[ CAS No. 261762-35-0 ] {[proInfo.proName]}

Name: 261762-35-0|5-Bromo-1,2-difluoro-3-methoxybenzene|97%
Brand: Ambeed
SKU: A131388
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Quality Control of [ 261762-35-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 261762-35-0 ]

Product Details of [ 261762-35-0 ]

CAS No. :	261762-35-0	MDL No. :	MFCD01631352
Formula :	C₇H₅BrF₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UDTVFZBQFYOZST-UHFFFAOYSA-N
M.W :	223.02	Pubchem ID :	2773288
Synonyms :

Calculated chemistry of [ 261762-35-0 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	40.55
TPSA :	9.23 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.68 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.31
Log Po/w (XLOGP3) :	2.79
Log Po/w (WLOGP) :	3.58
Log Po/w (MLOGP) :	3.41
Log Po/w (SILICOS-IT) :	3.34
Consensus Log Po/w :	3.09

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.32
Solubility :	0.107 mg/ml ; 0.000481 mol/l
Class :	Soluble
Log S (Ali) :	-2.64
Solubility :	0.511 mg/ml ; 0.00229 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.94
Solubility :	0.0254 mg/ml ; 0.000114 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.73

Safety of [ 261762-35-0 ]

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

Application In Synthesis of [ 261762-35-0 ]

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

Upstream synthesis route of [ 261762-35-0 ]
Downstream synthetic route of [ 261762-35-0 ]

[ 261762-35-0 ] Synthesis Path-Upstream 1~3

1
[ 74-88-4 ]
[ 261762-35-0 ]

Yield	Reaction Conditions	Operation in experiment
1.58 g	With potassium carbonate In N,N-dimethyl-formamide at 20 - 45℃;	To a solution of 81 (1.5 g, 7.1 mmol) and ₂C0₃ (1.96 g, 14.2 mmol) in DMF (10 mL) was added iodomethane (0.49 mL, 7.8 mmol) dropwise at rt. The reaction mixture was heated at 45 °C overnight. After completion, EtOAc (10 mL) was added and the solution was filtered. The filtrate was washed with brine, dried over anhydrous MgS0₄ and evaporated in vacuo to give crude 82 (1.58 g, 100percent).

Reference： [1] Journal of Medicinal Chemistry, 2011, vol. 54, # 24, p. 8582 - 8591
[2] Patent: WO2011/156518, 2011, A2, . Location in patent: Page/Page column 119; 120
[3] Patent: WO2013/56003, 2013, A2, . Location in patent: Page/Page column 70
[4] Patent: US2006/4013, 2006, A1, . Location in patent: Page/Page column 58

2
[ 67-56-1 ]
[ 138526-69-9 ]
[ 261762-35-0 ]

Yield	Reaction Conditions	Operation in experiment
92%	at 60℃; for 6 h; Large scale	In a 3000 L reactor, 201.6 kg of KOH was added,Pumped 253.2 kg of 3,4,5-trifluorobromobenzene and 1500 L of methanol,Close the reaction kettle, stirring up to 60 ,After 6 hours of reaction,Raw materials have been basically complete.The material into the crystallization pot with nitrogen into the pot,Stirring and cooling to -5 ° C,Insulation 5h filter,To give 2,3-difluoro-5-bromoanisole,Yield 92.0percentContent of 99.2percent. The methanol recovery in the filtrate can be reused.

