[ CAS No. 22062-53-9 ] {[proInfo.proName]}

Name: 22062-53-9|5-Fluoro-2-methylbenzaldehyde|97%
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Quality Control of [ 22062-53-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 22062-53-9 ]

CAS No. :	22062-53-9	MDL No. :	MFCD02261763
Formula :	C₈H₇FO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MBOXPKNOGZJXPK-UHFFFAOYSA-N
M.W :	138.14	Pubchem ID :	2759012
Synonyms :

Calculated chemistry of [ 22062-53-9 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	36.75
TPSA :	17.07 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) :	-5.83 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.68
Log Po/w (XLOGP3) :	1.85
Log Po/w (WLOGP) :	2.37
Log Po/w (MLOGP) :	2.21
Log Po/w (SILICOS-IT) :	2.86
Consensus Log Po/w :	2.19

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.24
Solubility :	0.795 mg/ml ; 0.00575 mol/l
Class :	Soluble
Log S (Ali) :	-1.83
Solubility :	2.05 mg/ml ; 0.0148 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.98
Solubility :	0.144 mg/ml ; 0.00104 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.03

Safety of [ 22062-53-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P210-P305+P351+P338	UN#:	N/A
Hazard Statements:	H227-H315-H319	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 22062-53-9 ]

* 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 [ 22062-53-9 ]
Downstream synthetic route of [ 22062-53-9 ]

[ 22062-53-9 ] Synthesis Path-Upstream 1~6

1
[ 1422-53-3 ]
[ 68-12-2 ]
[ 22062-53-9 ]

Reference： [1] Patent: EP1182194, 2002, A1, . Location in patent: Page 28
[2] Patent: US6350749, 2002, B1, . Location in patent: Page column 133 - 134

2
[ 352-32-9 ]
[ 4885-02-3 ]
[ 93249-44-6 ]
[ 22062-53-9 ]

Reference： [1] Patent: US6350749, 2002, B1, . Location in patent: Page column 134 - 135

3
[ 1422-53-3 ]
[ 22062-53-9 ]

Reference： [1] Patent: EP950418, 1999, A2,
[2] Patent: EP1229019, 2002, A1,

4
[ 33184-16-6 ]
[ 22062-53-9 ]

Reference： [1] Chemical Communications, 2017, vol. 53, # 73, p. 10228 - 10231

5
[ 13194-67-7 ]
[ 122-51-0 ]
[ 22062-53-9 ]

Reference： [1] Journal of the American Chemical Society, 1968, vol. 90, # 24, p. 6712 - 6717

6
[ 352-32-9 ]
[ 4885-02-3 ]
[ 93249-44-6 ]
[ 22062-53-9 ]

Reference： [1] Patent: US6350749, 2002, B1, . Location in patent: Page column 134 - 135

[ 22062-53-9 ] Synthesis Path-Downstream 1~88

1
[ 7677-24-9 ]
[ 22062-53-9 ]
[ 82129-34-8 ]

Yield	Reaction Conditions	Operation in experiment
	zinc diiodide; In dichloromethane;	EXAMPLE 64 2-(5-Fluoro-2-methylphenyl)-2-trimethylsiloxyethanenitrile By the procedure of Example 1, but using a stirring time of 16 hours at room temperature, <strong>[22062-53-9]5-fluoro-2-methylbenzaldehyde</strong> (8.2 g., 0.059 mole) in 200 ml. of methylene chloride was reacted with trimethylsilylcarbonitrile (8.0 g., 0.09 mole) in the presence of zinc iodide (100 mg.) to yield 2-(5-fluoro-2-methylphenyl)-2-trimethylsiloxyethanenitrile as an oil (13.6 g., pnmr/CDCl3 includes 0.2 ppm peak due to protons of the trimethylsilyl group).

Reference： [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 770 - 778
[2]Patent: US4367234,1983,A

2
[ 22062-53-9 ]
[ 84194-48-9 ]
[ 94569-77-4 ]

Reference： [1]Journal of Organic Chemistry,1985,vol. 50,p. 457 - 461

3
[ 22062-53-9 ]
Diaethyl-<2-methyl-5-fluorbenzyl>-phosphonat [ No CAS ]
[ 19451-45-7 ]

Reference： [1]Journal of the American Chemical Society,1968,vol. 90,p. 6712 - 6717

4
[ 22062-53-9 ]
[ 22062-54-0 ]

Yield	Reaction Conditions	Operation in experiment
92.5%	With sodium tetrahydroborate; In ethanol; at 20℃; for 3h;	General procedure: To a solution of substituted phenylaldehyde 13, 15a-15d (8 mmol) in anhydrous ethyl alcohol (12 ml) was added 96% NaBH4 (0.32 g, 8 mmol) and then stirred at room temperature for 3.0 h. After the solvent was evaporated, the residue was extracted with ethyl acetate, washed with brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure to afford 14a, 17a-17d as pale yellow oils. The 14a, 17a-17d were used directly for the next step without further purification.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 163,p. 864 - 882
[2]Journal of the American Chemical Society,1968,vol. 90,p. 6712 - 6717

5
[ 13194-67-7 ]
[ 122-51-0 ]
[ 22062-53-9 ]

Reference： [1]Journal of the American Chemical Society,1968,vol. 90,p. 6712 - 6717

6
[ 22062-53-9 ]
[ 82129-36-0 ]

Reference： [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 770 - 778

7
[ 22062-53-9 ]
[ 82129-35-9 ]

Reference： [1]Journal of Medicinal Chemistry,1986,vol. 29,p. 770 - 778

8
[ 22062-53-9 ]
[ 22062-55-1 ]

Reference： [1]Journal of the American Chemical Society,1968,vol. 90,p. 6712 - 6717

9
[ 22062-53-9 ]
2-Methyl-4.7-difluor-phenanthren [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1968,vol. 90,p. 6712 - 6717

10
[ 22062-53-9 ]
[ 19451-45-7 ]

Reference： [1]Journal of the American Chemical Society,1968,vol. 90,p. 6712 - 6717

11
[ 22062-53-9 ]
Diaethyl-<2-methyl-5-fluorbenzyl>-phosphonat [ No CAS ]

Reference： [1]Journal of the American Chemical Society,1968,vol. 90,p. 6712 - 6717

