[ CAS No. 74587-12-5 ] {[proInfo.proName]}

Name: 74587-12-5|3-Iodo-4-methoxyaniline|98%
Brand: Ambeed
SKU: A293237
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Quality Control of [ 74587-12-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 74587-12-5 ]

SDS Specification

Alternatived Products of [ 74587-12-5 ]

Product Details of [ 74587-12-5 ]

CAS No. :	74587-12-5	MDL No. :	MFCD06656566
Formula :	C₇H₈INO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UHPNLGCUIGEZRB-UHFFFAOYSA-N
M.W :	249.05	Pubchem ID :	22054596
Synonyms :

Calculated chemistry of [ 74587-12-5 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	50.06
TPSA :	35.25 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) :	-6.5 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.83
Log Po/w (XLOGP3) :	1.86
Log Po/w (WLOGP) :	1.89
Log Po/w (MLOGP) :	2.06
Log Po/w (SILICOS-IT) :	2.07
Consensus Log Po/w :	1.94

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.93
Solubility :	0.29 mg/ml ; 0.00116 mol/l
Class :	Soluble
Log S (Ali) :	-2.22
Solubility :	1.5 mg/ml ; 0.006 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.12
Solubility :	0.188 mg/ml ; 0.000757 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.82

Safety of [ 74587-12-5 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 74587-12-5 ]

* 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 [ 74587-12-5 ]
Downstream synthetic route of [ 74587-12-5 ]

[ 74587-12-5 ] Synthesis Path-Upstream 1~5

1
[ 5399-03-1 ]
[ 74587-12-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With iron; ammonium chloride In ethanol; water at 85℃; for 1 h;	Into a 250-mL round-bottom flask was placed 2-iodo-l -methoxy-4-nitrobenzene (6 g, 21 ,50 mmol, 1.00 equiv), Fe (3.61 g, 3.00 equiv), NH₄C1 (3.42 g, 63.94 nimol, 3 ,00 equiv), ethanol (50 mL), and water (10 mL). The resulting solution was stirred for 1 h at 85 °C. The solid were filtered out, and the resulting mixture was concentrated under vacuum. This resulted in 5 ,35 g (100percent) of the title compound as a brown solid. LC-MS: (ES, m/z) RT = 0.847 min, LCMS 53 : m/z = 250 [M+1].
93%	With ethanol; iron; ammonium chloride In water for 5 h; Reflux	NH₄C1 (38.3 g, 716.8 mmol) dissolved in H₂0 (-100 ml) was added to a solution of compound 49 (50g, 179.2 mmol) in ethanol (600 mmol). Iron powder (40.15 g, 716.8) was added to this mixture, and the mixture was refluxed for 5 h. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water and brine, dried over Na₂S0₄, filtered and concentrated under reduced pressure to give the title compound 50. (42 g, 93percent) . ^XHNMR (400 MHz , DMSO-d δ: 7.02 (d, J = 2.4 Hz, 1H) , 6.72 (d, J= 8.8 Hz, 1H) , 6.55 (dd, J = 2.8, 8.8 Hz, 1H) , 4.81 (brs, 2H) , 3.66 (s, 3H) .
83%	With iron; ammonium chloride In methanol; water for 3 h;	To 2-iodo-1-methoxy-4-nitrobenzene (485 mg, 1.74 mmol) suspended in methanol (6 mL) a solution of NH₄CI (465 mg, 8.69 mmol) in water (4.9 mL) and powdered Fe (290 mg, 5.192 mmol) were added and the mixture was heated to reflux for 3 h. The precipitate formed was filtered off and the filtrate was evaporated until the methanol was eliminated. After diluting with water and alkalinization with sodium carbonate the mixture was extracted with EtOAc (4 x 20 mL). The combined organic extracts were washed with brine (3 x 10 mL), water (10 mL), dried over sodium sulfate and the solvent was removed under vacuum. The crude dark oil was purified by flash chromatography on silica gel (hexane/EtOAc 1/1) to afford 400 mg of solid that was crystallized from n-pentane and diethyl ether to yield the title compound (363 mg, 83percent). ¹H NMR (400 MHz, DMSO-cie) δ ppm 3.66 (s, 3 H) 4.79 (s, 2 H) 6.56 (dd, J=8.61 , 2.62 Hz, 1 H) 6.73 (d, J=8.67 Hz, 1 H) 7.02 (d, J=2.69 Hz, 1 H)