Reference： [1] Patent: CN106478377, 2017, A, . Location in patent: Paragraph 0037; 0038; 0053; 0054; 0055; 0056; 0061; 0062

3
[ 68-12-2 ]
[ 261762-35-0 ]
[ 881190-46-1 ]

Reference： [1] Patent: EP1795524, 2007, A1, . Location in patent: Page/Page column 26

[ 261762-35-0 ] Synthesis Path-Downstream 1~71

1
[ 261762-35-0 ]
(4aR)-1-(4-fluorophenyl)-4a-methyl-4,4a,5,6,7,8-hyxahydro-1H-benzo[f]indazole-5-carbaldehyde [ No CAS ]
(3,4-difluoro-5-methoxy-phenyl)-[1-(4-fluoro-phenyl)-4a-methyl-4,4a,5,6,7,8-hexahydro-1<i>H</i>-benzo[<i>f</i>]indazol-5-yl]-methanol [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 2441 - 2452

2
5-bromo-2,3-difluoro-phenol [ No CAS ]
[ 74-88-4 ]
[ 261762-35-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetone; for 4h;Reflux;	To a solution of 5-bromo-2,3-difluorophenol (19 g, 90 mmol) in acetone (180 mL), K2CC>3 (18 g, 0.13 mol) and iodomethane (25.8 g, 0.18 mol) were added. The resulting mixture was refluxed for 4 h. Upon completion, the mixture was cooled to room temperature and filtered, and the filtrate was evaporated to give the crude product, which was further purified by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate = 80/1 ~ 40/1) to give a light yellow liquid 5-bromo-l,2-difluoro-3-methoxybenzene (19 g). lR NMR (CDC13): delta 7.00-6.88 (m, 2H), 3.89 (s, 3H).
1.58 g	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 45℃;	To a solution of 81 (1.5 g, 7.1 mmol) and 2C03 (1.96 g, 14.2 mmol) in DMF (10 mL) was added iodomethane (0.49 mL, 7.8 mmol) dropwise at rt. The reaction mixture was heated at 45 C overnight. After completion, EtOAc (10 mL) was added and the solution was filtered. The filtrate was washed with brine, dried over anhydrous MgS04 and evaporated in vacuo to give crude 82 (1.58 g, 100%).
	With potassium carbonate; In acetone; for 4h;Heating / reflux;	To an acetone (10 mL) solution of 5-bromo-2,3-difluoro phenol (600 muL), potassium carbonate (1.10 g) and iodomethane (654 muL) were added one by one, and the reaction solution was refluxed for 4 hours. The reaction solution was concentrated under reduced pressure and the crude bromo compound was obtained. Potassium carbonate (1.10 g) and imidazole (429 mg) were added to a DMF (10 mL) solution of the obtained bromo compound (1.17 g) one by one, and the reaction solution was agitated at 80 C. overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent:hexane:ethyl acetate=3:1?ethyl acetate:ethanol=10:1), and 510 mg of the title compound was obtained. The physical properties of the compound are as follows. 1H-NMR (CDCl3) delta (ppm): 7.82 (s, 1H), 7.24 (s, 1H), 7.21 (s, 1H), 7.05-7.08 (m, 2H), 3.98 (s, 3H).

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 8582 - 8591
[2]Patent: WO2011/156518,2011,A2 .Location in patent: Page/Page column 119; 120
[3]Patent: WO2013/56003,2013,A2 .Location in patent: Page/Page column 70
[4]Patent: US2006/4013,2006,A1 .Location in patent: Page/Page column 58

3
[ 288-32-4 ]
[ 261762-35-0 ]
[ 870837-60-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃;	To an acetone (10 mL) solution of 5-bromo-2,3-difluoro phenol (600 muL), potassium carbonate (1.10 g) and iodomethane (654 muL) were added one by one, and the reaction solution was refluxed for 4 hours. The reaction solution was concentrated under reduced pressure and the crude bromo compound was obtained. Potassium carbonate (1.10 g) and imidazole (429 mg) were added to a DMF (10 mL) solution of the obtained bromo compound (1.17 g) one by one, and the reaction solution was agitated at 80 C. overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent:hexane:ethyl acetate=3:1?ethyl acetate:ethanol=10:1), and 510 mg of the title compound was obtained. The physical properties of the compound are as follows. 1H-NMR (CDCl3) delta (ppm): 7.82 (s, 1H), 7.24 (s, 1H), 7.21 (s, 1H), 7.05-7.08 (m, 2H), 3.98 (s, 3H).

