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[ CAS No. 22236-10-8 ] {[proInfo.proName]}

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Chemical Structure| 22236-10-8

Chemical Structure| 22236-10-8

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Quality Control of [ 22236-10-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 22236-10-8 ]

Product Details of [ 22236-10-8 ]

CAS No. :	22236-10-8	MDL No. :	MFCD00085005
Formula :	C₇H₇F₂NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NDEZTSHWEPQVBX-UHFFFAOYSA-N
M.W :	159.13	Pubchem ID :	737363
Synonyms :

Calculated chemistry of [ 22236-10-8 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	37.44
TPSA :	35.25 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.92 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.45
Log Po/w (XLOGP3) :	1.9
Log Po/w (WLOGP) :	2.72
Log Po/w (MLOGP) :	1.48
Log Po/w (SILICOS-IT) :	1.51
Consensus Log Po/w :	1.81

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.3
Solubility :	0.806 mg/ml ; 0.00507 mol/l
Class :	Soluble
Log S (Ali) :	-2.26
Solubility :	0.868 mg/ml ; 0.00546 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.37
Solubility :	0.674 mg/ml ; 0.00424 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	1.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.21

Safety of [ 22236-10-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P210-P261-P264-P270-P271-P280-P301+P312+P330-P302+P352+P312-P304+P340+P312-P370+P378-P403+P235-P501	UN#:	N/A
Hazard Statements:	H227-H302+H312+H332	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 22236-10-8 ]

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

Upstream synthesis route of [ 22236-10-8 ]
Downstream synthetic route of [ 22236-10-8 ]

[ 22236-10-8 ] Synthesis Path-Upstream 1~4

1
[ 1544-86-1 ]
[ 22236-10-8 ]

Reference： [1] Patent: WO2005/63767, 2005, A2, . Location in patent: Page/Page column 47-48
[2] Patent: WO2005/111038, 2005, A2, . Location in patent: Page/Page column 72-75
[3] Patent: US2005/250808, 2005, A1, . Location in patent: Page/Page column 41
[4] Patent: WO2006/69097, 2006, A2, . Location in patent: Page/Page column 43-44
[5] Patent: US2007/78147, 2007, A1, . Location in patent: Page/Page column 64

2
[ 128140-82-9 ]
[ 22236-10-8 ]

Reference： [1] Journal of Organic Chemistry, 2012, vol. 77, # 17, p. 7471 - 7478

3
[ 1544-86-1 ]
[ 7440-66-6 ]
[ 22236-10-8 ]

Reference： [1] Patent: US4897415, 1990, A,

4
[ 4472-44-0 ]
[ 22236-10-8 ]

Reference： [1] Patent: US4783459, 1988, A,

[ 22236-10-8 ] Synthesis Path-Downstream 1~88

1
[ 22236-10-8 ]
[ 101799-75-1 ]
[ 122551-45-5 ]

Reference： [1]Journal of Pharmaceutical Sciences,1989,vol. 78,p. 585 - 588

2
[ 22236-10-8 ]
[ 4083-64-1 ]
[ 128924-22-1 ]

Reference： [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 2393 - 2407

3
[ 30132-23-1 ]
[ 22236-10-8 ]
[ 871586-76-4 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 8045 - 8054

4
[ 22236-10-8 ]
[ 541-41-3 ]
[ 638192-11-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2621 - 2627

5
[ 22455-52-3 ]
[ 22236-10-8 ]
N-(4-difluoromethoxyphenyl)-N'-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)urea [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,2006,vol. 42,p. 139 - 141

6
[ 22236-10-8 ]
[ 101348-32-7 ]
6-[(4-difluoromethoxy-phenylamino)-methyl]-5-methyl-pyrido[2,3-<i>d</i>]pyrimidine-2,4-diamine [ No CAS ]

Reference： [1]Antimicrobial Agents and Chemotherapy,2000,vol. 44,p. 2784 - 2793

7
[ 859826-43-0 ]
[ 22236-10-8 ]
7-(3-chloropyridin-2-yl)-N-(4-(difluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In acetonitrile;	D. 7-(3-Chloropyridin-2-yl)-N-(4-(difluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine A mixture of 4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.103 g, 0.000366 mol) and <strong>[22236-10-8]4-(difluoromethoxy)aniline</strong> (0.091 mL, 0.00073 mol) in acetonitrile (3 mL, 0.06 mol) was heated via microwave in a sealed tube at 160 C. for 10 minutes. After cooling to room temperature, the mixture was added to saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. Concentrated to leave an oil. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane gradient 0 to 100%) to give 0.113 g of a light yellow solid. MS: M+H=404 1H NMR (DMSO-d6): delta 2.80 (t, J=5.6 Hz, 2H); 3.68 (t, J=5.6 Hz, 2H); 4.35 (s, 2H); 7.04 (dd, J=7.6 Hz, 4,7 Hz, 1H); 7.15 (d, J=9.0 Hz, 2H); 7.17 (t, J=75.0 Hz, 1H); 7.69-7.74 (m, 2H); 7.86 (dd, J=7.9 Hz, 1.6 Hz, 1H); 8.24 (dd, J=4.7 Hz, 1.6 Hz, 1H); 8.40 (s, 1H); 8.57 (s, 1H).

Reference： [1]Patent: US2005/277643,2005,A1

8
[ 22236-10-8 ]
[ 140477-28-7 ]

Reference： [1]Journal of Organic Chemistry USSR (English Translation),1991,vol. 27,p. 1737 - 1742
Zhurnal Organicheskoi Khimii,1991,vol. 27,p. 1965 - 1972

9
[ 22236-10-8 ]
[ 140477-29-8 ]

Reference： [1]Journal of Organic Chemistry USSR (English Translation),1991,vol. 27,p. 1737 - 1742
Zhurnal Organicheskoi Khimii,1991,vol. 27,p. 1965 - 1972

10
[ 22236-10-8 ]
[ 638192-10-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2621 - 2627

11
[ 22236-10-8 ]
[ 638192-12-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2621 - 2627

12
[ 22236-10-8 ]
trifluoro-methanesulfonic acid 6-difluoromethoxy-1-methyl-2-oxo-1,2-dihydro-quinolin-4-yl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2621 - 2627

13
[ 22236-10-8 ]
6-difluoromethoxy-1-methyl-4-(piperidin-4-ylamino)-1<i>H</i>-quinolin-2-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2621 - 2627

14
[ 22236-10-8 ]
[ 889849-80-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2621 - 2627

15
[ 22236-10-8 ]
4-(1-benzo[1,3]dioxol-5-ylmethyl-piperidin-4-ylamino)-6-difluoromethoxy-1-methyl-1H-quinolin-2-one [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2621 - 2627

16
[ 22236-10-8 ]
[ 342779-35-5 ]

Reference： [1]Chemistry of Heterocyclic Compounds,2003,vol. 39,p. 1002 - 1012

17
[ 22236-10-8 ]
3-(4-difluoromethoxy-phenyl)-2-[2-(4-fluoro-phenyl)-2-oxo-ethylsulfanyl]-5,6,7,8-tetrahydro-3<i>H</i>-benzo[4,5]thieno[2,3-<i>d</i>]pyrimidin-4-one [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,2003,vol. 39,p. 1002 - 1012

18
[ 22236-10-8 ]
2-[2-(4-chloro-phenyl)-2-oxo-ethylsulfanyl]-3-(4-difluoromethoxy-phenyl)-5,6,7,8-tetrahydro-3<i>H</i>-benzo[4,5]thieno[2,3-<i>d</i>]pyrimidin-4-one [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,2003,vol. 39,p. 1002 - 1012

19
[ 22236-10-8 ]
2-[2-(4-chloro-phenyl)-1-methyl-2-oxo-ethylsulfanyl]-3-(4-difluoromethoxy-phenyl)-5,6,7,8-tetrahydro-3<i>H</i>-benzo[4,5]thieno[2,3-<i>d</i>]pyrimidin-4-one [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,2003,vol. 39,p. 1002 - 1012

20
[ 22236-10-8 ]
3-(4-difluoromethoxy-phenyl)-2-[2-(4-difluoromethoxy-phenyl)-2-oxo-ethylsulfanyl]-5,6,7,8-tetrahydro-3<i>H</i>-benzo[4,5]thieno[2,3-<i>d</i>]pyrimidin-4-one [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,2003,vol. 39,p. 1002 - 1012

21
[ 22236-10-8 ]
3-(4-difluoromethoxy-phenyl)-2-[2-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-oxo-ethylsulfanyl]-5,6,7,8-tetrahydro-3<i>H</i>-benzo[4,5]thieno[2,3-<i>d</i>]pyrimidin-4-one [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,2003,vol. 39,p. 1002 - 1012

22
[ 22236-10-8 ]
[ 122551-51-3 ]

Reference： [1]Journal of Pharmaceutical Sciences,1989,vol. 78,p. 585 - 588

23
[ 22236-10-8 ]
[ 122551-48-8 ]

Reference： [1]Journal of Pharmaceutical Sciences,1989,vol. 78,p. 585 - 588

24
[ 22236-10-8 ]
1-(4-Difluoromethoxy-phenyl)-6-fluoro-4-oxo-7-piperazin-1-yl-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

Reference： [1]Journal of Pharmaceutical Sciences,1989,vol. 78,p. 585 - 588

25
[ 22236-10-8 ]
1-(4-Difluoromethoxy-phenyl)-6-fluoro-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid [ No CAS ]