12
[ 1422-53-3 ]
[ 68-12-2 ]
[ 22062-53-9 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 2-bromo-4-fluorotoluene (16.0 g) in anhydrous tetrahydrofuran was added dropwise at -78 C. a solution of 1.6M butyllithium in hexane (55.5 ml), and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of dimethylformamide (6.8 g) in tetrahydrofuran (20 ml), and the mixture was allowed to stand to warm up to 0 C. To the reaction solution was added ice-water, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give oil of 5-fluoro-2-methylbenzaldehyde (11.5 g). To a mixture of acetone (80 ml), sodium hydroxide (3.7 g) and water (100 ml) was added dropwise at room temperature a solution of 5-fluoro-2-methylbenzaldehyde (11.5 g) in acetone (30 ml), and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, acetone was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure to give 4-(5-fluoro-2-methylphenyl)-3-buten-2-one (13.4 g). To a solution of 20% sodium ethoxide in ethanol (5.9 g) was added at room temperature diethyl malonate (14.0 g), and then added little by little 4-(5-fluoro-2-methylphenyl)-3-buten-2-one (13.4 g), and the mixture was stirred at room temperature for 30 minutes and then for 2 hours while heating, and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (46 ml), and the mixture was refluxed for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (46 ml) for 10 minutes, and the mixture was refluxed for 30 minutes and cooled. Precipitated crystals were filtered and washed with water and isopropylether to give 5-(5-fluoro-2-methylphenyl)cyclohexane-1,3-dione (8.6 g) as colorless crystals. mp 175-176 C. 1H-NMR(CDCl3) delta: 2.30 (3H, s), 2.27-2.56 (4H, m), 2.5-4.3 (1H, br), 3.44-3.63 (1H, m), 5.55 (1H, s), 6.77-7.01 (2H, m), 7.09-7.17 (1H, m).

Reference： [1]Patent: EP1182194,2002,A1 .Location in patent: Page 28
[2]Patent: US6350749,2002,B1 .Location in patent: Page column 133 - 134

13
[ 22062-53-9 ]
[ 67-64-1 ]
4-(5-fluoro-2-methylphenyl)-3-buten-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; In water; at 20℃; for 1h;	To a solution of 2-bromo-4-fluorotoluene (16.0 g) in anhydrous tetrahydrofuran was added dropwise at -78 C. a solution of 1.6M butyllithium in hexane (55.5 ml), and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of dimethylformamide (6.8 g) in tetrahydrofuran (20 ml), and the mixture was allowed to stand to warm up to 0 C. To the reaction solution was added ice-water, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give oil of <strong>[22062-53-9]5-fluoro-2-methylbenzaldehyde</strong> (11.5 g). To a mixture of acetone (80 ml), sodium hydroxide (3.7 g) and water (100 ml) was added dropwise at room temperature a solution of <strong>[22062-53-9]5-fluoro-2-methylbenzaldehyde</strong> (11.5 g) in acetone (30 ml), and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, acetone was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure to give 4-(5-fluoro-2-methylphenyl)-3-buten-2-one (13.4 g). To a solution of 20% sodium ethoxide in ethanol (5.9 g) was added at room temperature diethyl malonate (14.0 g), and then added little by little 4-(5-fluoro-2-methylphenyl)-3-buten-2-one (13.4 g), and the mixture was stirred at room temperature for 30 minutes and then for 2 hours while heating, and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (46 ml), and the mixture was refluxed for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (46 ml) for 10 minutes, and the mixture was refluxed for 30 minutes and cooled. Precipitated crystals were filtered and washed with water and isopropylether to give 5-(5-fluoro-2-methylphenyl)cyclohexane-1,3-dione (8.6 g) as colorless crystals. mp 175-176 C. 1H-NMR(CDCl3) delta: 2.30 (3H, s), 2.27-2.56 (4H, m), 2.5-4.3 (1H, br), 3.44-3.63 (1H, m), 5.55 (1H, s), 6.77-7.01 (2H, m), 7.09-7.17 (1H, m).

Reference： [1]Patent: EP1182194,2002,A1 .Location in patent: Page 28
[2]Patent: US6350749,2002,B1 .Location in patent: Page column 133 - 134

14
[ 352-32-9 ]
[ 4885-02-3 ]
[ 93249-44-6 ]
[ 22062-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	With titanium tetrachloride; In dichloromethane; at 20℃; for 5h;	To a solution of 4-fluorotoluene (21.5 g) and dichloromethylmethylether (56.1 g) in dichloromethane (160 ml) was added dropwise at room temperature a solution of titanium tetrachloride (92.6 g) in dichloromethane (50 ml), and the mixture was stirred at the same temperature for 5 hours. The reaction solution was poured into ice, and the organic layer was washed with water, sodium hydrogen carbonate solution, water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give oil of a mixture of 2-fluoro-5-methylbenzaldehyde and 5-fluoro-2-methylbenzaldehyde (about 1:7) (28.1 g). To a mixture of acetone (160 ml), sodium hydroxide (6.4 g) and water (200 ml) was added dropwise at 0 C. a mixture of 2-fluoro-5-methylbenzaldehyde and 5-fluoro-2-methylbenzaldehyde (about 1:7) (28.1 g) in acetone (40 ml), and the mixture was stirred at the same temperature for 1 hour. To the mixture was added 1N hydrochloric acid (160 ml), and acetone was evaporated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate-hexane) to give 4-(2-fluoro-5-methylphenyl)-3-buten-2-one (18.2 g). To a solution of 20% sodium ethoxide in ethanol (1.4 g) was added at room temperature diethyl malonate (3.3 g) and then was added little by little 4-(2-fluoro-5-methylphenyl)-3-buten-2-one (3.5 g), and the reaction mixture was stirred at room temperature for 30 minutes, refluxed for 2 hours and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated. To the residue was added 2M sodium hydroxide (11 ml), and the mixture was refluxed for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (11 ml) for 5 minutes, and the mixture was refluxed for 30 minutes and cooled. Precipitated crystals were filtered, washed with water and isopropylether to give 5-(2-fluoro-5-methylphenyl)cyclohexane-1,3-dione (1.6 g) as colorless crystals. mp 174 C. (decomp.). 1H-NMR(CDCl3-DMSO-d6) delta: 2.31 (3H,s), 2.47-2.93 (4H,m), 3.48-3.68 (1H,m), 5.56 (1H,s), 6.77-7.30 (1H,br), 6.86-7.07 (3H,m).
	With aluminum (III) chloride; In dichloromethane; at 20℃; for 2.08333h;Cooling with ice;	2a (502.0 mg, 4.36 mmol) was added to a mixture of 3e (383.5 mg, 3.48 mmol) and AlCl3 (560.4 mg, 4.21 mmol) in CH2Cl2 (3.5 mL) over a period of 5 min with cooling in an ice bath. The mixture was stirred at room temperature for 2 h. Standard work-up gave the formylation product (586.0 mg). The crude product was purified by bulb-to-bulb distillation (150C, 5 Torr) afforded 275.3 mg (57%) of an inseparable isomer mixture (85:15) as a colorless liquid. Major product: 2-fluoro-5-methylbenzaldehyde (4e); 1H-NMR (300MHz, CDCl3) delta: 2.37 (s, 3H), 7.06 (dd, J = 10.2, 8.4 Hz, 1H), 7.37-7.43 (m, 1H), 7.66 (dd, J = 6.3, 2.1Hz,1H), 10.34 (s, 1H). GC-MS: m/z = 138 (M+, 74%), 137 (91%), 109 (100%), 83 (51%). Minor product: 5-fluoro-2-methylbenzaldehyde (5e); 1H-NMR (300 MHz, CDCl3) delta: 2.64 (s, 1H), 7.18 (dd, J = 8.7, 2.7 Hz, 1H), 7.23-7.25 (m, 1H), 7.50 (dd, J = 8.7, 2.7 Hz, 1H), 10.26 (d, J = 1.8 Hz, 1H). GC-MS: m/z = 138 (M+, 53%), 137 (44%), 109 (100%), 83 (35%). The NMR spectroscopic data matched with those of ref. 22.

