[ CAS No. 189628-37-3 ] {[proInfo.proName]}

Name: 189628-37-3|5-Bromo-2-chlorobenzaldehyde|98%
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Quality Control of [ 189628-37-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 189628-37-3 ]

Product Details of [ 189628-37-3 ]

CAS No. :	189628-37-3	MDL No. :	MFCD08445659
Formula :	C₇H₄BrClO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DPKKRQAEYWOISP-UHFFFAOYSA-N
M.W :	219.46	Pubchem ID :	10608925
Synonyms :

Calculated chemistry of [ 189628-37-3 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	44.54
TPSA :	17.07 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) :	-5.3 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.94
Log Po/w (XLOGP3) :	3.29
Log Po/w (WLOGP) :	2.92
Log Po/w (MLOGP) :	2.79
Log Po/w (SILICOS-IT) :	3.3
Consensus Log Po/w :	2.85

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.65
Solubility :	0.049 mg/ml ; 0.000223 mol/l
Class :	Soluble
Log S (Ali) :	-3.32
Solubility :	0.104 mg/ml ; 0.000475 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.82
Solubility :	0.0331 mg/ml ; 0.000151 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 189628-37-3 ]

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

Application In Synthesis of [ 189628-37-3 ]

* 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 [ 189628-37-3 ]
Downstream synthetic route of [ 189628-37-3 ]

[ 189628-37-3 ] Synthesis Path-Upstream 1~10

1
[ 189628-37-3 ]
[ 21739-92-4 ]

Reference： [1] Angewandte Chemie - International Edition, 2017, vol. 56, # 14, p. 3867 - 3871[2] Angew. Chem., 2017, vol. 129, # 14, p. 3925 - 3929,5
[3] ChemCatChem, 2018, vol. 10, # 6, p. 1253 - 1257

2
[ 189628-37-3 ]
[ 149965-40-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium tetrahydroborate In ethanol at 20℃; for 4 h; Large scale	Take 5-bromo-2-chlorobenzaldehyde 108 kg, dissolved in 250 kg of anhydrous ethanol, add 25 kg of sodium borohydride, react at room temperature for 4 hours, after the end of the reaction, vacuum recovery of most of the anhydrous ethanol,The reaction system was quenched with dilute hydrochloric acid dropwise on an ice bath, and the system was extracted with ethyl acetate at a pH of 4-5 and 300 kg, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, and the filtrate was recovered under reduced pressure.Petroleum ether: Ethyl acetate (1:1) was recrystallized to obtain a pale yellow solid powder (107 kg) with a yield of 99percent.
99%	Stage #1: With sodium tetrahydroborate In ethanol at 20℃; for 4 h; Large scale Stage #2: With hydrogenchloride In waterCooling with ice; Large scale	Take 108 kg of 5-bromo-2-chlorobenzaldehyde, dissolve in 250 kg of absolute ethanol, add 25 kg of sodium borohydride, and react at room temperature for 4 h.After the reaction is completed, most of the anhydrous ethanol is recovered under reduced pressure, and the reaction system is quenched by dropwise addition of dilute hydrochloric acid in an ice bath, and the pH of the system is 4-5.Extracted with 300 kg of ethyl acetate, washed with water until neutral, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure, petroleum ether: acetic acidThe ethyl ester (1:1) was recrystallized to obtain 107 kg of a pale yellow solid powder, yield 99percent.

Reference： [1] Patent: CN107540648, 2018, A, . Location in patent: Paragraph 0033; 0034; 0046; 0047
[2] Patent: CN107652277, 2018, A, . Location in patent: Paragraph 0018
[3] Patent: WO2016/102347, 2016, A1, . Location in patent: Paragraph 0383

3
[ 149965-40-2 ]
[ 189628-37-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -60℃; for 0.0833333 h; Stage #2: at -60℃; for 0.25 h; Stage #3: With triethylamine In tetrahydrofuran; dichloromethane at -60 - 20℃;	EXAMPLE IX 5-bromo-2-chloro-benzaldehyde 7 ml dimethylsulphoxide in 25 ml dichloromethane are added dropwise to a solution of 4.4 ml oxalyl chloride in 125 ml dichloromethane cooled to -60° C. After 5 min stirring a solution of 10.0 g 5-bromo-2-chloro-benzylalcohol in 50 ml of tetrahydrofuran is added and the mixture is stirred for a further 15 min at -60° C. Then 31.5 ml triethylamine are added and the reaction solution is allowed to come up to ambient temperature in the cooling bath. At ambient temperature water is added, the organic phase is separated off and washed with 1 M hydrochloric acid. After drying through sodium sulphate the solvent is eliminated totally. Yield: 9.7 g (98percent of theory) Mass spectrum (ESI⁺): m/z=218/220/222 (bromine+chlorine) [M+H]⁺
94%	With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane; chloroform at -78 - 20℃;	Example 2B 5-Bromo-2-chlorobenzaldehyde 18 ml (0.26 mol) of DMSO are introduced into 64 ml of dichloromethane and, at -78° C., 16.1 g (0.127 mol, 11.1 ml) of oxalyl chloride are added. After 30 min, a solution of 13.1 g (59 mmol) of (5-bromo-2-chlorophenyl)methanol in 100 ml of chloroform is added dropwise. After 20 min, 40 ml of triethylamine are added and the reaction mixture is slowly warmed to RT. After the addition of 50 ml of water the mixture is extracted several times with ethyl acetate. The combined organic phases are washed successively with 2N hydrochloric acid, water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The resulting solid is dried Yunder high vacuum to constant weight. Yield: 12.7 g (94percent of theory) HPLC (method 11): R_t=4.65 min MS (EI): m/z=218 (M)+¹H-NMR (300 MHz, CDCl₃): δ=7.32 (d, 1H), 7.65 (dd, 1H), 8.03 (d, 1H), 10.4 (s, 1H).
90%	With pyridinium chlorochromate In dichloromethane at 0℃;	60 g PCC and 60 g silica gel powder were added to a round bottom flask; after mixing, 500 mL dichloromethane was added; cooled to 0° C., and 45 g of compound 1-1 in dichloromethane (300 mL) was added dropwise with stirring; maintaining 0° C.The reaction was monitored by TLC; after the reaction was completed, the reaction solution was spin-dried; 38 g of Compound 1-2 was isolated by column separation, and the yield in two steps was 90percent.

89%	With pyridinium chlorochromate In dichloromethane	Step 1: 5-Bromo-2-chlorobenzaldehyde. To a suspension of 5.23 g (23.6 mmol) of 5-bromo-2-chlorobenzyl alcohol in 50 ml of CH₂Cl₂ at 0° C., 8.36 g (38.7 mmol) of pyridinium chlorochromate was added. The reaction mixture was stirred at room temperature for 3 hours at which time the reaction was complete. The mixture was filtered, washed with EtOAc, dried (MgSO₄), filtered, and concentrated. Flash column chromatography (10percent EtOAc/hexane) yielded a pale yellow solid (4.62 g, 89percent): m.p. 56-58° C.: R_f 0.73 (20percent EtOAc/hexane). ¹H NMR (400 MHz, CDCl₃) δ7.34 (d, J=8.4 Hz, 1, ArH), 7.65 (dd, J=8.4, 2.4 Hz, 1, ArH), 8.04 (d, J=2.4 Hz, 1, ArH), 10.41 ppm (s, 1, CHO).
86%	Stage #1: With dipyridinium dichromate In dichloromethane for 5 h; Stage #2: With Celite In dichloromethane for 0.333333 h;	Pyridinium dichromate (3.82 g, 10.2 mmol) was added to a solution of 5-bromo-2- chlorobenzylalcohol (1.5g, 6.8 mmol) in CH2CI2 (30 mL). The reaction was stirred for 5 hours and then celite was added. The mixture was stirred for 20 mins and then filtered through a pad of celite washing with ether. The filtrate was concentrated to a brown oil. The residue was purified by flash silica gel chromatography (0percent to 10percent EtOAc in hexanes) to give the title compound as a clear oil (1.28g, 86percent).'H NMR (400 MHz, CDCI3) : 5 7.35 (d, J=8.6 Hz, 1 H), 7.65 (dd, J=8.3, 2.5 Hz, 1 H), 8.04 (d, J=2.5 Hz, 1 H), 10.41 (s, 1 H).
86%	With pyridinium dichromate In dichloromethane for 5 h;	Pyridinium dichromate (3.82 g, 10.2 mmol) was added to a solution of 5-bromo-2-chlorobenzylalcohol (1.5 g, 6.8 mmol) in CH₂Cl₂(30 mL). The reaction was stirred for 5 hours and then celite was added. The mixture was stirred for 20 mins and then filtered through a pad of celite washing with ether. The filtrate was concentrated to a brown oil. The residue was purified by flash silica gel chromatography (0percent to 10percent EtOAc in hexanes) to give the title compound as a clear oil (1.28 g, 86percent). ¹H NMR (400 MHz, CDCl₃): δ 7.35 (d, J=8.6 Hz, 1H), 7.65 (dd, J=8.3, 2.5 Hz, 1H), 8.04 (d, J=2.5 Hz, 1H), 10.41 (s, 1H).

