Organometallic complex and organic electroluminescent device comprising same

Abstract

Provided is an organometallic complex contributing to substantial improvements in the light color and light efficiency of an organic electroluminescent device. An organic electroluminescent device, according to the present invention, comprises: a first electrode; a second electrode; one or more organic layers disposed between the first electrode and the second electrode; and an emission layer, wherein the emission layer comprises an organometallic complex represented by chemical formula 1 of the present invention.

Description

Organometallic complexes and organic electroluminescent devices containing the same

[0001] The present invention relates to an organic metal complex and an organic electroluminescent device including the same, and more particularly, to an organic electroluminescent device having high luminous efficiency and a novel organic metal complex therefor.

[0002] In the display industry, OLED (Organic Light Emitting Diodes) is attracting attention as a display that utilizes the self-luminous phenomenon.

[0003] In OLEDs, the first attempt at carrier-injected electroluminescence (EL) using a single crystal of the aromatic hydrocarbon anthracene was made by Pope et al. in 1963. From this research, the basic mechanisms of charge injection, recombination, exciton generation, and luminescence in organic materials, as well as electroluminescence characteristics, have been understood and studied.

[0004] In particular, various approaches are being taken to increase luminous efficiency, including structural changes in the device and material development [Sun, S., Forrest, SR, Appl. Phys. Lett. 91, 263503 (2007) / Ken-Tsung Wong, Org. Lett., 7, 2005, 5361-5364].

[0005] The basic structure of an OLED display is generally composed of a multilayer structure of an anode, a hole injection layer (HIL), a hole transporting layer (HTL), an emission layer (EML), an electron transporting layer (ETL), and a cathode, and the electro-organic multilayer film is formed in a sandwich structure between two electrodes.

[0006] Generally, organic light emitting diodes (OLEDs) are devices that convert electrical energy into light energy using organic materials. Organic light emitting diodes (OLEDs) typically have a structure comprising an anode, a cathode, and an organic layer between them. These organic layers are often multilayered, composed of different materials, to enhance the efficiency and stability of the device. For example, they may include a hole injection layer, a hole transport layer, a light emitting layer, an electron transport layer, and an electron injection layer.

[0007] In the structure of these organic light-emitting devices, when a voltage is applied between the two electrodes, holes are injected from the anode and electrons are injected from the cathode into the organic layer, and when the injected holes and electrons meet, excitons are formed, and when these excitons fall to the ground state, light is emitted. These organic light-emitting devices are known to have characteristics such as self-luminescence, high brightness, high efficiency, low operating voltage, wide viewing angle, high contrast, and high-speed response.

[0008] Materials used as organic layers in organic light-emitting devices can be classified according to their function into light-emitting materials and charge transport materials, such as hole injection materials, hole transport materials, electron transport materials, and electron injection materials.

[0009] Luminescent materials are available in blue, green, and red depending on their luminescent color, as well as in yellow and orange luminescent materials for better natural color realization. In addition, a host / dopant system can be used as a luminescent material to increase color purity and luminescent efficiency through energy transfer. The principle is that when a small amount of a dopant with a smaller energy band gap and superior luminescent efficiency than the host, which mainly constitutes the luminescent layer, is mixed into the luminescent layer, excitons generated in the host are transported to the dopant, resulting in high efficiency light emission. At this time, the wavelength of the host shifts to the wavelength of the dopant, so light of a desired wavelength can be obtained depending on the type of dopant used.

[0010] To improve the characteristics of light-emitting devices, the use of phosphorescent materials in the light-emitting layer of organic EL devices has been proposed. Phosphorescence, a phenomenon in which light emission occurs from a singlet excited state to a triplet excited state through a nonradiative transition called interstitial crossing, is known to exhibit higher quantum efficiency than fluorescence, a phenomenon in which light emission occurs from a singlet excited state. Using organic compounds exhibiting these properties as light-emitting materials is expected to achieve high luminous efficiency.

[0011] Organic EL devices using these phosphorescent materials have been developed to date using various complexes with iridium as the central metal, but recently, development of complexes with platinum as the central metal is also in progress. Among them, an organic EL device using a red phosphorescent material has been reported that uses the platinum complex (2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphinato-N,N,N,N)platinum(II) (Pt(OEP)) in the light-emitting layer (Patent Document: Japanese Patent Laid-Open No. 2002-175884).

[0012] As described above, various approaches are actively being studied to improve the performance and lifespan of next-generation display devices. Among these, organic EL devices utilizing phosphorescent materials derived from platinum complexes are attracting particular attention for their potential to enhance device characteristics. However, this research is still in its infancy, and numerous challenges remain, including optimization of device luminescence characteristics, luminescence efficiency, color purity, and structure. To address these challenges, the development of novel phosphorescent materials and efficient methods for supplying these materials are urgently needed.

[0013] The present inventors have discovered a compound having a novel structure.

[0014] In addition, it was discovered that when the organic layer of an organic light-emitting device is formed using the novel compound, the device can exhibit effects such as increased efficiency, decreased operating voltage, and increased stability.

[0015] Accordingly, the present invention aims to provide a novel organic metal complex and an organic electroluminescent device using the same.

[0016] The present invention provides an organometallic complex represented by the following chemical formula 1.

[0017] [Chemical Formula 1]

[0018]

[0019] In the above chemical formula 1,

[0020] L1 and L2 are independently selected from a substituted or unsubstituted phenylene group, a biphenylene group, a pyridylene group, and a naphthylene group,

[0021] Ar1 and Ar2 are independently selected from a substituted or unsubstituted phenyl group, a pyridyl group, a naphthyl group, a benzofuran group, a benzothiophene group, a benzoxazole group, a benzothiazole group, a dibenzofuran group, and a dibenzothiophene group,

[0022] R1 to R4 are independently selected from hydrogen, deuterium, -CD3, -F, -CF3, an alkyl group and a cycloalkyl group,

[0023] a to d and o to r are independently integers from 0 to 4.

[0024] According to another aspect of the present invention, an organic electroluminescent device comprising the above-described organometallic complex is provided.

[0025] According to another aspect of the present invention, an organic light-emitting device is provided, comprising a first electrode, a second electrode, and at least one organic layer disposed between the electrodes, wherein the organic layer includes the organic metal complex.

[0026] According to another aspect of the present invention, an organic electroluminescent device is provided, characterized in that the organic metal complex is included in any one layer selected from the group consisting of an electron blocking layer, an electron transport layer, an electron injection layer, a functional layer having both an electron transport function and an electron injection function, and a light-emitting layer constituting the organic material layer.

[0027] The novel organometallic complex according to the present invention can be used as an organic material layer material for organic electronic devices, including organic light-emitting devices, by introducing various aryl groups, heteroaryl groups, etc. Organic electronic devices, including organic light-emitting devices, using the compound represented by Chemical Formula 1 according to the present invention as an organic material layer material exhibit excellent characteristics in terms of efficiency, operating voltage, lifespan, etc.

[0028] FIG. 1 is a schematic cross-sectional view of an organic light-emitting device according to one embodiment of the present invention.

[0029] As used herein, the term "aryl" means a polyunsaturated, aromatic, hydrocarbon substituent which may be a single ring or multiple rings (one to three rings) fused or covalently bonded together, unless otherwise specified.

[0030] The term "heteroaryl" means an aryl group (or ring) containing from one to four heteroatoms selected from N, O and S (in each separate ring in the case of multiple rings), the nitrogen and sulfur atoms being optionally oxidized and the nitrogen atom(s) being optionally quaternized. The heteroaryl group may be bonded to the remainder of the molecule through carbon or a heteroatom.

[0031] The above aryl includes a single or fused ring system, suitably containing 4 to 7 ring atoms in each ring, preferably 5 or 6 ring atoms. It also includes a structure in which one or more aryls are bonded through a chemical bond. Specific examples of the above aryl include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, phenanthryl, triphenylenyl, pyrenyl, perylenyl, chrysenyl, naphthacenyl, pyrenyl, fluoranthenyl, and the like.

[0032] The above heteroaryl includes a 5-6 membered monocyclic heteroaryl, and a polycyclic heteroaryl fused with one or more benzene rings, and may be partially saturated. Also included is a structure in which one or more heteroaryls are bonded via a chemical bond. The above heteroaryl group includes a divalent aryl group in which a heteroatom within the ring is oxidized or quaternized to form, for example, an N-oxide or a quaternary salt.

[0033] Specific examples of the above heteroaryl include monocyclic heteroaryls such as furyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, furazanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzothiophenyl, isobenzofuranyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoisoxazolyl, benzoxazolyl, isoindolyl, indolyl, indazolyl, benzothiadiazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, carbazolyl, phenanthridinyl, Polycyclic heteroaryls such as benzodioxolyl and their corresponding N-oxides (e.g., pyridyl N-oxide, quinolyl N-oxide), quaternary salts thereof, etc. are included, but are not limited thereto.

[0034] As used herein, the term "substituted or unsubstituted" means that one or more hydrogen atoms in a hydrocarbon are each, independently of one another, replaced by the same or different substituent. Useful substituents include, but are not limited to, the following:

[0035] These substituents are, -F; -Cl; -Br; -CN; -NO2; -OH; C1~C20 alkyl group unsubstituted or substituted with -F, -Cl, -Br, -CN, -NO2 or -OH; C1~C20 alkoxy group unsubstituted or substituted with -F, -Cl, -Br, -CN, -NO2 or -OH; C6~C30 aryl group unsubstituted or substituted with C1~C20 alkyl group, C1~C20 alkoxy group, -F, -Cl, -Br, -CN, -NO2 or -OH; C6~C30 heteroaryl group unsubstituted or substituted with C1~C20 alkyl group, C1~C20 alkoxy group, -F, -Cl, -Br, -CN, -NO2 or -OH; It may be at least one selected from the group consisting of a C1~C20 alkyl group, a C1~C20 alkoxy group, a C5~C20 cycloalkyl group unsubstituted or substituted with -F, -Cl, -Br, -CN, -NO2 or -OH; a C5~C30 heterocycloalkyl group unsubstituted or substituted with a C1~C20 alkyl group, a C1~C20 alkoxy group, -F, -Cl, -Br, -CN, -NO2 or -OH; and a group represented by -N(G1)(G2). At this time, G1 and G2 may each independently be hydrogen; a C1~C10 alkyl group; or a C6~C30 aryl group unsubstituted or substituted with a C1~C10 alkyl group.

[0036]

[0037] Hereinafter, the present invention will be described in detail.

[0038] An organic metal complex according to one embodiment of the present invention can be represented by the following chemical formula 1.

[0039] [Chemical Formula 1]

[0040]

[0041] In the above chemical formula 1,

[0042] L1 and L2 are independently selected from a substituted or unsubstituted phenylene group, a biphenylene group, a pyridylene group, and a naphthylene group,

[0043] Ar1 and Ar2 are independently selected from a substituted or unsubstituted phenyl group, a pyridyl group, a naphthyl group, a benzofuran group, a benzothiophene group, a benzoxazole group, a benzothiazole group, a dibenzofuran group, and a dibenzothiophene group,

[0044] R1 to R4 are independently selected from hydrogen, deuterium, -CD3, -F, -CF3, an alkyl group and a cycloalkyl group,

[0045] a to d and o to r are independently integers from 0 to 4.

[0046] The above chemical formula 1 can provide an organometallic complex represented by the following chemical formulas 2 to 4.

[0047] [Chemical Formula 2]

[0048]

[0049] [Chemical Formula 3]

[0050]

[0051] [Chemical Formula 4]

[0052]

[0053] In the above chemical formulas 2 to 4,

[0054] X1 is CH or N,

[0055] Z1 and Z2 are independently O or S,

[0056] R5 is independently selected from hydrogen, deuterium, -CD3, -F, -CF3, an alkyl group and a cycloalkyl group,

[0057] e is an integer from 0 to 5

[0058] Ar1, R1 to R4, a to d, and o to r are the same as defined in Chemical Formula 1.

[0059] Specific examples of the compounds represented by the chemical formula 1 of the present invention include those represented by the following chemical formulas 5 to 7. However, the compounds represented by the chemical formula 1 of the present invention are not limited to the compounds represented by the following chemical formulas 5 to 7.

[0060] [Chemical Formula 5]

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[0514] The organometallic complex represented by the above chemical formula 1 can be synthesized using a known organic synthesis method. The synthesis method of the organometallic complex can be easily understood by those skilled in the art by referring to the manufacturing examples described below.

[0515] In addition, according to the present invention, an organic electroluminescent device including an organic metal complex represented by the above chemical formula 1 is provided.

[0516] The organic metal complex of the above chemical formula 1 is useful as a light-emitting layer material and can be used as a material for other multi-layer organic electroluminescent devices.

[0517] In addition, the organic electroluminescent device according to the present invention includes a first electrode, a second electrode, and at least one organic layer disposed between the electrodes. The organic layer may include at least one organic metal complex represented by the chemical formula 1.

[0518] The first electrode and the second electrode can function as a cathode and an anode, respectively, and have the roles of a cathode and an anode depending on the work function energy position of the electrode material. When voltage is applied, the anode injects holes into the organic layer, and the cathode injects electrons. The injected holes and electrons move through the organic layer in opposite voltage directions. When the moving electrons meet within the van der Waals radius in the organic layer, an electron-hole pair, an "exciton", is formed. Since a hole is a positive polaron, it is actually a particle with a mobility that is one electron short, so when it meets an electron, it receives the missing electron and relaxes to a stable state, and at this time, light is emitted in the amount of the difference in energy between the electron and the hole.

[0519] While OLEDs have traditionally been known to operate solely through the singlet-state emission phenomenon of "fluorescence," recent advances have yielded OLEDs that utilize the triplet-state emission phenomenon of "phosphorescence." This approach utilizes organometallic complexes centered on transition metals such as Ir, Pt, and Re, which possess high heavy-atom effects, to induce light emission from triplet-state electrons, enabling phosphorescent OLEDs to achieve 100% internal quantum efficiency.

[0520] The present invention relates to an organometallic complex to be used as an additive in a light-emitting layer of a phosphorescent OLED having an internal quantum efficiency of 100%.

[0521] Figure 1 illustrates a cross-sectional view of a schematic structure of an organic light-emitting device according to one embodiment of the present invention. The material of each layer is not limited, and any material with electrical and chemical properties suitable for the corresponding role may be used in duplicate.

[0522] The device (100) forms an electrode and an organic layer on a substrate (110), and at this time, a hard or soft material can be used as the substrate material. For example, as a hard material, soda lime glass, alkali-free glass, aluminosilicate glass, etc. can be used, and as a soft material, PC (polycarbonate), PES (polyethersulfone), COC (cyclic olefin copolymer), PET (polyethylene ether phthalate), PEN (polyethylene naphthalate), etc. can be used.

[0523] The anode (120) can be formed on the upper part of the substrate using a material deposition method, electron beam evaporation method, sputtering method, etc. The anode material can be selected from materials having a high work function to facilitate hole injection into the organic light emitting device. Depending on the light emitting direction of the organic light emitting device, a reflective electrode is used for front emission, a transmissive electrode is used for back emission, and a semi-transmissive electrode is used for double-sided emission. These materials are formed using ITO (indium tin oxide), IZO (indium zinc oxide), SnO2 (tin oxide), ZnO (zinc oxide), etc. to an appropriate thickness and are manufactured by controlling the transmittance. Alternatively, it can be manufactured using a metal such as Mg (magnesium), Al (aluminum), Al-Li (aluminum-lithium), Ca (calcium), Mg-In (magnesium-indium), Mg-Ag (magnesium-silver), which is not an oxide. Recently, carbon substrate flexible electrode materials such as CNT (carbon nanotube) and Graphene may also be used.

[0524] The hole injection layer (130), hole transport layer (140), and electron blocking layer (150) are also called hole transport regions and play a role in smoothly injecting and transporting holes into the organic light-emitting device. In general, since the hole mobility of the organic layer is faster than the electron mobility, they have a thickness greater than that of the electron transport region.

[0525] Among the above hole transport regions, the hole injection layer (130) can be formed on the anode by various methods such as vacuum deposition, spin coating, casting, and LB.

[0526] When forming a hole injection layer by vacuum deposition, the deposition conditions can be freely adjusted at a deposition rate of about 1Å / s at 100 to 500°C depending on the compound used as the hole injection layer material, the structure and thermal characteristics of the target hole injection layer, etc., and are not limited to specific conditions.

[0527] When forming a hole injection layer by spin coating, the coating conditions vary depending on the characteristics of the compound used as the hole injection layer material and the layers formed at the interface, but for uniform film formation, coating speed and heat treatment to remove the solvent after coating are required.

[0528] The above hole transport region is, for example, m-MTDATA, TDATA, 2-TNATA, NPB, β-NPB, TPD, Spiro-TPD, Spiro-NPB, methylated-NPB, TAPC, HMTPD, TCTA (4,4',4"-tris(Ncarbazolyl) triphenylamine), Pani / DBSA (Polyaniline / Dodecylbenzenesulfonic acid), PEDOT / PSS (Poly(3,4-ethylenedioxythiophene) / Poly(4-styrene sulfonate)), Pani / CSA (Polyaniline / Camphor sulfonicacid), PANI / PSS (Polyaniline) / Poly(4-styrenesulfonate): It may include polyaniline) / poly(4-styrenesulfonate) etc.

[0529]

[0530]

[0531] The thickness of the above hole transport region can be formed to be about 100 to about 10,000 Å, and the corresponding organic layers of each hole transport region are not limited to the same thickness. For example, if the thickness of the hole injection layer is 50 Å, the thickness of the hole transport layer can be formed to be 1000 Å, and the thickness of the electron blocking layer can be formed to be 500 Å. The thickness condition of the hole transport region can be determined to a degree that satisfies efficiency and lifespan within a range where the driving voltage increase of the organic light-emitting device does not increase significantly.

[0532] The hole transport region, like the emissive layer, can be doped to enhance its properties, and doping of charge-generating materials into this hole transport region can improve the electrical properties of the organic light-emitting device.

[0533] Charge-generating materials are generally composed of materials with very low HOMO and LUMO. For example, the LUMO of the charge-generating material has a value similar to the HOMO of the hole transport layer (215) material. Due to this low LUMO, the empty electron characteristic of the LUMO is utilized to easily transfer holes to the adjacent hole transport layer (215), thereby improving the electrical properties.

[0534] The charge-generating material may be, for example, a p-dopant. The p-dopant may be, but is not limited to, one of a quinone derivative, a metal oxide, and a cyano group-containing compound. For example, non-limiting examples of the p-dopant include, but are not limited to, quinone derivatives such as tetracyanoquinonedimethane (TCNQ) and 2,3,5,6-tetrafluoro-tetracyano-1,4-benzoquinonedimethane (F4-TCNQ); metal oxides such as tungsten oxide and molybdenum oxide; and cyano group-containing compounds.

[0535]

[0536] The electron blocking layer (150) is a layer that prevents electron injection from the electron transport region to the hole transport region. The electron blocking layer not only blocks electrons moving to the hole transport region, but also uses a material having a high T1 value to prevent excitons formed in the light-emitting layer (220) from diffusing into the hole transport region. For example, a host of the light-emitting layer, which generally has a high T1 value, can be used as the electron blocking layer material.

[0537] The light-emitting layer (160) is a region where holes and electrons meet to form excitons. The material forming the light-emitting layer must have an appropriate energy band gap to exhibit high light-emitting characteristics and a desired light-emitting color, and is generally composed of two materials that have two roles as a host and a dopant, but is not limited thereto.

[0538] The above host may include at least one of the following: TPBi, TBADN, ADN (also referred to as "DNA"), CBP, CDBP, TCP, mCP, and the material is not limited thereto, provided the properties are appropriate.

[0539]

[0540] The dopant of the light-emitting layer uses an organic metal compound represented by the chemical formula 1 mentioned in the present invention as a material, and the content of the general dopant can be selected from 0.01% to 20%, but is not limited thereto in some cases.

[0541] An electron transport region is deposited on the light-emitting layer, and the electron transport region is composed of a hole blocking layer (170), an electron transport layer (180), and an electron injection layer (190), and an organic electroluminescent device is manufactured by including at least one organic layer.

[0542] The formation of the above electron transport region is formed under the same conditions as the hole transport region, and the formation conditions and method refer to the hole transport region formation conditions.

[0543] The hole blocking layer (170) in the electron transport region may include one of BCP, Bphen, and Balq below, but the composition of the material may vary depending on the characteristics of the material and the purpose of the organic electroluminescent device.

[0544]

[0545] The electron transport layer (180) may include at least one of the above BCP, Bphen, and the following Alq3, Balq, TAZ, and NTAZ.

[0546]

[0547] The electron transport layer is selected from a material with fast or slow electron mobility depending on the structure of the organic light-emitting device, so a variety of materials must be selected, and in some cases, Liq or Li is doped.

[0548] The electron injection layer (190) is made of a metal material that facilitates the injection of electrons, and may include at least one selected from among LiF, NaCl, CsF, Li2O, and BaO.

[0549] Unlike the anode, the cathode (200) can be used by combining metals, electrically conductive compounds, alloys, etc. having a relatively low work function. For example, Li (lithium), Mg (magnesium), Al (aluminum), Al-Li (aluminum-lithium), Ca (calcium), Mg-In (magnesium-indium), Mg-Ag (magnesium-silver), etc. can be used as the cathode.

[0550] The cathode's transmittance and material are determined by the light-emitting direction of the organic electroluminescent device. For top-emitting devices, a semi-transparent electrode material and thickness are selected to maximize the micro-resonance effect. For bottom-emitting devices, a material with high reflectivity is selected.

[0551] The above organic light-emitting device can have low voltage operation, high efficiency, and long life by including the organometallic compound applied to the present invention in the light-emitting layer as described above.

[0552] To further illustrate the present specification, examples will be provided in detail. However, the embodiments described herein may be modified in various ways, and the scope of this application is not limited to the embodiments described below. The embodiments of this application are provided to more fully explain the present specification to those of average skill in the art.

[0553]

[0554] [Manufacturing example]

[0555] Intermediate synthesis example 1: Synthesis of intermediate (5)

[0556]

[0557] (Synthesis of intermediate (1))

[0558] 20.0 g (134.0 mmol) of 4-(tert-butyl)aniline and 400 mL of acetonitrile were mixed and cooled to 0°C. 23.9 g (134.0 mmol) of N-bromosuccinimide was slowly added at 0°C and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure to remove the solvent to obtain 32.1 g (yield: 100.0%) of a red liquid compound (intermediate (1)).

[0559] (Synthesis of intermediate (2))

[0560] Intermediate (1) 15.0 g (65.7 mmol), naphthalen-2-ylboronic acid 13.6 g (78.9 mmol), Pd(PPh3) 43.8 g (3.2 mmol), K2CO3 27.2 g (197.0 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. The mixture was stirred under reflux for one day and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, the concentrate was purified by silica gel column chromatography (DCM / n-hexane), and then recrystallized from DCM and n-hexane to obtain 17.0 g (yield: 93.9%) of the compound (intermediate (2)) as a yellow solid.

[0561] (Synthesis of intermediate (3))

[0562] Intermediate (2) 17.0 g (61.7 mmol) was mixed with 340 mL of THF, and then cooled to -78°C. 27.1 mL (2.5 M in hexane, 67.8 mmol) of n-BuLi was slowly added, and the mixture was stirred at -78°C for 2 hours. 13.6 g (61.7 mmol) of 1-bromo-3-fluoro-2-nitrobenzene was dissolved in 30 mL of THF, and then slowly added to the reaction mixture. The mixture was stirred at -78°C for 2 hours, and then at room temperature for 2 hours. Distilled water was added, the reaction was terminated, and the mixture was concentrated under reduced pressure to remove THF. Dichloromethane was added, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 22.5 g (yield: 76.8%) of the compound (intermediate (3)) as a light purple solid was obtained by slurrying with n-hexane.

[0563] (Synthesis of intermediate (4))

[0564] Intermediate (3) 22.5 g (47.3 mmol), Fe 13.2 g (236.0 mmol), ammonium chloride 2.5 g (47.3 mmol), EtOH 230 mL, and distilled water 47.3 mL were mixed and stirred under reflux for one day. The mixture was passed through a pad of Celite and washed with dichloromethane. Distilled water was added, and the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), 14.0 g (yield: 66.3%) of the compound (intermediate (4)) as a white solid was obtained by recrystallization from DCM and n-hexane.

[0565] (Synthesis of intermediate (5))

[0566] Intermediate (4) 14.0 g (31.4 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 8.1 g (34.6 mmol), Na2S2O 57.1 g (37.6 mmol), and DMF 140 mL were mixed and stirred at 110°C for one day. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 10.0 g (yield: 48.3%) of the compound (intermediate (5)) as a white solid was obtained.

