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[ CAS No. 179897-89-3 ] {[proInfo.proName]}

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Cat. No.: {[proInfo.prAm]}

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3d Animation Molecule Structure of 179897-89-3

Chemical Structure| 179897-89-3

Chemical Structure| 179897-89-3

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Quality Control of [ 179897-89-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 179897-89-3 ]

SDS Specification

Alternatived Products of [ 179897-89-3 ]

Product Details of [ 179897-89-3 ]

CAS No. :	179897-89-3	MDL No. :	MFCD00143424
Formula :	C₇H₃BrFN	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GYCNHFWRPJXTSB-UHFFFAOYSA-N
M.W :	200.01	Pubchem ID :	2724900
Synonyms :

Calculated chemistry of [ 179897-89-3 ]

Physicochemical Properties

Num. heavy atoms :	10
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 :	38.81
TPSA :	23.79 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) :	-5.79 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.93
Log Po/w (XLOGP3) :	2.43
Log Po/w (WLOGP) :	2.88
Log Po/w (MLOGP) :	2.63
Log Po/w (SILICOS-IT) :	2.9
Consensus Log Po/w :	2.55

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.05
Solubility :	0.176 mg/ml ; 0.000881 mol/l
Class :	Soluble
Log S (Ali) :	-2.57
Solubility :	0.535 mg/ml ; 0.00268 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.62
Solubility :	0.0481 mg/ml ; 0.00024 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.82

Safety of [ 179897-89-3 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312+P330-P302+P352+P312-P304+P340+P312-P305+P351+P338-P332+P313-P337+P313-P403+P233-P405-P501	UN#:	N/A
Hazard Statements:	H302+H312+H332-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 179897-89-3 ]

* 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 [ 179897-89-3 ]
Downstream synthetic route of [ 179897-89-3 ]

[ 179897-89-3 ] Synthesis Path-Upstream 1~18

1
[ 67-56-1 ]
[ 179897-89-3 ]
[ 127667-01-0 ]

Reference： [1] Organic Letters, 2013, vol. 15, # 15, p. 3998 - 4001

2
[ 67-56-1 ]
[ 179897-89-3 ]
[ 144649-99-0 ]

Reference： [1] Organic Letters, 2013, vol. 15, # 15, p. 3998 - 4001

3
[ 546-88-3 ]
[ 179897-89-3 ]
[ 177995-39-0 ]

Reference： [1] Patent: US9174994, 2015, B2, . Location in patent: Page/Page column 117

4
[ 202865-65-4 ]
[ 179897-89-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 1, p. 279 - 282

5
[ 201230-82-2 ]
[ 179897-89-3 ]
[ 171050-06-9 ]

Reference： [1] Tetrahedron Letters, 1997, vol. 38, # 18, p. 3131 - 3134

6
[ 920-39-8 ]
[ 179897-89-3 ]
[ 218301-22-5 ]

Reference： [1] Patent: WO2004/20414, 2004, A1, . Location in patent: Page 98-99

7
[ 97674-02-7 ]
[ 179897-89-3 ]
[ 288309-07-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In tolueneInert atmosphere; Reflux Stage #2: With hydrogenchloride; water In tetrahydrofuran at 20℃; for 4 h;	Example 27A 3-Acetyl-6-fluorobenzenecarbonitrile Under an argon atmosphere, 449 mg (0.490 mmol) of tris(dibenzylideneacetone)dipalladium and 671 mg (1.078 mmol) of rac-1,1'-binaphthalene-2,2'diylbis(diphenylphosphane) are added to 4.90 g (24.5 mmol) of 3-bromo-6-fluorobenzenecarbonitrile in 180 ml of toluene. After the addition of 10.6 g (29.4 mmol) of (1-ethoxyvinyl)tributylstannane, the mixture is stirred under reflux overnight. The reaction mixture is subsequently concentrated and the residue is taken up in 200 ml of THF. After the addition of an aqueous 2N hydrogen chloride solution (50 ml), the mixture is stirred at room temperature for 4 h. The reaction mixture is subsequently neutralized using a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 10:1→3:1). 3.50 g (88percent of theory) of the title compound are obtained. ¹H-NMR (400 MHz, DMSO-d₆): δ=8.55 (dd, 1H), 8.31 (ddd, 1H), 7.68 (t, 1H), 2.63 (s, 3H). GC-MS (Method 11): R_t=4.34 min; MS (EIpos): m/z=163 [M]⁺.

Reference： [1] Patent: US2013/45999, 2013, A1, . Location in patent: Paragraph 0247; 0248; 0249; 0250

8
[ 179897-89-3 ]
[ 288067-35-6 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium hydroxide; potassium acetate In ethyl acetate; acetonitrile	a 2-Hydroxyl-4-bromobenzonitrile A mixture of 2-fluoro-5-bromobenzonitrile (30 g, 152.3 mmole), potassium acetate (222.4 g, 228.5 mmole), and 18-crown-6 ether (60.4 g, 288.5 mmole) in MeCN (400 mL) was heated at reflux in 36 h. The mixture was cooled, added 2.5 N NaOH (200 mL), stirred at RT overnight. The mixture was extracted with ether (discarded). The aqueous layer was acidified with 6N HCl, extracted with EtOAc, dried over MgSO₄, concentrated, purified by flash column chromatography (40percent EtOAc/Hex) to give a light yellow foam (24.45 g, 81percent). ¹H-NMR (300 MHz, DMSO-d₆): δ7.13 (dd, J=1.7, 8.3 Hz, 1H), 7.17 (d, J=1.7 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H).

Reference： [1] Patent: US6417215, 2002, B1,

9
[ 67-56-1 ]
[ 201230-82-2 ]
[ 179897-89-3 ]
[ 676602-31-6 ]

Yield	Reaction Conditions	Operation in experiment
43%	With triethylamine; triphenylphosphine In acetonitrile at 60℃; for 96 h;	To CH3CN (100 mL) and MEOH (25 mL) in a sealed tube apparatus is added 5-bromo-2- fluorobenzonitrile (5.00 g, 25. 0 MMOL), TEA (6.97 mL, 50.0 mmol), palladium (II) acetate (393 mg, 1.75 mmol), and triphenylphosphine (269 mg, 1.03 mmol). The reaction is sealed, purged with carbon monoxide twice, and placed under 60 psi of carbon monoxide at 60 C for 4 d. Upon cooling, the reaction is filtered through diatomaceous earth, washing with MeOH. The filtrate is concentrated under reduced pressure, and the residue suspended in 4: 1 EtOAc/Hex (100 mL) then filtered. The filtrate is concentrated under reduced pressure then subjected to flash chromatography (silica gel, CHC13) to afford the sub-title compound (1.91 g, 43percent). 'H NMR (300 MHz, DMSO-d6) 8 3.87 (s, 3H), 7.66 (t, J= 9. 0 Hz, 1H), 8.30 (ddd, J = 2.2, 5.3, 8.6 Hz, 1H), 8.43 (dd, J = 2.2, 6.3 Hz, 1H). FAB MS nez 154 [C9H6FN02 + H-HCN] +, 136 [C9H6FN02 + H-CO2]-

Reference： [1] Patent: WO2004/67529, 2004, A1, . Location in patent: Page 193 - 194

10
[ 179897-89-3 ]
[ 57260-71-6 ]
[ 791846-40-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine In dimethyl sulfoxide at 100℃;	In a pressure tube, 5-bromo-2-fluorobenzonitrile (2500 mg, 12.5 mmol), tert-butyl piperazine-1-carboxylate (2444.45 mg, 13.12 mmol), triethylamine (5.23 ml, 37.5 mmol) in dimethylsulfoxide (10 ml) were combined and refluxed at 100 C for ovn. The mixture was cooled, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried using sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel 5-60percent ethyl acetate/hexane to provide a light brown oil, tert-butyl 4-(4-bromo-2-cyanophenyl)piperazine-1-carboxylate (3660 mg, 80percent).
44%	With caesium carbonate In dimethyl sulfoxide at 120℃; for 1 h;	A mixture of 1—15 (3.0 g, 14.99 mmcl), 1-Boc-piperizine(3.33 g, 17.99 mmcl) and Cs2003 (9.68 g, 29.98 mci) in DMSO(60 ml) was stirred at 12000 for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with diethyl ether (100 ml x 3) . The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give thedesired product 1—16 (2.5 g, 44percent) as yellow solid which wasused in the next step without purification; LCMS: m/z 312 [MtBu+1]

Reference： [1] Patent: KR2016/37198, 2016, A, . Location in patent: Paragraph 2392-2394
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 20, p. 5095 - 5098
[3] Patent: WO2017/38909, 2017, A1, . Location in patent: Paragraph 0290; 0291
[4] Patent: WO2009/79593, 2009, A1, . Location in patent: Page/Page column 120

11
[ 5419-55-6 ]
[ 179897-89-3 ]
[ 214210-21-6 ]

Reference： [1] Patent: US6300352, 2001, B1,

12
[ 179897-89-3 ]
[ 214210-21-6 ]

Reference： [1] Patent: WO2006/45350, 2006, A1, . Location in patent: Page/Page column 62-63

13
[ 179897-89-3 ]
[ 73183-34-3 ]
[ 214210-21-6 ]

Reference： [1] Patent: US6339099, 2002, B1, . Location in patent: Page column 83-86

14
[ 179897-89-3 ]
[ 73183-34-3 ]
[ 775351-57-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In 1,4-dioxane; dichloromethane; N,N-dimethyl-formamide at 100℃; Sealed tube	2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile A mixture of 5-Bromo-2-fluoro-benzonitrile (1000.00 mg; 5.00 mmol; 1.00 eq.), 4,4,5,5,4',4',5',5'-Octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (1396.61 mg; 5.50 mmol; 1.10 eq.), potassium acetate (1472.07 mg; 15.00 mmol; 3.00 eq.) in dioxane (10 mL) and DMf (1 mL) was degassed, then [1,1']-bis(diphenyl phosphino) ferrocene]dichloropalladium(II), complex with dichloromethane(1:) (366.85 mg; 0.50 mmol; 0.10 eq.) was added and the sealed vial was heated at 100° C. for overnight. The reaction mixture was cooled and filtered through a pad of Celite. The solvent was removed and the crude product was purified through flash chromatography on silica gel (EtOAc:hexanes from 0percent to 5percent) to obtain 2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (1.0 g, 81percent)
72%	With potassium acetate In 1,4-dioxane at 100℃; Inert atmosphere	6(pinacolato)diboron (1.9 g, 7.48 mmol), and KOAc (1.47 g, 14.98 mmol) in 1,4- dioxane (10.0 mL) that was degassed with argon for 10 min was added PdCl2(dppf) (10 mg, 0.014 mmol). The reaction mixture was heated to 100 ⁰C overnight. The reaction mixture was filtered through Celite 521^.(R). and rinsed through with EtOAc (10 mL). The filtrate was concentrated in vacuo and treated with CH₂Cl₂ (10 mL) and water (10 mL). The layers were separated, and the aqueous layer was extracted with CH₂Cl₂ (5 mL). The combined organic layers were washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo onto Isolute^.(R).. Purification via flash column chromatography (0- 20percent EtOAc/hexanes) afforded the title compound (1.03 g, 72percent). LC-MS m/z 248 (M+H)⁺, 1.15 min (ret time).

Reference： [1] Patent: US2016/376283, 2016, A1, . Location in patent: Paragraph 0504; 0505; 0506
[2] Patent: WO2011/25799, 2011, A1, . Location in patent: Page/Page column 50
[3] Organic Letters, 2004, vol. 6, # 19, p. 3265 - 3268

15
[ 179897-89-3 ]
[ 105-34-0 ]
[ 925672-89-5 ]

Reference： [1] Tetrahedron Letters, 2007, vol. 48, # 3, p. 487 - 489

16
[ 546-88-3 ]
[ 179897-89-3 ]
[ 455280-00-9 ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 30℃; Stage #3: With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide	The title compound was prepared by a modification of the literature procedure as described in Palermo, M. G., Tetrahedron Lett, 37:2885 (1996). A single neck 50 mL flask equipped with a magnetic stirred was charged with N-hydroxyacetamide (2.63 g, 35.0 mmol) and DMF (100 mL). Then, KOtBu (3.93 g, 35.0 mmol) was added in one portion. The temperature rose to 30⁰C. The mixture was stirred for Ih and, 5-bromo~2-fluorobenzonitrile (7 g, 35.0 mmol) was added. The reaction mixture was stirred for overnight. A further portion of KOtBu (1.96 g, 17.5mmo) was added and the solution was again stirred overnight. The mixture was poured into brine and CH2CI2 and the layers were separated. The organic phase was dried (Na₂SO₄) and concentrated in vacuo. The residue was purified by flash column chromatography (BIOTAGE.(R)., eluting with a gradient of 0 to 40percent EtOAc in hexanes) to afford the title compound (4.59 g, 62percent) as a colorless solid. ¹H NMR (500 MHz, DMSOd₆) δ 8.09 (d, J = 1.8 HZ, IH), 7.65 (dd, J = 2.1, 8.9 Hz, IH), 7.45 (d, J = 8.9 Hz₅ IH), 6.49 (s, 2H). LCMS: Anal. Calcd. for C₇H₅BrN₂O: 211₅ 213; found: 212, 214 (M+H)⁺.

