Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](F)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1.[F:24][C:25]([F:39])([F:38])[C@H:26]([O:36][CH3:37])[CH2:27][NH:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH2:35])[CH2:31][CH2:30]1.N1C(C)=CC=CC=1C>CS(C)=O>[Cl:1][C:2]1[C:3]([C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([NH:35][C@H:32]3[CH2:31][CH2:30][C@H:29]([NH:28][CH2:27][C@@H:26]([O:36][CH3:37])[C:25]([F:38])([F:39])[F:24])[CH2:34][CH2:33]3)[CH:17]=2)=[N:4][C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Cl)c(Cl)cn1
Reactant: CO[C@H](CN[C@H]1CC[C@H](N)CC1)C(F)(F)F
Solvent: CS(C)=O
Solvent: Cc1cccc(C)n1
Product: CO[C@H](CN[C@H]1CC[C@H](Nc2cc(-c3nc(NCC4CCOCC4)ccc3Cl)c(Cl)cn2)CC1)C(F)(F)F
Temperature: 120 °C
Reaction time: 20 h

Procedure:
To a solution of 3,5′-dichloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (36 mg, 0.10 mmol) in DMSO (0.4 mL) was added trans-N1-((R)-3,3,3-trifluoro-2-methoxypropyl)cyclohexane-1,4-diamine (48 mg, 0.20 mmol) and 2,6-lutidine (0.023 mL, 0.20 mmol). The mixture was stirred at 120° C. for 20 hr. The cooled reaction mixture was purified by reverse phase HPLC and lyophilized to give 11.4 mg of 3,5′-dichloro-N6-((tetrahydro-2H-pyran-4-yl)methyl)-N2′-(trans-4-((R)-3,3,3-trifluoro-2-methoxypropylamino)cyclohexyl)-2,4′-bipyridine-2′,6-diamine as its TFA salt. LCMS (m/z): 576.2 (MH+), retention time=0.68 min.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:6]([C:33]([OH:35])=O)[CH2:5]1.[NH2:36][OH:37]>>[OH:37][NH:36][C:33]([CH:6]1[CH:7]([NH:10][S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:18][CH:19]=2)(=[O:12])=[O:13])[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5]1)=[O:35]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3CCN(CCO)CC3C(=O)O)cc2)c2ccccc2n1
Reactant: NO
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3CCN(CCO)CC3C(=O)NO)cc2)c2ccccc2n1

Procedure:
According to the procedure of Example 24, Step 3, 0.4 g (0.8 mmol) of 1-(2-hydroxy-ethyl)-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid and hydroxylamine afforded a ˜2:1 mixture of cis- and trans-1-(2-hydroxy-ethyl)-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid hydroxyamide as an amorphous white solid (0.040 g, 9.7%) after purification using reverse phase HPLC (Gilson) on a Phenomex C-18 semi-prep column eluting an acetonitrile:water gradient. MS: 515 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:18]O>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([C:8]([O:10][CH3:18])=[O:9])=[N:6][CH:7]=1
Reactant: COc1cc(Cl)cnc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ncc(Cl)cc1OC
Temperature: 0 °C
Yield: 67 %

