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[ CAS No. 185315-48-4 ] {[proInfo.proName]}

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Chemical Structure| 185315-48-4

Chemical Structure| 185315-48-4

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Quality Control of [ 185315-48-4 ]

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SDS Specification

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Product Details of [ 185315-48-4 ]

CAS No. :	185315-48-4	MDL No. :	MFCD12065643
Formula :	C₇H₆BrClO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PAQVZCDJJABVMB-UHFFFAOYSA-N
M.W :	221.48	Pubchem ID :	43805739
Synonyms :

Calculated chemistry of [ 185315-48-4 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	45.28
TPSA :	20.23 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.8 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.19
Log Po/w (XLOGP3) :	2.61
Log Po/w (WLOGP) :	2.44
Log Po/w (MLOGP) :	2.88
Log Po/w (SILICOS-IT) :	2.99
Consensus Log Po/w :	2.62

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.24
Solubility :	0.129 mg/ml ; 0.000581 mol/l
Class :	Soluble
Log S (Ali) :	-2.68
Solubility :	0.458 mg/ml ; 0.00207 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.7
Solubility :	0.044 mg/ml ; 0.000199 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.46

Safety of [ 185315-48-4 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P264-P270-P271-P280-P301+P312-P302+P352-P304+P340-P305+P351+P338-P330-P332+P313-P337+P313-P362-P403+P233-P405-P501	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 185315-48-4 ]

* 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 [ 185315-48-4 ]
Downstream synthetic route of [ 185315-48-4 ]

[ 185315-48-4 ] Synthesis Path-Upstream 1~5

1
[ 185315-48-4 ]
[ 89720-77-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; for 4 h;	To a magnetically stirring solution of 4-Bromo-2-chloro-phenyl)-methanol (2.80g, 12.67 mmol) from step 1 below in CH2CI2 (60.0 mL) under argon at 0 C, was added carbon tetrabromide (4.41 g, 13.30 mmol) followed by triphenylphosphine (3.48 g, 13.30 mmol). The resulting mixture was stirred for 4 hours at room temperature. The resulting reaction mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography (10percent EtOAc in Hexanes) to yield the intermediate bromide as a clear oil (3.59 g, 100percent). H NMR (400MHZ, CDC13) : 5 4.53 (s, 2H), 7.29 (d, J = 8.2 Hz, 1H), 7.39 (dd, J = 8.2, 1.9 Hz, 1 H), 7.56 (d, J = 1.9 Hz, 1H).
100%	With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; for 4 h;	To a magnetically stirring solution of (4-bromo-2-chloro-phenyl)-methanol (2.80g, 12.67 mmol) from step 1 above in CH₂CI₂ (60.0 mL) under argon at 0 °C, was added carbon tetrabromide (4.41 g, 13.30 mmol) followed by triphenylphosphine (3.48 g, 13.30 mmol). The resulting mixture was stirred for 4 hours at room temperature. The resulting reaction mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography (10percent EtOAc in Hexanes) to yield the intermediate bromide as a clear oil (3.59 g, 100percent). ¹H NMR (400MHz, CDCI₃): 5 4.53 (s, 2H), 7.29 (d, J= 8.2 Hz, 1H), 7.39 (dd, J = 8.2,1.9 Hz, 1 H), 7.56 (d, J= 1.9 Hz, 1H).
100%	With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; for 16 h;	Step b intermediate 57 <n="67"/>4-bromo- 1 -(bromomethy l)-2-chlorobenzeneTo a stirred solution of (4-bromo-2-chlorophenyl)methanol (4.34g, 19.6mmol) in dichloromethane (98mL) at 0 ⁰C is added carbon tetrabromide (6.5g, 19.6mmol) and triphenylphosphine (5.14g, 19.6 mmol). The reaction mixture is stirred 16 h at room temperature. Then, the solvent is removed and the crude solid suspended in hexanes / EtOAc 9:1 (100 mL) and filtered on a silica gel pad. The pad is rinsed with hexanes / EtOAc 9:1 (100 mL) and the filtrate is concentrated in vacuo to provide the expected product 4-bromo-l-(bromomethyl)-2- chlorobenzene (7.19 g, 129percent) contaminated with bromoform. IH NMR (300 MHz, CHLOROFORM-D): δ 7.57 (IH, d, / = 2.0 Hz), 7.39 (IH, dd, / = 8.2, 2.0 Hz), 7.30 (IH, d, / = 8.2 Hz), 4.53 (2H, s).

99%	With phosphorus tribromide In dichloromethane at 0 - 20℃;	Intermediate 107: 4-bromo-1 -(bromomethyl)-2-chlorobenzene; To a solution of (4-bromo-2-chlorophenyl)methanol, intermediate 106, (6.9 g, 31 mmol) in dicholoromethane (200 ml.) was added dropwise a solution of phosphorus tribromide in DCM (12.5 ml_, 1 M in DCM, 12.5 mmol, 0.4 equiv.) at 0 ⁰C. After addition, the reaction mixture was stirred for 16 hours at RT. Water was added and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo to give the title product 4-bromo-1-(bromomethyl)-2-chlorobenzene (8.1 g, 99percent yield). ¹H NMR: (300 MHZ, CDCI₃) δ 7.52 (m, 1 H), 7.35 (m, 1 H), 7.22 (m, 1 H), 4.48 (s, 2H).
92%	With phosphorus tribromide In dichloromethane at 0 - 20℃; Inert atmosphere	In a flame-dried flask under inert atmosphere, S1 (17.3 g, 78 mmol, 1.0 equiv.) was dissolved in DCM (186 mL) and cooled to 0 °C. Once cooled, PBr3 (3.7 mL, 39 mmol, 0.5 equiv.) was added via syringe. The reaction was allowed to stir overnight, warming to room temperature. The resulting solution, a very strong lachrymator, was cooled to 0 °C and water was added to quench the reaction. The aqueous layer was extracted with DCM (150 mL x 3) and the combined organics were then washed with brine, dried over MgSO4, filtered, and then reduced to yield S2 as a viscous yellow oil (20.3 g, 92 percent). Characterization data was identical to previous reports.[19]
57%	With phosphorus tribromide In 1,2-dichloro-ethane at 0 - 10℃; for 0.666667 h;	Phosphorus tribromide (40.5 mL, 0.431 mol) was added dropwise to a solution of (4- brorno-2-chlorophenyl)-methanol (15, 86.1 g, 0.386 mol) in dichloroethane (430 mL) at 0 °C. The reaction mixture was stirred for 10 minutes at this temperature then for 0.5 h at 10 °C. The mixture was cooled to 0 °C and a sodium hydroxide solution (600 mL, 2N) was added dropwise. The two layers were separated and the aqueous layer was extracted with dichloroethane (200 mL). The combined organic layers were washed with water (200 mL), dried over sodium sulfate and evaporated in vacuo. The crude product (91 g) was distilled under reduced pressure (7 mmHg), to give 4-bromo-l -bromomethyl-2-chlorobenzene (62.5 g, 0.22 mol, 57 percent) as a colorless oil.
36 g	With phosphorus tribromide In dichloromethane at 0℃; Inert atmosphere	To a solution of Compound 1 (46.8 g, 21.1 mmol) in dry DCM (500 mL) was added phosphorous tribromide (68.6 g, 25.3 mmol) dropwise at 0° C. under nitrogen. The mixture was stirred for 2 hours and then washed with saturated aqueous NaHCO₃(2×200 mL) and saturated aqueous NaCl (200 mL), dried over anhydrous Na₂SO₄, concentrated under vacuum to yield Compound 2 (36 g) as a colorless oil.
36 g	With phosphorus tribromide In dichloromethane at 0℃; for 2 h; Inert atmosphere	To a solution of Compound 1 (46.8 g, 21.1 mmol) in dry DCM (500 mL) was added phosphorous tribromide (68.6 g, 25.3 mmol) dropwise at 0° C. under nitrogen. The mixture was stirred for 2 hours and then washed with saturated aqueous NaHCO₃(200 mL×2) and saturated aqueous NaCl (200 mL), dried over anhydrous Na₂SO₄, concentrated under vacuum to yield Compound 2 (36 g) as a colorless oil.
36 g	With phosphorus tribromide In dichloromethane at 0℃; for 2 h; Inert atmosphere	[0291] To a solution of Compound 1 (46.8 g, 21.1 mmol) indry DCM (500 mL) was added phosphorous tribromide (68.6g, 25.3 mmol) dropwise at oo C. under nitrogen. The mixturewas stirred for 2 hours and then washed with saturated aqueousNaHC03 (200 mLx2) and saturated aqueous NaCl (200mL ), dried over N a2SO 4 , concentrated in vacuo to yield Compound2 (36 g) as a colorless oil.
36 g	With phosphorus tribromide In dichloromethane at 0℃; for 2 h; Inert atmosphere	To a solution of Compound 1 (46.8 g, 21.1 mmol) in dry DCM (500 mL) was added phosphorous tribromide (68.6 g, 25.3 mmol) dropwise at 0°C under nitrogen. The mixture was stirred for 2 hours and then washed with saturated aqueous NaHC0₃ (200 mLx2) and saturated aqueous NaCl (200 mL), dried over Na₂S0₄, concentrated in vacuo to yield Compound 2 (36 g) as a colorless oil.
2.4 g	With hydrogen bromide In toluene at 95℃; for 5 h;	(1) (4-bromo-2-chlorophenyl) methanol (2.0 g) in toluene (10 mL) solution of 48percent hydrobromic acid (10 mL) was added and stirred for 5 hours at an external temperature of 95 ° C.. After the reaction mixture was allowed to cool, it was neutralized by the addition of a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. Washing the organic layer with saturated brine, dried over anhydrous magnesium sulfate, after filtration, the solvent was distilled off under reduced pressure of 4-bromo-1- (bromomethyl) -2-chlorobenzene (2.4 g) as a colorless oily substance It was obtained as a.

Reference： [1] Patent: WO2004/74270, 2004, A2, . Location in patent: Page 175
[2] Patent: WO2006/18725, 2006, A1, . Location in patent: Page/Page column 235-236
[3] Patent: WO2008/18827, 2008, A1, . Location in patent: Page/Page column 65-66
[4] Patent: WO2010/15652, 2010, A2, . Location in patent: Page/Page column 68
[5] Tetrahedron Letters, 2016, vol. 57, # 3, p. 449 - 451
[6] Patent: WO2013/43232, 2013, A2, . Location in patent: Paragraph 00500
[7] Patent: EP2017257, 2009, A1, . Location in patent: Page/Page column 21
[8] Patent: WO2009/23964, 2009, A1, . Location in patent: Page/Page column 25
[9] Patent: US2013/109639, 2013, A1, . Location in patent: Paragraph 0349
[10] Patent: WO2014/8223, 2014, A2, . Location in patent: Page/Page column 88
[11] Patent: US2014/256702, 2014, A1, . Location in patent: Paragraph 0297
[12] Patent: US2015/210690, 2015, A1, . Location in patent: Paragraph 0231; 0291
[13] Patent: WO2015/116786, 2015, A1, . Location in patent: Paragraph 77
[14] Patent: JP2015/231988, 2015, A, . Location in patent: Paragraph 0361; 0362

2
[ 185315-48-4 ]
[ 151-50-8 ]
[ 89720-77-4 ]

Reference： [1] Patent: EP1764075, 2007, A1, . Location in patent: Page/Page column 92

3
[ 185315-48-4 ]
[ 158435-41-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 2 h; Stage #2: With triethylamine In dichloromethane at 20℃; for 0.5 h;	Compound 44; Oxalylchloride (6.9 g, 54 mmol, 1.3 equiv.) was dissolved in DCM (153 ml) and cooled to -78 ⁰C. To the cooled solution was a solution of DMSO ( 4.72 ml, 66.5 mmol, 1.6 equiv.) in DCM (57 ml) added dropwise and stirred for 15 minutes at -78 ⁰C. Compound 43 (9.2 g, 41.5 mmol, 1.0 equiv.) was dissolved in DCM (116ml) and added dropwise while the temperature was maintained at -78 ⁰C. The r.m. was stirred for 2 h at -78 ⁰C. Then TEA (28.7 ml, 207 mmol, 5 equiv.) was added and the mixture was allowed to reach room temperature. After stirring for 30 minutes at r.t., the reaction mixture was diluted with 300 ml DCM and washed with saturated NH₄C 1, brine, dried on Na₂SO₄, filtered and concentrated in vacuo. Compound 44 was obtained in 96 percent yield (8.8 g).
81%	With pyridinium chlorochromate In dichloromethane at 25℃; for 3 h;	4-bromo-2-chlorobenzaldehyde. A mixture of (4-bromo-3-chlorophenyl)methanol (2.0 g, 9.0 mmol), pyridinium chlorochromate (2912 mg, 13.5 mmol) in dichloromethane (50 mLO was stirred at 25°C for 3 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ ethyl acetate = 1 : 1) to give (4-bromo-2-chlorophenyl)methanol as a white solid (4.12g g, 81percent). 1H NMR (300 MHz, d⁶-DMSO): δ 9.96 (s, 1H), 7.69 (d, J=8.1,1H), 7.53 (d, J =0.9,1H), 7.19 (dd, Ji=8.1,lH J₂=0.9, 1H).
81%	With pyridinium chlorochromate In dichloromethane at 25℃; for 3 h;	A mixture of (4-bromo-3-chlorophenyl)methanol (2.0 g, 9.0 mmol), pyridinium chlorochromate (2912 mg, 13.5 mmol) in dichloromethane (50 mL0 was stirred at 25° C. for 3 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=1:1) to give (4-bromo-2-chlorophenyl)methanol as a white solid (4.12 g g, 81percent). ¹H NMR (300 MHz, d⁶-DMSO): δ 9.96 (s, 1H), 7.69 (d, J=8.1, 1H), 7.53 (d, J=0.9, 1H), 7.19 (dd, J₁=8.1, 1H J₂=0.9, 1H).

70%

With dipyridinium dichromate In dichloromethane at 20℃; for 1 h;

To a solution of (4-bromo-2-chlorophenyl)methanol (2.8 g, 12.8 mmol) that was obtained in Example 24 (24e) in dichloromethane (50 ml) was added pyridinium dichromate (7.2 g, 19.2 mmol) with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, ether (250 ml) was added to the reaction mixture under stirring, and the resulting mixture was filtered with Celite. The filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:20) as the eluent to afford the title compound (2.0 g, yield: 70 percent) as a white crystalline solid. ¹HNMR Spectrum (400 MHz, CDCl₃) δ ppm: 7.55 (dd, 1H, J=8.2 Hz, 1.6 Hz), 7.66 (d, 1H, J=1.6 Hz), 7.79 (d, 1H, J=8.2 Hz), 10.42 (s, 1H). IR Spectrum (KBr): 1201, 1374, 1577, 1693 cm^-1. Mass Spectrum (EI⁺) m/z: 218 (M⁺).