Reference： [1] Patent: US2006/25349, 2006, A1, . Location in patent: Page/Page column 20
[2] Patent: US2007/99885, 2007, A1, . Location in patent: Page/Page column 13-14
[3] Patent: CN107556276, 2018, A, . Location in patent: Paragraph 0068; 0072-0073
[4] Patent: US2003/176506, 2003, A1,
[5] Patent: WO2004/74270, 2004, A2, . Location in patent: Page 364
[6] Patent: US2005/176701, 2005, A1, . Location in patent: Page/Page column 178
[7] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 14, p. 2744 - 2748

4
[ 89-98-5 ]
[ 189628-37-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	With N-Bromosuccinimide In dichloromethane at 5℃; for 10.5 h; Large scale	140kg of 2-chlorobenzaldehyde was dissolved in 400kg of methylene chloride and stirred in an ice bath for 30min. Then 180kg of NBS was added in batches to keep the temperature of the reaction system below 5°C. After the addition was completed, the reaction was performed for 10h.After the reaction was completed, the mixture was filtered, and the filtrate was washed with 300 kg of a saturated aqueous solution of sodium hydrogencarbonate, and the organic layer was washed with water until neutral to recover methylene chloride.The residual solid was recrystallized from petroleum ether:ethyl acetate (1:1) to give 212 kg of a white solid with a yield of 98percent.
98%	With N-Bromosuccinimide In dichloromethane at 5℃; for 10 h; Large scale	Take 140 kg of 2-chlorobenzaldehyde and dissolve it in 400 kg of dichloromethane.Stir for 30 min in an ice bath, then add 180 kg of NBS in batches.Keep the temperature of the reaction system below 5 ° C. After the addition, the reaction is carried out for 10 h. After the reaction is completed,Filtration, the filtrate was washed with 300 kg of saturated sodium bicarbonate solution,The organic layer is then washed with water until neutral, and dichloromethane is recovered.The residual solid was recrystallized from petroleum ether: ethyl acetate (1:1) to yield a white solid (yield: 98percent).

Reference： [1] Patent: CN107540648, 2018, A, . Location in patent: Paragraph 0031; 0032; 0044; 0045
[2] Patent: CN107652277, 2018, A, . Location in patent: Paragraph 0017

5
[ 251085-87-7 ]
[ 189628-37-3 ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: With pyrrolidine; sodium bis(2-methoxyethoxy)aluminium dihydride In tert-butyl methyl ether; toluene at -20 - 25℃; for 1.33333 h; Stage #2: With potassium <i>tert</i>-butylate In tetrahydrofuran; tert-butyl methyl ether; toluene Stage #3: at 10℃; for 0.25 h;	5-Bromo-2-chlorobenzaldehyde (74c). A solution of pyrrolidine (4.00 g, 56.0 mmol) in MTBE (12 mL) was added dropwise over 20 min to a solution of Red-Al.(R). (3.4 M solution in toluene, 16 ml, 54.4 mmol) in MTBE (33 mL) maintained at -20 °C. The mixture was stirred for 1 h at 25 °C. A solution of potassium tert-butoxide (0.60 g, 5.36 mmol) in THF (3 mL) was added. The resulting solution was added dropwise to a solution of 2-chloro-5-bromobenzoic acid methyl ester (72, 6.80 g, 27.3 mmol) in MTBE (15 mL) at 10 °C. After 15 min the mixture was quenched with 2 N HCl (300 mL). Repeated recystallizations (hexanes) of the recovered material gave a crude solid (3.22 g, 54percent, mp 43-46 °C), which was used without further purification in the next step.; The synthesis of benzaldehyde chlorooxime synthons 52 is depicted in Scheme 4, below. Of the eight aldehydes 44e-f and 74a-f, only 44e and 74d were commercially available. The preparation of aldehyde 44f began with the known three-step transformation of 4-methyl-3-nitrobenzonitrile 63 to methoxy compound 64. See Reiner, J. E., et al., Bioorg. Med. Chem. Lett., 12, 1203-1208 (2002). α-Bromination of 64 using one equivalent of N-bromosuccinimide gave little selectivity between the mono- and dibromo adducts, but the analogous reaction using 2.5 equivalents gave dibromide 65 almost exclusively. Silver nitrate oxidation of dibromide 65 gave aldehyde 44f. See Hill. R. A., et al., J. Chem. Soc., Perkin Trans., 1, 2209-2215 (1987). The reaction of the o-nitrotoluene 63 with N,N-dimethylformamide dimethyl acetal in DMF gave the enamine 66, which underwent oxidative cleavage using sodium periodate in THF, see Riesgo, E. C., et al., J. Org. Chem., 61, 3017-3022 (1996), to give aldehyde 74a via a more facile preparation than previously reported. See Dann, O., et al., Liebigs Ann. Chem., 3, 409-425 (1984). Aldehyde 74b also has been prepared previously. See Schultz, E. M., et al., J. Med. Chem., 19(6), 783-787 (1976). A more expedient preparation of 74b began with chlorotoluene 67 undergoing α-bromination to 68, see Gilbert, A. M., et al., J. Med. Chem., 43, 1203-1214 (2000), by a modification of the original procedure. See Liu, P., et al., Synthesis, 14, 2078-2080 (2001). The reaction of 68 with 2-nitropropane and sodium ethoxide in ethanol gave 74b. See Mallory, F. M., et al., Tetrahedron, 57, 3715-3724 (2001). Commercially available aldehyde 69 and aldehyde 71, see Hino, K., et al., Chem. Pharm. Bull., 36(6), 3462-3467 (1988), which had been prepared via a Sandmeyer reaction from commercially available 70, were converted to methyl esters 72 and 73, respectively. The esters were converted to aldehydes 74c and 74e, respectively, using Red-Al.(R).(sodium bis(2-methoxyethoxy)aluminium hydride) (Aldrich Chemical Co., Inc., Milwaukee, Wisconsin, United States of America), pyrrolidine, and potassium tert-butoxide in methyl tert-butyl ether. See Abe, T., et al., Tetrahedron, 57, 2701-2710 (2001). Cyanoaldehyde 74f was prepared by debromocyanation of 44d. See Laali, K. K., et al., J. Org. Chem., 58, 1385-1392 (1993). Aldehydes 44e-44f and 74a-74f were converted to oxime derivatives 75a-h (of which 75a,e were known previously), see Quan, M. L., et al., J. Med. Chem., 42(15), 2752-2759 (1999), using hydroxylamine hydrochloride in either water/ethanol or pyridine/ethanol. The oximes were treated with N-chlorosuccinimide in DMF to give chlorooximes 52a-h, following the procedure reported for 52e. See Liu. K.-C., et al., J. Org. Chem., 45, 3916-3918 (1980). The chlorooximes 52 were reacted with acetylenes 51 without further purification.; Reagents and conditions: (a) H₂, 10percent Pd/C, EtOH; (b) NaNO₂, aq. H₂SO₄; (c) CH₃l, NaH, DMF; (d) NBS, benzoyl peroxide, CCl₄; (e) AgNO₃, aq. EtOH; (f) DMFDMA, DMF; (g) NalO₄; aq. THF; (h) diethyl phosphite, (i-Pr)₂NEt, THF; (j) 2-nitropropane, NaOEt, EtOH; (k) NaNO₂, aq. HCl, then CuCN, KCN; (I) MeOH, H₂SO₄; (m) DCC, DMAP, MeOH, CH₂Cl₂; (n) Red-Al.(R)., t-BuOK, pyrrolidine, MTBE; (o) NH₂OH HCl, H₂O/EtOH or Py/EtOH (p) NCS, DMF.