Procedure:
In a 350-mL resealable vessel, 5-chloro-3-methoxypicolinic acid (intermediate 14, 7.51 g, 40.0 mmol) was dissolved in MeOH (120 mL). The solution was cooled to 0° C., and concentrated sulfuric acid (7.57 mL, 140 mmol) was added. The vessel was sealed and heated to 95° C. for 1.5 h. The reaction mixture was cooled to 0° C., and quenched with Na2CO3 (1M, 140 mL). The reaction mixture was concentrated under reduced pressure and the residue was extracted with EtOAc (3×100 mL). The combined organics extracts were dried over MgSO4 and the filtrate was concentrated under reduced pressure. The residue was by silica gel chromatography (gradient 20%-33% EtOAc/hexane) to afford the title compound as a yellow solid (5.59 g, 27.7 mmol, 67%). MS m/z=202 [M+H]+. Calculated for C8H8ClNO3: 201. 1H NMR in CDCl3 δ: 8.24 (d, 1H, J=1.9), 7.37 (d, 1H, J=1.9), 3.97 (s, 3H), 3.94 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH2:28][CH3:29])[N:16]=[C:17]([C@H:18]4[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[CH:31]=[CH2:32].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:24]([C@@H:21]1[CH2:20][CH2:19][C@H:18]([C:17]2[N:10]3[C:11]([C:12](=[O:14])[NH:13][C:8]([C:4]4[CH:3]=[C:2](/[CH:32]=[CH:31]/[C:30]([O:34][CH2:35][CH3:36])=[O:33])[CH:7]=[CH:6][CH:5]=4)=[N:9]3)=[C:15]([CH2:28][CH3:29])[N:16]=2)[CH2:23][CH2:22]1)([CH3:25])([CH3:27])[CH3:26]
Reactant: C=CC(=O)OCC
Reactant: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3cccc(Br)c3)[nH]c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cccc(-c2nn3c(c(CC)nc3[C@H]3CC[C@@H](C(C)(C)C)CC3)c(=O)[nH]2)c1
Temperature: 25 °C

Procedure:
740 mg (1.62 mmol) cis-2-(3-bromophenyl)-7-(4-tert-butylcyclohexyl)-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (Example 27A), 1.6 g (16.2 mmol) ethyl acrylate, 327 mg (3.24 mmol) triethylamine and 227 mg (0.32 mmol) dichlorobis(triphenylphosphine)palladium(II) are stirred at 120° C. in 20 ml DMF in an argon atmosphere for 18 hours. After cooling down to room temperature, the mixture is filtrated over Celite, and the product is isolated by column chromatography or preparative HPLC.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][C:9]#[N:10].[CH2:11]([OH:14])[C:12]#[CH:13]>CCN(CC)CC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:14][CH2:11][C:12]#[C:13][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][C:9]#[N:10]
Reactant: N#CCCc1ccsc1Br
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: N#CCCc1ccsc1C#CCO
Temperature: 50 °C
Reaction time: 9 h
Yield: 61.1 %

Procedure:
To a stirred solution of 3-(2-bromo-thiophen-3-yl)-propionitrile 81 (0.5 g, 2.31 mmol), CuI (0.04 g, 0.23 mmol), PdCl2(PPh3)2 (0.08 g, 0.12 mmol) in NEt3 (6 mL) at room temperature was added propargyl alcohol (0.28 mL, 4.62 mmole) and the reaction mixture was stirred at 50° C. for 9 h. The mixture was concentrated in vacuo and purified by silica gel column chromatography (eluent: 50% EtOAc in hexane). The major fractions were combined and concentrated to give 82 (0.27 g) as a yellow syrup. 1H NMR (400 MHz, d6-DMSO) δ: 7.54 (d, J=5.0 Hz, 1H), 7.10 (d, J=5.0 Hz, 1H), 5.37 (t, J=6.0 Hz, 1H), 4.34 (d, J=6.0 Hz, 2H), 2.93 (t, J=7.0 Hz, 2H), 2.84 (t, J=7.0 Hz, 2H). MS (EI) m/z (M−OH+) 174.
Reaction SMILES: CS(O)(=O)=O.[C:6]1([CH3:16])[C:7](S(O)(=O)=O)=[CH:8][CH:9]=[CH:10][CH:11]=1.S(=O)(=O)(O)O.[C:22]([OH:25])(=O)[CH3:23]>>[CH:11]1[C:6]2[CH2:16][C:23]3[C:22](=[CH:7][CH:6]=[CH:11][CH:10]=3)[O:25][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=O)O
Reactant: Cc1ccccc1S(=O)(=O)O
Agent: CS(=O)(=O)O
Agent: O=S(=O)(O)O
Product: c1ccc2c(c1)Cc1ccccc1O2