[0567]

[0568] Intermediate synthesis example 2: Synthesis of intermediate (8)

[0569]

[0570] (Synthesis of intermediate (6))

[0571] 2-chloro-4-iodopyridine (50.0 g, 208.8 mmol), 4-tolylboronic acid (34.1 g, 250.5 mmol), Pd(PPh3) (47.2 g, 6.3 mmol), Na2CO3 (55.3 g, 522.0 mmol), toluene (1044 mL), EtOH (261 mL), and H2O (261 mL) were mixed and stirred at 65°C for 12 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (EtOAc:Hexanes) and then solidified with hexane to obtain 26.5 g (yield: 62.3%) of a white solid compound (intermediate (6)).

[0572] (Synthesis of intermediate (7))

[0573] Intermediate (6) 30.0 g (147.3 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 40.7 g (191.5 mmol), Pd(PPh3) 48.5 g (7.4 mmol), K2CO3 61.1 g (441.9 mmol), toluene 589 mL, EtOH 147 mL, and H2O 147 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel and Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was solidified with methanol to obtain 42.5 g (yield: 86.0%) of a gray solid compound (intermediate (7)).

[0574] (Synthesis of intermediate (8))

[0575] Intermediate (7) 42.5 g (126.5 mmol), PIN2B 248.2 g (189.8 mmol), Pd(dba) 23.6 g (6.3 mmol), XPhos 9.0 g (19.0 mmol), KOAc 31.0 g (316.3 mmol), and toluene 632 mL were mixed and stirred under reflux for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc), and then solidified with methanol to obtain 36.0 g (yield: 66.6%) of a gray solid compound (intermediate (8)).

[0576]

[0577] Intermediate synthesis example 3: Synthesis of intermediate (9)

[0578]

[0579] (Synthesis of intermediate (9))

[0580] Intermediate (5) 4.0 g (6.0 mmol), intermediate (8) 3.1 g (7.2 mmol), Pd(OAc) 20.1 g (0.6 mmol), K3PO4 3.8 g (18.2 mmol), S-phos 0.5 g (1.2 mmol), toluene 36 mL, ethanol 4 mL, and distilled water 4 mL were mixed. The reaction mixture was stirred under reflux for one day. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 4.1 g (yield: 77.3%) of intermediate (9) as a white solid was obtained.

[0581]

[0582] Intermediate synthesis example 4: Synthesis of intermediate (10)

[0583]

[0584] (Synthesis of intermediate (10))

[0585] Intermediate (4) 5.3 g (11.9 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 2.1 g (11.9 mmol), Na2S2O5 2.7 g (14.3 mmol), and DMF 50 mL were mixed and stirred at 110°C for one day. After cooling to 60°C, DMF was removed under reduced pressure. DCM and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 6.7 g (yield: 92.9%) of the compound (intermediate (10)) as a white solid was obtained.

[0586]

[0587] Intermediate synthesis example 5: Synthesis of intermediate (11)

[0588]

[0589] (Synthesis of intermediate (11))

[0590] Intermediate (10) 5.1 g (8.6 mmol), intermediate (8) 4.4 g (10.3 mmol), Pd(PPh3) 40.5 g (0.4 mmol), K2CO3 3.5 g (25.8 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for one day. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 6.2 g (yield: 88.5%) of the compound (intermediate (11)) as a white solid was obtained.

[0591]

[0592] Intermediate synthesis example 6: Synthesis of intermediate (16)

[0593]

[0594] (Synthesis of intermediate (12))

[0595] 4-(trifluoromethyl)aniline (30.0 g, 186.2 mmol) and acetonitrile (600 mL) were mixed and cooled to 0°C. At 0°C, 33.2 g (186.2 mmol) of N-bromosuccinimide was slowly added and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure to remove the solvent to obtain 44.7 g (yield: 100.0%) of a yellow liquid compound (intermediate (12)).

[0596] (Synthesis of intermediate (13))

[0597] Intermediate (12) 15.0 g (62.5 mmol), 2-naphthylboronic acid 12.9 g (75.0 mmol), Pd(PPh3) 43.6 g (3.1 mmol), K2CO3 25.9 g (187.5 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. The mixture was stirred under reflux for one day and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 16.2 g (yield: 90.2%) of the compound (intermediate (13)) as an ivory solid.

[0598] (Synthesis of intermediate (14))

[0599] Intermediate (13) 16.2 g (56.4 mmol) and 340 mL of tetrahydrofuran were mixed and cooled to -78°C. 24.8 mL (2.5 M in hexane, 62.0 mmol) of n-BuLi was slowly added and stirred at -78°C for 2 hours. 12.4 g (56.4 mmol) of 1-bromo-3-fluoro-2-nitrobenzene was dissolved in 30 mL of THF and slowly added to the reaction mixture. After stirring at -78°C for 2 hours, the mixture was stirred at room temperature for 2 hours. Distilled water was added to terminate the reaction, and the mixture was concentrated under reduced pressure. Dichloromethane was added, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 20.8 g (yield: 75.7%) of the compound (intermediate (14)) as a white solid was obtained by slurrying with n-hexane.

[0600] (Synthesis of intermediate (15))

[0601] Intermediate (14) 20.8 g (42.7 mmol), Fe 11.9 g (213.4 mmol), ammonium chloride 2.3 g (42.7 mmol), EtOH 230 mL, and distilled water 47.3 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. Distilled water was added, and the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (15)) as a white solid was obtained at 12.5 g (yield: 64.0%) by recrystallization.

[0602] (Synthesis of intermediate (16))

[0603] Intermediate (15) 12.5 g (27.3 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 5.4 g (30.1 mmol), Na2S2O 56.2 g (32.8 mmol), and DMF 140 mL were mixed and stirred at 110°C for one day. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound (intermediate (16)) 8.6 g (yield: 51.1%) was obtained as a white solid.

[0604]

[0605] Intermediate synthesis example 7: Synthesis of intermediate (18)

[0606]

[0607] (Synthesis of intermediate (17))

[0608] Intermediate (6) 30.0 g (147.3 mmol), (3-chloro-5-methylphenyl)boronic acid 30.1 g (176.8 mmol), Pd(PPh3) 48.5 g (7.4 mmol), K2CO 361.1 g (441.9 mmol), toluene 589 mL, EtOH 147 mL, and H2O 147 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel and Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was solidified with methanol to obtain 37.5 g (yield: 86.7%) of a gray solid compound (intermediate (17)).

[0609] (Synthesis of intermediate (18))

[0610] Intermediate (17) 37.5 g (127.6 mmol), PIN2B 248.6 g (191.5 mmol), Pd(dba) 23.7 g (6.4 mmol), XPhos 9.1 g (19.2 mmol), KOAc 31.3 g (319.1 mmol) and toluene 630 mL were mixed and stirred under reflux for 5 hours. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc), and then solidified with methanol to obtain 31.9 g (yield: 64.9%) of the compound (intermediate (18)) as a gray solid.

[0611]

[0612] Intermediate synthesis example 8: Synthesis of intermediate (19)

[0613]

[0614] (Synthesis of intermediate (19))

[0615] Intermediate (16) 4.0 g (7.5 mmol), intermediate (18) 3.5 g (9.0 mmol), Pd(OAc) 20.2 g (0.7 mmol), K3PO4 4.8 g (22.4 mmol), S-phos 0.6 g (1.5 mmol), toluene 36 mL, and ethanol 4 mL distilled water were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.7 g (yield: 62.5%) of compound intermediate (19) was obtained as a white solid.

[0616]

[0617] Intermediate synthesis example 9: Synthesis of intermediate (20)

[0618]

[0619] (Synthesis of intermediate (20))

[0620] Intermediate (4) 5.0 g (11.2 mmol), 5-fluoro-2-hydroxybenzaldehyde 1.7 g (12.4 mmol), Na2S2O5 2.6 g (13.5 mmol) and DMF 50 mL were mixed, and the temperature was gradually increased to 130℃ and reacted for 12 hours. After the reaction was completed, it was cooled to room temperature, water was added, and stirred. The solid produced at this time was filtered, washed with water and methanol, dried, purified by silica gel column chromatography (CHCl3), and solidified with methanol to obtain 5.0 g (yield: 78.0%) of a yellow solid compound (intermediate (20)).

[0621]

[0622] Intermediate synthesis example 10: Synthesis of intermediate (21)

[0623]

[0624] (Synthesis of intermediate (21))

[0625] Intermediate (20) 5.0 g (8.8 mmol), intermediate (8) 3.7 g (8.8 mmol), Pd(OAc) 2196.5 mg (875.4 μmol), X-Phos 834.6 mg (1.8 mmol), K2CO3 3.6 g (26.3 mmol), xylene 40 mL and water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, water was added, extracted with chloroform and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (DCM) and solidified with a mixed solvent (CHCl3 / MeOH) to obtain 4.7 g (yield: 68.5%) of a yellow solid compound (intermediate (21)).

[0626]

[0627] Intermediate synthesis example 11: Synthesis of intermediate (22)

[0628]

[0629] (Synthesis of intermediate (22))

[0630] 1-Bromo-3-(tert-butyl)-5-chlorobenzene (10.0 g (34.2 mmol), naphthalen-2-ylboronic acid (6.5 g (37.7 mmol), Pd(PPh3) (41.2 g (1.0 mmol), K2CO3 (11.8 g (85.6 mmol), toluene (200 mL), ethanol (50 mL), and distilled water (50 mL)) were mixed and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extraction was performed with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting mixture was filtered through a silica gel pad (toluene) and solidified with a mixed solution (Hex / MeOH) to obtain 7.4 g (yield: 63.7%) of a white solid compound (intermediate (22)).

[0631]

[0632] Intermediate synthesis example 12: Synthesis of intermediate (23)

[0633]

[0634] (Synthesis of intermediate (23))

[0635] Intermediate (8) 42.0 g (98.3 mmol), 3-bromo-2-nitroaniline 25.6 g (117.9 mmol), Pd(PPh3) 43.4 g (2.9 mmol), K2CO3 34.0 g (245.7 mmol), toluene 500 mL, ethanol 125 mL, and distilled water 125 mL were mixed, and stirred at 90°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the solid was filtered, and washed with distilled water and methanol. The resulting mixture was purified by silica gel column chromatography (CHCl3 → CHCl3:EA), and solidified with a mixed solution (DCM / EtOH) to obtain 23.4 g (yield: 54.4%) of the compound (intermediate (23)) as a yellow solid.

[0636]

[0637] Intermediate synthesis example 13: Synthesis of intermediate (26)

[0638]

[0639] (Synthesis of intermediate (24))

[0640] Intermediate (22) 4.0 g (13.6 mmol), intermediate (23) 6.5 g (14.9 mmol), Pd(dba)2390.1 mg (678.4 μmol), X-Phos 646.8 mg (1.4 mmol), K3PO48.6 g (40.7 mmol) and xylene 70 mL were mixed and reacted at 110 ℃ for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extracted with chloroform. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting mixture was purified by silica gel column chromatography (Hex:EA) to obtain 9.4 g (yield: 99.6%) of an orange solid compound (intermediate (24)).

[0641] (Synthesis of intermediate (25))

[0642] Intermediate (24) 9.4 g (18.2 mmol), SnCl 25.1 g (91.2 mmol), and ethanol 100 mL were mixed and stirred at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and the resulting mixture was purified by silica gel column chromatography (warm Hex:EA) after filtration with a Celite pad (DCM), to obtain 6.2 g (yield: 70.0%) of a light yellow solid compound (intermediate (25)).

[0643] (Synthesis of intermediate (26))

[0644] Intermediate (25) 6.2 g (9.3 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 2.0 g (11.2 mmol), Na2S2O5 2.3 g (12.1 mmol) and DMF 50 mL were mixed and reacted at 110°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added, filtered, and washed with distilled water and methanol. The obtained mixture was purified by silica gel column chromatography (Hex:EA) to obtain 7.0 g (yield: 91.2%) of a white solid compound (intermediate (26)).

[0645]

[0646] Intermediate synthesis example 14: Synthesis of intermediate (29)

[0647]

[0648] (Synthesis of intermediate (27))

[0649] 2-chloro-4-iodopyridine (300 g, 1252.9 mmol), (4-fluorophenyl)boronic acid (210.4 g, 1503.5 mmol), Pd(PPh3) (443.4 g, 37.6 mmol), Na2CO3 (332.0 g, 3132.3 mmol), toluene (4000 mL), ethanol (1200 mL), and distilled water (1200 mL) were mixed and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extraction was performed with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting mixture was recrystallized twice with hexane to obtain 218.0 g (yield: 83.8%) of a light yellow solid compound (intermediate (27)).

[0650] (Synthesis of intermediate (28))

[0651] Intermediate (27) 218.0 g (1049.9 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 245.4 g (1154.9 mmol), Pd(PPh3) 436.4 g (31.5 mmol), K2CO3 362.8 g (2624.9 mmol), toluene 3500 mL, ethanol 1300 mL, and distilled water 1300 mL were mixed, and stirred at 80°C for 12 hours. After the reaction was completed, it was cooled to room temperature, distilled water was added to the reaction mass, and extraction was performed with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting mixture was filtered through a silica gel pad (toluene) and solidified with hexane to obtain 230.7 g (yield: 64.7%) of compound (28) as an ivory-colored solid.

[0652] (Synthesis of intermediate (29))

[0653] Intermediate (28) 230.7 g (678.8 mmol), pinacol diboron (Bis(pinacolato)diboron) 172.4 g (678.8 mmol), Pd(dba) 219.5 g (33.9 mmol), X-Phos 32.4 g (67.9 mmol), KOAc 166.6 g (1697.1 mmol) and toluene 1700 mL were mixed and reacted at 110°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a Celite pad (toluene), and the obtained mixture was purified by silica gel column chromatography (toluene), and solidified with hexane to obtain 271.6 g (yield: 92.8%) of a white solid compound (intermediate (29)).

[0654]

[0655] Intermediate synthesis example 15: Synthesis of intermediate (30)

[0656]

[0657] (Synthesis of intermediate (30))

[0658] Intermediate (29) 159.3 g (369.3 mmol), 3-bromo-2-nitroaniline 96.2 g (443.2 mmol), Pd(PPh3) 412.8 g (11.1 mmol), K2CO3 127.6 g (923.2 mmol), toluene 920 mL, ethanol 460 mL, and distilled water 460 mL were mixed, and stirred at 85°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the solid was filtered, and washed with distilled water and methanol. The resulting mixture was purified by silica gel column chromatography (tol: EA), and solidified with ethanol and ethyl acetate to obtain 104.5 g (yield: 64.1%) of a yellow solid compound (intermediate (30)).

[0659]

[0660] Intermediate synthesis example 16: Synthesis of intermediate (33)

[0661]

[0662] (Synthesis of intermediate (31))

[0663] Intermediate (22) 3.1 g (10.5 mmol), intermediate (30) 5.1 g (11.6 mmol), Pd(dba)2 302.3 mg (525.7 μmol), X-Phos 501.3 mg (1.1 mmol), K3PO4 6.7 g (31.5 mmol) and xylene 50 mL were mixed and reacted at 110°C for 12 hours. When the reaction was completed, the obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was solidified with ethanol to obtain 6.1 g (yield: 83.4%) of a red solid compound (intermediate (31)).

[0664] (Synthesis of intermediate (32))

[0665] Intermediate (31) 6.1 g (8.7 mmol), SnCl 5.0 g (26.1 mmol), and ethanol 100 mL were mixed and stirred at 100°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and the resulting mixture was purified by silica gel column chromatography (CHCl3:EA) after celite pad filtration (DCM), to obtain 4.0 g (yield: 68.5%) of a yellow solid compound (intermediate (32)).

[0666] (Synthesis of intermediate (33))

[0667] Intermediate (32) 4.0 g (6.0 mmol), 3,5-(di-tert-butyl)-2-hydroxybenzaldehyde 1.7 g (7.2 mmol), Na2S2O5 1.5 g (7.8 mmol) and DMF 30 mL were mixed and reacted at 110°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added, filtered, and washed with distilled water and methanol. The obtained mixture was purified by silica gel column chromatography (Hex:EA) to obtain 2.7 g (yield: 51.1%) of the compound (intermediate (33)) as a white solid.

[0668]

[0669] Intermediate synthesis example 17: Synthesis of intermediate (36)

[0670]

[0671] (Synthesis of intermediate (34))

[0672] 2-chloro-4-iodopyridine (10.0 g (41.8 mmol), (4-(methyl-d3)phenyl)boronic acid) (6.4 g (45.9 mmol), Pd(PPh3) (41.4 g (1.3 mmol), K2CO3 (14.4 g (104.4 mmol), toluene (200 mL), ethanol (50 mL), and distilled water (50 mL)) were mixed and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extraction was performed with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting mixture was purified by silica gel column chromatography (toluene), obtaining 7.6 g (yield: 88.0%) of a yellow solid compound (intermediate (34)).

[0673] (Synthesis of intermediate (35))

[0674] Intermediate (34) 7.6 g (36.8 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 10.2 g (47.8 mmol), Pd(PPh3) 41.3 g (1.1 mmol), K2CO3 12.7 g (91.9 mmol), toluene 180 mL, ethanol 45 mL, and distilled water 45 mL were mixed and stirred at 90°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extraction was performed with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting mixture was filtered through a silica gel pad (toluene) and solidified with nuclease to obtain 10.4 g (yield: 83.5%) of a white solid compound (intermediate (35)).

[0675] (Synthesis of intermediate (36))

[0676] Intermediate (35) 10.4 g (30.7 mmol), pinacol diboron (Bis(pinacolato)diboron) 9.4 g (36.8 mmol), Pd(dba) 2882.3 mg (1.5 mmol), KOAc 9.0 g (98.1 mmol), X-Phos 1.5 g (3.1 mmol) and toluene 150 mL were mixed and reacted at 110°C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a Celite pad (tol), and the obtained mixture was purified by silica gel column chromatography (CHCl3:EtOAc) and solidified with nuclease to obtain 10.1 g (yield: 76.5%) of a compound (intermediate (36)) as a pale yellow solid.

[0677]

[0678] Intermediate synthesis example 18: Synthesis of intermediate (37)

[0679]

[0680] (Synthesis of intermediate (37))

[0681] Intermediate (5) 4.0 g (6.1 mmol), intermediate (36) 3.1 g (7.3 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.5 g (18.2 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for one day. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 4.2 g (yield: 78.4%) of the compound (intermediate (37)) as a white solid was obtained.

[0682]

[0683] Intermediate synthesis example 19: Synthesis of intermediate (41)

[0684]

[0685] (Synthesis of intermediate (38))

[0686] Intermediate (1) 20.0 g (87.6 mmol), 1-naphthaleneboronic acid 18.1 g (105.0 mmol), Pd(PPh3) 45.1 g (4.4 mmol), K2CO3 36.3 g (262.0 mmol), toluene 200 mL, ethanol 100 mL, and distilled water 100 mL were mixed. The reaction mixture was stirred under reflux for one day. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 24.1 g (yield: 100.0%) of the compound (intermediate (38)) as a red liquid was obtained.

[0687] (Synthesis of intermediate (39))

[0688] Intermediate (38) 24.0 g (87.1 mmol) was mixed with THF, and the mixture was cooled to -78°C while stirring. 43.5 ml (87.1 mmol) of n-BuLi (2.0 M) and 17.4 g (79.2 mmol) of 1-bromo-3-fluoro-2-nitrobenzene were added, and the mixture was stirred at -78°C for 1 hour and then at room temperature for 1 day. After quenching the reaction with distilled water, the reaction solution was washed with ethyl acetate and distilled water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the mixture was purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 22.6 g (yield: 54.5%) of the compound (intermediate (39)) as a red liquid was obtained.

[0689] (Synthesis of intermediate (40))

[0690] In a 1 L two-necked flask, 22.6 g (47.0 mmol) of intermediate (39), 13.1 g (235.0 mmol) of Fe, 2.5 g (47.0 mmol) of NH4Cl, 230 mL of ethanol, and 47 mL of distilled water were mixed. The reaction mixture was stirred under reflux for one day. After completion of the reaction, the reaction solution was filtered through Celite at 70°C. The filtrate was concentrated under reduced pressure, and dichloromethane and distilled water were added to the concentrated residue and washed. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 15.8 g (yield: 75.5%) of the compound (intermediate (40)) as a red liquid was obtained.

[0691] (Synthesis of intermediate (41))

[0692] Intermediate (40) 15.8 g (35.5 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 9.1 g (39.0 mmol), Na2S2O 58.1 g (42.6 mmol), and DMF 140 mL were mixed and stirred at 110°C for 12 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 13.5 g (yield: 57.7%) of the compound (intermediate (41)) as a white solid was obtained by recrystallization with dichloromethane and normal hexane.

[0693]

[0694] Intermediate synthesis example 20: Synthesis of intermediate (42)

[0695]

[0696] (Synthesis of intermediate (42))

[0697] Intermediate (41) 4.0 g (6.1 mmol), intermediate (8) 3.1 g (7.3 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.5 g (18.2 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for one day. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.8 g (yield: 71.2%) of the compound (intermediate (42)) as a white solid was obtained.

[0698]

[0699] Intermediate synthesis example 21: Synthesis of intermediate (43)

[0700]

[0701] (Synthesis of intermediate (43))

[0702] Intermediate (40) 15.8 g (35.0 mmol), 5-tert-butyl-2-hydroxybenzaldehyde 6.9 g (39.0 mmol), Na2S2O 57.9 g (42.0 mmol), and DMF 160 mL were mixed. The reaction mixture was stirred at 110°C for one day. After quenching the reaction with distilled water, dichloromethane and Brine were added to the reaction solution and washed. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 8.9 g (yield: 42.0%) of the compound (intermediate (43)) as a white solid was obtained.

[0703]

[0704] Intermediate synthesis example 22: Synthesis of intermediate (44)

[0705]

[0706] (Synthesis of intermediate (44))

[0707] Intermediate (43) 4.0 g (6.6 mmol), intermediate (8) 3.1 g (7.3 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.7 g (19.0 mmol), toluene 40 mL, ethanol 20 mL, and distilled water 20 mL were mixed. The reaction mixture was stirred under reflux for one day. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (EA:Hex). After concentration and drying, 4.0 g (yield: 74.0%) of the compound (intermediate (44)) as a light green solid was obtained.

[0708]

[0709] Intermediate synthesis example 23: Synthesis of intermediate (47)

[0710]

[0711] (Synthesis of intermediate (45))

[0712] 2-chloro-4-iodopyridine (10.0 g (41.8 mmol), (4-(trifluoromethyl)phenyl)boronic acid) (9.5 g (50.1 mmol), Pd(PPh3) (41.4 g (1.3 mmol), Na2CO3 (11.1 g (104.4 mmol), toluene (200 mL), ethanol (50 mL), and distilled water (50 mL)) were mixed and reacted at 75°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extraction was performed with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting mixture was filtered through a silica gel pad (toluene) and solidified with a nuclease to obtain 3.7 g (yield: 34.4%) of a white solid compound (intermediate (45)).

[0713] (Synthesis of intermediate (46))

[0714] Intermediate (45) 3.7 g (14.4 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 3.7 g (17.2 mmol), Pd(PPh3) 4829.8 mg (0.7 mmol), K2CO3 4.0 g (28.7 mmol), toluene 40 mL, EtOH 15 mL, and H2O 15 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes) to obtain 5.6 g (yield: 100.0%) of a yellow oily compound (intermediate (46)).

[0715] (Synthesis of intermediate (47))

[0716] Intermediate (46) 5.6 g (14.4 mmol), pinacol diboron (Bis(pinacolato)diboron) 4.4 g (17.2 mmol), Pd(dba) 2659.3 mg (0.7 mmol), X-Phos 748.7 g (2.2 mmol), KOAc 4.2 g (43.1 mmol) and xylene 57 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, passed through a silica gel pad (Hexanes:EtOAc), and concentrated under reduced pressure to obtain 5.1 g (yield: 73.7%) of the compound (intermediate (47)) as a yellow solid.

[0717]

[0718] Intermediate synthesis example 24: Synthesis of intermediate (48)

[0719]

[0720] (Synthesis of intermediate (48))

[0721] Intermediate (43) 4.0 g (6.6 mmol), intermediate (47) 3.8 g (8.0 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.8 g (19.9 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for one day. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 4.2 g (yield: 72.2%) of the compound (intermediate (48)) as a white solid was obtained.

[0722]

[0723] Intermediate synthesis example 25: Synthesis of intermediate (51)

[0724]

[0725] (Synthesis of intermediate (49))

[0726] 2-chloro-4-iodopyridine (20.0 g, 83.5 mmol), 4-(tert-butyl)phenyl)boronic acid (16.4 g, 91.9 mmol), Pd(PPh3) (42.9 g, 2.5 mmol), K2CO3 (34.6 g, 250.6 mmol), 210 mL toluene, 70 mL ethanol, and 70 mL distilled water were mixed and stirred under reflux for 12 hours. After the reaction was completed, distilled water was added, the mixture was extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (Hexanes: CHCl3) to obtain 20.1 g (yield: 97.9%) of a red liquid compound (intermediate (49)).

