mass was filtered and bed was washed with water (300 mL) and dried at 25 to 30°C for 12 h. The dried mass was dissolved in ethyl acetate (2250 mL) and washed with 5percent sodium bicarbonate solution (750 mL). The separated organic layer was washed with 10percent sodium chloride solution (750 mL). Clean organic layer was distilled out completely to obtain the title compound (183 g). Yield: 82percent Purity: 99.52percent 1H NMR (300 MHz, DMSO-<): δ 8.25 (s, 1H), 7.89 (s, 1H), 6.7 (bs, 2H). MS: m/z 242 (M+l)
81%	With N-Bromosuccinimide In acetonitrile at 0 - 25℃; for 1 h;	To a solution of 3-(trifluoromethyl)pyridin-2-amine (5.4 g, 33.3 mmol) in acetonitrile (100 mL) was added NBS (5.93 g, 33.3 mmol) at OeC and reaction mixture was stirred at 25eC for 1H. After completion of the reaction, reaction mixture was quenched with saturated sodium bicarbonate (25 mL) and extracted with EtOAc (25 mL/13). The combined organic phase was washed with brine (20 mL), dried over Na2S04, filtered. The filtrate was rotary evaporated and residue was purified by flash column chromatography (silica gel) to afford 6.5 g (81percent) of the titled product. 1HNMR (400 MHz, DMSO-d6) U8.28 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 6.72 (s, 2H); ESI-MS (m/z) 241.08 (MH)\
74%	at 20℃; for 2 h;	3-(trifluoromethyl)pyridin-2-amine (20 g, 123 mmol) was stirred in acetic acid (200 ml) at RT. Bromine (19.72 g, 123 mmol) was added drop wise with stirring. The reaction mixture was stirred for 2 h; followed by dilution with water. The product was extracted with ethyl acetate. Organic layer was washed with water, dried over sodium sulfate and concentrated to obtain the title product in 74percent yield.
3.8 g	With N-Bromosuccinimide In N,N-dimethyl-formamide for 4 h; Cooling with ice	Synthesis of 5-bromo-3-trifluoromethyl-pyridin-2-ylamine To a stirred solution of R-10 (2.70 g, 16.66 mmol) in DMF (15 ml) is added N-bromosuccinimide (3.00 g, 16.85 mmol) as a DMF solution (15 ml, dropwise). After 4 h the reaction is poured onto ice. The resulting precipitate is collected via filtration to give the product as an off-white solid. Dissolved into DCM and washed with brine. The layers are separated and the organic phase is dried (MgSO₄), filtered and concentrated to give the title intermediate (3.8 g); m/z 241.2/243.2 [M/M+2H].

Reference： [1] Patent: US2007/72879, 2007, A1, . Location in patent: Page/Page column 18
[2] Patent: WO2010/8847, 2010, A2, . Location in patent: Page/Page column 147
[3] Patent: CN105732602, 2016, A, . Location in patent: Paragraph 0364; 0366; 0367; 0368; 0369
[4] Patent: WO2009/23179, 2009, A2, . Location in patent: Page/Page column 196-197
[5] Patent: WO2015/158427, 2015, A1, . Location in patent: Page/Page column 87; 88
[6] Journal of Medicinal Chemistry, 2016, vol. 59, # 3, p. 1078 - 1101
[7] Patent: WO2011/41713, 2011, A2, . Location in patent: Page/Page column 142
[8] Patent: WO2010/91411, 2010, A1, . Location in patent: Page/Page column 79
[9] Patent: CN105541792, 2016, A, . Location in patent: Paragraph 0454; 0455; 0456
[10] Patent: WO2015/145369, 2015, A1, . Location in patent: Page/Page column 36-37
[11] Patent: WO2018/20474, 2018, A1, . Location in patent: Page/Page column 314-315
[12] Patent: WO2012/7926, 2012, A1, . Location in patent: Page/Page column 49
[13] Patent: WO2008/12326, 2008, A1, . Location in patent: Page/Page column 69
[14] Patent: WO2010/139731, 2010, A1, . Location in patent: Page/Page column 135
[15] Patent: WO2012/24150, 2012, A1, . Location in patent: Page/Page column 135
[16] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 16, p. 4652 - 4656
[17] Patent: US2013/195879, 2013, A1, . Location in patent: Paragraph 0278; 0279
[18] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 5, p. 507 - 512
[19] Patent: WO2007/134828, 2007, A1, . Location in patent: Page/Page column 68
[20] Patent: WO2008/138889, 2008, A2, . Location in patent: Page/Page column 85
[21] Patent: WO2008/138834, 2008, A1, . Location in patent: Page/Page column 89
[22] Patent: WO2010/139747, 2010, A1, . Location in patent: Page/Page column 102

2
[ 79456-34-1 ]
[ 73183-34-3 ]
[ 947249-01-6 ]

Yield	Reaction Conditions	Operation in experiment
97.47%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In 1,4-dioxane at 25 - 100℃;	A mixture of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (180 g) and 1,4-dioxane (3600 mL) was stirred in a flask. Bis(pinacolato)diboron (284.47 g), potassium acetate (109.95 g) and l,l-bis(diphenylphosphino)ferrocene dichloropalladium (II) DCM complex (18 g), were then added under stirring at a temperature of about 25 to 30°C. Reaction mass was heated to 95 to 100°C and maintained for 15-16 hr. After the completion of reaction, the mass was cooled to 25 to 30°C, filtered through celite bed and the bed was washed with ethyl acetate (1800 mL). The filtrate was distilled out completely under vacuum to get crude title compound (450 g). Purification The crude title compound was dissolved in methanol (1800 mL) in a round bottom flask. Charcoal (45 g) and silica gel (60-120 mesh size, 450 g) were added to the mass and maintained under stirring at a temperature of about 25 to 30°C for 1 h. The mass was filtered through celite bed and washed the bed with methanol (450 mL). The filtrate was added into a flask containing cold water (6750 mL) at 0-5°C, over a period of 1 h. The precipitated solid was filtered out, washed with cold water (900 mL). The wet compound was unloaded and dried at 45 to 50°C to obtain the title compound (209 g). Yield: 97.47percent Purity: 98.43percent ¹H NMR (300 MHz, DMSO-d6): δ 8.38 (s, 1H), 7.80 (s, 1H), 6.92 (s, 2H), 1.27 (s, 12H). MS: m/z 289.1 (M+l)
94%	With potassium acetate In 1,4-dioxane at 110℃; for 10 h;	An orange suspension of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (4 g, 16.60 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane)(5.90 g, 23.24 mmol), KOAc (4.07 g, 41 .5 mmol) and PdCI₂(dppf).CH₂CI₂ (0.678 g, 0.830 mmol) in Dioxane (60 mL) was heated to 1 10°C for 10 h under N₂. After concentration under vacuum to remove the solvent, the crude product was purified using a silica gel column, with PE/EtOAc as eluant to give pure product as pale yellow solid (4.5g, yield 94percent). MS (m/z): 289 (M+H)⁺.
94%	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate In 1,4-dioxane at 110℃; for 10 h; Inert atmosphere	An orange suspension of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (4 g, 16.60 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (5.90 g, 23.24 mmol), KOAc (4.07 g, 41.5 mmol) and PdCl₂(dppf).CH₂Cl₂(0.678 g, 0.830 mmol) in Dioxane (60 mL) was heated to 110° C. for 10 h under N₂. After concentration under vacuum to remove the solvent, the crude product was purified using a silica gel column, with PE/EtOAc as eluant to give pure product as pale yellow solid (4.5 g, yield 94percent). MS (m/z): 289 (M+H)⁺.