Reference： [1]Patent: US2006/4013,2006,A1 .Location in patent: Page/Page column 58

4
[ 1227162-95-9 ]
[ 261762-35-0 ]
[ 1227163-09-8 ]

Yield	Reaction Conditions	Operation in experiment
14%		Example 37i 1-(3-Bromophenyl)-1-(3,4-difluoro-5-methoxyphenyl)-4-fluoro-1H-isoindol-3-amine Magnesium turnings (0.692 g, 28.47 mmol) were stirred under Ar(g) for 10 min and LiCl 0.5M in THF (28.5 mL, 14.24 mmol) was added followed by DIBAL-H 1M in THF (0.228 mL, 0.23 mmol). The mixture was stirred for 5 min and then <strong>[261762-35-0]5-bromo-1,2-difluoro-3-methoxybenzene</strong> (2.54 g, 11.39 mmol) in 5 mL THF was added in one portion and stirred for 1 h. The mixture was added to N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (4.64 g, 11.39 mmol) in THF (20 mL) and stirred 1 h. MeOH (3 mL) was added and the mixture was treated with HCl in 2.0 MeOH (22.78 mL, 22.78 mmol) for 1 h. NaHCO3(sat) was added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4 and concentrated. The residue was purified by preparative HPLC to give 714 mg (14%) of the title product as a solid. MS (ES+) m/z 447, 449 [M+H]+.

Reference： [1]Patent: US2010/125082,2010,A1 .Location in patent: Page/Page column 26; 27

5
[ 68-12-2 ]
[ 261762-35-0 ]
[ 881190-46-1 ]

Yield	Reaction Conditions	Operation in experiment
		Reference Example 97; 3,4-Difluoro-5-methoxybenzaldehyde; 1.58 M n-BuLi/hexane solution (1.4 ml) was added to a diethyl ether solution of <strong>[261762-35-0]5-bromo-1,2-difluoro-3-methoxybenzene</strong> (497 mg) in an argon atmosphere at -70C, followed by stirring at that temperature for 1 hour. DMF (0.259 ml) was added, followed by stirring for 30 minutes. After completion of the reaction, water was added, followed by extraction with diethyl ether, washing with saturated brine, and drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain the compound (317 mg) of Reference Example 97.

Reference： [1]Patent: EP1795524,2007,A1 .Location in patent: Page/Page column 26

6
[ 72824-04-5 ]
[ 261762-35-0 ]
[ 1227845-61-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	With cesium fluoride;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; for 48h;Inert atmosphere; Reflux;	5-Allyl-1,2-difluoro-3-methoxybenzene (C2)3.06 g of <strong>[261762-35-0]1-bromo-3,4-difluoro-5-methoxybenzene</strong> (D2), 4.54 ml of pinacolyl allylboronate, 3.04 g of tetrakis(triphenylphosphine)palladium(0) and 7.62 g of caesium fluoride are suspended in 115 ml of tetrahydrofuran under an argon atmosphere. The reaction mixture is subsequently heated under reflux for 48 h. For work-up, the mixture is diluted with 400 ml of diethyl ether and extracted with 100 ml of water and 100 ml of saturated NaCl solution. The combined organic phases are dried over Na2SO4, filtered and evaporated to dryness in vacuo. The residue is purified by flash column chromatography on silica gel (solvent: cyclohexane), giving 1.59 g of the title compound as a colourless oil; MS: 184.0 (M+); TLC: Rf=0.69 (cyclohexane/ethyl acetate 8:1 parts by volume).

