[ CAS No. 5464-12-0 ] {[proInfo.proName]}

Name: 5464-12-0|1-(2-Hydroxyethyl)-4-methylpiperazine|97%
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COA NMR CNMR HPLC LC-MS

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Product Details of [ 5464-12-0 ]

CAS No. :	5464-12-0	MDL No. :	MFCD03840691
Formula :	C₇H₁₆N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QHTUMQYGZQYEOZ-UHFFFAOYSA-N
M.W :	144.22	Pubchem ID :	231184
Synonyms :

Calculated chemistry of [ 5464-12-0 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	48.43
TPSA :	26.71 Å²

Pharmacokinetics

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.61 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.94
Log Po/w (XLOGP3) :	-0.61
Log Po/w (WLOGP) :	-1.54
Log Po/w (MLOGP) :	-0.31
Log Po/w (SILICOS-IT) :	0.04
Consensus Log Po/w :	-0.1

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.22
Solubility :	87.3 mg/ml ; 0.606 mol/l
Class :	Very soluble
Log S (Ali) :	0.52
Solubility :	479.0 mg/ml ; 3.32 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-0.26
Solubility :	79.3 mg/ml ; 0.55 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.52

Safety of [ 5464-12-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280	UN#:	N/A
Hazard Statements:	H302+H312+H332	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 5464-12-0 ]

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

Upstream synthesis route of [ 5464-12-0 ]
Downstream synthetic route of [ 5464-12-0 ]

[ 5464-12-0 ] Synthesis Path-Upstream 1~11

1
[ 109-01-3 ]
[ 540-51-2 ]
[ 5464-12-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate In butanone at 90℃; for 4 h;	A mixture [OF N-METHYLPIPERAZINE] (0. [0499MOL),] [2-BROMOETHANOL] (0. [0749MOL)] and [K2CO3] (0. [0998MOL)] in 2-butanon (90mL) was stirred for [4H] at [90°C.] The cooled reaction mixture was filtered. The filtrate was evaporated. Yielding 90percent of intermediate 14. (Remark: lower yields were obtained on [A] higher scale and purification by short column chromatography was necessary).
48%	With potassium carbonate In ethanol; dichloromethane; acetone	The starting material was ptepared as follows: 2-Bromoethanol (2.36 g, 19 mmol) was added dropwise to a mixture of 1-methylpiperazine (1.26 g, 13 mmol) and potassium carbonate (5.0 g, 36 mmol) in absolute ethanol (150 ml) and the mixture heated at reflux for 18 hours. The mixture was allowed to cool and the precipitates were removed by filtration and the solvent volatiles were removed by evaporation. The residue was treated with acetone/methylene chloride, the insolubles were removed by filtration and the solvent was removed from the filtrate by evaporation to give 1-(2-hydroxyethyl)-4-methylpiperazine (870 mg, 48percent) as a light brown oil. ¹H NMR Spectrum: (CDCl₃) 2.1 8(s, 3H); 2.3-2.7(br m, 8H); 2.56(t, 2H); 3.61 (t, 2H) MS-ESI: 145 [MH]⁺

Reference： [1] Patent: WO2004/7498, 2004, A2, . Location in patent: Page 29
[2] ACS Medicinal Chemistry Letters, 2013, vol. 4, # 7, p. 622 - 626
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 14, p. 6305 - 6320
[4] Patent: US6291455, 2001, B1,
[5] Patent: US2003/225111, 2003, A1, . Location in patent: Page 41
[6] Patent: US6806274, 2004, B1, . Location in patent: Page/Page column 69

2
[ 103-76-4 ]
[ 50-00-0 ]
[ 5464-12-0 ]

Yield	Reaction Conditions	Operation in experiment
67%	With sodium cyanoborohydride In tetrahydrofuran at 50℃;	In THF (30 ml) were added N-(2-hydroxyethyl)piperazine (500 mg, 3.84 mmol), a solution of formaldehyde (3117 mg, 38.41 mmol) and sodium cyanoborohydride (1207 mg, 19.20 mmol). The mixture was heated up to 50° C. overnight under stirring. After cooling some water was added and the mixture was extracted with DCM (3.x.). The organic layers were dried over MgSO4 and evaporated. The residue was purified over a silica plug with DCM/MeOH 9:1 as eluant to afford an oil (370 mg, Y=67percent). ¹H NMR (DMSO-d6) δ 4.45 (t, J=5.3 Hz, 1H), 3.51-3.45 (m, 2H), 3.02-2.84 (m, 4H), 2.71-2.64 (m, 2H), 2.61 (s, 3H), 2.58-2.53 (m, 2H), 2.47-2.43 (m, 2H).
44%	With formic acid In water at 20 - 100℃;	2-(4-Methylpiperazin-l-yl)ethyl 4-nitrophenyl carbonate To a stirred solution of l-(2-hydroxyethyl)piperazine (26.0 g, 0.2 mol) in DMF (200 mL) was added formic acid (752 mL, 0.2 mol) and formaldehyde (16.2 g, 0.2 mol, 37percent solution in water) The reaction mixture was cautiously heated at 100 ⁰C for 2 hours and then stirred overnight at room temperature. The solvent was removed in vacuo. This procedure was repeated 3 further times to give -100 g of product. The crude products were combined and distilled under vacuum to give, at ~74 ⁰C, 2-(4-methylpiperazin-l-yl)ethanol (51 g, 44percent) as a colourless liquid. Analytical LCMS: (System B, R_τ = 0.70 min), ES⁺: 145.1 (100percent) [MH]⁺.
44%	With formic acid In water; N,N-dimethyl-formamide at 20 - 100℃;	To a stirred solution of 1-(2-hydroxyethyl)piperazine (26 g, 0.2 mol) in DMF (200 mL) was added formic acid (752 mL, 0.2 mol) and formaldehyde (16.2 g, 0.2 mol, 37percent solution in water). The reaction mixture was cautiously heated at 100° C. for 2 hours then stirred overnight at room temperature. The solvent was removed in vacuo. This procedure was repeated 3 further times to give 100 g of product. The crude products were combined and distilled under vacuum to give, at 74° C., 2-(4-methylpiperazin-1-yl)ethanol (51 g, 44percent) as a colourless liquid.Analytical LCMS: (System B, R_T=0.70 min), ES⁺: 145.1 [MH]⁺.

44%

With formic acid In water; N,N-dimethyl-formamide at 20 - 100℃;

2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate
To a stirred solution of 1-(2-hydroxyethyl)piperazine (26.0 g, 0.2 mol) in DMF (200 mL) was added formic acid (752 mL, 0.2 mol) and formaldehyde (16.2 g, 0.2 mol, 37percent solution in water) The reaction mixture was cautiously heated at 100° C. for 2 hours then stirred overnight at room temperature.
The solvent was removed in vacuo.
This procedure was repeated 3 further times to give ~100 g of product.
The crude products were combined and distilled under vacuum to give, at 74° C., 2-(4-methylpiperazin-1-yl)ethanol (51 g, 44percent) as a colourless liquid.
Analytical LCMS: (System C, R_T=0.70 min), ES⁺: 145.1 [MH]⁺.

Reference： [1] Patent: US2008/51397, 2008, A1, . Location in patent: Page/Page column 10; 26
[2] Synthesis, 2008, # 7, p. 1049 - 1060
[3] Patent: WO2009/71677, 2009, A1, . Location in patent: Page/Page column 23
[4] Patent: US2009/203695, 2009, A1, . Location in patent: Page/Page column 9
[5] Patent: US2009/281087, 2009, A1, . Location in patent: Page/Page column 10
[6] Journal of the American Chemical Society, 1948, vol. 70, p. 3098
[7] Australian Journal of Chemistry, 1956, vol. 9, p. 89,92

3
[ 103-76-4 ]
[ 5464-12-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With hydrogenchloride; sodium hydroxide; formaldehyd In methanol	(1) 1-(2-Hydroxyethyl)-4-methylpiperazine A mixture of 1-(2-hydroxyethyl)piperazine (10.0 g, 76.8 mmol), 37percent aqueous formaldehyde solution (11.5 ml, 154 mmol), 10percent palladium carbon catalyst (1.0 g) and methanol (100 ml) was stirred for 13 hr at room temperature in a hydrogen atmosphere. The reaction mixture was filtrated and the filtrate was concentrated. To the obtained residue was added 2N hydrochloric acid, and the mixture was washed with diethyl ether (200 ml). Sodium hydroxide (16 g) was added to the aqueous layer to make the layer alkaline, and the mixture was extracted with chloroform (4*200 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound (9.3 g, 84percent) as a pale-yellow liquid. ¹H-NMR (300 MHz, CDCl₃) δ 3.61 (t, J=5.4 Hz, 2H), 2.90-2.30 (m, 8H), 2.55 (t, J=5.4 Hz, 2H), 2.29 (s, 3H).

Reference： [1] Patent: US6610729, 2003, B1,

4
[ 109-01-3 ]
[ 107-07-3 ]
[ 5464-12-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine In acetone	A/Preparation of N-(2-hydroxyethyl)-N'-methylpiperazine: N-methylpiperazine (10 g; 100 mmol) and 2-chloroethanol (8.05 g; 100 mmol) are stirred at 100° C. for 4 h. The highly viscous reaction medium is supplemented with 250 ml of acetone and the resulting suspension is neutralized with 15 ml of triethylamine. After filtration of the triethylamine hydrochloride, the solvent is evaporated under reduced pressure. The desired compound is obtained after purification by chromatography on an alumina column (Merck.(R).; Aluminum Oxide 90; 63-200 μm, eluent: ethyl acetate) in the form of a colorless oil. Yield: 75percent

Reference： [1] Patent: US6056965, 2000, A,
[2] Patent: US6218538, 2001, B1,
[3] Chemical Biology and Drug Design, 2016, vol. 87, # 6, p. 946 - 957

5
[ 109-01-3 ]
[ 107-04-0 ]
[ 5464-12-0 ]

Reference： [1] Patent: US2011/190299, 2011, A1, . Location in patent: Page/Page column 26

6
[ 28920-67-4 ]
[ 5464-12-0 ]

Reference： [1] Medicinal Chemistry, 2012, vol. 8, # 5, p. 865 - 873

7
[ 103-76-4 ]
[ 67-56-1 ]
[ 5464-12-0 ]

Reference： [1] Organic Process Research and Development, 2015, vol. 19, # 10, p. 1400 - 1410

8
[ 75-21-8 ]
[ 110-85-0 ]
[ 5464-12-0 ]

Reference： [1] Journal of the American Chemical Society, 1954, vol. 76, p. 1122,1123

9
[ 109-01-3 ]
[ 5464-12-0 ]

Reference： [1] Medicinal Chemistry, 2012, vol. 8, # 5, p. 865 - 873

10
[ 109-01-3 ]
[ 107-21-1 ]
[ 5464-12-0 ]
[ 77267-14-2 ]

Reference： [1] Organic Process Research and Development, 2015, vol. 19, # 10, p. 1400 - 1410

11
[ 75-21-8 ]
[ 109-01-3 ]
[ 5464-12-0 ]

Reference： [1] 9. Congr. Soc. Pharm. Clermont-Ferrand, 1957, p. 175,178

[ 5464-12-0 ] Synthesis Path-Downstream 1~68

1
[ 103-76-4 ]
[ 50-00-0 ]
[ 5464-12-0 ]

Yield	Reaction Conditions	Operation in experiment
67%	With sodium cyanoborohydride; In tetrahydrofuran; at 50℃;	In THF (30 ml) were added N-(2-hydroxyethyl)piperazine (500 mg, 3.84 mmol), a solution of formaldehyde (3117 mg, 38.41 mmol) and sodium cyanoborohydride (1207 mg, 19.20 mmol). The mixture was heated up to 50° C. overnight under stirring. After cooling some water was added and the mixture was extracted with DCM (3.x.). The organic layers were dried over MgSO4 and evaporated. The residue was purified over a silica plug with DCM/MeOH 9:1 as eluant to afford an oil (370 mg, Y=67percent). 1H NMR (DMSO-d6) delta 4.45 (t, J=5.3 Hz, 1H), 3.51-3.45 (m, 2H), 3.02-2.84 (m, 4H), 2.71-2.64 (m, 2H), 2.61 (s, 3H), 2.58-2.53 (m, 2H), 2.47-2.43 (m, 2H).
44%	With formic acid; In water; at 20 - 100℃;	2-(4-Methylpiperazin-l-yl)ethyl 4-nitrophenyl carbonate To a stirred solution of l-(2-hydroxyethyl)piperazine (26.0 g, 0.2 mol) in DMF (200 mL) was added formic acid (752 mL, 0.2 mol) and formaldehyde (16.2 g, 0.2 mol, 37percent solution in water) The reaction mixture was cautiously heated at 100 0C for 2 hours and then stirred overnight at room temperature. The solvent was removed in vacuo. This procedure was repeated 3 further times to give -100 g of product. The crude products were combined and distilled under vacuum to give, at ~74 0C, 2-(4-methylpiperazin-l-yl)ethanol (51 g, 44percent) as a colourless liquid. Analytical LCMS: (System B, Rtau = 0.70 min), ES+: 145.1 (100percent) [MH]+.
44%	With formic acid; In water; N,N-dimethyl-formamide; at 20 - 100℃;	To a stirred solution of 1-(2-hydroxyethyl)piperazine (26 g, 0.2 mol) in DMF (200 mL) was added formic acid (752 mL, 0.2 mol) and formaldehyde (16.2 g, 0.2 mol, 37percent solution in water). The reaction mixture was cautiously heated at 100° C. for 2 hours then stirred overnight at room temperature. The solvent was removed in vacuo. This procedure was repeated 3 further times to give 100 g of product. The crude products were combined and distilled under vacuum to give, at 74° C., 2-(4-methylpiperazin-1-yl)ethanol (51 g, 44percent) as a colourless liquid.Analytical LCMS: (System B, RT=0.70 min), ES+: 145.1 [MH]+.

44%

With formic acid; In water; N,N-dimethyl-formamide; at 20 - 100℃;

2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate To a stirred solution of 1-(2-hydroxyethyl)piperazine (26.0 g, 0.2 mol) in DMF (200 mL) was added formic acid (752 mL, 0.2 mol) and formaldehyde (16.2 g, 0.2 mol, 37percent solution in water) The reaction mixture was cautiously heated at 100° C. for 2 hours then stirred overnight at room temperature. The solvent was removed in vacuo. This procedure was repeated 3 further times to give ~100 g of product. The crude products were combined and distilled under vacuum to give, at 74° C., 2-(4-methylpiperazin-1-yl)ethanol (51 g, 44percent) as a colourless liquid. Analytical LCMS: (System C, RT=0.70 min), ES+: 145.1 [MH]+.

Reference： [1]Patent: US2008/51397,2008,A1 .Location in patent: Page/Page column 10; 26
[2]Synthesis,2008,p. 1049 - 1060
[3]Patent: WO2009/71677,2009,A1 .Location in patent: Page/Page column 23
[4]Patent: US2009/203695,2009,A1 .Location in patent: Page/Page column 9
[5]Patent: US2009/281087,2009,A1 .Location in patent: Page/Page column 10
[6]Journal of the American Chemical Society,1948,vol. 70,p. 3098
[7]Australian Journal of Chemistry,1956,vol. 9,p. 89,92

2
[ 5464-12-0 ]
[ 39123-20-1 ]

Yield	Reaction Conditions	Operation in experiment
35%	With thionyl chloride; In chloroform; for 4h;Reflux;	a) 1 -(2-Chloroethyl)-4-methylpiperazine (1-96) Thionyl chloride (2.4 mL; 33 mmol; 1.1 eq) was added to a solution of 2- (4- methylpiperazin-l-yl)ethan-l-ol (4 g; 29 mmol; 1 eq) in dry chloroforme (40 mL). The reaction mixture was stirred at reflux for 4 hours, then, concentrated to dryness. 1M sodium hydroxide solution (100 mL) was added and the aqueous layer was extracted with ethyl acetate (3 x 150 mL). The combined organic layers were washed with saturated sodium chloride (1 x 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound, l-(2-chloroethyl)- 4-methylpiperazine in 35percent yield (1.66 g) as an brown oil. 1H NMR (CDC13): 2.36 (s, 3H), 2.59 (m, 8H), 2.79 (t, 2H), 3.64 (t, 2H); MS (ESI+): m/z = 163.1-165.1 [M+H]+.
	With thionyl chloride; at 20℃;Reflux;	1-(2-Chloroethyl)-4-methylpiperazine (58b) was prepared by refluxing 2-(4- methylpiperazin-1-yl)ethanol (58a) (1.1 g, 7.33 mmol) with thionyl chloride (10 mL). The reaction mixture was cooled to 20 °C, and poured into ice/water. The aqueous solution was then treated with 6-bromo-4-hydroxy-2-methyl-9H-xanthen-9-one (28b) (260 mg, 0.85 mmol), tetrabutylammonium bromide (100 mg), KOH (1.12 g, 20 mmol), and CH2C12 (50mL), and the mixture was stirred for 3 days. The CH2C12 layer was separated, and the aqueous layer was further extracted with CH2C12. The combined CH2C12 extracts were dried (Na2SO4) and the solvent was removed. Chromatography on neutral alumina eluting with 0-20percent hexanes/EtOAc followed by 0-1percent CH2C12/MeOH gave crude material which was re-columned in Si02 eluting with 20percent hexanes/EtOAc to remove impurities, then with0-4percent CH2C12/MeOH to elute 6-bromo-2-methyl-4-(2-(4-methylpiperazin- 1 -yl)ethoxy)-9H- xanthen-9-one (58c): MS (APCI) m/z: 431 and 433 (M+H). This was used directly without further purification.

