[ CAS No. 51388-20-6 ] {[proInfo.proName]}

Name: 51388-20-6|4-(Benzyloxy)aniline hydrochloride|99%
Brand: Ambeed
SKU: A118850
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Quality Control of [ 51388-20-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 51388-20-6 ]

CAS No. :	51388-20-6	MDL No. :	MFCD00012995
Formula :	C₁₃H₁₄ClNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KQBDLOVXZHOAJI-UHFFFAOYSA-N
M.W :	235.71	Pubchem ID :	2723831
Synonyms :

Calculated chemistry of [ 51388-20-6 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.08
Num. rotatable bonds :	3
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	67.68
TPSA :	35.25 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-4.96 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	3.91
Log Po/w (WLOGP) :	-0.18
Log Po/w (MLOGP) :	2.95
Log Po/w (SILICOS-IT) :	2.68
Consensus Log Po/w :	1.87

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-4.12
Solubility :	0.0178 mg/ml ; 0.0000756 mol/l
Class :	Moderately soluble
Log S (Ali) :	-4.35
Solubility :	0.0106 mg/ml ; 0.0000448 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-4.71
Solubility :	0.00465 mg/ml ; 0.0000197 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	1.0 alert
Brenk :	1.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.5

Safety of [ 51388-20-6 ]

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

Application In Synthesis of [ 51388-20-6 ]

* 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 [ 51388-20-6 ]
Downstream synthetic route of [ 51388-20-6 ]

[ 51388-20-6 ] Synthesis Path-Upstream 1~9

1
[ 100-02-7 ]
[ 100-39-0 ]
[ 51388-20-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate In ethanol	(11-1) Synthesis of 4-Benzyloxyaniline Hydrochloride: In 40 ml of ethanol was dissolved 4.17 g of p-nitrophenol and after adding 2.5 g of potassium carbonate and 3.9 ml of benzyl bromide to the solution, the mixture was refluxed for 1.5 hours. The reaction mixture thus obtained was cooled and the crystals deposited were collected by filtration and washed with purified water. Then, the crude crystals obtained were recrystallized from ethanol to provide 6.4 g (yield 94percent) of colorless acicular p-nitrophenol benzyl ether.

Reference： [1] Patent: US5166403, 1992, A,

2
[ 1145-76-2 ]
[ 51388-20-6 ]

Reference： [1] Journal of Organic Chemistry, 2009, vol. 74, # 18, p. 6960 - 6964

3
[ 41927-14-4 ]
[ 51388-20-6 ]

Reference： [1] Indian Journal of Heterocyclic Chemistry, 2010, vol. 20, # 2, p. 149 - 152

4
[ 103-90-2 ]
[ 51388-20-6 ]

Reference： [1] Indian Journal of Heterocyclic Chemistry, 2010, vol. 20, # 2, p. 149 - 152

5
[ 100-44-7 ]
[ 51388-20-6 ]

Reference： [1] Indian Journal of Heterocyclic Chemistry, 2010, vol. 20, # 2, p. 149 - 152

6
[ 51388-20-6 ]
[ 52068-30-1 ]

Yield	Reaction Conditions	Operation in experiment
96%	Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5 h; Stage #2: With tin(ll) chloride In water at 0℃; for 1 h;	(4-(Benzyloxy)phenyl)hydrazine hydrochloride (2).; Note: The reaction mixture and all added solutions were maintained at 0 °C during this procedure. 4-Benzyloxyaniline hydrochloride (3.00 g, 12.5 mmol) was added to cone. aq. HC1 (25 mL) and stirred for 10 min at 0 °C, followed by dropwise addition of a solution of NaN0₂ (852 mg, 12.3 mmol) in water (6 mL) over the course of 15 min. The mixture was stirred for an additional 15 min-period and then a solution of SnCl₂ (6.40 g, 33.1 mmol) in cone. aq. HC1 (7.5 mL) was added dropwise. The reaction mixture was stirred for 1 h and filtered to yield an off-white precipitate, which was washed with water and triturated with Et₂0, to yield 2 (3.01 g, 96percent):IR (ATR, neat) 3232, 2906 (br), 2693, 1568, 1508, 1242, 1177 cm^"1; 1H NMR (DMSO-d₆, 600 MHz) δ 10.11 (bs, 3 H), 7.44-7.40 (m, 2 H), 7.40-7.35 (m, 2 H), 7.33-7.29 (m, 1 H), 7.01-6.93 (m, 4 H), 5.05 (s, 2 H); ¹³C NMR (DMSO-d₆, 150 MHz) δ 153.7, 139.1, 137.3, 128.5, 128.4, 128.3, 127.9, 127.7, 127.5, 117.1, 116.9, 115.5, 115.3, 69.5; HRMS (EI) m/z calcd for Ci₃Hi₄N₂0 214.1106, found 214.1110.
92%	Stage #1: With hydrogenchloride In water at 0℃; for 0.166667 h; Stage #2: With sodium nitrite In water at 0℃; for 0.5 h; Stage #3: With tin(ll) chloride In water at 0℃; for 1 h;	Note: The reaction mixture and all added solutions were maintainedat 0 C during this procedure. 4-Benzyloxyanilinehydrochloride (3) (3.0 g, 12.5 mmol) was added to concd aq HCl(25 mL) and stirred for 10 min at 0 C, followed by dropwise additionof NaNO2 (852 mg, 12.3 mmol) in water (6 mL) over the courseof 15 min. The mixture was stirred for additional 15 min and then asolution of SnCl2 (6.4 g, 33.1 mmol) in concd aq HCl (7.5 mL) wasadded dropwise. The reaction mixture was stirred for 1 h and filteredto yield an off-white precipitate, which was washed withwater and triturated with Et2O, to afford an off-white solid (2.9 g,92percent); Mp 179–181 C. IR: mmax (KBr) cm1: 3232, 2907 (br), 1638,1618, 1511, 1246, 1178. 1H NMR (DMSO-d6, 400 MHz) d 10.14(br s, 3H, NH–NH2), 7.35–7.48 (m, 4H, Ar-H), 7.27–7.35 (m, 1H,Ar-H), 6.92–7.05 (m, 4H, Ar-H), 5.06 (s, 2H, CH2). 13C NMR(DMSO-d6, 100 MHz) d 153.7 (ArC–O), 139.1 (ArC–N), 137.3(ArC), 128.5 (ArC), 128.4 (ArC), 128.3 (ArC), 127.9 (ArC), 127.7(ArC), 117.1 (ArC), 116.9 (ArC), 115.5 (ArC), 115.3 (ArC), 69.5(CH2). HRMS (EI): Found 215.1180 (M+H)+, C13H15N2O requires215.1184.
82%	With hydrogenchloride; stannous chloride; sodium nitrite In diethyl ether; water	(a) 4-Benzyloxyphenylhydrazine hydrochloride To 4-benzyloxyaniline hydrochloride (250 g, 1.56 mol) are added water (355 ml) and con. hydrochloric acid (175 ml), and the mixture is stirred while suspending. A solution of NaNO₂ (73.2 g, 1.06 mol) in water (180 ml) is dropwise added at a temperature of 0 - 5°C, followed by stirring at the same temperature for 1 hour (A solution). To con. hydrochloric acid (2.65) is added SnCl₂ (604 g), and the A solution is added dropwise at a temperature of 0 - 5°C while stirring. After stirring at the same temperature for 30 minutes, Et₂O (2) is further added thereto, followed by further stirring for 30 minutes. The precipitated crystals are filtered off, the crystals are added to methanol (3), and the mixture is stirred for 30 minutes. The crystals are filtered off, and dried to give 220 g of (a) (Yield 82percent). m.p. 187°C (MeOH-H₂O) TLC (Merck No. 5714 Sol. CHCl₃:MeOH=10:1) Rf=0.49 IR (Nujol) cm-¹: 3230, 1585, 1510 ¹H-NMR (DMSO-D₆) δ ppm: 5.03 (2H, s, -CH₂-O), 7.35 (5H, s, C-phenyl), 11.0 (3H, br-s, -NH-NH₂ * HCl)

Reference： [1] Patent: WO2012/78859, 2012, A2, . Location in patent: Page/Page column 47
[2] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 18, p. 4075 - 4099
[3] Patent: EP427860, 1991, A1,
[4] Bioorganic and Medicinal Chemistry, 2010, vol. 18, # 10, p. 3387 - 3402
[5] Patent: US5102891, 1992, A,
[6] Patent: US3959309, 1976, A,
[7] Patent: US4062864, 1977, A,
[8] Patent: WO2014/186325, 2014, A1, . Location in patent: Page/Page column 25

7
[ 51388-20-6 ]
[ 52068-30-1 ]

Reference： [1] Patent: US4725615, 1988, A,

8
[ 35081-45-9 ]
[ 51388-20-6 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
94.6%	With triethylamine In N,N-dimethyl-formamide at 115℃; for 4 h;	10 g of 4 '-benzyloxy-2-bromophenylacetone (II-a) 15 g of p-benzyloxyaniline hydrochloride (II-b), 50 mL of N, N-dimethylformamide and 8 mL of triethylamine at 115 ° C for 4 hours. The reaction solution was completely purified by thin layer chromatography (TLC). The reaction solution was poured into 250 mL of ice water to precipitate a solid. The crude product was stirred with 20 mL of methanol and dried at 40 ° C for 24 h to give 12.5 g of a yellowish brown solid product, 5-benzyloxy-2-[(4-benzyloxy)phenyl]-3-methyl-1H-indole (Intermediate II) in a yield of 94.6percent
90.5%	Stage #1: With triethylamine In butan-1-ol at 118℃; for 3 h; Stage #2: With hydrogenchloride In water; butan-1-ol at 118℃; for 7 h;	2-bromo- (4-benzyloxyphenyl) acetone (12. 7 g, 0.04 mol)Benzyloxyaniline hydrochloride (11. lg, 0.04 mol) was added to n-butanol (120 ml)Triethylamine (12.2 ml) was added and the temperature was raised to 118 ° (after refluxing, 3 hours later,2_ bromo- (4-benzyloxyphenyl) acetone was completely reacted; concentrated hydrochloric acid (1. 0 ml) was added,The temperature was raised to 118 ° C for 7 hours.The reaction solution was cooled, suction filtered and dried to give a white solid 15. 2 g, HPLC purity: 98percent yield 90.5percent.
65.14%	With triethylamine In N,N-dimethyl-formamide at 100 - 125℃;	4'-Benzyloxy-2-bromophenylpropiophenone (50 g), 4-benzyloxyaniline hydrochloride (40.5 g), triethylamine (50 mL) and N,N-dimethylformamide (300 mL) are mixed and heated to about 100⁰C, and maintained at that temperature for 3-3.5 hours until reaction completion as verified using thin layer chromatography (TLC). The mixture is cooled to 50-55⁰C and additional 4-benzyloxyaniline hydrochloride (40.5 g) is added and stirred. The temperature is raised to 120- 125°C and maintained for 5-5.5 hours, with completion of the reaction verified using TLC. After completion of the reaction, the mixture is allowed to cool to room temperature, then the mixture is added to a solution of 5percent acetic acid (1000 mL) in water, followed by mixing with ethyl acetate (2000 mL). The organic layer is separated and washed with 5percent sodium bicarbonate solution (1000 mL) and brine solution (1000 mL). The organic layer is distilled completely under vacuum and the residue is cooled to 45°C, then methanol (400 ml_) is added and the mixture is stirred for 1 -1.5 hours. The formed solid is filtered and washed with methanol (300 ml_), then dried under vacuum at 65°C for 4 hours to afford the title compound in 65.14percent yield.

Reference： [1] Patent: CN106810487, 2017, A, . Location in patent: Paragraph 0078-0083; 0096; 0110; 0117
[2] Patent: CN104098499, 2016, B, . Location in patent: Paragraph 0035-0037
[3] Chemico-Biological Interactions, 2012, vol. 197, # 1, p. 8 - 15
[4] Patent: WO2011/22596, 2011, A2, . Location in patent: Page/Page column 4; 21; 22
[5] Journal of Medicinal Chemistry, 2001, vol. 44, # 11, p. 1654 - 1657
[6] Patent: EP1212335, 2006, B1, . Location in patent: Page/Page column 22-23

9
[ 1048697-94-4 ]
[ 51388-20-6 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	at 110 - 115℃; for 5 h;	2) The starting iV-(4-benzyloxyphenyl)-α-amino-4-benzyloxypropiophenone (22) (30.4 g; 69.7 mmol) and 4-benzyloxyaniline hydrochloride (3.3 g; 13.9 mmol) were suspended in propan-2- ol (380 ml) and the mixture was heated up to 110-115°C under an inert atmosphere in a pressure vessel. After 5 hours the heating was disconnected and the reaction mixture was stirred overnight. The crystallized beige product was filtered and washed with a small quantity of propan-2-ol. 24.2 g (82 percent) of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole (3b) with the melting temperature of 152.0-153.2°C were obtained.
79%	at 110 - 115℃; for 5 h;	Preparation of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-li7-indole (1)1) The starting N-(4-benzyloxyphenyl)-α-amino-4-benzyloxypropiophenone (22) (30.4 g; 69.7 mmol) and 4-benzyloxyaniline hydrochloride (3.3 g; 13.9 mmol) were suspended in ethanol (380 ml) and the mixture was heated to 110-115⁰C under an inert atmosphere in a pressure vessel. After 5 hours the heating was disconnected and the reaction mixture was stirred overnight. The crystallized white product was filtered and washed with ethanol. 23.3 g (79percent) of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole (3b) with the melting temperature of 152.4-153.4°C were obtained. ¹H-NMR (DMSO) δ 10.65 (s, IH); 7.55 (d, 2H); 7.50 (d, <n="11"/>4H); 7.30-7.45 (m, 6H); 7.21(d, IH); 7.10 (d, 2H); 7.10 (d, IH); 6.91 (dd, IH); 5.16 (s, 2H); 5.11 (s, 2H); 2.33 (s, 3H). MS el m/z 419.

Reference： [1] Patent: WO2008/98527, 2008, A1, . Location in patent: Page/Page column 5; 8; 9; 12
[2] Patent: WO2008/98527, 2008, A1, . Location in patent: Page/Page column 5; 8-9

[ 51388-20-6 ] Synthesis Path-Downstream 1~80

1
[ 75-21-8 ]
[ 51388-20-6 ]
[ 101582-69-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With triethylamine; In P2O5; acetic acid;	Example 1 4-Benzyloxy-N,N-bis(2-hydroxyethyl)aniline (2A) <strong>[51388-20-6]4-Benzyloxyaniline hydrochloride</strong> 1A (9.32 g, 39.5 mmol) was dissolved in acetic acid (400 mL), triethylamine (6 mL, 43 mmol) was added followed by ethylene oxide (20 mL). The reaction mixture was stirred at room temperature for 72 h, the solvent was evaporated in a rotary evaporator under water pump then under oil pump at 50 C. for 1 h. The residue was then diluted with water (500 mL) and the precipitate recovered by filtration, washed with more water, then dried in dessicator over P2O5 to afford 2A (9.6 g, 84%) as a pale brown powder. 1H-NMR (DMSO-d6) deltaH: 3.32 (t, 4H, N(CH2CH2OH)2), 3.42-3.52 (m, 4H, N(CH2CH2OH)2), 4.65 (t, 2H, OH, J=5.90 Hz), 4.97 (s, 2H, PhCH2), 6.60 (d, 2H, Harom3+5, J=9.10 Hz), 6.83 (d, 2H, Harom2+6), 7.25-7.44 (m, 5H, Harom benzyl).