Reference： [1] Patent: WO2010/138488, 2010, A1, . Location in patent: Page/Page column 57-58
[2] Patent: WO2010/51042, 2010, A1, . Location in patent: Page/Page column 134
[3] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00502
[4] Patent: US2014/357651, 2014, A1, . Location in patent: Paragraph 0485

17
[ 179897-89-3 ]
[ 455280-00-9 ]

Reference： [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 18, p. 7624 - 7643
[2] Patent: WO2006/122799, 2006, A1, . Location in patent: Page/Page column 60-61
[3] ACS Medicinal Chemistry Letters, 2016, vol. 7, # 3, p. 277 - 282

18
[ 61260-15-9 ]
[ 179897-89-3 ]
[ 763114-25-6 ]

Reference： [1] Patent: CN106905243, 2017, A, . Location in patent: Paragraph 0062; 0063

[ 179897-89-3 ] Synthesis Path-Downstream 1~70

1
[ 201230-82-2 ]
[ 179897-89-3 ]
[ 171050-06-9 ]

Reference： [1]Tetrahedron Letters,1997,vol. 38,p. 3131 - 3134

2
[ 179897-89-3 ]
[ 286961-15-7 ]
4-(3-cyano-4-fluoro-phenyl)-3,6-dihydro-2<i>H</i>-pyridine-1-carboxylic acid benzyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,2000,vol. 41,p. 3705 - 3708

3
[ 179897-89-3 ]
[ 57260-71-6 ]
[ 791846-40-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triethylamine; In dimethyl sulfoxide; at 100℃;	In a pressure tube, 5-bromo-2-fluorobenzonitrile (2500 mg, 12.5 mmol), tert-butyl piperazine-1-carboxylate (2444.45 mg, 13.12 mmol), triethylamine (5.23 ml, 37.5 mmol) in dimethylsulfoxide (10 ml) were combined and refluxed at 100 C for ovn. The mixture was cooled, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried using sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel 5-60% ethyl acetate/hexane to provide a light brown oil, tert-butyl 4-(4-bromo-2-cyanophenyl)piperazine-1-carboxylate (3660 mg, 80%).
44%	With caesium carbonate; In dimethyl sulfoxide; at 120℃; for 1h;	A mixture of 1-15 (3.0 g, 14.99 mmcl), 1-Boc-piperizine(3.33 g, 17.99 mmcl) and Cs2003 (9.68 g, 29.98 mci) in DMSO(60 ml) was stirred at 12000 for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with diethyl ether (100 ml x 3) . The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give thedesired product 1-16 (2.5 g, 44%) as yellow solid which wasused in the next step without purification; LCMS: m/z 312 [MtBu+1]
	With sodium carbonate; In N,N-dimethyl-formamide; at 100℃; for 24h;	STEP A: 4-(4-Bromo-2-cvano-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. A mixture of 5-bromo-2-fluoro-benzonitrile (1.05g), piperazine-1 -carboxylic acid tert-butyl ester (1.08g) and Na2CO3 (1.03g) in DMF was heated to 1000C for 24h. The resulting mixture was cooled, diluted with water (50 ml_) and extracted with diethyl ether. The resulting mixture was dried over MgSO4, the solvent was removed and the resulting residue purified on SiO2 (hexanes/ EtOAc 0 to 25%) to yield the title compound.

Reference： [1]Patent: KR2016/37198,2016,A .Location in patent: Paragraph 2392-2394
[2]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5095 - 5098
[3]Patent: WO2017/38909,2017,A1 .Location in patent: Paragraph 0290; 0291
[4]Patent: WO2009/79593,2009,A1 .Location in patent: Page/Page column 120

4
[ 179897-89-3 ]
[ 73183-34-3 ]
[ 775351-57-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; dichloromethane; N,N-dimethyl-formamide; at 100.0℃;Sealed tube;	2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile A mixture of 5-Bromo-2-fluoro-benzonitrile (1000.00 mg; 5.00 mmol; 1.00 eq.), 4,4,5,5,4',4',5',5'-Octamethyl-[2,2']bi[[1,3,2]dioxaborolanyl] (1396.61 mg; 5.50 mmol; 1.10 eq.), potassium acetate (1472.07 mg; 15.00 mmol; 3.00 eq.) in dioxane (10 mL) and DMf (1 mL) was degassed, then [1,1']-bis(diphenyl phosphino) ferrocene]dichloropalladium(II), complex with dichloromethane(1:) (366.85 mg; 0.50 mmol; 0.10 eq.) was added and the sealed vial was heated at 100 C. for overnight. The reaction mixture was cooled and filtered through a pad of Celite. The solvent was removed and the crude product was purified through flash chromatography on silica gel (EtOAc:hexanes from 0% to 5%) to obtain 2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (1.0 g, 81%)
72%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 100.0℃;Inert atmosphere;	6(pinacolato)diboron (1.9 g, 7.48 mmol), and KOAc (1.47 g, 14.98 mmol) in 1,4- dioxane (10.0 mL) that was degassed with argon for 10 min was added PdCl2(dppf) (10 mg, 0.014 mmol). The reaction mixture was heated to 100 0C overnight. The reaction mixture was filtered through Celite 521 and rinsed through with EtOAc (10 mL). The filtrate was concentrated in vacuo and treated with CH2Cl2 (10 mL) and water (10 mL). The layers were separated, and the aqueous layer was extracted with CH2Cl2 (5 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo onto Isolute. Purification via flash column chromatography (0- 20% EtOAc/hexanes) afforded the title compound (1.03 g, 72%). LC-MS m/z 248 (M+H)+, 1.15 min (ret time).

Reference： [1]Patent: US2016/376283,2016,A1 .Location in patent: Paragraph 0504; 0505; 0506
[2]Patent: WO2011/25799,2011,A1 .Location in patent: Page/Page column 50
[3]Chemistry - An Asian Journal,2019,vol. 14,p. 2251 - 2258
[4]Organic Letters,2004,vol. 6,p. 3265 - 3268

5
[ 179897-89-3 ]
[ 105-34-0 ]
[ 925672-89-5 ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 487 - 489
[2]Chemistry - An Asian Journal,2020,vol. 15,p. 106 - 111

6
[ 179897-89-3 ]
[ 925672-86-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: NaH / dimethylsulfoxide / 0.5 h / 20 °C 1.2: dimethylsulfoxide / 90 °C 1.3: 81 percent / H₂O / dimethylsulfoxide / Heating 2.1: 73 percent / HBr; dichloroacetic acid / 0 - 20 °C

Reference： [1]Frohn, Mike; Bürli, Roland W.; Riahi, Bobby; Hungate, Randall W. [Tetrahedron Letters, 2007, vol. 48, # 3, p. 487 - 489]

7
[ 179897-89-3 ]
[ 1009303-56-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: 22 percent / KOAc; Pd(dppf)Cl₂ / dimethylformamide / 0.17 h / 150 °C / Irradiation; microwave 2.1: TMSN₃; Bu₂Sn(O) / dimethyl ether / 0.33 h / 150 °C / Irradiation 2.2: 85 percent / NaOH / H₂O

Reference： [1]Schulz, Mark J.; Coats, Steven J.; Hlasta, Dennis J. [Organic Letters, 2004, vol. 6, # 19, p. 3265 - 3268]

8
[ 179897-89-3 ]
[ 73183-34-3 ]
[ 214210-21-6 ]

Reference： [1]Patent: US6339099,2002,B1 .Location in patent: Page column 83-86

9
[ 67-56-1 ]
[ 201230-82-2 ]
[ 179897-89-3 ]
[ 676602-31-6 ]

Yield	Reaction Conditions	Operation in experiment
43%	With triethylamine; triphenylphosphine;palladium diacetate; In acetonitrile; at 60℃; under 3102.97 Torr; for 96h;	To CH3CN (100 mL) and MEOH (25 mL) in a sealed tube apparatus is added 5-bromo-2- fluorobenzonitrile (5.00 g, 25. 0 MMOL), TEA (6.97 mL, 50.0 mmol), palladium (II) acetate (393 mg, 1.75 mmol), and triphenylphosphine (269 mg, 1.03 mmol). The reaction is sealed, purged with carbon monoxide twice, and placed under 60 psi of carbon monoxide at 60 C for 4 d. Upon cooling, the reaction is filtered through diatomaceous earth, washing with MeOH. The filtrate is concentrated under reduced pressure, and the residue suspended in 4: 1 EtOAc/Hex (100 mL) then filtered. The filtrate is concentrated under reduced pressure then subjected to flash chromatography (silica gel, CHC13) to afford the sub-title compound (1.91 g, 43%). 'H NMR (300 MHz, DMSO-d6) 8 3.87 (s, 3H), 7.66 (t, J= 9. 0 Hz, 1H), 8.30 (ddd, J = 2.2, 5.3, 8.6 Hz, 1H), 8.43 (dd, J = 2.2, 6.3 Hz, 1H). FAB MS nez 154 [C9H6FN02 + H-HCN] +, 136 [C9H6FN02 + H-CO2]-

Reference： [1]Patent: WO2004/67529,2004,A1 .Location in patent: Page 193 - 194

10
[ 822-36-6 ]
[ 179897-89-3 ]
[ 870837-41-5 ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium carbonate In dimethyl sulfoxide at 90℃; for 16h;	84.a a) 5-Bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile A mixture of 5-bromo-2-fluorobenzonitrile (25.0 g, 125 mmol), 4-methylimidazole (12.5 g, 152 mmol), potassium carbonate (34.55 g, 250 mmol) in DMSO (500 mL) was stirred at 90° C. for 16 h. Water (1.5 L) was added and the resulting suspension was stirred with ice-bath cooling for 1 h. The precipitate was then filtered off, washed with water (0.5 L) and dried at 50° C. over KOH. The resulting raw material (25.6 g) was dissolved in boiling ethyl acetate (300 mL). After addition of diisopropylether (300 mL) the solution was allowed to cool to room temperature. Filtration and drying afforded the title compound (19.35 g, 59%) as a white solid. Mp 166° C.
59%	With potassium carbonate In dimethyl sulfoxide at 90℃; for 16h;	5.a a) 5-Bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile A mixture of 5-bromo-2-fluoro-benzonitrile (25.0 g, 125 mmol), 4-methylimidazole (12.5 g, 152 mmol), potassium carbonate (34.55 g, 250 mmol) in DMSO (500 mL) was stirred at 90° C. for 16 h. Water (1.5 L) was added and the resulting suspension was stirred with ice-bath cooling for 1 h. The precipitate was filtered, washed with water (0.5 L) and dried at 50° C. over KOH. The resulting raw material (25.6 g) was dissolved in boiling Ethyl acetate (300 ml). After addition of diisopropylether (300 ml) the solution was allowed to cool to room temperature. Filtration and drying afforded the title compound (19.35 g, 59%) as a white solid. Mp 166° C.
	With potassium carbonate In dimethyl sulfoxide at 90℃;

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2007/82890, 2007, A1 Location in patent: Page/Page column 30
[2]Current Patent Assignee: ROCHE HOLDING AG - US2006/128691, 2006, A1 Location in patent: Page/Page column 16-17
[3]Location in patent: scheme or table Buettelmann, Bernd; Ballard, Theresa M.; Gasser, Rodolfo; Fischer, Holger; Hernandez, Maria-Clemencia; Knoflach, Frederic; Knust, Henner; Stadler, Heinz; Thomas, Andrew W.; Trube, Gerhard [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 20, p. 5958 - 5961]

11
[ 179897-89-3 ]
[ 61272-71-7 ]

Yield	Reaction Conditions	Operation in experiment
99.5%	With hydrazine; at 100℃; for 0.08333330000000001h;	To a 250 mL round-bottom flask was added 5-bromo-2-fluorobenzonitrile (15.54 g, 77.7 mmol) and hydrazine (124 g, 3885 mmol). The reaction mixture was heated to 100 C. for 5 minutes. The hydrazine was then removed under reduced pressure to give 5-bromo-1H-indazol-3-amine (16.4 g, 99.5% yield). MS m/z: 213 (M+1).
91%	With hydrazine; at 20℃; for 1200.0h;Heating / reflux;	A mixture of 5-bromo-2-fluorobenzonitrile (5.00 g, 25 mmol) and hydrazine hydrate (10 mL) was heated at reflux for two hours and then it was allowed to stand at room temperature for two days. The reaction was treated with water (50 mL) and the solids were collected by filtration to give 3-Amino-5-bromo-indazole as a white solid (4.82 g, 91%): mp 165-175 C.; MS [M+H]+ 212, 214.
91%	With ethanol; hydrazine; at 20℃; for 4.0h;Heating / reflux;	Example 7: 5-Brorno-N-l,3-thiazol-2-yl-lH-indazol-3-amne <n="89"/>SCN[0275] Hydrazine monohydrate (2.6 mL, 52.5 mmol) was added to a solution of 5-bromo- 2-fluorobenzonitrile (3.50 g, 17.5 mmol) in ethanol (50 mL) at room temperature. The mixture was stirred for 4 h under reflux condition. After cooling, the mixture was diluted with EtOAc (300 mL), washed with H2O and brine, dried (MgSO4), filtered, and concentrated in vacuo. Purification by recrystallization (EtOAc-hexane) gave 3.37g (91%) of 5-bromo- lH-indazol-3-amine (compound 7A) as a white solid. 1H NMR (300 MHz, CDCl3) delta 4.07 (brs, 2 H) 7.20 (d, IH77=8.85 Hz) 7.42 (dd, IH, J=8.85, 1.70 Hz) 7.71 (d, IH, 7=1.51 Hz) 8.98 (brs, 1 H). MS (ES) [m+H] calc'd for C7H6BrN^, 213; found 211, 213. [0276] Ammonium thiocyanate (229 mg, 3 mmol) was added to a suspension of 5-bromo- lH-indazol-3-amine (212 mg, 1 mmol) in IN hydrochloric acid (3 mL). The mixture was stirred for 4 days at 1000C. The precipitate was collected, and washed with eta2O to give 231 mg (85%) of N-(5-bromo-lH-indazol-3-yI)thiourea (compound 7B) as a yellow solid. 1H NMR (300 MHz, DMSO-rf6) delta 7.43 (d, IH, 7=8.85 Hz) 7.50 (dd, IH, 7=8.85, 1.88 Hz) 8.49 (d, IH, 7=1.32 Hz) 8.79 (brs, IH) 9.18 (brs, IH) 10.85 (s, IH) 12.86 (s, IH). MS (ES) [m+H] calc'd for C8H7BrN4S, 272; found 270, 272.[0277] To a stirred solution of N-(5-bromo-lH-indazol-3-yl)thiourea (104 mg, 0.38 mmol) in ethanol (2 mL) and H2O (1 mL) was added 1 ,2-dichloroethyl ethyl ether (0.05 mL, 0.41 mmol) at room temperature. The mixture was stirred for 3 h at 8O0C. After dilution with EtOAc, the organic layer was washed with H2O and brine, dried (MgSO4), filtered, and concentrated in vacuo. Crystallization from EtOAc-diisopropyl ether gave 62.7 mg (55%) of 5-Bromo-N-l,3-thiazol-2-yl-lH-indazol-3-amine (compound 7) as a white solid. 1H NMR (300 MHz, DMSO-^6) delta 7.01 (d, IH, 7=3.58 Hz) 7.36 (d, IH, 7=3.58 Hz) 7.37 - 7.42 (m, IH) 7.44 - 7.49 (m, IH) 8.35 (d, IH, 7=1.32 Hz) 11.34 (brs, IH) 12.53 (s, IH). MS (ES) [m+H] calc'd for C10H7BrN4S, 296; found 294, 296.