Reference： [1] Patent: WO2008/51826, 2008, A2, . Location in patent: Page/Page column 53; 54
[2] Patent: WO2008/103277, 2008, A2, . Location in patent: Page/Page column 197
[3] Journal of Medicinal Chemistry, 2017, vol. 60, # 18, p. 7820 - 7834
[4] Patent: WO2013/75083, 2013, A1, . Location in patent: Paragraph 006309; 00632
[5] Patent: US9206128, 2015, B2, . Location in patent: Page/Page column 275; 276; 277
[6] Patent: EP1873153, 2008, A1, . Location in patent: Page/Page column 92-93

4
[ 185315-48-4 ]
[ 916516-89-7 ]

Reference： [1] Patent: WO2013/43232, 2013, A2,
[2] Tetrahedron Letters, 2016, vol. 57, # 3, p. 449 - 451
[3] Patent: JP2015/231988, 2015, A,

5
[ 185315-48-4 ]
[ 1432908-05-8 ]

Reference： [1] Tetrahedron Letters, 2016, vol. 57, # 3, p. 449 - 451

[ 185315-48-4 ] Synthesis Path-Downstream 1~88

1
[ 185315-48-4 ]
[ 158435-41-7 ]

Yield	Reaction Conditions	Operation in experiment
96%		Compound 44; Oxalylchloride (6.9 g, 54 mmol, 1.3 equiv.) was dissolved in DCM (153 ml) and cooled to -78 0C. To the cooled solution was a solution of DMSO ( 4.72 ml, 66.5 mmol, 1.6 equiv.) in DCM (57 ml) added dropwise and stirred for 15 minutes at -78 0C. Compound 43 (9.2 g, 41.5 mmol, 1.0 equiv.) was dissolved in DCM (116ml) and added dropwise while the temperature was maintained at -78 0C. The r.m. was stirred for 2 h at -78 0C. Then TEA (28.7 ml, 207 mmol, 5 equiv.) was added and the mixture was allowed to reach room temperature. After stirring for 30 minutes at r.t., the reaction mixture was diluted with 300 ml DCM and washed with saturated NH4C 1, brine, dried on Na2SO4, filtered and concentrated in vacuo. Compound 44 was obtained in 96 % yield (8.8 g).
81%	With pyridinium chlorochromate; In dichloromethane; at 25℃; for 3h;	4-bromo-2-chlorobenzaldehyde. A mixture of (4-bromo-3-chlorophenyl)methanol (2.0 g, 9.0 mmol), pyridinium chlorochromate (2912 mg, 13.5 mmol) in dichloromethane (50 mLO was stirred at 25C for 3 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ ethyl acetate = 1 : 1) to give (4-bromo-2-chlorophenyl)methanol as a white solid (4.12g g, 81%). 1H NMR (300 MHz, d6-DMSO): delta 9.96 (s, 1H), 7.69 (d, J=8.1,1H), 7.53 (d, J =0.9,1H), 7.19 (dd, Ji=8.1,lH J2=0.9, 1H).
81%	With pyridinium chlorochromate; In dichloromethane; at 25℃; for 3h;	A mixture of (4-bromo-3-chlorophenyl)methanol (2.0 g, 9.0 mmol), pyridinium chlorochromate (2912 mg, 13.5 mmol) in dichloromethane (50 mL0 was stirred at 25 C. for 3 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=1:1) to give (4-bromo-2-chlorophenyl)methanol as a white solid (4.12 g g, 81%). 1H NMR (300 MHz, d6-DMSO): delta 9.96 (s, 1H), 7.69 (d, J=8.1, 1H), 7.53 (d, J=0.9, 1H), 7.19 (dd, J1=8.1, 1H J2=0.9, 1H).

70%

With dipyridinium dichromate; In dichloromethane; at 20℃; for 1h;

To a solution of (4-bromo-2-chlorophenyl)methanol (2.8 g, 12.8 mmol) that was obtained in Example 24 (24e) in dichloromethane (50 ml) was added pyridinium dichromate (7.2 g, 19.2 mmol) with stirring, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, ether (250 ml) was added to the reaction mixture under stirring, and the resulting mixture was filtered with Celite. The filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:20) as the eluent to afford the title compound (2.0 g, yield: 70 %) as a white crystalline solid. 1HNMR Spectrum (400 MHz, CDCl3) delta ppm: 7.55 (dd, 1H, J=8.2 Hz, 1.6 Hz), 7.66 (d, 1H, J=1.6 Hz), 7.79 (d, 1H, J=8.2 Hz), 10.42 (s, 1H). IR Spectrum (KBr): 1201, 1374, 1577, 1693 cm-1. Mass Spectrum (EI+) m/z: 218 (M+).

Reference： [1]Patent: WO2008/51826,2008,A2 .Location in patent: Page/Page column 53; 54
[2]Patent: WO2008/103277,2008,A2 .Location in patent: Page/Page column 197
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 7820 - 7834
[4]Patent: WO2013/75083,2013,A1 .Location in patent: Paragraph 006309; 00632
[5]Patent: US9206128,2015,B2 .Location in patent: Page/Page column 275; 276; 277
[6]Patent: EP1873153,2008,A1 .Location in patent: Page/Page column 92-93

2
[ 185315-48-4 ]
[ 7486-35-3 ]
[ 219764-24-6 ]

Yield	Reaction Conditions	Operation in experiment
		67.1 Preparation Example 67-1 2-Chloro-4-vinylbenzyl alcohol In the same manner as in Preparation Example 11-1, the object compound (1.23 g) was obtained as a colorless solid from 4-bromo-2-chlorobenzyl alcohol (2.0 g) and tributyl(vinyl)tin (3.32 g). 1H-NMR(CDCl3): 1.91(1H, t, J=7 Hz), 4.78(2H, d, J=7 Hz), 5.30(1H, d, J=10 Hz), 5.76(1H, d, J=16 Hz), 6.65(1H, dd, J=16, 10 Hz), 7.30(1H, d, J=8 Hz), 7.39-7.47(2H, m)

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1 Location in patent: Page column 100,101

3
[ 185315-48-4 ]
[ 124-63-0 ]
[ 219762-46-6 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane	P.9 Preparation Example 9 Preparation Example 9 To a solution of 4-bromo-2--chlorobenzyl alcohol (3.56 g) and anhydrous triethylamine (3 ml) in anhydrous dichloromethane (36 ml) was added dropwise methanesulfonyl chloride (1.4 ml) under ice-cooling in a nitrogen atmosphere. The mixture was stirred for 1 hr, and the reaction mixture was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The filtrate was concentrated to give 4-bromo-2-chloro-1-((methanesulfonyloxy)-methyl)benzene as a pale-brown solid (4.77 g). 1H-NMR(CDCl3): 3.03(3H, s), 5.29(2H, s), 7.37(1H, d, J=8Hz), 7.47(1H, dd, J=8, 1Hz), 7.60(1H, d, J=1Hz). Mass(ESI): m/z 298(M-1).
	With triethylamine In dichloromethane	P.19.1 PREPARATION EXAMPLE 19-1 PREPARATION EXAMPLE 19-1 To a solution of 4-bromo-2-chlorobenzyl alcohol (3.56 g) and anhydrous triethylamine (3 ml) in anhydrous dichloromethane (36 ml) was added dropwise methanesulfonyl chloride (1.4 ml) under a nitrogen flow under ice-cooling. The mixture was stirred for 1 hr and the reaction mixture was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The filtrate was concentrated to give 4-bromo-2-chloro-1-(methanesulfonyloxymethyl)benzene as a pale-brown solid (4.77 g). 1H-NMR (CDCl3): 3.03 (3H, s), 5.29 (2H, s), 7.37 (1H, d, J=8 Hz), 7.47 (1H, dd, J=8, 1 Hz), 7.60 (1H, d, J=1 Hz). MASS (ESI): m/e 298 (M-1).
	With triethylamine In dichloromethane at 0℃; for 1h;	14.1 Preparation Example 14-1 4-Bromo-2-chloro-1-methanesulfonyloxymethyl To a solution of 4-bromo-2-chlorobenzyl alcohol (3.56 g) and anhydrous triethylamine (3 ml) in anhydrous dichloromethane (36 ml) was dropwise added methanesulfonyl chloride (1.4 ml) under a nitrogen atmosphere and ice-cooling. The reaction mixture was stirred for 1 hr, washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The filtrate was concentrated to give the objective compound (4.77 g) as a light brown sold. 1H-NMR(CDCl3): 3.03(3H, s), 5.29(2H, s), 7.37(1H, d, J=8 Hz), 7.47(1H, dd, J=8, 1 Hz), 7.60(1H, d, J=1 Hz) MASS(ESI): m/z 298(M-1)

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - EP1142879, 2001, A1
[2]Current Patent Assignee: ASTELLAS PHARMA INC. - US6573274, 2003, B1
[3]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1 Location in patent: Page column 49

4
[ 185315-48-4 ]
[ 124-63-0 ]
4-bromo-1-((tert-butyldimethylsilyloxy)methyl)-2-chlorobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		73.1 Preparation Example 73-1 4-Bromo-1-((tert-butyldimethylsilyloxy)methyl)-2-chlorobenzene In the same manner as in Preparation Example 70-1, the objective compound (6.10 g) was obtained as a colorless oil from 4-bromo-2-chlorobenzyl alcohol (4.42 g). 1H-NMR(CDCl3): 0.12(6H, s), 0.95(9H, s), 4.71(2H, s), 7.37-7.50(3H, m).

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1 Location in patent: Page column 107

5
[ 185315-48-4 ]
[ 960-16-7 ]
[ 219762-34-2 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium chloride In 1,4-dioxane for 5h; Heating / reflux;	11.1 Preparation Example 11-1 2-Chloro-4-phenylbenzyl alcohol Preparation Example 11-1 2-Chloro-4-phenylbenzyl alcohol To a suspension of lithium chloride (482 mg) in anhydrous 1,4-dioxane (12 ml) were added 4-bromo-2-chlorobenzyl alcohol (1.05 g), phenyl tributyl tin (1.74 g) and tetrakis(triphenylphosphine)palladium(O) (110 mg) under a nitrogen atmosphere, and the mixture was refluxed under heating.. After 5 hr, the reaction mixture was cooled and water was added.. The mixture was extracted with ethyl acetate.. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.. The filtrate was concentrated, and the residue was subjected to flash silica gel column chromatography (silica gel, 50 ml, eluent: hexane-ethyl acetate=2-1).. The elude was washed with hexane to give the objective compound (220 mg) as colorless crystals. 1H-NMR(CDCl3): 4.72(2H, s), 7.32-7.61(8H, m) mp 69-70° C.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1 Location in patent: Page column 46

6
[ 185315-48-4 ]
[ 58479-61-1 ]
[ 279252-19-6 ]

Yield	Reaction Conditions	Operation in experiment
	With 1H-imidazole In DMF (N,N-dimethyl-formamide) at 0℃; for 1h;	70.1 Preparation Example 70-1 4-Bromo-1-((tert-butyldiphenylsilyloxy)methyl)-2-chlorobenzene Preparation Example 70-1 4-Bromo-1-((tert-butyldiphenylsilyloxy)methyl)-2-chlorobenzene To a solution of 4-bromo-2-chlorobenzyl alcohol (14.48 g) in N,N-dimethylformamide (72 ml) were added imidazole (5.34 g) and tert-butylchlorodiphenylsilane (19.8 g) under ice-cooling and the mixture was stirred for 1 hr.. water was added to the reaction mixture and the resulting product was extracted twice with hexane.. The organic layers were combined, and washed successively with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine and dried over anhydrous magnesium sulfate.. The solvent was evaporated and the residue was subjected to silica gel column chromatography (hexane) to give the objective compound (29.22 g) as colorless oil. 1H-NMR(CDCl3): 1.10(9H, s), 4.75(2H, s), 7.32-7.50(8H, m), 7.55-7.72(5H, m)

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1 Location in patent: Page column 103

7
[ 185315-48-4 ]
[ 98-80-6 ]
[ 219762-34-2 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water; toluene at 20℃; for 1.16667h; Heating / reflux;	11.2 Preparation Example 11-2 2-Chloro-4-phenylbenzyl alcohol Preparation Example 11-2 2-Chloro-4-phenylbenzyl alcohol To a suspension of tetrakis(triphenylphosphine)palladium(O) (16 mg) in toluene (1 ml) was added 4bromo-2-chlorobenzyl alcohol (100 mg) at room temperature, and the mixture was stirred.. After 10 min, to the reaction mixture were added a solution of phenylboric acid (83 mg) in ethanol (0.1 ml) and a 2M aqueous sodium carbonate solution (0.9 ml), and the mixture was refluxed under heating.. After 1 hr, the reaction mixture was cooled, ethyl acetate was added, and the mixture was filtered through Celite. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate.. The filtrate was concentrated, and the residue was subjected to flash silica gel column chromatography (silica gel, 40 ml, eluent: hexane-ethyl acetate=3-1) to give crude crystals.. The crystals were washed with hexane to give the objective compound (76 mg) as colorless crystals. 1H-NMR(CDCl3): 4.72(2H, s), 7.32-7.61(8H, m) mp 69-70° C.