Procedure:
The compounds according to the present invention can be synthesized by reference to the methods described in Journal of the American Chemical Society, Vol. 72, pages 3651 to 3655 or similar methods. A nuclear-substituted hydroquinone, as a starting material, is dissolved in a weak acidic carboxylic acid solvent such as acetic acid in an amount of about 10-2 mol/l to 5 mol/l and, a strong acidic compound such as hydrochloric acid is added to the solution in an amount of about 0.1 to 5 times w/w (weight ratio) based on the starting material. A condensing agent such as formalin, acetone or aldehydes is added to the solution in an amount of about 0.5 to 5 moles based on the starting material and the resulting solution is stirred at about 10° to 100° C. to obtain a diarylmethane compound. The resulting diarylmethane compound is dissolved in a solvent such as a hydrocarbon solvent (for example, benzene, toluene), an alcohol solvent (for example, ethanol, propanol), or an organic acid (for example, acetic acid) and, the solution is heated with refluxing in the presence or non-presence of a strong acid (for example, methane sulfonic acid, toluene sulfonic acid, sulfuric acid) in an amount of about 0.1 to 1.0 mole based on the starting material to obtain an objective compound of a xanthene compound. Specific synthesis examples are illustrated below for reference.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1.CN(C)C=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>C(N(CC)CC)C>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33](=[O:34])[NH:2][C:3]1[CH:19]=[CH:18][C:17]2[C:8]3[NH:9][C:10](=[O:16])[C:11]4[N:12]([CH:13]=[CH:14][N:15]=4)[C:7]=3[CH2:6][C:5]=2[CH:4]=1
Reactant: O=C=Nc1ccccc1F
Reactant: Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12)Nc1ccccc1F
Yield: 36.6 %

Procedure:
The preparation is carried out as in Example 36 but from 2 g of 8-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride, 40 ml of dimethylformamide, 1.3 g of triethylamine and 1.76 g of 2-fluorophenyl isocyanate. There is obtained 1 g of 8-[3-(2-fluorophenyl)ureido]-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one in the form of a beige solid melting above 260° C. (Analysis, % calculated C: 64.00, H: 3.76, F: 5.06, N: 18.66, O: 8.52, % found C: 64.0, H: 3.5, F: 4.6, N: 18.6).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:10]([OH:14])[C:11]([OH:13])=[O:12])=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][C@H:9]([CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@H:10]([OH:14])[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCc1ccccc1)[C@H](O)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](CCCc1ccccc1)[C@H](O)C(=O)O

Procedure:
A solution of Example 9D (25.7 mg, 0.08 mmol) in 4M HCl in dioxane (2 mL) was stirred at room temperature for 1 hour and concentrated to provide the desired product. MS (ESI) m/e 224 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 7.29 (m, 2H), 7.18 (m, 3H), 4.11 (d, 1H), 3.69 (m, 1H), 2.57 (m, 2H), 1.73–1.49 (m, 4H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](C(OC)=O)([C:7]([O:9]C)=[O:8])[CH2:3][CH2:2]1.Cl>O>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1
Reactant: COC(=O)C1(C(=O)OC)CCOCC1
Agent: Cl
Solvent: O
Product: O=C(O)C1CCOCC1
Yield: 101.1 %