Reference： [1]Bioorganic and Medicinal Chemistry,1999,vol. 7,p. 1775 - 1780
[2]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 1549 - 1558
[3]Tetrahedron Letters,2005,vol. 46,p. 6919 - 6922
[4]Patent: US2004/87813,2004,A1

2
[ 51388-20-6 ]
[ 79099-07-3 ]
[ 220741-33-3 ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 4239 - 4249

3
[ 35081-45-9 ]
[ 51388-20-6 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
94.6%	With triethylamine; In N,N-dimethyl-formamide; at 115℃; for 4h;	10 g of 4 '-benzyloxy-2-bromophenylacetone (II-a) 15 g of p-benzyloxyaniline hydrochloride (II-b), 50 mL of N, N-dimethylformamide and 8 mL of triethylamine at 115 C for 4 hours. The reaction solution was completely purified by thin layer chromatography (TLC). The reaction solution was poured into 250 mL of ice water to precipitate a solid. The crude product was stirred with 20 mL of methanol and dried at 40 C for 24 h to give 12.5 g of a yellowish brown solid product, 5-benzyloxy-2-[(4-benzyloxy)phenyl]-3-methyl-1H-indole (Intermediate II) in a yield of 94.6%
90.5%		2-bromo- (4-benzyloxyphenyl) acetone (12. 7 g, 0.04 mol)Benzyloxyaniline hydrochloride (11. lg, 0.04 mol) was added to n-butanol (120 ml)Triethylamine (12.2 ml) was added and the temperature was raised to 118 (after refluxing, 3 hours later,2_ bromo- (4-benzyloxyphenyl) acetone was completely reacted; concentrated hydrochloric acid (1. 0 ml) was added,The temperature was raised to 118 C for 7 hours.The reaction solution was cooled, suction filtered and dried to give a white solid 15. 2 g, HPLC purity: 98% yield 90.5%.
65.14%	With triethylamine; In N,N-dimethyl-formamide; at 100 - 125℃;	4'-Benzyloxy-2-bromophenylpropiophenone (50 g), 4-benzyloxyaniline hydrochloride (40.5 g), triethylamine (50 mL) and N,N-dimethylformamide (300 mL) are mixed and heated to about 1000C, and maintained at that temperature for 3-3.5 hours until reaction completion as verified using thin layer chromatography (TLC). The mixture is cooled to 50-550C and additional 4-benzyloxyaniline hydrochloride (40.5 g) is added and stirred. The temperature is raised to 120- 125C and maintained for 5-5.5 hours, with completion of the reaction verified using TLC. After completion of the reaction, the mixture is allowed to cool to room temperature, then the mixture is added to a solution of 5% acetic acid (1000 mL) in water, followed by mixing with ethyl acetate (2000 mL). The organic layer is separated and washed with 5% sodium bicarbonate solution (1000 mL) and brine solution (1000 mL). The organic layer is distilled completely under vacuum and the residue is cooled to 45C, then methanol (400 ml_) is added and the mixture is stirred for 1 -1.5 hours. The formed solid is filtered and washed with methanol (300 ml_), then dried under vacuum at 65C for 4 hours to afford the title compound in 65.14% yield.

With triethylamine; In N,N-dimethyl-formamide; at 120 - 150℃; for 4.66667h;

The bromoketone CAS No. [66414-19-5] (50.0 g, 0.16 mol) in 200 mL DMF was treated with the 4-benzyloxyaniline hydrochloride CAS No. [51145-58-5] (44 g, 0.22 mol) and the reaction purged with nitrogen for about 10 minutes. The triethylamine (54.6 mL) was added and the reaction was heated at 120C for 2 hours. TLC analysis (EtOAc/hexanes) shows the starting material disappeared forming a more polar spot. The reaction mixture was allowed to cool down and an additional 48 g of the aniline hydrochloride was added. The reaction was heated to 150C for 2 hours. An additional 5 grams of the aniline hydrochloride was added and the reaction was heated at 150C for an additional 30 minutes. The reaction mixture was allowed to cool to room temperature and then poured into approximately 1.5 liters of water and extracted with 2 liters of ethyl acetate. Solids are dissolved with additional ethyl acetate as necessary. The ethyl acetate layer is washed with 1 liter of 1 N NaOH solution aq., 1 liter of water, brine, then dried over magnesium sulfate and filtered. The organic layers were concentrated down to yield a crude solid which was stirred with 500 mL of methanol and filtered. This solid was then stirred with 500 mL of ethyl ether and filtered. The solid was stirred alternatively with methanol and ether until it is of whitish color. Reaction yields 36 g of product: Mp = 150-152C; 1H NMR (DMSO) delta 10.88 (s, 1 H), 7.56 (d, 2 H, J = 8.8 Hz), 7.48 (d, 4 H, J = 7.9 Hz), 7.42-7.29 (m, 6 H), 7.21 (d, 1 H, J = 7.0 Hz), 7.13 (d, 2 H, J = 8.8 Hz), 7.08 (d, 1 H, J = 2.2 Hz), 6.94 (dd, 1 H, J = 8.8, 2.4 Hz), 5.16 (s, 2 H), 5.11 (s, 2 H), 2.33 (s, 3 H); IR (KBr) 3470, 2880, 2820, 1620 cm-1; MS eI m/z 419.

Reference： [1]Patent: CN106810487,2017,A .Location in patent: Paragraph 0078-0083; 0096; 0110; 0117
[2]Patent: CN104098499,2016,B .Location in patent: Paragraph 0035-0037
[3]Chemico-Biological Interactions,2012,vol. 197,p. 8 - 15
[4]Patent: WO2011/22596,2011,A2 .Location in patent: Page/Page column 4; 21; 22
[5]Journal of Medicinal Chemistry,2001,vol. 44,p. 1654 - 1657
[6]Patent: EP1212335,2006,B1 .Location in patent: Page/Page column 22-23

4
[ 463-71-8 ]
[ 51388-20-6 ]
[ 139768-71-1 ]

Reference： [1]Organic and Biomolecular Chemistry,2005,vol. 3,p. 4002 - 4010
[2]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 915 - 918

5
[ 51388-20-6 ]
[ 51145-58-5 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 3730 - 3745
[2]Journal of Medicinal Chemistry,2001,vol. 44,p. 1718 - 1728
[3]Patent: US6670387,2003,B1

6
[ 51388-20-6 ]
[ 79-04-9 ]
[ 19514-92-2 ]

Yield	Reaction Conditions	Operation in experiment
94%		<strong>[51388-20-6]4-Benzyloxyaniline hydrochloride</strong> (50 g, 0.21 mol) was dissolved in 750 mL of THF. Solid potassium carbonate (44 g, 0.32 mol) was added and the mixture stirred at room temperature for 15 min. Chloroacetyl chloride (26. 35 g, 0.23 mol) was added via syringe at room temperature and the reaction mixture stirred at room temperature for 6 h. Diethyl ether was added (300 mL) and the mixture filtered through a pad of celite. The solution was concentrated under reduced pressure to a brown solid. The solid was washed with hexanes to afford 54.85 g (94 %) of N- (4- BENZYLOXYPHENYL)-2-CHLOROACETAMIDE as a brown solid. MS : RAZ 276.1 (M+1).

Reference： [1]Organic Letters,2004,vol. 6,p. 4069 - 4072
[2]Patent: WO2004/89915,2004,A1 .Location in patent: Page 57-58; 61
[3]Journal of Medicinal Chemistry,2007,vol. 50,p. 6706 - 6717

7
[ 51388-20-6 ]
[ 65069-53-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: aq. NaHCO₃ / CHCl₃ / 0.5 h 2: NH₃ / methanol / 12 h

Reference： [1]Wilson, Kenneth J.; Illig, Carl R.; Subasinghe, Nalin; Hoffman, James B.; Jonathan Rudolph; Soll, Richard; Molloy, Christopher J.; Bone, Roger; Green, David; Randall, Troy; Zhang, Marie; Lewandowski, Frank A.; Zhou, Zhao; Sharp, Celia; Maguire, Diane; Grasberger, Bruce; DesJarlais, Renee L.; Spurlino, John [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 7, p. 915 - 918]

8
[ 51388-20-6 ]
[ 198481-32-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: 51 percent / Et₃N / dimethylformamide / Heating 2.1: sodium hydride / dimethylformamide / 0.33 h / 0 °C 2.2: 59 percent / dimethylformamide / 18 h / 20 °C 3.1: 78 percent / LiAlH₄ / tetrahydrofuran / 0.5 h / 0 °C 4.1: 87 percent / CBr₄; Ph₃P / tetrahydrofuran / 3 h / 20 °C 5.1: tetrahydrofuran 6.1: H₂ / Pd/C / ethanol; tetrahydrofuran / 20 °C
	Multi-step reaction with 3 steps 1.1: triethylamine / N,N-dimethyl-formamide / 100 - 125 °C 2.1: sodium hydride / N,N-dimethyl-formamide; toluene / -5 - -1 °C 2.2: 5 °C 3.1: hydrogen / palladium 10% on activated carbon / water; acetone; methanol / 40 °C / 7355.72 Torr
	Multi-step reaction with 3 steps 1: triethylamine / N,N-dimethyl-formamide / 4 h / 115 °C 2: sodium hydride / N,N-dimethyl-formamide / 10 h / 20 °C 3: boron trifluoride diethyl etherate / dichloromethane; ethanethiol / 4 h / 0 - 25 °C

Reference： [1]Miller; Collini; Tran; Harris; Kharode; Marzolf; Moran; Henderson; Bender; Unwalla; Greenberger; Yardley; Abou-Gharbia; Lyttle; Komm [Journal of Medicinal Chemistry, 2001, vol. 44, # 11, p. 1654 - 1657]
[2]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2011/22596, 2011, A2
[3]Current Patent Assignee: SICHUAN KELUN PHARMACEUTICAL COMPANY LIMITED - CN106810487, 2017, A

9
[ 51388-20-6 ]
[ 198480-21-6 ]

Reference： [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 1654 - 1657
[2]Patent: WO2011/22596,2011,A2
[3]Patent: CN106810487,2017,A

10
[ 51388-20-6 ]
[ 6373-46-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In water;	4-Benzyloxyaniline is commercially available as the hydrochloride salt; this is treated with aqueous sodium carbonate solution, and the mixture extracted with ethyl acetate; the organic solution is dried (MgSO4) and concentrated to give the free base as a brown solid, used without further purification.
	With sodium hydroxide; In methanol; water;	A solution of <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (compound Ia, 12 g) in MeOH (200 mL) was treated with aqueous NaOH (2.04 g in 80 mL deionized water) and the resulting clear solution was concentrated to dryness to provide a residue of crude aniline free base.
	With sodium hydroxide; In diethyl ether; water;	Intermediate 29: 6-(at) f 2-((at)2- f (2-aminoethyl)oxyl ethyl(at) oxy)ethyll oxy)-1-ethyl-4-oxo-1,4-dihydro-3- quinolinecarboxylic acid formate a) Ethyl 4-oxo-6-[(phenylmethyl)oxy]-1,4-dihydro-3-quinolinecarboxylate p-Benzyloxy aniline hydrochloride (25 g) was shaken with 1M NaOH (120 mL) and diethyl ether (200 mL). The organic layer was washed with brine, dried (MgS04) and evaporated to a solid (21.3 g). This material was heated with ethoxymethylene malonate (27.9 g) at 130C for 1.5 h using a Dean and Stark condenser. Dowtherm (100 mL) was added and the mixture heated to 250C using a Dean and Stark condenser for 70 min. The mixture was cooled and treated with petroleum ether (bp 60-80C) to precipitate a brown solid. This was slurried in dichloromethane, the pale yellow solid was filtered and dried to give the title compound (11.06 g). (at)H-NMR(400 MHz, DMSO-d6) No.: 1.28 (3H, t, J = 7.2 Hz), 4.21 (2H, q, J = 7.2 Hz), 5.21 (2H, s), 7.3 (1H, m), 7.4 (3H, m), 7.4 (2H, m), 7.59 (1H, d, J=8.8 Hz), 7.66 (1H, d, J= 2.8 Hz) , 8.49 (1H, s) and 12.3 (lH, br).

Reference： [1]Tetrahedron,1998,vol. 54,p. 13981 - 13996
[2]Patent: US2005/143401,2005,A1 .Location in patent: Page/Page column 45
[3]Indian Journal of Heterocyclic Chemistry,2010,vol. 20,p. 149 - 152
[4]Patent: WO2009/140553,2009,A2 .Location in patent: Page/Page column 55
[5]Patent: WO2005/108413,2005,A1 .Location in patent: Page/Page column 61-62

11
[ 51388-20-6 ]
[ 97389-25-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: 35 percent / KOH / ethanol / 6 h / Heating 2: 1) HBr / 1) 4 h, reflux, 2) ethyl acetate, RT, overnight

Reference： [1]Fayadh, J. M.; Swan, G. A. [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1985, vol. 24, p. 222 - 224]

12
[ 51388-20-6 ]
23-diazo [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With hydrogenchloride; sodium nitrite; In water; at 0℃; for 0.166667h;	a) 4-Benzyloxyphenylhydrazine [00218] A solution of <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (11.3 g; 0.048 mole) in concentrated hydrochloric acid (40.0 mL) was cooled to 0 then treated dropwise with a solution of sodium nitrite (3.28 g; 0.048 mole) in water (20.0 mL). The mixture was stirred 0 for a further 10 min. then poured into a cold (-10) solution of tin dichloride hydrate (40.0 g; 0.18 mole) in concentrated hydrochloric acid (40.0 mL). The mixture was allowed to warm to room temperature with stirring for 1 h. [00219] The mixture was basified with 10% aqu. sodium hydroxide, ethyl acetate (1 L) was added and the mixture filtered to remove unwanted tin residues. The organic layer was then dried and evaporated to afford the title compound as a yellow solid (6.9 g; 67%). mp 105-107. [00220] b) 1-(4-Benzyloxyphenyl)-3-methyl-3-pyrazolin-5-one [00221] Following the procedure of Example 22a), except the compound from Example 23a) for 2-hydrazinopyridine, the title compound was prepared (1.6 g; 60%). MS(ES) m/z 281 [M+H]. [00222] c) 4-[1-(4-Benzyloxyphenyl)-5-hydroxy-3-methyl-1H-pyrazol-4-yl]azo}-3-hydroxy-1-naphthalenesulfonic acid [00223] Following the procedure of Example 1, except the compound from Example 23b) for 2-naphthol, the title compound was prepared as a red solid (2.8 g; 98%). MS(ES) m/z 529 [M-H].

Reference： [1]Patent: US6670387,2003,B1 .Location in patent: Page column 21

13
[ 51388-20-6 ]
[ 726196-29-8 ]

Yield	Reaction Conditions	Operation in experiment
		Example 52-1 NL- (4-benzyloxyphenyl)-4-methoxybenzamidine To a solutionof <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (3g) in tetrahydrofuran (15ML), 1.OM sodium bis (trimethylsilyl) amide in tetrahydrofuran (26. 7ML) wasadded dropwise at room temperature. After the mixture was stirred for20min, anisonitrile (1.69g) was added.The reaction mixture was stirred for 4hrs, and then poured into 300ML OFice-water. The precipitates were collected by filtration, washed withdiisopropyl ether to give the target compound (3.3g).1H NMR (200MHZ, DMSO-D6, D) : 3.8 (3H, s), 5.05 (2H, s), 6.09 (2H, bs),6.74-6. 8 (2H, m), 6.96 (4H, d, J=8.5Hz), 7.29-7. 49 (5H, m), 7.92 (2H,d, J=8.9Hz).MS m/e: 333 (M+H) +.

Reference： [1]Patent: WO2004/99130,2004,A2 .Location in patent: Page 55

14
[ 51388-20-6 ]
[ 76315-01-0 ]
[ 777934-40-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-ethyl-N,N-diisopropylamine; diisopropyl-carbodiimide;dmap; In dichloromethane; at 20℃; for 18h;	4-BENZYLOXYANILINE hydrochloride (4.68 g, 19. 8 mmole) was suspended in anhydrous dichloromethane (66 ML). DIISOPROPYLETHYLAMINE (8. 64 mL, 49.6 MMOLE), 4-(19 DIMETHYLAMINO) pyridine (240 mg, 2.0 mmole), NN -DIISOPROPYLCARBODIIMIDE (3. 88 mL, 24.8 mmole), and (N-BENZYL-N-TERT-BUTOXYCARBONYL) glycine (5.79 g, 21. 8 mmole) were added sequentially. The resulting solution was stirred at room temperature for 18H, diluted with dichloromethane, washed with water, aqueous saturated sodium bicarbonate, aqueous 10% citric acid, and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, gradient: 10% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) to yield 8. 23 g (93%) OF BENZYL- [ (4-BENZYLOXYPHENYLCARBAMOYL)-METHYL]-CARBAMIC acid tert-butyl ester as a orange viscous oil. MS: RAZ 447.2 (M+1).

