Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].N1CCCC1.[C:18]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:29]1[CH2:30][CH2:31][N:26]([C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:25])[CH2:27][CH:28]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Solvent: CCO
Solvent: C1CCNC1
Product: O=C(c1ccccc1)N1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of 5-nitroindole (38) (0.5 g, 3.083 mmol) in dry ethanol (15 mL) was treated with pyrrolidine (0.77 mL, 9.250 mmol), 1-benzoyl-4-piperidone (1.0 g, 4.933 mmol) at room temperature and resulting solution was refluxed for 3 days. The reaction cooled to room temperature and the solid was filtered off. The product was washed with cold ethanol (2×10 mL) and dried under vacuum to obtain compound 68 (1.05 g, 98%) as a solid. mp 280-282° C.; 1H NMR (DMSO-d6) δ 2.55-2.61 (m, 2H), 3.54-3.58 (m, 1H), 3.86-3.90 (m, 1H), 4.15-4.34 (m, 2H), 6.14-6.30 (m, 1H), 7.39-7.55 (m, 5H), 7.67 (d, 1H, J=9.6 Hz), 7.72 (s, 1H), 8.03 (d, 1H, J=8.1 Hz), 8.70-8.78 (m, 1H), 11.94 (s, 1H); ESI-MS m/z (%): 348 (M+, 100), 276 (83), 244 (40).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH3:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH:34][C:11]([C:3]2[N:2]=[CH:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)=[O:13])[CH2:30][CH2:29]1
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H](NC(=O)c2cc3ccccc3cn2)CC1
Temperature: 50 °C

Procedure:
A solution of isoquinoline-3-carboxylic acid (346 mg, 2 mmol), and 1,1′-carbonyldiimidazole (325 mg, 2 mmol) in dimethylformamide (4 mL) was heated at 50° C. for 1 hour. After this time, trans-4-methylcyclohexylamine hydrochloride (300 mg, 2 mmol), and N,N-diisopropylethylamine (0.523 mL, 3 mmol) were added and the mixture heated at 50° C. for 16 hours. The reaction mixture was cooled, and diluted with ethyl acetate (20 mL). The organic solution was washed with water (3×15 mL), brine (20 mL), dried over anhydrous MgSO4, filtered and concentrated to afford 377 mg (70%) of 406:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1.F[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14]2)[CH:3]=1
Reactant: Fc1ccccn1
Reactant: Oc1ccc2nc(N3CCCc4ccccc4C3)cc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Clc1cc(N2CCCc3ccccc3C2)nc2ccc(Oc3ccccn3)cc12
Temperature: 130 °C
Reaction time: 0.67 h
Yield: 44.4 %

Procedure:
The mixture of 4-chloro-2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-6-ol (200 mg, 0.617 mmol), 2-fluoro-pyridine (180 mg, 1.85 mmol), potassium carbonate (73 mg, 0.53 mmol) and dry dimethylsulfoxide was heated with stirring in a sealed tube for 40 minutes at 130° C. under microwave irradiation. The resulting mixture was cooled to room temperature, then diluted with water (10 mL) and extracted with ethyl acetate (10 mL×2). The combined organic layer was washed with brine (10 mL×3), and then dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether, 1:5) to give 110 mg of product as a yellow solid (yield was 45%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]([CH3:18])=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O[CH:20](C1OC(C)=CC(=O)C=1O)[CH2:21]C.C(Br)C1C=CC=CC=1>>[OH:1][CH:2]([C:3]1[O:4][C:5]([CH3:18])=[CH:6][C:7](=[O:17])[C:8]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:20][CH3:21]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1
Reactant: CCC(O)c1oc(C)cc(=O)c1O
Agent: BrCc1ccccc1
Product: CCC(O)c1oc(C)cc(=O)c1OCc1ccccc1