Reference： [1]Patent: WO2013/171281,2013,A1 .Location in patent: Page/Page column 188
[2]Patent: US2851458,1956,
[3]Australian Journal of Chemistry,1956,vol. 9,p. 89,92
[4]Chemical Biology and Drug Design,2016,vol. 87,p. 946 - 957
[5]Patent: WO2018/83635,2018,A2 .Location in patent: Page/Page column 156

3
[ 5464-12-0 ]
[ 379229-54-6 ]
saracatinib [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16.1 g	With sulfuric acid; at 140℃;	The intermediate N-(5-chloro-1,3-benzodioxolane-4-yl)-7-hydroxy-5-[(tetrahydro-2H-pyran-4-yl)oxy]- 4-quinazolinamine 10 (9.26 g, 1.13 mol) was mixed with 4-methyl-1-piperazinyl-ethanol 11 (10.5 g, 1.5 mol), mixed and stirred in the presence of 80percent concentrated sulfuric acid (100 ml) and rapidly heat to 140°C, an intermolecular dehydration reaction occurs to produce N-(5-chloro-1,3-benzodioxolane-4-yl)-7-[2-(4-methyl-1-piperazinyl)ethoxy]-5-[(4- Hydrogen-2H-pyran-4-yl)oxy]-4-quinazolinamine 12 (16.1 g, 1.86 mol).
29.9 g	With sulfuric acid; at 140℃;	(7) produced in the step (6) N-(5-chloro-1,3-benzodioxolan-4-yl)-7-Hydroxy-5-[(tetrahydro-2H-pyran-4-yl)oxy]-4-quinazolinamine 9 (21.46 g, 2.0 mol) Mixed with (4-methyl-1-pyridazinyl)ethane 10 (16.5 g, 1.74 mol), Rapidly heated to 140 °C in the presence of 75percent sulfuric acid solution (150 ml), Intermolecular dehydration reaction occurs, Formation of N-(5-chloro-1,3-benzodioxolan-4-yl)-7- [2-(4-methyl-1-pyridazinyl)ethoxy]-5-[(tetrahydro-2H-pyran-4-yl)oxy]-4-quinazolinamine 11 (29.9 g, 2.5 mol).

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 6465 - 6488
[2]Patent: CN107814793,2018,A .Location in patent: Paragraph 0018; 0021
[3]Patent: CN107987064,2018,A .Location in patent: Paragraph 0013; 0014; 0015

4
[ 109-01-3 ]
[ 540-51-2 ]
[ 5464-12-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In butanone; at 90℃; for 4h;	A mixture [OF N-METHYLPIPERAZINE] (0. [0499MOL),] [2-BROMOETHANOL] (0. [0749MOL)] and [K2CO3] (0. [0998MOL)] in 2-butanon (90mL) was stirred for [4H] at [90°C.] The cooled reaction mixture was filtered. The filtrate was evaporated. Yielding 90percent of intermediate 14. (Remark: lower yields were obtained on [A] higher scale and purification by short column chromatography was necessary).
48%	With potassium carbonate; In ethanol; dichloromethane; acetone;	The starting material was ptepared as follows: 2-Bromoethanol (2.36 g, 19 mmol) was added dropwise to a mixture of 1-methylpiperazine (1.26 g, 13 mmol) and potassium carbonate (5.0 g, 36 mmol) in absolute ethanol (150 ml) and the mixture heated at reflux for 18 hours. The mixture was allowed to cool and the precipitates were removed by filtration and the solvent volatiles were removed by evaporation. The residue was treated with acetone/methylene chloride, the insolubles were removed by filtration and the solvent was removed from the filtrate by evaporation to give 1-(2-hydroxyethyl)-4-methylpiperazine (870 mg, 48percent) as a light brown oil. 1H NMR Spectrum: (CDCl3) 2.1 8(s, 3H); 2.3-2.7(br m, 8H); 2.56(t, 2H); 3.61 (t, 2H) MS-ESI: 145 [MH]+
	With potassium carbonate; In ethanol; for 18h;Heating / reflux;	The 1-(2-hydroxyethyl)-4-methylpiperazine used as a starting material was prepared as follows: A mixture of 2-bromoethanol (2.36 g), N-methylpiperazine (1.26 g), potassium carbonate (5.0 g) and ethanol (150 ml) was stirred and heated to reflux for 18 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was triturated under a mixture of methylene chloride and acetone. The resultant mixture was filtered and the filtrate was evaporated to give the required starting material as an oil (0.87 g); NMR Spectrum: (CDCl3) 2.18 (s, 3H), 2.3-2.7 (br m, 81), 2.56 (t, 2H), 3.61 (t, 2H).

With potassium carbonate; In ethanol; for 1.8h;Heating / reflux;

The 1-(2-hydroxyethyl)-4-methylpiperazine used as a stating material was prepared as follows: [00711] A mixture of 2-bromoethanol (2.36 g), N-methylpiperzine (1.26 g), potassium carbonate (5.0 g) and ethanol (150 ml) was stirred and heated to reflux for 1.8 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was triturated under a mixture of methylene chloride and acetone. The resultant mixture was filtered and the filtrate was evaporated to give the required starting material as an oil (0.87 g); NMR Spectrum: (CDCl3) 2.18 (s, 3H), 2.3-2.7 (br m, 8H), 2.56 (t, 2H), 3.61 (t, 2H).

Reference： [1]Patent: WO2004/7498,2004,A2 .Location in patent: Page 29
[2]ACS Medicinal Chemistry Letters,2013,vol. 4,p. 622 - 626
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 6305 - 6320
[4]Patent: US6291455,2001,B1
[5]Patent: US2003/225111,2003,A1 .Location in patent: Page 41
[6]Patent: US6806274,2004,B1 .Location in patent: Page/Page column 69

5
[ 5464-12-0 ]
[ 541522-48-9 ]
[ 541522-01-4 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 0 - 20℃;	Example 7 N-((1S,2R)-2-[(cyanomethyl)amino]carbonyl}cyclohexyl)-6-[2-(4-methylpiperazin-1-yl)ethoxy]-1H-indole-2-carboxamide To 85 mg (0.25 MM) 6-Hydroxy-1H-indole-2-carboxylic acid [2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide in 5 ml dichloromethane at 0° C. was added 144 mg (1 MM) 2-(4-Methyl-piperazin-1-yl)-ethanol, 262 mg (1 MM) triphenylphosphine and 131 mg (0.75 MM) DEAD. After several hours the mixture was allowed to warm to room temperature and stir overnight.The reaction mixture was purified directly on a preparative TLC plate and eluted with 10percent methanol/dichloromethane.The product was then partitioned between 1 M HCl and ethyl acetate, the aqueous layer was neutralized and extracted with ethyl acetate, dried over magnesium sulfate and stripped to give 18.9 mg 6-[2-(4-Methyl-piperazin-1-yl)-ethoxy]-1H-indole-2-carboxylic acid [2-(cyanomethyl-carbamoyl)-cyclohexyl]-amide. Similarly prepared were: N-((1S,2R)-2-[(cyanomethyl)amino]carbonyl}cyclohexyl)-1-methyl-6-(2-morpholin-4-ylethoxy)-1H-indole-2-carboxamide using Mitsunobu coupling with 2-Morpholin-4-yl-ethanol. N-((1S,2R)-2-[(cyanomethyl)amino]carbonyl}cyclohexyl)-6-(2-morpholin-4-ylethoxy)-1H-indole-2-carboxamide using Mitsunobu coupling with 2-morpholin-4-yl-ethanol.

Reference： [1]Patent: US2004/77646,2004,A1 .Location in patent: Page 92

6
[ 5464-12-0 ]
[ 121-33-5 ]
[ 646071-39-8 ]

Yield	Reaction Conditions	Operation in experiment
56%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 18h;	PPh3 (0.0325 mol) was added dropwise at a temperature between 0 and [5°C] to a solution of Vanillin (CA No : [121-33-5)] (0. [025 MOL),] intermediate 14 (0.03 mol) and DIAD (0.0375 mol) in THF (60ml). The mixture was stirred at room temperature for 18 hours. EtOAc was added. The mixture was extracted twice with [HC13N.] The acidic layer was washed with EtOAc, basified with [K,, C03] and extracted with EtOAc. The organic layer was dried [(MGS04),] filtered, and the solvent was evaporated. Yielding: 3.9g of intermediate 15 [(56percent).

Reference： [1]Patent: WO2004/7498,2004,A2 .Location in patent: Page 30

7
[ 5464-12-0 ]
[ 622369-82-8 ]
[ 753005-94-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In DMF (N,N-dimethyl-formamide); at 100 - 125℃; for 3h;	A mixture of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-ethoxy-7-fluoro-3- quinolinecarbonitrile (200 mg, 0.49 mmol) and 2- 1-piperazinyl) ethanol (141 mg, 0.98 mmol)) in 5 mL of N, N-dimethylformamide was heated to 100°C. Sodium hydride (60percent) (196 mg, 4.9 mmol) was added in portions and the mixture was heated at 125°C for 3 hours. The reaction mixture was cooled to room temperature and treated with 25 mL of water. The mixture was stirred for 2 hours. The precipitate was collected, washed with water and dried in vacuo. The residue was purified by flash column chromatography, eluting with a gradient of 5percent methanol in dichloromethane to 15percent methanol in dichloromethane. Trituation with diethyl ether provided 123 mg of 4- [ (2, 4-dichloro-5-methoxyphenyl) amino]-6-ethoxy-7- [2- (4- methyl-1-piperazinyl) ethoxy] quinoline-3-carbonitrile as an off-white solid, mp 141- 143°C. MS 530.2 (M+H) + Analysis for C26H29CI2N503 Calcd : C, 58.87 ; H, 5.51 ; N, 13.20. Found: C, 58.48 ; H, 5.45 ; N, 12.95.

Reference： [1]Patent: WO2005/47259,2005,A1 .Location in patent: Page/Page column 32

8
[ 5464-12-0 ]
[ 379230-38-3 ]
saracatinib [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In di-(2-methoxyethyl) ether; at 120℃; for 12h;Product distribution / selectivity;	4-(6-Chloro-2,3-metliylenedioxyanilino)-7-fluoro-5-tetrahydropyran-4-yloxyquinazoli'ne (0.5 g) was added to a stirred mixture of potassium hydroxide (0.168 g), l-(2-hydroxyethyl)-4-methylpiperazine (0.69 g) and di-(2-methoxyethyl) ether (10 ml) that had been warmed to 12O0C and the resultant reaction mixture was heated to 12O0C for EPO <DP n="61"/>12 hours. The reaction mixture was cooled to ambient temperature, acidified to pH 1 to 3 by the addition of IM aqueous hydrochloric acid (9 ml) and washed with isopropyl acetate (20 ml). The aqueous solution was stirred and basified to pH 13 to 14 by the addition of 2M aqueous sodium hydroxide (5 ml). After 10 minutes, water (22 ml) was added and the mixture was stirred for 2 hours to allow precipitation of a solid to finish. The mixture was cooled to 1O0C and filtered. The resultant solid was washed with water (20 ml) and dried in vacuo at 400C. There was thus obtained 4-(6-chloro-2,3-methylenedioxyanilino)- 7-[2-(4-methylpiperazin-l-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.47 g, 92.5% purity by HPLC using Method B, retention time 7.3 minutes); NMR Spectrum: (CDCl3) 1.65 (br s, 3H), 1.9-2.05 (m, 2H), 2.2-2.3 (m, 2H), 2.31 (s, 3H), 2.4-2.8 (m, 8H), 2.9 (m, 2H), 3.6- 3.7 (m, 2H), 3.95-4.05 (m, 2H),-4.2-4.25 (m, 2H), 4.8 (m,lH), 6.05 (s, 2H), 6.55 (s, IH), 6.75 (d, IH), 6.85 (s, IH), 7.0 (d, IH), 8.55 (s, IH), 9.25 (s, IH).

Reference： [1]Patent: WO2006/64217,2006,A2 .Location in patent: Page/Page column 59-60
[2]Organic Process Research and Development,2010,vol. 14,p. 1088 - 1093

9
[ 5464-12-0 ]
[ 379230-38-3 ]
4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline trihydrate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Under an atmosphere of nitrogen gas, l-(2-hydroxyethyl)-4-methylpiperazine (13.93 g) was added to a stirred mixture of 4-(6-chloro-2,3-methylenedioxyanilino)-7-fluoro- 5-tetrahydropyran-4-yloxyquinazoline (12.9 g), sodium te/t-pentoxide (9.87 g) and 1 ,2-diethoxyethane (37.5 ml). Water (1.34 g) and 1,2-diethoxyethane (25 ml) were added and the resultant reaction mixture was stirred and heated to 86°C for 18 hours. The reaction mixture was cooled to 5O0C and, under vacuum distillation at approximately 60 millibar pressure, approximately 50 ml of reaction solvent was distilled off. The reaction mixture was neutralised to pH 7.0 to 7.6 by the addition of a mixture of concentrated aqueous hydrochloric acid (36percent, 10 ml) and water (84 ml) at a rate that kept the temperature of the reaction mixture at a maximum of 6O0C. With the temperature of the reaction mixture being kept at 6O0C, the reaction mixture was extracted with ethyl acetate (225 ml). The organic solution was washed with water (50 ml). Water (25 ml) was added and, with the temperature being kept at 6O0C, the mixture was stirred for 10 minutes, then allowed to stand for 30 minutes and the aqueous layer was separated. The organic layer was concentrated to a volume of about 100 ml by distillation of solvent at about 9O0C under atmospheric pressure. The residual mixture was cooled during 1 hour to 450C and held at that temperature for 2 hours to allow crystallisation of product. The mixture was warmed briefly to 550C and then cooled during 4 hours to 180C EPO <DP n="62"/>and held at that temperature for 1 hour. The crystalline precipitate was isolated by filtration and washed in turn with water (17 ml) and with toe't-butyl methyl ether (17 ml). There was thus obtained 4-(6-chloro-2,3-piiethylenedioxyanilino)-7-[2-(4-methylpiperazin-l-yl)ethoxy]- 5-tetrahydropyran-4-yloxyquinazoline as a trihydrate (11 g; 88percent purity by HPLC using Method B, retention time 7.3 minutes); NMR Spectrum: (CDCl3) 1.65 (br s, 3H), 1.9-2.05 (m, 2H), 2.2-2.3 (m, 2H), 2.31 (s, 3H), 2.4-2.8 (m, 8H), 2.9 (m, 2H), 3.6-3.7 (m, 2H), 3.95-4.05 (m, 2H), 4.2-4.25 (m, 2H), 4.8 (m,lH), 6.05 (s, 2H), 6.55 (s, IH), 6.75 (d, IH), 6.85 (s, IH), 7.0 (d, IH), 8.55 (s, IH), 9.25 (s, IH).A portion (10 g) of the material so obtained was placed on a filter and dried at ambient temperature in a stream of dry nitrogen gas. The resultant material was dissolved at 6O0C in dry isopropanol (140 ml) whilst maintaining a dry nitrogen atmosphere. The solution was allowed to cool to ambient temperature and to stand under a dry nitrogen atmosphere for 2 days. The resultant crystalline solid was isolated by filtration under a dry nitrogen atmosphere. The material (8 g) so obtained was a crystalline anhydrous form of 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-l -yl)ethoxy]- 5-tetrahydropyran-4-yloxyquinazoline, m.p. 142 to 1440C.

Reference： [1]Patent: WO2006/64217,2006,A2 .Location in patent: Page/Page column 60-61

10
[ 5464-12-0 ]
[ 121219-03-2 ]
[ 897017-01-5 ]

Yield	Reaction Conditions	Operation in experiment
33%	With di-isopropyl azodicarboxylate; triphenylphosphine; In dichloromethane; at 0 - 20℃;	1-(2-(4-bromo-3-fluorophenoxy)ethyl)-4-methylpiperazine: A flask was charged with <strong>[121219-03-2]4-bromo-3-fluorophenol</strong> (5.00 g, 26 mmol) and triphenylphosphine (10.30 g, 39 mmol). Methylene chloride (120 mL) was added followed by 2-(4-methylpiperazin-1-yl)ethanol (4.61 g, 32 mmol) and the solution was stirred on an ice water bath to cool. After 5 minutes, diisopropyl azodicarboxylate (7.6 ml, 39.1 mmol) was added over 6 to 8 minutes. The reaction was left stirring on the cold bath to slowly warm to room temperature overnight. The reaction was concentrated and the residue purified by flash chromatography (25% to 100% EtOAc in hexanes) to provide the product as a colorless oil (2.62 g, 33%).
	With di-tert-butyl-diazodicarboxylate; In toluene; at 50℃; for 6h;Inert atmosphere;	1.91 g 4-bromo-3-fluoro-phcnol (10.0 mmol), 1.73 g 2-(4-methylpiperazin-1 -yl)ethanol(12.0 mmol) and 5.00 g immobilized PPh3 (15.0 mrnol) were dissolved in 30 mL drytoluene under N2, then 2.99 g diterrbutyl azodicarboxylate (13.0 mmol) was added and themixture was stirred at 50C for 6 hours. Then it was filtered, the filtrate was concentrated under reduced pressure and purified via flash chromatography using EtOAc and MeOll as eluents to obtain I -[2-(4-bromo-3 -fluoro-phenoxy)ethyl] -4-methyl-piperazine.MS (M+H): 317.2.

Reference： [1]Patent: US2006/160800,2006,A1 .Location in patent: Page/Page column 85-86
[2]Patent: WO2015/97123,2015,A1 .Location in patent: Page/Page column 73

11
[ 103-76-4 ]
[ 5464-12-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With hydrogenchloride; sodium hydroxide; formaldehyd;palladium-carbon; In methanol;	(1) 1-(2-Hydroxyethyl)-4-methylpiperazine A mixture of 1-(2-hydroxyethyl)piperazine (10.0 g, 76.8 mmol), 37percent aqueous formaldehyde solution (11.5 ml, 154 mmol), 10percent palladium carbon catalyst (1.0 g) and methanol (100 ml) was stirred for 13 hr at room temperature in a hydrogen atmosphere. The reaction mixture was filtrated and the filtrate was concentrated. To the obtained residue was added 2N hydrochloric acid, and the mixture was washed with diethyl ether (200 ml). Sodium hydroxide (16 g) was added to the aqueous layer to make the layer alkaline, and the mixture was extracted with chloroform (4*200 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated to give the title compound (9.3 g, 84percent) as a pale-yellow liquid. 1H-NMR (300 MHz, CDCl3) delta 3.61 (t, J=5.4 Hz, 2H), 2.90-2.30 (m, 8H), 2.55 (t, J=5.4 Hz, 2H), 2.29 (s, 3H).