[0727] (Synthesis of intermediate (50))

[0728] Intermediate (49) 20.1 g (81.8 mmol), 3-(tert-butyl)-5-chlorophenyl)boronic acid 17.4 g (81.8 mmol), Pd(PPh3) 44.7 g (4.1 mmol), K2CO3 33.9 g (245.4 mmol), toluene 240 mL, ethanol 80 mL, and distilled water 80 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, distilled water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (CHCl3) to obtain 23.8 g (yield: 77.0%) of a yellow solid compound (intermediate (50)).

[0729] (Synthesis of intermediate (51))

[0730] Intermediate (50) 23.8 g (63.0 mmol), pinacol diboron (Bis(pinacolato)diboron) 24.0 g (94.5 mmol), Pd(dba) 21.8 g (3.2 mmol), X-Phos 3.0 g (6.3 mmol), KOAc 18.5 g (188.9 mmol) and xylene 250 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, passed through a silica gel pad (Hex:EA), concentrated under reduced pressure, and purified with hexane to obtain 23.1 g (yield: 78.1%) of the compound (intermediate (51)) as a white solid.

[0731]

[0732] Intermediate synthesis example 26: Synthesis of intermediate (52)

[0733]

[0734] (Synthesis of intermediate (52))

[0735] Intermediate (41) 4.0 g (6.1 mmol), intermediate (51) 3.4 g (7.3 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.5 g (18.2 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for one day. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.8 g (yield: 68.0%) of the compound (intermediate (52)) as a white solid was obtained.

[0736]

[0737] Intermediate synthesis example 27: Synthesis of intermediate (56)

[0738]

[0739] (Synthesis of intermediate (53))

[0740] Intermediate (1) 15.0 g (65.8 mmol), pyridin-2-ylboronic acid 9.7 g (78.9 mmol), Pd(PPh3) 43.8 g (3.3 mmol), K2CO3 27.3 g (197.3 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. The mixture was stirred under reflux for 12 hours, then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane), and then recrystallized to obtain 13.5 g (yield: 90.7%) of the compound (intermediate (53)) as a white solid.

[0741] (Synthesis of intermediate (54))

[0742] Intermediate (53) 13.5 g (59.7 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 26.2 mL (2.5 M in hexane, 65.6 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 13.1 g (59.7 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours, the mixture was stirred at room temperature for 2 hours. Distilled water was added to terminate the reaction, and the mixture was concentrated under reduced pressure. Dichloromethane was added, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), slurry was made with n-hexane to obtain 19.2 g (yield: 75.5%) of a white solid compound (intermediate (54).

[0743] (Synthesis of intermediate (55))

[0744] Intermediate (54) 19.2 g (45.0 mmol), Fe 12.6 g (225.2 mmol), ammonium chloride 2.4 g (46.0 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After adding distilled water, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (55)) as a white solid was obtained at 11.8 g (yield: 66.1%) by recrystallization.

[0745] (Synthesis of intermediate (56))

[0746] Intermediate (55) 11.8 g (29.8 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 7.7 g (32.8 mmol), Na2S2O 56.8 g (35.7 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound (intermediate (56)) 9.2 g (yield: 50.6%) was obtained as a white solid by recrystallization.

[0747]

[0748] Intermediate synthesis example 28: Synthesis of intermediate (57)

[0749]

[0750] (Synthesis of intermediate (57))

[0751] Intermediate (56) 4.0 g (7.5 mmol), intermediate (8) 3.9 g (9.0 mmol), Pd(PPh3) 40.4 g (0.4 mmol), K2CO3 3.1 g (22.6 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 4.5 g (yield: 72.0%) of the compound (intermediate (57)) as a white solid was obtained.

[0752]

[0753] Intermediate synthesis example 29: Synthesis of intermediate (58)

[0754]

[0755] (Synthesis of intermediate (58))

[0756] Intermediate (55) 10.0 g (25.2 mmol), 5-fluoro-2-hydroxybenzaldehyde 3.9 g (27.8 mmol), Na2S2O 55.8 g (30.3 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound (intermediate (58)) 10.1 g (yield: 77.5%) was obtained as a white solid by recrystallization.

[0757]

[0758] Intermediate synthesis example 30: Synthesis of intermediate (59)

[0759]

[0760] (Synthesis of intermediate (59))

[0761] Intermediate (58) 4.0 g (7.8 mmol), intermediate (8) 4.0 g (9.3 mmol), Pd(PPh3) 40.4 g (0.4 mmol), K2CO3 3.2 g (23.2 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.6 g (yield: 63.1%) of the compound (intermediate (59)) as a white solid was obtained.

[0762]

[0763] Intermediate synthesis example 31: Synthesis of intermediate (63)

[0764]

[0765] (Synthesis of intermediate (60))

[0766] 1-Bromo-3-(tert-butyl)-5-chlorobenzene (10.0 g (40.4 mmol), pyridin-2-ylboronic acid (6.0 g (48.5 mmol), Pd(PPh3) (42.3 g (2.0 mmol), K2CO3 (16.8 g (121.2 mmol), toluene (120 mL), ethanol (50 mL), and distilled water (50 mL)) were added. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the organic layer was separated to obtain the organic layer, which was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 7.6 g (yield: 76.6%) of a white solid compound (intermediate (60)).

[0767] (Synthesis of intermediate (61))

[0768] Intermediate (60) 5.0 g (20.4 mmol), intermediate (23) 9.8 g (22.4 mmol), Pd(dba) 20.6 g (1.0 mmol), X-Phos 1.0 g (2.0 mmol), K3PO4 13.0 g (61.0 mmol) and xylene 70 mL were mixed and reacted at 110°C for 24 hours. After the reaction was completed, the obtained mixture was filtered through a silica gel pad, and the obtained mixture was recrystallized to obtain 7.7 g (yield: 58.5%) of the compound (intermediate (61)) as a white solid.

[0769] (Synthesis of intermediate (62))

[0770] Intermediate (61) 7.7 g (11.9 mmol), SnCl 5.5 g (35.7 mmol), and ethanol 100 mL were mixed and stirred at 100°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a Celite pad, and the obtained mixture was purified by silica gel column chromatography (CHCl3:EA) to obtain 5.2 g (yield: 70.8%) of a white solid compound (intermediate (62)).

[0771] (Synthesis of intermediate (63))

[0772] Intermediate (62) 5.2 g (6.0 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 1.7 g (7.2 mmol), Na2S2O5 1.5 g (7.8 mmol) and DMF 30 mL were mixed and reacted at 110°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added, filtered, and washed with distilled water and methanol. The obtained mixture was purified by silica gel column chromatography (Hex:EA) to obtain 4.2 g (yield: 64.3%) of the compound (intermediate (63)) as a white solid.

[0773]

[0774] Intermediate synthesis example 32: Synthesis of intermediate (64)

[0775]

[0776] (Synthesis of intermediate (64))

[0777] Intermediate (56) 4.0 g (6.6 mmol), intermediate (36) 3.4 g (7.9 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.7 g (19.7 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.3 g (yield: 60.4%) of the compound (intermediate (64)) as a white solid was obtained.

[0778]

[0779] Intermediate synthesis example 33: Synthesis of intermediate (68)

[0780]

[0781] (Synthesis of intermediate (65))

[0782] 15.0 g (70.1 mmol) of 2-bromo-4-(tert-butyl)pyridine, 11.5 g (84.1 mmol) of (2-aminophenyl)boronic acid, 44.1 g (3.5 mmol) of Pd(PPh3), 29.1 g (201.2 mmol) of K2CO3, 150 mL of toluene, 70 mL of ethanol, and 70 mL of distilled water were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, the organic layer was filtered, and the residue was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 13.7 g (yield: 86.4%) of a white solid compound (intermediate (65)).

[0783] (Synthesis of intermediate (66))

[0784] Intermediate (65) 13.7 g (60.5 mmol) was mixed with 360 mL of THF, and then cooled to -78°C. 26.6 mL of n-BuLi (2.5 M in hexane, 66.6 mmol) was slowly added, and the mixture was stirred at -78°C for 2 hours. 13.3 g (60.5 mmol) of 1-bromo-3-fluoro-2-nitrobenzene was dissolved in 30 mL of THF, and then slowly added to the reaction mixture. The mixture was stirred at -78°C for 2 hours, and then at room temperature for 2 hours. Distilled water was added, the reaction was terminated, and the mixture was concentrated under reduced pressure. Dichloromethane was added, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 19.6 g (yield: 76.0%) of the compound (intermediate (66)) as a white solid was obtained by slurrying with n-hexane.

[0785] (Synthesis of intermediate (67))

[0786] Intermediate (66) 19.6 g (46.0 mmol), Fe 12.8 g (229.9 mmol), ammonium chloride 2.5 g (46.0 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After distilled water was added, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (67)) as a white solid was obtained at 11.9 g (yield: 65.3%) by recrystallization.

[0787] (Synthesis of intermediate (68))

[0788] Intermediate (67) 11.9 g (30.0 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 5.9 g (33.0 mmol), Na2S2O 56.9 g (36.0 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound (intermediate (68)) 8.0 g (yield: 48.1%) was obtained as a white solid by recrystallization.

[0789]

[0790] Intermediate synthesis example 34: Synthesis of intermediate (69)

[0791]

[0792] (Synthesis of intermediate (69))

[0793] Intermediate (68) 4.0 g (7.2 mmol), intermediate (8) 3.7 g (8.7 mmol), Pd(PPh3) 40.4 g (0.4 mmol), K2CO3 3.0 g (21.6 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.5 g (yield: 62.6%) of the compound (intermediate (69)) as a white solid was obtained.

[0794]

[0795] Intermediate synthesis example 35: Synthesis of intermediate (73)

[0796]

[0797] (Synthesis of intermediate (70))

[0798] Intermediate (1) 15.0 g (65.8 mmol), pyridin-3-ylboronic acid 9.7 g (78.9 mmol), Pd(PPh3) 43.8 g (3.3 mmol), K2CO3 27.3 g (197.3 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. The mixture was stirred under reflux for 12 hours, then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane), and then recrystallized to obtain 12.9 g (yield: 86.7%) of the compound (intermediate (70)) as a white solid.

[0799] (Synthesis of intermediate (71))

[0800] Intermediate (70) 12.9 g (57.0 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 25.1 mL (2.5 M in hexane, 62.7 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 12.5 g (57.0 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours, the mixture was stirred at room temperature for 2 hours. Distilled water was added to terminate the reaction, and the mixture was concentrated under reduced pressure. Dichloromethane was added, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 20.3 g (yield: 83.5%) of the compound (intermediate (71)) as a white solid was obtained by slurrying with n-hexane.

[0801] (Synthesis of intermediate (72))

[0802] Intermediate (71) 20.3 g (47.6 mmol), Fe 13.3 g (238.1 mmol), ammonium chloride 2.6 g (47.6 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After adding distilled water, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound was recrystallized to obtain 11.1 g (yield: 58.8%) of the compound (intermediate (72)) as a white solid.

[0803] (Synthesis of intermediate (73))

[0804] Intermediate (72) 11.1 g (28.0 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 7.2 g (30.8 mmol), Na2S2O5 6.4 g (33.6 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 8.4 g (yield: 49.1%) of the compound (intermediate (73)) as a white solid.

[0805]

[0806] Intermediate synthesis example 36: Synthesis of intermediate (74)

[0807]

[0808] (Synthesis of intermediate (74))

[0809] Intermediate (73) 4.0 g (6.6 mmol), intermediate (8) 3.4 g (7.9 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.7 g (19.7 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.7 g (yield: 68.0%) of the compound (intermediate (74)) as a white solid was obtained.

[0810]

[0811] Intermediate synthesis example 37: Synthesis of intermediate (78)

[0812]

[0813] (Synthesis of intermediate (75))

[0814] Intermediate (12) 15.0 g (62.5 mmol), pyridin-3-ylboronic acid 9.2 g (75.0 mmol), Pd(PPh3) 43.6 g (3.1 mmol), K2CO3 25.9 g (187.5 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 13.2 g (yield: 88.7%) of the compound (intermediate (75)) as a white solid.

[0815] (Synthesis of intermediate (76))

[0816] Intermediate (75) 13.2 g (55.4 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 24.4 mL (2.5 M in hexane, 61.0 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 12.2 g (55.4 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 17.6 g (yield: 72.5%) of a white solid compound (intermediate (76)) was obtained by slurrying with n-hexane.

[0817] (Synthesis of intermediate (77))

[0818] Intermediate (76) 17.6 g (40.2 mmol), Fe 11.2 g (200.8 mmol), ammonium chloride 2.2 g (40.2 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After distilled water was added, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (77)) 10.6 g (yield: 64.7%) was obtained as a white solid by recrystallization.

[0819] (Synthesis of intermediate (78))

[0820] Intermediate (77) 10.6 g (26.0 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 5.1 g (28.6 mmol), Na2S2O 55.9 g (31.2 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 7.0 g (yield: 47.6%) of the compound (intermediate (78)) as a white solid was obtained.

[0821]

[0822] Intermediate synthesis example 38: Synthesis of intermediate (79)

[0823]

[0824] (Synthesis of intermediate (79))

[0825] Intermediate (78) 4.0 g (7.1 mmol), intermediate (8) 3.6 g (8.5 mmol), Pd(PPh3) 40.4 g (0.4 mmol), K2CO3 2.9 g (21.2 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.4 g (yield: 61.2%) of the compound (intermediate (79)) as a white solid was obtained.

[0826]

[0827] Intermediate synthesis example 39: Synthesis of intermediate (84)

[0828]

[0829] (Synthesis of intermediate (80))

[0830] Intermediate (1) 30.0 g (131.5 mmol), PIN2B 250.1 g (197.3 mmol), Pd(dba) 23.8 g (6.6 mmol), XPhos 9.4 g (19.7 mmol), KOAc 32.3 g (328.8 mmol) and toluene 650 mL were mixed and stirred under reflux for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc), and then solidified with methanol to obtain 25.4 g (yield: 70.2%) of a white solid compound (intermediate (80)).

[0831] (Synthesis of intermediate (81))

[0832] Intermediate (80) 15.0 g (62.5 mmol), 3-bromo-2,6-dimethylpyridine 12.2 g (65.4 mmol), Pd(PPh3) 43.2 g (2.7 mmol), K2CO3 22.6 g (163.5 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 10.4 g (yield: 75.0%) of the compound (intermediate (81)) as a white solid.

[0833] (Synthesis of intermediate (82))

[0834] Intermediate (81) 10.4 g (40.9 mmol) was mixed with 340 mL of THF, and then cooled to -78°C. n-BuLi 18.0 mL (2.5 M in hexane, 45.0 mmol) was slowly added, and the mixture was stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene (1-bromo-3-fluoro-2-nitrobenzene) 9.0 g (40.9 mmol) was dissolved in 30 mL of THF, and then slowly added to the reaction mixture. After stirring at -78°C for 2 hours, the mixture was stirred at room temperature for 2 hours. Distilled water was added, the reaction was terminated, and the mixture was concentrated under reduced pressure. Dichloromethane was added, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 15.3 g (yield: 82.4%) of a white solid compound (intermediate (82)) was obtained by slurrying with n-hexane.

[0835] (Synthesis of intermediate (83))

[0836] Intermediate (82) 15.3 g (15.3 mmol), Fe 9.4 g (168.4 mmol), ammonium chloride 1.8 g (33.7 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After adding distilled water, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (83)) 9.7 g (yield: 67.9%) was obtained as a white solid by recrystallization.

[0837] (Synthesis of intermediate (84))

[0838] Intermediate (83) 9.7 g (22.9 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 4.5 g (25.1 mmol), Na2S2O5 5.2 g (27.4 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound (intermediate (84)) 5.9 g (yield: 44.3%) was obtained as a white solid.

[0839]

[0840] Intermediate synthesis example 40: Synthesis of intermediate (85)

[0841]

[0842] (Synthesis of intermediate (85))

[0843] Intermediate (84) 4.0 g (7.9 mmol), intermediate (8) 4.1 g (9.5 mmol), Pd(PPh3) 40.5 g (0.4 mmol), K2CO3 3.3 g (23.8 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 4.4 g (yield: 69.0%) of the compound (intermediate (85)) as a white solid was obtained.

[0844]

[0845] Intermediate synthesis example 41: Synthesis of intermediate (89)

[0846]

[0847] (Synthesis of intermediate (86))

[0848] Intermediate (1) 15.0 g (65.8 mmol), pyridin-4-ylboronic acid 9.7 g (78.9 mmol), Pd(PPh3) 43.8 g (3.3 mmol), K2CO3 27.3 g (197.3 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. The mixture was stirred under reflux for 12 hours, then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane), and then recrystallized to obtain 11.4 g (yield: 76.6%) of the compound (intermediate (86)) as a white solid.

[0849] (Synthesis of intermediate (87))

[0850] Intermediate (86) 11.4 g (50.4 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 22.2 mL (2.5 M in hexane, 55.4 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 11.1 g (50.4 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 16.9 g (yield: 78.7%) of a white solid compound (intermediate (87)) was obtained by slurrying with n-hexane.

[0851] (Synthesis of intermediate (88))

[0852] Intermediate (87) 16.9 g (39.6 mmol), Fe 11.1 g (198.2 mmol), ammonium chloride 2.1 g (39.6 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After adding distilled water, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (88)) 12.1 g (yield: 77.0%) was obtained as a white solid by recrystallization.

[0853] (Synthesis of intermediate (89))

[0854] Intermediate (88) 12.1 g (30.5 mmol), 5-fluoro-2-hydroxybenzaldehyde 4.7 g (33.6 mmol), Na2S2O5 7.0 g (36.6 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound (intermediate (89)) as a white solid was obtained at 7.6 g (yield: 48.2%) by recrystallization.

[0855]

[0856] Intermediate synthesis example 42: Synthesis of intermediate (90)

[0857]

[0858] (Synthesis of intermediate (90))

[0859] Intermediate (89) 4.0 g (7.8 mmol), intermediate (8) 4.0 g (9.3 mmol), Pd(PPh3) 40.4 g (0.4 mmol), K2CO3 3.2 g (23.2 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.4 g (yield: 59.6%) of the compound (intermediate (90)) as a white solid was obtained.

[0860]

[0861] Intermediate synthesis example 43: Synthesis of intermediate (94)

[0862]

[0863] (Synthesis of intermediate (91))

[0864] 2-Bromoaniline (15.0 g, 87.2 mmol), pyridin-4-ylboronic acid (12.9 g, 104.6 mmol), Pd(PPh3) (45.0 g, 4.4 mmol), K2CO3 (36.2 g, 261.6 mmol), toluene (150 mL), ethanol (70 mL), and distilled water (70 mL) were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, the organic layer was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-hexane) and recrystallized to obtain 13.4 g (yield: 90.3%) of the compound (intermediate (91)) as a white solid.

[0865] (Synthesis of intermediate (92))

[0866] Intermediate (91) 13.4 g (78.7 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 30.6 mL (2.5 M in hexane, 76.6 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 17.3 g (78.7 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 21.2 g (yield: 72.7%) of the compound (intermediate (92)) as a white solid was obtained by slurrying with n-hexane.

[0867] (Synthesis of intermediate (93))

[0868] Intermediate (92) 21.2 g (57.3 mmol), Fe 16.0 g (286.3 mmol), ammonium chloride 3.1 g (57.3 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After distilled water was added, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (93)) as a white solid was obtained at 13.1 g (yield: 67.2%) by recrystallization.

[0869] (Synthesis of intermediate (94))

[0870] Intermediate (93) 13.1 g (38.5 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 7.6 g (42.4 mmol), Na2S2O 58.8 g (46.2 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound (intermediate (94)) 9.5 g (yield: 49.5%) was obtained as a white solid.

[0871]

[0872] Intermediate synthesis example 44: Synthesis of intermediate (95)

[0873]

[0874] (Synthesis of intermediate (95))

[0875] Intermediate (94) 4.0 g (8.0 mmol), intermediate (8) 4.1 g (9.6 mmol), Pd(PPh3) 40.5 g (0.4 mmol), K2CO3 3.3 g (24.1 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.6 g (yield: 62.4%) of the compound (intermediate (95)) as a white solid was obtained.

[0876]

[0877] Intermediate synthesis example 45: Synthesis of intermediate (96)

[0878]

[0879] (Synthesis of intermediate (96))

[0880] Intermediate (88) 10.0 g (25.2 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 6.5 g (27.8 mmol), Na2S2O5 5.7 g (30.3 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound (intermediate (96)) as a white solid was obtained 7.4 g (yield: 48.0%) by recrystallization.

[0881]

[0882] Intermediate synthesis example 46: Synthesis of intermediate (99)

[0883]

[0884] (Synthesis of intermediate (97))

[0885] 2-chloro-4-iodopyridine 30.0 g (125.3 mmol), (4-((1s,3s)-adamantan-1-yl)phenyl)boronic acid 38.5 g (150.4 mmol), Pd(PPh3) 44.3 g (3.8 mmol), Na2CO3 33.2 g (313.2 mmol), toluene 600 mL, ethanol 240 mL, and H2O 240 mL were mixed and stirred at 65°C for 24 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water, and the extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (EtOAc:Hexanes) and then solidified with hexane to obtain 20.7 g (yield: 51.0%) of a white solid compound (intermediate (97)).

[0886] (Synthesis of intermediate (98))

[0887] Intermediate (97) 20.7 g (63.9 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 17.7 g (83.1 mmol), Pd(PPh3) 43.7 g (3.2 mmol), K2CO3 26.5 g (191.8 mmol), toluene 300 mL, ethanol 120 mL, and H2O 120 mL were mixed and stirred under reflux for 24 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel and celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was solidified with methanol to obtain 23.9 g (yield: 82.0%) of the compound (intermediate (98)) as a white solid.

[0888] (Synthesis of intermediate (99))

[0889] Intermediate (98) 23.9 g (52.4 mmol), PIN2B 220.0 g (78.6 mmol), Pd(dba) 21.5 g (2.6 mmol), XPhos 3.8 g (7.9 mmol), KOAc 12.9 g (131.0 mmol) and toluene 300 mL were mixed and stirred under reflux for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc), and then solidified with methanol to obtain 18.6 g (yield: 64.8%) of the compound (intermediate (99)) as a white solid.

[0890]

[0891] Intermediate Synthesis Example 47: Synthesis of Intermediate (100)

[0892]

[0893] (Synthesis of intermediate (100))

[0894] Intermediate (96) 4.0 g (6.6 mmol), intermediate (99) 4.3 g (7.9 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.7 g (19.7 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 4.3 g (yield: 69.0%) of the compound (intermediate (100)) as a white solid was obtained.

[0895]

[0896] Intermediate Synthesis Example 48: Synthesis of Intermediate (104)

[0897]

[0898] (Synthesis of intermediate (101))

[0899] 15.0 g (97.7 mmol) of 2-chlorobenzo[d]oxazole, 32.3 g (117.2 mmol) of intermediate (80), 45.6 g (4.9 mmol) of Pd(PPh3), 40.5 g (293.0 mmol) of K2CO3, 180 mL of toluene, 80 mL of ethanol, and 80 mL of distilled water were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-hexane) and then recrystallized to obtain 18.4 g (yield: 70.7%) of the compound (intermediate (101)) as a white solid.

[0900] (Synthesis of intermediate (102))

[0901] Intermediate (101) 18.4 g (69.1 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 30.4 mL (2.5 M in hexane, 76.0 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 15.2 g (69.1 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 22.6 g (yield: 70.2%) of the compound (intermediate (102)) as a white solid was obtained by slurrying with n-hexane.

[0902] (Synthesis of intermediate (103))

[0903] Intermediate (102) 22.6 g (48.5 mmol), Fe 13.5 g (242.3 mmol), ammonium chloride 2.6 g (48.5 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After distilled water was added, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (103)) as a white solid was obtained at 14.2 g (yield: 67.2%) by recrystallization.

[0904] (Synthesis of intermediate (104))

[0905] Intermediate (103) 14.2 g (32.5 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 8.4 g (35.8 mmol), Na2S2O5 7.4 g (39.1 mmol), and DMF 140 mL were mixed, dichloromethane and distilled water were added at 110°C, and the layers were separated. The organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the product was recrystallized to obtain 10.8 g (yield: 51.0%) of the compound (intermediate (104)) as a white solid.

[0906]

[0907] Intermediate Synthesis Example 49: Synthesis of Intermediate (105)

[0908]

[0909] (Synthesis of intermediate (105))

[0910] Intermediate (104) 4.0 g (6.2 mmol), intermediate (8) 3.2 g (7.4 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.6 g (18.4 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.2 g (yield: 59.8%) of the compound (intermediate (105)) as a white solid was obtained.

[0911]

[0912] Intermediate synthesis example 50: Synthesis of intermediate (106)

[0913]

[0914] (Synthesis of intermediate (106))

[0915] Intermediate (104) 4.0 g (6.2 mmol), intermediate (29) 3.2 g (7.4 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.6 g (18.4 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 4.0 g (yield: 74.4%) of the compound (intermediate (106)) as a white solid was obtained.