72%

With potassium acetate In 1,2-dimethoxyethane at 80℃; Inert atmosphere

[0429] To a solution of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (46B, 1.21 g, 5.0 mmol) in DME (50 mL) were added bis(pinacolato)diboron (1.65 g, 6.5 mmol), Pd(dppf)Cl₂ CH₂Cl₂ (122 mg, 0.15 mmol), and potassium acetate (1.47 g, 15 mmol). The mixture was stirred overnight at 80 ⁰C under Ar and then allowed to cool to room temperature. Insoluble materials were removed by filtration and washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with a 20percent- 50percent mixture of ethyl acetate and hexane. After concentration of appropriate fractions, the residue was dissolved in ethyl acetate (100 mL), and the solution was washed with saturated aqueous solution of NaHCψ3 (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL). The organic extracts were combined and washed with brine (50 mL) and dried over anhydrous MgSO₄. Insoluble materials were removed by filtration and the filtrate was concentrated in vacuo. The residue was re-crystallized from hexane to yield 5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (46C 1.04 g, 72percent) as white crystalline solid. ¹H NMR (300 MHz, CDCl₃): δ 8.56 (d, 1 H, J = 0.9 Hz), 8.07 (d, 1 H, J = 0.8 Hz), 5.15 (br s, 2 H), 1.33 (s, 12 H). MS (ES) [M+H] calc'd for C₆H₆BF₃N₂O₂ (In situ hydrolysis of the titled compound to the boronic acid on LC), 207; found 207.

Reference： [1] Patent: WO2015/145369, 2015, A1, . Location in patent: Page/Page column 37
[2] Patent: WO2012/34526, 2012, A1, . Location in patent: Page/Page column 36-37
[3] Patent: US2013/190307, 2013, A1, . Location in patent: Paragraph 0172; 0173
[4] Patent: WO2010/8847, 2010, A2, . Location in patent: Page/Page column 147-148
[5] Patent: WO2008/12326, 2008, A1, . Location in patent: Page/Page column 69
[6] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 16, p. 4652 - 4656
[7] Patent: WO2007/134828, 2007, A1, . Location in patent: Page/Page column 68
[8] Patent: WO2008/138889, 2008, A2, . Location in patent: Page/Page column 85
[9] Patent: WO2008/138834, 2008, A1, . Location in patent: Page/Page column 88-89
[10] Patent: WO2010/139747, 2010, A1, . Location in patent: Page/Page column 102

[ 79456-34-1 ] Synthesis Path-Downstream 1~88

1
[ 79456-34-1 ]
[ 73183-34-3 ]
[ 947249-01-6 ]

Yield	Reaction Conditions	Operation in experiment
97.47%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 25 - 100℃;	A mixture of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (180 g) and 1,4-dioxane (3600 mL) was stirred in a flask. Bis(pinacolato)diboron (284.47 g), potassium acetate (109.95 g) and l,l-bis(diphenylphosphino)ferrocene dichloropalladium (II) DCM complex (18 g), were then added under stirring at a temperature of about 25 to 30C. Reaction mass was heated to 95 to 100C and maintained for 15-16 hr. After the completion of reaction, the mass was cooled to 25 to 30C, filtered through celite bed and the bed was washed with ethyl acetate (1800 mL). The filtrate was distilled out completely under vacuum to get crude title compound (450 g). Purification The crude title compound was dissolved in methanol (1800 mL) in a round bottom flask. Charcoal (45 g) and silica gel (60-120 mesh size, 450 g) were added to the mass and maintained under stirring at a temperature of about 25 to 30C for 1 h. The mass was filtered through celite bed and washed the bed with methanol (450 mL). The filtrate was added into a flask containing cold water (6750 mL) at 0-5C, over a period of 1 h. The precipitated solid was filtered out, washed with cold water (900 mL). The wet compound was unloaded and dried at 45 to 50C to obtain the title compound (209 g). Yield: 97.47% Purity: 98.43% 1H NMR (300 MHz, DMSO-d6): delta 8.38 (s, 1H), 7.80 (s, 1H), 6.92 (s, 2H), 1.27 (s, 12H). MS: m/z 289.1 (M+l)
94%	With potassium acetate; In 1,4-dioxane; at 110℃; for 10h;	An orange suspension of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (4 g, 16.60 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane)(5.90 g, 23.24 mmol), KOAc (4.07 g, 41 .5 mmol) and PdCI2(dppf).CH2CI2 (0.678 g, 0.830 mmol) in Dioxane (60 mL) was heated to 1 10C for 10 h under N2. After concentration under vacuum to remove the solvent, the crude product was purified using a silica gel column, with PE/EtOAc as eluant to give pure product as pale yellow solid (4.5g, yield 94%). MS (m/z): 289 (M+H)+.
94%	With palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 10h;Inert atmosphere;	An orange suspension of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (4 g, 16.60 mmol), 4,4,4?,4?,5,5,5?,5?-octamethyl-2,2?-bi(1,3,2-dioxaborolane) (5.90 g, 23.24 mmol), KOAc (4.07 g, 41.5 mmol) and PdCl2(dppf).CH2Cl2 (0.678 g, 0.830 mmol) in Dioxane (60 mL) was heated to 110 C. for 10 h under N2. After concentration under vacuum to remove the solvent, the crude product was purified using a silica gel column, with PE/EtOAc as eluant to give pure product as pale yellow solid (4.5 g, yield 94%). MS (m/z): 289 (M+H)+.