Reference： [1]Patent: US6610729,2003,B1

12
[ 109-01-3 ]
[ 107-07-3 ]
[ 5464-12-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	With triethylamine; In acetone;	A/Preparation of N-(2-hydroxyethyl)-N'-methylpiperazine: N-methylpiperazine (10 g; 100 mmol) and 2-chloroethanol (8.05 g; 100 mmol) are stirred at 100° C. for 4 h. The highly viscous reaction medium is supplemented with 250 ml of acetone and the resulting suspension is neutralized with 15 ml of triethylamine. After filtration of the triethylamine hydrochloride, the solvent is evaporated under reduced pressure. The desired compound is obtained after purification by chromatography on an alumina column (Merck.(R).; Aluminum Oxide 90; 63-200 mum, eluent: ethyl acetate) in the form of a colorless oil. Yield: 75percent
	With potassium carbonate; In acetonitrile;	PREPARATION 6 2-(4-Methyl-1-piperazinyl)ethanol 2-Chloroethanol (36.0 g, 30 mL, 0.44 mol) was added to 1-methylpiperazine (27.0 g, 30 mL, 0.27 mol) and potassium carbonate (40 g, 0.29 mol) in acetonitrile (100 mL) with stirring. The reaction mixture was heated under reflux for 48 h, then filtered, and the solids were washed with acetonitrile. The combined filtrates were evaporated under reduced pressure and the resulting oil was distilled at 12 mm Hg to give the title compound (31 g, 0.21 mol) as a light tan oil. Electrospray MS m/z 145 [M+H]+.

Reference： [1]Patent: US6056965,2000,A
[2]Patent: US6218538,2001,B1
[3]Chemical Biology and Drug Design,2016,vol. 87,p. 946 - 957

13
[ 5464-12-0 ]
ethereal hydrogen chloride [ No CAS ]
[ 196603-96-0 ]
[ 1972-28-7 ]
4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With triphenylphosphine; In dichloromethane;	EXAMPLE 24 Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to a suspension of <strong>[196603-96-0]4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline</strong> (146 mg, 0.4 mmol), triphenylphosphine (314 mg, 1.2 mmol) and 1-(2-hydroxyethyl)4-methylpiperazine (86 mg, 0.6 mmol), (prepared as described for the starting material in Example 17), in methylene chloride (5 ml). The mixture was stirred for 1 hour at ambient temperature and the mixture was purified by column chrormatography eluding with methylene chloride/methanol (90/10 followed by 80/20). The purified product was triturated with ether, collected by filtration and dried under vacuum. The solid was dissolved in methylene chloride and 3M ethereal hydrogen chloride (0.5 ml) was added. The volatiles were removed by evaporation and the resulting oil was triturated with ether. The solid was collected by filtration, washed with ether and dried under vacuum to give 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(2-(4-methylpiperazin-1-yl)ethoxy)quinazoline hydrochloride (100 mg, 41%). 1H NMR Spectrum: (DMSOd6; CF3COOD; 60 C.) 2.89(s, 3H); 3.55-3.7(m, 8H); 3.74(t, 2H); 4.04(s, 3H); 4.68(t, 2H); 7.49(s, 1H); 7.55(m, 1H); 7.56(s, 1H); 7.75(d, 1H); 8.29(s, 1H); 8.84(s, 1H) MS-EI: 490 [M]+

Reference： [1]Patent: US6291455,2001,B1

14
[ 5464-12-0 ]
[ 872206-54-7 ]
[ 888720-36-3 ]

Yield	Reaction Conditions	Operation in experiment
24%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; dichloromethane; at 20℃; for 12h;	G) 4-(2-Fluoro-4-nitrophenoxy)-5-methyl-6-(2-(4-methylpiperazin-1-yl)-ethoxy)pyrrolo[2,1-f][1,2,4]triazine To a homogeneous mixture of 4-(2-fluoro-4-nitrophenoxy)-5-methylpyrrolo[2,1-f][1,2,4]-triazin-6-ol (100 mg, 0.33 mmol) and triphenylphosphine (129 mg, 0.49 mmol) in 4 mL of 1:1 anhydrous dichlormethane/anhydrous tetrahydrofuran, cooled to 0° C. under a nitrogen atmosphere, was added dropwise a mixture of <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong> (71 mg, 0.49 mmol) and diisopropylazodicarboxylate (0.10 muL, 0.49 mmol) in 2 mL of 1:1 anhydrous dichlormethane/anhydrous tetrahydrofuran. The mixture was stirred and allowed to warm to room temperature. The reaction was stirred for twelve hours before being concentrated in vacuo. The residue was purified by preparative HPLC (YMC S10 ODS, 30500 mm, 30 minute gradient from 50percent to 90percent aqueous methanol with 0.1percent TFA). The appropriate fractions were combined, neutralized with saturated aqueous sodium bicarbonate, and then concentrated in vacuo to remove methanol. The mixture was extracted with chloroform (310 mL). The combined organic layers were washed once each with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to yield the title compound (34 mg, 24percent) as a yellow solid. 1H NMR (CDCl3) delta 8.20-8.10 (m, 2H), 7.82 (s, 1H), 7.58-7.52 (m, 1H), 7.49 (s, 1H), 4.16 (t, 2H, J=5.7 Hz), 2.87 (t, 2H, J=5.7 Hz), 2.80-2.40 (m, 8H), 2.45 (s, 3H), 2.31 (s, 3H); MS(ESI+) m/z 431.3 (M+H)+.

Reference： [1]Patent: US2007/123534,2007,A1 .Location in patent: Page/Page column 15
[2]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1945 - 1951

15
[ 5464-12-0 ]
[ 7693-46-1 ]
[ 1159928-40-1 ]

Yield	Reaction Conditions	Operation in experiment
71%	With 4-methyl-morpholine; In dichloromethane; at 0 - 20℃;	4-Nitrophenyl chloroformate (9.85 g, 49 mmol) was dissolved in DCM (200 mL), and cooled to 0° C. <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong> from the previous step (7.2 g, 50 mmol) and NMM (6 mL) were added, and the reaction mixture allowed to warm gradually to room temperature over 16 hours. The reaction mixture was washed with 1M aq Na2CO3 solution. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give 2-(4-methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (10.7 g, 71percent) as a yellow oil which solidified on standing.Analytical LCMS: purity 80percent (System B, RT=1.70 min), ES+: 310.4 [MH]+.
71%		2-(4-Methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate To a stirred solution of 1-(2-hydroxyethyl)piperazine (26.0 g, 0.2 mol) in DMF (200 mL) was added formic acid (752 mL, 0.2 mol) and formaldehyde (16.2 g, 0.2 mol, 37percent solution in water) The reaction mixture was cautiously heated at 100° C. for 2 hours then stirred overnight at room temperature. The solvent was removed in vacuo. This procedure was repeated 3 further times to give ~100 g of product. The crude products were combined and distilled under vacuum to give, at 74° C., <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong> (51 g, 44percent) as a colourless liquid. Analytical LCMS: (System C, RT=0.70 min), ES+: 145.1 [MH]+. 4-Nitrophenyl chloroformate (9.85 g, 49 mmol) was dissolved in DCM (200 mL), and cooled to 0° C. <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong> (7.2 g, 50 mmol) and NMM (6 mL) were added, and the reaction mixture was allowed to warm gradually to room temperature over 16 hours. The reaction mixture was washed with 1M aq Na2CO3 solution until the yellow colour extracted into the aqueous layer had disappeared. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give 2-(4-methylpiperazin-1-yl)ethyl 4-nitrophenyl carbonate (10.7 g, 71percent) as a yellow oil which solidified on standing. Analytical LCMS: purity ~80percent (System C, RT=1.70 min), ES+: 310.4 [MH]+.
	With 4-methyl-morpholine; In dichloromethane; at 20℃; for 16h;	4-Nitrophenyl chloroformate (9.85 g, 49 mmol) was dissolved in DCM (200 mL), and cooled to O0C. 2-(4-methylpiperazin-l-yl)ethanol (7.2 g, 50 mmol) and NMM (6 mL) were added, and the reaction mixture was allowed to warm gradually to room temperature over16 hours. The reaction mixture was washed with IM aq Na2CO3 solution. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give 2-(4-methylpiperazin- l-yl)ethyl 4-nitrophenyl carbonate (10.7 g, 71percent) as a yellow oil which solidified on standing.Analytical LCMS: purity -80percent (System B, Rtau = 1.70 min), ES+: 310.4 [MH]+.

Reference： [1]Patent: US2009/203695,2009,A1 .Location in patent: Page/Page column 9
[2]Patent: US2009/281087,2009,A1 .Location in patent: Page/Page column 10-11
[3]Patent: WO2009/71677,2009,A1 .Location in patent: Page/Page column 23

16
[ 5464-12-0 ]
[ 4548-45-2 ]
[ 1190380-58-5 ]

Yield	Reaction Conditions	Operation in experiment
24%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃;Cooling with ice;	Sodium hydride, 60percent dispersion in mineral oil (252 mg, 6.29 mmol) was added, portionwise, to an ice-cooled solution of 2-(4-methyl-piperazin-l-yl)-ethanol (863 mg, 5.99 mmol) and 2-chloro-5- nitropyridine (1.0 g, 6.29 mmol) in DMF (20 ml). The ice-cooling was removed after 1 hour and the mixture was allowed to stir at rt overnight. The reaction mixture was added to ice/water and subsequently extracted with EtOAc (x2). The combined organic extracts were washed with water (x4) and brine (xl), dried and concentrated. The crude product was purified by flash column chromatography on silica gel (60 g) eluting with 10:1 DCM:MeOH to give the product as a brown oil (400 mg, 24percent). 1H NMR (400 MHz, DMSO-^6) delta ppm 2.13 (s, 3 H), 2.21 - 2.54 (m, 8 H), 2.70 (t, /=5.95 Hz, 2 H), 4.50 (t, J=5.95 Hz, 2 H), 7.04 (d, .7=9.16 Hz, 1 H), 8.47 (dd, 7=9.16, 2.75 Hz, 1 H), 9.07 (d, 7=2.29 Hz, 1 H); m/z (ES+APCI)+: 267 [M+H]+.

Reference： [1]Patent: WO2009/122180,2009,A1 .Location in patent: Page/Page column 117

17
[ 5464-12-0 ]
[ 23145-88-2 ]
[ 7693-46-1 ]
[ 1159929-78-8 ]

Yield	Reaction Conditions	Operation in experiment
28%		Example 43 2-(4-Methylpiperazin-1-yl)ethyl 4-(4-chlorobenzyl)piperazine-1-carboxylate 2-(4-Methyl-piperazin-1-yl)-ethanol (0.86 g, 6 mmol) and NMM (0.58 mL, 6 mmol) were dissolved in DCM (8 mL) and the reaction mixture was cooled to 0° C. 4-Nitrophenyl chloroformate (1.29 g, 6 mmol) was added and stirred for 1 h. To the reaction mixture was added a solution of 1-(4-chloro-benzyl)-piperazine (1.05 g, 5 mmol) and DIPEA (6.0 mL, excess) in DMF (20 mL). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in EtOAc (150 mL), washed with sat aq Na2CO3 solution (6100 mL), dried (MgSO4) and dried in vacuo. The residue was initially purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, 20 mL/min, gradient 0percent to 15percent MeOH in DCM) and then further purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 mum, 46026 mm (100 g), 30 mL/min, gradient 0percent to 30percent (over 40 min) MeOH in water with 1percent formic acid). The residue was stirred for 2 h in DCM (10 mL) with K2CO3 (~0.20 g), filtered and then dried in a vacuum oven overnight to give 2-(4-methylpiperazin-1-yl)ethyl 4-(4-chlorobenzyl)piperazine-1-carboxylate (0.51 g, 28percent) as a pale yellow oil. Analytical HPLC: purity 99.7percent (System A, RT=3.39 min); Analytical LCMS: purity 100percent (System A, RT=3.83 min), ES+: 381.5 [MH]; HRMS calcd for C19H29ClN4O2: 380.1979, found 380.1996.

Reference： [1]Patent: US2009/281087,2009,A1 .Location in patent: Page/Page column 25

18
[ 5464-12-0 ]
[ 70931-28-1 ]
[ 7693-46-1 ]
[ 1159929-75-5 ]

Yield	Reaction Conditions	Operation in experiment
21%		Example 42 2-(4-Methylpiperazin-1-yl)ethyl 4-(4-fluorobenzyl)piperazine-1-carboxylate 2-(4-Methyl-piperazin-1-yl)-ethanol (0.86 g, 6 mmol) and NMM (0.58 mL, 6 mmol) were dissolved in DCM (8 mL) and the reaction mixture was cooled to 0° C. 4-nitrophenyl chloroformate (1.29 g, 6 mmol) was added and the reaction mixture stirred for 1 h. To the reaction mixture was added a solution of 1-(4-fluoro-benzyl)-piperazine (0.97 g, 5 mmol) and DIPEA (6.0 mL, excess) in DMF (20 mL). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in EtOAc (150 mL), washed with sat aq Na2CO3 solution (6100 mL), dried (MgSO4) and the solvent removed in vacuo. The residue was initially purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, 20 mL/min, gradient 0percent to 15percent MeOH in DCM) and then further purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 mum, 46026 mm (100 g), 30 mL/min, gradient 0percent to 30percent (over 40 min) MeOH in water with 1percent formic acid). The residue was stirred for 2 h in DCM (10 mL) with K2CO3 (~0.20 g), filtered and then dried in a vacuum oven overnight to give 2-(4-methylpiperazin-1-yl)ethyl 4-(4-fluorobenzyl)piperazine-1-carboxylate (0.39 g, 21percent) as a pale yellow oil. Analytical HPLC: purity 99.7percent (System A, RT=3.09 min); Analytical LCMS: purity 100percent (System A, RT=3.55 min), ES+: 365.6 [MH]+; HRMS calcd for C19H29FN4O2: 364.2275, found 364.2292.

Reference： [1]Patent: US2009/281087,2009,A1 .Location in patent: Page/Page column 25

19
[ 5464-12-0 ]
[ 1159598-28-3 ]
[ 1159929-70-0 ]

Yield	Reaction Conditions	Operation in experiment
17%		Example 412-(4-Methylpiperazin-1-yl)ethyl 4-(4-fluorophenyl)piperazine-1-carboxylate 2-(4-Methyl-piperazin-1-yl)-ethanol (1.44 g, 10 mmol) was dissolved in anhydrous THF (50 mL) and the reaction mixture was cooled to 0° C. NaH (60percent dispersion in oil; 0.40 g, 10 mmol) was added and stirred for 10 minutes and then 4-(4-fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (3.45 g, 10 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was cautiously quenched by the dropwise addition of a water (1 mL)/THF (10 mL) mixture. The THF was removed in vacuo and the residue was suspended between sat aq Na2CO3 solution (50 mL) and EtOAc (200 mL). The organic layer was washed with sat aq Na2CO3 solution (5.x.50 mL), dried (MgSO4) and the solvent removed in vacuo.The residue was initially purified by reverse phase column chromatography (LiChroprep RP-18, 40-63 mum, 460.x.26 mm (10g), 30 mL/min, gradient 0percent to 60percent (over 60 min) MeOH in water). Further purification by reverse phase column chromatography in two batches (LiChroprep RP-18, 40-63 mum, 460.x.26 mm (100 g),30 mL/min, gradient 0percent to 20percent (over 70 min) to 100percent (over 5 min) MeOH in water with 1percent formic acid) gave pure 2-(4-methylpiperazin-1-yl)ethyl 4-(4-fluorophenyl)piperazine-1-carboxylate formate. The formic acid was removed using K2CO3 in DCM and then dried in a vacuum oven overnight to give 2-(4-methylpiperazin-1-yl)ethyl 4-(4-fluorophenyl)piperazine-1-carboxylate (0.60 g, 17percent) as a colourless gum.Analytical HPLC: purity 99.5percent (System A, RT=3.70 min); Analytical LCMS: purity 100percent (System A, RT=4.08 min), ES+: 351.1 [MH]+; HRMS calcd for C18H27FN4O2: 350.2118, found 350.2133.

Reference： [1]Patent: US2009/281087,2009,A1 .Location in patent: Page/Page column 24-25

20
[ 5464-12-0 ]
[ 1201895-28-4 ]
C₂₅H₄₈BN₅O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A suspension of 60percent Sodium hydride in mineral oil (131.3 mg, 3.28 mmol) was washed with anhydrous hexane (5 mL) and suspended in anhydrous DMF (5 mL). l-(2- Hydroxyethyl)-4-methylpiperizine (473.6 mg, 3.28 mmol) was dissolved in DMF (5 mL) and added slowly to the above suspension at room temperature. The reaction mixture was stirred for 1 h at room temperature. Compound 99 (397 mg, 0.831 mmol) in DMF (5 mL) was slowly added to the reaction mixture. The reaction mixture was stirred for 3 h at room temperature. Ice water (25 mL) was added and the suspension was extracted with chloroform (2 x 100 mL). The solvent was removed under vacuum. After silica gel column chromatography (chloroform: methanol (9:1)), the resulting compound was dissolved in acetone (5 mL) and acidic solution (10 mL, acetone: 3N HCl (3:1)) was added. The reaction was stirred for 1 h at room temperature. The solvent was removed under vacuum and the pH was adjusted to 10 with concentrated ammonium hydroxide solution and extracted with chloroform (2 x 50 mL). The solvent was removed under vacuum. After silica gel column chromatography (methanol: cone, ammonium hydroxide (20:1)), the resulting compound was purified on alumina (dichloromethane: methanol (25:1)) to yield (CDD-0356) compound 113 (146 mg, 34.33percent) as a colorless oil. The free base CDD-0356 (113) was treated with fumaric acid in ethanol to <n="34"/>yield the difumarate salt CDD-0356 (114) (130 mg) as white solid. CDD-0356F; 1H NMR (D2O): delta 1.49-1.67 (6H, m), 1.85-2.0 (4H, m), 2.26-2.32 (IH, m), 2.72 (3H, s), 2.76-3.6 (28H, m), 3.74-3.82 (IH, m), 4.26-4.34 (2H, m), 6.46 (4H, s).13C NMR (D2O/CD3OD): delta 19.05, 23.70, 24.22, 29.20, 29.61, 29.63, 29.7, 34.91, 34.93, 43.82(m), 47.3, 47.55, 50.1, 50.47 (m), 52.38 (m), 56.83, 56.85, 66.22 (m), 67.93, 67.97, 68.36, 68.37, 68.44, 68.48, 68.73, 68.74, 68.96, 135.73, 151.26, 163.31, 172.40. Anal: [C33H55N5Oi3S] C, H, N.

