[ CAS No. 114772-40-6 ]

Name: 114772-40-6|2-Boc-4'-(Bromomethyl)biphenyl|97%
Brand: Ambeed
SKU: A245097
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Quality Control of [ 114772-40-6 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 114772-40-6 ]

SDS Specification

Alternatived Products of [ 114772-40-6 ]

Product Details of [ 114772-40-6 ]

CAS No. :	114772-40-6	MDL No. :	MFCD06657561
Formula :	C₁₈H₁₉BrO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	YHXCWNQNVMAENQ-UHFFFAOYSA-N
M.W :	347.25	Pubchem ID :	9906257
Synonyms :

Calculated chemistry of [ 114772-40-6 ]

Physicochemical Properties

Num. heavy atoms :	21
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.28
Num. rotatable bonds :	5
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	90.45
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.04 cm/s

Lipophilicity

Log Po/w (iLOGP) :	3.54
Log Po/w (XLOGP3) :	4.76
Log Po/w (WLOGP) :	5.05
Log Po/w (MLOGP) :	4.75
Log Po/w (SILICOS-IT) :	5.27
Consensus Log Po/w :	4.67

Druglikeness

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

Water Solubility

Log S (ESOL) :	-5.08
Solubility :	0.00286 mg/ml ; 0.00000823 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.04
Solubility :	0.00315 mg/ml ; 0.00000906 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-7.03
Solubility :	0.0000322 mg/ml ; 0.0000000927 mol/l
Class :	Poorly soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.68

Safety of [ 114772-40-6 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P501-P260-P270-P271-P264-P280-P362+P364-P303+P361+P353-P301+P330+P331-P301+P312+P330-P304+P340+P310-P305+P351+P338+P310-P405	UN#:	3261
Hazard Statements:	H302+H312+H332-H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 114772-40-6 ]

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

Upstream synthesis route of [ 114772-40-6 ]
Downstream synthetic route of [ 114772-40-6 ]

[ 114772-40-6 ] Synthesis Path-Upstream 1~20

1
[ 114772-36-0 ]
[ 114772-40-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With azobisisobutyronitrile; sodium acetate In acetic acid methyl ester; water; isopropyl alcohol; acetone	EXAMPLE 4 268.0 kg of tert-butyl 4-methylbiphenyl-2'-carboxylate, 157.3 kg of DDH, 1.6 kg of AIBN, and 572 liters of methyl acetate are placed in a 1200-liter enamel stirring apparatus and the mixture is heated to 60° C. to 65° C. As soon as the solution has become practically colorless, 458 liters of solvent are distilled off under normal pressure and then 530 liters of isopropanol, 148 liters of water, and 16.4 kg of sodium acetate (anhydrous) are added. The resulting mixture is cooled to 15° C. to 25° C. and stirred for a further 1 hour. The product precipitated is separated by centrifugation, washed with a mixture of 530 liters of acetone and 148 liters of water, and dried. Yield: 295 kg of tert-butyl 4-bromomethylbiphenyl-2'-carboxylate (85percent of theory).
80%	With N-Bromosuccinimide; azobisisobutyronitrile; sodium acetate In acetic acid methyl ester; water; isopropyl alcohol	EXAMPLE 1 241.2 kg of tert-butyl 4-methylbiphenyl-2'-carboxylate, 168.2 kg of NBS, 0.3 kg of AIBN, and 724 liters of methyl acetate are placed in a 1200-liter enamel stirring apparatus and the mixture is heated to 60° C. to 65° C. The reaction mixture begins to boil and after about 80percent of the reaction time the NBS goes into solution. As soon as the solution has become practically colorless, 603 liters of solvent are distilled off under normal pressure, and then 482 liters of isopropanol, 121 liters of water, and 14.8 kg of sodium acetate (anhydrous) are added. The resulting mixture is cooled to 15° C. to 25° C. and stirred for a further 1 hour. The product precipitated is separated by centrifugation, washed with a mixture of 482 liters of isopropanol and 121 liters of water, and dried. Yield: 250 kg of tert-butyl 4-bromomethylbiphenyl-2'-carboxylate (80percent of theory).
80%	With N-Bromosuccinimide; azobisisobutyronitrile; sodium acetate In acetic acid methyl ester; water; acetone	EXAMPLE 2 241.2 kg of tert-butyl 4-methylbiphenyl-2'-carboxylate, 168.2 kg of NBS, 0.3 kg of AIBN, and 724 liters of methyl acetate are placed in a 1200-liter enamel stirring apparatus and the mixture is heated to 60° C. to 65° C. The reaction mixture begins to boil and after about 80percent of the reaction time the NBS goes into solution. As soon as the solution has become practically colorless, 603 liters of solvent are distilled off under normal pressure and then 482 liters of acetone, 121 liters of water, and 14.8 kg of sodium acetate (anhydrous) are added. The resulting mixture is cooled to 15° C. to 25° C. and stirred for a further 1 hour. The product precipitated is separated by centrifugation, washed with a mixture of 482 liters of acetone and 121 liters of water, and dried. Yield: 250 kg of tert-butyl 4-bromomethylbiphenyl-2'-carboxylate (80percent of theory).

88%	With sodium hydrogen sulfate; N-Bromosuccinimide; sodium hydrogencarbonate; sodium chloride; dibenzoyl peroxide In tetrachloromethane; hexane; water	EXAMPLE 2 4-Bromomethyl-2'-t-butoxycarbonylbiphenyl To a solution of 2-t-butoxycarbonyl-4'-methylbiphenyl (25.3 g, 95 mmol) in CCl₄ (200 ml) were added freshly opened N-bromosuccinimide (17.6 g, 0.099 mole) and dibenzoyl peroxide (2.28 g, 0.0094 moles). The mixture was refluxed for 4 hours, cooled to room temperature and filtered. The filtrate was washed with sat. NaHSO₃ (150 ml), sat. NaHCO₃ (150 ml), water (150 ml), sat. NaCl (150 ml) and dried over MgSO₄. The solution was filtered, and concentrated in vacuo. The residue was dissolved in 100 ml of hot hexane. Crystallization gradually took place as the solution cooled. The flask was finally cooled to -20° C. and the precipitate recovered by filtration. The solid was washed with ice cold hexanes and dried in vacuo to give 27 g (88percent) of a white solid. ¹ H-NMR (CDCl₃): 1.23 (s, 9H), 4.53 (s, 2H), 7.2-7.5 (m, 7H), 7.68 (d, 1H).
88%	With sodium hydrogen sulfate; N-Bromosuccinimide; sodium hydrogencarbonate; sodium chloride; dibenzoyl peroxide In tetrachloromethane; hexane; water	4-BROMOMETHYL-2'-t-BUTOXYCARBONYL-BIPHENYL To a solution of 2-t-butoxycarbonyl-4'-methylbiphenyl (25.3 g, 95 mmol) in CCl₄ (200 ml) were added freshly opened N-bromosuccinimide (17.6 g, 0.099 mole) and dibenzoyl peroxide (2.28 g, 0.0094 moles). The mixture was refluxed for 4 hours, cooled to room temperature and filtered. The filtrate was washed with sat. NaHSO₃ (150 ml), sat. NaHCO₃ (150 ml), water (150 ml), sat. NaCl (150 ml) and dried over MgSO₄. The solution was filtered and concentrated in vacuo. The residue was dissolved in 100 ml of hot hexane. Crystallization gradually took place as the solution cooled. The flask was finally cooled to -20° C. and the precipitate recovered by filtration. The solid was washed with ice cold hexanes and dried in vacuo to give 27 g (88percent) of a white solid. ¹ H-NMR (CDCl₃): 1.23 (s, 9H), 4.53 (s, 2H), 7.2-7.5 (m, 7H), 7.68 (d, 1H).
88%	With sodium hydrogen sulfate; N-Bromosuccinimide; sodium hydrogencarbonate; sodium chloride; dibenzoyl peroxide In tetrachloromethane; hexane; water	4-Bromomethyl-2'-t-butoxycarbonylbiphenyl To a solution of 2-t-butoxycarbonyl-4'-methylbiphenyl (25.3 g, 95 mmol) in CCl₄ (200 ml) were added freshly opened N-bromosuccinimide (17.6 g, 0.099 mole) and dibenzoyl peroxide (2.28 g, 0.0094 moles). the mixture was refluxed for 4 hours, cooled to room temperature and filtered. The filtrate was washed with sat. NaHSO₃ (150 ml), sat. NaHCO₃ (150 ml), water (150 ml), sat. NaCl (150 ml) and dried over MgSO₄. The solution was filtered, and concentrated in vacuo. The residue was dissolved in 100 ml of hot hexane. Crystallization gradually took place as the solution cooled. The flask was finally cooled to -20° C. and the precipitate recovered by filtration. The solid was washed with ice cold hexanes and dried in vacuo to give 27 g (88percent) of a white solid. ¹ H-NMR (CDCl₃): 1.23 (s, 9H), 4.53 (s, 2H), 7.2-7.5 (m, 7H), 7.68 (d, 1H).