72%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; at 80℃;Inert atmosphere;	[0429] To a solution of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (46B, 1.21 g, 5.0 mmol) in DME (50 mL) were added bis(pinacolato)diboron (1.65 g, 6.5 mmol), Pd(dppf)Cl2 CH2Cl2 (122 mg, 0.15 mmol), and potassium acetate (1.47 g, 15 mmol). The mixture was stirred overnight at 80 0C under Ar and then allowed to cool to room temperature. Insoluble materials were removed by filtration and washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with a 20%- 50% mixture of ethyl acetate and hexane. After concentration of appropriate fractions, the residue was dissolved in ethyl acetate (100 mL), and the solution was washed with saturated aqueous solution of NaHCtheta3 (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL). The organic extracts were combined and washed with brine (50 mL) and dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated in vacuo. The residue was re-crystallized from hexane to yield 5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)pyridin-2-amine (46C 1.04 g, 72%) as white crystalline solid. 1H NMR (300 MHz, CDCl3): delta 8.56 (d, 1 H, J = 0.9 Hz), 8.07 (d, 1 H, J = 0.8 Hz), 5.15 (br s, 2 H), 1.33 (s, 12 H). MS (ES) [M+H] calc'd for C6H6BF3N2O2 (In situ hydrolysis of the titled compound to the boronic acid on LC), 207; found 207.
	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 115℃; for 8.5h;	8.04 g (31.7 mmol) of 5-Bromo-3-trifluoromethyl-pyridin-2-ylamine (B57a), 10.5 g (41.2 mmol) of 4,4,5,5,4',4',5',5'-Octamethyl-[2,2']bi[[1 ,3,2]dioxaborolanyl] (Aldrich, Buchs,Switzerland), 9.62 g (95.1 mmol) of KOAc in 100 ml dioxane are degassed with argon for 15 min. 776 mg (0.951 mmol) of bis(diphenylphosphino)ferrocene dichloro- palladium(ll)dichloromethane are added and the mixture is degassed for 15 more minutes.The reaction mixture is heated at 115C for 8 h. After that time, the reaction mixture is filtered and the solvent evaporated. The residue is purified by simple filtration on silicagel (solvent system: t-butyl-methyl ether-EtOAc-NEt3 = 50:50:0.1 ) to yield the title compound as almost colorless solid. ES-MS 289 (M+H)+; analytical HPLC: tret= 1.68 min (Grad 1 ).
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In N,N-dimethyl-formamide; at 150℃; for 2h;Inert atmosphere;	A mixture comprising 5-bromo-3-trifluoromethyl-pyridin-2-ylamine (1.0 g, 4.1 mmol), bis(pinacolato) diboron (1.3 g, 5.0 mmol), Pd(dppf)Cl2(0.90 g, 0.12 mmol) and potassium acetate (1.14 g, 11.6 mmol) in dry DMF (20 ml) was flushed with argon and heated for 2 hours at 150oC. After cooling to room temperature, the mixture was filtered through celite and concentratedin vacuoto afford a black residue. The residue was dissolved in EtOAc, loaded onto a SCX column (silica based cation exchange sorbent) and eluted with a mixture of EtOAc (200 ml) and 0.35M NH3in methanol (200 ml). The resulting solution was concentrated to afford the title compound, which was used in the next step without further purification.
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 150℃; for 2h;Microwave irradiation;	Step 2: 5-(4,4,5,5-Tetramethyl-[l ,3»2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2- ylamine5-Bromo-3-trifluoromethyl-pyridin-2-ylamine (1.0 g, 4.14 mmol), bis(pinacolato) diboron (1.26 g, 4.98 mmol), Pd(dppf)Cl2 (0.90 g, 0.1242 mmol), potassium acetate (1.14 g, 11.6 mmol) and dry DMF (20 ml) are mixed together under an inert atmosphere of argon and heated using microwave radiation at 150 C for 2 hours. The reaction mixture is cooled to room temperature, filtered through Celite (filter agent) and concentrated in vacuo. The resulting residue is dissolved in EtOAc and loaded onto an Isolute SCX column (silica based cation exchange sorbent) eluting with 200 ml 0.35M NH3 in methanol. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound. [M+H]+ 381
	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 115℃; for 8h;	Stage 4.2: 5-(4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-yl- amine. 8.04 g (31.7 mmol) of 5-bromo-3-trifluoromethyl-pyridin-2-ylamine (preparation see Stage 24.4.), 10.5 g (41.2 mmol) of 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[1,3,2]dioxaborolanyl] (Aldrich), and 9.62 g (95.1 mmol) of KOAc in 100 ml dioxane are degassed with argon for 15 min. Then 776 mg (0.951 mmol) of bis(diphenylphosphino)ferrocene dichloro-palla- dium(ll)dichloromethane (ABCR) are added and the mixture is degassed for 15 more min. The reaction mixture is heated at 115C for 8 h. After that time, the reaction mixture is filtered and the solvent evaporated. The residue is purified by simple filtration on silicagel (solvent system: t-butyl-methyl ether-EtOAc-NEt3 = 50:50:0.1) to yield the title compound as almost colorless solid. MS(ESI+):m/z= 289.1 (M+H)+; HPLC: tRet = 3.292 min (System 2).
	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 115℃; for 8h;	8.04 g (31.7 mmol) of 5-bromo-3-trifluoromethyl-pyridin-2-ylamine (preparation see Stage 24.4.), 10.5 g (41.2 mmol) of 4>4,5,5)4',4l,5ll5I-octamethyl-[2,2I]bi[[1 ,3,2]dioxaborolanyl] (Aldrich), 9.62 g (95.1 mmol) of KOAc in 100 ml dioxane are degassed with argon for 15 min. Then 776 mg (0.951 mmol) of bis(diphenylphosphino)ferrocene dichloropalladium(ll)di- chloromethane (ABCR) are added and the mixture is degassed for 15 more minutes. The reaction mixture is heated at 1150C for 8 h. After that time, the reaction mixture is filtered and the solvent evaporated. The residue is purified by simple filtration on silicagel (solvent <n="90"/>system: t-butyl-methyl ether- EtOAc-N Et3 = 50:50:0.1 ) to yield the title compound as almost colorless solid. ES-MS: (M+1 ) = 289; TIc: Rf=0.77 in t-buthyl-methyl ether-EtOAc 1 :1.-
	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 115℃; for 8h;Inert atmosphere;	8.04 g (31.7 mmol) of 5-bromo-3-trifluoromethyl-pyridin-2-ylamine (preparation see Stage 1.3.2), 10.5 g (41.2 mmol) of 4,4,5,5,4',4',5',5'-octamethyl-[2,2']bi[[1 ,3,2]dioxaborolanyl] (Aldrich), 9.62 g (95.1 mmol) of KOAc in 100 ml dioxane are degassed with argon for 15 min. Then 776 mg (0.951 mmol) of bis(diphenylphosphino)ferrocene dichloropalla-dium(ll)di-chloromethane (ABCR) are added and the mixture is degassed for 15 more minutes. The reaction mixture is heated at 1 15C for 8 h. After that time, the reaction mixture is filtered and the solvent evaporated. The residue is purified by simple filtration on silicagel (solvent system: t-butyl-methyl ether-EtOAc-NEt3 = 50:50:0.1 ) to yield the title compound as almost colorless solid. ES-MS: (M+1 ) = 289; TIc: Rf=O.77 in t-buthyl-methyl ether-EtOAc 1 :1.

