[ CAS No. 20885-12-5 ] {[proInfo.proName]}

Name: 20885-12-5|2-Chloro-6-fluoropyridine|98%
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Quality Control of [ 20885-12-5 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 20885-12-5 ]

Product Details of [ 20885-12-5 ]

CAS No. :	20885-12-5	MDL No. :	MFCD00077483
Formula :	C₅H₃ClFN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LXOHKRGLGLETIJ-UHFFFAOYSA-N
M.W :	131.54	Pubchem ID :	639437
Synonyms :

Calculated chemistry of [ 20885-12-5 ]

Physicochemical Properties

Num. heavy atoms :	8
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	29.2
TPSA :	12.89 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) :	-5.9 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.64
Log Po/w (XLOGP3) :	1.7
Log Po/w (WLOGP) :	2.29
Log Po/w (MLOGP) :	1.51
Log Po/w (SILICOS-IT) :	2.51
Consensus Log Po/w :	1.93

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.28
Solubility :	0.688 mg/ml ; 0.00523 mol/l
Class :	Soluble
Log S (Ali) :	-1.59
Solubility :	3.41 mg/ml ; 0.0259 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.88
Solubility :	0.172 mg/ml ; 0.00131 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.74

Safety of [ 20885-12-5 ]

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 [ 20885-12-5 ]

* 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 [ 20885-12-5 ]
Downstream synthetic route of [ 20885-12-5 ]

[ 20885-12-5 ] Synthesis Path-Upstream 1~12

1
[ 109-09-1 ]
[ 2402-78-0 ]
[ 1513-65-1 ]
[ 20885-12-5 ]

Reference： [1] Tetrahedron Letters, 1987, vol. 28, # 3, p. 255 - 258

2
[ 119071-51-1 ]
[ 109-09-1 ]
[ 2402-78-0 ]
[ 1513-65-1 ]
[ 20885-12-5 ]

Reference： [1] Journal of Organic Chemistry, 1989, vol. 54, # 7, p. 1726 - 1731

3
[ 20885-12-5 ]
[ 45644-21-1 ]

Reference： [1] Organic and Biomolecular Chemistry, 2018, vol. 16, # 41, p. 7564 - 7567

4
[ 109-09-1 ]
[ 2402-78-0 ]
[ 1513-65-1 ]
[ 20885-12-5 ]

Reference： [1] Tetrahedron Letters, 1987, vol. 28, # 3, p. 255 - 258

5
[ 119071-51-1 ]
[ 109-09-1 ]
[ 2402-78-0 ]
[ 1513-65-1 ]
[ 20885-12-5 ]

Reference： [1] Journal of Organic Chemistry, 1989, vol. 54, # 7, p. 1726 - 1731

6
[ 94166-64-0 ]
[ 20885-12-5 ]

Reference： [1] Tetrahedron Letters, 2010, vol. 51, # 14, p. 1906 - 1909

7
[ 109-09-1 ]
[ 372-48-5 ]
[ 20885-12-5 ]

Reference： [1] Journal of the Chemical Society - Perkin Transactions 1, 1999, # 7, p. 803 - 810

8
[ 109-09-1 ]
[ 2402-78-0 ]
[ 1513-65-1 ]
[ 20885-12-5 ]

Reference： [1] Tetrahedron Letters, 1987, vol. 28, # 3, p. 255 - 258

9
[ 109-09-1 ]
[ 20885-12-5 ]

Reference： [1] Journal of Organic Chemistry, 1989, vol. 54, # 7, p. 1726 - 1731
[2] Science, 2013, vol. 342, # 6161, p. 956 - 960

10
[ 119071-51-1 ]
[ 109-09-1 ]
[ 2402-78-0 ]
[ 1513-65-1 ]
[ 20885-12-5 ]

Reference： [1] Journal of Organic Chemistry, 1989, vol. 54, # 7, p. 1726 - 1731

11
[ 20885-12-5 ]
[ 68-12-2 ]
[ 1093880-37-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexanes at -78℃; for 1 h; Inert atmosphere Stage #2: at -78℃; for 1 h; Inert atmosphere	Example 3 - Synthesis of Phantasmidine (Figure 3) 6-Chloro-2-fluoropyridine-3-carboxaldehyde (8b). A solution of diisopropylamine (5.80 mL, 41.5 mmol) in anhydrous THF (100 mL) was treated with n- BuLi (2.1 M in hexanes, 18.0 mL, 37.8 mmol) at -78 °C. The cold bath was removed and the resulting solution was stirred at 0 °C for 30 min. The light yellow solution was re- cooled to -78 °C and 2-chloro-6-fluoropyridine (15, 3.80 g, 29.0 mmol) in anhydrous THF (20 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 1 h. Dimethylformamide (4.49 mL, 58.0 mmol) was added dropwise and the mixture was stirred an additional 1 h and saturated HCl in ether was added at -78 °C slowly to the mixture until pH 1 was reached. The reaction was warmed to 25 °C and H₂0 (50 mL) was added. The layers were separated. The aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with H₂0 (50 mL) and brine (50 mL), dried (MgS0₄), and concentrated to give crystalline crude 8b. The crude needles were recrystallized from hexanes to give 4.14 g (90percent) of 8b: R_f = 0.27 (10: 1 hexanes/EtOAc); mp 49-50 °C; 1H NMR 10.27 (s, 1), 8.27 (dd, 1, J = 8.8, 8.0), 7.41 (d, J = 8.0); ¹³C NMR 185.0, 162.6 (d, J = 254), 154.8 (d, J = 15), 141.3, 123.0 (d, J = 5.3), 116.9 (d, J1697, 1595, 1562. The 1H NMR spectrum is identical to that previously reported.

