[ CAS No. 101990-45-8 ] {[proInfo.proName]}

Name: 101990-45-8|2-Bromo-5-(bromomethyl)pyridine|98%
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Product Details of [ 101990-45-8 ]

CAS No. :	101990-45-8	MDL No. :	MFCD11656267
Formula :	C₆H₅Br₂N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CRRMIKBAPPOPNW-UHFFFAOYSA-N
M.W :	250.92	Pubchem ID :	6424660
Synonyms :

Safety of [ 101990-45-8 ]

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

Application In Synthesis of [ 101990-45-8 ]

* 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 [ 101990-45-8 ]
Downstream synthetic route of [ 101990-45-8 ]

[ 101990-45-8 ] Synthesis Path-Upstream 1~20

1
[ 3510-66-5 ]
[ 101990-45-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In 1,2-dichloro-ethane at 85℃; for 0.5 h;	(Referential Example 8) Synthesis of 2-bromo-5-(bromomethyl)pyridine (referential compound 8) N-Bromosuccinimide (16 g, 91 mmol) and 0.40 g (2.4 mmol) of 2,2'-azobis(isobutyronitrile) were added to a solution of 12 g (70 mmol) of 2-bromo-5-methylpyridine in 100 ml of 1,2-dichloroethane and the mixture was stirred at 85°C. After 15 minutes, 0.40 g (2.4 mmol) of 2,2'-azobis(isobutyronitrile) was added thereto and the mixture was stirred for 15 minutes. After the reaction was finished, water was added to the reaction solution and the organic layer was separated therefrom. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was subjected to a silica gel column chromatography (eluding solvent: n-hexane: ethyl acetate = 10:1 to 9:1 (v/v)) and the fraction containing the aimed substance was concentrated in vacuo to give 15 g of the title compound as white powder (yield: 89percent). Rf value: 0.63 (n-hexane: ethyl acetate = 9:1 (v/v)) Mass spectrum (CI, m/z): 250, 252, 254 (M⁺ + 1) ¹H-NMR spectrum (CDCl₃, δ ppm): 4.42 (s, 2H), 7.49 (d, J = 8.3Hz, 1H), 7.61 (dd, J1 = 8.3Hz, J2 = 2.7Hz, 1H), 8.39 (d, J = 2.7Hz, 1H)
59%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethaneReflux	Synthesized from 2-bromo-5-methylpyridine (3.00 g, 17.40 mmol), NBS (3.41 g, 19.20 mmol) and DBPO (230 mg, 0.80 mmol) in carbon tetrachloride according to Method A. Yield: 2.56 g (59 percent); lachrymatory yellow needles; ¹ H NMR (CDCIs, 500 MHz): δ_Η (ppm) = 4.14 (s, 2H), 7.47 (d, J = 8.2 Hz, 1 H), 7.59 (d, J = 8.2 Hz, 1 H), 8.38 (s, 1 H); MS (ESI): m/z = 252.37 [M+H]⁺.Methylpyridine was dissolved in 40 ml_ of dry carbon tetrachloride. To this solution was added /V-bromsuccinimide (NBS) (1.1 eq) and benzoyl peroxide (5 molpercent) and the mixture was refluxed over night. After cooling, the succinimide was removed by filtration and the filtrate was concentrated under vacuum. The crude product was further purified by flash column chromatography on silica gel using a mixture of petroleum ether / ethyl acetate (95:5) as eluent.
52.6%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane at 80℃; for 2 h; Inert atmosphere	To a solution of 169-51 (5.0 g, 29.1 mmol) in Cd4 (40 mL) was added NBS (5.22 g, 29.1 mmol) and BPO (350 mg, 1.4 mmol). The reaction mixture was stirred at 80 °C under an atmosphere of nitrogen for 2 hours. The mixturewas diluted with DCM, washed with water and brine, dried, and concentrated to dryness. The remaining residue was purified by column chromatography on silica gel (eluted with PE/EtOAc = 120:1) to afford 169-S2 (3.81g, 52.6percent yield) as a yellow oil. LC/MS (ESI) m/z: 250 (M+H)t

49%	With N-Bromosuccinimide In tetrachloromethane for 4 h; Heating / reflux	2-Bromo-5-bromomethylpyridine. 2-Bromo-5-methylpyridine (5.00 g, 29.1 mmoles) and N-bromosuccinimide (5.22 g, 29.3 mmoles) were dissolved in carbon tetrachloride (40 mL) under nitrogen. Benzoyl peroxide (0.35 g, 1.4 mmoles) was added and the mixture heated at reflux for four hours. The mixture was cooled to room temperature, filtered, and washed with NaHCO₃/H₂O. The mixture was adsorbed onto silica gel and then chromatographed. eluting with a gradient of hexane to 10percent ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the desired mono-brominated product as a pale yellow solid, 3.60 g (49percent). LC/MS (M+H)⁺ m/z=249.8, 251.8, 253.8.
49%	Stage #1: With N-Bromosuccinimide In tetrachloromethane for 4 h; Inert atmosphere; Reflux Stage #2: With sodium hydrogencarbonate In tetrachloromethane; water at 20℃;	Step A2-Bromo-5-bromomethylpyridine. 2-Bromo-5-methylpyridine (5.00 g, 29.1 mmoles) and N-bromosuccinimide (5.22 g, 29.3 mmoles) were dissolved in carbon tetrachloride (40 mL) under nitrogen. Benzoyl peroxide (0.35 g, 1 .4 mmoles) was added and the mixture heated at reflux for four hours. The mixture was cooled to room temperature, filtered, and washed with NaHC0₃/H₂O.The mixture was adsorbed onto silica gel and thenchromatographed. eluting with a gradient of hexane to 10percent ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the desired mono-brominated product as a pale yellow solid, 3.60 g (49percent). LC/MS (M+H)⁺ m/z = 249.8, 251.8, 253.8.
46%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In dichloromethane at 55℃; for 6 h; Heating; Irradiation	Example 16 Step 1: A mixture of 2-bromo-5-methylpyridine (10 g, 58 MMOL), N-bromosuccinimide (15.5 g, 87.2 MMOL), and AZOBISISOBUTYRONITRILE (0.25 g) in anhydrous CH2CI2 (100 ml) was heated at 55 °C under irradiation (200W lamp) for 6 h. The mixture was cooled down to RT, diluted with CH2CI2 (200 ML), washed with saturated NaHCO3 solution, dried (MGS04), filtered and concentrated. The residue was subjected to silica gel flash chromatography (5<7percent EtOAc/hexanes) to afford the product (6.75 g, 46percent).
20%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 19 h; Reflux	Synthesis Example 18 N-[1-((6-bromopyridin-3-yl)methyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoroacetamide (Compound 231) An amount of 500 mg (2.92 mmol) of 2-bromo-5-methylpyridine was dissolved in 15 mL of carbon tetrachloride, following which 623 mg (3.50 mmol) of N-bromosuccinimide and 10 mg of benzoyl peroxide were added and the mixture was refluxed under heating for 19 hours. Following reaction completion, the reaction mixture was returned to room temperature and concentrated under reduced pressure, then purified by silica gel column chromatography (hexane/ethyl acetate=19:1), giving 143 mg of 2-bromo-5-bromomethylpyridine (yield, 20percent). ¹H-NMR (CDCl₃, δ, ppm): 4.42 (2H, s), 7.47 (1H, d), 7.59 (1H, dd), 8.38 (1H, d)
20%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 19 h; Reflux	500 mg (2.92 mmol) of 2-bromo-5-methylpyridine was dissolved in 15 ml of carbon tetrachloride, 623 mg (3.50 mmol) of N-bromosuccinimide and 10 mg of benzoyl peroxide were added thereto, and the resulting mixture was heated and refluxed for 19 hours. After the reaction was completed, the reaction solution was returned to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 19:1) to obtain 143 mg (yield 20percent) of 2-bromo-5-bromomethylpyridine. [0250] 1H-NMR (CDCl3, δ, ppm): 4.42(2H, s), 7.47(1H, d), 7.59(1H, dd), 8.38(1H, d)
20%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 19 h; Reflux	500 mg (2.92 mmol) of 2-bromo-5-methylpyridine was dissolved in 15 ml of carbon tetrachloride, 623 mg (3.50 mmol) of N-bromosuccinimide and 10 mg of benzoyl peroxide were added thereto, and the resulting mixture was heated and refluxed for 19 hours. After the reaction was completed, the reaction solution was returned to room temperature, concentrated under reduced pressure and purified by silica gel column chromatography (hexane: ethyl acetate = 19:1) to obtain 143 mg (yield 20percent) of 2-bromo-5-bromomethylpyridine. [0240] 1H-NMR (CDCl3, δ, ppm) : 4.42(2H, s), 7.47 (1H, d), 7.59 (1H, dd), 8.38 (1H, d)
20%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 19 h; Reflux	In 15 ml of carbon tetrachloride, 500 mg (2.92 mmol) of 2-bromo-5-methylpyridine was dissolved. To this solution, 623 mg (3.50 mmol) of N-bromosuccinimide and 10 mg of benzoyl peroxide were added, followed by heating under reflux for 19 hours. After completion of the reaction, the reaction liquid was returned to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1). Thus, 143 mg of 2-bromo-5-bromomethylpyridine was obtained (Percentage Yield: 20percent). 1H-NMR (CDCl3, δ, ppm): 4.42 (2H, s), 7.47 (1H, d), 7.59 (1H, dd), 8.38 (1H, d)

Reference： [1] Patent: EP1679308, 2006, A1, . Location in patent: Page/Page column 35
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[3] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 1, p. 2 - 6
[4] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 8, p. 559 - 564
[5] Patent: WO2012/52540, 2012, A1, . Location in patent: Page/Page column 47; 48-49
[6] Patent: WO2018/160889, 2018, A1, . Location in patent: Page/Page column 602; 603
[7] Patent: US2005/192302, 2005, A1, . Location in patent: Page/Page column 23
[8] Patent: WO2012/114223, 2012, A1, . Location in patent: Page/Page column 40
[9] Patent: WO2005/16876, 2005, A2, . Location in patent: Page/Page column 69
[10] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6022 - 6032
[11] Patent: US2013/150414, 2013, A1, . Location in patent: Paragraph 0406; 407
[12] Patent: EP2633756, 2013, A1, . Location in patent: Paragraph 0249; 0250
[13] Patent: EP2634174, 2013, A2, . Location in patent: Paragraph 0239; 0240
[14] Patent: EP2749555, 2014, A1, . Location in patent: Paragraph 0122
[15] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 15, p. 1989 - 1992
[16] Patent: US2003/8861, 2003, A1,
[17] Patent: US2002/22633, 2002, A1,
[18] Patent: US5861420, 1999, A,
[19] Patent: US6127390, 2000, A,
[20] Patent: WO2008/8747, 2008, A1, . Location in patent: Page/Page column 35, 63
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[24] Patent: US2011/9409, 2011, A1, . Location in patent: Page/Page column 36-37
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[29] Patent: WO2017/156165, 2017, A1, . Location in patent: Paragraph 00615-00617

2
[ 122306-01-8 ]
[ 101990-45-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 3.5 h;	A solution of (6-bromo-3-ρyridinyl)methanol (50) (2.503 g, 13.3 mmol) and triphenylphosphine (4.026 g, 15.4 mmol) in anhydrous CH₂Cl₂ (100 mL) was carefully treated with recrystallized N-bromosuccinimide (2.732 g, 15.4 mmol) (water bath cooling), and the mixture was stirred at room temperature for 3.5 h. The resulting solution was concentrated, and then added to excess petroleum ether at the top of a silica gel column (100 g in petroleum ether), rinsing on with minimal extra CH₂Cl₂. Elution with petroleum ether firstly gave foreruns, and then further elution with 15-25percent Et₂O/pentane gave pure 2-bromo-5-(bromomethyl)pyridine (51) (Schubert et al., 1999) (3.045 g, 91percent) as a lachrymatory white solid that was used directly in the next step; ¹II NMR (CDCl₃) δ 8.38 (d, J = 2.5 Hz, 1 H), 7.59 (dd, J - 8.2, 2.6 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 4.42 (s, 2 H).
91%	With N-Bromosuccinimide; triphenylphosphine In dichloromethane at 20℃; for 3.5 h;	F. Synthesis of (6S)-6-[6-(4-fluorophenyl)-3-pyridinyl]methoxy}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (5) by the method of Scheme 4 A solution of (6-bromo-3-pyridinyl)methanol (50) (2.503 g, 13.3 mmol) and triphenylphosphine (4.026 g, 15.4 mmol) in anhydrous CH₂Cl₂(100 mL) was carefully treated with recrystallized N-bromosuccinimide (2.732 g, 15.4 mmol) (water bath cooling), and the mixture was stirred at room temperature for 3.5 h. The resulting solution was concentrated, and then added to excess petroleum ether at the top of a silica gel column (100 g in petroleum ether), rinsing on with minimal extra CH₂Cl₂. Elution with petroleum ether firstly gave foreruns, and then further elution with 15-25percent Et₂O/pentane gave pure 2-bromo-5-(bromomethyl)pyridine (51) (Schubert et al., 1999) (3.045 g, 91percent) as a lachrymatory white solid that was used directly in the next step; ¹H NMR (CDCl₃) δ 8.38 (d, J=2.5 Hz, 1H), 7.59 (dd, J=8.2, 2.6 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 4.42 (s, 2H).
87%	With carbon tetrabromide; triphenylphosphine In dichloromethane at 0 - 20℃; Inert atmosphere	To a solution of (6-bromopyridin-3-yl)methanol (3.0 g, 16.0 mmol) in DCM (60 mL) was added triphenylphosphine (4.82 g, 18.4 mmol). After addition was completed, themixture was degassed three times under N2. Then a solution of CBr4 (5.84 g, 17.6 mmol) in DCM (15 mL) was added dropwise at 0°C, and the reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1 to 15: 1) to give 2-bromo-5-(bromomethyl)pyridine (3.46 g, 87.0percent yield) as a white solid. LC10 MS: m/z 252 [M+Hj