Reference： [1]Journal of Pharmaceutical Sciences,1989,vol. 78,p. 585 - 588

26
[ 1372861-83-0 ]
[ 22236-10-8 ]
N-((S)-1-(2-(4-(difluoromethoxy)phenylamino)ethylcarbamoyl)-2-cyclohexylethyl)-5-(3-(trifluoromethyl)phenyl)furan-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	With sodium cyanoborohydride; In methanol; acetic acid; at 0 - 20℃;	(S)-5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid [2-cyclohexyl-1-(2-hydroxy-ethylcarbamoyl)-ethyl]-amide 4 (170 mg, 0.38 mmol) was dissolved in CH2Cl2 (5 mL, 0.07M) under a N2 atmosphere. Dess-Martin Periodinane (210 mg, 0.49 mmol, 1.3 eq.) was added in one portion and allowed the reaction to stir at room temperature for 3 hours. After the reaction was judged to be complete by TLC, the reaction was diluted with EtOAc (50 mL) and extracted with 1M sodium thiosulfate (30 mL). The organic layer was extracted with saturated NaHCO3 and saturated NaCl. The organic layer was dried over MgSO4 and filtered. The organic solvent was removed in vacuo and the resulting aldehyde (158 mg, 0.35 mmol, 93%) was used directly without storage: R=0.67 (1:1 hexanes:EtOAc). The aldehyde (43 mg, 0.10 mmol) was dissolved in MeOH (2.5 mL, 0.04M) and brought to 0 C. in an ice bath. 4-Difluoromethoxyaniline (50 muL, 0.31 mol, 3.3 eq.) and acetic acid (20 mL, 0.34 mmol, 3.6 eq.) were added via syringe followed by sodium cyanoborohydride (20 mg, 0.32 mmol) in one portion. The clear reaction mixture was allowed to slowly warm to room temperature and monitored to completion by LC/MS. The reaction was worked up by rotary evaporation of MeOH, dilution with EtOAc (20 mL) and water (20 mL). The organic phase was separated and washed with 1M NaOH (15 mL) and saturated NaCl (15 mL). The organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporation. Purification by mass-directed HPLC, evaporation and lyophilization provided (S)-5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid {2-cyclohexyl-1-[2-(4-difluoromethoxy-phenylamino)-ethylcarbamoyl]-ethyl}-amide 5 as a white amorphous solid (15 mg, 0.02 mmol, 22%): 1H NMR (CD3OD, 400 MHz) delta 0.95-1.06 (m, 2H), 1.19-1.29 (m, 3H), 1.40-1.44 (m, 1H), 1.66-1.86 (m, 7H), 3.26-3.29 (m, 2H), 3.43-3.46 (m, 2H), 4.64 (dd, 1H, J=9.2, 6.0 Hz), 6.59 (t, 1H, J=74.8 Hz), 6.76 (d, 2H, J=8.8 Hz), 6.95 (d, 2H, J=8.8 Hz), 7.11 (s, 1H), 7.29 (d, 1H, J=3.6 Hz), 7.66 (s, 2H), 8.13 (s, 1H), 8.25 (s, 1H); HPLC-MS calcd. for C30H32F5N3O4 (M+H+) 594.2, found 594.5.

Reference： [1]Patent: US2004/198780,2004,A1 .Location in patent: Page 25-26

27
[ 22236-10-8 ]
[ 6484-24-8 ]
[ 827031-10-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium acetate; In tetrahydrofuran; water; at 70℃; for 1h;	A mixture of 4-CHLORO-2-METHYL-QUINAZOLINE (450 mg, 2.52 mmol), 4- difluoromethoxy-phenylamine (0.32 ml, 2.52 mmol) and sodium acetate (248.07 mg, 3.02 mmol) in 6 mL of solvent (THF: water = 1 : 1) was stirred at 70 C for 1 h. The reaction mixture was diluted with 30 mL of ethyl acetate. It was washed with brine, dried over anhydrous NA2S04, filtered and concentrated. The crude product was purified by chromatography on silica gel with acetate and hexane (1: 5) as eluent, yielding 713 mg of title compound (94 %). H NMR (CDC13) : 7.87-7. 76 (m, 5H), 7.51 (t, J = 8.4 Hz, 1H)), 7.40 (brs, 1H), 7.19 (d, J = 8.7 Hz, 2H), 6.76-6. 27 (three single peaks, 1H), 2.71 (s, 3H).

Reference： [1]Patent: WO2005/3100,2005,A2 .Location in patent: Page 198
[2]Journal of Medicinal Chemistry,2009,vol. 52,p. 2341 - 2351

28
[ 828932-24-7 ]
[ 22236-10-8 ]
3-[4-(difluoromethoxy)phenyl]amino}-1-(2-methoxyethyl)-4-phenyl-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%	In DMF (N,N-dimethyl-formamide); at 150℃; for 0.333333h;Microwave irradiation;	Example 2 3- { [4- (DIFLUOROMETHOXY) PHENYL] AMINO}-1- (2-METHOXYETHYL)-4-PHENYL-LH-PYRROLE-2, 5- dione 3-CHLORO-1-(2-METHOXYETHYL)-4-PHENYL-LH-PYRROLE-2, 5-dione (0.13 mmol, 36 mg) AND 4- difluoromethoxyaniline (0.28 mmol, 45 mg) were dissolved in DMF (1 mL). The mixture was heated in a microwave reactor at 150C for 20 min.. After cooling, the reaction mixture was purified by HPLC (95% 0. 1M ammonium acetate buffer: 5% CH3CN No. 100% CH3CN) to give 13 mg (24%) of the title COMPOUND. 1H NMR (400 MHz, CDC13) : 8 7.25 (bs, 1H), 7.19-7. 08 (m, 3H), 7.02-6. 97 (m, 2H), 6.81-6. 75 (m, 2H), 6.66-6. 60 (m, 2H), 6.36 (t, J=74.0 Hz, 1H), 3. 83 (t, J=5.7 Hz, 2H), 3.63 (t, J=5.7 Hz, 2H), 3. 38 (s, 3H)

Reference： [1]Patent: WO2005/5417,2005,A1 .Location in patent: Page/Page column 40

29
[ 828932-26-9 ]
[ 22236-10-8 ]
3-[4-(difluoromethoxy)phenyl]amino}-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	In acetonitrile; at 140℃; for 1h;Microwave irradiation;	Example 12 3- [4-(Difluoromethoxy)phenyl]amino}-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole- 2, 5-DIODE 4- (DIFLUOROMETHOXY) ANILINE (0.94 mmol, 149 mg) dissolved in dry CHSCN (2.3 mL) was added to crude 3-chloro-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2, 5-dione (0.39 mmol, 115 mg) and the reaction mixture was subjected to microwave heating single node 140C, one h. The reaction mixture was purified using HPLC (57% 0. 1M ammonium acetate buffer: 43% CH3CN E 100% CH3CN, 20 mL/min) to give 122 mg (75%) of the title COMPOUND. H NMR (400 MHZ, CD3CN) 8 8. 63 (d, 1H), 8. 51 (dd,1H), 7.92 (bs, 1H), 7.79-7. 74 (m, 1H), 7.34 (dd, 1H), 7.20-7. 07 (m, 3H), 7.00-6. 94 (m, 2H), 6.78 (s, 4H), 6.59 (t, J=74. 1 HZ, 1H), 4.76 (s, 2H).

Reference： [1]Patent: WO2005/5417,2005,A1 .Location in patent: Page/Page column 43-44

30
[ 828932-23-6 ]
[ 22236-10-8 ]
[ 828932-16-7 ]

Yield	Reaction Conditions	Operation in experiment
54%	In DMF (N,N-dimethyl-formamide); at 150℃; for 0.133333h;Microwave irradiation;	1-[(6-AMINOPYRIDIN-3-YL) METHYL]-3-[4-(DIFLUOROMETHOXY) phenyl] AMINO} « 4-PHENYL- 1H-PYRROLE-2, 5-dione A mixture OF TERT-BUTYL {5- [ (3-CHLORO-2, 5-dioxo-4-phenyl-2, 5-dihydro-1H-pyrrol-1- yl) methyl] PYRIDIN-2-YL} CARBAMATE (0.70 g, 1.7 mmol) and 4- (difluoromethoxy) aniline (0.54 g, 3.4 mmol) in DMF (4 mL) was heated in a microwave reactor at 150C for 8 min.. The solvent was evaporated and the residue was purified on a pre-packed SIO2COLUMN (ISOLUTE0 SI, lOg/70 mL) using CH2C12 and then CH30HL CH2CL2 (1: 99,2 : 98 and then 5: 95) as eluant to give 0.4 g (54%) of the title COMPOUND. 1H NMR (400 MHz, CDC13) 8 7.99 (bs, 1H), 7.67-7. 62 (m, 2H), 7.14-7. 04 (m, 3H), 6.91 (d, J =8 Hz, 2H), 6.78 (d, J=8 Hz, 1H), 6.72 (d, J=9 Hz, 2H), 6.63 (d, J=9 Hz, 2H), 6.33 (t, J=74 Hz, 1H) and 4.60 (s, 2H).
54%	In N,N-dimethyl-formamide; at 150℃; for 8h;Microwave irradiation;	l-[(6-Aminopyridin-3-yl)methyl]-3-[4-(difluoromethoxy)phenyl]amino}-4-phenyI- lH-pyrroIe-2,5-dione30 A mixture of tert-butyl { 5-[(3-chloro-2,5-dioxo-4-phenyl-2,5-dihydro~lH-pyrrol-l- yl)methyl]pyridin-2-yl} carbamate ( 0.7Og, 1.7mmol) and <strong>[22236-10-8]4-(difluoromethoxy)aniline</strong> (0.54g, 3.4mmol) in DMF (4mL) was heated in a microwave reactor at 15O0C for 8 EPO <DP n="37"/>minutes. The solvent was evaporated and the residue was purified on a pre-packed Sitheta2column (Isolute SI, 10g/70 mL) using CH2Cl2 and then CH3OH/ CH2Cl2 (1:99, 2:98 and then 5:95) as eluant to give 0.4g (54%) of the title compound; 1H NMR (400 MHz, CDCl3) 6 7.99 (bs, IH), 7.67-7.62 (m, 2H), 7.14-7.04 (m, 3H), 6.91 (d, J =8 Hz, 2H), 6.78 (d, J=8 Hz, IH), 6.72 (d, J=9 Hz, 2H), 6.63 (d, J=9 Hz, 2H), 6.33 (t, J=74 Hz, IH) and 4.60 (s, 2H).
54%	In DMF (N,N-dimethyl-formamide); at 150℃; for 0.133333h;Microwave irradiation;	Example 26 1- [(6-Aminopyridin-3-yl)methyl]-3-[4-(diffuromethoxy)phenyl]amino}-4-phenyl- 1H-PYRROLE-2, 5-dione A mixture of tert-butyl {5- [ (3-chloro-2, 5-dioxo-4-phenyl-2, 5-dihydro-lH-pyrrol-l- yl) methyl]pyridin-2-yl} carbamate (0.70 g, 1.7 mmol) and 4- (difluoromethoxy)-aniline (0.54 g, 3.4 mmol) in DMF (4 mL) was heated in a microwave reactor at 150C for eight min.. The sovent was evaporated and the residue was purified on a column (ISOLUTE SI, LOG/70 mL), using CH2Cl2 and then CH30H/CH2C12 (1: 99,2 : 98 and then 5: 95) as eluant, to give 0.4 g (54%) of the title COMPOUND. 1H NMR (400 MHz, CDC13) 8 7.99 (bs, 1H), 7.67-7. 62 (m, 2H), 7.14-7. 04 (m, 3H), 6.91 (d, J =8 Hz, 2H), 6.78 (d, J=8 Hz, 1H), 6.72 (d, J=9 Hz, 2H), 6.63 (d, J=9 Hz, 2H), 6.33 (t, J=74 Hz, 1H), 4.60 (s, 2H).

