[ CAS No. 1544-85-0 ] {[proInfo.proName]}

Name: 1544-85-0|2,2-Difluorobenzo[d][1,3]dioxol-5-amine|97%
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SKU: A122948
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Quality Control of [ 1544-85-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1544-85-0 ]

SDS Specification

Alternatived Products of [ 1544-85-0 ]

Product Details of [ 1544-85-0 ]

CAS No. :	1544-85-0	MDL No. :	MFCD00190144
Formula :	C₇H₅F₂NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CVYQRDKVWVBOFP-UHFFFAOYSA-N
M.W :	173.12	Pubchem ID :	2736893
Synonyms :

Calculated chemistry of [ 1544-85-0 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	0
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	37.05
TPSA :	44.48 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) :	-6.06 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.63
Log Po/w (XLOGP3) :	1.82
Log Po/w (WLOGP) :	2.44
Log Po/w (MLOGP) :	0.88
Log Po/w (SILICOS-IT) :	1.58
Consensus Log Po/w :	1.67

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.43
Solubility :	0.643 mg/ml ; 0.00372 mol/l
Class :	Soluble
Log S (Ali) :	-2.37
Solubility :	0.732 mg/ml ; 0.00423 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.33
Solubility :	0.802 mg/ml ; 0.00463 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.27

Safety of [ 1544-85-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H317-H319-H412	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1544-85-0 ]

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

Upstream synthesis route of [ 1544-85-0 ]
Downstream synthetic route of [ 1544-85-0 ]

[ 1544-85-0 ] Synthesis Path-Upstream 1~2

1
[ 1645-96-1 ]
[ 1544-85-0 ]

Yield	Reaction Conditions	Operation in experiment
72.5%	With palladium 10% on activated carbon; hydrogen In methanol for 2 h;	To a suspension of 10percent Pd/C (0.05 g) in MeOH (5.0 mL) was added a solution of 69.1 (0.5 g, 2.46 mmol, 1.0 eq) in MeOH (3.0 mL) under nitrogen. Reaction was purged with H₂ gas for 2 hours. After completion of the reaction, mixture was filtered through celite and washed with MeOH. Obtained filtrate was concentrated under reduced pressure to get crude which was purified by trituration with n-hexane to provide 69.2 (0.31 g, 72.5percent). MS(ES): m/z 173.12 [M+H]⁺.

Reference： [1] Journal of Organic Chemistry, 2008, vol. 73, # 17, p. 6780 - 6783
[2] Patent: US2016/251376, 2016, A1, . Location in patent: Paragraph 0895; 0896; 0897

2
[ 1645-96-1 ]
[ 1544-85-0 ]

Reference： [1] Patent: EP634413, 1995, A1,

[ 1544-85-0 ] Synthesis Path-Downstream 1~88

Yield	Reaction Conditions	Operation in experiment
27%		General procedure: To a flame-dried 25 mL round bottom flask was charged activated Mg (7.5 mmol, 1.5 eq.) and 5 mL anhydrous THF. To this suspension was added 2 drops of 1,2-dibromoethane. After 5 min, a solution of Aryl bromide (5 mmol, 1.0 eq.) in 5 mL anhydrous THF was slowly added to the suspension of Mg at room temperature. The reaction was mildly exothermic. The Grignard reagent was titrated and 1 mmol of this reagent was added to a flame-dried reaction vial. The solution was diluted with 3 mL anhydrous toluene and after cooling to the target temperature T, a solution of oxaziridine (1.2 mmol, 1.2 eq.) in 1 mL anhydrous toluene was added. The reaction was maintained at the targeted temperature T for time t before being quenched with saturated aqueous NH4Cl. (The actual temperature/reaction time is listed for each substrate.)

2
[ 874143-25-6 ]
[ 1544-85-0 ]
N-(3-(6-(2,2-difluorobenzo[d][1,3]dioxol-5-ylamino)pyrazin-2-yl)phenyl)acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 407 - 416

3
[ 1544-85-0 ]
[ 1147550-11-5 ]
[ 1057344-56-5 ]

Yield	Reaction Conditions	Operation in experiment
		Example Al l; a) Preparation of intermediate 242-Chloro-4-pyridinecarbonyl chloride (0.16 mol) was added dropwise to a stirring mixture of thiocyanic acid ammonium salt (0.175 mol) in 2-propanone (250 ml) at room temperature and the resulting mixture was stirred for 2 hours. 2,2-Difluoro- 1 ,3- benzodioxol-5-amine (25 g, 0.145 mol) was added and the reaction mixture was stirred overnight at room temperature. Then the mixture was poured out on ice. The precipitate was filtered off and dried, yielding intermediate 24 which was used as such in the next reaction step.

Reference： [1]Patent: WO2007/118903,2007,A1 .Location in patent: Page/Page column 52

4
2-methyl-4-pyridinecarbonyl chloride [ No CAS ]
[ 1544-85-0 ]
[ 953429-08-8 ]

Yield	Reaction Conditions	Operation in experiment
		Example A 14; si) Preparation of intermediate 32Dissolved 2-methyl-4-pyridinecarbonyl chloride (0.1160 mol) in 2-propanone (400 ml) at room temperature, thiocyanic acid ammonium salt (0.1300 mol) was added. The reaction mixture was stirred for 30 minutes, then 2,2-difluoro-l,3-benzodioxol-5-amine (0.1160 mol) was added slowly by an additional funnel. The reaction mixture was stirred at room temperature for 2 hours, then quenched by H2O (100 ml), extracted by CH2Cl2 (3 x 100 ml), the combined organic phase was dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (gradient heptane/EtOAc from 70/30 to 50/50).The product fractions were collected and the solvent was evaporated, yielding 6.5 g of intermediate 32.

Reference： [1]Patent: WO2007/118903,2007,A1 .Location in patent: Page/Page column 55

5
[ 1544-85-0 ]
[ 918792-69-5 ]

Yield	Reaction Conditions	Operation in experiment
26%	With hydrogenchloride; tin(ll) chloride; sodium nitrite; In water; at -5 - 10℃; for 1h;	Preparation 10; (2,2-Difluoro-benzo[l ,3]dioxol-5-yl)-hydrazine hydrochloride saltAdd slowly a solution of sodium nitrite (1.40 g, 20.3 mmol) in water (11 mL) to a flask containing 2,2-difluoro-benzo[l,3]dioxol-5-ylamine (3.41 g, 19.7 mmol), water (14 mL), and concentrated hydrochloric acid (5 mL) at -5 0C. Cool the reaction to -10 0C then add tin(II) chloride (11.20 g, 49.6 mmol) in concentrated hydrochloric acid (9 mL). Stir the reaction for one hour and collect the resultant solid by filtration. Dissolve the solid in methylene chloride (20 mL) and treat with acetone (5 mL). Wash the resultant organic solution with water (50 mL), dry over magnesium sulfate, filter, and evaporate under reduced pressure. Stir the resultant oil with 2N hydrochloric acid (100 mL) for 12 h. Collect a solid by filtration, wash with water and dry in a vacuum oven at 40 0C overnight to give the subtitled compound (1.14 g, 26%) as a red powder. 1H NMR (300 MHz, DMSO-J6): delta 10.32 (br s, 3H), 8.45 (br s, IH), 7.34 (d, J= 8.7 Hz, IH), 7.11 (d, /= 2.3 Hz, IH), 6.79 (dd, /= 8.7, 2.3 Hz, IH).