[0916]

[0917] Intermediate Synthesis Example 51: Synthesis of Intermediate (109)

[0918]

[0919] (Synthesis of intermediate (107))

[0920] 2-chloro-4-iodopyridine 7.0 g (29.2 mmol), (phenyl-d5)boronic acid 4.1 g (32.2 mmol), Pd(PPh3) 41.7 g (1.5 mmol), K2CO3 10.1 g (73.1 mmol), toluene 90 mL, ethanol 30 mL, and distilled water 30 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, distilled water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (CHCl3) to obtain 5.6 g (yield: 99.1%) of a yellow solid compound (intermediate (107)).

[0921] (Synthesis of intermediate (108))

[0922] Intermediate (107) 3.6 g (18.5 mmol), 3.9 g (18.5 mmol) of 3-(tert-butyl)-5-chlorophenyl)boronic acid, 41.1 g (924.6 μmol) of Pd(PPh3), 7.7 g (55.5 mmol) of K2CO3, 60 mL of toluene, 15 mL of ethanol, and 15 mL of water were mixed and stirred under reflux for 12 hours. After the reaction was completed, distilled water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (Hex:DCM) to obtain 4.6 g (yield: 75.3%) of a yellow liquid compound (intermediate (108)).

[0923] (Synthesis of intermediate (109))

[0924] Intermediate (108) 4.6 g (13.9 mmol), pinacol diboron (Bis(pinacolato)diboron) 5.3 g (20.9 mmol), Pd(dba) 2800.4 mg (1.4 mmol), X-Phos 1.3 g (2.8 mmol), KOAc 4.1 g (41.8 mmol) and xylene 50 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, it was cooled to room temperature, passed through a silica gel pad (CHCl3), and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (Hexanes:EtOAc) to obtain 5.2 g (yield: 88.8%) of the compound (intermediate (109)) as a yellow liquid.

[0925]

[0926] Intermediate Synthesis Example 52: Synthesis of Intermediate (110)

[0927]

[0928] (Synthesis of intermediate (110))

[0929] Intermediate (104) 4.0 g (6.2 mmol), intermediate (109) 3.1 g (7.4 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.6 g (18.4 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.3 g (yield: 62.3%) of the compound (intermediate (110)) as a white solid was obtained.

[0930]

[0931] Intermediate Synthesis Example 53: Synthesis of Intermediate (115)

[0932]

[0933] (Synthesis of intermediate (111))

[0934] 2-chlorobenzo[d]thiazole (20.0 g, 117.9 mmol), (2-nitrophenyl)boronic acid (23.6 g, 141.5 mmol), Pd(PPh3) (46.8 g, 5.9 mmol), K2CO3 (40.7 g, 294.8 mmol), toluene (160 mL), ethanol (60 mL), and water (60 mL) were mixed and stirred under reflux for 12 hours. After the reaction was completed, water was added, the mixture was extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (CHCl3) and solidified with methanol to obtain 24.2 g (yield: 80.1%) of the compound (intermediate (111)) as a yellow solid.

[0935] (Synthesis of intermediate (112))

[0936] Intermediate (111) 24.2 g (94.4 mmol), Fe 26.4 g (472.1 mmol), 95 mL of sat. NH4Cl aqueous solution, and 400 mL of ethanol were mixed and reacted at 70°C for 12 hours. After the reaction was completed, the mixture was filtered through Celite, water was added, extracted with chloroform, and distilled under reduced pressure. The reaction mixture was passed through a silica pad (CHCl3) and concentrated under reduced pressure to obtain 11.6 g (yield: 54.2%) of the compound (intermediate (112)) as a yellow solid.

[0937] (Synthesis of intermediate (113))

[0938] Intermediate (112) 11.3 g (50.0 mmol) was dissolved in 110 mL of THF, and BuLi 31.3 mL (1.6 M, 50.0 mmol) was added dropwise at -78°C, followed by stirring for 1 hour. 1-Bromo-3-fluoro-2-nitrobenzene 10.0 g (45.5 mmol) was dissolved in 40 mL of THF, added dropwise, and the mixture was heated to room temperature. The mixture was reacted for 12 hours, cooled to 0°C, water was added, and extraction was performed with chloroform. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting reaction mixture was purified by silica gel column chromatography (Hex:CHCl3) to obtain 10.0 g (yield: 51.6%) of an orange solid compound (intermediate (113)).

[0939] (Synthesis of intermediate (114))

[0940] Intermediate (113) 10.0 g (24.5 mmol), Fe 6.6 g (117.3 mmol), 23 mL of sat. NH4Cl aqueous solution, and 117 mL of ethanol were mixed and reacted at 70°C for 12 hours. After the reaction was completed, the mixture was filtered through Celite, water was added, extracted with chloroform, and distilled under reduced pressure. The reaction mixture was passed through a silica pad (CHCl3) and concentrated under reduced pressure to obtain 9.0 g (yield: 96.8%) of the compound (intermediate (114)) as a yellow solid.

[0941] (Synthesis of intermediate (115))

[0942] Intermediate (114) 9.0 g (22.7 mmol), 5-tert-butyl-2-hydroxybenzaldehyde 4.5 g (25.0 mmol), Na2S2O5 5.2 g (27.3 mmol), and DMF 90 mL were mixed, and the temperature was gradually increased to 140°C and the mixture was reacted for 12 hours. After the reaction was completed, it was cooled to room temperature, water was added, and the mixture was stirred. The solid produced at this time was filtered, washed with water and methanol, dried, and purified by silica gel column chromatography (Hex:CHCl3) to obtain 10.2 g (yield: 81.0%) of the compound (intermediate (115)) as a yellow solid.

[0943]

[0944] Intermediate Synthesis Example 54: Synthesis of Intermediate (116)

[0945]

[0946] (Synthesis of intermediate (116))

[0947] Intermediate (115) 5.0 g (9.0 mmol), intermediate (8) 3.9 g (9.0 mmol), Pd(PPh3)4521.0 mg (328.1 μmol), K2CO3 3.7 g (27.1 mmol), toluene 30 mL, ethanol 10 mL, and water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (DCM) and solidified with a mixed solvent (Acetoene / MeOH) to obtain 3.7 g (yield: 52.9%) of the compound (intermediate (116)) as a white solid.

[0948]

[0949] Intermediate Synthesis Example 55: Synthesis of Intermediate (120)

[0950]

[0951] (Synthesis of intermediate (117))

[0952] 15.0 g (88.4 mmol) of 2-chlorobenzo[d]thiazole, 29.2 g (106.1 mmol) of intermediate (80), 45.1 g (4.4 mmol) of Pd(PPh3), 36.7 g (265.3 mmol) of K2CO3, 200 mL of toluene, 80 mL of ethanol, and 80 mL of distilled water were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-hexane) and then recrystallized to obtain 21.9 g (yield: 87.7%) of the compound (intermediate (117)) as a white solid.

[0953] (Synthesis of intermediate (118))

[0954] Intermediate (117) 21.9 g (77.6 mmol) and THF 360 mL were mixed and cooled to -78°C. n-BuLi 34.1 mL (2.5 M in hexane, 85.3 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 17.1 g (77.6 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 19.5 g (yield: 52.1%) of the compound (intermediate (118)) as a white solid was obtained by slurrying with n-hexane.

[0955] (Synthesis of intermediate (119))

[0956] Intermediate (118) 19.5 g (40.4 mmol), Fe 11.3 g (202.1 mmol), ammonium chloride 2.2 g (40.4 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After adding distilled water, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (119)) 10.6 g (yield: 58.0%) was obtained as a white solid by recrystallization.

[0957] (Synthesis of intermediate (120))

[0958] Intermediate (119) 10.6 g (23.4 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 6.0 g (25.8 mmol), Na2S2O5 5.3 g (28.1 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 7.4 g (yield: 47.4%) of the compound (intermediate (120)) as a white solid.

[0959]

[0960] Intermediate Synthesis Example 56: Synthesis of Intermediate (121)

[0961]

[0962] (Synthesis of intermediate (121))

[0963] Intermediate (120) 4.0 g (6.0 mmol), intermediate (8) 3.1 g (7.2 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.5 g (18.0 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.6 g (yield: 67.6%) of the compound (intermediate (121)) as a white solid was obtained.

[0964]

[0965] Intermediate Synthesis Example 57: Synthesis of Intermediate (123)

[0966]

[0967] (Synthesis of intermediate (122))

[0968] 1-bromo-3-(tert-butyl)-5-chlorobenzene 20.0 g (80.8 mmol), Bis(pinacolato)diboron 24.6 g (96.9 mmol), Pd(dppf)Cl 2- CH2Cl2 1.3 g (1.6 mmol), KOAc 23.8 g (242.4 mmol), and xylene 270 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, passed through a silica gel pad (Hexanes:EtOAc), and concentrated under reduced pressure to obtain 23.8 g (yield: 99.9%) of a white liquid compound (intermediate (122)).

[0969] (Synthesis of intermediate (123))

[0970] Intermediate (122) 23.8 g (80.8 mmol), 2-chlorobenzo[d]thiazole 16.4 g (96.9 mmol), Pd(PPh3) 44.7 g (4.0 mmol), K2CO3 33.5 g (242.3 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. After stirring under reflux for 12 hours, the mixture was cooled to room temperature. After distilled water was added, the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 19.2 g (yield: 78.8%) of the compound (intermediate (123)) as a white solid.

[0971]

[0972] Intermediate Synthesis Example 58: Synthesis of Intermediate (126)

[0973]

[0974] (Synthesis of intermediate (124))

[0975] 2-chloro-4-iodopyridine 30.0 g (125.3 mmol), (3,5-difluorophenyl)boronic acid 23.7 g (150.4 mmol), Pd(PPh3) 47.2 g (6.3 mmol), Na2CO3 39.8 g (375.9 mmol), toluene 500 mL, ethanol 200 mL, and H2O 200 mL were mixed and stirred at 65°C for 24 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (EtOAc:Hexanes) and then solidified with hexane to obtain 20.4 g (yield: 72.2%) of a white solid compound (intermediate (124)).

[0976] (Synthesis of intermediate (125))

[0977] Intermediate (124) 20.4 g (90.4 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 23.1 g (108.5 mmol), Pd(PPh3) 45.2 g (7.4 mmol), K2CO3 37.5 g (271.3 mmol), toluene 300 mL, ethanol 120 mL, and H2O 120 mL were mixed and stirred under reflux for 24 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel and celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was solidified with methanol to obtain 23.7 g (yield: 73.3%) of the compound (intermediate (125)) as a white solid.

[0978] (Synthesis of intermediate (126))

[0979] Intermediate (125) 23.7 g (66.2 mmol), PIN2B 225.2 g (99.4 mmol), Pd(dba) 21.9 g (3.3 mmol), XPhos 4.7 g (9.90 mmol), KOAc 16.3 g (165.6 mmol) and toluene 300 mL were mixed and stirred under reflux for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc), and then solidified with methanol to obtain 22.5 g (yield: 75.6%) of the compound (intermediate (126)) as a white solid.

[0980]

[0981] Intermediate Synthesis Example 59: Synthesis of Intermediate (130)

[0982]

[0983] (Synthesis of intermediate (127))

[0984] Intermediate (126) 20.0 g (44.5 mmol), 3-bromo-2-nitroaniline 11.5 g (53.4 mmol), Pd(PPh3) 42.6 g (2.2 mmol), K2CO3 18.5 g (133.5 mmol), toluene 160 mL, ethanol 70 mL, and distilled water 70 mL were mixed, and stirred at 85°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the solid was filtered, and washed with distilled water and methanol. The resulting mixture was purified by silica gel column chromatography (tol: EA), and solidified with ethanol and ethyl acetate to obtain 15.3 g (yield: 74.8%) of the compound (intermediate (127)) as a white solid.

[0985] (Synthesis of intermediate (128))

[0986] Intermediate (127) 10.0 g (21.8 mmol), intermediate (123) 7.2 g (23.9 mmol), Pd(dba) 20.6 g (1.1 mmol), X-Phos 1.0 g (2.2 mmol), K3PO4 13.8 g (65.3 mmol) and xylene 70 mL were mixed and reacted at 110°C for 24 hours. After the reaction was completed, the obtained mixture was filtered through a silica gel pad, and the obtained mixture was recrystallized to obtain 8.7 g (yield: 55.2%) of the compound (intermediate (128)) as a white solid.

[0987] (Synthesis of intermediate (129))

[0988] Intermediate (128) 8.7 g (12.0 mmol), SnCl 5.6 g (36.0 mmol), and ethanol 100 mL were mixed and stirred at 100°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a Celite pad, and purified by silica gel column chromatography (CHCl3:EA) to obtain 6.3 g (yield: 72.4%) of a white solid compound (intermediate (129)).

[0989] (Synthesis of intermediate (130))

[0990] Intermediate (129) 6.3 g (8.7 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 1.9 g (10.4 mmol), Na2S2O5 2.2 g (11.3 mmol) and DMF 40 mL were mixed and reacted at 110°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added, filtered, and washed with distilled water and methanol. The obtained mixture was purified by silica gel column chromatography (Hex:EA) to obtain 5.1 g (yield: 64.5%) of the compound (intermediate (130)) as a white solid.

[0991]

[0992] Intermediate synthesis example 60: Synthesis of intermediate (134)

[0993]

[0994] (Synthesis of intermediate (131))

[0995] Intermediate (1) 32.1 g (140.7 mmol), benzofuran-2-ylboronic acid 34.2 g (211.1 mmol), Pd(PPh3) 48.1 g (7.0 mmol), 2.0 M Cs2CO3 After mixing 176.0 mL (351.8 mmol) of aqueous solution and 703.5 mL of tetrahydrofuran, the mixture was stirred at 70°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) to obtain 26.6 g (yield: 71.4%) of a red liquid compound (intermediate (131)).

[0996] (Synthesis of intermediate (132))

[0997] Intermediate (131) 26.6 g (100.2 mmol) and tetrahydrofuran 532.0 mL were mixed and cooled to -78°C. 2.0 M n-BuLi (in cyclohexane) 60.1 mL (120.3 mmol) was slowly added dropwise at -78°C and stirred for 1 hour. 1-bromo-3-fluoro-2-nitrobenzene 26.5 g (120.3 mmol) was dissolved in 53.0 mL of tetrahydrofuran and slowly added dropwise at -78°C and stirred for 1 hour. After stirring for 1 hour, the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the organic layer was extracted using dichloromethane and distilled water, and the extracted organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM:Hexanes), and then recrystallized from hexane and ethanol to obtain 21.6 g (yield: 46.3%) of an orange solid compound (intermediate (132)).

[0998] (Synthesis of intermediate (133))

[0999] Intermediate (132) 21.6 g (46.4 mmol), Fe 15.5 g (278.5 mmol), and EtOH 432.0 mL were mixed, and 2.0 M NH4Cl aqueous solution 46.4 mL (92.8 mmol) was added and stirred under reflux for 3 hours. After the reaction was completed, the reaction solution was filtered through a pad of Celite to remove inorganic substances, and the organic layer was extracted with dichloromethane. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) to obtain 18.0 g (yield: 89.6%) of a red liquid compound (intermediate (133)).

[1000] (Synthesis of intermediate (134))

[1001] Intermediate (133) 10.0 g (23.0 mmol), 5-tert-butyl-2-hydroxybenzaldehyde 4.9 g (27.6 mmol), Na2S2O 56.6 g (34.5 mmol), and dimethylformamide (N,N'-Dimethylformamide) 200.0 mL were mixed and stirred at 130°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, and the organic layer was extracted using ethyl acetate and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) and then recrystallized with dichloromethane and methanol to obtain 7.8 g (yield: 57.6%) of an ivory-colored solid compound (intermediate (134)).

[1002]

[1003] Intermediate synthesis example 61: Synthesis of intermediate (135)

[1004]

[1005] (Synthesis of intermediate (135))

[1006] Intermediate (134) 3.0 g (5.1 mmol), intermediate (8) 3.2 g (7.6 mmol), Pd(OAc) 257.2 mg (0.3 mmol), SPhos 314.1 mg (0.8 mmol), K2CO3 2.1 g (15.3 mmol), xylene 60.0 mL, and H2O 6.7 mL were mixed and stirred at 130°C for 2 hours. After the reaction was completed, the organic layer was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (DCM: Hexanes) and then recrystallized with dichloromethane and methanol to obtain 3.6 g (yield: 87.1%) of an ivory-colored solid compound (intermediate (135)).

[1007]

[1008] Intermediate synthesis example 62: Synthesis of intermediate (139)

[1009]

[1010] (Synthesis of intermediate (136))

[1011] 2-Bromoaniline (15.0 g, 87.2 mmol), benzofuran-2-ylboronic acid (17.0 g, 104.6 mmol), Pd(PPh3) (45.0 g, 4.4 mmol), K2CO3 (36.2 g, 261.6 mmol), toluene (180 mL), ethanol (80 mL), and distilled water (80 mL) were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, the organic layer was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-hexane) and then recrystallized to obtain 13.5 g (yield: 74.0%) of the compound (intermediate (136)) as a white solid.

[1012] (Synthesis of intermediate (137))

[1013] Intermediate (136) 13.5 g (64.5 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 28.4 mL (2.5 M in hexane, 71.0 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 14.2 g (64.5 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 19.3 g (yield: 73.1%) of the compound (intermediate (137)) as a white solid was obtained by slurrying with n-hexane.

[1014] (Synthesis of intermediate (138))

[1015] Intermediate (137) 19.3 g (47.2 mmol), Fe 13.2 g (235.8 mmol), ammonium chloride 2.5 g (47.2 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After distilled water was added, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound was recrystallized to obtain 11.4 g (yield: 63.7%) of the compound (intermediate (138)) as a white solid.

[1016] (Synthesis of intermediate (139))

[1017] Intermediate (138) 11.4 g (30.1 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 5.9 g (33.1 mmol), Na2S2O 56.9 g (36.1 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 7.9 g (yield: 48.9%) of the compound (intermediate (139)) as a white solid.

[1018]

[1019] Intermediate synthesis example 63: Synthesis of intermediate (140)

[1020]

[1021] (Synthesis of intermediate (140))

[1022] Intermediate (139) 4.0 g (7.4 mmol), intermediate (8) 3.8 g (8.9 mmol), Pd(PPh3) 40.4 g (0.4 mmol), K2CO3 3.1 g (22.3 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.9 g (yield: 69.1%) of the compound (intermediate (140)) as a white solid was obtained.

[1023]

[1024] Intermediate synthesis example 64: Synthesis of intermediate (141)

[1025]

[1026] (Synthesis of intermediate (141))

[1027] Intermediate (138) 10.0 g (23.0 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 5.9 g (25.3 mmol), Na2S2O 55.2 g (27.6 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 7.7 g (yield: 51.6%) of the compound (intermediate (141)) as a white solid.

[1028]

[1029] Intermediate synthesis example 65: Synthesis of intermediate (142)

[1030]

[1031] (Synthesis of intermediate (142))

[1032] Intermediate (141) 4.0 g (6.2 mmol), intermediate (29) 3.2 g (7.4 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.6 g (18.5 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.5 g (yield: 65.0%) of the compound (intermediate (142)) as a white solid was obtained.

[1033]

[1034] Intermediate synthesis example 66: Synthesis of intermediate (143)

[1035]

[1036] (Synthesis of intermediate (143))

[1037] Intermediate (138) 10.0 g (23.0 mmol), 5-fluoro-2-hydroxybenzaldehyde 3.5 g (25.3 mmol), Na2S2O5 5.2 g (27.6 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 6.3 g (yield: 49.4%) of the compound (intermediate (143)) as a white solid.

[1038]

[1039] Intermediate Synthesis Example 67: Synthesis of Intermediate (144)

[1040]

[1041] (Synthesis of intermediate (144))

[1042] Intermediate (143) 4.0 g (7.2 mmol), intermediate (8) 3.7 g (8.6 mmol), Pd(PPh3) 40.4 g (0.4 mmol), K2CO3 3.0 g (21.6 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.7 g (yield: 66.2%) of the compound (intermediate (144)) as a white solid was obtained.

[1043]

[1044] Intermediate Synthesis Example 68: Synthesis of Intermediate (148)

[1045]

[1046] (Synthesis of intermediate (145))

[1047] 1-Bromo-3-(tert-butyl)-5-chlorobenzene (10.0 g (40.4 mmol), benzofuran-2-ylboronic acid (7.9 g (48.5 mmol), Pd(PPh3) (42.3 g (2.0 mmol), K2CO3 (16.8 g (121.2 mmol), toluene (120 mL), ethanol (50 mL), and distilled water (50 mL)) were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. The mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 5.8 g (yield: 50.4%) of a white solid compound (intermediate (145)).

[1048] (Synthesis of intermediate (146))

[1049] 5.0 g (17.6 mmol) of intermediate (145), 8.5 g (19.3 mmol) of intermediate (23), 20.5 g (0.9 mmol) of Pd(dba), 0.8 g (1.8 mmol) of X-Phos, 11.2 g (52.7 mmol) of K3PO4, and 70 mL of xylene were mixed and reacted at 110°C for 24 hours. After the reaction was completed, the obtained mixture was filtered through a silica gel pad, and the obtained mixture was recrystallized to obtain 6.8 g (yield: 56.5%) of the compound (intermediate (146)) as a white solid.

[1050] (Synthesis of intermediate (147))

[1051] Intermediate (146) 6.8 g (9.9 mmol), SnCl 4.6 g (29.7 mmol), and ethanol 100 mL were mixed and stirred at 100°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a Celite pad, and purified by silica gel column chromatography (CHCl3:EA) to obtain 4.7 g (yield: 72.3%) of the compound (intermediate (147)) as a white solid.

[1052] (Synthesis of intermediate (148))

[1053] Intermediate (147) 4.7 g (7.2 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 1.5 g (8.6 mmol), Na2S2O5 1.8 g (9.3 mmol) and DMF 30 mL were mixed and reacted at 110°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added, filtered, and washed with distilled water and methanol. The obtained mixture was purified by silica gel column chromatography (Hex:EA) to obtain 4.2 g (yield: 67.4%) of the compound (intermediate (148)) as a white solid.

[1054]

[1055] Intermediate synthesis example 69: Synthesis of intermediate (149)

[1056]

[1057] (Synthesis of intermediate (149))

[1058] Intermediate (141) 4.0 g (6.2 mmol), intermediate (36) 3.2 g (7.4 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.6 g (18.5 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.4 g (yield: 63.2%) of the compound (intermediate (149)) as a white solid was obtained.

[1059]

[1060] Intermediate synthesis example 70: Synthesis of intermediate (150)

[1061]

[1062] (Synthesis of intermediate (150))

[1063] Intermediate (141) 4.0 g (6.2 mmol), intermediate (51) 3.5 g (7.4 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.6 g (18.5 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.8 g (yield: 67.7%) of the compound (intermediate (150)) as a white solid was obtained.

[1064]

[1065] Intermediate synthesis example 71: Synthesis of intermediate (154)

[1066]

[1067] (Synthesis of intermediate (151))

[1068] Intermediate (1) 15.0 g (65.8 mmol), benzo[b]thiophen-2-ylboronic acid 14.1 g (78.9 mmol), Pd(PPh3) 43.8 g (3.3 mmol), K2CO3 27.3 g (197.3 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. After stirring under reflux for 12 hours, the mixture was cooled to room temperature. After distilled water was added, the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 14.3 g (yield: 77.3%) of the compound (intermediate (151)) as a white solid.

[1069] (Synthesis of intermediate (152))

[1070] Intermediate (151) 14.3 g (50.8 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 22.4 mL (2.5 M in hexane, 55.9 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 11.2 g (50.8 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 18.6 g (yield: 76.0%) of the compound (intermediate (152)) as a white solid was obtained by slurrying with n-hexane.

[1071] (Synthesis of intermediate (153))

[1072] Intermediate (152) 18.6 g (38.6 mmol), Fe 10.8 g (193.2 mmol), ammonium chloride 2.1 g (38.6 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After adding distilled water, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound was recrystallized to obtain 11.9 g (yield: 68.2%) of the compound (intermediate (153)) as a white solid.

[1073] (Synthesis of intermediate (154))

[1074] Intermediate (153) 11.9 g (26.4 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 6.8 g (29.0 mmol), Na2S2O5 6.0 g (31.6 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound (intermediate (154)) 8.4 g (yield: 47.9%) was obtained as a white solid.

[1075]

[1076] Intermediate synthesis example 72: Synthesis of intermediate (155)

[1077]

[1078] (Synthesis of intermediate (155))

[1079] Intermediate (154) 4.0 g (6.0 mmol), intermediate (8) 3.1 g (7.2 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.5 g (18.0 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.2 g (yield: 60.1%) of the compound (intermediate (155)) as a white solid was obtained.

[1080]

[1081] Intermediate Synthesis Example 73: Synthesis of Intermediate (156)

[1082]

[1083] (Synthesis of intermediate (156))

[1084] Intermediate (153) 10.0 g (22.2 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 4.3 g (24.4 mmol), Na2S2O5 5.1 g (26.6 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 6.6 g (yield: 48.9%) of the compound (intermediate (156)) as a white solid.