Reference： [1]Patent: WO2004/89915,2004,A1 .Location in patent: Page 58; 61

15
[ 59237-53-5 ]
[ 51388-20-6 ]
[ 847777-84-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In methanol; at 20℃;	To a solution of 6-chloro-5-nitro-nicotinic acid methyl ester (216mg, 1. OMMOL) and 4- benzyloxyaniline hydrochloride (280mg, 1. 2MMOL) in MEOH (LOML) was added PR2NET (0.35mL, 2. 0MMOL). The resulting mixture was stirred at rt overnight, a red solid precipitated from the mixture, which was collected by filtration. MS (ES, Pos. ) : m/z 380 [MH+]. 1H NMR (CDC13, 400 MHz) : 8 = 3.94 (s, 3H), 5.10 (s, 2H), 7.03 (d, J= 8. 8 Hz, 2H), 7.38-7. 46 (M, 5H), 7.50 (d, J= 8. 8 Hz, 2H), 9.01 (d, J= 2.0 Hz, 1H), 9.08 (d, J= 2.0 Hz, 1H), 10.2 (br s, 1H).
	With N-ethyl-N,N-diisopropylamine; In methanol; at 20℃;	6-(4-Benzyloxyphenylamino)-5-nitronicotinic acid methyl ester (XXIV): To a solution of 6-chloro-5-nitro-nicotinic acid methyl ester (216 mg, 1.0 mmol) and 4-benzyloxyaniline hydrochloride (280 mg, 1.2 mmol) in MeOH (10 mL) was added iPr2NEt (0.35 mL, 2.0 mmol). The resulting mixture was stirred at rt overnight, a red solid precipitated from the mixture, which was collected by filtration. MS (ES, Pos.): m/z 380 [MH+]. 1H NMR (CDCl3, 400 MHz): delta=3.94 (s, 3H), 5.10 (s, 2H), 7.03 (d, J=8.8 Hz, 2H), 7.38-7.46 (m, 5H), 7.50 (d, J=8.8 Hz, 2H), 9.01 (d, J=2.0 Hz, 1H), 9.08 (d, J=2.0 Hz, 1H), 10.2 (br s, 1H).

Reference： [1]Patent: WO2005/21544,2005,A2 .Location in patent: Page/Page column 29
[2]Patent: US2006/35921,2006,A1 .Location in patent: Page/Page column 11; 15

16
[ 51388-20-6 ]
[ 4498-67-3 ]
1H-Indazole-3-carboxylic acid (4-benzyloxy-phenyl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20 - 70℃; for 28h;	DIEA (9.3 mL, 53.4 mmol) was added to a solution of <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (4.0 g, 17.0 mmol), indazole-3-carboxylic acid (2.89 g, 17.8 mmol) and HBTU (7.1 g, 18.7 mmol) in DMF (60 mL), and the resulting solution was stirred at ambient temperature for 24 hours. The solution was heated to 70 C. for 4 hours, and then poured into a mixture of saturated aqueous sodium bicarbonate on ice. The product, an off white solid, 6.0 g, was collected by filtration, washed with water and used without further purification in the subsequent reaction. MS m/z 344 (MH+). 1H NMR(DMSO-d6) delta 5.11 (s, 2H), 7.02 (d, 2H), 7.26-7.48 (m, 7H), 7.67 (d, 1H), 7.75 (d, 2H), 7.81 (d, 1H), 8.24 (d, 1H) and 10.24 (s, 1H).
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20 - 70℃; for 28h;	A. 1H-Indazole-3-carboxylic acid (4-benzyloxy-phenyl)-amide DIEA (9.3 mL, 53.4 mmol) was added to a solution of <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (4.0 g, 17.0 mmol), indazole-3-carboxylic acid (2.89 g, 17.8 mmol) and HBTU (7.1 g, 18.7 mmol) in DMF (60 mL), and the resulting solution was stirred at ambient temperature for 24 hours. The solution was heated to 70 C for 4 hours, and then poured into a mixture of saturated aqueous sodium bicarbonate on ice. The product, an off white solid, 6.0 g, was collected by filtration, washed with water and used without further purification in the subsequent reaction. MS m/z344 (MH+).'H NMR (DMSO-d6) 8 5.11 (s, 2H), 7.02 (d, 2H), 7.26-7. 48 (m, 7H), 7.67 (d, 1 H), 7.75 (d, 2H), 7.81 (d, 1 H), 8. 24 (d, 1 H) and 10.24 (s, 1H).

Reference： [1]Patent: US2005/182108,2005,A1 .Location in patent: Page/Page column 14
[2]Patent: WO2005/84663,2005,A1 .Location in patent: Page/Page column 41

17
[ 2516-97-4 ]
[ 51388-20-6 ]
N-(4-benzyloxy-phenyl)-2-methanesulfonyl-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃;	A solution of 4-benzyloxyaniline hydrochloride (4.0 g, 17.0 mmol), methanesulfonylacetic acid (2.35 g, 17.0 mmol) and HBTU (6.89 g, 18.2 mmol) in DMF (70 mL) was stirred at ambient temperature one minute. DIEA (6.5 mL, 37.2 mmol) was added all at once, and the resultant solution was stirred at ambient temperature. The solution was poured into water, and the product crystallized. The product, 5.4 g (99%), was collected by filtration and was used without any further purification in the subsequent reaction. MS m/z 320 (MH+). 1H NMR(DMSO-d6) delta 3.17 (s, 3H), 4.25 (s, 2H), 5.07 (s, 2H), 7.00 (d, 2H), 7.32-7.55 (m, 7H) and 10.32 (s, 1H).
99%		A. N- (4-Benzyloxy-phenyl)-2-methanesulfonyl-acetamide A solution of 4-benzyloxyaniline hydrochloride (4.0 g, 17.0 mmol), methanesulfonylacetic acid (2.35 g, 17.0 mmol) and HBTU (6.89 g, 18. 2 mmol) in DMF (70 mL) was stirred at ambient temperature one minute. DIEA (6.5 mL, 37.2 mmol) was added all at once, and the resultant solution was stirred at ambient temperature. The solution was poured into water, and the product crystallized. The product, 5.4 g (99%), was collected by filtration and was used without any further purification in the subsequent reaction. MS m/z 320 (MH+). 1H NMR (DMSO-d6) 8 3.17 (s, 3H), 4.25 (s, 2H), 5.07 (s, 2H), 7.00 (d, 2H), 7.32- 7.55 (m, 7H) and 10.32 (s, 1 H).

Reference： [1]Patent: US2005/182108,2005,A1 .Location in patent: Page/Page column 13
[2]Patent: WO2005/84663,2005,A1 .Location in patent: Page/Page column 38

18
[ 231278-11-8 ]
[ 51388-20-6 ]
[ 231278-17-4 ]

Yield	Reaction Conditions	Operation in experiment
79%	In 1,4-dioxane; dichloromethane; at 110℃; for 16h;	Prepared according to Procedure A from 4-chloro-6-iodo-7-fluoro-quinazoline hydrochloride (4.02 grams, 11.65 mmoles), anhydrous dioxane (70 ml), dichloromethane (20 ml), and <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (2.83 grams, 12 mmoles). The mixture was stirred and heated to 110 C. (oil bath temperature) for 16 hours. cooled to room temperature and filtered to remove the precipitated solids. The solids were washed with cold anhydrous dioxane (100 ml) followed by cold anhydrous diethyl ether. The yellowish solid was collected and dried under vacuum at room temperature to yield 4.68 grams (79%) of the title compound. deltaH NMR (400 MHz, DMSO-d6): 11.2(s, 1H), 9.3(d, 1H), 8.79(s, 1H), 7.64(d, 1H), 7.58(d, 2H), 7.44(d, 2H), 7.38(m, 2H), 7.31(m, 1H), 7.09(d, 2H), 5.14(s, 2H) ESI-MS m/z 472(M+1).
79%	In 1,4-dioxane; dichloromethane; at 110℃; for 16h;Reflux;	(4-Benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride (0638) Prepared according to Procedure A from 4-chloro-6-iodo-7-fluoro-quinazoline hydrochloride (4.02 grams, 11.65 mmoles), anhydrous dioxane (70 ml), dichloromethane (20 ml) and <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (2.83 grams, 12 mmoles). The mixture was stirred and heated to 110 C. (oil bath temperature) for 16 hours. The mixture was cooled to room temperature and filtered to remove the precipitated solids. The solids were washed with cold anhydrous dioxane (100 ml) followed by cold anhydrous diethyl ether. The yellowish solid was collected and dried under vacuum at room temperature to yield 4.68 grams (79%) of the title compound. deltaH (400 MHz, DMSO-d6): 11.2 (s, 1H), 9.3 (d, 1H), 8.79 (s, 1H), 7.64 (d, 1H), 7.58 (d, 2H), 7.44 (d, 2H), 7.38 (m, 2H), 7.31 (m, 1H), 7.09 (d, 2H), 5.14 (s, 2H) ESI-MS m/z 472 (M+1).

Reference： [1]Patent: US6933299,2005,B1 .Location in patent: Page/Page column 75
[2]Patent: US9199973,2015,B2 .Location in patent: Page/Page column 44

19
[ 389796-28-5 ]
[ 51388-20-6 ]
[ 863332-13-2 ]

Yield	Reaction Conditions	Operation in experiment
39%	With acetic acid; In ethanol; for 18h;Heating / reflux;	A solution of Ethyl 2-Acetyl-4- (2, 4-dichlorophenyl)-4-oxobutanoate from Exl, Step A (2.85 g, 9.0 mmol) and <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (2.14 g, 9.1 mmol) in 1: 1 ethanol/acetic acid (80 mL) was heated at reflux for 18h. After cooling, the solution was partially concentrated and diluted with ethyl acetate. It was washed with saturated NaHC03 solution, and the organic layer was dried (MgS04) and concentrated. The residue was purified by flash column chromatography (10: 1 hexanes/EtOAc) to afford the title compound as a white solid (1.67 g, 39%) :'H NMR (300 MHz, CDC13) 8 6.90-7. 40 (m, 12H), 6.73 (s, 1H), 5.02 (s, 2H), 4.31 (q, J= 7.1 Hz, 2H), 2.40 (s, 3H), 1.36 (t, J= 7.1 Hz); ESI MS m/z 480 [C27H23Cl2NO3 + H] + ; HPLC (Method A) 99.6% (AUC), {R = 36.2 min.

Reference： [1]Patent: WO2005/80328,2005,A1 .Location in patent: Page/Page column 28-29

20
[ 51388-20-6 ]
[ 535-11-5 ]
[ 677703-46-7 ]

Yield	Reaction Conditions	Operation in experiment
52%	With triethylamine; In DMF (N,N-dimethyl-formamide); at 100℃; for 24h;	Preparation XXV N-[4-(phenylmethoxy)phenyl]alanine ethyl ester A solution of 15 g (63.6 mmol) of 4-(phenylmethoxy)aniline hydrochloride in 200 ml of dimethylformamide is prepared and 13.8 g (76.4 mmol) of ethyl 2-bromopropionate are added, followed by 8.9 ml (63.6 mmol) of triethylamine. The reaction mixture is stirred for 24 h at 100 C. and then cooled and poured into 200 ml of iced water. The mixture is extracted with 2 times 200 ml of ethyl acetate and the combined organic phases are washed with water and then dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (95/5; v/v) as the eluent to give 10 g of the expected product in the form of an oil, which turns to beige crystals (yield=52%). M.p.=70 C.

Reference： [1]Patent: US2006/25589,2006,A1 .Location in patent: Page/Page column 9

21
[ 23426-63-3 ]
[ 51388-20-6 ]
[ 677703-47-8 ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium hydrogencarbonate; at 140℃; for 5h;Neat (no solvent);	Preparation XXVIII Methyl 2-methyl-2-[[4-(phenylmethoxy)phenyl]amino]propionate 3 g (15 mmol) of 4-(phenylmethoxy)aniline and 5.5 g (30 mmol) of methyl 2-bromo-2-methylpropionate are mixed and 1.95 g of sodium bicarbonate are added. The reaction medium is stirred for 5 h at 140 C. and then cooled and taken up with 50 ml of water and 100 ml of ethyl ether. The aqueous phase is separated off and re-extracted with 50 ml of ethyl ether and the combined organic phases are washed with water and then dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel using a cyclohexane/ethyl acetate mixture (8/2; v/v) as the eluent to give the expected product in the form of a beige crystalline solid (yield=75%). M.p.<50 C.

Reference： [1]Patent: US2006/25589,2006,A1 .Location in patent: Page/Page column 10

22
[ 51388-20-6 ]
[ 685-87-0 ]
[ 620628-25-3 ]

Yield	Reaction Conditions	Operation in experiment
45%	With N-ethyl-N,N-diisopropylamine; In toluene; at 100℃; for 36h;	4-BenzyloxyanilineHCl (86.1 mmol, 20.3 g), diethylbromomalonate (86. 1mmol, 14.7 ml) and N, N-diisopropylethylamine (86.1 mmol, 15 ml) in toluene (200 ml) was heated at 100C for 36 hours. The reaction mixture was concentrated, dissolved in water (500 ml) and extracted with EtOAc (3 X 300 ml). The organic phase was dried over Na2S04, concentrated and purified by flash chromatography (Si02, 50% EtOAc/hexanes) to provide compound 4A as a brown solid (13.7 g, 45%)

Reference： [1]Patent: WO2003/91252,2003,A1 .Location in patent: Page/Page column 49

23
[ 51388-20-6 ]
[ 196195-13-8 ]
C₂₉H₃₂N₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydrogenchloride; In diethyl ether; isopropyl alcohol; at 40 - 83℃; for 12.5h;	EXAMPLE 30; Preparation of Compound No. 30 in Table 3; A solution of 1.0N hydrochloric acid in ether (0.50 ml, 0.50 mmol) was added to a solution of <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (118 mg, 0.50 mmol) and 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (168 mg, 0.50 mmol), in isopropanol (5.0 ml). The reaction was heated at 40 C. for 30 minutes and then at 83 C. for 12 hours. The reaction was allowed to cool to ambient temperature and the solid which had precipitated was collected by suction filtration and washed with diethyl ether (2×10 ml). Drying of this material yielded the title compound (228 mg, 85% yield) as a white solid:1H-NMR (DMSO d6): 15.00 (s, 1H), 11.34 (s, 1H), 11.12 (s, 1H), 8.75 (s, 1H), 8.33 (s, 1H), 7.59 (d, 2H), 7.30-7.52 (m, 6H), 7.12 (d, 2H), 5.16 (s, 1H), 4.30 (t, 2H), 4.01 (s, 3H), 3.73-4.01 (m, 4H), 2.92-3.58 (m, 6H), 2.21-2.39 (m, 2H):MS (+ve ESI): 501 (M+H)+.

Reference： [1]Patent: US7081461,2006,B1 .Location in patent: Page/Page column 30

24
[ 328933-47-7 ]
[ 51388-20-6 ]
C₂₇H₂₉NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In N,N-dimethyl-formamide; at 130℃; for 1.5h;	A solution of DMF (350 mL) containing bromo ketone 19 (44.82 g, 143 mmol), para-benzyloxy aniline hydrochloride (37.1g, 157.4 mmol, 1.1 eq), Et3N (31.85 g, 314.8 mmol, 2.2 eq) was heated to 130C for 1.5 h and the rxn followed by TLC (15% EtOAc/Hex). The intermediate product alpha-anilino propiophenone was observed as a more polar spot than the alpha-bromo 4'-pivaloyl propiophenone. After all of the starting material was consumed, at 130C the reaction solution was treated with additional para-benzyloxy aniline hydrochloride (42 g, 177 mmol). The reaction mixture was then heated for an additional 3.5 h at 130C. The reaction mixture was allowed to come to rt, washed with water (800 mL), extracted by EtOAc (3 x 300 mL), washed with brine, and dried over with MgSO4. The organic layer was concentrated to give a crude product which was triturated with MeOH (3 times) to give a white solid (38 g, 64%): Mp = 156 - 158C; 1H NMR (DMSO) 11.0 (s, 1 H), 7.67 (d, 2 H, J = 8.6 Hz), 7.49 (d, 2 H, J = 7.1 Hz), 7.43 - 7.29 (m, 3 H), 7.28 - 7.19 (m, 3 H), 7.12 (d, 1 H, J = 2.3 Hz), 6.83 (dd, 1 H, J = 8.7 Hz, 2.3 Hz), 5.13 (s, 2 H), 2.37 (s, 3 H), 1.33 (s, 9 H); MS 414 (M+H)+; IR (KBr) 3380, 2970, 1745 cm-1.

