[ CAS No. 27996-87-8 ] {[proInfo.proName]}

Name: 27996-87-8|2-Fluoro-5-nitrobenzaldehyde|98%
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Quality Control of [ 27996-87-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 27996-87-8 ]

Product Details of [ 27996-87-8 ]

CAS No. :	27996-87-8	MDL No. :	MFCD00042298
Formula :	C₇H₄FNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	VVXFDFQEIRGULC-UHFFFAOYSA-N
M.W :	169.11	Pubchem ID :	2734770
Synonyms :

Calculated chemistry of [ 27996-87-8 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	40.61
TPSA :	62.89 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.4 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.03
Log Po/w (XLOGP3) :	1.31
Log Po/w (WLOGP) :	1.97
Log Po/w (MLOGP) :	0.69
Log Po/w (SILICOS-IT) :	0.26
Consensus Log Po/w :	1.05

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.95
Solubility :	1.89 mg/ml ; 0.0112 mol/l
Class :	Very soluble
Log S (Ali) :	-2.23
Solubility :	0.993 mg/ml ; 0.00587 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.0
Solubility :	1.69 mg/ml ; 0.01 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	3.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.66

Safety of [ 27996-87-8 ]

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

Application In Synthesis of [ 27996-87-8 ]

* 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 [ 27996-87-8 ]
Downstream synthetic route of [ 27996-87-8 ]

[ 27996-87-8 ] Synthesis Path-Upstream 1~14

1
[ 27996-87-8 ]
[ 5401-94-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrazine hydrate In N,N-dimethyl-formamide at 23℃; for 2 h; Inert atmosphere	General procedure: To a stirred solution of 5 or 6 (1.0 mmol) in DMF (5 mL) at 23 °C was added NH2NH2.H2O(3.0 mmol for 5, 2.0 mmol for 6). The solution was stirred at 23 °C for 2 h at which time thinlayer chromatography (TLC, 20percent EtOAc in hexanes) indicated complete consumption of the startingcarbonyl compound. The crude mixture was added to water and extracted with EtOAc (2 Χ 15 mL).The combined organic layers were washed with water and saturated aq NaCl, dried (MgSO₄), filtered,and concentrated under vacuum to give the pure indazole products.

Reference： [1] Molecules, 2018, vol. 23, # 3,
[2] Organic Process Research and Development, 2011, vol. 15, # 3, p. 565 - 569

2
[ 27996-87-8 ]
[ 53473-85-1 ]

Reference： [1] Patent: WO2017/218960, 2017, A1,

3
[ 27996-87-8 ]
[ 555-96-4 ]
[ 23856-20-4 ]

Reference： [1] Organic Process Research and Development, 2011, vol. 15, # 3, p. 565 - 569

4
[ 27996-87-8 ]
[ 2365-48-2 ]
[ 20699-86-9 ]

Yield	Reaction Conditions	Operation in experiment
5.8 g	With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 2 h;	A mixture of 5.00 g of 2-fluoro-5-nitrobenzaldehyde, 3.76 g of methyl thioglycolate, 4.18 g of potassium carbonate,and 30 ml of N,N-dimethylformamide was stirred for 2 hours at 60°C. The reaction mixture was cooled to roomtemperature. Water was added to the reaction mixture, and extraction was performed three times by using ethyl acetate.The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and thenconcentrated under reduced pressure. The residues were recrystallized from methanol, thereby obtaining 5.8 g of methyl5-nitrobenzo[b]thiophene-2-carboxylate

Reference： [1] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 9, p. 963 - 967
[2] ACS Medicinal Chemistry Letters, 2015, vol. 6, # 9, p. 1010 - 1014
[3] Patent: EP2926660, 2015, A1, . Location in patent: Paragraph 0271
[4] Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 19, p. 4684 - 4686

5
[ 27996-87-8 ]
[ 20699-85-8 ]

Reference： [1] Patent: EP2926660, 2015, A1,

6
[ 27996-87-8 ]
[ 63878-73-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	at 0℃; for 3 h;	Example 29 - Preparation of 7-chloro-A/-(3-((diethylamino)methyl)-4- fluorophenyl)quinolin-4-amine (compound 84); Step A: (2-Fluoro-5-nitro-phenyl)-methanol; To a solution of 2-fluoro-5-nitro-benzaldehyde (1000mg, 5.91 mmoles) in MeOH (10mL) was added NaBH₄ (182mg, 4.82mmoles). The reaction mixture was stirred for 3h at 0°C. The reaction mixture was acidified with HCI 1 M until pH4, concentrated. 50mL of water was added and the compound was extracted with Et₂0. The organic layer was dried over MgS0₄, filtered, evaporated. Expected compound was obtained as a pale yellow solid (1007 mg, 99percent yield), mp = 62-64 ^<C. H NMR (300 MHz, CDCI₃) δ 8.43 (dd, 6-CH, J= 6.2Hz and 2.9Hz, 1 H), 8.19 (ddd, J= 9Hz, 4.5Hz and 2.9Hz, 1 H), 7.20 (dd, J= 9.0Hz and 9.0Hz, 1 H), 4.85 (d, J = 3.6Hz, 2H), 2.12 (s large, 1 H). ³C NMR (75 MHz, CDCI₃) δ 125.0 (CH, d, J = 10.0Hz), 124.7 (CH, d, J= 6.9Hz), 1 16.2 (CH, d, J= 23.6Hz), 58.2 (CH₂).
99.8%	at 0 - 20℃; for 1 h;	Step 1 (2-Fluoro-5-nitrophenyl)methanol To a stirred solution of 2-fluoro-5-nitrobenzaldehyde (30 g, 177.5 mmol) in methanol (350 mL) NaBH₄ (8.1 g, 213.01 mmol) was added portion wise at 0° C. The reaction mixture was allowed warm to room temperature and stirred for 1 h. After completion of the reaction as indicated by TLC, the solvents were removed by rotary evaporation. The residue was diluted with ice-cold water (100 mL) and the aqueous layer was extracted with EtOAc (3*150 mL), washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to afford (2-fluoro-5-nitrophenyl)methanol (30.3 g, yield: 99.8percent, LC-MS: 96.7percent) as an off-white solid. ES+, m/z 172.3 [M+1].

Reference： [1] Heterocyclic Communications, 2010, vol. 16, # 4-6, p. 235 - 239
[2] Patent: WO2011/73322, 2011, A1, . Location in patent: Page/Page column 48
[3] Patent: US2017/369489, 2017, A1, . Location in patent: Paragraph 0453; 0465
[4] Journal of Heterocyclic Chemistry, 2008, vol. 45, # 2, p. 547 - 550
[5] Chemistry - A European Journal, 2015, vol. 21, # 32, p. 11462 - 11474
[6] Journal of Medicinal Chemistry, 1990, vol. 33, # 1, p. 327 - 336
[7] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 5, p. 527 - 532
[8] Patent: WO2013/96744, 2013, A1, . Location in patent: Page/Page column 226

7
[ 27996-87-8 ]
[ 63878-68-2 ]

Reference： [1] Patent: WO2013/96744, 2013, A1,

8
[ 6361-21-3 ]
[ 27996-87-8 ]

Reference： [1] Patent: US4456772, 1984, A,
[2] Patent: US2009/264426, 2009, A1, . Location in patent: Page/Page column 44
[3] Patent: WO2007/29847, 2007, A1, . Location in patent: Page/Page column 67
[4] Dyes and Pigments, 2016, vol. 124, p. 72 - 81

9
[ 6361-21-3 ]
[ 27996-87-8 ]

Reference： [1] Patent: US4456772, 1984, A,

10
[ 374538-01-9 ]
[ 27996-87-8 ]

Reference： [1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 28, p. 6751 - 6756

11
[ 446-52-6 ]
[ 27996-87-8 ]

Reference： [1] Journal of Organic Chemistry, 2011, vol. 76, # 19, p. 8088 - 8094

12
[ 455-88-9 ]
[ 27996-87-8 ]

Reference： [1] Canadian Journal of Chemistry, 1960, vol. 38, p. 712 - 719

13
[ 27996-87-8 ]
[ 84832-00-8 ]

Reference： [1] Journal of Medicinal Chemistry, 1990, vol. 33, # 1, p. 327 - 336
[2] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 5, p. 527 - 532
[3] Patent: WO2014/98831, 2014, A1, . Location in patent: Page/Page column 35; 36

14
[ 27996-87-8 ]
[ 84832-00-8 ]

Reference： [1] Patent: US4873238, 1989, A,

[ 27996-87-8 ] Synthesis Path-Downstream 1~88

1
[ 27996-87-8 ]
[ 63878-73-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With methanol; sodium tetrahydroborate; at 0℃; for 3h;	Example 29 - Preparation of 7-chloro-A/-(3-((diethylamino)methyl)-4- fluorophenyl)quinolin-4-amine (compound 84); Step A: (2-Fluoro-5-nitro-phenyl)-methanol; To a solution of <strong>[27996-87-8]2-fluoro-5-nitro-benzaldehyde</strong> (1000mg, 5.91 mmoles) in MeOH (10mL) was added NaBH4 (182mg, 4.82mmoles). The reaction mixture was stirred for 3h at 0C. The reaction mixture was acidified with HCI 1 M until pH4, concentrated. 50mL of water was added and the compound was extracted with Et20. The organic layer was dried over MgS04, filtered, evaporated. Expected compound was obtained as a pale yellow solid (1007 mg, 99% yield), mp = 62-64 <C. H NMR (300 MHz, CDCI3) delta 8.43 (dd, 6-CH, J= 6.2Hz and 2.9Hz, 1 H), 8.19 (ddd, J= 9Hz, 4.5Hz and 2.9Hz, 1 H), 7.20 (dd, J= 9.0Hz and 9.0Hz, 1 H), 4.85 (d, J = 3.6Hz, 2H), 2.12 (s large, 1 H). 3C NMR (75 MHz, CDCI3) delta 125.0 (CH, d, J = 10.0Hz), 124.7 (CH, d, J= 6.9Hz), 1 16.2 (CH, d, J= 23.6Hz), 58.2 (CH2).
99.8%	With methanol; sodium tetrahydroborate; at 0 - 20℃; for 1h;	Step 1 (2-Fluoro-5-nitrophenyl)methanol To a stirred solution of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (30 g, 177.5 mmol) in methanol (350 mL) NaBH4 (8.1 g, 213.01 mmol) was added portion wise at 0 C. The reaction mixture was allowed warm to room temperature and stirred for 1 h. After completion of the reaction as indicated by TLC, the solvents were removed by rotary evaporation. The residue was diluted with ice-cold water (100 mL) and the aqueous layer was extracted with EtOAc (3*150 mL), washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford (2-fluoro-5-nitrophenyl)methanol (30.3 g, yield: 99.8%, LC-MS: 96.7%) as an off-white solid. ES+, m/z 172.3 [M+1].
	With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 1h;	A mixture of Compound 1 (9.6 g, 56.8 mmol) in MeOH (100 mL) was added NaBHj in portions at 0 C. After addition, the reaction mixture was stirred for 1 h at rt. The reaction mixture was quenched with 1 N HC1, and concentrated in vacuo. The residue was extracted with EtOAc (100 mL3). The organic layer was concentrated to give the crude product, which was used for the next step directly. (9.8 g, crude)

Reference： [1]Heterocyclic Communications,2010,vol. 16,p. 235 - 239
[2]Patent: WO2011/73322,2011,A1 .Location in patent: Page/Page column 48
[3]Patent: US2017/369489,2017,A1 .Location in patent: Paragraph 0453; 0465
[4]Journal of Heterocyclic Chemistry,2008,vol. 45,p. 547 - 550
[5]Chemistry - A European Journal,2015,vol. 21,p. 11462 - 11474
[6]Journal of Medicinal Chemistry,1990,vol. 33,p. 327 - 336
[7]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 527 - 532
[8]Patent: WO2013/96744,2013,A1 .Location in patent: Page/Page column 226

2
[ 27996-87-8 ]
[ 63878-71-7 ]

Yield	Reaction Conditions	Operation in experiment
98%	With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃;Cooling with ice;	<strong>[27996-87-8]2-Fluoro-5-nitrobenzaldehyde</strong> Int-3a (3.7 g, 22.0 mmol) was dissolved in anhydrous DCM (35 mL)Cooling in the ice water bath,DAST (17.7 g, 110 mmol) DCM solution (15 mL) was slowly added dropwise.After the addition, the reaction was carried out for 1 hour in an ice water bath and allowed to react at room temperature overnight.The reaction mixture was slowly added dropwise with EtOAc EtOAc (EtOAc m.Purified by column chromatography to give the title compound Int-3b (4.1g), yield 98%.
82%	With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 16h;Inert atmosphere;	To a stirred solution of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (3 g, 17.75 mmol) in CH2Cl2 (30 mL) under an argon atmosphere was added DAST (2.8 mL, 21.30 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After consumption of the starting material (monitored by TLC), the reaction was quenched with cold water (500 mL) and extracted with CH2Cl2 (2 x 500 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain 2- (difluoromethyl)-1-fluoro-4-nitrobenzene (2.8 g, 82%) as pale brown oil.1H-NMR (CD3OD, 400 MHz): delta 8.55-8.50 (m, 2H), 7.75 (t, 1H), 7.35 (t, 1 H); TLC: 20% EtOAc:hexanes (Rf: 0.5).
82%	With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 16h;Inert atmosphere;	Synthesis of 2-(difluoromethyl)-1-fluoro-4-nitrobenzene To a stirred solution of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (3 g, 17.75 mmol) in CH2Cl2 (30 mL) under an argon atmosphere was added DAST (2.8 mL, 21.30 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. After consumption of the starting material (monitored by TLC), the reaction was quenched with cold water (500 mL) and extracted with CH2Cl2 (2*500 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to obtain 2-(difluoromethyl)-1-fluoro-4-nitrobenzene (2.8 g, 82%) as pale brown oil. 1H-NMR (CD3OD, 400 MHz): delta 8.55-8.50 (m, 2H), 7.75 (t, 1H), 7.35 (t, 1H); TLC: 20% EtOAc:hexanes (Rf: 0.5).