Reference： [1]Patent: WO2007/2181,2007,A2 .Location in patent: Page/Page column 97

6
[ 1544-85-0 ]
[ 106-96-7 ]
[ 213967-08-9 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; at 80℃;	Example 1 N-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-prop-2-ynylamine To a stirred solution of 5-amino-2,2-difluorobenzo-1,3-dioxole (2.8 g, 16.17 mmmol) in 25 mL of anhydrous toluene was dropwise added propargyl bromide (0.99 mL, 11 mmol). The mixture was heated to 80 C. overnight after which it was allowed to cool to ambient temperature and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography using DCM as eluant to provide the titled compound. 1H NMR (CDCl3) delta ppm 2.22 (1H), 3.85 (2H), 6.30-6.85 (3H); MS (ESI) 212 (M+H).

Reference： [1]Patent: US2008/70929,2008,A1 .Location in patent: Page/Page column 31

7
[ 1544-85-0 ]
[ 506-68-3 ]
[ 1000858-57-0 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; for 16h;	Example 18 2,2-difluoro-1,3-benzodioxol-5-ylcyanamide To a mixture of 2,2-difluorobenzo[d][1,3]dioxol-5-amine (1.0 g, 5.77 mmol) in anhydrous DCM (15 mL) cyanogen bromide (3M, 1.55 mL) was added dropwise; after 16 hours the mixture was diluted with 150 mL of DCM and filtered. The organic phase was evaporated under vacuum and the residue purified by column chromatography using a mixture of DCM-MeOH (95:5) as eluant to provide the titled compound. 1H NMR (CDCl3) delta ppm 5.82 (1H), 6.65-7.25 (3H); MS (DCI) 216 (M+NH4+).

Reference： [1]Patent: US2008/70929,2008,A1 .Location in patent: Page/Page column 32

8
[ 75-77-4 ]
[ 1544-85-0 ]
[ 17422-74-1 ]
C₂₀H₁₇F₂NO₄Si [ No CAS ]

Reference： [1]Synthesis,2007,p. 1861 - 1871

9
[ 1544-85-0 ]
C₁₇H₉F₂NO₄ [ No CAS ]

Reference： [1]Synthesis,2007,p. 1861 - 1871

10
[ 1544-85-0 ]
[ 659726-70-2 ]

Reference： [1]Patent: US2004/82615,2004,A1 .Location in patent: Page 16-17

11
[ 1544-85-0 ]
[ 121794-40-9 ]
C₁₅H₁₀BrF₂NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With triethylamine;dmap; In acetonitrile; at 0℃;	2.0 g (11.7 mmol ; 1.0 eq) of 5-amino-2, 2-difluorobenzo-1, 3-DIOXOLE are dissolved in 100 ML of acetonitrile, and 2.5 ml (17.6 mmol ; 1.5 eq) of triethylamine and a catalytic amount of 4-DIMETHYLAMINOPYRIDINE are then added to the reaction medium. The solution is then cooled to 0C and 3.0 g (12.9 mmol ; 1.1 eq) of 2- BROMO-3-METHYLBENZOYL chloride in 40 mi of acetonitrile are added dropwise to this solution. The reaction medium is stirred overnight and then concentrated under reduced pressure. The residue is then dissolved in DICHLOROMETHANE and washed with aqueous 10% potassium carbonate solution, with water, with aque- ous 10% citric acid solution and with saline solution. The organic phase is then dried over anhydrous magnesium sulfate and concentrated under reduced pres- sure. The solid obtained is purified by flash chromatography on silica, using DICHLOROMETHANE as eluent. A cream-coloured solid is thus obtained (2.35 g; 54%).

Reference： [1]Patent: WO2004/37806,2004,A1 .Location in patent: Page 69

12
[ 1544-85-0 ]
[ 682339-53-3 ]
[ 682340-40-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine;dmap; In acetonitrile; at 0℃;	0.028 g (0.16 mmol ; 1.0 eq) of 5-amino-2, 2-difluorobenzo-1, 3-DIOXOLE is dissolved in 1.0 mi of acetonitrile, followed by addition of 0.034 ml (0.26 mmol ; 1.6 eq) of triethylamine and a catalytic amount of 4-dimethylaminopyridine. The solution is cooled to 0C, after which 0.062 g (0.17 mmol ; 1.1 eq) of the acid CHLO- ride obtained in step d') above in 1.0 ml of acetonitrile is added dropwise to the reaction medium. The reaction medium is then stirred overnight, after which it is concentrated under reduced pressure. The residue is dissolved in dichloro- methane and then washed with aqueous 10% potassium carbonate solution, with water, with aqueous 10% citric acid solution, with water and then with saline solu- tion. The organic phase is then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The solid obtained is purified by flash chromatography on silica, using as eluent a mixture of ethyl acetate and hexane in a 1: 4 ratio, so as to obtain the expected product in the form of a colourless oil (0.072 g; 90%).

Reference： [1]Patent: WO2004/37806,2004,A1 .Location in patent: Page 66; 72-73

13
4'-acetoxyethylbiphenyl-2-carboxylic acid [ No CAS ]
[ 1544-85-0 ]
C₂₄H₁₉F₂NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃;	664 mg (1.75 MMOL) of 0- (7-AZABENZOTRIAZOL-1-YL)-N, N, N', N'-TETRAMETHYL- uronium hexafluorophosphate (HBTU) are added to a solution of 415 mg (1.46 MMOL) of 4'-acetoxyethylbiphenyl-2-carboxylic acid and 303 mg (1.75 MMOL) of 5-amino-2, 2-difluorobenzodioxole in 14.6 mi of acetonitrile comprising 381 1LL (2.19 MMOL) of diisopropylethylamine. The reaction mixture is stirred at room temperature overnight and then diluted with ethyl acetate. The organic phase is washed with 1 N HCI, with saturated sodium bicarbonate solution, with water and with saturated salt solution, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product is purified by flash chromatography using an ethyl acetate/hexane mixture as eluent, to give 391 g (61 %) of pure product.