Reference： [1]Patent: EP1212335,2006,B1 .Location in patent: Page/Page column 17

25
[ 898270-94-5 ]
[ 51388-20-6 ]
4-[4-(benzyloxy)phenyl]amino}-2-tert-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine; In dimethyl sulfoxide; at 110℃; for 0.416667h;Microwave irradiation;	4-[4-(Benzyloxy)phenyI]amino}-2-tert-butyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide; 2-fert-Butyl-4-chloro-5~phenylisothiazol-3(2H)-one 1,1-dioxide (0.3g, 1 mmol), 4- benzyloxyaniline hydrochloride (0.307g, 1.3 mmol) and TEA (0.304g, 3 mmol) was dissolved in dry DMSO (10 ml). The reaction was heated at 110 C for 25 min in a microwave reactor. The reaction mixture was diluted with water (200 ml) and extracted with EtOAc (200 ml), the organic phase was dried (MgSO4), filtered and evaporated. The residue was purified by silica gel column chromatography using a 65:35 mixture of heptane:EtOAc as eluant to give the title compound (0.345 g, 75 %).

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

26
[ 610-10-6 ]
[ 51388-20-6 ]
trans-N-Hydroxy-N'-[4-(phenylmethoxy)phenyl]-1,2-cyclohexanedicarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 9 trans-N-Hydroxy-N'-[4-(phenylmethoxy)phenyl]-1,2-cyclohexanedicarboxamide This compound was produced using procedures analogous to those for example 4 starting from 4-benzyloxyaniline hydrochloride and trans-1,2-cyclohexanedicarboxylic acid. MS(ESI): (M+TFA-H)-=480.9.

Reference： [1]Patent: US6429213,2002,B1

27
aquo-dichloro-tin(II) [ No CAS ]
sodium hydroxide, ethyl acetate [ No CAS ]
[ 51388-20-6 ]
[ 51145-58-5 ]

Yield	Reaction Conditions	Operation in experiment
67%	With sodium nitrite; In hydrogenchloride; water;	a 4-Benzyloxyphenylhydrazine A solution of 4-benzyloxyaniline hydrochloride (11.3 g; 0.048 mole) in concentrated hydrochloric acid (40.0 mL) was cooled to 0 then treated dropwise with a solution of sodium nitrite (3.28 g; 0.048 mole) in water (20.0 mL). The mixture was stirred at 0 for a further 10 min. then poured into a cold (-10) solution of tin dichloride hydrate (40.0 g; 0.18 mole) in concentrated hydrochloric acid (40.0 mL). The mixture was allowed to warm to room temperature with stirring for 1 h. The mixture was basified with 10% aqu. sodium hydroxide, ethyl acetate (1L) was added and the mixture filtered to remove unwanted tin residues. The organic layer was then dried and evaporated to afford the title compound as a yellow solid (6.9 g; 67%). mp 105-107.

Reference： [1]Patent: US6642265,2003,B1

28
[ 100-02-7 ]
[ 100-39-0 ]
[ 51388-20-6 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate; In ethanol;	(11-1) Synthesis of 4-Benzyloxyaniline Hydrochloride: In 40 ml of ethanol was dissolved 4.17 g of p-nitrophenol and after adding 2.5 g of potassium carbonate and 3.9 ml of benzyl bromide to the solution, the mixture was refluxed for 1.5 hours. The reaction mixture thus obtained was cooled and the crystals deposited were collected by filtration and washed with purified water. Then, the crude crystals obtained were recrystallized from ethanol to provide 6.4 g (yield 94%) of colorless acicular p-nitrophenol benzyl ether.

Reference： [1]Patent: US5166403,1992,A

29
NaBH₃ CN [ No CAS ]
[ 51388-20-6 ]
4-Benzyloxy-N-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-naphthalenyl)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydrogencarbonate;silica gel; In methanol; ethyl acetate;	A. 4-Benzyloxy-N-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-naphthalenyl)aniline A solution of 500 mg (2.42 mmol, Aldrich) of 6,7-dimethoxy-2-tetralone and 570 mg (2.42 mmol, Aldrich) of <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> in 20 ml of MeOH was stirred over 3A molecular sieves at 25 C., then 76 mg (1.21 mmol, Aldrich) of NaBH3 CN were added. This mixture was stirred for 3.5 hours, filtered and then saturated NaHCO3 was added to the filtrate. This solution was extracted with EtOAc twice, the organic layers were combined, dried (MgSO4) and concentrated in vacuo. Purification via flash chromatography (silica gel, 8, 1:5 then 1:3 EtOAc/petroleum ether) afforded mg (90%) of title compound as a pale pink solid:m.p. 85-88 C. 270 MHz 1 H NMR(CDCl3) delta 1.74 (m, 1H, aliphatic H of dimethoxytetralin) 2.13 (m, 1H, aliphatic H of dimethoxytetralin) 2.58 (dd, J=6, 12, 1H, aliphatic H of dimethoxytetralin) 2.82 (t, J=5, 2H, aliphatic H of dimethoxytetralin) 3.10 (dd, J=4, 12, 1H, aliphatic H of dimethoxytetralin 3.40 (br s, 1H, --NH--) 3.70 (crude m, 1H, --NH--CH--) 3.84 (s, 3H, --OCH3) 3.86 (s, 3H, --OCH3) 5.00 (s, 2H, --CH2 --Ph) 6.55 (s, 1H, aromatic H of dimethoxytetralin) 6.60 (s, 1H, aromatic H of dimethoxytetralin) 6.61 (d, J=6, 2H, phenol H's) 6.86 (d, J=6, 2H, phenol H's) 7.29-7.46 (m, 5H, ---C6 H5) TLC: Rf (1:1 EtOAc/petroleum ether)=0.66, UV and PMA, homogeneous.

Reference： [1]Patent: US4975461,1990,A

30
[ 51388-20-6 ]
[ 52068-30-1 ]

Yield	Reaction Conditions	Operation in experiment
96%		(4-(Benzyloxy)phenyl)hydrazine hydrochloride (2).; Note: The reaction mixture and all added solutions were maintained at 0 °C during this procedure. 4-Benzyloxyaniline hydrochloride (3.00 g, 12.5 mmol) was added to cone. aq. HC1 (25 mL) and stirred for 10 min at 0 °C, followed by dropwise addition of a solution of NaN02 (852 mg, 12.3 mmol) in water (6 mL) over the course of 15 min. The mixture was stirred for an additional 15 min-period and then a solution of SnCl2 (6.40 g, 33.1 mmol) in cone. aq. HC1 (7.5 mL) was added dropwise. The reaction mixture was stirred for 1 h and filtered to yield an off-white precipitate, which was washed with water and triturated with Et20, to yield 2 (3.01 g, 96percent):IR (ATR, neat) 3232, 2906 (br), 2693, 1568, 1508, 1242, 1177 cm"1; 1H NMR (DMSO-d6, 600 MHz) delta 10.11 (bs, 3 H), 7.44-7.40 (m, 2 H), 7.40-7.35 (m, 2 H), 7.33-7.29 (m, 1 H), 7.01-6.93 (m, 4 H), 5.05 (s, 2 H); 13C NMR (DMSO-d6, 150 MHz) delta 153.7, 139.1, 137.3, 128.5, 128.4, 128.3, 127.9, 127.7, 127.5, 117.1, 116.9, 115.5, 115.3, 69.5; HRMS (EI) m/z calcd for Ci3Hi4N20 214.1106, found 214.1110.
92%		Note: The reaction mixture and all added solutions were maintainedat 0 C during this procedure. 4-Benzyloxyanilinehydrochloride (3) (3.0 g, 12.5 mmol) was added to concd aq HCl(25 mL) and stirred for 10 min at 0 C, followed by dropwise additionof NaNO2 (852 mg, 12.3 mmol) in water (6 mL) over the courseof 15 min. The mixture was stirred for additional 15 min and then asolution of SnCl2 (6.4 g, 33.1 mmol) in concd aq HCl (7.5 mL) wasadded dropwise. The reaction mixture was stirred for 1 h and filteredto yield an off-white precipitate, which was washed withwater and triturated with Et2O, to afford an off-white solid (2.9 g,92percent); Mp 179?181 C. IR: mmax (KBr) cm1: 3232, 2907 (br), 1638,1618, 1511, 1246, 1178. 1H NMR (DMSO-d6, 400 MHz) d 10.14(br s, 3H, NH?NH2), 7.35?7.48 (m, 4H, Ar-H), 7.27?7.35 (m, 1H,Ar-H), 6.92?7.05 (m, 4H, Ar-H), 5.06 (s, 2H, CH2). 13C NMR(DMSO-d6, 100 MHz) d 153.7 (ArC?O), 139.1 (ArC?N), 137.3(ArC), 128.5 (ArC), 128.4 (ArC), 128.3 (ArC), 127.9 (ArC), 127.7(ArC), 117.1 (ArC), 116.9 (ArC), 115.5 (ArC), 115.3 (ArC), 69.5(CH2). HRMS (EI): Found 215.1180 (M+H)+, C13H15N2O requires215.1184.
82%	With hydrogenchloride; stannous chloride; sodium nitrite; In diethyl ether; water;	(a) 4-Benzyloxyphenylhydrazine hydrochloride To 4-benzyloxyaniline hydrochloride (250 g, 1.56 mol) are added water (355 ml) and con. hydrochloric acid (175 ml), and the mixture is stirred while suspending. A solution of NaNO2 (73.2 g, 1.06 mol) in water (180 ml) is dropwise added at a temperature of 0 - 5°C, followed by stirring at the same temperature for 1 hour (A solution). To con. hydrochloric acid (2.65) is added SnCl2 (604 g), and the A solution is added dropwise at a temperature of 0 - 5°C while stirring. After stirring at the same temperature for 30 minutes, Et2O (2) is further added thereto, followed by further stirring for 30 minutes. The precipitated crystals are filtered off, the crystals are added to methanol (3), and the mixture is stirred for 30 minutes. The crystals are filtered off, and dried to give 220 g of (a) (Yield 82percent). m.p. 187°C (MeOH-H2O) TLC (Merck No. 5714 Sol. CHCl3:MeOH=10:1) Rf=0.49 IR (Nujol) cm-1: 3230, 1585, 1510 1H-NMR (DMSO-D6) delta ppm: 5.03 (2H, s, -CH2-O), 7.35 (5H, s, C-phenyl), 11.0 (3H, br-s, -NH-NH2 * HCl)

	With stannous chloride; sodium nitrite; In hydrogenchloride; methanol; ethanol; water;	Thus, p-benzyloxyaniline hydrochloride (72.6 g) was diazotized with conc. HCl (174 ml) and sodium nitrite (23.2 g) in water (40 ml) at 0° C. A solution of stannous chloride (169.3 g) in conc. HCl (435 ml) was added rapidly and the reaction mixture stirred for two hours. The solid product was filtered and washed with absolute ethanol, then partially dissolved in boiling methanol/ethanol (1:1) and filtered hot, yielding 52.5 g of p-benzyloxyphenylhydrazine hydrochloride.
	With stannous chloride; sodium nitrite; In hydrogenchloride; ethanol; water;	To a stirred slurry of 12.5 g. of 4-benzyloxyaniline hydrochloride in 30 ml. concentrated hydrochloric acid and 30 ml. of water, cooled to -5°C., was added dropwise a solution of 4 g. sodium nitrite in 5 ml. of water. With continued cooling at 0° to -5°C. there was added 35 g. of stannous chloride in 90 ml. of concentrated hydrochloric acid and the mixture was allowed to stand with ice-bath cooling for 3 hours. The solid was collected, slurried in ethyl alcohol and filtered to give 11.9 g. of 4-benzyloxyphenylhydrazine hydrochloride; m.p. 185°-187°C. (aqueous ethyl alcohol).
	With stannous chloride; sodium nitrite; In hydrogenchloride; ethanol; water;	To a stirred slurry of 12.5 g. of 4-benzyloxyaniline hydrochloride in 30 ml. concentrated hydrochloric acid and 30 ml. of water, cooled to -5° C., was added dropwise a solution of 4 g. sodium nitrite in 5 ml. of water. With continued cooling at 0° to -5° C. there was added 35 g. of stannous chloride in 90 ml. of concentrated hydrochloric acid and the mixture was allowed to stand with ice-bath cooling for 3 hours. The solid was collected, slurried in ethyl alcohol and filtered to give 11.9 g. of 4-benzyloxyphenylhydrazine hydrochloride; m.p. 185°-187° C. (aqueous ethyl alcohol).

Reference： [1]Patent: WO2012/78859,2012,A2 .Location in patent: Page/Page column 47
[2]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 4075 - 4099
[3]Patent: EP427860,1991,A1
[4]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 3387 - 3402
[5]Patent: US5102891,1992,A
[6]Patent: US3959309,1976,A
[7]Patent: US4062864,1977,A
[8]Patent: WO2014/186325,2014,A1 .Location in patent: Page/Page column 25

31
tin(II)chloride dihydrate [ No CAS ]
[ 51388-20-6 ]
[ 52068-30-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium nitrite; In hydrogenchloride; water;	(i) [4-(Phenylmethoxy)phenyl]hydrazine hydrochloride A solution of sodium nitrite (16.1 g) in water was added dropwise over a period of ca 0.75 h to a cold (salt-ice bath) stirred suspension of 4-benzyloxyaniline hydrochloride (50 g) in concentrated hydrochloric acid (120 ml). The temperature was kept between -6° and -12° during the addition and stirring was continued for 1 h at the same temperature. The mixture was filtered (Hyflo) and the filtrate cooled to ca -18°. The solution of the diazonium salt was then added to a cold (-12°) stirred solution of tin (II) chloride dihydrate (157.9 g) in concentrated hydrochloric acid (400 ml) over a period of ca 0.5 h. During the addition the temperature gradually rose to 0°, and subsequently stirring was continued for 2 h while allowing the reaction mixture to reach room temperature. Filtration of the suspension afforded a solid. This material was washed with anhydrous ether (750 ml) and dried at room temperature for ca 16 h to present the title compound as a powder (34.4 g) m.p. 165°-170°. T.l.c. (E), Rf 0.5.

Reference： [1]Patent: US4725615,1988,A

32
[ 51388-20-6 ]
[ 6046-93-1 ]
[ 22921-68-2 ]
[ 54197-69-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; acetic acid; In N-methyl-acetamide; water;	(a) 2-(4-Benzyloxyphenylamino)-5-methoxybenzoic acid. To a 5 L 3-neck flask was added 282 g (2.06 moles) milled potassium carbonate and 1.0 L dimethylformamide. While stirring the resulting mixture at room temperature, 250 g (1.06 moles) <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> was added portionwise over 15 minutes. After this was completed, 231 g (1.0 mole) 2-bromo-5-methoxybenzoic acid was added over 15 minutes and the mixture was stirred for another 15 minutes. The suspension was cooled to 10-15 C. and 13.8 g cupric acetate monohydrate (0.06 moles) was added portionwise over 20 minutes. Gas evolved slowly and after stirring 15 minutes at room temperature the reaction was warmed on a steam bath over 40 minutes to 70 C. whereupon a vigorous evolution of carbon dioxide was observed. Stirring and heating was continued for 90 minutes at 80-85 C., heat was removed and the mixture was allowed to cool to room temperature. The brownish red suspension was transferred to a 12 L flask containing 1 L ice-cold water. Acetic acid (650 ml) was added dropwise and the dark green precipitate was stirred vigorously until homogenous. After filtering and washing well with water, the crude product was dried overnight at 55-60 C. in a vacuum oven. The crude product (approximately 350 g) was diluted with 5.8 L toluene, heated to reflux temperature and filtered. The dark green filtrate was alowed to cool to room temperature for 2-3 hours, and the solid product was collected by filtration and rinsed with cold (5-10 C.) toluene. The bright yellow crystalline product was obtained in 80% yield.
80%	With potassium carbonate; acetic acid; In N-methyl-acetamide; water;	(a) 2-(4-Benzyloxyphenylamino)-5-methoxybenzoic acid To a 5 L 3-neck flask was added 284 g (2.06 moles) milled potassium carbonate and 1.0 L dimethylformamide. While stirring the resulting mixture at room temperature, 250 g (1.06 moles) <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> was added portionwise over 15 minutes. After this was completed, 231 g (1.0 mole) 2-bromo-5-methoxybenzoic acid was added over 15 minutes and the mixture was stirred for another 15 minutes. The suspension was cooled to 10-15 C. and 13.8 g cupric acetate monohydrate (0.06 moles) was added portionwise over 20 minutes. Gas evolved slowly and after stirring 15 minutes at room temperature the reaction was warmed on a steam bath over 40 minutes to 70 C. whereupon a vigorous evolution of carbon dioxide was observed. Stirring and heating was continued for 90 minutes at 80-85C., heat was removed and the mixture was allowed to cool to room temperature. The brownish red suspension was transferred to a 12 L flask containing 1 L ice-cold water. Acetic acid (650 ml) was added dropwise and the dark green precipitate was stirred vigorously until homogeneous. After filtering and washing well with water, the crude product was dried overnight at 55-60 C. in a vacuum oven. The crude product (approximately 350 g) was diluted with 5.8 L toluene, heated to reflux temperature and filtered. The dark green filtrate was allowed to cool to room temperature for 2-3 hours, and the solid product was collected by filtration and rinsed with cold (5-10 C.) toluene. The bright yellow crystalline product was obtained in 80% yield. A sample of the compound had the m.p. 167-168 C. when recrystallized from a benzene-cyclohexane mixture.