Reference： [1]Patent: WO2005/5416,2005,A1 .Location in patent: Page/Page column 41
[2]Patent: WO2006/73367,2006,A1 .Location in patent: Page/Page column 35
[3]Patent: WO2005/5417,2005,A1 .Location in patent: Page/Page column 48-49

31
[ 22236-10-8 ]
[ 108-24-7 ]
[ 22236-11-9 ]

Yield	Reaction Conditions	Operation in experiment
62%		4-Nitrophenol (162 mmol) was added to a suspension of sodium hydroxide (485 mmol) in NN-dimethylformamide (150 mL) and the suspension was maintained for 15 min at rt. The reaction mixture was cooled to 0 C and was treated with ethyl chlorodifluoroacetate (329 mmol). The reaction mixture was heated at 70 C for 16 h and was concentrated. The residue was diluted with ice water (200 mL) and was extracted with ethyl acetate (3x100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the difluoromethyl ether in 59% yield as yellow oil. The nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and was treated with ammonium chloride (84.7 mmol) and iron powder (105 mmol). The reaction mixture was heated at reflux for 30 minutes and the suspension was filtered through Celite. The filter cake was washed with ethanol three times and the combined filtrates were concentrated. The residue was dissolved in water and the pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3x100mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was maintained at rt for 16 h. The reaction mixture was diluted with water (50 mL) and was neutralized with solid sodium bicarbonate. The precipitated solids were isolated by filtration, washed with water, and dried to provide the acetamide in 62% yield as a light yellow solid. Acetic anhydride (19.6 mmol) was added to a solution of the acetamide (13.2 mmol) in chloroform (20 mL) and the reaction mixture was warmed to reflux. Fuming nitric acid (16.0 mmol) was added dropwise and the reaction mixture was maintained at reflux for 30 min: The cooled solution was diluted with water (20 mL) and the aqueous layer was extracted with dichloromethane (3xlOmL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the nitro-amide in 83% yield. The amide (11.0 mmol), sodium hydroxide (43.8 mmol), and water (10 mL) were combined and the reaction mixture was maintained for 1.5 hour at 60 C. the reaction was allowed to cool to rt and the precipitated solids were isolated by filtration, and washed with water, and dried to provide the aniline in 98% yield as a light yellow solid. The aniline (15.7 mmol) was mixed with 40% hydrobromic acid (14.3 g) and water (10 mL) and the reaction mixture was warmed to 80-90 C in order to completely dissolve the aniline. The reaction mixture. was cooled to 0 C and a solution of sodium nitrite (23.2 mmol) in water (5.3 mL) was added during a 15 min period. The solution was maintained for 40 minutes at 0-5 C and filtered. Copper (I) bromide (18.8 mmol) was dissolved in 40% hydrobromic acid (21 mL) and was cooled to 0 C. The solution of the diazo salt was added slowly to the copper solution and the mixture was maintained for 30 min at 0-10 C. The reaction mixture was heated at 60 C for 30 min and then at 100 C for 10 min to ensure completion. The reaction mixture was allowed to cool to rt and was extracted with dichloromethane (3x40mL). The combined organic layers were washed with 1 M sodium hydroxide, water, 1 N hydrochloric acid, and water. The organic layer was dried (magnesium sulfate) and concentrated to provide the nitro bromide in 76% yield as a light yellow solid. Diethyl malonate (25.7 mmol) was added dropwise to a suspension of sodium hydride (25.8 mmol) in dimethylsulfoxide (5 mL) at 0 C. The reaction mixture was warmed to 60 C and maintained for 30 min. A solution of the nitro bromide (11.7 mmol) in dimethylsulfoxide (7 mL) was added dropwise and the reaction mixture was heated at 100 C for 5 h. The cooled solution was poured onto ice water and the aqueous layer was extracted with dichloromethane (3x100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the crude diester as an oil. The diester (11.7 mmol), sodium hydroxide (35 mmol), and water (20 mL) were combined and heated at 60 C for 1 h. The reaction mixture was allowed to cool to rt and the aqueous layer was washed with dichloromethane (3x100 mL). The pH of the aqueous layer was cautiously adjusted to 1 with concentrated hydrochloric acid and the reaction mixture was heated at 60 C for 1 h. The suspension was cooled to 0 C and the solids were collected by filtration and dried to provide the acid in 64% yield. Acetyl chloride (15.3 mmol) was added dropwise to ethanol (50 mL) at 0 C. After 30 min, the acid (7.69 mmol) was added and the reaction mixture was heated at reflux for 15 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (20 mL) and saturated sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (2x20 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the ester in 94% yield ...
62%	at 20℃; for 16h;	The nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and was treated with ammonium chloride (84.7 mmol) and iron powder (105 mmol). The reaction mixture was heated at reflux for 30 minutes and the suspension was filtered through Celite. The filter cake was washed with ethanol three times and the combined filtrates were concentrated. The residue was dissolved in water and the pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3×100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was maintained at rt for 16 h. The reaction mixture was diluted with water (50 mL) and was neutralized with solid sodium bicarbonate. The precipitated solids were isolated by filtration, washed with water, and dried to provide the acetamide in 62% yield as a light yellow solid.
	at 20℃; for 16h;	The nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and was treated with ammonium chloride (84.7 mmol) and iron powder (105 mmol). The reaction mixture was heated at reflux for 30 minutes and the suspension was filtered through Celite. The filter cake was washed with ethanol three times and the combined filtrates were concentrated. The residue was dissolved in water and the pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3xlOOmL) and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was maintained at rt for 16 h. The reaction mixture was diluted with water (50 mL) and was neutralized with solid sodium bicarbonate. The precipitated solids were isolated by filtration, washed with water, and dried to provide the acetamide in 62% yield as a light yellow solid.

	at 20℃; for 16h;	The nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and was treated with ammonium chloride (84.7 mmol) and iron powder EPO <DP n="45"/>(105 mmol). The reaction mixture was heated at reflux for 30 minutes and the suspension was filtered through Celite. The filter cake was washed with ethanol three times and the combined filtrates were concentrated. The residue was dissolved in water and .the pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3xl00mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was maintained at rt for 16 h. The reaction mixture was diluted with water (50 mL) and was neutralized with solid sodium bicarbonate. The precipitated solids were isolated by filtration, washed with water, and dried to provide the acetamide in 62% yield as a light yellow solid.
	at 20℃; for 16h;	The nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and was treated with ammonium chloride (84.7 mmol) and iron powder (105 mmol). The reaction mixture was heated at reflux for 30 minutes and the suspension was filtered through Celite. The filter cake was washed with ethanol three times and the combined filtrates were concentrated. The residue was dissolved in water and the pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3*100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was maintained at rt for 16 h. The reaction mixture was diluted with water (50 mL) and was neutralized with solid sodium bicarbonate. The precipitated solids were isolated by filtration, washed with water, and dried to provide the acetamide in 62% yield as a light yellow solid.

Reference： [1]Patent: WO2005/111038,2005,A2 .Location in patent: Page/Page column 72-75
[2]Patent: US2005/250808,2005,A1 .Location in patent: Page/Page column 41
[3]Patent: WO2005/63767,2005,A2 .Location in patent: Page/Page column 47-48
[4]Patent: WO2006/69097,2006,A2 .Location in patent: Page/Page column 43-44
[5]Patent: US2007/78147,2007,A1 .Location in patent: Page/Page column 64

32
[ 1544-86-1 ]
[ 22236-10-8 ]

Yield	Reaction Conditions	Operation in experiment
	With iron; ammonium chloride; In ethanol; water; for 0.5h;Heating / reflux;	The nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and was treated with ammonium chloride (84.7 mmol) and iron powder (105 mmol). The reaction mixture was heated at reflux for 30 minutes and the suspension was filtered through Celite. The filter cake was washed with ethanol three times and the combined filtrates were concentrated. The residue was dissolved in water and the pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3xlOOmL) and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was maintained at rt for 16 h. The reaction mixture was diluted with water (50 mL) and was neutralized with solid sodium bicarbonate. The precipitated solids were isolated by filtration, washed with water, and dried to provide the acetamide in 62% yield as a light yellow solid.
	With iron; ammonium chloride; In ethanol; water; for 0.5h;Heating / reflux;	4-Nitrophenol (162 mmol) was added to a suspension of sodium hydroxide (485 mmol) in NN-dimethylformamide (150 mL) and the suspension was maintained for 15 min at rt. The reaction mixture was cooled to 0 C and was treated with ethyl chlorodifluoroacetate (329 mmol). The reaction mixture was heated at 70 C for 16 h and was concentrated. The residue was diluted with ice water (200 mL) and was extracted with ethyl acetate (3x100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the difluoromethyl ether in 59% yield as yellow oil. The nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and was treated with ammonium chloride (84.7 mmol) and iron powder (105 mmol). The reaction mixture was heated at reflux for 30 minutes and the suspension was filtered through Celite. The filter cake was washed with ethanol three times and the combined filtrates were concentrated. The residue was dissolved in water and the pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3x100mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was maintained at rt for 16 h. The reaction mixture was diluted with water (50 mL) and was neutralized with solid sodium bicarbonate. The precipitated solids were isolated by filtration, washed with water, and dried to provide the acetamide in 62% yield as a light yellow solid. Acetic anhydride (19.6 mmol) was added to a solution of the acetamide (13.2 mmol) in chloroform (20 mL) and the reaction mixture was warmed to reflux. Fuming nitric acid (16.0 mmol) was added dropwise and the reaction mixture was maintained at reflux for 30 min: The cooled solution was diluted with water (20 mL) and the aqueous layer was extracted with dichloromethane (3xlOmL). The combined organic layers were dried (magnesium sulfate) and concentrated to provide the nitro-amide in 83% yield. The amide (11.0 mmol), sodium hydroxide (43.8 mmol), and water (10 mL) were combined and the reaction mixture was maintained for 1.5 hour at 60 C. the reaction was allowed to cool to rt and the precipitated solids were isolated by filtration, and washed with water, and dried to provide the aniline in 98% yield as a light yellow solid. The aniline (15.7 mmol) was mixed with 40% hydrobromic acid (14.3 g) and water (10 mL) and the reaction mixture was warmed to 80-90 C in order to completely dissolve the aniline. The reaction mixture. was cooled to 0 C and a solution of sodium nitrite (23.2 mmol) in water (5.3 mL) was added during a 15 min period. The solution was maintained for 40 minutes at 0-5 C and filtered. Copper (I) bromide (18.8 mmol) was dissolved in 40% hydrobromic acid (21 mL) and was cooled to 0 C. The solution of the diazo salt was added slowly to the copper solution and the mixture was maintained for 30 min at 0-10 C. The reaction mixture was heated at 60 C for 30 min and then at 100 C for 10 min to ensure completion. The reaction mixture was allowed to cool to rt and was extracted with dichloromethane (3x40mL). The combined organic layers were washed with 1 M sodium hydroxide, water, 1 N hydrochloric acid, and water. The organic layer was dried (magnesium sulfate) and concentrated to provide the nitro bromide in 76% yield as a light yellow solid. Diethyl malonate (25.7 mmol) was added dropwise to a suspension of sodium hydride (25.8 mmol) in dimethylsulfoxide (5 mL) at 0 C. The reaction mixture was warmed to 60 C and maintained for 30 min. A solution of the nitro bromide (11.7 mmol) in dimethylsulfoxide (7 mL) was added dropwise and the reaction mixture was heated at 100 C for 5 h. The cooled solution was poured onto ice water and the aqueous layer was extracted with dichloromethane (3x100 mL). The combined organic layers were dried (magnesium sulfate) and concentrated to give the crude diester as an oil. The diester (11.7 mmol), sodium hydroxide (35 mmol), and water (20 mL) were combined and heated at 60 C for 1 h. The reaction mixture was allowed to cool to rt and the aqueous layer was washed with dichloromethane (3x100 mL). The pH of the aqueous layer was cautiously adjusted to 1 with concentrated hydrochloric acid and the reaction mixture was heated at 60 C for 1 h. The suspension was cooled to 0 C and the solids were collected by filtration and dried to provide the acid in 64% yield. Acetyl chloride (15.3 mmol) was added dropwise to ethanol (50 mL) at 0 C. After 30 min, the acid (7.69 mmol) was added and the reaction mixture was heated at reflux for 15 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane (20 mL) and saturated sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (2x20 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to provide the ester in 94% yield ...
		The nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and was treated with ammonium chloride (84.7 mmol) and iron powder (105 mmol). The reaction mixture was heated at reflux for 30 minutes and the suspension was filtered through Celite. The filter cake was washed with ethanol three times and the combined filtrates were concentrated. The residue was dissolved in water and the pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3×100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was maintained at rt for 16 h. The reaction mixture was diluted with water (50 mL) and was neutralized with solid sodium bicarbonate. The precipitated solids were isolated by filtration, washed with water, and dried to provide the acetamide in 62% yield as a light yellow solid.