	With hydrazine; at 140℃; for 0.333333h;Microwave heating;	Preparation of 3-amino-5-bromoindazole 165.; Scheme 25To a solution of 5-bromo-2-fluorobenzonitrile (0.40 g, 2.0 mmol.) in ethanol (3 mL) was added hydrazine (0.64 g, 20 mmol.). The reaction mixture was heated in a microwave reactor at 1400C for 20 minutes. Ethyl acetate (100 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to yield 3-amino-5-bromoindazole 165 (0.41 g, 1.93 mmol.). The crude product was used in the next step without further purification.
		Example 256A 5-Bromo-1H-indazol-3-ylamine The desired product was prepared by substituting 5-bromo-2-fluorobenzonitrile for 5-bromo-2-fluorobenzaldehyde in Example 35A.
5.3 g	With hydrazine hydrate; In ethanol; at 90℃; for 12.0h;	At room temperature,to2-Fluoro-5-bromobenzonitrile (5.0 g)Soluble in ethanol (30mL)80% hydrated hydrazine (7.82g) was added to the solution.After refluxing at 90 C. for 12 h, the reaction solution was cooled to room temperature.Concentrate under reduced pressure to remove the ethanol.The residue was slurried with dichloromethane for 1 h.Filter, wash with dichloromethane, dry,The title compound (5.3 g) was obtained.

Reference： [1]Patent: US2007/173506,2007,A1 .Location in patent: Page/Page column 47
[2]Patent: US2008/153813,2008,A1 .Location in patent: Page/Page column 21
[3]Patent: WO2007/75847,2007,A2 .Location in patent: Page/Page column 87-88
[4]Patent: WO2006/81230,2006,A2 .Location in patent: Page/Page column 91
[5]Patent: US2003/187026,2003,A1
[6]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 279 - 282
[7]Patent: CN108003161,2018,A .Location in patent: Paragraph 0447; 0449-0451

12
[ 179897-89-3 ]
[ 288067-35-6 ]

Yield	Reaction Conditions	Operation in experiment
81%	With sodium hydroxide; potassium acetate;18-crown-6 ether; In ethyl acetate; acetonitrile;	a 2-Hydroxyl-4-bromobenzonitrile A mixture of 2-fluoro-5-bromobenzonitrile (30 g, 152.3 mmole), potassium acetate (222.4 g, 228.5 mmole), and 18-crown-6 ether (60.4 g, 288.5 mmole) in MeCN (400 mL) was heated at reflux in 36 h. The mixture was cooled, added 2.5 N NaOH (200 mL), stirred at RT overnight. The mixture was extracted with ether (discarded). The aqueous layer was acidified with 6N HCl, extracted with EtOAc, dried over MgSO4, concentrated, purified by flash column chromatography (40% EtOAc/Hex) to give a light yellow foam (24.45 g, 81%). 1H-NMR (300 MHz, DMSO-d6): delta7.13 (dd, J=1.7, 8.3 Hz, 1H), 7.17 (d, J=1.7 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H).

Reference： [1]Patent: US6417215,2002,B1

13
[ 5419-55-6 ]
[ 179897-89-3 ]
[ 214210-21-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; n-butyllithium; In tetrahydrofuran; diethyl ether; hexane;	EXAMPLE 86 3-Cyano-4-fluorobenzeneboronic Acid A solution of n-butyllithium (5.6 ml, 2.5M in hexanes) was added over a 20 minute period to a solution of 5-bromo-2-fluorobenzonitrile and triisopropylborate (3.46 ml) in tetrahydrofuran (10 ml) at -78 C. The resulting solution was stirred at -78 C. for 30 minutes and then quenched by the addition of a 2M hydrochloric acid (20 ml) and extracted into ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by trituration using diethyl ether: hexane 1:2 to afford the sub-title compound as a solid (1.24 g). m.p.>250 C. MS (APCI -ve) 164 (M-H)- 1H NMR (DMSO/D2O) 8.20 (1H, dd); 8.16-8.12 (1H, m); 7.53-7.49 (1H, m).

Reference： [1]Patent: US6300352,2001,B1

14
[ 179897-89-3 ]
[ 214210-21-6 ]

Reference： [1]Patent: WO2006/45350,2006,A1 .Location in patent: Page/Page column 62-63

15
[ 179897-89-3 ]
[ 455280-00-9 ]

Yield	Reaction Conditions	Operation in experiment
62%	With acetylhydroxamic acid; potassium tert-butylate; In N,N-dimethyl-formamide;	A-hydroxyacetamide (2.63 g, 35.0 mmol) was dissolved in DMF (100 mL), and then /-BuOK (3.93 g, 35.0 mmol) was added in one portion. The temperature rose to 30C. The mixture was stirred for lh, and 5-bromo-2-fluorobenzonitrile (7 g, 35.0 mmol) was added. The reaction mixture was stirred for overnight. An additional portion of /-BuOK (1.96 g, l7.5mmo) was added and the reaction was allowed to stir overnight. The mixture was poured into brine and CH2CI2 and the layers were separated. The organic phase was dried over MgS04 and concentrated in vacuo. The residue was purified by flash column chromatography using EtO Ac/Hexane (1/2) to afford the Compound 122 ( 5 - Brom obcn zo [ d] i soxazo - 3 -am i n c ) (4.59 g, 62%) as a white-off solid.

Reference： [1]Patent: WO2019/108943,2019,A1 .Location in patent: Paragraph 0280; 0352-0354
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 7624 - 7643
[3]Patent: WO2006/122799,2006,A1 .Location in patent: Page/Page column 60-61
[4]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 277 - 282

16
[ 84110-40-7 ]
[ 179897-89-3 ]
[ 676137-86-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; toluene; at 20 - 80℃;	Example 29: 5-Isobutyl-N-l,3-thiazol-2-yl-lH-indazol-3-amine[0344] To a stirred solution of 5-bromo-2-fluorobenzonitrile (1.00 g, 5.0 mmol) in toluene (12 mL) and THF (8 ml) were added potassium carbonate (2.07 g, 15 mmol), isobutyl boronic acid (0.77 g, 7.5 mmol), and tetrakis(triphenylphosphine)palladium (289 mg, 0.25 mmol) under nitrogen atmosphere at room temperature. The mixture was stirred at 800C overnight. After cooling, the mixture was diluted with EtOAc, washed with H2O and brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude oil was passed through a short SiO2 pad (NH-SiO2, EtOAc), and the elution fraction was concentrated in vacuo to give crude product (compound 29A), which was used for the next step without further purification. [0345] To a stirred solution of the crude product of compond 29A in n-BuOH (20 mL) was added hydrazine monohydrate (0.73 mL, 15 mmol) at room temperature. The mixture was stirred under reflux condition overnight, and concentrated in vacuo. The mixture was diluted with EtOAc-THF, washed with H2O and brine, dried (MgSO4), filtered, and concentrated in vacuo to give the crude product of compound 29B, which was used for the next step without further purification.[0346] To a solution of the crude product of compound 29B in THF (20 mL) was added l ,l'-thiocarbonyldi-2(lH)-pyridone (920 mg, 3.95 mmol) at 00C, and the reaction was stirred for 1 h at 00C. Aqueous ammonia (28%, 5 mL) was added to the mixture, and the reaction mixture was stirred for 1 h at room temperature. After dilution with EtOAc, the organic layer was washed with H2O and brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude product (N-(5-isobutyl-lH-indazol-3-yl)thiourea; compound 29C) was passed through <n="114"/>a short SiO2 pad (EtOAc), and concentrated in vacuo. Prification by preparative HPLC gave 97.4 mg (7.8% in 3 steps) of compound 29C as a colorless solid. 1H NMR (300 MHz, DMSO-J6) delta 0.88 (d, 6H, 7=6.44 Hz) 1.75 - 1.95 (m, IH) 2.52 (d, 2H, 7=3.79 Hz) 7.21 (dd, IH, 7=8.71, 1.51 Hz) 7.34 (d, IH, 7=8.71 Hz) 7.98 (s, IH) 8.68 (brs, IH) 9.25 (brs, IH) 10.76 (s, IH) 12.53 (s, IH). MS (ES) [m+H] calc'd for C12Hi6N4S, 249; found 249. [0347] To a stirred solution of N-(5-isobutyl-lH-indazol-3-yl)thiourea (compound 29C; 97.4 mg, 0.392 mmol) in ethanol (3 mL) and IN HCl (1 mL) was added bromoacetaldehyde diethyl acetal (0.097 mL, 0.784 mmol) at room temperature. The mixture was stirred for 2 h at 800C, dilution with EtOAc, washed with saturated aqueous NaHCO3, H2O, and brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude oil was passed through a short Sitheta2 pad (NH-SiO2, EtOAc), concentrated in vacuo. Purification by recrystallization (EtOAc- diisopropylether) gave 24.9 mg (23%) of the title compound as a colorless solid. 1H NMR (300 MHz, DMSO-J6) delta 0.89 (d, 6H, 7=6.59 Hz) 1.75 - 1.97 (m, IH) 2.53 (d, 2H, 7=6.97 Hz) 6.97 (d, IH, 7=3.58 Hz) 7.18 (dd, IH, 7=8.57, 1.41 Hz) 7.31 (d, IH, 7=8.48 Hz) 7.34 (d, IH, 7=3.58 Hz) 7.86 (s, IH) 1 1.20 (s, IH) 12.20 (s, IH). MS (ES) [m+H] calc'd for C14H16N4S, 273; found 273.

Reference： [1]Patent: WO2007/75847,2007,A2 .Location in patent: Page/Page column 112-113

17
[ 2365-48-2 ]
[ 179897-89-3 ]
[ 1036380-75-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	Stage #1: Methyl thioglycolate; 5-Bromo-2-fluoro-benzonitrile In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: With sodium hydroxide; water In N,N-dimethyl-formamide at 0℃; for 3h;	1.1A EXAMPLE 1A methyl 3-amino-5-bromobenzo[b]thiophene-2-carboxylate To a solution of 5-bromo-2-fluorobenzonitrile (13.5 g, 67.5 mmol) in N,N-dimethylformamide at 0° C. was added methyl 2-mercaptoacetate (6.45 mL, 70.88 mmol). The mixture was stirred at 0° C. for 30 minutes and 5N sodium hydroxide (20.25 mL) added. After stirring at 0° C. for 3 hours, the mixture was quenched with ice-water and the resulting precipitate collected by filtration and dried to give 18.5 g (96%) of a white solid. LCMS (APCI) m/z: 287 (M+H)+.
96%	Stage #1: Methyl thioglycolate; 5-Bromo-2-fluoro-benzonitrile In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: With sodium hydroxide; water In N,N-dimethyl-formamide at 0℃; for 3h;	1.1A EXAMPLE 1A methyl 3-amino-5-bromobenzo[b]thiophene-2-carboxylate To a solution of 5-bromo-2-fluorobenzonitrile (13.5 g, 67.5 mmol) in N,N-dimethylformamide at 0° C. was added methyl 2-mercaptoacetate (6.45 mL, 70.88 mmol). The mixture was stirred at 0° C. for 30 minutes and 5N sodium hydroxide (20.25 mL) added. After stirring at 0° C. for 3 hours, the mixture was quenched with ice-water and the resulting precipitate collected by filtration and dried to give 18.5 g (96%) of a white solid. LCMS (APCI) m/z: 287 (M+H)+.
96%	Stage #1: Methyl thioglycolate; 5-Bromo-2-fluoro-benzonitrile In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide at 0℃; for 3h; Inert atmosphere;