Reference： [1]Patent: WO2015/145369,2015,A1 .Location in patent: Page/Page column 37
[2]Patent: WO2012/34526,2012,A1 .Location in patent: Page/Page column 36-37
[3]Patent: US2013/190307,2013,A1 .Location in patent: Paragraph 0172; 0173
[4]Patent: WO2010/8847,2010,A2 .Location in patent: Page/Page column 147-148
[5]Patent: WO2008/12326,2008,A1 .Location in patent: Page/Page column 69
[6]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4652 - 4656
[7]Patent: WO2007/134828,2007,A1 .Location in patent: Page/Page column 68
[8]Patent: WO2008/138889,2008,A2 .Location in patent: Page/Page column 85
[9]Patent: WO2008/138834,2008,A1 .Location in patent: Page/Page column 88-89
[10]Patent: WO2010/139747,2010,A1 .Location in patent: Page/Page column 102

2
[ 79456-34-1 ]
5-iodo-3-(trifluoromethyl)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
~ 100%	With potassium iodide;copper(l) iodide; N,N`-dimethylethylenediamine; In butan-1-ol; for 18h;Heating / reflux;	A mixture of <strong>[79456-34-1]5-bromo-3-trifluoromethyl-pyridin-2-ylamine</strong> (example C.18 step 3) (723 mg, 3 mmol), sodium iodide (900 mg, 6 mmol), copper (I) iodide (29 mg, 5 mol %) and N,N'-dimethylethylendiamine (26 mg, 10 mol %) in n-butanol (6 mL) was stirred at reflux under argon atmosphere for 18 h. The reaction mixture was cooled to 23 C., extracted with ethyl acetate and water, the organic layers were dried over MgSO4, filtered and evaporated to leave the title compound as a brown solid (880 mg, 102%), which was used without further purification. MS (ISN) 287.0 [(M-H)-].

Reference： [1]Patent: US2006/217387,2006,A1 .Location in patent: Page/Page column 31

3
[ 79456-34-1 ]
[ 128796-39-4 ]
[ 911112-73-7 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; for 1h;Heating / reflux;	Step 4) 3-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyridin-2-ylamine; A mixture of the above <strong>[79456-34-1]5-bromo-3-trifluoromethyl-pyridin-2-ylamine</strong> (9.90 g, 41.1 mmol), commercially available 4-(trifluoromethyl)benzeneboronic acid CAS-No. [128796-39-4] (8.58 g, 45.2 mmol), 1N aqueous Na2CO3-solution (98.6 mL, 98.6 mmol) and Pd(PPh3)4 (475 mg, 1 mol %) in DME (205 mL) was refluxed under argon atmosphere for 1 h. Poured into 5% citric acid, extracted with EtOAc, washed the organic layers with sat. NaHCO3-sol. and brine, dried over Na2SO4. Removal of the solvent in vacuum left a grey solid (13.96 g) which was purified by silica gel flash chromatography with heptane/EtOAc 4:1 to 2:1 to give the title compound as a light yellow solid (10.90 g, 87%). MS (ISN) 305 [(M-H)-]; mp 168 C.

Reference： [1]Patent: US2007/72879,2007,A1 .Location in patent: Page/Page column 18-19

4
[ 183610-70-0 ]
[ 79456-34-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With N-Bromosuccinimide; In acetonitrile; at 5 - 23℃; for 1h;	Step 3) 5-Bromo-<strong>[183610-70-0]3-trifluoromethyl-pyridin-2-ylamine</strong> CAS-No. [79456-34-11; To a solution of the above <strong>[183610-70-0]3-trifluoromethyl-pyridin-2-ylamine</strong> (16.21 g, 100 mmol) in acetonitrile (300 mL) at 5 C. was added NBS (17.8 g, 100 mmol) and the mixture was stirred at 23 C. for 1 h. Poured into ice and additional sat. NaHCO3-sol., extracted with EtOAc, washed with brine, dried over Na2SO4. Removal of the solvent in vacuum left a yellow solid, which was filtered through a silica gel and cotton wool column with dichloromethane to give the title compound as a yellow solid (23.71 g, 98%). MS (EI) 240.1 [(M)+], 242.0 [(M+2)+].
93%	With N-Bromosuccinimide; In acetonitrile; at 20℃;	Example 46; Preparation of iV-(5-(6-Amino-5-(trifluoromethyl)pyridin-3- yl)thiazolo [5,4-</] pyrimidin-2-yl)acetamide (46); 46C 43D Example 46[0428] To a solution of <strong>[183610-70-0]3-(trifluoromethyl)pyridin-2-amine</strong> (46A, 2.10 g, 13 mmol) in acetonitrile (40 mL) was added N-bromosuccinimide (2.54 g, 14.2 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL x 2). The organic extract was washed with brine (50 mL) and dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with a 10%- 30% mixture of ethyl acetate and hexane. Concentration of appropriate fractions afforded the titled compound 5-Bromo-3- (trifluoromethyl)pyridin-2-amine (46B, 2.91 g, 93%) as pale yellow crystalline solid. 1H NMR (300 MHz, CDCl3): delta 8.26 (d, 1 H, J = 1.9 Hz), 7.79 (d, 1 H, J = 1.9 Hz), 5.00 (br s, 2 H). MS (ES) [M+H] calc'd for C6H4BrF3N2 241; found 241.
89.7%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 2h;	Compound BB-21-1 (42.0g, 259mmol) was dissolved in N, N - dimethylformamide (400mL), then was addedN - bromosuccinimide (46.1g, 259mmol).The reaction was stirred at 20 2 hours.The reaction solution was poured into stirred5% mixture of sodium bisulfite and water (10:1), the precipitate was filtered, washed with water, dissolved in methylene chloride (a 500 mL), dried over sodium sulfatedrying, filtered, and concentrated to give the title compound BB -20-2 (yellow solid, 51.0g, yield: 89.7%).