Reference： [1]Patent: US2011/224302,2011,A1 .Location in patent: Page/Page column 11; 14

7
[ 261762-35-0 ]
[ 1227845-38-6 ]

Reference： [1]Patent: US2011/224302,2011,A1

8
[ 261762-35-0 ]
[ 1227845-64-8 ]

Reference： [1]Patent: US2011/224302,2011,A1

9
[ 261762-35-0 ]
[ 887585-35-5 ]

Reference： [1]Patent: US2011/224302,2011,A1

10
[ 1201-38-3 ]
[ 261762-35-0 ]
[ 1352306-26-3 ]

Yield	Reaction Conditions	Operation in experiment
34%	With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In tetrahydrofuran; at 70℃;Inert atmosphere;	A mixture of tris(dibenzylideneacetone)dipalladium(0) (345 mg, 0.38 mmol), 2,2'- bis(diphenylphosphino)- l, l'-binaphthalene (560 mg, 0.90 mmol), and sodium ie/t-butoxide (3.25 g, 33.8 mmol) was degassed by vaccuum/ nitrogen cycles (3x). Tetrahydrofuran (70 mL), 5-bromo-l,2-difluoro-3-methoxybenzene (5.50 g, 24.7 mmol), and l-(2,5- dimethoxyphenyl)ethanone (5.40 g, 30.0 mmol) were added to the reaction mixture. The reaction mixture was heated at 70 C overnight, allowed to cool to room temperature, diluted with H20, and then extracted with ether (2x). The organic phase was washed (brine), dried (Na2S04), and concentrated under reduced pressure. The crude material was purified on a silica gel column to give the title compound (2.69 g, 34%) as a white solid. 1H NMR (400 MHz, DMSO-J6): delta 7.16-7.10 (m, 3H), 6.91-6.87 (m, IH), 6.86-6.80 (m, IH), 4.26 (s, 2H), 3.87 (s, 3H), 3.86 (s, 3H), 3.73 (s, 3H).
	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In tetrahydrofuran; at 70℃; for 16h;Inert atmosphere;	A 100-mL round-bottom flask charged with Pd2dba3 (69 mg, 0.075 mmol), BINAP (112 mg, 0.18 mmol), and NaOt_Bu (650 mg, 6.5 mmol) was degassed and filled with N2. THF (20 mL) was added, followed by a solution 5-bromo-l,2-difluoro-3-methoxybenzene (1.1 g, 5 mmol) and l-(2,5-dimethoxyphenyl)ethanone (1.08 g, 6 mmol) in THF (10 mL). The resulting mixture was heated at 70 C for 16 h. Water (30 mL) was added, and the mixture was extracted with ether (3 x 50 mL). The combined organics were dried over anhydrous Na2S04, filtered, and concentrated to give the crude product, which was purified by column chromatography on silica gel (eluting with petroleum ether/ethyl acetate = 80/1 ~ 40/1) to give 2-(3,4-difluoro-5- methoxyphenyl)-l-(2,5-dimethoxyphenyl)ethanone (0.4 g) as a light yellow solid. ¾ NMR (CDCI3): delta 7.24 (d, 1H), 7.04 (dd, 1H), 6.92 (d, 1H), 6.68-6.61 (m, 2H), 4.23 (s, 2H), 3.90 (s, 3H), 3.87 (s, 3H), 3.78 (s, 3H); LCMS: 323 (M+H)+.

Reference： [1]Patent: WO2016/189011,2016,A1 .Location in patent: Page/Page column 94; 95
[2]Patent: WO2011/156518,2011,A2 .Location in patent: Page/Page column 120

11
copper(l) cyanide [ No CAS ]
[ 261762-35-0 ]
[ 1262552-14-6 ]

Yield	Reaction Conditions	Operation in experiment
1.05 g	In N,N-dimethyl-formamide; for 6h;Inert atmosphere; Reflux;	A solution of 82 (3.18 g, 14.26 mmol) and CuCN (1.27 g, 14.26 mmol) in DMF (30 mL) was heated at reflux under N2 atmosphere for 6 h. After this period, the reaction mixture was diluted with EtOAc and washed with water (20 mL). The organic layer was washed with brine (2 x 15 mL), dried over anhydrous Na2S04, and concentrated in vacuo. The crude product was purified by column chromatography (Si02, hexane/EtOAc 75:25) to give 58 (1.05 g, 43 %). 1H NMR (400 MHz, CDC13) delta 7.29 (d, J= 2.2 Hz, IH), 6.90 (s, IH), 3.89 (s, 3H). 13C NMR (126 MHz, CDC13) delta 151.16, 150.90, 149.00, 118.69, 116.33, 112.96, 110.09, 41.02.