Reference： [1]Patent: WO2009/152392,2009,A2 .Location in patent: Page/Page column 26-27; 32-33

21
[ 5464-12-0 ]
[ 1214208-18-0 ]
[ 1214208-23-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;	To a solution of 4-(3-chloro-9-(benzenesulfonyl)-9H-pyrido[2,3-b]indol-6-yl)phenol (240 mg, 0.55 mmol, 1equiv.) in anhydrous THF (14ml), triphenylphosphin (577 mg, 2.2 mmol, 4equiv.) and <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong> (397 mg, 2.75 mmol, 5equiv.) are added. DIAD (445 mg, 2.2 mmol, 4equiv.) is then added dropwise to the solution which is stirred at room temperature for 12hours. The mixture is then extracted with a solution of HCl 0.1M (3x10ml). The aqueus layer is treated with Na2CO3 until pH = 9 and then extracted with AcOEt (3x20ml). The organic layers are dried over MgSO4, filtered and concentrated under reduced pressure. The residue (yellow solid) is purified over silica chromatography (eluted with AcOEt/MeOH 9:1 and then THF/MeOH 9:1) to give the product as a white solid (259mg, 0.44 mmol) in 80percent yield. 1H NMR (300MHz, CDCl3) delta 8.47 (dd, 2H, J = 2.5, 7.7 Hz), 8.17 (d, 1H, J = 2.1 Hz), 8.13 (d, 2H, J = 7.5Hz), 8.00 (d, 1H, J = 0.9Hz), 7.76 (dd, 1H, J = 1.5, 8.6 Hz), 7.57-7.39 (m, 5H), 7.55 (d, 2H, J = 8.6 Hz), 7.01 (d, 2H, J = 8.5 Hz), 4.17 (t, 2H, J = 5.6 Hz), 2.87 (t, 2H, J = 5.6 Hz), 2.70-2.58 (br d, 8H), 2.35 (s, 3H).

Reference： [1]Patent: EP2161271,2010,A1 .Location in patent: Page/Page column 66

22
[ 5464-12-0 ]
[ 1228471-03-1 ]
2-(4-methylpiperazin-1-yl)ethyl 3-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]propionate dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
17%	With dmap; dicyclohexyl-carbodiimide; In N,N-dimethyl-formamide; at 20℃;	1- (2-Hydroxyethyl) -4-methylpiperazine (199 mg, 1.38 mmol) , dicyclohexylcarbodiimide (310 mg, 1.50 mmol) and 4-dimethylaminopyridine (168 mg, 1.38 mmol) were added to a DMF solution (10 ml) of 3- [5-fluoro-3- (4- methoxyphenyl) -4-oxo-8-propoxy-4H-quinolin-l-yl] propionic acid (500 mg, 1.25 piunol) and stirred overnight at room temperature. Water was added to the reaction mixture, the mixture was extracted with dichloromethane and washed with water and then dried over anhydrous sodium sulfate. The dried product was concentrated under reduced pressure, and the resulting residue was purified using silica gel column chromatography (ethyl acetate --> dichloromethane : methanol = 10 : 1) . The residue was dissolved in ethyl acetate and a 4N hydrogen chloride ethylacetate solution was added thereto and stirred. The mixture was concentrated to dryness under reduced pressure, giving a pale yellow powder of 2-(4-methyl piperazin-1-yl) ethyl 3- [5-fluoro-3- (4-methoxyphenyl) -4-oxo-8-propoxy-4H-quinolin~ 1-yl] propionate dihydrochloride (110 mg, yield: 17percent) . Melting point: 150-1520C1H-NMR (DMSOd6) deltappm: 0.99-1.05 (3H, t, J=7.4 Hz), 1.69- 1.88 (2H, m) , 2.78 (3H, s) , 2.87-3.04 (2H, m) , 3.10-3.60 (1OH, m) , 3.77 (3H, s) , 4.01-4.11 (2H, t, J=6.8 Hz), 4.27- 4.44 (2H, m) , 4.67-4.94 (2H, m) , 6.76-7.09 (3H, m) , 7.16- 7.33 (IH, m) , 7.58-7.63 (2H, d, J=8.8 Hz), 8.07 (IH, s) .

Reference： [1]Patent: WO2010/64735,2010,A1 .Location in patent: Page/Page column 162-163

23
[ 5464-12-0 ]
[ 952409-24-4 ]
C₆₅H₇₀N₁₄O₁₈S₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of the acid of example 1 (20 nig, 0.015 mmol), triethylamine (6.3 muL, 0.045 mmol), and 4-dimethylarninopyridine (catalytic amount) in dichloromethane (1 mL) was isopropenylchloroformate (5 muL, 0.045 mmol) at room temperature. After 5 minutes, l-(2- hydroxyethyl)-4-methylpiperazine (43 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated, and the residue was purified on preparative reversed-phase HPLC. The product was obtained as a light yellow solid after lyophilization. 1H NMR (CD3OD, 500MHz): d 8.61 (d, J=9.5, 1 H), 8.57 (m, 2 H), 8.43 (s, 1 H), 8.18 (s, 1 H)5 8.14 (d, J=ILOHz, 1 H)5 7.87 (m, 1 H), 7.82 (m, 1 H), 7.42 (t, J=7.8Hz, 1 H), 7.22 (d, J=7.0 Hz. 1 H), 6.19 (d, J=12.5 Hz, 1 H)3 5.90 (m, 1 H), 5.78 (dd, J-10.5 Hz, 4.5 Hz, 1 H), 5.39 (m, 1 H), 5.21 (s, 1 H), 5.06 (d, J=12.5 Hz, IH)5 4.96 (d, J=10.5Hz, 1 H), 4.57 (m, 3 H)5 4.41 (d5 J=9.5 Hz5 1 H)5 4.37 (m, 1 H), 4.30 (d, 10.5 Hz, 1 H), 4.06 (m, 1 H), 3.95 (s, 3 H), 3.20 (S5 2 H)5 3.02 (s, 6 H)5 2.96 (m, 2 H)5 2.89 (s, 3 H), 2.80 (m, 1 H)5 2.17 (m, 2 H), 2.05 (s, 3 H)5 1.75 (s, 3 H)5 1.40 (d, J=6 Hz, 3 H), 0.99 (d, J=7.5 Hz, 3 H).
		To a solution of the acid of example 1 (20 mg, 0.015 mmol), triethylamine (6.3 DL, 0.045 mmol), and 4-dimethylaminopyridine (catalytic amount) in dichloromethane (1 mL) was isopropenylchloroformate (5DL, 0.045 mmol) at room temperature. After 5 minutes, l-(2- hydroxyethyl)-4-methylpiperazine (43 mg, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated, and the residue was purified on preparative reversed-phase HPLC. The product was obtained as a light yellow solid after lyophilization. 1H NMR (CD3OD5 500MHz): d 8.61 (d, J=9.5, 1 H), 8.57 (m, 2 H)3 8.43 (s, 1 H), 8.18 (S5 1 H)5 8.14 (d5 J=Il. OHz, 1 H), 7.87 (m, 1 H)5 7.82 (m, 1 H), 7.42 (t, J=7.8Hz, 1 H)5 7.22 (d, J=7.0 Hz, 1 H), 6.19 (d, J=12.5 Hz, 1 H), 5.90 (m, 1 H)5 5.78 (dd, J=10.5 Hz, 4.5 Hz5 1 H), 5.39 (m5 1 H)5 5.21 (s, 1 H), 5.06 (d, J=12.5 Hz, IH), 4.96 (d, J=10.5Hz, 1 H), 4.57 (m, 3 H), 4.41 (d, J=9.5 Hz, 1 H), 4.37 (m5 1 H), 4.30 (d, 10.5 Hz, 1 H), 4.06 (m, 1 H), 3.95 (s, 3 H), 3.20 (s, 2 H)5 3.02 (s, 6 H), 2.96 (m5 2 H)5 2.89 (s, 3 H), 2.80 (m, 1 H)5 2.17 (m, 2 H), 2.05 (s, 3 H), 1.75 (s, 3 H), 1.40 (d, J=6 Hz5 3 H)5 0.99 (d, J=7.5 Hz5 3 H).

Reference： [1]Patent: WO2007/127136,2007,A2 .Location in patent: Page/Page column 25-26
[2]Patent: WO2007/127135,2007,A2 .Location in patent: Page/Page column 62

24
[ 5464-12-0 ]
[ 66222-29-5 ]
1-methyl-4-(2-tributylstannylmethoxyethyl)piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%		To a mixture of 1-(2-hydroxyethyl)-4-methylpiperazine (1.0 g, 6.9 mmol) and tetrahydrofuran (15 ml) was added sodium hydride (60percent, 277 mg, 6.9 mmol) at 0°C (external temperature), and the reaction mixture was stirred at room temperature for 30 minutes. Then, to the reaction mixture was added dropwise a mixture of tributyl-iodomethyl-tin (2.0 g, 4.6 mmol) and N,N-dimethylformamide (15 ml) at 0°C (external temperature). Then, the reaction mixture was stirred at room temperature for 1. 5 hours. To the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The organic layer was washed with water and an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane: ethyl acetate=10:1, NH silica gel) to obtain the title compound (1.9 g, 4.2 mmol, 92percent). 1H-NMR Spectrum (CDCl3) delta (ppm): 0.89(15H, t, J=7.6Hz), 1. 25-1. 34 (6H, m), 1.46-1. 54 (6H, m), 2.28 (3H, s), 2.46 (8H, brs), 2.56(2H, t, J=5.6Hz), 3.47(2H, t, J=5.6Hz), 3.73(2H, s).

Reference： [1]Patent: EP1867650,2007,A1 .Location in patent: Page/Page column 31

25
[ 5464-12-0 ]
[ 379230-38-3 ]
N-(5-chlorobenzo[d][1,3]dioxol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)-5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine difumarate [ No CAS ]

Reference： [1]Organic Process Research and Development,2010,vol. 14,p. 1088 - 1093

26
[ 5464-12-0 ]
[ 19798-80-2 ]
[ 1313408-96-6 ]

Yield	Reaction Conditions	Operation in experiment
72%		Sodium hydride (60percent, 0.87 g, 21.80 mmol) was added to diglyme (10 mL). A solution of 2-(4-methyl-piperazin-1-yl)-ethanol (3.14 g, 21.80 mmol) in diglyme (10 mL) was added slowly. The reaction mixture was heated at 40 00 for 1 hour, 4-chloro-pyridin-2- ylamine (1.40 g, 10.9 mmol) was added and the reaction mixture was heated at 80 0 o for 1 hour, then at 15700 for 16 hours. The reaction mixture was cooled, diluted with water (20 mL), and then THF (20 mL) and NaCI were added. The organic phase was separated and the aqueous phase was extracted with THF. The combined organic phase was dried, and then the solvent was evaporated. Diethyl ether was added to the residue. The resulting solid was filtered, washed with ether, and dried to afford white solid (1.86 g, 72percent), (M+H)=237.
72%		Sodium hydride (60percent, 0.87 g, 21.80 mmol) was added to diglyme (10 mL). A solution of 2-(4-methyl-piperazin-1-yl)-ethanol (3.14 g, 21.80 mmol) in diglyme (10 mL) was added slowly. The reaction mixture was heated at 40 00 for 1 hour, 4-chloro-pyridin- 2-ylamine (1.40 g, 10.9 mmol) was added and the reaction mixture was heated at 8000 for 1 hour, then at 15700 for 16 hours. The reaction mixture was cooled, diluted with water (20 mL), and THF (20 mL) was added, then NaCI. The organic phase was separated, and the aqueous phase was extracted with THF. The combined organic phase was dried, and the solvent was evaporated. Diethyl ether was added to the residue. The resulting solid was filtered, washed with ether, and dried to afford a white solid (1.86 g, 72percent), (M+H)=237.
		Sodium hydride (60percent in mineral oil; 43.56 g; 1089 mmol) was added to a 3L reaction flask under nitrogen. A mechanical stirrer and thermocouple was attached. Dry diglyme (400 mL) was added. A solution of 2-(4-methylpiperazin-l-yl)ethanol (157 g; 1089 mmol) in diglyme (450 mL) was added slowly with stirring. The mixture was stirred with warming to 40 °C for 1 hour. 4-Chloropyridin-2-amine (70.0 g; 544.5 mmol) was added as a solid. The mixture was heated to 80 °C with stirring until effervescence had ceased. The temperature was increased to 157 °C for 16 hours. The mixture was allowed to cool and diluted with water (500 mL). THF (1000 mL) was added followed by sodium chloride (sufficient to saturate the aqueous phase). The phases were separated and the aqueous phase was further extracted with THF (3 x 800 mL). Additional water was added as required to aid in phase separation. The combined organic phases were dried with sodium sulfate (1000 g) for 16 hours and filtered. The solvent was removed under vacuum to remove the majority of the THF. The solution was filtered through Celite.(R). to remove fine particulates rinsing with diglyme. The diglyme was removed under vacuum (10 mm Hg vacuum, with the bath temperature increased to 60 °C). The residue was placed under high vacuum for 1 hour and then triturated with ether (400 mL). The resulting solids were collected by filtration, washed with ether and dried under vacuum to give the product (100.4 g) as an off white solid.

Sodium hydride (60percent in mineral oil; 43.56 g; 1089 mmol) was added to a 3L reaction flask under nitrogen. A mechanical stirrer and thermocouple was attached. Dry diglyme (400 mL) was added. A solution of 2-(4-methylpiperazin-l-yl)ethanol (157 g; 1089 mmol) in diglyme (450 mL) was added slowly with stirring. The mixture was stirred with warming to 40 °C for 1 hour. 4-Chloropyridin-2-amine (70.0 g; 544.5 mmol) was added as a solid. The mixture was heated to 80 °C with stirring until effervescence had ceased. The temperature was increased to 157 °C for 16 hours. The mixture was allowed to cool and diluted with water (500 mL). THF (1000 mL) was added followed by sodium chloride (sufficient to saturate the aqueous phase). The phases were separated and the aqueous phase was further extracted with THF (3 x 800 mL). Additional water was added as required to aid in phase separation. The combined organic phases were dried with sodium sulfate (1000 g) for 16 hours and filtered. The solvent was removed under vacuum to remove the majority of the THF. The solution was filtered through Celite to remove fine particulates rinsing with diglyme. The diglyme was removed under vacuum (10 mm Hg vacuum, with the bath temperature increased to 60°C). The residue was placed under high vacuum for 1 hour and then triturated with ether (400 mL). The resulting solids were collected by filtration, washed with ether and dried under vacuum to give the product (100.4 g) as an off white solid.

Reference： [1]Patent: WO2015/4481,2015,A1 .Location in patent: Page/Page column 104; 105
[2]Patent: WO2015/4481,2015,A1 .Location in patent: Page/Page column 106
[3]Patent: WO2011/79076,2011,A1 .Location in patent: Page/Page column 69; 70
[4]Patent: WO2012/82689,2012,A1 .Location in patent: Page/Page column 53-54

27
[ 5464-12-0 ]
[ 1313410-26-2 ]
[ 1313407-95-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In dimethyl sulfoxide; at 95℃; for 16h;Inert atmosphere;	7-Chloro-N-(3-cyclopropyl-l-((6-methylpyridin-2-yl)methyl)-lH-indazol-4- yl)imidazo[l,2-a]pyridine-3-carboxamide (5.0 g, 10.9 mmol), potassium hydroxide (3.38 g, 60.2 mmol), DMSO (50 mL), and 2-(4-methylpiperazin-l-yl)ethanol (3.16 g, 21.9 mmol) were combined under nitrogen and heated to 95 °C for 16 hours. The mixture was cooled to ambient temperature and THF (300 mL) was added. The slurry was stirred at ambient temperature for 3 hours. The solids were filtered off and the THF removed from the filtrates under vacuum to give a DMSO solution of the product. The DMSO solution was heated to 60 °C and water (100 mL) was added to precipitate out the product. The slurry was cooled to ambient temperature and stirred for 18 hours. The solids were collected by filtration and washed with water (100 mL) and MTBE (50 mL). The material was dried under vacuum at 40 °C to give N-(3-cyclopropyl-l-((6-methylpyridin-2-yl)methyl)-lH-indazol-4-yl)-7-(2-(4- methylpiperazin-l-yl)ethoxy)imidazo[l,2-a]pyridine-3-carboxamide (4.54 g). MS (ES+APCI) m/z = 565.1 (M+H).

Reference： [1]Patent: WO2011/79076,2011,A1 .Location in patent: Page/Page column 142

28
[ 5464-12-0 ]
[ 1313410-38-6 ]
[ 1313408-06-8 ]

Yield	Reaction Conditions	Operation in experiment
		A one dram vial was charged with solid potassium tert-butoxide (54 mg, 0.48 mmol), 2-(4-methylpiperazin-l-yl)ethanol (0.075 g, 0.52 mmol), and tert-butanol (0.3 mL, 3.4 mmol). The mixture was stirred at ambient temperature for 30 minutes. N-(3-cyclopropyl-l-((l-methyl-2-oxo-l,2-dihydropyridin-3- yl)methyl)-lH-indazol-4-yl)-7-fluoroimidazo[l,2-a]pyridine-3-carboxamide (0.032 g, 0.070 mmol) was added in one portion. The mixture was heated at 88 °C with stirring for 16 hours. The mixture was cooled to ambient temperature and diluted with water until a precipitate formed. The precipitate was isolated by filtration and dried under high vacuum. Purification using silica preparative thin layer chromatography plate (20 x 20 cm, 0.5 mm) developed in a chamber with 10percent methanol/dichloromethane with 0.6percent concentrated ammonium hydroxide gave the product. MS (APCI), positive scan, m/z = 581.2 (M+).