96%	With triethylamine In dimethyl sulfoxide at 130℃; for 0.183333h; Microwave irradiation;
92%	Stage #1: Methyl thioglycolate; 5-Bromo-2-fluoro-benzonitrile In N,N-dimethyl-formamide at 0℃; for 0.5h; Stage #2: With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0 - 20℃; for 3.75h;	12 Scheme 11.1 To a cold solution of 5-bromo-2-fluorobenzonitrile (7.43 g, 37.15 mmol) in DMF at 0°C was added dropwise methyl 2-mercaptoacetate (6.65 mL, 74.3 mmol). The reaction mixture was stirred at 0°C for 30 minutes, and then potassium tert- butoxide (8.4 g, 74.5 mmol) was added over 15 minutes with vigorous stirring. After stirring at 0°C for 0.5 hour, allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was quenched with ice-water. The resulting precipitate was collected by filtration and dried to give 9.8 g of white solid of Compound 83 (methyl 3-amino-5-bromobenzo[b]thiophene-2-carboxylate) in 92% yield.
	With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide
	With potassium hydroxide In N,N-dimethyl-formamide at 0 - 20℃; for 3h;

Reference： [1]Current Patent Assignee: ABBVIE INC - US2008/161559, 2008, A1 Location in patent: Page/Page column 8
[2]Current Patent Assignee: ABBOTT LABORATORIES INC - US2008/161578, 2008, A1 Location in patent: Page/Page column 9
[3]Location in patent: experimental part Tao, Zhi-Fu; Hasvold, Lisa A.; Leverson, Joel D.; Han, Edward K.; Guan, Ran; Johnson, Eric F.; Stoll, Vincent S.; Stewart, Kent D.; Stamper, Geoff; Soni, Nirupama; Bouska, Jennifer J.; Luo, Yan; Sowin, Thomas J.; Lin, Nan-Horng; Giranda, Vincent S.; Rosenberg, Saul H.; Penning, Thomas D. [Journal of Medicinal Chemistry, 2009, vol. 52, # 21, p. 6621 - 6636]
[4]Bagley, Mark C.; Dwyer, Jessica E.; Molina, Maria D. Beltran; Rand, Alexander W.; Rand, Hayley L.; Tomkinson, Nicholas C. O. [Organic and Biomolecular Chemistry, 2015, vol. 13, # 24, p. 6814 - 6824]
[5]Current Patent Assignee: TAIWANJ PHARMACEUTICALS CO LTD - WO2019/108943, 2019, A1 Location in patent: Paragraph 0280; 0281; 0283; 0284
[6]Location in patent: scheme or table Savall, Brad M.; Gomez, Laurent; Chavez, Frank; Curtis, Michael; Meduna, Steven P.; Kearney, Aaron; Dunford, Paul; Cowden, Jeffery; Thurmond, Robin L.; Grice, Cheryl; Edwards, James P. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 21, p. 6577 - 6581]
[7]Ekambaram, Ramesh; Enkvist, Erki; Vaasa, Angela; Kasari, Marje; Raidaru, Gerda; Knapp, Stefan; Uri, Asko [ChemMedChem, 2013, vol. 8, # 6, p. 909 - 913]

18
[ 761446-45-1 ]
[ 179897-89-3 ]
[ 1093307-32-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 110℃;	5-Bromo-2-fluorobenzonitrile (484 mg, 2.42 mmol), l-benzyl-4-(4,4,5,5-tetramethyl- <n="150"/>l,3,2-dioxaborolan-2-yl)-lH-pyrazole (736 mg, 2.59 mmol), dichlorobis(triphenylphosphine)palladium(II) (174 mg, 0.248 mmol), and potassium carbonate (1.36 g, 9.84 mmol) were combined in a sealed vial with dioxane (10 mL) and water (1 mL) under an inert atmosphere of nitrogen, and the mixture was heated to 1100C overnight. The mixture was diluted with methylene chloride and washed with water. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 10-50% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 290.0 (M+H)+

Reference： [1]Patent: WO2008/154241,2008,A1 .Location in patent: Page/Page column 148-149

19
[ 179897-89-3 ]
[ 190656-34-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With lithium borohydride; diisopropopylaminoborane In tetrahydrofuran at 25℃; for 5h;

Reference： [1]Haddenham, Dustin; Pasumansky, Lubov; DeSoto, Jamie; Eagon, Scott; Singaram, Bakthan [Journal of Organic Chemistry, 2009, vol. 74, # 5, p. 1964 - 1970]

20
[ 546-88-3 ]
[ 179897-89-3 ]
[ 455280-00-9 ]

Yield	Reaction Conditions	Operation in experiment
86%		xv) 5-Bromobenzo[d]isoxazol-3-amine I40 To a solution of acetohydroxamic acid (23.7 g, 0.315 mol) in DMF (800 ml.) at 0 C under N2 was added t-BuOK (35.4 g, 0.315 mol) and the mixture was stirred at 15 C for 2 h. 5-Bromo-2-fluorobenzonitrile (21.0 g, 0.105 mol) was then added and the mixture was stirred at RT overnight. The mixture was diluted with EtOAc (1.5 L) and washed with water (400 ml. x 4). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by column chromatography (Pet. ether/EtOAc = 50/1 to 3/1) to give the title compound (19 g, 86%) as a white solid. LCMS-D: Rt2.13 min; m/z 212.9/214.9 [M+H]+.
62%		The title compound was prepared by a modification of the literature procedure as described in Palermo, M. G., Tetrahedron Lett, 37:2885 (1996). A single neck 50 mL flask equipped with a magnetic stirred was charged with N-hydroxyacetamide (2.63 g, 35.0 mmol) and DMF (100 mL). Then, KOtBu (3.93 g, 35.0 mmol) was added in one portion. The temperature rose to 300C. The mixture was stirred for Ih and, 5-bromo~2-fluorobenzonitrile (7 g, 35.0 mmol) was added. The reaction mixture was stirred for overnight. A further portion of KOtBu (1.96 g, 17.5mmo) was added and the solution was again stirred overnight. The mixture was poured into brine and CH2CI2 and the layers were separated. The organic phase was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash column chromatography (BIOTAGE, eluting with a gradient of 0 to 40% EtOAc in hexanes) to afford the title compound (4.59 g, 62%) as a colorless solid. 1H NMR (500 MHz, DMSOd6) delta 8.09 (d, J = 1.8 HZ, IH), 7.65 (dd, J = 2.1, 8.9 Hz, IH), 7.45 (d, J = 8.9 Hz5 IH), 6.49 (s, 2H). LCMS: Anal. Calcd. for C7H5BrN2O: 2115 213; found: 212, 214 (M+H)+.

Reference： [1]Patent: WO2019/243491,2019,A1 .Location in patent: Page/Page column 83
[2]Patent: WO2010/138488,2010,A1 .Location in patent: Page/Page column 57-58
[3]Patent: WO2010/51042,2010,A1 .Location in patent: Page/Page column 134
[4]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00502
[5]Patent: US2014/357651,2014,A1 .Location in patent: Paragraph 0485

21
[ 51207-86-4 ]
[ 179897-89-3 ]
[ 1235467-34-1 ]

Yield	Reaction Conditions	Operation in experiment
		KOtBu (2.78 g, 24.75 mmol) was dissolved into 20ml DMSO in a round bottom flask. <strong>[51207-86-4](4-aminophenyl)(morpholino)methanone</strong> (5.10 g, 24.75 mmol) in 10ml DMSO was added and the resulting mixture was stirred for 35mins at r.t. The mixture was cooled in an iced bath for 5mins. 5-bromo-2-fluorobenzonitrile (4.5g, 22.50 mmol) in 10ml DMSO was added dropwise. Iced bath was removed and the mixture was stirred for lhr at r.t. The mixture was diluted with ethyl acetate, 100ml saturated NH4Cl water solution was added. The organic layer was separated. The water layer was extracted with ethyl acetate. The organic layers were combined and washed with H2O (4X), brine, dried over MgSO4 and concentrated. 8g crude product (84% purity) was obtained. MS (ESI) m/z 386 (M+H)+. 1H NMR (CDCl3) delta ppm 7.61 (d, 1H, J= 2.3), 7.47 (dd, 1H, J= 9, 2.5), 7.41 (m, 2H), 7.15 (m, 3H), 6.35 (bs, 1H), 3.65 (bm, 8H).

Reference： [1]Patent: WO2010/80474,2010,A1 .Location in patent: Page/Page column 128; 129
[2]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 2809 - 2812

22
[ 55121-99-8 ]
[ 179897-89-3 ]
[ 1235467-36-3 ]

Yield	Reaction Conditions	Operation in experiment
		KOtBu (2.81 g, 25.08 mmol) was dissolved in 20 ml DMSO in a round bottom flask. <strong>[55121-99-8](4-aminophenyl)(4-methylpiperazin-1-yl)methanone</strong> (5.0 g, 22.80 mmol) in 30 ml DMSO was added and the resulting mixture was stirred for 15 minutes at r.t. The mixture was cooled in an iced bath for 5 minutes. 5-bromo-2- fluorobenzonitrile (4.6 g, 23.00 mmol) in 20 ml DMSO was added. The ice bath was removed and the mixture stirred for 5 hours while warming to room temperature. Additional KOtBu (2g, 17.82 mmol) was added and the mixture stirred at room temperature overnight. The mixture was diluted with dichloromethane, extracted twice with water, once with brine, then dried over MgSO4, filtered and concentrated. 8.8 g crude brown oil were isolated. The crude product was recrystallized from dichloromethane + ethyl acetate + hexanes. 5.012 g pale yellow crystals were collected by filtration. The mother liquor was concentrated and purified by chromatography on silica, using a gradient from 100% Solvent A to 50% Solvent A+50% Solvent B. Solvent A: 99% dichloromethane + 1% Triethylamine, Solvent B: 99% Ethylacetate + 1% Triethylamine. Evaporation of product containing fractions gave additional 1.8 g product of -70% purity. MS (ESI) m/z 399/401(M+H). 1H NMR (CDCl3) delta ppm 7.63 (s, 1 H), 7.48 (d, 1H, J= 9.2), 7.42 (d, 2 H, J= 7.9), 7.18- 7.14 (m, 3H), 6.41 (s, 1 H), 3.80-3.40 (bm, 4 H), 2.42 (bs, 4H), 2.32 (s, 3H).

Reference： [1]Patent: WO2010/80474,2010,A1 .Location in patent: Page/Page column 134; 135
[2]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 2809 - 2812

23
[ 350684-49-0 ]
[ 179897-89-3 ]
[ 1235467-40-9 ]

Yield	Reaction Conditions	Operation in experiment
		KOtBu (2.81 g, 25.08 mmol) was dissolved into 20 ml DMSO in a round bottom flask, <strong>[350684-49-0]tert-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate</strong> (7 g, 22.92 mmol) in 30 ml DMSO was added and the resulting mixture was stirred for 15 minutes at room temperature, then cooled in an iced bath for 5 minutes. 5-bromo-2- fluorobenzonitrile (4.6 g, 23.00 mmol) in 20 ml DMSO was added. The ice bath was removed and the mixture stirred for 5 hours while warming to room temperature. LCMS showed product and unreacted starting materials. Additional KOtBu (2g, 17.82 mmol) was added and the reaction stirred at room temperature overnight. The mixture was transferred into a separating funnel that was loaded with dichloromethane and dilute aq. NH4CI solution. The layers were separated, the organic layer washed one more time with water, then brine, dried over MgStheta4, filtered and concentrated in vacuum. The crude was dissolved in dichloromethane, and refluxed while adding ethyl acetate until the solution becomes cloudy, then allowed to stand and cool to room temperature. The product precipitated and was collected by filtration. 6.40 g tert-butyl 4-(4-(4-bromo-2-cyanophenylamino)- benzoyl)piperazine-1-carboxylate were isolated as a white solid. The mother liquor was concentrated in vacuum and purified by column chromatography on silica, gradient from 100% dichloromethane to 50% ethyl acetate in dichloromethane. Product containing fractions were combined and evaporate to give additional 0.90 g product as a pale yellow solid. MS (ESI) m/z 485/487 (1 Br isotope pattern) (M+H), 429/431 (1 Br isotope pattern) (M+H-C4H8). 1H NMR (CDCl3) delta ppm 7.64 (s, 1 H), 7.50 (d, 1H, J= 9.2), 7.42 (d, 2 H, J= 8.3), 7.19-7.15 (m, 3H), 6.39 (s, 1 H), 3.80- 3.40 (b, 8 H), 1.47 (s, 9H).

Reference： [1]Patent: WO2010/80474,2010,A1 .Location in patent: Page/Page column 142

24
[ 179897-89-3 ]
[ 1292310-49-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: sodium hydride / N,N-dimethyl-formamide / 16 h / 0 - 45 °C 2: potassium acetate / (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / 1,4-dioxane / 16 h / 90 °C 3: potassium carbonate / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane; water / 16 h / 90 °C 4: 1,4-dioxane; ethanol / 72 h / 80 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: MYREXIS, INC.; ALZHEIMER'S INSTITUTE OF AMERICA, INC. - WO2011/46970, 2011, A1

25
[ 179897-89-3 ]
[ 160844-75-7 ]

Reference： [1]Patent: US2011/313169,2011,A1

26
[ 179897-89-3 ]
[ 1240593-43-4 ]
[ 160844-75-7 ]

Reference： [1]Patent: US2011/313169,2011,A1

27
[ 121359-48-6 ]
[ 179897-89-3 ]
[ 1093965-00-4 ]

Yield	Reaction Conditions	Operation in experiment
18%		To a solution of 5-bromo-2-fluorobenzonitrile (1.0 g) in N,N-dimethylformamide (30 mL) were added 2- (tributylstannyl) thiazole (1.9 mL) and tetrakis (triphenylphosphine)palladium(O) (290 mg) under nitrogen stream, and the mixture was stirred at 800C overnight. The reaction mixture was allowed to cool, diluted with ethyl acetate, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to NH-silica gel chromatography (eluate: ethyl acetate) . The residue was brought into an ethanol solution (20 mL) , hydrazine monohydrate (0.50 mL) was added, and the mixture was heated overnight under reflux. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography (hexane: ethyl acetate = 1:1 - 0:1) gave the title compound (27.3 mg, yield 18%) as colorless crystals. 1H NMR (300 MHz, DMSO-cfe) delta ppm 5.60 (s, 2 H) 7.31 (d, J=8.71 Hz, 1 H) 7.65 (d, J=3.41 Hz, 1 H) 7.74 - 7.94 (m, 2 H) 8.39 (s, 1 H) 11.65 (br. s., 1 H).