Procedure:
The title compound was prepared by the method outlined for 2-hydroxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one, using 7.36 g (40 mmol, 1 eq.) of 2-(1-hydroxypropyl)-3-hydroxy-6-methyl-pyran-4(1H)-one and 7.5 g benzyl bromide (44 mmol, 1.1 eq.) to yield the pure product 8.9 g (81.2%) after recrystallisation from CH2Cl2/Pet. ether 40/60, as a white crystalline solid. m.p. 88-89° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37].[NH4+].[Cl-]>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.[Cu]I.O>[CH3:22][C:20]1([CH3:23])[CH2:19][C:18]([CH3:24])([CH3:25])[CH2:17][C:16](=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:40]#[C:39][Si:36]([CH3:38])([CH3:37])[CH3:35])=[CH:7][CH:6]=2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:21]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(I)cc2)CC(C)(C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C#C[Si](C)(C)C)cc2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a degassed solution of 4-[(4-Iodophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (144) (0.305 g, 0.68 mmol) in DMF (8 mL) were added Pd(PPh3)2Cl2 (48 mg, 0.07 mmol), CuI (13 mg, 0.07 mmol), N,N-diisopropylethylamine (0.55 mL, 3.10 mmol) and trimethylsilyl acetylene (0.12 mL, 0.82 mmol). The reaction mixture was stirred at room temperature overnight, poured into saturated aqueous NH4Cl (20 mL) and water (10 mL), extracted with EtOAc (2×50 mL). The combined organic phase was washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as dark brown oil. The crude product was purified by chromatography on a silica gel column eluted with a gradient from hexanes to 15% EtOAc:hexanes to give light brown solid, which was washed with cold hexanes to yield 0.18 g (64%) of the title compound 146 as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 0.22 (s, 9H), 0.89 (s, 6H), 0.92 (s, 6H), 1.27 (s, 2H), 1.91 (s, 2H), 1.97 (s, 2H), 4.55 (br s, 1H), 6.72 (d, J=8.5 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.2 Hz, 2H), 7.36 (d, J=8.3 Hz, 2H). LCMS (ESI): m/z 415 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:47]([O:50][CH2:51][CH2:52][CH2:53][NH:54][C:55](=[O:66])[C@H:56]([NH:64][CH3:65])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)(=[O:49])[CH3:48]>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:47]([O:50][CH2:51][CH2:52][CH2:53][NH:54][C:55](=[O:66])[C@H:56]([N:64]([C:11](=[O:13])[C@H:10]([N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH3:9])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[CH3:65])[CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)(=[O:49])[CH3:48]
Reactant: CN[C@H](Cc1ccccc1)C(=O)NCCCOC(C)=O
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)OCCCNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)-propionic acid (659 mg, 2.0 mmol) was dissolved in N,N-dimethylformamide (3 mL) and dichloromethane (3 mL). The solution was cooled to 0° C. 1-Hydroxy-7-azabenzotriazole (272 mg, 2.0 mmol) was added. After 10 min N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (460 mg, 2.4 mmol) was added. The reaction mixture was stirred for 10 min. A solution of 3-((2R)-2-(methylamino)-3-phenylpropionylamino)propyl acetate (567 mg, 2.0 mmol) in dichloromethane (4 mL) was added. The solution was stirred for 16 hours, while the temperature rose to room temperature. The reaction mixture was diluted with ethyl acetate (150 mL). It was extracted with 10% sodium hydrogensulfate solution (150 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL) and the organic phases were combined and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (70 g) with ethyl acetate/heptane (2:1) to give 973 mg of 3-((2R)-2-(N-((2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphthyl)-propionyl)-N-methylamino)-3-phenylpropionylamino)propyl acetate.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[S:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[O:21][C:20]3=[O:33])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.C[OH:35].C(Cl)Cl>CO.O>[O:35]=[S:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[O:21][C:20]3=[O:33])=[CH:17][CH:18]=2)[CH2:9][CH2:8]1
Reactant: CO
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(N3CCSCC3)cc2)C(=O)O1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(N3CCS(=O)CC3)cc2)C(=O)O1
Temperature: 4 °C
Reaction time: 20 h