78%	With phosphorus tribromide In dichloromethane at 0 - 20℃; for 3 h;	To a stirred solution of (6-Bromopyridin-3-yl) methanol (2 g, 0.01 mol) in DCM (40 mL), PBr₃ (14.3 g, 0.05 mol)) was added at 0°C and allowed to stir RT for 3 h. The reaction was monitored by TLC and LC S. The crude reaction mass was diluted with 20 mL of ice cold water and basified with sat. NaHC03 solution to a pH- 8 extracted with DCM (2 X 20 mL), washed with brine, the organic layer was dried over anhydrous NaaSC^, evaporated to get crude resiude that was purified in 100-200 silica gel in 10 percent EtOAc/Hexane to get 2.1 g (78percent) of the title compound as an off white gummy solid. (0771) LC-MS (method 23): R, = 1.91 min; m/z = 251.74 (M+H⁺+2).
62%	With phosphorus tribromide In diethyl ether at 20℃; for 1 h;	EXAMPLE 474-((6-(2-(2,4-Difluorophenyl)-l,l-difluoro-2-hydroxy-3-(lH-tetrazol-l- yl)propyl)pyridin-3-yl)methoxy)benzonitrile (79) and 4-((6-(2-(2,4-difluorophenyl)-l,l- difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl)methoxy)benzonitrile (80)To a stirred solution of compound J (prepared as in the first step of Example 17; 2.0 g, 10.75 mmol) in CH₃OH (30 mL) was added NaBH₄ (0.53 g, 13.97 mmol) portionwise at 0 °C and the reaction mixture was stirred at 0 °C for 1 h. After completion of the reaction (by TLC), CH₃OH was removed under reduced pressure, and the reaction mixture was diluted with ice- cold water (75 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with water (75 mL) and brine (75 mL), dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 40percent EtOAc/hexanes) afforded compound AV (1.4 g, 7.44 mmol, 69percent) as a yellow solid. 1H NMR (400 MHz, CDC1₃): δ 8.35 (s, 1H), 7.59 (dd, J = 8.0, 2.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.71 (d, J = 6.0 Hz, 2H), 2.03 (t, J = 6.0 Hz, OH). MS (ESI): m/z 188 [M⁺] .To a stirred solution of compound AV (1.0 g, 5.31 mmol) in Et₂0 (20 mL) was added phosphorus tribromide (PBr₃; 1.5 mL, 15.95 mmol) at 0 °C, and the mixture was stirred for 1 h at RT. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with ice-cold water (30 mL), adjusted to pH~8 using satd NaHC0₃ and extracted with EtOAc (2 x 100 mL). The combined orgainc extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (10percent EtOAc/hexanes) afforded compound AW (0.83 g, 3.30 mmol, 62percent) as a colorless liquid. 1H NMR (400 MHz, CDC1₃): δ 8.38 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 8.0, 2.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.41 (s, 2H).To a stirred suspension of 4-hydroxybenzonitrile (0.39 g, 3.30 mmol) and Cs₂C0₃ (1.62 g, 4.96 mmol) in DMF (10 mL) was added compound AW (0.83 g, 3.30 mmol) at RT, and the mixture was stirred for 4 h. After completion of the reaction (by TLC), the reaction mixture was quenched with ice-cold water (25 mL) and extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 10percent EtOAc/hexanes) afforded compound AX (0.90 g, 3.11 mmol, 94percent) as a pale yellow solid. 1H NMR (500 MHz, CDC1₃): δ 8.44 (d, J = 2.0 Hz, 1H), 7.64-7.61 (m, 3H), 7.54 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H), 5.08 (s, 2H). MS (ESI): m/z 291 [M+2]⁺.To a stirred suspension of copper powder (1.55 g, 6.22 mmol) in DMSO (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate (0.63 g, 3.11 mmol) at RT and the mixture was stirred for 1 h. A solution of compound AX (0.9 g, 3.11 mmol) in DMSO (5 mL) was added to the reaction mixture and stirring was continued for another 16 h at RT. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with satd NH₄C1 solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 25percent EtOAc/hexane) afforded compound AY (0.5 g, 1.5 mmol, 49percent) as a pale yellow solid. 1H NMR (500 MHz, CDC1₃): δ 8.71 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 5.18 (s, 2H), 4.38 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). MS (ESI): m/z 334 [M+2]⁺.To a stirred solution of l-bromo-2,4-difluorobenzene (348 mg, 1.80 mmol) in Et₂0 (10 mL) was added w-BuLi (1.6 M in hexane; 0.7 mL, 1.80 mmol) at -78 °C, and the mixture was stirred for 30 min under inert atmosphere. A solution of compound AY (500 mg, 1.50 mmol) in Et₂0 (30 mL) was added to the reaction mixture at -78 °C and stirring was continued for another 2 h. After completion of the reaction (by TLC), the reaction mixture was quenched with satd NH₄C1 solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to afford the crude AZ (1.5 g) as a brownish liquid. This crude material was used in the next step without any further purification. MS (ESI): m/z 401 [M+H]⁺.To a stirred solution of crude AZ (650 mg, crude) in Et₂0 (100 mL) was added freshly prepared diazomethane [prepared by dissolving NMU (1.67 g, 16.25 mmol) in a 1 : 1 mixture of 10percent KOH solution (100 mL) and Et₂0 (100 mL) at 0 °C followed by separation and drying of the organic layer using KOH pellets] at -5 °C and the mixture was stirred for 2 h. The resulting reaction mixture was allowed to warm to RT and stirring was continued for another 16 h; progress of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 25percent EtOAc/hexanes) afforded compound BA (250 mg, 0.60 mmol, 37percent) as a yellow liquid. 1H NMR (400 MHz, CDC1₃): δ 8.73 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.65-7.53 (m, 3H), 7.38-7.36 (m, 1H), 7.03 (d, J = 8.0 Hz, 2H), 6.86-6.71 (m, 2H), 5.18 (s, 2H), 3.45 (d, J = 5.2 Hz, 1H), 2.98 (t, J = 5.2 Hz, 1H). MS (ESI): m/z 415 [M+H]⁺.To a stirred solution of compound BA (250 mg, 0.60 mmol) in dry DMF (8 mL) was added iH-tetrazole (62.5 mg, 0.90 mmol) followed by K₂C0₃ (83.3 mg, 0.60 mmol) at RT under inert atmosphere. The reaction mixture was heated to 65 °C and stirred for 16 h. After completion of the reaction (by TLC), the reaction mixture was quenched with ice-cold water and extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over Na₂S0₄ and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography afforded 80 (40 mg, 0.15 mmol, 13percent; eluent: 35percent EtOAc/hexanes) as a yellow liquid and 79 (75 mg, 0.28 mmol, 25percent; eluent: 60percent EtOAc/hexanes) as a thick yellow solid. Compound 79: 1H NMR (400 MHz, CDC1₃): δ 8.74 (s, 1H), 8.58 (s, 1H), 7.90 (dd, J = 8.0, 2,0 Hz, 1H), 7.66-7.62 (m, 3H), 7.45 (br s, OH), 7.40-7.34 (m, 1H), 7.02 (d, J = 8.0 Hz, 2H), 6.80-6.65 (m, 2H), 5.52 (d, J = 14.0 Hz, 1H), 5.18 (d, J = 14.0 Hz, 1H), 5.16 (s, 2H). MS (ESI): m/z 485 [M+H]⁺. HPLC: 97percent. Compound 80: 1H NMR (400 MHz, CDC1₃): δ 8.63 (s, 1H), 8.31 (s, 1H), 7.90 (dd, J = 8.4, 1.6 Hz, 1H), 7.66-7.62 (m, 3H), 7.44-7.38 (m, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.83-6.67 (m, 2H), 6.63 (br s, OH), 5.82 (d, J = 14.0 Hz, 1H), 5.40 (d, J = 14.0 Hz, 1H), 5.16 (s, 2H). MS (ESI): m/z 485 [M+H]⁺. HPLC: 97percent.

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[2] Patent: US2012/28973, 2012, A1, . Location in patent: Page/Page column 10
[3] Patent: WO2017/27684, 2017, A1, . Location in patent: Paragraph 00291
[4] Patent: WO2018/219478, 2018, A1, . Location in patent: Page/Page column 87
[5] Patent: WO2012/177603, 2012, A2, . Location in patent: Page/Page column 105-108
[6] Journal of Medicinal Chemistry, 2010, vol. 53, # 23, p. 8421 - 8439
[7] Patent: WO2015/171474, 2015, A1, . Location in patent: Page/Page column 63

3
[ 21543-49-7 ]
[ 101990-45-8 ]

Yield	Reaction Conditions	Operation in experiment
44%	at 0 - 160℃; for 2.5 h;	Phosphorous tribromide (100 mmol, 27. 1 g, 2. 0 eq.) was added carefully to 2- CHLORO-5-HYDROXYMETHYL pyridine (50. 0 mmol, 7. 18 g, 1. 0 eq.). The pyridine clumped together and the mixture was heated to 160 degrees C. Within 5 minutes of stirring at > 150 degrees C the mixture was seen to go very dark in color with gas evolution. The mixture was stirred at this same temperature for approximately 2. 5 hours at which point it was cooled to room temperature. The mixture was cooled further to 0 degrees C whereupon saturated sodium bicarbonate was added very cautiously (highly exothermic .). As foaming became less vigorous, ice was added to the mixture until foaming subsided. Solid sodium bicarbonate was then carefully added to achieve a pH of-8-9. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Concentrated in vacuo to afford a dark solid. This material was dissolved in a minimal amount of DCM and purified using a Biotage Sp4 65i over a gradient of 0-100 percent ethyl acetate in hexanes to afford the title compound as a pale yellow solid (5. 57 g, 44percent). LRMS : 252 (M+H) +. 'H NMR (DMSO-d6, 400 MHz) ; 8. 39 (1H, s) 7. 59 (1H, D, J = 8. 5 Hz) 7. 48 (1H, d, J = 8. 5 Hz) 4. 46 (2H, s)

Reference： [1] Synlett, 1999, # 3, p. 342 - 344
[2] Patent: WO2004/92145, 2004, A1, . Location in patent: Page 119; 154-155

4
[ 21543-49-7 ]
[ 7789-60-8 ]
[ 101990-45-8 ]

Yield	Reaction Conditions	Operation in experiment
44%	With sodium hydrogencarbonate In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate	Preparation c-80 2-Bromo-5-(bromomethyl)pyridine Phosphorous tribromide (100 mmol, 27.1 g, 2.0 eq.) was added carefully to 2-chloro-5-hydroxymethyl pyridine (50.0 mmol, 7.18 g, 1.0 eq.). The pyridine clumped together and the mixture was heated to 160 degrees C. Within 5 minutes of stirring at >150 degrees C. the mixture was seen to go very dark in color with gas evolution. The mixture was stirred at this same temperature for approximately 2.5 hours at which point it was cooled to room temperature. The mixture was cooled further to 0 degrees C. whereupon saturated sodium bicarbonate was added very cautiously (highly[exothermic]). As foaming became less vigorous, ice was added to the mixture until foaming subsided. Solid sodium bicarbonate was then carefully added to achieve a pH of ~8-9. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Concentrated in vacuo to afford a dark solid. This material was dissolved in a minimal amount of DCM and purified using a Biotage Sp4 65i over a gradient of 0-100percent ethyl acetate in hexanes to afford the title compound as a pale yellow solid (5.57 g, 44percent). LRMS: 252 (M+H)⁺. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.39 (1H, s) 7.59 (1H, d, J=8.5 Hz) 7.48 (1H, d, J=8.5 Hz) 4.46 (2H, s).
44%	With sodium hydrogencarbonate In 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran; ethyl acetate	Preparation d-19 2-Bromo-5-(bromomethyl)pyridine Phosphorous tribromide (100 mmol, 27.1 g, 2.0 eq.) was added carefully to 2-chloro-5-hydroxymethyl pyridine (50.0 mmol, 7.18 g, 1.0 eq.). The pyridine clumped together and the mixture was heated to 160° C. Within 5 minutes of stirring at >150° C. the mixture went very dark in color with gas evolution. The mixture was stirred at this same temperature for approximately 2.5 hours at which point it was cooled to room temperature. The mixture was cooled further to 0° C. whereupon saturated sodium bicarbonate was added very cautiously (highly[exothermic]). As foaming became less vigorous, ice was added to the mixture until foaming subsided. Solid sodium bicarbonate was then carefully added to achieve a pH of ~8-9. The mixture was extracted with ethyl acetate and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Concentrated in vacuo to afford a dark solid. This material was dissolved in a minimal amount of DCM and purified using a Biotage Sp4 65i over a gradient of 0-100percent ethyl acetate in hexanes to afford the title compound as a pale yellow solid (5.57 g, 44percent). LRMS: 252 (M+H)⁺. ¹H NMR (DMSO-d₆, 400 MHz): δ 8.39 (1H, s) 7.59 (1H, d, J=8.5 Hz) 7.48 (1H, d, J=8.5 Hz) 4.46 (2H, s).

Reference： [1] Patent: US2005/187266, 2005, A1,
[2] Patent: US2005/187266, 2005, A1,

5
[ 70258-18-3 ]
[ 101990-45-8 ]

Yield	Reaction Conditions	Operation in experiment
144.9 g	With hydrogen bromide; acetic acid In toluene at 90 - 100℃; for 10 h; Sealed tube	Take 100g raw material 2-chloro-5-chloromethyl pyridine and 200g of toluene was added to the reaction flask, 25percent hydrobromic acidSolution 400g. Heating to 90 ~ 100 . The reaction for 10 hours, desolventizing. The residue was taken up in 200 g of DCM and adjusted to pH = 6-8 with 10percent NaOH solution. The solution was separated and the organic phase was obtained. The DCM was removed by desolvation. The residue is 2-bromo-5-bromomethylpyridine, mass 144.9g, content of 93percent.

Reference： [1] Patent: CN107253930, 2017, A, . Location in patent: Paragraph 0077; 0080; 0083; 0086; 0089

6
[ 23100-12-1 ]
[ 101990-45-8 ]

Reference： [1] Patent: CN107698497, 2018, A, . Location in patent: Paragraph 0090; 0091

7
[ 3510-66-5 ]
[ 101990-45-8 ]
[ 154321-32-1 ]

Reference： [1] Tetrahedron Letters, 2002, vol. 43, # 9, p. 1697 - 1700
[2] Tetrahedron Letters, 2002, vol. 43, # 9, p. 1697 - 1700
[3] Synthesis, 1994, # 1, p. 87 - 92
[4] Patent: US2007/219276, 2007, A1, . Location in patent: Page/Page column 41

8
[ 3510-66-5 ]
[ 101990-45-8 ]

Reference： [1] Patent: US5196537, 1993, A,
[2] Patent: US5451593, 1995, A,

9
[ 3510-66-5 ]
[ 101990-45-8 ]

Reference： [1] Patent: US6090828, 2000, A,

10
[ 3510-66-5 ]
[ 101990-45-8 ]
[ 154321-32-1 ]

Reference： [1] Organic Letters, 2000, vol. 2, # 24, p. 3845 - 3848

11
[ 3510-66-5 ]
[ 128-08-5 ]
[ 101990-45-8 ]

Reference： [1] Patent: WO2003/106455, 2003, A1, . Location in patent: Page 55

12
[ 1603-41-4 ]
[ 101990-45-8 ]

Reference： [1] Synthesis, 1994, # 1, p. 87 - 92

13
[ 843646-70-8 ]
[ 101990-45-8 ]

Reference： [1] Journal of Medicinal Chemistry, 2010, vol. 53, # 23, p. 8421 - 8439

14
[ 149806-06-4 ]
[ 101990-45-8 ]

Reference： [1] Patent: WO2012/177603, 2012, A2,

15
[ 58757-38-3 ]
[ 101990-45-8 ]

Reference： [1] Synlett, 1999, # 3, p. 342 - 344

16
[ 5326-23-8 ]
[ 101990-45-8 ]

Reference： [1] Synlett, 1999, # 3, p. 342 - 344

17
[ 101990-45-8 ]
[ 149806-06-4 ]

Yield	Reaction Conditions	Operation in experiment
58.6 g	With disodium hydrogenphosphate; potassium iodide In dimethyl sulfoxide at 90 - 100℃; for 8 h; Inert atmosphere	Take 100g of 2-bromo-5-bromomethyl pyridine,500 g of DMSO and 55 g of disodium hydrogen phosphate were added,5g potassium iodide, stirring, bubbling nitrogen under the surface. Heating to 90 ~ 100 reaction. The reaction was completed for 8 hours. After completion of the reaction, the DMSO was distilled off, the mixture was cooled and 100 g of water and 300 g of MTBE were added, and the mixture was washed and separated to obtain MTBE. The remaining 2-bromo-5-aldehyde pyridine 58.6 g with a purity of more than 95percent.