[1085]

[1086] Intermediate Synthesis Example 74: Synthesis of Intermediate (157)

[1087]

[1088] (Synthesis of intermediate (157))

[1089] Intermediate (156) 4.0 g (6.6 mmol), intermediate (8) 3.4 g (7.9 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.7 g (19.7 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.3 g (yield: 60.6%) of the compound (intermediate (157)) as a white solid was obtained.

[1090]

[1091] Intermediate Synthesis Example 75: Synthesis of Intermediate (161)

[1092]

[1093] (Synthesis of intermediate (158))

[1094] Benzo[b]thiophene-2-ylboronic acid (10.0 g, 58.1 mmol), 2-bromoaniline (15.5 g, 87.2 mmol), Pd(PPh3) (41.34 g, 1.16 mmol), Cs2CO3 (37.9 g, 113 mmol), tetrahydrofuran (90 mL), and distilled water (10 mL) were mixed and stirred under reflux for one day. After cooling to room temperature, DCM and distilled water were added, the layers were separated, and the organic layer was extracted. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 5.72 g (43.7%) of the compound (intermediate (158)) as a white solid was obtained by recrystallization in DCM / Hex.

[1095] (Synthesis of intermediate (159))

[1096] Intermediate (158) 5.63 g (25.0 mmol) was added to 50 mL of tetrahydrofuran and stirred at -78 °C. n-BuLi (2.5 M) 10 mL (27.3 mmol) was slowly added dropwise and stirred for 4 hours. A solution of 5.0 g (22.7 mmol) of 1-bromo-3-fluoro-2-nitrobenzene dissolved in 20 mL of tetrahydrofuran at -78 °C was slowly added dropwise to the reaction mixture and stirred at room temperature for one day. Ammonium chloride aqueous solution and DCM were added, and the organic layer was separated. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was recrystallized with DCM / Hex to obtain 4.10 g (42.4%) of the compound (intermediate (159)) as an orange solid.

[1097] (Synthesis of intermediate (160))

[1098] Intermediate (159) 4.10 g (9.64 mmol), iron (Fe) 2.69 g (4.82 mmol), ammonium chloride 0.62 g (11.5 mmol), distilled water 4 mL, and ethanol 40 mL were mixed and stirred under reflux for 8 hours. After the reaction was completed, celite filter was performed. DCM was added, the organic layer was separated, washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Hexane was added to the concentrate, stirred for 30 minutes, and filtered to obtain 3.26 g (85.6%) of an orange solid compound (intermediate (160)).

[1099] (Synthesis of intermediate (161))

[1100] Intermediate (160) 3.20 g (8.09 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 1.59 g (8.90 mmol), sodium metabisulfite 2.00 g (10.5 mmol), and DMF 32 mL were added and stirred at 120°C for 12 hours. After completion of the reaction, distilled water and DCM were added and the organic layer was extracted. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The compound (intermediate (161)) 4.03 g (90.0%) was obtained as an orange liquid by purification by silica gel column chromatography (DCM:Hex).

[1101]

[1102] Intermediate Synthesis Example 76: Synthesis of Intermediate (162)

[1103]

[1104] (Synthesis of intermediate (162))

[1105] Intermediate (161) 4 g (7.23 mmol), intermediate (8) 3.40 g (7.95 mmol), Pd(PPh3) 40.25 g (0.22 mmol), K2CO3 3.00 g (21.7 mmol), toluene 32 mL, distilled water 16 mL, and ethanol 8 mL were mixed and stirred under reflux for one day. After cooling to room temperature, DCM and distilled water were added, and the layers were separated to extract the organic layer. The organic layer was washed with distilled water, dried over anhydrous magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / n-hexane) to obtain 4.99 g (96.3%) of the compound (intermediate (162)) as an ivory solid.

[1106]

[1107] Intermediate Synthesis Example 77: Synthesis of Intermediate (163)

[1108]

[1109] (Synthesis of intermediate (163))

[1110] Intermediate (153) 10.0 g (22.2 mmol), 3,5-difluoro-2-hydroxybenzaldehyde 3.9 g (24.4 mmol), Na2S2O5 5.1 g (26.6 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 6.2 g (yield: 47.5%) of the compound (intermediate (163)) as a white solid.

[1111]

[1112] Intermediate Synthesis Example 78: Synthesis of Intermediate (164)

[1113]

[1114] (Synthesis of intermediate (164))

[1115] Intermediate (163) 4.0 g (6.8 mmol), intermediate (8) 3.5 g (8.1 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.8 g (20.4 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.9 g (yield: 71.0%) of the compound (intermediate (164)) as a white solid was obtained.

[1116]

[1117] Intermediate synthesis example 79: Synthesis of intermediate (168)

[1118]

[1119] (Synthesis of intermediate (165))

[1120] Intermediate (1) 20.0 g (87.7 mmol), dibenzo[b,d]furan-4-ylboronic acid 20.4 g (96.4 mmol), Pd(PPh3) 43.0 g (2.6 mmol), K2CO3 30.3 g (219.2 mmol), toluene 400 mL, ethanol 100 mL, and distilled water 100 mL were mixed and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extraction was performed with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting mixture was purified by silica gel column chromatography (Hex:EA), and solidified with a mixed solution (DCM / EtOH) to obtain 16.0 g (yield: 57.9%) of a white solid compound (intermediate (165)).

[1121] (Synthesis of intermediate (166))

[1122] After mixing 16.0 g (50.7 mmol) of intermediate (165) and 250 ml of THF, 20.9 ml (52.2 mmol, 2.5 M in hex) of n-BuLi was slowly added dropwise at -78°C. After stirring for 2 hours, 47.3 g (170.9 mmol) of 1-bromo-3-fluoro-2-nitrobenzene was added dropwise as a mixed solution, and the mixture was reacted for 2 hours. When the reaction was complete, distilled water was added to the reactant at room temperature, and extracted with dichloromethane. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The obtained mixture was solidified with ethanol to obtain 11.8 g (yield: 45.1%) of a red solid compound (intermediate (166)).

[1123] (Synthesis of intermediate (167))

[1124] Intermediate (166) 11.8 g (22.9 mmol), Fe 6.4 g (114.5 mmol), NH4Cl 2.4 g (45.8 mmol) and ethanol 115 mL were mixed and stirred at 90°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a Celite pad (DCM), and the resulting mixture was filtered through a silica gel pad (Hex:EA) and solidified with ethanol to obtain 8.9 g (yield: 80.1%) of a yellow solid compound (intermediate (167)).

[1125] (Synthesis of intermediate (168))

[1126] Intermediate (167) 8.9 g (18.3 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 4.7 g (20.2 mmol), Na2S2O5 4.2 g (22.0 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 7.0 g (yield: 54.6%) of the compound (intermediate (168)) as a white solid was obtained.

[1127]

[1128] Intermediate synthesis example 80: Synthesis of intermediate (169)

[1129]

[1130] (Synthesis of intermediate (169))

[1131] Intermediate (168) 4.0 g (5.7 mmol), intermediate (8) 2.9 g (6.9 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.4 g (17.2 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.4 g (yield: 64.6%) of the compound (intermediate (169)) as a white solid was obtained.

[1132]

[1133] Intermediate synthesis example 81: Synthesis of intermediate (170)

[1134]

[1135] (Synthesis of intermediate (170))

[1136] Intermediate (167) 4.5 g (9.3 mmol), 5-fluoro-2-hydroxybenzaldehyde 1.6 g (11.1 mmol), Na2S2O5 2.3 g (12.1 mmol), and DMF 45 mL were mixed and reacted at 130°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added, the precipitated solid was filtered, and washed with distilled water and methanol. The obtained mixture was solidified with methanol to obtain 5.6 g (yield: 99.8%) of a white solid compound (intermediate (170)).

[1137]

[1138] Intermediate Synthesis Example 82: Synthesis of Intermediate (171)

[1139]

[1140] (Synthesis of intermediate (171))

[1141] Intermediate (170) 5.6 g (9.2 mmol), intermediate (8) 4.3 g (10.2 mmol), Pd(PPh3)4 320.6 mg (277.5 μmol), K2CO3 3.2 g (23.1 mmol), toluene 46 mL, ethanol 11 mL, and distilled water 11 mL were mixed and reacted at 90°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extracted with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The obtained mixture was filtered through a silica gel pad (Hex:EA), and solidified with a mixed solution (DCM / MeOH) to obtain 6.6 g (yield: 86.4%) of the compound (intermediate (171)) as a white solid.

[1142]

[1143] Intermediate synthesis example 83: Synthesis of intermediate (172)

[1144]

[1145] (Synthesis of intermediate (172))

[1146] Intermediate (167) 10.0 g (20.6 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 4.0 g (22.7 mmol), Na2S2O5 4.7 g (24.7 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 9.5 g (yield: 71.7%) of the compound (intermediate (172)) as a white solid.

[1147]

[1148] Intermediate Synthesis Example 84: Synthesis of Intermediate (173)

[1149]

[1150] (Synthesis of intermediate (173))

[1151] Intermediate (172) 4.0 g (6.2 mmol), intermediate (29) 3.2 g (7.5 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.6 g (18.6 mmol), toluene 40 mL, ethanol 10 mL, and distilled water 10 mL were mixed and reacted at 90°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extracted with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting mixture was filtered through a silica gel pad (toluene→Hex:EA), and after recrystallization, 3.7 g (yield: 68.6%) of the compound (intermediate (173)) as a white solid was obtained.

[1152]

[1153] Intermediate Synthesis Example 85: Synthesis of Intermediate (177)

[1154]

[1155] (Synthesis of intermediate (174))

[1156] 1-Bromo-3-(tert-butyl)-5-chlorobenzene (10.0 g (34.2 mmol), dibenzo[b,d]furan-4-ylboronic acid (10.3 g (48.5 mmol), Pd(PPh3) (41.4 g (1.2 mmol), K2CO3 (14.0 g (101.0 mmol), toluene (200 mL), ethanol (50 mL), and distilled water (50 mL)) were mixed and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extraction was performed with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting mixture was filtered through a silica gel pad (Hexane) to obtain 13.0 g (yield: 96.1%) of a white solid compound (intermediate (174)).

[1157] (Synthesis of intermediate (175))

[1158] Intermediate (30) 5.0 g (11.3 mmol), intermediate (174) 4.2 g (12.5 mmol), Pd(dba)2325.6 mg (566.2 μmol), X-Phos 539.9 mg (1.1 mmol), K3PO4 7.2 g (34.0 mmol) and xylene 60 mL were mixed and reacted at 110°C for 12 hours. After the reaction was completed, it was cooled to room temperature, distilled water was added to the reaction mixture, and extracted with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The obtained mixture was purified by silica gel column chromatography (EA:Hex), and the obtained mixture was solidified with ethanol to obtain 6.3 g (yield: 74.9%) of a red solid compound (intermediate (175)).

[1159] (Synthesis of intermediate (176))

[1160] Intermediate (175) 6.3 g (8.5 mmol), SnCl 24.8 g (25.5 mmol) and ethanol 100 mL were mixed and stirred at 80°C for 12 hours. After the reaction was completed, it was cooled to room temperature, 100 mL of 2N NaOH aqueous solution was added, and the mixture was stirred for 2 hours. After stirring, distilled water was added to the reaction mixture and extracted with chloroform. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The obtained mixture was purified by silica gel column chromatography (Hex:EA), and the volatile compound was solidified with ethanol to obtain 3.2 g (yield: 52.9%) of the compound (intermediate (176)) as a white solid.

[1161] (Synthesis of intermediate (177))

[1162] Intermediate (176) 3.2 g (4.5 mmol), 3,5-(di-tert-butyl)-2-hydroxybenzaldehyde 1.3 g (5.4 mmol), Na2S2O5 1.1 g (5.9 mmol) and DMF 25 mL were mixed and reacted at 130°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added, filtered, and washed with distilled water and ethanol. The obtained mixture was purified by silica gel column chromatography (Hex:EA), and the obtained mixture was solidified with a mixed solution (EtOH / DCM) to obtain 3.1 g (yield: 74.4%) of the compound (intermediate (177)) as a white solid.

[1163]

[1164] Intermediate Synthesis Example 86: Synthesis of Intermediate (178)

[1165]

[1166] (Synthesis of intermediate (178))

[1167] Intermediate (168) 4.0 g (5.7 mmol), intermediate (109) 2.9 g (6.9 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.4 g (17.2 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.2 g (yield: 61.4%) of the compound (intermediate (178)) as a white solid was obtained.

[1168]

[1169] Intermediate Synthesis Example 87: Synthesis of Intermediate (179)

[1170]

[1171] (Synthesis of intermediate (179))

[1172] Intermediate (168) 4.0 g (5.7 mmol), intermediate (51) 3.2 g (6.9 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.4 g (17.2 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.5 g (yield: 63.6%) of the compound (intermediate (179)) as a white solid was obtained.

[1173]

[1174] Intermediate Synthesis Example 88: Synthesis of Intermediate (184)

[1175]

[1176] (Synthesis of intermediate (180))

[1177] 2-Bromo-4-(tert-butyl)phenol (50.0 g, 218.2 mmol), bis(pinacolato)diboron (66.5 g, 261.9 mmol), Pd(dppf)Cl2CH2Cl2 (3.6 g, 4.4 mmol), KOAc (64.3 g, 654.7 mmol), and xylene (700 mL) were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, passed through a silica gel pad (Hex:EA), and concentrated under reduced pressure to obtain 60.0 g (yield: 99.6%) of a gray liquid compound (intermediate (180)).

[1178] (Synthesis of intermediate (181))

[1179] Intermediate (180) 60.0 g (217.2 mmol), 1-bromo-3-chloro-2-fluorobenzene 35.0 g (167.1 mmol), Pd(PPh3) 49.7 g (8.4 mmol), K2CO3 69.3 g (501.3 mmol), toluene 400 mL, ethanol 100 mL, and water 100 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (CHCl3) to obtain 32.0 g (yield: 68.7%) of a white liquid compound (intermediate (181)).

[1180] (Synthesis of intermediate (182))

[1181] Intermediate (181) 32.0 g (114.8 mmol), K2CO3 47.6 g (344.4 mmol), and DMF 400 mL were mixed, slowly heated to 100 ℃, and reacted for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added, and stirred. The solid produced at this time was filtered, washed with water, dried, purified by silica gel column chromatography (CHCl3), and solidified with ethanol to obtain 23.2 g (yield: 78.4%) of the compound (intermediate (182)) as a white solid.

[1182] (Synthesis of intermediate (183))

[1183] Intermediate (182) 18.6 g (71.9 mmol), pinacol diboron (Bis(pinacolato)diboron) 27.4 g (107.8 mmol), Pd(dba) 22.1 g (3.6 mmol), X-Phos 3.4 g (7.2 mmol), KOAc 21.2 g (215.7 mmol) and xylene 240 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, it was cooled to room temperature, passed through a silica gel pad (CHCl3), and concentrated under reduced pressure to obtain 25.0 g (yield: 99.3%) of the compound (intermediate (183)) as a white solid.

[1184] (Synthesis of intermediate (184))

[1185] Intermediate (183) 25.0 g (71.4 mmol), 2-bromo-4-(tert-butyl)-1-chlorobenzene 17.6 g (71.4 mmol), Pd(PPh3) 44.1 g (3.6 mmol), K2CO3 25.6 g (214.1 mmol), toluene 220 mL, ethanol 70 mL, and water 70 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (Hex) to obtain 24.4 g (yield: 87.4%) of a yellow solid compound (intermediate (184)).

[1186]

[1187] Intermediate synthesis example 89: Synthesis of intermediate (187)

[1188]

[1189] (Synthesis of intermediate (185))

[1190] Intermediate (23) 4.0 g (9.1 mmol), intermediate (184) 3.6 g (9.1 mmol), Pd(dba) 2525.7 mg (914.2 μmol), X-Phos 871.7 mg (1.8 mmol), K3PO4 5.8 g (27.4 mmol) and xylene 45 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (DCM) to obtain 5.7 g (yield: 78.7%) of a red solid compound (intermediate (185)).

[1191] (Synthesis of intermediate (186))

[1192] Intermediate (185) 5.7 g (7.2 mmol), SnCl 24.8 g (25.2 mmol), and ethanol 36 mL were mixed and reacted at 70°C for 12 hours. After the reaction was completed, the mixture was neutralized with 2 N NaOH aqueous solution, extracted with chloroform, and distilled under reduced pressure. The reaction mixture was passed through a silica pad (DCM) and concentrated under reduced pressure to obtain 4.0 g (yield: 72.9%) of the compound (intermediate (186)) as a yellow solid.

[1193] (Synthesis of intermediate (187))

[1194] Intermediate (186) 4.0 g (5.3 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 1.4 g (5.7 mmol), Na2S2O5 1.2 g (6.3 mmol) and DMF 26 mL were mixed, and the temperature was gradually increased to 130℃ and the mixture was reacted for 12 hours. After the reaction was completed, it was cooled to room temperature, water was added, and the mixture was stirred. The solid produced at this time was filtered, washed with water and methanol, dried, purified by silica gel column chromatography (DCM), and solidified with a mixed solvent (DCM / EtOH) to obtain 3.3 g (yield: 64.2%) of the compound (intermediate (187)) as a white solid.

[1195]

[1196] Intermediate synthesis example 90: Synthesis of intermediate (192)

[1197]

[1198] (Synthesis of intermediate (188))

[1199] 3-bromodibenzo[b,d]furan (20.0 g, 80.9 mmol), bis(pinacolato)diboron (30.8 g, 121.4 mmol), Pd(dppf)Cl2CH2Cl2 (3.3 g, 4.1 mmol), KOAc (23.8 g, 242.8 mmol), and dioxane (270 mL) were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and the solvent was concentrated under reduced pressure. The reaction mixture was passed through a silica gel pad (CHCl3), concentrated under reduced pressure, and solidified with methanol to obtain 10.0 g (yield: 42.0%) of the compound (intermediate (188)) as a white solid.

[1200] (Synthesis of intermediate (189))

[1201] Intermediate (1) 7.0 g (30.7 mmol), intermediate (188) 9.9 g (33.8 mmol), Pd(PPh3) 41.8 g (1.5 mmol), K2CO3 17.0 g (122.7 mmol), dioxane 90 mL, and water 30 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (Hex:CHCl3) to obtain 8.5 g (yield: 87.8%) of a yellow solid compound (intermediate (189)).

[1202] (Synthesis of intermediate (190))

[1203] Intermediate (189) 8.5 g (26.9 mmol) was dissolved in 130 mL of THF, and BuLi 10.8 mL (2.5 M, 29.6 mmol) was added dropwise at -78°C, followed by stirring for 1 hour. 1-Bromo-3-fluoro-2-nitrobenzene 5.9 g (26.9 mmol) was added, stirred for 1 hour, and then warmed to room temperature. The mixture was reacted for 12 hours, cooled to 0°C, water was added, and extracted with chloroform. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting reaction mixture was purified by silica gel column chromatography (Hex:CHCl3) to obtain 6.7 g (yield: 48.2%) of a red solid compound (intermediate (190)).

[1204] (Synthesis of intermediate (191))

[1205] Intermediate (190) 6.7 g (13.0 mmol), Fe 3.6 g (65.0 mmol), 13.0 mL of sat. NH4Cl aqueous solution, and 65 mL of ethanol were mixed and reacted at 70°C for 3 hours. After completion of the reaction, aq. Na2CO3 aqueous solution was added, filtered through Celite, water was added, extracted with chloroform, and distilled under reduced pressure. The reaction mixture was passed through a silica pad (CHCl3) and concentrated under reduced pressure to obtain 5.9 g (yield: 92.9%) of the compound (intermediate (191)) as a yellow solid.

[1206] (Synthesis of intermediate (192))

[1207] Intermediate (191) 5.9 g (12.1 mmol), 5-tert-butyl-2-hydroxybenzaldehyde (5-(tert-butyl)-2-hydroxybenzaldehyde) 2.4 g (13.3 mmol), Na2S2O5 2.8 g (14.5 mmol) and DMF 60 mL were mixed, and the temperature was gradually increased to 130℃ and the mixture was reacted for 12 hours. After the reaction was completed, it was cooled to room temperature, water was added, and the mixture was stirred. The solid produced at this time was filtered, washed with water and methanol, dried, purified by silica gel column chromatography (CHCl3), and solidified with ethanol to obtain 6.4 g (yield: 82.5%) of the compound (intermediate (192)) as a yellow solid.

[1208]

[1209] Intermediate synthesis example 91: Synthesis of intermediate (193)

[1210]

[1211] (Synthesis of intermediate (193))

[1212] Intermediate (192) 3.2 g (5.0 mmol), intermediate (8) 2.1 g (5.0 mmol), Pd(OAc) 2111.6 mg (497.2 μmol), X-Phos 474.0 mg (994.4 μmol), K2CO 3 2.1 g (14.9 mmol), xylene 20 mL, and water 5 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (DCM) and solidified with a mixed solvent (DCM / MeOH) to obtain 2.3 g (yield: 52.6%) of the compound (intermediate (193)) as a yellow solid.

[1213]

[1214] Intermediate synthesis example 92: Synthesis of intermediate (194)

[1215]

[1216] (Synthesis of intermediate (194))

[1217] Intermediate (191) 10.0 g (20.6 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 5.3 g (22.7 mmol), Na2S2O 54.7 g (24.7 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 7.8 g (yield: 54.1%) of the compound (intermediate (194)) as a white solid.

[1218]

[1219] Intermediate synthesis example 93: Synthesis of intermediate (195)

[1220]

[1221] (Synthesis of intermediate (195))

[1222] Intermediate (194) 4.0 g (5.7 mmol), intermediate (29) 3.0 g (6.9 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.4 g (17.2 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.6 g (yield: 68.1%) of the compound (intermediate (195)) as a white solid was obtained.

[1223]

[1224] Intermediate synthesis example 94: Synthesis of intermediate (196)

[1225]

[1226] (Synthesis of intermediate (196))

[1227] Intermediate (192) 3.2 g (5.0 mmol), intermediate (29) 2.1 g (5.0 mmol), Pd(OAc) 2111.6 mg (497.2 μmol), X-Phos 474.0 mg (994.4 μmol), K2CO 3 2.1 g (14.9 mmol), xylene 20 mL, and water 5 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (DCM) and solidified with a mixed solvent (DCM / MeOH) to obtain 2.5 g (yield: 57.5%) of the compound (intermediate (196)) as a yellow solid.

[1228]

[1229] Intermediate synthesis example 95: Synthesis of intermediate (199)

[1230]

[1231] (Synthesis of intermediate (197))

[1232] Intermediate (180) 47.5 g (171.9 mmol), 1-bromo-4-chloro-2-fluorobenzene 30.0 g (143.2 mmol), Pd(PPh3) 48.3 g (7.2 mmol), K2CO3 59.4 g (429.7 mmol), toluene 400 mL, ethanol 100 mL, and water 100 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, water was added, the mixture was extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (CHCl3) to obtain 26.7 g (yield: 66.9%) of a white liquid compound (intermediate (197)).

[1233] (Synthesis of intermediate (198))

[1234] Intermediate (197) 26.7 g (95.8 mmol), K2CO3 39.7 g (287.4 mmol), and DMF 400 mL were mixed, slowly heated to 100°C, and reacted for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, water was added, and stirred. The resulting solid was filtered, washed with water, dried, purified by silica gel column chromatography (CHCl3), and then solidified with ethanol to obtain 21.5 g (yield: 86.8%) of the compound (intermediate (198)) as a white solid.

[1235] (Synthesis of intermediate (199))

[1236] Intermediate (198) 21.5 g (83.1 mmol), pinacol diboron (Bis(pinacolato)diboron) 31.7 g (124.6 mmol), Pd(dba) 22.4 g (4.2 mmol), X-Phos 4.0 g (8.3 mmol), KOAc 24.5 g (249.3 mmol) and xylene 240 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, it was cooled to room temperature, passed through a silica gel pad (CHCl3), and concentrated under reduced pressure to obtain 18.4 g (yield: 63.2%) of the compound (intermediate (199)) as a white solid.

[1237]

[1238] Intermediate synthesis example 96: Synthesis of intermediate (203)

[1239]

[1240] (Synthesis of intermediate (200))

[1241] Intermediate (1) 15.0 g (65.8 mmol), intermediate (199) 27.6 g (78.9 mmol), Pd(PPh3) 43.8 g (3.3 mmol), K2CO3 27.3 g (197.3 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. After stirring under reflux for 12 hours, the mixture was cooled to room temperature. After distilled water was added, the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane), and then recrystallized to obtain 21.2 g (yield: 86.8%) of the compound (intermediate (200)) as a white solid.

[1242] (Synthesis of intermediate (201))

[1243] Intermediate (200) 21.2 g (57.1 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 25.1 mL (2.5 M in hexane, 62.8 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 12.6 g (57.1 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 25.5 g (yield: 78.2%) of the compound (intermediate (201)) as a white solid was obtained by slurrying with n-hexane.