Reference： [1]Patent: US4496590,1985,A
[2]Patent: US4515980,1985,A

33
WSCI·HCl [ No CAS ]
[ 267416-43-3 ]
[ 51388-20-6 ]
[ 267415-89-4 ]

Yield	Reaction Conditions	Operation in experiment
59%	With benzotriazol-1-ol; triethylamine; In chloroform;	Example 39 3-Hydroxy-4-methoxy-4'-benzyloxypicolinanilide: <strong>[51388-20-6]4-Benzyloxyaniline hydrochloride</strong> (0.21 g, 0.87 mmol), 0.15 g (0.73 mmol) of 3-hydroxy-4-methoxypicolinic acid hydrochloride, 0.15 g (1.10 mmol) of 1-hydroxybenzotriazole, and 0.16 g (1.10 mmol) of triethylamine were mixed into chloroform to prepare a suspension (2 ml). A chloroform solution (2 ml) of WSCI·HCl (0.21 g, 1.10 mmol) and 0.11 g (1.10 mmol) of triethylamine were added dropwise at -20C to this suspension, and a reaction was then allowed to proceed at room temperature overnight. The reaction mixture was concentrated under the reduced pressure. The concentrate was redissolved in chloroform. The solution was washed with saturated brine, and was then dried over anhydrous sodium sulfate. The dried solution was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform) to give 0.15 g (yield 59%) of title compound.

Reference： [1]Patent: EP1134214,2001,A1

34
[ 453-71-4 ]
[ 51388-20-6 ]
[ 1056618-42-8 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 1; -V-(Pyridin-3-ylmethyl')-l-(4-f[4-(trifluoro-nethoxy'>benzylloxy)phenylVl/r-benzotriazole-5- carboxamide; 4-[4-(Benzyloxy)phenyl]amino}-3-nitrobenzoic acid; [88] A solution of 4-fluoro-3-nitrobenzoic acid (10.Og, 54.0mmol), <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (12.7g, 54.0mmol) and Et3N (7.5mL, 54.0mmol) in EtOH (54mL) was heated at reflux under N2 overnight. The reaction was then cooled to rt and acidified with aq HCl (4mL, few drops) to afford 4- [4-(benzyloxy)phenyl]amino}-3-nitrobenzoic acid as a red solid which was collected by filtration.

Reference： [1]Patent: WO2007/92403,2007,A1 .Location in patent: Page/Page column 15

35
[ 1027258-06-5 ]
[ 51388-20-6 ]
[ 1027257-19-7 ]

Yield	Reaction Conditions	Operation in experiment
27%		To a solution of lithium 3-(4-methyl-piperazin-l-yl)-lH-indazole-6-carboxylate (93mg, 0.35 mmol) in anhydrous DMF (5mL) was added EDC (81mg, 0.42mmol) and etaOBt (57mg, 0.42mmol). The mixture was stirred for 10 min. then Et3N (0.24mL, 1.75 mmol) and 4-benzoxyaniline»etaCl (78mg, 0.33 mmol) were added. The mixture was heated at 50 0C for 15 hr. The mixture was allowed to cool, diluted with ethyl acetate (50 mL) and washed with aqueous sodium bicarbonate (25 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography on silica yielded the title compound (35mg, 27%). m/z (M+H) = 442.54

Reference： [1]Patent: WO2008/61109,2008,A2 .Location in patent: Page/Page column 37-38

36
[ 1027258-14-5 ]
[ 51388-20-6 ]
[ 1027257-33-5 ]

Yield	Reaction Conditions	Operation in experiment
27%		To a solution of lithium l-methyl-3-(4-methyl-piperazin-l-yl)-lH-indazole-6- carboxylate (88mg, 0.32 mmol) in anhydrous DMF (5mL) was added EDC (73mg, 0.38mmol) and etaOBt (51mg, 0.38mmol). The mixture was stirred for 10 min. then Et3N (0.1 ImL, 0.80mmol) and 4-benzyloxyaniline»etaCl (0.09Og, 0.38 mmol) were added. The mixture was heated at 50 0C for 15 hr. The mixture was allowed to cool, diluted with ethyl acetate (50 mL) and washed with aqueous sodium bicarbonate (25 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography on silica yielded the title compound (32mg, 27%). m/z (M+H) = 456.56

Reference： [1]Patent: WO2008/61109,2008,A2 .Location in patent: Page/Page column 41

37
[ 1027258-94-1 ]
[ 51388-20-6 ]
[ 1027257-47-1 ]

Yield	Reaction Conditions	Operation in experiment
27%		To a solution of lithium 3-[(2-Dimethylamino-emyl)-methyl-amino]-lH-indazole- 6-carboxylate (77mg, 0.29 mmol) in anhydrous DMF (5mL) was added EDC (140mg, 0.73mmol) and etaOBt (47mg, 0.35mmol). The mixture was stirred for 10 min. then Et3N (0.16mL, O.l.lmmol) and 4-benzyloxyaniline»etaCl (0.076g, 0.32 mmol) were added. The mixture was heated at 50 0C for 15 hr. The mixture was allowed to cool, diluted with ethyl acetate (50 mL) and washed with aqueous sodium bicarbonate (25 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography on silica yielded the title compound (35mg, 27%). m/z (M+H) = 444.45.

Reference： [1]Patent: WO2008/61109,2008,A2 .Location in patent: Page/Page column 45

38
[ 1027258-97-4 ]
[ 51388-20-6 ]
[ 1027257-48-2 ]

Yield	Reaction Conditions	Operation in experiment
41%		To a solution of lithium 3-(4-Methyl-piperazin-l-yl)-lH-indazole-5-carboxylate (117mg, 0.44 mmol) in anhydrous DMF (5mL) was added EDC (102mg, 0.53mmol) and etaOBt (71mg, 0.53 mmol). The mixture was stirred for 10 min. then Et3N (0.18mL, <n="47"/>1.32mmol) and 4-benzyloxyaniline»HCl (0.114g, 0.48 mmol) were added. The mixture was heated at 50 C for 15 hr. The mixture was allowed to cool, diluted with ethyl acetate (50 niL) and washed with aqueous sodium bicarbonate (25 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography on silica yielded the title compound (80mg, 41%). m/z (M+H) = 442.54

Reference： [1]Patent: WO2008/61109,2008,A2 .Location in patent: Page/Page column 45-46

39
[ 1027258-97-4 ]
[ 51388-20-6 ]
[ 1027257-53-9 ]

Yield	Reaction Conditions	Operation in experiment
25%		To a solution of lithium 3-(4-Methyl-piperazin-l-yl)-lH-indazole-5-carboxylate (67mg, 0.24 mmol) in anhydrous DMF (5mL) was added EDC (56mg, 0.29mmol) and etaOBt (39mg, 0.29mmol). The mixture was stirred for 10 min. then Et3N (0.1OmL, 0.72 mmol) and 4-benzyloxyaniline*etaCl (0.062g, 0.26 mmol) were added. The mixture was heated at 50 0C for 15 hr. The mixture was allowed to cool, diluted with ethyl acetate (50 mL) and washed with aqueous sodium bicarbonate (25 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Chromatography on silica yielded the title compound (27mg, 25%). m/z (M+H) = 456.54

Reference： [1]Patent: WO2008/61109,2008,A2 .Location in patent: Page/Page column 47

40
[ 32315-10-9 ]
[ 951895-34-4 ]
[ 51388-20-6 ]
[ 1035233-28-3 ]

Yield	Reaction Conditions	Operation in experiment
28.2%		Example 6 Synthesis of N-[2-(benzyloxy)phenyl]-5-(2-hydroxyphenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazole-1-carboxamide (I-269) To a solution of <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (34.5 mg, 0.146 mmol) in DCE (1 mL) was added a solution of DIPEA (0.0525 mL, 0.302 mmol) in DCE (0.5 mL) at rt. Upon cooling to -78 C., triphosgene (14.4 mg, 0.0487 mmol) in DCE (1.0 mL) was added and the reaction mixture was allowed to warm to rt and stir for 1 h. The reaction mixture was then heated at 60 C. for and 2 h. The solution was allowed to cool to rt and then cooled to -78 C. whereupon a solution of 2-(3-pyridin-3-yl-4,5-dihydro-1H-pyrazol-5-yl)phenol (35.0 mg, 0.146 mmol) in DMF (0.5 mL) was added. The reaction mixture was shaken at rt for 15 hours. The reaction was quenched with the addition of water (2 mL) and extracted with DCM. The organic solutions were combined, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by RP-HPLC to give N-[2-(benzyloxy)phenyl]-5-(2-hydroxyphenyl)-3-pyridin-3-yl-4,5-dihydro-1H-pyrazole-1-carboxamide (19.20 mg, 28.2%). LCMS: (FA) ES+465.6, ES-463.2.

Reference： [1]Patent: US2008/171754,2008,A1 .Location in patent: Page/Page column 109-110

41
[ 1048697-94-4 ]
[ 51388-20-6 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	In isopropyl alcohol; at 110 - 115℃; for 5h;Product distribution / selectivity;	2) The starting iV-(4-benzyloxyphenyl)-alpha-amino-4-benzyloxypropiophenone (22) (30.4 g; 69.7 mmol) and 4-benzyloxyaniline hydrochloride (3.3 g; 13.9 mmol) were suspended in propan-2- ol (380 ml) and the mixture was heated up to 110-115C under an inert atmosphere in a pressure vessel. After 5 hours the heating was disconnected and the reaction mixture was stirred overnight. The crystallized beige product was filtered and washed with a small quantity of propan-2-ol. 24.2 g (82 %) of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole (3b) with the melting temperature of 152.0-153.2C were obtained.
79%	In ethanol; at 110 - 115℃; for 5h;Product distribution / selectivity;	Preparation of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-li7-indole (1)1) The starting N-(4-benzyloxyphenyl)-alpha-amino-4-benzyloxypropiophenone (22) (30.4 g; 69.7 mmol) and 4-benzyloxyaniline hydrochloride (3.3 g; 13.9 mmol) were suspended in ethanol (380 ml) and the mixture was heated to 110-1150C under an inert atmosphere in a pressure vessel. After 5 hours the heating was disconnected and the reaction mixture was stirred overnight. The crystallized white product was filtered and washed with ethanol. 23.3 g (79%) of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole (3b) with the melting temperature of 152.4-153.4C were obtained. 1H-NMR (DMSO) delta 10.65 (s, IH); 7.55 (d, 2H); 7.50 (d, <n="11"/>4H); 7.30-7.45 (m, 6H); 7.21(d, IH); 7.10 (d, 2H); 7.10 (d, IH); 6.91 (dd, IH); 5.16 (s, 2H); 5.11 (s, 2H); 2.33 (s, 3H). MS el m/z 419.

Reference： [1]Patent: WO2008/98527,2008,A1 .Location in patent: Page/Page column 5; 8; 9; 12
[2]Patent: WO2008/98527,2008,A1 .Location in patent: Page/Page column 5; 8-9

42
[ 51388-20-6 ]
[ 1655-07-8 ]
E-1-(4-benzyloxy-phenylazo)-2-oxo-cyclohexanecarboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%		<strong>[51388-20-6]4-Benzyloxyaniline hydrochloride</strong> (24.5 g, 99 mmol, 1.0 equiv) was crushed into a free-flowing powder and suspended in 100 g of ice-water in a 500 rnL round-bottomed flask with a stir bar. Concentrated HCl (16.8 rnL) was added and the flask was immersed in an ice-water bath and stirring was begun. A solution of sodium nitrite (6.8 g, 99 mmol, 1.0 equiv) in 25 mL of deionized water was slowly added over a period of 15 min to the aniline mixture. At each 5 min interval 5 g of ice was added to the reaction mix to maintain the internal temperature close to 0 0C. After the addition of the nitrite, most of the solid had dissolved and the tan solution was stirred at O 0C for 10 min.A second round-bottomed- flask (1000 mL in size with a stir bar) was charged with potassium hydroxide (17.5 g, 312 mmol, 3.15 equiv) and 100 mL of water. After the base dissolved (about 1 min), 100 g of ice was added followed by addition of ethyl 2-oxocyclohexanecarboxylate (16.4 g, 96 mmol, 0.97 equiv) which quickly dissolved in the basic solution. The beta-keto ester <n="45"/>anion solution was vigorously stirred while the diazonium solution was slowly poured into the cold basic solution. Immediately, a bright yellow-orange precipitate formed which hindered the stir bar. After the addition, the flask was swirled for 10 min on the rotovap and then 26 mL of concentrated HCl was added. The precipitate immediately began to coalesce into a dark red- orange gum. The water was carefully decanted and the gum was washed 3 x 250 mL of water followed by decantation of the supernatant. The red-orange gum was dried at 30 0C under high- vacuum. The crude l-(4-benzyloxy-phenylazo)-2-oxo-cyclohexanecarboxylic acid ethyl ester (35g, 93%) was used in the next step without further manipulation.

Reference： [1]Patent: WO2008/98096,2008,A1 .Location in patent: Page/Page column 43-44

43
[ 849217-48-7 ]
[ 51388-20-6 ]
[ 849217-59-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 2 - 4h;	To a 0 °C suspension of 4-benzyloxyaniline hydrochloride (47.0 g, 200 mmol) and 1- (4-FLUORO-PHENYLCARBAMOYL)-CYCLOPROPANECARBOXYLIC acid (49.1 g, 220 mmol) in CHUCK (400 mL) was added EDCI (38.2 g, 200 mmol). Stirring was continued at rt for 2-4 h until the reaction was complete. CH2C12 was removed under reduced pressure. H2O (300 mL) and MeOH (200 mL) were added, and the resulting mixture was stirred at rt for 30 min. After filtration and wash with H20, the solid was transferred to another flask containing 300 ML of sat. aqueous NAHCO3 solution. The mixture was stirred for another 30 min. The solid was filtered, washed with water, and dried over night on a lyophilizer, affording cyclopropane-l, L-DICARBOXYLIC acid (4-benzyloxy-phenyl)- amide (4-fluoro-phenyl) -amide (75.8g, 95percent yield) as an off-white solid.

Reference： [1]Patent: WO2005/30140,2005,A2 .Location in patent: Page/Page column 204

44
[ 4487-56-3 ]
[ 51388-20-6 ]
[ 850663-93-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 1h;	Step 1. 2-Chloro-5-nitro-N-{4-[(phenylmethyl) oxy] phenyl3-4-pyridinamine The product of Example 1, Step 3 (15.2 g, 78.7 mmol), 4- benzyloxyaniline'HCl (15.6 g, 78.7 mmol) and Et3N (27 mL, 196.9 mmol) were combined in DMF (125 mL) and heated to 60 °C for 1h. The reaction mixture was cooled and H20 (200 mL) was added dropwise over lh. The resulting yellow/orange precipitate was filtered and washed with Et20 to provide the title compound as a yellow powder (25.8 g, 92percent).