Reference： [1]Patent: WO2004/37806,2004,A1 .Location in patent: Page 51; 60

14
4'-(1-oxo-2-methylpropyl)biphenyl-2-carboxylic acid [ No CAS ]
[ 1544-85-0 ]
C₂₄H₁₉F₂NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 72h;	2.37 g (6.24 MMOL) of HBTU are added to a solution of 1.4 g (5.2 MMOL) of 4'-isopropylcarbonylbiphenyl-2-carboxylic acid and 1.08 g (6.2 MMOL) of 5-amino- 2, 2-difluorobenzodioxole in 52 ml of acetonitrile comprising 1.36 ml (7.81 MMOL) of diisopropylethylamine. The reaction mixture is stirred at room temperature for three days and then diluted with ethyl acetate. The organic phase is washed with 1N HCI, with saturated sodium bicarbonate solution, with water and with satu- rated aqueous salt solution, and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product is purified by flash chromatography using an ethyl acetate/hexane mixture as eluent. The product thus obtained is purified after taking up in ether and washing twice with 10% potassium carbonate solution, with water and with saturated aqueous salt SOLU- tion. The organic phase is dried over anhydrous magnesium sulfate and concen- trated under reduced pressure to finally give 1.62 g (74%) of the pure expected product.

Reference： [1]Patent: WO2004/37806,2004,A1 .Location in patent: Page 52; 60

15
[ 1544-85-0 ]
[ 682339-52-2 ]
[ 682339-90-8 ]

Yield	Reaction Conditions	Operation in experiment
38.7%	With triethylamine; In dichloromethane; at 0 - 20℃; for 3h;	A solution of 4.57 g (0.036 mol) of oxalyl chloride in 10 ml of dichloro- methane is added to a mixture, maintained between 0 and 5C, of 4.8 g (0.020 mol) of 4'-isopropylbiphenyl-2-carboxylic acid in 50 ml of dichloromethane, followed by addition of 2 drops of N, N-dimethylformamide. The resulting mixture is stirred for 3 hours at room temperature and then concentrated under reduced pressure to give the 4'-isopropylbiphenyl-2-carboxylic acid chloride. A solution of this acid chloride in 30 ml of dichloromethane is added at between 0 and 5C to a solution of 3.4 g (0.196 mol) of 2, 2-difluoro-5-aminobenzodioxole and 5.3 g of triethylamine (0.0524 mol) in 50 ml of DICHLOROMETHANE. After stirring for 3 hours at room temperature, aqueous sodium bicarbonate solution is added. The organic phase is washed with water, dried over sodium sulfate and concentrated to dry- ness under reduced pressure to give a solid, which is purified by recrystallisation from 150 ml of heptane, followed by chromatography on a column of silica (ELU- ent: 2/1 hexane/ethyl acetate) and a further recrystallisation from a mixture of 70 mi of heptane and 20 ml of ethyl acetate. 3.0 g (38.7%) of a white powder corresponding to the title compound are obtained. 1H NMR: (CDC13) 8 (PPM) : 1.28 (6 H, d, J = 7 Hz); 2.97 (1 H, sept, J = 7 Hz); 6.24-6. 38 (1 H, m); 6.73-6. 91 (2 H, m); 7.11-7, 21 (1 H, m); 7.28-7. 62 (7 H, m); 7.83-7. 98 (1 H, m).

Reference： [1]Patent: WO2004/37806,2004,A1 .Location in patent: Page 50-51; 59

16
[ 50634-05-4 ]
[ 1544-85-0 ]
1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-1H-pyrrole-3-carbaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With acetic acid; at 60℃;	Example R 1- (2, 2-difluoro-benzo [1, 3] dioxol-5-yl)-lH-pyrrole-3-carbaldehyde; To a solution of 2,5-dimethoxy-3-tetrahydrofurancarboxaldehyde (1.0 g, 6.4 mmol) in acetic acid (40 mL) was added 2,2-difluoro-benzo [1, 3] dioxol-5-ylamine (1.0 g, 5.8 mmol) and the mixture was heated at 60C under an atmosphere of nitrogen until HPLC indicated that starting material was consumed. The reaction mixture was concentrated and the residue was purified on SiO2 eluted with heptane: EtOAc (4: 1) to give 0.64 g (44%) of the title compound. H NMR (CDC13) o 9.85 (s, 1H), 7.58 (m, 1H), 7.16 (m, 3H), 7.00 (m, 1H), 6.80 (m, 1H). l3C NMR (CDC13) 8 185. 5,144. 6,142. 9,136. 1,135. 4,132. 0,128. 6,127. 4,122. 9,117. 1, 110.3, 110.2, 104. 4. MS (ESI) 252 (M + H+).

Reference： [1]Patent: WO2005/90330,2005,A1 .Location in patent: Page/Page column 53-54

17
[ 1544-85-0 ]
[ 610-14-0 ]
[ 872707-15-8 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; for 4h;	Intermediate W: Preparation of 2-amino-N-(2,2-difluoro-l,3-benzodioxol-5-yl)benzaniide; Step 1 : Preparation of N-(2,2-difluoro-l,3-benzodioxol-5-yl)-2-nitrobenzamide; To a solution of 2,2-difluoro-l,3-benzodioxol-5-amine (19.08 g, 110.21 mmol) in CH2C12 (250 mL) was added triethylamine (38 mL, 275.54 mmol). 2-Nitrobenzoyl chloride (17 mL, 113.52) was dissolved in CH2C12 (70 mL) and added dropwise to the 2,2-difluoro-l,3-benzodioxol-5-amine solution over Ih. The reaction was allowed to stir for 3h. The solids formed were filtered off and the organic layer was washed with water, dried with Na2SO4, and evaporated. The crude material was used in the next step with out further purification LCMS: 322.9 [M+H]+, RT 3.11 min.

Reference： [1]Patent: WO2006/2383,2006,A2 .Location in patent: Page/Page column 59

18
[ 1544-85-0 ]
[ 243134-92-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hydroxide; sodium cyanoborohydride; In tetrahydrofuran; methanol; dichloromethane; acetic acid; acetone;	a) 2,2-Difluoro-5-isopropylamino-1,3-benzodioxole. A mixture of 5-amino-2,2-difluoro-1,3-benzodioxole (2.00 g, 11.56 mmol) and acetone (890 mL, 12.14 mmol) in 50 mL of 1:1 THF:MeOH at 0 C. was treated with 10 mL of glacial acetic acid and stirred at 0 C. for 1 hour. Sodium cyanoborohydride (1.53 g, 24.28 mmol) was then added in one portion as a solid, and the mixture stirred with warming to RT overnight. The reaction was treated with 20 mL of 3N NaOH and partitioned between 100 mL of CH2Cl2 and 100 mL of 1N NaOH. The aqueous layer was extracted with 100 mL of CH2C2 and the combined CH2Cl2 layers were washed with 2*100 mL of 1N NaOH followed by 100 mL of brine. The solution was dried with MgSO4 and then concentrated in vacuo to dryness, resulting in the title compound as a colorless oil (2.36 g, 95%). 1H NMR (CDCl3): 6.82 (d, 1H, J=8.5 Hz), 6.34 (d, 1H, J=2.1 Hz), 6.20 (dd, 1H, J=8.5 and 2.1 Hz), 3.52 (hp, 1H, J=6.1 Hz), 3.10-3.30 (bs, 1H, NH), 1.20 (d, 6H, J=6.1 Hz).