Procedure:
Dimethyl tetrahydro-4H-pyrane-4,4-dicarboxylate (4.04 g) was added to 20% hydrochloric acid (20 ml), and the mixture was heated under reflux for 19 hours. Water was added to the reaction mixture to conduct extraction with diethyl ether. After the resultant organic layer was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. After the resultant residue was solidified with hexane, the resultant solides were collected by filtration and washed to obtain the title compound (2.63 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][OH:67])C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][OH:67])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: N#Cc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCO)CC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: NC(=O)c1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2CCO)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-hydroxy-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=494, obsd.=494).
Reaction SMILES: C(OC([N:11]1[CH2:20][C@@H:19]2[C@@:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([CH2:14][C:15]3([CH2:18]2)[CH2:17][CH2:16]3)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[C].[Pd].CO>[C:25]([O:24][C:22]([NH:21][C@@:13]12[CH2:14][C:15]3([CH2:16][CH2:17]3)[CH2:18][C@@H:19]1[CH2:20][NH:11][CH2:12]2)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@]12CN(C(=O)OCc3ccccc3)C[C@H]1CC1(CC1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@]12CNC[C@H]1CC1(CC1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
A 10% palladium-carbon catalyst (45.6 mg, 30 wt %) was added to a solution of (1S,5R)-3-benzyloxycarbonyl-1-tert-butoxycarbonylaminospiro(3-azabicyclo[3.3.0]octane-7,1′-cyclopropane) (152 mg, 0.393 mmol) in methanol (3.93 ml) in a nitrogen atmosphere. After the atmosphere was replaced with hydrogen, the mixture was stirred at room temperature for 30 minutes. After the atmosphere was replaced with nitrogen, the reaction solution was filtered through Celite and concentrated under reduced pressure to give 97.9 mg of the title compound as a transparent oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3([CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[CH2:11][CH2:10]3)[C:7](=O)[C:6]=2[CH:21]=1.C[Si](C)(C)[N:24]=[C:25]=[N:26][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3([CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[CH2:11][CH2:10]3)[C:7](=[N:26][C:25]#[N:24])[C:6]=2[CH:21]=1
Reactant: O=C1c2cc(Br)ccc2OC12CCc1ccccc1CC2
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1c2cc(Br)ccc2OC12CCc1ccccc1CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5′-bromo-5,6,8,9-tetrahydro-3′H-spiro[benzo[7]annulene-7,2′-benzofuran]-3′-one (0.1660 g, 0.48 mmol) in CH2Cl2 (5 mL) was added TiCl4 (1.0 Min CH2Cl2, 1.0 mL, 1.0 mmol) dropwise at room temperature. The reaction mixture was turned into orange precipitates in a few minutes. After 1 h, 1,3-bis(trimethylsilyl)carbodiimide (0.30 mL, 1.32 mmol) was added via a syringe. The precipitates were disappeared and the reaction mixture was turned into a red solution. The mixture was stirred at room temperature for 15 h and then quenched with ice, extracted with CH2Cl2, dried over Na2SO4. After the solvent was removed under reduced pressure, the crude product was directly used in the next step without further purification. LC-MS tR=2.27 min in 3 min chromatography, m/z 367, 369 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[C:24]1([N:30]2[CH:34]=[C:33]([CH2:35][CH2:36][C:37]3[N:38]=[CH:39][S:40][CH:41]=3)[C:32]([OH:42])=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C)C=O.[H-].[Na+]>O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:42][C:32]3[C:33]([CH2:35][CH2:36][C:37]4[N:38]=[CH:39][S:40][CH:41]=4)=[CH:34][N:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:31]=3)=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: Oc1nn(-c2ccccc2)cc1CCc1cscn1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2CCc2cscn2)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-5-methyl-1,3-oxazole (0.57 g), 1-phenyl-4-[2-(1,3-thiazol-4-yl)ethyl]-1H-pyrazol-3-ol (0.38 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.060 g) at room temperature, and the mixture was stirred at room temperature for 4 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(2-furyl)-4-({2-methoxy-4-[({1-phenyl-4-[2-(1,3-thiazol-4-yl)ethyl]-1H-pyrazol-3-yl}oxy)methyl]phenoxy}methyl)-5-methyl-1,3-oxazole as colorless crystals (0.53 g, yield 66%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 127-128° C.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][CH:9]=[CH2:10])[N:3]=1.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH2:11]([O:18][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][CH:9]=[CH2:10])[N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=CCSc1nsc(Cl)n1
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCSc1nsc(OCc2ccccc2)n1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
Into 4 ml of N,N-dimethylformamide were dissolved 193 mg of 5-chloro-3-allylthio-1,2,4-thiadiazole and 108 mg of benzyl alcohol, 48 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 240 mg of 5-benzyloxy-3-allylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (30)).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.C(N(CC)CC)C.[CH2:24](Br)[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>C(Cl)(Cl)Cl>[O:26]=[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][N:10]1[CH2:9][CH2:8][CH:7]([N:6]2[C:5]3[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=3[NH:3][C:2]2=[O:1])[CH2:12][CH2:11]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C(CBr)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccccc1
Yield: 82.2 %