71%	With diethylamino-sulfur trifluoride; In ethanol; dichloromethane; at 20℃; for 2h;	To a solution of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (2.00 g, 11.83 mmol) in DCM (50 mL) was added ethanol (0.069 mL, 1.183 mmol) followed by the addition of DAST (3.28 mL, 24.84 mmol) dropwise at RT. Reaction mixture was stirred at RT for the 2 h before quenching with aqueous saturated solution of NaHCC at OeC. The layers were separated and aqueous layer was extracted with DCM (2/150 mL). The combined organic layers were washed with brine (50 mL), dried (Na2S04) and filtered. The filtrate was concentrated in vacuum and the crude product was purified by flash column chromatography (silica gel) to afford 1.6 g (71%) of the titled compound. 1HNMR (400 MHz, DMSO-d6) \|\|8.54-8.48 (m, 2H), 7.72 (t, J = 9.5 Hz, 1H), 7.35 (t, J = 53.5 Hz, 1H); GC-MS (m/z) 191.05 (M)
2.5 g	With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 18h;Inert atmosphere;	A solution of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (3.0 g, 17 mmol) in DCM (50 mL) was added DAST (3.42 g, 21 mmol) and stirred at RT for 18 h under nitrogen atmosphere. The reaction mass was quenched in ice-water and extracted with DCM. The organic layer was dried and concentrated to afford 2.5 g of desired product. 1H NMR (300 MHz, DMSO 6): delta 7.31 (s, 1H), 7.69 (t, / = 8.7 Hz, 1H), 8.46-8.50 (m, 2H).
2.5 g	With diethylamino-sulfur trifluoride; In dichloromethane; at 20℃; for 18h;Inert atmosphere;	A solution of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (3.0 g, 17 mmol) in DCM (50 mL) was added DAST (3.42 g, 21 mmol) and stirred at RT for 18 h under nitrogen atmosphere. The reaction mass was quenched in ice-water and extracted with DCM. The organic layer was dried and concentrated to afford 2.5 g of desired product.
3.6 g		4.48 g (3.5 ml) of N-ethyl-N-(trifluoro-lambda4-sulphanyl)ethanamine are added, at a temperature in the region of 20 C. and under argon, to a solution of 3.36 g of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> in 100 ml of dichloromethane. After stirring for 3h 30 at a temperature in the region of 20 C., 300 ml of a saturated aqueous solution of sodium hydrogen carbonate are slowly added. After stirring for one hour, the organic phase is washed with 40 ml of water, and then dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 3.6 g of 2-(difluoromethyl)-1-fluoro-4-nitrobenzene are obtained in the form of a yellow liquid

Reference： [1]Patent: CN109897011,2019,A .Location in patent: Paragraph 0319-0321
[2]Patent: WO2015/109109,2015,A1 .Location in patent: Paragraph 0749
[3]Patent: US2017/44182,2017,A1 .Location in patent: Paragraph 1035
[4]Patent: WO2018/20474,2018,A1 .Location in patent: Page/Page column 160
[5]Australian Journal of Chemistry,1977,vol. 30,p. 1611 - 1615
[6]Patent: WO2013/186692,2013,A1 .Location in patent: Page/Page column 83; 84
[7]Patent: WO2016/25917,2016,A1 .Location in patent: Paragraph 106
[8]Patent: JP5680638,2015,B2 .Location in patent: Paragraph 0306-0308

3
[ 27996-87-8 ]
[ 18257-46-0 ]
2-butyl-6-nitro-quinazoline [ No CAS ]

Reference： [1]Synlett,1999,p. 1993 - 1995

4
[ 27996-87-8 ]
[ 57508-48-2 ]
2-amino-3-ethoxycarbonyl-6-nitroquinoline [ No CAS ]
[ 851266-02-9 ]
diethyl 2,6-diamino-4-(2-fluoro-5-nitrophenyl)-4,5-dihydropyridine-3,5-dicarboxylate [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,2004,vol. 40,p. 888 - 894

5
[ 27996-87-8 ]
[ 34570-17-7 ]
3-amino-7-nitroisoquinoline-4-carboxamide [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,2004,vol. 40,p. 888 - 894

6
[ 27996-87-8 ]
[ 108-95-2 ]
[ 99847-09-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; In 1,4-dioxane; at 70℃;	Example 90a 5-nitro-2-phenoxybenzaldehyde A mixture of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (1.0 g, 5.91 mmol), phenol (0.557 g, 5.91 mmol), and K2CO3 (1.635 g, 11.83 mmol) in dioxane (6 mL) was heated at 70 C. overnight. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate (60 mL). The solution was washed with water (2*30 mL) and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated by rotary evaporation to give the title compound (1.43 g, 99% yield).

Reference： [1]Patent: US2014/256705,2014,A1 .Location in patent: Paragraph 0646
[2]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 2225 - 2233
[3]Journal of the American Chemical Society,2007,vol. 129,p. 5288 - 5295

7
[ 27996-87-8 ]
[ 84832-00-8 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation 20 (5-amino-2-fluoro henyl)methanol To a solution of 2-fluoro-5-nitrobenzaldehyde (5 g, 29.6 mmol) in MeOH (118 ml) was added NaBH4 (1.119 g, 29.6 mmol) portion wise with stirring (gas evolution). The addition took approx. 20 min. When the addition was complete, the reaction mixture was stirred at rt for 30 min. The mixture was quenched by the slow addition of water (100 mL). The mixture was then concentrated to remove MeOH. The remaining aqueous mixture was extracted with EtOAc (3 x 25 mL). The combined extracts were washed with brine, dried over MgS04, filtered and concentrated in vacuo. The resulting residue was taken up in MeOH (118 ml). Pd/C (0.157 g, 1.478 mmol) was added and the resulting mixture was stirred vigorously under an atmosphere of hydrogen for 2 h. The reaction mixture was then filtered through Celite and concentrated in vacuo to give (5- amino-2-fluorophenyl)methanol (80 % yield) which was used without further purification; MS (M+H)+ = 142.1.

Reference： [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 327 - 336
[2]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 527 - 532
[3]Patent: WO2014/98831,2014,A1 .Location in patent: Page/Page column 35; 36

8
[ 109-56-8 ]
[ 57727-06-7 ]
[ 27996-87-8 ]
[ 216008-32-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; sodium tris(acetoxy)borohydride; acetic acid In tetrahydrofuran; ethanol	4.a a a 2-[(2-Fluoro-5-nitrobenzyl)(isopropyl)amino]ethanol oxalate To acetic acid (25.76 ml, 450 mmol) and 2-(isopropylamino)ethanol (51.76 ml, 450 mmol) in dry THF (750 ml) at 0° C. was added 2-fluoro-5-nitrobenzaldehyde (75.88 g, 450 mmol) and sodium triacetoxyborohydride (141.99 g, 670 mmol) portionwise. The reaction was allowed to warm to room temperature and was stirred for 3 h. The mixture was taken up in acidic water and washed with methylene chloride (250 ml), made basic with 50% sodium hydroxide (150 ml) and extracted with methylene chloride (3*250 ml). The extracts were dried with magnesium sulfate, filtered, and concentrated to an oil. The oil was dissolved in 95% ethanol and treated with isopropanol-oxalic acid. The oxalate salt was collected by filtration (31.2 g, 20%), m.p. 106-107° C.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US6489322, 2002, B1

9
[ 6361-21-3 ]
[ 27996-87-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium fluoride; In N-methyl-acetamide; water;	EXAMPLE 6 18.6 g (0.1 mol) of 2-chloro-5-nitrobenzaldehyde and 11.6 g (0.2 mol) of dry potassium fluoride in 50 ml of dimethylformamide are stirred for 12 hours at 100 C. The solvent is then distilled off in vacuo and the residue is stirred in 100 ml of water. The crude 2-fluoro-5-nitrobenzaldehyde is filtered off under suction, washed with water and dried. 16.7 g of 2-fluoro-5-nitrobenzaldehyde with a content of 96% are obtained. Yield: 94.8% of the theoretical yield.
	With potassium fluoride; In N,N-dimethyl-formamide; at 20 - 160℃;	Production Example 28-1 2-Fluoro-5-nitrobenzaldehyde At room temperature, potassium fluoride (15.7 g) was added to a DMF solution (100 mL) of 2-chloro-5-nitrobenzaldehyde (25.0 g). The reaction liquid was stirred at 160 C. for 1.5 hours, then poured into water with ice. After extracted with ethyl acetate, the organic layer was washed with saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1 to 3:1) to obtain the entitled compound (17.1 g).

Reference： [1]Patent: US4456772,1984,A
[2]Patent: US2009/264426,2009,A1 .Location in patent: Page/Page column 44
[3]Patent: WO2007/29847,2007,A1 .Location in patent: Page/Page column 67
[4]Dyes and Pigments,2016,vol. 124,p. 72 - 81

10
tin(II)chloride dihydrate [ No CAS ]
[ 27996-87-8 ]
[ 84832-00-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide; sodium borohydrid; In methanol; ethyl acetate; Petroleum ether;	Step 1 Preparation of 3-Hydroxymethyl-4-fluoroaniline Sodium borohydride (15.0 g, 0.397 mol) was added portionwise to a 0 C. solution of 2-fluoro-5-nitrobenzaldehyde (82.4 g, 0.487 mol) in anhydrous methanol (1 L). The reaction mixture was stirred at 0 C. for 0.5 hours and was quenched by adding 1N hydrochloric acid solution (500 mL), which resulted in a pH range of between 4 and 5. The product, which precipitated out when methanol was removed, was collected by filtration. To obtain additional product, the filtrate was extracted with ether (4500 mL). The ether layer was washed with brine and dried to give crude material which was combined with the other material and recrystallized from ethyl acetate in petroleum ether to give 1-fluoro-2-hydroxymethyl-4-nitrobenzene (69.4 g, 0.406 mol, 83%, mp 50-53 C.). This material was dissolved in ethyl acetate (1 L) and treated with stannous chloride dihydrate (451 g, 1.99 mol) at reflux temperature for 24 hours. The reaction mixture was poured into ice water (1.5 L), basified using 2.5N sodium hydroxide solution to pH 9, and extracted with ethyl acetate (41 L), which was washed with brine and dried. Removal of ethyl acetate gave 3-hydroxymethyl-4-fluoroaniline (34.2 g, 60%, mp 80-84 C.; Tani et al., Chem. Pharm. Bull. 30, 3530, 1982: mp 95-98 C.). 1 H NMR (DMSO, 400 MHz): delta 6.78(d of d, J=10 and 9 Hz, 1H), 6.67(d of d, J=6 and 3 Hz, 1H), 6.41(m, 1H), 5.11(t, J=6 Hz, OH), 4.97(br s, NH2), 4.43(d, J=6 Hz, 2H) IR (KBr, cm-1): 3360, 1250, 1040 MS (m/z): 141(M+, 100), 124(43), 120(47), 112(57), 92(45), 83(32), 65(29).