	With water; iron; ammonium chloride; In ethanol; for 0.5h;Heating / reflux;	The nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and was treated with ammonium chloride (84.7 mmol) and iron powder EPO <DP n="45"/>(105 mmol). The reaction mixture was heated at reflux for 30 minutes and the suspension was filtered through Celite. The filter cake was washed with ethanol three times and the combined filtrates were concentrated. The residue was dissolved in water and .the pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3xl00mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was maintained at rt for 16 h. The reaction mixture was diluted with water (50 mL) and was neutralized with solid sodium bicarbonate. The precipitated solids were isolated by filtration, washed with water, and dried to provide the acetamide in 62% yield as a light yellow solid.
	With iron; ammonium chloride; In ethanol; water; for 0.5h;Heating / reflux;	The nitro ether (149 mmol) was dissolved in ethanol (37.5 mL), diluted with water (25 mL), and was treated with ammonium chloride (84.7 mmol) and iron powder (105 mmol). The reaction mixture was heated at reflux for 30 minutes and the suspension was filtered through Celite. The filter cake was washed with ethanol three times and the combined filtrates were concentrated. The residue was dissolved in water and the pH adjusted to 9-10 with 5 M sodium hydroxide. The aqueous layer was extracted with ethyl acetate (3*100 mL) and the combined organic layers were dried (magnesium sulfate) and concentrated to a yellow oil. The oil was dissolved in acetic anhydride (23.5 mmol) and the reaction mixture was maintained at rt for 16 h. The reaction mixture was diluted with water (50 mL) and was neutralized with solid sodium bicarbonate. The precipitated solids were isolated by filtration, washed with water, and dried to provide the acetamide in 62% yield as a light yellow solid.

Reference： [1]Patent: WO2005/63767,2005,A2 .Location in patent: Page/Page column 47-48
[2]Patent: WO2005/111038,2005,A2 .Location in patent: Page/Page column 72-75
[3]Patent: US2005/250808,2005,A1 .Location in patent: Page/Page column 41
[4]Patent: WO2006/69097,2006,A2 .Location in patent: Page/Page column 43-44
[5]Patent: US2007/78147,2007,A1 .Location in patent: Page/Page column 64

33
[ 22236-10-8 ]
2,6-dichloro-4-(difluoromethoxy)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-chloro-succinimide; In acetonitrile; for 2h;	Preparation 110; 2, 6-dichloro-4- (difluoromethoxy) phenylamine; To a solution of 4-[(difluoromethoxy) methyl] aniline (15.0 g, 94.3 mmol) in acetonitrile (150 ml) was added N-chlorosuccinimide (25.2 g, 18.9 mmol) and the reaction mixture was stirred under nitrogen for 2 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between diethyl ether (500 ml) and water (125 ml). The organic layer was separated, washed with aqueous sodium thiosulphate solution, water and brine, dried (MgS04) and treated with charcoal. The solution was then filtered and concentrated in vacuo. The residue was extracted with hexane (2 x 300 mi) and the combined extracts were concentrated in vacuo to give the titled compound (13.8 g). Experimental MH+ 228. 0; expected 228.0

Reference： [1]Organic Process Research and Development,2012,vol. 16,p. 156 - 159
[2]Patent: WO2005/90313,2005,A1 .Location in patent: Page/Page column 140-141

34
[ 856931-48-1 ]
[ 22236-10-8 ]
[ 871492-77-2 ]

Yield	Reaction Conditions	Operation in experiment
76%	With sodium tris(acetoxy)borohydride; acetic acid; In dichloromethane; at 20℃; for 16h;	Following General Procedure A, a solution of <strong>[22236-10-8]4-difluoromethoxyaniline</strong> (0.50 g, 3.1 mmol) and (R)-3-(4-oxo-piperidin-1-yl)-butyronitrile (0.44 g, 2.6 mmol) in CH2Cl2 (10 mL), was treated with glacial AcOH (3 drops) and NaBH(OAc)3 (0.83 g, 3.9 mmol), stirring for 16 h at room temperature. Saturated aqueous NaHCO3 solution (15 mL) and 1N NaOH (2 mL) was added and the phases were separated and the aqueous extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was then purified by flash column chromatography on silica gel (1:1 EtOAc/CH2Cl2) to afford (R)-3-[4-(4-difluoromethoxy-phenylamino)-piperidin-1-yl]-butyronitrile as a white solid (0.61 g, 76%). 1H NMR (CDCl3) delta 1.20 (d, 3H, J=6.6 Hz), 1.43 (m, 2H), 2.06 (br d, 2H), 2.36 (m, 3H), 2.52 (m, 1H), 2.82 (m, 2H), 3.07 (sex, 1H, J=7.2 Hz), 3.24 (m, 1H), 6.36 (t, 1H, J=75 Hz), 6.54 (d, 2H, J=9.0 Hz), 6.95 (d, 2H, J=9.0 Hz).

Reference： [1]Patent: US2005/277668,2005,A1 .Location in patent: Page/Page column 26

35
3-(4-bromophenyl)-N-cyano-4-(2-oxo-pyrrolidin-1-yl)-4,5-dihydro-pyrazol-1-phenylimidate [ No CAS ]
[ 22236-10-8 ]
3-(4-bromophenyl)-N-cyano-N'-(4-difluoromethoxyphenyl)-4-(2-oxo-pyrrolidin-1-yl)-4,5-dihydro-pyrazol-1-carboxamidine [ No CAS ]

Reference： [1]Patent: WO2005/7157,2005,A1 .Location in patent: Page/Page column 78; 79

36
[ 22236-10-8 ]
[ 304873-96-9 ]
tert-butyl (5-[4-[4-(difluoromethoxy)phenyl]amino}-1,1-dioxido-3-oxo-5-phenylisothiazol-2(3H)-yl]methyl}pyridin-2-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%		te/t-ButyI (5-[4-[4-(difluoromethoxy)phenyl]amino}-l,l-dioxido-3-oxo-5-phenyIisothiazol-2(3/T)-yl]inethyI}pyridin-2-yl)carbamate; [4-[Difluoromethoxy)phenyl]amine (0.27g, 1.7mmol) was added to an ice cold solution of 4- chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.41g, 1.7mmol) in DMF (4ml) and the mixture was stirred for Ih. tert-Butyl[5-(bromomethyl)pyridin-2-yl]carbamate (0.48g, EPO <DP n="143"/>1.7mmol) and anhydrous poatassium carbonate (0.23 g, lJmmol) were added. The reaction mixture was stirred over night, concentrated and the residue was dissolved in DCM. The mixture was washed with water and concentrated and the residue was purified using preparative HPLC to give the title compound (0.12g, 13%).

Reference： [1]Patent: WO2006/73363,2006,A1 .Location in patent: Page/Page column 141-142

37
[ 898252-84-1 ]
[ 22236-10-8 ]
2-butyl-4-[4-(difluoromethoxy)phenyl]amino}-5-phenylisothiazol-3(2H)-one 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	In acetonitrile; at 160℃; for 2h;Microwave irradiation;	Example 9; 2-ButyI-4-[4-(difluoromethoxy)phenyl]amino}-5-phenyIisothiazol-3(2H)-one 1,1-dioxide; 2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.63g, 2.1 mmol) and 4- (difluoromethoxy)-aniline (0.67g, 4.2mmol) were mixed in MeCN (4 mL, dry). The mixture EPO <DP n="147"/>was put in the microwave reactor at 160 0C for 1 h, then additional 1 h and then 1 h more. It was evaporated to dryness. The residue was purified by column chromatography (ISOLUTE SI, 50 g/150 mL), eluting with DCM/heptane (50:50, then 75:25), to give the title compound (0.688g, 78%) as a yellow solid;
78%	In acetonitrile; at 160℃; for 3h;Microwave irradiation;	2-Butyl-4-[4-(difluoromethoxy)phenyl]amino}-5-phenylisothiazol-3(2H)-one 1,1-dioxide; 2-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.63g, 2.1mmol) and 4-(difluoromethoxy)-aniline (0.67g, 4.2mmol) were mixed in MeCN (4mL, dry). The mixture was put in a microwave reactor at 1600C for 1 hour, then for additional 1 hour then for 1 hour more. It was evaporated to dryness. The residue was purified by column chromatography (ISOLUTE SI, 50g/150mL), eluting with dichloromethane/heptane (50:50, then 75:25), to give the title compound (0.688g, 78%) as a yellow solid;

Reference： [1]Patent: WO2006/73363,2006,A1 .Location in patent: Page/Page column 145-146
[2]Patent: WO2006/73364,2006,A1 .Location in patent: Page/Page column 107

38
[ 898800-11-8 ]
[ 22236-10-8 ]
2-butyl-5-(3-chlorophenyl)-4-[4-(difluoromethoxy)phenyl]amino}isothiazol-3(2H)-one 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72.9%	In acetonitrile; at 160℃; for 1h;Microwave irradiation;	Example 31; 2-ButyI-5-(3-chlorophenyl)-4-[4-(difluoromethoxy)phenyl]amino}isothiazol-3(2H)-one 1,1-dioxide; 2-Butyl-4-chloro-5-(3-chlorophenyl)isothiazol-3(2H)-one 1,1-dioxide (0.25Og, 0.75mmol) and <strong>[22236-10-8]4-(difluoromethoxy)aniline</strong> (0.238g, 1.50mmol) were mixed in MeCN (2mL) and heated in a microwave reactor at 160C for 60 mins. The reaction mixture was evaporated and the residue was purified on a Horizon TM flash system using Heptane and EetOAc as eluant giving the title compound (0.25g, 72.9%).