Reference： [1] Patent: EP1719767, 2006, A1, . Location in patent: Page/Page column 24-28; 41-42
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 10, p. 2468 - 2485

6
[ 842136-59-8 ]
[ 189628-37-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at -15 - -10℃; for 1 h; Stage #2: With water; ammonium chloride In tetrahydrofuran	Preparation Example 5 Synthesis of 2-(5-bromo-2-chlorobenzyl)-1-benzothiophene; Oxalyl chloride (3.78 mL, 0.0441 mmol) and N,N-dimethylformamide (0.06 mL) were added to a chloroform (20 mL) solution of 5-bromo-2-chlorobenzoic acid (10.0 g, 0.0425 mol). After the reaction mixture was stirred at room temperature for one day, the reaction mixture was evaporated under reduced pressure. The obtained yellow oily substance was dissolved in chloroform (20 mL). This solution was added dropwise to a mixture of N,O-dimethoxyhydroxylamine hydrochloride (4.56 g, 0.0468 mol), triethylamine (12.3 mL, 0.0882 mol) and chloroform (50 mL) for 15 minutes, while maintaining the reaction temperature at 5°C to 10°C. After stirred for 15 minutes, the reaction mixture was warmed to room temperature. After water (20 mL) was added to the reaction mixture, the organic layer was separated and the organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine, and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to obtain 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (11.8 g, 99.7percent) as a colorless crystal. This was used in the next reaction without purification. LiAlH₄(1.47 g, 0.0388 mol) was added little by little to a tetrahydrofuran (108 mL) solution of 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (10.8 g, 0.0388 mol) so that the internal temperature did not exceed -10°C. The reaction mixture was stirred at -15°C for one hour and carefully added with a saturated ammonium chloride aqueous solution and deposited insolubles were filtered off with celite. After the filtrate was extracted with ethyl acetate, the organic layer was washed with 1M hydrochloric acid, a saturated sodium bicarbonate aqueous solution, brine, and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to obtain 5-bromo-2-chlorobenzaldehyde (8.1 g, 95percent) as a pale yellow crystal. This was used in the next reaction without purification. 1.6 M n-butylithium hexane solution (26.9 mL) was added to a mixture of benzo[b]thiophene (5.8 g, 0.043 mol) and tetrahydrofuran (58 mL) at -78°C over 20 minutes. After stirred for 0.5 hours, the mixture was added with a tetrahydrofuran (50 mL) solution of 5-bromo-2-chlorobenzaldehyde (9.0 g, 0.041 mol) and stirred for further five minutes. The reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain pale yellow oily (1-benzothien-2-yl)(5-bromo-2-chlorophenyl)methanol (10.3 g, 71percent). Then, Et₃SiH (9.2 mL, 0.058 mol) and BF₃*Et₂O (3.6 mL, 0.029 mol) were added sequentially to a chloroform (110 mL) solution of (1-benzothien-2-yl)(5-bromo-2-chlorophenyl)methanol (10.2 g, 0.0288 mol) at -15°C. The reaction mixture was warmed to room temperature and stirred at the temperature for ten hours. After the reaction mixture was added with a saturated sodium bicarbonate aqueous solution, the organic phase was separated, washed with brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=60:1) to obtain a colorless oily title compound (5.5 g, 56percent). ¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 4.30 (s, 2 H) 6.98 - 7.06 (m, 1 H) 7.22 -7.37 (m, 4 H) 7.43 (d, J=2.3 Hz, 1 H) 7.64 - 7.71 (m, 1 H) 7.72 - 7.80 (m, 1 H). EI 336(M⁺), 338(M+2), 340(M+4).
65 g	With diisobutylaluminium hydride In toluene at -70 - -65℃; for 0.5 h;	Amide compound of Formula III (wherein X=bromo; 88 gms) and toluene (440ml) were added in to a round bottom flask at 25-35°C and allowed to cool to -65°C to -70°C. Diisobutyl aluminium hydride (lLt, 25percentsolution in toluene) was added to the reaction mass and stirred for 30 min at same temperature. The reaction mass was quenched with aqueous sodium potassium tartrate solution and heated the reaction mass to 25-35°C. The layers were separated and the aqueous layer was extracted with toluene then the organic layers were combined and washed with aqueous sodium chloride and dried over sodium sulphate. The organic layer was concentrated under reduced pressure at 45 °C and the obtained residue was diluted in heptane (200ml) and allowed to cool to 5-10°C. The reaction mass was stirred for l-2hrs at 5-10°C, filtered, washed with chilled heptane and dried at 30-35 °C to get the title compound. Yield: 65gms.

Reference： [1] Patent: EP1845095, 2007, A1, . Location in patent: Page/Page column 36-37
[2] Patent: US2008/27014, 2008, A1, . Location in patent: Page/Page column 40
[3] Patent: WO2018/29611, 2018, A1, . Location in patent: Page/Page column 60
[4] Patent: WO2007/136116, 2007, A2, . Location in patent: Page/Page column 91-92

7
[ 3132-99-8 ]
[ 189628-37-3 ]

Reference： [1] Journal of the American Chemical Society, 2017, vol. 139, # 2, p. 888 - 896

8
[ 21739-92-4 ]
[ 189628-37-3 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 10, p. 2468 - 2485
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 14, p. 2744 - 2748
[3] Patent: WO2018/29611, 2018, A1,
[4] Patent: CN107556276, 2018, A,
[5] Patent: WO2007/136116, 2007, A2,

9
[ 21900-52-7 ]
[ 189628-37-3 ]

Reference： [1] Patent: WO2007/136116, 2007, A2,

10
[ 189628-37-3 ]
[ 915095-89-5 ]

Reference： [1] Patent: CN107652277, 2018, A,

[ 189628-37-3 ] Synthesis Path-Downstream 1~88

1
[ 842136-59-8 ]
[ 189628-37-3 ]

Yield	Reaction Conditions	Operation in experiment
95%		Preparation Example 5 Synthesis of 2-(5-bromo-2-chlorobenzyl)-1-benzothiophene; Oxalyl chloride (3.78 mL, 0.0441 mmol) and N,N-dimethylformamide (0.06 mL) were added to a chloroform (20 mL) solution of 5-bromo-2-chlorobenzoic acid (10.0 g, 0.0425 mol). After the reaction mixture was stirred at room temperature for one day, the reaction mixture was evaporated under reduced pressure. The obtained yellow oily substance was dissolved in chloroform (20 mL). This solution was added dropwise to a mixture of N,O-dimethoxyhydroxylamine hydrochloride (4.56 g, 0.0468 mol), triethylamine (12.3 mL, 0.0882 mol) and chloroform (50 mL) for 15 minutes, while maintaining the reaction temperature at 5C to 10C. After stirred for 15 minutes, the reaction mixture was warmed to room temperature. After water (20 mL) was added to the reaction mixture, the organic layer was separated and the organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine, and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to obtain 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (11.8 g, 99.7%) as a colorless crystal. This was used in the next reaction without purification. LiAlH4(1.47 g, 0.0388 mol) was added little by little to a tetrahydrofuran (108 mL) solution of 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (10.8 g, 0.0388 mol) so that the internal temperature did not exceed -10C. The reaction mixture was stirred at -15C for one hour and carefully added with a saturated ammonium chloride aqueous solution and deposited insolubles were filtered off with celite. After the filtrate was extracted with ethyl acetate, the organic layer was washed with 1M hydrochloric acid, a saturated sodium bicarbonate aqueous solution, brine, and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to obtain 5-bromo-2-chlorobenzaldehyde (8.1 g, 95%) as a pale yellow crystal. This was used in the next reaction without purification. 1.6 M n-butylithium hexane solution (26.9 mL) was added to a mixture of benzo[b]thiophene (5.8 g, 0.043 mol) and tetrahydrofuran (58 mL) at -78C over 20 minutes. After stirred for 0.5 hours, the mixture was added with a tetrahydrofuran (50 mL) solution of 5-bromo-2-chlorobenzaldehyde (9.0 g, 0.041 mol) and stirred for further five minutes. The reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain pale yellow oily (1-benzothien-2-yl)(5-bromo-2-chlorophenyl)methanol (10.3 g, 71%). Then, Et3SiH (9.2 mL, 0.058 mol) and BF3·Et2O (3.6 mL, 0.029 mol) were added sequentially to a chloroform (110 mL) solution of (1-benzothien-2-yl)(5-bromo-2-chlorophenyl)methanol (10.2 g, 0.0288 mol) at -15C. The reaction mixture was warmed to room temperature and stirred at the temperature for ten hours. After the reaction mixture was added with a saturated sodium bicarbonate aqueous solution, the organic phase was separated, washed with brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=60:1) to obtain a colorless oily title compound (5.5 g, 56%). 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 4.30 (s, 2 H) 6.98 - 7.06 (m, 1 H) 7.22 -7.37 (m, 4 H) 7.43 (d, J=2.3 Hz, 1 H) 7.64 - 7.71 (m, 1 H) 7.72 - 7.80 (m, 1 H). EI 336(M+), 338(M+2), 340(M+4).
	With diisobutylaluminium hydride; In tetrahydrofuran; toluene; at -78 - 0℃; for 1.16667h;	A solution of the above compound in tetrahydrofuran (200 ml) was cooled to -78 C. under argon atmosphere, and thereto was added dropwise diisobutylaluminum hydride (1.0 M toluene solution, 64 ml). The mixture was stirred at -78 C. for 30 minutes and at 0 C. for 40 minutes. To the resultant mixture was added a 10% aqueous hydrochloric acid solution at 0, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1) to give 5-bromo-2-chlorobenzaldehyde (8.90 g) as a colorless solid.
65 g	With diisobutylaluminium hydride; In toluene; at -70 - -65℃; for 0.5h;	Amide compound of Formula III (wherein X=bromo; 88 gms) and toluene (440ml) were added in to a round bottom flask at 25-35C and allowed to cool to -65C to -70C. Diisobutyl aluminium hydride (lLt, 25%solution in toluene) was added to the reaction mass and stirred for 30 min at same temperature. The reaction mass was quenched with aqueous sodium potassium tartrate solution and heated the reaction mass to 25-35C. The layers were separated and the aqueous layer was extracted with toluene then the organic layers were combined and washed with aqueous sodium chloride and dried over sodium sulphate. The organic layer was concentrated under reduced pressure at 45 C and the obtained residue was diluted in heptane (200ml) and allowed to cool to 5-10C. The reaction mass was stirred for l-2hrs at 5-10C, filtered, washed with chilled heptane and dried at 30-35 C to get the title compound. Yield: 65gms.