Reference： [1]Patent: US4873238,1989,A

11
[ 27996-87-8 ]
[ 23356-96-9 ]
[ 918900-48-8 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium cyanoborohydride; acetic acid; In tetrahydrofuran; at 0 - 20℃; for 16h;	To a solution of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (595 mg, 3.52 mmol) in THF (10 ml) was added a solution of (S)-(+)-2-(hydroxymethyl)pyrrolidine in THF (10 ml) followed by 5 acetic acid (251 mul, 4.40 mmol). The mixture was cooled to 0C and sodium cyanoborohydride (276 mg, 4.40 mmol) was added. The cooling bath was removed and the mixture was stirred at RT for 16 h. The mixture was diluted with EtOAc and washed with saturated aqueous sodium hydrogen carbonate. The organic phase was dried (Na2SO4) and the solvent was evaporated. The residue was purified by column chromatography on silica EPO <DP n="45"/>eluting with a gradient of 0-7% methanol in dichloromethane to give an oil (629 mg, 70%). MS ESI m/z M+H+ 255.

Reference： [1]Patent: WO2007/4959,2007,A1 .Location in patent: Page/Page column 43-44

12
[ 27996-87-8 ]
[ 75-08-1 ]
[ 960232-60-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 8h;	Intermediate 3A: [00189] To <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (25 g, 148 mmol) and ethylthiol (15.1 mL, 203 mmol) in DMF (100 mL) was added potassium carbonate (35.8 g, 260 mmol). The reaction mixture was stirred at 60 0C for 8.0 h. After it cooled to rt, cold water (200 mL) was added and stirred at rt for 15 min. The precipitate was collected by filtration and washed with water. After drying, Intermediate 3A (25 g) was obtained as a yellow solid. The filtrate was extracted with EtOAc, washed with brine and dried over ^2SO4. After evaporation of solvent, the crude was triturated withEtOAc/hexane (1 :3) to give a second crop of Intermediate 3A (3 g, total 90% yield). 1H NMR (400 MHz, CDCl3) delta ppm 1.44 (t, J=7.47 Hz, 3 H) 3.08 (q, J=7.47 Hz, 2 H) 7.46 (d, J=8.79 Hz, 1 H) 8.30 (dd, J=8.79, 2.64 Hz, 1 H) 8.62 (d, J=2.20 Hz, 1 H) 10.25 (s, 1 H).
90%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 8h;	To <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (25 g, 148 mmol) and ethylthiol (15.1 mL, 203 mmol) in DMF (100 mL) was added potassium carbonate (35.8 g, 260 mmol). The reaction mixture was stirred at 60 C. for 8.0 h. After it cooled to rt, cold water (200 mL) was added and stirred at rt for 15 min. The precipitate was collected by filtration and washed with water. After drying, 35A (25 g) was obtained as a yellow solid. The filtrate was extracted with EtOAc, washed with brine and dried over Na2SO4. After evaporation of solvent, the crude was triturated with EtOAc/hexane (1:3) to give a second crop of 35A (3 g, total 90% yield). 1H NMR (400 MHz, CDCl3) delta ppm 1.44 (t, J=7.47 Hz, 3H) 3.08 (q, J=7.47 Hz, 2H) 7.46 (d, J=8.79 Hz, 1H) 8.30 (dd, J=8.79, 2.64 Hz, 1H) 8.62 (d, J=2.20 Hz, 1H) 10.25 (s, 1H).

Reference： [1]Patent: WO2008/79759,2008,A1 .Location in patent: Page/Page column 84
[2]Patent: US2010/227894,2010,A1 .Location in patent: Page/Page column 39

13
[ 6863-32-7 ]
[ 27996-87-8 ]
[ 960234-41-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 45℃;	Example 22: methyl 4-(cyclopropylsulfonyl)-3-((R)-l-((R)-2-(4-fluoro-3- methoxyphenyl)-2-(4-oxo-3,4-dihydroquinazolin-6-ylamino)acetyl)pyrrolidin-2- yl)phenylcarbamate; <n="141"/>[00298] Freshly prepared cyclopropyl thiol in THF/diethyl ether (J. Am. Chem. Soc. 1992, 114(9), 3497) was added to <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (3.4 g, 20 mmol, 1.0 eq.) and K2CO3 (4.83 g, 35 mmol) in DMF (20 mL). The mixture was stirred at45 0C for 1.0 h and at rt over night. It was diluted with EtOAc and washed with water. The aqueous was extracted with EtOAc and the combined organic layers were washed with brine and dried OVCr Na2SO4. After evaporation of solvent, the crude was triturated with EtOAc/hexanes (70/120). The solid was collected to give 22 A (3.2 g). The filtrate was condensed and triturated again to give a second crop of 22A (0.5 g, total yield 85%). 1H NMR (400 MHz, CDCl3) delta ppm 0.74 - 0.83 (m, 2 H) 1.20 -1.28 (m, 2 H) 2.13 - 2.19 (m, 1 H) 7.95 (d, J=9.23 Hz, 1 H) 8.33 (dd, J=8.79, 2.64 Hz, 1 H) 8.62 (d, J=2.64 Hz, 1 H) 10.15 (s, 1 H).
85%	With potassium carbonate; In tetrahydrofuran; diethyl ether; N,N-dimethyl-formamide; at 20 - 45℃;	Freshly prepared cyclopropyl thiol in THF/diethyl ether (J. Am. Chem. Soc. 1992, 114(9), 3497) was added to <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (3.4 g, 20 mmol, 1.0 eq.) and K2CO3 (4.83 g, 35 mmol) in DMF (20 mL). The mixture was stirred at 45 C. for 1.0 h and at rt over night. It was diluted with EtOAc and washed with water. The aqueous was extracted with EtOAc and the combined organic layers were washed with brine and dried over Na2SO4. After evaporation of solvent, the crude was tritutated with EtOAc/hexanes (70/120). The solid was collected to give 76A (3.2 g). The filtrate was condensed and triturated again to give a second crop of 76A (0.5 g, total yield 85%). 1H NMR (400 MHz, CDCl3) delta ppm 0.74-0.83 (m, 2H) 1.20-1.28 (m, 2H) 2.13-2.19 (m, 1H) 7.95 (d, J=9.23 Hz, 1H) 8.33 (dd, J=8.79, 2.64 Hz, 1H) 8.62 (d, J=2.64 Hz, 1H) 10.15 (s, 1H).

Reference： [1]Patent: WO2008/79759,2008,A1 .Location in patent: Page/Page column 139-140
[2]Patent: US2010/227894,2010,A1 .Location in patent: Page/Page column 61

14
cis-2,6-dimethylmorpholine [ No CAS ]
[ 27996-87-8 ]
[ 679839-07-7 ]

Yield	Reaction Conditions	Operation in experiment
93.5%	With triethylamine; In acetonitrile; at 85℃; for 12h;	To a stirred solution of <strong>[27996-87-8]2-fluoro-5-nitro-benzaldehyde</strong> (5 g, 29.6 mmol) in dry acetonitrile (50 mL), was added triethylamine (8.98 g, 88.6 mmol) followed by cis-2,6 dimethyl morpholine (4.09 g, 35.5 mmol). The reaction mixture was heated at 85 0C for 12 hours under a nitrogen atmosphere, cooled to room temperature, quenched with sat. NaHCO3 solution (25 mL), and extracted with ethyl acetate (3 x 25 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4, and evaporated under reduced pressure to give the title compound as a yellow solid. (Yield: 7.3 g, 93.5 %). MS(ES) MH +: 265.2 for Ci3Hi6N2O4 <n="88"/>1H NMR (400 MHz, CDCl3) delta: 1.27 (d, 6H), 2.84 (t, 2H), 3.34 (d, 2H), 3.91-3.96 (m, 2H), 7.09 (d, IH), 8.34 (dd, IH), 8.65 (s, IH), 10.08 (s, IH).

Reference： [1]Patent: WO2009/4382,2009,A2 .Location in patent: Page/Page column 86-87

15
[ 22300-52-3 ]
[ 27996-87-8 ]
[ 1192847-35-0 ]

Reference： [1]Organic Letters,2009,vol. 11,p. 5026 - 5028

16
[ 27996-87-8 ]
[ 78-95-5 ]
[ 114305-93-0 ]

Yield	Reaction Conditions	Operation in experiment
62%		A mixture of sulfur (90 mg, 2.96 mmol), sodium hydrosulfide hydrate (250 mg, 4.44 mmol) and sodium carbonate (330 mg, 2.37 mmol) in N-methylpyrrolidine (10 mL) was stirred at it for 1 h. A solution of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (500 mg, 2.96 mmol) in N- methylpyrrolidine (2 mL) was added dropwise and the mixture was stirred at rt for 3 h. Chloroacetone (270 mg, 2.96 mmol) was added slowly with cooling and the resulting mixture was stirred at rt overnight. The reaction was quenched with 20 mL of water and sodium hydroxide (1 M) was added to adjust pH to 11. The mixture was extracted with diethyl ether (3 x 50 mL) and the combined organic layer was washed with brine (100 mL), dried over sodium sulfate and filtered. After removing the solvent in vacuo the product was recrystallized from methanol to give a yellow solid (400 mg, 62%). MS (M+H)+ 222.

Reference： [1]Patent: WO2006/66172,2006,A1 .Location in patent: Page/Page column 34

17
[ 27996-87-8 ]
[ 57260-71-6 ]
[ 1017782-93-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;Inert atmosphere;	A suspension of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (3 g, 17.74mmol), tert-butyl piperazine-1-carboxylate (3.30 g, 17.74mmol) and potassium carbonate (3.68 g, 26.6 mmol) inanhydrous DMF (15 mL) was heated to 50 C under anitrogen atmosphere overnight. The reaction mixture was allowed to cool to room temperature, diluted with water (70 mL) and stirred at room temperature for 15 minutes. The precipitated solid was isolated by filtration, washedwith water, sucked dry and freeze-dried overnight to give the title compound as a yellow solid (5.89 g, 99%) . ?H NMR (300 MHz, CDC13) : 3 10.11 (s, 1H) , 8.65 (d, 1H) , 8.33 (dd, 1H), 7.09 (d, 1H), 3.68 (t, 4H), 3.26 (t, 4H), 1.49 (s, 9H) . LCMS (Method C) RT = 1.60 mi m/z = 336 [M+H].
94.8%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;	Add <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (1g, 5.91mmol), piperazine-1-carboxylic acid tert-butyl ester (1.1g, 5.91mmol)Potassium carbonate (1.23 g, 8.87 mmol) was added to DMF (5 mL) and reacted at 50 C overnight.The reaction solution was cooled, poured into water, filtered, and the solid was dried to obtain the title compound (1.88 g, yield: 94.8%) in this step.
78.9%	With potassium carbonate; In dimethyl sulfoxide; at 95℃; for 32h;	To a stirred mixture of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (1.0 g, 1.0 eq) and iert-butyl piperazine-l-carboxylate (1.20 g, 1.1 eq) in DMSO (10 mL) in a vial, K2C03 (2.4 g, 3.0 eq) was added and the mixture was heated to 95C for 32 h. After TLC showed completion of reaction, the mixture was cooled to rt, poured in to ice water and extracted with EtOAc (3 x 25 mL). The organic layer was washed with brine, cold water, dried over anhydrous sodium sulphate, and concentrated to obtain crude yellow solid which was washed with n-hexane to obtain ie/t-butyl 4-(2-formyl-4-nitrophenyl)piperazine-l- carboxylatas yellow solid (1.5 g, 78.9%). 1H NMR (400 MHz, DMSO-d6): delta 10.045 (s, 1H), 8.529 (d, 1H), 8.315 (m, 1H), 7.294 (d, 1H), 3.536 (m, 4H), 3.324 (m, 2H), 2.539 (m, 2H), 1.394 (s, 9H). LCMS calculated for (M) 335.15 found (M+H) 336.15

55%

With potassium carbonate; In N,N-dimethyl-formamide; for 12h;