Reference： [1]Patent: WO2008/156757,2008,A1 .Location in patent: Page/Page column 121

28
[ 824-51-1 ]
[ 179897-89-3 ]
[ 1420532-28-0 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In N,N-dimethyl-formamide; at 150℃; for 3h;	PREPARATION 124 5-Bromo-2-(6-methyl-1 H-pyrrolo[2,3-b]pyridin-1 -yl)benzonitrile The title compound of Preparation 58 (0.05 g, 0.38 mmol) was dissolved in 1 ml dimethylformamide. Potassium carbonate (0.105 g, 0.76 mmol) and 5-bromo-2- fluorobenzonitrile (0.1 14 g, 0.57 mmol) were added and the reaction mixture was stirred at 150 C for 3h. The mixture was allowed to cool to room temperature and was partitioned between ethyl acetate and water. The organic layer was washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified using the Isolera Purification System (ether-hexane gradient, 0: 100 rising to 100:0) to give 0.1 10 g (0.35 mmol, 93%) of the title compound as a yellow solid. Purity 99%. UPLC/MS (3 min) retention time 1 .84 min. LRMS: m/z 312 (M+1 ).

Reference： [1]Patent: WO2013/10880,2013,A1 .Location in patent: Page/Page column 140

29
[ 97674-02-7 ]
[ 179897-89-3 ]
[ 288309-07-9 ]

Yield	Reaction Conditions	Operation in experiment
88%		Example 27A 3-Acetyl-6-fluorobenzenecarbonitrile Under an argon atmosphere, 449 mg (0.490 mmol) of tris(dibenzylideneacetone)dipalladium and 671 mg (1.078 mmol) of rac-1,1'-binaphthalene-2,2'diylbis(diphenylphosphane) are added to 4.90 g (24.5 mmol) of 3-bromo-6-fluorobenzenecarbonitrile in 180 ml of toluene. After the addition of 10.6 g (29.4 mmol) of (1-ethoxyvinyl)tributylstannane, the mixture is stirred under reflux overnight. The reaction mixture is subsequently concentrated and the residue is taken up in 200 ml of THF. After the addition of an aqueous 2N hydrogen chloride solution (50 ml), the mixture is stirred at room temperature for 4 h. The reaction mixture is subsequently neutralized using a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 10:1?3:1). 3.50 g (88% of theory) of the title compound are obtained. 1H-NMR (400 MHz, DMSO-d6): delta=8.55 (dd, 1H), 8.31 (ddd, 1H), 7.68 (t, 1H), 2.63 (s, 3H). GC-MS (Method 11): Rt=4.34 min; MS (EIpos): m/z=163 [M]+.

Reference： [1]Patent: US2013/45999,2013,A1 .Location in patent: Paragraph 0247; 0248; 0249; 0250

30
[ 67-56-1 ]
[ 179897-89-3 ]
[ 127667-01-0 ]

Reference： [1]Organic Letters,2013,vol. 15,p. 3998 - 4001

31
[ 67-56-1 ]
[ 179897-89-3 ]
[ 144649-99-0 ]

Reference： [1]Organic Letters,2013,vol. 15,p. 3998 - 4001

32
[ 35691-93-1 ]
[ 179897-89-3 ]
[ 1590405-86-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	With caesium carbonate; In dimethyl sulfoxide; at 120℃; for 16h;	General procedure: 4.3.1. Ethyl 5-amino-2-methylpyrazolo[1,5-a]quinoline-3-carboxylate (7a). Condition C: A mixture of 2-fluorobenzonitrile6a (121 mg, 1.00 mmol), 1H-pyrazole 4 (202 mg, 1.20 mmol) andCs2CO3 (980 mg, 3.00 mmol) in DMF (5.0 mL) was stirred at 120 Cfor 16 h. After monitoring the end of the reaction on TLC, themixture was cooled to room temperature and diluted with water.The resulting mixture was extracted with ethyl acetate twice. Thecombined organic layers werewashed with water twice, dried overMgSO4 and the solvent was removed in vacuo to afford a residue.The residue was purified by flash column chromatography(hexane:EtOAc1:1) on silica gel to afford 7a (124 mg, 46% yield).Condition D: The reaction was carried out in DMSO instead of DMFunder the same conditions as that of condition C to afford 7a (175 mg, 65% yield).

Reference： [1]Tetrahedron,2014,vol. 70,p. 2766 - 2775

33
[ 179897-89-3 ]
[ 214360-65-3 ]
[ 1261787-72-7 ]

Yield	Reaction Conditions	Operation in experiment
37%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In N,N-dimethyl-formamide at 120℃; for 14h; Inert atmosphere; Sealed tube;	12 Example 12 2- [(4-Fluoro-benzenesulfonyl)-methyl-amino]-N-(4-fluoro-4’ -trifluoromethyl-biphenyl-3-ylmethyl)-acetamide A solution of 4,4,5 ,5-tetramethyl-2-(4-trifluoromethyl-phenyl)- [1,3,2] dioxaborolane( 1.00 g, 3.68 mmol), 5-bromo-2-fluoro-benzonitrile (0.74 g, 3.68 mmol) and potassium carbonate (0.51 g, 3.68 mmol) in DMF (5 mL) at 25°C was purged with nitrogen gas and evacuated three times. The solution was then treated with tetrakis(triphenylphosphine)palladium(0) (212 mg, 184 tmol) and then sealed and heated to 120°C for 14 h. The reaction mixture was cooled to 25°C, unsealed and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (80/20 hexanes/ethyl acetate) afforded 4-fluoro-4’- trifluoromethyl-biphenyl-3-carbonitrile (360 mg, 37%) as a white solid.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/49047, 2014, A1 Location in patent: Page/Page column 56; 57

34
[ 100114-57-6 ]
[ 179897-89-3 ]
5-bromo-2-(3-cyclopropyl-1H-pyrazol-1-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.7 g	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	In a 50 mL round-bottomed flask was added <strong>[100114-57-6]3-cyclopropyl-1H-pyrazole</strong> (2.0 g, 18 mmol), K2C03 (5.1 g, 37 mmol) and 5-bromo-2-fluorobenzonitrile (3.7 g, 18 mmol) in DMF (15 mL) to give a yellow suspension.Then reaction mixture was stirred at rt for overnight under nitrogen atmosphere. The excess DMF was distilled from the mixture at reduced pressure, and the residue was diluted with water (50 mL). The aq layer wasextracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 25 mL). The organic solution was dried over Na2SO4, filtered and concentrated at reduced pressure to give crude product. The crude material was added to a silica gel column and was eluted with 2%-i 0% of ethyl acetate-petether to afford a white color solid (3.7 g, i2 mmol). ?H NMR (400 MHz, CD3OD) oe ppm 8.05 (d, J= 2 Hz, iH), 7.84 (d, J=2 Hz, iH), 7.76 (dd, J= 2, 8.8 Hz, iH), 7.70 (d, J= 8.8 Hz, iH), 6.22 (d, J 2 Hz, iH),2.00 (m, iH), i.00 (m, 2H), 0.86 (m, 2H).

Reference： [1]Patent: WO2014/152738,2014,A1 .Location in patent: Page/Page column 195; 196

35
[ 100114-57-6 ]
[ 179897-89-3 ]
5-bromo-2-(3-cyclopropyl-1H-pyrazol-1-yl)benzaldehyde [ No CAS ]

Reference： [1]Patent: WO2014/152738,2014,A1

36
[ 33468-67-6 ]
[ 179897-89-3 ]
5-bromo-2-(2-methyl-4-(trifluoromethyl)-1H-imidazol-1-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃;	In a 100 mL round bottom flask, <strong>[33468-67-6]2-methyl-4-(trifluoromethyl)-lH-imidazole</strong> (8.0 g, 53 mmol), 5-bromo-2-fluorobenzonitrile (11 g, 53 mmol) and K2CO3 (22 g, 160 mmol) were brought up in solution with DMF (80 mL) to give a yellow suspension. The reaction mixture was stirred overnight at 100 C. The DMF was removed from the mixture in vacuo, and the residue was diluted with EtOAc (350 mL). The organic solution was washed with saturated NH4CI, followed by H20, and then brine. The organic solution was dried over Na2S04, filtered and concentrated to give the crude product. The crude material was purified by chromatography thru a Si02 column using a mobile phase gradient of 5 % to 15 % EtOAc in petroleum ethers to afford the title compound as a white solid (17 g, 52 mmol, 97 % yield). 1H NMR (400 MHz, CHLOROFORM- ) delta ppm 8.00 (d, 1 H, J=2 Hz), 7.92 (m, 1 H), 7.34 (m, 2 H), 2.36 (s, 3 H).

Reference： [1]Patent: WO2014/144037,2014,A1 .Location in patent: Page/Page column 245

37
[ 33420-52-9 ]
[ 179897-89-3 ]
C₁₀H₈BrF₂NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.4%		Step 4 (ME-54):A solution of crude ME-53 (3.8 g, 39.58 mmol) in Dimethyl formamide (5 mL) was added to asuspension of sodium hydride (60%; 1 .3 g, 32.5 mmol) in dry dimethyl formamide (20 mL) at 0C and the mixture was stirred at room temperature for 1 h. The reaction mass was again cooled to 0C and a solution of 5-bromo-2-fluoro benzonitrile (2.36 g, 11.8 mmol) in dimethyl formamide (5 mL) was added. The reaction mass was warmed to room temperature and stirred for 30 mm, quenched with saturated ammonium chloride solution and extracted withdiethyl ether. The combined organic layer was washed successively with water, brine; dried over anhydrous sodium sulfate and concentrated in vacuum to afford the crude intermediate. Purification by column chromatography over silica gel (60-l20mesh) and using 8% ethyl acetate in pet ether as the eluent afforded 2.5 g (69.4%) of ME-S4 as a yellow gummy liquid.

Reference： [1]Patent: WO2014/140279,2014,A1 .Location in patent: Page/Page column 69; 125; 126

38
[ 672883-23-7 ]
[ 179897-89-3 ]
tert-butyl N-[(3S)-1-(4-bromo-2-cyanophenyl)-5-oxopyrrolidin-3-yl]carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.5 g		Step 1 tert-Butyl N-[(3S)-1-(4-bromo-2-cyanophenyl)-5-oxopyrrolidin-3-yl]carbamate To a solution of <strong>[672883-23-7]tert-butyl ((S)-5-oxopyrrolidin-3-yl)carbamate</strong> (2.0 g) in N,N-dimethylformamide (50 ml), sodium hydride (55percent oil, 0.65 g) was added under ice cooling, and the mixture was stirred at the same temperature as above for 10 minutes. 5-Bromo-2-fluorobenzonitrile (3.0 g) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Ice water and a saturated aqueous solution of ammonium chloride were added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (1.5 g). 1H-NMR (CDCl3) delta: 1.46 (9H, s), 2.52 (1H, dd, J=17.5, 4.8 Hz), 2.96 (1H, dd, J=17.5, 7.9 Hz), 3.81 (1H, d, J=6.7 Hz), 4.19 (1H, dd, J=10.0, 6.3 Hz), 4.49 (1H, br s), 4.98 (1H, br s), 7.32 (1H, d, J=8.5 Hz), 7.76 (1H, dd, J=8.8, 2.1 Hz), 7.83 (1H, d, J=2.4 Hz).
1.5 g		To a solution of <strong>[672883-23-7]tert-butyl ((S)-5-oxopyrrolidin-3-yl)carbamate</strong> (2.0 g) in N,N-dimethylformamide (50 ml), sodium hydride (55percent oil, 0.65 g) was added under ice cooling, and the mixture was stirred at the same temperature as above for 10 minutes. 5-Bromo-2-fluorobenzonitrile (3.0 g) was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. Ice water and a saturated aqueous solution of ammonium chloride were added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (1.5 g). (0462) 1H-NMR (CDCl3) delta: 1.46 (9H, s), 2.52 (1H, dd, J=17.5, 4.8 Hz), 2.96 (1H, dd, J=17.5, 7.9 Hz), 3.81 (1H, d, J=6.7 Hz), 4.19 (1H, dd, J=10.0, 6.3 Hz), 4.49 (1H, br s), 4.98 (1H, br s), 7.32 (1H, d, J=8.5 Hz), 7.76 (1H, dd, J=8.8, 2.1 Hz), 7.83 (1H, d, J=2.4 Hz).