Reference： [1] Organic Letters, 2011, vol. 13, # 3, p. 526 - 529
[2] Patent: WO2012/78608, 2012, A1, . Location in patent: Page/Page column 30-31
[3] Heterocycles, 2014, vol. 88, # 1, p. 779 - 787
[4] Patent: WO2015/75023, 2015, A1, . Location in patent: Page/Page column 112-113
[5] Patent: WO2016/177690, 2016, A1, . Location in patent: Page/Page column 75-76

12
[ 20885-12-5 ]
[ 883107-68-4 ]

Reference： [1] Patent: WO2011/115928, 2011, A1, . Location in patent: Page/Page column 59
[2] Patent: WO2013/44092, 2013, A1, . Location in patent: Page/Page column 82; 83
[3] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 2, p. 210 - 215
[4] Patent: WO2015/153720, 2015, A1,
[5] Patent: WO2017/59085, 2017, A1,

[ 20885-12-5 ] Synthesis Path-Downstream 1~88

1
[ 109-09-1 ]
[ 2402-78-0 ]
[ 1513-65-1 ]
[ 20885-12-5 ]

Reference： [1]Tetrahedron Letters,1987,vol. 28,p. 255 - 258

2
[ 119071-51-1 ]
[ 109-09-1 ]
[ 2402-78-0 ]
[ 1513-65-1 ]
[ 20885-12-5 ]

Reference： [1]Journal of Organic Chemistry,1989,vol. 54,p. 1726 - 1731

3
[ 109-09-1 ]
[ 20885-12-5 ]

Reference： [1]Journal of Organic Chemistry,1989,vol. 54,p. 1726 - 1731
[2]Science,2013,vol. 342,p. 956 - 960

4
[ 20885-12-5 ]
[ 1095223-06-5 ]
[ 1095223-59-8 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 789 - 794

5
[ 20885-12-5 ]
[ 18232-70-7 ]
[ 1095223-57-6 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 789 - 794

6
[ 20885-12-5 ]
[ 91012-53-2 ]
[ 1095223-55-4 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 789 - 794

7
[ 20885-12-5 ]
[ 104863-68-5 ]
[ 1095223-51-0 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 789 - 794

8
[ 20885-12-5 ]
[ 104863-69-6 ]
[ 1095223-53-2 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 789 - 794

9
[ 20885-12-5 ]
[ 91419-52-2 ]
[ 1196973-44-0 ]

Reference： [1]Tetrahedron Letters,2009,vol. 50,p. 6303 - 6306

10
[ 4254-02-8 ]
[ 20885-12-5 ]
[ 916176-89-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hexamethyldisilazane; In tetrahydrofuran; toluene; at 0 - 20℃;	A solution of cyclopentanecarbonitrile (0.7 g, 0.8 ml, 8 mmol) and 2-chloro-6- fluoropyridine (1.0 g, 8 mmol) in toluene (25 mL) at 00C was added sodium <n="75"/>bis(trimethylsilyl)amide (8 mL, 8 mmol) IM in THF dropwise. After addition, the mixture was stirred at 00C for 1 h and 3 h at room temperature. Then, H2O (20 mL) was added and the mixture was stirred at room temperature for 15 minutes. Then, the mixture was extracted with EtOAC (2 x 20 mL) and the combined organic extracts were dried over MgSO4 and concentrated. The residue was mixed with silica gel and the solid mixture was then purified by silica gel column chromatography using ISCO instrument (solid loading, 0%-30% EtOAc/hexane) to give l-(6-chloropyridin-2-yl)cyclopentanecarbonitrile as a colorless oil. MS (ESI, positive ion) m/z: 207 (M+l).

Reference： [1]Patent: WO2009/137404,2009,A1 .Location in patent: Page/Page column 73-74

11
[ 20885-12-5 ]
[ 99-76-3 ]
[ 869109-01-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 5617 - 5622

12
[ 20885-12-5 ]
(2aS,4aR,9aR)-7-chloro-1,2,2a,3,4,4a-hexahydrobenzofuro[2,3-c]cyclobuta[b]pyrrole [ No CAS ]
(2aR,4aS,9aS)-7-chloro-1,2,2a,3,4,4a-hexahydrobenzofuro[2,3-c]cyclobuta[b]pyrrole [ No CAS ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529

13
[ 20885-12-5 ]
[ 1227509-94-5 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1

14
[ 20885-12-5 ]
[ 1227577-88-9 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1
[3]Organic Letters,2014,vol. 16,p. 2422 - 2425

15
[ 20885-12-5 ]
[ 1227598-89-1 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1

16
[ 20885-12-5 ]
[ 1261593-73-0 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1

17
[ 20885-12-5 ]
[ 1261593-74-1 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529

18
[ 20885-12-5 ]
(2aS,4aS,9aR)-rac-7-chloro-1,2,2a,3,4,4a-hexahydrobenzofuro[2,3-c]cyclobuta[b]pyrrol-4-one [ No CAS ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1

19
[ 20885-12-5 ]
(2aS,4aR,9aR)-rac-7-chloro-1,2,2a,3,4,4a-hexahydrobenzofuro[2,3-c]cyclobuta[b]pyrrole [ No CAS ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1

20
[ 20885-12-5 ]
phantasmidine trifluoroacetate [ No CAS ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1

21
[ 20885-12-5 ]
1-[(2aS,4aR,9aR)-rac-7-chloro-2,2a,4,4a-tetrahydrobenzofuro[2,3-c]cyclobuta[b]pyrrol-3(1H)-yl]-ethanone [ No CAS ]

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1

22
[ 20885-12-5 ]
[ 68-12-2 ]
[ 1093880-37-5 ]

Yield	Reaction Conditions	Operation in experiment
90%		Example 3 - Synthesis of Phantasmidine (Figure 3) 6-Chloro-2-fluoropyridine-3-carboxaldehyde (8b). A solution of diisopropylamine (5.80 mL, 41.5 mmol) in anhydrous THF (100 mL) was treated with n- BuLi (2.1 M in hexanes, 18.0 mL, 37.8 mmol) at -78 C. The cold bath was removed and the resulting solution was stirred at 0 C for 30 min. The light yellow solution was re- cooled to -78 C and <strong>[20885-12-5]2-chloro-6-fluoropyridine</strong> (15, 3.80 g, 29.0 mmol) in anhydrous THF (20 mL) was added dropwise. The reaction mixture was stirred at -78 C for 1 h. Dimethylformamide (4.49 mL, 58.0 mmol) was added dropwise and the mixture was stirred an additional 1 h and saturated HCl in ether was added at -78 C slowly to the mixture until pH 1 was reached. The reaction was warmed to 25 C and H20 (50 mL) was added. The layers were separated. The aqueous layer was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with H20 (50 mL) and brine (50 mL), dried (MgS04), and concentrated to give crystalline crude 8b. The crude needles were recrystallized from hexanes to give 4.14 g (90%) of 8b: Rf = 0.27 (10: 1 hexanes/EtOAc); mp 49-50 C; 1H NMR 10.27 (s, 1), 8.27 (dd, 1, J = 8.8, 8.0), 7.41 (d, J = 8.0); 13C NMR 185.0, 162.6 (d, J = 254), 154.8 (d, J = 15), 141.3, 123.0 (d, J = 5.3), 116.9 (d, J1697, 1595, 1562. The 1H NMR spectrum is identical to that previously reported.
		To a solution of diisopropylamine (5.26 mL) in THF (70 mL) was added at -78C nBuLi 1.6M in hexanes (21.6 mL). The mixture was stirred at 0C for 45 min. 2-Chloro-6-fluoropyridine (3.5g) in THF (36 mL) was added dropwise at -78C over 1 h under nitrogen to the previous mixture and the reaction mixture was stirred at -78C for 1.5h. DMF (4.12 mL) was added dropwise over 1 h and the reaction mixture was stirred an additional 1 .5h. HCI 2M in diethylether (45 mL) was added slowly at -78C, water (30 mL) was added and the layers were separated. The aq. phase was extracted with EA and the combined org. layers were washed with sat. aq. NaCI, dried over Na2S04, filtrated off and evaporated in vacuo. The crude (4.4g of an orange solid) was used without purification in the next step. GC-MS (A): tR = 1 .55 min; [M+H]+: 159.80.
		To a solution of diisopropylamine (5.26ml) in THF (70ml) was added at -78C nBuLi 1.6M in hexanes (21.6ml). The mixture was stirred at 0C for 45min. <strong>[20885-12-5]2-chloro-6-fluoropyridine</strong> (3.5g) in THF (36ml) was added dropwise at -78C over 1 h under nitrogen to the previous mixture and the reaction mixture was stirred at -78C for 1.5h. DMF (4.12ml) was added dropwise over 1 h and the reaction mixture was stirred an additional 1.5h. HCI 2M in diethylether (45ml) was added slowly at -78C, water (30ml) was added and the layers were separated. The aq. phase was extracted with EA and the combined org. layers were washed with sat. aq. NaCI, dried over Na2S04, filtrated off and evaporated in vacuo. The crude (4.4g of an orange solid) was used without purification in the next step. GC-MS (A): tR = 1.55min; [M+H]+: 159.80.