To a stirred solution of 160 5-fluoro-2-nitro-benzaldehyde (500 mg, 2.95 mmol, 1.0 eq) and 63 tert-butyl piperazine-1-carboxylate (550 mg, 2.95 mmol, 1.0 eq) in 47 DMF (10 mL) was added 64 K2CO3 (611 mg, 4.42 mmol, 1.5 eq). Reaction mixture was heated at 50 C. for 12 h. Progress of the reaction was monitored by LCMS. Upon the consumption of starting material, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL×2). Combined organic layer was washed with water (50 mL×3), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude. The crude was purified by combi-flash (0-50% EtOAc-hexane) to obtain 161 tert-butyl 4-(3-formyl-4-nitro-phenyl)piperazine-1-carboxylate (500 mg, 55%). LCMS: 336 [M+1]+

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 124; 125
[2]Patent: CN110467615,2019,A .Location in patent: Paragraph 0239-0243
[3]Synthesis,2010,p. 4287 - 4299
[4]Patent: WO2015/38417,2015,A1 .Location in patent: Page/Page column 103
[5]Patent: US2019/106436,2019,A1 .Location in patent: Paragraph 0310-0312

18
[ 27996-87-8 ]
[ 13078-04-1 ]
[ 924778-95-0 ]

Reference： [1]Chemistry of Natural Compounds,2011,vol. 46,p. 915 - 919

19
[ 27996-87-8 ]
[ 98-59-9 ]
[ 1071216-94-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydroxide; In tetrahydrofuran; water; at 0 - 10℃; for 2h;	Step B: Toluene-4-sulfonic acid 2-fluoro-5-nitro-benzyl ester; To a solution of NaOH (0.537g, 13.42mmoles) in H20 (4mL) was added a solution of 2-fluoro-5-nitro-phenyl)-methanol (0.999g, 5.84 mmoles) in THF (20mL) at 0C. A solution of TsCI (1 .892g, 9.92mmoles) in THF(10mL) is then added dropwise. The reaction mixture was stirred for 2h at 5-10 C. 50m L of water was added and the compound was extracted with CH2CI2 (3x100ml_). The organic layer was dried over MgS04, filtered, evaporated. Expected compound was precipited with MeOH and purified by TLC (Hex/AcOEt//7/3) and obtained as a white solid (1 .700g, 90% yield), mp = 89-91 <C. H NMR (300 MHz, CDCI3) delta 8.18-8.26 (m, 2H), 7.82 (m, 2H), 7.35 (m, 2H), 7.20 (dd, J= 8.7Hz et 8.7Hz, 1 H), 5.17 (s, 2H), 2.46 (s, 3H). 3C NMR (75 MHz, CDCI3) delta 130.1 (CH), 128.1 (CH), 126.7 (CH, d, J = 10.0Hz), 126.3 (CH, d, J= 5.0Hz), 1 16.7 (CH, d, J= 23.6Hz), 64.1 (CH2), 22.2 (CH3).

Reference： [1]Patent: WO2011/73322,2011,A1 .Location in patent: Page/Page column 48-49

20
[ 27996-87-8 ]
[ 5401-94-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrazine hydrate; In N,N-dimethyl-formamide; at 23℃; for 2h;Inert atmosphere;	General procedure: To a stirred solution of 5 or 6 (1.0 mmol) in DMF (5 mL) at 23 C was added NH2NH2.H2O(3.0 mmol for 5, 2.0 mmol for 6). The solution was stirred at 23 C for 2 h at which time thinlayer chromatography (TLC, 20% EtOAc in hexanes) indicated complete consumption of the startingcarbonyl compound. The crude mixture was added to water and extracted with EtOAc (2 Chi 15 mL).The combined organic layers were washed with water and saturated aq NaCl, dried (MgSO4), filtered,and concentrated under vacuum to give the pure indazole products.

Reference： [1]Molecules,2018,vol. 23
[2]Organic process research and development,2011,vol. 15,p. 565 - 569

21
[ 27996-87-8 ]
[ 555-96-4 ]
[ 23856-20-4 ]

Reference： [1]Organic process research and development,2011,vol. 15,p. 565 - 569

22
[ 123-75-1 ]
[ 27996-87-8 ]
[ 30742-59-7 ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	<strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (1 g, 5.91 mmol) wasdissolved in DMF (10 mL) and pyrrolidine (0.54 mL, 6.50 mmol) was added, followed by DIPEA (2.27 mL, 13.0 mmol) The mixture was stirred overnight at room temperature. Water was added and the resulting precipitate was collected by filtration and dried in vacuo to give thetitle compound (1.30 g, 99%) as a yellow solid which was used without further purification. LCMS (Method C) : = 1.34 mm, m/z = 221 [M+H].

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 269
[2]Organic Letters,2012,vol. 14,p. 1600 - 1603
[3]Organic Letters,2017,vol. 19,p. 1566 - 1569
[4]Green Chemistry,2017,vol. 19,p. 5653 - 5658

23
[ 371-41-5 ]
[ 27996-87-8 ]
[ 57388-43-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 3h;Inert atmosphere;	To a solution of <strong>[27996-87-8]2-fluoro-5-nitro-benzaldehyde</strong> (34) (676 mg, 4.0 mmol) and 4- fluoroorophenol (35) (537 mg, 4.8 mmol) in DMSO (5 mL) was added K2C03 (1.10 g, 8.0 mmol) at room temperature ("rt"). The resulting mixture was flushed with N2 and heated in a sealed vessel with stirring at 120 C for 3 h. After the reaction mixture was cooled to rt and poured into brine, the mixture was extracted with ethyl acetate (35 mL x 3). The combined extracts were washed with brine (10 mL x 2), dried over anhydrous MgS04, filtered, and evaporated to dryness. The residue was purified by a Si02 plug (eluted by 15% EtOAc in hexanes) to afford pure 2-(4-fluoro-phenoxy)-5-nitro-benzaldehyde (36) (1.05 g, 4.0 mmol, 99%) as a viscous oil. ESI MS m/z 262.2 (M+H)+.

Reference： [1]Patent: WO2013/101600,2013,A1 .Location in patent: Paragraph 00383

24
[ 27996-87-8 ]
[ 2365-48-2 ]
[ 20699-86-9 ]

Yield	Reaction Conditions	Operation in experiment
76%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 15h;	General procedure: To a stirred solution of compound 1a-1n (9.90 mmol) in DMF (20 mL) were added methyl thioglycolate (10.9 mmol) and potassium carbonate (39.6 mmol). The resulting mixture was stirred at 60 C for 15 h. The DMF was removed under reduced pressure,water (50 mL) was added and the mixture was extracted with ethylacetate (2 x 40 mL). The combined organic layers were dried withsodium sulfate, filtered, and the solvents were removed under reduced pressure to afford the title compound 2a-2n [31,34].
5.8 g	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 2h;	A mixture of 5.00 g of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong>, 3.76 g of methyl thioglycolate, 4.18 g of potassium carbonate,and 30 ml of N,N-dimethylformamide was stirred for 2 hours at 60C. The reaction mixture was cooled to roomtemperature. Water was added to the reaction mixture, and extraction was performed three times by using ethyl acetate.The collected organic layer was washed with water and saturated saline, dried over magnesium sulfate, and thenconcentrated under reduced pressure. The residues were recrystallized from methanol, thereby obtaining 5.8 g of methyl5-nitrobenzo[b]thiophene-2-carboxylate

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 174,p. 236 - 251
[2]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 963 - 967
[3]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1010 - 1014
[4]Patent: EP2926660,2015,A1 .Location in patent: Paragraph 0271
[5]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 4684 - 4686

25
[ 123-75-1 ]
[ 27996-87-8 ]
[ 1530-45-6 ]
ethyl (E)-3-(5-nitro-2-(pyrrolidin-1-yl)phenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium hydroxide; In water; at 20 - 80℃; for 0.5h;Inert atmosphere; Green chemistry;	General procedure: To a 25 mL three-necked round-bottomed flask was added 4-fluoro-3-nitrobenzaldehyde (2b, 0.1691 g, 1.0 mmol), NaOH(0.0600 g, 1.5 mmol), (2-ethoxy-2-oxoethyl)triphenylphosphoniumbromide (4a, 0.6440 g, 1.5 mmol), piperidine (3b, 0.2968mL, 3.0 mmol), and H2O (5 mL), then heated to 50 C. The reactionprogress was carefully monitored by TLC. After 10 min, thesolvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography.

Reference： [1]Synlett,2015,vol. 26,p. 820 - 826

26
[ 1121-92-2 ]
[ 27996-87-8 ]
[ 1530-45-6 ]
ethyl (E)-3-(2-(azocan-1-yl)-5-nitrophenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium hydroxide In water for 1h; Inert atmosphere; Reflux; Green chemistry; stereoselective reaction;	Typical Procedure for the Preparation of Compound 1 -Wittig-SNAr Reaction General procedure: To a 25 mL three-necked round-bottomed flask was added 4-fluoro-3-nitrobenzaldehyde (2b, 0.1691 g, 1.0 mmol), NaOH(0.0600 g, 1.5 mmol), (2-ethoxy-2-oxoethyl)triphenylphosphoniumbromide (4a, 0.6440 g, 1.5 mmol), piperidine (3b, 0.2968mL, 3.0 mmol), and H2O (5 mL), then heated to 50 °C. The reactionprogress was carefully monitored by TLC. After 10 min, thesolvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography.

Reference： [1]Xu, Zian; Zhai, Wanwan; Feng, Congpeng; Liu, Hongwei; Zhao, Jianhong; Yu, Xinhong [Synlett, 2015, vol. 26, # 6, p. 820 - 826]

27
[ 27996-87-8 ]
[ 147081-29-6 ]
(S)-tert-butyl 4-(2-formyl-4-nitrophenyl)-3-methylpiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 16h;	A stirred mixture of (^-iert-butyl 3-methylpiperazine-l -carboxylate (1.0 g, 1.0 eq), <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (1.26 g, 1.5 eq) and K2C03 (2.0 g, 3.0 eq) in DMF (15.0 mL) in a two necked round bottomed flask was heated at 120C for 16 h. After completion of starting material on TLC, the mixture was quenched with ice cold water and extracted with EtOAc (2 x 250 mL). The organic layer was dried over anhydrous Na2S04> filtered and concentrated to obtain (S)-tert-butyl 4-(2-formyl-4-nitrophenyl)-3- methylpiperazine-1 -carboxylate as yellow liquid (1.4 g, 80%). 1H NMR (400 MHz, CDC13): delta 10.150 (s, 1H), 8.645-8.638 (d, 1H), 8.340-8.310 (dd, 1H), 7.124-7.101 (d, 1H), 4.138-4.077 (m, 1H), 3.810-3.711 (m, 1H), 3.628 (s, 1H), 3.553-3.512 (dd, 1H), 3.418-3.393 (d, 1H), 3.296 (bs, 1H), 3.090-3.061 (d, 1H), 1.455 (s, 9H), 1.091-1.075 (d, 3H). LCMS calculated for (M) 349.38 and found (M+H) 350.00. LCMS showed 98.69% purity

Reference： [1]Patent: WO2015/38417,2015,A1 .Location in patent: Page/Page column 110; 111

28
[ 27996-87-8 ]
[ 170033-47-3 ]
(R)-tert-butyl 4-(2-formyl-4-nitrophenyl)-2-methylpiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;Inert atmosphere;	A suspension of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (2.53 g,14.98 mmol), (R)-tert-butyl 2-methylpiperazine-1- carboxylate (3 g, 14.98 mmol) and potassium carbonate (3.11 g, 22.47 mmol) in anhydrous DMF (10 mL) was heated to 50 C under a nitrogen atmosphere overnight. The reaction mixture was allowed to cool to room temperature,diluted with water (70 mL) and stirred at room temperature for 15 minutes. The mixture was then extracted into ethyl acetate (100 mL) and washed with 50:50 water:brine. The organic phase was dried over Na2504, filtered and concentrated to dryness under reducedpressure to give the title compound as a yellow solid(4.72 g, 90%) . ?H NMR (300 MHz, CDC13) : 3 10.15 (s, 1H),8.63 (d, 1H), 8.31 (dd, 1H), 7.08 (d, 1H), 4.41 (br s,1H), 3.97 (dt, 1H), 3.20-3.53 (m, 4H), 3.08 (td, 1H),1.48 (d, 9H), 1.31 (d, 3H) . LCMS (Method C): = 1.68mm, m/z = 350 [M+H].