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 8582 - 8591
[2]Patent: WO2013/56003,2013,A2 .Location in patent: Page/Page column 70-71

12
[ 261762-35-0 ]
C₁₄H₉ClFNO₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 8582 - 8591

13
[ 261762-35-0 ]
C₁₅H₁₀BrClFNO₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 8582 - 8591

14
[ 261762-35-0 ]
C₁₃H₇ClFNO₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 8582 - 8591

15
[ 261762-35-0 ]
C₂₆H₁₇ClFN₃O₅ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 8582 - 8591

16
[ 261762-35-0 ]
[ 1351862-65-1 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 8582 - 8591

17
[ 261762-35-0 ]
N-(1-(7-chloro-4,5-difluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yloxy)-2-cyanopropan-2-yl)-4-(trifluoromethoxy)benzamide [ No CAS ]

Reference： [1]Patent: WO2014/149793,2014,A1

18
[ 261762-35-0 ]
(6-bromo-2,3-difluoro-4-methoxyphenyl)methanol [ No CAS ]

Reference： [1]Patent: WO2014/149793,2014,A1

19
[ 261762-35-0 ]
2-((6-bromo-2,3-difluoro-4-methoxybenzyl)oxy)tetrahydro-2H-pyran [ No CAS ]

Reference： [1]Patent: WO2014/149793,2014,A1

20
[ 261762-35-0 ]
4,5-difluoro-6-methoxybenzo[c][1,2]oxaborol-1(3H)-ol [ No CAS ]

Reference： [1]Patent: WO2014/149793,2014,A1

21
[ 261762-35-0 ]
4,5-difluorobenzo[c][1,2]oxaborole-1,6(3H)-diol [ No CAS ]

Reference： [1]Patent: WO2014/149793,2014,A1

22
[ 261762-35-0 ]
7-chloro-4,5-difluorobenzo[c][1,2]oxaborole-1,6(3H)-diol [ No CAS ]

Reference： [1]Patent: WO2014/149793,2014,A1

23
[ 261762-35-0 ]
1-((7-chloro-4,5-difluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)propan-2-one [ No CAS ]

Reference： [1]Patent: WO2014/149793,2014,A1

24
[ 261762-35-0 ]
2-amino-3-((7-chloro-4,5-difluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)oxy)-2-methylpropanenitrile [ No CAS ]

Reference： [1]Patent: WO2014/149793,2014,A1

25
[ 68-12-2 ]
[ 261762-35-0 ]
6-bromo-2,3-difluoro-4-methoxybenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		Example 20 N-( 1 -(7-chloro-4,5 -difluoro- 1 -hydroxy- 1 ,3-dihydrobenzo[cl [ 1 ,2"\|oxaborol-6-yloxy")-2-cva nopropan-2-yl)-4-(trifluoromethoxy)benzamide To a solution of 5-bromo-l,2-difluoro-3-methoxybenzene (8.9 g, 39.9 mmol) in THF (200 mL), LDA (17.6 mL, 43.9 mmol) is added dropwise at -78C and the mixture is stirred at the same temperature for 2 h. DMF (9.6 g, 131.7 mmol) is added at -78 C, and the mixture is stirred at -78C for 4 h. The reaction is quenched with saturated aq. NH4C1, extracted with EA, dried over Na2S04, and recrystallized to afford the desired product as a white solid (6 g, yield 60 %). :H NMR (400 MHz, CDC13): delta 10.20 (s, IH), 7.04-7.06 (m, 1H), 3.99 (s, 3H) ppm.