Reference： [1]Patent: US6350749,2002,B1 .Location in patent: Page column 134 - 135
[2]Chemical and Pharmaceutical Bulletin,2019,vol. 67,p. 587 - 593

Yield	Reaction Conditions	Operation in experiment
		PREPARATION 6 5-Fluoro-2-methylbenzaldehyde By the procedure of Preparation 1, allowing the reaction mixture to warm to room temperature and stir for 16 hours after addition of reagents was complete, p-fluorotoluene (10 g., 0.09 mole) in 300 ml. of methylene chloride was converted to 5-fluoro-2-methylbenzaldehyde [8.2 g., Rf 0.6 (CHCl3)].

16
[ 1422-53-3 ]
[ 22062-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium; In tetrahydrofuran; N-methyl-acetamide; hexane;	To a solution of 2-bromo-4-fluorotoluene (16.0g) in anhydrous tetrahydrofuran was added dropwise at -78C a solution of 1.6M butyllithium in hexane (55.5ml), and the mixture was stirred at the same temperature for 30 minutes. To the mixture was added dropwise a solution of dimethylformamide (6.8g) in tetrahydrofuran (20ml), and the mixture was allowed to stand to warm up to 0C. The reaction solution was poured into ice-water, and the reaction solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give oil of 5-fluoro-2-methylbenzaldehyde (11.5g).
	With iodine; magnesium; In tetrahydrofuran;	Reference Example 3 Production of 5-fluoro-2-methylbenzaldehyde: Iodine (about 1 mg) was added to a mixture of magnesium (26.28 g) and tetrahydrofuran (600 ml) and 2-bromo-4-fluorotoluene (200.4 g) was added dropwise thereto with ice-cooling (the inner temperature was kept at 65C or lower). After completion of the dropwise addition, the mixture was stirred for 1 hour to prepare a Grignard reagent.

Reference： [1]Patent: EP950418,1999,A2
[2]Patent: EP1229019,2002,A1

17
[ 22062-53-9 ]
4-(5-fluoro-2-methylphenyl)-3-buten-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.3%	With sodium hydroxide; In water; acetone;	Reference Example 4 Production of 4-(5-fluoro-2-methylphenyl)3-buten-2-one: A solution of <strong>[22062-53-9]5-fluoro-2-methylbenzaldehyde</strong> (100 g) in acetone (136 ml) was added dropwise to a mixture of a solution of sodium hydroxide (30.35 g) in water (815 ml) and acetone (543 ml) over about 2 minutes. After stirring at 30C for 20 minutes, acetone was removed by distillation under reduced pressure and extracted with ethyl acetate. The extract was successively washed with 5% salt water and water and then the solvent was removed by distillation to obtain the titled compound (122.97 g, 95.3%). 1H-NMR (CDCl3) delta: 2.39 (3H, s), 2.41 (3H, s), 6.63 (1H, d, J =16 Hz), 6.94-7.27 (2H, m), 7.74 (1H, dd, J = 1.4, 16 Hz).
	With sodium hydroxide; In water; acetone;	To a mixture of acetone (80ml), sodium hydroxide (3.7g) and water (100ml) was added dropwise at room temperature a solution of <strong>[22062-53-9]5-fluoro-2-methylbenzaldehyde</strong> (11.5g) in acetone (30ml), and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, acetone was evaporated, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure to give 4-(5-fluoro-2-methylphenyl)-3-buten-2-one (13.4g).

Reference： [1]Patent: EP1229019,2002,A1
[2]Patent: EP950418,1999,A2

18
[ 124931-12-0 ]
[ 22062-53-9 ]
[ 1019841-01-0 ]