[1244] (Synthesis of intermediate (202))

[1245] After adding 25.5 g (44.6 mmol) of intermediate (201), 12.5 g (223.1 mmol) of Fe, 2.4 g (44.6 mmol) of ammonium chloride, 230 mL of EtOH, and 45 mL of distilled water, the mixture was stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After adding distilled water, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound was recrystallized to obtain 16.8 g (yield: 69.5%) of the compound (intermediate (202)) as a white solid.

[1246] (Synthesis of intermediate (203))

[1247] Intermediate (202) 16.8 g (31.0 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 8.0 g (34.1 mmol), Na2S2O 57.1 g (37.2 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 13.7 g (yield: 58.4%) of the compound (intermediate (203)) as a white solid.

[1248]

[1249] Intermediate synthesis example 97: Synthesis of intermediate (204)

[1250]

[1251] (Synthesis of intermediate (204))

[1252] Intermediate (203) 4.0 g (5.3 mmol), intermediate (8) 2.7 g (6.4 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.2 g (15.9 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.3 g (yield: 63.9%) of the compound (intermediate (204)) as a white solid was obtained.

[1253]

[1254] Intermediate synthesis example 98: Synthesis of intermediate (208)

[1255]

[1256] (Synthesis of intermediate (205))

[1257] Intermediate (1) 20.0 g (87.7 mmol), dibenzo[b,d]furan-2-ylboronic acid 20.4 g (96.4 mmol), Pd(PPh3) 43.0 g (2.6 mmol), K2CO3 30.3 g (219.2 mmol), toluene 400 mL, ethanol 100 mL, and distilled water 100 mL were mixed and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extraction was performed with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting mixture was purified by silica gel column chromatography (CHCl3:EA) to obtain 16.9 g (yield: 61.1%) of a white solid compound (intermediate (205)).

[1258] (Synthesis of intermediate (206))

[1259] After mixing 16.9 g (53.6 mmol) of intermediate (205) and 270 ml of THF, 22.5 ml (56.3 mmol, 2.5 M in hex) of n-BuLi was slowly added dropwise at -78°C. After stirring for 2 hours, 13.0 g (58.9 mmol) of 1-bromo-3-fluoro-2-nitrobenzene was added dropwise to the reaction solution, and the mixture was reacted at room temperature for 12 hours. When the reaction was complete, distilled water was added to the reaction mixture at room temperature, and the mixture was extracted with dichloromethane. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The obtained mixture was solidified with ethanol to obtain 11.5 g (yield: 41.6%) of a yellow solid compound (intermediate (206)).

[1260] (Synthesis of intermediate (207))

[1261] Intermediate (206) 8.7 g (16.9 mmol), Fe 4.7 g (84.4 mmol), NH4Cl 1.8 g (33.8 mmol) and ethanol 85 mL were mixed and stirred at 110°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a Celite pad (CHCl3), and the resulting mixture was filtered through a silica gel pad (CHCl3). The resulting mixture was purified by silica gel column chromatography (Hex:DCM) to obtain 8.3 g (yield: 76.6%) of a white solid compound (intermediate (207)).

[1262] (Synthesis of intermediate (208))

[1263] Intermediate (207) 8.3 g (17.1 mmol), 3,5-(di-tert-butyl)-2-hydroxybenzaldehyde 4.8 g (20.5 mmol), Na2S2O5 4.2 g (22.2 mmol), and DMF 85 mL were mixed and reacted at 110°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added, the precipitated solid was filtered, and washed with distilled water and methanol. The obtained mixture was solidified with a mixed solution (DCM / EtOH) to obtain 9.0 g (yield: 75.2%) of the compound (intermediate (208)) as a white solid.

[1264]

[1265] Intermediate synthesis example 99: Synthesis of intermediate (209)

[1266]

[1267] (Synthesis of intermediate (209))

[1268] Intermediate (208) 3.0 g (4.3 mmol), intermediate (8) 2.2 g (5.1 mmol), Pd(PPh3)4 148.6 mg (128.6 μmol), K2CO3 1.5 g (10.7 mmol), toluene 40 mL, ethanol 5 mL, and distilled water 5 mL were mixed and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.2 g (yield: 81.1%) of the compound (intermediate (209)) as a white solid.

[1269]

[1270] Intermediate synthesis example 100: Synthesis of intermediate (210)

[1271]

[1272] (Synthesis of intermediate (210))

[1273] Intermediate (207) 7.2 g (14.8 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 3.2 g (17.8 mmol), Na2S2O5 3.7 g (19.3 mmol) and DMF 75 mL were mixed and reacted at 130°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added, the precipitated solid was filtered, and washed with distilled water and methanol. The obtained mixture was solidified with a mixed solution (DCM / MeOH) to obtain 7.7 g (yield: 80.7%) of the compound (intermediate (210)) as a white solid.

[1274]

[1275] Intermediate Synthesis Example 101: Synthesis of Intermediate (211)

[1276]

[1277] (Synthesis of intermediate (211))

[1278] Intermediate (210) 4.0 g (6.2 mmol), intermediate (8) 2.9 g (6.8 mmol), Pd(PPh3)4215.4 mg (186.4 μmol), K2CO32.1 g (15.5 mmol), toluene 30 mL, ethanol 8 mL, and distilled water 8 mL were mixed and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extraction was performed with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The obtained mixture was filtered through a silica gel pad (Hex:EA), and the obtained mixture was purified by silica gel column chromatography (Hex:EA) to obtain 4.8 g (yield: 89.4%) of a white solid compound (intermediate (211)).

[1279]

[1280] Intermediate Synthesis Example 102: Synthesis of Intermediate (212)

[1281]

[1282] (Synthesis of intermediate (212))

[1283] Intermediate (208) 3.0 g (4.3 mmol), intermediate (29) 2.2 g (5.1 mmol), Pd(PPh3)4 148.6 mg (128.6 μmol), K2CO3 1.5 g (10.7 mmol), toluene 40 mL, ethanol 5 mL, and distilled water 5 mL were mixed and reacted at 80°C for 12 hours. When the reaction was complete, distilled water was added to the reaction mixture at room temperature, and extraction was performed with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The obtained mixture was purified by silica gel column chromatography (Hex:EA), and the obtained mixture was recrystallized with ethanol to obtain 1.6 g (yield: 40.4%) of a white solid compound (intermediate (212)).

[1284]

[1285] Intermediate Synthesis Example 103: Synthesis of Intermediate (215)

[1286]

[1287] (Synthesis of intermediate (213))

[1288] 2-Bromo-4-(tert-butyl)phenol (50.0 g (202.0 mmol), (5-chloro-2-fluorophenyl)boronic acid (42.3 g (242.4 mmol), Pd(PPh3) (47.0 g (6.1 mmol), K2CO3 (69.8 g (504.9 mmol), toluene (1000 mL), ethanol (150 ml), and distilled water (150 ml)) were mixed and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extraction was performed with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting mixture was filtered through a silica gel filter to obtain 56.0 g (yield: 99.5%) of a brown liquid compound (intermediate (213)).

[1289] (Synthesis of intermediate (214))

[1290] Intermediate (213) 56.0 g (200.9 mmol), K2CO3 83.3 g (602.7 mmol), and DMF 500 ml were mixed and reacted at 120°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, filtered, and washed with distilled water and methanol. The obtained compound was solidified with a mixed solution (DCM / MeOH), and 35.7 g (yield: 68.7%) of the compound (intermediate (214)) as a white solid was obtained.

[1291] (Synthesis of intermediate (215))

[1292] Intermediate (214) 20.0 g (77.3 mmol), pinacol diboron (Bis(pinacolato)diboron) 23.6 g (92.8 mmol), Pd (dba) 22.2 g (3.9 mmol), X-Phos 3.7 g (7.7 mmol), KOAc 22.8 g (231.9 mmol) and toluene 350 mL were mixed and reacted at 110°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a Celite pad, and washed with toluene. The obtained liquid mixture was purified by silica gel pad filtration (tolene), and after stirring and suspending in ethanol, it was filtered to obtain 21.7 g (yield: 80.2%) of the compound (intermediate (215)) as an ivory-colored solid.

[1293]

[1294] Intermediate Synthesis Example 104: Synthesis of Intermediate (219)

[1295]

[1296] (Synthesis of intermediate (216))

[1297] Intermediate (215) 21.7 g (62.0 mmol), intermediate (1) 16.9 g (68.1 mmol), Pd(PPh3) 42.1 g (1.9 mmol), K2CO3 21.4 g (154.9 mmol), toluene 300 mL, ethanol 75 mL, and distilled water 75 mL were mixed and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extracted with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting mixture was purified by silica gel column chromatography (Hex:EA), and the mixture was suspended in ethanol, stirred, and filtered to obtain 15.0 g (yield: 61.9%) of a white solid compound (intermediate (216)).

[1298] (Synthesis of intermediate (217))

[1299] After mixing 15.0 g (40.4 mmol) of intermediate (216) and 200 ml of THF, 16.6 ml (41.6 mmol, 2.5 M in hex) of n-BuLi was slowly added dropwise at -78°C. After stirring for 2 hours, 9.8 g (44.4 mmol) of 1-bromo-3-fluoro-2-nitrobenzene was added dropwise to the reaction solution, and the mixture was reacted at room temperature for 12 hours. When the reaction was complete, distilled water was added to the reaction mixture at room temperature, and extracted with dichloromethane. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The obtained mixture was solidified with ethanol to obtain 11.1 g (yield: 48.1%) of a yellow solid compound (intermediate (217)).

[1300] (Synthesis of intermediate (218))

[1301] Intermediate (217) 11.1 g (19.4 mmol), Fe 5.4 g (97.1 mmol), NH4Cl 2.1 g (38.8 mmol) and ethanol 100 mL were mixed and stirred at 100°C for 5 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a Celite pad (CHCl3), and purified by silica gel column chromatography (Hex:EA), and solidified with a mixed solution (Ac / EtOH) to obtain 10.4 g (yield: 98.9%) of the compound (intermediate (218)) as a white solid.

[1302] (Synthesis of intermediate (219))

[1303] Intermediate (218) 10.4 g (19.2 mmol), 3,5-(di-tert-butyl)-2-hydroxybenzaldehyde 5.4 g (23.0 mmol), Na2S2O 54.7 g (25.0 mmol), and DMF 100 mL were mixed and reacted at 130°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added, the precipitated solid was filtered, and washed with distilled water and methanol. The obtained mixture was purified by silica gel column chromatography (Hex:EA) to obtain 9.5 g (yield: 65.4%) of the compound (intermediate (219)) as a white solid.

[1304]

[1305] Intermediate Synthesis Example 105: Synthesis of Intermediate (220)

[1306]

[1307] (Synthesis of intermediate (220))

[1308] Intermediate (219) 3.0 g (4.0 mmol), intermediate (8) 2.0 g (4.8 mmol), Pd(PPh3)4 137.6 mg (119.1 μmol), K2CO3 1.4 g (9.9 mmol), toluene 20 mL, ethanol 5 mL, and distilled water 5 mL were mixed and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extracted with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with a mixed solution (Ac / EtOH) to obtain 3.6 g (yield: 92.9%) of the compound (intermediate (220)) as a white solid.

[1309]

[1310] Intermediate Synthesis Example 106: Synthesis of Intermediate (221)

[1311]

[1312] (Synthesis of intermediate (221))

[1313] Intermediate (219) 3.0 g (4.0 mmol), intermediate (51) 2.2 g (4.8 mmol), Pd(PPh3)4 137.6 mg (119.1 μmol), K2CO3 1.4 g (9.9 mmol), toluene 20 mL, ethanol 5 mL, and distilled water 5 mL were mixed and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extracted with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with a mixed solution (Ac / EtOH) to obtain 3.5 g (yield: 86.6%) of the compound (intermediate (221)) as a white solid.

[1314]

[1315] Intermediate Synthesis Example 107: Synthesis of Intermediate (222)

[1316]

[1317] (Synthesis of intermediate (222))

[1318] Intermediate (219) 3.0 g (4.0 mmol), intermediate (29) 2.1 g (4.8 mmol), Pd(PPh3)4 137.6 mg (119.1 μmol), K2CO3 1.4 g (9.9 mmol), toluene 20 mL, ethanol 5 mL, and distilled water 5 mL were mixed and reacted at 80°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, and extracted with toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with a mixed solution (Ac / EtOH) to obtain 1.7 g (yield: 43.7%) of the compound (intermediate (222)) as a white solid.

[1319]

[1320] Intermediate Synthesis Example 108: Synthesis of Intermediate (226)

[1321]

[1322] (Synthesis of intermediate (223))

[1323] Intermediate (1) 10.0 g (43.8 mmol), dibenzo[b,d]furan-1-ylboronic acid 11.2 g (52.6 mmol), Pd(PPh3) 42.5 g (2.2 mmol), K2CO3 24.2 g (175.3 mmol), dioxane 130 mL, and water 50 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (Hex:CHCl3) to obtain 8.5 g (yield: 61.5%) of compound (223) as a yellow solid.

[1324] (Synthesis of intermediate (224))

[1325] Intermediate (223) 8.5 g (26.8 mmol) was dissolved in 130 mL of THF, and BuLi 10.7 mL (2.5 M, 26.8 mmol) was added dropwise at -78°C, followed by stirring for 1 hour. 1-Bromo-3-fluoro-2-nitrobenzene 5.9 g (26.8 mmol) was added, stirred for 1 hour, and then warmed to room temperature. The mixture was reacted for 12 hours, cooled to 0°C, added water, and extracted with chloroform. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure. The resulting reaction mixture was purified by silica gel column chromatography (Hex:CHCl3) to obtain 4.9 g (yield: 35.6%) of compound (224) as a red solid.

[1326] (Synthesis of intermediate (225))

[1327] Intermediate (224) 4.9 g (9.5 mmol), Fe 2.7 g (47.6 mmol), 10.0 mL of sat. NH4Cl aqueous solution, and 48 mL of ethanol were mixed and reacted at 70°C for 12 hours. After the reaction was completed, aq. Na2CO3 aqueous solution was added, filtered through Celite, water was added, extracted with chloroform, and distilled under reduced pressure. The reaction mixture was passed through a silica pad (CHCl3) and concentrated under reduced pressure to obtain 4.6 g (yield: 99.9%) of the compound (intermediate (225)) as a yellow solid.

[1328] (Synthesis of intermediate (226))

[1329] Intermediate (225) 4.6 g (9.5 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 2.5 g (10.4 mmol), Na2S2O5 2.2 g (11.4 mmol), and DMF 120 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound (intermediate (226)) 4.2 g (yield: 63.3%) was obtained as a white solid.

[1330]

[1331] Intermediate Synthesis Example 109: Synthesis of Intermediate (227)

[1332]

[1333] (Synthesis of intermediate (227))

[1334] Intermediate (226) 4.0 g (5.7 mmol), intermediate (8) 2.9 g (6.9 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.4 g (17.2 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.5 g (yield: 66.5%) of the compound (intermediate (227)) as a white solid was obtained.

[1335]

[1336] Intermediate synthesis example 110: Synthesis of intermediate (228)

[1337]

[1338] (Synthesis of intermediate (228))

[1339] Intermediate (225) 4.6 g (9.5 mmol), 5-tert-butyl-2-hydroxybenzaldehyde (5-(tert-butyl)-2-hydroxybenzaldehyde) 1.9 g (10.5 mmol), Na2S2O5 2.2 g (11.4 mmol) and DMF 50 mL were mixed, and the temperature was gradually increased to 130℃ and the mixture was reacted for 12 hours. After the reaction was completed, it was cooled to room temperature, water was added, and the mixture was stirred. The solid produced at this time was filtered, washed with water and methanol, dried, purified by silica gel column chromatography (CHCl3), and solidified with methanol to obtain 4.8 g (yield: 78.7%) of the compound (intermediate (228)) as a yellow solid.

[1340]

[1341] Intermediate Synthesis Example 111: Synthesis of Intermediate (229)

[1342]

[1343] (Synthesis of intermediate (229))

[1344] Intermediate (228) 4.8 g (7.5 mmol), intermediate (8) 3.2 g (7.5 mmol), Pd(OAc) 2168.1 mg (748.9 μmol), X-Phos 714.0 mg (1.5 mmol), K2CO 3 3.1 g (22.5 mmol), xylene 30 mL, and water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, water was added, extracted with chloroform, and concentrated under reduced pressure. The reaction mixture was purified by silica gel column chromatography (DCM) and solidified with a mixed solvent (DCM / MeOH) to obtain 4.3 g (yield: 66.3%) of the compound (intermediate (229)) as a yellow solid.

[1345]

[1346] Intermediate Synthesis Example 112: Synthesis of Intermediate (230)

[1347]

[1348] (Synthesis of intermediate (230))

[1349] Intermediate (228) 4.0 g (6.2 mmol), intermediate (51) 3.5 g (7.5 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.6 g (18.6 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.9 g (yield: 69.3%) of the compound (intermediate (230)) as a white solid was obtained.

[1350]

[1351] Intermediate Synthesis Example 113: Synthesis of Intermediate (231)

[1352]

[1353] (Synthesis of intermediate (231))

[1354] Intermediate (226) 4.0 g (5.7 mmol), intermediate (29) 3.0 g (6.9 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.4 g (17.2 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.4 g (yield: 64.4%) of the compound (intermediate (231)) as a white solid was obtained.

[1355]

[1356] Intermediate Synthesis Example 114: Synthesis of Intermediate (235)

[1357]

[1358] (Synthesis of intermediate (232))

[1359] Intermediate (1) 15.0 g (65.8 mmol), dibenzo[b,d]thiophen-4-ylboronic acid 18.0 g (78.9 mmol), Pd(PPh3) 43.8 g (3.3 mmol), K2CO3 27.3 g (197.5 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. After stirring under reflux for 12 hours, the mixture was cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, the mixture was filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 17.6 g (yield: 80.7%) of a white solid compound (intermediate (232)).

[1360] (Synthesis of intermediate (233))

[1361] Intermediate (232) 17.6 g (53.1 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 23.4 mL (2.5 M in hexane, 58.4 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 11.7 g (53.1 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 22.1 g (yield: 78.3%) of the compound (intermediate (233)) as a white solid was obtained by slurrying with n-hexane.

[1362] (Synthesis of intermediate (234))

[1363] Intermediate (233) 22.1 g (42.6 mmol), Fe 11.6 g (207.9 mmol), ammonium chloride 2.2 g (41.6 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After distilled water was added, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (234)) was recrystallized to obtain 15.3 g (yield: 73.4%) as a white solid.

[1364] (Synthesis of intermediate (235))

[1365] Intermediate (234) 15.3 g (30.5 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 7.9 g (33.6 mmol), Na2S2O5 7.0 g (36.6 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 12.8 g (yield: 58.6%) of the compound (intermediate (235)) as a white solid.

[1366]

[1367] Intermediate Synthesis Example 115: Synthesis of Intermediate (236)

[1368]

[1369] (Synthesis of intermediate (236))

[1370] Intermediate (235) 4.0 g (5.6 mmol), intermediate (8) 2.9 g (6.7 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.3 g (16.8 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.7 g (yield: 70.7%) of the compound (intermediate (236)) as a white solid was obtained.

[1371]

[1372] Intermediate Synthesis Example 116: Synthesis of Intermediate (237)

[1373]

[1374] (Synthesis of intermediate (237))

[1375] Intermediate (235) 4.0 g (5.6 mmol), intermediate (29) 2.9 g (6.7 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.3 g (16.8 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.5 g (yield: 66.6%) of the compound (intermediate (237)) as a white solid was obtained.

[1376]

[1377] Intermediate Synthesis Example 117: Synthesis of Intermediate (238)

[1378]

[1379] (Synthesis of intermediate (238))

[1380] Intermediate (235) 4.0 g (5.6 mmol), intermediate (36) 2.9 g (6.7 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.3 g (16.8 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.2 g (yield: 61.0%) of the compound (intermediate (238)) as a white solid was obtained.

[1381]

[1382] Intermediate Synthesis Example 118: Synthesis of Intermediate (243)

[1383]

[1384] (Synthesis of intermediate (239))

[1385] 3-bromodibenzo[b,d]thiophene (40.0 g, 152.0 mmol), PIN2B (257.9 g, 228.0 mmol), Pd(dba) (24.4 g, 7.6 mmol), XPhos (10.9 g, 22.8 mmol), KOAc (37.3 g, 380.0 mmol), and toluene (650 mL) were mixed and stirred under reflux for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc) and then solidified with methanol to obtain 35.2 g (yield: 74.7%) of a white solid compound (intermediate (239)).

[1386] (Synthesis of intermediate (240))

[1387] Intermediate (1) 15.0 g (65.8 mmol), intermediate (239) 24.5 g (78.9 mmol), Pd(PPh3) 43.8 g (3.3 mmol), K2CO3 27.3 g (197.3 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. After stirring under reflux for 12 hours, the mixture was cooled to room temperature. After distilled water was added, the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 16.4 g (yield: 75.3%) of the compound (intermediate (240)) as a white solid.

[1388] (Synthesis of intermediate (241))

[1389] Intermediate (240) 16.4 g (49.5 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 21.8 mL (2.5 M in hexane, 54.4 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 10.9 g (49.5 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 22.3 g (yield: 84.8%) of the compound (intermediate (241)) as a white solid was obtained by slurrying with n-hexane.

[1390] (Synthesis of intermediate (242))

[1391] Intermediate (241) 22.3 g (42.0 mmol), Fe 11.7 g (209.8 mmol), ammonium chloride 2.2 g (42.0 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After distilled water was added, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound was recrystallized to obtain 14.6 g (yield: 69.4%) of the compound (intermediate (242)) as a white solid.

[1392] (Synthesis of intermediate (243))

[1393] Intermediate (242) 14.6 g (29.1 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 7.5 g (32.0 mmol), Na2S2O5 6.6 g (34.9 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 13.7 g (yield: 65.7%) of the compound (intermediate (243)) as a white solid.

[1394]

[1395] Intermediate Synthesis Example 119: Synthesis of Intermediate (244)

[1396]

[1397] (Synthesis of intermediate (244))

[1398] Intermediate (243) 4.0 g (5.6 mmol), intermediate (8) 2.9 g (6.7 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.3 g (16.8 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.6 g (yield: 68.8%) of the compound (intermediate (244)) as a white solid was obtained.

[1399]

[1400] Intermediate synthesis example 120: Synthesis of intermediate (248)

[1401]

[1402] (Synthesis of intermediate (245))

[1403] 2-Bromo-4-(tert-butyl)-1-chlorobenzene (10.0 g (40.4 mmol), dibenzo[b,d]thiophen-2-ylboronic acid (11.1 g (48.5 mmol), Pd(PPh3) (42.3 g (2.0 mmol), K2CO3 (16.8 g (121.2 mmol), toluene (120 mL), ethanol (50 mL), and distilled water (50 mL)) were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. The mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 8.4 g (yield: 59.3%) of a white solid compound (intermediate (245)).

[1404] (Synthesis of intermediate (246))

[1405] Intermediate (245) 5.0 g (14.3 mmol), intermediate (23) 6.9 g (15.7 mmol), Pd(dba) 20.4 g (0.7 mmol), X-Phos 0.7 g (1.4 mmol), K3PO4 9.1 g (42.8 mmol) and xylene 60 mL were mixed and reacted at 110°C for 24 hours. After the reaction was completed, the obtained mixture was filtered through a silica gel pad, and the obtained mixture was recrystallized to obtain 8.1 g (yield: 75.6%) of the compound (intermediate (246)) as a white solid.

[1406] (Synthesis of intermediate (247))

[1407] Intermediate (246) 8.1 g (10.8 mmol), SnCl 5.0 g (32.3 mmol), and ethanol 100 mL were mixed and stirred at 100°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a Celite pad, and the obtained mixture was purified by silica gel column chromatography (CHCl3:EA) to obtain 5.7 g (yield: 73.3%) of a white solid compound (intermediate (247)).

[1408] (Synthesis of intermediate (248))

[1409] Intermediate (247) 5.7 g (7.9 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 2.2 g (9.5 mmol), Na2S2O5 2.0 g (10.3 mmol), and DMF 30 mL were mixed and reacted at 110°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added, filtered, and washed with distilled water and methanol. The obtained mixture was purified by silica gel column chromatography (Hex:EA) to obtain 5.1 g (yield: 69.0%) of the compound (intermediate (248)) as a white solid.

[1410]

[1411] Intermediate Synthesis Example 121: Synthesis of Intermediate (252)

[1412]

[1413] (Synthesis of intermediate (249))

[1414] Intermediate (1) 15.0 g (65.8 mmol), dibenzo[b,d]thiophen-2-ylboronic acid 18.0 g (78.9 mmol), Pd(PPh3) 43.8 g (3.3 mmol), K2CO3 27.3 g (197.3 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. After stirring under reflux for 12 hours, the mixture was cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, the mixture was filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 17.9 g (yield: 82.1%) of a white solid compound (intermediate (249)).