To a suspension of 5-bromo-2-chlorobenzoic acid (18.5 g, 78.5 mmol)in chloroform (157 mL) was addedN,N-dimethyIformamide (0.5 mL) , and oxalylchloride (8.1 mL, 94.2 mmol) was added dropwise thereto at room temperature. This reaction solution was stirred for 30 minutes, and then concentrated under reduced pressure. Thus obtained residue was dissolved in chloroform(157 mL) , and added dropwise at 0C to a suspension of N,O-dimethylhydroxylamine hydrochloride (9.19 g, 94.2 mmol) and triethylamine (26.3 mL, 188 mmol) in chloroform. This reaction solution was stirred for 30 minutes at the same temperature, and then washed with water, a saturated sodium bicarbonate aqueous solution and brine. And an organic layer was dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain 24.0 g of a residue. Thus obtained residue was dissolved in tetrahydrofuran (157 mL), and lithium aluminum hydroxide (1.19 g, 29.0 mmol) was gradually added thereto at 00C. After this <n="94"/>T/JP2007/060653reaction solution was cooled to 00C, 2 M hydrochloric acid was gradually added thereto, and the mixture was stirred at room temperature for 30 minutes. The organic layer was washed with a saturated sodium bicarbonate aqueous solution and then brine, and dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure. Thus obtained residue was recrystallized from a mixed solution of ethyl acetate:hexane (1:9) to obtain the title compound (11.3 g, 65%) as colorless crystals.IH NMR (300 MHz, CHLOROFORM-D) delta ppm 7.35 (d, J=8.47 Hz, IH) 7.65 (dd, J=8.47, 2.56 Hz, IH) 8.04 (d, J=2.56 Hz, IH) 10.41 (s, IH).

Reference： [1]Patent: EP1845095,2007,A1 .Location in patent: Page/Page column 36-37
[2]Patent: US2008/27014,2008,A1 .Location in patent: Page/Page column 40
[3]Patent: WO2018/29611,2018,A1 .Location in patent: Page/Page column 60
[4]Patent: WO2007/136116,2007,A2 .Location in patent: Page/Page column 91-92

2
[ 189628-37-3 ]
[ 761425-04-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of thianaphthene (5.18 g) in tetrahydrofuran (60 ml) was added dropwise n-butyl lithium (2.44 M hexane solution, 15.8 ml) at -78 C. under argon atmosphere, and the mixture was stirred at -78 C. for 30 minutes and at 0 C. for 30 minutes. The mixture was cooled to -78 C., and thereto was added a solution of the above compound (8.90 g) in tetrahydrofuran (60 ml) in one portion. After being stirred at the same temperature for 1.5 hours, thereto was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to give benzo[b]thiophen-2-yl-(5-bromo-2-chlorophenyl)methanol (12.25 g) as a orange oil.

Reference： [1]Patent: US2008/27014,2008,A1 .Location in patent: Page/Page column 40

3
[ 189628-37-3 ]
[ 914106-40-4 ]

Reference： [1]Patent: EP1719767,2006,A1 .Location in patent: Page/Page column 24-28; 42
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

4
[ 21739-92-4 ]
[ 189628-37-3 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485
[2]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 2744 - 2748
[3]Patent: WO2018/29611,2018,A1
[4]Patent: CN107556276,2018,A
[5]Patent: WO2007/136116,2007,A2

5
[ 189628-37-3 ]
[ 914106-04-0 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

6
[ 189628-37-3 ]
[ 914106-15-3 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

7
[ 189628-37-3 ]
[ 914105-96-7 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

8
[ 189628-37-3 ]
C₁₇H₁₄ClN₅O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 2468 - 2485

9
[ 189628-37-3 ]
[ 724767-82-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3601 - 3605

10
[ 189628-37-3 ]
[ 724767-85-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3601 - 3605

11
[ 189628-37-3 ]
[5-(3-amino-3-methyl-but-1-ynyl)-2-chloro-phenyl]-[4-(2,4-difluoro-phenylamino)-phenyl]-methanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3601 - 3605

12
[ 917-54-4 ]
[ 189628-37-3 ]
[ 749932-77-2 ]

Yield	Reaction Conditions	Operation in experiment
91%	In tetrahydrofuran; at -78℃; for 15h;	Methyl lithium (11. 6mL, 16.3 mmol, 1.4M in ether) was added to a COOLED-78 C solution of 5-BROMO-2-CHLORO-BENZALDEHYDE (2. 75G, 12.5 mmol) dissolved in THF (40mL). The reaction mixture was stirred for 15 hours and then quenched with saturated NH4CI and extracted with EtOAc. The organic extracts were washed with 1 N HCI, brine, dried over NA2SO4 and concentrated to an oil. The oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a solid (2. 63G, 91%). H NMR (400 MHz, CDCI3) : 5 6.32 (d, J=6.3 Hz, 3 H), 2.00 (d, J=3.8 Hz, 1 H), 5.24 (m, 1 H), 7.19 (d, J=8.6 Hz, 1 H), 7.33 (dd, J=8.6, 2.5 Hz, 1 H), 7.75 (d, J=2.5 Hz, 1 H).
91%	In tetrahydrofuran; diethyl ether; at -78℃; for 15h;	Methyl lithium (11.6 mL, 16.3 mmol, 1.4M in ether) was added to a cooled -78 C. solution of <strong>[189628-37-3]5-bromo-2-chloro-benzaldehyde</strong> (2.75 g, 12.5 mmol) dissolved in THF (40 mL). The reaction mixture was stirred for 15 hours and then quenched with saturated NH4Cl and extracted with EtOAc. The organic extracts were washed with 1N HCl, brine, dried over Na2SO4 and concentrated to an oil. The oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a solid (2.63 g, 91%). 1H NMR (400 MHz, CDCl3): delta 6.32 (d, J=6.3 Hz, 3H), 2.00 (d, J=3.8 Hz, 1H), 5.24 (m, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.33 (dd, J=8.6, 2.5 Hz, 1H), 7.75 (d, J=2.5 Hz, 1H).