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 4978 - 4983

19
[ 75-77-4 ]
[ 22062-53-9 ]
[ 75-36-5 ]
[ 950188-80-4 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 1d; Preparation of intermediate 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene; To 1,1,1,3,3,3-hexamethyldisilazane (2.18 mL, 10.5 mmol) (Aldrich) under nitrogen at room temperature was added n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 10 minutes. Then dry tetrahydrofuran (30 mL) was added, followed by the addition of <strong>[22062-53-9]5-fluoro-2-methyl-benzaldehyde</strong> (1.38 g, 10 mmol) (Platte). After the mixture was stirred at room temperature for 0.5 h, trimethylsilyl chloride (1.33 mL, 10.5 mmol) (Aldrich) was added dropwise. Then the temperature of the mixture was lowered to 0 C. on a cooling ice bath. To this mixture was added triethylamine (1.9 mL, 13.6 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (0.97 mL, 13.6 mmol) in diethyl ether (50 mL). The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.
		To 1,1,1,3,3,3-hexamethyldisilazane (2.18 mL, 10.5 mmol) (Aldrich) under nitrogen at room temperature was added n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 10 minutes. Then dry tetrahydrofuran (30 mL) was added, followed by the addition of <strong>[22062-53-9]5-fluoro-2-methyl-benzaldehyde</strong> (1.38 g, 10 mmol) (Platte). After the mixture was stirred at room temperature for 0.5 h, trimethylsilyl chloride (1.33 mL, 10.5 mmol) (Aldrich) was added dropwise. Then the temperature of the mixture was lowered to 0 C. on a cooling ice bath. To this mixture was added triethylamine (1.9 mL, 13.6 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (0.97 mL, 13.6 mmol) in diethyl ether (50 mL). The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.
		Example 4; Preparation of intermediate 1 -(5-fluoro-2-methy-lphenyl)-3-trimethylsilyoxy-2-aza- 1,3- butadiene; M.W. 265.41 Ci4H20FNOSiTo dry tetrahydrofuran (400 mL) was added IM THF solution of LiHMDS (420 mmol, 420 mL) under argon at room temperature, followed by the addition of <strong>[22062-53-9]5-fluoro-2-methyl-benzaldehyde</strong> (58 g, 420 mmol). After the mixture was stirred at room temperature for 1 h, trimethylsilyl chloride (53.2 mL, 420 mmol) was added dropwise. Then the temperature of the mixture was lowered to 0 0C on a cooling ice bath. To this mixture was added triethylamine (76 mL, 544 mmol) in one portion, followed by the drop wise addition of a solution of acetyl chloride (38.8 ml, 544 mmol) in diethyl ether (500 mL). The cooling bath was removed, and the mixture was stirred at room temperature overnight. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude l-(5-fluoro-2-methylphenyl)- 3-trimethylsilyoxy-2-aza-l,3-butadiene as a yellow gum and used for the next step without further purification.

		EXAMPLE 1c Preparation of intermediate 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene To 1,1,3,3,3-hexamethyldisilazane (1.61 g, 10 mmol) (Aldrich) under nitrogen at room temperature was added n-butyllithium (2.5 M, 4 mL, 10 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 10 minutes. Then dry tetrahydrofuran (30 mL) was added, followed by the addition of <strong>[22062-53-9]5-fluoro-2-methyl-benzaldehyde</strong> (1.38 g, 10 mmol) (Platte). After the mixture was stirred at room temperature for 0.5 h, trimethylsilyl chloride (1.1 g, 10 mmol) (Aldrich) was added dropwise. Then the temperature of the mixture was lowered to 0 C. on a cooling ice bath. To this mixture was added triethylamine (1.4 g, 13.6 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (1 g, 13.6 mmol) in diethyl ether (50 mL). The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.
		To 1,1,1,3,3,3-hexamethyldisilazane (2.18 mL, 10.5 mmol) (Aldrich) under nitrogen at room temperature was added n-butyllithium (2.5 M, 4.2 mL, 10.5 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 10 minutes. Then dry tetrahydrofuran (30 mL) was added, followed by the addition of <strong>[22062-53-9]5-fluoro-2-methyl-benzaldehyde</strong> (1.38 g, 10 mmol) (Platte). After the mixture was stirred at room temperature for 0.5 h, trimethylsilyl chloride (1.33 mL, 10.5 mmol) (Aldrich) was added dropwise. Then the temperature of the mixture was lowered to 0 C. on a cooling ice bath. To this mixture was added triethylamine (1.9 mL, 13.6 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (0.97 mL, 13.6 mmol) in diethyl ether (50 mL). The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1-(5-fluoro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Reference： [1]Patent: US2009/163512,2009,A1 .Location in patent: Page/Page column 10-11
[2]Patent: US2010/190814,2010,A1 .Location in patent: Page/Page column 9
[3]Patent: WO2010/121995,2010,A1 .Location in patent: Page/Page column 15-16
[4]Patent: US2008/293723,2008,A1 .Location in patent: Page/Page column 9
[5]Patent: US2010/204257,2010,A1 .Location in patent: Page/Page column 7

20
[ 75-77-4 ]
[ 22062-53-9 ]
[ 79-04-9 ]
[ 1240310-54-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 3 Preparation of intermediate 4-chloro-1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene To 1,1,1,3,3,3-hexamethyldisilazane (6.54 mL, 31.5 mmol) (Aldrich) under nitrogen at room temperature was added n-butyllithium (2.5 M, 12.6 mL, 31.5 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 10 minutes. Then dry tetrahydrofuran (50 mL) was added, followed by the addition of <strong>[22062-53-9]5-fluoro-2-methyl-benzaldehyde</strong> (4.35 g, 10.5 mmol) (Platte). After the mixture was stirred at room temperature for 0.5 h, trimethylsilyl chloride (4.11 mL, 31.5 mmol) (Aldrich) was added dropwise. Then the temperature of the mixture was lowered to 0 C. on a cooling ice bath. To this mixture was added triethylamine (5.86 mL, 41 mmol) in one portion, followed by the dropwise addition of a solution of chloroacetyl chloride (3.35 mL, 41 mmol) (Aldrich) in diethyl ether (120 mL). The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 4-chloro-1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.

Reference： [1]Patent: US2010/210674,2010,A1 .Location in patent: Page/Page column 6

21
[ 22062-53-9 ]
[ 1204654-03-4 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 2741 - 2745

22
[ 22062-53-9 ]
[ 101336-63-4 ]
[ 109-77-3 ]
[ 1204654-03-4 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 2741 - 2745

23
[ 22062-53-9 ]
[ 109-77-3 ]
[ 771564-49-9 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 2741 - 2745
[2]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 6296 - 6299

24
[ 22062-53-9 ]
[ 1227682-48-5 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 6296 - 6299

25
[ 22062-53-9 ]
[ 1343456-23-4 ]

Reference： [1]Patent: WO2011/128251,2011,A1
[2]Patent: US2011/257151,2011,A1

26
[ 22062-53-9 ]
[ 1343456-24-5 ]

Reference： [1]Patent: WO2011/128251,2011,A1
[2]Patent: US2011/257151,2011,A1

27
[ 22062-53-9 ]
[ 1343456-28-9 ]

Reference： [1]Patent: WO2011/128251,2011,A1
[2]Patent: US2011/257151,2011,A1

28
[ 22062-53-9 ]
[ 1343456-26-7 ]