Reference： [1]Organic Letters,2011,vol. 13,p. 526 - 529
[2]Patent: WO2012/78608,2012,A1 .Location in patent: Page/Page column 30-31
[3]Heterocycles,2014,vol. 88,p. 779 - 787
[4]Patent: WO2015/75023,2015,A1 .Location in patent: Page/Page column 112-113
[5]Patent: WO2016/177690,2016,A1 .Location in patent: Page/Page column 75-76

23
[ 20885-12-5 ]
[ 1300695-54-8 ]
[ 1300695-84-4 ]

Yield	Reaction Conditions	Operation in experiment
72.4%	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In 1,4-dioxane; at 110℃; for 16h;Inert atmosphere;	Intermediate 731 ,1 -Dimethylethyl r2-(4-{(2S,4/?)-1 -acetyl-4-r(6-fluoro-2-pyridinyl)aminol-2-methyl-1 ,2,3,4- tetrahvdro-6-quinolinyl)-1 /-/-pyrazol-1 -yl)ethyllmethylcarbamate1 ,1 -Dimethylethyl (2-{4-[(2S,4R)-1 -acetyl-4-amino-2-methyl-1 .2.3,4-tetrahydro-6- quinolinyl]-1 H-pyrazol-1 -yl}ethyl)methylcarbamate (for a preparation see intermediate 55) (250 mg, 0.585 mmol) was taken up in 1 ,4-dioxane (5 mL) under nitrogen and 2-chloro-6- fluoropyridine (154 mg, 1 .169 mmol) added followed by sodium tert-butoxide (1 12 mg, 1 .169 mmol), 2'-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (DavePhos) (46.0 mg, 0.1 17 mmol) then tris(dibenzylideneacetone)dipalladium(0) (53.5 mg, 0.058 mmol) and the resulting mixture was stirred at 1 10C for 16 h then cooled to room temperature and partitioned between EtOAc (25 mL) and water (25 mL). The layers were separated and the aqueous phase was extracted with EtOAc (25 mL). The combined organic phases were washed with brine (50 mL), dried over Na2S04 and concentrated in vacuo.Purification of the residue on SP4 using a 100 G silica cartridge (gradient: 1 to 10% MeOH in DCM) gave 1 ,1 -dimethylethyl [2-(4-{(2S,4R)-1 -acetyl-4-[(6-fluoro-2- pyridinyl)amino]-2-methyl-1 ,2,3,4-tetrahydro-6-quinolinyl}-1 H-pyrazol-1 - yl)ethyl]methylcarbamate (260.2 mg, 0.423 mmol, 72.4 % yield) as an orange oil.LCMS (Method B): Retention time 1 .06 min, [M+H]+ = 523.25

Reference： [1]Patent: WO2011/54848,2011,A1 .Location in patent: Page/Page column 81-82

24
[ 20885-12-5 ]
[ 1215868-74-8 ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 210 - 215
[2]Patent: WO2011/115928,2011,A1
[3]Patent: WO2013/44092,2013,A1

25
[ 20885-12-5 ]
[ 883107-68-4 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1 : A solution of i-Pr2NH (828 mL, 5.85 mol) in anhydrous THF (1.3 L) was cooled to -10 C. n-BuLi (1.6 M in hexanes, 3660 mL, 5.85 mol) was added and the solution was stirred for 10 min at 0 C. The reaction mixture was cooled to -78 C and a solution of 2- chloro-6-fluoropyridine (700 g, 5.32 mol) in anhydrous THF (1.3 L) was slowly added keeping the internal temperature below -60 C. After the addition was complete, the reaction mixture was stirred for an additional hour and then a solution of triisopropyl borate (1221 mL, 5.32 mol) in anhydrous THF (620 mL) was added drop wise keeping the internal temperature below -60 C. After the addition, the reaction mixture was warmed to RT and stirred over night. Water (3 L) was added and the mixture was stirred vigorously. The reaction mixture was concentrated under reduced pressure. The residue was treated with a cold aqueous solution of NaOH (10 M , 1610 mL, 16.0 mol) and 50% H2O2 (392 mL, 6.92 mol) and stirred over night (Note: the internal temperature increased slowly from 5 to 60 C). The reaction mixture was quenched with ice and 4N HCI until pH of the mixture was ~5. EtOAc (5 L) was added and stirred well. After phase separation, the aqueous layer was extracted with EtOAc (1.5 L x 2). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to provide 6-chloro-2-fluoropyridin-3-ol as an off white solid.
		Step 1 : A solution of i-Pr2NH (828 mL, 5.85 mol) in anhydrous THF (1.3 L) was cooled to -10 C. n-BuLi (1.6 M in hexanes, 3660 mL, 5.85 mol) was added and the solution was stirred for 10 min at 0 C. The reaction mixture was cooled to -78 C and a solution of 2- chloro-6-fluoropyridine (700 g, 5.32 mol) in anhydrous THF (1.3 L) was slowly added keeping the internal temperature below -60 C. After the addition was complete, the reaction mixture was stirred for an additional hour and then a solution of triisopropyl borate (1221 mL, 5.32 mol) in anhydrous THF (620 mL) was added drop wise keeping the internal temperature below -60 C. After the addition, the reaction mixture was warmed to RT and stirred over night. Water (3 L) was added and the mixture was stirred vigorously. The reaction mixture was concentrated under reduced pressure. The residue was treated with a cold aqueous solution of NaOH (10 M , 1610 mL, 16.0 mol) and 50% H2O2 (392 mL, 6.92 mol) and stirred over night (Note: the internal temperature increased slowly from 5 to 60 C). The reaction mixture was quenched with ice and 4N HC1 until pH of the mixture was ~5. EtOAc (5 L) was added and stirred well. After phase separation, the aqueous layer was extracted with EtOAc (1.5 L x 2). The combined organic layers were washed with brine, dried over anhydrous Na2S04, and concentrated under reduced pressure to provide 6-chloro-2-fluoropyridin-3-ol as an off white solid.