88%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; for 4h;	2-Amino-3-trifluoromethyl pyridine (5.4 gm, 33.3 mmol) was dissolved in DMF (31 mL) and N-bromosuccinimide (5.9 gm, 33.3 mmol) dissolved in DMF (31 mL) was added <n="198"/>dropwise. The mixture was stirred for 4 hours, concentrated to ~ 20 mL and added dropwise into ice-water (600 mL). The product crashed out, was filtered, washed with water (100 mL) and dried under vacuum to afford 5-bromo-<strong>[183610-70-0]3-trifluoromethyl-pyridin-2-ylamine</strong> as a light brown solid (7.12 gm, 88%). 1H NMR (d6-DMSO, 300 MHz) delta 8.22 (s, IH), 7.85 (s, IH), 6.66 (s, 2H); MS (ESI) m/z = 242.9 (MH+).
88%	With N-Bromosuccinimide; In acetonitrile; at 0 - 23℃; for 4h;	N-bromosuccinimide (20.83g, 117.28 mmol) was portion wise added to a stirred solution of 3-(trifluoro- methyl)pyridin-2-amine (19g, 117.28 mmol) in MeCN (380 mL) at 0C. The RM was stirred for4h at RT. The RM was quenched with aq. NaHCO3 solution (pH-8) and then filtered. The solid was washed with water (200 mL), and the product was dissolved with EtOAc (300 mL). The organic layer was dried over anhydr. Na2SO4, filtered and solvent was concentrated under reduced pressure to give 5-bromo-<strong>[183610-70-0]3-(trifluoromethyl)pyridin-2-amine</strong> (25g, 88%) as a solid.
85%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a solution of 2-amino-3~trifluoromethylpyridine (100 g, 0.62 mol) in D F (500 mL) was added a solution of NBS (1 10 g, 0,62 mol) in DMF (500 mL) dropwise at room temperature. The solution was stirred at room temperature for 2 hours and then concentrated to 300 mL. The residue was added slowly to the beaker containing a mixture of 5% aqueous NaHS03 and H20 (3 L, 1 :10 v/v). The precipitate was filtered, washed with H20 (2 x 500 mL) and dried under vacuum to give the title compound (120 g, 85%) as a light brown solid.
84.6%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 2h;	Example 1 l-ll-beta-Chloro-6-furan-3-yl-8Arifluoromethyl4midazoll,2-a]pyridine-2-carbonyl)-piperidin-4- yl]-pyrrolidin-2-one (Compound 101) Step l 5-Bromo-<strong>[183610-70-0]3-trifluoromethyl-pyridin-2-ylamine</strong>[0102] A solution of N-Bromosuccinimide (54.89 g, 308.41 mmol) in DMF (250 niL) was rapidly added dropwise via addition funnel to a stirring solution of 2-Amino-3-(trifluoromethyl) pyridine (50.00 g, 308.41 mmol) in DMF (250 mL) at room temperature. The mixture was stirred for 2 hours, concentrated to a volume of 200 mL and added slowly into a beaker containing a cold stirring mixture of 5% NaHSO3 and water (1.5 L, 1 :10 v/v). The precipitate was filtered, washed with water (3 x 500 mL) and dried under vacuum to afford 5-bromo-3- trifluoromethyl-pyridin-2-ylamine (62.89 g, 84.6%) as a light brown solid. MS 242.9 (M+H+).
84.1%	With N-Bromosuccinimide; In acetonitrile; at 0 - 25℃; for 2h;	The 3 - (trifluoromethyl) pyridin-2-amine (1.0g, 6 . 17mmol) dissolved in acetonitrile (30 ml) in, then dropped to 0 C, then the NBS (1.2g, 6 . 74mmol) is slowly added to the system, is omitted, the temperature is increased to 25 C reaction 2 hours. The concentrated, the residue by silica gel column chromatography (PE:EA=5:1) purification, to obtain the title compound (1.25g, yield 84.1%).
82%	With bromine; In acetic acid; at 25 - 30℃;	3-(Trifluoromethyl)-2-pyridinamine (150 g) was added to acetic acid (1500 mL) and stirred the mass for 10 to 15 min. Bromine (47.54 mL) was added to the mixture over a period of 45-60 min at 25-30C. The reaction mass was maintained under stirring at 25-30C for 2-3 h. After completion of the reaction, the mass was cooled to 10 to 15C and diluted with water (2500 mL) subsequently neutralized the mass with solid sodium carbonate (420 g). The reaction mass was filtered and bed was washed with water (300 mL) and dried at 25 to 30C for 12 h. The dried mass was dissolved in ethyl acetate (2250 mL) and washed with 5% sodium bicarbonate solution (750 mL). The separated organic layer was washed with 10% sodium chloride solution (750 mL). Clean organic layer was distilled out completely to obtain the title compound (183 g). Yield: 82% Purity: 99.52% 1H NMR (300 MHz, DMSO-<): delta 8.25 (s, 1H), 7.89 (s, 1H), 6.7 (bs, 2H). MS: m/z 242 (M+l)
81%	With N-Bromosuccinimide; In acetonitrile; at 0 - 25℃; for 1h;	To a solution of <strong>[183610-70-0]3-(trifluoromethyl)pyridin-2-amine</strong> (5.4 g, 33.3 mmol) in acetonitrile (100 mL) was added NBS (5.93 g, 33.3 mmol) at OeC and reaction mixture was stirred at 25eC for 1H. After completion of the reaction, reaction mixture was quenched with saturated sodium bicarbonate (25 mL) and extracted with EtOAc (25 mL/13). The combined organic phase was washed with brine (20 mL), dried over Na2S04, filtered. The filtrate was rotary evaporated and residue was purified by flash column chromatography (silica gel) to afford 6.5 g (81%) of the titled product. 1HNMR (400 MHz, DMSO-d6) U8.28 (d, J = 2.4 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 6.72 (s, 2H); ESI-MS (m/z) 241.08 (MH)
74%	With bromine; acetic acid; at 20℃; for 2h;	<strong>[183610-70-0]3-(trifluoromethyl)pyridin-2-amine</strong> (20 g, 123 mmol) was stirred in acetic acid (200 ml) at RT. Bromine (19.72 g, 123 mmol) was added drop wise with stirring. The reaction mixture was stirred for 2 h; followed by dilution with water. The product was extracted with ethyl acetate. Organic layer was washed with water, dried over sodium sulfate and concentrated to obtain the title product in 74% yield.
	With N-Bromosuccinimide; In acetonitrile; at 0 - 5℃; for 4h;	The starting material 5-Bromo-<strong>[183610-70-0]3-trifluoromethyl-pyridin-2-ylamine</strong> (B57a) is prepared as follows:To a solution of 5.37 g (32.8 mmol) of <strong>[183610-70-0]3-trifluoromethyl-pyridin-2-ylamine</strong> (Fluorochem,Derbyshire, UK) in 100 ml of dry CH3CN, 6.45 g of N-bromosuccinimide are added in 4 equal portions over a period of 1 h at 0-50C under argon. The cooling bath is removed and stirring is continued for 3 h. The solvent is evaporated under vacuum, the residue is dissolved inEtOAc and washed with water and brine. The organic phase is dried over Na2SO4 and evaporated. The title compound is a reddish-yellow oil which is used after drying in the dark for 5 h at RT and under high vacuum in the next step without further purification. ES-MS: 241(M-H)".
	With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃; for 4h;Inert atmosphere;	To a solution of 3-trifluoromethylpyridin-2-ylamine (Fluorochem Ltd , Derbyshire, United Kingdom 5 37 g, 32 8 mmol) in 100 ml of dry CH3CN under argon were added N- bromosuccinimide (645 g, 36 2 mmol) in 4 equal portions over a period of 1 h at 0-5C The cooling bath was removed and stirring was continued for 3 h The solvent was evaporated under vacuum, then the residue was dissolved in EtOAc and washed with water and brine The organic layer was dned over Na?SO and evaporated to give the title compound as a orange oil. (M+H = 239, 241).
	With N-Bromosuccinimide; In N,N-dimethyl-formamide; for 4h;	To a stirred solution of R-10 (2.70 g, 16.66 mmol) in DMF (15 ml) is added N- bromosuccinimide (3.00 g, 16.85 mmol) as a DMF solution (15 ml, dropwise). After 4 h the reaction is poured onto ice. The resulting precipitate is collected via filtration to give the product as an off-white solid. Dissolved into DCM and washed with brine. The layers are separated and the organic phase is dried (MgS04), filtered and concentrated to give the title intermediate (3.8 g); m/z 241.2/243.2 [M/M+2H] .
	With N-Bromosuccinimide; In acetonitrile; for 6h;Darkness;	To a solution of 2-amino-3-trifluoromethyl pyridine (15.4 g, 95 mmol) in ACN (300 mL) was added NBS (18.6 g, 104 mmol). The reaction mixture was stirred in the dark for 6 hours. The solvent was removedin vacuoand the residue was partitioned between EtOAc (500 mL) and water. The two phases were separated and the organic layer was washed with water (200 mL), sat. aq. NaCl (200 mL), dried (Na2SO4) filtered and concentrated yielding 22.8 g of the title compound, which was used in the next step without further purification.
3.8 g	With N-Bromosuccinimide; In N,N-dimethyl-formamide; for 4h;Cooling with ice;	Synthesis of 5-bromo-<strong>[183610-70-0]3-trifluoromethyl-pyridin-2-ylamine</strong> To a stirred solution of R-10 (2.70 g, 16.66 mmol) in DMF (15 ml) is added N-bromosuccinimide (3.00 g, 16.85 mmol) as a DMF solution (15 ml, dropwise). After 4 h the reaction is poured onto ice. The resulting precipitate is collected via filtration to give the product as an off-white solid. Dissolved into DCM and washed with brine. The layers are separated and the organic phase is dried (MgSO4), filtered and concentrated to give the title intermediate (3.8 g); m/z 241.2/243.2 [M/M+2H].
		Step 1 : 5-Bromo-<strong>[183610-70-0]3-trifluoromethyl-pyridin-2-ylamine</strong><strong>[183610-70-0]2-amino-3-trifluoromethylpyridine</strong> (0.980 g, 5.92 mmol) is dissolved in CHCb (7ml) and AcOH (5 ml). The reaction mixture is cooled to 0-10 C (ice-bath) and bromine (0.424 ml, 8.3 mmol) dissolved in CHCb is slowly added drop wise. The reaction mixture is stirred at this temperature for 1 hour then allowed to warm room temperature. The solvents are removed in vacuo and the residue is dissolved in EtOAc washing with saturated NaHCO3. The organic portion is dried over MgSO<», filtered and concentrated to afford the title compound.
	With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃; for 4h;	Stage 4.1: 5-Bromo-<strong>[183610-70-0]3-trifluoromethyl-pyridin-2-ylamine</strong>. To a solution of 5.37 g (32.8 mmol) of <strong>[183610-70-0]3-trifluoromethyl-pyridin-2-ylamine</strong> (Fluorochem) in 100 ml of dry CH3CN, 6.45 g of N-bromosuccinimide are added in 4 equal portions over a period of 1 h at 0-5C under argon. The cooling bath is removed and stirring is continued for 3 h. The solvent is evaporated under vacuum, the residue is dissolved in EtOAc and washed with water and brine. The organic phase is dried over Na2SO4 and evaporated. The title compound is a reddish-yellow oil which is used after drying in the dark for 5 h at RT and under high vacuum in the next step without further purification. MS(ESI-):m/z= 241.0 (M-H) tRet = 4.992 min (System 2).
	With N-Bromosuccinimide; In acetonitrile; at 0 - 20℃; for 4h;	To a solution of 5.37 g (32.8 mmol) of <strong>[183610-70-0]3-trifluoromethyl-pyridin-2-ylamine</strong> (Fluorochem) in 100 ml of dry CH3CN, 6.45 g of NBS are added in 4 equal portions over a period of 1 h at 0- 5C under argon. The cooling bath is removed and stirring is continued for 3 h. The solvent is evaporated under vacuum, the residue is dissolved in EtOAc and washed with water and brine. The organic phase is dried over Na2SO4 and evaporated. The title compound is a reddish-yellow oil which is used after drying in the dark for 5 h at RT and under high vacuum in the next step without further purification. ES-MS (M+1): = 239; 241 ; HPLC: tR = 5.501 min.-
	With N-Bromosuccinimide; In acetonitrile; at 0 - 5℃; for 4h;Inert atmosphere;	To a solution of 5.37 g (32.8 mmol) of <strong>[183610-70-0]3-trifluoromethyl-pyridin-2-ylamine</strong> (Fluorochem Ltd., Derbyshire, United Kingdom) in 100 ml of dry CH3CN, 6.45 g of NBS are added in 4 equal portions over a period of 1 h at 0-50C under argon. The cooling bath is removed and stirring is continued for 3 h. The solvent is evaporated under vacuum, the residue is dissolved in EtOAc and washed with water and brine. The organic phase is dried over Na2SO4 and evaporated. The title compound is a red-dish-yellow oil which is used after drying in the dark for 5 h at RT and under high vacuum in the next step without further purification. ES-MS (M+1 ): = 239; 241 ; HPLC: tR = 5.501 min. Example 1.4 1 -(2-Methoxy-pyridin-3-yl)-3-methyl-8-(6-methylamino-pyridin-3-yl)-1 ,3-dihydro- imidazo[4,5-c]quinolin-2-one