Procedure:
Sodium periodate (1.7 g, 8.0 mmol) is added to a suspension of the product from Step 3 (3.0 g, 7.6 mmol) in 125 mL of 2:1 methanol:H2O. The mixture is stirred for 20 h at 4° C. in a cold room and then filtered to remove solids. The solids are washed with CHCl3 and the combined filtrate concentrated to give an aqueous solution that is diluted with H2O. This aqueous solution is extracted with five portions of CHCl3 and the combined organic extracts are dried (Na2SO4), filtered and concentrated to provide the crude product. Column chromatography (0–5% MeOH-DCM) provides the title compound as a foam.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9](I)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][N:13]([CH3:30])[C:14]1[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][C:17]([CH:23]([OH:26])[C:24]#[CH:25])=[CH:16][C:15]=1[CH:27]([CH3:29])[CH3:28]>[Cu](I)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>[CH3:30][N:13]([CH3:12])[C:14]1[C:19]([CH:20]([CH3:21])[CH3:22])=[CH:18][C:17]([CH:23]([OH:26])[C:24]#[C:25][C:9]2[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([OH:1])[CH:10]=2)=[CH:16][C:15]=1[CH:27]([CH3:29])[CH3:28]
Reactant: O=C(O)c1ccc(I)cc1O
Reactant: C#CC(O)c1cc(C(C)C)c(N(C)C)c(C(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CC(C)c1cc(C(O)C#Cc2ccc(C(=O)O)c(O)c2)cc(C(C)C)c1N(C)C
Yield: 22.5 %

Procedure:
In a manner analogous to example 1 f, the process is carried out by a reaction of 360 mg (1.35 mmol) of 2-hydroxy-4-iodobenzoic acid with 500 mg (1.9 mmol) of 1-(4-dimethylamino-3,5-diisopropylphenyl)prop-2-yn-1-ol in the presence of 15 mg (0.08 mmol) of copper iodide and 27 mg (0.04 mmol) of bis(triphenylphosphine)-palladium chloride. 120 mg of 4-[3-(4-dimethylamino-3,5-diisopropylphenyl)-3-hydroxyprop-1-ynyl]-2-hydroxy-benzoic acid are obtained in the form of a yellowish solid (Mp: dec>250° C., yield=22%).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH2:2][OH:3].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][O:3][S:21]([CH3:20])(=[O:23])=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CO)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of benzyl glycolate (2.0 mL, 14.1 mmol) and triethylamine (2.35 mL, 16.9 mmol) in dichloromethane (30 mL) at 0° C. was added dropwise methanesulfonyl chloride (1.20 mL, 15.1 mL). The reaction was stirred overnight, diluted with dichloromethane, washed with saturated aqueous NH4Cl, and then with saturated NaHCO3, dried with Na2SO4, and concentrated in vacuo to give 2.50 g (73%) of methanesulfonyloxy-acetic acid benzyl ester which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][C:6]([CH3:12])=[CH:5][N:4]=1)#[N:2].C([O-])(O)=O.[Na+].O>C(O)(=O)C.CCOC(C)=O.[Fe]>[NH2:9][C:8]1[C:3]([C:1]#[N:2])=[N:4][CH:5]=[C:6]([CH3:12])[CH:7]=1
Reactant: Cc1cnc(C#N)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cnc(C#N)c(N)c1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 76.4 %

Procedure:
To acetic acid (300 mL) in a 3-neck 2 liter round bottom flask equipped with mechanical stirrer and a thermometer was added Fe powder (99.6 g, 1.78 mol) with stirring at 60° C. 2-Cyano-5-methyl-3-nitropyridine (97 g, 0.59 mol) was dissolved in acetic acid (400 mL) with gentle warming and added to the above reaction mixture drop wise with efficient stirring so that the reaction temperature kept below 80° C. over 3.5 hours. The reaction mixture was further stirred for an addition 30 min, cooled, diluted with EtOAc (750 mL), filtered through celite and washed with EtOAc (1×500 mL, 3×250 mL). Combined EtOAc layers were evaporated to dryness to obtain dark brown solid which was neutralized with saturated NaHCO3 solution (850 mL), after addition of water (250 mL) to obtain homogeneous, this aqueous layer was extracted with EtOAc (1×750 mL, 2×500 mL). Combined EtOAc layers were filtered through small pad of silica gel (sand-SiO2-sand in sintered funnel), dried (Na2SO4) and evaporated to obtain 3-amino-2-cyano-5-methylpyridine (60 g) as yellow solid in 76% yield including ˜10% corresponding amide.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[CH2:9]([NH:16][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(I)cc1
Reactant: NCc1ccccc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CC(C)O
Solvent: OCCO
Product: Nc1ccc(NCc2ccccc2)cc1
Yield: 50.9 %