Reference： [1]Patent: WO2004/74270,2004,A2 .Location in patent: Page 364
[2]Patent: US2005/176701,2005,A1 .Location in patent: Page/Page column 178

13
[ 149965-40-2 ]
[ 189628-37-3 ]

Yield	Reaction Conditions	Operation in experiment
98%		EXAMPLE IX 5-bromo-2-chloro-benzaldehyde 7 ml dimethylsulphoxide in 25 ml dichloromethane are added dropwise to a solution of 4.4 ml oxalyl chloride in 125 ml dichloromethane cooled to -60 C. After 5 min stirring a solution of 10.0 g 5-bromo-2-chloro-benzylalcohol in 50 ml of tetrahydrofuran is added and the mixture is stirred for a further 15 min at -60 C. Then 31.5 ml triethylamine are added and the reaction solution is allowed to come up to ambient temperature in the cooling bath. At ambient temperature water is added, the organic phase is separated off and washed with 1 M hydrochloric acid. After drying through sodium sulphate the solvent is eliminated totally. Yield: 9.7 g (98% of theory) Mass spectrum (ESI+): m/z=218/220/222 (bromine+chlorine) [M+H]+
94%	With oxalyl dichloride; dimethyl sulfoxide; triethylamine; In dichloromethane; chloroform; at -78 - 20℃;	Example 2B 5-Bromo-2-chlorobenzaldehyde 18 ml (0.26 mol) of DMSO are introduced into 64 ml of dichloromethane and, at -78 C., 16.1 g (0.127 mol, 11.1 ml) of oxalyl chloride are added. After 30 min, a solution of 13.1 g (59 mmol) of (5-bromo-2-chlorophenyl)methanol in 100 ml of chloroform is added dropwise. After 20 min, 40 ml of triethylamine are added and the reaction mixture is slowly warmed to RT. After the addition of 50 ml of water the mixture is extracted several times with ethyl acetate. The combined organic phases are washed successively with 2N hydrochloric acid, water, a saturated sodium bicarbonate solution and a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated in vacuo. The resulting solid is dried Yunder high vacuum to constant weight. Yield: 12.7 g (94% of theory) HPLC (method 11): Rt=4.65 min MS (EI): m/z=218 (M)+1H-NMR (300 MHz, CDCl3): delta=7.32 (d, 1H), 7.65 (dd, 1H), 8.03 (d, 1H), 10.4 (s, 1H).
90%	With pyridinium chlorochromate; In dichloromethane; at 0℃;	60 g PCC and 60 g silica gel powder were added to a round bottom flask; after mixing, 500 mL dichloromethane was added; cooled to 0 C., and 45 g of compound 1-1 in dichloromethane (300 mL) was added dropwise with stirring; maintaining 0 C.The reaction was monitored by TLC; after the reaction was completed, the reaction solution was spin-dried; 38 g of Compound 1-2 was isolated by column separation, and the yield in two steps was 90%.

89%	With pyridinium chlorochromate; In dichloromethane;	Step 1: 5-Bromo-2-chlorobenzaldehyde. To a suspension of 5.23 g (23.6 mmol) of 5-bromo-2-chlorobenzyl alcohol in 50 ml of CH2Cl2 at 0 C., 8.36 g (38.7 mmol) of pyridinium chlorochromate was added. The reaction mixture was stirred at room temperature for 3 hours at which time the reaction was complete. The mixture was filtered, washed with EtOAc, dried (MgSO4), filtered, and concentrated. Flash column chromatography (10% EtOAc/hexane) yielded a pale yellow solid (4.62 g, 89%): m.p. 56-58 C.: Rf 0.73 (20% EtOAc/hexane). 1H NMR (400 MHz, CDCl3) delta7.34 (d, J=8.4 Hz, 1, ArH), 7.65 (dd, J=8.4, 2.4 Hz, 1, ArH), 8.04 (d, J=2.4 Hz, 1, ArH), 10.41 ppm (s, 1, CHO).
86%		Pyridinium dichromate (3.82 g, 10.2 mmol) was added to a solution of 5-bromo-2- chlorobenzylalcohol (1.5g, 6.8 mmol) in CH2CI2 (30 mL). The reaction was stirred for 5 hours and then celite was added. The mixture was stirred for 20 mins and then filtered through a pad of celite washing with ether. The filtrate was concentrated to a brown oil. The residue was purified by flash silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a clear oil (1.28g, 86%).'H NMR (400 MHz, CDCI3) : 5 7.35 (d, J=8.6 Hz, 1 H), 7.65 (dd, J=8.3, 2.5 Hz, 1 H), 8.04 (d, J=2.5 Hz, 1 H), 10.41 (s, 1 H).
86%	With pyridinium dichromate; In dichloromethane; for 5h;	Pyridinium dichromate (3.82 g, 10.2 mmol) was added to a solution of 5-bromo-2-chlorobenzylalcohol (1.5 g, 6.8 mmol) in CH2Cl2 (30 mL). The reaction was stirred for 5 hours and then celite was added. The mixture was stirred for 20 mins and then filtered through a pad of celite washing with ether. The filtrate was concentrated to a brown oil. The residue was purified by flash silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a clear oil (1.28 g, 86%). 1H NMR (400 MHz, CDCl3): delta 7.35 (d, J=8.6 Hz, 1H), 7.65 (dd, J=8.3, 2.5 Hz, 1H), 8.04 (d, J=2.5 Hz, 1H), 10.41 (s, 1H).
	With Dess-Martin periodane; In dichloromethane; at 0 - 20℃; for 2h;	General procedure: . To a solution of the benzyl alcohol in DCM (400mL) was added Dess-Martinperiodinane (216g, 510mmol) at 0oC,the mixture was allowed to warm to room temperature and stirred for 2h. Thereaction mixture was cooled to 0oC. Saturated NaHCO3 solution was added slowly to quench the reaction and stirred until it no gasgenerated. The reaction mixture washed with brine. The organic layer was driedover Na2SO4, filtered and evaporated in vacuo. The cruderesidue was purified by column chromatography on silica gel (hexane) to yield the title compound.

Reference： [1]Patent: US2006/25349,2006,A1 .Location in patent: Page/Page column 20
[2]Patent: US2007/99885,2007,A1 .Location in patent: Page/Page column 13-14
[3]Patent: CN107556276,2018,A .Location in patent: Paragraph 0068; 0072-0073
[4]Patent: US2003/176506,2003,A1
[5]Patent: WO2004/74270,2004,A2 .Location in patent: Page 364
[6]Patent: US2005/176701,2005,A1 .Location in patent: Page/Page column 178
[7]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 2744 - 2748

14
[ 189628-37-3 ]
[ 540778-90-3 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In tetrahydrofuran;	Step 2: Ethyl (E)-5-bromo-2-chlorocinnamate. To a suspension of 4.60 g (20.9 mmol) of <strong>[189628-37-3]5-bromo-2-chlorobenzaldehyde</strong> and 11.47 g (82.9 mmol) of K2CO3 in 100 ml of anhydrous THF under Ar, 14.0 ml (70.6 mmol) of triethyl phosphonoacetate was added. The reaction mixture was stirred at room temperature for 4 days at which time the reaction was complete. The mixture was extracted with EtOAc, washed with brine and water, dried (MgSO4), filtered, and concentrated. Flash column chromatography (10% EtOAc/hexane) yielded a white solid (5.62 g, 93%): m.p. 42-44 C.: Rf 0.68 (20% EtOAc/hexane). 1H NMR (400 MHz, CDCl3) 6 1.34 (t, J=6.8 Hz, 3, CH3), 4.28 (q, J=7.2 Hz, 2, CH2), 6.42 (d, J=16.0 Hz, 1, HC=CCO), 7.28 (d, J=8.4 Hz, 1, ArH), 7.42 (dd, J=8.4, 2.4 Hz, 1, ArH), 7.74 (d, J=2.8 Hz, 1, ArH), 7.98 ppm (d, J=16.0 Hz, 1, C=CHCO),.

Reference： [1]Patent: US2003/176506,2003,A1

15
[ 637-81-0 ]
[ 189628-37-3 ]
[ 1073494-42-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium ethanolate; In tetrahydrofuran; ethanol; at -10 - 10℃; for 6h;	To a solution of sodium ethoxide in ethanol (15 mL) cooled to -10 0C was added dropwise a solution of 5-bromo-2- chlorobenzaldehyde (1.0 g) and ethyl 2-azidoacetate (11 mL, 18 mmol) in ethanol-tetrahydrofuran (15 mL-3 mL). The reaction mixture was stirred at -10 0C for 3 hours, allowed to warm to 10 0C over 3 hours and poured onto crushed ice. The solid was collected by filtration and dried in a vacuum oven to provide the title compound.