Reference： [1]Patent: US2007/72879,2007,A1 .Location in patent: Page/Page column 18
[2]Patent: WO2010/8847,2010,A2 .Location in patent: Page/Page column 147
[3]Patent: CN105732602,2016,A .Location in patent: Paragraph 0364; 0366; 0367; 0368; 0369
[4]Patent: WO2009/23179,2009,A2 .Location in patent: Page/Page column 196-197
[5]Patent: WO2015/158427,2015,A1 .Location in patent: Page/Page column 87; 88
[6]Journal of Medicinal Chemistry,2016,vol. 59,p. 1078 - 1101
[7]Patent: WO2011/41713,2011,A2 .Location in patent: Page/Page column 142
[8]Patent: WO2010/91411,2010,A1 .Location in patent: Page/Page column 79
[9]Patent: CN105541792,2016,A .Location in patent: Paragraph 0454; 0455; 0456
[10]Patent: WO2015/145369,2015,A1 .Location in patent: Page/Page column 36-37
[11]Patent: WO2018/20474,2018,A1 .Location in patent: Page/Page column 314-315
[12]Patent: WO2012/7926,2012,A1 .Location in patent: Page/Page column 49
[13]Patent: WO2008/12326,2008,A1 .Location in patent: Page/Page column 69
[14]Patent: WO2010/139731,2010,A1 .Location in patent: Page/Page column 135
[15]Patent: WO2012/24150,2012,A1 .Location in patent: Page/Page column 135
[16]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4652 - 4656
[17]Patent: US2013/195879,2013,A1 .Location in patent: Paragraph 0278; 0279
[18]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 507 - 512
[19]Patent: WO2007/134828,2007,A1 .Location in patent: Page/Page column 68
[20]Patent: WO2008/138889,2008,A2 .Location in patent: Page/Page column 85
[21]Patent: WO2008/138834,2008,A1 .Location in patent: Page/Page column 89
[22]Patent: WO2010/139747,2010,A1 .Location in patent: Page/Page column 102