Reference： [1]Patent: WO2011/115928,2011,A1 .Location in patent: Page/Page column 59
[2]Patent: WO2013/44092,2013,A1 .Location in patent: Page/Page column 82; 83
[3]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 210 - 215
[4]Patent: WO2015/153720,2015,A1
[5]Patent: WO2017/59085,2017,A1

26
[ 20885-12-5 ]
[ 1335218-41-1 ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 210 - 215
[2]Patent: WO2015/153720,2015,A1
[3]Patent: WO2017/59085,2017,A1
[4]Patent: WO2011/115928,2011,A1
[5]Patent: WO2013/44092,2013,A1

27
[ 20885-12-5 ]
[ 1335218-42-2 ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 210 - 215
[2]Patent: WO2011/115928,2011,A1
[3]Patent: WO2013/44092,2013,A1

28
[ 20885-12-5 ]
[ 1335218-43-3 ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 210 - 215
[2]Patent: WO2011/115928,2011,A1
[3]Patent: WO2013/44092,2013,A1

29
[ 20885-12-5 ]
[ 1335218-44-4 ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 210 - 215
[2]Patent: WO2011/115928,2011,A1
[3]Patent: WO2013/44092,2013,A1

30
[ 20885-12-5 ]
[ 1357366-78-9 ]

Reference： [1]Patent: WO2011/115928,2011,A1
[2]Patent: WO2013/44092,2013,A1

31
[ 20885-12-5 ]
[ 375853-82-0 ]
[ 1137949-61-1 ]

Yield	Reaction Conditions	Operation in experiment
28%	With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; for 18h;	Preparation of tert-Butyl 6-fluoro-5',6'-dihydro-[2,4'-bipyridine]-l'(2'H)- carboxylateA mixture of ieri-butyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-5,6- dihydropyridine-l(2H)-carboxylate (1 g, 3.24 mmol, potassium carbonate (1.34 g, 9.71 mmol), PdCl2dppf (0.16 g, 0.20 mmol) and <strong>[20885-12-5]2-chloro-6-fluoropyridine</strong> (0.44 g, 3.40 mmol) in anhydrous dimethylformamide (5 mL) was heated at 80 C for 18 hours. The reaction mixture was cooled to room temperature, filtered through Celite and the resulting solution was partitioned between ethyl acetate and brine. The organic portion was separated, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure to afford a dark brown oil. This oil was purified by silica gel chromatography eluting with 0 - 50 % ethyl acetate in petroleum ether (50 g, 27 CV, 40 mL/min) afford tert-butyl 6-fluoro-5',6'-dihydro-[2,4'-bipyridine]- (2'H)-carboxylate as a colourless oil (254 mg, 28 ).*H NMR (300 MHz, CDC13): delta: 1.43 (9H, s, (CH3)3), 2.53 (2H, bs, CH2), 3.58 (2H, t, NCH2), 4.07 (2H, m, NCH2), 6.65 (1H, p, C=CH), 6.72 (1Eta, dd, CHAr), 7.16 (1H, dd, CHAr), 7.69 (1H, q, CHAT). 13C NMR (75 MHz, CDC13): delta: 25.6, 28.3, 40.1, 43.7, 79.6, 107.4, 115.7, 125.7, 133.7, 141.3, 154.7, 161.1, 164.3. MS expected for Ci5H19FN202: 278.14; found: 223.14 (M-C(CH3)3]+.

Reference： [1]Patent: WO2011/150183,2011,A1 .Location in patent: Page/Page column 183-184

32
[ 20885-12-5 ]
[ 1351412-11-7 ]

Reference： [1]Patent: WO2011/150183,2011,A1

33
[ 20885-12-5 ]
[ 1351409-66-9 ]

Reference： [1]Patent: WO2011/150183,2011,A1

34
[ 20885-12-5 ]
[ 1338090-89-3 ]
[ 69739-34-0 ]
C₁₄H₂₃ClN₂OSi [ No CAS ]

Reference： [1]Heterocycles,2012,vol. 85,p. 65 - 72

35
[ 20885-12-5 ]
[ 577711-86-5 ]

Reference： [1]Heterocycles,2012,vol. 85,p. 65 - 72

36
[ 20885-12-5 ]
(2aS,4aR,9aR)-7-chloro-1,2,2a,3,4,4a-hexahydrobenzofuro[2,3-c]cyclobuta[b]pyrrole [ No CAS ]

Reference： [1]Patent: WO2012/78608,2012,A1

37
[ 20885-12-5 ]
[ 1261593-74-1 ]
[ 1227598-64-2 ]

Reference： [1]Patent: WO2012/78608,2012,A1

38
[ 20885-12-5 ]
(2aR,4aS,9aS)-7-chloro-1,2,2a,3,4,4a-hexahydrobenzofuro[2,3-c]cyclobuta[b]pyrrole [ No CAS ]

Reference： [1]Patent: WO2012/78608,2012,A1

39
[ 20885-12-5 ]
[ 1380601-17-1 ]

Reference： [1]Patent: WO2012/78608,2012,A1

40
[ 20885-12-5 ]
[ 1380584-11-1 ]