Reference： [1]Patent: WO2011/79076,2011,A1 .Location in patent: Page/Page column 155; 156

29
[ 5464-12-0 ]
[ 2581-34-2 ]
[ 1003805-16-0 ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃;	Compound 132 was synthesized according to the following production scheme.

Reference： [1]Patent: US2011/190299,2011,A1 .Location in patent: Page/Page column 26

30
[ 5464-12-0 ]
[ 379230-38-3 ]
saracatinib [ No CAS ]
[ 893428-67-6 ]

Reference： [1]Organic process research and development,2011,vol. 15,p. 688 - 692

31
[ 5464-12-0 ]
[ 1351564-86-7 ]
[ 1351564-90-3 ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 2h;	Example 12(5Z)-5-[(1-[4-(Methyloxy)-2-(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-3-[2-(4-methyl piperazin-1-yl)ethyl]-1,3-thiazolidine-2,4-dione (5Z)-5-[(1-[4-(Methyloxy)-2-(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-3-[2-(4-methylpiperazin-1-yl)ethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8) and <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong> following General Procedure J.1H NMR (400 MHz, CDCl3): delta 8.15 (d, 1H), 8.09 (m, 1H), 7.92 (s, 1H), 7.56 (dd, 1H), 7.29 (d, 1H), 7.22 (d, 1H), 6.86 (dd, 1H), 6.67 (d, 1H), 5.75 (s, 2H), 3.98 (br, 2H), 3.79 (s, 3H), 3.73 (br, 2H), 3.45 (br, 2H), 3.15 (t, 2H), 2.50 (br, 4H), 2.34 (s, 3H).LC/MS: mass calcd. for C17H28F3N5O3S: 559.19, found 560.3 [M+H]+ General Procedure J. To a mixture of 5-[1-(substituted benzyl)-1H-heteroar-5-ylmethylene]-1,3-thiazolidine-2,4-dione from Procedure E (0.25 mmol), an aliphatic alcohol (0.375 mmol) and Ph3P (0.375 mmol), in THF (2 mL) was added DIAD (0.375 mmol) and the solution was stirred at rt for 2 h. The reaction was concentrated in vacuo and the resultant residue was purified by silica gel chromatography (DCM/MeOH) to afford the desired 5-[1-(substituted benzyl)-1H-heteroar-5-ylmethylene]-(3-alkylated)-1,3-thiazolidine-2,4-dione product

Reference： [1]Patent: US2011/294780,2011,A1 .Location in patent: Page/Page column 131-132; 136

32
[ 5464-12-0 ]
[ 1386980-87-5 ]
[ 1386979-82-3 ]

Yield	Reaction Conditions	Operation in experiment
18%		To a 25 mL round bottom flask equipped with a stir bar was added 2-(4-methyl-piperazin-1-yl)-ethanol (0.079 mL, 0.65 mmol) and DMF (5 mL) and the solution was cooled to 0° C. in an ice-water bath after which sodium hydride (0.026 g, 0.65 mmol, 60percent oil dispersion) was added. The solution was allowed to stir at 0° C. for 20 minutes after which 2-methanesulfonyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid [2-chloro-5-(3-chloro-benzylcarbamoyl)-phenyl]-amide (0.050 g, 0.093 mmol) (from Example 75 supra) was added all at once. The reaction was allowed to warm to room temperature and stir for 16 hours. The reaction was filtered and then purified by reverse-phase HPLC (Gilson, C-18 Polaris column; eluting with 30-100percent acetonitrile/water with 0.1percent TFA) to provide, after basification to remove the TFA, 2-[2-(4-methyl-piperazin-1-yl)-ethoxy]-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid [2-chloro-5-(3-chloro-benzylcarbamoyl)-phenyl]amide. (Yield 0.010 g, 18percent). LR-MS: [M+H]+: 610.

Reference： [1]Patent: US2012/184542,2012,A1 .Location in patent: Page/Page column 49

33
[ 5464-12-0 ]
[ 1311423-91-2 ]
[ 1383934-25-5 ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 24h;	DIAD (0.14 mL) was added dropwise to a solution of 25 (200.0 mg), 2-(4- methylpiperazin-l-yl)ethanol (0.103 mL) and PPh3 (188.8 mg) in THF (2 mL) at 0 °C. The solution was stirred at room temperature for 24 h. The solvent was evaporated and the residue was diluted in AcOEt (30 mL) and washed with H20 (3x30 mL). The organic layer was dried over Na2SC"4, filtered and evaporated. Purification by flash chromatography (AcOE MeOH 7:3) gave a white solid (38.0 mg).1H NMR (CDC13, 300 MHz) delta 7.95-7.92 (m, 2H), 7.82 (s, 1H), 7.46 (d, 1H, J= 9.0 Hz), 7.28-7.25 (m, 1H), 6.60-6.55 (m, 2H), 4.15 (t, 2H, J= 5.4 Hz), 4.08 (q, 2H, J= 6.9 Hz), 2.76 (t, 2H, J= 5.4 Hz), 2.53 (s, 4H), 2.33 (s, 4H), 2.21 (s, 3H), 1.37 (t, 3H, J= 6.9 Hz).

Reference： [1]Patent: WO2012/88420,2012,A1 .Location in patent: Page/Page column 93

34
[ 5464-12-0 ]
[ 13526-66-4 ]
[ 1400873-92-8 ]

Yield	Reaction Conditions	Operation in experiment
62%		a) 3-Bromo-6-(2-(4-methylpiperazin-1 - l)ethoxy)imidazo[1 ,2-6]pyridazineTo a solution of <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong> (4.60 g, 32.2 mmol, 1.5 eq) in anhydrous THF (50 mL) was added NaH (60percent in mineral oil, 1.00 g, 42.9 mmol, 2.0 eq) at 0°C and the mixture was stirred at RT. After 1 h, 3-bromo-6-chloro-imidazo[1 ,2-j ]pyridazine (500 mg, 2.14 mmol, 1 eq) was added at 0°C. The mixture was heated to 65°C for 2 h, then allowed to cool, poured into crushed ice and the precipitated solid was collected by filtration to obtain an off-white solid (4.5 g, 62percent); H NMR (400 MHz, DMSO-dB) delta ppm 8.04 (d, J=10.0 Hz, 1 H), 7.74 (s, 1 H), 6.96 (d, J=9.6 Hz, 1 H), 4.46 (t, J=11.6 Hz, 2H), 3.40- 3.30 (m, 4H), 2.74 (t, J=11.6 Hz, 2H), 2.32-2.28 (m, 4H), 2.12 (s, 3H); m/z (APCI)+: 340/342 [M+H]+.

Reference： [1]Patent: WO2012/127212,2012,A1 .Location in patent: Page/Page column 98

35
[ 5464-12-0 ]
[ 1407520-42-6 ]
[ 1407520-43-7 ]

Yield	Reaction Conditions	Operation in experiment
		Step 4: NaH (0.039g, 0.96 mmol, 60percent dispersion in oil) was taken up in a dry capped microwave vial. To this, l -(2-hydroxyethyl)-4-methylpiperazine (0.023g, 0.16mmol) dissolved in dry tetrahydrofuran ( 1 .6mL) was added dropwise. The mixture was stirred at rt for 20 min. Intermediate C ( 0.075g, 0.16mmol) was then added in one portion to this suspension and the mixture was heated to 67° C in the closed seal tube for 25 min. The mixture was allowed to reach at rt and quenched with a few drops of methanol. Solvent was removed under vacuum and the resultant crude was subjected to FCC eluting with DCM- MeOH (95/5) to furnish the desired product D ( 0.081 g).
81 mg		NaH (0.039g, 0.96 mmol, 60percent dispersion in oil) was taken up in a dry capped microwave vial. To this, 1-(2-hydroxyethyl)-4-methylpiperazine (0.023g, 0.16mmol) dissolved in dry tetrahydrofuran ( 1.6mL) was added dropwise. The mixture was stirred at rt for 20 min. Intermediate C ( 0.075g, 0.16mmol) was then added in one portion to this suspension and the mixture was heated to 67° C in the closed seal tube for 25 min. The mixture was allowed to reach at rt and quenched with a few drops of methanol. Solvent was removed under vacuum and the resultant crude was subjected to FCC eluting with DCM- MeOH (95/5) to furnish the desired product D ( 0.081g).

Reference： [1]Patent: WO2012/151561,2012,A1 .Location in patent: Page/Page column 61
[2]Patent: WO2013/169401,2013,A1 .Location in patent: Page/Page column 61-62

36
[ 5464-12-0 ]
[ 4774-14-5 ]
2-chloro-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%		EXAMPLE 22: 2-Chloro-6-(2-(4-methylpiperazin- 1 -yl)methoxy)pyridine31To a suspension of 2-(4-methylpiperazine-l-yl)ethanol (50mg, 0.347mmol) in dioxane (3ml) at 0°C, KOlBu (50mg, 0.347mmol) was added and the reaction mixture was stirred for lOmin. Ice bath was removed and the reaction mixture was allowed to attain room temperature. The mixture was again cooled to 0°C and 2, 6-Dichloropyrazine (200mg, 1.04mmol) was added. Reaction mixture was allowed to stir at RT for 24h after which it was concentrated and was purified by flash column chromatography over 230-400 silica gel using 5-8percent MeOH/DCM system to afford the desired product 31, 30mg (Yield:35 percent) as brown gummy liquid. The product was confirmed by 1HNMR (not clean but characteristic peaks were present); MS: 256, (M+l), LCMS -90percent.

Reference： [1]Patent: WO2012/135631,2012,A1 .Location in patent: Page/Page column 28

37
[ 5464-12-0 ]
[ 69411-67-2 ]
[ 1428555-24-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 48h;	General procedure: A vial was charged with 2-trifluoromethyl, 5-nitroflurobenzaldehyde (1.4 mmol), various aminoalcohols (1.4 mmol) and anhydrous tetrahydrofuran (10 mL). The reagents were stirred vigorously and cooled to 0 °C in an ice-water bath. Sodium hydride (2.8 mmol) was added portionwise to the mixture over 5 minutes and the resulting suspension warmed to room temperature and stirred for 48 hours. The reaction was quenched by the addition of water (5 mL) and brine (5 mL) and product extracted into diethyl ether. The organic layer was dried, decolorized with activated charcoal, filtered, and evaporated in vacuo to afford the crude product that was purified on silica with methanol/ethyl acetate as the eluent.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 2177 - 2180

38
[ 5464-12-0 ]
[ 869663-58-1 ]
[ 1443248-12-1 ]

Yield	Reaction Conditions	Operation in experiment
15%	With di-isopropyl azodicarboxylate; triphenylphosphine; at 20℃; for 1.25h;	To a solution of Intermediate 13b (1.15 g, 5.0 mmol), 2-(4-methyl- piperazin-l -yl)-ethanol (864 mg, 6.0 mmol) and triphenylphosphine (2.62 g, 10.0 mmol) in THF (10 mL) was added diisopropyl azodicarboxylate (2.0 g, 10.0 mmol) dropwise and stirred for 75 min. The mixture was diluted with diethyl ether (50 mL) and extracted with 10percent aqueous citric acid soln (2 x). The combined aqueous layers were basified with solid potassium carbonate until pH = 9. The aqueous layer was then extracted with ethyl acetate (3 x). The combined ethyl acetate layers were washed with brine, dried (NaSO4) and evaporated in vacuo. Purification by FCC using 0- 12percent [9: 1 MeOH/880 ammonia] in DCM. The resulting product was crystallised (diethyl ether) to give the title compound (270 mg, 0.756 mmol, 15percent). LCMS (Method 1): Rt 2.31 , 1.72 min, m/z 358/359 [MH+].
15%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; for 1.25h;	c. 5-tert-Butyl-2-{4-[2-(4-methyl-piperazin-1-yl)-ethoxy]-phenyl}-2H-pyrazol-3-ylamine (Intermediate 13c) To a solution of Intermediate 13b (1.15 g, 5.0 mmol), 2-(4-methyl-piperazin-1-yl)-ethanol (864 mg, 6.0 mmol), and triphenylphosphine (2.62 g, 10.0 mmol) in THF (10 mL), was added diisopropyl azodicarboxylate (2.0 g, 10.0 mmol) dropwise and stirred for 75 min. The mixture was diluted with diethyl ether (50 mL) and extracted with 10percent aqueous citric acid soln (2). The combined aqueous layers were basified with solid potassium carbonate until pH=9. The aqueous layer was then extracted with ethyl acetate (3). The combined ethyl acetate layers were washed with brine, dried (NaSO4) and evaporated in vacuo. Purification by FCC using 0-12percent [9:1 MeOH/880 ammonia] in DCM. The resulting product was crystallised (diethyl ether) to give the title compound (270 mg, 0.756 mmol, 15percent). LCMS (Method 1): Rt 2.31, 1.72 min, m/z 358/359 [MH+].

Reference： [1]Patent: WO2013/83606,2013,A1 .Location in patent: Page/Page column 107
[2]Patent: US2013/150361,2013,A1 .Location in patent: Paragraph 0432; 0433

39
[ 5464-12-0 ]
[ 2369-13-3 ]
[ 1443499-50-0 ]

Yield	Reaction Conditions	Operation in experiment
9.3 g		50 ml of THF and 5 g (0.153 mol) of 1- hydroxyethylpiperazine are placed in a 500 ml three-necked flask equipped with a thermometer, a condenser and a bubbler, with magnetic stirring and under a stream of nitrogen. After cooling to 0°C, 1.539 g (0.064 mol) of sodium hydride are added and this medium is stirred for 1 hour to obtain the alkoxide. A solution derived from 250 ml of THF and 4.3 g (0.028 mol) of 3-fluoro-4-nitroaniline is added dropwise to this alkoxide. The medium obtained is stirred for 24 hours while monitoring by TLC (9/1 CH2Cl2/MeOH). The solvent is removed by evaporation on a rotavapor, followed by purification on a column of silica, eluting with dichloromethane/methanol. The compound thus obtained in the form of a yellow powder, in a mass of 9.3 g, corresponds to the expected compound. Analysis by mass spectrometry confirms the structure of the expected compound. The quasi-molecular ions [M+H]+ and [M+Na] + of the expected molecule C13H20N4O3 are mainly detected.

Reference： [1]Patent: WO2013/87934,2013,A1 .Location in patent: Page/Page column 39-40

40
[ 5464-12-0 ]
[ 1448611-61-7 ]
[ 1448611-62-8 ]

Yield	Reaction Conditions	Operation in experiment
52 mg		Method 20 Synthesis of 3-[1-(4-iodophenyl)-1,2-dimethyl-propyl]-1-[2-(4-methylpiperazin-1-yl)ethyl]indole (Intermediate 26) To a solution of I-11 (150 mg, 0.39 mmol) in anhydrous DMF (4.5 mL) is added NaH (60percent dispersion in mineral oil) (18 mg, 0.46 mmol). The mixture is stirred at room temperature for 10 minutes and then methanesulfonyl chloride (0.032 mL, 0.42 mmol) is added and stifling continued for 18 h. The reaction is retreated with more methane sulfonyl chloride (0.03 mL) and NaH (60percent dispersion in mineral oil) (18 mg) and stirring is continued for another 2 h before quenching with water. The reaction is partitioned between saturated aqueous NaHCO3 and DCM. The combined organics are washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give I-25 (193 mg). To a solution of 1-(2-hydroxyethyl)-4-methylpiperazine (54 mg, 0.37 mmol) in toluene (3 mL) is added NaH (60percent dispersion in mineral oil) (18 mg, 0.45 mmol) and the suspension stirred at room temperature for 10 min. A solution of I-25 (175 mg, 0.37 mmol) in toluene (1.5 mL) is added and the reaction heated to 110° C. for 3 h. A further 1 eq of 1-(2-hydroxyethyl)-4-methylpiperazine and 1.2 eq of NaH are added and heating continued for 3 h. The reaction is quenched by dropwise addition of water and extracted with DCM. The combined organics are washed with water and brine, and dried over anhydrous Na2SO4. The solvent is removed in vacuo and the crude material purified by flash chromatography (SiO2, 2percent MeOH in DCM) to give the title intermediate I-26 (52 mg) m/z 516.1 [M+H].

Reference： [1]Patent: US2013/196967,2013,A1 .Location in patent: Paragraph 0217; 0218; 0219

41
[ 5464-12-0 ]
[ 70-34-8 ]
[ 1565766-61-1 ]

Yield	Reaction Conditions	Operation in experiment
63.7%		A 250 ml three-necked flask equipped with a thermometer, a condenser, a bubble counter and a dropping funnel, and with magnetic stirring, is charged with 60 ml of THF and 7.9 g (50.94 mmol) of 2-(4-methylpiperazin-1 -yl)ethanol. The solution obtained is cooled to zero degrees and 2.04 g (50.94 mmol) of sodium hydride are gently added at this temperature. Stirring is continued at zero degrees for 1 hour. A solution of 7.9 g (42.45 mmol) of 1 -fluoro-2,4-dinitrobenzene and of 70 ml of THF, cooled beforehand to zero degrees, is then added dropwise to the previous medium. The reaction is monitored by TLC, elution being carried out with MeOH/CH2CI2. After stirring overnight at ambient temperature, the solvent is eliminated by evaporation under vacuum until a brown-yellow solid is obtained which, via purification by silica column flash chromatography (CH2Cl2/MeOH) gives, after evaporation of the solvent, a brown solid with a mass of 8.39 g (63.7percent yield) corresponding to the expected compound.