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1 Location in patent: Page column 46,47

8
[ 6165-68-0 ]
[ 185315-48-4 ]
[ 219764-17-7 ]

Yield	Reaction Conditions	Operation in experiment
		65.1 Preparation Example 65-1 2-Chloro-4-(thiophene-2-yl)benzyl alcohol In the same manner as in Preparation Example 11-2, the object compound (196 mg) was obtained as a pale yellow oil from 4-bromo-2-chlorobenzyl alcohol (500 mg) and 2-thiopheneboronic acid (318 mg). 1H-NMR(CDCl3): 1.93(1H, t, J=8 Hz), 4.79(2H, d, J=8 Hz), 7.09(1H, t, J=3 Hz), 7.29-7.34(2H, m), 7.46-7.54(2H, m), 7.61(1H, s)

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1 Location in patent: Page column 99

9
[ 185315-48-4 ]
[ 89720-77-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 4h;	To a magnetically stirring solution of 4-Bromo-2-chloro-phenyl)-methanol (2.80g, 12.67 mmol) from step 1 below in CH2CI2 (60.0 mL) under argon at 0 C, was added carbon tetrabromide (4.41 g, 13.30 mmol) followed by triphenylphosphine (3.48 g, 13.30 mmol). The resulting mixture was stirred for 4 hours at room temperature. The resulting reaction mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography (10% EtOAc in Hexanes) to yield the intermediate bromide as a clear oil (3.59 g, 100%). H NMR (400MHZ, CDC13) : 5 4.53 (s, 2H), 7.29 (d, J = 8.2 Hz, 1H), 7.39 (dd, J = 8.2, 1.9 Hz, 1 H), 7.56 (d, J = 1.9 Hz, 1H).
100%	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 4h;	To a magnetically stirring solution of (4-bromo-2-chloro-phenyl)-methanol (2.80g, 12.67 mmol) from step 1 above in CH2CI2 (60.0 mL) under argon at 0 C, was added carbon tetrabromide (4.41 g, 13.30 mmol) followed by triphenylphosphine (3.48 g, 13.30 mmol). The resulting mixture was stirred for 4 hours at room temperature. The resulting reaction mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography (10% EtOAc in Hexanes) to yield the intermediate bromide as a clear oil (3.59 g, 100%). 1H NMR (400MHz, CDCI3): 5 4.53 (s, 2H), 7.29 (d, J= 8.2 Hz, 1H), 7.39 (dd, J = 8.2,1.9 Hz, 1 H), 7.56 (d, J= 1.9 Hz, 1H).
100%	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 16h;	Step b intermediate 57 <n="67"/>4-bromo- 1 -(bromomethy l)-2-chlorobenzeneTo a stirred solution of (4-bromo-2-chlorophenyl)methanol (4.34g, 19.6mmol) in dichloromethane (98mL) at 0 0C is added carbon tetrabromide (6.5g, 19.6mmol) and triphenylphosphine (5.14g, 19.6 mmol). The reaction mixture is stirred 16 h at room temperature. Then, the solvent is removed and the crude solid suspended in hexanes / EtOAc 9:1 (100 mL) and filtered on a silica gel pad. The pad is rinsed with hexanes / EtOAc 9:1 (100 mL) and the filtrate is concentrated in vacuo to provide the expected product 4-bromo-l-(bromomethyl)-2- chlorobenzene (7.19 g, 129%) contaminated with bromoform. IH NMR (300 MHz, CHLOROFORM-D): delta 7.57 (IH, d, / = 2.0 Hz), 7.39 (IH, dd, / = 8.2, 2.0 Hz), 7.30 (IH, d, / = 8.2 Hz), 4.53 (2H, s).

99%	With phosphorus tribromide; In dichloromethane; at 0 - 20℃;	Intermediate 107: 4-bromo-1 -(bromomethyl)-2-chlorobenzene; To a solution of (4-bromo-2-chlorophenyl)methanol, intermediate 106, (6.9 g, 31 mmol) in dicholoromethane (200 ml.) was added dropwise a solution of phosphorus tribromide in DCM (12.5 ml_, 1 M in DCM, 12.5 mmol, 0.4 equiv.) at 0 0C. After addition, the reaction mixture was stirred for 16 hours at RT. Water was added and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo to give the title product 4-bromo-1-(bromomethyl)-2-chlorobenzene (8.1 g, 99% yield). 1H NMR: (300 MHZ, CDCI3) delta 7.52 (m, 1 H), 7.35 (m, 1 H), 7.22 (m, 1 H), 4.48 (s, 2H).
92%	With phosphorus tribromide; In dichloromethane; at 0 - 20℃;Inert atmosphere;	In a flame-dried flask under inert atmosphere, S1 (17.3 g, 78 mmol, 1.0 equiv.) was dissolved in DCM (186 mL) and cooled to 0 C. Once cooled, PBr3 (3.7 mL, 39 mmol, 0.5 equiv.) was added via syringe. The reaction was allowed to stir overnight, warming to room temperature. The resulting solution, a very strong lachrymator, was cooled to 0 C and water was added to quench the reaction. The aqueous layer was extracted with DCM (150 mL x 3) and the combined organics were then washed with brine, dried over MgSO4, filtered, and then reduced to yield S2 as a viscous yellow oil (20.3 g, 92 %). Characterization data was identical to previous reports.[19]
57%	With phosphorus tribromide; In 1,2-dichloro-ethane; at 0 - 10℃; for 0.666667h;	Phosphorus tribromide (40.5 mL, 0.431 mol) was added dropwise to a solution of (4- brorno-2-chlorophenyl)-methanol (15, 86.1 g, 0.386 mol) in dichloroethane (430 mL) at 0 C. The reaction mixture was stirred for 10 minutes at this temperature then for 0.5 h at 10 C. The mixture was cooled to 0 C and a sodium hydroxide solution (600 mL, 2N) was added dropwise. The two layers were separated and the aqueous layer was extracted with dichloroethane (200 mL). The combined organic layers were washed with water (200 mL), dried over sodium sulfate and evaporated in vacuo. The crude product (91 g) was distilled under reduced pressure (7 mmHg), to give 4-bromo-l -bromomethyl-2-chlorobenzene (62.5 g, 0.22 mol, 57 %) as a colorless oil.
	With hydrogen bromide; In water; toluene; for 2h;Heating / reflux;	Reference Example 13 4-bromo-2-chlorobenzyl bromide To 4-bromo-2-chlorobenzyl alcohol (399 g) of Reference Example 12 were added toluene (2452 mL) and 48% aqueous hydrogen bromide solution (2453 mL), and the mixture was refluxed with stirring for 2 hr. After cooling, water and ethyl acetate were added to the reaction mixture. After partitioning and extraction, the organic layer was washed with water, 1M aqueous sodium hydroxide solution and 25% brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (535 g) as a pale-yellow oil. 1H-NMR(CDCl3)delta(ppm):4.53(2H, s), 7.31(1H, d, J=8.2Hz), 7.39(1H, dd, J=1.8, 8.2Hz), 7.56(1H, d, J=1.8Hz).
	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0 - 20℃; for 12h;	Step 2 : 4-bromo- 1 -(bromomethyl )-2-chlorobenzene; To a solution of the benzyl alcohol from step 1 (1 eq.) in CH2Cl2 (0.1 M) at O0C was added CBr4 (1.2 eq.) and PPh3 (1.2 eq.). The mixture was stirred for 12h at room temperature and concentrated. Purification of the residue by column chromatography on silica gel, eluting with Hex, afforded the desired compound as an off-white solid.
36 g	With phosphorus tribromide; In dichloromethane; at 0℃;Inert atmosphere;	To a solution of Compound 1 (46.8 g, 21.1 mmol) in dry DCM (500 mL) was added phosphorous tribromide (68.6 g, 25.3 mmol) dropwise at 0 C. under nitrogen. The mixture was stirred for 2 hours and then washed with saturated aqueous NaHCO3 (2×200 mL) and saturated aqueous NaCl (200 mL), dried over anhydrous Na2SO4, concentrated under vacuum to yield Compound 2 (36 g) as a colorless oil.
	With phosphorus tribromide; In dichloromethane; at 0 - 20℃; for 18h;	A 500 mL round bottom flask equipped with a stir bar and pressure equalizing addition funnel was charged with a solution of (4-bromo-2-chlorophenyl)methanol (9.165 g, 41.4 mmol) in dichloromethane (123 mL). The flask was then fitted with an ice bath (0 C) and the addition funnel charged with a solution of phosphorus tribromide (1.951 mL, 20.69 mmol) in dichloromethane (40.9 mL), which was then added to the substrate solution over the course of ~10 minutes with vigorous stirring. After the addition was complete, the addition funnel was removed and the reaction mixture was allowed to warm to room temperature overnight. After-18 h, the flask was re-fitted with an ice bath, and the reaction mixture was quenched by slow addition of saturated sodium bicarbonate solution. The quenched solution was transferred to a 1 L separatory funnel and extracted. The organic layer was isolated, dried over sodium sulfate, filtered, and concentrated to a residue to afford the title compound, which was used without purification in the next step.
36 g	With phosphorus tribromide; In dichloromethane; at 0℃; for 2h;Inert atmosphere;	To a solution of Compound 1 (46.8 g, 21.1 mmol) in dry DCM (500 mL) was added phosphorous tribromide (68.6 g, 25.3 mmol) dropwise at 0 C. under nitrogen. The mixture was stirred for 2 hours and then washed with saturated aqueous NaHCO3 (200 mL×2) and saturated aqueous NaCl (200 mL), dried over anhydrous Na2SO4, concentrated under vacuum to yield Compound 2 (36 g) as a colorless oil.
36 g	With phosphorus tribromide; In dichloromethane; at 0℃; for 2h;Inert atmosphere;	[0291] To a solution of Compound 1 (46.8 g, 21.1 mmol) indry DCM (500 mL) was added phosphorous tribromide (68.6g, 25.3 mmol) dropwise at oo C. under nitrogen. The mixturewas stirred for 2 hours and then washed with saturated aqueousNaHC03 (200 mLx2) and saturated aqueous NaCl (200mL ), dried over N a2SO 4 , concentrated in vacuo to yield Compound2 (36 g) as a colorless oil.
36 g	With phosphorus tribromide; In dichloromethane; at 0℃; for 2h;Inert atmosphere;	To a solution of Compound 1 (46.8 g, 21.1 mmol) in dry DCM (500 mL) was added phosphorous tribromide (68.6 g, 25.3 mmol) dropwise at 0C under nitrogen. The mixture was stirred for 2 hours and then washed with saturated aqueous NaHC03 (200 mLx2) and saturated aqueous NaCl (200 mL), dried over Na2S04, concentrated in vacuo to yield Compound 2 (36 g) as a colorless oil.
2.4 g	With hydrogen bromide; In toluene; at 95℃; for 5h;	(1) (4-bromo-2-chlorophenyl) methanol (2.0 g) in toluene (10 mL) solution of 48% hydrobromic acid (10 mL) was added and stirred for 5 hours at an external temperature of 95 C.. After the reaction mixture was allowed to cool, it was neutralized by the addition of a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. Washing the organic layer with saturated brine, dried over anhydrous magnesium sulfate, after filtration, the solvent was distilled off under reduced pressure of 4-bromo-1- (bromomethyl) -2-chlorobenzene (2.4 g) as a colorless oily substance It was obtained as a.
0.95 g	With N-Bromosuccinimide; triphenylphosphine; In dichloromethane;Inert atmosphere; Cooling with ice;	4-Bromo-2-chlorobenzyl alcohol (1.6 g, 7.34 mmol) and triphenylphosphine (3.85 g, 14.68 mol) were dissolved in 50 mL of dichloromethane. NBS (2.74 g, 15.41 mmol) was slowly added in an ice water bath under a nitrogen atmosphere and stirred at this temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the residues were purified by column chromatography (eluent: petroleum ether:ethyl acetate 100:0-60:1) to give 0.95 g of title product.

Reference： [1]Patent: WO2004/74270,2004,A2 .Location in patent: Page 175
[2]Patent: WO2006/18725,2006,A1 .Location in patent: Page/Page column 235-236
[3]Patent: WO2008/18827,2008,A1 .Location in patent: Page/Page column 65-66
[4]Patent: WO2010/15652,2010,A2 .Location in patent: Page/Page column 68
[5]Tetrahedron Letters,2016,vol. 57,p. 449 - 451
[6]Patent: WO2013/43232,2013,A2 .Location in patent: Paragraph 00500
[7]Patent: EP2017257,2009,A1 .Location in patent: Page/Page column 21
[8]Patent: WO2009/23964,2009,A1 .Location in patent: Page/Page column 25
[9]Patent: US2013/109639,2013,A1 .Location in patent: Paragraph 0349
[10]Patent: WO2014/8223,2014,A2 .Location in patent: Page/Page column 88
[11]Patent: US2014/256702,2014,A1 .Location in patent: Paragraph 0297
[12]Patent: US2015/210690,2015,A1 .Location in patent: Paragraph 0231; 0291
[13]Patent: WO2015/116786,2015,A1 .Location in patent: Paragraph 77
[14]Patent: JP2015/231988,2015,A .Location in patent: Paragraph 0361; 0362
[15]Patent: US2019/345139,2019,A1 .Location in patent: Paragraph 0407

10
[ 59748-90-2 ]
[ 185315-48-4 ]

Yield	Reaction Conditions	Operation in experiment
100%		Step a intermediate 56(4-Bromo-2-chlorophenyl)methanolTo a stirred solution of <strong>[59748-90-2]4-bromo-2-chlorobenzoic acid</strong> (4.27 g, 18.1 mmol) in tetrahydrofuran (39 mL) at O0C is added borane-tetrahydrofuran complex (1 M in THF) (36.3 mL, 36.3 mmol). The reaction mixture is stirred 16 h at room temperature. At O0C, water is slowly added then NaHCO3 aq. sat. is also slowly added The resulting solution is extracted with EtOAc (3 x 50 mL). The combined organic layer is washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flashchromatography (eluent: Hexanes / EtOAc 85:15 to 70:30) to provide the expected product (4-bromo-2- chlorophenyl)methanol (4.34 g, 108%). IH NMR (300 MHz, CHLOROFORM-D): delta 7.53 (IH, d, /= 1.8 Hz), 7.43 (IH, dd, /= 8.2,1.8 Hz), 7.38 (IH, d, / = 8.2 Hz), 4.74 (2H, d, / = 6.2 Hz), 1.90 (IH, t, /= 6.3 Hz).
98%	With borane-THF; In tetrahydrofuran; at 0 - 20℃;	In a flame-dried flask under inert atmosphere, <strong>[59748-90-2]4-bromo-2-chlorobenzoic acid</strong> (25.0 g, ,106 mmol, 1.0 equiv.) was dissolved in THF (221 mL) and subsequently cooled to 0 C. Once cooled, BH3-THF (265 mL, 1.0 M, 265 mmol, 2.5 equiv.) was added via syringe. The reaction was allowed to stir overnight, warming to room temperature; after stirring 12-16 h, the reaction mixture was once again cooled to 0 C and slowly quenched with water. The resulting mixture was washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (250 mL x 3) and the combined organics washed with brine, dried over MgSO4, filtered, and then reduced to yield S1 as a white solid (23.0 g, 98 %). Characterization data was identical to previous reports.[19]
97%		(24e) (4-Bromo-2-chlorophenyl)methanol To a solution of <strong>[59748-90-2]4-bromo-2-chlorobenzoic acid</strong> (3.1 g, 13.2 mmol) in tetrahydrofuran (30 ml) was added a 1.0 M solution of borane-tetrahydrofuran complex in tetrahydrofuran (13.8 ml, 13.8 mmol) at 0C with stirring, and the resulting mixture was stirred at the same temperature for 20 minutes, and after raising the reaction temperature to room temperature, the reaction mixture was furthermore stirred for 4 hours. After stirring, water (10 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate (50 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:9 to 7:3) as the eluent to afford the title compound (2.8 g) in a yield of 97 % as a white crystalline solid. 1H-NMR Spectrum (400 MHz, CDCl3) delta ppm: 7.51 (d, 1H, J=2.0 Hz), 7.40 (dd, 1H, J=8.2 Hz, 2.0 Hz), 7.36 (d, 1H, J=8.2 Hz), 4.73 (d, 2H, J=6.3 Hz), 1.90 (t, 1H, J=6.3 Hz). IR Spectrum (KBr): 1036, 1063, 1385, 1469, 1561, 1586, 3239 cm-1. Mass Spectrum (EI+) m/z: 220 (M+).