Reference： [1] Patent: CN107253930, 2017, A, . Location in patent: Paragraph 0078; 0081; 0084; 0087; 0090

18
[ 101990-45-8 ]
[ 122306-01-8 ]

Reference： [1] Patent: US2002/22633, 2002, A1,

19
[ 110-91-8 ]
[ 101990-45-8 ]
[ 364793-93-1 ]

Reference： [1] Patent: WO2008/8747, 2008, A1, . Location in patent: Page/Page column 35, 36, 63
[2] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 17, p. 5071 - 5074

20
[ 101990-45-8 ]
[ 120740-10-5 ]

Yield	Reaction Conditions	Operation in experiment
40%	Stage #1: With hexamethylenetetramine In chloroform at 20℃; for 16 h; Stage #2: With ammonium hydroxide In water for 1.5 h; Reflux Stage #3: With formaldehyd In water at 20℃;	2-bromo-5-methyl-pyridine (70.0 mmol) and N-bromosuccinimide (80.0 mmol) were dissolved in 1,2- dichioroethane (150 ml) and to this mixture 2,2’-azobis(2- ethylpropionitrile) (1.50 mmol) was added. The reaction mixture was heated under reflux at 85° C. for 15 minutes and next portion of 2,2’-azobis(2-methylpropionitrile) (1.50 mmol) was added and reaction mixture was heated at 85° C. for further 15 minutes. After cooling to room temperature was the reaction mixture kept at 5° C. for 2 hours and the precipitate was filtered off and washed with small amount of 1 ,2-dichlo- roethane. The filtrate was evaporated under reduced pressure and the crude product was used for further reaction step without purification. The crude 2-bromo-5-bromomethyl-py- ridine was dissolved in chloroform (100 ml) and urotropine (70.0 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off, washed with small amount of chloroform and dried on air. The crude urotropine salt was refluxed in a mixture of conc. ammonium hydroxide (12 ml) and water (80 ml) for 90 minutes and afier cooling to room temperature, 40percent formaldehyde (5.0 ml) was added with stirring. The precipitate was filtered off, washed with ice-cold water and dried in vacuum dessicator. The crude product was crystallized from ethanol. Yield: 40percent m.p. 105-106° C. Elemental analysis: Calcd. for C5H7HrN2 (187.04): C, 38.53; H, 3.77; N, 14.98. Found: C, 38.22; H, 3.72; N, 14.71. HPLC-MS (ESI+): 188.02(97.2percent). ‘H NMR (DMSO, d5): 4.04 (t, J=5.67, 2H, CH2), 7.71 (d, J=8.19, 1H,ArH), 7.95 (dd, J=8.19, J’=i.95, 1H,ArH), 8.51 (d, J=i .95, 1H, ArH), 8.74 (s(br), 2H, NH2).

Reference： [1] Patent: US2015/368248, 2015, A1, . Location in patent: Paragraph 0089
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 15, p. 6234 - 6247

[ 101990-45-8 ] Synthesis Path-Downstream 1~88

1
[ 3510-66-5 ]
[ 101990-45-8 ]
[ 154321-32-1 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; In dichloromethane; water; for 0.5h;Heating / reflux;	Generally, to a refluxing mixture of 2-bromo-methyl-pyridine (5 g, 29 mmol) in a biphasic medium of DCM (500 ml) and water (500 ml) was added Br2 (1.65 ml, 31.9 mmol). The mixture was illuminated using a halogen lamp (500 W, distance: 5-10 cm) under reflux for 30 min. The solution was cooled to room temperature and neutralized with a 10% Na2CO3 aqueous solution and solid NaCl was added. The aqueous layer was extracted three times with DCM, the combined organic extracts were dried over MgSO4 and evaporated in vacuo. HPLC analysis of the crude product showed the relative ratio of 13.6:76.5:9.9 (Retention time: 8.1, 10.6 and 13.4 min, respectively) for starting material 2-bromo-methyl-pyridine:2-bromo-5-(bromomethyl)pyridine: 2-bromo-5-(dibromomethyl)pyridine.

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 1697 - 1700
[2]Tetrahedron Letters,2002,vol. 43,p. 1697 - 1700
[3]Synthesis,1994,p. 87 - 92
[4]Patent: US2007/219276,2007,A1 .Location in patent: Page/Page column 41

2
[ 101990-45-8 ]
[ 603-35-0 ]
((6-bromopyridin-3-yl)methyl)triphenylphosphonium bromide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.5%	In toluene; at 119℃; for 2h;Inert atmosphere;	To a solution of 2-bromo-5-(bromomethyl)pyridine (3.7 g, 14.7 mmol) in toluene (30 mL) was added triphenylphosphine (5.02 g, 19.2 mmol). The reaction mixture was degassed three times under N2 and stirred at 119C for 2 hrs. The mixture was filtrated, and theresidue was washed with hexane and filtrated again to give ((6-bromopyridin-3- yl)methyl)triphenylphosphonium bromide (7.3 g, 96.5% yield) as a white solid. LC-MS: m/z 433 [M+Hj.

Reference： [1]Patent: WO2017/27684,2017,A1 .Location in patent: Paragraph 00292
[2]Chemistry - A European Journal,2019,vol. 25,p. 8719 - 8724
[3]Synthesis,1994,p. 87 - 92

3
[ 101990-45-8 ]
[ 122-52-1 ]
[ 154321-18-3 ]

Reference： [1]Synthesis,1994,p. 87 - 92

4
[ 3510-66-5 ]
2-bromo-5-tribromomethyl-pyridine [ No CAS ]
[ 101990-45-8 ]
[ 154321-32-1 ]

Reference： [1]Organic Letters,2000,vol. 2,p. 3845 - 3848

5
[ 16874-34-3 ]
[ 101990-45-8 ]
[ 784149-56-0 ]

Yield	Reaction Conditions	Operation in experiment
78%	With ammonium chloride; lithium diisopropyl amide; In tetrahydrofuran; n-heptane; ethylbenzene; ethyl acetate;	Preparation c-81 Ethyl 2-[(6-bromopyridin-3-yl)methyl]tetrahydrofuran-2-carboxylate To a solution of <strong>[16874-34-3]ethyl tetrahydrofuran-2-carboxylate</strong> (52.9 mmol, 9.10 g, 1.5 eq.) cooled to -78 degrees C. in THF (90 mL) was added dropwise a solution of 2 M lithium diisopropylamide (52.9 mmol, 1.5 eq.) in a mixture of heptane/THF/ethylbenzene. The enolate was allowed to form for one hour at the same low temperature whereupon a solution of 2-bromo-5-(bromomethyl)pyridine (35.3 mmol, 8.85 g, 1.0 eq.) in THF was added dropwise. The reaction was allowed to warm slowly to room temperature overnight. The reaction was quenched with saturated ammonium chloride. The mixture was extracted with ethyl acetate and the organic extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a yellow oil. This crude product was purified on a Biotage Sp4 65i over a gradient of 5% to 95% ethyl acetate in hexanes to afford a golden oil (8.70 g, 78%). LRMS: 315 (M+H)+. 1H NMR (DMSO-d6, 400 MHz): delta 8.21 (1 H, s) 7.40-7.49 (2 H, m) 3.94 (2 H, q, J=7.0 Hz) 3.71-3.85 (2 H, m) 3.05-3.11 (1 H, m) 2.91-2.97 (1 H, m) 2.38-2.47 (1 H, m) 1.83-2.09 (3 H, m) 1.09 (3 H, t, J=7.0 Hz)
78%		To a solution of <strong>[16874-34-3]ethyl tetrahydrofuran-2-carboxylate</strong> (52. 9 mmol, 9. 10 g, 1. 5 eq.) cooled to-78 degrees C in THF (90 mL) was added dropwise a solution of 2 M lithium DIISOPROPYLAMIDE (52. 9 mmol, 1. 5 eq.) in a mixture of heptane/THF/ethylbenzene. The enolate was allowed to form for one hour at the same low temperature whereupon a solution of 2-BROMO-5- (BROMOMETHYL) pyridine (35. 3 MMOL, 8. 85 g, 1. 0 eq.) in THF was added dropwise. The reaction was allowed to warm slowly to room temperature overnight. The reaction was quenched with saturated ammonium chloride. The mixture was extracted with ethyl acetate and the organic extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a yellow oil. This crude product was purified on a Biotage SP4 65i over a gradient of 5% to 95 % ethyl acetate in hexanes to afford a golden oil (8. 70 g, 78%). LRMS : 315 (M+H) T. H NMR (DMSO-D6, 400 MHz) :. 8. 21 (1 H, s) 7. 40-7. 49 (2 H, m) 3. 94 (2 H, q, J=7. 0 Hz) 3. 71-3. 85 (2 H, m) 3. 05-3. 11 (1 H, m) 2. 91-2. 97 (1 H, m) 2. 38-2. 47 (1 H, m) 1. 83-2. 09 (3 H, m) 1. 09 (3 H, t, J=7. 0 HZ)

Reference： [1]Patent: US2005/187266,2005,A1
[2]Patent: WO2004/92145,2004,A1 .Location in patent: Page 119-120

6
[ 101990-45-8 ]
[ 784149-99-1 ]

Yield	Reaction Conditions	Operation in experiment
	In methoxy dimethylmalonate; ethyl acetate;	Preparation d-20 Dimethyl [(6-bromopyridin-3-yl)methyl](methoxy)malonate To a slurry of potassium t-butoxide (46.6 mmol, 5.22 g, 1,3 eq.) in anhydrous DMF (250 mL) cooled to 0 C. was added methoxy dimethylmalonate (46.6 mmol, 7.55 g, 1,3 eq.) via syringe in small portions. The enolate was allowed to form over approximately 30 minutes at which point 2-bromo-5-(bromomethyl)pyridine was added portionwise. The reaction mixture was allowed to warm slowly to room temperature over 3 hours. The reaction mixture was diluted with ethyl ether and transferred to a separatory funnel containing saturated ammonium chloride. The layers were shaken and separated and the organic layer was washed with water. The organic layer was then dried over anhydrous magnesium sulfate and concentrated in vacuo. The yellow oil obtained was purified on a Biotage Sp4 65i over a gradient of 0-100% ethyl acetate in hexanes to afford a colorless oil that solidified on standing (12.1 g, quant.) LRMS: 333 (M+H)+. 1H NMR (DMSO-d6, 400 MHz): δ 8.27 (1 H, s) 7.45-7.55 (2 H, m) 3.82 (6 H, s) 3.57 (3 H, s) 3.42 (2 H, s).

Reference： [1]Patent: US2005/187266,2005,A1

7
[ 101990-45-8 ]
[ 20246-63-3 ]
[ 950207-78-0 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 0 - 20℃;	2-bromo-5-(bromomethyl)pyridine 1 in 5 ml dry THF was added to the solutions of 2a-c at 0 C. under argon and stirred at room temperature overnight. The reactions were monitored by HPLC. After the reaction was completed, 2 ml of MeOH-AcOH (1:1) was added to quench the reaction and the resulting solution was extracted with DCM (3*30 ml). The collected DCM phase was washed twice with H2O and dried over Mg2SO4 overnight. Purification by chromatography on silica with DCM containing MeOH (0.5~2.0%) as an eluant following evaporation solvent gave the products 3a-c as sticky oils. 2-bromo-5-((2-methoxyethoxy)methyl)pyridine 3a was obtained over two steps. CI-MS: m/z 246 (M)+; CI-HRMS [M]+ calcd. for C9H13BrNO2: 246.0130 found: 246.0131. δH (400 Hz, CDCl3): 8.27 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 4.49 (s, 2H), 3.60-3.58 (m, 2H), 3.53-3.51 (m, 2H), 3.33 (s, 3H). δC (75 Hz, CDCl3): 149.1, 141.0, 137.9, 133.0, 127.7, 71.7, 69.8, 69.7 and 58.9. 2-bromo-5-((2-(2-methoxyethoxy)ethoxy)methyl)pyridine 3b over two steps. CI-MS: m/z 290 (M)+; CI-HRMS [M]+ calcd. for C11H17BrNO3: 290.0389 found: 290.0392. δH (400 Hz, CDCl3): 8.28 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 4.50 (s, 2H), 3.64-3.63 (m, 4H), 3.61-3.59 (m, 2H), 3.51-3.49 (m, 2H), 3.33 (s, 3H). δC (75 Hz, CDCl3): 149.1, 141.0, 137.9, 133.0, 127.7, 71.7, 70.4(2), 70.4(1), 69.8, 69.7 and 58.9. 2-bromo-5-((2-(2-(2-methoxyethoxy)ethoxy)ethoxy)methyl)pyridine 3c over two steps. CI-MS: m/z 334 (M+H)+; CI-HRMS [M+H]+ calcd. for C13H21BrNO4: 334.0654 found: 334.0656. δH (400 Hz, CDCl3): 8.28 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.42 (d, J=8.4 Hz, 1H), 4.50 (s, 2H), 3.64-3.59 (m, 10H), 3.52-3.49 (m, 2H), 3.33 (s, 3H). δC (75 Hz, CDCl3): 149.3, 141.2, 138.0, 133.2, 127.8, 71.9, 70.6, 70.5(4), 70.4(6), 69.9, 69.8 and 59.0.

Reference： [1]Patent: US2007/219276,2007,A1 .Location in patent: Page/Page column 41-42

8
[ 110-91-8 ]
[ 101990-45-8 ]
[ 364793-93-1 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1.0h;	The crude is dissolved in anhydrous THF (40 mL). DIEA (5.03 mL, 29mmol) is added, followed by addition of morpholine (3.0 mL, 34.3 mmol). After stirring at room temperature for 1 hour, the reaction is partitioned between saturated NaHCO3 (30 mL) and EtOAc (100 mL) and separated. EtOAc is washed with brine (30 mL), dried and evaporated. The crude is purified by flash column chromatography (SiO2, 1%NH3 in CH3OH/CH2C12 from 0 to 10%) to give a light tan colored solid: 1H NMR 400 MHz (DMSO-d6) δ 8.31 (d, J = 2.4 Hz, IH), 7.69 (dd, J = 2.4, 8.4 Hz, IH), 7.62 (d, J = 8.0 Hz, IH), 3.57 (t, J = 4.8 Hz, 4H), 3.48 (s, 2H), 2.35 (t, J = 4.4 Hz, 4H); MS m/z 257.1 (M+l).

Reference： [1]Patent: WO2008/8747,2008,A1 .Location in patent: Page/Page column 35, 36, 63
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 5071 - 5074

9
6-(3-(2,6-dichloro-3,5-dimethoxyphenylamino)pyrazin-2-yl)pyrimidin-4-ylamine [ No CAS ]
[ 101990-45-8 ]
(6-(3-(2,6-dichloro-3,5-dimethoxyphenylamino)pyrazin-2-yl)pyrimidin-4-yl)-(5-morpholin-4-ylmethylpyridin-2-yl)amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;palladium diacetate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; at 150℃; for 0.333333h;Irradiation;	{6-[3-(2,6-Dichloro-3,5-dimethoxy-phenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-(5- morpholin-4-ylmethyl-pyridin-2-yl)-amine (41). A suspension of (6-[3-(2,6-dichloro-3,5-dimethoxy-phenylamino)-pyrazin-2-yl]-pyrimidin- 4-ylamine (41) (30 g, 0.076 mmol), 4-(6-bromo-pyridin-3-ylmethyl)-morpholine 12 (29 mg, 0.1 14mmol), Xantphos (10 mg, 0.0178 mmol), palladium (II) acetate (2 mg, 0.0089 mmol) and cesium carbonate (50 mg, 0.152 mmol) in dioxane (1.5 mL) is degassed. After purging with Ar, the vial is sealed by the cap and irradiated at 15O0C for 20 minutes in Smith Synthesizer. The reaction mixture is treated with 4 ml of 5% diethyl dithiocabamyl acid sodium salt solution. The solid is collected by filtration and washed with water, then dried. The crude is purified by silica gel flash chromatography eluting with 1%NH3 in CH3OH/EtOAc from 0 to 10%) to afford the desired product {6-[3-(2,6-dichloro-3,5- dimethoxy-phenylamino)-pyrazin-2-yl]-pyrimidin-4-yl}-(5-morpholin-4-ylmethyl-pyridin-2-yl)-amine (41) (Example 94).