Reference： [1] Patent: US2002/95042, 2002, A1,
[2] Journal of Medicinal Chemistry, 1994, vol. 37, # 7, p. 897 - 906
[3] Patent: US2002/95042, 2002, A1,
[4] Patent: US2002/95042, 2002, A1,
[5] Patent: WO2013/78237, 2013, A1, . Location in patent: Page/Page column 78
[6] ACS Medicinal Chemistry Letters, 2019, vol. 10, # 1, p. 86 - 91
[7] Journal of Medicinal Chemistry, 1991, vol. 34, # 8, p. 2525 - 2547
[8] Journal of Medicinal Chemistry, 1993, vol. 36, # 15, p. 2172 - 2181
[9] Patent: US2001/20100, 2001, A1,
[10] Patent: US5236928, 1993, A,
[11] Patent: US5238942, 1993, A,
[12] Patent: US5250521, 1993, A,
[13] Patent: US5102880, 1992, A,
[14] Patent: US2008/269305, 2008, A1, . Location in patent: Page/Page column 42
[15] Patent: US2008/188533, 2008, A1, . Location in patent: Page/Page column 39
[16] Patent: US2008/318951, 2008, A1, . Location in patent: Page/Page column 44
[17] Patent: WO2009/35543, 2009, A1, . Location in patent: Page/Page column 88-89
[18] Patent: US2010/22599, 2010, A1, . Location in patent: Page/Page column 49-50
[19] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 358 - 374,17
[20] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 358 - 374
[21] Patent: US2012/309757, 2012, A1, . Location in patent: Page/Page column 90
[22] Patent: WO2015/161108, 2015, A1, . Location in patent: Page/Page column 241
[23] Patent: US5240928, 1993, A,
[24] Patent: US5332744, 1994, A,

2
[ 50-00-0 ]
[ 114772-40-6 ]

Yield	Reaction Conditions	Operation in experiment
81.9%	Stage #1: With zinc dibromide In dichloromethane at 30 - 35℃; for 0.333333 h; Stage #2: With phosphorus pentabromide In tetrachloromethane; dichloromethane	In the four reaction flask was added biphenyl-2-carboxylic acid isopropyl ester feedstock 17g (70.7mmol), paraformaldehyde 2.75g (91.7mmol) and methylene chloride 120g, controlling the temperature 30 ~ 35 (53.3 mmol) of zinc bromide was added under stirring, and the reaction was stirred for 20 min. Slowly dropped PBr515.5g (36mmol) and carbon tetrachloride 15g mixed solution, the dropping time of about 1h, the addition was complete, HPLC analysis of raw material sampling the reaction was complete, about 3 ~ 4h. After cooling to 10 ° C, the oil layer was washed three times with ice water, and dried to recover methylene chloride. The crude product was recrystallized to give 19.3 g of pure product of 4'-bromomethylbiphenyl-2-carboxylic acid isopropyl ester in a yield of 81.9percent.

Reference： [1] Patent: CN105330541, 2016, A, . Location in patent: Paragraph 0056; 0058

3
[ 7148-03-0 ]
[ 114772-40-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 15, p. 2172 - 2181
[2] Journal of Medicinal Chemistry, 1991, vol. 34, # 8, p. 2525 - 2547
[3] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 358 - 374,17
[4] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 358 - 374
[5] ACS Medicinal Chemistry Letters, 2019, vol. 10, # 1, p. 86 - 91

4
[ 55666-42-7 ]
[ 114772-40-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 7, p. 897 - 906
[2] Patent: US2012/309757, 2012, A1,
[3] Patent: WO2013/78237, 2013, A1,
[4] Patent: WO2015/161108, 2015, A1,

5
[ 88-65-3 ]
[ 114772-40-6 ]

Reference： [1] Patent: US2012/309757, 2012, A1,
[2] Patent: WO2013/78237, 2013, A1,
[3] Patent: WO2015/161108, 2015, A1,

6
[ 145319-09-1 ]
[ 114772-40-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 6, p. 1913 - 1917

7
[ 5720-05-8 ]
[ 114772-40-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1994, vol. 37, # 7, p. 897 - 906

8
[ 114772-34-8 ]
[ 114772-40-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1993, vol. 36, # 15, p. 2172 - 2181

9
[ 57598-33-1 ]
[ 114772-40-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 8, p. 2525 - 2547

10
[ 114772-35-9 ]
[ 114772-40-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 8, p. 2525 - 2547

11
[ 74201-13-1 ]
[ 114772-40-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 8, p. 2525 - 2547

12
[ 84392-32-5 ]
[ 114772-40-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 8, p. 2525 - 2547

13
[ 579-75-9 ]
[ 114772-40-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 8, p. 2525 - 2547

14
[ 21615-34-9 ]
[ 114772-40-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1991, vol. 34, # 8, p. 2525 - 2547

15
[ 100-47-0 ]
[ 114772-40-6 ]

Reference： [1] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 358 - 374,17
[2] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 358 - 374

16
[ 214360-47-1 ]
[ 114772-40-6 ]

Reference： [1] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 358 - 374,17
[2] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 358 - 374

17
[ 114772-53-1 ]
[ 114772-40-6 ]

Reference： [1] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 358 - 374,17
[2] European Journal of Medicinal Chemistry, 2012, vol. 55, p. 358 - 374

18
[ 106-38-7 ]
[ 110349-26-3 ]
[ 114772-40-6 ]

Reference： [1] Patent: US5332744, 1994, A,

19
[ 947-84-2 ]
[ 114772-40-6 ]

Reference： [1] Patent: CN105330541, 2016, A,

20
[ 114772-36-0 ]
[ 901768-33-0 ]
[ 114772-40-6 ]

Reference： [1] Journal of Chemical Research, 2010, # 2, p. 95 - 97

[ 114772-40-6 ] Synthesis Path-Downstream 1~68

1
[ 50790-93-7 ]
[ 114772-40-6 ]
1-<<2'-(tert-butoxycarbonyl)biphenyl-4-yl>methyl>-2-butylimidazole [ No CAS ]

Reference： [1]Arzneimittel-Forschung/Drug Research,1993,vol. 43,p. 828 - 830
[2]Arzneimittel-Forschung/Drug Research,1993,vol. 43,p. 1157 - 1168

2
[ 114772-36-0 ]
[ 114772-40-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With azobisisobutyronitrile; sodium acetate; In acetic acid methyl ester; water; isopropyl alcohol; acetone;	EXAMPLE 4 268.0 kg of tert-butyl 4-methylbiphenyl-2'-carboxylate, 157.3 kg of DDH, 1.6 kg of AIBN, and 572 liters of methyl acetate are placed in a 1200-liter enamel stirring apparatus and the mixture is heated to 60 C. to 65 C. As soon as the solution has become practically colorless, 458 liters of solvent are distilled off under normal pressure and then 530 liters of isopropanol, 148 liters of water, and 16.4 kg of sodium acetate (anhydrous) are added. The resulting mixture is cooled to 15 C. to 25 C. and stirred for a further 1 hour. The product precipitated is separated by centrifugation, washed with a mixture of 530 liters of acetone and 148 liters of water, and dried. Yield: 295 kg of tert-butyl 4-bromomethylbiphenyl-2'-carboxylate (85% of theory).
80%	With N-Bromosuccinimide; azobisisobutyronitrile; sodium acetate; In acetic acid methyl ester; water; isopropyl alcohol;	EXAMPLE 1 241.2 kg of tert-butyl 4-methylbiphenyl-2'-carboxylate, 168.2 kg of NBS, 0.3 kg of AIBN, and 724 liters of methyl acetate are placed in a 1200-liter enamel stirring apparatus and the mixture is heated to 60 C. to 65 C. The reaction mixture begins to boil and after about 80% of the reaction time the NBS goes into solution. As soon as the solution has become practically colorless, 603 liters of solvent are distilled off under normal pressure, and then 482 liters of isopropanol, 121 liters of water, and 14.8 kg of sodium acetate (anhydrous) are added. The resulting mixture is cooled to 15 C. to 25 C. and stirred for a further 1 hour. The product precipitated is separated by centrifugation, washed with a mixture of 482 liters of isopropanol and 121 liters of water, and dried. Yield: 250 kg of tert-butyl 4-bromomethylbiphenyl-2'-carboxylate (80% of theory).
80%	With N-Bromosuccinimide; azobisisobutyronitrile; sodium acetate; In acetic acid methyl ester; water; acetone;	EXAMPLE 2 241.2 kg of tert-butyl 4-methylbiphenyl-2'-carboxylate, 168.2 kg of NBS, 0.3 kg of AIBN, and 724 liters of methyl acetate are placed in a 1200-liter enamel stirring apparatus and the mixture is heated to 60 C. to 65 C. The reaction mixture begins to boil and after about 80% of the reaction time the NBS goes into solution. As soon as the solution has become practically colorless, 603 liters of solvent are distilled off under normal pressure and then 482 liters of acetone, 121 liters of water, and 14.8 kg of sodium acetate (anhydrous) are added. The resulting mixture is cooled to 15 C. to 25 C. and stirred for a further 1 hour. The product precipitated is separated by centrifugation, washed with a mixture of 482 liters of acetone and 121 liters of water, and dried. Yield: 250 kg of tert-butyl 4-bromomethylbiphenyl-2'-carboxylate (80% of theory).