Reference： [1]Patent: WO2008/131000,2008,A2 .Location in patent: Page/Page column 168

16
[ 7333-51-9 ]
[ 189628-37-3 ]
[ 874650-46-1 ]

Yield	Reaction Conditions	Operation in experiment
34%		EXAMPLE X 1-bromo-4-chloro-3-cyclohexylidenemethyl-benzene 3.55 ml of a 1.9 M solution phenyllithium in diethyl ether/cyclohexane (70/30) are added dropwise to an ice-cooled solution of 2.9 g cyclohexyl-triphenylphosphonium bromide in 5 ml of tetrahydrofuran. The solution is stirred for 1 h in the ice bath. Then a solution of 1.5 g <strong>[189628-37-3]5-bromo-2-chloro-benzaldehyde</strong> in 5 ml of tetrahydrofuran is added and the reaction solution is stirred for 4 h at ambient temperature. Then water is added, the mixture is extracted with ethyl acetate and the organic phase is dried over sodium sulphate. After the solvent has been eliminated the residue is purified on silica gel (cyclohexane/ethyl acetate 1:1). Yield: 0.66 g (34% of theory) Mass spectrum (ESI+): m/z=284/286/288 (bromine+chlorine) [M]+

Reference： [1]Patent: US2006/25349,2006,A1 .Location in patent: Page/Page column 20

17
[ 95-15-8 ]
[ 189628-37-3 ]
[ 761425-04-1 ]

Yield	Reaction Conditions	Operation in experiment
71%		Preparation Example 5 Synthesis of 2-(5-bromo-2-chlorobenzyl)-1-benzothiophene; Oxalyl chloride (3.78 mL, 0.0441 mmol) and N,N-dimethylformamide (0.06 mL) were added to a chloroform (20 mL) solution of 5-bromo-2-chlorobenzoic acid (10.0 g, 0.0425 mol). After the reaction mixture was stirred at room temperature for one day, the reaction mixture was evaporated under reduced pressure. The obtained yellow oily substance was dissolved in chloroform (20 mL). This solution was added dropwise to a mixture of N,O-dimethoxyhydroxylamine hydrochloride (4.56 g, 0.0468 mol), triethylamine (12.3 mL, 0.0882 mol) and chloroform (50 mL) for 15 minutes, while maintaining the reaction temperature at 5C to 10C. After stirred for 15 minutes, the reaction mixture was warmed to room temperature. After water (20 mL) was added to the reaction mixture, the organic layer was separated and the organic layer was washed with a saturated sodium bicarbonate aqueous solution and brine, and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to obtain 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (11.8 g, 99.7%) as a colorless crystal. This was used in the next reaction without purification. LiAlH4(1.47 g, 0.0388 mol) was added little by little to a tetrahydrofuran (108 mL) solution of 5-bromo-2-chloro-N-methoxy-N-methylbenzamide (10.8 g, 0.0388 mol) so that the internal temperature did not exceed -10C. The reaction mixture was stirred at -15C for one hour and carefully added with a saturated ammonium chloride aqueous solution and deposited insolubles were filtered off with celite. After the filtrate was extracted with ethyl acetate, the organic layer was washed with 1M hydrochloric acid, a saturated sodium bicarbonate aqueous solution, brine, and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to obtain <strong>[189628-37-3]5-bromo-2-chlorobenzaldehyde</strong> (8.1 g, 95%) as a pale yellow crystal. This was used in the next reaction without purification. 1.6 M n-butylithium hexane solution (26.9 mL) was added to a mixture of benzo[b]thiophene (5.8 g, 0.043 mol) and tetrahydrofuran (58 mL) at -78C over 20 minutes. After stirred for 0.5 hours, the mixture was added with a tetrahydrofuran (50 mL) solution of <strong>[189628-37-3]5-bromo-2-chlorobenzaldehyde</strong> (9.0 g, 0.041 mol) and stirred for further five minutes. The reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain pale yellow oily (1-benzothien-2-yl)(5-bromo-2-chlorophenyl)methanol (10.3 g, 71%). Then, Et3SiH (9.2 mL, 0.058 mol) and BF3·Et2O (3.6 mL, 0.029 mol) were added sequentially to a chloroform (110 mL) solution of (1-benzothien-2-yl)(5-bromo-2-chlorophenyl)methanol (10.2 g, 0.0288 mol) at -15C. The reaction mixture was warmed to room temperature and stirred at the temperature for ten hours. After the reaction mixture was added with a saturated sodium bicarbonate aqueous solution, the organic phase was separated, washed with brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=60:1) to obtain a colorless oily title compound (5.5 g, 56%). 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 4.30 (s, 2 H) 6.98 - 7.06 (m, 1 H) 7.22 -7.37 (m, 4 H) 7.43 (d, J=2.3 Hz, 1 H) 7.64 - 7.71 (m, 1 H) 7.72 - 7.80 (m, 1 H). EI 336(M+), 338(M+2), 340(M+4).
		General procedure: To a cold (-78 C) solution of 50 (16.6 g, 124 mmol) in THF (200 mL) was added n-BuLi (1.60 M in hexane; 78.5 mL, 124 mmol) and the mixture was stirred at -78 C for 1.5 h. To the reaction mixture was added a solution of 64 (29.0 g, 118 mmol) in THF (300 mL) and the mixture was stirred at -78 C for 2 h. To the reaction mixture was added H2O and Et2O and the organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (EtOAc-hexane) to give alcohol as a pale yellow oil. To a cold (-20 C) solution of this oil (43.3 g, 114 mmol) in CH2Cl2 (800 mL) was added Et3SiH (36.5 mL, 229 mmol) and BF3·OEt2 (15.2 mL, 120 mmol) and the mixture was stirred at -20 C for 30 min. To the reaction mixture was added saturated aqueous sodium bicarbonate solution and the organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (EtOAc-hexane) to give the title compound (66) (35.6 g, 86%) as a pale yellow oil.

Reference： [1]Patent: EP1845095,2007,A1 .Location in patent: Page/Page column 36-37
[2]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 3263 - 3279

18
[ 1291094-47-7 ]
[ 189628-37-3 ]
[ 1291094-48-8 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of 4-benzyl-6-bromo-spiro[3H-1 ,4-benzoxazine-2,1'- cyclopropane] (1.12 g, 3.4 mmol) in THF (10 mL) was added 1.6 M solution of n-BuLi in hexanes (2.12 mL, 3.4 mmol) at -78 C. The reaction mixture was stirred for 30 min, and then transferred to a stirred solution of <strong>[189628-37-3]5-bromo-2-chlorobenzaldehyde</strong> (745 mg, 3.4 mmol) in THF (10 mL) at -78 C. After stirring for 1 h, the reaction was quenched by the addition of saturated ammonium chloride solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine, dried over sodium sulphate, and concentrated. The resulting residue was purified by silica gel column chromatography to furnish (4-benzylspiro[3H-1 ,4-benzoxazine-2,1'-cyclopropane]-6-yl)-(5-bromo-2- chloro-phenyl)methanol (790 mg).MS {ES) m/z 470.0 (M+1).

Reference： [1]Patent: WO2011/48112,2011,A1 .Location in patent: Page/Page column 119; 121

19
[ 1290629-66-1 ]
[ 189628-37-3 ]
[ 1291093-98-5 ]

Yield	Reaction Conditions	Operation in experiment
		To a cooled solution of 6-bromo-1-(4-methoxy-benzyl)-1 ,2,3,4-tetrahydro- quinoline (2,5 g, 7.5 mmol) in THF (30 mL) was added 1.6 M n-butyl lithium in hexanes (4.7 mL, 7.5 mmol) at -78 C, stirred for 30 min. This was transferred to a stirred solution of <strong>[189628-37-3]5-bromo-2-chlorobenzaldehyde</strong> (1.73 g, 7.9 mmol) in THF (30 mL) at -78 C. After stirring for 30 min, reaction was quenched by the addition of saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (2X50 mL). The ethyl acetate layer was washed with water, brine, dried over sodium sulphate, and concentrated. The resulting residue was purified by silica gel column chromatography to give (5-bromo-2-chloro-phenyl)-[1-(4-methoxy-benzyl)-1 ,2,3,4-tetrahydro-quinolin-6- yl]-methanol (2.31 g).1H NMR (400 MHz, CDCI3): delta 1.95-2.10 (m, 3H), 2.77 (t, J = 6.4 Hz, 2H), 3.33 (t, J = 5.6 Hz, 2H), 3.78 (s, 3H), 4.39 (s, 2H), 5.96 (d, J = 3.6 Hz, 1 H), 6.46 (d, J = 8.0 Hz, 1 H), 6.84 (d, J = 7.6 Hz, 2H), 6.91-7.91 (m, 7H). MS (ES) m/z 474.1 (M+2).
		Step I: To a cooled solution of 6-bromo-1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinoline (2.5 g, 7.5 mmol) in THF (30 mL) was added 1.6 M n-butyl lithium in hexanes (4.7 mL, 7.5 mmol) at -78 C., stirred for 30 min. This was transferred to a stirred solution of <strong>[189628-37-3]5-bromo-2-chlorobenzaldehyde</strong> (1.73 g, 7.9 mmol) in THF (30 mL) at -78 C. After stirring for 30 min, reaction was quenched by the addition of saturated aqueous solution of ammonium chloride and extracted with ethyl acetate (2*50 mL). The ethyl acetate layer was washed with water, brine, dried over sodium sulphate, and concentrated. The resulting residue was purified by silica gel column chromatography to give (5-bromo-2-chloro-phenyl)-[1-(4-methoxy-benzyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-methanol (2.31 g). 1H NMR (400 MHz, CDCl3): delta 1.95-2.10 (m, 3H), 2.77 (t, J=6.4 Hz, 2H), 3.33 (t, J=5.6 Hz, 2H), 3.78 (s, 3H), 4.39 (s, 2H), 5.96 (d, J=3.6 Hz, 1H), 6.46 (d, J=8.0 Hz, 1H), 6.84 (d, J=7.6 Hz, 2H), 6.91-7.91 (m, 7H). MS (ES) m/z 474.1 (M+2).