Reference： [1]Patent: US6465472,2002,B1

19
[ 1544-85-0 ]
[ 909404-02-0 ]
[ 909404-03-1 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In N,N-dimethyl-formamide; at 60℃; for 22h;	A solution of 4-[(tert-butoxycarbonyl)amino]-l,3-thiazole-5-cai"boxylic acid (200 mg, 0.82 mmol), 2,2-difluoro-l,3-benzodioxol-5-amine (170 mg, 0.98 mmol), triethylamine (0.34 mL, 2.46 mmol) and (lH-l,2,3-benzotriazol-l-yloxy)(tripyrrolidin-l- yl)phosphonium hexafluorophosphate (PyBOP, 511 mg, 0.98 mmol) in anhydrous dimethylformamide (2 mL) was stirred at 60 0C for 22 h under nitrogen and then cooled. EPO <DP n="34"/>The resulting solution was diluted with ethyl acetate and washed with water and then saturated brine. The organic layer was dried (Na2SO4) and evaporated in vacuo. The resulting residue was chromatographed on 60 mL of silica gel using dichloromethane to charge the crude product to the top of the column and a gradient from 30 - 100% ethyl acetate in hexane was used to elute the products. Fractions containing the title compound were combined and evaporated to yield 254 mg of product, determined to be about 95% pure by NMR and HPLC. This was used directly in the next step.1E NMR (300 MHz, DMSO-J6) delta 10.28 (s, IH), 9.87 (s, IH), 9.08 (s, IH), 7.73 (d, IH, meta coupling, 7.3-7.36 (dd, 2H) and 1.38 ppm (s, 9H); HPLC RT (min) 3.51.

Reference： [1]Patent: WO2006/96338,2006,A1 .Location in patent: Page/Page column 32-33

20
[ 1544-85-0 ]
[ 138813-24-8 ]
pyrazole-3-carbxylic acid (3,4-(difluoromethylenedioxy)phenyl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	In N,N-dimethyl-formamide; at 120℃; for 18h;	A mixture of 3,4-(difluoromethylenediox3')aniline (346 mg, 2.0 mmol) and dipyrazolo[l,5-alpha;l5'-<i]pyrazine-4,9-dione (intermediate (i)) in DMF (5 mL) was stirred at 120 0C for IS h. The solvent was removed in vacuo and water (10 mL) was added to the residue. The mixture was extracted with EtOAc (3x10 mL), and the combined extracts were filtered through silica gel and concentrated. The title compound was precipitated by addition of isohexane and recrystallised from toluene (10 mL). Yield: 241 mg (45 %) as a white solid. MS (M++H) r°/z = 268.1H NMR (DMSO-J6, 400 MHz) delta 10.35 (s, IH), 7.95 (s, IH), 7.92 (s, IH)5 7.63(d, IH), 7.37 (d, IH)5 6.79 (s, IH).13C NMR (DMSO-J6, 100 MHz) delta 161.2, 146.9, 143.0, 138.9, 136.2, 131.9 (t, J =252 Hz)5 131.1 116.3, 110.4, 106.4, 103.4.

Reference： [1]Patent: WO2006/32851,2006,A1 .Location in patent: Page/Page column 65

21
tin(II)chloride dihydrate [ No CAS ]
[ 1544-85-0 ]
[ 161886-20-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium nitrite; In hydrogenchloride; sulfuric acid; propionic acid;	Reference Example 6 A solution of sodium nitrite (3g) in concentrated sulphuric acid (25ml) was added dropwise to a cooled (0oC) solution of 3,4-(difluoromethylenedioxy)aniline (6.92g) in propionic acid (50ml) and concentrated sulphuric acid (5ml) such that the reaction temperature did not exceed 5oC. The resulting mixture was stirred at 0-5oC for a further 1 hour and then allowed to reach room temperature over a period of 1 hour. The mixture was recooled to 0oC. A solution of stannous chloride dihydrate (28.8g) in concentrated hydrochloric acid (21ml) was then added to the stirred mixture so that the reaction temperature did not exceed 5oC. The resulting mixture was stirred at room temperature for one hour and then diluted with 50% sodium hydroxide to pH 14. The mixture was extracted with diethyl ether. The organic extracts were washed with water, dried and evaporated to yield 3,4-(difluoromethylenedioxy)phenyl hydrazine as a dark oil (6.15g), NMR (CDCl3) 3.6 (br.s,2H), 5.2(br.s,1H), 6.47(dd,1H), 6.65(d,1H), 6.88(d,1H).

Reference： [1]Patent: EP634413,1995,A1

22
tin(II)chloride dihydrate [ No CAS ]
[ 1645-96-1 ]
[ 1544-85-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In tetrahydrofuran; water;	Reference Example 7 Stannous chloride dihydrate (39.5g) was added to a cooled mixture of <strong>[1645-96-1]3,4-(difluoromethylenedioxy)nitrobenzene</strong> (11g), concentrated hydrochloric acid (66ml), water and tetrahydrofuran. The reaction temperature was not allowed to exceed 40oC. The mixture was stirred at room temperature, under an inert atmosphere for 3 days. The mixture was diluted with water, basified with 50% sodium hydroxide and extracted with diethyl ether. The ether extracts were washed with brine, dried and evaporated to yield 3,4-(difluoromethylenedioxy)aniline as a dark oil (2.2g). NMR (CDCl3) 3.65 (brs,2H), 6.3(dd,1H), 6.4(d,1H), 6.82(d,1H).

Reference： [1]Patent: EP634413,1995,A1

23
5-[(2-chloropyridin-4-yl)methyl]amino}-1-methyl-1H-pyrazole-4-carboxylic acid [ No CAS ]
[ 1544-85-0 ]
5-[(2-chloropyridin-4-yl)methyl]amino}-N-(2.2-difluoro-1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazole-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68.6%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 16h;	5-( Ff 2-chloropyridin-4-yl)methyH amino } -N-(2.2-difluoro- 1 ,3-benzodioxol-5-yl)-1 -methyl- 1 H-pyrazole-4-carboxamide A solution of 5-{ [(2-chloropyridin-4-yl)methyl]amino}-l-methyl-lH-pyrazole- 4-carboxylic acid (50.0mg, 0.19mmol) in dry DMF (3mL) was treated with N5N- diisopropylethylamine (0.1OmL, 0.56mmol), followed by PyBOP (97.57mg, 0.19mmol) and allowed to stir for 30 minutes. 5-Amino-2, 2-difluorobenzo-l,3-dioxole (64.91mg, 0.37mmol) was added, and the reaction mixture was allowed to stir for 16 h at 6O C. The reaction mixture was then diluted with EtOAc, and the organics were washed with concentrated NaHCO3 solution, followed by water, and then brine. The organics were then dried over Na2SO4 and concentrated in vacuo. The crude residue was triturated with hot hexanes yielding 55.0mg (68.6%) product.1H NMR(300 MHz, CD3CN) ? 8.43 (bs, IH), 8.29 (d, IH), 7.75 (d, 2H), 7.40 (s, IH), 7.23-7.32 (m, 2H), 7.17 (d, IH), 6.76 (bs, IH), 4.53 (d, 2H), 3.68 (s, 3H); ES-MS m/z 422.0 [M+H]+, HPLC RT (min) 3.12.