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 134

29
[ 27996-87-8 ]
[ 113451-59-5 ]
(1S,4S)-tert-butyl 5-(2-formyl-4-nitrophenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;Inert atmosphere;	A suspension of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (1.00 g,5.91 mmol), (1S,4S)-tert-butyl 2,5- diazabicyclo[2.2.1]heptane-2-carboxylate (1.172 g, 5.91mmol) and potassium carbonate (2.452 g, 17.74 mmol) inanhydrous DMF (5 mL) was heated to 50 C under a nitrogenatmosphere overnight. The reaction mixture was allowed to cool to room temperature, diluted with water (30 mL) and stirred at room temperature for 15 minutes. The precipitated solid was isolated by filtration, washed with water, sucked dry and freeze-dried overnight to give5 the title compound as a yellow solid (1.82 g, 89%) . ?H NMR(300 MHz, CDC13) : 3 9.91 (s, 1H) , 8.62 (d, 1H) , 8.22 (dd,1H), 6.78 (dd, 1H), 4.50-4.76 (m, 2H), 3.96 (dd, 1H),3.46-3.66 (m, 2H), 2.91 (dd, 1H), 1.95-2.19 (m, 2H), 1.42(s, 9H) . LCMS (Method C) : = 1.47 mi m/z = 348 [M+H].

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 317; 318

30
[ 27996-87-8 ]
tert-butyl 3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate [ No CAS ]
tert-butyl 7-(2-formyl-4-nitrophenyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h;	General procedure: A mixture of 2-chloro-5-nitrobenzaldehyde (2 g, 10.8 mmol), 1-isopropylpiperazine (2.07 g, 16.2 mmol) and potassium carbonate (2.68 g, 19.4 mmol) in DMF (10 mL) was heated at 90 C for 4 h. The reaction mixture wascooled to room temperature and diluted with water. The resulting precipitate was collected by filtration, then washed on the filter with water and dried in a vacuum oven to give the title compound (2.8 g, 96%) . LCMS (Method A) : = 0.49 mi m/z = 278 [M+H].<strong>[27996-87-8]2-Fluoro-5-nitrobenzaldehyde</strong> (37 mg, 0.219 mol) was reacted with tert-butyl 3-oxa-7,9- diazabicyclo[3.3.1]nonane-9-carboxylate following the procedure for example 21 to give the title compound (85 mg, 93 %) that was used directly in the following step.

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 109; 331

31
[ 5308-25-8 ]
[ 27996-87-8 ]
2-(4-ethylpiperazin-1-yl)-5-nitrobenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;Inert atmosphere;	A suspension of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (3 g, 17.74mmol), 1-ethylpiperazine (2.026 g, 17.74 mmol) andpotassium carbonate (3.68 g, 26.6 mmol) in anhydrous DMF(15 mL) was heated to 50 C under a nitrogen atmosphereovernight. The reaction mixture was allowed to cool toroom temperature, diluted with water (70 mL) and stirred at room temperature for 15 minutes. The precipitated solid was isolated by filtration, washed with water, sucked dry and freeze-dried overnight to give the titlecompound as a yellow solid (4.38 g, 94%) . ?H NMR (300 MHz,CDC13) : 3 10.10 (s, 1H) , 8.62 (d, 1H) , 8.30 (dd, 1H) , 7.09(d, 1H), 3.35 (t, 4H), 2.68 (t, 4H), 2.52 (q, 2H), 1.14(t, 3H) . LCMS (Method C) : = 0.38 mi m/z = 264 [M+H].

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 178

32
[ 27996-87-8 ]
[ 149771-44-8 ]
tert-butyl 3-(2-formyl-4-nitrophenyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
360 mg	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h;Inert atmosphere;	A suspension of 2-fluoro-5-nitrobenzaldehyde (0.358 g,2.120 mmol) tert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (0.45 g, 2.120 mmol) and potassium carbonate(0.439 g, 3.18 mmol) in anhydrous DMF (2 mL) was heatedto 50 C under a nitrogen atmosphere for 16 h. Thereaction mixture was allowed to cool to room temperature, partitioned between water (50 mL) and ethyl acetate (50 mL) . The ethyl acetate was separated and washed with water (3 x 20 mL), dried (anhydrous sodium sulfate),filtered and reduced in vacuo. The residue was purified by flash chromatography (0-100% ethyl acetate in cyclohexane) to afford the title compound (360 mg, 0.996 mmol) . LCMS (Method C) : = 1.69 mi m/z = 384 [M+Na].

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 202

33
[ 27996-87-8 ]
[ 21655-48-1 ]
2-((3R,5S)-3,5-dimethylpiperazin-1-yl)-5-nitrobenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.1%	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h;	To a stirring suspension of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (2.69 g, 15.9 mmol) and potassium carbonate (8.80 g, 63.7 mmol) in anhydrous DMF (10 mL) was added (25,6R)-2,6-dimethylpiperazine (2 g, 17.51 mmol) and the mixture washeated at 90 C for 16 h. After cooling the mixture was partitioned between brine/water (100 mL) and ethyl acetate (25 mL) . The aqueous layer was separated and extracted with ethyl acetate (3 x 25 mL) . The combinedethyl acetate fractions were washed with brine/water (1:1, 4 x 25 mL), dried (anhydrous sodium sulfate), filtered and reduced in vacuo. The resulting residue was chromatographed (gradient 20-100% ethyl acetate in cyclohexane) to afford the title compound (2.77 g, 66.1 %) . ?H NMR (400 MHz, CDC13) : 3 10.07 (s, 1H), 8.62 (d,1H), 8.28 (dd, 1H), 7.06 (d, 1H), 3.35 (d, 2H), 3.14-3.17 (m, 2H) , 2.72 (dd, 2H) , 1.13 (d, 6H) . LCMS (Method C) := 0.43 mi m/z = 264 [M+H].

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 310; 311

34
[ 110-89-4 ]
[ 27996-87-8 ]
[ 30742-60-0 ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	<strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (1 g, 5.91 mmol) wasdissolved in DMF (10 mL) and piperidine (0.64 mL, 6.50 mmol) was added, followed by DIPEA (2.27 mL, 13.0 mmol) The mixture was stirred overnight at room temperature. Water was added and the resulting precipitate was collected by filtration and dried in vacuo to give thetitle compound (1.3 g, 94%) as a yellow solid which was used without further purification. LCMS (Method C) : =1.59 mm, m/z = 235 [M+H].

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 266; 267
[2]Green Chemistry,2017,vol. 19,p. 5653 - 5658

35
[ 1089759-42-1 ]
[ 27996-87-8 ]
(S)-2-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-5-nitrobenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;Inert atmosphere;	A suspension of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (400 mg,2.365 mmol), (S)-octahydropyrazino[2, 1-cl [1, 4loxazine(336 mg, 2.365 mmol) [prepared as described for the R- enantiomer in J. Med. Chem., 2012, 55(12), 5887-5900, butusing the opposite enantiomer of the starting materiall and potassium carbonate (490 mg, 3.55 mmol) in anhydrous DMF (2.5 mL) was heated to 50 C under a nitrogen atmosphere overnight. The reaction mixture was allowed to cool to room temperature, diluted with water (25 mL) andextracted into ethyl acetate (3 x 10 mL) . The combined organic phases were dried over Na2504, filtered and concentrated to dryness under reduced pressure. The residue was chromatographed (silica 50g cartridge, cyclohexane:ethyl acetate:methanol, gradient elution from90:10:0 to 0:100:0 to 0:80:20) to give the title compoundas an orange solid (506 mg, 73%) . ?H NMR (300 MHz, CDC13)o 10.09 (s, 1H), 8.62 (d, 1H), 8.31 (dd, 1H), 7.08 (d,1H), 3.90 (dd, 1H), 3.65-3.79 (m, 2H), 3.25-3.47 (m, 3H),3.20 (dt, 1H), 2.79-2.93 (m, 2H), 2.74 (dt, 1H), 2.43-2.68 (m, 3H) . LCMS (Method C) : = 0.48 mm, m/z = 292 [M+H] .

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 261

36
[ 27996-87-8 ]
[ 1023301-73-6 ]
(R)-tert-butyl 4-(2-formyl-4-nitrophenyl)-2-(methoxymethyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h;	General procedure: A mixture of 2-chloro-5-nitrobenzaldehyde (2 g, 10.8 mmol), 1-isopropylpiperazine (2.07 g, 16.2 mmol) and potassium carbonate (2.68 g, 19.4 mmol) in DMF (10 mL) was heated at 90 C for 4 h. The reaction mixture wascooled to room temperature and diluted with water. The resulting precipitate was collected by filtration, then washed on the filter with water and dried in a vacuum oven to give the title compound (2.8 g, 96%) . LCMS (Method A) : = 0.49 mi m/z = 278 [M+H].Step 1: (R)-tert-butyl 4-(2-formyl-4-nitrophenyl)-2- (methoxymethyl)piperazine-1-carboxylate<strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (1g. 5.91 mmol) was reactedwith (R)-tert-butyl 2-(methoxymethyl)piperazine-1-carboxylate (1g. 4.34 mmol) following the procedure forexample 21 to give the title compound (1.30 g, 79%)

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 109; 265

37
[ 13889-98-0 ]
[ 27996-87-8 ]
2-(4-acetylpiperazin-1-yl)-5-nitrobenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	<strong>[27996-87-8]2-Fluoro-5-nitrobenzaldehyde</strong> (1.00 g, 5.91 mmol) wasdissolved in DMF (10 mL) and 1-(piperazin-1-yl)ethanone (0.83 g, 6.50 mmol) was added, followed by DIPEA (2.27 mL, 13.0 mmol) . The mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with ethyl acetate (x2) . The combined organiclayers were washed with brine and concentrated in vacuo. The residue was dried by toluene azeotrope to give the title compound (1.20 g, 73%) as a yellow syrup that partially crystallised on standing. LCMS (Method C) : = 0.95 mi m/z = 278 [M+H].

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 281

38
[ 39093-93-1 ]
[ 27996-87-8 ]
2-(1,1-dioxidothiomorpholino)-5-nitrobenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;Inert atmosphere;	A suspension of 2?fluoro?5?nitrobenzaldehyde (2 g, 11.83mmol), thiomorpholine 1,1?dioxide (1.599 g, 11.83 mmol)and potassium carbonate (2.452 g, 17.74 mmol) inanhydrous DMF (10 mL) was heated to 50 °C under anitrogen atmosphere overnight. The reaction mixture was allowed to cool to room temperature, diluted with water (70 mL) and stirred at room temperature for 15 minutes. The precipitated solid was isolated by filtration, washed with water, slurried in 1M HC1 solution (50 mL), isolatedby filtration, sucked dry and freeze?dried overnight to give the title compound as a yellow solid (2.68 g, 80percent) ?H NMR (300 MHz, DMSO?d6) : 5 10.11 (s, 1H), 8.54 (d, 1H), 8.34 (dd, 1H), 7.43 (d, 1H), 3.69?3.80 (m, 4H), 3.36?3.45 (m, 4H) . LCMS (Method C) : = 0.95 mi m/z = 285 [M+H].

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 286; 287

39
[ 27996-87-8 ]
4,4-difluoropiperidine hydrochloride [ No CAS ]
2-(4,4-difluoropiperidin-1-yl)-5-nitrobenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;Inert atmosphere;	A suspension of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (1 g, 5.91mmol), 4,4-difluoropiperidine hydrochloride (0.932 g,5.91 mmol) and potassium carbonate (1.635 g, 11.83 mmol)in anhydrous DMF (5 mL) was heated to 50 C under a nitrogen atmosphere overnight. The reaction mixture was allowed to cool to room temperature, diluted with water (40 mL) and stirred at room temperature for 15 minutes. The precipitated solid was isolated by filtration, washedwith water, sucked dry and freeze-dried overnight to give the title compound as a yellow solid (1.52 g, 95%) . ?H NMR (300 MHz, CDC13) : 5 10.09 (s, 1H) , 8.65 (d, 1H) , 8.33 (dd, 1H), 7.13 (d, 1H), 3.41 (dd, 4H), 2.17-2.34 (m, 4H) . LCMS (Method C) : = 1.47 mi m/z = 271 [M+H].