Reference： [1]Patent: WO2005/37197,2005,A2 .Location in patent: Page/Page column 100-101

45
[ 636-98-6 ]
[ 51388-20-6 ]
[ 1181377-25-2 ]

Yield	Reaction Conditions	Operation in experiment
31%		4-(BenzyIoxy)-N-(4-nitrophenyl)aniline 1: To a oven dried flask was charged with Pd(OAc)2 (81 mg, 0.36 mmol) and (S)-(-)-BINAP (336 mg, 0.54 mmol), followed by toluene (10 mL). The mixture was stirred under Ar at room temperature for 5 min. To this mixture was added 4-nitroiodobenzene (3.0 g, 12 mmol), <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (3.39 g, 14.4 mmol), Cs2CO3 (9.8 g, 30 mmol) and toluene (40 mL). The resulting mixture was heated under Ar at 100 C for 16 hrs, and then cooled to room temperature and poured into H2O (100 mL). The layers were separated. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried (MgSO4) and filtered. The filtrate was concentrated. The residue was purified via column chromatography (silica gel, 5-40% EtOAc/hexane) to give the desired product as an orange solid (1.2 g, 31 %). 1H NMR (CDCl3, 400 MHz) delta: 8.09 (d, J = 9.2 Hz, 2H), 7.30-7.49 (m, 5H), 7.15 (d, J = 9.2 Hz, 2H), 7.01 (d, J = 9.2 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 6.10 (br s, IH), 5.09 (s, 2H). MS: mJz = 321 (M+H+)+.

Reference： [1]Patent: WO2009/102498,2009,A1 .Location in patent: Page/Page column 120

46
[ 51388-20-6 ]
[ 460-00-4 ]
[ 1192319-10-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 110℃; for 2h;Sealed tube;	Example 12:1 (Procedure N)2-(3.4-Difluorophenylamino)-5-(4-(4-fluorophenylamino)phenoxy)benzoic acidStep 1 : 4-(Benzyloxy)-lambda/-(4-fluorophenyl)anilineA mixture of <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (400 mg, 1.7 mmol), 4-fluoro- bromobenzene (350 mg, 2.0 mmol), Pd(OAc)2 (7.06 mg, 0.03 mmol), BINAP (42.3 mg, 0.068 mmol), Cs2CO3 (1.66 g, 5.10 mmol) and toluene (10 mL) was stirred at 110 0C for 2 h in a sealed tube. The mixture was diluted (EtOAc), filtered and concentrated. Purification by chromatography gave the sub-title compound. Yield: 400 mg (80%).

Reference： [1]Patent: WO2009/127822,2009,A2 .Location in patent: Page/Page column 94

47
[ 348-61-8 ]
[ 51388-20-6 ]
[ 1192319-30-4 ]

Yield	Reaction Conditions	Operation in experiment
73%	With caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl;palladium diacetate; In toluene; at 110℃; for 12h;Sealed tube;	Examples 24:1 - 24:3 (Procedure AF)Step 1 : 4-Benzyloxy-lambda/-(3.4-difluorophenyl)anilineA mixture of 4-benzyloxyaniline hydrochloride (3.40 g, 14.4 mmol), 3,4-difluoro- bromobenzene (1.35 mL, 12.0 mmol), Pd(OAc)2 (54 mg, 0.24 mmol), BINAP (299 mg, 0.48 mmol), Cs2CO3 (11.7 g, 3.60 mmol) and toluene (50 mL) was stirred at 110 0C for 12 h in a sealed tube. The mixture was diluted (EtOAc), filtered and concentrated. Purification by chromatography gave the sub-title compound. Yield: 2.73 g (73%).

Reference： [1]Patent: WO2009/127822,2009,A2 .Location in patent: Page/Page column 108

48
[ 51388-20-6 ]
[ 874-90-8 ]
[ 726196-29-8 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (3g) in tetrahydrofuran (15ML), 1. OM sodium bis (trimethylsilyl) amide in tetrahydrofuran (26. 7ML) was added dropwise at room temperature. After the mixture was stirred for 20min, anisonitrile (1.69g) was added. The reaction mixture was stirred for 4hrs, and then poured into 300ML of ice-water. The precipitate was collected by filtration, washed with diisopropyl ether to give the target compound (3.3g). 1H NMR (200MHZ, DMSO-D6, D) : 3.8 (3H, s), 5. 05 (2H, s), 6.09 (2H, bs), 6.74-6. 8 (2H, m), 6.96 (4H, d, J=8.5Hz), 7.29-7. 49 (5H, m), 7.92 (2H, d, J=8.9Hz). MS m/e : 333 (M+H) +.

Reference： [1]Patent: WO2004/60367,2004,A1 .Location in patent: Page/Page column 29

49
[ 98-98-6 ]
[ 51388-20-6 ]
N-(4-(benzyloxy)phenyl)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%		A solution of pyridine-2-carboxylic acid (2.0 g, 8.48 mmol) in N,N-dimethylformamide (DMF) was treated with O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) (3.5 g, 9.33 mmol) and N,N-diisopropylethylamine (DIEA) (0.742 mL, 32.7 mmol) and stirred at room temperature for 10 min. <strong>[51388-20-6]4-Benzyloxyaniline hydrochloride</strong> (2.0 g, 8.48 mmol) was added to the solution, and stirring was continued for an additional 30 min. The solution was poured into a saturated aqueous solution of sodium bicarbonate on ice. Mechanically mixing the gummy residue in the bottom of the flask caused it to solidify. The product was collected by filtration, washed with water and dried to give a beige solid, 2.46 g (95%), which was used without further purification in the subsequent reaction. MS m/z 305 (MH+). 1H NMR(CDCl3) delta 5.07 (s, 2H), 7.0 (d, 2H), 7.30-7.50 (m, 6H), 7.70 (d, 2H), 7.92 (t, 1H), 8.32 (d, 1H) and 8.58 (d, 1H).
95%		A. Pyridine-2-carboxylic acid (4-benzyloxyphenyl) amide. A solution of pyridine-2-carboxylic acid (2.0 g, 8.48 mmol) in N, N- dimethylformamide (DMF) was treated with O-benzotriazol-1-yl-N, N, N ; N'- tetramethyluronium hexafluorophosphate (HBTU) (3.5 g, 9.33 mmol) and N, N- diisopropylethylamine (DIEA) (0.742 mL, 32.7 mmol) and stirred at room temperature for 10 min. <strong>[51388-20-6]4-Benzyloxyaniline hydrochloride</strong> (2.0 g, 8.48 mmol) was added to the solution, and stirring was continued for an additional 30 min. The solution was poured into a saturated aqueous solution of sodium bicarbonate on ice. Mechanically mixing the gummy residue in the bottom of the flask caused it to solidify. The product was collected by filtration, washed with water and dried to give a beige solid, 2.46 g (95%), which was used without further purification in the subsequent reaction. MS m/z 305 (MH+). 1H NMR (CDCI3). 6 5.07 (s, 2H), 7.0 (d, 2H), 7.30-7. 50 (m, 6H), 7.70 (d, 2H), 7.92 (t, 1 H), 8.32 (d, 1 H) and 8.58 (d, 1 H).

Reference： [1]Patent: US2005/182108,2005,A1 .Location in patent: Page/Page column 12
[2]Patent: WO2005/84663,2005,A1 .Location in patent: Page/Page column 37

50
[ 51388-20-6 ]
[ 6574-98-7 ]
[ 866598-55-2 ]

Yield	Reaction Conditions	Operation in experiment
98%		N- (4-Benzyvpheny)-2, 4-dichloro-benzamidine <strong>[51388-20-6]4-Benzyloxyaniline hydrochloride</strong> (5.0 g, 21.2 mmol) was dropwise added to a solution of ethylmagnesium bromide (44.5 ml, 1M in THF, 44.5 mmol) in 25 ml dry THF under nitrogen atmosphere. After stirring for 20 minutes a solution of 2, 4-dichlorobenzonitrile (3.65 g, 21.2 mmol) in 25 ml THF was added. The reaction mixture was stirred for 20 hours at room temperature. Water (50 ml) was carefully added. Extraction with EtOAc (2xlOO ml), drying (Na2S04), filtration and evaporation to dryness afforded 7.7 g (98%) of the title compound.

Reference： [1]Patent: WO2005/95354,2005,A1 .Location in patent: Page/Page column 33; 43

51
[ 1145-76-2 ]
[ 51388-20-6 ]

Yield	Reaction Conditions	Operation in experiment
91%	With hydrogenchloride; tin(II) chloride dihdyrate In ethanol at 80℃; for 9h;	4.1.1.2. Synthesis of intermediates 3a-c. General procedure: To a solution of 2 (0.06 mol) inEtOH (90 mL) was added SnCl22H2O (0.18 mol) and HCl (Conc. 15.40mL), and the resulting mixture was stirred at 80 C for 9 h. Removed most of the solvent in vacuo and the remanent mixture was cooled to0 C for 12 h. The precipitate was collected and washed with cool EtOH(5.0 mL) to give intermediate 3. 4-(Benzyloxy)aniline hydrochloride (3a) [26]. White solid; Yield91.0%; mp: 222-224 C; 1H NMR (400 MHz, DMS-d6) δ 10.16 (s, 2H),7.49-7.42 (m, 2H), 7.40 (t, J = 7.3 Hz, 2H), 7.34 (dq, J = 4.5, 2.6, 2.1Hz, 2H), 7.32 (d, J = 2.2 Hz, 1H), 7.15-7.08 (m, 2H), 5.13 (s, 2H); HRMS(ESI) calcd. for C13H14NO[M + H]+ 200.1075, found: 200.1085.
71%	Stage #1: benzyl 4-nitrophenyl ether With iododioxobis(triphenylphosphine)rhenium(V); Dimethylphenylsilane In toluene for 24h; Reflux; Stage #2: With hydrogenchloride In diethyl ether; toluene

Reference： [1]Chen, Rui; Cheng, Fei; Cui, Xing; Du, Yao; Fan, Ling-Ling; Guo, Bing; Li, Shu-Min; Tang, Lei; Wang, Jian-Ta; Wang, Li-Li; Wu, Hao-Shu; Yang, Sheng-Gang; Zhang, Ji-Quan; Zhang, Na-Na [Bioorganic Chemistry, 2021, vol. 115]
[2]De Noronha, Rita G.; Romao, Carlos C.; Fernandes, Ana C. [Journal of Organic Chemistry, 2009, vol. 74, # 18, p. 6960 - 6964]

52
[ 32315-10-9 ]
[ 51388-20-6 ]
[ 99931-82-5 ]
[ 1215855-10-9 ]

Yield	Reaction Conditions	Operation in experiment
66%		Example 1a) 4-(5-Bromo-pyrimidin-2-yl)-piperazine-1-carboxylic acid (4-benzyloxy-phenyl)-amideA solution of 707 mg (3 mmol) of 4-benzyloxy-phenylamine hydrochloride (Aldrich) and 1.13 ml. (6.6 mmol) of N,N-ethyl diisopropylamine in 10 ml_ of dichloromethane are added drop- wise to a solution of 297 mg (1 mmol) of triphosgene in 10 ml_ of dichloromethane at 00C. The reaction mixture is stirred for 15 minutes at 0C, then a mixture of 0.73 g (3 mmol) of 5- bromo-2-piperazin-1-yl-pyrimidine and 1.13 ml_ (6.6 mmol) of N.N-ethyl diisopropylamine in 10 ml_ of dichloromethane are added. After 30 min at 00C and overnight at room temperature, the solvent is evaporated and the residue is chromatographed on silica gel using a di- chloromethane/ethyl acetate gradient. Yield: 0.93 g (66 %)Elemental analysis: calcd.: C 56.42 H 4. 73 Br 17 .06 N 14 .95 found: C 56.11 H 4. 83 Br 16 .94 N 14 .77

Reference： [1]Patent: WO2010/28776,2010,A1 .Location in patent: Page/Page column 26

53
[ 51388-20-6 ]
[ 79463-77-7 ]
[ 929267-13-0 ]

Yield	Reaction Conditions	Operation in experiment
98%		Specifically, a mixture of 4-benzyloxyaniline hydrochloride 2b (10.26 g, 43.5 mmol) and triethylamine (4.40 g, 43.5 mmol) in 2-propanol (100 ml.) was stirred at ambient temperature. After 10 min, diphenylcyanocarbimidate 1 (10.37 g, 43.5 mmol) was added and stirring continued at ambient temperature. After 3.5 h the solids that formed were collected by filtration, washing with 2-propanol, to afford 3b (14.64 g, 98percent) as an off-white solid: 1H NMR (300 MHz, DMSO-d6) delta 10.68 (br s, 1H), 7.47-7.02 (m, 14H), 5.11 (s, 2H).

Reference： [1]Patent: WO2007/30680,2007,A2 .Location in patent: Page/Page column 138

54
[ 1256450-57-3 ]
[ 51388-20-6 ]
[ 118-92-3 ]
[ 1256450-59-5 ]

Yield	Reaction Conditions	Operation in experiment
46%		2-(2- { 3- [4-(benzyloxy)phenyl J-4-QXQ-3 ,4-dihydroquinazolin-2-yU ethyl)-4-isopropoxy- 1 H- isoindole-1.3f2ffl-dione (D-5) Anthranilic acid (1.0 g, 7.29 mmol), D-4 (2.02 g, 7.29 mmol), and triphenylphosphite (2.01 mL, 7.66 mmol) were dissolved in pyridine (20 mL) and heated in a sealed tube at 1000C for 2 hours. After cooling to room temperature, the tube was opened, 4- benzyloxyaniline hydrochloride (1.89 g, 8.02 mmol) was added and heating at 1000C was resumed for 4 hours. The pyridine was removed by azeotroping with toluene, and the residue was suspended in CHCI3 and toluene. The solids that crashed out were removed, and the residue was purified by silica gel chromatography with gradient elution (0 to 100% EtOAc in hexanes) to provide D-5 (1.9 g, 46%) as a while solid. Data for D-5: HRMS (ES) calculated M + H for C34H29N3O5: 560.2180; Found: 560.2195.

Reference： [1]Patent: WO2010/138585,2010,A1 .Location in patent: Page/Page column 48-49

55
5-[4-chloro-6-(4-methoxyphenylamino)[1,3,5]triazin-2-ylamino]-3-methylimidazolidine-2,4-dione [ No CAS ]
[ 51388-20-6 ]
5-[4-(4-benzyloxyphenylamino)-6-(4-methoxyphenylamino)[1,3,5]triazin-2-ylamino]-3-methylimidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With caesium carbonate; In N,N-dimethyl-formamide; at 30℃; for 19h;Inert atmosphere;	A suspension of 5-[4-Chloro-6-(4-methoxy-phenylamino)-[l ,3,5]triazin-2-ylamino]-3- methyl-imidazolidine-2,4-dione (Example 1.10, Part A) (93mg, 0.26mmol), p- benzyloxyaniline hydrochloride (132mg, 0.56mmol) and cesium carbonate (184mg, 0.56mmol) in anhydrous DMF (5 mL) was stirred under a nitrogen atmosphere over a 30C oil bath for 19h. The reaction mixture was diluted with water and the crude product was extracted with ethyl acetate. The organic layer was dried and evaporated and the crude product was purified by column chromatography (silica; dichloromethane:ethyl acetate starting with a solvent ratio of 10: 1 and increasing the polarity to dichloromethane:methanol, 20: 1). Recrystallization from PS/DCM/EtOAc gave the product as a cream solid (90mg, 62%). (Found: C, 61.5; H, 5.1 ; N, 21.2%. C27H26N804 requires C, 61.6; H, 5.0; N, 21.3%). deltaEta (300 MHz, CD3CN) 7.58-7.30 (m, 1 1H, ArH {ortho to NH attach), PhH and 2 NH), 6.94 (d, J 8.7 Hz, 2H, ArH {ortho to O attach)), 6.87 (d, J 8.7 Hz, 2H, ArH (ortho to O attach)), 6.49 (br s, 1H, NH), 6.14 (m, 1H, NH), 5.67 (d, J 7.2 Hz, 1H, CH), 5.09 (s, 2H, CH2), 3.78 (s, 3H, OCH3), 2.88 (br s, 3H, NCH3). Mass spectrum (ESI) m/z 527 (100%, MH+).