	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); azobisisobutyronitrile; In tetrachloromethane; ethyl acetate n-hexane;	Step 3 Preparation of 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl To a mixture of 57 g (0.213 mol) of tert-butyl 2-(p-tolyl)benzoate from step 2 in 1.7 L of carbon tetrachloride at about 65 C. was added 36.4 g (0.204 mol) of N-bromosuccinimide (NBS) and 0.82 g (5 mmol) of azobisisobutyronitrile (AIBN) in one portion. The resulting solution was stirred at reflux for about 6 h followed by addition of another 1.7 g (9.6 mmol) of N-bromosuccinimide and 0.1 g (0.6 mmol) of AIBN. The mixture was stirred at reflux for additional 13 h, and concentrated in vacuo. The residue was dissolved in ethyl acetate-hexane (1:3) and filtered through a pad of silica gel, eluted with ethyl acetate-hexane (1:3) to give 79 g (quantitative) of a sample which contained mostly desired product, 4-bromomethyl-2'-tert-butoxycarbonylbiphenyl, with a small amount of dibrominated product and starting material. No further purification, however, was attempted and the mixture was used directly in subsequent reactions: 1H NMR (CDC13) delta 1.26 (s, 9H), 4.56 (s, 2H), 7.2-7.9 (m, 8H)
		Step 2 2-t-Butoxycarbonyl-4'-bromomethylbiphenyl The titled compound was prepared from 2-t-Butoxycarbonyl-4'-methylbiphenyl (obtained from Step 1) according to the procedure described in European Patent Application EP 0,253,310.
27 g (88%)	With sodium hydrogen sulfate; N-Bromosuccinimide; sodium hydrogencarbonate; sodium chloride; dibenzoyl peroxide; In tetrachloromethane; hexane; water;	EXAMPLE 2 4-Bromomethyl-2'-t-butoxycarbonylbiphenyl To a solution of 2-t-butoxycarbonyl-4'-methylbiphenyl (25.3 g, 95 mmol) in CCl4 (200 ml) were added freshly opened N-bromosuccinimide (17.6 g, 0.099 mole) and dibenzoyl peroxide (2.28 g, 0.0094 moles). The mixture was refluxed for 4 hours, cooled to room temperature and filtered. The filtrate was washed with sat. NaHSO3 (150 ml), sat. NaHCO3 (150 ml), water (150 ml), sat. NaCl (150 ml) and dried over MgSO4. The solution was filtered, and concentrated in vacuo. The residue was dissolved in 100 ml of hot hexane. Crystallization gradually took place as the solution cooled. The flask was finally cooled to -20 C. and the precipitate recovered by filtration. The solid was washed with ice cold hexanes and dried in vacuo to give 27 g (88%) of a white solid. 1 H-NMR (CDCl3): 1.23 (s, 9H), 4.53 (s, 2H), 7.2-7.5 (m, 7H), 7.68 (d, 1H).
27 g (88%)	With sodium hydrogen sulfate; N-Bromosuccinimide; sodium hydrogencarbonate; sodium chloride; dibenzoyl peroxide; In tetrachloromethane; hexane; water;	4-BROMOMETHYL-2'-t-BUTOXYCARBONYL-BIPHENYL To a solution of 2-t-butoxycarbonyl-4'-methylbiphenyl (25.3 g, 95 mmol) in CCl4 (200 ml) were added freshly opened N-bromosuccinimide (17.6 g, 0.099 mole) and dibenzoyl peroxide (2.28 g, 0.0094 moles). The mixture was refluxed for 4 hours, cooled to room temperature and filtered. The filtrate was washed with sat. NaHSO3 (150 ml), sat. NaHCO3 (150 ml), water (150 ml), sat. NaCl (150 ml) and dried over MgSO4. The solution was filtered and concentrated in vacuo. The residue was dissolved in 100 ml of hot hexane. Crystallization gradually took place as the solution cooled. The flask was finally cooled to -20 C. and the precipitate recovered by filtration. The solid was washed with ice cold hexanes and dried in vacuo to give 27 g (88%) of a white solid. 1 H-NMR (CDCl3): 1.23 (s, 9H), 4.53 (s, 2H), 7.2-7.5 (m, 7H), 7.68 (d, 1H).
		Step 2: 2-t-Butoxycarbonyl-4'-bromomethylbiphenyl The titled compound was prepared from 2-t-Butoxycarbonyl-4'-methylbiphenyl (obtained from Step 1) according to the procedure described in European Patent Application EP 0,253,310.
	With N-Bromosuccinimide; dibenzoyl peroxide; for 11h;Heating / reflux;	Benzoyl peroxide (3.9 g, 16.0 mmol) was added to a solution of intermediate (3a) (62 g, 230 mmol) and NBS (41.2 g, 230 mmol) in benzene (800 mL). The mixture was then heated at reflux. After 4.5 hours, benzoyl peroxide (1 g) was added, followed by NBS (16 g, 66.0 mmol) 30 minutes later. The mixture was stirred for a total of 6 hours, cooled, filtered, and concentrated in vacuo. The resulting residue was then crystallized from diethyl ether and hexane at 4 C. overnight to give the title compound as a pale yellow solid (40.7 g). 1H-NMR (DMSO): 6 (ppm) 1.1 (s, 9H), 4.6 (s, 2H), 7.1-7.6 (m, 8H).
	With N-Bromosuccinimide;dibenzoyl peroxide; In benzene; for 6h;Heating / reflux;	Benzoyl peroxide (3.9 g, 16 mmol) was added to a solution of the above oil (62 g, 230 mmol) in benzene (800 mL) and NBS (41.2 g, 230 mmol) and was heated at reflux. After 4.5 hours, benzoyl peroxide (1 g) was added, followed by NBS (16 g, 66 mmol) 30 minutes later. The mixture was stirred for a total of 6 hours and then cooled, filtered, and concentrated in vacuo. The resulting residue was then crystallized from diethyl ether and hexane at 4 C. overnight to give the title compound (40.7 g) as a pale yellow solid. 1H NMR (DMSO) delta (ppm) 1.1 (s, 9H), 4.6 (s, 2H), 7.1-7.6 (m, 8H).
	With N-Bromosuccinimide; dibenzoyl peroxide; In benzene; for 6h;Heating / reflux;	This oil (62 g, 230 mmol), benzoyl peroxide (3.9 g, 16.0 mmol), and NBS (41.2 g, 230 mmol) were mixed with benzene (800 mL) and heated to reflux. After 4.5 hours, benzoyl peroxide (1 g) was added, followed by NBS (16 g, 66.0 mmol) 30 minutes later. The mixture was stirred for a total of 6 hours, then cooled, filtered, and concentrated in vacuo. The resulting residue was crystallized from diethyl ether and hexane at 4 C. overnight to give the title compound (40.7 g) as a pale yellow solid. 1H NMR (DMSO) delta (ppm) 1.1 (s, 9H), 4.6 (s, 2H), 7.1-7.6 (m, 8H).
	With N-Bromosuccinimide; dibenzoyl peroxide; In benzene; for 4.5h;Heating / reflux;	Preparation 13. 4'-Bromomethylbiphenyl-2-carboxylic Acid t-Butyl Ester. A solution of 4'-methylbiphenyl-2-carboxylic acid (48.7 g, 230 mmol) and thionyl chloride (150 mL) was stirred at room temperature. After 5.5 hours, the mixture was concentrated in vacuo. Excess thionyl chloride was removed by co-distillation with toluene to afford a yellow solid (52.6 g). This material was then dissolved in THF (500 mL) and cooled to 0 0C. Potassium t-butoxide (15.0 g, 0.13 mol) was added portion wise, followed by addition of a IM solution of potassium t-butoxide in THF (250 mL). Additional solid potassium t-butoxide (21.4 g, 100 mmol) was added and the mixture was stirred at 0 C for 1.5 hours. The mixture was then partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated to afford 4'-methylbiphenyl-2-carboxylic acid t-butyl ester (62.3 g) as a yellow oil, which was used directly in the next step.This oil (62 g, 230 mmol), benzoyl peroxide (3.9 g, 16.0 mmol), and NBS (41.2 g, 230 mmol) were mixed with benzene (800 mL) and heated to reflux. After 4.5 hours, benzoyl peroxide (1 g) was added, followed by NBS (16 g, 66.0 mmol) 30 minutes later. The mixture was stirred for a total of 6 hours, then cooled, filtered, and concentrated in vacuo. The resulting residue was crystallized from diethyl ether and hexane at 4 0C overnight to give the title compound (40.7 g) as a pale yellow solid. 1H NMR (DMSO) delta (ppm) 1.1 (s, 9H), 4.6 (s, 2H), 7.1-7.6 (m, 8H).
	With N-Bromosuccinimide;dibenzoyl peroxide; In benzene;Reflux;	Benzoyl peroxide (3.9 g, 16 mmol) was added to a solution of the above oil (62 g, 230 mmol) in benzene (800 mL) and NBS (41.2 g, 230 mmol) and was heated at reflux. After 4.5 hours, benzoyl peroxide (1 g) was added, followed by NBS (16 g, 66 mmol) 30 minutes later. The mixture was stirred for a total of 6 hours and then cooled, filtered, and concentrated in vacuo. The resulting residue was then crystallized from diethyl ether and hexane at 4 C. overnight to give the title compound (40.7 g) as a pale yellow solid. 1H NMR (DMSO) delta (ppm) 1.1 (s, 9H), 4.6 (s, 2H), 7.1-7.6 (m, 8H).
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 100℃; for 2h;	To a 500 mL round-bottom flask was added tert-butyl 4'-methylbiphenyl-2-carboxylate (7.04 g, 26.23 mmol), NBS (5.14 g, 28.85 mmol), AIBN (0.43 g, 2.62 mmol) and CCl4 (200 mL). The reaction mixture was refluxed for 2 h at 100 C. The completion of the reaction was monitored by analytical HPLC. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated to obtain the crude product which was purified by flash chromatography (AcOEt/Hexane 0->30%) to obtain the title compound.
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 100℃; for 2h;	To a 500 mL round-bottom flask was added tert-butyl 4'-methylbiphenyl-2- carboxylate (7.04 g, 26.23 mmol), NBS (5.14 g, 28.85 mmol), AIBN (0.43 g, 2.62 mmol) and CCl4(200 mL). The reaction mixture was refluxed for 2 h at 100C. The completion of the reaction was monitored by analytical HPLC. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated to obtain the crude product which was purified by flash chromatography (AcOEt/Hexane 0->30%) to obtain the title compound
27 g (88%)	With sodium hydrogen sulfate; N-Bromosuccinimide; sodium hydrogencarbonate; sodium chloride; dibenzoyl peroxide; In tetrachloromethane; hexane; water;	4-Bromomethyl-2'-t-butoxycarbonylbiphenyl To a solution of 2-t-butoxycarbonyl-4'-methylbiphenyl (25.3 g, 95 mmol) in CCl4 (200 ml) were added freshly opened N-bromosuccinimide (17.6 g, 0.099 mole) and dibenzoyl peroxide (2.28 g, 0.0094 moles). the mixture was refluxed for 4 hours, cooled to room temperature and filtered. The filtrate was washed with sat. NaHSO3 (150 ml), sat. NaHCO3 (150 ml), water (150 ml), sat. NaCl (150 ml) and dried over MgSO4. The solution was filtered, and concentrated in vacuo. The residue was dissolved in 100 ml of hot hexane. Crystallization gradually took place as the solution cooled. The flask was finally cooled to -20 C. and the precipitate recovered by filtration. The solid was washed with ice cold hexanes and dried in vacuo to give 27 g (88%) of a white solid. 1 H-NMR (CDCl3): 1.23 (s, 9H), 4.53 (s, 2H), 7.2-7.5 (m, 7H), 7.68 (d, 1H).
		Step 2: 2-t-Butoxycarbonyl-4'-bromomethylbiphenyl The titled compound was prepared from 2-t-Butoxycarbonyl-4'-methylbiphenyl (obtained from Step 1) according to the procedure described in European Patent Application EP 0,253,310.

Reference： [1]Patent: US2002/95042,2002,A1
[2]Journal of Medicinal Chemistry,1994,vol. 37,p. 897 - 906
[3]Patent: US2002/95042,2002,A1
[4]Patent: US2002/95042,2002,A1
[5]Patent: WO2013/78237,2013,A1 .Location in patent: Page/Page column 78
[6]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 86 - 91
[7]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547
[8]Journal of Medicinal Chemistry,1993,vol. 36,p. 2172 - 2181
[9]Patent: US2001/20100,2001,A1
[10]Patent: US5236928,1993,A
[11]Patent: US5238942,1993,A
[12]Patent: US5250521,1993,A
[13]Patent: US5102880,1992,A
[14]Patent: US2008/269305,2008,A1 .Location in patent: Page/Page column 42
[15]Patent: US2008/188533,2008,A1 .Location in patent: Page/Page column 39
[16]Patent: US2008/318951,2008,A1 .Location in patent: Page/Page column 44
[17]Patent: WO2009/35543,2009,A1 .Location in patent: Page/Page column 88-89
[18]Patent: US2010/22599,2010,A1 .Location in patent: Page/Page column 49-50
[19]European Journal of Medicinal Chemistry,2012,vol. 55,p. 358 - 374,17
[20]Patent: US2012/309757,2012,A1 .Location in patent: Page/Page column 90
[21]Patent: WO2015/161108,2015,A1 .Location in patent: Page/Page column 241
[22]Patent: US5240928,1993,A
[23]Patent: US5332744,1994,A

3
[ 114772-40-6 ]
[ 142385-35-1 ]
[ 142385-36-2 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4751 - 4763

4
[ 114772-40-6 ]
[ 142385-29-3 ]
[ 142385-30-6 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4751 - 4763

5
[ 114772-40-6 ]
[ 142385-38-4 ]
[ 142385-39-5 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4751 - 4763

6
[ 114772-40-6 ]
[ 150694-23-8 ]
[ 150694-24-9 ]

Reference： [1]Heterocycles,1993,vol. 36,p. 1027 - 1038

7
[ 114772-40-6 ]
[ 150694-19-2 ]
[ 150694-20-5 ]

Reference： [1]Heterocycles,1993,vol. 36,p. 1027 - 1038

8
[ 114772-40-6 ]
[ 150758-58-0 ]
4'-<<(oxophenylacetyl)amino>methyl><1,1'-biphenyl>-2-carboxylic acid t-butyl ester [ No CAS ]

Reference： [1]Heterocycles,1993,vol. 36,p. 1027 - 1038

9
[ 114772-40-6 ]
[ 150694-39-6 ]
[ 150694-40-9 ]

Reference： [1]Heterocycles,1993,vol. 36,p. 1027 - 1038

10
[ 114772-40-6 ]
[ 150849-84-6 ]
[ 150694-45-4 ]

Reference： [1]Heterocycles,1993,vol. 36,p. 1027 - 1038

11
[ 114772-40-6 ]
[ 152628-02-9 ]
[ 144702-26-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium tert-butylate; In 1-methyl-pyrrolidin-2-one; at 10℃; for 4h;	To a 100 mL flask was added 2-n-propyl-4-methyl-6- (1'-methylbenzimidazol-2-yl) benzimidazole1.0 g (3.3 mmol), N-methylpyrrolidone4 g of potassium tert-butoxide and 0.4 g (3.6 mmol) of potassium tert-And stirring was started with a magnetic stirrer.While cooling to below 10 C.,A solution of 1.2 g (3.5 mmol) of 4'-bromomethylbiphenyl-2-carboxylic acid tert-butyl ester dissolved in 4.1 g of N-methylpyrrolidone was added dropwise over 2 hours. After the dropwise addition, the mixture was stirred at an internal temperature of 0 to 10 C. for 2 hours. As a result of sampling the reaction solution and conducting liquid chromatography analysis, it was found that 2 - n - propyl - 4 - methyl - 6 - (1 '- methylbenzimidazol - 2 - yl) benzimidazole was not detected and 4' - [[4- Methyl-6- (1-methyl-1 H-benzimidazol-2-yl) -2-propyl- 1 H- benzimidazol- 1 - yl] methyl] biphenyl-2-carboxylic acid tert-butyl ester was 86.0% Area percentage) was generated.
71%	With sodium; In methanol; at 70℃;	Compound c, represented by Formula 3, was synthesized using Compound a and Compound b purified in Example 1-1. Lithium tert-butoxide was reacted in an inexpensive t-BuOH (tert-butyl alcohol) solvent to obtain compound c in a yield of 54%. As a result of comparing various base conditions such as pyridine, DMAP, Et3N, K2CO3, KOAc, NaOEt, NaH, and Na / MeOH, Compound c was obtained in a yield of 66% at a room temperature of Na / MeOH and 71% at 70 C. Also, a reaction of 1 g scale was carried out to synthesize compound c in the final 70% yield. Then, in order to hydrolyze the obtained compound c, hydrolysis optimum reaction conditions were searched under various acid or base conditions.The reaction was detected in the acid hydrolysis conditions of HCl / CH2Cl2 or H2SO4 / H2O, but the yield was not improved, and the hydrolysis reaction was carried out using the base conditions.The reaction was optimized using sodium hydroxide (NaOH) and THF, DMSO, toluene or H2O solvent, and 3N NaOH / THF at 100 was selected. As a result, telmisartan, a compound represented by the following formula (4), was obtained in a yield of 93%.
	With potassium tert-butylate; In dimethyl sulfoxide; at 25 - 30℃; for 3.5h;Product distribution / selectivity;	10 g (0.0329 mol) of 2-propyl-4-methyl-6-(r-methylbenzimidazole-2- yl)benzimidazole (1) was dissolved in 60 ml of dimethylsulfoxide (DMSO). 3.7 g (0.0329 mol) of Potassium tert-butoxide was added to the aforementioned solution and stirred at room temperature (25-3O0C) for 30 min. Afterwards, 11.45 g (0.0329 mol) of tert-Butyl-4-bromomethylbiphenyl-2-carboxylate (2) was added and the obtained mixture was stirred at room temperature (25-3O0C) for 3 h. At this stage, the reaction was quenched with water (400 ml) and stirred for 30 min. The reaction mass was filtered. The resulting wet cake was slurried in water (200 ml) and stirred for 30 min. The reaction mass was filtered and the obtained solid was dried under vacuum at 60-650C until constant weight. 18.3 g obtained (93% HPLC).

Reference： [1]Patent: JP5711888,2015,B2 .Location in patent: Paragraph 0049
[2]Patent: KR2018/29401,2018,A .Location in patent: Paragraph 0111; 0112; 0118
[3]Journal of Chemical Research,2010,p. 95 - 97
[4]Journal of Medicinal Chemistry,1993,vol. 36,p. 4040 - 4051
[5]Patent: WO2010/149565,2010,A1 .Location in patent: Page/Page column 14

12
[ 114772-40-6 ]
[ 138402-05-8 ]
[ 138401-20-4 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 3371 - 3380

13
[ 114772-40-6 ]
[ 145319-08-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With hexamethylenetetramine; water; sodium dodecyl-sulfate; lanthanum(lll) triflate; at 100℃; for 4.5h;Green chemistry;	General procedure: Hexamethylenetetramine 1 (70.1 mg), SDS (3.4 mg) and lanthanum triflate (17.6 mg) were dissolved in water (0.5 mL). Then 1o (271 mg) was added to the flask. The mixture was refluxed for 4 h to complete the reaction, which was monitored by TLC. The reaction mixture was extracted with EtOAc three times and the combined organic phases were distilled under reduced pressure. The crude product was purifiedby column chromatography on silica gel using hexane: EtOAc (5 : 1) as eluent to give 3o, recrystallisation of which from EtOH gave white crystals, 147 mg (71%) (Table 3, entry 1).

Reference： [1]Journal of Chemical Research,2014,vol. 38,p. 710 - 714
[2]Journal of Medicinal Chemistry,1992,vol. 35,p. 4751 - 4763

14
[ 114772-40-6 ]
[ 139476-12-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium azide; In N,N-dimethyl-formamide; at 100℃; for 1.5h;Inert atmosphere;	To a solution of 1 (336 mg, 0.90 mmol) in dry DMF (10mL) under argon was added sodium azide (117 mg, 1.80mmol) and the mixture was stirred for 1.5 h at 100 C.EtOAc (50 mL) was added and the organic phase was washed with water (4 × 20 mL), dried (MgSO4), and the solvent was removed in vacuo to give a yellow liquid (278 mg,0.90 mmol, 100% yield) which was used without furtherpurification. 1H NMR (250 MHz, CDCl3): delta 1.17 (s, 9 H,tBu), 4.29 (s, 2 H, CH2N3), 7.12-7.44 (m, 7 H, Harom), 7.71(d, J = 7.4 Hz, 1 H, Harom).
	In N-methyl-acetamide; water;	Step 4 Preparation of 4-azidomethyl-2'-tert-butoxycarbonylbiphenyl The mixture of 11.0 g (0.032 mol) of 4-bromomethyl-2'-tert-butoxycarbonyl-biphenyl from step 3 and 4.6 g (0.071 mol) of sodium azide in 42 mL of dimethylformamide and 4.2 mL of water was stirred at room temperature for about 24 h and concentrated in vacuo. The residue was extracted with ethyl acetate, and the combined extracts were washed with water, dried (MgSO4) and concentrated in vacuo to give 10 g (quantitative) of 4-azidomethyl-2'-tert-butoxycarbonyl biphenyl as a yellow oil: 1H NMR (CDCl3) delta 1.26 (s, 9H), 4.38 (s, 2H), 7.2-7.9 (m, 8H).
		EXAMPLE 11A t-Butyl 4'-aminomethyl-biphenyl-2-carboxylate Following the procedures described in Example 1A, replacing N-triphenylmethyl-5-[2-(4'-bromomethyl)biphenyl)]tetrazole with t-butyl 4'-bromomethyl-biphenyl-2-carboxylate, prepared as described by D. J. Carini, et al. in European Patent Application Number 324,377, published Jul. 19, 1989, the intermediate t-butyl 4'-azidomethyl-biphenyl-2-carboxylate is prepared.

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2172 - 2181
[2]Letters in drug design and discovery,2014,vol. 11,p. 256 - 264
[3]Patent: US2001/20100,2001,A1
[4]Patent: US5250548,1993,A

15
[ 114772-40-6 ]
[ 137997-30-9 ]
3-(2'-tert-Butoxycarbonyl-biphenyl-4-ylmethyl)-2-butyl-5-methylsulfanyl-3H-imidazole-4-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 2357 - 2377

16
[ 114772-40-6 ]
[ 144689-94-1 ]
[ 144690-85-7 ]

Yield	Reaction Conditions	Operation in experiment
		60(a) Diethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-propylimidazole-4,5-dicarboxylate Following a procedure similar to that described in Example 1(a), but using 9.0 g of <strong>[144689-94-1]di<strong>[144689-94-1]ethyl 2-propylimidazole-4,5-dicarboxylate</strong></strong> (prepared as described in Preparation 12), 12.3 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate and 4.1 g of potassium t-butoxide as a base, 16.47 g of the title compound were obtained as a viscous oil. Nuclear Magnetic Resonance Spectrum (CDCl3) delta ppm: 0.95 (3H, triplet, J=7.5 Hz); 1.5-2.0 (2H, multiplet); 1.23 (9H, singlet); 1.25 (3H, triplet, J=7 Hz); 1.37 (3H, triplet, J=7 Hz); 2.69 (2H, triplet, J=7 Hz); 4.26 (2H, quartet, J=7 Hz); 4.38 (2H, quartet, J=7 Hz); 5.38 (2H, singlet); 7.0-7.9 (8H, multiplet);

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 323 - 338
[2]Patent: US5616599,1997,A

17
[ 114772-40-6 ]
[ 144689-93-0 ]
[ 144689-20-3 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 15 Ethyl 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (Compound No. 1-119) Following a procedure similar to that described in Example 1(a), but using 0.845 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9) and 1.22 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate, 1.31 g of the title compound were obtained as a gum. This compound was allowed to stand at room temperature, which caused it to crystallize. It was then recrystallized from a mixture of diisopropyl ether and hexane, to give pure title compound, melting at 90-91 C. Nuclear Magnetic Resonance Spectrum (CDCl3) delta ppm: 0.97 (3H, triplet, J=7 Hz); 1.23 (3H, triplet, J=7 Hz); 1.25 (9H, singlet); 1.60 (6H, singlet); 1.82 (2H, sextet, J=7 Hz); 2.67 (2H, triplet, J=7 Hz); 4.24 (2H, quartet, J=7 Hz); 5.51 (2H, singlet); 5.72 (1H, singlet); 6.87-7.85 (8H, multiplet).

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 323 - 338
[2]Patent: US5616599,1997,A

18
[ 114772-40-6 ]
[ 291773-97-2 ]
[ 291774-10-2 ]

Reference： [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2685 - 2697

19
[ 54855-81-1 ]
[ 114772-40-6 ]
4'-(2-methylsulfanyl-4-oxo-4H-quinazolin-3-ylmethyl)biphenyl-2-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 1526 - 1535

20
[ 114772-40-6 ]
[ 13906-09-7 ]
4'-(4-oxo-3,4-dihydroquinazolin-2-ylsulfanylmethyl)biphenyl-2-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 1526 - 1535

22
[ 7148-03-0 ]
[ 114772-40-6 ]

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 2172 - 2181
[2]Journal of Medicinal Chemistry,1991,vol. 34,p. 2525 - 2547
[3]European Journal of Medicinal Chemistry,2012,vol. 55,p. 358 - 374,17
[4]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 86 - 91

23
[ 114772-40-6 ]
tert-butyl (3RS,4RS)-3-(2'-tert-butoxycarbonyl-biphenyl-4-ylmethoxy)-4-(4-fluoro-phenyl)-piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium iodide; In N-methyl-acetamide; ice-water; mineral oil;	(a) 2.95 g (10 mmol) of tert-butyl (3RS,4RS)-4-(4-fluoro-phenyl)-3-hydroxy-piperidine-1-carboxylate [Example 88 (a)] and 3.82 g (11 mmol) of tert-butyl 4'-bromomethyl-biphenyl-2-carboxylate [J. Med. Chem. 34, 2525 (1991)] were dissolved in 100 ml of dimethylformamide under argon at room temperature, then firstly 2.49 g (15 mmol) of potassium iodide and thereafter 0.57 g (13 mmol) of sodium hydride dispersion (55% in mineral oil) were added. After stirring at room temperature for 4 hours the reaction mixture was poured on to ice-water, the product was extracted 3 times with methylene chloride, the organic phases were washed twice with distilled water, then dried over magnesium sulphate, filtered and concentrated in a water-jet vacuum. The thus-obtained crude product was chromatographed on silica gel with n-hexane and ethyl acetate. There were thus obtained 5.08 g (90% of theory) of tert-butyl (3RS,4RS)-3-(2'-tert-butoxycarbonyl-biphenyl-4-ylmethoxy)-4-(4-fluoro-phenyl)-piperidine-1-carboxylate as an amorphous, colourless foam.

Reference： [1]Patent: US6051712,2000,A

24
[ 524-38-9 ]
KHSO₄ -K₂ SO₄ [ No CAS ]
[ 114772-40-6 ]
[ 147247-44-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium bicarbonate; sodium chloride; N-ethyl-N,N-diisopropylamine; In water; ethyl acetate; N,N-dimethyl-formamide;	A) N-[(2'-tert-Butoxycarbonyl-4-biphenylyl)methoxy]phthalimide. 4.66 ml of DIPEA and 6.26 g of 4-bromomethyl(2'-tert-butoxycarbonyl)biphenyl are added successively to a solution of 2.95 g of N-hydroxyphthalimide in 30 ml of DMF. The mixture is left stirring for 2 hours at RT and for 4 hours at 80 C. and then the reaction mixture is taken up with 250 ml of ethyl acetate, and washed successively with 50 ml of water, a saturated solution of sodium hydrogen carbonate, with a saturated solution of sodium chloride, a 5% solution of KHSO4 --K2 SO4 and then a saturated solution of sodium chloride. After drying and concentrating, the residue is recrystallized from a methanol-water mixture. m=7.15 g m.p.=140-145 C.

Reference： [1]Patent: US5274104,1993,A

25
aqueous sodium hypochlorite [ No CAS ]
[ 96042-30-7 ]
[ 114772-40-6 ]
[ 147247-53-8 ]

Yield	Reaction Conditions	Operation in experiment
	With chlorine; In water; tetra(n-butyl)ammonium hydrogen sulfate; acetonitrile;	A) 2'-tert-Butoxycarbonyl-4-biphenylcarboxylic acid. This compound is prepared according to S. Cacchi et al., Chem. Ind., 1986, 286. 3 g of 4-bromomethyl-(2'-tert-butoxycarbonyl)biphenyl in solution in 37 ml of acetonitrile and 5 ml of DCM are treated with 27.6 ml of an aqueous sodium hypochlorite solution, containing 15% of chlorine, in the presence of 2.95 g of tetrabutylammonium hydrogen sulphate. After stirring for 24 hours at RT, 200 ml of ether and 50 ml of water are added. The organic phase is washed with 100 ml of water, dried and concentrated to give a yellow oil which is purified by chromatography on silica by eluding with the heptane/AcOEt/AcOH (80/20/2; v/v/v) mixture, 1.02 g of the expected product are obtained. m.p.=174-176 C.

Reference： [1]Patent: US5274104,1993,A

26
[ 7711-39-9 ]
[ 114772-40-6 ]
[ 145982-29-2 ]

Yield	Reaction Conditions	Operation in experiment
58%	With ammonium chloride; In N-methyl-acetamide;	This has the following NMR spectrum. delta ppm (CDCl3): 0.90 (3H, t, J=7 Hz), 1.34-1.42 (2H, m), 1.75-1.86 (2H, m), 2.07 (6H, s), 2.93 (2H, t, J=8 Hz) 340 mg (1.5 mmol) Of the benzimidazol-4,7-dione was dissolved in 15 ml of dimehtylformarnide, and this was cooled to 0 C. After 65 mg (1.6 mmol) of 60% sodium hydride was added and the mixture was stirred for 30 min. A solution of 503 mg (1.5 mmol) of (2'-t-butoxycarbonylbiphenyl-4-yl)methyl bromide in 2 ml of dimethylformamide was added dropwise and the mixture was stirred for 1 hour. To the reaction mixture was added an aqueous saturated solution of ammonium chloride, and this was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and this was dried over anhydrous sodium sulphate, and the solvent was distilled off under the reduced pressure. The resultant crude product was purified by silica gel chromatography (ethyl acetate: n-hexane=5:1) to obtain 421 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-n-butyl-5,6-dimethyl-1H-benzimidazol-4,7-dione as yellow oily material (Yield 58%).