[1415] (Synthesis of intermediate (250))

[1416] Intermediate (249) 17.9 g (54.0 mmol) was mixed with 340 mL of THF, and then cooled to -78°C. n-BuLi 23.8 mL (2.5 M in hexane, 59.4 mmol) was slowly added, and the mixture was stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 11.9 g (54.0 mmol) was dissolved in 30 mL of THF, and then slowly added to the reaction mixture. After stirring at -78°C for 2 hours, the mixture was stirred at room temperature for 2 hours. Distilled water was added, the reaction was terminated, and the mixture was concentrated under reduced pressure. Dichloromethane was added, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 23.3 g (yield: 81.2%) of the compound (intermediate (250)) as a white solid was obtained by slurrying with n-hexane.

[1417] (Synthesis of intermediate (251))

[1418] Intermediate (250) 23.3 g (43.8 mmol), Fe 12.2 g (219.2 mmol), ammonium chloride 2.4 g (43.8 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After distilled water was added, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (251)) as a white solid was obtained at 14.7 g (yield: 66.9%) by recrystallization.

[1419] (Synthesis of intermediate (252))

[1420] Intermediate (251) 14.7 g (29.3 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 7.6 g (32.2 mmol), Na2S2O5 6.7 g (35.2 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 12.4 g (yield: 59.1%) of the compound (intermediate (252)) as a white solid.

[1421]

[1422] Intermediate Synthesis Example 122: Synthesis of Intermediate (253)

[1423]

[1424] (Synthesis of intermediate (253))

[1425] Intermediate (252) 4.0 g (5.6 mmol), intermediate (109) 2.8 g (6.7 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.3 g (16.8 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.1 g (yield: 59.8%) of the compound (intermediate (253)) as a white solid was obtained.

[1426]

[1427] Intermediate Synthesis Example 123: Synthesis of Intermediate (258)

[1428]

[1429] (Synthesis of intermediate (254))

[1430] 1-bromodibenzo[b,d]thiophene (30.0 g, 114.0 mmol), PIN2B (243.4 g, 171.0 mmol), Pd(dba) (23.3 g, 5.7 mmol), XPhos (8.2 g, 17.1 mmol), KOAc (28.0 g, 285.0 mmol), and toluene (630 mL) were mixed and stirred under reflux for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc) and then solidified with methanol to obtain 28.1 g (yield: 79.5%) of a white solid compound (intermediate (254)).

[1431] (Synthesis of intermediate (255))

[1432] 15.0 g (65.8 mmol) of 2-bromo-4-(tert-butyl)aniline, 24.5 g (78.9 mmol) of intermediate (254), 43.8 g (3.3 mmol) of Pd(PPh3), 27.3 g (197.3 mmol) of K2CO3, 150 mL of toluene, 70 mL of ethanol, and 70 mL of distilled water were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, the organic layer was filtered, and the residue was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 15.4 g (yield: 70.7%) of a white solid compound (intermediate (255)).

[1433] (Synthesis of intermediate (256))

[1434] Intermediate (255) 16.2 g (46.5 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 20.4 mL (2.5 M in hexane, 51.1 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 10.2 g (46.5 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 19.3 g (yield: 78.2%) of the compound (intermediate (256)) as a white solid was obtained by slurrying with n-hexane.

[1435] (Synthesis of intermediate (257))

[1436] Intermediate (256) 19.3 g (36.3 mmol), Fe 10.1 g (181.6 mmol), ammonium chloride 1.9 g (36.3 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After adding distilled water, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (257)) was recrystallized to obtain 13.7 g (yield: 75.2%) as a white solid.

[1437] (Synthesis of intermediate (258))

[1438] Intermediate (257) 13.7 g (27.3 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 7.0 g (30.1 mmol), Na2S2O 56.2 g (32.8 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 10.6 g (yield: 54.2%) of the compound (intermediate (258)) as a white solid.

[1439]

[1440] Intermediate Synthesis Example 124: Synthesis of Intermediate (259)

[1441]

[1442] (Synthesis of intermediate (259))

[1443] Intermediate (258) 4.0 g (5.6 mmol), intermediate (8) 2.9 g (6.7 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.3 g (16.8 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.4 g (yield: 65.0%) of the compound (intermediate (259)) as a white solid was obtained.

[1444]

[1445] Intermediate Synthesis Example 125: Synthesis of Intermediate (260)

[1446]

[1447] (Synthesis of intermediate (260))

[1448] Intermediate (258) 4.0 g (5.6 mmol), intermediate (29) 2.9 g (6.7 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.3 g (16.8 mmol), toluene 50 mL, ethanol 25 mL, and distilled water 25 mL were mixed. The reaction mixture was stirred under reflux for 12 hours. After the reaction was quenched with distilled water, the reaction solution was separated into layers. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (DCM:Hex). After concentration and drying, 3.3 g (yield: 62.8%) of the compound (intermediate (260)) as a white solid was obtained.

[1449]

[1450] Intermediate Synthesis Example 126: Synthesis of Intermediate (264)

[1451]

[1452] (Synthesis of intermediate (261))

[1453] Intermediate (1) 15.0 g (62.8 mmol), phenylboronic acid 9.6 g (78.9 mmol), Pd(PPh3) 43.8 g (3.3 mmol), K2CO3 27.3 g (197.3 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. After stirring under reflux for 12 hours, the mixture was cooled to room temperature. After distilled water was added, the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 11.5 g (yield: 77.62%) of the compound (intermediate (261)) as a white solid.

[1454] (Synthesis of intermediate (262))

[1455] Intermediate (261) 11.5 g (51.0 mmol) was mixed with 340 mL of THF, and then cooled to -78°C. n-BuLi 22.5 mL (2.5 M in hexane, 56.1 mmol) was slowly added, and the mixture was stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 11.2 g (51.0 mmol) was dissolved in 30 mL of THF, and then slowly added to the reaction mixture. The mixture was stirred at -78°C for 2 hours, and then at room temperature for 2 hours. Distilled water was added to terminate the reaction, and the mixture was concentrated under reduced pressure. Dichloromethane was added, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 14.3 g (yield: 65.9%) of the compound (intermediate (262)) as a white solid was obtained by slurrying with n-hexane.

[1456] (Synthesis of intermediate (263))

[1457] Intermediate (262) 14.3 g (33.6 mmol), Fe 9.4 g (168.1 mmol), ammonium chloride 1.8 g (33.6 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After adding distilled water, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (263)) 9.4 g (yield: 70.7%) was obtained as a white solid by recrystallization.

[1458] (Synthesis of intermediate (264))

[1459] Intermediate (263) 9.4 g (23.8 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 4.7 g (26.2 mmol), Na2S2O5 5.4 g (28.5 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 6.7 g (yield: 50.9%) of the compound (intermediate (264)) as a white solid.

[1460]

[1461] Intermediate Synthesis Example 127: Synthesis of Intermediate (268)

[1462]

[1463] (Synthesis of intermediate (265))

[1464] 2-chloro-4-iodopyridine (30.0 g, 125.3 mmol), PIN2B (247.7 g, 187.9 mmol), Pd(dba) (23.6 g, 6.3 mmol), XPhos (9.0 g, 18.8 mmol), KOAc (30.7 g, 313.2 mmol), and toluene (600 mL) were mixed and stirred under reflux for 6 hours. After the reaction was completed, the mixture was cooled to room temperature, and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc) and then solidified with methanol to obtain 23.4 g (yield: 78.0%) of a white solid compound (intermediate (265)).

[1465] (Synthesis of intermediate (266))

[1466] Intermediate (265) 23.4 g (97.7 mmol), 2-chlorobenzo[d]oxazole 18.0 g (117.24.5 mmol), Pd(PPh3) 43.4 g (2.9 mmol), Na2CO3 25.9 g (244.3 mmol), toluene 500 mL, ethanol 150 mL, and H2O 150 mL were mixed and stirred at 65°C for 24 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water, and the extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (EtOAc:Hexanes) and then solidified with hexane to obtain 18.3 g (yield: 81.2%) of a white solid compound (intermediate (266)).

[1467] (Synthesis of intermediate (267))

[1468] Intermediate (266) 18.3 g (79.3 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 20.2 g (95.2 mmol), Pd(PPh3) 44.6 g (4.0 mmol), K2CO3 32.9 g (238.0 mmol), toluene 300 mL, ethanol 100 mL, and H2O 100 mL were mixed and stirred under reflux for 24 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel and celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was solidified with methanol to obtain 22.4 g (yield: 77.8%) of the compound (intermediate (267)) as a white solid.

[1469] (Synthesis of intermediate (268))

[1470] Intermediate (267) 22.4 g (61.7 mmol), PIN2B 223.5 g (92.6 mmol), Pd(dba) 21.8 g (3.1 mmol), XPhos 4.4 g (9.3 mmol), KOAc 15.2 g (154.3 mmol) and toluene 300 mL were mixed and stirred under reflux for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc), and then solidified with methanol to obtain 22.9 g (yield: 81.6%) of the compound (intermediate (268)) as a white solid.

[1471]

[1472] Intermediate Synthesis Example 128: Synthesis of Intermediate (269)

[1473]

[1474] (Synthesis of intermediate (269))

[1475] Intermediate (264) 4.0 g (7.2 mmol), intermediate (268) 3.9 g (8.7 mmol), Pd(PPh3) 40.4 g (0.4 mmol), K2CO3 3.0 g (21.7 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.7 g (yield: 63.9%) of the compound (intermediate (269)) as a white solid.

[1476]

[1477] Intermediate Synthesis Example 129: Synthesis of Intermediate (273)

[1478]

[1479] (Synthesis of intermediate (270))

[1480] 2-Bromoaniline (15.0 g, 87.2 mmol), naphthyl-1-ylboronic acid (18.0 g, 104.6 mmol), Pd(PPh3) (45.0 g, 4.4 mmol), K2CO3 (36.2 g, 261.6 mmol), toluene (150 mL), ethanol (70 mL), and distilled water (70 mL) were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, the organic layer was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 17.1 g (yield: 87.4%) of the compound (intermediate (270)) as a white solid.

[1481] (Synthesis of intermediate (271))

[1482] Intermediate (270) 17.1 g (78.0 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 34.3 mL (2.5 M in hexane, 85.8 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 17.2 g (78.0 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 23.4 g (yield: 71.6%) of the compound (intermediate (271)) as a white solid was obtained by slurrying with n-hexane.

[1483] (Synthesis of intermediate (272))

[1484] Intermediate (271) 23.4 g (55.8 mmol), Fe 15.6 g (279.1 mmol), ammonium chloride 3.0 g (55.8 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After adding distilled water, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound was recrystallized to obtain 14.8 g (yield: 64.1%) of the compound (intermediate (272)) as a white solid.

[1485] (Synthesis of intermediate (273))

[1486] Intermediate (272) 14.8 g (38.0 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 9.8 g (41.8 mmol), Na2S2O 58.7 g (45.6 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 13.1 g (yield: 57.1%) of the compound (intermediate (273)) as a white solid.

[1487]

[1488] Intermediate synthesis example 130: Synthesis of intermediate (274)

[1489]

[1490] (Synthesis of intermediate (274))

[1491] Intermediate (273) 4.0 g (6.6 mmol), intermediate (268) 3.6 g (8.0 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.8 g (19.9 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 4.1 g (yield: 72.7%) of the compound (intermediate (274)) as a white solid.

[1492]

[1493] Intermediate Synthesis Example 131: Synthesis of Intermediate (275)

[1494]

[1495] (Synthesis of intermediate (275))

[1496] Intermediate (68) 4.0 g (7.2 mmol), intermediate (268) 3.9 g (8.7 mmol), Pd(PPh3) 40.4 g (0.4 mmol), K2CO3 3.0 g (21.7 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 4.5 g (yield: 77.8%) of the compound (intermediate (275)) as a white solid.

[1497]

[1498] Intermediate Synthesis Example 132: Synthesis of Intermediate (279)

[1499]

[1500] (Synthesis of intermediate (276))

[1501] Intermediate (12) 15.0 g (62.5 mmol), benzo[b]thiophen-2-ylboronic acid 13.4 g (75.0 mmol), Pd(PPh3) 43.6 g (3.1 mmol), K2CO3 25.9 g (187.5 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 12.6 g (yield: 68.7%) of the compound (intermediate (276)) as a white solid.

[1502] (Synthesis of intermediate (277))

[1503] Intermediate (276) 12.6 g (43.0 mmol) was mixed with 340 mL of THF, and then cooled to -78°C. n-BuLi 18.9 mL (2.5 M in hexane, 47.3 mmol) was slowly added, and the mixture was stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene (1-bromo-3-fluoro-2-nitrobenzene) 9.5 g (43.0 mmol) was dissolved in 30 mL of THF, and then slowly added to the reaction mixture. After stirring at -78°C for 2 hours, the mixture was stirred at room temperature for 2 hours. Distilled water was added, the reaction was terminated, and the mixture was concentrated under reduced pressure. Dichloromethane was added, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 12.9 g (yield: 60.9%) of a white solid compound (intermediate (277)) was obtained by slurrying with n-hexane.

[1504] (Synthesis of intermediate (278))

[1505] Intermediate (277) 12.9 g (26.2 mmol), Fe 7.3 g (130.8 mmol), ammonium chloride 1.4 g (26.2 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After distilled water was added, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound was recrystallized to obtain 10.1 g (yield: 83.4%) of the compound (intermediate (278)) as a white solid.

[1506] (Synthesis of intermediate (279))

[1507] Intermediate (278) 10.1 g (21.8 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 5.6 g (24.0 mmol), Na2S2O5 5.0 g (26.2 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound (intermediate (279)) 8.4 g (yield: 56.9%) was obtained as a white solid.

[1508]

[1509] Intermediate synthesis example 133: Synthesis of intermediate (280)

[1510]

[1511] (Synthesis of intermediate (280))

[1512] Intermediate (279) 4.0 g (5.9 mmol), intermediate (268) 3.2 g (7.1 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.5 g (17.7 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.8 g (yield: 69.6%) of the compound (intermediate (280)) as a white solid.

[1513]

[1514] Intermediate Synthesis Example 134: Synthesis of Intermediate (281)

[1515]

[1516] (Synthesis of intermediate (281))

[1517] Intermediate (243) 4.0 g (5.6 mmol), intermediate (268) 3.1 g (6.7 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.3 g (16.8 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.3 g (yield: 61.3%) of the compound (intermediate (281)) as a white solid.

[1518]

[1519] Intermediate Synthesis Example 135: Synthesis of Intermediate (282)

[1520]

[1521] (Synthesis of intermediate (282))

[1522] Intermediate (263) 15.0 g (37.9 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 9.8 g (41.7 mmol), Na2S2O 58.7 g (45.5 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 17.5 g (yield: 75.7%) of the compound (intermediate (282)) as a white solid.

[1523]

[1524] Intermediate Synthesis Example 136: Synthesis of Intermediate (285)

[1525]

[1526] (Synthesis of intermediate (283))

[1527] Intermediate (265) 50.0 g (208.8 mmol), 2-chlorobenzo[d]thiazole 42.5 g (250.5 mmol), Pd(PPh3) 47.2 g (6.3 mmol), Na2CO3 55.3 g (522.0 mmol), toluene 1050 mL, ethanol 270 mL, and H2O 270 mL were mixed and stirred at 65°C for 24 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water, and the extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (EtOAc:Hexanes) and then solidified with hexane to obtain 34.7 g (yield: 67.4%) of a white solid compound (intermediate (283)).

[1528] (Synthesis of intermediate (284))

[1529] Intermediate (283) 34.7.0 g (140.7 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 38.9 g (182.8 mmol), Pd(PPh3) 48.1 g (7.0 mmol), K2CO 3 58.3 g (422.0 mmol), toluene 580 mL, ethanol 140 mL, and H2O 140 mL were mixed and stirred under reflux for 24 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel and celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was solidified with methanol to obtain 38.8 g (yield: 72.8%) of a white solid compound (intermediate (284)).

[1530] (Synthesis of intermediate (285))

[1531] Intermediate (284) 38.8 g (102.4 mmol), PIN2B 239.0 g (153.6 mmol), Pd(dba) 22.9 g (5.1 mmol), XPhos 7.3 g (15.4 mmol), KOAc 25.1 g (256.0 mmol) and toluene 600 mL were mixed and stirred under reflux for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc), and then solidified with methanol to obtain 33.1 g (yield: 68.7%) of the compound (intermediate (285)) as a white solid.

[1532]

[1533] Intermediate Synthesis Example 137: Synthesis of Intermediate (286)

[1534]

[1535] (Synthesis of intermediate (286))

[1536] Intermediate (282) 4.0 g (6.6 mmol), intermediate (285) 3.7 g (7.9 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.7 g (19.7 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 4.7 g (yield: 82.0%) of the compound (intermediate (286)) as a white solid.

[1537]

[1538] Intermediate Synthesis Example 138: Synthesis of Intermediate (287)

[1539]

[1540] (Synthesis of intermediate (287))

[1541] Intermediate (20) 4.0 g (7.1 mmol), intermediate (285) 4.0 g (8.5 mmol), Pd(PPh3) 40.4 g (0.4 mmol), K2CO3 2.9 g (21.2 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.2 g (yield: 54.6%) of the compound (intermediate (287)) as a white solid.

[1542]

[1543] Intermediate Synthesis Example 139: Synthesis of Intermediate (291)

[1544]

[1545] (Synthesis of intermediate (288))

[1546] Intermediate (12) 15.0 g (62.5 mmol), pyridin-2-ylboronic acid 9.2 g (75.0 mmol), Pd(PPh3) 43.6 g (3.1 mmol), K2CO3 25.9 g (187.5 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 11.4 g (yield: 76.6%) of the compound (intermediate (288)) as a white solid.

[1547] (Synthesis of intermediate (289))

[1548] Intermediate (288) 11.4 g (47.9 mmol) was mixed with 340 mL of THF, and then cooled to -78°C. n-BuLi 21.1 mL (2.5 M in hexane, 52.6 mmol) was slowly added, and the mixture was stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 10.5 g (47.9 mmol) was dissolved in 30 mL of THF, and then slowly added to the reaction mixture. The mixture was stirred at -78°C for 2 hours, and then at room temperature for 2 hours. Distilled water was added, the reaction was terminated, and the mixture was concentrated under reduced pressure. Dichloromethane was added, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 14.0 g (yield: 66.8%) of the compound (intermediate (289)) as a white solid was obtained by slurrying with n-hexane.

[1549] (Synthesis of intermediate (290))

[1550] Intermediate (289) 14.0 g (32.0 mmol), Fe 8.9 g (159.7 mmol), ammonium chloride 1.7 g (32.0 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After distilled water was added, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (290)) 9.6 g (yield: 73.6%) was obtained as a white solid by recrystallization.

[1551] (Synthesis of intermediate (291))

[1552] Intermediate (290) 9.6 g (23.5 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 6.1 g (25.9 mmol), Na2S2O 55.4 g (28.2 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 8.3 g (yield: 56.7%) of the compound (intermediate (291)) as a white solid.

[1553]

[1554] Intermediate synthesis example 140: Synthesis of intermediate (292)

[1555]

[1556] (Synthesis of intermediate (292))

[1557] Intermediate (291) 4.0 g (6.4 mmol), intermediate (285) 3.6 g (7.7 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.7 g (19.3 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 4.4 g (yield: 77.3%) of the compound (intermediate (292)) as a white solid.

[1558]

[1559] Intermediate Synthesis Example 141: Synthesis of Intermediate (297)

[1560]

[1561] (Synthesis of intermediate (293))

[1562] 30.0 g (270.0 mmol) of 4-fluoroaniline and 800 mL of acetonitrile were mixed and cooled to 0°C. 48.1 g (270.0 mmol) of N-bromosuccinimide was slowly added at 0°C and stirred at room temperature for one day. After completion of the reaction, the organic matter was extracted using dichloromethane and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel, and concentrated under reduced pressure to remove the solvent to obtain 37.3 g (yield: 72.7%) of a yellow solid compound (intermediate (293)).

[1563] (Synthesis of intermediate (294))

[1564] Intermediate (293) 15.0 g (78.9 mmol), benzofuran-2-ylboronic acid 15.3 g (94.7 mmol), Pd(PPh3) 44.6 g (4.0 mmol), K2CO3 32.7 g (236.8 mmol), toluene 200 mL, ethanol 90 mL, and distilled water 90 mL were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 14.7 g (yield: 82.0%) of the compound (intermediate (294)) as a white solid.

[1565] (Synthesis of intermediate (295))

[1566] Intermediate (294) 14.7 g (64.7 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 28.5 mL (2.5 M in hexane, 71.2 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 14.2 g (64.7 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 19.4 g (yield: 70.2%) of the compound (intermediate (295)) as a white solid was obtained by slurrying with n-hexane.

[1567] (Synthesis of intermediate (296))

[1568] Intermediate (295) 19.4 g (45.4 mmol), Fe 12.7 g (227.0 mmol), ammonium chloride 2.4 g (45.4 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After distilled water was added, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (296)) 11.1 g (yield: 61.5%) was obtained as a white solid by recrystallization.

[1569] (Synthesis of intermediate (297))

[1570] Intermediate (296) 11.1 g (27.9 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 7.2 g (30.7 mmol), Na2S2O 56.4 g (33.5 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound (intermediate (297)) 9.3 g (yield: 54.4%) was obtained as a white solid.

[1571]

[1572] Intermediate Synthesis Example 142: Synthesis of Intermediate (298)

[1573]

[1574] (Synthesis of intermediate (298))

[1575] Intermediate (297) 4.0 g (6.5 mmol), intermediate (285) 3.7 g (7.9 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.7 g (19.6 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 4.0 g (yield: 69.9%) of the compound (intermediate (298)) as a white solid.

[1576]

[1577] Intermediate Synthesis Example 143: Synthesis of Intermediate (299)

[1578]

[1579] (Synthesis of intermediate (299))

[1580] Intermediate (153) 10.0 g (22.2 mmol), 5-fluoro-2-hydroxybenzaldehyde 3.4 g (24.4 mmol), Na2S2O5 5.1 g (26.6 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 6.6 g (yield: 52.1%) of the compound (intermediate (299)) as a white solid.

[1581]

[1582] Intermediate synthesis example 144: Synthesis of intermediate (300)

[1583]

[1584] (Synthesis of intermediate (300))

[1585] Intermediate (299) 4.0 g (7.0 mmol), intermediate (285) 4.0 g (8.4 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.9 g (21.0 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 4.6 g (yield: 78.7%) of the compound (intermediate (300)) as a white solid.

[1586]

[1587] Intermediate Synthesis Example 145: Synthesis of Intermediate (301)

[1588]

[1589] (Synthesis of intermediate (301))

[1590] Intermediate (168) 4.0 g (5.7 mmol), intermediate (285) 3.2 g (6.9 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.4 g (17.2 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 4.3 g (yield: 78.1%) of the compound (intermediate (301)) as a white solid.

[1591]

[1592] Intermediate Synthesis Example 146: Synthesis of Intermediate (304)

[1593]

[1594] (Synthesis of intermediate (302))

[1595] 2-chloro-4-iodopyridine (50.0 g, 208.8 mmol), benzofuran-2-ylboronic acid (40.6 g, 250.6 mmol), Pd(PPh3) (47.2 g, 6.3 mmol), Na2CO3 (55.3 g, 522.0 mmol), toluene (1044 mL), ethanol (261 mL), and H2O (261 mL) were mixed and stirred at 65°C for 24 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (EtOAc:Hexanes) and then solidified with hexane to obtain 36.3 g (yield: 75.7%) of a white solid compound (intermediate (302)).

[1596] (Synthesis of intermediate (303))

[1597] Intermediate (302) 30.0 g (130.6 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 33.3 g (156.8 mmol), Pd(PPh3) 47.6 g (6.5 mmol), K2CO 354.2 g (391.9 mmol), toluene 580 mL, ethanol 140 mL, and H2O 140 mL were mixed and stirred under reflux for 24 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel and celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was solidified with methanol to obtain 40.2 g (yield: 85.0%) of a white solid compound (intermediate (303)).

[1598] (Synthesis of intermediate (304))

[1599] Intermediate (303) 40.2 g (111.1 mmol), PIN2B 242.3 g (166.6 mmol), Pd(dba) 23.2 g (5.6 mmol), XPhos 7.9 g (16.7 mmol), KOAc 27.3 g (277.7 mmol) and toluene 600 mL were mixed and stirred under reflux for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc), and then solidified with methanol to obtain 27.1 g (yield: 53.8%) of the compound (intermediate (304)) as a white solid.

[1600]

[1601] Intermediate Synthesis Example 147: Synthesis of Intermediate (305)

[1602]

[1603] (Synthesis of intermediate (305))

[1604] Intermediate (282) 4.0 g (6.6 mmol), intermediate (304) 3.6 g (7.9 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.7 g (19.7 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 4.1 g (yield: 73.0%) of the compound (intermediate (305)) as a white solid.