Reference： [1]Patent: WO2006/73363,2006,A1 .Location in patent: Page/Page column 154

39
2-butyl-4-chloro-5-(4-chlorophenyl)isothiazol-3(2H)-one 1,1-dioxide [ No CAS ]
[ 22236-10-8 ]
2-butyl-5-(4-chlorophenyl)-4-[4-(difluoromethoxy)phenyl]amino}isothiazol-3(2H)-one 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	In acetonitrile; at 130 - 140℃; for 2h;Microwave irradiation;	Example 12; 2-ButyI-5-(4-chIorophenyl)-4-[4-(difluoromethoxy)phenyl]amino}isothiazol-3(2H)-one 1,1-dioxide; 2-Butyl-4-chloro-5-(4-chlorophenyl)isothiazol-3(2H)-one 1,1-dioxide (0.2Og, 0.60mmol) and 4-(difiuoromethoxy)-aniline (0.19Og, 1.20mmol) were mixed in MeCN (2.5mL). The mixture was heated in a microwave reactor at 130 C for 15 mins, then additional 60 mins and then at 140 0C for 15 mins, then additional 30 mins. The mixture was evaporated and the residue was purified by column chromatography (ISOLUTE SI 20 g/70 mL), eluting with heptane, then DCM:heptane (25:75, then 50:50), to give the title compound (0.122g, 45%);

Reference： [1]Patent: WO2006/73363,2006,A1 .Location in patent: Page/Page column 147

40
[ 898800-19-6 ]
[ 22236-10-8 ]
2-[4-(difluoromethoxy)benzyl]-4-[4-(difluoromethoxy)phenyl]amino}-5-phenylisothiazol-3(2H)-one 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6%	In acetonitrile; at 130 - 140℃; for 0.75h;Microwave irradiation;	Example 14; 2-[4-(Difluoromethoxy)benzyl]-4-[4-(difluoromethoxy)phenyl]amino}-5- phenylisothiazol-3(2H)-one l,l-dioxide; 4-Chloro-2-[4-(difluoromethoxy)benzyl]-5-phenylisothiazol-3(2H)-one 1,1-dioxide (80mg, 0.2mmol) and 4-(difluoromethoxy)-aniline (64mg, 0.4mmol) were mixed in MeCN (2mL). The mixture was heated in a microwave rector at 130 0C for 15 mins, then an additional 15 mins and then at 140 C for 15 mins. It was then evaporated to dry. Column chromatography (ISOLUTE SI 10 g/70 mL) of the residue, eluting with EtOAc:heptane (10:90, then 20:80), gave a product mixture. It was further purified by re-chromatography (ISOLUTE SI, 5 g/25 mL), eluting with EtOAc:heptane (10:90, then 20:80), to give the title compound (6mg, 6%);

Reference： [1]Patent: WO2006/73363,2006,A1 .Location in patent: Page/Page column 148

41
[ 58417-15-5 ]
[ 22236-10-8 ]
N,N'-bis[4-(difluoromethoxy)phenyl]urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; at 70℃; for 1.5h;	A solution of 4-difiuoromethoxyaniline (258 mg, 1.62 mmol) and 4-difluoromethoxyphenyl isocyanate (300 mg, 1.62 mmol) in toluene (8.1 niL) is heated at 7O0C for 1.5 h. The resulting white solid is collected by suction filtration and dried with suction for 30 min to obtain N,N'-bis[4- (difluoromethoxy)phenyl]urea as a white solid. 1H NMR: (CD3OD) 7.45 (dd, 4H), 7.09 (dd, 4H), 6.91(dt, 2H, Ji = 56 Hz).

Reference： [1]Patent: WO2006/49941,2006,A2 .Location in patent: Page/Page column 34; 35

42
[ 1544-86-1 ]
[ 7440-66-6 ]
[ 22236-10-8 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; In ethanol; water;	14.7 g (0.077 mol) 4-Difluoromethoxynitrobenzene was dissolved in a mixture of 180 ml ethanol and 110 ml water. It was added to 7.34 g (0.137 mol) ammonium chloride. At a temperature of 30 C. 36.98 g (0.566 mol) zinc powder wasadded portionwise. It was then stirred for another 1.5 hours. It was then separated from the undissolved material and the aqueous phase concentrated to half, extracted 3 times with 50 ml diethyl ether, dried over magnesium sulphate and concentrated. 8.72 g (70.5% of theory) 4-Difluoromethoxyaniline was obtained.

Reference： [1]Patent: US4897415,1990,A

43
[ 4472-44-0 ]
[ 22236-10-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium hydroxide;	This was then converted by treatment in a conventional manner with zinc and ammonium chloride to give 4-difluoromethoxyaniline as a yellow oil. 2-Chloro-4,6-dimethylpyrimidine (4.7 g) was added with stirring to this product (6 g) followed by concentrated hydrochloric acid (0.25 ml) and the mixture heated to 140. It was then cooled, added to aqueous sodium hydroxide and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride, dried and evaporated.

Reference： [1]Patent: US4783459,1988,A

44
[ 1122-17-4 ]
[ 22236-10-8 ]
3,4-dichloro-1-[4-(difluoromethoxy)-phenyl]-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In toluene;	EXAMPLE 3 Preparation of 2,3-dichloro-N-(p-difluoromethoxyphenyl)maleimide A solution of 16.7 g (0.1 mole) of 2,3-dichloromaleic anhydride in 70 ml of toluene is heated to boiling. A solution of 15.9 g (0.1 mole) of p-difluoromethoxyaniline in 30 ml of toluene is added dropwise to it over 20 minutes with stirring. Thereafter, the resulting solution is refluxed until water is no longer distilled. This requires about 2 hours. The mixture is cooled to room temperature to precipitate crystals. The precipitated crystals are filtered off and washed with hexane to obtain 29.2 g of 2,3-dichloro-N-(p-difluoromethoxyphenyl)maleimide melting at 217.5-218 C. in the form of light yellow plate crystals.

Reference： [1]Patent: US4455315,1984,A

45
[ 916730-95-5 ]
[ 22236-10-8 ]
4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-difluoromethoxy-phenyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 2h;	EXAMPLE 51; 4-(6,7-Dimethoxy-quinazolin-4-yl)-piperidine-1-carboxylic acid (4-difluoromethoxy-phenyl)-amide; To a solution of 4-(6,7-dimethoxy-quinazolin-4-yl)-piperidine-1-carbonyl chloride (46.9 mg, 0.14 mmol), as prepared in Example 3a, in DMSO (1 mL) was added <strong>[22236-10-8]4-(difluoromethoxy)aniline</strong> (26.6 mg, 0.17 mmol), followed by DIEA (35.9 mg, 0.28 mmol). The mixture was heated at 100 C. with stirring. After 2 h, it was cooled to room temperature and partitioned between EtOAc and water. The combined EtOAc extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc?5% MeOH/EtOAc as eluent) to afford the title compound as a white solid (20.4 mg, 32%). 1H NMR (300 MHz, CDCl3) delta 9.09 (s, 1H), 7.40 (s, 1H), 7.38 (d, J=8.99 Hz, 2H), 7.27 (s, 1H), 7.07 (d, J=8.93 Hz, 2H), 6.48 (s, 1H), 6.45 (t, J=74.22 Hz, 1H), 4.28 (m, 2H), 4.08 (s, 3H), 4.07 (s, 3H), 3.62 (m, 1H), 3.20 (td, J=13.02 and 2.64 Hz, 2H), 2.14 (m, 2H), 2.01 (m, 2H). LC-MS (ESI) calcd mass 458.2, found 459.3 (MH+).

Reference： [1]Patent: US2006/281772,2006,A1 .Location in patent: Page/Page column 75

46
[ 17159-79-4 ]
[ 22236-10-8 ]
C₁₆H₂₁F₂NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 35 (4-Cyclopentyl-piperazin-1-yl)-[4-(2-fluoro-phenylamino)-cyclohexyl]-methanone A mixture of 86 mg (0.5 mmol) 4-oxo-cyclohexanecarboxylic acid ethyl ester (commercially available), 100 mg (0.6 mmol) 2-fluoro-phenylamine and 300 mg (5 mmol) acetic acid in 5 mL THF was stirred for 1 h at 60 C. Afterwards 159 mg (0.75 mmol) sodium triacetoxyborohydride were added and the mixture was heated to 65 C. for 16 h. After evaporation of the volatiles 10 mL 1N NaHCO3 aq. was added and the mixture was extracted with DCM. The combined organic layers were evaporated and methanol and DMF were added and the mixture was subjected to preparative HPLC purification on reversed phase eluding with a gradient of acetonitrile/water (0.1% NEt3). The combined product fractions were evaporated to dryness to yield the intermediate 3-(2-fluoro-phenylamino)-cyclohexanecarboxylic acid ethyl ester. MS(m/e): 266.2 (MH+).

Reference： [1]Patent: US2007/167436,2007,A1 .Location in patent: Page/Page column 23

47
[ 944404-26-6 ]
[ 22236-10-8 ]
[4-(4-difluoromethoxy-phenylamino)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 2: (4-Isopropyl-piperazin-1-yl)-(4-p-tolylamino-cyclohexyl)-methanone A mixture of 25 mg (0.1 mmol) 4-(4-isopropyl-piperazine-1-carbonyl)-cyclohexanone, 27 mg (0.25 mmol) p-tolylamine, 60 mg acetic acid and 42 mg (0.2 mmol) sodium triacetoxyborohydride in 2 ml THF was shaken for 16 h at 70 C. After evaporation methanol and DMF were added and the mixture was subjected to preparative HPLC purification on reversed phase eluding with a gradient of acetonitrile/water (0.1% NEt3). The combined product fractions were evaporated to dryness to yield 5.1 mg (15%) of the title compound. MS(m/e): 344.3 (MH+).

Reference： [1]Patent: US2007/167436,2007,A1 .Location in patent: Page/Page column 19-20

48
[ 1093101-67-7 ]
[ 22236-10-8 ]
[ 1093100-61-8 ]

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 (0.060 g, 0.12 mmol), 4- (difluoromethoxy)benzenamine (0.039 g, 0.25 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 C for 12 minutes. The reaction was diluted with 2M ammonia in MeOH and EtOAc. The mixture was loaded unto 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-(4-(difluoromethoxy)phenyl)-7-methylquinazoline-4,8-diamine as a yellow solid. MS Found: (ESI pos. ion) m/z 512 01+H+).