91%	With borane-THF; In tetrahydrofuran; at 0 - 40℃;	4-bromo-2-chlorophenyl)methanol. A solution of BH3 (34 mL, 1M in tetrahydrofuran) was added dropwise to the solution of 4-bromo-3-chlorobenzoic acid (2.5 g, 11.4 mmol) in tetrahydrofuran at 0C. The mixture was stirred at 40C overnight. Acetic acid (5 mL) was added dropwise to the reaction mixture. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ ethyl acetate = 1 : 1) to give (4-bromo-2-chlorophenyl)methanol as a white solid (4.47 g, 91%). 1H NMR (300 MHz, d6-DMSO): 7.69 (d, J=8.1,1H), delta 7.53 (d, J =0.9,1H), 7.19 (dd, Ji=8.1,lH J2=0.9, 1H), 5.38 (s, 1H), delta 4.48 (s, 2H). [00632] 4-bromo-2-chlorobenzaldehyde. A mixture of (4-bromo-3-chlorophenyl)methanol (2.0 g, 9.0 mmol), pyridinium chlorochromate (2912 mg, 13.5 mmol) in dichloromethane (50 mLO was stirred at 25C for 3 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ ethyl acetate = 1 : 1) to give (4-bromo-2-chlorophenyl)methanol as a white solid (4.12g g, 81%). 1H NMR (300 MHz, d6-DMSO): delta 9.96 (s, 1H), 7.69 (d, J=8.1,1H), 7.53 (d, J =0.9,1H), 7.19 (dd, Ji=8.1,lH J2=0.9, 1H).
74%		Intermediate 106: (4-bromo-2-chlorophenyl)methanol; To a solution of commercially available <strong>[59748-90-2]4-bromo-2-chlorobenzoic acid</strong> (10 g, 42.5 mmol) in THF (150 ml.) was added a solution of lithium aluminium hydride in THF (42.5 ml_, 1 M in THF, 42.5 mmol) at 00C. After addition, the reaction mixture was allowed to stir from 00C to RT for 48 h before being quenched with wet sodium sulphate and filtered through Celite. The filtrate was concentrated in vacuo to give the title compound (4-bromo-2-chlorophenyl)methanol (6.9 g, 74% yield). 1H NMR: (CDCI3, 300MHZ) delta 7.55-7.35 (m, 2H), 7.28 (m, 1 H), 4.74 (s, 2H).
68%		Compound 43; To a -10 0C cooled solution of <strong>[59748-90-2]4-bromo-2-chlorobenzoic acid</strong> 42 (14.4 g, 61 mmol, 1.0 equiv.) in THF (280 ml) was added dropwise a 1 M solution of BH3 THF (91.4 ml, 1.5 equiv.), temperature was maintained at -10 0C. The reaction mixture was stirred overnight to reach room temperature. EPO <DP n="55"/>For workup, the mixture was added carefully to a solution OfK2COs (4 g) in water (500 ml). The solution was stirred 15 minutes and concentrated in vacuo. The remaining water layer was diluted with EtOAc, washed with 1 N HCl and brine, dried on Na2SO4, filtered and concentrated in vacuo to obtain compound 43 in 68% yield (9.2 g, 41.5 mmol).
50%		4-Bromo-2-chlorobenzoic acid (5 g, 21.23 mmol) was dissolved in dry THF (100 mL) and cooled to 0 C. A 1 M solution of BH3. THF in THF (31.85 mL, 31.85 mmol) was slowly added. The reaction was stirred overnight, allowing it to gradually reach room temperature. K2CO3 solid (1G) and H20 (100 mL) were added and the reaction was stirred for 30 minutes. THF was evaporated and residue extracted with EtOAc (30 mL). The organic phase was washed with 1N HCI (3 x 50 mL), brine (3 x 50 mL), dried over NA2SO4 and evaporated. The residue was purified by flash column chromatography (30% EtOAc in hexanes) to give the product (2.80 G, 50%) as a color less OIL. 1H NMR (400MHZ, CDCI3) : 5 4.73 (d, J = 5.8 Hz, 2H), 7.37 (d, J = 8.1 Hz, 1H), 7.42 (dd, J = 8.1 Hz, 1.7), 7.52 (d, J= 1.7 Hz, 1H).
50%		4-Bromo-2-chlorobenzoic acid (5 g, 21.23 mmol) was dissolved in dry THF (100 mL) and cooled to 0 C. A 1M solution of BH3.THF in THF (31.85 mL, 31.85 mmol) was slowly added. The reaction was stirred overnight, allowing it to gradually reach room temperature. K2CO3 solid (1g) and H2O (100 mL) were added and the reaction was stirred for 30 minutes. THF was evaporated and residue extracted with EtOAc (30 mL). The organic phase was washed wijh 1N HCI (3 x 50 mL), brine (3 x 50 mL), dried over Na2SO4 and evaporated. The residue was purified by flash column chromatography (30% EtOAc in.hexanes) to give the product (2.80 g, 50%) as'a^lir^s's oil. 1H NMR (400MHz; CDCI3): 5 4.73 (d,' J= 5.8 Hz, 2H), 7.37 (d, J= 8.1 Hz, 1H),l7.42l'(dd,''J= 8.1 Hz, 1.7), 7.52 (d, J= 1.7 Hz, 1H)
		Potassium carbonate (1.38 g, 10 mmol) and methyl iodide (0.623 ml, 10 mmol) were added to a solution of <strong>[59748-90-2]4-bromo-2-chlorobenzoic acid</strong> (2.8 g, 8.5 mmol) in N,N-dimethylformamide (8 ml) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and, after the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. Diisobutyl aluminum hydride-1.0M toluene solution (24 ml, 24 mmol) was added dropwise to a solution of the oily residue obtained by evaporating the solvent under reduced pressure in toluene (30 ml) at -78C, and the mixture was raised to room temperature over 3 hours. Sodium sulfate decahydrate (12 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Celite and anhydrous magnesium sulfate were added thereto, and the mixture was stirred at room temperature for 30 minutes, followed by removal by filtration of the insolubles. The solvent was evaporated from the obtained filtrate under reduced pressure to obtain crude (4-bromo-2-chlorophenyl)methanol as a solid. Carbon tetrabromide (3.2 g, 9.5 mmol) and triphenylphosphine (2.5 g, 9.5 mmol) were added to a solution of the obtained crude (4-bromo-2-chlorophenyl)methanol (1.84 g, 8.4 mmol) in tetrahydrofuran (12 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. n-Hexane was added to the reaction mixture, and the insolubles were removed by filtration. The thus obtained filtrate was poured into water and, after the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=15/1-12/1) to obtain the crude compound. Potassium cyanide (640 mg, 9.8 mmol) was added to a mixed solution of the obtained crude compound in ethanol-water (3:1, 20 ml) and the mixture was stirred at 60C for 1.5 hours. The reaction mixture was poured into water and, after the mixture was extracted with ethyl acetate, the organic layer was washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=10/1-4/1) to obtain (4-bromo-2-chlorophenyl)acetonitrile as a pale yellow solid (1.4 g, yield: 71%). 1H-NMR (400MHz, CDCl3) : delta 7.61 (1H, d, J = 1.6 Hz), 7.47 (1H, br d, J = 8.0 Hz), 7.40 (1H, d, J = 8.0 Hz), 3.79 (2H, s) .
	With borane-THF; In tetrahydrofuran; at 20℃;	General procedure: 4-Bromo-2-chlorobenzoic acid (4.70g, 20.0mmol) was dissolved in THF (50mL), cooled and 1M BH3 in THF (22mL, 22.0mmol) was added drop-wise. The reaction mixture was stirred at room temperature overnight, cooled to -10C, quenched with water (15mL), poured onto sat aq NaHCOs (lOOmL) and extracted with EtOAc. The combined organic fractions were washed with water, brine, dried (MgSO^ and concentrated in vacuo to give the crude title compound (4.45g) as a white solid. LCMS: ES+ 220 [MH]+.
	With diborane; In tetrahydrofuran; at 20℃;	4-Bromo-2-chlorobenzoic acid (4.70g, 20.Ommol) was dissolved in THF (5OmL), cooled and 1M BH3 in THF (22mL, 22.Ommol) was added drop-wise. The reaction mixture wasstirred at room temperature overnight, cooled to -10C, quenched with water (l5mL), poured onto sat aq NaHCO3 (lOOmL) and extracted with EtOAc. The combined organic fractions were washed with water, brine, dried (MgSO4) and concentrated in vacuo to give the crude title compound (4.45g) as a white solid. LCMS: ES 220 [IVIHf.
	With borane; In tetrahydrofuran;Inert atmosphere; Cooling with ice;	4-Bromo-2-chlorobenzoic acid (1.5 g, 6.41 mmol) was dissolved in 20 mL of THF. 15 mL of a solution of borane in tetrahydrofuran (1 M) was added dropwise in an ice water bath under a nitrogen atmosphere and stirred for 3 h. The reaction mixture was slowly poured into water, and extracted with ethyl acetate. The organic phase was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give 1.6g of crude title product which was used directly in the next step without purification.

Reference： [1]Patent: WO2008/18827,2008,A1 .Location in patent: Page/Page column 65
[2]Tetrahedron Letters,2016,vol. 57,p. 449 - 451
[3]Patent: EP1873153,2008,A1 .Location in patent: Page/Page column 92
[4]Patent: WO2006/109633,2006,A1 .Location in patent: Page/Page column 166-167
[5]Patent: WO2013/75083,2013,A1 .Location in patent: Paragraph 006309; 00631
[6]Patent: WO2008/103277,2008,A2 .Location in patent: Page/Page column 197
[7]Patent: WO2010/15652,2010,A2 .Location in patent: Page/Page column 68
[8]Patent: WO2008/51826,2008,A2 .Location in patent: Page/Page column 53-54
[9]Patent: WO2004/74270,2004,A2 .Location in patent: Page 175-176
[10]Patent: WO2006/18725,2006,A1 .Location in patent: Page/Page column 235
[11]Patent: WO2006/46593,2006,A1 .Location in patent: Page/Page column 196-197
[12]Patent: EP1764075,2007,A1 .Location in patent: Page/Page column 92
[13]Patent: WO2013/43232,2013,A2
[14]Patent: WO2014/8223,2014,A2
[15]Patent: WO2014/20350,2014,A1 .Location in patent: Page/Page column 33
[16]Patent: WO2014/20351,2014,A1 .Location in patent: Page/Page column 19
[17]Patent: EP3048103,2016,A1
[18]Journal of Medicinal Chemistry,2017,vol. 60,p. 7820 - 7834
[19]Patent: US2019/345139,2019,A1 .Location in patent: Paragraph 0406

11
[ 288-32-4 ]
[ 185315-48-4 ]
[ 58479-61-1 ]
[ 279252-19-6 ]

Yield	Reaction Conditions	Operation in experiment
	In water; N,N-dimethyl-formamide	P.13.1 Preparation Example 13-1 Preparation Example 13-1 To a solution of 4-bromo-2-chlorobenzyl alcohol (14.48 g) in N,N-dimethylformamide (72 ml) were added imidazole (5.34 g) and tert-butylchlorodiphenylsilane (19.8 g) under ice-cooling, and the mixture was stirred for 1 hr. Water was added to the reaction mixture and the resulting product was extracted twice with hexane. The organic layers were combined, washed successively with water,saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was applied to silica gel column chromatography (hexane) to give 4-bromo-1-((tert-butyldiphenylsiloxy)methyl)-2-chlorobenzene (29.22 g) as a colorless oil. 1H-NMR(CDCl3): 1.10(9H, s), 4.75(2H, s), 7.32-7.50(8H, m), 7.55-7.72(5H, m).

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - EP1142879, 2001, A1

12
[ 185312-82-7 ]
[ 185315-48-4 ]

Yield	Reaction Conditions	Operation in experiment
80%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 1h;	At 0C, lithium aluminum hydride (1.09 g, 30 mmol) was dropped into a solution of <strong>[185312-82-7]methyl 4-bromo-2-chlorobenzoate</strong> (4.78 g, 19.16 mmol) in tetrahydrofuran (100 mL) slowly. The ice-salt bath used was removed after that dropping. The reaction was complete (detected with LCMS and TLC) after stirred for 1 hour at room temperature. The mixture was cooled to 0C again and the reaction was quenched with water (1.09 mL) and 10% NaOH solution (10.9 mL) respectively. After stirred for 15 min at room temperature, the mixture was filtered and then the filter cake was washed with tetrahydrofuran (50 mLx2) and ethyl acetate EA (50 mLx2). The filtrate was dried with anhydrous sodium sulfate, filtered, and then concentrated to obtain a colorless oil product (3.4 g, 80% yield). The molecular ion peak shown by liquid chromatography-mass spectrometry was: MS (ESI): m/z 202.9/204.9 [M-OH]+.
		Reference Example 12 4-bromo-2-chlorobenzyl alcohol Methyl 4-bromo-2-chlorobenzoate (477 g) of Reference Example 11 was dissolved in a mixed solution of ethanol (3000 mL) and water (680 mL), calcium chloride (212.2 g) was added at 10C, and the mixture was stirred for 30 min. To the solution was added sodium borohydride (144.7 g) by portions so that the inside temperature would not exceed 25C, and the mixture was stirred at room temperature for 5 hr. 1M Hydrochloric acid (5100 mL) was added dropwise to the reaction mixture, and the reaction solvent was evaporated under reduced pressure. Water and ethyl acetate were added to the residue. After partitioning and extraction, the organic layer was washed with 25% brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (399 g) as white crystals. 1H-NMR(CDCl3)delta(ppm):1.87(1H, t, J=5.8Hz), 4.74(2H, d, J=5.8Hz), 7.38(1H, d, J=8.2Hz), 7.42(1H, dd, J=1.8, 8.2Hz), 7.53(1H, d, J=1.8Hz).
	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃;	A 500 mL round bottom flask equipped with a stir bar and pressure equalizing addition funnel was charged with 95% lithium aluminum hydride (4.85 g, 121 mmol) dry powder. The solid material was taken up in anhydrous tetrahydrofuran (119 mL) and the resulting suspension cooled to 0 C with an ice bath. The addition funnel was charged with a solution of <strong>[185312-82-7]methyl 4-bromo-2-chlorobenzoate</strong> (13.77 g, 55.2 mmol) in anhydrous tetrahydrofuran (THF) (47.8 mL) and was slowly added to the lithium aluminum hydride suspension over the course of 10 minutes, maintaining the bath at 0 C. Once the addition was complete, the addition funnel was washed with an additional 20 mL of anhydrous THF and then the funnel removed. The resulting reaction mixture was stirred overnight, allowing the system to warm naturally to room temperature. The mixture was cooled to 0 C with vigorous stirring and treated, sequentially and carefully, with the following: 1) 4.85 mL DI water 2) 4.85 mL freshly made (last 24 hours) 15 wt% sodium hydroxide in water (728 mg NaOH in 4.122 mL water) 3) 14.55 mL DI water. A precipitate of aluminum salts that generated over the course of 1 h of stirring was removed from the mixture by suction filtration through a pad of sodium sulfate into a 1 L round bottom flask. The filter pad was washed with tetrahydrofuran (100 mL) and the resulting organic solution was concentrated in vacuo to a residue. The material was transferred by dissolution in dichloromethane (~25 mL) to a 100 mL round bottom flask. The dichloromethane solution was concentrated in vacuo to a residue to afford that title compound as a honey-colored solid upon standing. The solid was carried through to the next step "as-is." MS(ES)+ m/e 203.0 [M-OH]+.