Reference： [1]Patent: WO2011/128251,2011,A1
[2]Patent: US2011/257151,2011,A1

29
[ 22062-53-9 ]
[ 94-09-7 ]
[ 1343456-21-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	In ethanol; for 2h;Reflux;	Example 60Cyclopropanesulfonic acid [2-(5-fluoro-2-methyl-phenyl)-3,3-dimethyl-l,2,3,4- tetrahydro-quinoline-6-carbonyl] -amideA mixture of 4-amino-benzoic acid ethyl ester (1.65 g, 10 mmol) and 5-fiuoro-2-methyl- benzaldehyde (1.38 g, 10 mmol) in ethanol (10 mL) was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[l-(5-fiuoro-2-methyl-phenyl)- methylidene]-amino}-benzoic acid ethyl ester (2.0 g, 70%) as a white solid: LC/MS m/e calcd for Ci7Hi6FN02 (M+H)+: 285.3, observed: 286.3.
70%	In ethanol; for 2h;Reflux;	A mixture of 4-amino-benzoic acid ethyl ester (1.65 g, 10 mmol) and <strong>[22062-53-9]5-fluoro-2-methyl-benzaldehyde</strong> (1.38 g, 10 mmol) in ethanol (10 mL) was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[1-(5-fluoro-2-methyl-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (2.0 g, 70%) as a white solid: LC/MS m/e calcd for C17H16FNO2 (M+H)+: 285.3, observed: 286.3

Reference： [1]Patent: WO2011/128251,2011,A1 .Location in patent: Page/Page column 140
[2]Patent: US2011/257151,2011,A1 .Location in patent: Page/Page column 52

30
[ 22062-53-9 ]
[ 1353970-91-8 ]

Reference： [1]Patent: US2012/4218,2012,A1
[2]Patent: US2012/190677,2012,A1
[3]Patent: WO2012/101068,2012,A1

31
[ 22062-53-9 ]
[ 1353968-56-5 ]

Reference： [1]Patent: US2012/4218,2012,A1
[2]Patent: US2012/190677,2012,A1
[3]Patent: WO2012/101068,2012,A1

32
[ 22062-53-9 ]
[ 1353969-31-9 ]

Reference： [1]Patent: US2012/4218,2012,A1

33
[ 22062-53-9 ]
[ 619-45-4 ]
[ 1353970-87-2 ]

Yield	Reaction Conditions	Operation in experiment
82.6%	With toluene-4-sulfonic acid; In toluene; for 12h;Reflux;	A mixture of 4-aminobenzoic acid methyl ester (10.8 g, 71.4 mmol), <strong>[22062-53-9]5-fluoro-2-methylbenzaldehyde</strong> (10.0 g, 72.4 mmol) and p-toluenesulfonic acid (271.8 mg, 1.4 mmol) in toluene (150 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(5-fluoro-2-methyl-benzylidene)-amino]-benzoic acid methyl (16.0 g, 82.6%) as a light yellow solid. MS (ESI+) [(M+H)+] 272.0.
82.6%	With toluene-4-sulfonic acid; In toluene; for 12h;Reflux;	Example 1 2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid 4-[(5-Fluoro-2-methyl-benzylidene)-amino]-benzoic acid methylA mixture of 4-aminobenzoic acid methyl ester (10.8 g, 71.4 mmol), 5-fluoro-2- methylbenzaldehyde (10.0 g, 72.4 mmol) and p-toluenesulfonic acid (271.8 mg, 1.4 mmol) in toluene (150 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4- [(5-fluoro-2-methyl-benzylidene)-amino] -benzoic acid methyl (16.0 g, 82.6%) as a light yellow solid. MS (ESI+) [(M+H)+] 272.0.
82.6%	With toluene-4-sulfonic acid; In toluene; for 12h;Reflux;	The mixture solution of 4-aminobenzoic acid methyl ester (10.8 g, 71.4 mmol), <strong>[22062-53-9]5-fluoro-2-methylbenzaldehyde</strong> (10.0 g, 72.4 mmol) and p-toluenesulfonic acid (271.8 mg, 1.4 mmol) in toluene (150 mL) was heated to reflux for 12 h. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(5-fluoro-2-methyl-benzylidene)-amino]-benzoic acid methyl (16.0 g, 82.6%) as a light yellow solid: MS (ESI) M+1=272.0.

82.6%

With toluene-4-sulfonic acid; In toluene; for 12h;Reflux;

Example 2 2'-(5-Fluoro-2-methylphenyl)-N-(methylsulfonyl)-2',3'-dihydro-l'H- spiro[cyclopropane- 1 ,4 ' - quinoline] -6 ' -carboxamideThe mixture solution of 4-aminobenzoic acid methyl ester (10.8 g, 71.4 mmol), 5-fluoro-2- methylbenzaldehyde (10.0 g, 72.4 mmol) and /?-toluenesulfonic acid (271.8 mg, 1.4 mmol) in toluene (150 mL) was heated to reflux for 12 h. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(5-fluoro-2-methyl-benzylidene)-amino]-benzoic acid methyl (16.0 g, 82.6%) as a light yellow solid: MS(ESI) M+l = 272.0.To a stirred solution 4-[(5-fluoro-2-methyl-benzylidene)-amino]-benzoic acid methyl (2.7 g, 10.0 mmol) in acetonitrile (16.0 mL) were added methylene-cyclopropane (2.8 mL, 40.0 mol) and scandium(III) trifluoromethanesulfonate (Sc(OTf)3) (980.0 mg, 2.0 mmol). The resulting mixture solution was stirred at 80 C for 16 h in sealed tube. The mixture solution was diluted with ethyl acetate (300 mL) and washed with water (100 mL x 2) and brine (100 mL x 2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10 - 50% ethyl acetate in petroleum ether) to afford 2-(5-fluoro-2-methyl-phenyl)- spiro(cyclopropane-l,4'- ,2',3',4'-tetrahydroquinoline)-6-carboxylic acid methyl ester (1.2 g, 37%) as a light yellow solid: MS(ESI) M+l = 326.2.To a stirred solution of 2-(5-fluoro-2-methyl-phenyl)-spiro(cyclopropane-l,4'- ,2',3',4'- tetrahydroquinoline)-6-carboxylic acid methyl ester (800.0 mg, 2.5 mmol) intetrahydrofuran (10.0 mL) and methanol (10.0 mL) was added 3 N sodium hydroxide (2.0 mL). The reaction mixture was stirred at 80C for 6 h, and then diluted with water (10.0 mL), extracted with diethyl ether (20.0 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate. The solvent was removed in vacuo and afforded 2-(5-fluoro-2-methyl-phenyl)- spiro(cyclopropane-l,4'- ,2',3',4'-tetrahydroquinoline)-6-carboxylic acid (650 mg, 85%) as a light yellow powder: MS(ESI) M+l = 312.3. To a suspension of 60% sodium hydride (128 mg, 3.2 mmol) in N, N-dimethylformamide (1.5 mL) was added methanesulfonamide (314 mg, 3.3 mmol) at room temperature. The resulting mixture was stirred at 25C for 1 h to afford Solution A2. A solution of 2-(5- fluoro-2-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid (102.0 mg, 0.33 mmol) and Iota,Gamma-carbonyldiimidazole (136 mg, 0.84 mmol) in N, N-dimethylformamide (2.0 mL) was stirred at 70C for 1 h and cooled to room temperature to afford Solution B2. Solution B2 was added to Solution A2 and the resulting mixture was stirred at 25C for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2'-(5-fluoro-2-methylphenyl)-N-(methylsulfonyl)-2',3'- dihydro-1 'H-spiro [cyclopropane- l,4'-quinoline]-6'-carboxamide (38.4 mg, 30%) as a white solid: MS(ESI) M+l = 389.2.