Reference： [1]Patent: WO2008/8747,2008,A1 .Location in patent: Page/Page column 60, 62-63

10
[ 101990-45-8 ]
[ 161315-62-4 ]
tert-butyl (R)-2-(N-((6-bromopyridin-3-yl)methyl)-4-methoxyphenylsulfonamido)-3-methylbutanoate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 5752 - 5764

11
[ 101990-45-8 ]
5,5''-Bis(hydroxytetramethylenoxymethyl)-2,2':6',2''-terpyridine [ No CAS ]

Reference： [1]Synlett,1999,p. 342 - 344

12
[ 101990-45-8 ]
[ 143-33-9 ]
[ 144873-99-4 ]

Yield	Reaction Conditions	Operation in experiment
49%	In 1,3-dioxane; water; at 20℃; for 15h;	Step 3: (6-Bromopyridin-3-yl) acetonitrile To a stirred solution [OF NACN (117G,] 2. [38MOL)] in dioxane (1L) and water (1L), was added the above crude 2-bromo-5-bromomethylpyridine (275g) and the mixture was stirred at rt for 15h. The reaction mixture was quenched with cold water [(15L)] and extracted with EtOAc [(3X1L).] The organic layer was washed with water [(3X1 L),] brine [(2X1 L),] dried with [NA2S04] and concentrated under reduced pressure to give crude title compound. The crude residue was purified by column chromatography over silica gel (pet. [ETHER/ETHYLACETATE,] 7: 3) to give 95g [(6-BROMOPYRIDIN-3-YL)] acetonitrile as a pale yellow solid (49%). [TLC, [RF=] 0.5, pet. [ETHER/ETHYLACETATE] 7: 3]

Reference： [1]Patent: WO2003/106455,2003,A1 .Location in patent: Page 55-56

13
[ 3510-66-5 ]
[ 128-08-5 ]
[ 101990-45-8 ]

Yield	Reaction Conditions	Operation in experiment
	With dibenzoyl peroxide; In chloroform; for 6h;Heating / reflux;	Step 2: 2-Bromo-5-bromomethylpyridine To a suspension of 2-bromo-5-methylpyridine (170g, 0. [95MO1)] in [CC14] (2L) was added NBS (193g, [1.] [08MOL)] and benzoylperoxide (15g) and the mixture was refluxed for 6h. The reaction mixture was cooled down to rt and the solid formed was filtered off. The filtrate was concentrated affording 275g of crude 2-bromo-5-bromomethylpyridine which was used without further purification in the next step (mixture of mono-bromo and di-bromo). [TLC, [RF=] 0.7, pet. ether/ethylacetate 9: 1].

Reference： [1]Patent: WO2003/106455,2003,A1 .Location in patent: Page 55

14
[ 101990-45-8 ]
[ 5018-30-4 ]
[ 784149-99-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium tert-butylate; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 3.5h;	To a slurry of potassium t-butoxid (46. 6 mmol, 5. 22 G, 1. 3 eq.) in anhydrous DMF (250 mL) cooled to 0 C was added methoxy dimethylmalonate (46. 6 MMOL, 7. 55 G, 1. 3 eq.) via syringe in small portions. The ENOLATE was allowed to form over approximately 30 minutes at which point 2-BROMO-5- (BROMOMETHYL) pyridine was added portionwise. The reaction mixture was allowed to warm slowly to room temperature over 3 hours. The reaction mixture was diluted with ethyl ether and transferred to a separator funnel containing saturated ammonium chloride. The layers were shaken and separated and the organic layer was washed with water. The organic layer was then dried over anhydrous magnesium sulfate and concentrated in vacuo. The yellow oil obtained was purified on a Biotage Sp4 65i over a gradient of 0-100 % ethyl acetate in hexanes to afford a colorless oil that solidified on standing (12. 1 g, quant.) LRMS : 333 (M+H) +. H NMR (DMSO-D6, 400 MHz) ; 8. 27 (1 H, s) 7. 45-7. 55 (2 H, m) 3. 82 (6 H, s) 3. 57 (3 H, s) 3. 42 (2 H, s)

Reference： [1]Patent: WO2004/92145,2004,A1 .Location in patent: Page 155

15
[ 101990-45-8 ]
[ 6921-34-2 ]
[ 845973-17-3 ]

Yield	Reaction Conditions	Operation in experiment
66%		Step 2: To a solution of the product from Step 1 (3.5 g, 14 mmol) in anhydrous THF (60 ml) at 0 C was added benzylmagnesium chloride (2.0 M/THF, 10.6 ML, 21 MMOL). The reaction mixture was stirred at 0 C for 30 min and at RT for 2 h. The reaction was quenched with saturated NH4CI aqueous solution, extracted with EtOAc, dried (MGS04), filtered and concentrated. The residue was subjected to silica gel flash chromatography (5: 95 EtOAc/hexanes) to afford the product (2.4 g, 66%).

Reference： [1]Patent: WO2005/16876,2005,A2 .Location in patent: Page/Page column 69

16
[ 101990-45-8 ]
[ 108-00-9 ]
[ 791789-98-5 ]

Yield	Reaction Conditions	Operation in experiment
25%	In DMF (N,N-dimethyl-formamide); at 20℃; for 15h;	A solution of the amine (1 equiv) and <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> [Windscheif, P-M.; Voegtle, F.; Synthesis 1994; 87-92] in DMF were stirred at room temperature for 15h. The solvent was removed under vacuum and the residue purified by silica gel chromatography. Examples a) R1 = dimethylaminoethyl The general procedure was followed using <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> (3.9 G) and dimethylamino ethylamine (5.5 g) in DMF (100 ML). Silica gel chromatography (4% MeOH in DCM) gave the pure product (0.62 g, 25%). LC-MS-SHOWS a single peak, M+H.

Reference： [1]Patent: WO2004/96771,2004,A1 .Location in patent: Page 19-20

17
[ 101990-45-8 ]
[ 64-04-0 ]
[ 791789-97-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	In DMF (N,N-dimethyl-formamide); at 20℃; for 15h;	A solution of the amine (1 equiv) and <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> [Windscheif, P-M.; Voegtle, F.; Synthesis 1994; 87-92] in DMF were stirred at room temperature for 15h. The solvent was removed under vacuum and the residue purified by silica gel chromatography. Examples a) R1 = phenethyl The general procedure was followed using 2-BROMO-5-BROMOMETHYLPYRIDINE (8.7 g) and phenylethylamine (16.7 g) in DMF (250 ML). Silica gel chromatography (4% ICAEOH in DCM) gave the pure product (10.0 g, 99%). 1H NMR (CDCI3, 400MHZ) : 8 2.77-2. 90 (4H, M), 3.76 (2H, S), 7.18-7. 32 (5H, m), 7.45 (1H, d), 7.52 (1H, dd), 8.27 (1H, d). LC-MS- shows a single peak, M+H 291,293

Reference： [1]Patent: WO2004/96771,2004,A1 .Location in patent: Page 14-15

18
[ 101990-45-8 ]
[ 108-95-2 ]
[ 845973-23-1 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 90℃; for 2h;	Example 17 Step 1: A mixture of the product from Example 16, Step 1 (0.70 g, 2.8 MMOL), phenol (0.19 g, 2.0 MMOL), and K2CO3 (0.58 g, 4.2 mmol) in anhydrous DMF (10 ml) was heated to 90 C for 2 h. The mixture was cooled down to RT, diluted with water, extracted with ether, dried (MGS04), filtered and concentrated. The residue was subjected to flash chromatography (5: 95 EtOAc/hexanes) to afford the product as white solid (0.38 g, 71 %).

Reference： [1]Patent: WO2005/16876,2005,A2 .Location in patent: Page/Page column 70-71

19
[ 123-75-1 ]
[ 101990-45-8 ]
[ 742085-62-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 20℃; for 6h;	Reference Example 76; 2-bromo-5-(1-pyrrolidinylmethyl)pyridine; [] A solution of 2-bromo-5-(bromomethyl)pyridine (9.06 g, 36.1 mmol), pyrrolidine (3.62 ml, 43.3 mmol) and potassium carbonate (9.98 g, 72.2 mmol) in acetonitrile (45 ml) was stirred at room temperature for 6 hrs. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated aqueous potassium carbonate solution and saturated, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (developing solvent; ethyl acetate) to give the title compound (7.31 g).

Reference： [1]Patent: EP1593667,2005,A1 .Location in patent: Page/Page column 64

20
[ 101990-45-8 ]
[ 124-41-4 ]
[ 708273-70-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	In methanol; at 20℃; for 3h;	2-Bromo-5-(methoxymethyl)pyridine. 2-Bromo-5-bromomethyl-pyridine, 4 (3.58 g, 14.3 mmoles) was dissolved in methanol (20 mL) under nitrogen. Sodium methoxide (0.89 g, 15.7 mmoles, 95%) was added and the mixture stirred at room temperature. After 3 hours, the methanol was rotovapped off and the residue dissolved in dichloromethane and washed with water. The organic extract was adsorbed onto silica gel and chromatographed. The column was eluted with a gradient of hexane to 20% ethyl acetate/hekane. Pure fractions were combined and concentrated to provide the title compound as a colorless oil, 2.62 g (90%). LC/MS (M+H)+ m/z=202.0.
90%	In methanol; at 20℃; for 3h;Inert atmosphere;	Step B2-Bromo-5-(methoxymethyl)pyridine. 2-Bromo-5-bromomethyl-pyridine, 4 (3.58 g, 14.3 mmoles) was dissolved in methanol (20 mL) under nitrogen. Sodium methoxide (0.89 g, 15.7 mmoles, 95%) was added and the mixture stirred at room temperature. After 3 hours, the methanol was rotovapped off and the residue dissolved in dichloromethane and washed with water. The organic extract was adsorbed onto silica gel and chromatographed. The column was eluted with a gradient of hexane to 20% ethyl acetate/hexane. Pure fractions were combined and concentrated to provide the title compound as a colorless oil, 2.62 g (90%). LC/MS (M+H)+ m/z = 202.0.

Reference： [1]Patent: WO2021/259208,2021,A1 .Location in patent: Paragraph 0568-0570
[2]Patent: US2005/192302,2005,A1 .Location in patent: Page/Page column 23
[3]Patent: WO2012/114223,2012,A1 .Location in patent: Page/Page column 40-41

21
[ 101990-45-8 ]
[ 151-50-8 ]
[ 144873-99-4 ]

Yield	Reaction Conditions	Operation in experiment
61%	In N,N-dimethyl-formamide; at 60℃; for 0.5h;	(Referential Example 10) Synthesis of 2-bromo-5-(cyanomethyl)pyridine (referential compound 10-1) Potassium cyanide (7.80 g, 120 mmol) was added to a solution of 15.0 g (60.0 mmol) of <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong>(referential compound 8) in 150 ml of N,N-dimethylformamide and the mixture was slowly stirred at 60C for 15 minutes. After that, water was added thereto little by little until potassium cyanide was completely dissolved and then the mixture was stirred at 60C for 15 minutes. After the reaction was finished, the reaction solution was poured into ethyl acetate/saturated aqueous solution of ammonium chloride and the organic layer was separated therefrom. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was subjected to a silica gel column chromatography (eluding solvent: n-hexane: ethyl acetate = 9:1 to 7:3 (v/v)) and the fraction containing the aimed substance was concentrated in vacuo to give 9.24 g of the title compound as pale yellow powder (yield: 61%). Rf value: 0.15 (n-hexane: ethyl acetate = 4:1 (v/v)) Mass spectrum (CI, m/z): 197, 199 (M+ + 1) IR spectrum (KBr, cm-1): 2253 1H-NMR spectrum (CDCl3, δ ppm): 3.74 (s, 2H), 7.61-7.53 (m, 2H), 8.36-8.35 (m, 1H)

Reference： [1]Patent: EP1679308,2006,A1 .Location in patent: Page/Page column 35-36

22
[ 101990-45-8 ]
[ 69555-14-2 ]
2-[(N-diphenylmethylene)amino]-3-(4-bromo-3-pyridinyl) propanoic acid, ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With diisopropylamine;	Step B 2-[(N-Diphenylmethylene)amino]-3-(4-bromo-3-pyridinyl) propanoic acid, ethyl ester To a solution of N-(diphenylmethylene)glycine ethyl ester (4.30 g, 16.11 mmol) in TEE (25 mL) at -78 C. was added dropwise a 2.0M solution of LDA in TEE (8.0 mL, 16.0 mmol). After being stirred for 30 min at -78 C., a solution of 2-bromo-5-bromomethyl-pyridine in 10 mL of TEE was added and the reaction allowed to warm to rt. After 1 h, the reaction was diluted with EtOAc (50 mL) and washed with water (50 mL) and saturated aqueous NaCl (50 mL). The organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to give a yellow oil. The oil was purified by flash column chromatography on silica gel eluted with hexane/EtOAc (10:1) to yield 2-[(N-diphenylmethylene)amino]-3-(4-bromo-3-pyridinyl) propanoic acid, ethyl ester as a pale yellow oil.

Reference： [1]Patent: US2003/8861,2003,A1

23
[ 101990-45-8 ]
[ 122306-01-8 ]

Yield	Reaction Conditions	Operation in experiment
	With silver nitrate; In water; acetone;	Step E Preparation of 2-bromo-5-(hydroxymethyl)pyridine To a solution of 2-bromo-5-(bromomethyl)pyridine, as described above in Step D, (2.15 g, 8.57 mmol) in acetone (100 mL) was added a solution of silver nitrate (2.18 g, 12.9 mmol) in water (100 mL). The reaction was stirred in the dark at 25 C. for 72 hours. The reaction was filtered and the acetone was removed in vacuo. The residue was partitioned between methylene chloride (100 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (1*100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (40?90% ethyl acetate/hexane) to provide the title compound as a clear oil.

Reference： [1]Patent: US2002/22633,2002,A1

24
[ 715652-45-2 ]
[ 101990-45-8 ]
(+)-6-(2-bromopyridin-5-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; N,N-dimethyl-formamide;	REFERENCE EXAMPLE 99 (+)-6-(2-Bromopyridin-5-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin Dihydrochloride To a solution of (+)-2-[2-(N,N-dimethylamino)ethyl]-6-hydroxytetralin (0.220 g) in DMF (5 ml) was added sodium hydride (60% in oil, 0.049 g) at room temperature. The reaction mixture was stirred at 50 C. for 30 min. To the reaction mixture, cooled at 0 C., was added a solution of 2-bromo-5-pyridylmethylbromide (0.462 g) in THF (5 ml). After stirring at 0 C. for 2 hr, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate:hexane=1:4) and converted into its dihydrochloride, which was recrystallized from ethanol-ethyl acetate to obtain the titled compound (295 mg). m.p.: 171-181 C. (decomposed). [α]D20=+41.2 C. (c=0.500 in methanol).

Reference： [1]Patent: US6310107,2001,B1

25
2-bromo-S-bromomethylpyridine [ No CAS ]
[ 101990-45-8 ]
[ 144873-99-4 ]

Yield	Reaction Conditions	Operation in experiment
109 g (32% from 2-bromo-5-picoline)	In N-methyl-acetamide; water;	Step 5. Preparation of 2-bromo-5-cyanomethyl-pyridine The 476 g of crude 2-bromo-5-bromomethylpyridine from step 4 was dissolved in 4000 mL of dimethylformamide (DMF)/water (7:1) and treated with 168 g (2.58 mol) of potassium cyanide. The reaction was allowed to stir at ambient temperature for 72 h, concentrated in vacuo, and partitioned between ethyl acetate and water; the organic layer was washed with water, washed with brine, dried (MgSO4), and reconcentrated in vacuo to provide the crude nitrile. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (25:75) gave 109 g (32% from 2-bromo-5-picoline) of 2-bromo-5-cyanomethylpyridine as a yellowish orange solid: mp 55.5-57.5 C.; NMR (CDCl3) δ 3.74 (s, 2H), 7.54 (d, J=8 Hz, 1H), 7.59 (dd, J=8 and 2 HZ, 1H), 8.35 (d, J=2 Hz, 1H); MS (FAB) m/e (rel intensity) 199 (85), 197 (100).