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 7820 - 7834
[2]Patent: EP3048103,2016,A1 .Location in patent: Paragraph 0065; 0066
[3]Patent: EP2017257,2009,A1 .Location in patent: Page/Page column 20-21
[4]Patent: WO2014/8223,2014,A2 .Location in patent: Page/Page column 87-88

13
[ 185315-48-4 ]
[ 151-50-8 ]
[ 89720-77-4 ]

Yield	Reaction Conditions	Operation in experiment
		Potassium carbonate (1.38 g, 10 mmol) and methyl iodide (0.623 ml, 10 mmol) were added to a solution of 4-bromo-2-chlorobenzoic acid (2.8 g, 8.5 mmol) in N,N-dimethylformamide (8 ml) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and, after the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. Diisobutyl aluminum hydride-1.0M toluene solution (24 ml, 24 mmol) was added dropwise to a solution of the oily residue obtained by evaporating the solvent under reduced pressure in toluene (30 ml) at -78C, and the mixture was raised to room temperature over 3 hours. Sodium sulfate decahydrate (12 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. Celite and anhydrous magnesium sulfate were added thereto, and the mixture was stirred at room temperature for 30 minutes, followed by removal by filtration of the insolubles. The solvent was evaporated from the obtained filtrate under reduced pressure to obtain crude (4-bromo-2-chlorophenyl)methanol as a solid. Carbon tetrabromide (3.2 g, 9.5 mmol) and triphenylphosphine (2.5 g, 9.5 mmol) were added to a solution of the obtained crude (4-bromo-2-chlorophenyl)methanol (1.84 g, 8.4 mmol) in tetrahydrofuran (12 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. n-Hexane was added to the reaction mixture, and the insolubles were removed by filtration. The thus obtained filtrate was poured into water and, after the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=15/1-12/1) to obtain the crude compound. Potassium cyanide (640 mg, 9.8 mmol) was added to a mixed solution of the obtained crude compound in ethanol-water (3:1, 20 ml) and the mixture was stirred at 60C for 1.5 hours. The reaction mixture was poured into water and, after the mixture was extracted with ethyl acetate, the organic layer was washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=10/1-4/1) to obtain (4-bromo-2-chlorophenyl)acetonitrile as a pale yellow solid (1.4 g, yield: 71%). 1H-NMR (400MHz, CDCl3) : delta 7.61 (1H, d, J = 1.6 Hz), 7.47 (1H, br d, J = 8.0 Hz), 7.40 (1H, d, J = 8.0 Hz), 3.79 (2H, s) .

Reference： [1]Patent: EP1764075,2007,A1 .Location in patent: Page/Page column 92

14
[ 185315-48-4 ]
[ 1417736-63-0 ]
[ 1417736-19-6 ]

Yield	Reaction Conditions	Operation in experiment
23%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In 1,4-dioxane; water at 140℃; for 1h; Microwave irradiation;	22 Example 22 {4-[4-Amino-7-(mo^holin-4-ylmethyl)pyrrolo[2,l -f][l,2,4]triazin-5-yl]-2-chlorophenyl}methanol Example 22 {4-[4-Amino-7-(mo^holin-4-ylmethyl)pyrrolo[2,l -f][l,2,4]triazin-5-yl]-2-chlorophenyl}methanol Intermediate 39A (200 mg, 0.56 mmol), Intermediate 3A (1 12 mg, 0.5 1 mmol) and tetrakis- (triphenylphosphine)palladium(O) (58 mg, 0.05 mmol) were dissolved in a mixture of 1,4-dioxane (4.0 mL) and 2 M aqueous sodium carbonate solution (1.0 mL) in a microwave reactor vial. The reaction vessel was crimp-capped, and the mixture was heated to 140°C for 1 h in a single-mode microwave device. After cooling, the mixture was filtered, and the filtrate was purified by preparative HPLC (method 3) to give 48 mg (23% of th.) of the title compound. LC-MS (method 6): Rt = 0.53 min; MS (ESIpos): m/z (%) = 374.1 (80) [M+H]+, MS (ESIneg): m/z (%) = 372.2 (100) [M-H]~ ¾ NMR (400 MHz,

Reference： [1]Current Patent Assignee: BAYER AG - WO2013/4551, 2013, A1 Location in patent: Page/Page column 100

15
[ 158435-41-7 ]
[ 185315-48-4 ]

Yield	Reaction Conditions	Operation in experiment
48 g	With sodium tetrahydroborate; In methanol; at 0℃;	To a suspension of <strong>[158435-41-7]4-bromo-2-chlorobenzaldehyde</strong> (50 g, 22.8 mmol) in MeOH (500 mL) was added NaBH4 (17.3 g, 45.6 mmol) in portions at 0 C. The mixture was stirred for 30 minutes and then aqueous NH4Cl was added to quench the reaction. The mixture was concentrated in vacuo. The residue was extracted with EtOAc (2×200 mL) and the combined organic layers were dried over anhydrous Na2SO4, and concentrated under vacuum to yield Compound 1 (48 g) as a white solid.
48 g	With methanol; sodium tetrahydroborate; at 0℃; for 0.5h;	To a suspension of <strong>[158435-41-7]4-bromo-2-chlorobenzaldehyde</strong> (50 g, 22.8 mmol) in MeOH (500 mL) was added NaBH4 (17.3 g, 45.6 mmol) in portions at 0 C. The mixture was stirred for 30 minutes and then aqueous NH4Cl was added to quench the reaction. The mixture was concentrated in vacuo. The residue was extracted with EtOAc (200 mL×2) and the combined organic layers were dried over anhydrous Na2SO4, and concentrated under vacuum to yield Compound 1 (48 g) as a white solid.
48 g	With sodium tetrahydroborate; In methanol; at 0℃; for 0.5h;Inert atmosphere;	[0290] To a suspension of <strong>[158435-41-7]4-bromo-2-chlorobenzaldehyde</strong>(50 g, 22.8 mmol) in MeOH (500 mL) was added NaBH4(17 .3 g, 45.6 mmol) in portions at oo C. The mixture wasstirred for 30 minutes and then aqueous NH4Cl was added toquench the reaction. The mixture was concentrated in vacuo.The residue was extracted with EtOAc (200 mLx2) and thecombined organic layers were dried over Na2S04 , and concentratedin vacuo to yield Compound 1 ( 48 g) as a whitesolid

48 g

With sodium tetrahydroborate; In methanol; at 0℃; for 0.5h;

To a suspension of <strong>[158435-41-7]4-bromo-2-chlorobenzaldehyde</strong> (50g, 22.8mmol) in MeOH (500 mL) was added NaBH4 (17.3 g, 45.6 mmol) in portions at 0C. The mixture was stirred for 30 minutes and then aqueous NH4C1 was added to quench the reaction. The mixture was concentrated in vacuo. The residue was extracted with EtOAc (200 mLx2) and the combined organic layers were dried over Na2S04, and concentrated in vacuo to yield Compound 1 (48g) as a white solid

Reference： [1]Patent: US2013/109639,2013,A1 .Location in patent: Paragraph 0348
[2]Patent: US2014/256702,2014,A1 .Location in patent: Paragraph 0296
[3]Patent: US2015/210690,2015,A1 .Location in patent: Paragraph 0231; 0290
[4]Patent: WO2015/116786,2015,A1 .Location in patent: Paragraph 77

16
[ 185315-48-4 ]
[ 1432501-54-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 13 steps 1.1: phosphorus tribromide / dichloromethane / 0 °C / Inert atmosphere 2.1: sodium hydroxide / N,N-dimethyl-formamide / 0.08 h / 0 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / methanol / Reflux 4.1: sodium hydroxide / water; acetonitrile / 0 - 20 °C 5.1: dmap / dichloromethane / 0.17 h / -5 °C / Inert atmosphere 5.2: -5 - 20 °C 6.1: acetic acid / dichloromethane / 0.17 h / 0 °C 6.2: 1 h / 0 °C 7.1: toluene / 2 h / Reflux 8.1: trifluoroacetic acid / dichloromethane / 4 h / 0 °C 9.1: sodium hydride / tetrahydrofuran; mineral oil / 1 h / 0 °C / Inert atmosphere 9.2: 2 h 10.1: sodium hexamethyldisilazane / tetrahydrofuran / -78 °C / Inert atmosphere 10.2: -78 °C 11.1: hydrogenchloride; water / Reflux 12.1: hydrogenchloride / 50 °C 13.1: triethylamine / dichloromethane / 0.33 h / 20 °C 13.2: SilicaCat® DPP-Pd / 0.33 h / 120 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2013/109639, 2013, A1

17
[ 185315-48-4 ]
C₃₄H₃₁BrClN₃NiO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: phosphorus tribromide / dichloromethane / 0 °C / Inert atmosphere 2.1: sodium hydroxide / N,N-dimethyl-formamide / 0.08 h / 0 °C 2.2: 0.5 h / 20 °C

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2013/109639, 2013, A1

18
[ 185315-48-4 ]
[ 1213929-66-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: phosphorus tribromide / dichloromethane / 0 °C / Inert atmosphere 2.1: sodium hydroxide / N,N-dimethyl-formamide / 0.08 h / 0 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / methanol / Reflux

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2013/109639, 2013, A1

19
[ 185315-48-4 ]
[ 1432502-36-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: phosphorus tribromide / dichloromethane / 0 °C / Inert atmosphere 2.1: sodium hydroxide / N,N-dimethyl-formamide / 0.08 h / 0 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / methanol / Reflux 4.1: sodium hydroxide / water; acetonitrile / 0 - 20 °C

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2013/109639, 2013, A1

20
[ 185315-48-4 ]
[ 1432502-37-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: phosphorus tribromide / dichloromethane / 0 °C / Inert atmosphere 2.1: sodium hydroxide / N,N-dimethyl-formamide / 0.08 h / 0 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / methanol / Reflux 4.1: sodium hydroxide / water; acetonitrile / 0 - 20 °C 5.1: dmap / dichloromethane / 0.17 h / -5 °C / Inert atmosphere 5.2: -5 - 20 °C

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2013/109639, 2013, A1

21
[ 185315-48-4 ]
[ 1432502-38-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: phosphorus tribromide / dichloromethane / 0 °C / Inert atmosphere 2.1: sodium hydroxide / N,N-dimethyl-formamide / 0.08 h / 0 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / methanol / Reflux 4.1: sodium hydroxide / water; acetonitrile / 0 - 20 °C 5.1: dmap / dichloromethane / 0.17 h / -5 °C / Inert atmosphere 5.2: -5 - 20 °C 6.1: acetic acid / dichloromethane / 0.17 h / 0 °C 6.2: 1 h / 0 °C

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2013/109639, 2013, A1

22
[ 185315-48-4 ]
[ 1432502-39-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: phosphorus tribromide / dichloromethane / 0 °C / Inert atmosphere 2.1: sodium hydroxide / N,N-dimethyl-formamide / 0.08 h / 0 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / methanol / Reflux 4.1: sodium hydroxide / water; acetonitrile / 0 - 20 °C 5.1: dmap / dichloromethane / 0.17 h / -5 °C / Inert atmosphere 5.2: -5 - 20 °C 6.1: acetic acid / dichloromethane / 0.17 h / 0 °C 6.2: 1 h / 0 °C 7.1: toluene / 2 h / Reflux

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2013/109639, 2013, A1

23
[ 185315-48-4 ]
[ 1432502-40-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: phosphorus tribromide / dichloromethane / 0 °C / Inert atmosphere 2.1: sodium hydroxide / N,N-dimethyl-formamide / 0.08 h / 0 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / methanol / Reflux 4.1: sodium hydroxide / water; acetonitrile / 0 - 20 °C 5.1: dmap / dichloromethane / 0.17 h / -5 °C / Inert atmosphere 5.2: -5 - 20 °C 6.1: acetic acid / dichloromethane / 0.17 h / 0 °C 6.2: 1 h / 0 °C 7.1: toluene / 2 h / Reflux 8.1: trifluoroacetic acid / dichloromethane / 4 h / 0 °C

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2013/109639, 2013, A1

24
[ 185315-48-4 ]
[ 1432502-41-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1.1: phosphorus tribromide / dichloromethane / 0 °C / Inert atmosphere 2.1: sodium hydroxide / N,N-dimethyl-formamide / 0.08 h / 0 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / methanol / Reflux 4.1: sodium hydroxide / water; acetonitrile / 0 - 20 °C 5.1: dmap / dichloromethane / 0.17 h / -5 °C / Inert atmosphere 5.2: -5 - 20 °C 6.1: acetic acid / dichloromethane / 0.17 h / 0 °C 6.2: 1 h / 0 °C 7.1: toluene / 2 h / Reflux 8.1: trifluoroacetic acid / dichloromethane / 4 h / 0 °C 9.1: sodium hydride / tetrahydrofuran; mineral oil / 1 h / 0 °C / Inert atmosphere 9.2: 2 h