Reference： [1]Patent: WO2006/133006,2006,A2 .Location in patent: Page/Page column 60-61

24
[ 1544-85-0 ]
[ 916850-80-1 ]
[ 916850-82-3 ]

Yield	Reaction Conditions	Operation in experiment
> 60%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In dichloromethane; N,N-dimethyl-formamide; at 60℃; for 12h;Under nitrogen;	Preparation of 5-amino-N-(2,2-difluoro-l,3-benzodioxol-5-yl)-l -methyl- IH- pvrazole-4-carboxamideA solution of 5-[(tert-butoxycarbonyl)amino]-l-methyl-lH-pyrazole- 4-carboxylic acid (1 g , 4.15 mmol), 2,2-difluoro-l,3-benzodioxol-5-amine (861 mg, 4.97 mmol), triethylamine (1.19 mL, 8.55 mmol) and (lH-l,2,3-benzotriazol-l- yloxy)(tripyrrolidin-l-yl)phosphonium hexafluorophosphate (PyBOP, 2.15 g, 4.15 mmol) in anhydrous dimethylformamide (20 niL) and dichloromethane (1 niL) was stirred at 60 C for 12 h under nitrogen and then cooled. The resulting solution was diluted with ethyl acetate and washed with water and then saturated brine. The organic layer was dried (Na2SO4) and evaporated in vacuo. The resulting residue was chromatographed using silica gel with 0 - 100% ethyl acetate in hexane to yield tert-butyl (4-{ [(2,2-difluoro-l,3- benzodioxol-5-yl)amino]carbonyl}-l-methyl-lH-pyrazol-5-yl)carbamate (500 mg, >60% in purity) which was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (3 niL) and was stirred under nitrogen for 2 h and evaporated in vacuo. The residue was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3. The organic phase was dried (Na2SO4), evaporated in vacuo and purified using silica gel with 0-80 % ethyl acetate in hexanes to yield 250 mg of the title compound.1H NMR (300 MHz, CD3OD-d4) ? 7.85 (bs, IH), 7.70 (s, IH), 7.25 (dd, IH), 7.10(dd, IH), 3.60 (s, 3H); ES-MS m/z 297.2 [M+H]+, LCMS RT (min) 3.03.

Reference： [1]Patent: WO2006/133006,2006,A2 .Location in patent: Page/Page column 38-39

25
[ 1544-85-0 ]
[ 101537-64-8 ]
[ 877997-59-6 ]

Yield	Reaction Conditions	Operation in experiment
67%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In dichloromethane; N,N-dimethyl-formamide; at 60℃; for 16h;	3-[(Tert-butoxycarbonyl)amino]thiophene-2-carboxylic acid (7.3 g, 30.3 mmol) (step 2) was dissolved in DCM (155 niL), triethyl amine (12 mL), DMF (31 mL) and 2,2-difluoro- l,3-benzodioxol-5-amine (5 g, 29 mmol) was added. PyBOP (16.5 g, 32 mmol) was added and the mixture was stirred at 600C for 16 h. The reaction mixture was cooled and diluted with water and EtOAc. The organic layer was washed with water, dried with Na2SO4, and evaporated. The crude residue was purified using silica gel chromatography to yield the desired product (7.7 g, 67 %). 1H NMR (DMSO-J6) 69.95 (bs, IH), 7.95 (d, IH), 7.65, (s, IH), 7.45 (m, 2H), 7.10 (s, 2H), 1.50 (s, 9H); LCMS: 398.9 [M+H]+, RT 4.12 min.

Reference： [1]Patent: WO2006/23707,2006,A2 .Location in patent: Page/Page column 35

26
[ 1544-85-0 ]
[ 877997-62-1 ]
4-[(2-[(2,2-difluoro-1,3-benzodioxol-5-yl)amino]carbonyl}-3-thienyl)amino]methyl}-N-methylpyridine-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 16h;	3-[({2-[(methylamino)carbonyl]pyridin-4-yl}methyl)amino]thiophene-2-carboxylic acid (90 mg, 0.31 mmol) was dissolved into dichloromethane (1 mL) and 2,2-Difluoro- Benzo[l,3]dioxol-5-ylamine (59.4 mg, 0.31 mmol) was added followed by the addition of triethylamine (0.05 mL, 0.31mmol). To the solution was added pyBOP (178.6 mg, 0.31 mmol). The solution was allowed to stir for 16 h at room temperature. The solution was made dilute with dichloromethane (15 mL) and washed with water. The mixture was neutralized with a IM solution of potassium dihydrogen phosphate. The mixture was extracted with dichloromethane (3x, 15 mL). The organic fractions were combined, dried with sodium sulfate, and concentrated to an oil. The oil was purified via flash chromatography (35% EtOAc in Hex) to yield 21 mg (15%) of the final product as a white solid. 1H NMR (DMSO-J6) delta 9.58 (s, IH) 8.73 (d, J = 5.5 Hz, IH), 8.55 (d, J = 5.0 Hz, IH), 8.09, (bs, IH), 7.98 (s, IH), 7.80 (s, IH), 7.59 (d, J = 8.4 Hz, IH), 7.45 (d, J = 7.2 Hz, IH), 7.40 (d, J = 8.4 Hz, IH), 7.37 (d, J = 8.8 Hz, IH), 6.69 (d, J = 8.8 Hz, IH), 4.63 (d, J = 8.4 Hz, 2H), 2.79 (d, J = 8.4 Hz, 3H); LCMS 447.1 [M+H+], RT 3.59 min.