Reference： [1]Patent: WO2014/149793,2014,A1 .Location in patent: Page/Page column 76

26
7-indan-2-yl-5H-pyrrolo[3,2-d]pyrimidin-4-amine [ No CAS ]
[ 261762-35-0 ]
5-[4-amino-7-(2,3-dihydro-1H-inden-2-yl)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]-2,3-difluorophenol [ No CAS ]

Reference： [1]Patent: WO2015/58084,2015,A1

27
7-indan-2-yl-5H-pyrrolo[3,2-d]pyrimidin-4-amine [ No CAS ]
[ 261762-35-0 ]
5-(3,4-difluoro-5-methoxyphenyl)-7-indan-2-ylpyrrolo[3,2-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; potassium carbonate; L-proline; In dimethyl sulfoxide; at 90℃;Inert atmosphere;	7-Indan-2-yl-5H-pyrrolo [3 ,2-d]pyrimidin-4-amine (70 mg, 0.33 mmol), and 5- bromo-1,2-difluoro-3-methoxy-benzene were dissolved in 3 mL of DMSO followed by addition of K2C03 (273 mg, 1.98 mmol) and L-proline (23 mg, 0.2 mmol). Then N2 gas was purged through the reaction mixture for 5 mm, and CuT (18 mg, 0.1 mmol) was added and N2 gas was purged again for 5 more mm. The mixture was heated at 90 C overnight. The progress of the reaction was monitored by TLC and LCMS. Then the mixture was allowed to cool at RT followed by dilution with water (10 mL) and then the mixture was extracted with EtOAc (3x10 mL). The combined organic layer was washed with water (10 mL), brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the crude product which was taken for the next reaction without any further purification.

Reference： [1]Patent: WO2015/58084,2015,A1 .Location in patent: Paragraph 0445

28
[ 893566-81-9 ]
[ 261762-35-0 ]
2-(3,4-difluoro-5-methoxyphenyl)-6-methoxy-3,4-dihydro-1H-2,7-naphthyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
560 mg	With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; ruphos; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere;	To a mixture of 6-methoxy-1,2,3,4-tetrahydro-2,7-naphthyridine (500 mg, 3.04 mmol) and <strong>[261762-35-0]5-bromo-2,3-difluoroanisole</strong> (883 mg, 3.96 mmol) in dioxane (8 mL) was added t-BuONa (438 mg, 4.56 mmol), Pd2(dba)3 (40 mg, 0.04 mmol) and Ruphos (30 mg, 0.06 mmol) under N2. After being heated with stirring at 100 C for 12 hrs, the resulting reaction mixture was filtered. Thefiltrate was concentrated in vacuo, diluted with DCM (100 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column to give 2- (3 ,4-difluoro-5-methoxy-phenyl)-6-methoxy-3 ,4-dihydro- 1H- 2,7-naphthyridine (560 mg) as a gray solid.

Reference： [1]Patent: WO2016/107832,2016,A1 .Location in patent: Page/Page column 158; 159

29
2-benzyloxy-5,6,7,8-tetrahydro-1,6-naphthyridine [ No CAS ]
[ 261762-35-0 ]
2-benzyloxy-6-(3,4-difluoro-5-methoxyphenyl)-7,8-dihydro-5H-1,6-naphthyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
500 mg	With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; ruphos; In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere;	To a solution of 2-benzyloxy-5,6,7,8-tetrahydro-1,6-naphthyridine (500 mg, 2.4 mmol) and <strong>[261762-35-0]5-bromo-1,2-difluoro-3-methoxy-benzene</strong> (696 mg, 3.1 mmol) in dioxane (10 mL) was added tBuONa (345.6 mg, 3.6 mmol), Pd2(dba)3 (44 mg, 0.05 mmol) and RuPhos (34 mg, 0.07 mmol)under N2. After being heated with stuffing at 100 C for 12 hrs, the resulting mixture was filtered and concentrated in vacuo. The residue was purified to give 2-benzyloxy-6-(3,4-difluoro-5- methoxy-phenyl)-7,8-dihydro-5H-1,6-naphthyridine (500 mg), which was used in the next step without further purification.