Reference： [1]Patent: US2015/51190,2015,A1 .Location in patent: Paragraph 0405-0407
[2]Patent: US2016/46639,2016,A1 .Location in patent: Paragraph 0461; 0462

39
[ 1174020-40-6 ]
[ 179897-89-3 ]
tert-butyl (3S,4R)-4-[4-bromo-2-cyanophenoxy]-3-fluoropiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With caesium carbonate; In N,N-dimethyl-formamide; at 110℃; for 16h;Sealed tube;	Preparation 120tert-butyl (35,4R)-4-[4-bromo-2-cyanophenoxyl-3-fluoropiperidine- 1 -carboxylateTo a solution of tert-butyl-(35,4R)-3-fluoro-4-hydroxypiperidine- 1 -carboxylate (WO 20131011402Al, 1.00 g, 4.56 mmol) in DMF (20 mL) was added cesium carbonate (4.47 g, 13.68 mmol)followed by 5-bromo-2-fluorobenzonitrile (912 mg, 4.56 mmol) and the reaction was heated to110C for 16 hours in a sealed tube. The reaction was cooled, poured onto ice water andextracted into EtOAc twice. The combined organic layers were washed with water, brine, dried over sodium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 10% EtOAc in heptanes to afford the title compound (1.50 g, 82%).1H NMR (400 MHz, DMSO-d6): O ppm 1.40 (5, 9H), 1.86 (m, 2H), 3.00-3.20 (m, 1H), 3.20-3.40 (m, 1H), 3.75-3.85 (m, 1H), 4.00-4.07 (m, 1H), 4.87-4.99 (m, 2H), 7.40 (d, 1H), 7.85 (dd, 1H), 8.04(s, 1H).MS mlz 301 [M-Boc81Br+H]

Reference： [1]Patent: WO2015/92610,2015,A1 .Location in patent: Page/Page column 165

40
[ 849061-99-0 ]
[ 179897-89-3 ]
methyl (E)-3-amino-5-(2-cyclopropylvinyl)benzo[b]thiophene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: bis-triphenylphosphine-palladium(II) chloride / water; 1,2-dimethoxyethane; ethanol / 3 h / Reflux 2: triethylamine / dimethyl sulfoxide / 0.58 h / 130 °C / Microwave irradiation

Reference： [1]Bagley, Mark C.; Dwyer, Jessica E.; Molina, Maria D. Beltran; Rand, Alexander W.; Rand, Hayley L.; Tomkinson, Nicholas C. O. [Organic and Biomolecular Chemistry, 2015, vol. 13, # 24, p. 6814 - 6824]

41
[ 849061-99-0 ]
[ 179897-89-3 ]
(E)-5-(2-cyclopropylvinyl)-2-fluorobenzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With bis-triphenylphosphine-palladium(II) chloride In 1,2-dimethoxyethane; ethanol; water for 3h; Reflux;

Reference： [1]Bagley, Mark C.; Dwyer, Jessica E.; Molina, Maria D. Beltran; Rand, Alexander W.; Rand, Hayley L.; Tomkinson, Nicholas C. O. [Organic and Biomolecular Chemistry, 2015, vol. 13, # 24, p. 6814 - 6824]

42
[ 546-88-3 ]
[ 179897-89-3 ]
[ 177995-39-0 ]

Reference： [1]Patent: US9174994,2015,B2 .Location in patent: Page/Page column 117

43
[ 19752-84-2 ]
[ 179897-89-3 ]
5-bromo-2-((tetrahydro-2H-pyran-3-yl)oxy)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of <strong>[19752-84-2]3-hydroxytetrahydropyran</strong> (Astatech, 2.0 g, 20 mmol) in N,N- dimethylformamide (40 mL) was stirred in an ice-water bath under an atmosphere of Argon. Sodium hydride (60 % in mineral oil, 0.79 g, 20 mmol) was added in a single portion. The mixture was stirred at 0 C for one hour and then the cooling bath was removed. To the mixture was added via syringe 5-bromo-2-fluorobenzonitrile (Matrix Scientific, 3.3 g, 17 mmol) as a solution in A/,A/-dimethylformamide (20 mL) at room temperature. Mixture was stirred for 3 hours at 50 C block and then allowed to cool to room temperature. Water was added and the resulting precipitate was collected by filtration, washed with water, dried under house vacuum and then in vacuum oven over P205 to provide the desired material. 1H NMR (400 MHz, DMSO-d6) delta 8.04 (d, J = 2.5 Hz, 1 H), 7.84 (dd, J = 9.1 , 2.6 Hz, 1 H), 7.35 (d, J = 9.1 Hz, 1 H), 4.64 (m, 1 H), 3.82 (m, 1 H), 3.63 (m, 3H), 2.05 (m, 1 H), 1.83 (m, 2H), 1.57 (m, 1 H).
		A solution of <strong>[19752-84-2]3-hydroxytetrahydropyran</strong> (Astatech, 2.0 g, 20 mmol) in N,N-dimethylformamide (40 mL) was stirred in an ice-water bath under an atmosphere of Argon. Sodium hydride (60% in mineral oil, 0.79 g, 20 mmol) was added in a single portion. Mixture was stirred at 0 C. for one hour and then the cooling bath was removed. To the mixture was added via syringe 5-bromo-2-fluorobenzonitrile (Matrix Scientific, 3.3 g, 17 mmol) as a solution in N,N-dimethylformamide (20 mL) at room temperature. Mixture was stirred for 3 hours at 50 C. block and then allowed to cool to room temperature. Water was added and the resulting precipitate was collected by filtration, washed with water, dried under house vacuum and then in vacuum oven over P2O5 to provide the desired material. 1H NMR (400 MHz, DMSO-d6) delta 8.04 (d, J=2.5 Hz, 1H), 7.84 (dd, J=9.1, 2.6 Hz, 1H), 7.35 (d, J=9.1 Hz, 1H), 4.64 (m, 1H), 3.82 (m, 1H), 3.63 (m, 3H), 2.05 (m, 1H), 1.83 (m, 2H), 1.57 (m, 1H).

Reference： [1]Patent: WO2015/187684,2015,A1 .Location in patent: Page/Page column 270
[2]Patent: US2016/96827,2016,A1 .Location in patent: Paragraph 0309

44
[ 29683-23-6 ]
[ 179897-89-3 ]
5-bromo-2-((tetrahydro-2H-thiopyran-4-yl)oxy)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of <strong>[29683-23-6]tetrahydrothiopyran-4-ol</strong> (Sigma Aldrich, 2.0 g, 17 mmol) in N,N- dimethylformamide (DMF, 30ml_) was treated with sodium hydride (60 % in mineral oil, 0.68 g, 17 mmol) in a single portion at room temperature. The mixture was stirred for one hour at room temperature before 5-bromo-2-fluorobenzonitrile (2.8 g, 14 mmol) was added in a single portion. An additional volume of DMF (20 ml.) was added. The mixture was stirred on a 50 C heating block for two hours before it was poured onto ice (approximately 100 g), precipitating a solid that was then collected by vacuum filtration and dried in a vacuum oven over phosphorus pentoxide to provide the desired product. 1H NM (400 MHz, DMSO-d6) delta 8.03 (d, J = 2.5 Hz, 1 H), 7.82 (dd, J = 9.1 , 2.6 Hz, 1 H), 7.31 (d, J = 9.1 Hz, 1 H), 4.74 (m, 1 H), 2.83 (m, 2H), 2.63 (m, 2H), 2.16 (m, 2H), 1.90 (m, 2H).
		A solution of <strong>[29683-23-6]tetrahydrothiopyran-4-ol</strong> (Sigma Aldrich, 2.0 g, 17 mmol) in N,N-dimethylformamide (DMF, 30 mL) was treated with sodium hydride (60% in mineral oil, 0.68 g, 17 mmol) in a single portion at room temperature. The mixture was stirred for one hour at room temperature before 5-bromo-2-fluorobenzonitrile (2.8 g, 14 mmol) was added in a single portion. An additional volume of DMF (20 mL) was added. The mixture was stirred on a 50 C. heating block for two hours before it was poured onto ice (approximately 100 g), precipitating a solid that was then collected by vacuum filtration and dried in a vacuum oven over phosphorus pentoxide to provide the desired product. 1H NMR (400 MHz, DMSO-d6) delta 8.03 (d, J=2.5 Hz, 1H), 7.82 (dd, J=9.1, 2.6 Hz, 1H), 7.31 (d, J=9.1 Hz, 1H), 4.74 (m, 1H), 2.83 (m, 2H), 2.63 (m, 2H), 2.16 (m, 2H), 1.90 (m, 2H).

Reference： [1]Patent: WO2015/187684,2015,A1 .Location in patent: Page/Page column 272
[2]Patent: US2016/96827,2016,A1 .Location in patent: Paragraph 0248

45
[ 1209780-71-1 ]
[ 179897-89-3 ]
tert-butyl 4-(4-bromo-2-cyanophenoxy)-3,3-difluoropiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of NaH (8.35 g, 208.0 mmol, 60.0% purity, 1.1 eq) in DMF (225 mL) was added a solution of compound Z9 (45.0 g, 190.0 mmol, 1 eq) in DMF (90 mL) at 0 C and the mixture was stirred at 0 C for 0.5 h. A solution of compound 1A (37.9 g, 190.0 mmol, 1 eq) in DMF (45 mL) was added dropwise and the mixture was stirred at 25 C for 0.5 h. The reaction mixture was poured into aqueous saturated NH4C1 (500 mL), extracted with ethyl acetate (800 mL x 2). The organic phase was washed with water (300 mL x 2), brine (300 mL), dried over sodium sulfate, filtered and concentrated under vacuum to give a crude product. The crude product was purified by silica gel chromatography (Petroleum ether/Ethyl acetate=10/l, 1/2) to afford compound Z10 (79.0 g, 177.0 mmol, 93.3% yield, 93.5% purity) as an yellow oil. LCMS: RT = 0.994 min, MS[M+Na]+ = 439.0; NMR:, CDC13 400MHz. delta 7.69 (d, / = 3.6 Hz, 1H), 7.65 (dd, J = 3.6, 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 4.65 (dd, J = 3.2, 6.4 Hz, 1H), 4.38 - 4.13 (m, 1H), 4.05 - 3.84 (m, 1H), 3.76 - 3.51 (m, 1H), 3.48 - 3.22 (m, 1H), 2.14 - 2.05 (m, 2H), 1.48 (s, 9H).

Reference： [1]Patent: WO2019/79373,2019,A1 .Location in patent: Paragraph 00561; 00380

46
[ 6200-60-8 ]
[ 179897-89-3 ]
2-fluoro-5-(imidazo[1,2-a]pyridin-3-yl)benzonitrile [ No CAS ]

Reference： [1]RSC Advances,2016,vol. 6,p. 65095 - 65104

47
[ 86087-24-3 ]
[ 179897-89-3 ]
(R)-5-bromo-2-((tetrahydrofuran-3-yl)oxy)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of (R)-(-)-3-hydroxytetrahydrofuran (Sigma Aldrich, 2.0 g, 22 mmol) in N,N-dimethylformamide (40 mL) was stirred in an ice-water bath under an atmosphere of Argon. Sodium hydride (60% in mineral oil, 0.91 g, 23 mmol) was added in a single portion. The mixture was stirred at 0 C. for 10 minutes and then the cooling bath was removed. The mixture was stirred overnight at room temperature. To the mixture was added via syringe 5-bromo-2-fluorobenzonitrile (Matrix Scientific, 3.8 g, 19 mmol) as a solution in N,N-dimethylformamide (20 mL) at room temperature. Mixture was stirred for 2 hours on a 50 C. block and then allowed to cool to room temperature. Water was added and the resulting precipitate was collected by filtration, washed with water, dried under house vacuum and then in vacuum oven over P2O5 to provide the desired material. 1H NMR (400 MHz, DMSO-d6) delta 8.06 (d, J=2.5 Hz, 1H), 7.87 (dd, J=9.1, 2.5 Hz, 1H), 7.26 (d, J=9.1 Hz, 1H), 5.24 (m, 1H), 3.87 (m, 4H), 2.31 (m, 1H), 2.02 (m, 1H).

Reference： [1]Patent: US2016/96827,2016,A1 .Location in patent: Paragraph 0289

48
[ 1893408-11-1 ]
[ 179897-89-3 ]
[ 1893405-00-9 ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: (S)-tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate; 5-Bromo-2-fluoro-benzonitrile With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: 5-Bromo-2-fluoro-benzonitrile In N,N-dimethyl-formamide; mineral oil at 60℃;	301.1 Step 1: Preparation of (S)-tert-butyl 4-(4-bromo-2-cyanophenoxy)-3,3-difluoropiperidine-1-carboxylate Sodium hydride (60% dispersion in mineral oil, 88 mg, 2.2 mmol) was added slowly in a single portion to a stirred solution of (S)-tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (0.52 g, 2.2 mmol) in N,N-dimethylformamide at room temperature. After the passage of 30 minutes, 5-bromo-2-fluorobenzonitrile (0.42 g, 2.1 mmol) was added in a single portion. The mixture was stirred overnight while heating at 60° C. Water was added to the reaction mixture. The resulting aqueous suspension was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to provide crude (S)-tert-butyl 4-(4-bromo-2-cyanophenoxy)-3,3-difluoropiperidine-1-carboxylate, which was carried forward without further purification. LCMS-ESI+ (m/z): [M-Boc+H]+ calcd for C12H12BrF2N2O: 317.0. found: 317.1

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2016/96827, 2016, A1 Location in patent: Paragraph 1074; 1075

49
[ 179897-89-3 ]
[ 1893397-65-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium hydride / N,N-dimethyl-formamide / 16 h / 0 - 45 °C 2: palladium bis[bis(diphenylphosphino)ferrocene] dichloride; potassium acetate / 16 h / 90 °C 3: palladium diacetate; triphenylphosphine; sodium carbonate / N,N-dimethyl-formamide; 1,2-dimethoxyethane; water / 1 h / 130 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: GILEAD SCIENCES INC - US2016/96827, 2016, A1

50
[ 22419-35-8 ]
[ 179897-89-3 ]
5-bromo-2-((4,4-difluorocyclohexyl)oxy)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of <strong>[22419-35-8]4,4-difluorocyclohexanol</strong> (Sigma Aldrich, 1.0 g, 7.3 mmol) in N,N-dimethylformamide (DMF, 17 mL) was treated with sodium hydride (60percent dispersion in mineral oil, 0.29, 7.3 mmol) in a single portion at room temperature. The mixture was stirred for two hours at room temperature before 5-bromo-2-fluorobenzonitrile (1.3 g, 6.7 mmol) was added in a single portion at room temperature. The mixture was stirred on a 50° C. block for 1 hour. Ice-water was added to the mixture, which was then partitioned with ethyl acetate. The aqueous phase was extracted three times with ethyl acetate. The combined extracts were washed twice with water and once with saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel) to provide the desired material. 1H NMR (400 MHz, DMSO-d6) delta 8.06 (d, J=2.5 Hz, 1H), 7.87 (dd, J=9.1, 2.6 Hz, 1H), 7.38 (d, J=9.1 Hz, 1H), 4.89 (m, 1H), 2.23-1.98 (m, 4H), 1.98-1.90 (m, 4H).