Reference： [1]Patent: WO2008/153947,2008,A2 .Location in patent: Page/Page column 84

49
[ 24415-66-5 ]
[ 22236-10-8 ]
[ 1141892-47-8 ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 1864 - 1872

50
[ 24424-99-5 ]
[ 22236-10-8 ]
[ 1198109-73-7 ]

Yield	Reaction Conditions	Operation in experiment
54%	With triethylamine; In acetonitrile; at 50℃; for 18h;	Preparation 30; Tert-butyl 4-(difluoromethoxy)phenylcarbamate; To a mixture of <strong>[22236-10-8]4-difluoromethoxyaniline</strong> (20.00 g, 126 mMol), MeCN (100 ml_) and triethylamine (35 ml_, 250 mMol) was added BoC2O (40.98 g, 187 mMol). The reaction mixture was heated to 500C and stirred for 18 hours. The reaction mixture was cooled to RT then concentrated to dryness and EtOAc (300 ml_) was added, washed with water (200 ml_), brine (200 ml_), dried over MgSO4 then concentrated. The crude product was purified by column chromatography using 1 :1 (EtOAc/Hex) as eluent which gave the title compound (17.90 g, 54%).1H NMR (300MHz, CDCI3) delta = 1.50 (s, 9H), 6.20-6.70 (t, 1 H), 6.50 (bs, 1 H), 7.04 (d, 2H), 7.36 (d, 1 H).LCMS (System 5): 2.48 mins m/z = 204.13 [M-'bu]

Reference： [1]Patent: WO2009/144632,2009,A1 .Location in patent: Page/Page column 68

51
[ 39906-04-2 ]
[ 22236-10-8 ]
[ 1198109-55-5 ]

Yield	Reaction Conditions	Operation in experiment
45%	With hydrogenchloride; In ethanol; at 85℃;	Preparation 9 6-Chloro-N4-(4-difluoromethoxyphenyl)-2-methylpyrimidine-4,5-diamine; 4,6-dichloro-2-methyl-pyrimidin-5-ylamine (20.0 g, 110 MoI) was added with stirring to EtOH (80 mL) over 3 minutes to give complete solution. 4-Difluoromethyoxyaniline (18.8 g, 118 MoI) was then added with stirring over 3 minutes. A dark brown solution was observed. EtOH (20 mL) was then added followed by a premixed solution of c.HCI (10 mL) in EtOH (40 mL) at a steady rate over 20 minutes. A slight exotherm up to approx 2O0C was noted. The solution was then warmed to 850C and held at that <n="59"/>temperature for 4 hours. The reaction mixture was then cooled to room temperature, and a beige solid precipitated. This reaction mixture was filtered then washed with EtOH (100 ml_) followed by MTBE (3OmL) to remove EtOH traces. The resultant solid was dried in vacuo over the weekend to give the title compound, as the hydrochloride salt, as a beige solid (17.2 g, 45%) 1H NMR (400MHz, CD3OD) delta = 2.55 (s, 3H), 6.89 (t, 1 H), 7.27 (d, 2H), 7.75 (d, 2H) LCMS (System 4) 3.07 mins; m/z (APCI) = 301 [MH+]

Reference： [1]Patent: WO2009/144632,2009,A1 .Location in patent: Page/Page column 56-57

52
[ 22236-10-8 ]
[ 123-54-6 ]
[ 1228535-32-7 ]

Yield	Reaction Conditions	Operation in experiment
		A-9: l-(4-Difluoromethoxy-phenyl)-3-((E)-3-dimethylamino-acryloyl)-lH-pyridazin-4-one; a) 3-(4-Difluoromethoxy-phenylazo)-pentane-2,4-dione; A solution of 4-difluromethoxy-phenylamine (2 g, 13 mmol) was cooled at -6C and phosphoric acid (85%, 13 mL) followed by nitric acid (65%, 9 mL) very slowly. When the mixture reached the room temperature it was stirred 15 minutes for complete dissolution. The solution was cooled again to -6C and solid sodium nitrite (0.954 g, 13.8 mmol) was added during 5 minutes followed by crushed ice. The reaction mixture was added into a suspension of pentane-2,4-dione (1.32g, 13.2 mmol) and potassium acetate (24.1g, 251 mmol) in ethanol ( 130 mL) at 00C. Stirring is continued for 15 min at 0-5 0C and an aqueous solution 2M of sodium carbonate is added until the pH is 9-10. The solution is extracted with dichloromethane (4 x 200 mL). The combined organic layers were washed with water, dried with magnesium sulphate, filtrated and the solvent was removed in the vacuum to obtain 3.6 g (100%) of the final product that was used as a crude on the next step.MS: M = 269.1 (M-H)+

Reference： [1]Patent: WO2010/63610,2010,A1 .Location in patent: Page/Page column 51-52

53
[ 22236-10-8 ]
[ 123-54-6 ]
[ 1238700-28-1 ]

Yield	Reaction Conditions	Operation in experiment
82%		Reference Example 373-[4-(Difluoromethoxy)phenyl]hydrazono}pentane-2,4-dione To a solution of <strong>[22236-10-8]4-(difluoromethoxy)aniline</strong> (1000 mg, 6.25 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (518 mg, 7.50 mmol) in 4 mL of water was added dropwise at 0 C., and the mixture was stirred at 0 C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (1538 mg, 18.75 mmol) and acetylacetone (812 mg, 8.12 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water,EtOH/H2O (1:1) and hexane, and dried to give 3-[4-(difluoromethoxy)phenyl]hydrazono}pentane-2,4-dione (1400 mg, yield 82%).LCMS: m/z=271 [M++H].

Reference： [1]Patent: US2010/197651,2010,A1 .Location in patent: Page/Page column 48

54
[ 22236-10-8 ]
[ 99-90-1 ]
[ 1242457-29-9 ]

Yield	Reaction Conditions	Operation in experiment
33%	With potassium carbonate; L-proline;copper(l) iodide; In dimethyl sulfoxide; at 95℃; for 72h;	The reaction is carried out under protective gas (argon). A mixture of 2.39 g (12 mmol) 1-(4-bromophenyl)ethanone, 0.99 mL (8 mmol) <strong>[22236-10-8]4-(difluoromethoxy)aniline</strong>, 2.21 g (16 mmol) potassium carbonate, 150 mg (0.8 mmol) copper iodide and 180 mg (1.6 mmol) L-proline in 12 mL DMSO was stirred for 72 hours at 95 C. The reaction mixture was added to water, mixed with a little ammonia extracted twice with tert-butyl-methylether. The combined organic phases were dried on sodium sulphate and evaporated to dryness in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether+30% ethyl acetate). The product was further reacted directly.Yield: 33% of theoryC15H13F2NO2 (277.27)Rt=1.98 min. method 1

Reference： [1]Patent: US2010/240669,2010,A1 .Location in patent: Page/Page column 140

55
[ 22236-10-8 ]
[ 206257-39-8 ]
[ 1256468-42-4 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,4-dioxane; at 150℃; for 0.333333h;Microwave irradiation;	(a) Preparation of intermediary compound ethyl-6-bromo-4-[[4-(difluoromethoxy)- phenyl]amino]quinoline-3-carboxylate:6-bromo-4-chloroquinoline-3-carboxylic acid ethyl ester (0.30 g, 0.95 mmol) and 4- difluoromethoxyaniline (0.23 g, 1.43 mmol) was mixed in dioxane (4 mL) and heated under microwave conditions at 150Cfor 20 minutes. The reaction mixture was cooled, concentrated in vacuo and suspended in dichloromethane. The reaction mixture was filtered, the residue evaporated and triturated with diethyl ether. The yellow crystals were washed twice with cold diethyl ether and dried in vacuo to afford ethyl-6-bromo-4-[[4-(difluoromethoxy)phenyl] amino] - quinoline-3-carboxylate in 90% purity (monitored by LC-MS). Yield: 250 mg (60 %). LC-MS (m/z) 437 (M+l).

Reference： [1]Patent: WO2010/133672,2010,A1 .Location in patent: Page/Page column 28

56
[ 22236-10-8 ]
[ 1192813-20-9 ]

Reference： [1]Patent: WO2011/53292,2011,A1
[2]Patent: JP5714745,2015,B2

57
[ 39906-04-2 ]
[ 22236-10-8 ]
[ 1198115-49-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6108 - 6111

58
[ 22236-10-8 ]
[ 1198108-95-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6108 - 6111
[2]Patent: WO2009/144632,2009,A1

59
[ 22236-10-8 ]
[ 1198109-56-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6108 - 6111
[2]Patent: WO2009/144632,2009,A1

60
[ 1345869-58-0 ]
[ 22236-10-8 ]
[ 1345868-72-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6652 - 6656

61
[ 22236-10-8 ]
4-(2-oxoimidazolidin-1-yl)benzene-1-sulfonyl chloride [ No CAS ]
[ 1328951-82-1 ]

Yield	Reaction Conditions	Operation in experiment
81%	With dmap; In acetonitrile; at 25℃;Inert atmosphere;	General procedure: Compound 51 (1.00 mmol) was suspended in dry acetonitrile (10 mL) under nitrogen atmosphere. Relevant aniline (1.00 mmol) and 4-dimethylaminopyridine (4.00 mmol) were successively added dropwise and the mixture was stirred at room temperature for 48 h. Ethyl acetate was added and the solution was washed with hydrochloric acid 1N, brine, dried over sodium sulfate, filtered, and evaporated to dryness under vacuum. The white solid was purified by flash chromatography on silica gel.