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2013/109639, 2013, A1

25
[ 185315-48-4 ]
[ 1432502-42-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1.1: phosphorus tribromide / dichloromethane / 0 °C / Inert atmosphere 2.1: sodium hydroxide / N,N-dimethyl-formamide / 0.08 h / 0 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / methanol / Reflux 4.1: sodium hydroxide / water; acetonitrile / 0 - 20 °C 5.1: dmap / dichloromethane / 0.17 h / -5 °C / Inert atmosphere 5.2: -5 - 20 °C 6.1: acetic acid / dichloromethane / 0.17 h / 0 °C 6.2: 1 h / 0 °C 7.1: toluene / 2 h / Reflux 8.1: trifluoroacetic acid / dichloromethane / 4 h / 0 °C 9.1: sodium hydride / tetrahydrofuran; mineral oil / 1 h / 0 °C / Inert atmosphere 9.2: 2 h 10.1: sodium hexamethyldisilazane / tetrahydrofuran / -78 °C / Inert atmosphere 10.2: -78 °C

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2013/109639, 2013, A1

26
[ 185315-48-4 ]
[ 1432502-43-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 11 steps 1.1: phosphorus tribromide / dichloromethane / 0 °C / Inert atmosphere 2.1: sodium hydroxide / N,N-dimethyl-formamide / 0.08 h / 0 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / methanol / Reflux 4.1: sodium hydroxide / water; acetonitrile / 0 - 20 °C 5.1: dmap / dichloromethane / 0.17 h / -5 °C / Inert atmosphere 5.2: -5 - 20 °C 6.1: acetic acid / dichloromethane / 0.17 h / 0 °C 6.2: 1 h / 0 °C 7.1: toluene / 2 h / Reflux 8.1: trifluoroacetic acid / dichloromethane / 4 h / 0 °C 9.1: sodium hydride / tetrahydrofuran; mineral oil / 1 h / 0 °C / Inert atmosphere 9.2: 2 h 10.1: sodium hexamethyldisilazane / tetrahydrofuran / -78 °C / Inert atmosphere 10.2: -78 °C 11.1: hydrogenchloride; water / Reflux

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2013/109639, 2013, A1

27
[ 185315-48-4 ]
[ 1432502-44-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 12 steps 1.1: phosphorus tribromide / dichloromethane / 0 °C / Inert atmosphere 2.1: sodium hydroxide / N,N-dimethyl-formamide / 0.08 h / 0 °C 2.2: 0.5 h / 20 °C 3.1: hydrogenchloride / methanol / Reflux 4.1: sodium hydroxide / water; acetonitrile / 0 - 20 °C 5.1: dmap / dichloromethane / 0.17 h / -5 °C / Inert atmosphere 5.2: -5 - 20 °C 6.1: acetic acid / dichloromethane / 0.17 h / 0 °C 6.2: 1 h / 0 °C 7.1: toluene / 2 h / Reflux 8.1: trifluoroacetic acid / dichloromethane / 4 h / 0 °C 9.1: sodium hydride / tetrahydrofuran; mineral oil / 1 h / 0 °C / Inert atmosphere 9.2: 2 h 10.1: sodium hexamethyldisilazane / tetrahydrofuran / -78 °C / Inert atmosphere 10.2: -78 °C 11.1: hydrogenchloride; water / Reflux 12.1: hydrogenchloride / 50 °C

Reference： [1]Current Patent Assignee: THERAVANCE BIOPHARMA, INC. - US2013/109639, 2013, A1

28
[ 185315-48-4 ]
[ 1428758-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 5 h / 0 - 5 °C 7: 3 h / 120 °C 8: sodium carbonate; tetrakis(triphenylphosphine) palladium⁽⁰⁾ / water; 1,4-dioxane / 18 h / Inert atmosphere; Reflux

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

29
[ 185315-48-4 ]
[ 1330065-78-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 5 h / 0 - 5 °C 7: 3 h / 120 °C 8: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / toluene / 1.5 h / 140 °C / Microwave irradiation; Inert atmosphere

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

30
[ 185315-48-4 ]
[ 67197-54-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C
	Multi-step reaction with 2 steps 1: phosphorus tribromide / dichloromethane / 0 - 20 °C / Inert atmosphere 2: N,N-dimethyl-formamide; water / 0 - 20 °C
	Multi-step reaction with 2 steps 1: hydrogen bromide / toluene / 5 h / 95 °C 2: dimethyl sulfoxide / 72 h / 20 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2
[2]Koval, Alexander B.; Wuest, William M. [Tetrahedron Letters, 2016, vol. 57, # 3, p. 449 - 451]
[3]Current Patent Assignee: NISSAN CHEMICAL CORPORATION; TAISHO PHARMACEUTICAL HOLDINGS CO., LTD. - JP2015/231988, 2015, A

31
[ 185315-48-4 ]
[ 1428760-83-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 5 h / 0 - 5 °C 7: 3 h / 120 °C 8: 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

32
[ 185315-48-4 ]
[ 1428759-01-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 5 h / 0 - 5 °C 7: 3 h / 120 °C 8: 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 9: sodium azide / N,N-dimethyl-formamide / 15 h / 100 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

33
[ 185315-48-4 ]
[ 1428760-84-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 5 h / 0 - 5 °C 7: 3 h / 120 °C 8: 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 9: sodium carbonate; hydroxylamine hydrochloride / ethanol / 3 h / 50 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

34
[ 185315-48-4 ]
ethyl 3-(3-chloro-4-(8-ethyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-1,2,4-oxadiazole-5-carboxylate trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 5 h / 0 - 5 °C 7: 3 h / 120 °C 8: 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 9: sodium carbonate; hydroxylamine hydrochloride / ethanol / 3 h / 50 °C 10: pyridine / 2 h / 90 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

35
[ 185315-48-4 ]
[ 916516-89-7 ]

Reference： [1]Patent: WO2013/43232,2013,A2
[2]Tetrahedron Letters,2016,vol. 57,p. 449 - 451
[3]Patent: JP2015/231988,2015,A

36
[ 185315-48-4 ]
6-(2-chloro-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-8-ethyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 5 h / 0 - 5 °C 7: 3 h / 120 °C 8: 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / N,N-dimethyl-formamide / 15 h / 70 °C / Inert atmosphere 9: sodium carbonate; hydroxylamine hydrochloride / ethanol / 3 h / 50 °C 10: pyridine / 15 h / 90 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

37
[ 185315-48-4 ]
[ 1428760-85-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

38
[ 185315-48-4 ]
[ 1428760-86-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 7: hydroxylamine hydrochloride; potassium <i>tert</i>-butylate / dimethyl sulfoxide / 5 - 20 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

39
[ 185315-48-4 ]
[ 1428760-87-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 7: hydroxylamine hydrochloride; potassium <i>tert</i>-butylate / dimethyl sulfoxide / 5 - 20 °C 8: pyridine / 5 - 90 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

40
[ 185315-48-4 ]
[ 1261606-45-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

41
[ 185315-48-4 ]
[ 1428760-88-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 7: hydroxylamine hydrochloride; potassium <i>tert</i>-butylate / dimethyl sulfoxide / 5 - 20 °C 8: pyridine / 5 - 90 °C 9: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 5 - 20 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

42
[ 185315-48-4 ]
[ 1428759-09-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 7: hydroxylamine hydrochloride; potassium <i>tert</i>-butylate / dimethyl sulfoxide / 5 - 20 °C 8: pyridine / 5 - 90 °C 9: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 1 h / 5 - 20 °C 10: 140 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

43
[ 185315-48-4 ]
[ 1428759-13-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 1,1'-bis-(diphenylphosphino)ferrocene; tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / N,N-dimethyl-formamide / 12 h / 70 °C / Inert atmosphere 7: hydroxylamine hydrochloride; potassium <i>tert</i>-butylate / dimethyl sulfoxide / 5 - 20 °C 8: pyridine / 5 - 90 °C 9: 140 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

44
[ 185315-48-4 ]
[ 1428760-89-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium acetate; ISOPROPYLAMIDE / 24 h / 110 °C / Sealed tube

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

45
[ 185315-48-4 ]
[ 1428760-90-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium acetate; ISOPROPYLAMIDE / 24 h / 110 °C / Sealed tube 7: 3-chloro-benzenecarboperoxoic acid / dichloromethane / -5 - 20 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

46
[ 185315-48-4 ]
[ 1428759-18-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium acetate; ISOPROPYLAMIDE / 24 h / 110 °C / Sealed tube 7: 3-chloro-benzenecarboperoxoic acid / dichloromethane / -5 - 20 °C 8: 1 h / 100 - 120 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

47
[ 185315-48-4 ]
[ 1428759-19-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1.1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2.1: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3.1: sodium hydroxide / 4 h / Reflux 4.1: thionyl chloride / 1 h / Reflux 5.1: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium acetate; ISOPROPYLAMIDE / 24 h / 110 °C / Sealed tube 7.1: 3-chloro-benzenecarboperoxoic acid / dichloromethane / -5 - 20 °C 8.1: 1 h / 100 - 120 °C 8.2: Acidic conditions

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

48
[ 185315-48-4 ]
[ 1286738-66-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

49
[ 185315-48-4 ]
[ 1286738-67-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 5 h / 0 - 5 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

50
[ 185315-48-4 ]
[ 1286738-68-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 5 h / 0 - 5 °C 7: 3 h / 120 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

51
[ 185315-48-4 ]
[ 1286738-65-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 5 h / 0 - 5 °C 7: 3 h / 120 °C 8: potassium phosphate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide; water / 0.5 h / 140 °C / Inert atmosphere; Microwave irradiation

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

52
[ 185315-48-4 ]
6-[2-chloro-4-(thiophen-2-yl)phenyl]-8-ethyl-2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 5 h / 0 - 5 °C 7: 3 h / 120 °C 8: potassium phosphate; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride / N,N-dimethyl-formamide; water / 0.5 h / 140 °C / Inert atmosphere; Microwave irradiation 9: hydrogenchloride / 1,4-dioxane; chloroform

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

53
[ 185315-48-4 ]
[ 1286738-81-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: phosphorus tribromide / 1,2-dichloro-ethane / 0.67 h / 0 - 10 °C 2: tetrabutyl-ammonium chloride / water; 1,2-dichloro-ethane / 4 h / 20 °C 3: sodium hydroxide / 4 h / Reflux 4: thionyl chloride / 1 h / Reflux 5: ISOPROPYLAMIDE; caesium carbonate / 2 h / 100 °C 6: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 5 h / 0 - 5 °C 7: 150 °C

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2

54
C₁₂H₁₂BrClO₄ [ No CAS ]
[ 185315-48-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium tetrahydroborate; water In tetrahydrofuran at -5 - 0℃; for 1h;	2.2.1 Step 1: Synthesis of (4-bromo-2-chlorophenyl)methanol (15) 4-Bromo-2-chlorobenzoic acid (14, 92.0 g, 0.39 mol) was dissolved in dry tetrahydrofuran (920 mL) and cooled to -15 °C. Isobutyryl choroformate (51.0 mL, 0.39 mol) was added followed by N-methylmorpholine (43.5 mL, 0.39 mol). The resulting mixture was stirred for 10 minutes at -15 °C, cooled to -25 °C and the precipitated N-methylmorpholine hydrochloride salt was filtered off. The filtrate was warmed to -5 °C and a solution of sodium borohydride (22.19 g, 0.586 mol) in water (190 mL) was added dropwise to the mixture keeping the temperature below 0 °C. After stirring for 1 h at 0 °C, the volatiles were evaporated, and the residue was diluted with water (500 mL) and dichloromethane (450 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (150 mL). The combined organic layers were washed with water ( 150 mL), dried over sodium sulfate and evaporated. The product (86.1 g, 0.39 mol, 99%) was obtained as a white crystalline solid.

Reference： [1]Current Patent Assignee: AFRAXIS INC - WO2013/43232, 2013, A2 Location in patent: Paragraph 00499

55
[ 185315-48-4 ]
[ 1002309-96-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: pyridinium chlorochromate / dichloromethane / 3 h / 25 °C 2: tetrahydrofuran / 3 h / -40 - 25 °C
	Multi-step reaction with 2 steps 1: pyridinium chlorochromate / dichloromethane / 3 h / 25 °C 2: tetrahydrofuran / 3 h / -40 - 25 °C

Reference： [1]Current Patent Assignee: MORPHOSYS AG - WO2013/75083, 2013, A1
[2]Current Patent Assignee: MORPHOSYS AG - US9206128, 2015, B2

56
[ 185315-48-4 ]
4-bromo-2-chloro-1-(1-phenoxyethyl)benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: pyridinium chlorochromate / dichloromethane / 3 h / 25 °C 2.1: tetrahydrofuran / 3 h / -40 - 25 °C 3.1: triphenylphosphine / tetrahydrofuran / 0.5 h / 20 °C 3.2: 12 h / 20 °C
	Multi-step reaction with 3 steps 1.1: pyridinium chlorochromate / dichloromethane / 3 h / 25 °C 2.1: tetrahydrofuran / 3 h / -40 - 25 °C 3.1: triphenylphosphine / tetrahydrofuran / 0.5 h / 20 °C 3.2: 12 h / 20 °C

Reference： [1]Current Patent Assignee: MORPHOSYS AG - WO2013/75083, 2013, A1
[2]Current Patent Assignee: MORPHOSYS AG - US9206128, 2015, B2

57
[ 185315-48-4 ]
methyl 3-chloro-4-(1-phenoxyethyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: pyridinium chlorochromate / dichloromethane / 3 h / 25 °C 2.1: tetrahydrofuran / 3 h / -40 - 25 °C 3.1: triphenylphosphine / tetrahydrofuran / 0.5 h / 20 °C 3.2: 12 h / 20 °C 4.1: palladium diacetate; 1,3-bis-(diphenylphosphino)propane; triethylamine / 12 h / 100 °C / 15201 Torr
	Multi-step reaction with 4 steps 1.1: pyridinium chlorochromate / dichloromethane / 3 h / 25 °C 2.1: tetrahydrofuran / 3 h / -40 - 25 °C 3.1: triphenylphosphine / tetrahydrofuran / 0.5 h / 20 °C 3.2: 12 h / 20 °C 4.1: palladium diacetate; 1,3-bis-(diphenylphosphino)propane; triethylamine / methanol / 12 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: MORPHOSYS AG - WO2013/75083, 2013, A1
[2]Current Patent Assignee: MORPHOSYS AG - US9206128, 2015, B2