Reference： [1]Patent: WO2012/78608,2012,A1

41
[ 20885-12-5 ]
[ 51605-32-4 ]
[ 1398414-93-1 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In ISOPROPYLAMIDE; at 150℃; for 0.5h;	Example 31: Preparation of 5-methyl-l-[6-[3-methyl-2-[(2-tetrahydropyran-4-yl-3,4- dihydro-lH-isoquinolin-6-yl)methoxy]phenyl]-2-pyridyl]imidazole-4-carboxylic acid (Compound 57, Table 1) Imidazole 30-107 (3.0 g, 19.5 mmol) is combined with pyridine 30-108 (5.16 g, 39.2 mmol) and Cs2C03 (12.7 g, 38.9 mmol) in N,N-DMA (60 mL), then irradiated at 150 C for 30 min. The resulting mixture is evaporated to dryness. Crude intermediate 30-109 (1.0 g, 3.76 mmol) is combined with Pd(PPh3)4 (400 mg, 0.35 mmol), 2M aqueous Na2C03 solution (4 mL, 8 mmol), and 30-110 (740 mg, 4.87 mmol) in 1,2-DME (15 mL). The mixture is irradiated for 40 min at 120 C, then evaporated to dryness. The crude residue is purified by column chromatography on silica gel (using a gradient of 0-10% MeOH/DCM) to provide the intermediate 30-111 (1.36 g). Intermediate 30-111 (100 mg, 0.3 mmol), bromide 30-106 (120 mg, 0.36 mmol) and Cs2C03 (180 mg, 0.55 mmol) are combined in DMF (6 mL) and heated to 40 C for 3d. The solvent is then evaporated and the crude residue is purified by column chromatography on silica gel (using a gradient of 5-100% EtOAc/heptane) to provide the intermediate carbamate. The carbamate is dissolved in DCM (10 mL) and treated with TFA (1 mL) at room temperature. After 1.5 h, the mixture is neutralized with saturated NaHC03 solution and the layers are separated with a hydrophobic frit. The organic filtrate is concentrated to afford the crude amine. This material is combined with 4A molecular sieves (30 mg), tetrahydropyran 4-one (38 mu, 0.41 mmol), AcOH (10 munu>, and NaBH3CN (24 mg, 0.38 mmol) in MeOH (4 mL). The mixture is stirred at room temperature for 45 minutes, and then heated to 50 C for 16 h. The mixture is concentrated to dryness, and then the residue is purified by column chromatorgraphy on C18 silica gel (using a gradient of 5-95% MeCN/water + 0.1% TFA) to afford the title compound 57 (69 mg). MS, electro spray, m/z = 539.3 [M+H], rt 0.64min.

Reference： [1]Patent: WO2012/122340,2012,A1 .Location in patent: Page/Page column 84-85

42
[ 20885-12-5 ]
[ 80714-39-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrazine hydrate; In ethanol; at 55℃; for 72h;	General procedure: 2-Chloropyridines were dissolved in EtOH and hydrazine hydrate added. The solution was heated in a thick walled sealed vial for 72h at 55 C, concentrated under a stream of nitrogen and purified by silica gel chromatography, (hexanes/ethylacetate).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1743 - 1747

43
[ 20885-12-5 ]
[ 1427301-05-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1743 - 1747

44
[ 20885-12-5 ]
[ 1431142-67-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1743 - 1747

45
[ 20885-12-5 ]
[ 1335218-63-7 ]

Reference： [1]Patent: WO2013/44092,2013,A1
[2]Patent: WO2013/44092,2013,A1

46
[ 20885-12-5 ]
[ 1335218-65-9 ]

Reference： [1]Patent: WO2013/44092,2013,A1

47
[ 20885-12-5 ]
[ 1335218-66-0 ]

Reference： [1]Patent: WO2013/44092,2013,A1

48
[ 20885-12-5 ]
[ 1335218-67-1 ]

Reference： [1]Patent: WO2013/44092,2013,A1

49
[ 20885-12-5 ]
[ 1215868-75-9 ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 210 - 215
[2]Patent: WO2013/44092,2013,A1

50
[ 20885-12-5 ]
[ 1335218-68-2 ]

Reference： [1]Patent: WO2013/44092,2013,A1

51
[ 20885-12-5 ]
[ 1335218-69-3 ]

Reference： [1]Patent: WO2013/44092,2013,A1

52
[ 20885-12-5 ]
[ 1335218-70-6 ]

Reference： [1]Patent: WO2013/44092,2013,A1

53
[ 20885-12-5 ]
[ 1335218-71-7 ]

Reference： [1]Patent: WO2013/44092,2013,A1

54
[ 20885-12-5 ]
[ 1335219-42-5 ]

Reference： [1]Patent: WO2013/44092,2013,A1

55
[ 20885-12-5 ]
[ 1428633-57-1 ]

Reference： [1]Patent: WO2013/44092,2013,A1
[2]Patent: WO2013/44092,2013,A1

56
[ 20885-12-5 ]
[ 1428633-58-2 ]
[ 1428633-59-3 ]

Reference： [1]Patent: WO2013/44092,2013,A1
[2]Patent: WO2013/44092,2013,A1

57
[ 20885-12-5 ]
[ 1428633-60-6 ]

Reference： [1]Patent: WO2013/44092,2013,A1
[2]Patent: WO2013/44092,2013,A1

58
[ 20885-12-5 ]
[ 1335218-64-8 ]

Reference： [1]Patent: WO2013/44092,2013,A1

59
[ 20885-12-5 ]
tert-butyl 2-(7-bromo-3-chloro-5-(1,1-dimethylethylsulfinamido)-1-fluoro-5H-chromeno[2,3-c]pyridin-5-yl)acetate [ No CAS ]

Reference： [1]Patent: WO2013/44092,2013,A1

60
[ 20885-12-5 ]
[ 1335218-61-5 ]

Reference： [1]Patent: WO2013/44092,2013,A1
[2]Patent: WO2013/44092,2013,A1

61
[ 20885-12-5 ]
N-(7-bromo-3-chloro-1-fluoro-5-(2-hydroxyethyl)-5H-chromeno[2,3-c]pyridin-5-yl)-2-methylpropane-2-sulfinamide [ No CAS ]

Reference： [1]Patent: WO2013/44092,2013,A1

62
[ 20885-12-5 ]
[ 1335218-62-6 ]

Reference： [1]Patent: WO2013/44092,2013,A1
[2]Patent: WO2013/44092,2013,A1

63
[ 20885-12-5 ]
[ 1374342-52-5 ]
[ 1374342-54-7 ]

Yield	Reaction Conditions	Operation in experiment
	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In water; acetonitrile; at 90℃; for 4h;Inert atmosphere; Sealed tube;	Step A. 2-fluoro-6-{4-methyl-4'-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]biphenyl-2-yl}pyridine The title compound from Example 284 Step B (150 mg, 0.33 mmol), <strong>[20885-12-5]2-chloro-6-fluoropyridine</strong> (43 mg, 0.33 mmol), dichloro bis(triphenylphosphine)palladium(II) (23 mg, 0.033 mmol), sodium carbonate (0.653 mL of a 1 M aq. solution, 0.653 mmol) and MeCN (1.5 mL) were mixed in a sealed vial under nitrogen and heated at 90 C. for 4 h. Organic layer was separated. Aqueous layer was extracted with hexanes-EtOAc. The organic layers were combined and concentrated. Silica gel flash chromatography (4:1 to 1:1 hexanes-DCM, then 20:1 to 7:1 hexanes-EtOAc, v/v) gave the title compound: LCMS m/z 429.3 [M+H]+; 1H NMR (500 MHz, CDCl3) delta 7.57 (s, 1H), 7.47 (dd, J=8.0, 8.0 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.16-7.11 (m, 4H), 6.77 (m, 2H), 3.12 (m, 2H), 3.06 (q, J=9.7 Hz, 2H), 2.52 (m, 3H), 2.49 (s, 3H). 1.89-1.78 (m, 4H).