Reference： [1]Patent: WO2011/48112,2011,A1 .Location in patent: Page/Page column 97
[2]Patent: US2011/171159,2011,A1 .Location in patent: Page/Page column 43-44

20
[ 98-80-6 ]
[ 189628-37-3 ]
[ 1159512-12-5 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In tetrahydrofuran; water; for 5h;Reflux;	After 5-bromo-2-chloi'obenzaldehyde (2.19 g, 10.0 mmol) and phenylboronic acid (1.22 g, 10.0 mmol) were completely dissolved in tetrahydrofuran (50 mL), 2M potassium carbonate aqueous solution (30 mL) was added thereto, and tetrakistriphenylphosphino palladium (231 mg, 2 mol%) was put thereinto, agitated and refluxed for 5 hours. After the reaction was finished, the temperature was cooled to normal temperature, and the produced solid was filtered. The filtered solid was dissolved in chloroform, dried with anhydrous magnesium sulfate, concentrated under the reduced pressure, and recrystallized with chloroform and hexane to prepare the compound C-7 (1.73 g, 80%). MS: [M]+=216

Reference： [1]Patent: EP2311826,2011,A2 .Location in patent: Page/Page column 103

21
[ 189628-37-3 ]
[ 1291093-99-6 ]

Reference： [1]Patent: US2011/171159,2011,A1

22
[ 189628-37-3 ]
[ 1291094-00-2 ]

Reference： [1]Patent: US2011/171159,2011,A1

23
[ 189628-37-3 ]
[ 1291094-01-3 ]

Reference： [1]Patent: US2011/171159,2011,A1

24
[ 189628-37-3 ]
[ 1291094-02-4 ]

Reference： [1]Patent: US2011/171159,2011,A1

25
[ 790-04-5 ]
[ 189628-37-3 ]
5-(2-chloro-5-bromobenzylidene)-3-phenyl-2-(phenylimino)thiazolidin-4-one [ No CAS ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 704 - 708

26
[ 790-04-5 ]
[ 189628-37-3 ]
[ 1370366-63-4 ]

Reference： [1]Letters in drug design and discovery,2011,vol. 8,p. 704 - 708

27
[ 189628-37-3 ]
[ 898538-19-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 3263 - 3279

28
[ 189628-37-3 ]
(1S)-1,5-anhydro-1-[3-(1-benzothiophen-2-ylmethyl)-4-chlorophenyl]-2,3,4,6-tetra-O-benzyl-D-glucitol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 3263 - 3279

29
[ 189628-37-3 ]
(1S)-1,5-anhydro-1-[3-(1-benzothiophen-2-ylmethyl)-4-chlorophenyl]-D-glucitol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 3263 - 3279

30
[ 94-09-7 ]
[ 115-11-7 ]
[ 189628-37-3 ]
2-(5-bromo-2-chloro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With ytterbium(III) triflate; In acetonitrile; at 85℃; for 16h;sealed tube;	To a stirred solution of 4-amino-benzoic acid methyl ester (8.25 g, 50 mmol) and <strong>[189628-37-3]5-bromo-2-chloro-benzaldehyde</strong> (13.2 g, 60 mmol) in acetonitrile (200 mL) were added isobutene (14 mL, 0.2 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (4.65 g, 7.5 mmol). The resulting mixture was stirred at 85 C. for 16 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10-50% ethyl acetate in petroleum ether) to afford 2-(5-bromo-2-chloro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (6.99 g, 33%) as a light yellow solid: MS (ESI) M+1=422.0.
33%	ytterbium(III) triflate; In acetonitrile; at 85℃; for 16h;Sealed tube;	Example 23N-[2-(2-chloro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carbonyl] -methanesulfonamideTo a stirred solution of 4-amino-benzoic acid methyl ester (8.25 g, 50 mmol) and 5-bromo- 2-chloro-benzaldehyde (13.2 g, 60 mmol) in acetonitrile (200 mL) were added isobutene (14 mL, 0.2 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (4.65 g, 7.5 mmol). The resulting mixture was stirred at 85 C for 16 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL x 2) and brine (100 mL x 2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 10 - 50% ethyl acetate in petroleum ether) to afford 2-(5-bromo-2-chloro-phenyl)-4,4-dimethyl- l,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (6.99 g, 33%) as a light yellow solid: MS(ESI) M+l = 422.0.A mixture solution of 2-(5-bromo-2-chloro-phenyl)-4,4-dimethyl- 1,2,3, 4-tetrahydro- quinoline-6-carboxylic acid methyl ester (3 g, 7 mmol), morpholine (6.2 mL, 71 mmol), copper(I) iodide (0.8 g, 4.2 mmol), N,N-dimethylglycine hydrochloride (0.78 g, 5.6 mmol), and potassium carbonate (2.9 g, 21 mmol) in dimethyl sulfoxide (25 mL) was stirred at 120C for 16 h. Then the reaction mixture was cooled to room temperature. The reaction mixture was extracted with ethyl acetate (200 mL x 2), washed with saturated aqueous ammonium chloride solution (50 mL x 3) and brine (50 mL x 2), dried over anhydrous sodium sulfate and then concentrated in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30 - 50% ethyl acetate in petroleum ether) to afford 2-(2-chloro-5-morpholin-4-yl-phenyl)-4,4-dimethyl- 1,2,3, 4-tetrahydro-quinoline- 6-carboxylic acid ethyl ester (2.8 g, 93%) as a white solid: MS(ESI) M+l = 429.1.To a stirred mixture solution of 2-(2-chloro-5-morpholin-4-yl-phenyl)-4,4-dimethyl- l,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.8 g, 6.5 mmol) in methanol (50 mL) and tetrahydrofuran (50 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60C for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (100 mL x 2), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(2-chloro-5-morpholin-4-yl-phenyl)-4,4-dimethyl- 1 ,2,3, 4-tetrahydro-quinoline-6- carboxylic acid (2.4 g, 92%) as a light white solid which was used for next step without further purification: MS(ESI) M+l = 401.1.To a suspension of 60% sodium hydride (650 mg, 16 mmol) in N,N-dimethylformamide (5 mL) was added methanesulfonamide (1.53 g, 16 mmol) at room temperature. The resulting mixture was stirred at 25C for 1 h to afford Solution A23. A solution of 2-(2-chloro-5- morpholin-4-yl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (900 mg, 2.3 mmol) and Iota, Gamma-carbonyldiimidazole (730 mg, 4.5 mmol) in N,N- dimethylformamide (3 mL) was stirred at 70C for 1 h and cooled to room temperature to afford Solution B23. Solution B23 was added to Solution A23 and the resulting mixture was stirred at 25C for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[2-(2-chloro-5-morpholin-4-yl-phenyl)-4,4-dimethyl- 1, 2,3, 4-tetrahydro-quinoline-6-carbonyl] -methanesulfonamide (190 mg, 17%) as a white solid: MS(ESI) M+l = 478.0.