58
[ 185315-48-4 ]
3-chloro-4-(1-phenoxyethyl)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: pyridinium chlorochromate / dichloromethane / 3 h / 25 °C 2.1: tetrahydrofuran / 3 h / -40 - 25 °C 3.1: triphenylphosphine / tetrahydrofuran / 0.5 h / 20 °C 3.2: 12 h / 20 °C 4.1: palladium diacetate; 1,3-bis-(diphenylphosphino)propane; triethylamine / 12 h / 100 °C / 15201 Torr 5.1: water; lithium hydroxide monohydrate / methanol; tetrahydrofuran / 5 h / 20 °C
	Multi-step reaction with 5 steps 1.1: pyridinium chlorochromate / dichloromethane / 3 h / 25 °C 2.1: tetrahydrofuran / 3 h / -40 - 25 °C 3.1: triphenylphosphine / tetrahydrofuran / 0.5 h / 20 °C 3.2: 12 h / 20 °C 4.1: palladium diacetate; 1,3-bis-(diphenylphosphino)propane; triethylamine / methanol / 12 h / 100 °C / Inert atmosphere 5.1: water; lithium hydroxide monohydrate / methanol; tetrahydrofuran / 5 h / 20 °C

Reference： [1]Current Patent Assignee: MORPHOSYS AG - WO2013/75083, 2013, A1
[2]Current Patent Assignee: MORPHOSYS AG - US9206128, 2015, B2

59
[ 185315-48-4 ]
3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenoxyethyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: pyridinium chlorochromate / dichloromethane / 3 h / 25 °C 2.1: tetrahydrofuran / 3 h / -40 - 25 °C 3.1: triphenylphosphine / tetrahydrofuran / 0.5 h / 20 °C 3.2: 12 h / 20 °C 4.1: palladium diacetate; 1,3-bis-(diphenylphosphino)propane; triethylamine / 12 h / 100 °C / 15201 Torr 5.1: water; lithium hydroxide monohydrate / methanol; tetrahydrofuran / 5 h / 20 °C 6.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane / 13 h / 20 °C
	Multi-step reaction with 6 steps 1.1: pyridinium chlorochromate / dichloromethane / 3 h / 25 °C 2.1: tetrahydrofuran / 3 h / -40 - 25 °C 3.1: triphenylphosphine / tetrahydrofuran / 0.5 h / 20 °C 3.2: 12 h / 20 °C 4.1: palladium diacetate; 1,3-bis-(diphenylphosphino)propane; triethylamine / methanol / 12 h / 100 °C / Inert atmosphere 5.1: water; lithium hydroxide monohydrate / methanol; tetrahydrofuran / 5 h / 20 °C 6.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane / 13 h / 20 °C

Reference： [1]Current Patent Assignee: MORPHOSYS AG - WO2013/75083, 2013, A1
[2]Current Patent Assignee: MORPHOSYS AG - US9206128, 2015, B2

60
[ 185315-48-4 ]
(R)-3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenoxyethyl)benzamide [ No CAS ]
(S)-3-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(1-phenoxyethyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1.1: pyridinium chlorochromate / dichloromethane / 3 h / 25 °C 2.1: tetrahydrofuran / 3 h / -40 - 25 °C 3.1: triphenylphosphine / tetrahydrofuran / 0.5 h / 20 °C 3.2: 12 h / 20 °C 4.1: palladium diacetate; 1,3-bis-(diphenylphosphino)propane; triethylamine / 12 h / 100 °C / 15201 Torr 5.1: water; lithium hydroxide monohydrate / methanol; tetrahydrofuran / 5 h / 20 °C 6.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane / 13 h / 20 °C 7.1: Daicel AD-H / ethanol; hexane; diethylamine / Resolution of racemate
	Multi-step reaction with 7 steps 1.1: pyridinium chlorochromate / dichloromethane / 3 h / 25 °C 2.1: tetrahydrofuran / 3 h / -40 - 25 °C 3.1: triphenylphosphine / tetrahydrofuran / 0.5 h / 20 °C 3.2: 12 h / 20 °C 4.1: palladium diacetate; 1,3-bis-(diphenylphosphino)propane; triethylamine / methanol / 12 h / 100 °C / Inert atmosphere 5.1: water; lithium hydroxide monohydrate / methanol; tetrahydrofuran / 5 h / 20 °C 6.1: benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine / dichloromethane / 13 h / 20 °C 7.1: diethylamine / ethanol; hexane / Resolution of racemate

Reference： [1]Current Patent Assignee: MORPHOSYS AG - WO2013/75083, 2013, A1
[2]Current Patent Assignee: MORPHOSYS AG - US9206128, 2015, B2

61
[ 185315-48-4 ]
[ 1534373-26-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: phosphorus tribromide / dichloromethane / 18 h / 0 - 20 °C 2: N-ethyl-N,N-diisopropylamine / acetonitrile / 0.33 h / 120 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2014/8223, 2014, A2

62
[ 185315-48-4 ]
[ 21924-83-4 ]

Reference： [1]Patent: WO2014/20350,2014,A1
[2]Patent: WO2014/20351,2014,A1

63
[ 185315-48-4 ]
di-tert-butyl [2-chloro-4-cyanobenzylamino]dicarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 100 °C 2.1: triphenylphosphine; carbon tetrabromide / dichloromethane / 2.5 h / 5 - 20 °C 3.1: sodium hydride / tetrahydrofuran; mineral oil / 5 °C 3.2: 5 - 20 °C
	Multi-step reaction with 3 steps 1: tetrakis(triphenylphosphine) palladium⁽⁰⁾ / N,N-dimethyl-formamide / 100 °C 2: carbon tetrabromide; triphenylphosphine / dichloromethane / 2.5 h / 5 - 20 °C 3: sodium hydride / tetrahydrofuran; mineral oil / 5 - 20 °C

Reference： [1]Current Patent Assignee: BENEVOLENTAI LIMITED - WO2014/20350, 2014, A1
[2]Current Patent Assignee: BENEVOLENTAI LIMITED - WO2014/20351, 2014, A1

64
[ 557-21-1 ]
[ 185315-48-4 ]
[ 1261618-25-0 ]

Yield	Reaction Conditions	Operation in experiment
40%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In N,N-dimethyl-formamide at 100℃; for 16h; Inert atmosphere;	1.3 1.3 3-chloro-4-hydroxymethyl benzonitrile (1-2) Zinc cyanide (0.67 g, 5.73 mmol) and tetrakis(triphenylphosphine) palladium (Pd(PPh3)4, 0.33 g, 0.287 mmol) were added into a solution of 4-bromo-2-chlorobenzyl alcohol (1-1, 1.27 g, 5.73 mmol) in DMF (15 mL). After deoxygenated via argon bubbling, the reaction mixture was heated at 100°C and reacted for 16 hours, cooled down to room temperature, diluted with ethyl acetate (50 mL), washed successively with water (50 mL3) and saturated brine (50 mL3), dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product. The crude product was then purified by column chromatography (elution system: petroleum ether: ethyl acetate = 15/1-4/1) to obtain a white solid product (0.387 g, 40% yield). The molecular ion peak shown by liquid chromatography-mass spectrometry was: MS (ESI): m/z 168.0/170.1 [M+H]+.
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In N,N-dimethyl-formamide at 100℃;	16 3-Chloro-4-(hydroxymethyl)benzonitrile General procedure: Intermediate 14 (1.77g, 8.00mmol), ZnCN2 (564mg, 4.80mmol) and Pd(PPh3)4 (370mg, 0.32mmol) were dissolved in DMF (20mL) and the reaction mixture was heated at 100°C overnight. The reaction mixture was cooled to room temperature, diluted with water, brine and EtOAc and filtered through celite. The aqueous fraction was extracted with EtOAc and the combined organic fractions were washed with 2M aq NH4OH, brine, dned (MgSO/t) and concentrated in vacuo. The residue was triturated from hexanes to give the crude title compound (1.15 g) as a pink solid. LCMS: ES+ 167.2 [MH]+.
	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In N,N-dimethyl-formamide at 100℃;	INTERMEDIATE 16 Intermediate 14 (1.77g, 8.OOmmol), ZnCN2 (564mg, 4.8Ommol) and Pd(PPh3)4 (370mg, 0.32mmol) were dissolved in DIVIF (2OmL) and the reaction mixture was heated at100°C overnight. The reaction mixture was cooled to room temperature, diluted withwater, brine and EtOAc and filtered through celite. The aqueous fraction was extracted with EtOAc and the combined organic fractions were washed with 2M aq NH4OH, brine, dried (MgSO4) and concentrated in vacuo. The residue was triturated from hexanes to give the crude title compound (1.15g) as a pink solid. LCMS: ES 167.2 [IVIHf.

Reference： [1]Current Patent Assignee: SUZHOU CONNECT BIOPHARMACEUTICALS - EP3048103, 2016, A1 Location in patent: Paragraph 0067; 0068
[2]Current Patent Assignee: BENEVOLENTAI LIMITED - WO2014/20350, 2014, A1 Location in patent: Page/Page column 33
[3]Current Patent Assignee: BENEVOLENTAI LIMITED - WO2014/20351, 2014, A1 Location in patent: Page/Page column 19; 20

65
[ 25118-59-6 ]
[ 185315-48-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	With diborane; In tetrahydrofuran; at 0 - 40℃;	A solution of BH3 (34 mL, IM in tetrahydrofuran) was added dropwise to the solution of <strong>[25118-59-6]4-bromo-3-chlorobenzoic acid</strong> (2.5 g, 11.4 mmol) in tetrahydrofuran at 0 C. The mixture was stirred at 40 C. overnight. Acetic acid (5 mL) was added dropwise to the reaction mixture. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=1:1) to give (4-bromo-2-chlorophenyl)methanol as a white solid (4.47 g, 91%). 1H NMR (300 MHz, d6-DMSO): 7.69 (d, J=8.1, 1H), delta 7.53 (d, J=0.9, 1H), 7.19 (dd, J1=8.1, 1H J2=0.9, 1H), 5.38 (s, 1H), delta 4.48 (s, 2H).

Reference： [1]Patent: US9206128,2015,B2 .Location in patent: Page/Page column 275; 276

66
[ 185315-48-4 ]
[ 849934-94-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: phosphorus tribromide / dichloromethane / 0 - 20 °C / Inert atmosphere 2: N,N-dimethyl-formamide; water / 0 - 20 °C 3: potassium hydroxide / water / Reflux 4: hydrogenchloride / Inert atmosphere
	Multi-step reaction with 4 steps 1: hydrogen bromide / toluene / 5 h / 95 °C 2: dimethyl sulfoxide / 72 h / 20 °C 3: sodium hydroxide / water; ethanol / 17 h / 80 - 95 °C 4: sulfuric acid / 18 h / 20 °C

Reference： [1]Koval, Alexander B.; Wuest, William M. [Tetrahedron Letters, 2016, vol. 57, # 3, p. 449 - 451]
[2]Current Patent Assignee: NISSAN CHEMICAL CORPORATION; TAISHO PHARMACEUTICAL HOLDINGS CO., LTD. - JP2015/231988, 2015, A

67
[ 185315-48-4 ]
[ 849934-95-8 ]

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 449 - 451

68
[ 185315-48-4 ]
[ 18162-48-6 ]
4-bromo-1-((tert-butyldimethylsilyloxy)methyl)-2-chlorobenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 1h;	2-12.1 [(4-bromo-2-chlorobenzyl) oxy] (tert-butyl) dimethylsilane (1) (4-bromo-2-chlorophenyl) methanol (2.36g)Of N, the N- dimethylformamide (24 mL) solution, at room temperature, tert-butyldimethylchlorosilane (3.24 g) and sequentially added imidazole (1.46 g), and stirred for 1 hour. Water was added to the reaction solution, hexane - ethyl acetate mixture (1: 1) and extracted with. The organic layer was dried over anhydrous magnesium sulfate, after filtration, concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 98: 2 → 90: 10) to give the [(4-bromo-2-chlorobenzyl) oxy] (tert-butyl) dimethylsilane (3. 52g, 98%) as a colorless oily substance.

Reference： [1]Current Patent Assignee: NISSAN CHEMICAL CORPORATION; TAISHO PHARMACEUTICAL HOLDINGS CO., LTD. - JP2015/231988, 2015, A Location in patent: Paragraph 0300; 0301

69
[ 185315-48-4 ]
[ 3179-31-5 ]
[ 98-59-9 ]
C₉H₇BrClN₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (4-bromo-2-chlorophenyl)methanol; p-toluenesulfonyl chloride With triethylamine In chloroform at 0 - 20℃; Stage #2: 1H-[1,2,4]triazole-3-thiol With potassium carbonate In acetonitrile at 50℃; for 1h;	2-23.2 (2) 4-bromo-2-chlorobenzyl-4-methylbenzene sulfonate and 4-bromo-2-chloro-1-acetonitrile (chloromethyl) a mixture of benzene (54 mL) solution ofAt room temperature for 3-mercapto-1,2,4-triazole (1.33g)And sequentially added potassium carbonate (3.58g), and stirred for 1 hour at 50 ° C.. Insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting water was added to the residue, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, after filtration, concentrated under reduced pressure. The resulting residue was used in the next reaction with unpurified.

Reference： [1]Current Patent Assignee: NISSAN CHEMICAL CORPORATION; TAISHO PHARMACEUTICAL HOLDINGS CO., LTD. - JP2015/231988, 2015, A Location in patent: Paragraph 0322; 0323

70
[ 185315-48-4 ]
[ 98-59-9 ]
[ 185315-49-5 ]
4-bromo-2-chlorobenzyl-4-methylbenzene-1-sulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In chloroform at 0 - 20℃;	2-23.1 (1) (4-bromo-2-chlorophenyl) methanol (3.10g)In chloroform (60mL) solution,At 0 , triethylamine (2.15mL)And p- toluenesulfonyl chloride were sequentially added (2.94g), and stirred at room temperature overnight.Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, after filtration, concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1 → 4: 1) was purified by,4-bromo-2-chloro-benzyl-4-methyl benzene sulfonate and4-bromo-2-chloro-1-(chloromethyl) benzeneThe mixture was obtained.