Reference： [1]Patent: WO2006/23707,2006,A2 .Location in patent: Page/Page column 37-38

27
[ 1544-85-0 ]
[ 530-62-1 ]
C₁₁H₇F₂N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; for 12h;	Example 28; l-(2,2-Difluoro-benzo[l,3]dioxol-5-yl)-3-{4-[2-(3-hydroxy-propylamino)- pyrimidin-4-yloxy] -phenyl} -urea 168 mg (1.04 mmol) l,l'-Carbonyl-diimidazol (CDI) were given to a solution of163 mg (0.941 mmol) 2,2-difluoro-5-amino-benzodioxole in 4.0 ml dichloromethane and stirred for 12 h. A solution of 245 mg (0.941 mmol) 3-[4-(4- Amino-phenoxy)-pyrimidin-2-ylamino]-propan-l-ol in 6 ml dichloromethane was added and the mixture stirred for 12 h at r.t. The reaction mixture was evaporated and the residue was purified by chromatography on silica gel(dichloromethane/ethanol 96:4). The obtained material was washed with dichloromethane, the precipitate was isolated by filtration and dried. Yield: 126 mg (29%) of the title compound. MS: 460.1 (AP+), 458.05 (AP-). <n="55"/>1H-NMR(400Hz, fP^lDMSO): delta = 1.59(br, 2H, CH2-CH2-CH2), 3.23(br, 2H, CH2-NH), 3.40(br, 2H, CH2-OH), 4.37(br, IH, OH), 6.05(br, IH, 5-H- pyrimidine), 7.05(br, IH, CH2NH), 7.09(d, 2H, 3-H/5-H-Ar-NH), 7.10(d, IH, 6- H-ArOCF2), 7.3 l(d, IH, 5-H-ArOCF2), 7.47(d, 2H, 2-H/6-H-Ar-NH), 7.66(s, IH, 2-H-ArOCF2), 8.12(d, IH, 6-H-pyrimidine), 8.77(s, IH, urea-NH), 8.88(s, IH, urea-NH).

Reference： [1]Patent: WO2008/77548,2008,A1 .Location in patent: Page/Page column 53-54

28
[ 1544-85-0 ]
[ 1037763-48-6 ]

Yield	Reaction Conditions	Operation in experiment
86%	With bromine; acetic acid; at 20℃; for 1h;	Example 9; Preparation of Compound 56; Step A - Synthesis of Compound 56A; Bromine (11.3 mL) was added into a solution of 5-amino-2,2-difluorobenzodioxole (Maybridge, 5.0 g, 28.9 mmol) in acetic acid (150 mL). The mixture was allowed to stir at room temperature for 1 hour, then concentrated in vacuo. The resulting residue was diluted with methylene chloride (50 mL) and the solid was filtered, washed with methylene chloride (4 x 15 mL) and dried under vacuum to provide compound 56A (8.2 g, 86%) as a yellow solid. M.S. found for C7H3Br2F2NO2: 331.93 (M+H)+.

Reference： [1]Patent: WO2008/82484,2008,A1 .Location in patent: Page/Page column 158

29
[ 1645-96-1 ]
[ 1544-85-0 ]

Yield	Reaction Conditions	Operation in experiment
72.5%	With palladium 10% on activated carbon; hydrogen; In methanol; for 2.0h;	To a suspension of 10% Pd/C (0.05 g) in MeOH (5.0 mL) was added a solution of 69.1 (0.5 g, 2.46 mmol, 1.0 eq) in MeOH (3.0 mL) under nitrogen. Reaction was purged with H2 gas for 2 hours. After completion of the reaction, mixture was filtered through celite and washed with MeOH. Obtained filtrate was concentrated under reduced pressure to get crude which was purified by trituration with n-hexane to provide 69.2 (0.31 g, 72.5%). MS(ES): m/z 173.12 [M+H]+.
67.05%	With 5%-palladium/activated carbon; hydrogen; potassium carbonate; In methanol; at 40.0℃; under 1500.15 Torr; for 4.0h;	A 500 ml autoclave was charged with 200 ml of methanol, 5% Pd/C 5 g (dry weight), and then 20 ml of a 5% potassium carbonate solution was added and stirred well. Then add 10.15 g (0.05 mol) of 2,2-difluoro-5-nitrobenz[d][1,3]dioxolane as M-02, substituted with nitrogen, heated to 40C, the control pressure 0.2MPa hydrogenation reaction was conducted for 4 hours. The temperature is lowered, the nitrogen is replaced, the catalyst is removed by filtration, and the mother liquid is concentrated to dryness, and recrystallized from ethanol to obtain 2,2-difluoro-5-aminobenzo[d][1,3]dioxane of the formula M-03. 5.8 g, yield 67.05%. This step adds potassium carbonate during the hydrogenation reduction process to reduce, occurrence of fluorine loss during the hydrogenation process.
67.05%	With 5%-palladium/activated carbon; hydrogen; In methanol; at 40.0℃; under 1500.15 Torr; for 4.0h;Autoclave;	Add 500 ml of methanol to a 500 ml autoclave, 5% Pd/C 5 g (dry weight).Add 20 ml of 5% potassium carbonate solution and mix well.Then, 10.15 g (0.05 mol) of <strong>[1645-96-1]2,2-difluoro-5-nitrobenzo[d][1,3]dioxolane</strong> represented by M-02 was added.After nitrogen substitution, the temperature was raised to 40 C, and the hydrogenation reaction was carried out for 4 hours under a control pressure of 0.2 MPa.Cooling, nitrogen replacement, filtration to remove the catalyst, the mother liquor is concentrated to dryness, recrystallized from ethanol,5.8 g of 2,2-difluoro-5-aminobenzo[d][1,3]dioxolane represented by the formula M-03 was obtained in a yield of 67.05%.In this step, potassium carbonate is added during the hydrogenation reduction to reduce the occurrence of the fluorine-reduction reaction during the hydrogenation.

67.05%

With 5%-palladium/activated carbon; hydrogen; potassium carbonate; In methanol; at 40.0℃; under 1500.15 Torr; for 4.0h;Autoclave;

200 ml of methanol was added to a 500 ml autoclave. 5% Pd/C 5g (dry weight), Add 20 ml of 5% potassium carbonate solution and mix well. Then add 10.15 g (0.05 mol) M-02 shows <strong>[1645-96-1]2,2-difluoro-5-nitrobenzo[d][1,3]dioxole</strong> , After nitrogen replacement, the temperature was raised to 40 C. The hydrogenation reaction was carried out for 4 hours under a controlled pressure of 0.2 MPa. The temperature is lowered, the nitrogen is replaced, the catalyst is removed by filtration, and the mother liquid is concentrated to dryness, and recrystallized from ethanol to obtain 2,2-difluoro-5-aminobenzo[d][1,3]dioxole of the formula M-03. 5.8 g, yield 67.05%. In this step, potassium carbonate is added during the hydrogenation reduction to reduce the occurrence of the fluorine-reduction reaction during the hydrogenation.

Reference： [1]Journal of Organic Chemistry,2008,vol. 73,p. 6780 - 6783
[2]Patent: US2016/251376,2016,A1 .Location in patent: Paragraph 0895; 0896; 0897
[3]Patent: CN109134442,2019,A .Location in patent: Paragraph 0050; 0053; 0055
[4]Patent: CN109053704,2018,A .Location in patent: Paragraph 0043-0044; 0047
[5]Patent: CN109232543,2019,A .Location in patent: Paragraph 0043; 0044; 0047-0050

30
[ 1544-85-0 ]
[ 1093101-64-4 ]
[ 1093100-54-9 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In isopropyl alcohol; at 150℃; for 0.666667h;microwave;	A mixture of 2,2-difluorobenzo[d][l,3]dioxol-5-amine (64 mg, 371 mumol), N-(3-(lH- pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-l-chloro-6-methylisoquinolin-5-amine (120 mg, 309 mumol) and 2,2,2-trifluoroacetic acid (95 mul, 1238 mumol) in i-PrOH (4 ml) was heated in a microwave reactor at 150 C for 40 min. The mixture was poured into MeOH (10 ml) and Et3N (0.25 ml) was added. Solvent was removed under vacuum and the product was purified by flash chromatography eluting with MeOH/DCM (1-5%) to give N5-(3-(lH-pyrazolo[3,4-d]pyrimidin-4-yl)pyridin-2-yl)-Nl-(2,2- difluorobenzo[d][l,3]dioxol-5-yl)-6-methylisoquinoline-l,5-diamine. MS Found: (ESI pos. ion) m/z 525 (M+fT).