Reference： [1]Patent: US2013/210798,2013,A1 .Location in patent: Paragraph 0292; 0293

64
[ 20885-12-5 ]
[ 1599474-46-0 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 2422 - 2425

65
[ 20885-12-5 ]
[ 1187732-65-5 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 2422 - 2425

66
[ 20885-12-5 ]
[ 1624604-02-9 ]

Yield	Reaction Conditions	Operation in experiment
		Example 100 Synthesis of (4S,6S)-4-(5-((6-chloropyridin-2-yl)oxy)-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine The title compound was synthesized by procedures and steps analogous to those described in Example 92, Method M, but using <strong>[20885-12-5]2-chloro-6-fluoropyridine</strong> in step 5. MS m/z=422 [M+H]+. Calculated for C17H13ClF5N3O2: 421.7. 1H NMR (400 MHz, CHLOROFORM-d) delta=7.64 (t, J=7.9 Hz, 1H), 7.33-7.23 (m, 1H), 7.16-7.01 (m, 3H), 6.79 (d, J=8.0 Hz, 1H), 4.81-4.40 (m, 2H), 4.33-4.15 (m, 3H), 2.66 (dd, J=2.7, 13.5 Hz, 1H), 2.16 (t, J=13.1 Hz, 1H).

Reference： [1]Patent: US2014/249104,2014,A1 .Location in patent: Page/Page column

67
[ 20885-12-5 ]
[ 61676-62-8 ]
6-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 31 Preparation of 6-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine A 2.5M solution of n-butyllithium (3.6 mL, 9.1 mmol, 1.2 equiv) was added to a stirred solution of diisopropylamine (1.4 mL, 9.9 mmol, 1.3 equiv) in tetrahydrofuran (11 mL) at -78 C. The resulting pale yellow solution was stirred at -78 C. for 15 min, warmed to 0 C. and stirred for 15 min, and then cooled back to -78 C. and stirred for 15 min. A solution of <strong>[20885-12-5]2-chloro-6-fluoropyridine</strong> (1.0 g, 7.6 mmol, 1.0 equiv) in tetrahydrofuran (9 mL) was added via cannula at -78 C. The resulting pale yellow mixture was stirred at -78 C. for 2 h. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.3 mL, 11 mmol, 1.5 equiv) was added and the reaction mixture was allowed to slowly warm to 23 C., by allowing the dry ice/acetone bath to melt, and stirred for 20 h. The reaction mixture was diluted with 2M sodium hydroxide (150 mL) and washed with Et2O (350 mL). The aqueous layer was adjusted to pH 2, using concentrated HCl, and extracted with dichloromethane (450 mL). The combined organic layers were dried (MgSO4), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a colorless oil (1.9 g, 95% crude yield): 1H NMR (300 MHz, CDCl3) delta 8.11 (t, J=8 Hz, 1H), 7.23 (dd, J=8, 2 Hz, 1H), 1.36 (s, 12H).

Reference： [1]Patent: US2014/274703,2014,A1 .Location in patent: Paragraph 0252; 0253

68
[ 20885-12-5 ]
methyl 4-amino-5,6'-dichloro-2'-fluoro-[2,3'-bipyridine]-6-carboxylate [ No CAS ]

Reference： [1]Patent: US2014/274703,2014,A1

69
[ 20885-12-5 ]
C₁₄H₁₀Cl₂FN₃O₃ [ No CAS ]

Reference： [1]Patent: US2014/274703,2014,A1

70
[ 461451-63-8 ]
[ 20885-12-5 ]
5-fluoro-2-(6-fluoropyridin-2-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); cesium fluoride; In 1,4-dioxane; water; at 110℃; for 2.5h;Inert atmosphere;	[00393] To a solution of the <strong>[20885-12-5]2-chloro-6-fluoropyridine</strong> (400 mg, 3.041 mmol, 1 eq.) in a mixture of dioxane (9 mL)/water (1 mL) under argon are successively added 5-Fluoro-2-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzonitrile (901.6 mg, 3.649 mmol, 1.2 eq.), CsF (970 mg, 3.041 mmol, 2.1 eq.) and Pd(amphos)Cl2 (107.7 mg, 0.152 mmol, 0.05 eq.). The reaction mixture is heated at 110C for 2.5 h. After cooling to r.t., the crude product is partionned between water and EtOAc and the layers are separated. The aqueous layer is extracted with EtOAc twice, the combined organic layers are washed with brine, dried over Na2S04 and concentrated in vacuo. The residue is purified by chromatography on silica gel (elution heptanes/EtOAc (100/0 to 80/20) to afford Intermediate Gen-9-d. [00394] LC-MS : MW (calcd) : 216 ; m/z MW (obsd) : 217 ( M+H)

Reference： [1]Patent: WO2014/202458,2014,A1 .Location in patent: Paragraph 00393; 00394

71
[ 20885-12-5 ]
[ 214360-58-4 ]
2-fluoro-6-(4-fluorophenyl)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water;Inert atmosphere;	[00392] To a solution of the halogenoheterocycle derivative (1 eq.) in a mixture of dioxane/water (9/1) or MeCN/water (3/1) under argon are successively added the corresponding boronic ester (1 to 1.2 eq.), CsF (2.1 eq.) and Pd(amphos)Cl2 (0.05 eq.) or Na2C03 (3 eq.), and Pd(PPh3)4 (0.1 eq.). The reaction mixture is heated between 90C and 110C until completion. After cooling to r.t, the crude product is partionned between water and EtOAc and the layers are separated. The aqueous layer is extracted with EtOAc twice, the combined organic layers are washed with brine, dried over Na2S04 and concentrated in vacuo. The residue is purified by chromatography on silica gel to afford the expected intermediate.