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 5327 - 5342

62
[ 1350641-46-1 ]
[ 22236-10-8 ]
[ 1350641-12-1 ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 85℃;Inert atmosphere;	General procedure: Step-1:4-amino-2,6-dichloro pyrimidine: 2,4,6-trichloro pyrimidine (1.0 mmol) in ethanol (5 mL) was treated with an aromatic amine (1.1 mmol) in the presence of Na2CO3 (1.1 mmol) at rt. The mixture was stirred at reflux for 2-4 h until completion of the reaction. The reaction progress was followed by TLC. After completion of the reaction, an equal volume of water was added with cooling. The resulting white precipitate was filtered, washed with water, and dried in vacuum over night to yield 4-substituted 2,6-dichloro pyrimidine. In case of no precipitation, ethanol was removed by rota vap., and the residue was dissolved in CH2Cl2. The organic layer was washed twice with water, brine, dried (Na2SO4), filtered, and concentrated. The resulting crude was purified by column chromatography to afford the 4-amino-2,6-dichloro pyrimidines in 85-95% yield. Step-2: 2,4-diamino-6-chloropyrimidine: 4-amino-2,6-dichloro pyrimidine (1.0 mmol) prepared from the above procedure was treated with another aliphatic amine or aromatic amine (2.0 mmol) in the presence of DIEPA (5.0 mmol) in n-BuOH (5 mL) at rt. For an aliphatic amine the reaction mixture was stirred at rt for overnight. For an aromatic amine the reaction mixture was refluxed for 24-72 h or placed in microwave (150 C, 2-7 h) until completion of the reaction. The reaction progress was followed by TLC. After completion of the reaction, solvents were removed by rota vap., and the residue was dissolved in CH2Cl2. The organic layer was washed twice with water, brine, dried (Na2SO4), filtered, and concentrated. The resulting crude was purified by column chromatography (EtOAc/hexane) to afford the 2,4-diammino-6-chloropyrimidines in 85-90% yield. Step-3: 2,4,6-triaminopyrimidine: 2,4-diamino-6-chloropyrimidine (1.0 mmol) prepared from the above procedure was treated with another suitable aliphatic amine or aromatic amine (3.0 mmol). For an aliphatic amine, 2,4-diamino-6-chloropyrimidine (1.0 mmol) was treated with aliphatic amine (3.0 mmol) and DIPEA (5.0 mmol) in n-BuOH (5 mL) and placed in microwave (150 C) for 3-7 h. After the completion of the reaction (monitored by TLC), solvents were removed and the residue was dissolved in EtOAc. The organic layer was washed twice with water, brine, dried (Na2SO4), filtered, and concentrated. The resulting crude was purified by column chromatography to afford the 2,4,6-triaminopyrimidines 90-95% yield. For aromatic amine; 2,4-diamino-6-chloropyrimidine (1.0 equiv) was dissolved in dioxane under argon and to that were added Pd2(dba)3 (10 mol %), Xantphos (10 mol %), aromatic amine (1.2 mmol), t-BuOK (1.2 mmol). The resulting solution was degassed with argon for 5 min and heated to 85 C for overnight. The reaction mixture was filtered through a pad of celite, washed with CH2Cl2 (2 × 10 mL) and the resulting filtrate was concentrated. The resulting crude was purified by flash column chromatography to yield 2,4,6-triaminopyrimidines in 90-95% yield.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7210 - 7215

63
[ 1355676-73-1 ]
[ 22236-10-8 ]
[ 1350641-27-8 ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 85℃;Inert atmosphere;	General procedure: Step-1:4-amino-2,6-dichloro pyrimidine: 2,4,6-trichloro pyrimidine (1.0 mmol) in ethanol (5 mL) was treated with an aromatic amine (1.1 mmol) in the presence of Na2CO3 (1.1 mmol) at rt. The mixture was stirred at reflux for 2-4 h until completion of the reaction. The reaction progress was followed by TLC. After completion of the reaction, an equal volume of water was added with cooling. The resulting white precipitate was filtered, washed with water, and dried in vacuum over night to yield 4-substituted 2,6-dichloro pyrimidine. In case of no precipitation, ethanol was removed by rota vap., and the residue was dissolved in CH2Cl2. The organic layer was washed twice with water, brine, dried (Na2SO4), filtered, and concentrated. The resulting crude was purified by column chromatography to afford the 4-amino-2,6-dichloro pyrimidines in 85-95% yield. Step-2: 2,4-diamino-6-chloropyrimidine: 4-amino-2,6-dichloro pyrimidine (1.0 mmol) prepared from the above procedure was treated with another aliphatic amine or aromatic amine (2.0 mmol) in the presence of DIEPA (5.0 mmol) in n-BuOH (5 mL) at rt. For an aliphatic amine the reaction mixture was stirred at rt for overnight. For an aromatic amine the reaction mixture was refluxed for 24-72 h or placed in microwave (150 C, 2-7 h) until completion of the reaction. The reaction progress was followed by TLC. After completion of the reaction, solvents were removed by rota vap., and the residue was dissolved in CH2Cl2. The organic layer was washed twice with water, brine, dried (Na2SO4), filtered, and concentrated. The resulting crude was purified by column chromatography (EtOAc/hexane) to afford the 2,4-diammino-6-chloropyrimidines in 85-90% yield. Step-3: 2,4,6-triaminopyrimidine: 2,4-diamino-6-chloropyrimidine (1.0 mmol) prepared from the above procedure was treated with another suitable aliphatic amine or aromatic amine (3.0 mmol). For an aliphatic amine, 2,4-diamino-6-chloropyrimidine (1.0 mmol) was treated with aliphatic amine (3.0 mmol) and DIPEA (5.0 mmol) in n-BuOH (5 mL) and placed in microwave (150 C) for 3-7 h. After the completion of the reaction (monitored by TLC), solvents were removed and the residue was dissolved in EtOAc. The organic layer was washed twice with water, brine, dried (Na2SO4), filtered, and concentrated. The resulting crude was purified by column chromatography to afford the 2,4,6-triaminopyrimidines 90-95% yield. For aromatic amine; 2,4-diamino-6-chloropyrimidine (1.0 equiv) was dissolved in dioxane under argon and to that were added Pd2(dba)3 (10 mol %), Xantphos (10 mol %), aromatic amine (1.2 mmol), t-BuOK (1.2 mmol). The resulting solution was degassed with argon for 5 min and heated to 85 C for overnight. The reaction mixture was filtered through a pad of celite, washed with CH2Cl2 (2 × 10 mL) and the resulting filtrate was concentrated. The resulting crude was purified by flash column chromatography to yield 2,4,6-triaminopyrimidines in 90-95% yield.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7210 - 7215

64
[ 22236-10-8 ]
(6-chloro-2-piperidin-1-yl-pyrimidin-4-yl)-phenyl-amine [ No CAS ]
[ 1350641-04-1 ]

Yield	Reaction Conditions	Operation in experiment
	With tris-(dibenzylideneacetone)dipalladium(0); potassium tert-butylate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 85℃;Inert atmosphere;	General procedure: Step-1:4-amino-2,6-dichloro pyrimidine: 2,4,6-trichloro pyrimidine (1.0 mmol) in ethanol (5 mL) was treated with an aromatic amine (1.1 mmol) in the presence of Na2CO3 (1.1 mmol) at rt. The mixture was stirred at reflux for 2-4 h until completion of the reaction. The reaction progress was followed by TLC. After completion of the reaction, an equal volume of water was added with cooling. The resulting white precipitate was filtered, washed with water, and dried in vacuum over night to yield 4-substituted 2,6-dichloro pyrimidine. In case of no precipitation, ethanol was removed by rota vap., and the residue was dissolved in CH2Cl2. The organic layer was washed twice with water, brine, dried (Na2SO4), filtered, and concentrated. The resulting crude was purified by column chromatography to afford the 4-amino-2,6-dichloro pyrimidines in 85-95% yield. Step-2: 2,4-diamino-6-chloropyrimidine: 4-amino-2,6-dichloro pyrimidine (1.0 mmol) prepared from the above procedure was treated with another aliphatic amine or aromatic amine (2.0 mmol) in the presence of DIEPA (5.0 mmol) in n-BuOH (5 mL) at rt. For an aliphatic amine the reaction mixture was stirred at rt for overnight. For an aromatic amine the reaction mixture was refluxed for 24-72 h or placed in microwave (150 C, 2-7 h) until completion of the reaction. The reaction progress was followed by TLC. After completion of the reaction, solvents were removed by rota vap., and the residue was dissolved in CH2Cl2. The organic layer was washed twice with water, brine, dried (Na2SO4), filtered, and concentrated. The resulting crude was purified by column chromatography (EtOAc/hexane) to afford the 2,4-diammino-6-chloropyrimidines in 85-90% yield. Step-3: 2,4,6-triaminopyrimidine: 2,4-diamino-6-chloropyrimidine (1.0 mmol) prepared from the above procedure was treated with another suitable aliphatic amine or aromatic amine (3.0 mmol). For an aliphatic amine, 2,4-diamino-6-chloropyrimidine (1.0 mmol) was treated with aliphatic amine (3.0 mmol) and DIPEA (5.0 mmol) in n-BuOH (5 mL) and placed in microwave (150 C) for 3-7 h. After the completion of the reaction (monitored by TLC), solvents were removed and the residue was dissolved in EtOAc. The organic layer was washed twice with water, brine, dried (Na2SO4), filtered, and concentrated. The resulting crude was purified by column chromatography to afford the 2,4,6-triaminopyrimidines 90-95% yield. For aromatic amine; 2,4-diamino-6-chloropyrimidine (1.0 equiv) was dissolved in dioxane under argon and to that were added Pd2(dba)3 (10 mol %), Xantphos (10 mol %), aromatic amine (1.2 mmol), t-BuOK (1.2 mmol). The resulting solution was degassed with argon for 5 min and heated to 85 C for overnight. The reaction mixture was filtered through a pad of celite, washed with CH2Cl2 (2 × 10 mL) and the resulting filtrate was concentrated. The resulting crude was purified by flash column chromatography to yield 2,4,6-triaminopyrimidines in 90-95% yield.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 7210 - 7215

65
[ 22236-10-8 ]
[ 1341200-84-7 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 907 - 912

66
[ 22236-10-8 ]
[ 1341200-85-8 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 907 - 912

67
[ 22236-10-8 ]
[ 1341200-56-3 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 907 - 912

68
[ 22236-10-8 ]
[ 5750-76-5 ]
[ 1341200-83-6 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 907 - 912

69
[ 3685-26-5 ]
[ 22236-10-8 ]
[ 1242558-74-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃;	Step 1 To a solution of cis-4-hydroxycyclohexane carbonic acid 6 (6.14 g, 42.6 mmol) in N,N'-dimethylformamide (40 mL) were added <strong>[22236-10-8]4-difluoromethoxyaniline</strong> 7 (5.12 g, 35.5 mmol), HOBt (691 mg, 5.11 mmol) and EDC hydrochloride (9.77 g, 51.1 mmol) at room temperature, and the mixture was stirred overnight at room temperature. The reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate, and then the organic layer was washed with saturated aqueous sodium bicarbonate and dried over magnesium sulfate, and then a solvent was removed in vacuo. The residue was washed with diethyl ether to yield the desired amide compound 8 (7.10 g, yield 70%) as a colorless solid.

Reference： [1]Patent: US2012/4227,2012,A1 .Location in patent: Page/Page column 18-19

70
[ 22236-10-8 ]
[ 84358-13-4 ]
[ 949993-23-1 ]

Yield	Reaction Conditions	Operation in experiment
70%		Example 1Synthesis of compound Ia-1Step 1 Compound 1 (3.44 g, 15.0 mmol) in N,N'-dimethylformamide (20 mL) at room temperature was added with <strong>[22236-10-8]4-difluoromethoxyaniline</strong> (2.23 mL, 18.0 mmol), HOBt (2.63 g, 19.5 mmol) and EDC hydrochloride (3.45 g, 18.0 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was poured into 0.05 N hydrochloride and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, and dried over magnesium sulfate, and then, the solvent was removed in vacuo. The residue was added with ethyl acetate and hexanes, and the precipitated crystals were collected by filtration to give the desired amide compound 2 (3.88 g, yield 70%).