Reference： [1]Patent: US6090828,2000,A

26
[ 3510-66-5 ]
2-bromo-S-bromomethylpyridine [ No CAS ]
[ 101990-45-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; In tetrachloromethane;	Step 4: Preparation of 2-bromo-S-bromomethylpyridine A solution of 296.3 g (1.72 mol) of 2-bromo-5-picoline from step 3 in 6 L of carbon tetrachloride was treated with 306.5 g (1.72 mol) of N-bromosuccinimide (NBS) and 28.3 g 173 mmol) of azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 60% monobromomethyl product): NMR (CDCl3) δ 4.42 (s, 2H), 7.48 (d, J=9 Hz, 1H), 7.60 (dd, J=9 and 3 Hz, 1H), 8.37 (d, J=3 Hz, 1H).

Reference： [1]Patent: US6090828,2000,A

27
[ 101990-45-8 ]
[ 144873-99-4 ]

Yield	Reaction Conditions	Operation in experiment
109 g (32% from 2-bromo-5-picoline)	In N-methyl-acetamide; water;	Step 5: Preparation of 2-bromo-5-cyanomethyl-pyridine. The 476 g of crude 2-bromo-5-bromomethylpyridine from step 4 was dissolved in 4000 mL of dimethylformamide (DMF)/water (7:1) and treated with 168 g (2.58 mol) of potassium cyanide. The reaction was allowed to stir at ambient temperature for 72 h, concentrated in vacuo, and partitioned between ethyl acetate and water; the organic layer was washed with water, washed with brine, dried (MgSO4), and reconcentrated in vacuo to provide the crude nitrile. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (25:75) gave 109 g (32% from 2-bromo-5-picoline) of 2-bromo-5-cyanomethylpyridine as a yellowish orange solid: mp 55.5-57.5 C.; NMR (CDCl3)δ3.74 (s, 2 H), 7.54 (d, J=8 Hz, 1 H), 7.59 (dd, J=8 and 2 HZ, 1 H), 8.35 (d, J=2 Hz, 1 H); MS (FAB) m/e (rel intensity) 199 (85), 197 (100).

Reference： [1]Patent: US5196537,1993,A

28
[ 101990-45-8 ]
[ 169503-35-9 ]
[ 222414-88-2 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; N,N-dimethyl-formamide;	Step 3 5-(4-Cyanobenzyl)-1-(2-bromopyrid-5-ylmethyl)imidazole To a flask was charged 1-trityl -4-p-cyanobenzyl imidazole (2.77 mmol, 1.18 g) from Step 1 and 2-bromo-5-bromomethyl pyridine (2.77 mmol, 0.67 g) from Step 2 in DMF (10 mL) and the mixture heated at 100 C. for 6 hr. The DMF was then removed in vacuo and the residue was triturated with ethyl ether. The ethyl ether was then decanted off and replaced with methanol (20 mL). This solution was then refluxed for 4 hr, cooled to ambient temperature and purified on a C18 preperative hplc column to provide the title compound. High resolution FAB-MS: calc; 353.040183 found; 353.040183. 1 H-NMR (CD3 OD): 4.2 ppm (s, 2H); 5.4 ppm (s, 2H); 7.2 and 7.6 ppm (d, 2H); 8.1 ppm (s, 1H); 9.1 ppm (s, 1H).

Reference： [1]Patent: US6127390,2000,A

29
[ 3510-66-5 ]
2-bromo-5-romomethylpyridine [ No CAS ]
[ 101990-45-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; In tetrachloromethane;	Step 4: Preparation of 2-bromo-5-romomethylpyridine. A solution of 296.3 g (1.72 mol) of 2-bromo-5-picoline from step 3 in 6 L of carbon tetrachloride was treated with 306.5 g (1.72 mol) of N-bromosuccinimide (NBS) and 28.3 g 173 mmol) of azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 60% monobromomethyl product): NMR (CDCl3)δ4.42 (s, 2 H), 7.48 (d, J=9 Hz, 1 H), 7.60 (dd, J=9 and 3 Hz, 1 H), 8.37 (d, J=3 Hz, 1 H).
	With N-Bromosuccinimide; In tetrachloromethane;	Step 4: Preparation of 2-bromo-5-romomethylpyridine A solution of 296.3 g (1.72 mol) of 2-bromo-5picoline from step 3 in 6 L of carbon tetrachloride was treated with 306.5 g (1.72 mol) of N-bromosuccinimide (NBS) and 28.3 g 173 mmol) of azobisisobutyronitrile (AIBN). The reaction was stirred at reflux under nitrogen for 3 h, filtered, and concentrated in vacuo providing 476 g of crude 2-bromo-5-bromomethylpyridine as a brownish yellow solid (NMR indicates that this material is only 60% monobromomethyl product): NMR (CDCl3) δ4.42 (s, 2H), 7.48 (d, J=9Hz, 1H), 7.60 (dd, J=9 and 3Hz, 1H), 8.37 (d, J=3Hz, 1H).

Reference： [1]Patent: US5196537,1993,A
[2]Patent: US5451593,1995,A

30
[ 101990-45-8 ]
[ 161367-73-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium chloride; N-butylamine; In 1,4-dioxane; methanol; dichloromethane; ethyl acetate;	EXAMPLE VI N-(6-Bromopyridin-3-ylmethyl)-N-butylamine STR27 A solution of 2 g (7.97 mmol) of <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> and 2.91 g (39.85 mmol) of n-butylamine in 20 ml of dioxane is heated under reflux for 2 h. Subsequently, the solvent is removed in vacuo and the residue is taken up in ethyl acetate/dichloromethane, which is then washed with water and a saturated solution of sodium chloride. The organic phase is dried over sodium sulphate and concentrated, and the residue is purified on silica gel using dichloromethane/methanol (95:5). Yield: 1.42 g (73% of theory) Rf =0.49 (dichloromethane/methanol=95:5)

Reference： [1]Patent: US5594010,1997,A

31
[ 7226-23-5 ]
[ 101990-45-8 ]
[ 141872-21-1 ]
Ethyl 2-[N-(6-bromopyridin-3-ylmethyl)-N-propyl]amino}pyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; n-butyllithium; 1,1,1,3,3,3-hexamethyl-disilazane; In tetrahydrofuran; ethyl acetate; Petroleum ether;	EXAMPLE VIII Ethyl 2-[N-(6-bromopyridin-3-ylmethyl)-N-propyl]amino}pyridine-3-carboxylate STR29 3.2 ml of a 1.6N solution of n-butyllithium are added at -20 C. to a solution of 0.87 g (5.4 mmol) of hexamethyldisilazane in 5.5 ml of THF. The solution prepared in this way is added dropwise at from -10 C. to 0 C. to a solution of 1.07 g (5.13 mmol) of ethyl 2-propylaminopyridine-3-carboxylate and 1.25 g of 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU) in 4 ml of THF. After stirring at this temperature for 10 min, 2 g (8 mmol) of <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> dissolved in 12 ml of THF are added slowly dropwise. After removing the cooling bath, the mixture is stirred at 20 C. for 36 h. After that, 2 drops of conc. hydrochloric acid are added, the solvent is removed in vacuo, and the residue is taken up in ethyl acetate, which is then washed three times with water. The organic phase is dried over sodium sulphate and concentrated, and the residue is purified on silica gel using petroleum ether/ethyl acetate (20:1). Yield: 1.14 g (59% of theory) Rf =0.35 (petroleum ether/ethyl acetate=5:1)

Reference： [1]Patent: US5594010,1997,A

32
2-bromo-5-romomethylpyridine [ No CAS ]
[ 101990-45-8 ]
[ 144873-99-4 ]

Yield	Reaction Conditions	Operation in experiment
109 g (32% from 2-bromo-5-picoline)	In N-methyl-acetamide; water;	Step 5: Preparation of 2-bromo-5-cyanomethyl-pyridine The 476 g of crude 2-bromo-5-bromomethylpyridine from step 4 was dissolved in 4000 mL of dimethylformamide (DMF)/water (7:1) and treated with 168 g (2.58 mol) of potassium cyanide. The reaction was allowed to stir at ambient temperature for 72 h, concentrated in vacuo, and partitioned between ethyl acetate and water; the organic layer was washed with water, washed with brine, dried (MgSO4), and reconcentrated in vacuo to provide the crude nitrile. Purification by silica gel chromatography (Waters Prep-500A) using ethyl acetate/hexane (25:75) gave 109 g (32% from 2-bromo-5-picoline) of 2-bromo-5-cyanomethylpyridine as a yellowish orange solid: mp 55.5-57.5 C.; NMR (CDCl3) δ3.74 (s, 2H), 7.54 (d, J=8Hz, 1H), 7.59 (dd, J=8 and 2 HZ, 1H), 8.35 (d, J=2Hz, 1H); MS (FAB) m/e (rel intensity) 199 (85), 197 (100).

Reference： [1]Patent: US5451593,1995,A

33
2-cyclopropyl-5,7-dimethylimidazo[4,5-b]pyridine [ No CAS ]
[ 101990-45-8 ]
[ 161367-68-6 ]

Yield	Reaction Conditions	Operation in experiment
69.7%	In dimethyl sulfoxide; ethyl acetate; Petroleum ether;	EXAMPLE I 2-Cyclopropyl-5,7-dimethyl-3-(6-bromopyridin-3-ylmethyl)imidazo[4,5-b]pyridine STR22 255 mg (6.4 mmol) of sodium hydride and 994 mg (5.3 mmol) of 2-cyclopropyl-5,7-dimethylimidazo[4,5-b]pyridine are stirred at 0 C. for 2 h in 15 ml of dimethyl sulphoxide. After adding 2 g (7.97 mmol) of <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong>, the mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and washed twice with ethyl acetate; the combined organic phases are washed with water and sodium chloride solution, dried over sodium sulphate and then chromatographed on 150 g of silica gel using ethyl acetate/petroleum ether mixtures 1:2→1:0 to yield 1.32 g of the title compound. Yield: 69.7% of theory Rf =0.45 (silica gel 60, ethyl acetate)

Reference： [1]Patent: US5594010,1997,A

34
[ 101990-45-8 ]
N¹-[(6-bromo-3-pyridinyl)methyl]-1,2-ethanediamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With ethylenediamine; In acetonitrile;	EXAMPLE 2 2-bromo-5-pyridylmethyl bromide (25 g) in a solution of acetonitrile was added dropwise to a solution of ethylenediamine (30 g) in acetonitrile (80 ml) at 0 C. After the reaction was stirred at room temperature for some time, the produced insoluble salts were filtrated off and then the filtrate was concentrated on a water bath at 40 C. to give N-(2-bromo-5-pyridylmethyl)ethylenediamine (22 g). nD26 1.5586 STR21

Reference： [1]Patent: US4678795,1987,A

35
[ 101990-45-8 ]
[ 154321-18-3 ]

Yield	Reaction Conditions	Operation in experiment
	With triethyl phosphite; In n-heptane; ethyl acetate;	(c) Diethyl (6-bromopyrid-3-ylmethyl)phosphonate. 3.0 g (11.9 mmol) of the compound obtained in Example 6(b) and 10 ml of triethyl phosphite were mixed together in a 100 ml round-bottomed flask. The mixture was refluxed for thirty minutes, cooled and evaporated to dryness. The residue obtained was purified by chromatography on a column of silica eluted with a mixture of ethyl acetate and heptane (6/4). After evaporation of the solvents, 3.12 g (80%) of the expected compound was collected in the form of a pale yellow oil.

Reference： [1]Patent: US6214878,2001,B1

36
[ 288-32-4 ]
[ 101990-45-8 ]
[ 1019780-48-3 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate; In N,N-dimethyl-formamide;	Step 1: Synthesis of 5- ((1H-imidazol- 1-yl)methyl)-2-bromopyridine. The starting material 2-bromo-5-(bromomethyl)pyridine was synthesized according to a published protocol (Tetr. Lett. 2002, 43, 1697). To a stirring solution ofthis compound (2 g, 8 mmol) in 20 mL of DMF was added imidazole (537 mg, 8 mmol, 1 eq) and K2C03 (3.32 g, 24 mmol, 3 eq) and stirred overnight. The reaction was concentrated in vacuo. The crude mixture was disolved in EtOAc and 10 mL of 10% citric acid and extracted. The organic layer was washed with H20 then brine, dried with Mg504, concentrated in vacuo, and purified byautomated chromatography to yield 1.35 g of an off-white solid (71% yield, R 0.30 in 10% MeOH in DCM). 1H NMR (400 MHz, CDCN) d 8.26 (d, J 2.4 Hz,111), 7.61 (s, 1H), 7.51 (d, J- 8.2 Hz, 1H), 7.45 (dd, J= 8.3, 2.5 Hz, 1H), 7.04 (s,1H), 6.97 (s, 1H), 5.15 (s, 2H).
60%	With 18-crown-6 ether; potassium carbonate; In acetonitrile;Reflux;	Synthesized using 1 b (1.32 g, 5.26 mmol), imidazole (0.75 g, 1 1.00 mmol), K2C03 (1.13 g, 8.16 mmol) and 18-crown-6 according to Method B. Yellow solid. Yield: 0.75 g, 60 %. 1 H NMR (CDCI3, 500 MHz): δΗ (ppm) = 5.12 (s, 2H), 6.88 (t, J = 1.2 Hz, 1 H), 7.13 (s, 1 H), 7.28 (d, J = 2.5 Hz, 1 H), 7.48 (d, J = 8.5 Hz, 1 H),7.56 (s, 1 H), 8.28 (d, J = 2.5 Hz, 1 H); MS (ESI): m/z = 239.08 [M+H]+.The cr-brominated compounds, imidazole (2 eq), a catalytic amount of 18-crown-6 and anhydrous K2C03 (1.5 eq) in dry acetonitrile were heated under reflux overnight. After cooling, water (50 ml_) was added, and the aqueous layer was extracted with ethyl acetate (3 x 30 ml_). The combined organic layers were washed with brine (25 ml_), dried over Na2S04 and evaporated in vacuo. The crude product was purified by column chromatography on silica-gel, using 5% methanol in ethyl acetate.

Reference： [1]Patent: WO2014/145331,2014,A1 .Location in patent: Page/Page column 60; 61
[2]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 1992 - 2010
[3]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 2 - 6
[4]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 559 - 564
[5]Patent: WO2012/52540,2012,A1 .Location in patent: Page/Page column 47-48; 49

37
[ 101990-45-8 ]
[ 1070292-75-9 ]
[ 1070293-19-4 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of the product of Example 11 (400 mg) in DMF (5 ml_) was added sodium hydride (60 mg) and the reaction stirred at room temperature for 10 minutes before the addition of a solution of 2-bromo-5-(bromomethyl)pyridine (760 mg) in DMF (5 ml_). The reaction mixture was stirred at room temperature for 30min.The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organics were dried over magnesium sulphate and evaporated. The residue was purified (SiO2 ethyl acetate:isohexane (1 :1) as eluent) to yield the sub-title compound (360mg).MS: APCI(+ve) 488,490 (1 :1) (M+H)+

Reference： [1]Patent: WO2008/122765,2008,A1 .Location in patent: Page/Page column 113

38
[ 616-45-5 ]
[ 101990-45-8 ]
[ 1057662-31-3 ]

Yield	Reaction Conditions	Operation in experiment
21%		A solution of 2-pyrrolidinone (170mg, 2mmol) in dimethylformamide (5ml) was cooled in an ice/methanol bath with stirring under argon. Solid sodium hydride (60% suspension in mineral oil, 160mg, 4mmol) was added portionwise over 10 minutes. The reaction was allowed to stir with cooling for 30 minutes. Then 2-bromo-5-(bromomethyl)pyridine [Ulrich et. al. Tetrahedron Letters 43, (2002), 1697-1700] (500mg, 2mmol) was added portionwise over 10 minutes and the whole mix was allowed to warm up slowly to room temperature and stirred under argon for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was removed and reduced to minimum volume under reduced pressure to give a golden oil which was added to a 5g isolute pre-packed silica column and eluted from ethyl acetate. The solvent was removed under reduced pressure to give the title compound as a yellow oil (108mg, 21%). LC/MS (ES): Found 255 & 257 (ES+), retention time 1.77mins. Ci0H11BrN2O requires 254 & 256.

Reference： [1]Patent: WO2008/110566,2008,A1 .Location in patent: Page/Page column 30

39
[ 101990-45-8 ]
[ 1074-82-4 ]
[ 120740-11-6 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2008,vol. 56,p. 204 - 212

40
[ 101990-45-8 ]
[ 81477-94-3 ]
[ 462123-60-0 ]

Yield	Reaction Conditions	Operation in experiment
	With 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine; (2S,4S,5R)-1-(anthracen-9-ylmethyl)-5-ethenyl-2-[(R)-(prop-2-en-1-yloxy)(quinolin-4-yl)methyl]-1-azabicyclo[2.2.2]octan-1-ium bromide; In dichloromethane; at -78 - 20℃;	This, together with tert-butyl 2- (diphenylmethyleneamino)acetate (4.71 g) and (2S,4S,5R)-2-((R)-allyloxy(quinolin-4- yl)methyl)-l-(anthracen-9-ylmethyl)-5-vinyl-l-azoniabicyclo[2.2.2]octane bromide (1.073 g)5 was dissolved in DCM (100 mL) and the solution was cooled to -78 0C under nitrogen. 2-tert- Butylimino-2-diethylamino-l,3-dimethyl-perhydro-l,3,2-diazaphosphorine (5 mL) was added drop wise over 5 min and the mixture was stirred at -78 0C for 7 h then allowed to reach RT overnight. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and water. The ethyl acetate was washed with brine, dried over magnesium sulfate, io filtered and concentrated in vacuo.

Reference： [1]Patent: WO2009/74829,2009,A1 .Location in patent: Page/Page column 53

41
[ 101990-45-8 ]
[ 92945-27-2 ]
[ 1260232-58-3 ]
[ 1260232-67-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	<strong>[92945-27-2]Ethyl 3-n-propylpyrazole-5-carboxylate</strong> (1.7 g, 9.1 mmol), 2-bromo-5-bromomethylpyridine (4.6 g, 9.1 mmol) and potassium carbonate (1.8 g, 12.7 mmol) were dissolved in DMF (70.0 mL, 904 mmol). The resulting suspension was stirred at room temperature overnight. The material was diluted with aqueous. NaHCO3 and diethyl ether. The aqueous layer was further extracted with diethyl ether. The combined organics were dried over MgSO4, filtered and concentrated. The residue was purified using flash chromatography [1st 30:1 hexanes/EtOAc; 2nd 10:1 hexanes/EtOAc]. The two isomers were separated and analyzed by NMR and NOE: 1-(6-bromopyridin-3-ylmethyl)-5-propyl-1H-pyrazole-3-carboxylic acid ethyl ester (1.2 g) and 2-(6-bromopyridin-3-ylmethyl)-<strong>[92945-27-2]5-propyl-2H-pyrazole-3-carboxylic acid ethyl ester</strong>.

Reference： [1]Patent: US2011/9409,2011,A1 .Location in patent: Page/Page column 36-37

42
[ 187235-08-1 ]
[ 101990-45-8 ]
[ 1188329-26-1 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃;	A solution of oxazine alcohol 41 (2.224 g, 12.0 mmol) and bromide 51 (3.045 g, 12.1 mmol) in anhydrous DMF (46 mL) under N2 at 0 0C was treated with 60% NaH (639 mg, 16.0 mmol) then quickly degassed and resealed under N2. After stirring at room temperature for 2.5 h, the reaction was cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (50 mL), added to brine (250 mL) and extracted with CH2Cl2 (12x 200 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-1% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 1-1.5% MeOH/CH2Cl2 gave (65')-6-[(6-bromo-3-pyridinyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,l-δ][l,3]oxazine (52) (3.739 g, 88%) as a cream solid: mp (MeOΗ/CΗ2Cl2/hexane) 200-203 0C; 1H NMR [(CD3)2SO] δ 8.35 (dd, J- 2.3, 0.4 Hz, 1 H), 8.02 (s, 1 H), 7.69 (dd, J= 8.2, 2.5 Hz, 1 H), 7.63 (dd, J= 8.1, 0.5 Hz, 1 H), 4.72-4.62 (m, 3 H), 4.47 (br d, J = 11.8 Hz, 1 H), 4.31 -4.19 (m, 3 H). Anal. (Ci2HnBrN4O4) C, H, N. HPLC purity: 100%.
88%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃; for 2.5h;Inert atmosphere;	A solution of oxazine alcohol 41 (2.224 g, 12.0 mmol) and bromide 51 (3.045 g, 12.1 mmol) in anhydrous DMF (46 mL) under N2 at 0 C. was treated with 60% NaH (639 mg, 16.0 mmol) then quickly degassed and resealed under N2. After stirring at room temperature for 2.5 h, the reaction was cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (50 mL), added to brine (250 mL) and extracted with CH2Cl2 (12*200 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-1% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 1-1.5% MeOH/CH2Cl2 gave (6S)-6-[(6-bromo-3-pyridinyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (52) (3.739 g, 88%) as a cream solid: mp (MeOH/CH2Cl2/hexane) 200-203 C.; 1H NMR [(CD3)2SO] δ 8.35 (dd, J=2.3, 0.4 Hz, 1H), 8.02 (s, 1H), 7.69 (dd, J=8.2, 2.5 Hz, 1H), 7.63 (dd, J=8.1, 0.5 Hz, 1H), 4.72-4.62 (m, 3H), 4.47 (br d, J=11.8 Hz, 1H), 4.31-4.19 (m, 3H). Anal. (C12H1lBrN4O4) C, H, N. HPLC purity: 100%.

Reference： [1]Patent: WO2011/14774,2011,A1 .Location in patent: Page/Page column 25; 26
[2]Patent: US2012/28973,2012,A1 .Location in patent: Page/Page column 10
[3]Journal of Medicinal Chemistry,2010,vol. 53,p. 8421 - 8439

43
[ 122306-01-8 ]
[ 101990-45-8 ]

Yield	Reaction Conditions	Operation in experiment
91%	With N-Bromosuccinimide; triphenylphosphine; In dichloromethane; at 20℃; for 3.5h;	A solution of (6-bromo-3-rhoyridinyl)methanol (50) (2.503 g, 13.3 mmol) and triphenylphosphine (4.026 g, 15.4 mmol) in anhydrous CH2Cl2 (100 mL) was carefully treated with recrystallized N-bromosuccinimide (2.732 g, 15.4 mmol) (water bath cooling), and the mixture was stirred at room temperature for 3.5 h. The resulting solution was concentrated, and then added to excess petroleum ether at the top of a silica gel column (100 g in petroleum ether), rinsing on with minimal extra CH2Cl2. Elution with petroleum ether firstly gave foreruns, and then further elution with 15-25% Et2O/pentane gave pure 2-bromo-5-(bromomethyl)pyridine (51) (Schubert et al., 1999) (3.045 g, 91%) as a lachrymatory white solid that was used directly in the next step; 1II NMR (CDCl3) delta 8.38 (d, J = 2.5 Hz, 1 H), 7.59 (dd, J - 8.2, 2.6 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 1 H), 4.42 (s, 2 H).
91%	With N-Bromosuccinimide; triphenylphosphine; In dichloromethane; at 20℃; for 3.5h;	F. Synthesis of (6S)-6-[6-(4-fluorophenyl)-3-pyridinyl]methoxy}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (5) by the method of Scheme 4 A solution of <strong>[122306-01-8](6-bromo-3-pyridinyl)methanol</strong> (50) (2.503 g, 13.3 mmol) and triphenylphosphine (4.026 g, 15.4 mmol) in anhydrous CH2Cl2 (100 mL) was carefully treated with recrystallized N-bromosuccinimide (2.732 g, 15.4 mmol) (water bath cooling), and the mixture was stirred at room temperature for 3.5 h. The resulting solution was concentrated, and then added to excess petroleum ether at the top of a silica gel column (100 g in petroleum ether), rinsing on with minimal extra CH2Cl2. Elution with petroleum ether firstly gave foreruns, and then further elution with 15-25% Et2O/pentane gave pure 2-bromo-5-(bromomethyl)pyridine (51) (Schubert et al., 1999) (3.045 g, 91%) as a lachrymatory white solid that was used directly in the next step; 1H NMR (CDCl3) delta 8.38 (d, J=2.5 Hz, 1H), 7.59 (dd, J=8.2, 2.6 Hz, 1H), 7.48 (d, J=8.2 Hz, 1H), 4.42 (s, 2H).
87.0%	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0 - 20℃;Inert atmosphere;	To a solution of (6-bromopyridin-3-yl)methanol (3.0 g, 16.0 mmol) in DCM (60 mL) was added triphenylphosphine (4.82 g, 18.4 mmol). After addition was completed, themixture was degassed three times under N2. Then a solution of CBr4 (5.84 g, 17.6 mmol) in DCM (15 mL) was added dropwise at 0C, and the reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1 to 15: 1) to give 2-bromo-5-(bromomethyl)pyridine (3.46 g, 87.0% yield) as a white solid. LC10 MS: m/z 252 [M+Hj

78%	With phosphorus tribromide; In dichloromethane; at 0 - 20℃; for 3h;	To a stirred solution of (6-Bromopyridin-3-yl) methanol (2 g, 0.01 mol) in DCM (40 mL), PBr3 (14.3 g, 0.05 mol)) was added at 0C and allowed to stir RT for 3 h. The reaction was monitored by TLC and LC S. The crude reaction mass was diluted with 20 mL of ice cold water and basified with sat. NaHC03 solution to a pH- 8 extracted with DCM (2 X 20 mL), washed with brine, the organic layer was dried over anhydrous NaaSC^, evaporated to get crude resiude that was purified in 100-200 silica gel in 10 % EtOAc/Hexane to get 2.1 g (78%) of the title compound as an off white gummy solid. (0771) LC-MS (method 23): R, = 1.91 min; m/z = 251.74 (M+H++2).
62%	With phosphorus tribromide; In diethyl ether; at 20℃; for 1h;	EXAMPLE 474-((6-(2-(2,4-Difluorophenyl)-l,l-difluoro-2-hydroxy-3-(lH-tetrazol-l- yl)propyl)pyridin-3-yl)methoxy)benzonitrile (79) and 4-((6-(2-(2,4-difluorophenyl)-l,l- difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl)methoxy)benzonitrile (80)To a stirred solution of compound J (prepared as in the first step of Example 17; 2.0 g, 10.75 mmol) in CH3OH (30 mL) was added NaBH4 (0.53 g, 13.97 mmol) portionwise at 0 C and the reaction mixture was stirred at 0 C for 1 h. After completion of the reaction (by TLC), CH3OH was removed under reduced pressure, and the reaction mixture was diluted with ice- cold water (75 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with water (75 mL) and brine (75 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 40% EtOAc/hexanes) afforded compound AV (1.4 g, 7.44 mmol, 69%) as a yellow solid. 1H NMR (400 MHz, CDC13): delta 8.35 (s, 1H), 7.59 (dd, J = 8.0, 2.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.71 (d, J = 6.0 Hz, 2H), 2.03 (t, J = 6.0 Hz, OH). MS (ESI): m/z 188 [M+] .To a stirred solution of compound AV (1.0 g, 5.31 mmol) in Et20 (20 mL) was added phosphorus tribromide (PBr3; 1.5 mL, 15.95 mmol) at 0 C, and the mixture was stirred for 1 h at RT. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with ice-cold water (30 mL), adjusted to pH~8 using satd NaHC03 and extracted with EtOAc (2 x 100 mL). The combined orgainc extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded compound AW (0.83 g, 3.30 mmol, 62%) as a colorless liquid. 1H NMR (400 MHz, CDC13): delta 8.38 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 8.0, 2.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.41 (s, 2H).To a stirred suspension of 4-hydroxybenzonitrile (0.39 g, 3.30 mmol) and Cs2C03 (1.62 g, 4.96 mmol) in DMF (10 mL) was added compound AW (0.83 g, 3.30 mmol) at RT, and the mixture was stirred for 4 h. After completion of the reaction (by TLC), the reaction mixture was quenched with ice-cold water (25 mL) and extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 10% EtOAc/hexanes) afforded compound AX (0.90 g, 3.11 mmol, 94%) as a pale yellow solid. 1H NMR (500 MHz, CDC13): delta 8.44 (d, J = 2.0 Hz, 1H), 7.64-7.61 (m, 3H), 7.54 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H), 5.08 (s, 2H). MS (ESI): m/z 291 [M+2]+.To a stirred suspension of copper powder (1.55 g, 6.22 mmol) in DMSO (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate (0.63 g, 3.11 mmol) at RT and the mixture was stirred for 1 h. A solution of compound AX (0.9 g, 3.11 mmol) in DMSO (5 mL) was added to the reaction mixture and stirring was continued for another 16 h at RT. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with satd NH4C1 solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 25% EtOAc/hexane) afforded compound AY (0.5 g, 1.5 mmol, 49%) as a pale yellow solid. 1H NMR (500 MHz, CDC13): delta 8.71 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 5.18 (s, 2H), 4.38 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). MS (ESI): m/z 334 [M+2]+.To a stirred solution of l-bromo-2,4-difluorobenzene (348 mg, 1.80 mmol) in Et20 (10 mL) was added w-BuLi (1.6 M in hexane; 0.7 mL, 1.80 mmol) at -78 C, and the mixture was stirred for 30 min under inert atmosphere. A solution of compound AY (500 mg, 1.50 mmol) in Et20 (30 mL) was added to the reaction mixture at -78 C and stirring was continued for another 2 h. After completion of the reaction (by TLC), the reaction mixture was quenched with satd NH4C1 solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude AZ (1.5 g) as a brownish liquid. This crude material was used in the next step without any further purification. MS (ESI): m/z 401 [M+H]+.To a stirred solution of crude AZ (650 mg, crude) in Et20 (100 mL) was added freshly prepared diazomethane [prepared by dissolving NMU (1.67 g, 16.25 mmol) in a 1 : 1 mixture of 10% KOH solution (100 mL) and Et20 (100 mL) at 0 C followed by separation and drying of the or...
	With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 0℃; for 0.0833333h;	To a solution of (6-bromopyridin-3 -yl)methanol (5.0 g, 27 mmol) in DCM (50 ml) was added triphenylphosphine (6.3 g, 24 mmol), at 0C. To this reaction mixture was added a solution of carbon tetrabromide (7.1 g, 21 mmol) in 15 ml DCM. The resulting mixture was stirred for 5 minutes, then evaporated, and purified using 0 to 10% ethyl acetate in hexanes toprovide 2-bromo-5-(bromomethyl)pyridine. LC-MS [M+H]: 251.89

Reference： [1]Patent: WO2011/14774,2011,A1 .Location in patent: Page/Page column 25
[2]Patent: US2012/28973,2012,A1 .Location in patent: Page/Page column 10
[3]Patent: WO2017/27684,2017,A1 .Location in patent: Paragraph 00291
[4]Patent: WO2018/219478,2018,A1 .Location in patent: Page/Page column 87
[5]Patent: WO2012/177603,2012,A2 .Location in patent: Page/Page column 105-108
[6]Journal of Medicinal Chemistry,2010,vol. 53,p. 8421 - 8439
[7]Patent: WO2015/171474,2015,A1 .Location in patent: Page/Page column 63

44
[ 101990-45-8 ]
[ 1257426-18-8 ]

Reference： [1]Patent: WO2011/14774,2011,A1
[2]Patent: US2012/28973,2012,A1

45
[ 101990-45-8 ]
[ 1257426-25-7 ]

Reference： [1]Patent: WO2011/14774,2011,A1
[2]Patent: US2012/28973,2012,A1

46
[ 101990-45-8 ]
[ 1311148-70-5 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 559 - 564
[2]Patent: WO2012/52540,2012,A1

47
[ 101990-45-8 ]
[ 154476-57-0 ]
[ 191987-32-3 ]

Reference： [1]Journal of Organic Chemistry,1997,vol. 62,p. 4867 - 4869

48
[ 101990-45-8 ]
[ 767-00-0 ]
[ 1416733-33-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 4h;	EXAMPLE 474-((6-(2-(2,4-Difluorophenyl)-l,l-difluoro-2-hydroxy-3-(lH-tetrazol-l- yl)propyl)pyridin-3-yl)methoxy)benzonitrile (79) and 4-((6-(2-(2,4-difluorophenyl)-l,l- difluoro-2-hydroxy-3-(2H-tetrazol-2-yl)propyl)pyridin-3-yl)methoxy)benzonitrile (80)To a stirred solution of compound J (prepared as in the first step of Example 17; 2.0 g, 10.75 mmol) in CH3OH (30 mL) was added NaBH4 (0.53 g, 13.97 mmol) portionwise at 0 C and the reaction mixture was stirred at 0 C for 1 h. After completion of the reaction (by TLC), CH3OH was removed under reduced pressure, and the reaction mixture was diluted with ice- cold water (75 mL) and extracted with EtOAc (2 x 75 mL). The combined organic layers were washed with water (75 mL) and brine (75 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 40% EtOAc/hexanes) afforded compound AV (1.4 g, 7.44 mmol, 69%) as a yellow solid. 1H NMR (400 MHz, CDC13): δ 8.35 (s, 1H), 7.59 (dd, J = 8.0, 2.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.71 (d, J = 6.0 Hz, 2H), 2.03 (t, J = 6.0 Hz, OH). MS (ESI): m/z 188 [M+] .To a stirred solution of compound AV (1.0 g, 5.31 mmol) in Et20 (20 mL) was added phosphorus tribromide (PBr3; 1.5 mL, 15.95 mmol) at 0 C, and the mixture was stirred for 1 h at RT. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with ice-cold water (30 mL), adjusted to pH~8 using satd NaHC03 and extracted with EtOAc (2 x 100 mL). The combined orgainc extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (10% EtOAc/hexanes) afforded compound AW (0.83 g, 3.30 mmol, 62%) as a colorless liquid. 1H NMR (400 MHz, CDC13): δ 8.38 (d, J = 2.4 Hz, 1H), 7.59 (dd, J = 8.0, 2.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 4.41 (s, 2H).To a stirred suspension of 4-hydroxybenzonitrile (0.39 g, 3.30 mmol) and Cs2C03 (1.62 g, 4.96 mmol) in DMF (10 mL) was added compound AW (0.83 g, 3.30 mmol) at RT, and the mixture was stirred for 4 h. After completion of the reaction (by TLC), the reaction mixture was quenched with ice-cold water (25 mL) and extracted with EtOAc (4 x 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 10% EtOAc/hexanes) afforded compound AX (0.90 g, 3.11 mmol, 94%) as a pale yellow solid. 1H NMR (500 MHz, CDC13): δ 8.44 (d, J = 2.0 Hz, 1H), 7.64-7.61 (m, 3H), 7.54 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H), 5.08 (s, 2H). MS (ESI): m/z 291 [M+2]+.To a stirred suspension of copper powder (1.55 g, 6.22 mmol) in DMSO (10 mL) was added ethyl 2-bromo-2,2-difluoroacetate (0.63 g, 3.11 mmol) at RT and the mixture was stirred for 1 h. A solution of compound AX (0.9 g, 3.11 mmol) in DMSO (5 mL) was added to the reaction mixture and stirring was continued for another 16 h at RT. After complete consumption of the starting material (by TLC), the reaction mixture was quenched with satd NH4C1 solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 25% EtOAc/hexane) afforded compound AY (0.5 g, 1.5 mmol, 49%) as a pale yellow solid. 1H NMR (500 MHz, CDC13): δ 8.71 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 2H), 5.18 (s, 2H), 4.38 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H). MS (ESI): m/z 334 [M+2]+.To a stirred solution of l-bromo-2,4-difluorobenzene (348 mg, 1.80 mmol) in Et20 (10 mL) was added w-BuLi (1.6 M in hexane; 0.7 mL, 1.80 mmol) at -78 C, and the mixture was stirred for 30 min under inert atmosphere. A solution of compound AY (500 mg, 1.50 mmol) in Et20 (30 mL) was added to the reaction mixture at -78 C and stirring was continued for another 2 h. After completion of the reaction (by TLC), the reaction mixture was quenched with satd NH4C1 solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (100 mL) and brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to afford the crude AZ (1.5 g) as a brownish liquid. This crude material was used in the next step without any further purification. MS (ESI): m/z 401 [M+H]+.To a stirred solution of crude AZ (650 mg, crude) in Et20 (100 mL) was added freshly prepared diazomethane [prepared by dissolving NMU (1.67 g, 16.25 mmol) in a 1 : 1 mixture of 10% KOH solution (100 mL) and Et20 (100 mL) at 0 C followed by separation and drying of the organic layer usin...

Reference： [1]Patent: WO2012/177603,2012,A2 .Location in patent: Page/Page column 105-108

49
potassium cyanide [ No CAS ]
[ 101990-45-8 ]
[ 144873-99-4 ]

Yield	Reaction Conditions	Operation in experiment
12.2 g	With tetrabutylammomium bromide; In dichloromethane; water; at 20℃; for 16h;	To a mixture of 2-bromo-5-bromomethyl-pyridine 140 (29.4 g, 1 16.96 mmol) and KCN (22 g, 350.88 mmol) in DCM/water (v:v = 1 :2, 300 mL) was added TBAB (3.77 g, 1 1.7 mmol). The mixture was stirred at r.t. for 16 hr. The mixture was diluted with DCM (100 mL) and the layers were separated. The aqueous layer was extracted with DCM (3x200 mL), The organic layers were combined , washed with brine (2x200 mL), dried over Na2S04, filtered and concentrated to afford the crude product. The crude product was purified by silica gel column chromatography (PE/EtOAc =10: 1→5 : 1 ) to afford the desired compound 141 ( 12.2 g, 53%). LCMS: m/z 199 (M+l )+.

Reference： [1]Patent: WO2013/43232,2013,A2 .Location in patent: Paragraph 00627

50
[ 101990-45-8 ]
[ 457-50-1 ]
[ 1363400-65-0 ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate; In acetonitrile; for 6h;Reflux;	An amount of 70 mg (0.28 mmol) of <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> obtained by the above method was dissolved in 10 mL of anhydrous acetonitrile, following which 54 mg (0.28 mmol) of 2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide synthesized by the method described in "Synthesis Example 14, Step (1)" and 46 mg (0.34 mmol) of potassium carbonate were added in this order and refluxing was carried out under heating for 6 hours. Following completion of the reaction, the reaction mixture was returned to room temperature, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. Diethyl ether was then added thereto, whereupon a solid separated out. The solid was collected by filtration, washed with diethyl ether, then dried under reduced pressure in a desiccator, giving the target compound in an amount of 81 mg (yield, 82%). 1H-NMR (CDCl3, δ, ppm): 5.52 (2H, s), 6.88 (1H, t), 7.48 (1H, d), 7.78 (2H, m), 7.84 (1H, d), 8.44 (1H, d), 8.53 (1H, d) MS: m/z=360 (M+H)
82%	With potassium carbonate; In acetonitrile; for 6h;Reflux;	70 mg (0.28 mmol) of the <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> obtained by the aforementioned method was dissolved in 10 ml of anhydrous acetonitrile, 54 mg (0.28 mmol) of 2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetoamide synthesized by the method described in (1) of Synthetic Example P1 and 46 mg (0.34 mmol) of potassium carbonate were added thereto in sequence, and the resulting mixture was heated and refluxed for 6 hours. After the reaction was completed, the reaction solution was returned to room temperature to filter insoluble materials, and the filtrate was concentrated under reduced pressure. Diethyl ether was added thereto to precipitate a solid, and thus the solid was collected, washed with diethyl ether, and then dried under reduced pressure in a desiccator to obtain the subject material. Amount obtained 81 mg (yield 82%). 1H-NMR (CDCl3, δ, ppm): 5.52(2H, s), 6.88(1H, t), 7.48(1H, d), 7.78(2H, m), 7.84(1H, d), 8.44(1H, d), 8.53(1H, d) MS: m/z = 360(M+H)
82%	With potassium carbonate; In acetonitrile; for 6h;Reflux;	Reference Example 5: N-[1-((6-bromopyridin-3-yl)methyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoroacetamide (Compound P231) 70 mg (0.28 mmol) of the <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> obtained by the aforementioned method was dissolved in 10 ml of anhydrous acetonitrile, 54 mg (0.28 mmol) of 2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide synthesized by the method described in (1) of Reference Example 1 and 46 mg (0.34 mmol) of potassium carbonate were added thereto in sequence, and the resulting mixture was heated and refluxed for 6 hours. After the reaction was completed, the reaction solution was returned to room temperature to filter insoluble materials, and the filtrate was concentrated under reduced pressure. Diethyl ether was added thereto to precipitate a solid, and thus the solid was collected, washed with diethyl ether, and then dried under reduced pressure in a desiccator to obtain the subject material. Amount obtained 81 mg (yield 82%). 1H-NMR (CDCl3, δ, ppm) : 5.52 (2H, s), 6.88 (1H, t), 7.48 (1H, d), 7.78 (2H, m), 7.84(1H, d), 8.44 (1H, d), 8.53 (1H, d) MS:m/z = 360(M+H)

82%

With potassium carbonate; In acetonitrile; for 6h;Reflux;

In 10 ml of anhydrous acetonitrile, 70 mg (0.28 mmol) of <strong>[101990-45-8]2-bromo-5-bromomethylpyridine</strong> obtained by the above-described method was dissolved. To this solution, 54 mg (0.28 mmol) of 2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide synthesized by the above-described method and 46 mg (0.34 mmol) of potassium carbonate were added in this order, followed by heating under reflux for 6 hours. After completion of the reaction, the reaction liquid was returned to room temperature. Then, the insoluble matters were filtered, and the filtrate was concentrated under reduced pressure. To the residue, diethyl ether was added. As a result, a solid was precipitated. The solid was collected by filtration, washed with diethyl ether, and then dried in a desiccator under reduced pressure. Thus, the target substance was obtained. Yield: 81 mg (Percentage Yield: 82%). 1H-NMR (CDCl3, δ, ppm): 5.52 (2H, s), 6.88 (1H, t), 7.48 (1H, d), 7.78 (2H, m), 7.84 (1H, d), 8.44 (1H, d), 8.53 (1H, d) MS: m/z = 360 (M+H)

Reference： [1]Patent: US2013/150414,2013,A1 .Location in patent: Paragraph 0408; 0409; 0410
[2]Patent: EP2633756,2013,A1 .Location in patent: Paragraph 0251; 0252; 0253
[3]Patent: EP2634174,2013,A2 .Location in patent: Paragraph 0241; 0242; 0243
[4]Patent: EP2749555,2014,A1 .Location in patent: Paragraph 0123

51
[ 101990-45-8 ]
cis-13-1,4,7,10-tetraazatetracyclo<5.5.2.0^4,140^10,13>tetradecane [ No CAS ]
2a,6a-bis[(6-bromopyridine-3-yl)methyl]decahydro-4a,8a-diaza-2a,6a-diazoniacyclopenta[fg]acenaphthene dibromide [ No CAS ]

Reference： [1]Heterocycles,2012,vol. 86,p. 1341 - 1366

52
[ 101990-45-8 ]
[ 75920-10-4 ]
1,8-bis[(6-bromopyridin-3-yl)methyl]-4,11-diaza-1,8-diazoniatricyclo[9.3.1.1^4,8]hexadecane dibromide [ No CAS ]

Reference： [1]Heterocycles,2012,vol. 86,p. 1341 - 1366

53
[ 101990-45-8 ]
[ 452972-09-7 ]
[ 1447908-65-7 ]

Reference： [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 6022 - 6032

54
[ 101990-45-8 ]
[ 304507-55-9 ]
[ 1453496-78-0 ]

Yield	Reaction Conditions	Operation in experiment
53%	With potassium carbonate; In acetonitrile; for 6h;Reflux;	4-3 50 mg (0.20 mmol) of 2-bromo-5-(bromomethyl)pyridine 35 mg (0.20 mmol) of 2,2-difluoro-N-(pyridin-2(1H)-ylidene))acetamide 33 mg (0.24 mmol) of potassium carbonate Acetonitrile reflux, 6h A 53
53%	With potassium carbonate; In acetonitrile; for 6h;Reflux;	4-3 50 mg (0.20 mmol) of 2-bromo-5-(bromomet hyl)pyridine 35 mg (0.20 mmol) of 2,2-difluoro-N-(pyrid in-2(1H)-ylidene))ace tamide 33 mg (0.24 mmol) of potassium carbonate Acetonitri le reflux, 6h A 53

Reference： [1]Patent: EP2633756,2013,A1 .Location in patent: Paragraph 0300; 0301
[2]Patent: EP2634174,2013,A2 .Location in patent: Paragraph 0292

55
[ 101990-45-8 ]
[ 120740-10-5 ]

Yield	Reaction Conditions	Operation in experiment
40%		2-bromo-5-methyl-pyridine (70.0 mmol) and N-bromosuccinimide (80.0 mmol) were dissolved in 1,2- dichioroethane (150 ml) and to this mixture 2,2?-azobis(2- ethylpropionitrile) (1.50 mmol) was added. The reaction mixture was heated under reflux at 85 C. for 15 minutes and next portion of 2,2?-azobis(2-methylpropionitrile) (1.50 mmol) was added and reaction mixture was heated at 85 C. for further 15 minutes. After cooling to room temperature was the reaction mixture kept at 5 C. for 2 hours and the precipitate was filtered off and washed with small amount of 1 ,2-dichlo- roethane. The filtrate was evaporated under reduced pressure and the crude product was used for further reaction step without purification. The crude 2-bromo-5-bromomethyl-py- ridine was dissolved in chloroform (100 ml) and urotropine (70.0 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off, washed with small amount of chloroform and dried on air. The crude urotropine salt was refluxed in a mixture of conc. ammonium hydroxide (12 ml) and water (80 ml) for 90 minutes and afier cooling to room temperature, 40% formaldehyde (5.0 ml) was added with stirring. The precipitate was filtered off, washed with ice-cold water and dried in vacuum dessicator. The crude product was crystallized from ethanol. Yield: 40% m.p. 105-106 C. Elemental analysis: Calcd. for C5H7HrN2 (187.04): C, 38.53; H, 3.77; N, 14.98. Found: C, 38.22; H, 3.72; N, 14.71. HPLC-MS (ESI+): 188.02(97.2%). ?H NMR (DMSO, d5): 4.04 (t, J=5.67, 2H, CH2), 7.71 (d, J=8.19, 1H,ArH), 7.95 (dd, J=8.19, J?=i.95, 1H,ArH), 8.51 (d, J=i .95, 1H, ArH), 8.74 (s(br), 2H, NH2).

Reference： [1]Patent: US2015/368248,2015,A1 .Location in patent: Paragraph 0089
[2]Journal of Medicinal Chemistry,2013,vol. 56,p. 6234 - 6247

56
[ 694-32-6 ]
[ 101990-45-8 ]
5-((1H-imidazol-1-yl)methyl)-2-bromopyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃;	Step 1: Synthesis of 5- ((1H-imidazol- 1 -yl)methyl)-2 -bromopyridine. The starting material 2-bromo-5-(bromomethyl)pyridine was synthesized according to a published protocol (Tetr. Lett. 2002, 43, 1697). To a 50 mL round bottom flask containing 1-methyl-2-imidazolidinone (250 mg, 2.5 mmol) and Nail 60%dispersion in mineral oil (110 mg, 2.75 mmol, 1.1 eq) at 0C was added 3 mL of DriSolv DMF. The reaction turned into a cloudy white solid, then warmed to room temperature, and stirred for an hour. 2-bromo-5-(bromomethyl)pyridine (750 mg, 1.2 mmol, 3 eq) was dissolved in 1 mL of DriSolv DMF and the reaction was stirred overnight at room temperature. The reaction wasconcentrated in vacuo, dissolved in EtOAc and a saturated solution of NH4C1, and extracted. The organic layer was concentrated in vacuo, and purified by automated chromatography to yield 173 mg (26%) of a light brown oil R 0.15 in 75% EtOAc in hexanes 1% MeOH). ?H NMR (600 MHz, CD3OD) d 8.26 (d, Jz 2.4 Hz, 1H), 7.62 (dd, J 8.2, 2.5 Hz, 1H), 7.56 (d, J 8.2 Hz, lET), 4.33 (s,2H), 3.36 - 3.31 (m, 2H), 3.28 - 3.23 (m, 2H), 2.77 (s, 3ET). 13C NMR (151 MHz, CD3OD) d 150.70, 141.72, 140.28, 134.46, 129.45, 45.97, 45.95, 43.46, 31.40.

Reference： [1]Patent: WO2014/145331,2014,A1 .Location in patent: Page/Page column 64

57
[ 101990-45-8 ]
(1-isopropylpiperidin-4-yl)-[4-(4-trifluoromethylphenyl)-pyrimidin-2-yl]-amine [ No CAS ]
(6-bromopyridin-3-ylmethyl)-(1-isopropylpiperidin-4-yl)-[4-(4-trifluoromethylphenyl)-pyrimidin-2-yl]-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Synthesis of (6-Bromo-pyridin-3-ylmethyl)-(1-isopropyl-piperidin-4-yI)-[4-(4-trifluoromethyl-phenyl)-pyrimidin-2-yI]-amineTo an ice-cooled solution of (1 -isopropyl-piperid in-4-yl)-[4-(4-trifluoromethyl-phenyl)- pyrimidin-2-yl]-amine (1.09 g, 3.0 mmol, 1.0 eq.) in DMF (15 mL), sodium hydride 60% dispersion in mineral oil (94 mg, 3.9 mmol, 1.3 eq.) was added. The resulting orange mixture was stirred at r.t. for 2 hours. Then a solution of 2-bromo-5-(bromomethyl)pyridine(828 mg, 3.3 mmol, 1.1 eq.) in DMF (5 mL) was added dropwise and the mixture was stirred at 60 C for 18 hours. The reaction mixture was quenched with sat. aq. Na2CO3 soln. (200 mL). The mixture was extracted with DCM (3 x 150 mL). The comb. org. phases were washed with water (1 x 150 mL), sat. aq. NaCI soln. (1 x 150 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flashmaster (column: 50 g, flow: 40 mL/min, 35 fractions of 45 mL, HeptIAcOEt-NEt3 (10% NEt3) 95:5 to Hept/AcOEt-NEt3 (10% NEt3) 1:1) to give the title compound as a yellow solid.5 LC-MS 4: tR = 0.81 mm; [M+H] = 534.2

Reference： [1]Patent: WO2015/28989,2015,A1 .Location in patent: Page/Page column 70; 71

58
[ 101990-45-8 ]
((S)-1-isopropylpiperidin-3-yl)-[4-(4-trifluoromethylphenyl)-pyrimidin-2-yl]-amine [ No CAS ]
(6-bromopyridin-3-ylmethyl)-((S)-1-isopropylpiperidin-3-yl)-[4-(4-trifluoromethylphenyl)-pyrimidin-2-yl]-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Method E: To an ice-cooled solution of C(S)-i -isopropyl-piperidin-3-yl)-[4-(4-trifluoromethyl- phenyl)-pyrimidin-2-yl]-amine (303 mg, 0.82 mmol, 1.0 eq.) in DMF (4 mL), sodium hydride 95% (25 mg, 1.06 mmol, 1.3 eq.) was added. The resulting mixture was stirred at r.t. for 45mm. Then a solution of 2-bromo-5-(bromomethyl)pyridine (234 mg, 0.90 mmol, 1.1 eq.) in DMF (4 mL) was added dropwise and the mixture was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo and the residue taken up in sat. aq. Na2CO3 soln. (10 mL). The mixture was extracted with DCM (3 x 6 mL). The comb. org. phases were washed with water (1 x 6 mL), sat. aq. NaCI soln. (1 x 6 mL), dried over Mg504, andconcentrated in vacuo. The residue was purified by prep. HPLC (column: Waters X-Bridge,30x75 mm, 10 tm, UV/MS, basic conditions) and concentrated in vacuo to give the desired product.

Reference： [1]Patent: WO2015/28989,2015,A1 .Location in patent: Page/Page column 70

59
[ 101990-45-8 ]
2-(methylthio)-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol [ No CAS ]
[ 1462875-81-5 ]

Yield	Reaction Conditions	Operation in experiment
55%	With potassium carbonate; In water; ethyl acetate; N,N-dimethyl-formamide; at 70℃; for 0.5h;	Comparative Example 1 Synthesis of 4-((6-bromopyridin-3-yl)methyl)-2-(methylthio)-[1,2,4]triazolo[1,5-a]pyrimidin-7(4H)-one (Compound E2.8 According to Patent Document 5, Reference Example 3 of the Present Specification) To a suspension of 2-(methylthio)-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol (0.18 g, 1.0 mmol) in N,N-dimethyl formamide (DMF, 2 mL) contained in a 100 mL branched flask, potassium carbonate (0.17 g, 1.2 mmol) and 2-bromo-5-(bromomethyl)pyridine (0.25 g, 1.0 mmol) were added and stirred fir 30 minutes after heating to 70 C. After cooling to room temperature, water (30 ml) and ethyl acetate (30 ml) were added. Accordingly, a solid was precipitated, and the obtained solid was collected by filtration to obtain the target product (0.19 g) as a white solid with yield of 55%. 1H-NMR (CDCl3) δ ppm: 8.46 (1H, d, J=2.4 Hz), 7.63 (1H, dd, J=8.3, 2.4 Hz), 7.53 (1H, d, J=8.3 Hz), 7.40 (1H, d, J=8.0 Hz), 6.06 (1H, d, J=8.0 Hz), 5.26 (2H, s), 2.70 (3H, s).

Reference： [1]Patent: US2015/368249,2015,A1 .Location in patent: Paragraph 0453; 0454

60
[ 101990-45-8 ]
(S)-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)methyl)pentanoic acid [ No CAS ]
(S)-2-((S)-2-(6-bromopyridin-3-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)ethyl)pentanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of diisopropylamine (7.04 ml, 49.4 mmol) in THF (8 mL) at -78C was added N-butyllithium (18.03 ml, 45.1 mmol). The resulting solution was stirred at -78C for15 mm before warming to 0C. To the solution of (S)-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)methyl)pentanoic acid (3.15 g, 10.02 mmol) in THF (50 mL) at -78 C was added LDA (21.04 ml, 21.04 mmol) dropwise. The resulting solution was stirred at -78C for 45 mm before addition of 2-bromo-5-(bromomethyl)pyridine (2.51 g, 10.02 mmol) in THF (20 mL). The resulting mixture was then stirred at -78C for 3 hr. The reaction was quenched by additionof saturated NH4C1 solution (50 mL), then the mixture was extracted with EtOAc twice, the combined organic phase was dried over Na2504, concentrated and the residue was purified on silica gel column using EtOAc (0.2% AcOH)/hexane as eluting solvents to give (S)-2-((S)-2-(6- bromopyridin-3 -yl)- 1 -(1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-tetrazol-5 -yl)ethyl)pentanoic acid. LC/MS: (M+1):484.1 and 486.2.

Reference： [1]Patent: WO2015/171474,2015,A1 .Location in patent: Page/Page column 222

61
[ 101990-45-8 ]
(R)-3,3-dimethyl-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)methyl)butanoic acid [ No CAS ]
(2R,3S)-4-(6-bromopyridin-3-yl)-2-(tert-butyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)butanoic acid [ No CAS ]
(2R,3R)-4-(6-bromopyridin-3-yl)-2-(tert-butyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		n-Butyllithium (1.29 ml of a 2.5M solution in hexanes, 3.2 mmol) was addeddropwise to a stirred solution of the tetrazole-acid (0.48 g, 1.5 mmol) in anhydrous THF (7 mL)at -7 8C under an atmosphere of nitrogen. The solution was maintained at this temperature for 1 hr., then 1 -bromo-4-(bromomethyl)pyridine in anhydrous THF (1 mL) was added. The resulting reaction mixture was maintained at -78C overnight. The reaction was quenched by the addition of saturated aq. ammonium chloride and the organics extracted into EtOAc. The organic phase was separated, washed with brine, dried (Mg504) and the volatiles removed under reducedpressure. The residue was purified by silica gel column chromatography (80g column) to give the desired mixture of diastereomers. LC/MS [M+H]: 500.59 and 500.61.

Reference： [1]Patent: WO2015/171474,2015,A1 .Location in patent: Page/Page column 237

62
[ 101990-45-8 ]
(R)-3,3-dimethyl-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)methyl)butanoic acid [ No CAS ]
(2R,3S)-4-(6-aminopyridin-3-yl)-2-(tert-butyl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)butanoic acid [ No CAS ]
(2R,3S)-2-(tert-butyl)-4-(6-hydroxypyridin-3-yl)-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Ammonium hydroxide (10.8 ml of a 29% aqueous solution, 80 mmol) was added to the diastereoisomeic mixture of tetrazoles (1.00 g, 2.00 mmol), N’, N2-dimethylethane-1,2-diamine 0.022 ml, 0.20 mmol), copper(I) oxide (0.057 g, 0.40 mmol) and potassium carbonate(0.333 g, 2.4 mmol) in ethylene glycol (5 ml) and stirred at 85C over a weekend. After cooling,the reaction mixture was concentrated under reduced pressure and the residue purified by Cl 8 column chromatography eluting with a gradient of acetonitrile (containing 0.1% TFA) in water (containing 0.1% TFA) as eluent to give the amino pyridine (LC/MS [M+H]: 435.67) followed by the hydroxy pyridine (LC/MS [M+H]: 436.66).

Reference： [1]Patent: WO2015/171474,2015,A1 .Location in patent: Page/Page column 237; 238

63
[ 101990-45-8 ]
(S)-4-phenyl-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)methyl)pentanoic acid [ No CAS ]
(2S)-2-((S)-2-(6-bromopyridin-3-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)ethyl)-4-phenylpentanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(2 S)-4-phenyl-2-(( 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1H-tetrazol-5 -yl)methyl) pentanoic acid (130 mg, 0.333 mmol) was dissolved in THF (lOml) and cooled to -78C. ThenLDA (1.300 ml,0.64M, 0.832 mmol) was added. The reaction was stirred for 45 mins then 2- bromo-5-(bromomethyl) pyridine (100 mg, 0.399 mmol) in THF (2 ml) was added. The reaction mixture was stirred at -70C for 5 hrs then quenched with saturated aq. NH4C1 solution, extracted with EtOAc (2x), washed with brine (lx), dried (Na2504) and concentrated. The residue was purified by reverse phase HPLC with ACN and water buffered with 0.05% TFA to yield (25)-2-((S)-2-(6-bromopyridin-3 -yl)- 1 -(1 -((2-(trimethylsilyl)ethoxy)methyl)- 1H-tetrazol-5 -yl)ethyl)-4- phenylpentanoic acid. LC/MS [M+H]+: 562.1.

Reference： [1]Patent: WO2015/171474,2015,A1 .Location in patent: Page/Page column 216

64
[ 101990-45-8 ]
(R)-4,4,4-trifluoro-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)methyl)butanoic acid [ No CAS ]
(S)-2-((S)-2-(6-bromopyridin-3-yl)-1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)ethyl)-4,4,4-trifluorobutanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(R)-4,4,4-trifluoro-2-(( 1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-tetrazol-5 -yl)methyl)butanoic acid (490 mg, 1.3 83 mmol) was dissolved in THF (15 ml) then cooled to-78C and then LDA (4.32 ml,0.64 M, 2.77 mmol) was added. The reaction mixture was stirred for 45 mins then 2-bromo-5-(bromomethyl)pyridine (416 mg, 1.659 mmol) in THF was added. The reaction was stirred at -78C for 5 hrs, then quenched with saturated NH4C1 solution, extracted with EtOAc (2x), dried (Na2504) then filtered and concentrated. The residue waspurified by reverse phase HPLC with ACN and water buffered with 0.05% TFA to yield (S)-2- ((S)-2-(6-bromopyridin-3 -yl)- 1 -(1 -((2-(trimethylsilyl)ethoxy) methyl)- 1 H-tetrazol-5-yl)ethyl)- 4,4,4-trifluorobutanoic acid. LC-MS [M+2]: 525.6

Reference： [1]Patent: WO2015/171474,2015,A1 .Location in patent: Page/Page column 251

65
[ 101990-45-8 ]
(R)-2-cyclopentyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)propanoic acid [ No CAS ]
(2S,3S)-4-(6-bromopyridin-3-yl)-2-cyclopentyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of diisopropylamine (0.50 ml, 3.5 mmol) in Tetrahydrofuran (5 ml) was added nBuLi (1.3 ml, 3.5 mmol) at -5C. Then the resulting solution was slowly warmed to RT, then cooled to -78C. To the solution was added a solution of (R)-2-cyclopentyl-3-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)propanoic acid (500 mg, 1.5 mmol) in 1 ml THF. The resulting mixture was stirred for 1 hr, then was added a solution of 2-bromo-5-(bromomethyl)pyridine (480 mg, 1.9 mmol) in 1 mL THF. The reaction mixture was slowly warmed to RT over 12 hr. The reaction mixture was diluted with saturated ammonium chloride, and then extrcated with ethyl acetate. The crude product was purified using 0 to 100% ethylacetate in hexanes to provide (2 S,3 S)-4-(6-bromopyridin-3 -yl)-2-cyclopentyl-3 -(1 -((2-+(trimethylsilyl)ethoxy)methyl)- 1H-tetrazol-5-yl)butanoic acid. LC-MS m/z [M+H] 510.19

Reference： [1]Patent: WO2015/171474,2015,A1 .Location in patent: Page/Page column 73; 74

66
[ 101990-45-8 ]
[ 148869-66-3 ]
4-(((6-bromopyridin-3-yl)methyl)(4H-1,2,4-triazol-4-yl)amino)benzonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 9370 - 9380

67
[ 101990-45-8 ]
[ 157911-57-4 ]
4-(((6-bromopyridin-3-yl)methyl)(pyrimidin-5-yl)amino)benzonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 9370 - 9380

68
[ 101990-45-8 ]
(E)-methyl 3-(3-(cyclohexanecarboxamido)phenyl)acrylate [ No CAS ]
(E)-methyl 3-(3-(N-((6-bromopyridin-3-yl)methyl)cyclohexanecarboxamido)phenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step 1: (E)-Methyl 3-(3-(N-((6-bromopyridin-3-yl)methyl)cyclohexanecarboxamido)phenyl) acrylate [00419] Sodium hydride (134 mg, 3.34 mmol, 60% purity) was added to a solution of Intermediate 2 (800 mg, 2.78 mmol) in anhydrous THF (40 mL) at 0 C. After stirring the mixture for 0.5 h, 2-bromo-5-(bromomethyl)pyridine (837 mg) in anhydrous THF (2 mL) was added dropwise. The mixture was then stirred at 15 C for 11.5 h, quenched with water (100 mL), and extracted with ethyl acetate (3 x50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2S04, filtered, and concentrated to give (E)-methyl 3-(3- (N-((6-bromopyridin-3-yl)methyl) cyclohexanecarboxamido)phenyl)acrylate (1.17 g, crude) as a light yellow oil.

Reference： [1]Patent: WO2017/49176,2017,A1 .Location in patent: Paragraph 00419

69
[ 199526-97-1 ]
[ 101990-45-8 ]
1-((6-bromopyridin-3-yl)methyl)-4,6-difluoro-1H-indole [ No CAS ]