Reference： [1]Patent: WO2008/153947,2008,A2 .Location in patent: Page/Page column 81

31
[ 1544-85-0 ]
[ 1093101-67-7 ]
[ 1093100-58-3 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; In 1,4-dioxane; at 160℃; for 0.2h;microwave;	A clear microwave vial was charged with 7-methyl-4-(methylthio)-N-(3-(9-(tetrahydro- 2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)quinazolin-8-amine (0.180 g, 0.37 mmol) and 2,2-difluorobenzo[d][l,3]dioxol-5-amine (0.13 g, 0.74 mmol) and 5 ml of dioxane. A few drops of TFA was added to the mixture and the reaction vial was capped. The vial was heated in a microwave reactor at 160 0C for 12 minutes. The reaction was diluted with 2M ammonia in MeOH and ethyl acetate. The mixture was loaded onto silica gel and purified by column chromatography on silica gel using a gradient of 0 to 10 %MeOH in DCM. The pure fractions were reduced and triturated with ether to give N-8-(3-(9H- purin-6-yl)pyridin-2-yl)-N-4-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-7- methylquinazoline-4,8-diamine as a yellow solid. MS Found: (ESI pos. ion) m/z 526 (M+Hi).

Reference： [1]Patent: WO2008/153947,2008,A2 .Location in patent: Page/Page column 83

32
[ 1544-85-0 ]
C₈H₅ClN₂OS [ No CAS ]
[ 1144500-98-0 ]

Yield	Reaction Conditions	Operation in experiment
	In acetone; at 20℃; for 1h;	Thiocyanic acid, ammonium salt (1 :1) (9.35 g; 0.1230 mol) was stirred in 2-propanone (300 ml) at room temperature. 2-Chloro-6-methyl-4-pyridinecarbonylchloride (22.2 g; 0.1170 mol) was then added and the reaction mixture was stirred for 2 hours at room temperature. 2,2-Difluoro-l,3-benzodioxol-5-amine (19.2 g; 0.1110 mol) in some 2- propane was added and the reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was then poured onto ice and the residue was filtered off and dried. Yield: 38.1 g of intermediate Dl.LCMS Retention time: 1.03; [M-H]" peak: 384; LCMS procedure 2

Reference： [1]Patent: WO2009/50185,2009,A1 .Location in patent: Page/Page column 5; 15

33
[ 541-57-1 ]
[ 1544-85-0 ]
[ 7311-34-4 ]
[ 867069-31-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 4160 - 4184

34
[ 541-57-1 ]
[ 1544-85-0 ]
[ 86-81-7 ]
[ 867069-21-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 4160 - 4184

35
[ 1544-85-0 ]
[ 839714-87-3 ]
1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-3-[4-(2-dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14.0%		To a solution of 4-(2-dimethylamino-ethoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (26.0 mg, 0.1 mmol) in methylene chloride (1 ml) pyridine (24.3 mul, 0.3 mmol) and 4-nitrophenyl chloroformate (20.2 mg, 0.1 mmol) were added and the mixture was stirred at room temperature for 1 hour. 5-Amino-2,2-difluoro-1,3-benzodioxole (11.6 mul, 0.1 mmol) was added, the reaction mixture stirred at room temperature for 48 hours and concentrated to give an oily residue that was subjected to a purification by flash chromatography (SiO2, CH2CI2/MeOH gradient elution) to afford Compound 144 as an off-white solid in 14.0% yield. LCMS m/z (%) = 460 (M+H, 100). 1H NMR (400 MHz, DMSO- d6) delta: 10.30 (s, 1H), 7.64 (d, J= 8.96 Hz, 1H), 7.53 (s, 1H), 7.42 (s, 1H), 7.40-7.34 (m, 4H), 7.13 (d, J= 8.92 Hz, 1H), 6.22 (s, 1H), 4.10 (t, J= 5.56 Hz, 2H), 3.65 (s, 3H), 3.63 (s, 2H), 2.76-2.65 (m, 2H), 2.22 (s, 6H).

Reference： [1]Patent: WO2005/12254,2005,A1 .Location in patent: Page/Page column 150

36
[ 1544-85-0 ]
[ 839715-07-0 ]
1-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-3-[4-(3-dimethylamino-propoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%		To a solution OF 4-NITROPHENYL CHLOROFORMATE (55.1 mg, 0.273 mmol) in 1,2-dichloroethane (7 mL) and pyridine (22 I1L, 0.272 mmol) was added 5-amino-2, 2-difluoro-1, 3-benzodioxole (28 PL, 0.241 mmol) and stirred for one hour. A spatula of StratoSpheres PL-DETA resin was added and stirring continued for an additional hour. The resulting mix was filtered (washing with 3 mL 1,2- dichloroethane) into a flask containing 4- (3-DIMETHYLAMINO-PROPOXY)-3- (2-METHYL-2H-PYRAZOL-3-YL)- phenylamine (49.7 mg, 0.181 mmol) and stirring continued overnight. The resulting material was purified by HPLC. The product was dried in vacuo to afford Compound 129 as a white solid (29.0 mg, 34%). LCMS m/z (%) = 474 (M+H, 100),'H NMR (400 MHz, DMSO-d6) 8 : 8.91 (bs, 1H), 8.61 (bs, 1H), 7.65 (d, J= 2.09 Hz, 1H), 7.44 (d, J= 1.86 Hz, 1H), 7. 44 (dd, J= 8.88, 2.82 Hz, 1H), 7. 37 (d, J= 2. 71 Hz, 1H), 7.29 (d, J= 8.75 Hz, 1H), 7.09 (d, J= 8.95 Hz, 1H), 7.07 (dd, J= 8.78, 2.18 Hz, 1H), 6.23 (d, J= 1. 81 Hz, 1H), 3. 97 (t, J= 6.35 HZ, 2H), 3.65 (s, 3H), 2.19 (T, J= 7. 03 Hz, 2H), 2.07 (s, 6H), 1.77-1. 67 (m, 2H).