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Page/Page column 290

40
[ 27996-87-8 ]
[ 141-91-3 ]
[ 679839-07-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;Inert atmosphere;	A suspension of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (2 g, 11.83mmol), cis-2,6-dimethylmorpholine (1.362 g, 11.83 mmol)and potassium carbonate (2.452 g, 17.74 mmol) inanhydrous DMF (20 mL) was heated to 50 C under anitrogen atmosphere overnight. The reaction mixture was allowed to cool to room temperature, diluted with water (70 mL) and stirred at room temperature for 15 minutes. The precipitated solid was isolated by filtration, washed with water, sucked dry and freeze-dried overnight to givethe title compound as a yellow solid (2.94 g, 94%) . ?H NMR (300 MHz, CDC13) : 3 10.07 (s, 1H) , 8.63 (d, 1H) , 8.31 (dd, 1H), 7.06 (d, 1H), 3.85-3.99 (m, 2H), 3.30 (d, 2H), 2.82 (dd, 2H), 1.25 (d, 6H). LCMS (Method C): RT = 1.43 mm, m/z = 265 [M+H].
	In water; at 25℃;Sealed tube;	To the 15mL magnetized sealed tube containing solvent (1mL) ,<strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (0.1 mmol), cis-2,6-dimethylmorpholine (0.15 mmol), were added, stirred at room temperature (25C) and detected by thin layer chromatography until the complete consumption of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong>. Barbituric acid (0.15 mmol) was then added to the reaction, which was heated to 60C, and stirred for 48 hours. The residue was purified on a silica gel column using a gradient of petroleum ether and ethyl acetate to give the product PNU-286607.

Reference： [1]Patent: WO2015/92431,2015,A1 .Location in patent: Paragraph 293; 294
[2]Journal of Organic Chemistry,2019,vol. 84,p. 9671 - 9683
[3]Green Chemistry,2017,vol. 19,p. 5653 - 5658
[4]Patent: CN107722039,2018,A .Location in patent: Paragraph 0041-0046; 0137

41
[ 27996-87-8 ]
[ 6345-55-7 ]

Reference： [1]ACS Medicinal Chemistry Letters,2015,vol. 6,p. 1010 - 1014
[2]Patent: EP2926660,2015,A1
[3]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 4684 - 4686
[4]European Journal of Medicinal Chemistry,2019,vol. 174,p. 236 - 251

42
[ 75-15-0 ]
[ 27996-87-8 ]
[ 109-81-9 ]
(RS)-1-methyl-9-nitro-1,2,3,10b-tetrahydro-5H-benzo[e]imidazo[1,2-c][1,3]thiazine-5-thione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	In N,N-dimethyl-formamide at 0 - 20℃; for 15h;	21 4.2.1. General procedure A (GP A) General procedure: 2-Fluoro-5-nitrobenzaldehyde (1.0 mmol, 1.0 equiv) was dissolved in anhydrous DMF (2 mL). A solution of the respective amine (2.0 mmol, 2.0 equiv) in 2 mL anhydrous DMF and then CS2 (3.0 mmol, 1.0 equiv) were added at 0 °C. After stirring 15 h at room temperature, ethyl acetate (40 mL) was added. The solution was washed with brine (80 mL) and the aqueous layer was extracted with ethyl acetate (340 mL). The combined organic layers were dried (MgSO4), and the solvent was removed (rotary evaporator). The crude mixture was purified by column chromatography on silica gel. 4.2.1.21 (RS)-1-Methyl-9-nitro-1,2,3,10b-tetrahydro-5H-benzo[e]imidazo[1,2-c][1,3]thiazine-5-thione (4b) Following GP A, 2-fluoro-5-nitrobenzaldehyde (169 mg, 1.00 mmol), N-methylethylenediamine (148 mg, 2.00 mmol) and CS2 (228 mg, 3.00 mmol) were used. Column chromatography on silica gel (CH2Cl2; Rf=0.51) provided the desired product 4b as a yellow solid (184 mg, 65%, mp: 191-193 °C (CH2Cl2)). IR (ATR): ṽ=3093 (w), 3001 (w), 2964 (w), 2919 (w), 2880 (w), 2823 (m), 1518 (m), 1474 (m), 1454 (m), 1334 (s), 1250 (m), 1180 (m), 1022 (m), 928 (m), 821 (m), 739 (s) cm-1; 1H NMR (500.1 MHz, DMSO-d6): δ=8.28 (dd, 3JH,H=8.6 Hz, 4JH,H=2.5 Hz, 1H, p-CHArCH), 8.23 (d, 4JH,H=2.3 Hz, 1H, o-CHArCH), 7.77 (d, 3JH,H=8.5 Hz, 1H, m-CHArCH), 5.07 (s, 1H, NCH), 4.19-4.14, 3.71-3.66 (2m, 2H, CH2NCS), 3.39-3.34, 3.16-3.11 (2m, 2H, CH2NCH3), 2.70 (s, 3H, CH3) ppm; 13C NMR (125.8 MHz, DMSO-d6): δ=181.3 (CS), 147.1 (CArNO2), 139.3 (CArS), 133.3 (CArCH), 126.2 (m-CHArCH), 123.8 (p-CHArCH), 119.2 (o-CHArCH), 82.6 (NCH), 53.0 (CH2NCH3), 49.4 (CH2NCS), 41.8 (CH3) ppm; MS (ESI-TOF): m/z (%)=282.1 (100) [M+H]+; HRMS (ESI-TOF): m/z calcd for [C11H12N3O2S2Na]+: 304.0190, found: 304.0190.

Reference： [1]Stalling, Timo; Pauly, Jan; Kröger, Denis; Martens, Jürgen [Tetrahedron, 2015, vol. 71, # 43, p. 8290 - 8301]

43
[ 75-15-0 ]
[ 19522-67-9 ]
[ 27996-87-8 ]
(RS)-1-isopropyl-9-nitro-1,2,3,10b-tetrahydro-5H-benzo[e]imidazo[1,2-c][1,3]thiazine-5-thione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	In N,N-dimethyl-formamide at 0 - 20℃; for 15h;	22 4.2.1. General procedure A (GP A) General procedure: 2-Fluoro-5-nitrobenzaldehyde (1.0 mmol, 1.0 equiv) was dissolved in anhydrous DMF (2 mL). A solution of the respective amine (2.0 mmol, 2.0 equiv) in 2 mL anhydrous DMF and then CS2 (3.0 mmol, 1.0 equiv) were added at 0 °C. After stirring 15 h at room temperature, ethyl acetate (40 mL) was added. The solution was washed with brine (80 mL) and the aqueous layer was extracted with ethyl acetate (340 mL). The combined organic layers were dried (MgSO4), and the solvent was removed (rotary evaporator). The crude mixture was purified by column chromatography on silica gel. 4.2.1.22 (RS)-1-Isopropyl-9-nitro-1,2,3,10b-tetrahydro-5H-benzo[e]imidazo[1,2-c][1,3]thiazine-5-thione (4c) Following GP A, 2-fluoro-5-nitrobenzaldehyde (169 mg, 1.00 mmol), (2-aminoethyl)(propan-2-yl)amine (204 mg, 2.00 mmol) and CS2 (228 mg, 3.00 mmol) were used. Column chromatography on silica gel (CH2Cl2; Rf=0.65) provided the desired product 4c as an orange solid (232 mg, 75%, mp: 130-131 °C (CH2Cl2)). IR (ATR): ṽ=3086 (w), 2971 (m), 1579 (m), 1510 (s), 1463 (s), 1335 (s), 1223 (m), 1167 (s), 1116 (m), 990 (s), 839 (m), 740 (m) cm-1; 1H NMR (500.1 MHz, DMSO-d6): δ=8.30 (d, 4JH,H=2.3 Hz, 1H, o-CHArCH), 8.26 (dd, 3JH,H=8.5 Hz, 4JH,H=2.5 Hz, 1H, p-CHArCH), 7.75 (d, 3JH,H=8.5 Hz, 1H, m-CHArCH), 5.39 (s, 1H, NCH), 3.85-3.79, 3.77-3.72 (2m, 2H, CH2NCS), 3.50 (ddd, 2JH,H=12.0 Hz, 3JH,H=9.3 Hz, 3JH,H=6.7 Hz, 1H, CH2NCHCH3), 3.29 (sept, 3J=6.5 Hz, 1H, CHCH3), 3.17 (ddd, 2JH,H=12.1 Hz, 3JH,H=9.4 Hz, 3JH,H=6.8 Hz, 1H, CH2NCHCH3), 1.20, 1.14 (2d, 3JH,H=6.5 Hz, 6H, CH3) ppm; 13C NMR (125.8 MHz, DMSO-d6): δ=181.5 (CS), 147.1 (CArNO2), 139.5 (CArS), 134.7 (CArCH), 126.1 (m-CHArCH), 123.7 (p-CHArCH), 119.1 (o-CHArCH), 79.3 (NCH), 52.4 (CHCH3), 51.4 (CH2NCS), 46.0 (CH2NCHCH3), 21.1, 19.5 (CH3) ppm; MS (EI, 70 eV): m/z (%)=309.0 (100) [M]+; HRMS (EI, 70 eV): calcd for [C13H15N3O2S2]+: 309.0600, found: 309.0609.

Reference： [1]Stalling, Timo; Pauly, Jan; Kröger, Denis; Martens, Jürgen [Tetrahedron, 2015, vol. 71, # 43, p. 8290 - 8301]

44
[ 75-15-0 ]
[ 27996-87-8 ]
[ 4152-09-4 ]
(RS)-1-benzyl-9-nitro-1,2,3,10b-tetrahydro-5H-benzo[e]imidazo[1,2-c][1,3]thiazine-5-thione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	In N,N-dimethyl-formamide; at 0 - 20℃; for 15h;	General procedure: 2-Fluoro-5-nitrobenzaldehyde (1.0 mmol, 1.0 equiv) was dissolved in anhydrous DMF (2 mL). A solution of the respective amine (2.0 mmol, 2.0 equiv) in 2 mL anhydrous DMF and then CS2 (3.0 mmol, 1.0 equiv) were added at 0 C. After stirring 15 h at room temperature, ethyl acetate (40 mL) was added. The solution was washed with brine (80 mL) and the aqueous layer was extracted with ethyl acetate (340 mL). The combined organic layers were dried (MgSO4), and the solvent was removed (rotary evaporator). The crude mixture was purified by column chromatography on silica gel. 4.2.1.23 (RS)-1-Benzyl-9-nitro-1,2,3,10b-tetrahydro-5H-benzo[e]imidazo[1,2-c][1,3]thiazine-5-thione (4d) _Following GP A, 2-fluoro-5-nitrobenzaldehyde (169 mg, 1.00 mmol), <strong>[4152-09-4]N-benzylethylenediamine</strong> (300 mg, 2.00 mmol) and CS2 (228 mg, 3.00 mmol) were used. Column chromatography on silica gel (1. CH2Cl2, Rf=0.88; 2. n-hexane/ethyl acetate 4:1, Rf=0.42) provided the desired product 4d as a yellow solid (212 mg, 56%, mp: 193-195 C (CH2Cl2)). IR (ATR): ?=3087 (w), 3044 (w), 3034 (w), 2939 (w), 2873 (w), 2843 (w), 2817 (w), 1580 (m), 1514 (m), 1474 (s), 1449 (s), 1337 (s), 1292 (m), 1158 (m), 991 (m), 854 (m), 847 (m), 740 (s) cm-1; 1H NMR (499.9 MHz, DMSO-d6): delta=8.38 (d, 4JH,H=1.7 Hz, 1H, o-CHArCH), 8.25 (dd, 3JH,H=8.5 Hz, 4JH,H=1.7 Hz, 1H, p-CHArCH), 7.74 (d, 3JH,H=8.6 Hz, 1H, m-CHArCH), 7.55-7.53 (m, 2H, o-CHArCH2), 7.42-7.39 (m, 2H, m-CHArCH2), 7.33-7.30 (m, 1H, p-CHArCH2), 5.31 (s, 1H, NCH), 4.23 (d, 2JH,H=13.5 Hz, 1H, CH2CAr), 4.12-4.07 (m, 1H, CH2NCS), 4.02 (d, 2JH,H=13.5 Hz, 1H, CH2CAr), 3.79-3.74 (m, 1H, CH2NCS), 3.24-3.21 (m, 2H, CH2NCH2CAr) ppm; 13C NMR (125.7 MHz, DMSO-d6): delta=181.4 (CS), 147.0 (CArNO2), 139.2 (CArS), 138.1 (CArCH2), 133.6 (CArCH), 128.6, 128.5 (2o-CHArCH2, 2m-CHArCH2), 127.5 (p-CHArCH2), 126.1 (m-CHArCH), 123.7 (p-CHArCH), 119.2 (o-CHArCH), 81.7 (NCH), 58.1 (CH2CAr), 50.3 (CH2NCH2CAr), 49.6 (CH2NCS) ppm; MS (EI, 70 eV): m/z (%)=357.1 (32) [M]+, 91.1 (100) [M-C10H8N3O2S2]+; HRMS (EI, 70 eV): m/z calcd for [C17H15N3O2S2]+: 357.0600, found: 357.0603.