Reference： [1]Synthesis,2010,p. 4312 - 4316
[2]Patent: WO2012/54978,2012,A1 .Location in patent: Page/Page column 38

56
[ 51388-20-6 ]
[ 198480-56-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: triethylamine / N,N-dimethyl-formamide / 100 - 125 °C 2.1: sodium hydride / N,N-dimethyl-formamide; toluene / -5 - -1 °C 2.2: 5 °C 3.1: hydrogen / palladium 10% on activated carbon / ethyl acetate / 45 - 50 °C / 7355.72 Torr
	Multi-step reaction with 4 steps 1.1: triethylamine / N,N-dimethyl-formamide / 100 - 125 °C 2.1: sodium hydride / N,N-dimethyl-formamide; toluene / -5 - -1 °C 2.2: 5 °C 3.1: hydrogen / palladium 10% on activated carbon / water; acetone; methanol / 40 °C / 7355.72 Torr 4.1: hydrogenchloride / methanol

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2011/22596, 2011, A2
[2]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2011/22596, 2011, A2

57
[ 51388-20-6 ]
[ 198481-33-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: triethylamine / N,N-dimethyl-formamide / 100 - 125 °C 2.1: sodium hydride / N,N-dimethyl-formamide; toluene / -5 - -1 °C 2.2: 5 °C 3.1: hydrogen / palladium 10% on activated carbon / ethyl acetate / 45 - 50 °C / 7355.72 Torr 4.1: triethylamine / ethyl acetate; water / 0.25 h 4.2: 30 - 40 °C
	Multi-step reaction with 4 steps 1.1: triethylamine / N,N-dimethyl-formamide / 100 - 125 °C 2.1: sodium hydride / N,N-dimethyl-formamide; toluene / -5 - -1 °C 2.2: 5 °C 3.1: hydrogen / palladium 10% on activated carbon / water; acetone; methanol / 40 °C / 7355.72 Torr 4.1: ethyl acetate / 50 °C
	Multi-step reaction with 5 steps 1.1: triethylamine / N,N-dimethyl-formamide / 100 - 125 °C 2.1: sodium hydride / N,N-dimethyl-formamide; toluene / -5 - -1 °C 2.2: 5 °C 3.1: hydrogen / palladium 10% on activated carbon / water; acetone; methanol / 40 °C / 7355.72 Torr 4.1: hydrogenchloride / methanol 5.1: triethylamine / ethyl acetate; water / 0.25 h 5.2: 30 - 40 °C

Reference： [1]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2011/22596, 2011, A2
[2]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2011/22596, 2011, A2
[3]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2011/22596, 2011, A2

58
[ 1346163-83-4 ]
[ 51388-20-6 ]
[ 1346163-85-6 ]

Yield	Reaction Conditions	Operation in experiment
80%	With palladium diacetate; potassium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 140℃; for 1h;Inert atmosphere; Microwave irradiation;	General procedure: A solution of the halogenated derivative, the corresponding amine (1.5 eq.) and K2CO3 (2.0 eq.) in 1,4-dioxane was degassed under vigorous stirring by argon bubbling for 20 min. Pd(OAc)2 (10% mol./halogenated derivative) and Xantphos (20% mol./halogenated derivative) were then added and the mixture was charged in a microwave vial equipped with a stirring bar. It was subjected to irradiation for 1 h at 140 C. After cooling, water was added and the aqueous layers were extracted with EtOAc. The combined organic layers were successively washed with brine (10 mL), dried with MgSO4 and filtered off. The solvents were removed under reduced pressure and the crude material was purified by flash chromatography.

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 5416 - 5434

59
[ 5470-18-8 ]
[ 51388-20-6 ]
[ 1353677-07-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 100℃; for 5h;	Example 7; 3-[4-(1H-benzimidazol-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 7a) N-[4-(benzyloxy)phenyl]-3-nitropyridin-2-amine A mixture of 2-chloro-3-nitropyridine (2.0 g), <strong>[51388-20-6]4-(benzyloxy)aniline hydrochloride</strong> (3.6 g), and cesium carbonate (12.3 g) in NMP (50 mL) was heated at 100 C. for 5 h. After cooling to rt, the mixture was partitioned between AcOEt and H2O. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=1/1) to give N-[4-(benzyloxy)phenyl]-3-nitropyridin-2-amine (3.04 g) as a brown solid.MS (ESI+): [M+H]+322.0.

Reference： [1]Patent: US2011/319394,2011,A1 .Location in patent: Page/Page column 58

60
[ 23056-40-8 ]
[ 51388-20-6 ]
[ 1353678-08-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; triethylamine; In N,N-dimethyl-formamide; at 60 - 100℃;	Example 118; 1-ethyl-6-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 118a) N-[4-(benzyloxy)phenyl]-5-methyl-3-nitropyridin-2-amine To a mixture of <strong>[51388-20-6]4-(benzyloxy)aniline hydrochloride</strong> (4.10 g) and 2-chloro-5-methyl-3-nitropyridine (3.0 g) in DMF (30 mL) was added TEA (7.27 mL) at room temperature, and the mixture was stirred at room temperature for 2 h. The mixture was heated to 60 C. After stirring at 60 C. overnight, K2CO3 (4.81 g) was added to the mixture. The mixture was heated to 100 C. and stirred at 100 C. overnight. The mixture was poured into water and the mixture was extracted with AcOEt. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (dry charge, silica gel, eluted with 5%-30% AcOEt in hexane) to give N-[4-(benzyloxy)phenyl]-5-methyl-3-nitropyridin-2-amine (1.33 g) as a red solid.1H NMR (300 MHz, DMSO-d6) delta 2.26 (3H, s), 5.11 (2H, s), 6.96-7.05 (2H, m), 7.29-7.54 (7H, m), 8.32-8.38 (2H, m), 9.78 (1H, s).

Reference： [1]Patent: US2011/319394,2011,A1 .Location in patent: Page/Page column 89

61
[ 23056-39-5 ]
[ 51388-20-6 ]
[ 1353678-19-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; for 64h;Reflux;	Method C; 120f) N-[4-(benzyloxy)phenyl]-4-methyl-3-nitropyridin-2-amine A mixture of 2-chloro-4-methyl-3-nitropyridine (120.9 g), <strong>[51388-20-6]4-(benzyloxy)aniline hydrochloride</strong> (163 g) and DIPEA (600 ml) in DMSO (1400 mL) was refluxed for 64 h. During cooling the mixture, water (1000 ml) was slowly added portionwise to the reaction mixture. The mixture was cooled to 15 C. in ice bath, and stirred for 2.5 h. The precipitate was collected by filtration, washed with water (2 L) and IPE (1.5 L), and dried in vacuo to give N-[4-(benzyloxy)phenyl]-4-methyl-3-nitropyridin-2-amine (158 g, 471 mmol, 93%) as a red powder.1H NMR (300 MHz, DMSO-d6) 5 ppm 2.34 (s, 3H) 5.09 (s, 2H) 6.79 (d, J=5.27 Hz, 1H) 6.86-7.04 (m, 2H) 7.25-7.50 (m, 7H) 8.12 (d, J=4.90 Hz, 1H) 8.87 (s, 1H).
10.7 g	With triethylamine; In dimethyl sulfoxide; at 120℃;	A suspension of 2-chloro-4-methyl-3-nitropyridine (8.63 g), <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (13.0 g) and triethylamine (20.9 ml) in DMSO (150 ml) was stirred at 120 C. overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (10.7 g). [0544] 1H NMR (300 MHz, CDCl3) delta 2.57 (3H, s), 5.07 (2H, s), 6.61 (1H, d, J=4.9 Hz), 6.96-7.01 (2H, m), 7.29-7.46 (7H, m), 8.15 (1H, d, J=4.9 Hz), 9.10 (1H, s).

Reference： [1]Patent: US2011/319394,2011,A1 .Location in patent: Page/Page column 93
[2]Patent: US2013/331409,2013,A1 .Location in patent: Paragraph 0543-0544

62
[ 75-30-9 ]
[ 1353677-93-6 ]
[ 51388-20-6 ]
[ 1353678-40-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1266-chloro-1-(1-methylethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 126a) 3-[4-(benzyloxy)phenyl]-6-chloro-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Di-tert-butyl dicarbonate (17.05 mL) was added to a solution of 2,5-dichloropyridin-3-amine (11.4 g) and NaHMDS (81 mL) in THF (dry) (200 mL) at 0 C. The mixture was stirred at 0 C. under a dry atmosphere for 1 h. The mixture was neutralized with 1N HCl at 0 C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-20% EtOAc in hexane) to give tert-butyl 2,5-dichloropyridin-3-ylcarbamate (15.6 g) as colorless oil. The mixture of tert-butyl 2,5-dichloropyridin-3-ylcarbamate (7.5 g), <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (10.08 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (1.319 g), Pd2(dba)3 (1.044 g) and sodium tert-butoxide (6.57 g) in toluene (160 mL)-2-propanol (40.0 mL) was stirred at 100 C. under Ar overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give intermediate. To the intermediate in DMF (100 mL) were added 2-iodopropane (5.69 mL) and NaH (2.280 g), and the mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) for 1 h. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-6-chloro-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (560 mg) as a colorless solid.MS (API+): [M+H]+ 394.2.1H NMR (300 MHz, DMSO-d6) delta 1.41-1.57 (6H, m), 4.57-4.78 (1H, m), 5.18 (2H, s), 7.09-7.21 (2H, m), 7.26-7.60 (7H, m), 7.81-8.08 (2H, m).

Reference： [1]Patent: US2011/319394,2011,A1 .Location in patent: Page/Page column 101-102

63
[ 61494-55-1 ]
[ 51388-20-6 ]
[ 1353677-15-2 ]

Yield	Reaction Conditions	Operation in experiment
	With toluene-4-sulfonic acid; In pentan-1-ol; at 140℃; for 24h;	Example 9; 1-[4-(1H-benzimidazol-2-yloxy)phenyl]-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one dihydrochloride 9a) 1-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one A mixture of 4-(benzyloxy)aniline hydrochloride (2.21 g), 4-methylbenzenesulfonic acid hydrate (0.178 g), and <strong>[61494-55-1](2-chloropyridin-3-yl)acetic acid</strong> (Journal of Medicinal Chemistry, 1990, 33, 2697-2706.) (1.61 g) in 1-pentanol (15 mL) was stirred at 140 C. for 24 h. After cooling to room temperature, the mixture was added to SiO2, and the mixture was concentrated and purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (1.39 g) as a pale yellow solid.MS (ESI+): [M+H]+317.0.

Reference： [1]Patent: US2011/319394,2011,A1 .Location in patent: Page/Page column 60

64
[ 51388-20-6 ]
[ 209798-48-1 ]
[ 1353677-08-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In isopropyl alcohol; toluene; at 100℃;Inert atmosphere;	Example 31; 1-ethyl-3-[4-(imidazo[1,2-a]pyridin-2-yloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 31a) 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one The mixture of tert-butyl 2-chloropyridin-3-ylcarbamate (12.5 g), <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (19.3 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (2.53 g), Pd2(dba)3 (2.0 g) and sodium tert-butoxide (12.6 g) in toluene (160 ml)-2-propanol (40.0 mL) was stirred at 100 C. under Ar overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-100% EtOAc in hexane) to give 3-[4-(benzyloxy)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (12 g) as a light brown solid.MS (API+): [M+H]+318.1.1H NMR (300 MHz, DMSO-d6) delta 5.18 (2H, s), 7.02-7.22 (3H, m), 7.29-7.59 (8H, m), 7.86-7.94 (1H, m), 11.11-11.64 (1H, m).

Reference： [1]Patent: US2011/319394,2011,A1 .Location in patent: Page/Page column 67

65
[ 1353677-48-1 ]
[ 51388-20-6 ]
[ 1353678-16-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In isopropyl alcohol; toluene; at 100℃; for 24h;Inert atmosphere;	Example 120; 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one Method A120a) 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one A mixture of tert-butyl (2-chloro-4-methylpyridin-3-yl)carbamate (2.00 g), <strong>[51388-20-6]4-(benzyloxy)aniline hydrochloride</strong> (2.91 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (381 mg), sodium t-butoxide (1.90 g) and Pd2(dba)3 (302 mg) in 2-propanol (6 mL) and toluene (24 mL) was stirred at 100 C. under N2 atmosphere for 24 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in MeOH, and the precipitate was removed by filtration. The filtrate was concentrated and the residue was purified by column chromatography (NH silica gel, eluted with 15%-50% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (988 mg) as a colorless solid.MS (API+): [M+H]+332.3.1H NMR (300 MHz, CDCl3) delta 2.39 (3H, s), 5.12 (2H, s), 6.87 (1H, d, J=5.3 Hz), 7.12 (2H, d, J=9.0 Hz), 7.28-7.50 (5H, m), 7.57 (2H, d, J=8.7 Hz), 7.96 (1H, d, J=5.3 Hz), 9.93 (1H, brs).
	With 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); In isopropyl alcohol; toluene; at 100℃; for 24h;Inert atmosphere;	a) 3- [ 4- (benzyloxy) phenyl] - -methyl-1 , 3-dihydro-2H-imidazo [4,5- b] pyridin-2-one[0095][0096]A mixture of tert-butyl (2-chloro-4-methylpyridin-3- yl) carbamate (2.00 g) , 4- (benzyloxy) aniline hydrochloride(2.91 g) , 9, 9-dimethyl-4 , 5-bis (diphenylphosphino) xanthene (381 mg) , sodium tert-butoxide (1.90 g) and Pd2(dba)3 (302 mg) in 2- propanol (6 mL) and toluene (24 mL) was stirred under anitrogen atmosphere at 100C for 24 hr. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol, and the precipitates were filtered off. The filtrate was concentrated, and the residue was purified by column chromatography (NH silica gel, eluted with 15% - 50% ethyl acetate in hexane) to give 3- [ 4- (benzyloxy) phenyl ] -7- methyl-1, 3-dihydro-2H-imidazo [4, 5-b] pyridin-2-one (988 mg) as a colorless solid. MS (API+) : [M+H]+ 332.3.XH NMR (300 MHz, CDC13) delta 2.39 (3H, s) , 5.12 (2H, s) , 6.87 (1H, d, J = 5.3 Hz), 7.12 (2H, d, J = 9.0 Hz), 7.28-7.50 (5H, m) , 7.57 (2H, d, J = 8.7 Hz), 7.96 (1H, d, J = 5.3 Hz), 9.93 (1H, brs) .

Reference： [1]Patent: US2011/319394,2011,A1 .Location in patent: Page/Page column 91-92
[2]Patent: WO2012/176934,2012,A1 .Location in patent: Page/Page column 31

66
[ 1252655-98-3 ]
[ 51388-20-6 ]
[ 1252657-57-0 ]

Yield	Reaction Conditions	Operation in experiment
90%		Example 198 N-[4-(Benzyloxy)phenyl]-2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetamide A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoacetic acid (Example 44, 2.5 g, 8.61 mmol), <strong>[51388-20-6]4-(benzyloxy)aniline hydrochloride</strong> (2.06 g, 10.3 mmol), triethylamine (1.8 mL, 12.9 mmol), EDCI (1.6 g, 10.3 mmol) and HOBt (1.58 g, 10.3 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with saturated NaHCO3 solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate 90:10 to 65:35) to give the title compound (3.64 g, 90%) as a white amorphous. 1H NMR (300 MHz, CDCl3) delta ppm 1.46 (s, 9H), 2.85-3.18 (m, 5H), 3.40-3.54 (m, 1H), 4.61 (dd, J=12.7, 2.1 Hz, 1H), 5.06 (s, 2H), 5.31 (dd, J=13.1, 2.1 Hz, 1H), 6.92-7.02 (m, 2H), 7.12-7.47 (m, 9H), 7.49-7.58 (m, 2H), 9.16 (s, 1H). LC/MS; ESI(+) m/z: 472 (M+H)+.

Reference： [1]Patent: US2012/71489,2012,A1 .Location in patent: Page/Page column 115

67
[ 51388-20-6 ]
[ 79-22-1 ]
[ 693830-78-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With triethylamine; In dichloromethane; at 20℃; for 8h;Inert atmosphere;	To a solution of <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (4 mmol) and triethylamine (4.4 mmol) in anhydrous dichloromethane (5 mL) was added methyl chloroformate (6 mmol). The mixture was stirred at ambient temperature for 8 h. Saturated NaHCO3 was added to the mixture. The compound was extracted with dichloromethane, dried over Na2SO4, and concentrated under reduced pressure. The residue was used in the next step without further purification (90% yield).