Reference： [1]Patent: WO2005/12254,2005,A1 .Location in patent: Page/Page column 157-158

37
[ 1544-85-0 ]
[ 463-71-8 ]
[ 869085-97-2 ]

Yield	Reaction Conditions	Operation in experiment
89%		Example 1 Preparation of 5-isothiocyanato-2,2-difluorobenzo[1,3]-dioxole: 34.6 g of 5-amino-2,2-difluorobenzodioxole were added dropwise to a solution of 90 ml of conc. hydrochloric acid in 350 ml of water. The mixture was stirred for a further 30 minutes and then 27 g of thiophosgene were metered in rapidly. The mixture was stirred at the given temperature for a further 3 hours, the almost colourless suspension was admixed with 150 ml of dichloromethane and the dichloromethane was removed. The crude product was distilled at 45 mbar. 28 g (=89% of theory) were obtained as a colourless to yellowish liquid. Boiling point: 136 C./45 mbar. 1H NMR (400 MHz, CDCl6): 6.96 (m, 2H), 7.02 (m, 1H)

Reference： [1]Patent: EP1595875,2005,A2 .Location in patent: Page/Page column 3
[2]Patent: US2005/272811,2005,A1 .Location in patent: Page/Page column 2

38
[ 1544-85-0 ]
[ 267891-88-3 ]
N-(2,2-difluoro-1,3-benzodioxol-5-yl)-2-[(pyridin-4-ylmethyl)amino]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
23%		Step 2: Preparation ofylmethyl)amino]benzamideN-(2,2-difluoro-l,3-benzodioxol-5-yl)-2-[(pyridin-4-; A solution of 2,2-difluoro-l,3-benzodioxol-5-amine (0.21 g, 1.24 mmol) in toluene (3.0 mL) at 0 C was with AlMe3 (2 M in heptane, 0.62 mL, 1.24 mmol). The resulting mixture was stirred at 0 C for 1 h, followed by addition of methyl 2-[(4-pyridylmethyl)amino]benzoate (0.10 g, 0.41 mmol). The resulting mixture was stirred at 80 C for 5 d, cooled to room temp., and treated with a saturated NaHCOs solution (100 mL). The resulting mixture was extracted with CHaC^ (3 x 100 mL). The combined organic layers were dried (NaiSC^) and concentrated reduced pressure. The residue was purified by MPLC (Biotage, Flash 12M column, 30% EtOAc/hexane) to give N-(2,2-difluoro-l,3-benzodioxol-5-yl)-2-[(pyridin-4-ylmethyl)amino]benzamide (0.037 g, 23%) as a beige solid: TLC (50% EtOAc/hexane) R/0.30; *H NMR (DMSO-4) 8 4.48 (d, .7=6.4 Hz, 2H), 6.54 (dd, J=8.5, 0.8 Hz, 1H), 6.65 (app td, .7=7.5, 1.0 Hz, 1H), 7.24 (app td, .7=7.8, 1.4 Hz, 1H), 7.32 (d, .7=6.0 Hz, 2H), 7.38 (dd, J=9.1, 0.4 Hz, 1H), 7.45 (dd, J=8.8, 2.0 Hz, 1H), 7.86 (d, .7=1.7 Hz, 1H), 7.89 (br t, J=6.5 Hz, 1H), 8.48 (d, J=6.05 Hz, 2H), 10.34 (br s, 1H); LCMS: 384 [M+H]+, RT 2.90 min.

Reference： [1]Patent: WO2006/2383,2006,A2 .Location in patent: Page/Page column 67

39
[ 1544-85-0 ]
[ 887937-90-8 ]
[ 7693-46-1 ]
1-[4-(2-azetidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%		To a solution of 4-nitrophenyl chloroformate (51.5 mg, 0.255 mmol) in 1,2-dichloroethane (4 mL) and pyridine (50 muL) was added 5-amino-2,2-difluoro-1,3-benzodioxole (32 muL, 0.275 mmol). After 1 hour, 4-(2-azetidin-1-yl-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylarnine (47.4 mg, 0.147 mmol) in 1,2-dichloroethane (5 mL) was added and stirring continued overnight. The resulting material was purified by HPLC. The product was dried in vacuo to afford Compound 87 as a white solid (40.7 mg, 50%). LCMS m/z (%)=472 (M+H, 100), 1H NMR (400 MHz, DMSO-d6) delta: 8.96 (bs, 1H), 8.73 (bs, 1H), 7.65 (d, J=2.10 Hz, 1H), 7.47-7.41 (m, 2H), 7.36 (d, J=2.71 Hz, 1H), 7.30 (d, J=8.74 Hz, 1H), 7.10-7.02 (m, 2H), 6.22 (d, J=1.84 Hz, 1H), 3.89 (t, J=5.51 Hz, 2H), 3.67 (s, 3H), 2.98 (t, J=6.92 Hz, 4H), 2.60 (t, J=5.47 Hz, 2H), 1.86 (quintet, J=6.90 Hz, 2H).

Reference： [1]Patent: US2007/207994,2007,A1 .Location in patent: Page/Page column 61

40
[ 1544-85-0 ]
[ 1190098-75-9 ]
[ 1190097-27-8 ]

Yield	Reaction Conditions	Operation in experiment
13%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	1-(4-(morpholine-4-carbonyl)benzyl)-1H-indazole-3-carboxylic acid(0.30 mmol) was taken up in N,N-dimethylformamide (2 mL), 2,2-difluorobenzo[d][1,3]dioxol-5-amine (62 mg, 0.36 mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (187 mg, 0.36 mmol) and diisopropylethylamine (0.157 mL, 0.90 mmol) were added and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between ethyl acetate and water, the organic phase washed with water (2×), the aqueous phase extracted with ethyl acetate (1×) and the combined organic phases washed with brine, dried over magnesium sulfate and concentrated. Purification by column chromatography eluting using a gradient (40/60 petroleum ether/1:0 v/v to 0:1 v/v) followed by preparative HPLC afforded 20 mg (13%). (LCMS RT=6.62 min, MH+=520.8), 1H NMR (CDCl3): 8.89 (1H, s), 8.44 (1H, d, J 8.1), 7.87 (1H, d, J 2.0), 7.48-7.31 (5H, br m), 7.29-7.19 (3H, br m), 7.03 (1H, d, J 8.7), 5.67 (2H, s), 3.91-3.25 (8H, br m).

Reference： [1]Patent: US2010/305120,2010,A1 .Location in patent: Page/Page column 50

41
[ 1544-85-0 ]
[ 689757-49-1 ]
C₂₂H₁₃F₃N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; for 6h;Reflux;	General procedure: A mixture of substituted isatin (0.3 mmol) and the appropriate aromatic amine (0.36 mmol) was refluxed in absolute EtOH (5 mL) for 6 h. EtOH was removed in vacuo and the obtained isatin-3-imine was used directly in the next step.

Reference： [1]Tetrahedron,2011,vol. 67,p. 6713 - 6729

42
[ 1121-60-4 ]
[ 1544-85-0 ]
[ 762-04-9 ]
[ 1334047-75-4 ]