Reference： [1]Patent: WO2014/202458,2014,A1 .Location in patent: Paragraph 00392; page 164

72
[ 20885-12-5 ]
(S)-7-bromo-3-chloro-1-fluoro-5'H-spiro[chromeno[2,3-c]pyridine-5,4'-oxazol]-2'-amine [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 210 - 215

73
[ 20885-12-5 ]
C₁₃H₈BrClFNO₂ [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 210 - 215

74
[ 20885-12-5 ]
[ 171230-81-2 ]
(R)-2-(tert-butyl-dimethyl-silanoxy)-1-(6-chloro-2-fluoro-pyridin-3-yl)-propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: 1.4.3. General meth A solution of LDA is prepared by adding dropwise a 2.5 M butyllithium solution in hexane (1.1 eq.) to a solution of DIPA (1.1 eq.) in THF under nitrogen at -78. The reaction mixture is stirred 15 min to 30 min at -78C. Then Intermediate Gen-6-a (1 eq.) in THF is added dropwise, and the reaction is stirred under nitrogen at -78C for 1 h. Then Intermediate Gen- 15 (1.1 to 1.2 eq.) is added, the mixture is stirred 1 h to 2 h at -78C, then the reaction mixture is quenched with a saturated aqueous NH4C1 solution. EtOAc is added, the organic layer is separated, dried over Na2S04, filtered and evaporated to dryness. The residue is purified by chromatography of silica gel to give Intermediate Gen-8.
		General procedure: A solution of LDA is prepared by adding dropwise a 2.5 M butyllithium solution in hexane (1.1 eq.) to a solution of DIPA (1.1 eq.) in THF undernitrogen at -78. The reaction mixture is stirred 15 mm to 30 mm at -78 C. Then Intermediate Gen-6-a (1 eq.) in THF is added dropwise, and the reaction is stirred under nitrogen at -78 C. for 1 h. Then Intermediate Gen-15 (1.1 to 1.2 eq.) is added, the mixture is stirred 1 h to 2 h at -78 C., then the reaction mixture is quenched with a saturated aqueous NH4C1 solution. EtOAc is added, the organic layer is separated, dried over Na2SO4, filtered and evaporated to dryness. The residue is purified by chromatography of silica gel to give Intermediate Gen-8.

Reference： [1]Patent: WO2015/24905,2015,A1 .Location in patent: Paragraph 00238
[2]Patent: US2015/80391,2015,A1 .Location in patent: Paragraph 0479; 0480; 0670

75
[ 20885-12-5 ]
[ 188660-03-9 ]
(S)-2-(tert-butyl-dimethyl-silanyloxy)-1-(6-chloro-2-fluoro-pyridin-3-yl)-propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1.4.2. Illustrative synthesis of Intermediate Gen-8-d: (S)-2-(tert-Butyl-dimethyl-silanyloxy)-l- -chloro-2-fluoro-pyridin-3-yl)-propan-l-one A solution of LDA is prepared by adding dropwise a 2.5 M butyllithium solution in hexane (308 mL, 0.77 mol, 1.167 eq.) to a solution of DIPA (100 g, 0.98 mol, 1.07 eq.) in THF (540 mL) under nitrogen at -5C. The reaction mixture is stirred 30 min at -5C. Then Intermediate Gen-6-a (86.8 g, 0.66 mol, 1 eq.) in THF (650 mL) is added dropwise below -60C, and the reaction is stirred under nitrogen at -78C for 1.33 h. Then Intermediate Gen-7-d (180 g, 0.73 mol, 1.1 eq.) is added dropwise whilst monitoring the temperature. The mixture is stirred 3 h at -70C and quenched with a saturated aqueous NH4C1 solution (400 mL). EtOAc (1 L) is added, then the organic layer is separated, dried over Na2S04, filtered and evaporated to dryness. The residue is purified by cake of silica gel (elution cyclohexane/EtOAc: 100/0 to 95/5) to give Intermediate Gen-8-d. lU NMR (300 MHz, CDCl3-i ) delta ppm 8.18 (1 H, dd), 7.34 (1 H, dd), 4.88 (1 H, dq), 1.43 (3.H, dd), 0.82 (9 H s), 0.65 (6 H, d).
		A solution of LDA is prepared by adding dropwise a 2.5 M butyllithium solution in hexane (308 mL, 0.77 mol, 1.167 eq.) to a solution of DIPA (100 g, 0.98 mol, 1.07 eq.) in THF (540 mL) under nitrogen at -5 C. The reaction mixture is stirred 30 min at -5 C. Then Intermediate Gen-6-a (86.8 g, 0.66 mol, 1 eq.) in THF (650 mL) is added dropwise below -60 C., and the reaction is stirred under nitrogen at -78 C. for 1.33 h. Then Intermediate Gen-7-d (180 g, 0.73 mol, 1.1 eq.) is added dropwise whilst monitoring the temperature. The mixture is stirred 3 h at -70 C. and quenched with a saturated aqueous NH4Cl solution (400 mL). EtOAc (1 L) is added, then the organic layer is separated, dried over Na2SO4, filtered and evaporated to dryness. The residue is purified by cake of silica gel (elution cyclohexane/EtOAc: 100/0 to 95/5) to give Intermediate Gen-8-d. 1H NMR (300 MHz, CDCl3-d) delta ppm 8.18 (1H, dd), 7.34 (1H, dd), 4.88 (1H, dq), 1.43 (3. H, dd), 0.82 (9H s), 0.65 (6H, d).

Reference： [1]Patent: WO2015/24905,2015,A1 .Location in patent: Paragraph 00236-00237; 00342-00343
[2]Patent: US2015/80391,2015,A1 .Location in patent: Paragraph 0476; 0477; 0478; 0651; 0652; 0653

76
[ 20885-12-5 ]
[ 119404-55-6 ]
N-(3-{5-[2-(tert-butyl-dimethyl-silanyloxy)-propionyl]-6-fluoro-pyridin-2-yl}-4-methyl-phenyl)-3,5-dimethoxy-benzamide [ No CAS ]