Reference： [1]Patent: US2012/190677,2012,A1 .Location in patent: Page/Page column 28
[2]Patent: WO2012/101068,2012,A1 .Location in patent: Page/Page column 74-76

31
[ 189628-37-3 ]
[ 1391609-24-7 ]

Reference： [1]Patent: US2012/190677,2012,A1
[2]Patent: WO2012/101068,2012,A1

32
[ 189628-37-3 ]
[ 1391609-29-2 ]

Reference： [1]Patent: US2012/190677,2012,A1
[2]Patent: WO2012/101068,2012,A1

33
[ 189628-37-3 ]
[ 1391609-30-5 ]

Reference： [1]Patent: US2012/190677,2012,A1

34
[ 189628-37-3 ]
[ 1391609-37-2 ]

Reference： [1]Patent: US2012/190677,2012,A1

35
[ 189628-37-3 ]
[ 1391609-26-9 ]

Reference： [1]Patent: US2012/190677,2012,A1
[2]Patent: WO2012/101068,2012,A1

36
[ 189628-37-3 ]
[ 1391609-27-0 ]

Reference： [1]Patent: US2012/190677,2012,A1
[2]Patent: WO2012/101068,2012,A1

37
[ 189628-37-3 ]
[ 1391609-31-6 ]

Reference： [1]Patent: US2012/190677,2012,A1

38
[ 189628-37-3 ]
[ 1391609-32-7 ]

Reference： [1]Patent: US2012/190677,2012,A1

39
[ 74990-30-0 ]
[ 189628-37-3 ]
[ 1450738-15-4 ]
[ 1450738-16-5 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of 21 (3.0g, 20mmol) in tetrahydrofuran (200mL) was added a solution of n-butyllithium (1.58N n-hexane solution, 12.6mL, 19.9mmol) at -78C dropwise over a period of 10min under argon atmosphere, and the mixture was stirred at the same temperature for 1h. To the mixture was added dropwise a solution of <strong>[189628-37-3]5-bromo-2-chlorobenzaldehyde</strong> (4.37g, 19.9mmol) in tetrahydrofuran (15mL). The resultant mixture was stirred at the same temperature for 30min. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (300mL), and extracted with ethyl acetate (200mL) twice. The organic layer was washed with brine (100mL), dried over sodium sulfate prior to filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (10-40% ethyl acetate in n-hexane) to give an inseparable 3:2 mixture of 22 and 23 (5.55g) as a pale yellow oil which was taken onto the next step. The obtained pale yellow oil (5.04g, 19.6mmol) was treated with dichloromethane (100mL), and cooled to 0C. To the mixture was added triethylsilane (6.50mL, 40.8mmol), followed by boron trifluoride diethyletherate dropwise over a period of 5min. The resultant mixture was allowed to warm to room temperature, and stirred for 3h, and quenched with saturated aqueous sodium hydrogen carbonate solution at 0C. The mixture was extracted with dichloromethane (80mL) twice, and the combined organic layers were washed with water (50mL), dried over sodium sulfate prior to filtration. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (0-40% ethyl acetate in n-hexane) to give titled compound 24 (1.85g, 29% in 2 steps) as a colorless solid.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5561 - 5572

40
[ 74990-30-0 ]
[ 189628-37-3 ]
[ 866607-08-1 ]

Yield	Reaction Conditions	Operation in experiment
29%		To a stirred solution of 21 (3.0g, 20mmol) in tetrahydrofuran (200mL) was added a solution of n-butyllithium (1.58N n-hexane solution, 12.6mL, 19.9mmol) at -78C dropwise over a period of 10min under argon atmosphere, and the mixture was stirred at the same temperature for 1h. To the mixture was added dropwise a solution of <strong>[189628-37-3]5-bromo-2-chlorobenzaldehyde</strong> (4.37g, 19.9mmol) in tetrahydrofuran (15mL). The resultant mixture was stirred at the same temperature for 30min. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (300mL), and extracted with ethyl acetate (200mL) twice. The organic layer was washed with brine (100mL), dried over sodium sulfate prior to filtration, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (10-40% ethyl acetate in n-hexane) to give an inseparable 3:2 mixture of 22 and 23 (5.55g) as a pale yellow oil which was taken onto the next step. The obtained pale yellow oil (5.04g, 19.6mmol) was treated with dichloromethane (100mL), and cooled to 0C. To the mixture was added triethylsilane (6.50mL, 40.8mmol), followed by boron trifluoride diethyletherate dropwise over a period of 5min. The resultant mixture was allowed to warm to room temperature, and stirred for 3h, and quenched with saturated aqueous sodium hydrogen carbonate solution at 0C. The mixture was extracted with dichloromethane (80mL) twice, and the combined organic layers were washed with water (50mL), dried over sodium sulfate prior to filtration. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (0-40% ethyl acetate in n-hexane) to give titled compound 24 (1.85g, 29% in 2 steps) as a colorless solid. 1H NMR (CDCl3) delta: 4.21 (s, 2H), 6.50 (t, J=2.3Hz, 1H), 6.81 (d, J=3.9Hz, 1H), 7.12, (d, J=3.9Hz, 1H), 7.44 (d, J=8.5Hz, 1H), 7.51 (dd, J=8.5, 2.4Hz, 1H), 7.64 (d, J=2.3Hz, 1H), 7.69 (d, J=2.3Hz, 1H), 8.33 (d, J=2.4Hz, 1H). Mass (APCI) m/z: 353/355/357 (M+H). HPLC: 99.8% (tR=3.2min, Sumipax ODS D-210SLP 4.6×50mm, 0.05% TFA in CH3CN/H2O (70/30), 1mL/min of flow rate). Anal. Calcd for C14H10BrClN2S: C, 47.55; H, 2.85; Br, 22.59; Cl, 10.02; N, 7.92; S, 9.07. Found: C, 47.39; H, 2.72; Br, 22.01; Cl, 9.97; N, 7.84; S, 8.90.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 5561 - 5572

41
[ 3558-24-5 ]
[ 126-81-8 ]
[ 189628-37-3 ]
[ 1609076-33-6 ]

Reference： [1]Advanced Synthesis and Catalysis,2014,vol. 356,p. 537 - 556

42
[ 41842-30-2 ]
[ 189628-37-3 ]
[ 1280647-32-6 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 66 - 81

43
[ 189628-37-3 ]
[ 1298086-15-3 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 66 - 81

44
[ 189628-37-3 ]
[ 1520113-11-4 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 66 - 81

45
[ 189628-37-3 ]
[ 1520113-13-6 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 66 - 81

46
[ 189628-37-3 ]
[ 1520113-15-8 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 66 - 81

47
[ 189628-37-3 ]
[ 1520113-17-0 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 66 - 81

48
[ 189628-37-3 ]
(2R,3S,4S)-2,3,4-tris(benzyloxy)-1-(3-((benzyloxy)(4-ethoxyphenyl)methyl)-4-chlorophenyl)-4-(4-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-butan-1-one [ No CAS ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 66 - 81

49
[ 61-82-5 ]
[ 189628-37-3 ]
[ 1614258-15-9 ]

Yield	Reaction Conditions	Operation in experiment
42%	With sodium hydroxide; In N,N-dimethyl-formamide; at 100℃; for 2h;Molecular sieve;	General procedure: A mixture of 1H-1,2,4-triazol-5-amine 3 (1.0mmol), 2-fluorobenzaldehyde 4a (1.2mmol) and Cs2CO3 (3.0mmol) in DMF (10mL) was heated to 100C, and TLC monitored the reaction. Then the mixture was cooled to room temperature and diluted with brine (60mL) and extracted with dichloromethane twice (2×30mL). The combined organic layers were dried with MgSO4 and the solvent was removed in vacuo to afford a residue. The residue was purified by column chromatography (silica gel, hexane/EtOAc=1:5) to afford 5a.

Reference： [1]Tetrahedron,2014,vol. 70,p. 4657 - 4660

50
[ 934-32-7 ]
[ 189628-37-3 ]
[ 1615711-93-7 ]

Reference： [1]ACS Combinatorial Science,2014,vol. 16,p. 328 - 332

51
[ 141-84-4 ]
[ 189628-37-3 ]
5-(5-bromo-2-chlorobenzylidene)-2-thioxothiazolidin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium hydroxide; In ethanol;Reflux;	General procedure: The 2-thioxo-4-thiazolidinone (1mmol), benzaldehydes (1 mmol) and NaOH (1.0 mmol) were added to ethanol withtotal volume of 15 mL. The reaction mixture was heated to reflux and stirredfor 2-24 h. After cooling to room temperature, the mixture was concentrated under reduced pressure, neutralized to pH 7.0 with dilute hydrochloric, and then extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated. The resulting residue was recrystallization from ethanol.

Reference： [1]Chinese Chemical Letters,2015,vol. 26,p. 63 - 68

52
[ 92-66-0 ]
[ 189628-37-3 ]
[1,1'-biphenyl]-4-yl(5-bromo-2-chlorophenyl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a cold (-78 oC) solution of 4-bromo-4'-methylbiphenyl 14d (2.5g, 10mmol) in THF (25mL) was added n-BuLi (2.5M in hexane; 4 mL, 10 mmol) and the mixture was stirredat -78 oC for 1 h. To the reaction mixture was added a solution of 10c(2.34 g, 11mmol) in THF (20 mL) and the mixture was stirred at -78 oCfor 3h. To the reaction mixture was added saturated ammonium chloride solutionand EtOAc, then the organic layer was separated and washed with brine, driedover Na2SO4, filtered and evaporated in vacuo. Theresulting residue was purified by column chromatography on silica gel(EtOAc/petroleum ether = 1:10) to give the title compound.