Reference： [1]Patent: WO2016/107832,2016,A1 .Location in patent: Page/Page column 161; 162

30
[ 177-11-7 ]
[ 261762-35-0 ]
8-(3,4-difluoro-5-methoxy-phenyl)-1,4-dioxa-8-azaspiro[4.5]decane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.57 g	With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; ruphos; In 1,4-dioxane; at 100℃;Inert atmosphere;	To a flask containing a mixture of 5-bromo- 1 ,2-difluoro-3-methoxy-benzene (1.1 g, 4.93 mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (0.85 g, 5.92 mmol) in 1,4-dioxane (10 mL) was added t-BuONa (0.95 g, 9.86 mmol), Pd2(dba)3 (92 mg, 0.10 mmol) and Ru-Phos (92 mg, 0.20 mmol) under N2. After being heated with stirring at 100 C overnight, the reaction mixture was cooled to rt and diluted with water (20 mL), The resulting mixture was extracted with EA (30 mL) for three times. The combined organic layer was washed with brine, dried over anhydrousNaSO and concentrated in vacuo to give 8-(3,4-difluoro-5-methoxy-phenyl)-1,4-dioxa-8- azaspiro[4.5]decane (1.57 g), which was used in the next step without further purification.
1.57 g	With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; ruphos; In 1,4-dioxane; at 100℃;Inert atmosphere;	Step 1: Preparation of 8-(3,4-difluoro-5-methoxy-phenyl)-1,4-dioxa-8- azaspiro[4.5]decane To a mixture of <strong>[261762-35-0]5-bromo-1,2-difluoro-3-methoxy-benzene</strong> (1.1 g, 4.93 mmol), 1,4-dioxa-8- azaspiro[4.5]decane (0.85 g, 5.92 mmol) and t-BuONa (0.95 g, 9.86 mmol) in 1,4-dioxane (10 mL) was added Pd2(dba)3 (92 mg, 0.10 mmol) and Ru-Phos (92 mg, 0.20 mmol) successively under N2. After being heated at 100 oC with stirring overnight, the reaction mixture was cooled down to rt, diluted with water (20 mL) and extracted with EA (30 mL) for three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give 8-(3,4-difluoro-5-methoxy-phenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.57 g) which was used in the next step directly without further purification.

Reference： [1]Patent: WO2016/107832,2016,A1 .Location in patent: Page/Page column 63; 64
[2]Patent: WO2016/177655,2016,A1 .Location in patent: Page/Page column 66; 67

31
[ 261762-35-0 ]
1-(3,4-difluoro-5-methoxy-phenyl)piperidin-4-one [ No CAS ]

Reference： [1]Patent: WO2016/107832,2016,A1
[2]Patent: WO2016/177655,2016,A1
[3]Patent: WO2018/83081,2018,A1

32
[ 261762-35-0 ]
6-(3,4-difluoro-5-methoxy-phenyl)-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]

Reference： [1]Patent: WO2016/107832,2016,A1
[2]Patent: WO2016/177655,2016,A1

33
[ 261762-35-0 ]
6-(3,4-difluoro-5-methoxyphenyl)-2-pyrazin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]

Reference： [1]Patent: WO2016/107832,2016,A1

34
[ 261762-35-0 ]
6-(3,4-difluoro-5-methoxyphenyl)-2-pyrimidin-4-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine [ No CAS ]

Reference： [1]Patent: WO2016/107832,2016,A1

35
[ 261762-35-0 ]
ethyl 2-[6-(3,4-difluoro-5-methoxy-phenyl)-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-5-yl]acetate [ No CAS ]