Reference： [1]Patent: WO2015/24905,2015,A1
[2]Patent: US2015/80391,2015,A1

77
[ 20885-12-5 ]
[ 119404-55-6 ]
2-(tert-butyl-dimethyl-silanyloxy)-1-(6-chloro-2-fluoro-piridin-3-yl)-propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1.4.4. Illustrative synthesis of Intermediate Gen-8-c: 2-(tert-Butyl-dimethyl-silanyloxy)-l-(6- A solution of LDA is prepared by adding dropwise a 2.5 M butyllithium solution in hexane (8.8 mL, 22 mmol, 1.1 eq.) to a solution of DIPA (7.1 mL, 22 mmol, 1.1 eq.) in THF (40 mL) under nitrogen at -78C. The reaction mixture is stirred 20 min at -78C. Then Intermediate Gen-6-a (2.63 g, 20 mmol, 1 eq.) in THF (20 mL) is added dropwise, and the reaction is stirred under nitrogen at -78C for 1 h. Then Intermediate Gen-15-a (4.8 g, 22 mmol, 1.2 eq.) is added in one portion. The mixture is stirred 2 h at -78C, then the reaction mixture is quenched with a saturated aqueous NH4C1 solution. EtOAc is added, the organic layer is separated, dried over Na2S04, filtered and evaporated to dryness. The residue is purified by chromatography of silica gel (elution heptanes/EtOAc: 95/5) to give Intermediate Gen-8-c. LCMS: MW (calcd): 317 (i5Cl), 319 (J C1); m/z MW (obsd): 318 (i5Cl M+H), 320 (J C1 M+H).
		A solution of LDA is prepared by adding dropwise a 2.5 M butyllithium solution in hexane (8.8 mL, 22 mmol, 1.1 eq.) to a solution of DIPA (7.1 mL, 22 mmol, 1.1 eq.) in THF (40 mL) under nitrogen at -78 C. The reaction mixture is stirred 20 min at -78 C. Then Intermediate Gen-6-a (2.63 g, 20 mmol, 1 eq.) in THF (20 mL) is added dropwise, and the reaction is stirred under nitrogen at -78 C. for 1 h. Then Intermediate Gen-15-a (4.8 g, 22 mmol, 1.2 eq.) is added in one portion. The mixture is stirred 2 h at -78 C., then the reaction mixture is quenched with a saturated aqueous NH4Cl solution. EtOAc is added, the organic layer is separated, dried over Na2SO4, filtered and evaporated to dryness. The residue is purified by chromatography of silica gel (elution heptanes/EtOAc: 95/5) to give Intermediate Gen-8-c. LCMS: MW (calcd): 317 (35Cl), 319 (37Cl); m/z MW (obsd): 318 (35Cl M+H), 320 (37Cl M+H).

Reference： [1]Patent: WO2015/24905,2015,A1 .Location in patent: Paragraph 00239-00240
[2]Patent: US2015/80391,2015,A1 .Location in patent: Paragraph 0481; 0482; 0483; 0479; 0480; 0670

78
[ 20885-12-5 ]
[ 104863-65-2 ]
1-(6-chloro-2-fluoro-pyridin-3-yl)-propan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: 1.4. General method E: Synthesis of Intermediate Gen-8 Gen-7 Gen-8 Gen General method A solution of LDA is prepared by adding dropwise a 2.5 M butyllithium solution in hexane (1.1 to 1.2 eq.) to a solution of DIPA (1.07 to 1.2 eq.) in THF under nitrogen at a temperature comprised between -78C and -5C. The reaction mixture is stirred 15 min to 30 min at the same temperature. Then Intermediate Gen-6-a (1 to 1.2 eq.) in THF is added dropwise between -78C and -60C, and the reaction is stirred under nitrogen at -78C for 1 h to 1.33 h. Then Intermediate Gen-7 (1.1 to 1.2 eq.) is added dropwise or portionwise by monitoring the temperature. The mixture is stirred 1.5 h to 3 h between -78C and -70C and quenched with a saturated aqueous NH4C1 solution. EtOAc is added, then the organic layer is separated, dried over Na2S04, filtered and evaporated to dryness. The residue is purified by chromatography of silica gel to give Intermediate Gen-8.

Reference： [1]Patent: WO2015/24905,2015,A1 .Location in patent: Paragraph 00235; 00355

79
[ 20885-12-5 ]
N-(5-acetyl-6-fluoro-2'-methyl-[2,3]bipyridinyl-5'-yl)-3,5-dimethoxy-benzamide [ No CAS ]

Reference： [1]Patent: US2015/80391,2015,A1

80
[ 20885-12-5 ]
[ 78191-00-1 ]
1-(6-chloro-2-fluoro-pyridin-3-yl)-ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: A solution of LDA is prepared by adding dropwise a 2.5 M butyllithium solution in hexane (1.1 to 1.2 eq.) to a solution of DIPA (1.07 to 1.2 eq.) in THF under nitrogen at a temperature comprised between -78 C. and -5 C. The reaction mixture is stirred 15 mm to 30 mm at the same temperature. Then Intermediate Gen-6-a (ito 1.2 eq.) in THF is added dropwise between -78 C. and -60 C., and the reaction is stirred under nitrogen at -78 C. for 1 h to 1.33 h. Then Intermediate Gen-7 (1.1 to 1.2 eq.) is added dropwise or portionwise by monitoring the temperature. The mixture is stirred 1.5 h to 3 h between -78C. and -70C. and quenched with a saturated aqueous NH4C1 solution. EtOAc is added, then the organic layer is separated, dried over Na2SO4, filtered and evaporated to dryness. The residue is purified by chromatography of silica gel to give Intermediate Gen-8.

Reference： [1]Patent: US2015/80391,2015,A1 .Location in patent: Paragraph 0474; 0475; 0670

81
[ 20885-12-5 ]
[ 3156-72-7 ]
6-chloro-2-fluoro-3-(1-nitropentan-2-yl)pyridine [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 4292 - 4295

82
[ 20885-12-5 ]
C₁₀H₁₁ClFNO [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 4292 - 4295

83
[ 20885-12-5 ]
6-chloro-1-(4-methoxyphenyl)-3-propyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 4292 - 4295

84
[ 20885-12-5 ]
1-(tert-butyl)-6-chloro-3-propyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 4292 - 4295

85
[ 20885-12-5 ]
1-benzyl-6-chloro-3-propyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 4292 - 4295

86
[ 20885-12-5 ]
6-chloro-1-(4-methoxyphenyl)-3-propyl-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 4292 - 4295

87
[ 20885-12-5 ]
1-benzyl-6-chloro-3-propyl-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 4292 - 4295

88
[ 20885-12-5 ]
1-(tert-butyl)-6-chloro-3-propyl-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 4292 - 4295

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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. 20885-12-5 ] {[proInfo.proName]}

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Calculated chemistry of [ 20885-12-5 ]

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[ 20885-12-5 ] Synthesis Path-Upstream 1~12

[ 20885-12-5 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 20885-12-5 ]

Fluorinated Building Blocks

Chlorides

Related Parent Nucleus of [ 20885-12-5 ]

Pyridines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 20885-12-5 ]

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[ 20885-12-5 ]