5
[ 79456-34-1 ]
[ 1083429-88-2 ]
[ 1083428-83-4 ]

Yield	Reaction Conditions	Operation in experiment
	tetrakis(triphenylphosphine) palladium(0); In ISOPROPYLAMIDE; at 150℃; for 1h;Microwave irradiation;	In a 6 ml vial for microwave with crown cap and magnetic stir bar, 220 mg (ca. 0.277 mmol) of the crude tin compound prepared in Stage 15.1. and 186 mg (0.695 mmol) of 5-bromo-3- trifluoromethyl-pyridin-2-ylamine (for preparation see WO2006/099972-A, p. 87) are dissolved in 3 ml of DMA and degassed with argon. 16 mg of tetrakis-triphenylphosphin palladium are added, and the mixture is heated in the microwave oven at 1500C for 1 h. The solvent is evaporated, the residue is dissolved in acetonitrile and washed three times with hexane. After evaporating the solvent, the purification is done by chromatography on silicagel. Solvent system: A = CH2CI2; B = CH2CI2-MeOH- 95:5. Start with 100% A (15 min), then 45 min A:B=1 :1 , then end with 100% B for 45 min. The title compound is isolated as a yellow solid. LC-MS: (M+1) = 430.1; HPLC: tR = 4.216 min.-

Reference： [1]Patent: WO2008/138834,2008,A1 .Location in patent: Page/Page column 82

6
[ 79456-34-1 ]
[ 70-23-5 ]
[ 1121051-30-6 ]

Yield	Reaction Conditions	Operation in experiment
99.5%	In N,N-dimethyl-formamide; at 50℃; for 16h;	Compound BB-21-2 (51.0g, 212mmol) was dissolved in dimethylformamide (500mL), followed by addition of propan-bromo-one ethyl ester (82.5g, 423mmol).The reaction was stirred at 50 16 hours.Reaction solution was cooled to room temperature, the mixture was poured into ice water(1L) was stirred for 20 minutes, the precipitate was filtered, the filter cake was dissolved in ethyl acetate (a 500 mL), dried over sodium sulfate, filtered, and concentrated to yield the titlecompound were BB-21-3 ( as a yellow solid, 71.0g, yield: 99.5%).
89%	In N,N-dimethyl-formamide; at 50℃; for 24h;	A mixture of <strong>[79456-34-1]5-bromo-3-trifluoromethyl-pyridin-2-ylamine</strong> (21.78 g, 90.37 mmol) and ethyl bromopyruvate (90% pure, 25.3 mL, 180.74 mmol) was heated in DMF (180 mL) at 50 0C for 1 day. Upon cooling, the solvent was removed to half the volume under reduced pressure. The mixture was diluted with EtOAc (500 mL) and washed with water (3 x 150 mL), dried (Na2SO4), filtered and concentrated. The crude brown oil was dissolved in minimum amount of EtOAc and dripped slowly into n-hexanes (500 mL) with vigorous stirring. The suspension was allowed to stir overnight and filtered to give 6-bromo-8-trifluoromethyl-imidazo[l,2-a]pyridine- 2-carboxylic acid ethyl ester (26.83 g, 89%) as a yellow solid. 1H NMR (d6-DMSO, 300 MHz) delta 1.33 (t, 3H, J = 7 Hz), 4.34 (q, 2H, J = 7 Hz), 8.00 (brs, IH), 8.60 (s, IH), 9.16 (brs, IH); MS (ESI) m/z = 337, 339 (MH+).
89%	In N,N-dimethyl-formamide; at 50℃; for 24h;	Step 26-Bromo-8-trifluoromethyl-imidazo[l,2-a]pyridine-2-carboxylic acid ethyl ester [0103] A mixture of 2-amino-4-bromo-3-(trifluoromethyl)pyridine (21.78 g, 90.37 mmol) and ethyl bromopyruvate (90% pure, 25.3 mL, 180.74 mmol) was heated in DMF (180 mL) at 50 0C for 1 day. Upon cooling, the sovent was removed to half the volume under reduced pressure. The mixture was diluted with EtOAc (500 mL) and washed with water (3 x 150 mL), dried (Na2SO4), filtered and concentrated. The crude brown oil was dissolved in minimum amount of EtOAc and dripped slowly into n-hexanes (500 mL) with vigorous stirring. The suspension was allowed to stir overnight and filtered to give 6-bromo-8-trifluoromethyl-imidazo[l,2-a]pyridine- 2-carboxylic acid ethyl ester (26.83 g, 89%) as a yellow solid. MS (ESI) m/z = 337, 339 (MH+).

Reference： [1]Patent: CN105732602,2016,A .Location in patent: Paragraph 0364; 0366; 0367; 0370; 0371
[2]Patent: WO2009/23179,2009,A2 .Location in patent: Page/Page column 197
[3]Patent: WO2010/91411,2010,A1 .Location in patent: Page/Page column 79

7
[ 79456-34-1 ]
[ 148728-48-7 ]
[ 1121056-87-8 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 70℃; for 168h;	A mixture of <strong>[79456-34-1]5-bromo-3-trifluoromethyl-pyridin-2-ylamine</strong> (2.93 g, 12.14 mmol) and 3-bromo-2-oxo-pentanedioic acid dimethyl ester (prepared from bromination of dimethyl 2- oxoglutarate) (6.15 g, 24.29 mmol) was heated in DMF at 70 0C for a week. The mixture was poured into water (700 mL) to give a precipitate which was filtered and dried to give the product (1.74 g). The filtrate was extracted with EtOAc (300 mL) which after concentration of the solvent yielded 3.71 g of crude material. The crude prduct was absorbed on silica gel followed by column chromatography [(3: 1 v/v) n-hex:EtOAc)] to give 6-bromo-3- methoxycarbonylmethyl-8-trifluoromethyl-imidazo[l ,2-a]pyridine-2-carboxylic acid methyl ester as a yellow solid (1.37g). 1H NMR (d6-DMSO, 300 MHz) delta 3.65 (s, 3H), 3.86 (s, 3H), 4.51 (s, 2H), 8.02 (s, IH), 8.23 (s, IH); MS (ESI) m/z = 395 (MH+).