[1605]

[1606] Intermediate synthesis example 148: Synthesis of intermediate (308)

[1607]

[1608] (Synthesis of intermediate (306))

[1609] 3,5-difluoroaniline (10.0 g, 77.5 mmol) was mixed with 340 mL of THF, and the mixture was cooled to -78°C. n-BuLi (34.1 mL, 2.5 M in hexane, 85.2 mmol) was slowly added, and the mixture was stirred at -78°C for 2 hours. 1-bromo-3-fluoro-2-nitrobenzene (17.0 g, 77.5 mmol) was dissolved in 30 mL of THF, and then slowly added to the reaction mixture. The mixture was stirred at -78°C for 2 hours, and then at room temperature for 2 hours. Distilled water was added, the reaction was terminated, and the mixture was concentrated under reduced pressure. Dichloromethane was added, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 18.4 g (yield: 72.2%) of the compound (intermediate (306)) as a white solid was obtained by slurrying with n-hexane.

[1610] (Synthesis of intermediate (307))

[1611] Intermediate (306) 18.4 g (55.9 mmol), Fe 15.6 g (279.6 mmol), ammonium chloride 3.0 g (55.9 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After adding distilled water, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (307)) as a white solid was obtained at 11.5 g (yield: 68.8%) by recrystallization.

[1612] (Synthesis of intermediate (308))

[1613] Intermediate (307) 11.5 g (38.5 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 9.9 g (42.3 mmol), Na2S2O 58.8 g (46.1 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 10.4 g (yield: 52.7%) of the compound (intermediate (308)) as a white solid.

[1614]

[1615] Intermediate Synthesis Example 149: Synthesis of Intermediate (309)

[1616]

[1617] (Synthesis of intermediate (309))

[1618] Intermediate (308) 4.0 g (7.8 mmol), intermediate (304) 4.2 g (9.4 mmol), Pd(PPh3) 40.5 g (0.4 mmol), K2CO3 3.2 g (23.4 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 4.6 g (yield: 77.7%) of the compound (intermediate (309)) as a white solid.

[1619]

[1620] Intermediate synthesis example 150: Synthesis of intermediate (310)

[1621]

[1622] (Synthesis of intermediate (310))

[1623] Intermediate (5) 4.0 g (6.1 mmol), intermediate (304) 3.3 g (7.3 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.5 g (18.2 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.7 g (yield: 69.2%) of the compound (intermediate (310)) as a white solid.

[1624]

[1625] Intermediate Synthesis Example 151: Synthesis of Intermediate (314)

[1626]

[1627] (Synthesis of intermediate (311))

[1628] 15.0 g (109.5 mmol) of (2-aminophenyl)boronic acid, 20.8 g (131.4 mmol) of 2-bromopyridine, 46.3 g (5.5 mmol) of Pd(PPh3), 45.4 g (328.6 mmol) of K2CO3, 300 mL of toluene, 120 mL of ethanol, and 120 mL of distilled water were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, the concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and recrystallized to obtain 14.6 g (yield: 78.3%) of the compound (intermediate (311)) as a white solid.

[1629] (Synthesis of intermediate (312))

[1630] Intermediate (311) 14.6 g (85.8 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 37.7 mL (2.5 M in hexane, 94.4 mmol) was slowly added and stirred at -78°C for 2 hours. 18.9 g (85.8 mmol) of 1-bromo-3-fluoro-2-nitrobenzene was dissolved in 60 mL of THF and slowly added to the reaction mixture. After stirring at -78°C for 2 hours, the mixture was stirred at room temperature for 2 hours. Distilled water was added to terminate the reaction, and the mixture was concentrated under reduced pressure. Dichloromethane was added, and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 21.3 g (yield: 67.1%) of the compound (intermediate (312)) as a white solid was obtained by slurrying with n-hexane.

[1631] (Synthesis of intermediate (313))

[1632] Intermediate (312) 21.3 g (57.5 mmol), Fe 16.1 g (287.7 mmol), ammonium chloride 3.1 g (57.5 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After distilled water was added, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (313)) was recrystallized to obtain 15.2 g (yield: 77.7%) as a white solid.

[1633] (Synthesis of intermediate (314))

[1634] Intermediate (313) 15.2 g (44.7 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 11.5 g (49.1 mmol), Na2S2O5 10.2 g (53.6 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 15.7 g (yield: 63.4%) of the compound (intermediate (314)) as a white solid.

[1635]

[1636] Intermediate Synthesis Example 152: Synthesis of Intermediate (315)

[1637]

[1638] (Synthesis of intermediate (315))

[1639] Intermediate (314) 4.0 g (7.2 mmol), intermediate (304) 3.9 g (8.7 mmol), Pd(PPh3) 40.4 g (0.4 mmol), K2CO3 3.0 g (21.7 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 4.2 g (yield: 72.7%) of the compound (intermediate (315)) as a white solid.

[1640]

[1641] Intermediate Synthesis Example 153: Synthesis of Intermediate (319)

[1642]

[1643] (Synthesis of intermediate (316))

[1644] Intermediate (293) 15.0 g (78.9 mmol), pyridin-3-ylboronic acid 11.6 g (94.7 mmol), Pd(PPh3) 44.6 g (4.0 mmol), K2CO3 32.7 g (236.8 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, the concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 10.8 g (yield: 72.7%) of the compound (intermediate (316)) as a white solid.

[1645] (Synthesis of intermediate (317))

[1646] Intermediate (316) 10.8 g (57.4 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 25.2 mL (2.5 M in hexane, 63.1 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 12.6 g (57.4 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 16.4 g (yield: 73.6%) of the compound (intermediate (317)) as a white solid was obtained by slurrying with n-hexane.

[1647] (Synthesis of intermediate (318))

[1648] Intermediate (317) 16.4 g (42.3 mmol), Fe 11.8 g (211.2 mmol), ammonium chloride 2.3 g (42.3 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After distilled water was added, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (318)) 10.4 g (yield: 68.7%) was obtained as a white solid by recrystallization.

[1649] (Synthesis of intermediate (319))

[1650] Intermediate (318) 10.4 g (29.0 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 7.5 g (31.9 mmol), Na2S2O5 6.6 g (34.8 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 10.3 g (yield: 62.0%) of the compound (intermediate (319)) as a white solid.

[1651]

[1652] Intermediate Synthesis Example 154: Synthesis of Intermediate (320)

[1653]

[1654] (Synthesis of intermediate (320))

[1655] Intermediate (319) 4.0 g (7.0 mmol), intermediate (304) 3.8 g (8.4 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.9 g (21.0 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.9 g (yield: 68.2%) of the compound (intermediate (320)) as a white solid.

[1656]

[1657] Intermediate Synthesis Example 155: Synthesis of Intermediate (321)

[1658]

[1659] (Synthesis of intermediate (321))

[1660] Intermediate (89) 4.0 g (7.8 mmol), intermediate (304) 4.2 g (9.3 mmol), Pd(PPh3) 40.4 g (0.4 mmol), K2CO3 3.2 g (23.2 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.5 g (yield: 59.2%) of the compound (intermediate (321)) as a white solid.

[1661]

[1662] Intermediate Synthesis Example 156: Synthesis of Intermediate (326)

[1663]

[1664] (Synthesis of intermediate (322))

[1665] Intermediate (12) 30.0 g (125.0 mmol), PIN2B 247.6 g (187.5 mmol), Pd(dba) 23.6 g (6.3 mmol), XPhos 9.0 g (18.8 mmol), KOAc 30.7 g (312.5 mmol) and toluene 640 mL were mixed and stirred under reflux for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc), and then solidified with methanol to obtain 25.1 g (yield: 70.0%) of a white solid compound (intermediate (322)).

[1666] (Synthesis of intermediate (323))

[1667] Intermediate (322) 15.0 g (52.3 mmol), 2-chlorobenzo[d]oxazole 9.6 g (62.7 mmol), Pd(PPh3) 43.0 g (2.6 mmol), K2CO3 21.7 g (156.8 mmol), toluene 150 mL, ethanol 70 mL, and distilled water 70 mL were mixed. The mixture was stirred under reflux for 12 hours, then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 8.8 g (yield: 60.5%) of the compound (intermediate (323)) as a white solid.

[1668] (Synthesis of intermediate (324))

[1669] Intermediate (323) 8.8 g (31.6 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 13.9 mL (2.5 M in hexane, 34.8 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 7.0 g (31.6 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 10.9 g (yield: 72.1%) of the compound (intermediate (324)) as a white solid was obtained by slurrying with n-hexane.

[1670] (Synthesis of intermediate (325))

[1671] Intermediate (324) 10.9 g (22.8 mmol), Fe 6.4 g (114.0 mmol), ammonium chloride 1.2 g (22.8 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After distilled water was added, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (325)) was recrystallized to obtain 7.7 g (yield: 75.4%) as a white solid.

[1672] (Synthesis of intermediate (326))

[1673] Intermediate (325) 7.7 g (17.2 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 4.4 g (18.9 mmol), Na2S2O5 3.9 g (20.6 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound (intermediate (326)) as a white solid was obtained 5.4 g (yield: 47.5%) by recrystallization.

[1674]

[1675] Intermediate Synthesis Example 157: Synthesis of Intermediate (327)

[1676]

[1677] (Synthesis of intermediate (327))

[1678] Intermediate (326) 4.0 g (6.0 mmol), intermediate (304) 3.3 g (7.2 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.5 g (18.1 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.7 g (yield: 67.4%) of the compound (intermediate (327)) as a white solid.

[1679]

[1680] Intermediate Synthesis Example 158: Synthesis of Intermediate (329)

[1681]

[1682] (Synthesis of intermediate (328))

[1683] Intermediate (302) 15.0 g (65.3 mmol), (3-chloro-5-methylphenyl)boronic acid 13.4 g (78.4 mmol), Pd(PPh3) 43.8 g (3.3 mmol), K2CO3 27.3 g (195.9 mmol), toluene 300 mL, ethanol 120 mL, and H2O 120 mL were mixed and stirred under reflux for 24 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel and celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was solidified with methanol to obtain 16.1 g (yield: 77.1%) of the compound (intermediate (328)) as a white solid.

[1684] (Synthesis of intermediate (329))

[1685] Intermediate (328) 16.1 g (50.4 mmol), PIN2B 219.2 g (75.5 mmol), Pd(dba) 21.5 g (2.5 mmol), XPhos 3.6 g (7.6 mmol), KOAc 12.4 g (125.9 mmol) and toluene 400 mL were mixed and stirred under reflux for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc), and then solidified with methanol to obtain 17.4 g (yield: 84.0%) of the compound (intermediate (329)) as a white solid.

[1686]

[1687] Intermediate Synthesis Example 159: Synthesis of Intermediate (330)

[1688]

[1689] (Synthesis of intermediate (330))

[1690] Intermediate (141) 4.0 g (6.2 mmol), intermediate (329) 3.0 g (7.4 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.6 g (18.5 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.1 g (yield: 59.0%) of the compound (intermediate (330)) as a white solid.

[1691]

[1692] Intermediate synthesis example 160: Synthesis of intermediate (331)

[1693]

[1694] (Synthesis of intermediate (331))

[1695] Intermediate (279) 4.0 g (5.9 mmol), intermediate (304) 3.2 g (7.1 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.5 g (17.7 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.2 g (yield: 60.5%) of the compound (intermediate (331)) as a white solid.

[1696]

[1697] Intermediate Synthesis Example 161: Synthesis of Intermediate (332)

[1698]

[1699] (Synthesis of intermediate (332))

[1700] Intermediate (168) 4.0 g (5.7 mmol), intermediate (329) 2.8 g (6.9 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.4 g (17.2 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.5 g (yield: 67.7%) of the compound (intermediate (332)) as a white solid.

[1701]

[1702] Intermediate Synthesis Example 162: Synthesis of Intermediate (333)

[1703]

[1704] (Synthesis of intermediate (333))

[1705] Intermediate (304) 20.0 g (44.1 mmol), 3-bromo-2-nitroaniline 11.5 g (52.9 mmol), Pd(PPh3) 42.6 g (2.2 mmol), K2CO3 18.3 g (132.3 mmol), toluene 200 mL, ethanol 70 mL, and distilled water 70 mL were mixed, and stirred at 85°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the solid was filtered, and washed with distilled water and methanol. The resulting mixture was purified by silica gel column chromatography (tol: EA), and solidified with ethanol and ethyl acetate to obtain 13.7 g (yield: 67.0%) of the compound (intermediate (333)) as a white solid.

[1706]

[1707] Intermediate Synthesis Example 163: Synthesis of Intermediate (337)

[1708]

[1709] (Synthesis of intermediate (334))

[1710] 1-bromo-3-chlorobenzene (10.0 g (40.4 mmol), dibenzo[b,d]furan-2-ylboronic acid (10.3 g (48.5 mmol), Pd(PPh3) (42.3 g (2.0 mmol), K2CO3 (16.8 g (121.2 mmol), toluene (200 mL), ethanol (70 mL), and distilled water (70 mL)) were mixed and stirred at 85°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the solid was filtered, washed with distilled water and methanol, and the resulting mixture was purified by silica gel column chromatography (tol:EA), and solidified with ethanol and ethyl acetate to obtain 8.2 g (yield: 60.6%) of a white solid compound (intermediate (334)).

[1711] (Synthesis of intermediate (335))

[1712] Intermediate (334) 5.0 g (14.9 mmol), intermediate (333) 7.6 g (16.4 mmol), Pd(dba) 20.4 g (0.7 mmol), X-Phos 0.7 g (1.5 mmol), K3PO4 9.5 g (44.8 mmol) and xylene 50 mL were mixed and reacted at 110°C for 24 hours. After the reaction was completed, the obtained mixture was filtered through a silica gel pad, and the obtained mixture was recrystallized to obtain 7.1 g (yield: 62.4%) of the compound (intermediate (335)) as a white solid.

[1713] (Synthesis of intermediate (336))

[1714] Intermediate (335) 7.1 g (9.3 mmol), SnCl 4.3 g (28.0 mmol), and ethanol 100 mL were mixed and stirred at 100°C for 24 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered through a Celite pad, and the obtained mixture was purified by silica gel column chromatography (CHCl3:EA) to obtain 4.9 g (yield: 71.8%) of a white solid compound (intermediate (336)).

[1715] (Synthesis of intermediate (337))

[1716] Intermediate (336) 4.9 g (6.7 mmol), 3,5-di-tert-butyl-2-hydroxybenzaldehyde 1.7 g (7.4 mmol), Na2S2O5 1.5 g (8.0 mmol) and DMF 30 mL were mixed and reacted at 110°C for one day. After the reaction was completed, it was cooled to room temperature, distilled water was added, filtered, and washed with distilled water and methanol. The obtained mixture was purified by silica gel column chromatography (Hex:EA) to obtain 3.9 g (yield: 65.5%) of the compound (intermediate (337)) as a white solid.

[1717]

[1718] Intermediate Synthesis Example 164: Synthesis of Intermediate (338)

[1719]

[1720] (Synthesis of intermediate (338))

[1721] Intermediate (225) 10.0 g (20.6 mmol), 5-fluoro-2-hydroxybenzaldehyde 3.2 g (22.7 mmol), Na2S2O 54.7 g (24.7 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound was recrystallized to obtain 6.7 g (yield: 53.7%) of a white solid (intermediate (338)).

[1722]

[1723] Intermediate Synthesis Example 165: Synthesis of Intermediate (339)

[1724]

[1725] (Synthesis of intermediate (339))

[1726] Intermediate (338) 4.0 g (6.6 mmol), intermediate (304) 3.6 g (7.9 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.7 g (19.8 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.9 g (yield: 69.3%) of the compound (intermediate (339)) as a white solid.

[1727]

[1728] Intermediate Synthesis Example 166: Synthesis of Intermediate (340)

[1729]

[1730] (Synthesis of intermediate (340))

[1731] Intermediate (203) 4.0 g (5.3 mmol), intermediate (304) 2.9 g (6.4 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.2 g (15.9 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.1 g (yield: 58.4%) of the compound (intermediate (340)) as a white solid.

[1732]

[1733] Intermediate Synthesis Example 167: Synthesis of Intermediate (341)

[1734]

[1735] (Synthesis of intermediate (341))

[1736] Intermediate (219) 4.0 g (5.3 mmol), intermediate (304) 2.9 g (6.4 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.2 g (15.9 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 307 g (yield: 56.6%) of the compound (intermediate (341)) as a white solid.

[1737]

[1738] Intermediate Synthesis Example 168: Synthesis of Intermediate (342)

[1739]

[1740] (Synthesis of intermediate (342))

[1741] Intermediate (235) 4.0 g (5.6 mmol), intermediate (304) 3.0 g (6.7 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.3 g (16.8 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.3 g (yield: 61.4%) of the compound (intermediate (342)) as a white solid.

[1742]

[1743] Intermediate Synthesis Example 169: Synthesis of Intermediate (343)

[1744]

[1745] (Synthesis of intermediate (343))

[1746] Intermediate (252) 4.0 g (5.6 mmol), intermediate (304) 3.0 g (6.7 mmol), Pd(PPh3) 40.3 g (0.3 mmol), K2CO3 2.3 g (16.8 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.1 g (yield: 57.7%) of the compound (intermediate (343)) as a white solid.

[1747]

[1748] Intermediate synthesis example 170: Synthesis of intermediate (346)

[1749]

[1750] (Synthesis of intermediate (344))

[1751] 2-chloro-4-iodopyridine 30.0 g (125.3 mmol), benzo[b]thiophen-2-ylboronic acid 26.8 g (150.4 mmol), Pd(PPh3) 44.3 g (3.8 mmol), Na2CO3 33.2 g (313.2 mmol), toluene 600 mL, ethanol 200 mL, and H2O 200 mL were mixed and stirred at 65°C for 24 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was purified by silica gel column chromatography (EtOAc:Hexanes) and then solidified with hexane to obtain 30.4 g (yield: 83.6%) of a white solid compound (intermediate (344)).

[1752] (Synthesis of intermediate (345))

[1753] Intermediate (344) 30.0 g (103.4 mmol), (3-(tert-butyl)-5-chlorophenyl)boronic acid 26.4 g (124.1 mmol), Pd(PPh3) 46.0 g (5.2 mmol), K2CO 3 42.9 g (310.2 mmol), toluene 550 mL, ethanol 140 mL, and H2O 140 mL were mixed and stirred under reflux for 24 hours. After the reaction was completed, the organic layer was extracted using toluene and distilled water. The extracted organic layer was dried over anhydrous magnesium sulfate, filtered through silica gel and celite, and concentrated under reduced pressure to remove the solvent. The obtained reaction mixture was solidified with methanol to obtain 32.2 g (yield: 73.7%) of a white solid compound (intermediate (345)).

[1754] (Synthesis of intermediate (346))

[1755] Intermediate (345) 32.2 g (76.2 mmol), PIN2B 229.0 g (114.4 mmol), Pd(dba) 22.2 g (3.8 mmol), XPhos 5.5 g (11.4 mmol), KOAc 18.7 g (190.6 mmol) and toluene 500 mL were mixed and stirred under reflux for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and the organic layer was extracted using toluene. The separated organic layer was dried over anhydrous magnesium sulfate, filtered through Celite, and the solvent was removed under reduced pressure. The obtained reaction mixture was purified by silica gel column chromatography (DCM:EtOAc), and then solidified with methanol to obtain 24.1 g (yield: 67.3%) of the compound (intermediate (346)) as a white solid.

[1756]

[1757] Intermediate Synthesis Example 171: Synthesis of Intermediate (347)

[1758]

[1759] (Synthesis of intermediate (347))

[1760] Intermediate (282) 4.0 g (6.6 mmol), intermediate (346) 3.7 g (7.9 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.7 g (19.7 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipitated solid was filtered, and washed with distilled water and ethanol. The obtained mixture was filtered through a silica gel pad (CHCl3), and the obtained mixture was recrystallized with ethanol to obtain 3.2 g (yield: 55.9%) of the compound (intermediate (347)) as a white solid.

[1761]

[1762] Intermediate Synthesis Example 172: Synthesis of Intermediate (351)

[1763]

[1764] (Synthesis of intermediate (348))

[1765] Intermediate (293) 15.0 g (78.9 mmol), naphthyl-2-ylboronic acid 16.3 g (94.7 mmol), Pd(PPh3) 44.6 g (4.0 mmol), K2CO3 32.7 g (236.8 mmol), toluene 200 mL, ethanol 80 mL, and distilled water 80 mL were mixed. The mixture was stirred under reflux for 12 hours and then cooled to room temperature. Distilled water was added, and the layers were separated to obtain the organic layer, which was washed with distilled water. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (DCM / n-Hexane) and then recrystallized to obtain 12.0 g (yield: 64.1%) of the compound (intermediate (348)) as a white solid.

[1766] (Synthesis of intermediate (349))

[1767] Intermediate (348) 12.0 g (50.6 mmol) and THF 340 mL were mixed and cooled to -78°C. n-BuLi 22.3 mL (2.5 M in hexane, 55.6 mmol) was slowly added and stirred at -78°C for 2 hours. 1-Bromo-3-fluoro-2-nitrobenzene 11.3 g (50.6 mmol) was dissolved in THF 30 mL and slowly added to the reaction mixture. After stirring at -78°C for 2 hours and then at room temperature for 2 hours, distilled water was added to terminate the reaction and the mixture was concentrated under reduced pressure. Dichloromethane was added and the organic layer was extracted. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), 15.7 g (yield: 71.0%) of the compound (intermediate (349)) as a white solid was obtained by slurrying with n-hexane.

[1768] (Synthesis of intermediate (350))

[1769] Intermediate (349) 15.7 g (35.9 mmol), Fe 10.0 g (179.5 mmol), ammonium chloride 1.9 g (35.9 mmol), EtOH 230 mL, and distilled water 45 mL were mixed and stirred under reflux for 24 hours. The mixture was passed through a pad of Celite and washed with dichloromethane. After adding distilled water, the organic layer was obtained and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM), the compound (intermediate (350)) as a white solid was obtained 9.9 g (yield: 67.7%) by recrystallization.

[1770] (Synthesis of intermediate (351))

[1771] Intermediate (350) 9.9 g (24.3 mmol), 5-(tert-butyl)-2-hydroxybenzaldehyde 4.8 g (26.7 mmol), Na2S2O5 5.5 g (29.2 mmol), and DMF 140 mL were mixed and stirred at 110°C for 24 hours. After cooling to 60°C, DMF was removed under reduced pressure. Dichloromethane and distilled water were added, and the layers were separated, and the organic layer was washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. After purification by silica gel column chromatography (DCM / n-hexane), the compound (intermediate (351)) 5.1 g (yield: 37.1%) was obtained as a white solid.

[1772]

[1773] Intermediate Synthesis Example 173: Synthesis of Intermediate (352)

[1774]

[1775] (Synthesis of intermediate (352))

[1776] Intermediate (351) 4.0 g (6.4 mmol), intermediate (346) 3.6 g (7.7 mmol), Pd(PPh3) 40.4 g (0.3 mmol), K2CO3 2.7 g (19.3 mmol), toluene 60 mL, ethanol 10 mL, and distilled water 10 mL were mixed and stirred under reflux for 12 hours. After the reaction was completed, the mixture was cooled to room temperature, distilled water was added to the reaction mixture, the precipit...

Claims

An organic metal complex for use as an organic electroluminescent material represented by the following chemical formula 1. [Chemical Formula 1] In the above chemical formula 1, L1 and L2 are independently selected from a substituted or unsubstituted phenylene group, a biphenylene group, a pyridylene group, and a naphthylene group, Ar1 and Ar2 are independently selected from a substituted or unsubstituted phenyl group, a pyridyl group, a naphthyl group, a benzofuran group, a benzothiophene group, a benzoxazole group, a benzothiazole group, a dibenzofuran group, and a dibenzothiophene group, R1 to R4 are independently selected from hydrogen, deuterium, -CD3, -F, -CF3, an alkyl group and a cycloalkyl group, a to d and o to r are independently integers from 0 to 4. In paragraph 1, The above chemical formula 1 is an organic metal complex for an organic electroluminescent device represented by any one of the following chemical formulas 2 to 4. [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] In the above chemical formulas 2 to 4, X1 is CH or N, Z1 and Z2 are independently O or S, R5 is independently selected from hydrogen, deuterium, -CD3, -F, -CF3, an alkyl group and a cycloalkyl group, e is an integer from 0 to 5 Ar1, R1 to R4, a to d, and o to r are the same as defined in Chemical Formula 1. In paragraph 1, The organic metal complex of the above chemical formula 1 is an organic metal complex for an organic electroluminescent device selected from the group represented by the following chemical formulas 5 to 7. [Chemical Formula 5] [Chemical Formula 6] [Chemical Formula 7] An organic electroluminescent device comprising an organic metal complex according to any one of claims 1 to 3. In paragraph 4, An organic electroluminescent device characterized in that the above organic metal complex is used as a dopant material. In an organic electroluminescent device comprising a first electrode, a second electrode, and one or more organic layers disposed between the electrodes, An organic electroluminescent device, wherein the organic layer comprises an organic metal complex according to any one of claims 1 to 3. In paragraph 6, An organic electroluminescent device characterized in that the organic layer includes a light-emitting region, and the light-emitting region includes one or more compounds represented by the chemical formula 1 and one or more hosts.

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