Reference： [1]Patent: WO2014/26952,2014,A1 .Location in patent: Page/Page column 33

42
[ 5464-12-0 ]
[ 39856-50-3 ]
[ 1588423-95-3 ]

Yield	Reaction Conditions	Operation in experiment
33%	With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In toluene; at 90℃; for 12h;	To mixture of Scheme 41 compound 1 (2.00 g, 9.80 mmol), Scheme 41 compound 2 (1.41 g, 9.85 mmol), Cs2C03 (9.60 g, 29.55 mmol) and Xantphos (569 mg, 0.98 mmol) in dry toluene (20 mL) was added Pd(OAc)2 (221 mg, 0.98 mmol) and the reaction mixture was heated to 90°C for 12 h. After TLC showed the starting material was completely consumed, the reaction mixture was cooled to RT, passed through a pad of celite and washed with EtOAc. The filtrate was washed with water and brine, dried over Na2S04 and concentrated to give a residue which was purified by flash chromatography on silica gel (eluting with CH2Cl2/MeOH 100/0 gradually increasing to 95/5) to give Scheme 41 compound 3 (1.10 g, 33percent) as a pale yellow solid. MS [ESI, MH+] = 267.13.

Reference： [1]Patent: WO2014/52365,2014,A1 .Location in patent: Page/Page column 260

43
[ 5464-12-0 ]
[ 1606126-53-7 ]
[ 1606126-30-0 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate; In 1,4-dioxane; at 85 - 120℃;Microwave irradiation;	4-chloro-3-(3-fluorophenyl)-1-[2-(4-methylpiperazin-1-yl)ethyl]-5-phenyl-pyrazolo[3,4-c]pyridazine (Compound 8) A mixture of 4-chloro-3-(3-fluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (0.33 mmol), <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong> (0.65 mmol), diethyl azodicarboxylate (114 mg, 0.65 mmol) and triphenyl phosphine (171 mg, 0.65 mmol) in 1,4-dioxane (2 mL) was heated using microwave irradiation to a temperature between 85 and 120° C. for a 30 to 90 min period. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to provide Compound 8. 1H NMR delta (ppm)(CHCl3-d): 7.81-7.77 (2H, m), 7.57-7.44 (6H, m), 7.20-7.18 (1H, m), 4.95 (2H, t), 3.07 (2H, t), 2.65 (4H, bs), 2.35 (4H, bs), 2.25 (3H, s). LCMS (10 cm_Formic_ACE 3 C18 AR_HPLC_CH3CN) Rt 9.93 min; m/z 451 [M+H] 99.18percent purity.

Reference： [1]Patent: US2014/121205,2014,A1 .Location in patent: Paragraph 0144; 0145; 0146; 0147

44
[ 5464-12-0 ]
[ 1606126-59-3 ]
[ 1606126-32-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate; In 1,4-dioxane; at 85 - 120℃;Microwave irradiation;	4-chloro-3-(3,4-difluorophenyl)-1-[2-(4-methylpiperazin-1-yl)ethyl]-5-phenyl-pyrazolo[3,4-c]pyridazine (Compound 10) A mixture of 4-chloro-3-(3,4-difluorophenyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (0.33 mmol), <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong> (0.65 mmol), diethyl azodicarboxylate (114 mg, 0.65 mmol) and triphenyl phosphine (171 mg, 0.65 mmol) in 1,4-dioxane (2 mL) was heated using microwave irradiation to a temperature between 85 and 120° C. for a 30 to 90 min period. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to provide Compound 10. 1H NMR delta (ppm)(CHCl3-d): 7.78-7.75 (2H, m), 7.65-7.59 (1H, m), 7.58-7.51 (4H, m), 7.33-7.29 (1H, m), 4.93 (2H, t), 3.16 (2H, t), 3.08 (4H, bs), 1.59 (4H, bs), 2.67 (3H, s). LCMS (10 cm_ESCI_Bicarb_MeCN) Rt 4.27 min; m/z 469 [M+H] 96.02percent purity.

Reference： [1]Patent: US2014/121205,2014,A1 .Location in patent: Paragraph 0154; 0155; 0156; 0157

45
[ 5464-12-0 ]
[ 1608158-64-0 ]
[ 1608158-65-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate; In 1,4-dioxane; at 85 - 120℃;Microwave irradiation;	General procedure: A mixture of 4-chloro-3-methyl-5-phenyl-1,1-pyrazolo[3,4-c]pyridazine (0.33 mmol), the alcohol (0.65 mmol), diethyl azodicarboxylate (114 mg, 0.65 mmol) and triphenyl phosphine (171 mg, 0.65 mmol) in 1,4-dioxane (2 mL) was heated using microwave irradiation to a temperature between 85 and 120° C. for a 30 to 90 min period. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to provide the title compound.4-chloro-3-methyl-1-[2-(4-methylpiperazin-1-yl)ethyl]-5-phenyl-pyrazolo[3,4-c]pyridazine (Compound Iv) Compound Iv was synthesized from 4-chloro-3-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong> following the general procedure for the Mitsunobu reaction described above. 1H NMR delta (ppm) (CHCl3-d): 7.80-7.77 (2H, m), 7.56-7.48 (3H, m), 4.80 (2 t), 2.99 (2H, t), 2.80 (3H, s), 2.64 (4H, br s), 2.40 (4H, br s), 2.26 (3H, s). LCMS (10 cm_ESCI_Formic_MeCN) Rt 2.53 min; m/z 371 [M+H] 99.25percent purity.

Reference： [1]Patent: US2014/121197,2014,A1 .Location in patent: Paragraph 0246; 0247; 0248; 0249; 0250

46
[ 5464-12-0 ]
6-(6-fluoro-1H-indol-1-yl)-2-(3-(5-hydroxypyrimidin-2-yl)benzyl)pyridazin-3(2H)-one [ No CAS ]
6-(6-fluoro-1H-indol-1-yl)-2-(3-(5-(2-(4-methylpiperazin-1-yl)ethoxy)pyrimidin-2-yl)benzyl)pyridazin-3(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h;	General procedure: To a solution of triphenylphosphine (0.37 mmol) in THF (30 mL) was slowly added diisopropyl azodicarboxylate (0.37 mmol) in 15 min at 0 °C and the mixture was stirred for another 15 min. At the same temperature, to the resulting mixture was slowly added a solution of 20 (0.185 mmol) and corresponding alcohol (0.37 mmol) dissolved in 20 mL THF. The ice bar was removed and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was evaporated in vacuo, and the residue was purified by column chromatography to afford the product.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 95,p. 302 - 312

47
[ 5464-12-0 ]
2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol [ No CAS ]
1-(2-(2-chloro-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenoxy)ethyl)-4-methylpiperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine; diethylazodicarboxylate; In toluene; at 50℃; for 1.5h;Inert atmosphere;	10.0 g 2-chloro-3 -methyl-4-(4,4, 5,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)phenol(Preparation 5a) (37.2 mmol), 8.7 g <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong> (60.3 mmol) and15.8 g PPh3 (60.3 mrnol) were dissolved in 100 mL dry toluene and then 27 mL diethylazodicarboxylate (60.3 mmol, 40percent solution in toluene) was added dropwise. The mixturewas stirred at 50°C under argon for 1.5 hours. The volatiles were evaporated under reducedpressure and 100 rnL Et20 was added. The precipitated white crystals were filtered off and washed with Et20. The filtrate was concentrated under reduced pressure and pudfied via flash chromatography using CHC13 and MeOH as eluents. The resulting light brown oil was crystallized from hexanc to give Preparation Sb as an off-white solid.?11 NMR (500 MHz, DMSO-d6): 7.56 (d, 111), 6.99 (d, 1H), 4.15 (t, 2H), 2.72 (t, 2H), 2.51 (s, 311), 2.50 (br s, 4H), 2.29 (br s, 411), 2.13 (s, 311), 1.29 (s, 12H).
	With triphenylphosphine; diethylazodicarboxylate; In toluene; at 50℃;Inert atmosphere;	10.0 g Preparation B2 (37.2 mmol), 8.7 g <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong> (60.3 mmol) and 15.8 g PPh3 (60.3 mmol) were dissolved in 100 mL dry toluene and then 27 mL diethyl azodicarboxylate (60.3 mmol, 40 percent solution in toluene) was added dropwise. The mixture was stirred at 50 °C under argon until no further conversion was observed. The volatiles were evaporated under reduced pressure and 100 mL Et20 was added. Theprecipitated white crystals were filtered off and washed with Et20. The filtrate was concentrated under reduced pressure and purified via flash chromatography using CHC13 and MeOH as eluents. The resulting light brown oil was crystallized from hexane to give Preparation B4 as an off-white solid. 1H NMR (500 MHz, DMSO-d6) oe: 7.56 (d, 1H), 6.99 (d, 1H), 4.15 (t, 2H), 2.72 (t, 2H), 2.51 (s, 3H), 2.50 (br s, 4H), 2.29 (br s, 4H), 2.13(s, 3H), 1.29 (s, 12H)
	With triphenylphosphine; diethylazodicarboxylate; In toluene; at 50℃; for 1.5h;Inert atmosphere;	10.0 g 2-chloro-3-methyl-4-(4,4, 5, 5-tetramethyl-l, 3,2-dioxaborolan-2-yl)phenol (from Step K) (37.2 mmol), 8.7 g 2-(4-methylpiperazin-l-yl)ethanol (60.3 mmol) and 15.8 g PPh3 (60.3 mmol) were dissolved in 100 mL dry toluene and then 27 mL diethyl azodicarboxylate (60.3 mmol, 40 percent solution in toluene) was added dropwise. The mixture was stirred at 50 °C under argon for 1.5 hours. The volatiles were evaporated under reduced pressure and 100 mL Et20 was added. The precipitated white crystals were filtered off and washed with Et20. The filtrate was concentrated under reduced pressure and purified via flash chromatography using CHC13 and MeOH as eluents. The resulting light brown oil was crystallized from hexane to give l-[2-[2-chloro-3-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methyl-piperazine as an off-white solid. 1H NMR (500 MHz, DMSO-d6): 7.56 (d, 1H), 6.99 (d, 1H), 4.15 (t, 2H), 2.72 (t, 2H), 2.51 (s, 3H), 2.50 (br s, 4H), 2.29 (br s, 4H), 2.13 (s, 3H), 1.29 (s, 12H)

	With triphenylphosphine; diethylazodicarboxylate; In toluene; at 50℃;Inert atmosphere;	10.0 g Preparation 3a (37.2 mmol,), 8.7 g 2-(4-methylpiperazin-l-yl)ethanol (60.3 mmol) and 15.8 g PPh3 (60.3 mmol) were dissolved in 100 mL dry toluene and then 27 mL DEAD (60.3 mmol, 40 percent solution in toluene) was added dropwise. The mixture was stirred at 50 °C under argon atmosphere until no further conversion was observed. The volatiles were evaporated under reduced pressure and 100 mL Et20 was added. The precipitated white crystals were filtered off and washed with Et20. The filtrate was concentrated under reduced pressure and purified via flash chromatography using CHCI3 and MeOH as eluents. The resulting light brown oil was crystallized from hexane to give Preparation 3b as an off-white solid. 1H NMR (500 MHz, DMSO-d6) delta: 7.56 (d, 1H), 6.99 (d, 1H), 4.15 (t, 2H), 2.72 (t, 2H), 2.51 (s, 3H), 2.50 (br s, 4H), 2.29 (br s, 4H), 2.13 (s, 3H), 1.29 (s, 12H)
	With triphenylphosphine; diethylazodicarboxylate; In toluene; at 50℃;Inert atmosphere;	Step J: 1-f 2-f 2-Chloro-3-methyl-4-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2- yl)phenoxy] ethyl] -4-methyl-piperazine (0181) 10.0 g compound of Step I above (37.2 mmol), 8.7 g 2-(4-methylpiperazin-l-yl)ethanol (60.3 mmol) and 15.8 g triphenylphosphine (60.3 mmol) were dissolved in 100 mL dry toluene and then 27 mL diethyl azodicarboxylate (60.3 mmol, 40 percent solution in toluene) was added dropwise. The mixture was stirred at 50 °C under argon until no further conversion was observed. The volatiles were evaporated under reduced pressure and 100 mL diethyl ether was added. The precipitated white crystals were filtered off and washed with diethyl ether. The filtrate was concentrated under reduced pressure and purified via flash chromatography using chloroform and methanol as eluents. The resulting light brown oil was crystallized from hexane to give l-[2-[2-chloro-3-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methyl-piperazine as an off-white solid. 1H NMR (500 MHz, DMSO-d6) delta: 7.56 (d, 1H), 6.99 (d, 1H), 4.15 (t, 2H), 2.72 (t, 2H), 2.51 (s, 3H), 2.50 (br s, 4H), 2.29 (br s, 4H), 2.13 (s, 3H), 1.29 (s, 12H)

Reference： [1]Patent: WO2015/97123,2015,A1 .Location in patent: Page/Page column 69; 70
[2]Patent: WO2016/207226,2016,A1 .Location in patent: Page/Page column 68
[3]Patent: WO2016/207216,2016,A1 .Location in patent: Page/Page column 33; 37
[4]Patent: WO2016/207217,2016,A1 .Location in patent: Page/Page column 48-49
[5]Patent: WO2017/125224,2017,A1 .Location in patent: Page/Page column 32

48
[ 5464-12-0 ]
ethyl (2R)-2-[6-(5-chloro-2-furyl)-(5Sa)-5-(3-chloro-4-hydroxy-2-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[(4-methoxyphenyl)methoxy]phenyl]propanoate [ No CAS ]
ethyl (2R)-2-[6-(5-chloro-2-furyl)-5-(5Sa)-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[(4-methoxyphenyl)methoxy]phenyl]propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In toluene; at 50℃;Inert atmosphere;	5.30 g ethyl (2]?) -2- [6-(5 -chloro-2-furyl)-5 -(581j-(3 -chloro-4-hydroxy-2-methyl-phenyl)thieno [2,3 -dJpyrimidin-4-yI] oxy-3 -[2- [(4-methoxyphenyl)methoxy] phenyl]propanoate (Preparation 61) (7.5 mmol), 2.16 g 2-(4-methylpiperazin- 1 -yl)ethanol (15 minol) and 3.93 g PPh3 (15 rnmol) were dissolved in 30 mL dry toluene, then 3.45 g ditertbutyl azodicarboxylate (15 inmol) was added. The mixture was stirred at 50°C under N2 until no further conversion was observed. The toluene was evaporated under reducedpressure and the residue was purified via flash chromatography using EtOAc and MeOT-1 as cluents to obtain Preparation 71.MS: (M1-H)= 831,0.

Reference： [1]Patent: WO2015/97123,2015,A1 .Location in patent: Page/Page column 114; 115

49
[ 5464-12-0 ]
[ 3964-56-5 ]
1-[2-( 4-bromo-2-chlorophenoxy)ethyl]-4-methylpiperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In toluene; at 50℃;Inert atmosphere;	10.373 g (50 mmol) 4-bromo-2-chlorophenol, 14.442 g <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong>(100 mmol) and 26.229 g PPh3 (100 mmol) were dissolved in 250 mL toluene, then 23 .027g diter/butyl azodicarboxylate (100 nimol) was added. The mixture was stirred at 50°Cunder N2 until no further conversion was observed. The toluene was evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOll as eluentsMS (M+H)t 333.0.
	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In toluene; at 50℃;Inert atmosphere;	10.373 g 4-bromo-2-chlorophenol (50 mmol), 14.442 g 2-(4-methylpiperazin-l-yl)ethanol (100 mmol) and 26.229 g PPh3 (100 mmol) were dissolved in 250 mL dry toluene under N2 atmosphere, then 23.027 g DTAD (100 mmol) was added. The mixture was stirred at 50 °C until no further conversion was observed. The volatiles were evaporated under reduced pressure and the residue was purified via flash chromatography using EtOAc and MeOH as eluents. MS (M+H): 333.0

Reference： [1]Patent: WO2015/97123,2015,A1 .Location in patent: Page/Page column 92
[2]Patent: WO2016/207217,2016,A1 .Location in patent: Page/Page column 56-57

50
[ 5464-12-0 ]
[ 60710-39-6 ]
1-[2-(3-bromo-4-methylphenoxy)ethyl]-4-methylpiperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In tetrahydrofuran; toluene; at 20℃; for 2h;Inert atmosphere;	0.50 g <strong>[60710-39-6]3-bromo-4-methyl-phenol</strong> (2.67 mmol), 0.46 g 2-(4-methylpiperazin-1-yl)ethanol(3.21 mmol) and 0.84 g PPh3 (3.21 mmol) was dissolved in 10 mL dry THE under N2, then1.47 mL diethyl azodicarboxylate (3.21 mmol, 40% in toluene) was added and the mixturewas stirred at room temperature for 2 hours. Then it was concentrated under reducedpressure and purified via reversed phase chromatography using aqueous 0.1% TEAsolution and MeCN as eluents to obtain 1 -[2-(3-bromo-4-mcthyl-phenoxy)ethylj-4-methyl- piperazine.MS (M+H): 313.1.

Reference： [1]Patent: WO2015/97123,2015,A1 .Location in patent: Page/Page column 75; 76

51
[ 5464-12-0 ]
[ 22802-37-5 ]
1-[2-(4-bromo-2,3-dimethylphenoxy)ethyl]-4-methylpiperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In toluene; at 45℃; for 2h;Inert atmosphere;	1.54 g <strong>[22802-37-5]4-bromo-2,3-dimethyl-phenol</strong> (7.66 inmol), 2.21 g 2-(4-methylpiperazin-1-yl)ethanol (15.3 nirnol) and 6.03 g PPh3 (23.0 mmol) were dissolved in 20 rnL dry toluene under N2, then 5.29 g ditertbutyl azodiearboxylate (23.0 mmol) was added and the mixture was stirred at 45C for 2 hours. Then it was concentrated under reduced pressure and purified via flash chromatography using EtOAc and MeOH as eluents to obtain 1 -[2-(4- bromo-2,3 -dimethyl-phenoxy)ethyl}-4-methyl-piperazine.1 NMR (400 MHz, CDCI3): 7.31 (d, IH), 6.58 (d, 111), 4.06 (t, 2H), 2.83 (t, 2H), 2.70-2.38 (m, 811), 2.36 (s, 311), 2.29 (s, 311), 2.20 (s, 311).