Procedure:
The general procedure under argon was followed using copper(I) iodide (19 mg, 0.10 mmol), K3PO4 (425 mg, 2.00 mmol), benzylamine (218 μL, 2.0 mmol), 4-iodoaniline (219 mg, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL) at 90° C. Column chromatography using a solvent gradient (hexane/ethyl acetate=2/1 to 1/1, Rf=0.2) afforded 4-(N-benzyl)aminoaniline (101 mg, 51% isolated yield) as brown solid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Araki, T.; Tsukube, H. J. Polym. Sci., Polym. Lett. Ed. 1979, 17, 501-505.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)=[O:17].F[C:26]1[C:31]([CH:32]2[CH2:38][CH2:37][N:36]([CH3:39])[C:35](=[O:40])[CH2:34][CH2:33]2)=[CH:30][CH:29]=[CH:28][N:27]=1>CN1CCCC1=O>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:26]2[C:31]([CH:32]3[CH2:38][CH2:37][N:36]([CH3:39])[C:35](=[O:40])[CH2:34][CH2:33]3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: CN1CCC(c2cccnc2F)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CN1CCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CCC1=O
Temperature: 140 °C

Procedure:
A mixture of cesium carbonate (0.29 g, 0.88 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.21 g, 0.878 mmol), and 5-(2-fluoropyridin-3-yl)-1-methylazepan-2-one (0.07 g, 0.29 mmol) in 1-methyl-2-pyrrolidinone (0.5 mL) under argon was heated to 140° C. for 48 h, then cooled to room temperature. The resulting mixture was partitioned between ethyl acetate and water, the layers were separated, and the organic layer was washed with 1N aqueous sodium hydroxide (2×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The oil was purified by silica gel chromatography 5-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-1-methylazepan-2-one. MS (ESI, pos. ion) m/z: 441.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:19]([NH:11][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc2c(c1)OCO2)c1ccccc1
Yield: 84.2 %

Procedure:
To a mixture of piperonylamine (20.0 g, 0.133 mol), tetrahydrofuran (87.5 mL) and triethylamine (13.9 g, 0.137 mol) was added dropwise benzoyl chloride (18.6 g, 0.133 mol), at −10-+6° C., and during dropwise addition, tetrahydrofuran (total 123 mL) was appropriately added thereto to stir the content. After adding dropwise, the dropping funnel was washed with tetrahydrofuran (10 mL). The reaction mixture was stirred at 2-11° C. for 15 hr under a nitrogen atmosphere. The consumption of the starting material was confirmed by TLC (eluent: hexane/ethyl acetate 1:1)). To the reaction mixture was added water (50 mL) at 11° C., and then added ethyl acetate (128 mL). The organic layer was separated, and the aqueous layer was extracted twice with ethyl acetate (44 mL). The combined organic layers were washed successively with 10% hydrochloric acid (40 mL), saturated aqueous sodium hydrogen carbonate solution (40 mL), water (40 mL) and saturated brine (44 mL), and dried over magnesium sulfate (18 g). The large part of the solvent was evaporated under reduced pressure at 35° C. or lower (content 61 g), and ethyl acetate (61 mL) was added to the residue. The crystals were collected by filtration, washed with ethyl acetate (46 mL), and dried under reduced pressure at 50° C. or lower to give N-benzoylpiperonylamine (28.6 g, 84.7%) as white crystals.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][CH:10]=1.O>ClC1C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[Hf+4].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:18])=[CH:10][CH:11]=2)=[O:16])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: [Hf+4]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: Clc1ccccc1
Product: COc1ccc(C(=O)c2ccc(C)cc2)cc1
Reaction time: 3 h
Yield: 8.9 %