Reference： [1]Patent: US2016/96827,2016,A1 .Location in patent: Paragraph 0415

51
[ 2403-88-5 ]
[ 179897-89-3 ]
5-bromo-2-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%		5-bromo-2-(2,2,6,6-tetramethylpiperidin-4-yloxy)benzonitrile to a suspension of sodium hydride (60% in oil, 74 mg, 1.80 mmol) in DMF (10 mL) was added 2,2,6,6-tetramethylpiperidin-4-ol (652 mg, 4.15 mmol) slowly at 0 C. After stirring for 10 min at 0 C., to the mixture was added 5-bromo-2-fluorobenzonitrile (1.0 g, 5.00 mmol) slowly. The reaction mixture was then stirred for 2 h at 50 C., cooled to room temperature, and treated with water (10 mL). The mixture was extracted with ethyl acetate (30 mL*3). The organic phases were combined, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to yield 5-bromo-2-[(2,2,6,6-tetramethylpiperidin-4-yl)oxy]benzonitrile as light yellow solid (1.6 g, 95%). MS: m/z=337.0 [M+H]+.

Reference： [1]Patent: US2016/376283,2016,A1 .Location in patent: Paragraph 0318; 0319

52
[ 625-43-4 ]
[ 179897-89-3 ]
5-bromo-2-(N-methyl)isobutylamino-benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With caesium carbonate In dimethyl sulfoxide at 78℃;	4.1.6. General procedure for the preparation of compounds 11a-g and 12f-g General procedure: Alkylamine (30mmol) and K2CO3 (4.1g, 30mmol) or CsCO3 (9.8g, 30mmol) was added to compound 10 (10mmol) in DMF or DMSO (20mL). The mixture was heated at 25-120°C for 2-12h. The reaction was diluted with H2O (200mL) and then extracted with EtOAc (200mL×2). The combined organic phases were washed with H2O (200mL×2) and brine (200mL), dried over MgSO4 and concentrated in a vacuum. The residue was purified by flash column chromatography (0-10% EtOAc in petroleum ether).
97.3%	In dimethyl sulfoxide at 78℃; for 12h;	8.1 II1 (1.0 g, 5 mmol) was dissolved in DMSO (15 mL)N-methylisobutylamine (1.3 g, 15 mmol) was added,The reaction was carried out at 78 ° C for 12 h,TLC tracking reaction is complete. The reaction was cooled to room temperature, diluted with 80 mL of water,Ethyl acetate (80 mL x 3), washed with saturated brine, dried over anhydrous magnesium sulfate,The solvent was evaporated under reduced pressure to give 1.1 g of 5-bromo-2- (N-methyl) isobutylamine-benzonitrile (III8) as a yellow liquid in a yield of 97.3%.
95%	Stage #1: 5-Bromo-2-fluoro-benzonitrile With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 2-methylpropyl(methyl)amine In N,N-dimethyl-formamide at 80℃; for 3h;	10.1 Synthesis of 1-(3-cyano-4-isobutyl-methylamino-phenyl)-imidazole-4-carboxylic acid (A10) 5-bromo-2-fluorobenzonitrile (1.0 g, 5.0 mmol) was weighed and dissolved in DMF (10 mL), Add K2CO3 (2.1 g, 15.0 mmol), stir at room temperature for 1.0 h, add N-methylisobutylamine (1.3 g, 15.0 mmol), and react at 80 °C for 3 h. TLC followed the reaction completely.Cooled to room temperature, diluted with 100mL of water was added, ethyl acetate (100mL × 3). The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, purification by silica gel column (V ethyl acetate: V petroleum ether = 1: 20) afforded 5-bromo-2-isobutylmethylaminobenzonitrile (a10)1.27 g, yield 95%

93%

With potassium carbonate In N,N-dimethyl-formamide at 70 - 80℃;

4.1.1. General procedure for the preparation of compounds 2aee General procedure: A mixture of compound 1 (5.0 mmol), alkylamine (15.0 mmol),and K2CO3 (15.0 mmol) in DMF (10 mL) was reacted at 70e80 C for3e5 h. After the reaction was complete, the mixture was pouredinto H2O (100 mL) and extracted with ethyl acetate (100 mL 2).The organic layer was collected, washed with brine (100 mL 3),dried over anhydrous Na2SO4, and concentrated under vacuum toyield the crude product, which was purified by flash columnchromatography (0e15% ethyl acetate in petroleum ether). 4.1.1.1. 5-Bromo-2-(isobutyl(methyl)amino)-benzonitrile (2a).Yellow oil (yield: 93%); 1H NMR (400 MHz, CDCl3) d 7.54 (d, 1H,J 1.3 Hz, ArH), 7.42 (dd, 1H, J 9.1, 3.3 Hz, ArH), 6.75 (d, 1H,J 9.1 Hz, ArH), 3.19 (d, 2H, J 7.5 Hz, -NCH3CH2CH(CH3)2), 3.05 (s,3H, -NCH3CH2CH(CH3)2), 2.01 (m,1H, eNCH3CH2CH(CH3)2), 0.89 (d,6H, J 6.6 Hz, eNCH3CH2CH(CH3)2).

Reference： [1]Li, Jing; Wu, Fangping; Liu, Xingguo; Zou, Yake; Chen, Huixiong; Li, Zheng; Zhang, Lei [European Journal of Medicinal Chemistry, 2017, vol. 140, p. 20 - 30]
[2]Current Patent Assignee: SOUTH CHINA UNIVERSITY OF TECHNOLOGY - CN106632245, 2017, A Location in patent: Paragraph 0100
[3]Current Patent Assignee: SOUTH CHINA UNIVERSITY OF TECHNOLOGY - CN110078668, 2019, A Location in patent: Paragraph 0126-0128
[4]Li, Jing; Li, Xiaolei; Li, Yuanyuan; Zhang, Lei; Zhou, Haiyan; Zhu, Xinying [European Journal of Medicinal Chemistry, 2020, vol. 186]

53
[ 179897-89-3 ]
[ 765-38-8 ]
5-bromo-2-(2-methylpyrrolidin-1-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.7%	In dimethyl sulfoxide; at 70℃; for 5h;	II1 (1.0 g, 5 mmol) was dissolved in DMSO (15 mL)<strong>[765-38-8]2-methyl-tetrahydropyrrole</strong> (1.3 g, 15 mmol) was added, reacted at 70 C for 5 h,TLC tracking reaction is complete.The reaction solution was cooled to room temperature, diluted with 80 mL of water, extracted with ethyl acetate (80 mL x 3)Saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure,1.28 g of a yellow liquid 5-bromo-2- (methyl-tetrahydropyrrole) -benzonitrile (III10) in a yield of 96.7%.
76%	With potassium carbonate; In dimethyl sulfoxide; at 85℃;	General procedure: Alkylamine (30mmol) and K2CO3 (4.1g, 30mmol) or CsCO3 (9.8g, 30mmol) was added to compound 10 (10mmol) in DMF or DMSO (20mL). The mixture was heated at 25-120C for 2-12h. The reaction was diluted with H2O (200mL) and then extracted with EtOAc (200mL×2). The combined organic phases were washed with H2O (200mL×2) and brine (200mL), dried over MgSO4 and concentrated in a vacuum. The residue was purified by flash column chromatography (0-10% EtOAc in petroleum ether).

Reference： [1]Patent: CN106632245,2017,A .Location in patent: Paragraph 0112
[2]European Journal of Medicinal Chemistry,2017,vol. 140,p. 20 - 30

54
[ 61260-15-9 ]
[ 179897-89-3 ]
[ 763114-25-6 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 20℃; for 5h;	A solution of 12.11 g (3-oxo-1,3-dihydro-isobenzofuran-1-yl) phosphonic acid dimethyl ester was added 7.46 g of 2-fluoro-5-bromo-benzonitrile, 100 ml of tetrahydrofuran, The reaction was concentrated after drying, the reaction was concentrated to dryness. The mixture was stirred with 100.0 ml of water to stir the mixture, filtered, washed and dried to obtain a pale yellow solid, and the reaction mixture was stirred at room temperature for 5 hours. 2-fluoro-5- (3-oxo-1,3H-dihydroisobenzofuranylidene) benzonitrile, HPLC purity greater than 98percent.

Reference： [1]Patent: CN106905243,2017,A .Location in patent: Paragraph 0062; 0063

55
[ 149771-44-8 ]
[ 179897-89-3 ]
tert-butyl 3-(4-bromo-2-cyanophenyl)-3,8-diazabicycio[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 80℃; for 24h;	Into a 100-mL round-bottom flask was added tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (1.00 g, 4.71 mmol), 5-bromo-2-fluorobenzonitrile1.88 g, 9.40 mmol), DIEA (1.83 g, 2.47 mL, 14.2mmol), and DMSO (25 mL). The resulting mixture was stirred for 24 h at 80 C in an oil bath and then cooled to RT and quenched by the addition of water (20 mL). The resulting solution was extracted with ethyl acetate (2 x 20 mL). and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified via silica gel chromatography and eluted with ethyl acetate/petroleum ether (1 :5) to afford ferf-butyl 3-(4-bromo-2-cyanophenyl)-3,8- diazabicyclo[3.2.1 ]oetane-8-carboxylate as a yellow oil (550 mg, 30%). LCMS (ESI, m/z): 392, 394 [M+H]+
11%	In N,N-dimethyl acetamide; at 100℃; for 3h;	(1355) (1356) iniemsediate S3 (1357) Into a 50-mL round-bottom flask was added 5-bromo-2~fluorobenzonitrile (1.03 g, 5.17 mmol), tert-butyl 3,8-diazabicyco[3.2.1]octane-8-carboxylate (1 .00 g, 4.71 mmol), potassium carbonate (1.30 g, 9.43 mmol), and DMA (10 mL). The reaction mixture was stirred for 3 h at 100 C and then cooled and extracted with ethyl acetate (3 15 mL). The combined organic layers were then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by FCC eluting with ethyl acetate/petroleum ether (1 :3) to afford tert-butyl 3-(4-bromo-2-cyanophenyl)-3,8-diazabicycio[3.2.1]octane-8- carboxylate as a light yellow oil (196 nig. 11%). LCMS (ESI, m/z) 392, 394 j M I I ] .

Reference： [1]Patent: WO2017/139779,2017,A1 .Location in patent: Paragraph 00272
[2]Patent: WO2017/139778,2017,A1 .Location in patent: Paragraph 00440

56
[ 824-51-1 ]
[ 179897-89-3 ]
[ 1420532-29-1 ]

Reference： [1]Patent: WO2013/10880,2013,A1

57
[ 442150-49-4 ]
[ 179897-89-3 ]
5-bromo-2-((6-bromo-1-fluoronaphthalen-2-yl)oxy)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
4.25 g	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24.0h;	Step 2 (0296) 5-bromo-2-fluorobenzonitrile (2.293 g, 11.46 mmol), 6-bromo-l- fluoronaphthalen-2-ol (3.14 g, 11.46 mmol), and Cs2C03 (7.47 g, 22.93 mmol) were added into a 500 ML flask. DMF (115 ml) was added. The solution was stirred at 80C for 24 hours. (0297) EtOAc (150 mL) and water (100 mL) were added. The organic layer was separated and washed with water (100 mL x 2) , brine, dried over anhydrous Na2SC"4, filtered and concentrated. The product was purified by SiC"2 chromatography (120 g, Hexane/EtOAc 0% to 50%) to give 4- bromo-2-((6-bromo-l-fluoronaphthalen-2-yl)oxy)benzonitrile (4.25 g, 88%). LCMS: 424.0 (0298) [M+H]+

Reference： [1]Patent: WO2017/184476,2017,A1 .Location in patent: Page/Page column 45