Reference： [1]Chemical Communications,2012,vol. 48,p. 7380 - 7382

68
[ 124-07-2 ]
[ 51388-20-6 ]
[ 881771-86-4 ]

Yield	Reaction Conditions	Operation in experiment
70%		Octanoic acid (4-benzyloxyphenyl)amide (7). To an ice cooled solution of 6 (0.61 g, 4.2 mmol) in anhydrous dichloromethane was added EDCI (0.9 g, 4.7 mmol) followed by HOBt (0.63 g, 4.7 mmol) and stirred for 1 h. To this, was then added a solution of 4 (0.023 g, 0.14 mmol) and DIPEA (1.5 mL, 8.5 mmol) in anhydrous dichloromethane at 0 C and stirred for 8 h. The reaction mixture was treated with 2 N aqueous HCl solution and extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 solution followed by brine. The organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was further purified by flash chromatography (90:30 ? 50:50, hexanes:EtOAc) to afford 7 as a light brown solid (0.97 g, 70%). 1H NMR (400 MHz, CDCl3): delta 7.44-7.32 (m, 7H), 6.93 (d, J = 8.8 Hz, 2H), 5.05 (s, 2H), 2.34 (t, J = 7.6 Hz, 2H), 1.76-1.69 (m, 2H), 1.34-1.31 (m, 8H), 0.91 (t, J = 6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): delta 171.4, 155.5, 136.9, 131.4, 128.6 (2C), 127.9, 127.4 (2C), 121.7, 115.1, 70.3, 37.6, 31.7, 29.3, 29.0, 25.7, 22.6, 14.1.HRMS (ESI) m/z [M+H]+ calcd for C21H28NO2 326.2120, found 326.2119

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 6621 - 6627

69
[ 1282038-93-0 ]
[ 51388-20-6 ]
[ 1282038-94-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 65℃;	To a solution of cyanuric chloride (1.14 eqs.) and methyl 4-amino benzoate (1.0 eq.) in THF (3.0 mL) was added 'Pr2NEt (4.0 eqs.). The reaction mixture was stirred at ambient temperature for 1 hour. To the solution was then added 4-[(N- Boc)aminomethyl] aniline (1.3 eqs.) and the reaction mixture warmed to 50 C and stirred overnight. The reaction mixture was then cooled and partitioned between EtOAc and water. The layers were separated and the aqueous extracted with EtOAc (3x). The combined organics were dried over Na2S04, filtered and concentrated in vacuo. The residue was used without further purification.[000136] To a solution of the residue (1.0 eq.) and 4-benzyloxy aniline hydrochloride (2.0 eqs.) in THF (3.5 mL) was added 'Pr2NEt (4.0 eqs). The reaction mixture was warmed to 65 C and stirred overnight. The reaction mixture was concentrated in vacuo and the residue filtered over a plug of silica gel (2: l/hexanes:EtOAc 98:2/CH2Cl2:MeOH). The organics collected from the 98:2/CH2Cl2:MeOH elution were concentrated in vacuo and the obtained residue was used without further purification.

Reference： [1]Patent: WO2011/37610,2011,A1 .Location in patent: Page/Page column 61

70
[ 20920-99-4 ]
[ 51388-20-6 ]
N-(4-benzyloxyphenyl)-3-(2-hydroxy-5-nitrophenyl)propanamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With sodium hydrogencarbonate; In tetrahydrofuran;Reflux;	To a stirred solution of compound 14(1.00 g, 5.18 mmol) in THF (20 mL) was added NaHCO3 (0.66 g,7.77 mmol) and <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (1.22 g,5.18 mmol). The resulting mixture was stirred at reflux for 12 hand then was evaporated. The residue was recrystallized from ethanol(50 mL) affording compound 15e (1.20 g, 59%) as an orangepowder, mp 239-241 C. HRMS (NSI) for C22H20N2O5. Calculatedmass of molecular ion 393.1445 [M+H]+. Measured mass:393.1450; IR mmax cm1 3364, 1612, 1539, 1326, 1286, 1241, 827;1H NMR (270 MHz; d6-DMSO) dH 11.14 (1H, br, s, OH), 9.78 (1H,s, NH), 8.04 (1H, d, J = 3.0 Hz, Ar-H), 7.98 (1H, dd, J = 8.9 and3.0 Hz, Ar-H), 7.49-7.28 (7H, m, Ar-H), 6.94 (3H, t, J = 8.5 Hz, Ar-H), 5.03 (2H, s, CH2O), 2.88 (2H, t, J = 7.6 Hz, CH2CH2CO), 2.58(2H, t, J = 7.6 Hz, CH2CO); 13C NMR (68 MHz; d6-DMSO) dC 170.3(CO), 162.5 (Ar-C), 154.7 (Ar-C), 139.9 (Ar-C), 137.8 (Ar-C),133.1 (Ar-C), 129.2 (Ar-C), 129.0 (2 Ar-C), 128.3 (Ar-C), 128.2(2 Ar-C), 126.1 (Ar-C), 124.5 (Ar-C), 121.2 (2 Ar-C), 115.6(Ar-C), 115.4 (2 Ar-C), 69.9 (CH2O), 35.9 (CH2), 25.8 (CH2).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 5249 - 5269

71
2-(4-methyl-N-(3-(trifluoromethyl)phenyl)phenylsulfonamido)acetic acid [ No CAS ]
[ 51388-20-6 ]
N-(4-(benzyloxy)phenyl)-2-(4-methyl-N-(3-(trifluoromethyl)phenyl)phenylsulfonamido)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
28%		4.3.5 N-(4-(benzyloxy)phenyl)-2-(4-methyl-N-(3-(trifluoromethyl)phenyl)phenylsulfonamido)acetamide (15) To a solution of compound 13aa (80 mg, 0.2 mmol) in DMF was added HOBT (34.7 mg, 0.3 mmol) and DIC (32.4 mg, 0.3 mmol) and stirred at room temperature for 10 min. <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (75.7 mg, 0.3 mmol) was added and the reaction was stirred at room temperature for 5 h. Water was added, the aqueous layer was extracted with ethyl acetate (150 mL * 3), and the organic layer was washed with brine, dried with Na2SO4 and evaporated. The residue was purified by silica gel chromatography with petroleum ether/ethyl acetate (4/1, v/v) to afford 15 (33 mg, 28%) as white solid. 1H NMR (500 MHz, DMSO) delta 9.95 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.60 (m, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.1 Hz, 1H), 7.43 (m, 8H), 7.34 (m, 1H), 6.96 (m, 2H), 5.04 (s, 2H), 4.50 (s, 2H), 2.40 (s, 3H). 13C NMR (500 MHz, DMSO) delta 166.01, 155.44, 144.95, 141.63, 138.03, 135.75, 132.65, 132.30, 131.08, 130.68, 130.54 (q, JC-F = 130 Hz), 129.29, 128.67, 128.54, 128.31, 125.45, 124.99, 123.48, 121.78, 70.27, 54.15, 21.91. MS (ESI), m/z for C29H25F3N2O4S ([M+H]+): calcd 554.58, found 555.2.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 116,p. 13 - 26

72
[ 51388-20-6 ]
[ 3731-16-6 ]
[ 101783-07-7 ]

Yield	Reaction Conditions	Operation in experiment
		[0156] In a mixture of 84 mL of dimethyl formamide and 90 mL of 4.5 M hydrochloric acid was suspended 14.0 g of4-(benzyloxy) aniline hydrochloride. To the obtained mixture was slowly added 22.9 mL of an aqueous solution of 4.51g of sodium nitrite under ice-cooling, followed by stirring for 2.5 hours under ice-cooling (solution A). To 11.0 g of ethyl2-oxopiperidine-3-carboxylate was added 72.5 mL of a 1 M aqueous potassium hydroxide solution, followed by stirringat room temperature for 1.5 hours (solution B). To the previously obtained solution A was added the solution B underice-cooling, followed by adjusting to pH 4.6 by the addition of a saturated aqueous sodium acetate solution, and stirringfor 4 hours under ice-cooling. The precipitated solid was collected by filtration to obtain 5.94 g of 3-[4-(benzyloxy)phenyl]hydrazono}piperidin-2-one (a mixture of E and Z isomers) as a solid.

Reference： [1]Patent: EP3095781,2016,A1 .Location in patent: Paragraph 0156

73
5-chloro-2-(triisopropylsilyl)isoindole-1,3-dione [ No CAS ]
[ 51388-20-6 ]
5-(4-(benzyloxy)phenyl)amino-2-(triisopropylsilyl)isoindole-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.2%	With palladium diacetate; caesium carbonate; XPhos; In toluene; at 110℃; for 24h;Inert atmosphere;	The intermediate compound 5 (0.00059 mol) was reacted with <strong>[51388-20-6]4-(benzyloxy)aniline hydrochloride</strong> (0.00071 mol), Palladium acetate (0.000024 mol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (0.000048 mol), cesium carbonate (0.0015 mol) in 2 ml of toluene and heating at 110 C for 24 hours under nitrogen protection. The reaction mixture was distilled off on a silica gel column (petroleum ether / dichloromethane = 1/1) to give the intermediate compound 6 as a pale yellow solid in a yield of 55.2%

Reference： [1]Patent: CN104447496,2017,B .Location in patent: Paragraph 0067; 0076; 0077

74
5-chloro-6-nitro-2-(triisopropylsilyl)isoindole-1,3-dione [ No CAS ]
[ 51388-20-6 ]
5-((4-(benzyloxy)phenyl)amino)-6-nitro-2-(triisopropylsilyl)isoindole-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57.5%	With palladium diacetate; caesium carbonate; XPhos; In toluene; at 110℃; for 24h;Inert atmosphere;	The intermediate compound 12 (0.00059 mol), <strong>[51388-20-6]4-(benzyloxy)aniline hydrochloride</strong> (0.00071 mol), palladium acetate (000024 mol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (000048 mol) cesium carbonate (0 · 0015 mol), 2 ml of toluene was added, and heated at 110 C for 24 hours under nitrogen protection.The reaction solution was filtered and the filter cake was washed with hot toluene. The solvent was distilled off by steaming and the residue was recrystallized from ethanol to give intermediate compound 13 as a red solid in 57.5% yield,

Reference： [1]Patent: CN104447496,2017,B .Location in patent: Paragraph 0090;0095; 0096

75
[ 63197-17-1 ]
[ 51388-20-6 ]
2-methyl 5-((4-(benzyloxy)phenyl)amino)isoindole-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.7%	With palladium diacetate; caesium carbonate; XPhos; In toluene; at 110℃; for 24h;Inert atmosphere;	General procedure: A mixture of intermediate compound 17 (0.00059 mol), <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (0.0007 1 mol)Palladium acetate (000024 mol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (000048 mol)Cesium carbonate (0.0015 mol) was added to a solution of dry toluene (2 ml) and heated at 110 C for 24 hours under nitrogen. The reaction mixture was filtered and the filter cake was washed with hot toluene. The filtrate was steamed to remove most of the solvent. The resulting residue was combined with the cake and recrystallized from toluene. The resulting solid was recrystallized from ethanol to give the title compound 18. 18a: yellow solid in a yield of 62.7%

Reference： [1]Patent: CN104447496,2017,B .Location in patent: Paragraph 0090; 0110-0113

76
[ 51388-20-6 ]
[ 136860-33-8 ]
2-benzyl 5-((4-(benzyloxy)phenyl)amino)isoindole-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.4%	With palladium diacetate; caesium carbonate; XPhos; In toluene; at 110℃; for 24h;Inert atmosphere;	General procedure: A mixture of intermediate compound 17 (0.00059 mol), <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (0.0007 1 mol)Palladium acetate (000024 mol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (000048 mol)Cesium carbonate (0.0015 mol) was added to a solution of dry toluene (2 ml) and heated at 110 C for 24 hours under nitrogen. The reaction mixture was filtered and the filter cake was washed with hot toluene. The filtrate was steamed to remove most of the solvent. The resulting residue was combined with the cake and recrystallized from toluene. The resulting solid was recrystallized from ethanol to give the title compound 18. 18b: yellow solid, yield 53.4%

Reference： [1]Patent: CN104447496,2017,B .Location in patent: Paragraph 0090; 0110; 0111; 0112; 0114

77
[ 1136-45-4 ]
[ 51388-20-6 ]
N-[4-(benzyloxy)phenyl]-5-methyl-3-phenylisoxazole-4-carbothioamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 8284 - 8310

78
[ 1136-45-4 ]
[ 51388-20-6 ]
N-[4-(benzyloxy)phenyl]-5-methyl-3-phenylisoxazole-4-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 8284 - 8310

79
1-(4-benzyloxyphenyl)-2-morpholin-4-yl-propan-1-one [ No CAS ]
[ 51388-20-6 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
83.5%	In chlorobenzene; at 125 - 130℃; for 8h;Large scale;	The 1-(4-benzyloxyphenyl)-2-morpholin-4-yl-propan-1-one obtained in example 1 (26.0 Kg; 0.08 moles), chlorobenzene (104 Kg) and 4-(benzyloxy)aniline hydrochloride (20.8 Kg; 0.088 moles) are loaded into a reactor. The mass is heated at 125-130 C. for 8 hours. The mass is then cooled to 80-90 C., and distilled water is added to it. The lower organic phase is separated, and the upper aqueous phase is eliminated. The organic phase is distilled to residue, and methanol (104 Kg) is then added. The mass is cooled to 20-25 C. and then centrifuged, washing with methanol. After drying, 28.0 Kg of 3-methyl-5-(benzyloxy)-2-(4-benzyloxyphenyl)-1H-indole is obtained. Yield: 83.5%. HPLC analysis shows a total impurity content of 0.24%. The 4-(benzyloxy)aniline content amounts to 0.01%.

Reference： [1]Patent: US2019/389842,2019,A1 .Location in patent: Paragraph 0072-0074

80
4’-benzyloxy-2-bromophenyl propiophenone [ No CAS ]
[ 51388-20-6 ]
[ 198479-63-9 ]

Yield	Reaction Conditions	Operation in experiment
65%	With triethylamine; In N,N-dimethyl-formamide; for 2.5h;Reflux;	This protocol was modified from J. Med. Chem. 2001, 44, 1654-1657. A 50-mL 3-neck flask was charged with 4?- benzyloxy-2-bromophenylpropiophenone (1 g, 3.13 mmol) <strong>[51388-20-6]4-benzyloxyaniline hydrochloride</strong> (1.7 g, 7.21 mmol), triethylamine (1.04 mL, 7.21 mmol) and 25 mL of DMF. The reaction was heated at reflux for 2.5 hours, cooled to rt and partitioned between EtOAc (3 x 80 mL) and EhO (70 mL). The combined EtOAc fractions were washed with brine (80 mL) and dried over Na2S04. The obtained residue was purified by column chromatography (silica gel, (0262) EtO Ac/Hex, 1 :9 to 2:3) to afford the product as a pale yellow powder (845 mg, 65%). 'H NMR (400 MHz, CDCh) d 7.95 (br s, 1H, NH), 7.67 - 7.58 (m, 6H), 7.57 - 7.50 (m, 5H), 7.51 - 7.44 (m, 2H), 7.37 (d, J= 10.4 Hz, 1H), 7.21 (d, J= 6.9 Hz, 2H), 7.07 (d, J= 8.2 Hz, 1H), 5.28 (s, 2H), 5.26 (s, 2H), 2.53 (s, 3H).

Reference： [1]Patent: WO2019/241231,2019,A1 .Location in patent: Paragraph 0091

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Code	Phrase
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P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
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P222	Do not allow contact with air.
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P281	Use personal protective equipment as required.
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Code	Phrase
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P304	IF INHALED:
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P321
P322
P330	Rinse mouth.
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P332	IF SKIN irritation occurs:
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P372	Explosion risk in case of fire.
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P378
P380	Evacuate area.
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P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
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P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
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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:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
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P401
P402	Store in a dry place.
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P420	Store away from other materials.
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P411 + P235	Keep cool.
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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
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
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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
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
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
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
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

[ CAS No. 51388-20-6 ] {[proInfo.proName]}

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[ 51388-20-6 ] Synthesis Path-Upstream 1~9

[ 51388-20-6 ] Synthesis Path-Downstream 1~80

Related Functional Groups of [ 51388-20-6 ]

Aryls

Ethers

Amines

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 51388-20-6 ]