Reference： [1]Patent: US5506361,1996,A

27
[ 114772-40-6 ]
[ 76100-28-2 ]
[ 140199-52-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium; In methanol; N,N-dimethyl acetamide; ethyl acetate;	1(a) Dimethyl 1-[(2'-t-butoxycarbonylbiphenyl-4yl)methyl]-2-butylimidazole-4,5-dicarboxylate A sodium methoxide solution prepared from 0.69 g of sodium and 40 ml of methanol was added to a solution of 7.2 g of dimethyl 2-butylimidazole-4,5-dicarboxylate (prepared as described in Preparation 4) in 40 ml of methanol, and the resulting mixture was concentrated by evaporation under reduced pressure. The resulting residue was mixed with benzene, and the mixture was concentrated by distillation under reduced pressure. After this operation had been repeated three times, the solid thus obtained was dissolved in 72 ml of N,N-dimethylacetamide. A solution of 10.41 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate in 100 ml of N,N-dimethylacetamide was then added dropwise to the resulting solution. The reaction mixture was then stirred at room temperature for 1 hour and at 50-55 C. for 2 hours. At the end of this time, it was mixed with ethyl acetate and water, and the ethyl acetate layer was separated, and dried over anhydrous magnesium sulfate; the solvent was then removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 15.1 g of the title compound as a gum. Nuclear Magnetic Resonance Spectrum (CDCl3) delta ppm: 0.90 (3H, triplet, J=7 Hz); 1.26 (9H, triplet); 1.1-2.0 (4H, multiplet); 2.70 (2H, triplet, J=7 Hz); 3.81 (3H, singlet); 3.90 (3H, singlet); 5.47 (2H, singlet); 6.95-7.85 (8H, multiplet).

Reference： [1]Patent: US5616599,1997,A

28
[ 144689-87-2 ]
[ 114772-40-6 ]
[ 144690-27-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium chloride; potassium carbonate; In N,N-dimethyl acetamide; ethyl acetate;	11(a) 4-Acetyl-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-5-cyanoimidazole 0.87 g of potassium carbonate and 2.4 g of t-butyl 4'-bromomethylbiphenyl-2-carboxylate were added to a solution of 1.2 g of 4-acetyl-2-butyl-5-cyanoimidazole (prepared as described in Preparation 5) in 12 ml of N,N-dimethylacetamide, and the resulting mixture was shirred at room temperature for 3 hours. At the end of this time, the reaction mixture was diluted with 100 ml of ethyl acetate and washed with a saturated aqueous solution of sodium chloride. The aqueous layer was once again extracted with 50 ml of ethyl acetate, and the combined extracts were washed with a saturated aqueous solution of sodium chloride. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.31 g of the title compound. Nuclear Magnetic Resonance Spectrum (CDCl3) delta ppm: 0.93 (3H, triplet, J=7 Hz); 1.1-2.1 (4H, multiplet); 1.23 (9H, singlet); 2.58 (3H, singlet); 2.75 (2H, triplet, J=7 Hz); 5.32 (2H, singlet); 7.0-8.0 (8H, multiplet).
	With sodium chloride; In N,N-dimethyl acetamide; mineral oil;	45(a) 4-Acetyl-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butylimidazole-5-carbonitrile 0.192 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added to a solution of 0.843 g of 4-acetyl-2-butylimidazole-5-carbonitrile [prepared as described in Preparation 24(i)] in 17 ml of N,N-dimethylacetamide, and the resulting mixture was stirred at room temperature for 20 minutes. 1.68 g of t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate was then added, and the resulting mixture was stirred at 55 C. for 2.5 hours. At the end of this time, an aqueous solution of sodium chloride was added to the mixture, which was then extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting oily residue was purified by column chromatography through silica gel, using 4:1 and 2:1 by volume mixtures of hexane and ethyl acetate as the eluent, to afford 1.14 g of the title compound as a viscous oil. Nuclear Magnetic Resonance Spectrum (CDCl3) delta ppm: 0.93 (3H, triplet, J=7 Hz); 1.23 (9H, singlet); 1.3-2.1 (4H, multiplet); 2.58 (3H, singlet); 2.75 (2H, triplet, J=7 Hz); 5.32 (2H, singlet); 7.0-8.0 (8H, multiplet).

Reference： [1]Patent: US5616599,1997,A
[2]Patent: US5616599,1997,A

29
[ 133694-29-8 ]
[ 114772-40-6 ]
4'-[(2-butyl-1H-thieno[3,4-d]imidazol-1-yl)-methyl][1,1'-biphenyl]-2-carboxylic acid t-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64 mg (68%)	With NaH; In N,N-dimethyl-formamide;	Step B: 4'-[(2-butyl-1H-thieno[3,4-d]imidazol-1-yl)-methyl][1,1'-biphenyl]-2-carboxylic acid t-butyl ester To a stirred solution of 2-butyl-1H-thieno-[3,4-d]imidazole (38 mg, 0.211 mmol) in DMF (1.6 mL) at room temperature was added NaH (316 mmol). After 30 minutes, tert-butyl-4'-bromomethylbiphenyl-2-carboxylate (80.5 mg, 0.232 mmol) was added in one portion. The reaction mixture was stirred for 2 hours and brine (5 mL) was added. Extractive workup (EtOAc) and purification by flash chromatography (SiO2, 40% EtOAc/hexane) gave 64 mg (68%) of 4'-[(2-butyl-1H-thieno[3,4-d]imidazol-1-yl)methyl][1,1'-biphenyl]-2-carboxylic acid t-butyl ester as a thick oil: 1 H NMR (300 MHz, CDCl3) delta 7.78 (dd, 1H, J=7.5 and 1 Hz), 7.48 (td, 1H J=7.5 and 1 Hz), 7.40 (td, 1H, J=7.5 and 1 Hz) 7.32-7.26 (m, 3H), 7.19 (d, 2H, J=8 Hz), 6.99 (d, 1H, J=2.5 Hz), 6.28 (d, 1H, J=2.5 Hz), 5.17 (s, 2H), 2.78 (t, 2H, J=8 Hz), 1.91-1.81 (m, 2H), 1.54-1.41 (m, 2H), 1.23 (s, 9H), 0.96 (t, 3H, J=7 Hz).

Reference： [1]Patent: US5164407,1992,A

30
4⁽⁵⁾-methyl-2-propylimidazole-5⁽⁴⁾-carboxaldehyde [ No CAS ]
[ 114772-40-6 ]
[ 124750-54-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N-methyl-acetamide;	A solution of 3.60 g of 4(5)-methyl-2-propylimidazole-5(4)-carboxaldehyde, 8.64 g of tert-butyl 4'-bromomethylbiphenyl-2-carboxylate, 6.54 g of anhydrous potassium carbonate, and 60 mL of dimethylformamide was stirred at 25 C. for 18 hours. The reaction mixture was filtered, and the filtrate was diluted with water and then extracted with ethyl acetate. The combined organic sulfate, filtered, and concentrated. Column chromatography (elution: ethyl acetate/benzene) provided 6.31 g of 1-[(2'-tert-butoxycarbonylbiphenyl-4-yl)methyl]-4-methyl-2-propylimidazole-5-carboxaldehyde. NMR (200 MHz, CDCl3): delta9.77 (s, 1H), 7.78 (d, 1H), 7.51-7.35 (m, 2H), 7.27 (m, 3H), 7.05 (d, 2H), 5.59 (s, 2H), 2.64 (t, 2H), 2.50 (s, 3H), 1.78 (sext., 2H), 1.20 (s, 9H), 0.97 (t, 3H).

Reference： [1]Patent: US5138069,1992,A

31
4⁽⁵⁾-methyl-4-proylimidazole-5⁽⁴⁾-carboxaldehyde [ No CAS ]
[ 114772-40-6 ]
[ 124750-54-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N-methyl-acetamide;	A solution of 3.60 g of 4(5)-methyl-4-proylimidazole-5(4)-carboxaldehyde, 8.64 g of tert-butyl 4'-bromomethylbiphenyl-2-carboxylate, 6.54 g of anhydrous potassium carbonate, and 60 mL of dimethylformamide was stirred at 25 C. for 18 hours. The reaction mixture was filtered, and the filtrate was diluted with water and then extracted with ethyl acetate. The combined organic sulfate, filtered, and concentrated. Column chromatography (elution: ethyl acetate/benzene) provided 6.31 g of 1-[(2'-tertbutoxycarbonylbiphenyl-4-yl)methyl]-4-methyl-2-propylimidazole-5-carboxyaldehyde. NMR (200 MHz, CDCl3): delta 9.77 (s, 1H), 7.78 (d, 1H), 7.51-7.35 (m, 2H), 7.27 (m, 3H), 7.05 (d, 2H), 5.59 (s, 2H), 2.64 (t, 2H), 2.50 (s, 3H), 1.78 (sext., 2H), 1.20 (s, 9H), 0.97 (t, 3H).

Reference： [1]Patent: US5128355,1992,A

32
[ 143141-25-7 ]
[ 114772-40-6 ]
2-propyl-1-[(2'-(t-butoxycarbonyl)-[1,1']-biphenyl-4-yl)methyl]-1H-pyrrolo[2,3-b] pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With NaH; In water; N,N-dimethyl-formamide;	Step 1: 2-propyl-1-[(2'-(t-butoxycarbonyl)-[1,1']-biphenyl-4-yl)methyl]-1H-pyrrolo[2,3-b] pyridine To a mixture of 2-propyl-1H-pyrrolo[2,3-b]-pyridine prepared in Example 1 step 3 (0.1M in DMF) is added NaH (1.1 equivalent of an 80% dispersion in oil, 0.271 mmol). After 20 min, 2-t-butoxycarbonyl-4'-bromomethylbiphenyl (1.1 equivalent) is added and the mixture is stirred for 30 min. Water is added and the mixture extracted with EtOAc. Purification by flash chromatography (SiO2, 25% EtOAc/hexanes) gives 2-propyl-1-[(2'-t-butoxycarbonyl)-[1,1']-biphenyl-4-yl)methyl]-1H-pyrrolo[2,3-b]pyridine.