Reference： [1]Patent: US2012/4218,2012,A1 .Location in patent: Page/Page column 13
[2]Patent: WO2012/1020,2012,A1 .Location in patent: Page/Page column 32-33
[3]Patent: US2012/190677,2012,A1 .Location in patent: Page/Page column 18
[4]Patent: WO2012/101068,2012,A1 .Location in patent: Page/Page column 47-49

34
[ 22062-53-9 ]
[ 168079-19-4 ]
[ 1376615-35-8 ]

Yield	Reaction Conditions	Operation in experiment
18%		15b: (5H-Benzo[e]pyrrolo[1 ,2-a][1 ,4]diazepin-10(11 H)-yl)(2-chloro-4-(5-fluoro-2- methylbenzylamino)phenyl)methanone A solution of intermediate E (200 mg, 0.6 mmol, 1 .0 eq) and <strong>[22062-53-9]5-fluoro-2-methyl-benzaldehyde</strong> (124 mg, 0.9 mmol, 1 .5 eq) in MeOH (20 mL) was heated at reflux for 18 h then cooled to room temperature. NaBH4 (45 mg, 1 .2 mmol, 2.0 eq) was then added and the mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure to give a solid, which was purified by flash chromatography (Pet. ether/EtOAc, 5/1 , v/v) to give (5H- benzo[e]pyrrolo[1 ,2-a][1 ,4]diazepin-10(1 1 H)-yl)(2-chloro-4-(5-fluoro-2- methylbenzylamino)phenyl)methanone (50 mg, 18%) as a white solid.LC-MS (Agilent): Rt 3.49 min; m/z calculated for C27H23CIFN3O [M+H]+ 460.15, found 460.1 .1H NMR: (400 MHz, CDCI3) delta (ppm): 7.25 (m, 1 H), 7.19-6.79 (m, 7H) , 6.65 (m, 1 H), 6.43 (m, 1 H), 6.24 (m, 1 H), 6.10-5.98 (m, 2H), 5.38-4.77 (m, 4H), 4.17 (m, 2H), 2.26 (s, 3H).
18%		A solution of intermediate E (200 mg, 0.6 mmol, 1.0 eq) and <strong>[22062-53-9]5-fluoro-2-methyl-benzaldehyde</strong> (124 mg, 0.9 mmol, 1.5 eq) in MeOH (20 mL) was heated at reflux for 18 h then cooled to room temperature. NaBH4 (45 mg, 1.2 mmol, 2.0 eq) was then added and the mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure to give a solid, which was purified by flash chromatography (Pet. ether/EtOAc, 5/1, v/v) to give (5H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-10(11H)-yl)(2-chloro-4-(5-fluoro-2-methylbenzylamino)phenyl)methanone (50 mg, 18%) as a white solid. LC-MS (Agilent): Rt 3.49 min; m/z calculated for C27H23ClFN3O [M+H]+ 460.15. found 460.1. 1H NMR: (400 MHz, CDCl3) delta (ppm): 7.25 (m, 1H), 7.19-6.79 (m, 7H), 6.65 (m, 1H), 6.43 (m, 1H), 6.24 (m, 1H), 6.10-5.98 (m, 2H), 5.38-4.77 (m, 4H), 4.17 (m, 2H), 2.26 (s, 3H).

Reference： [1]Patent: WO2012/63085,2012,A2 .Location in patent: Page/Page column 91-92
[2]Patent: US2013/225594,2013,A1 .Location in patent: Paragraph 0303; 0310

35
[ 22062-53-9 ]
[ 1391608-78-8 ]

Reference： [1]Patent: US2012/190677,2012,A1
[2]Patent: WO2012/101068,2012,A1

36
[ 22062-53-9 ]
C₁₃H₈BrFS [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 2593 - 2598
Angew. Chem.,2013,vol. 125,p. 2653 - 2659,7

37
[ 22062-53-9 ]
[ 1429937-66-5 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 2593 - 2598
Angew. Chem.,2013,vol. 125,p. 2653 - 2659,7
[2]Angewandte Chemie - International Edition,2013,vol. 52,p. 2593 - 2598
Angew. Chem.,2013,vol. 125,p. 2653 - 2659,7

38
[ 22062-53-9 ]
[ 1429938-20-4 ]

39
[ 22062-53-9 ]
[ 1429937-83-6 ]

40
[ 22062-53-9 ]
[ 90965-06-3 ]
[ 1233512-88-3 ]

Reference： [1]Angewandte Chemie - International Edition,2013,vol. 52,p. 2593 - 2598
Angew. Chem.,2013,vol. 125,p. 2653 - 2659,7

41
[ 1492924-33-0 ]
[ 22062-53-9 ]
1-allyl-3-(5-fluoro-2-methylbenzylidene)-6-(2-methoxybenzylidene)piperazine-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 5h;	General procedure: Cs2CO3 (1.5 equiv.) was added into the solution containing intermediate 3 (1.0 equiv., 50.0 mg) and aromatic aldehyde (1.2 equiv.) in dry DMF (1.5 mL), and the mixture was stirred at room temperature for about 5 h. After the reaction was completed, the mixture was slowly poured into water and extracted with AcOEt for three times, and the organic layer was dried, filtered, and purified with silica gel column to afford the target compound.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 83,p. 236 - 244