Reference： [1]Current Patent Assignee: NISSAN CHEMICAL CORPORATION; TAISHO PHARMACEUTICAL HOLDINGS CO., LTD. - JP2015/231988, 2015, A Location in patent: Paragraph 0322; 0323

71
[ 89794-02-5 ]
[ 185315-48-4 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 7820 - 7834

72
[ 185315-48-4 ]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -60 °C 2.2: 2.05 h / -40 - 0 °C 3.1: sodium hydride / DMF (N,N-dimethyl-formamide) / 2 h / 20 - 40 °C 9.1: hydrogen / platinum(IV) oxide / 1,4-dioxane; methanol; chloroform / 6.5 h / 20 °C / 760.05 Torr

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1

73
[ 185315-48-4 ]
3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-5-((4-methylbenzene)sulfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -60 °C 2.2: 2.05 h / -40 - 0 °C 3.1: sodium hydride / DMF (N,N-dimethyl-formamide) / 2 h / 20 - 40 °C 7.1: hydrogen / platinum(IV) oxide / methanol; chloroform / 10 h

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1

74
[ 185315-48-4 ]
3-(2-chloro-4-(2-phenylethyl)-benzyl)-2-methyl-5-(E)-((2-phenylethenyl)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -60 °C 2.2: 2.05 h / -40 - 0 °C 3.1: sodium hydride / DMF (N,N-dimethyl-formamide) / 2 h / 20 - 40 °C 7.1: hydrogen / platinum(IV) oxide / methanol; chloroform / 10 h

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1

75
[ 185315-48-4 ]
3-(2-chloro-4-(2-phenylethyl)-benzyl)-5-((5-chlorothiophen-2-yl)sulfonylcarbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -60 °C 2.2: 2.05 h / -40 - 0 °C 3.1: sodium hydride / DMF (N,N-dimethyl-formamide) / 2 h / 20 - 40 °C 7.1: hydrogen / platinum(IV) oxide / methanol; chloroform / 10 h

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1

76
[ 185315-48-4 ]
3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-5-((4-vinylbenzene)sulfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -60 °C 2.2: 2.05 h / -40 - 0 °C 3.1: sodium hydride / DMF (N,N-dimethyl-formamide) / 2 h / 20 - 40 °C 7.1: hydrogen / platinum(IV) oxide / methanol; chloroform / 10 h

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1

77
[ 185315-48-4 ]
3-(2-chloro-4-piperidinobenzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: triethylamine / dichloromethane / 1 h / 0 °C 5: (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl; sodium t-butanolate / tris-(dibenzylideneacetone)dipalladium⁽⁰⁾ / toluene / 30 h / 90 °C

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1

78
[ 185315-48-4 ]
3-(2-chloro-4-(2-phenylethyl)-benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -60 °C 2.2: 2.05 h / -40 - 0 °C 3.1: sodium hydride / DMF (N,N-dimethyl-formamide) / 2 h / 20 - 40 °C 7.1: hydrogen / platinum(IV) oxide / methanol; chloroform / 10 h

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1

79
[ 185315-48-4 ]
5-((5-bromothiophen-2-yl)sulfonylcarbamoyl)-3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 9 steps 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -60 °C 2.2: 2.05 h / -40 - 0 °C 3.1: sodium hydride / DMF (N,N-dimethyl-formamide) / 2 h / 20 - 40 °C 7.1: hydrogen / platinum(IV) oxide / methanol; chloroform / 10 h

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1

80
[ 185315-48-4 ]
[ 219767-24-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -60 °C 2.2: 2.05 h / -40 - 0 °C 3.1: sodium hydride / DMF (N,N-dimethyl-formamide) / 2 h / 20 - 40 °C 7.1: hydrogen / platinum(IV) oxide / methanol; chloroform / 10 h

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1

81
[ 185315-48-4 ]
methyl 3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 2.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -60 °C 2.2: 2.05 h / -40 - 0 °C 3.1: sodium hydride / DMF (N,N-dimethyl-formamide) / 2 h / 20 - 40 °C 7.1: hydrogen / platinum(IV) oxide / methanol; chloroform / 10 h

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1

82
[ 185315-48-4 ]
[ 960-16-7 ]
[ 219762-35-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: lithium chloride / tetrakis(triphenylphosphine) palladium⁽⁰⁾ / 1,4-dioxane / 5 h / Heating / reflux

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US6348474, 2002, B1

83
[ 59748-90-2 ]
[ 185315-48-4 ]

Yield	Reaction Conditions	Operation in experiment
	With diisobutylaluminium hydride In toluene	18.1 (18-1) (18-1) Potassium carbonate (1.38 g, 10 mmol) and methyl iodide (0.623 ml, 10 mmol) were added to a solution of 4-bromo-2-chlorobenzoic acid (2.0 g, 8.5 mmol) in N,N-dimethylformamide (8 ml) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give an oily residue. After diisobutyl aluminum hydride-1.0M toluene solution (24 ml, 24 mmol) was added dropwise to a solution of the obtained residue in toluene (30 ml) at -78°C, the temperature of the mixture was raised to room temperature over 3 hours. After sodium sulfate decahydrate (12 g) was added to the reaction mixture and the mixture was stirred at room temperature for 30 minutes, Celite (12 g) and anhydrous magnesium sulfate (12 g) were added thereto and the mixture was stirred at room temperature for 30 minutes. After the insolubles were removed by filtration, the solvent was removed from the obtained filtrate under reduced pressure to give crudely purified (4-bromo-2-chlorophenyl)methanol as a solid. According to a method similar to Example (17-1), from crude (4-bromo-2-chlorophenyl)methanol obtained in the above, (4-bromo-2-chlorophenyl)acetonitrile was obtained as a pale yellow solid (1.4 g, yield: 71%). 1H-NMR (400MHz, CDCl3): δ 7.61 (1H, d, J = 1.6 Hz), 7.47 (1H, app d, J = 8.0 Hz), 7.40 (1H, d, J = 8.0 Hz), 3.79 (2H, s).

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - EP1806332, 2007, A1

84
[ 185315-48-4 ]
[ 73183-34-3 ]
(2‐chloro‐4‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)phenyl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In 1,4-dioxane at 100℃; Inert atmosphere;	1 To a stirred solution of (4-bromo-2-chlorophenyl)methanol (500 mg, 2.273 mmol) in dry 1 ,4-Dioxane (10 ml_), potassium acetate (669 mg, 6.820 mmol) and bis(pinacolato)diboron (692 mg, 2.728 mmol) were added at RT and the reaction mixture was flushed with nitrogen for 10 min. Then Pd(dppf)Cl2-DCM (185 mg, 0.227 mmol) was added and the resulting mixture was heated overnight at 100°C. It was filtered through celite pad that was washed with EtOAc (50 ml_). Combined filtrate was dried over Na2S04 and concentrated under vacuum to afford the title compound that was used in the next step without further purification. Yield: 100% (610 mg, black colour liquid).

Reference： [1]Current Patent Assignee: ASCENEURON SA - WO2020/39027, 2020, A1 Location in patent: Page/Page column 159

85
[ 185315-48-4 ]
[ 329214-79-1 ]
(2-chloro-4-(pyridin-3-yl)phenyl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere;	1 Step 1: (2-chloro-4-(pyridin-3-yl)phenyl)methanol To a stirred solution of 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (350 mg, 1.68 mmol) and (4-bromo-2-chlorophenyl)methanol (340 mg, 1.85 mmol) in dry dioxane (4 ml_), a solution of potassium carbonate (710 mg, 5.04 mmol) in water (1 mL) was added at RT and the resulting solution was flushed with nitrogen for 10 min. Tetrakis (triphenylphosphine)palladium(O) (190 mg, 0.68 mmol) was added and the reaction mixture was heated at 100 °C overnight. After completion of reaction, the reaction mixture was filtered through celite pad and the filtrate was concentrated under vacuum. The resulting crude product was purified by flash chromatography (Eluent: 55% EtOAc in pet ether) to afford the title compound. Yield: 62% (230 mg, off white solid). 1H NMR (400 MHz, DMSO-cfe): <5 8.93 (d, J = 2.8 Hz, 1 H), 8.58-8.60 (m, 1 H), 8.12 (dd, J = 6.6, 2.8 Hz, 1 H), 7.73- 7.80 (m, 3H), 7.73-7.75 (m, 1 H), 5.48 (t, J = 7.6 Hz, 1 H), 4.62 (d, J = 7.6 Hz, 2H). LCMS: (Method A) 220.2. (M+H), Rt. 1.12 min, 98.33% (max).

Reference： [1]Current Patent Assignee: ASCENEURON SA - WO2020/39027, 2020, A1 Location in patent: Page/Page column 146

86
[ 185315-48-4 ]
[ 185315-49-5 ]

Yield	Reaction Conditions	Operation in experiment
74.4%	With thionyl chloride at 0 - 70℃; for 1.08333h;	1 Add SOCl2 (164.2 mg, 1.4 mmol, 3.0 eq) in 4-bromo-2-chlorobenzyl alcohol (94.3 mg, 0.4 mmol, 1.0 eq) dropwise at 0° C. After reacting for 5 min,Move to 70°C under reflux, and after stirring for 1h, TLC thin layer chromatography monitors the completion of the reaction and stops stirring.Extracted with ethyl acetate, the pH of the solid NaHCO3 was adjusted to neutral, and then saturated aqueous NaCl,Anhydrous MgSO4 was dried to obtain 81.1mg 4-bromo-2-chlorobenzyl chloride with a yield of 74.4%.

Reference： [1]Current Patent Assignee: CHENGDU NEWSUN CROP SCIENCE; XIHUA UNIVERSITY - CN111196785, 2020, A Location in patent: Paragraph 0053; 0070-0071; 0074

87
[ 185315-48-4 ]
tert-butyl 2'-isopropyl-2-oxo-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)spiro[indoline-3,3'-pyrrolidine]-1'-carboxylate [ No CAS ]
tert-butyl 1-(3'-chloro-4’-(hydroxymethyl)-[1,1'-biphenyl]-3-yl)-2'-isopropyl-2-oxospiro[indoline-3,3'-pyrrolidine]-1'-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate at 85℃; Inert atmosphere;	4.1.8. Synthesis of compounds 10 to 24 General procedure: Compounds 10 to 24 were synthesized by the general methoddescribed here. Aryl bromide (0.25 mmol, 1.1 equiv.), potassiumcarbonate (35 mg, 0.25 mmol, 1.1 equiv.) and Pd (DPPF)Cl2 (20 mg,0.025 mmol, 0.1 equiv.) were added under an N2 atmosphere to asolution of S-3 (100 mg, 0.2 mmol, 1.0 equiv.) in 2,4-dioxane (3 mL),and the mixture was stirred at 85 C overnight. The mixture wascooled in an ice bath, and thiswas followed by addition of saturatedaq. NH4Cl to quench the reaction. The mixture was extracted three times with 20 mL EtOAc, washed with brine, dried over Na2SO4,filtered and concentrated in vacuo. The residue was purified bysilica gel flash chromatography (Biotage SP-1, 20 g SiO2 column,gradient elution from 20 to 60% EtOAc) to afford the derivatives.Then, the Boc moiety was replace by other R2. The Boc derivative(0.25 mmol, 1.0 equiv.) was dissolved in DCM. HCl (1 mL, 1 M inDCM) was added to the mixture, stirred for 2 h. Then the mixturewas concentrated in vacuo to afford the crude. To the solution of thecrude in DCM/pyridine (v/v: 2/1), was added by R2OR2 (0.25 mmol,1.0 equiv.) and stirred overnight. The mixture was diluted withDCM, washed with brine, dried over Na2SO4, filtered and concentratedin vacuo. The residue was purified by silica gel flash chromatography(Biotage SP-1, 20 g SiO2 column, gradient elution from20 to 60% EtOAc).

Reference： [1]Chen, Ziyang; Chen, Hao; Zhang, Zizhen; Ding, Peng; Yan, Xin; Li, Yanwen; Zhang, Songxuan; Gu, Qiong; Zhou, Huihao; Xu, Jun [European Journal of Medicinal Chemistry, 2020, vol. 206]

88
[ 110-87-2 ]
[ 185315-48-4 ]
2-[(4-bromo-2-chlorophenyl)methoxy]oxane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.97%	With toluene-4-sulfonic acid In dichloromethane at 20℃; for 48h;	172 3,4-Dihydro-2H-pyran (0.62 mL, 6.77 mmol) and 4-methylbenzenesulfonic acid hydrate (42.94 mg, 0.230 mmol) were added to a solution of (4-bromo-2- chlorophenyl)methanol (1.0 g, 4.52 mmol) in DCM (15 mL). The mixture was stirred at room temperature for 48h, diluted with DCM (40 mL) and washed with aqueous saturated NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by column chromatography (KP-Sil, SNAP 25g) eluting with a gradient of EtOAc in cyclohexane from 0% to 15% to give 2-[(4-bromo-2- chlorophenyl)methoxy]oxane (1.2 g, 3.927 mmol, 86.97% yield) as an oil.1H NMR (400 MHz, DMSO-d6) δ 1.42 - 1.92 (m, 6H), 3.44 - 3.54 (m, 1H), 3.73 - 3.83 (m, 1H), 4.50 (d, J = 13.30 Hz, 1H), 4.69 (d, J = 13.30 Hz, 1H), 4.72 - 4.79 (m, 1H), 7.44 - 7.51 (m, 1H), 7.58 (dd, J = 8.26, 1.98 Hz, 1H), 7.73 (d, J = 1.98 Hz, 1H). LC-MS (Method A): r.t.1.43 min, MS (ESI) m/z of product not observed due to poor ionization.
86.97%	With toluene-4-sulfonic acid In dichloromethane at 20℃; for 48h;	172 3,4-Dihydro-2H-pyran (0.62 mL, 6.77 mmol) and 4-methylbenzenesulfonic acid hydrate (42.94 mg, 0.230 mmol) were added to a solution of (4-bromo-2- chlorophenyl)methanol (1.0 g, 4.52 mmol) in DCM (15 mL). The mixture was stirred at room temperature for 48h, diluted with DCM (40 mL) and washed with aqueous saturated NaHCO3 solution. The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by column chromatography (KP-Sil, SNAP 25g) eluting with a gradient of EtOAc in cyclohexane from 0% to 15% to give 2-[(4-bromo-2- chlorophenyl)methoxy]oxane (1.2 g, 3.927 mmol, 86.97% yield) as an oil.1H NMR (400 MHz, DMSO-d6) δ 1.42 - 1.92 (m, 6H), 3.44 - 3.54 (m, 1H), 3.73 - 3.83 (m, 1H), 4.50 (d, J = 13.30 Hz, 1H), 4.69 (d, J = 13.30 Hz, 1H), 4.72 - 4.79 (m, 1H), 7.44 - 7.51 (m, 1H), 7.58 (dd, J = 8.26, 1.98 Hz, 1H), 7.73 (d, J = 1.98 Hz, 1H). LC-MS (Method A): r.t.1.43 min, MS (ESI) m/z of product not observed due to poor ionization.

Reference： [1]Current Patent Assignee: ANNEXON INC - WO2022/20244, 2022, A1 Location in patent: Page/Page column 229
[2]Current Patent Assignee: ANNEXON INC - WO2022/20244, 2022, A1 Location in patent: Page/Page column 229

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
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Prevention
Code	Phrase
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P233	Keep container tightly closed.
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Code	Phrase
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P321
P322
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P378
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Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
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H220	Extremely flammable gas
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H240	Heating may cause an explosion
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H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
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Health hazards
Code	Phrase
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H310	Fatal in contact with skin
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H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
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H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
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H332	Harmful if inhaled
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H361d	Suspected of damaging the unborn child
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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