71%

With dithionite In methanol; water for 0.0833333 h;

Intermediate step 4 toward Example 1: 3-iodo-4-methoxy-aniline [00230] Dithionite (3.85 g, 22.15 mmol) as a slurry in water (20 mL) was added to mixture of 2-iodo-l-methoxy-4-nitro-benzene (1.03 g, 3.69 mmol) in MeOH (50 mL). The mixture was stirred for 5 m and then diluted with a saturated aq solution of NaHCC>3 (100 mL). The mixture was concentrated to half its volume under reduced pressure. The aq phase was extracted with EtOAc (3X50 mL), and the combined organic phases were washed with brine, dried over MgSC^, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography on silica gel, eluting with mixtures of hexanes and EtOAc to provide the title compound as a solid (0.652 g, 71percent). 1H NMR (300 MHz, CDC1₃) δ 7.16 (dd, J = 0.8, 2.0 Hz, 1H), 6.68-6.64 (m, 2H), 3.79 (s, 3H), 3.42 (s, 2H).

Reference： [1] Patent: WO2018/118842, 2018, A1, . Location in patent: Paragraph 0421-0424
[2] Patent: WO2016/199943, 2016, A1, . Location in patent: Paragraph 0303
[3] Patent: WO2013/14039, 2013, A1, . Location in patent: Page/Page column 45-46
[4] Patent: WO2014/152029, 2014, A2, . Location in patent: Paragraph 00230
[5] Journal of the American Chemical Society, 1941, vol. 63, p. 2482,2484
[6] Chemische Berichte, 1896, vol. 29, p. 1000,2595[7] Bulletin de la Societe Chimique de France, 1896, vol. <3> 15, p. 641
[8] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1980, p. 832 - 834

2
[ 529-28-2 ]
[ 74587-12-5 ]

Reference： [1] Journal of the American Chemical Society, 2013, vol. 135, # 13, p. 5000 - 5003
[2] Chemische Berichte, 1896, vol. 29, p. 1000,2595[3] Bulletin de la Societe Chimique de France, 1896, vol. <3> 15, p. 641

3
[ 104-94-9 ]
[ 74587-12-5 ]

Reference： [1] Journal of the American Chemical Society, 1930, vol. 52, p. 1570

4
[ 100-17-4 ]
[ 74587-12-5 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1980, p. 832 - 834

5
[ 90-04-0 ]
[ 74587-12-5 ]

Reference： [1] Chemische Berichte, 1896, vol. 29, p. 1000,2595[2] Bulletin de la Societe Chimique de France, 1896, vol. <3> 15, p. 641

[ 74587-12-5 ] Synthesis Path-Downstream 1~88

1
[ 512-56-1 ]
[ 74587-12-5 ]
[ 103796-37-8 ]

Reference： [1]Journal of the Chemical Society,1959,p. 1808,1809

2
[ 5399-03-1 ]
[ 74587-12-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With iron; ammonium chloride; In ethanol; water; at 85℃; for 1h;	Into a 250-mL round-bottom flask was placed 2-iodo-l -methoxy-4-nitrobenzene (6 g, 21 ,50 mmol, 1.00 equiv), Fe (3.61 g, 3.00 equiv), NH4C1 (3.42 g, 63.94 nimol, 3 ,00 equiv), ethanol (50 mL), and water (10 mL). The resulting solution was stirred for 1 h at 85 C. The solid were filtered out, and the resulting mixture was concentrated under vacuum. This resulted in 5 ,35 g (100%) of the title compound as a brown solid. LC-MS: (ES, m/z) RT = 0.847 min, LCMS 53 : m/z = 250 [M+1].
95%	With iron; ammonium chloride; In ethanol; water; at 70 - 80℃; for 1h;Inert atmosphere;	Fe (490 g, 8.78 mol, 3.5 eq.) and Xi i iC'i (684 g, 12.8 mol, 5.1 eq.) were charged into EtOH (10 L, 14 vol.) and water (4.2 L, 6 vol.) in a flask (20 L) under a ? atmosphere. The mixture was heated to 70-80 C. Nitroarene 1 (700 g, 2.51 mol, 1 ,0 eq.) was added into the mixture in portions (gas was released). The mixture was stirred at 70-80 C for 1 h. The reaction was monitored by HPLC until 1 was consumed completely. The mixture was cooled to room temperature and filtered with the aid of diatomite (210 g, 0.3 w/w). The filter cake was washed with EtOH (300 mL x4). The filtrates were combined and the majority of EtOH was removed by distillation. EtOAc (7.0 L, 10.0 vol.) and water (3,5 L, 5.0 vol.) were added to the residue. The mixture was stirred for 30 min and the organic layer was separated. The aqueous layer was extracted with EtOAc (7.0 L, 10,0 vol .) and the organic layer was separated. The organic layers were combined and dried over anhydrous Na2S04 (250 g). The mixture was filtered and the filter cake was washed with EtOAc (500 mL). The filter solutions were combined and concentrated to 56 dryness, 609 g of aniline 2 as a dark brown solid was afforded with 98.1A% HPLC purity in 95% isolated yield.
93%	With ethanol; iron; ammonium chloride; In water; for 5h;Reflux;	NH4C1 (38.3 g, 716.8 mmol) dissolved in H20 (-100 ml) was added to a solution of compound 49 (50g, 179.2 mmol) in ethanol (600 mmol). Iron powder (40.15 g, 716.8) was added to this mixture, and the mixture was refluxed for 5 h. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with water and brine, dried over Na2S04, filtered and concentrated under reduced pressure to give the title compound 50. (42 g, 93%) . XHNMR (400 MHz , DMSO-d delta: 7.02 (d, J = 2.4 Hz, 1H) , 6.72 (d, J= 8.8 Hz, 1H) , 6.55 (dd, J = 2.8, 8.8 Hz, 1H) , 4.81 (brs, 2H) , 3.66 (s, 3H) .

83%	With iron; ammonium chloride; In methanol; water; for 3h;	To 2-iodo-1-methoxy-4-nitrobenzene (485 mg, 1.74 mmol) suspended in methanol (6 mL) a solution of NH4CI (465 mg, 8.69 mmol) in water (4.9 mL) and powdered Fe (290 mg, 5.192 mmol) were added and the mixture was heated to reflux for 3 h. The precipitate formed was filtered off and the filtrate was evaporated until the methanol was eliminated. After diluting with water and alkalinization with sodium carbonate the mixture was extracted with EtOAc (4 x 20 mL). The combined organic extracts were washed with brine (3 x 10 mL), water (10 mL), dried over sodium sulfate and the solvent was removed under vacuum. The crude dark oil was purified by flash chromatography on silica gel (hexane/EtOAc 1/1) to afford 400 mg of solid that was crystallized from n-pentane and diethyl ether to yield the title compound (363 mg, 83%). 1H NMR (400 MHz, DMSO-cie) delta ppm 3.66 (s, 3 H) 4.79 (s, 2 H) 6.56 (dd, J=8.61 , 2.62 Hz, 1 H) 6.73 (d, J=8.67 Hz, 1 H) 7.02 (d, J=2.69 Hz, 1 H)
71%	With dithionite; In methanol; water; for 0.0833333h;	Intermediate step 4 toward Example 1: 3-iodo-4-methoxy-aniline [00230] Dithionite (3.85 g, 22.15 mmol) as a slurry in water (20 mL) was added to mixture of 2-iodo-l-methoxy-4-nitro-benzene (1.03 g, 3.69 mmol) in MeOH (50 mL). The mixture was stirred for 5 m and then diluted with a saturated aq solution of NaHCC>3 (100 mL). The mixture was concentrated to half its volume under reduced pressure. The aq phase was extracted with EtOAc (3X50 mL), and the combined organic phases were washed with brine, dried over MgSC^, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography on silica gel, eluting with mixtures of hexanes and EtOAc to provide the title compound as a solid (0.652 g, 71%). 1H NMR (300 MHz, CDC13) delta 7.16 (dd, J = 0.8, 2.0 Hz, 1H), 6.68-6.64 (m, 2H), 3.79 (s, 3H), 3.42 (s, 2H).

Reference： [1]Patent: WO2018/118842,2018,A1 .Location in patent: Paragraph 0421-0424
[2]Patent: WO2019/79540,2019,A1 .Location in patent: Paragraph 01611
[3]Patent: WO2016/199943,2016,A1 .Location in patent: Paragraph 0303
[4]Patent: WO2013/14039,2013,A1 .Location in patent: Page/Page column 45-46
[5]Patent: WO2014/152029,2014,A2 .Location in patent: Paragraph 00230
[6]Journal of the American Chemical Society,1941,vol. 63,p. 2482,2484
[7]Chemische Berichte,1896,vol. 29,p. 1000,2595
Bulletin de la Societe Chimique de France,1896,vol. <3> 15,p. 641
[8]Journal of the Chemical Society. Perkin transactions II,1980,p. 832 - 834

3
[ 74587-12-5 ]
[ 28896-47-1 ]

Reference： [1]Chemische Berichte,1896,vol. 29,p. 1000,2595
Bulletin de la Societe Chimique de France,1896,vol. <3> 15,p. 641

4
[ 74587-12-5 ]
2-iodo-4-nitroso-anisole [ No CAS ]

Reference： [1]Journal of the Chemical Society,1940,p. 810

5
[ 74587-12-5 ]
[ 98-88-4 ]
benzoic acid-(3-iodo-4-methoxy-anilide) [ No CAS ]

Reference： [1]Journal of the Chemical Society,1927,p. 2869

6
[ 104-94-9 ]
[ 74587-12-5 ]

Reference： [1]Journal of the American Chemical Society,1930,vol. 52,p. 1570

7
[ 74587-12-5 ]
[ 122-51-0 ]
[ 261173-07-3 ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2000,vol. 43,p. 29 - 45

11
[ 64-17-5 ]
[ 74587-12-5 ]
sodium amalgam [ No CAS ]
[ 104-94-9 ]

Reference： [1]Chemische Berichte,1896,vol. 29,p. 1000,2595
Bulletin de la Societe Chimique de France,1896,vol. <3> 15,p. 641

12
C₁₀H₁₇BN₂O₃ [ No CAS ]
[ 74587-12-5 ]
[ 846023-60-7 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7868 - 7876

13
[ 17722-32-6 ]
[ 74587-12-5 ]
[ 122-51-0 ]
[ 929716-52-9 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1358 - 1361

14
[ 846023-24-3 ]
[ 74587-12-5 ]
[ 122-51-0 ]
[ 846023-38-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	In isopropyl alcohol;Heating / reflux;	EXAMPLE 20 2-Cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-iodo-4-methoxyphenyl)amino]prop-2-enamide To a suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (5.00 g, 19.30 mol) in 400 mL of iso-propanol, under N2, was added 3-iodo-p-anisidine (5.80 g, 23.16 mmol). This mixture was heated to reflux to give a clear yellow solution. To this solution, triethylorthoformate (8.60 mL, 52.11 mmol) was added dropwise and the reaction mixture was heated at reflux overnight. An additional 10 mL of triethylorthoformate was added and the mixture was heated at reflux overnight. The mixture was allowed to cool to room temperature and the white solid was collected by filtration, washed with isopropanol, and dried overnight at ~40 C. under reduced pressure. Purification by suspension in hot ethyl acetate followed by addition of cold hexanes gave 8.50 g (85%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-iodo-4-methoxyphenyl)amino]prop-2-enamide as a yellow solid, mp 289-290 C.; MS (ES) m/z 516.7 (M-H)- Analysis for C18H14Cl2IN3O3; Calcd: C, 41.73; H, 2.72; N, 8.11. Found: C, 40.66; H, 2.94; N, 7.90.
85%	In isopropyl alcohol;Heating / reflux;	Reference Example 2; 2-Cyano-N-(2,4-dichloro-5-methoxyphenyl )-3-r(3-iodo-4-methoxyphenv?amino1- prop-2-enamide; To a suspension of <strong>[846023-24-3]2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide</strong> (5.00 g, 19.30 mol) in 400 ml_ of /so-propanol, under N2, is added 3-iodo-p-anisidine (5.80 g, 23.16 mmol). This mixture is heated to reflux to give a clear yellow solution. To this solution, triethylorthoformate (8.60 ml_, 52.11 mmol) is added dropwise and the reaction mixture is heated at reflux overnight. An additional 10 ml_ of triethylorthoformate is added and the mixture is heated at reflux overnight. The mixture is allowed to cool to room temperature and the white solid is collected by filtration, washing with /so-propanol, and dried overnight at -4O0C under reduced pressure. Purification by suspension in hot ethyl acetate followed by addition of cold hexanes gives 8.50 g (85%) of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-iodo- 4-methoxyphenyl)amino]prop-2-enamide as a yellow solid, mp 289-290 0C; MS (ES) m/z 516.7 (M-H)-. Analysis for C18H14CI2IN3O3:Calcd: C, 41.73; H, 2.72; N, 8.11. Found: C, 40.88; H, 2.64; N, 7.90.

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 7868 - 7876
[2]Patent: US2005/43537,2005,A1 .Location in patent: Page/Page column 9
[3]Patent: WO2006/47262,2006,A1 .Location in patent: Page/Page column 14
[4]Letters in drug design and discovery,2011,vol. 8,p. 9 - 13

15
[ 74587-12-5 ]
[ 168267-02-5 ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2000,vol. 43,p. 29 - 45

16
[ 74587-12-5 ]
(+/-)-GR 203040 [ No CAS ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2000,vol. 43,p. 29 - 45

17
[ 74587-12-5 ]
[ 261173-16-4 ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2000,vol. 43,p. 29 - 45

18
[ 100-17-4 ]
[ 74587-12-5 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions II,1980,p. 832 - 834

19
[ 529-28-2 ]
[ 74587-12-5 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 5000 - 5003
[2]Chemische Berichte,1896,vol. 29,p. 1000,2595
Bulletin de la Societe Chimique de France,1896,vol. <3> 15,p. 641

20
[ 74587-12-5 ]
glyoxal-bis-[<i>N</i>-(3-iodo-4-methoxy-phenyl)-oxime ] [ No CAS ]

Reference： [1]Journal of the Chemical Society,1940,p. 810

21
[ 90-04-0 ]
[ 74587-12-5 ]

Reference： [1]Chemische Berichte,1896,vol. 29,p. 1000,2595
Bulletin de la Societe Chimique de France,1896,vol. <3> 15,p. 641

22
[ 74587-12-5 ]
[ 507242-34-4 ]

Yield	Reaction Conditions	Operation in experiment
		a 4-Chloro-7-iodo-6-methoxy-2-methyl-quinoline The title compound was produced in accordance with the general method of example 59a from <strong>[74587-12-5]3-iodo-4-methoxyaniline</strong> (J. Chem. Soc. Perkin 2 1980, 832) and separated from the isomeric 4-chloro-5-iodo-6-methoxy-2-methyl-quinoline by flash chromatography (SiO2, hexane/ethyl acetate gradient). White solid, ISP-MS: m/e=334.1 ([M+H]+).

Reference： [1]Patent: US2003/158179,2003,A1

23
[ 876343-11-2 ]
[ 74587-12-5 ]
[ 876341-31-0 ]

Yield	Reaction Conditions	Operation in experiment
	In butan-1-ol; at 95℃; for 15h;	EXAMPLE 254: tert-Butyl 4-[4-(3-iodo-4-methoxyphenylamino)-7fl-pyrrolo [2,3-d pyrimidin-6-yl] -3,6-dihydro-2JH-py ridine-1 -carboxylate; .[731] 3-Iodo-4-methoxyaniline (0.670g, 2.0mmol) was added to a solution of /ert-butyl4-(chloro-7//-pyrrolo[2,3-</jpyriniidin-6-yl)-3,6-diliydro-27:f-pyridine-l-carboxylate(0.598g, 2.4mmol) in n-butanol (lOmL). The mixture was heated to 95C for 15h. Thesolvent was removed and the residue was purified by silica gel chromatography (5% MeOHin dichloromethane) to afford the title compound. 'H-NMR (DMSO-d6,400 MHz): 5 = 1.43(s, 9 H), 2.46 (m, 2 H), 3.56 (m, 2 H), 3.80 (s, 3 H), 4.03 (m, 2 H), 6.38 (s, 1 H), 6.72 (s, 1 H),7.00 (d, .7= 9.2 Hz, 1 H), 7.85 (dd, ,7=2.8, 8.8 Hz, 1 H), 8.34 (s, 1 H), 9.27 (s, 1 H), 11.93 (s,1 H). MS (ES+): m/z 547.91 [MH+], HPLC: fe = 3.39 min (ZQ2000, polar_5min).

Reference： [1]Patent: WO2006/17443,2006,A2 .Location in patent: Page/Page column 162

24
[ 2033-24-1 ]
[ 74587-12-5 ]
[ 149-73-5 ]
[ 1300031-69-9 ]

Yield	Reaction Conditions	Operation in experiment
85.9%		Intermediate 12: 5-([3-iodo-4-(methoxy)phenyl]amino}methylidene)-2,2-dimethyl- 1 ,3-dioxane-4,6-dione; A mixture of 2,2-dimethyl-1 ,3-dioxane-4,6-dione (203g, 1.4mol) and trimethoxymethane (1 -51) was heated to reflux for 1 h, then the <strong>[74587-12-5]3-iodo-4-methoxy-aniline</strong> (349.2g, 1 .402mol) was added portionwise. The reaction mixture was stirred at reflux for 1 h, then cooled to room temperature. The resulting precipitate was filtered off, washed with diisopropyl ether and dried to give the title compound as a beige powder (485g, 85.9%)1H NMR (300 MHz, DMSO-d6, ppm) delta : 1 1.2 (d, J=14.6Hz, 1 H), 8.50-8.39 (m,1 H), 8.05 (d, J=2.7Hz, 1 H), 7.60 (dd, J=8.9, 2.7Hz, 1 H), 7.05 (d, J=8.9Hz, 1 H), 3.84 (s, 3H), 1.67 (s,6H).
85.9%		Intermediate 12: 5-([3-iodo-4-(methoxy)phenyl]amino}methylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione A mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (203 g, 1.4 mol) and trimethoxymethane (1.51) was heated to reflux for 1 h, then the <strong>[74587-12-5]3-iodo-4-methoxy-aniline</strong> (349.2 g, 1.402mol) was added portionwise. The reaction mixture was stirred at reflux for 1 h, then cooled to room temperature. The resulting precipitate was filtered off, washed with diisopropyl ether and dried to give the title compound as a beige powder (485 g, 85.9%) 1H NMR (300 MHz, DMSO-d6, ppm) delta: 11.2 (d, J=14.6 Hz, 1H), 8.50-8.39 (m, 1H), 8.05 (d, J=2.7 Hz, 1H), 7.60 (dd, J=8.9, 2.7 Hz, 1H), 7.05 (d, J=8.9 Hz, 1H), 3.84 (s, 3H), 1.67 (s, 6H).
80%	In ethanol; for 2h;Reflux;	To a solution of compound 50 (22.0 g, 883 mmol) in ethanol (120 ml) were added trimethyl orthoformate (10.6 ml, 97.1 mmol) and Meldrums acid (15.2 g, 106 mmol). The resulting mixture was heated to reflux for 2 h, cooled to room temperature and filtered. The filtrate was washed with ethanol and dried under vacuum to give the title compound 63 (29.0 g, 80%) . 1HNMR (400 MHz, DMSO-dc) delta : 11.15 (d, J = 14.8 Hz, IH) , 8.42 (d, J = 14.4 Hz, IH) , 8.01 (d, J = 2.8 Hz, IH) , 7.56 (dd, J = 6.0, 8.8 Hz, IH) , 7.01 (d, J = 9.2 Hz, IH) , 3.81 (s, 3H) , 1.64 (s, 6H) .

Reference： [1]Patent: WO2011/54846,2011,A1 .Location in patent: Page/Page column 45
[2]Patent: US2012/232074,2012,A1 .Location in patent: Page/Page column 19-20
[3]Patent: WO2016/199943,2016,A1 .Location in patent: Paragraph 0329

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[2]Patent: WO2011/54846,2011,A1

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[2]Patent: WO2016/199943,2016,A1
[3]Patent: WO2011/54846,2011,A1

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[2]Patent: WO2015/49629,2015,A1
[3]Patent: WO2011/54846,2011,A1

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[2]Patent: WO2015/49629,2015,A1
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[2]Patent: WO2015/49629,2015,A1
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[2]Patent: WO2015/49629,2015,A1
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[2]Patent: WO2015/49629,2015,A1
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[2]Patent: WO2015/49629,2015,A1
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C₂₈H₃₁N₅O₄ [ No CAS ]

Reference： [1]Patent: US2012/232074,2012,A1

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C₂₅H₂₇N₅O₄ [ No CAS ]

Reference： [1]Patent: US2012/232074,2012,A1

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[ 1394130-71-2 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 4560 - 4563

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[ 1394130-77-8 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 4560 - 4563

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[ 1421581-08-9 ]

Reference： [1]Patent: WO2013/14039,2013,A1

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[ 1421581-05-6 ]

Reference： [1]Patent: WO2013/14039,2013,A1

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[ 74587-12-5 ]
[ 1421581-06-7 ]

Yield	Reaction Conditions	Operation in experiment
79%	With trifluoroacetic acid; tetramethylammonium triacetoxyborohydride; In dichloromethane; for 0.5h;	To a solution of <strong>[74587-12-5]3-iodo-4-methoxyaniline</strong> (180 mg, 0723 mmol) in DCM (5 mL) 1 -methyl-4-piperidone (0.116 mL, 106 mg, 0.940 mmol), TFA (0.290 mL, 429 mg, 3.760 mmol) and tetramethylammonium triacetoxyborohydride (285 mg, 1.084 mmol) were added in sequence. The reaction is completed in 30 min. The reaction mixture was diluted with DCM, washed with saturated solution of sodium hydrogen carbonate (3 x 5 mL), brine (3 x 5 mL), dried over sodium sulfate and the solvent was removed under vacuum. The solid crude so obtained was purified by flash chromatography (EtOAc/TEA 99/1) to afford a beige solid that was crystallized from diethylether to afford the title compound as a whitish solid (197 mg, 79%).1H NMR (400 MHz, DMSO-de) delta ppm 1.32 (qd, J=11.50, 3.60 Hz, 2 H) 1.82 (d, J=11.96 Hz, 2 H) 1.99 (t, J=11.17 Hz, 2 H) 2.15 (s, 3 H) 2.70 (d, J=11.96 Hz, 2 H) 2.99 - 3.13 (m, 1 H) 3.67 (s, 3 H) 5.14 (d, J=8.54 Hz, 1 H) 6.57 (dd, J=8.79, 2.69 Hz, 1 H) 6.77 (d, J=8.79 Hz, 1 H) 7.01 (d, J=2.81 Hz, 1 H).HRMS m/z calcd for [M + H] 347.0615; found 347.0627.

Reference： [1]Patent: WO2013/14039,2013,A1 .Location in patent: Page/Page column 46

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C₂₇H₃₈N₂O₆ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 16010 - 16013

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C₂₃H₃₆N₂O₆ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 16010 - 16013

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[ 74587-12-5 ]
tert-butyl (6-methoxy-[1,1'-biphenyl]-3-yl)carbamate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 16010 - 16013
[2]Angewandte Chemie - International Edition,2016,vol. 55,p. 2243 - 2247

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N-(tert-butoxycarbonyl)-4-methoxy-3-vinylaniline [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 16010 - 16013

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tert-butyl (4,4-dimethoxy-3-phenylcyclohexa-2,5-dien-1-ylidene)carbamate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 16010 - 16013

61
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tert-butyl (4,4-dimethoxy-3-vinylcyclohexa-2,5-dien-1-ylidene)carbamate [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 16010 - 16013

62
[ 24424-99-5 ]
[ 74587-12-5 ]
N-(tert-butoxycarbonyl)-3-iodo-4-methoxyaniline [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 16010 - 16013
[2]Angewandte Chemie - International Edition,2016,vol. 55,p. 2243 - 2247

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4-[(1R)-1-[7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-2-oxo-3a,4,5,9b-tetrahydrooxazolo[5,4-c]quinolin-1-yl]ethyl]benzonitrile [ No CAS ]