Procedure:
To a solution comprising 2.3 g of 4-(2-keto-1-benzimidazolinyl)-piperidine, 1.1 g of triethylamine, and 20 ml of chloroform is added 2.2 g of phenacyl bromide, and the reaction is carried out under the same conditions as in Example 1. The same post-treatment as in Example 1 is conducted to obtain 3.2 g of a crude product. Recrystallization of the product from a mixture solution of ethanol and ethyl acetate (2:3 by volume) yields 2.92 g of 1-[2-oxo-2-phenyl-1-ethyl]-4-(2-keto-1-benzimidazolinyl)-piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7](O)=[O:8])=[O:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[Br:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[N:47]=[C:48]([C@@H:51]3[CH2:55][C@H:54]([S:56][CH3:57])[CH2:53][NH:52]3)[NH:49][CH:50]=2)=[CH:42][CH:41]=1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@H:6]([C:7]([N:52]1[CH2:53][C@@H:54]([S:56][CH3:57])[CH2:55][C@H:51]1[C:48]1[NH:49][CH:50]=[C:46]([C:43]2[CH:44]=[CH:45][C:40]([Br:39])=[CH:41][CH:42]=2)[N:47]=1)=[O:8])[CH:10]([CH3:12])[CH3:11]
Reactant: CS[C@@H]1CN[C@H](c2nc(-c3ccc(Br)cc3)c[nH]2)C1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](SC)C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of (S)-2-methoxycarbonylamino-3-methyl-butyric acid (156 mg, 0.89 mmol) and HATU (407 mg, 1.07 mmol) was stirred in DMA (3.0 mL) for 10 min, then 4-(4-bromo-phenyl)-2-((2S,4S)-4-methylsulfanyl-pyrrolidin-2-yl)-1H-imidazole di-HCl (367 mg, 0.89 mmol; Preparation 18) and N,N-diisopropylethylamine (777.3 μL, 4.46 mmol) were added. The resulting mixture was stirred at RT overnight, concentrated, and purified by silica gel chromatography (0 to 90% EtOAc/hexane). Fractions with desired product were combined and concentrated to give the title intermediate (366 mg, 82% yield). (m/z): [M+H]+ calcd for C21H27BrN4O3S 495.10; 497.10. found 495.
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([NH:34][C:35](=[O:48])[CH2:36][C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][CH3:47])=[O:38])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][CH2:20][N:21](C)[C:22](=O)OC(C)(C)C)[CH:18]=3)[S:13][C:6]=12.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:33]=[C:32]([NH:34][C:35](=[O:48])[CH2:36][C:37]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][CH3:47])=[O:38])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][CH2:20][NH:21][CH3:22])[CH:18]=3)[S:13][C:6]=12
Reactant: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4cn(CCN(C)C(=O)OC(C)(C)C)cn4)sc23)c(F)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CNCCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5ccccc5OC)cc4F)c3s2)c1
Temperature: 25 °C
Yield: 177.8 %

Procedure:
To a solution of 101 (31 mg, 0.046 mmol) in toluene (1 ml) was added TFA (excess) and the reaction mixture was stirred at RT for an hour. The solvents were removed and the title compound 96 (47 mg, 100% yield) was obtained after trituration of the resultant solid. MS (m/z): 575.1 (M+H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH2:84])[CH2:59][C:60]2[N:61]([C:65]([C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)([C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH:62]=[CH:63][N:64]=2)=[CH:54][CH:53]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH:84][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:38][CH2:37][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:35][CH2:34]2)=[O:50])[CH2:59][C:60]2[N:61]([C:65]([C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)([C:72]3[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=3)[C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH:62]=[CH:63][N:64]=2)=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(Cc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (166 mg, 0.44 mmol) was added portionwise to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (150 mg, 0.42 mmol), 1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethanamine (Intermediate 88) (193 mg, 0.42 mmol) and N-ethyldiisopropylamine (0.087 mL, 0.50 mmol) in DMF (2.0 mL) at room temperature. The resulting solution was stirred at room temperature for 3 hours then quenched in water (10 mL) to give a pale yellow ppt. The precipitate was collected by filtration, washed with water and dried under vacuum to afford tert-butyl 4-(1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (320 mg, 95%) as a cream solid, which was used without further purification.