Reference： [1]Patent: WO2015/97123,2015,A1 .Location in patent: Page/Page column 91

52
[ 5464-12-0 ]
ethyl 3-(6-chloropyridazin-3-yl)indolizine-2-carboxylate [ No CAS ]
ethyl 3-{6-[2-(4-methylpiperazin-1-yl)ethoxy]pyridazin-3-yl}indolizine-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%		Intermediate H63: ethyl 3-{6-[2-(4-methylpiperazin-1-yl)ethoxy]pyridazin-3-yl}indolizine-2-carboxylate 2-(4-Methylpiperazin-1-yl)ethan-1-ol (0.2676 g, 1.85 mmol) was dissolved in 5.5 ml of THF, potassium tert-butoxide (0.309 g, 2.76 mmol) was added and the mixture was stirred at room temperature for 30 min. Ethyl 3-(6-chloropyridazin-3-yl)indolizine-2-carboxylate 1157 (0.280 g 0.92 mmol) was added and the mixture was stirred at RT for 5 min. The mixture was diluted with ethyl acetate and washed with brine, the phases were separated and the organic layer was dried over sodium sulphate. The solvent was removed and the residue was purified by flash chromatography on Biotage silica-NH cartridge (DCM to DCM:MeOH=98:2) to afford title compound (0.187 g, 0.45 mmol, 49percent yield). MS/ESI+ 410.4 [MH]+, Rt=0.57 min (Method A).

Reference： [1]Patent: US2015/361100,2015,A1 .Location in patent: Paragraph 0451; 0452

53
[ 5464-12-0 ]
[ 56-05-3 ]
4-chloro-6-[2-(4-methylpiperazin-1-yl)ethoxy]pyrimidin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%		To a suspension of sodium hydride (13.4 mg, 0.3 mmol) in tetrahydrofuran (5.0 mL) was added <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong> (43.9 mg, 0.3 mmol) at 0° C. The reaction mixture was stirred at room temperature for 30 min. A solution of 4,6-dichloropyrimidin-2-amine (50 mg, 0.3 mmol) in dimethylformamide (0.5 mL) was added to the reaction mixture at 0° C. The resulting reaction mixture was stirred at room temperature for 3 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue obtained was washed with diethyl ether to afford compound 1 (20 mg, 24percent) as a brown solid. 1H NMR (400 MHz, DMSO-d6): delta 2.11 (s, 3H), 2.26 (br s, 4H), 2.41 (br s, 4H), 2.58-2.61 (t, J=5.8 Hz, 2H), 4.29-4.32 (t, J=5.9 Hz, 2H), 6.06 (d, J=3.1 Hz, 1H), 6.99 (br s, 2H). MS m/z (M+H): 272.1.

Reference： [1]Patent: US2016/75720,2016,A1 .Location in patent: Paragraph 0314

54
[ 5464-12-0 ]
[ 143-15-7 ]
N-dodecyl-N-methyl-N'-dodecyl-N'-hydroxylethylpiperazinium dibromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	In isopropyl alcohol; at 80℃; for 55h;	General procedure: N,N",N"-trimethylaminoethylpiperazine (manufactured by Tosoh Corporation, TOYOCAT-NP) was dissolved in 10.0g of acetonitrile, & heated to 80°C and thereto 1-bromododecane (manufactured by Tokyo Kasei Kogyo Co., Ltd.) 32.0g was added dropwise over 5 hours. After 50 hours of reaction at 80°C, the solvent was distilled off, and washed with hexane and ethyl acetate. After washing, solid-liquid separation was done by centrifugation, and further by repeating the recrystallization, N'-(N-dodecyl-N,N-dimethylethylammonium)-N"-methylpiperazinium dibromide 36.4g (93percent yield) was obtained. The structure was confirmed by 1H-NMR and elemental analysis. using N-methyl-N'-hydroxylethylpiperazine(manufactured by Tosoh Corporation, TOYOCAT-HP) 10.0 g, 1-bromododecane 44.3 g, 2-propanol for solvent, except these, by the procedure analogous to that described in Example 1, N-dodecyl-N-methyl-N'-dodecyl-N'-hydroxylethylpiperazinium dibromide 32.4g (72percent yield) was obtained. The structure was confirmed by 1H-NMR, elemental analysis.

Reference： [1]Patent: JP2015/168680,2015,A .Location in patent: Paragraph 0068

55
[ 5464-12-0 ]
(R)-2-hydroxy-3-(2-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)phenyl)propionic acid ethyl ester [ No CAS ]
4-chloro-5-(3,5-dichloro-4-methoxy-2,6-dimethylphenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine [ No CAS ]
ethyl (2R)-2-[5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		200 mg mixture of 4-chloro-5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-l-yl) ethoxy]phenyl] -6-(4-fluorophenyl)thieno [2,3 - ]pyrimidine and 4-bromo-5 - [3 ,5 -dichloro- 2,6-dimethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-(i] pyrimidine (0.33 mmol), 211 mg ethyl (2i?)-2-hydroxy-3-[2-[[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy]phenyl]propanoate (0.52 mmol) and 202 mg Cs2C03 (0.62 mmol) was dissolved in 5 mL tert-butanol and the mixture was stirred at 70 °C until no further conversion was observed. It was diluted with ethyl acetate and then it was washed with brine. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure and purified via flash chromatography using EtOAc and methanol as eluents to obtain ethyl (2i?)-2-[5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl] -6-(4-fluorophenyl)thieno [2,3 - ]pyrimidin-4-yl]oxy-3 - [2- [ [2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy]phenyl]propanoate. The obtained intermediate was dissolved in 5 mL dioxane-water 1 : 1 (10 mL/mmol) and 145 mg LiOH x H20 (3.45 mmol) was added. The mixture was stirred at r.t. until no further conversion was observed. Then it was diluted with brine, neutralized with 2 M HC1, extracted with DCM, dried over Na2S04, filtered and concentrated under reduced pressure and purified via preparative reversed phase chromatography using 5 mM aqueous NH4HC03 solution and MeCN as eluents to obtain Preparation 13. 1H NMR (400 MHz, DMSO-d6): 8.89 (d, 1H), 8.60 (s, 1H), 7.81 (d, 1H), 7.53 (dd, 1H), 7.45 (td, 1H), 7.29-7.21 (m, 4H), 7.17-7.13 (m, 1H), 7.14 (d, 1H), 7.04 (td, 1H), 7.01 (d, 1H), 6.76 (t, 1H), 6.20 (d, 1H), 5.45 (dd, 1H), 5.26 (d, 1H), 5.20 (d, 1H), 4.06-4.01 (m, 2H), 3.76 (s, 3H), 3.46 (dd, 1H), 2.79-2.74 (m, 2H), 2.67-2.38 (m, 8H), 2.33 (s, 3H), 2.26 (s, 3H), 2.22 (dd, 1H), 1.73 (s, 3H) HRMS (M+2H)2+ = 462.1310
		Step L: 2, 6-Dichloro-4-[ 4-chloro-6- ( 4-fluorophenyl) thienof 2, 3-dJpyrimidin-5-ylJ-3, 5- dimethyl-phenol and 4-f 4-bromo-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-5-yl]-2, 6- dichloro-3, 5 -dimethyl-phenol (0234) To a stirred solution of 700 mg compound of Step K above (1.50 mmol, 1.0 eq.) in 15 mL dichloromethane, 3.0 mL boron tribromide (1M in dichloromethane) (3.0 mmol, 2.0 eq.) was added at 0 °C and the mixture was allowed to warm up to room temperature and it was stirred until no further conversion was observed. The mixture was quenched with saturated aqueous NH4C1 and extracted with dichloromethane. The combined organic phases were dried over Na2S04 and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain 2,6-dichloro-4- [4-chloro-6-(4-fluorophenyl)thieno[2,3-(i]pyrimidin-5-yl]-3,5-dimethyl-phenol and 4-[4- bromo-6-(4-fluorophenyl)thieno[2,3- ]pyrimidin-5-yl]-2,6-dichloro-3,5-dimethyl-phenol as a 37:63 mixture of products. (0235) 1H NMR (400 MHz, DMSO-d6): 10.14 (br s, 1H), 9.01 (s, 1H), 7.40-7.23 (m, 4H), 1.95 (s, 6H) and 10.14 (br s, 1H), 8.93 (s, 1H), 7.40-7.23 (m, 4H), 1.93 (s, 6H) (0236) HRMS (M+H)+ = 452.9800 and 496.9287 Step M: 4-Chloro-5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-l- yl) ethoxy] phenyl] -6- ( 4-fluorophenyl) thienof 2, 3-dJpyrimidine and 4-bromo-5-[ 3, 5- dichloro-2, 6-dimethyl-4-[ 2- ( 4-methylpiperazin-l-yl) ethoxy] phenyl] -6- ( 4- fluorophenyl) thienof 2, 3-d]pyrimidine (0238) 300 mg mixture of 2,6-dichloro-4-[4-chloro-6-(4-fluorophenyl)thieno[2,3-<i]pyrimidin-5- yl] -3 ,5 -dimethyl-pheno 1 and 4- [4-bromo-6-(4-fluorophenyl)thieno [2,3 - ]pyrimidin-5 -yl] - 2,6-dichloro-3,5-dimethyl-phenol (0.62 mmol), 286 mg 2-(4-methylpiperazin-l-yl)ethanol (1.98 mmol, 3.0 eq.) and 520 mg triphenyl phosphine (1.98 mmol, 3.0) were dissolved in 10 mL dry toluene, then 460 mg di-tert-butyl azodicarboxylate (1.98 mmol, 3.0 eq.) was added. The mixture was stirred at 50 °C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents to obtain 4-chloro-5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl] -6-(4-fluorophenyl)thieno[2,3-(i]pyrimidine and 4-bromo-5-[3,5-dichloro-2,6-dimethyl-4- [2-(4-methylpiperazin- 1 -yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-<i]pyrimidine as a 35:65 mixture of products. (0239) 1H NMR (400 MHz, DMSO-d6): 9.02 (s, 1H), 7.40-7.22 (m, 4H), 4.11 (t, 2H), 2.78 (t, 2H), 2.63-2.20 (m, 8H), 2.17 (br s, 3H), 1.98 (s, 6H) and 8.94 (s, 1H), 7.40-7.22 (m, 4H), 4.1 1 (t, 2H), 2.78 (t, 2H), 2.63-2.20 (m, 8H), 2.15 (br s, 3H), 1.98 (s, 6H) (0240) HRMS (M+H)+ = 579.0968 and 623.0455 Step N: Ethyl (2R)-2-f5-f3,5-dichloro-2,6-dimethyl-4-f2-(4-methylpiperazin-l- yl) ethoxy] phenyl] -6- ( 4-fluorophenyl) thienof 2, 3-dJpyrimidin-4-ylJoxy-3-f 2-f [2- (2- methoxyphenyl)pyrimidin-4-yl]methoxy] phenyl] propanoate (0241) 200 mg mixture of 4-chloro-5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-l-yl) ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-(i]pyrimidine and 4-bromo-5-[3,5-dichloro- 2,6-dimethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-(i] pyrimidine (0.33 mmol, 1.0 eq.), 211 mg ethyl (2i?)-2-hydroxy-3-[2-[[2-(2- methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate (0.52 mmol, 1.58 eq.) and 202 mg CS2CO3 (0.62 mmol, 1.88 eq.) was dissolved in 5 mL tert-butanol and the mixture was stirred at 70 °C until no further conversion was observed. It was diluted with ethyl acetate and then it was washed with brine. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure and purified via flash chromatography using ethyl acetate and methanol as eluents to obtain ethyl (2i?)-2-[5-[3,5-dichloro-2,6- dimethyl-4- [2-(4-methylpiperazin- 1 -yl)ethoxy]phenyl] -6-(4-fluorophenyl)thieno [2,3 - J] pyrimidin-4-yl]oxy-3 - [2- [ [2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl] propanoate. MS: (M+H) = 951.0

Reference： [1]Patent: WO2016/207225,2016,A1 .Location in patent: Page/Page column 43-44
[2]Patent: WO2017/125224,2017,A1 .Location in patent: Page/Page column 41-43

56
[ 5464-12-0 ]
4-chloro-5-(3,5-dichloro-4-methoxy-2,6-dimethylphenyl)-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine [ No CAS ]
4-chloro-5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine [ No CAS ]
4-bromo-5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(4-fluorophenyl) thieno[2,3-d]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		300 mg mixture of 2,6-dichloro-4-[4-chloro-6-(4-fluorophenyl)thieno[2,3-<i]pyrimidin-5- yl] -3 ,5 -dimethyl-pheno 1 and 4- [4-bromo-6-(4-fluorophenyl)thieno [2,3 - ]pyrimidin-5 -yl] - 2,6-dichloro-3,5-dimethyl-phenol (0.62 mmol), 286 mg 2-(4-methylpiperazin-l-yl)ethanol (1.98 mmol) and 520 mg triphenyl phosphine (1.98 mmol) were dissolved in 10 mL dry toluene, then 460 mg ditert-butyl azodicarboxylate (1.98 mmol) was added. The mixture was stirred at 50 °C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and methanol as eluents to obtain 4-chloro-5-[3,5-dichloro- 2,6-dimethyl-4-[2-(4-methylpiperazin- 1 -yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-<i] pyrimidine and 4-bromo-5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-l-yl) ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-(i]pyrimidine as a 35:65 mixture of products. 1H NMR (400 MHz, DMSO-d6): 9.02 (S, 1H), 7.40-7.22 (m, 4H), 4.11 (t, 2H), 2.78 (t, 2H), 2.63-2.20 (m, 8H), 2.17 (br s, 3H), 1.98 (s, 6H) and 8.94 (S, 1H), 7.40-7.22 (m, 4H), 4.11 (t, 2H), 2.78 (t, 2H), 2.63-2.20 (m, 8H), 2.15 (br s, 3H), 1.98 (s, 6H) HRMS (M+H)+ = 579.0968 and 623.0455
		300 mg mixture of 2,6-dichloro-4- [4-chloro-6-(4-fluorophenyl)thieno [2,3 -d]pyrimidin-5 -yl] -3,5 -dimethyl-pheno 1 and 4- [4-bromo-6-(4-fluorophenyl)thieno [2,3 -d]pyrimidin-5 -yl] -2,6-dichloro-3 ,5 -dimethyl-pheno 1 (0.62 mmo 1), 286 mg 2-(4-methylpiperazin- 1 -yl)ethano 1(1.98 mmol) and 520 mg triphenyl phosphine (1.98 mmol) were dissolved in 10 mL drytoluene, then 460 mg ditertbutyl azodicarboxylate (1.98 mmol) was added. The mixturewas stirred at 50 °C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using EtOAc and methanol as eluents to obtain 4-chloro-5-[3,5-dichloro- 2,6-dimethyl-4- [2-(4-methylpiperazin- 1 -yl)ethoxy]phenyl] -6-(4-fluorophenyl)thieno [2,3 -d]pyrimidine and 4-bromo-5 -[3 ,5-dichloro-2,6-dimethyl-4- [2-(4-methylpiperazin- 1-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine as a 35:65 mixture of products.
		Step L: 2, 6-Dichloro-4-[ 4-chloro-6- ( 4-fluorophenyl) thienof 2, 3-dJpyrimidin-5-ylJ-3, 5- dimethyl-phenol and 4-f 4-bromo-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-5-yl]-2, 6- dichloro-3, 5 -dimethyl-phenol (0234) To a stirred solution of 700 mg compound of Step K above (1.50 mmol, 1.0 eq.) in 15 mL dichloromethane, 3.0 mL boron tribromide (1M in dichloromethane) (3.0 mmol, 2.0 eq.) was added at 0 °C and the mixture was allowed to warm up to room temperature and it was stirred until no further conversion was observed. The mixture was quenched with saturated aqueous NH4C1 and extracted with dichloromethane. The combined organic phases were dried over Na2S04 and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain 2,6-dichloro-4- [4-chloro-6-(4-fluorophenyl)thieno[2,3-(i]pyrimidin-5-yl]-3,5-dimethyl-phenol and 4-[4- bromo-6-(4-fluorophenyl)thieno[2,3- ]pyrimidin-5-yl]-2,6-dichloro-3,5-dimethyl-phenol as a 37:63 mixture of products. (0235) 1H NMR (400 MHz, DMSO-d6): 10.14 (br s, 1H), 9.01 (s, 1H), 7.40-7.23 (m, 4H), 1.95 (s, 6H) and 10.14 (br s, 1H), 8.93 (s, 1H), 7.40-7.23 (m, 4H), 1.93 (s, 6H) (0236) HRMS (M+H)+ = 452.9800 and 496.9287 Step M: 4-Chloro-5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-l- yl) ethoxy] phenyl] -6- ( 4-fluorophenyl) thienof 2, 3-dJpyrimidine and 4-bromo-5-[ 3, 5- dichloro-2, 6-dimethyl-4-[ 2- ( 4-methylpiperazin-l-yl) ethoxy] phenyl] -6- ( 4- fluorophenyl) thienof 2, 3-d]pyrimidine (0238) 300 mg mixture of 2,6-dichloro-4-[4-chloro-6-(4-fluorophenyl)thieno[2,3-<i]pyrimidin-5- yl] -3 ,5 -dimethyl-pheno 1 and 4- [4-bromo-6-(4-fluorophenyl)thieno [2,3 - ]pyrimidin-5 -yl] - 2,6-dichloro-3,5-dimethyl-phenol (0.62 mmol), 286 mg 2-(4-methylpiperazin-l-yl)ethanol (1.98 mmol, 3.0 eq.) and 520 mg triphenyl phosphine (1.98 mmol, 3.0) were dissolved in 10 mL dry toluene, then 460 mg di-tert-butyl azodicarboxylate (1.98 mmol, 3.0 eq.) was added. The mixture was stirred at 50 °C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermediate was purified via flash chromatography using ethyl acetate and methanol as eluents to obtain 4-chloro-5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl] -6-(4-fluorophenyl)thieno[2,3-(i]pyrimidine and 4-bromo-5-[3,5-dichloro-2,6-dimethyl-4- [2-(4-methylpiperazin- 1 -yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-<i]pyrimidine as a 35:65 mixture of products. (0239) 1H NMR (400 MHz, DMSO-d6): 9.02 (s, 1H), 7.40-7.22 (m, 4H), 4.11 (t, 2H), 2.78 (t, 2H), 2.63-2.20 (m, 8H), 2.17 (br s, 3H), 1.98 (s, 6H) and 8.94 (s, 1H), 7.40-7.22 (m, 4H), 4.1 1 (t, 2H), 2.78 (t, 2H), 2.63-2.20 (m, 8H), 2.15 (br s, 3H), 1.98 (s, 6H) (0240) HRMS (M+H)+ = 579.0968 and 623.0455