42
[ 22062-53-9 ]
(E)-3-(5-fluoro-2-methylphenyl)-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)acrylamide [ No CAS ]

Reference： [1]Letters in drug design and discovery,2015,vol. 12,p. 20 - 28

43
[ 22062-53-9 ]
C₁₀H₈ClFO [ No CAS ]

Reference： [1]Letters in drug design and discovery,2015,vol. 12,p. 20 - 28

44
[ 22062-53-9 ]
malonic [ No CAS ]
C₁₀H₉FO₂ [ No CAS ]

Reference： [1]Letters in drug design and discovery,2015,vol. 12,p. 20 - 28

45
[ 645-00-1 ]
[ 22062-53-9 ]
5-fluoro-2-(3-nitrobenzyl)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With palladium(II) trifluoroacetate; (S)-2-amino-N-(1-hydroxy-2-methylpropan-2-yl)-3-phenylpropanamide; silver trifluoroacetate; acetic acid; In water; at 90℃; for 12h;	General procedure: O-Tolualdehyde (0.24 mmol), iodobenzene (0.2 mmol), silver trifluoroacetate (0.3 mmol, 66 mg), palladium trifluoroacetate (0.02 mmol, 7 mg), Phe-Me2AA ligand (0.08 mmol, 19 mg), acetic acid (1.8 mL) and H2O (0.2 mL) were added to a vial. The mixture was heated to 90 C for 12 h. The reaction mixture was allowed to cool to room temperature and filtered through a silica gel pad, concentrated in vacuum. The desired product was isolated by a silica gel column chromatography or preparative TLC.

Reference： [1]Advanced Synthesis and Catalysis,2020,vol. 362,p. 133 - 138
[2]Science,2016,vol. 351,p. 252 - 256
[3]Tetrahedron,2018,vol. 74,p. 2048 - 2055

46
[ 696-62-8 ]
[ 22062-53-9 ]
5-fluoro-2-(4-methoxybenzyl)benzaldehyde [ No CAS ]

Reference： [1]Organic Letters,2016,vol. 18,p. 2708 - 2711
[2]Advanced Synthesis and Catalysis,2020,vol. 362,p. 133 - 138

47
[ 22062-53-9 ]
[ 20948-67-8 ]
(E)-5-chloro-N’-(5-fluoro-2-methylbenzylidene)-1H-indole-2-carbohydrazide [ No CAS ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 1181 - 1192

48
[ 22062-53-9 ]
4-(6-(4-amino-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile [ No CAS ]
4-(6-(4-((5-fluoro-2-methylbenzyl)amino)-4-methylpiperidin-1-yl)pyridin-3-yl)-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%		To a solution of 4-(6-(4-amino-4-methylpiperidin-l-yl)pyridin-3-yl)-6-(2- hydroxy-2-methylpropoxy)pyrazolo[l,5-a]pyridine-3-carbonitrile (Intermediate P46; 50 mg, 0.119 mmol) in DCM (1 mL) was added DIEA (73 mu., 0.416 mmol). The solution stirred for 10 min at ambient temperature. 5-Fluoro-2-methylbenzaldehyde (29 iL, 0.238 mmol) was added, followed by NaBH(AcO)3 (76 mg, 0.357 mmol) The resulting reaction mixture was allowed to stir 12 h at ambient temperature. The reaction was diluted with DCM and washed with saturated NaHC03(aq). The combined organic extracts were dried over anhydrous Na2S04(S), filtered and concentrated in vacuo. The residue was purified by silica chromatography (1 - 10% MeOH in DCM with 0. 1 -1% H4OH as the gradient eluent) to cleanly provide the title compound (25 mg, 39% yield). MS (apci) m/z=543.3 (M+H)

Reference： [1]Patent: WO2018/71454,2018,A1 .Location in patent: Paragraph 001655; 001656; 001657

49
[ 22062-53-9 ]
racemic (2'S,3S,4'R)-6-chloro-4'-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)pyridin-3-yl]-2'-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dione [ No CAS ]

Reference： [1]Patent: US2010/204257,2010,A1

50
[ 22062-53-9 ]
[ 1239779-14-6 ]
[ 1239779-13-5 ]

Reference： [1]Patent: US2010/204257,2010,A1

51
[ 22062-53-9 ]
racemic (2'S,3S,4'R)-6-chloro-4'-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)pyridin-3-yl]-2'-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dione [ No CAS ]

Reference： [1]Patent: US2010/204257,2010,A1

52
[ 22062-53-9 ]
[ 1239779-17-9 ]
[ 1239779-16-8 ]

Reference： [1]Patent: US2010/204257,2010,A1

53
[ 22062-53-9 ]
racemic (2'S,3S,4'R)-4'-[5-chloro-2-(2-methanesulfonylamino-1,1-methyl-2-oxo-ethoxy)pyridin-3-yl]-6-chloro-2'-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3'-piperidine]-2,6'(1H)-dione [ No CAS ]

Reference： [1]Patent: US2010/204257,2010,A1

54
[ 22062-53-9 ]
C₃₄H₃₄Cl₂FN₃O₇ [ No CAS ]

Reference： [1]Patent: US2010/204257,2010,A1

55
[ 624-38-4 ]
[ 22062-53-9 ]
6,6'-(1,4-phenylenebis(methylene))bis(3-fluorobenzaldehyde) [ No CAS ]

Reference： [1]Organic Letters,2018,vol. 20,p. 7620 - 7623

56
[ 22062-53-9 ]
2-((5-fluoro-2-methyl)benzyloxy)-N-(pyridin-3-yl)benzamide [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 163,p. 864 - 882

57
[ 22062-53-9 ]
2-(bromomethyl)-4-fluoro-1-methylbenzene [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 163,p. 864 - 882

58
[ 1076-96-6 ]
[ 22062-53-9 ]
methyl-4-(1-azido-3-(5-fluoro-2-methylphenyl)-3-oxopropyl)benzoate [ No CAS ]

Reference： [1]Organic Letters,2019,vol. 21,p. 256 - 260

59
[ 22062-53-9 ]
[ 396075-97-1 ]

Reference： [1]Patent: WO2019/86142,2019,A1

60
[ 22062-53-9 ]
7-fluoro-4-methyl-1H-indole-2-carboxylic acid [ No CAS ]