Reference： [1]Patent: US5124335,1992,A

33
[ 124807-01-8 ]
[ 114772-40-6 ]
[ 124807-02-9 ]

Yield	Reaction Conditions	Operation in experiment
5.84 g (79%)	With sodium hydroxide; In dichloromethane;	Part B 5-n-propyl-1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]pyrrole-2-carboxaldehyde To a solution of 5-n-propylpyrrole-2-carboxaldehyde (2.5 g, 18.9 mmol) and t-butyl 4'-bromomethylbiphenyl-2-carboxylate (7.2 g, 20.7 mmol) in methylene chloride (75 ml) was added 2.5N NaOH (15 ml) and Aliquat 336 (1.5 g, 3.7 mmol). The mixture was vigorously stirred at room temperature overnight (~18 hours). The organic phase was washed with water (50 ml) and saturated aqueous sodium chloride (50 ml) before being dried (MgSO4), filtered and concentrated to leave 10.1 g of a dark oily residue. Flash chromatography (silica gel, 300 g; EtOAc/hexanes, 1/9) gave 5.84 g (79%) of a pale yellow viscous oil. NMR (200 MHz;CDCl3,TMS)delta: 9.46(s,1H), 7.78-6.96(m,9H), 6.15(d,J=3 Hz,1H), 5.69(s,2H), 2.53(t,J=7.5 Hz,2H), 1.72-1.61(m,2H), 1.20(s,9H), 0.97(t,J=7 Hz,3H).

Reference： [1]Patent: US5015651,1991,A

34
[ 35873-40-6 ]
[ 114772-40-6 ]
7-(2'-t-butoxycarbonylbiphenyl-4-yl)methyl-8-n-butyl-1,3-dimethylxanthine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.7%	In N,N-dimethyl-formamide; mineral oil;	Reference Example 35 7-(2'-t-Butoxycarbonylbiphenyl-4-yl)methyl-8-n-butyl-1,3-dimethylxanthine To an ice-cooled, stirred mixture of sodium hydride (60% dispersion in mineral oil)(90 mg, 2 mmole) in DMF(8 ml) was added a solution of 8-n-butyl-1,3-dimethylxanthine (0.43 g, 1.8 mmoles) in DMF (8 ml). After stirring for 20 minutes under cooling, a solution of t-butyl 4'-bromomethylbiphenyl-2-carboxylate (0.95 g, 2.7 mmol) in DMF (6 ml) was added to this mixture and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4), and evaporated in vacuo. The resulting oil was subjected to column chromatography employing silica gel and eluted with n-hexane-ethyl acetate (1:4 v/v). The resulting fractions containing the product were evaporated in vacuo to obtain a crystalline product. The product was recrystallized from ethyl acetate-ether to give the title compound (0.72 g, 78.7 %) as a colorless prism. M.p. 155-156C. IR (Nujol) cm-1: 1710, 1700, 1660. NMR (CDCl3)delta: 0.94(3H, t, J=7.2HZ), 1.22(9H, s), 1.31-1.52(2H, m), 1.64-1.81(2H, m), 2.73(2H, t, J=7.2HZ), 3.41(3H, s), 3.61(3H, s), 5.60(2H, s), 7.17-7.53(7H, m), 7.75-7.87(1H, m). Anal. Calc'd for C29H34N4O4: C, 69.30; H, 6.82; N, 11.15 Found: C, 68.91; H, 6.93; N, 10.94.

Reference： [1]Patent: EP430300,1991,A2

35
[ 114772-40-6 ]
[ 152628-02-9 ]
[ 921208-39-1 ]

Yield	Reaction Conditions	Operation in experiment
73%		4-Methyl-6-(l -methyl benzimidazol-2-yl)-2-n-propyl lH-benzimidazole (50gms) is suspended in acetone (500 ml), aqueous potassium hydroxide solution (13.8 gms in 31.4 ml of water) is added and mixed for 30 min at temperature of 25 - 3O0C. The mass is cooled, t-Butyl 4"-(bromomethyl)-2-biphenyl-2-carboxylate (50 gms) slowly added over 30 min and maintained the reaction mass at temperature of 0 - 50C for 6 hrs. The solvent is distilled off from the reaction mass at temperature below 5O0C under vacuum. Water (500 ml), Methylene chloride (300 ml) is added to the residue and mixed for about 15 min. pH of the reaction mass is adjusted with hydrochloric acid to 1.8 at temperature of 20 - 250C. Reaction mass is allowed to settle, layers are separated, aqueous layer is extracted with methylene chloride (100 ml). Combined organic layer is washed water (100 ml), treated with charcoal (5 gms) and dried the organic layer over anhydrous sodium sulphate (10 gms). Solvent is distilled off from the dried organic layer at EPO <DP n="13"/>temperature below 50upsilonC finally under vacuum. Acetone (100 ml) is added to the residue,* mixed for about 10 min and solvent is distilled off under vacuum at temperature below5O0C. Acetone (300 ml) is added to the residue, cooled the mass to 3O0C and pH of the mass is adjusted to 2.8 with IPA HCl (about 2 ml). Temperature of reaction mass is raised, maintained for 1 lir at reflux temperature, cooled and maintained for 30 min at 25- 3O0C. Product is filtered, wet cake is washed with acetone (50 ml) and dried the wet cake at temperature of 60 - 7O0C till becomes constant weight.The Dry weight of tert Butyl 4Lambda-[4-Methyl-6-(l-methyl-lH-benzimidazol-2-yl)-2-n- propyl- lH-benzimidazol-l-yl-methyl]biphenyl-2-carboxylate hydrochloride is 73 gms (Yield: 73%). HCl content: 5.85 % w/w

Reference： [1]Patent: WO2007/10558,2007,A1 .Location in patent: Page/Page column 11-12

36
[ 83857-96-9 ]
[ 114772-40-6 ]
[ 133694-34-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	4'-(2-Butyl-4-chloro-5-formylimidazol-1-ylmethyl)biphenyl-2-carboxylic acid t-butyl ester (4a): 2-Butyl-5-chloro-3H-imidazole-4-carbaldehyde (9.9 g, 53.3 mmol), 4'-bromomethylbiphenyl-2-carboxylic acid t-butyl ester (18.5 g, 53.3 mmol), and K2CO3 (7.4 g, 53.3 mmol) were combined in DMF (200 mL) and stirred at room temperature overnight. The reaction was quenched with water, extracted with EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude mixture was purified by flash chromatography (0-40% EtOAc:hexanes) to yield 21.5 g of intermediate (4a).

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 86 - 91
[2]Patent: US2008/269305,2008,A1 .Location in patent: Page/Page column 42-43

37
[ 57260-73-8 ]
[ 114772-40-6 ]
[ 1043607-99-3 ]

Yield	Reaction Conditions	Operation in experiment
98.4%	With potassium carbonate; In tetrahydrofuran; at 20℃;	4'-[(2-t-Butoxycarbonylaminoethylamino)methyl]biphenyl-2-carboxylic acid t-butyl ester (3a): A solution of 4'-bromomethylbiphenyl-2-carboxylic acid t-butyl ester made as described in Preparation 2 (7.2 g, 20.8 mmol), N-(2-aminoethyl)(t-butoxy)carboxamide (10 g, 62.4 mmol), and potassium carbonate (4.3 g, 31.2 mmol) in THF (40 mL) was stirred at room temperature overnight. The mixture was concentrated then extracted with EtOAc (3×150 mL) and water (80 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford crude intermediate (3a) (98.4% yield), which was used in the next step without further purification.

Reference： [1]Patent: US2008/188533,2008,A1 .Location in patent: Page/Page column 39

38
[ 114772-40-6 ]
[ 152628-00-7 ]
[ 1092951-00-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 75℃;	Preparation 3 3-(2'-t-Butoxycarbonylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic Acid 3-(2'-t-Butoxycarbonylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid methyl ester (3a): A solution of 7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid methyl ester (10.0 g, 43 mmol; prepared as described in Preparation 1) in DMF (300 mL) was cooled in an ice bath. Sodium hydride (4.5 g, 60 wt % in mineral oil) was slowly added over 5 minutes. 4'-Bromomethylbiphenyl-2-carboxylic acid t-butyl ester (15.7 g, 45.2 mmol; purchased from commercial source or prepared as described in Preparation 2) was then added. The mixture was gradually warmed to room temperature, then stirred at 75 C. overnight. The mixture was then cooled and concentrated in vacuo and the resultant residue was partitioned between saturated aqueous NaCl and EtOAc (1:1, 400 mL). The organic layer was collected, dried over MgSO4 and evaporated to dryness, yielding Intermediate (3a) as a pale yellow oil (16.0 g, 32.1 mmol). MS m/z: [M+H+] calcd for C31H34N2O4, 499.25; found 499.5.

Reference： [1]Patent: US2008/318951,2008,A1 .Location in patent: Page/Page column 45

39
[ 1092951-05-7 ]
[ 114772-40-6 ]
[ 1190092-28-4 ]

Yield	Reaction Conditions	Operation in experiment
73.5%	With potassium carbonate;tetra(n-butyl)ammonium hydrogensulfate; In acetonitrile; at 55℃; for 5h;Inert atmosphere;	To a solution of 2-n-propyl-4-methyl-6-(2-hydroxyethyl)-lH- benzimidazol (1,0 eq, 10 mmol, 2,04 g) in acetonitryle (40 mL), under argon, K2CO3 (dried at 1200C, 1,5 eq, 15 mmol, 2,07 g) and tetrabutylammonium hydrogen sulfate (0,2 eq, 2 mmol, 0,68 g) were added. 4'-(Bromomethyl)biphenyl-2-carboxylic acid tert-butyl ester (1,0 eq, 10 mmol, 3,47 g) was added. The reaction mixture was stirred at temperature 55C over 5h, and was left at room temperature overnight. To the reation mixture water (100 mL) and ethyl acetate (5 ml) were added, and the organic solvents were evaporated. The obtained solution was extracted with ethyl acetate (3*40 mL) and the combined organic phases were dried over MgStheta4, filtrated and contrated to give 4,72 g of the product as a white foam.The product was purified by chromatography on silica gel, using as eluent CHCI3 with gradually added MeOH (0-1%). Fractions containing the product were evaporated to give 3,46 g of the title compound as a white precipitate (yield 73,5%). M.p. 163-164CIH NMR (200 MHz, CDCl3), delta (ppm): 7,76 (dd, IH, J=l,8, J=7,3); 7.5-7,3 (m, 2H); 7,3-7,2 (m, 3H); 7,1-7,0 (m, 4H); 5,38 (s, 2H); 4,71 (s, 2H); 2,08 (t, 2H, J=8,2); 2,68 (s, 3H); 2,0-1,7 (bs+m, 3H); 1,00 (s, 9H), 1,02 (t, 3H, J=7,3); MS EI [M (m/z, rel. %): 470 (55,7), 442 (35,7), 386 (41,4), 211 (100)
10.61g	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	A solution of 10.22 g of 6-hydroxymethyl-4-methyl-2-propyl-1H-benzimidazole (the compound of Reference Example 5) and 17.5 g of 4'-(bromomethyl)biphenyl-2-carboxylic acid t-butyl ester in 100 mL of dry dimethylformamide was combined with 10.3 g of anhydrous potassium carbonate and stirred at room temperature overnight. The reaction solution was poured into water, a precipitated insoluble matter was collected using the gradient method, and this insoluble matter was dissolved in ethyl acetate, then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was refined by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 1/3) to give 10.61 g of the intended compound as a white solid. Rf value (relative difference) (silica gel thin layer chromatography, n-hexane/ethyl acetate = 1/3): 0.56.