Reference： [1]Patent: WO2016/207225,2016,A1 .Location in patent: Page/Page column 40-41
[2]Patent: WO2016/207226,2016,A1 .Location in patent: Page/Page column 155; 156
[3]Patent: WO2017/125224,2017,A1 .Location in patent: Page/Page column 41-42

57
[ 5464-12-0 ]
(S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate [ No CAS ]
(S)-2-( tert-butoxy)-2-( 4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)pyridin-3-yl)acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8.68%		(S)-2-( tert-Butoxy)-2-( 4-(4, 4-dimethylpiperidin-l-yl)-2, 6-dimethyl-5-( 4-( 2-( 4- methylpiperazin-l-yl)ethoxy)phenyl)pyridin-3-yl)acetic acid. To a stirred solution of (S)- ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-5-(4-hydroxyphenyl)-2,6- dimethylpyridin-3-yl)acetate (20 mg, 0.043 mmol), 2-(4-methylpiperazin-l-yl)ethanol (30.8 mg, 0.213 mmol) and Ph3P-resin (33.6 mg, 0.128 mmol) in THF (5 mL) was added DEAD (0.020 mL, 0.128 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with IN NaOH (0.854 mL, 0.854 mmol) in MeOH (1 mL) at 75 °C for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-l-yl)-2,6-dimethyl-5-(4-(2-(4- methylpiperazin-l-yl)ethoxy)phenyl)pyridin-3-yl)acetic acid (2.1 mg, 3.71 mupiiotaomicron, 8.68 percent yield). 1H MR (500MHz, DMSO-d6) delta 7.21 (d, J=8.4 Hz, 1H), 7.05 - 7.00 (m, 3H), 5.80 (s, 1H), 4.22 - 4.04 (m, 2H), 3.36 (br. s., 1H), 2.84 - 2.76 (m, 1H), 2.70 (t, J=5.7 Hz, 2H), 2.43 (s, 3H), 2.33 (br. s., 3H), 2.16 (s, 3H), 2.06 (s, 3H), 1.49 (br. s., 1H), 1.30 (br. s., 1H), 1.17 (d, J=11.4 Hz, 1H), 1.12 (s, 9H), 1.02 (d, J=12.5 Hz, 1H), 0.85 (s, 3H), 0.61 (s, 3H). 8H of piperidine were not resolved. LCMS (M+H) = 567.5

Reference： [1]Patent: WO2017/6260,2017,A1 .Location in patent: Page/Page column 37

58
[ 5464-12-0 ]
[ 524-38-9 ]
2-(2-(4-methylpiperazin-1-yl)ethoxy)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%		To a solution of 2-hydroxyisoindoline-1 ,3-dione (2.04 g, 12.5 mmol) and triphenylphosphine (3.27 g, 12.5 mmol) in THF (40 ml_) at 0 °C was added <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong> (1.50 ml_, 10.4 mmol) dropwise. The mixture was then stirred at 0 °C for 30 min before DIAD (2.43 ml_, 12.5 mmol) was added dropwise. The reaction was stirred for a further 30 min at 0 °C before being warmed to rt and stirred for 16 h. The solvent was removed under reduced pressure and the residue re-dissolved in EtOAc (75 ml_). The organic layer was washed with saturated NaHCC>3 solution (2 x 50 ml_) and then dried over Na2S04, filtered and concentrated under reduced pressure to approximately 30 ml_. The organic layer was cooled to 0 °C and cold 1 M aqueous HCI solution (30 ml_) was added. On complete addition, the mixture was warmed to rt and stirred for 20 min. The layers were separated and the aqueous layer washed with Et20 (2 x 30 ml_). After cooling to 0 °C, the aqueous layer was basified by slow addition of a saturated NaHCC>3 solution before being extracted with CHC (3 x 50 ml_). The organic extracts were combined and then dried over Na2S04, filtered and concentrated under reduced pressure to afford the subtitle compound 2-(2-(4-methylpiperazin-1- yl)ethoxy)isoindoline-1 ,3-dione as a beige solid (1.96 g, 63percent); 1 H NMR delta: 1.84-2.47 (8H, overlapping m), 1.98 (3H, s), 2.65 (2H, t), 4.24 (2H, t), 7.85-7.87 (4H, overlapping m).

Reference： [1]Patent: WO2017/109513,2017,A1 .Location in patent: Page/Page column 29

59
[ 5464-12-0 ]
[ 269410-08-4 ]
[ 104-92-7 ]
1-(2-(4-(4-methoxyphenyl)-1H-pyrazol-1-yl)ethyl)-4-methylpiperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		General procedure: 1) (Cyanomethylene)tributylphosphorane (262 muL, 1.00 mmol) was added to a solution of (tetrahydrofuran-3-yl)methanol (51 mg, 0.50 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (97 mg, 0.5 mmol) in degassed 1,4-dioxane (2 mL) sealed in a microwave tube at rt under nitrogen. The solution was heated to 150°C for 30 min in the microwave reactor and cooled to rt. 2) 1-Bromo-4-methoxybenzene (94 mg, 0.50 mmol), potassium carbonate (207 mg, 1.50 mmol) and [1,1?-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with CH2Cl2 (40.8 mg, 0.05 mmol) were added to the solution. The tube was sealed, evacuated and backfilled with nitrogen. Degassed water (1 mL) was added under nitrogen. The resulting mixture was stirred at 120°C for 20 min. The reaction mixture was diluted with EtOAc (25 mL) and water (15 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were washed with saturated brine (15 mL). The organic layer was dried with MgSO4, filtered and evaporated to afford the crude product. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 ODB column, 5mu silica, 30mm diameter, 100mm length), using decreasingly polar mixtures of water (containing 1percent by volume NH3OH (28-30percent in H2O)) and MeCN as eluents to afford 4-(4-methoxyphenyl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazole (89mg, 69percent) as a beige solid.

Reference： [1]Tetrahedron Letters,2018,vol. 59,p. 1708 - 1710

60
[ 5464-12-0 ]
4-bromo-2-chloro-3-methylphenol [ No CAS ]
1-[2-(4-bromo-2-chloro-3-methylphenoxy)ethyl]-4-methylpiperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With di-tert-butyl-diazodicarboxylate; triphenylphosphine; In toluene; at 50℃; for 2h;Inert atmosphere;	Compound 31g S6-2d was added to the reaction flask under nitrogen protection.33g 1-hydroxyethyl-4-methylpiperazine, 60g of triphenylphosphine, inject 625mL of toluene, stir to dissolve, and then add52.7 g of di-tert-butyl azodicarboxylate,The reaction was heated to 50°C and stirred for 2 hours.TLC showed that the compound S6-2d was completely reacted to produce the product S6-2e with increased polarity. After the treatment, 30percent hydrochloric acid in methanol was added and 300 mL was stirred at room temperature for two hours.Filtrate the filtrate,The cake was beaten with methyl tert-butyl ether to give a filtrate.Combine the filtrate dry powder mix,Column chromatography (dichloromethane/methanol=15/1) gave 22 g of a yellow liquid.That is, compound S6-2e with a yield of 57percent

Reference： [1]Patent: CN107573360,2018,A .Location in patent: Paragraph 0017; 0019; 0022; 0035; 0036; 0037; 0038; 0054

61
[ 5464-12-0 ]
4-(6-(benzylpiperazin-1-yl)pyridin-3-yl)-6-hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile [ No CAS ]
4-(6-(4-benzylpiperazin-1-yl)pyridin-3-yl)-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrazolo[1,5-a]pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; dichloromethane; at 0 - 20℃; for 16h;	A cold (0 °C) solution of PPh3 (32.6 mg, 0.124 mmol) in 1:1 DCM:THF (1.0 mL) was treated with DIAD (24.5 .iL, 0.124 mmol), and stirred for 15 mm at 0 °C. The resulting 0 °C mixture was treated with a solution of (4-(6-(4-benzylpiperazin- 1 -yl)pyridin-3 -yl)-6- hydroxypyrazolo[1,5-a]pyridine-3-carbonitrile (Example 1; 34.0 mg, 0.0828 mmol) and 1-(N- hydroxyethyl)-4-methyl piperazine (14.3 mg, 0.0994 mmol) in 1:1 DCM:THF (2.0 mL). The reaction mixture was stirred for 16 h at room temperature and then concentrated in vacuo. Purification of the crude residue by C18 reverse phase chromatography (5-95percent water-ACN with0.1percent TFA as the gradient eluent) cleanly provided the title compound as the TFA salt. The salt was converted to the free base by partitioning between 4:1 DCM:iPrOH and saturated NaHCO3(aq). The resulting organic extracts were combined, dried over anhydrous Na2SO4(), filtered and concentrated in vacuo to afford the title compound (20.1 mg, 45percent yield). MS (apci) m/z = 537.2 (M+H). ?H NMR (400 IVIHz, DMSO-P) : 8.70-8.69 (d, 1H), 8.57 (s, 1H), 8.32-8.3 1 (d, 1H), 7.78-7.75 (dd, 1H), 7.52 (s, 1H), 7.35-7.25 (m, 5H), 6.93-6.91 (d, 1H), 4.21-4.18 (t, 2H), 3.60-3.57 (m, 4H), 3.53 (s, 2H), 3.18-3.13 (q, 2H), 2.73-2.70 (t, 2H), 2.50-2.47 (m, 8H), 2.13 (s, 3H), 1.32- 1.28 (t, 2H).

Reference： [1]Patent: WO2018/71447,2018,A1 .Location in patent: Paragraph 001341; 001342; 001343

62
[ 5464-12-0 ]
6-hydroxy-4-(6-(4-(pyridin-2-yloxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile [ No CAS ]
4-(6-(4-benzyl-4-(morpholinomethyl)piperidin-1-yl)pyridin-3-yl)-6-ethoxypyrazolo[1,5-a]pyridine-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.8%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 0.5h;	A solution of triphenylphosphane (31.7966 mg, 0.121 mmol) in 1 : 1 DCM:THF (0.6 mL) was cooled to 0°C and treated with diisopropyl azodicarboxylate (0.023 mL, 0.121 mmol) and stirred at 0°C for 15 min. The reaction mixture was treated with 6-hydroxy-4-(6-(4- (pyridin-2-yloxy)piperidin-l-yl)pyridin-3-yl)pyrazolo[l,5-a]pyridine-3-carbonitrile(Intermediate P78, 25.0 mg, 0.0606 mmol) in a 1 : 1 DCM:THF (0.6 mL) and 1-(N- hydroxyethyl)-4-methyl piperazine (13.1 mg, 0.0909 mmol). The reaction mixture was allowed to warm to rt and was stirred at this temperature for 30 min. The reaction mixture was concentrated in vacuo, and the resultant crude residue was directly purified by C-18 reverse phase chromatography (5-95percent ACN in water [+ 0.1percent TFA] as the gradient eluent). The fractions containing the desired product were diluted with 4: 1 DCMTPA and washed with saturated NaHC03(aq). The organic extract was dried over anhydrous Na2S04(S), filtered, and concentrated in vacuo to afford the title compound (31.5 mg, 0.0526 mmol, 86.8percent yield). MS (apci) m/z = 539.2 (M+H).

Reference： [1]Patent: WO2018/71454,2018,A1 .Location in patent: Paragraph 002413; 002414; 002415

63
[ 5464-12-0 ]
[ 1201363-83-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triphenylphosphine; di-isopropyl azodicarboxylate / tetrahydrofuran / 1 h / 20 °C / Inert atmosphere 2: palladium 10% on activated carbon; hydrogen / methanol / 16 h / 25 °C / 760.05 Torr

Reference： [1]Current Patent Assignee: GUANGZHOU MAXINOVEL PHARMACEUTICALS - US2018/208604, 2018, A1

64
[ 5464-12-0 ]
[ 2075-46-9 ]
C₁₀H₁₇N₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.2%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 1h;Inert atmosphere;	4-Nitropyrazole (2.81 g, 13.88 mmol) and 1-hydroxyethyl-4-methylpiperazine (1.0 g, 6.94 mmol) were dissolved in anhydrous tetrahydrofuran (50 mL), and a solution of triphenylphosphine (3.64 g, 13.88 mmol) and diisopropyl azodicarboxylate (2.81 g, 13.88 mmol) in anhydrous tetrahydrofuran (6 mL) was added dropwise under nitrogen gas atmosphere. The reaction solution was stirred at room temperature for 1 hour, and then 1N hydrochloric acid (30 mL) and water (50 mL) was added. The aqueous phase was extracted with ethyl acetate (50 mL*2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane: methanol=10:1) to give compound 22-c (1.0 g, yield 60.2percent). LC-MS (ESI): m/z=240.2[M+H]+.

Reference： [1]Patent: US2018/208604,2018,A1 .Location in patent: Paragraph 0315-0316

65
[ 5464-12-0 ]
[ 55481-88-4 ]
2-(4-methylpiperazin-1-yl)ethyl 6-hydroxy-2,2-dimethyl-2H-benzo[h]chromene-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With toluene-4-sulfonic acid; at 160℃; for 3h;Microwave irradiation; Inert atmosphere;	General procedure: The mixture of mollugin (0.35 mmol), alcohol (3.52 mmol), and catalytic p-TsOH (0.035 mmol) in2 mL microwave vial was placed in the cavity of microwave reactor, and then stirred for 3 h at 160 °C.The produced brown mixture was dried under vacuum and subjected to purification (20 g silica gelcartridge, dichloromethane-MeOH) to give the title product.

Reference： [1]Molecules,2018,vol. 23

66
[ 5464-12-0 ]
[ 7184-60-3 ]
2-(4-methylpiperazin-1-yl)ethyl (1R,2R)-2-[(2S,4E,6Z,8R, 9S,11R,13S,15S,16S)-7-cyano-8,16-dihydroxy-9,11,13,15-tetra-methyl-18-oxooxacyclooctadeca-4,6-dien-2-yl]cyclopentane-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		General procedure: To a solution of borrelidin (40mg, 0.082mmol) in THF (2.0mL) was added 1-hydroxybenzotriazole (HoBt, 22.2mg, 0.164 mmoL) and N,N'-dicyclohexylcarbodiimide (DCC, 33.8mg, 0.164mmol) at room temperature. The reaction mixture was stirred at room temperature for 0.5h after which the appropriate alcohol (0.205mmol) was added. Keep stirring for 12-24h, the mixture was extracted with EtOAc (20mL). The organic layer was then washed with 3% HCl aqueous (2×10mL), saturated NaHCO3 aqueous (2×10mL), brine (2×10mL). The resulting organic layer wasdried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with appropriate mixture as indicated in each case. The data of compound 3e and 3f can be found at the literature.41,42

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 6035 - 6049

67
[ 5464-12-0 ]
4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)benzoic acid [ No CAS ]
2-(4-methylpiperazin-1-yl)ethyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at -20 - 20℃;Inert atmosphere;	To a solution of 70 mg (0.15 mmol) of 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)benzoic acid (enantiomer 2) in 2 ml of dichloromethane were added, under argon at -20° C., 27 mg (0.19 mmol, 1.25 eq.) of <strong>[5464-12-0]2-(4-methylpiperazin-1-yl)ethanol</strong>, 18 mg (0.15 mmol, 1.0 eq.) of 4-dimethylaminopyridine, 33 mul (0.19 mmol, 1.25 eq.) of N,N-diisopropylethylamine and, finally, 36 mg (0.19 mmol, 1.25 eq.) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The reaction mixture was stirred at -20° C. for 20 min and allowed to come to RT, and stirred at RT overnight. After addition of water/dichloromethane and phase separation, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The residue was purified by means of RP-HPLC (Reprosil C18, acetonitrile/water gradient). Yield: 54 mg (61percent of theory) LC/MS [Method 1]: Rt=0.76 min; MS (ESIpos): m/z=592 (M+H)+, 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=10.83 (s, 1H), 8.00 (d, 1H), 7.93 (d, 2H), 7.78 (d, 2H), 7.76-7.70 (m, 2H), 7.49 (s, 1H), 6.54 (s, 1H), 5.64 (dd, 1H), 4.34 (t, 2H), 3.69 (s, 3H), 2.66 (t, 2H), 2.48-2.40 (m, 4H), 2.35-2.24 (m, 4H), 2.24-2.15 (m, 2H), 2.13 (s, 3H), 0,91 (t, 3H).

Reference： [1]Patent: US2018/346424,2018,A1 .Location in patent: Paragraph 0645; 0646; 0647; 0648

68
[ 5464-12-0 ]
[ 50-65-7 ]
[ 1420290-85-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 1399 - 1402

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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.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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
H229	Pressurized container: may burst if heated
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. 5464-12-0 ] {[proInfo.proName]}

Quality Control of [ 5464-12-0 ]

Related Doc. of [ 5464-12-0 ]

Product Details of [ 5464-12-0 ]

Calculated chemistry of [ 5464-12-0 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 5464-12-0 ]

Application In Synthesis of [ 5464-12-0 ]

[ 5464-12-0 ] Synthesis Path-Upstream 1~11

[ 5464-12-0 ] Synthesis Path-Downstream 1~68

Related Functional Groups of [ 5464-12-0 ]

Alcohols

Related Parent Nucleus of [ 5464-12-0 ]

Aliphatic Heterocycles

Piperazines

Precautionary Statements-General

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Response

Storage

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Physical hazards

Health hazards

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[ 5464-12-0 ]

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[ 5464-12-0 ]