58
[ 7589-27-7 ]
[ 179897-89-3 ]
5-bromo-2-(4-fluorophenethoxy)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%	With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide for 3h;	5-Bromo-2-(4-fiuorophenethoxy)benzonitrile. To a solution of 2-(4-fluorophenyl)ethanol (2.57 g, 12.8 mmol, 1 equiv) in DMF (24 mL) was added KOtBu (2.02 g, 18.0 mmol, 1.4 equiv) and 5-bromo-2- fluorobenzonitrile (1.80 g, 12.8 mmol, 1 equiv). After stirring 3 h, the reaction was dilutewith ether. The ether solution was washed with water, brine, dried (Na2SO4), and concentrated in vacuo. The cmde product was purified by silica gel flash chromatography (0-30% EtOAc in hexane) to provide the product (2.24 g, 55%) as a pale yellow oil. ‘H NMR (500 MI-Tz, CDC13) 7.67 (d,J=2.4 Hz, 1H), 7.61 (dd,J= 9.0, 2.5 Hz, 1H), 7.32 (t,J 6.7 Hz, 2H), 7.04 (t, J 8.7 Hz, 2H), 6.82 (d, J 9.0 Hz, 1H), 4.23 (t, J 6.5 Hz, 2H), 3.15 (t, J= 6.5 Hz, 2H), 1.60 - 1.50 (m, 5H).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2018/127800, 2018, A1 Location in patent: Page/Page column 68; 69

59
[ 74-89-5 ]
[ 179897-89-3 ]
[ 106874-91-3 ]

Yield	Reaction Conditions	Operation in experiment
	In water; acetonitrile at 80℃; for 12h; Inert atmosphere;

Reference： [1]Whyte, Andrew; Burton, Katherine I.; Zhang, Jingli; Lautens, Mark [Angewandte Chemie - International Edition, 2018, vol. 57, # 42, p. 13927 - 13930][Angew. Chem., 2018, vol. 130, p. 14123 - 14126,4]

60
[ 761446-45-1 ]
[ 179897-89-3 ]
[ 1093304-86-9 ]

Reference： [1]Patent: WO2008/154241,2008,A1

61
[ 442150-49-4 ]
[ 179897-89-3 ]
C₁₇H₈Br₂FNO [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 700 - 706

62
[ 91270-68-7 ]
[ 179897-89-3 ]
C₁₇H₉Br₂NO [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 700 - 706

63
[ 624-39-5 ]
[ 179897-89-3 ]
6,6'-(1,4-phenylenebis(sulfanediyl))bis(3-bromobenzonitrile) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With sodium hydride In N,N-dimethyl-formamide at 130℃; for 5h;
438 mg	With sodium hydride In N,N-dimethyl-formamide at 130℃; for 5h; Inert atmosphere;	1 150mg compound 1,180mg compound sodium hydride is dissolved in 10ml ultra-dry N,N-dimethylformamide (DMF),Evacuate and vent nitrogen.Dissolve 500 mg of compound 2 in 10 ml of DMF,And added to the solution of compound 1,The reaction mixture was heated to 130°C for 5h.Add 100ml of water to the reacted solution,The precipitate was filtered out and column chromatography yielded 438 mg of product 3.

Reference： [1]Liu, Jianjun; Li, Zhiyi; Hu, Taiping; Wei, Xiaofang; Wang, Ruifang; Hu, Xiaoxiao; Gao, Honglei; Liu, Guanhao; Yi, Yuanping; Yamada-Takamura, Yukiko; Lee, Chun-Sing; Wang, Pengfei; Wang, Ying [Organic Letters, 2019, vol. 21, # 21, p. 8832 - 8836]
[2]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES; Technical Institute of Physics & Chemistry(in: CAS) - CN112390811, 2021, A Location in patent: Paragraph 0122-0125

64
[ 1121-92-2 ]
[ 179897-89-3 ]
5-bromo-2-(azocan-1-yl)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate In N,N-dimethyl-formamide at 70 - 80℃;	4.1.1. General procedure for the preparation of compounds 2aee General procedure: A mixture of compound 1 (5.0 mmol), alkylamine (15.0 mmol),and K2CO3 (15.0 mmol) in DMF (10 mL) was reacted at 70e80 C for3e5 h. After the reaction was complete, the mixture was pouredinto H2O (100 mL) and extracted with ethyl acetate (100 mL 2).The organic layer was collected, washed with brine (100 mL 3),dried over anhydrous Na2SO4, and concentrated under vacuum toyield the crude product, which was purified by flash columnchromatography (0e15% ethyl acetate in petroleum ether).

Reference： [1]Li, Jing; Li, Xiaolei; Li, Yuanyuan; Zhang, Lei; Zhou, Haiyan; Zhu, Xinying [European Journal of Medicinal Chemistry, 2020, vol. 186]

65
[ 57102-93-9 ]
[ 179897-89-3 ]
C₂₀H₁₀BrN₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12 g	Stage #1: (9H)-carbazole-3-carbonitrile With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.25h; Stage #2: 5-Bromo-2-fluoro-benzonitrile In N,N-dimethyl-formamide; mineral oil at 80℃;	1 Synthesis of Intermediate EH1(1) In a 500 ml round-bottom flask in a water bath at room temperature, 8.8 g (46 mmol) of 3-cyanide carbazole (Compound I-1) was mixed with 250 ml of N,N-dimethylformamide (DMF), and 1.84 g (46 mmol, 1 eq) of 60 wt % sodium hydride (NaH) in mineral oil was slowly added to the mixed solution at room temperature (resulting in the production of hydrogen). Afterwards, the resulting mixed solution was stirred at room temperature for 15 minutes, and then, 11.0 g (55 mmol, 1.2 eq) of Compound I-2 was added thereto at once. The temperature was slowly raised up to 80° C., and the resulting mixed solution was stirred overnight. The temperature of the mixed solution thus obtained was cooled to room temperature, and excess water was poured into the mixture to precipitate a solid product. 50 ml of ethyl acetate was added to the mixed solution which was then stirred. A solid product obtained by filtration was washed with 50 ml of ethyl acetate, and a resulting product obtained therefrom was dried without further purification, thereby obtaining 12 g (purity of 99.88% by LC-MS) of a white solid product, Intermediate EH1(1).

Reference： [1]Current Patent Assignee: SAMSUNG ELECTRONICS CO.,LTD. - US2020/91439, 2020, A1 Location in patent: Paragraph 0268-0270

66
[ 57103-03-4 ]
[ 179897-89-3 ]
C₃₉H₂₁N₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.17 h / 20 °C 1.2: 80 °C 2.1: potassium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / tetrahydrofuran; water

Reference： [1]Current Patent Assignee: SAMSUNG ELECTRONICS CO.,LTD. - US2020/91439, 2020, A1

67
[ 57103-03-4 ]
[ 179897-89-3 ]
C₂₁H₉BrN₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30 g	Stage #1: 9H-carbazole-3,6-dicarbonitrile With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.166667h; Stage #2: 5-Bromo-2-fluoro-benzonitrile In N,N-dimethyl-formamide; mineral oil at 80℃;	2 Synthesis of Intermediate EH2(1) In a 500 ml round-bottom flask in a water bath at room temperature, 17.4 g (80 mmol) of 3,6-dicyanide carbazole (Compound I-4) was mixed with 200 ml of N,N-dimethylformamide (DMF), and 3.6 g (90 mmol, 1 eq) of 60 wt % sodium hydride (NaH) in mineral oil was slowly added to the mixed solution at room temperature (resulting in the production of hydrogen). Here, 150 ml of N,N-dimethylformamide (DMF) was used to wash out the solid products attached to a container wall. Afterwards, the mixed solution containing the washed solid products was stirred for 10 minutes at room temperature, and 20 g (100 mmol, 1.25 eq) of Compound I-2 was added thereto at once. The temperature was slowly raised up to 80° C., and the resulting mixed solution was stirred overnight. The mixed solution thus obtained was cooled to room temperature, and excess water was poured into the mixture to precipitate a solid product. 50 ml of ethyl acetate was added to the mixed solution which was then stirred. A solid product obtained by filtration was washed with 50 ml of ethyl acetate, and a resulting product obtained therefrom was dried without further purification, thereby obtaining 30 g (purity of 99.69%) of Intermediate EH2(1).

Reference： [1]Current Patent Assignee: SAMSUNG ELECTRONICS CO.,LTD. - US2020/91439, 2020, A1 Location in patent: Paragraph 0274-0276

68
[ 1637752-63-6 ]
[ 179897-89-3 ]
[ 2593379-32-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With caesium carbonate In N,N-dimethyl-formamide at 150℃; for 16h;	1.2.3 (3) Synthesis of compound 2-3 20 g (60.17 mmol) of compound 2-2, 2.03 g (60.17 mmol) of 5-bromo-2-fluorobenzonitrile,And 39.20 g (120.33 mmol) of cesium carbonate was suspended in 300 ml of dimethylformamide and stirred at 150° C. for 16 hours. After completion of the reaction, extraction was performed with dichloromethane and distilled water, and the organic layer was distilled under reduced pressure and then subjected to silica gel column to obtain compound 2-3,24.66 g (yield: 80%) was obtained.
65%	With caesium carbonate In N,N-dimethyl-formamide at 150℃; for 16h;	5.5-3 5-3) Synthesis of compound 5-3 5-phenyl-5,8-dihydroindolo[2,3-c]carbazole 20g (60.2 mmol), 5-bromo-2-fluorobenzonitrile 12g (60.2 mmol), cesium carbonate 39.2g (120.3 mmol) was suspended in 300 ml of dimethylformamide and then stirred at 150° C. for 16 hours. After the reaction was completed, the mixture was extracted with dichloromethane and distilled water, and the organic layer was distilled under reduced pressure and then subjected to silica gel column to obtain Compound 5-3, 20g (yield: 65%).

Reference： [1]Current Patent Assignee: SOULBRAIN CO.,LTD. - KR2021/50829, 2021, A Location in patent: Paragraph 0122; 0127; 0134-0136
[2]Current Patent Assignee: SOULBRAIN CO.,LTD. - KR2021/33332, 2021, A Location in patent: Paragraph 0157; 0164-0166

69
[ 23719-80-4 ]
[ 179897-89-3 ]
[ 1222368-75-3 ]

Yield	Reaction Conditions	Operation in experiment
49.37%	Stage #1: cyclopropylmagnesium bromide; 5-Bromo-2-fluoro-benzonitrile In tetrahydrofuran at -78 - 25℃; for 2.5h; Inert atmosphere; Stage #2: With hydrogenchloride; water for 6h;	1 Step 1. Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 5-bromo-2-fluorobenzonitrile (5.5 g, 27.499 mmol, 1.00 equiv), tetrahydrofuran (110.00 mL). Bromo(cyclopropyl)magnesium(1M in THF) (68.75 mL, 68.748 mmol, 2.50 equiv) was added and the resulting solution was stirred for 2 h at -78 °C. The resulting solution was allowed to react, with stirring, for an additional 30 min at 25 °C.The reaction was then quenched by the addition of 100 mL of HCl (10%) and was stired for an additional 6 h.The resulting solution was extracted with 3 x 50 mL of ethyl acetate and the aqueous layers combined. The resulting mixture was washed with 3 x 50 mL of brine. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/hexane (1:10). This resulted in 3.3 g (49.37%) of (5-bromo-2- fluorophenyl)(cyclopropyl)methanone as a off-white solid. LCMS: [M+1]+=243.

Reference： [1]Current Patent Assignee: BRIDGE MEDICINES; MILLER MICHAEL; STAMFORD ANDREW; KHAN TANWEER; THE ROCKEFELLER UNIVERSITY - WO2021/127166, 2021, A1 Location in patent: Paragraph 00172-00173

70
[ 179897-89-3 ]
[ 188646-83-5 ]
[ 2762613-40-9 ]

Yield	Reaction Conditions	Operation in experiment
92%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 110℃; for 4h;	A Step A: 5-bromo-2-[4-(dimethoxymethyl)piperidin-1-yl]benzonitrile A solution of 5-bromo-2-fluorobenzonitrile (3.00 g, 15.0 mmol), dimethylsulfoxide (60 mL), diisopropylethylamine (3.88 g, 30.0 mmol), and 4-(dimethoxymethyl)piperidine (2.50 g, 15.7 mmol) was stirred for 4 h at 110 °C. The reaction mixture was cooled and water (300 mL) was added. The resulting mixture was extracted with 3 x 100 mL of ethyl acetate (3 x 100 mL). The combined organic fractions were washed with water (100 mL) and saturated aqueous sodium chloride (100 mL) and concentrated. Purification of the residue by silica gel column chromatography (1:1 ethyl acetate:petroleum ether) afforded 5-bromo-2-[4- (dimethoxymethyl)piperidin-1-yl]benzonitrile (4.7 g, 92%) as a yellow solid. MS (ESI): m/z 339.15 [M+H]+
92%	With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 110℃; for 4h;	A Step A: 5-bromo-2-[4-(dimethoxymethyl)piperidin-1-yl]benzonitrile A solution of 5-bromo-2-fluorobenzonitrile (3.00 g, 15.0 mmol), dimethylsulfoxide (60 mL), diisopropylethylamine (3.88 g, 30.0 mmol), and 4-(dimethoxymethyl)piperidine (2.50 g, 15.7 mmol) was stirred for 4 h at 110 °C. The reaction mixture was cooled and water (300 mL) was added. The resulting mixture was extracted with 3 x 100 mL of ethyl acetate (3 x 100 mL). The combined organic fractions were washed with water (100 mL) and saturated aqueous sodium chloride (100 mL) and concentrated. Purification of the residue by silica gel column chromatography (1:1 ethyl acetate:petroleum ether) afforded 5-bromo-2-[4- (dimethoxymethyl)piperidin-1-yl]benzonitrile (4.7 g, 92%) as a yellow solid. MS (ESI): m/z 339.15 [M+H]+

Reference： [1]Current Patent Assignee: ARVINAS - WO2022/47145, 2022, A1 Location in patent: Paragraph 00290
[2]Current Patent Assignee: ARVINAS - WO2022/47145, 2022, A1 Location in patent: Paragraph 00290

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Ghs Precautionary Statements

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

Ghs Hazard Statements

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