Reference： [1]Tetrahedron,2015,vol. 71,p. 8290 - 8301

45
[ 75-15-0 ]
[ 27996-87-8 ]
[ 1664-40-0 ]
(RS)-9-nitro-1-phenyl-1,2,3,10b-tetrahydro-5H-benzo[e]imidazo[1,2-c][1,3]thiazine-5-thione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	In N,N-dimethyl-formamide; at 0 - 20℃; for 15h;	General procedure: 2-Fluoro-5-nitrobenzaldehyde (1.0 mmol, 1.0 equiv) was dissolved in anhydrous DMF (2 mL). A solution of the respective amine (2.0 mmol, 2.0 equiv) in 2 mL anhydrous DMF and then CS2 (3.0 mmol, 1.0 equiv) were added at 0 C. After stirring 15 h at room temperature, ethyl acetate (40 mL) was added. The solution was washed with brine (80 mL) and the aqueous layer was extracted with ethyl acetate (340 mL). The combined organic layers were dried (MgSO4), and the solvent was removed (rotary evaporator). The crude mixture was purified by column chromatography on silica gel. 4.2.1.24 (RS)-9-Nitro-1-phenyl-1,2,3,10b-tetrahydro-5H-benzo[e]imidazo[1,2-c][1,3]thiazine-5-thione (4e) Following GP A, 2-fluoro-5-nitrobenzaldehyde (169 mg, 1.00 mmol), <strong>[1664-40-0]N-phenylethylenediamine</strong> (272 mg, 2.00 mmol) and CS2 (228 mg, 3.00 mmol) were used. Column chromatography on silica gel (CH2Cl2; Rf=0.83) provided the desired product 4e as a yellow solid (170 mg, 50%, mp: 226-228 C (CH2Cl2)). IR (ATR): ?=3080 (w), 3062 (w), 3040 (w), 2981 (w), 2949 (w), 2920 (w), 2893 (w), 2844 (w), 1598 (m), 1578 (m), 1515 (m), 1437 (m), 1334 (s), 1240 (m), 1171 (m), 998 (m), 930 (m), 756 (s), 739 (s) cm-1; 1H NMR (500.1 MHz, DMSO-d6): delta=8.30 (dd, 3JH,H=8.6 Hz, 4JH,H=2.3 Hz, 1H, p-CHArCH), 7.85 (d, 3JH,H=8.6 Hz, 1H, m-CHArCH), 7.77 (d, 4JH,H=2.0 Hz, 1H, o-CHArCH), 7.30-7.27 (m, 2H, m-CHArN), 6.90-6.87 (m, 1H, p-CHArN), 6.84-6.82 (m, 2H, o-CHArN), 6.05 (s, 1H, NCH), 4.15-3.95 (m, 4H, CH2) ppm; 13C NMR (125.8 MHz, DMSO-d6): delta=181.9 (CS), 146.8 (CArNO2), 145.9 (CArN), 139.6 (CArS), 132.7 (CArCH), 129.4 (2m-CHArN), 126.6 (m-CHArCH), 124.0 (p-CHArCH), 119.4, 119.1 (o-CHArCH, p-CHArN), 113.8 (2o-CHArN), 76.3 (NCH), 49.6, 46.7 (CH2) ppm; MS (EI, 70 eV): m/z (%)=343.1 (100) [M]+; HRMS (EI, 70 eV): m/z calcd for [C16H13N3O2S2]+: 343.0444, found: 343.0436.

Reference： [1]Tetrahedron,2015,vol. 71,p. 8290 - 8301

46
[ 27996-87-8 ]
[ 20699-85-8 ]

Reference： [1]Patent: EP2926660,2015,A1

47
[ 27996-87-8 ]
[ 107-21-1 ]
2-(2-fluoro-5-nitrophenyl)-1,3-dioxolane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With toluene-4-sulfonic acid; In toluene; for 3h;Reflux; Dean-Stark;	<strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> was dissolved in dry toluene. To it catalytic amount of p-toulenesulphonic acid monohydrate was added followed by 1.5 eq. of ethylene glycol. Reaction mixture was refluxed for 3 hours in a dean stark apparatus. Reaction monitoring was performed by TLC. On successful disappearance of starting material solvent was removed under reduced pressure using a rotary evaporator. Residue was partitioned between ethyl acetate and water. Organic layer was washed with brine and dried over sodium sulphate. Organic layer was removed over rotavapor to give the crude product. Purification was done over flash chromatography (Hexane/ ethyl acetate) to give the desired product as white solid. Yield:85%. 1H NMR (400 MHz, CHLOROFORM-d) delta (ppm) 7.46-7.61 (m, 2H), 7.17 (ddd, J=1.00, 2.64, 8.91 Hz, 1H), 4.63-4.76 (m, 1H), 4.01 (t, J=8.66 Hz, 1H), 3.86 (dd, J=6.78, 8.53 Hz, 1H), 3.14 (dd, J=4.14, 13.68 Hz, 1H), 2.92-3.03 (m, 1H), M/Z 214. LCMS purity: 95.16%
63%	With toluene-4-sulfonic acid; In toluene; for 10h;Dean-Stark; Reflux;	Example 5 2- (2-fluoro-5-nitrophenyl) -1,3-dioxolane (S5-1) The toluene 60mL was poured into 250mL three-necked flask, 2g 2- fluoro-5-nitro - benzaldehyde (11.8mmol), 1.47g of ethylene glycol (23.6mmol), 0.041g p-toluenesulfonic acid (catalytic amount) is set The reaction flask was heated with a Dean-Stark apparatus at reflux for 10h. The reaction was monitored by TLC, the raw material disappeared, the reaction was stopped. The reaction solution was cooled, was added 50mL of ethyl acetate. Respectively with 30mL saturated NaHCO3 and extracted three times with 20mL saturated NaCl solution respectively extracted twice. The organic layer was dried over anhydrous MgSO4 was added 5g, filtering to obtain filtrate. The solvent was removed by distillation under reduced pressure, and dried in vacuo to give a white solid. Product quality 1.59g, Yield: 63%.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 1198 - 1206
[2]Patent: CN105272970,2016,A .Location in patent: Paragraph 0070; 0071; 0072

48
[ 374538-01-9 ]
[ 27996-87-8 ]

Reference： [1]Organic and Biomolecular Chemistry,2016,vol. 14,p. 6751 - 6756

49
[ 27996-87-8 ]
[ 251940-06-4 ]
4-(4-fluorobenzoyl)-7-nitro-1,2-dihydroimidazo[1,2-a]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With piperidine; In 1,4-dioxane; at 65℃; for 2h;	To a 25 ml round bottom flask was added 1- (4-fluorophenyl) -2- (imidazolidin-2-ylidene) ethan-1-one (1 mmol) and <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (3 mmol)Was added to a solution of 1,4-dioxane (15 ml) and piperidine (1 mmol) under a magnetic stirrer to 65 C,Reaction for 2 hours.After filtration, the precipitate was washed with a mixed solvent of petroleum ether / dichloromethane = 10: 1,A yellow flocculent solid.Take a yellow solid,Adding trichloromethane and saturated aqueous sodium bicarbonate solution,After extraction, the organic phase was washed with saturated aqueous sodium chloride solution,The chloroform was collected and dried over anhydrous sodium sulfate,After the partial solvent was distilled off, petroleum ether was recrystallized,Filtered and dried to give the product as a yellow solid 4- (4-fluorobenzoyl) -7-nitro-1,2-dihydroimidazo [1,2-a] quinoline (Compound 1)

Reference： [1]Patent: CN106588920,2017,A .Location in patent: Paragraph 0059; 0060; 0061; 0062; 0063

50
[ 27996-87-8 ]
1-(4-fluorophenyl)-2-(imidazolidin-2-yl)ethanone [ No CAS ]
4-(4-chlorobenzoyl)-7-nitro-1,2-dihydro-imidazo[1,2-a]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With piperidine; In ethanol; at 40℃; for 12h;	(4-fluorophenyl) -2- (imidazolidin-2-yl) ethanone was prepared in the same manner as in Example 1, except that 1- (4-chlorophenyl) -2- (imidazolidin- -ylidene) ethan-1-one,The 1,4-dioxane as in Example 1 was replaced with ethanol as the reaction solvent,The reaction was carried out at 40 C for 12 hours,(4-chlorobenzoyl) 7-nitro-1,2-dihydro-imidazo [1,2-a] quinoline (Compound 4) was obtained as a yellow solid in 98% yield.

Reference： [1]Patent: CN106588920,2017,A .Location in patent: Paragraph 0075; 0076; 0077

51
[ 27996-87-8 ]
1-(4-fluorophenyl)-2-(imidazolidin-2-yl)ethanone [ No CAS ]
4-(4-bromobenzoyl)-7-nitro-1,2-dihydro-imidazo[1,2-a]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With triethylamine; In 1,4-dioxane; at 65℃; for 2h;	A solution of 1- (4-fluorophenyl) -2- (imidazolidine-2-yl) ethanone in place of 1- (4-bromophenyl) -2- (imidazolidin- -ylidene) ethan-1-one,The piperidine in Example 1 was replaced with triethylamine (0.75 mmol)(4-bromobenzoyl) (7-nitro-1,2-dihydro-imidazo [1,2-a] quinoline (Compound 5) was obtained as a yellow solid,The yield was 97%.

Reference： [1]Patent: CN106588920,2017,A .Location in patent: Paragraph 0078; 0079; 0080

52
[ 27996-87-8 ]
[ 64944-80-5 ]
4-benzoyl-7-nitro-1,2-dihydro-imidazo[1,2-a]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With piperidine; calcium chloride; In 1,4-dioxane; at 65℃; for 0.5h;	use2- (imidazolidin-2-ylidene) -1-phenylethan-1-oneWas used in place of Example 11- (4-fluorophenyl) -2- (imidazolidin-2-ylidene)And anhydrous calcium chloride (0.5 mmol) was added,Reaction for 30 minutes,To give 4-benzoyl-7-nitro-1,2-dihydro-imidazo [1,2-a] quinoline (Compound 6) as a yellow solid,The yield was 97%.

Reference： [1]Patent: CN106588920,2017,A .Location in patent: Paragraph 0081; 0082; 0083

53
[ 27996-87-8 ]
[ 82100-23-0 ]
4-p-toluyl-7-nitro-1,2-dihydro-imidazo[1,2-a]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With piperidine; calcium oxide; In 1,4-dioxane; at 65℃; for 2h;	Using 2- (imidazolidin-2-ylidene) -1- (p-tolyl) ethan-1-oneInstead of 1- (4-fluorophenyl) -2- (imidazolidin-2-ylidene) ethan-1-one in Example 1,And calcium oxide (0.5 mmol) was added,The reaction was carried out to give 4-p-toluoyl-7-nitro-1,2-dihydro-imidazo [1,2-a] quinoline (Compound 7) as a yellow solid,Yield 95%.

Reference： [1]Patent: CN106588920,2017,A .Location in patent: Paragraph 0084; 0085; 0086

54
[ 27996-87-8 ]
[ 107195-10-8 ]
4-(4-methoxybenzoyl)-7-nitro-1,2-dihydro-imidazo[1,2-a]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With piperidine; In methanol; water; at 65℃; for 24h;	use 2- (imidazolidin-2-ylidene) -1- (4-methoxyphenyl) ethan-1-oneInstead of 1- (4-fluorophenyl) -2- (imidazolidin-2-ylidene) ethan-1-one in Example 1,And the 1,4-dioxane ring in Example 1 was replaced with a mixed solvent of ethanol and water as a solvent,Reaction for 24 hours,(4-methoxybenzoyl) -7-nitro-1,2-dihydro-imidazo [1,2-a] quinoline (Compound No. 8) was obtained as a yellow solid,Yield 93%.