Reference： [1]Patent: WO2009/23179,2009,A2 .Location in patent: Page/Page column 229

8
[ 79456-34-1 ]
[ 55552-70-0 ]
[ 1239205-48-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; at 80℃; for 2.5h;	A mixture of <strong>[79456-34-1]5-bromo-3-trifluoromethyl-pyridin-2-ylamine</strong> (4.82 g, 20 mmol), 3-furanboronic acid (4.48 g, 40 mmol) and tetrakis(triphenylphosphine) palladium(0) (693 mg, 0.6 mmol) was stirred at 80 C. in 1,4-dioxane (100 mL) and 1M K3PO4 (25 mL) for 2.5 hours. Upon cooling, the organic solvent was removed under reduced pressure. The crude was diluted with EtOAc (300 mL) and washed with saturated NaHCO3, (2×100 mL), then brine (100 mL). The extracts were filtered through a pad of silica gel and washed with EtOAc (150 mL). Column chromatographed [n-hex/EtOAc (5:1 v/v) to (3:1 v/v)]of the crude gave 5-furan-3-yl-3-trifluoromethyl-pyridin-2-ylamine (3.82 g) as a solid. 1H NMR (d6-DMSO, 300 MHz) delta 6.47 (brs, 2H), 6.99 (dd, 1H, J=0.9, 2 Hz), 7.72 (t, 1H, J=1.8 Hz), 7.95 (d, 1H, J=2 Hz), 8.17 (dd, 1H, J=0.9, 1.8 Hz), 8.50 (dd, 1H, J=0.6, 2 Hz); MS (ESI) m/z=229 (MH+).

Reference： [1]Patent: US2010/204265,2010,A1 .Location in patent: Page/Page column 116

9
[ 79456-34-1 ]
[ 74-88-4 ]
[ 1257431-68-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[79456-34-1]5-bromo-3-trifluoromethyl-pyridin-2-ylamine</strong> (1.928 g, 8 mmol) in DMF anhydrous (10ml) cooled to 0 0C, was added NaH 55% (349 mg, 8 mmol) and stirred at 0 0C for 30 min. Then iodomethane (0.499 ml, 8 mmol) was added, the ice bath was removed and the RM was stirred at rt for 2 h After that, the RM was extracted with EtOAc / H2O. The organic layers were dried over Na2SO4 and evaporated. After filtration, the solvent was removed under reduced pressure to obtain the title compound as a light yellow solid (664 mg). (HPLC: tR 5.625 min (Method A); M+H = 257.0 MS-ES).

Reference： [1]Patent: WO2010/139747,2010,A1 .Location in patent: Page/Page column 158

10
[ 79456-34-1 ]
[ 865-50-9 ]
[ 1257554-28-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[79456-34-1]5-bromo-3-trifluoromethyl-pyridin-2-ylamine</strong> (Stage 25.1.2. 1 66 mmol) in DMF cooled with an ice-bath was added 55% sodium hydride in oil (1 66 mmol) The RM was stirred for 30 mm at 0betaC then was added d3-iodomethane (Ald?ch, Buchs. Switzerland, 1.66 mmol) and the RM was stirred for 30 mm at rt and the formed slurry was sonicated for 30 min at rt The RM was quenched with saturated aqueous NaHCO3 and extracted with EtOAc (2x). The combined organic layers were washed with saturated aqueous NaHCtheta3 (3x), with brine, dried over Na2Stheta4 filtered and evaporated The residue was purified by flash chromatography (hexane/CH2Cl2 1.1 to 1 :8) to give the title compound as an oil (HPLC tR 3.30 mm (Method A); M+H = 258, 260 MS-ES).

Reference： [1]Patent: WO2010/139731,2010,A1 .Location in patent: Page/Page column 248

Yield	Reaction Conditions	Operation in experiment
87%	With lithium hydroxide; In dimethyl sulfoxide; at 120℃; for 1h;Inert atmosphere; Sealed tube;	General procedure: In a 10mL dry sealed reaction tube,Add ethyl 1,2,3-triazine-5-carboxylate 3a (15.3mg, 0.10mmol), ethyl cyanoacetate 2b (13.6mg, 0.12mmol) and lithium hydroxide (0.5mg, 0.02mmol) in this order . The solvent nitrogen was added DMSO (1.0mL) was substituted three times, the reaction tube was sealed was placed 120 reaction 1h. The reaction was monitored by TLC. After the reaction was completed, it was extracted with dichloromethane (3 * 10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. After column chromatography, the target product 13c (16.0 mg, 67%) was obtained.
	With N-Bromosuccinimide; In chloroform; at 20℃; for 2h;	General procedure: N-bromosuccinimide (6.0 g, 34 mmol) was added to a solution of 1a-1 (5.0 g, 30 mmol) in trichloromethane (100 ml) and the mixture was stirred at room temperature for 2 hours. The reaction was complete and the mixture was concentrated under reduced pressure and extracted with dichloromethane. The organic phase was separated and concentrated under reduced pressure to give crude product which was purified by Combi-flash column chromatography to obtain compound 1a-2 (6.0g). Purity: 80%, spectrum data: MS m/z(ESI): 241[M+H]+.

12
[ 79456-34-1 ]
[ 7425-63-0 ]
[ 1121058-16-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	at 50℃; for 3h;	A solution of 5-bromo-3-(trifluoromethyl)-2-pyridinamine (100 g, 0.42 mol) and <strong>[7425-63-0]methyl 3-bromopyruvate</strong> (180 g, 1 mol) was heated at 50°C for 3 hours. The solvent was evaporated and the residue was poured slowly into ice water (3 L) to give a precipitate. The suspension was stirred vigorously for 1 hour. The precipitate was filtered off, washed with H20 (2 x 500 mL) and dried under vacuum to give the title compound (1 9 g, 82percent) as a yellow powder.

Reference： [1]Patent: WO2011/41713,2011,A2 .Location in patent: Page/Page column 142-143

13
[ 79456-34-1 ]
[ 1121056-92-5 ]