Reference： [1]Patent: WO2019/86142,2019,A1
[2]Patent: WO2019/86141,2019,A1

61
[ 637-81-0 ]
[ 22062-53-9 ]
C₁₂H₁₂FN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium methylate; In methanol; at -10 - 5℃; for 3h;	To a solution of sodium methoxide (21.6 g, 400 mmol) in methanol (300 mL) at at - 10C was added dropwise a solution of compound 4 (26.4 g, 183 mmol) and compound 5 (59.0 g, 457 mmol) in methanol (100 mL). The reaction mass was stirred for 3 h maintaining temperature below 5C and then quenched with ice water. The resulting mixture was stirred for 10 min, filtered, and washed with water to afford 35.0 g (156 mmol, 72%) of compound 6 as a white solid.
72%	With sodium methylate; In methanol; at -10 - 5℃; for 3h;	To a solution of sodium methoxide (21.6 g, 400 mmol) in methanol (300 mL) a solution of compound 4 (26.4 g, 183 mmol) and compound 5 (59.0 g, 457 mmol) in methanol (100 mL) was added dropwise at -10C. The reaction mass was stirred for 3 h maintaining temperaturebelow 5C and then quenched with ice water. The resulting mixture was stirred for 10 mm, filtered, and washed with water to afford 35.0 g (156 mmol, 72%) of compound 6 as a white solid.

Reference： [1]Patent: WO2019/86142,2019,A1 .Location in patent: Page/Page column 68; 69
[2]Patent: WO2019/86141,2019,A1 .Location in patent: Page/Page column 98

62
[ 22062-53-9 ]
5-(7-fluoro-4-methyl-1H-indole-2-carbonyl)-4H,5H,6H,7H-[1,3]thiazolo[5,4-c]pyridin-2-amine [ No CAS ]

Reference： [1]Patent: WO2019/86141,2019,A1

63
[ 591-50-4 ]
[ 22062-53-9 ]
[ 21454-60-4 ]

Yield	Reaction Conditions	Operation in experiment
84%	With trifluorormethanesulfonic acid; palladium diacetate; silver trifluoroacetate; acetic acid; glycine; at 100℃; for 24h;Sealed tube;	General procedure: A sealed tube with magnetic stir bar was charged with substrate 1 (0.24 mmol), glycine (0.1 mmol, 7.5 mg), Pd(OAc)2 (0.02 mmol, 4.45 mg), AgTFA (0.24 mmol, 53.01 mg) and 2 (0.2 mmol) under air. After addition of AcOH (2 mL) as solvent, TfOH (0.1 mmol, 15.0 mg) was added. The reaction mixture was allowed to stir at 100 C for 24 hours. Upon completion, the reaction mixture was cooled to room temperature, diluted with DCM, and then extracted with saturated NaHCO3 aqueous solution. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel using PE as the eluent to afford the desired products.

Reference： [1]Tetrahedron,2019,vol. 75,p. 4031 - 4041

64
[ 319906-43-9 ]
[ 22062-53-9 ]
8-fluoro-13,13-dioctyl-13H-indeno[1,2-b]anthracene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With trifluorormethanesulfonic acid; palladium diacetate; silver trifluoroacetate; glycine; In acetic acid; at 100℃; for 24h;Sealed tube;	General procedure: A sealed tube with magnetic stir bar was charged with substrate 1 (0.2 mmol), glycine (0.2 mmol, 15.0 mg), Pd(OAc)2 (0.02 mmol, 4.5 mg), AgTFA (0.6 mmol,132.8 mg) and 2 (0.3 mmol) under air. After addition of AcOH (2.0 mL) as solvent, TfOH (0.2 mmol, 30.0 mg) was added. The reaction mixture was allowed to stir at 100 C for 24 hours. Upon completion, the reaction mixture was cooled to room temperature, diluted with DCM, and then extracted with saturated NaHCO3 aqueous solution. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel using petroleum ether as the eluent to afford the desired products.

Reference： [1]Tetrahedron Letters,2019,vol. 60

65
9,9-bis(n-butyl)-2,7-diiodofluorene [ No CAS ]
[ 22062-53-9 ]
15,15-dibutyl-3,10-difluoro-15H-cyclopenta[1,2-b:3,4-b']dianthracene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With trifluorormethanesulfonic acid; palladium diacetate; silver trifluoroacetate; glycine; In acetic acid; at 100℃; for 24h;Sealed tube;	General procedure: A sealed tube with magnetic stir bar was charged with substrate 1 (0.2 mmol), glycine (0.2 mmol, 15.0 mg), Pd(OAc)2 (0.02 mmol, 4.5 mg), AgTFA (0.6 mmol,132.8 mg) and 2 (0.3 mmol) under air. After addition of AcOH (2.0 mL) as solvent, TfOH (0.2 mmol, 30.0 mg) was added. The reaction mixture was allowed to stir at 100 C for 24 hours. Upon completion, the reaction mixture was cooled to room temperature, diluted with DCM, and then extracted with saturated NaHCO3 aqueous solution. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel using petroleum ether as the eluent to afford the desired products.

Reference： [1]Tetrahedron Letters,2019,vol. 60

66
[ 22062-53-9 ]
2-bromo-3-fluoro-6-methylbenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With N-Bromosuccinimide; 4-chloro-2-(trifluoromethyl)aniline; palladium diacetate; In 1,2-dichloro-ethane; trifluoroacetic acid; at 60℃; for 24h;	General procedure: Compound 1 (0.4 mol), N-bromosuccinimide (NBS) (0.48 mol, 85.4 mg), and Pd(OAc)2(10 mol%, 8.9 mg), 2-Amino-5-chlorobenzotrifluoride (20 mol%, 15.6 mg) were mixed withDCE (2.5 mL) and TFA (0.5 mL) solvent. The reaction mixture was stirred 24 h at 60 C. Aftercompletion of the reaction, the solution was concentrated in vacuo and purified by columnchromatography on silica gel using PE/DCM/EtOAc as eluent to give the desired product.

Reference： [1]Tetrahedron Letters,2019,vol. 60

67
[ 22062-53-9 ]
12-fluoro-2,10-dimethyl-2,10,15,16-tetrahydro-4,8-(metheno)benzo[k]pyrazolo[4,3-g][1]oxa[4,9]diazacyclotridecin-7-amine [ No CAS ]