Procedure:
Hafnium (IV) trifluoromethanesulfonate (5.15 g), anisole (1.08 g) and para-toluic acid (1.36 g) were refluxed together in 125 mL chlorobenzene with azeotropic removal of the upper water layer (inverse Dean-Stark apparatus). After 3 hours, the mixture was cooled and extracted with 2×25 mL water, then 2×25 mL saturated sodium bicarbonate solution. The organic layer was dried using anhydrous sodium sulfate, filtered, then concentrated down in vacuo to give crude 4-methoxy-4′-methylbenzophenone (0.20 g, 9% yield) as a colored crystalline solid. The aqueous layer was concentrated in vacuo to give 4.41 g of a damp, white solid.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[C:9]2[C:10]([CH3:17])=[CH:11][C:12]([O:15]C)=[C:13]([F:14])[C:8]=2[S:7][CH:6]=1.CN(C=O)C.CC([S-])(C)C.[Na+]>O.Cl>[F:14][C:13]1[C:8]2[S:7][CH:6]=[C:5]([CH2:4][C:3]([OH:18])=[O:2])[C:9]=2[C:10]([CH3:17])=[CH:11][C:12]=1[OH:15]
Reactant: COC(=O)Cc1csc2c(F)c(OC)cc(C)c12
Agent: CC(C)(C)[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O)c(F)c2scc(CC(=O)O)c12
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 122.7 %

Procedure:
To a mixture of methyl(7-fluoro-6-methoxy-4-methyl-1-benzothiophen-3-yl)acetate (248.4 mg) and DMF (dry) (7.5 mL) was added sodium 2-methyl-2-propanethiolate (415 mg) at room temperature. The mixture was stirred at 160° C. for 20 min. After cooling, the mixture was diluted with water and 1N HCl and extracted with EtOAc. The organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo to give the title compound (273 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:31])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:9]=2)=[O:5])[CH3:2].[C:32]1([Mg]Cl)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:31])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:9]=2)=[O:5])[CH3:2]
Reactant: Cl[Mg]c1ccccc1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OCCCc3ccccc3)cc2C1(O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 113.9 %

Procedure:
1-Oxo-3-phenyl-6-(3-phenyl-propoxy)-1H-indene-2-carboxylic acid ethyl ester (350 mg, 0.85 mmol) obtained in Step 1 was dissolved in THF, and phenylmagnesium chloride (0.064 mL, 0.93 mmol) was added thereto, followed by stirring for 1 hr at 0° C. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 475 mg of the titled compound (yield: 100%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH2:16][CH:17]3[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]3)[C:12](Br)=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[O:29]1[CH2:34][CH2:33][N:32]([C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH2:31][CH2:30]1>>[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:14]=[C:13]([O:15][CH2:16][CH:17]3[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]3)[C:12]([C:38]3[CH:37]=[CH:36][C:35]([N:32]4[CH2:31][CH2:30][O:29][CH2:34][CH2:33]4)=[CH:40][CH:39]=3)=[CH:11][N:10]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)C1
Reactant: OB(O)c1ccc(N2CCOCC2)cc1
Product: CC(C)(C)OC(=O)N1CC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2-c2ccc(N3CCOCC3)cc2)C1

Procedure:
Using the procedure of Example 1 Step 3, tert-butyl 3-((2-(cis-4-methylcyclohexylamino)-5-bromopyrimidin-4-yloxy)methyl)azetidine-1-carboxylate was reacted with 4-morpholinophenylboronic acid to provide the title compound at 78% yield. 1H NMR (CDCl3, 400 MHz) 8.02 (s, 1H), 7.30 (d, 2H), 6.85 (d, 2H), 5.38 (sb, 1H), 4.41 (d, 2H), 4.07-3.80 (m, 3H), 4.79-3.70 (m, 5H), 3.11-3.09 (m, 4H), 2.95-2.88 (m, 2H), 1.76-1.45 (m, 6H), 1.44 (s, 9H), 1.20-1.16 (m, 3H), 0.87 (d, 3H); MS (ESI) m/z: Calc: 537.3 (M+). Found. 538.3 (M+1).