Reference： [1]Patent: CN106588920,2017,A .Location in patent: Paragraph 0087; 0088; 0089

55
[ 27996-87-8 ]
[ 82100-27-4 ]
7-nitro-4-(thiophene-2-carbonyl)-1H,2H-imidazo[1,2-a]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With piperidine; In water; at 65℃; for 24h;	use2- (imidazolidin-2-ylidene) -1- (thiophen-2-yl) ethan-1-oneInstead of 1- (4-fluorophenyl) -2- (imidazolidin-2-ylidene) ethan-1-one in Example 1,And the 1,4-dioxane ring in Example 1 was replaced with water as a solvent,Reaction for 24 hours,(2-phthaloyl) -7-nitro-1,2-dihydro-imidazo [1,2-a] quinoline (Compound No. 9) as an orange solid,Yield 90%.

Reference： [1]Patent: CN106588920,2017,A .Location in patent: Paragraph 0090; 0091; 0092

56
[ 27996-87-8 ]
[ 251940-05-3 ]
5-(4-fluorobenzoyl)-8-nitro-2,3-dihydro-1H-pyrimido[1,2-a]quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With piperidine; In 1,4-dioxane; ethanol; toluene; at 65℃; for 2h;	use1- (4-fluorophenyl) -2- (tetrahydropyrimidin-2 (1H) -ylidene) ethan-1-oneWas used in place of Example 11- (4-fluorophenyl) -2- (imidazolidin-2-ylidene) ethan-1-one,The 1,4-dioxane ring of Example 1 was replaced with a mixed solvent of ethanol, 1,4-dioxane and toluene as a solvent,(4-fluorobenzoyl) -8-nitro-2,3-dihydro-1H-pyrimido [1,2-a] quinoline (Compound 10) was obtained as a yellow solid,Yield 94%.

Reference： [1]Patent: CN106588920,2017,A .Location in patent: Paragraph 0093; 0094; 0095

57
[ 27996-87-8 ]
[ 56293-29-9 ]
N-(2-carboxy-5-nitrophenyl)aloperine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With calcined ground potash; In N,N-dimethyl-formamide; at 60℃; for 3.0h;	A solution of 2-fluoro-5-nitrobenzaldehyde (7, 3.82 g, 0.022 mol) infreshly distilled DMF (12 mL) was treated with freshly calcined ground potash (3.45 g, 0.025 mol) and <strong>[56293-29-9]aloperine</strong> (1, 4.64 g,0.02 mol), heated to 60°C, stirred for 3 h, cooled to room temperature, and poured into H2O (100 mL). The resulting precipitate was filtered off and rinsed thoroughly with H2O. The crude product was removed from the filter, treated with H2O (50 mL) with added AcOH (4 mL), and stirred for 15 min. The insoluble precipitate was separated by filtration and discarded. The filtrate was made basic (pH 9) with NH4OH (25percent). The resulting precipitate was filtered off, rinsed with H2O, and driedin a vacuum desiccator over KOH to afford 8 (6.17 g) as a finely crystalline yellow powder in 81percent yield; mp 71?73°C, Rf 0.39(EtOAc?NEt3, 10:1), C22H27N3O3.1 NMR spectrum (400 MHz, DCl3, , ppm, J/Hz): 1.42 (4, m, -10, 10, 11, H-11), 1.60 (2H, m, -9, 9),1.79 (2, m, -3, 3), 1.89 (1, m, -15), 2.01 (2, m, -17, 17), 2.09 (1, m, -7), 2.20 (1, m, -4), 2.30 (1, m,-4), 2.33 (1, m, J = 11.5, -14), 2.43 (2, m, H2-12), 2.54 (1, m, H-8), 2.71 (1, m, J = 11.5, -14), 2.99 (1, m,J = 14.5, -2), 3.35 (1, m, J = 14.5, -2), 4.05 (1, d, J = 4.6, H-16), 5.75 (1, d, J = 5.5, H-6), 7.44 (1, d, J = 8.9,H-19), 8.37 (1, dd, J = 8.9, 2.3, H-20), 8.71 (1, d, J = 2.3, H-22), 10.33 (1, s, -24).

Reference： [1]Chemistry of Natural Compounds,2017,vol. 53,p. 703 - 707
Khim. Prir. Soedin.,2017,p. 599 - 602,4

58
[ 119072-55-8 ]
[ 68076-36-8 ]
[ 27996-87-8 ]
[ 77128-73-5 ]
C₄₆H₅₄FN₅O₈ [ No CAS ]
C₄₆H₅₄FN₅O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; dichloromethane; at 20℃; for 72h;	General procedure: 2-Fluorobenzaldehyde (42.3 mg, 0.25 mmol) was first dissolved in a 15 mL conical centrifuge tube with MeOH (330 mL) and the amine (0.25 mmol) was added. The resulting mixture was agitated with an orbital mixer for 30 min and the Fmoc-protected amino acid (0.25 mmol) added to the reaction with CH2Cl2 (170 mL). After stirring for 15 min, the isocyanide (0.25 mmol) was added and the mixture agitated for 72 h. Finally, the solvent was removed under reduced pressure and the crude product dissolved in DMF to be purified by RP-HPLC. The fractions containing the desired product in >95percent purity were pooled and freeze dried.

Reference： [1]Tetrahedron,2017,vol. 73,p. 6347 - 6355

59
[ 119072-55-8 ]
[ 27996-87-8 ]
[ 100-46-9 ]
[ 220498-02-2 ]
C₄₃H₄₁FN₄O₆ [ No CAS ]
C₄₃H₄₁FN₄O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; dichloromethane; at 20.0℃; for 72.0h;	General procedure: 2-Fluorobenzaldehyde (42.3 mg, 0.25 mmol) was first dissolved in a 15 mL conical centrifuge tube with MeOH (330 mL) and the amine (0.25 mmol) was added. The resulting mixture was agitated with an orbital mixer for 30 min and the Fmoc-protected amino acid (0.25 mmol) added to the reaction with CH2Cl2 (170 mL). After stirring for 15 min, the isocyanide (0.25 mmol) was added and the mixture agitated for 72 h. Finally, the solvent was removed under reduced pressure and the crude product dissolved in DMF to be purified by RP-HPLC. The fractions containing the desired product in >95% purity were pooled and freeze dried.

Reference： [1]Tetrahedron,2017,vol. 73,p. 6347 - 6355

60
[ 119072-55-8 ]
[ 353245-98-4 ]
[ 27996-87-8 ]
[ 100-46-9 ]
C₄₆H₄₄FN₅O₆ [ No CAS ]
C₄₆H₄₄FN₅O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; dichloromethane; at 20℃; for 72h;	General procedure: 2-Fluorobenzaldehyde (42.3 mg, 0.25 mmol) was first dissolved in a 15 mL conical centrifuge tube with MeOH (330 mL) and the amine (0.25 mmol) was added. The resulting mixture was agitated with an orbital mixer for 30 min and the Fmoc-protected amino acid (0.25 mmol) added to the reaction with CH2Cl2 (170 mL). After stirring for 15 min, the isocyanide (0.25 mmol) was added and the mixture agitated for 72 h. Finally, the solvent was removed under reduced pressure and the crude product dissolved in DMF to be purified by RP-HPLC. The fractions containing the desired product in >95% purity were pooled and freeze dried.

Reference： [1]Tetrahedron,2017,vol. 73,p. 6347 - 6355

61
[ 27996-87-8 ]
[ 371-14-2 ]
1-(2-fluoro-5-nitrobenzylidene)-2-(4-fluorophenyl)hydrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With toluene-4-sulfonic acid; In ethanol; for 1h;Reflux;	<strong>[27996-87-8]2-Fluoro-5-nitrobenzaldehyde</strong> (50 mg, 0.27 mmol)Was dissolved in EtOH (1 ml)4-Fluorophenylhydrazine (37 mg, 0.29 mmol)And TSA.H2O (3 mg, 0.02 mmol) were added and refluxed for 1 hour.Concentrated and solidified to obtain the desired compound (65 mg, 87%).
87%	With toluene-4-sulfonic acid; In ethanol; for 1h;Reflux;	To asolution of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (50 mg,0.27 mmol) in ethanol was added 4-fluorophenylhydrazine(37 mg, 0.29 mmol) and toluenesulfonic acid monohydrate(3.0 mg, 0.02 mmol), and the mixture was stirred at refluxfor 1 h. After cooling to room temperature, the precipitatedsolid was collected by filtration to give 1-(2-fluoro-5-nitrobenzylidene)-2-(4-fluorophenyl)hydrazine (16a, 65 mg,87%). 1H NMR (300 MHz, CDCl3): delta 8.84 (dd, J = 6.2,2.9 Hz, 1H), 8.12 (m, 1H), 7.86 (s, 1H), 7.23 (t,J = 9.3 Hz, 1H), 7.08 (m, 4H); MS (ESI): m/z forC13H9F2N3O2, found 278 [M + H+].

Reference： [1]Patent: KR101796781,2017,B1 .Location in patent: Paragraph 0219; 0221; 0222
[2]Bulletin of the Korean Chemical Society,2018,vol. 39,p. 1125 - 1138

62
[ 40594-30-7 ]
[ 27996-87-8 ]
1-(2,4-difluorophenyl)-2-(2-fluoro-5-nitrobenzylidene)hydrazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With toluene-4-sulfonic acid; In ethanol; for 1h;Reflux;	<strong>[27996-87-8]2-Fluoro-5-nitrobenzaldehyde</strong> (50 mg, 0.27 mmol) was dissolved in EtOH (1 ml)2,4-difluorophenylhydrazine (43 mg, 0.30 mmol) and TSA.H2O (3 mg, 0.02 mmol) were added and refluxed for 1 hour.After concentration,Solidification yielded the desired compound (70 mg, 88%).
	With toluene-4-sulfonic acid; In ethanol; for 1h;Reflux;	General procedure: To asolution of <strong>[27996-87-8]2-fluoro-5-nitrobenzaldehyde</strong> (50 mg,0.27 mmol) in ethanol was added 4-fluorophenylhydrazine(37 mg, 0.29 mmol) and toluenesulfonic acid monohydrate(3.0 mg, 0.02 mmol), and the mixture was stirred at refluxfor 1 h. After cooling to room temperature, the precipitatedsolid was collected by filtration to give 1-(2-fluoro-5-nitrobenzylidene)-2-(4-fluorophenyl)hydrazine (16a, 65 mg,87%).

Reference： [1]Patent: KR101796781,2017,B1 .Location in patent: Paragraph 0255; 0257; 0258
[2]Bulletin of the Korean Chemical Society,2018,vol. 39,p. 1125 - 1138

63
[ 27996-87-8 ]
[ 454-15-9 ]

Reference： [1]Patent: US2017/369489,2017,A1

64
[ 27996-87-8 ]
[ 53473-85-1 ]

Reference： [1]Patent: WO2017/218960,2017,A1

65
[ 27996-87-8 ]
[ 59-88-1 ]
1-phenyl-5-nitro-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate; at 90℃; for 1.5h;Inert atmosphere; Molecular sieve;	General procedure: To a stirred solution of the carbonyl com.p.ound (1.0 mmol) in DMPU (5 mL) were addedpowdered 4 A molecular sieves (30 wt % relative to the carbonyl substrate), ArNHNH2.HCl (3.0 mmolfor 5, 2.0 mmol for 6), and K2CO3 (3.0 mmol for 5, 2.0 mmol for 6). For 5, all reagents were placed inthe flask and heated to 90 C; for 6, the hydrazone was allowed to form at 90 C (1.5 h) before K2CO3was added. The reaction was stirred at 90 C for the time indicated in Table 2. Workup was performedas described in Method A.

Reference： [1]Molecules,2018,vol. 23
[2]Molecules,2018,vol. 23

66
[ 27996-87-8 ]
[ 59-88-1 ]
C₁₃H₁₀FN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	In N,N-dimethyl-formamide; at 50℃; for 2h;Inert atmosphere;	General procedure: To a stirred solution of the carbonyl compound (1.0 mmol) in DMF (5 mL) at 50 C (oil bath)was added ArNHNH2.HCl (3.0 mmol for 5, 2.0 mmol for 6) and the solution was stirred until TLC(20% EtOAc in hexanes) indicated complete conversion (roughly 2 h). The crude reaction mixture wasadded to water and extracted with EtOAc (2 Chi 15 mL). The combined organic layers were washedwith water and saturated aq NaCl, dried (MgSO4), filtered, and concentrated under vacuum to givethe crude hydrazones. The crude products were stirred with 20% ether/pentane for 1 h, filtered anddried to give arylhydrazones 9 and 10. Characterization data for these materials are given in the ESI.