Reference： [1]Patent: WO2009/123483,2009,A1 .Location in patent: Page/Page column 14-15
[2]Patent: EP2581373,2013,A1 .Location in patent: Paragraph 0501

40
[ 1206697-02-0 ]
[ 114772-40-6 ]
[ 1315573-24-0 ]
[ 1315573-22-8 ]

Yield	Reaction Conditions	Operation in experiment
		(5-propyl-4H-1,2,4-triazol-3-ylmethyl)carbamic acid benzyl ester (100 mg, 370 mumol) was dissolved in dry DMF (1 mL) and added to a suspension of NaH (16 mg, 60% w/w, 1.1 equiv) in DMF (2 mL). The mixture was stirred at room temperature for 15 minutes, and then 4'-bromomethylbiphenyl-2-carboxylic acid t-butyl ester (126 mg, 1 equiv) was added. The mixture was stirred at room temperature for 2 hours, the reaction quenched with MeOH (5 mL), and the mixture evaporated to dryness. The residue was dissolved in EtOAc (20 mL), washed with water (5 mL) and saturated aqueous NaCl (5 mL), dried over Na2SO4, and evaporated to afford a 2:1 mix of the 4'-[3-(benzyloxycarbonylaminomethyl)-5-propyl-[1,2,4]triazol-1-ylmethyl]biphenyl-2-carboxylic acid t-butyl ester and 4'-[5-(benzyloxycarbonylaminomethyl)-3-propyl-1,2,4-triazol-1-ylmethyl]biphenyl-2-carboxylic acid t-butyl ester. This mixture (192 mg, 350 mumol) was used without further purification.The mixture (150 mg, 280 mumol) was dissolved in EtOH (7.5 mL) and added under nitrogen to Pd(OH)2 (20% w/w on carbon, 50 mg). The mixture was stirred under hydrogen for 2 hours, then filtered and evaporated to afford a mixture of 4'-[3-(aminomethyl)-5-propyl-1,2,4-triazol-1-ylmethyl]biphenyl-2-carboxylic acid t-butyl ester and 4'-[5-(aminomethyl)-3-propyl-1,2,4-triazol-1-ylmethyl]biphenyl-2-carboxylic acid t-butyl ester (113 mg, 280 mumol). This mixture was used directly without further purification.

Reference： [1]Patent: US2010/22599,2010,A1 .Location in patent: Page/Page column 50

41
[ 21523-62-6 ]
[ 114772-40-6 ]
[ 1220018-34-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of ethyl 2,3-dimethyl-1H-indole-5-carboxylate (1.493 g, 6.87 mmol) in dry DMF (10 mL) at 0 C. under argon was added NaH (0.3 g, 60% dispersion in mineral oil, 7.56 mmol) in portions. The reaction mixture was stirred at rt for 30 min and then re-cooled to 0 C. Tert-butyl 4'-(bromomethyl)biphenyl-2-carboxylate (2.62 g, 7.56 mmol) in DMF (2 mL) was slowly added. The reaction mixture was stirred at rt for another 1 h. The completion of the reaction was monitored by anal. HPLC. The reaction was quenched with MeOH, and then the solvent was removed in vacuo. The crude was dissolved in AcOEt, washed with saturated aqueous NaHCO3, brine and dried over Na2 SO4 and filtered. The filtrate was evaporated in vacuo to obtain the crude which was purified by flash chromatography (AcOEt/Hex 10->100%) to obtain the title compound. ESI-MS (m/z): 484 [M+H]+.
		To a mixture of ethyl 2,3-dimethyl-1H-indole-5-carboxylate (1.493 g, 6.87 mmol) in dry DMF (10 mL) at 0C under argon was added NaH (0.3 g, 60% dispersion in mineral oil, 7.56 mmol) in portions. The reaction mixture was stirred at rt for 30 min and then re-cooled to 0C. Tert-butyl 4'-(bromomethyl)biphenyl-2-carboxylate (2.62 g, 7.56 mmol) in DMF (2 mL) was slowly added. The reaction mixture was stirred at rt for another 1 h. The completion of the reaction was monitored by anal. HPLC. The reaction was quenched with MeOH, and then the solvent was removed in vacuo. The crude was dissolved in AcOEt, washed with saturated aqueous NaHCO3, brine and dried over Na2SO4and filtered. The filtrate was evaporated in vacuo to obtain the crude which was purified by flash chromatography (AcOEt/Hex 10->100%) to obtain the title compound. ESI-MS (m/z): 484 [M+H]+

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1399 - 1404
[2]Nature,2011,vol. 477,p. 477 - 481
[3]Patent: US2012/309757,2012,A1 .Location in patent: Page/Page column 90; 91
[4]Patent: WO2015/161108,2015,A1 .Location in patent: Page/Page column 242

42
[ 114772-40-6 ]
[ 184150-96-7 ]
[ 1220018-32-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1399 - 1404

43
[ 144-62-7 ]
[ 114772-40-6 ]
[ 152628-02-9 ]
telmisartan tert-butyl ester oxalate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		10 g (0.0329 mol) of 2-propyl-4-methyl-6-(l '-methylbenzimidazole-2- yl)benzimidazole (1) was dissolved in 60 ml of dimethylsulfoxide (DMSO). The resulting solution was stirred at room temperature (25-3O0C). 3.7 g (0.0329 mol) of Potassium tert-butoxide was added to the aforementioned solution and stirred at room temperature (25-3O0C) for 30 min. Afterwards, 11.45 g (0.0329 mol) of tert-Butyl-4- bromomethylbiphenyl-2-carboxylate (2) was added and the obtained mixture was stirred at room temperature (25-3O0C) for 2-3 h. At this stage, 100 ml of MDC and 400 ml of water were added and the reaction stirred for 30 min. The organic and aqueous layers were separated. The aqueous layer was extracted with MDC. The organic layers were combined and washed twice with water and once with NaCl solution. The resulting organic layer was dried over sodium sulphate and filtered. To the above organic solution, 4.56 g (0.0361 mol) of oxalic acid dissolved in hot methanol (6 ml) were added. The resulting mixture was refluxed and the solvent removed partially at 40-450C under atmospheric pressure. The reaction mass was stirred for 3 h at same temperature. The reaction mass was cooled to 10-15 0C and stirred for 3 h. Afterwards, the suspension was filtered and the obtained solid was washed with methyl ethyl ketone (20 ml). The resulting wet solid was stirred with methyl ethyl ketone (100 ml) under reflux for 2 hours. The reaction mass was cooled down to 15-2O0C and stirred for 2 h. The reaction mass was filtered and the solid was washed with methyl ethyl ketone. The resulting oxalate salt 3 was dried under vacuum at 80-820C until constant weight. Yield: 16.0 gYield (molar): 73.9% HPLC: 99.6%

Reference： [1]Patent: WO2010/149565,2010,A1 .Location in patent: Page/Page column 13; 14

44
[ 214360-47-1 ]
[ 114772-40-6 ]

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 55,p. 358 - 374,17

45
[ 1350440-78-6 ]
[ 114772-40-6 ]
[ 1350440-79-7 ]

Yield	Reaction Conditions	Operation in experiment
0.54g		A mixture of 4.41 g of 6-[6-(N-2-hydroxyethyl-N-methylamino)-1-methyl-1H-benzimidazol-2-yl]-4-methyl-2-propyl-1H-benzimidazole (the compound of Reference Example 82) and 0.47 g of 60% sodium hydride was combined with 20 mL of dry tetrahydrofuran and 30 mL of dry dimethylformamide and stirred at room temperature for one hour. The reaction mixture was combined with 4.90 g of 4'-bromomethylbiphenyl-2-carboxylic acid t-butyl ester while cooling with ice, and stirred at room temperature for five hours. The reaction mixture was combined with 4 g of anhydrous potassium carbonate and 2 g of 4'-bromomethylbiphenyl-2-carboxylic acid t-butyl ester, stirred at room temperature for twenty hours, then combined with 0.14 g of 60% sodium hydride and stirred at room temperature for ten hours. The residue resulting from distilling off the solvent was combined with ethyl acetate and water, and the ethyl acetate layer was separated. The ethyl acetate layer was washed with saturated physiological saline, then dried over anhydrous sodium sulfate. After the solvent had been distilled off, 8.46 g of the resulting residue was refined by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate = 1/3) to give 0.54 g of the intended compound as a white solid. Rf value (relative difference) (silica gel thin layer chromatography, elution solvent: ethyl acetate/methanol = 20/1): 0.36.

Reference： [1]Patent: EP2581373,2013,A1 .Location in patent: Paragraph 0601

46
[ 114772-40-6 ]
[ 146953-86-8 ]
[ 1431152-06-5 ]