Reference： [1]Patent: US2011/319412,2011,A1 .Location in patent: Page/Page column 35

71
[ 22236-10-8 ]
C₁₃H₁₆F₂N₂O₂*(x)ClH [ No CAS ]

Reference： [1]Patent: US2011/319412,2011,A1

72
[ 22236-10-8 ]
[ 1242622-31-6 ]

Reference： [1]Patent: US2011/319412,2011,A1

73
[ 22236-10-8 ]
[ 1242622-32-7 ]

Reference： [1]Patent: US2011/319412,2011,A1

74
[ 22236-10-8 ]
[ 1242622-33-8 ]

Reference： [1]Patent: US2011/319412,2011,A1

75
[ 22236-10-8 ]
[ 1242622-34-9 ]

Reference： [1]Patent: US2011/319412,2011,A1

76
[ 22236-10-8 ]
[ 1242622-35-0 ]

Reference： [1]Patent: US2011/319412,2011,A1

77
[ 412268-98-5 ]
[ 22236-10-8 ]
[ 412269-56-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1886 - 1890

78
[ 22236-10-8 ]
[ 412269-57-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1886 - 1890

79
[ 22236-10-8 ]
[ 412269-58-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1886 - 1890

80
[ 22236-10-8 ]
[ 414866-05-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1886 - 1890

81
[ 22236-10-8 ]
[ 1173435-64-7 ]

Reference： [1]Organic Process Research and Development,2012,vol. 16,p. 156 - 159

82
[ 22236-10-8 ]
[ 1247745-21-6 ]

Yield	Reaction Conditions	Operation in experiment
53.4%	With N-chloro-succinimide; In acetonitrile; for 3h;Reflux;	Preparation 97: 2-Chloro-<strong>[22236-10-8]4-(difluoromethoxy)aniline</strong>; [00267] N-Chlorosuccinimide (0.84g, 6.28mmol) was added to a solution of 4- (difluoromethoxy)aniline (1 g, 6.28mmol) in acetonitrile (10ml). The reaction was refluxed for 3 hours and then cooled to room temperature. The solvent was removed in vacuum and the residue purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to afford the title compound as a dark pink liquid (0.65g, 53.4%). 1 H NMR (500 MHz, CDCI3): delta 4.02 (s, 2H), 6.24 (t, J= 74Hz, 1 H), 6.72 (d, J=8.7, 1 H), 6.89 (dd, J= 2.7Hz, 8.8Hz, 1 H), 7.1 1 (d, J= 2.6Hz, 1 H).
53.4%	With N-chloro-succinimide; In acetonitrile; for 3h;Reflux;	Preparation 97 2-Chloro-<strong>[22236-10-8]4-(difluoromethoxy)aniline</strong> N-Chlorosuccinimide (0.84 g, 6.28 mmol) was added to a solution of <strong>[22236-10-8]4-(difluoromethoxy)aniline</strong> (1 g, 6.28 mmol) in acetonitrile (10 ml). The reaction was refluxed for 3 hours and then cooled to room temperature. The solvent was removed in vacuum and the residue purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to afford the title compound as a dark pink liquid (0.65 g, 53.4%). 1H NMR (500 MHz, CDCl3): delta 4.02 (s, 2H), 6.24 (t, J=74 Hz, 1H), 6.72 (d, J=8.7, 1H), 6.89 (dd, J=2.7 Hz, 8.8 Hz, 1H), 7.11 (d, J=2.6 Hz, 1H).

Reference： [1]Patent: WO2012/123745,2012,A1 .Location in patent: Page/Page column 95
[2]Patent: US2013/345181,2013,A1 .Location in patent: Paragraph 0706

83
[ 22236-10-8 ]
[ 68-11-1 ]
[ 108-93-0 ]
[ 1402049-38-0 ]

Yield	Reaction Conditions	Operation in experiment
97%		General procedure: To a solution of alcohol (1.1 mmol) in a mixture of solvents EtOAc: DMSO (4 ml: 2 ml), was added T3P (2.5 mmol, 50% solution in ethyl acetate) at 0 C, and the resulting mixture was stirred at room temperature for 1-2 h under nitrogen atmosphere. The reaction was monitored by TLC, amine (1.0 mmol) and thioglycolic acid (1.0 mmol) were added once and stirred further for 1-3 h at room temperature. After completion of the reaction, the mixture was diluted with water (20 ml) and neutralized by adding 10% NaHCO3 solution. The product was extracted with ethyl acetate (10 ml 2) and the combined organic layers were washed with water followed by brine solution. The organic phase was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford a crude product which was purified by column chromatography using hexane: ethyl acetate mixture (8:2) as an eluent.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 5619 - 5623
[2]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3616 - 3620

84
C₂₁H₂₈ClIN₄O₄ [ No CAS ]
[ 22236-10-8 ]
[ 853070-14-1 ]

Yield	Reaction Conditions	Operation in experiment
		5.1 Methyl 4-([2-{(3R)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-(2-chlorobenzyl)-4-iodo-1H-imidazol-5-yl]carbonyl}amino)benzoate (5t) To a solution of 4 (56.08 g, 100 mmol) in CH2Cl2 (1.3 L) were added (COCl)2 (16.5 g, 130 mmol) and DMF (5 ml) at 0 C. The reaction mixture was stirred at room temperature for 4 h and concentrated under reduced pressure. The residue was azeotroped with toluene and redissolved in toluene (1.3 L). To this solution was added DIPEA (38.8 g, 300 mmol) followed by methyl 4-aminobenzoate (19.7 g, 130 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then quenched with saturated NH4Cl aqueous solution, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography to give 5t (54.63 g, yield 79%) as a white amorphous. 1H NMR (300 MHz, CDCl3) delta 8.30 (br s, 1H), 8.01 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.39-7.36 (m, 1H), 7.22-7.13 (m, 2H), 6.82-6.78 (m, 1H), 5.58 (d, J = 16.2 Hz, 1H), 5.50 (d, J = 16.2 Hz, 1H), 4.93-4.90 (m, 1H), 3.90 (s, 3H), 3.77 (br s, 1H), 3.31 (dd, J = 3.3, 12.0 Hz, 1H), 2.93-2.84 (m, 3H), 1.78-1.54 (m, 4H), 1.49 (s, 9H); HRMS (ESI) [M+H]+ calcd for C29H34O5N5ClI 694.1288, found 694.1272; IR (ATR): 1714, 1675, 1591, 1513, 1434, 1405, 1311, 1280, 1243, 1222, 1172, 1110, 1060 cm-1; Anal. calcd for C29H33O5N5ClI: C, 50.19; H, 4.79; N, 10.09, found: C, 50.52; H, 4.95; N, 9.92.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 5864 - 5883

85
[ 128140-82-9 ]
[ 22236-10-8 ]

Reference： [1]Journal of Organic Chemistry,2012,vol. 77,p. 7471 - 7478

86
[ 22236-10-8 ]
[ 1415757-66-2 ]

Reference： [1]Patent: US2012/316165,2012,A1
[2]Patent: WO2012/168265,2012,A1

87
[ 22236-10-8 ]
[ 1415758-94-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium azide; sodium nitrite; In water; at 0 - 5℃; for 1h;	In a 20 mL four-necked flask, <strong>[22236-10-8]4-(difluoromethoxy)aniline</strong> (0.5 g, 3.14 mmol) and hydrochloric acid (37% in water, 0.54 ml, 6.6 mmol) were combined with water (5 ml) to give a light yellow solution. Cooled to 0 C. using an ice-bath, sodium nitrite (217 mg, 3.14 mmol) was dissolved in water (1 ml) and added carefully ensuring that the temperature did not increase above 5 C. Sodium azide (204 mg, 3.14 mmol) was dissolved in water (1 ml) and added drop-wise to the orange solution, keeping the temperature below 5 C. The reaction mixture was cooled at 0-5 C. for 1 hour and an orange emulsion was observed. The layers were separated using TBME and the organic layer was washed with brine, dried over sodium sulphate and filtered. The filtrate was concentrated under vacuum to yield 1-azido-4-(difluoromethoxy)benzene as an orange liquid.
	With hydrogenchloride; sodium azide; sodium nitrite; In water; at 0 - 5℃; for 1h;	In a 20 mL four-necked flask, <strong>[22236-10-8]4-(difluoromethoxy)aniline</strong> (0.5 g, 3.14 mmol) and hydrochloric acid (37% in water, 0.54 ml, 6.6 mmol) were combined with water (5 ml) to give a light yellow solution. Cooled to 0 C using an ice-bath, sodium nitrite (217 mg, 3.14 mmol) was dissolved in water (1 ml) and added carefully ensuring that the temperature did not increase above 5 C. Sodium azide (204 mg, 3.14 mmol) was dissolved in water (1 ml) and added drop-wise to the orange solution, keeping the temperature below 5 C. The reaction mixture was cooled at 0-5 C for 1 hour and an orange emulsion was observed. The layers were separated using TBME and the organic layer was washed with brine, dried over sodium sulphate and filtered. The filtrate was concentrated under vacuum to yield l-azido-4-(difluoromethoxy)benzene as an orange liquid. In a 50 ml round-bottomed flask, l-azido-4-(difluoromethoxy)benzene (540 mg, 2.92 mmol) was combined with THF (10 ml) and dimethylsulfoxide (0.16 ml) to give an orange solution. Then ethyl propiolate (858 mg, 0.89 ml, 8.75 mmol), copper (I) iodide (556 mg, 2.92 mmol) and 2,6- lutidine (625 mg, 0.68 ml, 5.83 mmol) were added and the reaction mixture was stirred for 2 hours at room temperature. Water and ethyl acetate were added and the layers were separated. The organic layer was washed with 1 N hydrochloric acid and brine, dried over MgS04 and filtered. The filtrate was concentrated under vacuum to yield a brown solid, which was adsorbed on silica gel and purified by flash chromatography (20 g Silica gel, 20% ethyl acetate in heptane) yielding 698 mg (84%) of a light yellow solid. MS (ISP): 284.2 ([M+H]+).

Reference： [1]Patent: US2012/316165,2012,A1 .Location in patent: Page/Page column 44; 45
[2]Patent: WO2012/168265,2012,A1 .Location in patent: Page/Page column 87; 88

88
[ 22236-10-8 ]
[ 1096995-13-9 ]

Reference： [1]Patent: US2012/316165,2012,A1
[2]Patent: WO2012/168265,2012,A1

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
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Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
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P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
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P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
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P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
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P362	Take off contaminated clothing and wash before reuse.
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P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
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P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
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P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
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P411
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P402 + P404	Store in a dry place. Store in a closed container.
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Disposal
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P501	Dispose of contents/container to ...
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Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
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H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
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H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
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H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
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H260	In contact with water releases flammable gases which may ignite spontaneously
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H270	May cause or intensify fire; oxidizer
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H281	Contains refrigerated gas; may cause cryogenic burns or injury
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Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
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H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
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H335	May cause respiratory irritation
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H341	Suspected of causing genetic defects
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H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
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H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere