Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1B1OC(C)(C)C(C)(C)O1)[C:5]#[N:6].Br[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=1)[C:5]#[N:6]
Reactant: CC1(C)OB(c2ccc(C#N)cc2F)OC1(C)C
Reactant: Cc1cc(Br)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc(-c2ccc(C#N)cc2F)ccn1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (14.0 g), 4-bromo-2-methylpyridine (5.84 mL), tetrakis(triphenylphosphine)palladium(0) (5.24 g) and 2N aqueous sodium carbonate solution (91 mL) in 1,2-dimethoxyethane (20 mL) was stirred at 80° C. for 30 min under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was separated, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.41 g).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH:26]2[O:28][CH2:27]2)[CH2:21][CH2:20]1>C(C(C)=O)C(C)C>[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH:26]([OH:28])[CH2:27][O:1][C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[O:5][C:4](=[O:12])[C:3]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:21][CH2:20]1
Reactant: C1CN(CC2CO2)CCO1
Reactant: O=c1oc2c(c(O)c1-c1ccccc1)CCCC2
Solvent: CC(=O)CC(C)C
Product: O=c1oc2c(c(OCC(O)CN3CCOCC3)c1-c1ccccc1)CCCC2
Reaction time: 0.25 h
Yield: 77 %

Procedure:
A solution of 4-hydroxy-3-phenyl-5,6,7,8-tetrahydrocoumarin and 3-morpholino-1,2-epoxypropane in methyl isobutyl ketone is brought under reflux for 8 hours. Evaporation is carried out under vacuum and the residue is taken up by a 5% solution of sodium bicarbonate and kept for 15 minutes at reflux. After cooling, extraction is carried out with chloroform, drying takes place on sodium sulphate and the chloroform is evaporated. An oil is obtained which cannot be crystallised. Yield 77%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([C:18]([OH:20])=[O:19])=[CH:12][C:13]([CH2:16][OH:17])=[CH:14][CH:15]=1.N1C=CC=CC=1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[CH3:29][C:28]([CH3:31])([CH3:30])[C:27]([O:17][CH2:16][C:13]1[CH:12]=[C:11]([C:18]([OH:20])=[O:19])[C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:15][CH:14]=1)=[O:32]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C(=O)O)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COC(=O)C(C)(C)C)cc2C(=O)O)c1
Temperature: 12.5 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
To a 0° C. mixture of 29.1 (2.2 g, 7.9 mmol) in THF (20 mL) was added pyridine (1.56 g, 19.8 mmol) followed by pivaloyl chloride (0.96 g, 7.9 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA). The resulting solution was stirred at 0-25° C. overnight and was then quenched with water and treated with 2.0 N HCl (15 mL). The mixture was extracted with EtOAc (3×30 mL). The organic layers were combined and washed with water (10 mL) and brine (10 mL). After removal of organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0-65% EtOAc/hexanes for elution gave 29.2 as white solid (1.60 g, 56%).
Reaction SMILES: [C:1]([Cl:4])(=[O:3])[CH3:2].C(O)C.[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]#[N:25])[CH2:20][CH2:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.Cl.C(N1N=NC(C2CCN([C@@H]3CN[C@H](C(N4CCSC4)=O)C3)CC2)=N1)(C)(C)C>C(Cl)(Cl)Cl>[ClH:4].[CH2:8]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:3][CH2:1][CH3:2])=[NH:25])[CH2:20][CH2:19]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)Cl
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)(C)n1nnc(C2CCN([C@@H]3CN[C@H](C(=O)N4CCSC4)C3)CC2)n1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=N)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
Acetyl chloride (180 mL) was dropwise added to a mixture of ethanol (160 mL) and chloroform (180 mL) under ice-cooling. After the mixture was stirred for 30 min, a solution of 1-benzyloxycarbonyl-4-cyanopiperidine [product of Example 298 (2), 20.6 g] in chloroform (180 mL) was added thereto under ice-cooling. The mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure to give 1-benzyloxycarbonyl-4-(ethoxycarbonimidoyl)piperidine hydrochloride (28.7 g) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[C:34]([F:35])=[CH:33][C:29]([C:30]([OH:32])=O)=[C:28]([N:36]2[N:40]=[CH:39][CH:38]=[N:37]2)[CH:27]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:30]([C:29]1[CH:33]=[C:34]([F:35])[C:26]([F:25])=[CH:27][C:28]=1[N:36]1[N:40]=[CH:39][CH:38]=[N:37]1)=[O:32]
Reactant: O=C(O)c1cc(F)c(F)cc1-n1nccn1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-n2nccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 4,5-difluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 336, (M+H).
Reaction SMILES: [OH:1][CH:2]([CH:8]([N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].[NH3:23]>>[OH:1][CH:2]([CH:8]([N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([NH2:23])=[O:4]
Reactant: N
Reactant: CCOC(=O)C(O)C(c1ccccc1)N(C)c1ccccc1
Product: CN(c1ccccc1)C(c1ccccc1)C(O)C(N)=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
A mixture of ethyl (2RS,3RS)-2-hydroxy-3-[methyl(phenyl)amino]-3-phenylpropanoate (1.20 g, 4.00 mmol) and methanolic ammonia solution (7 N, 20 mL) was stirred at 100° C. in a sealed tube for 5 hours. After cooling, all volatiles were removed under reduced pressure. The resulting yellow oil was purified via silica gel chromatography (15-30% isopropanol/hexane) and recrystallized (warm ethyl acetate/hexane/−25° C.) to yield 582 mg (54%) of (2RS,3RS)-2-hydroxy-3-[methyl(phenyl)amino]-3-phenylpropanamide as white needles. MS (ESI) m/z 268.9 ([M−H]−); HRMS: calculated for C16H18N2O2+H, 271.1447; found (ESI, [M+H]+), 271.1458.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].[CH:7]1([C:10](Cl)=[O:11])[CH2:9][CH2:8]1>C1COCC1>[CH:7]1([C:10]([O:4][C:2]([CH3:5])([CH3:3])[CH3:1])=[O:11])[CH2:9][CH2:8]1
Reactant: CC(C)(C)[O-]
Reactant: O=C(Cl)C1CC1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CC1

Procedure:
50.99 g (454.4 mmol) of potassium tert-butoxide were dissolved in 454 ml of abs. THF and cooled to 0° C. The solution was stirred vigorously, and 50 g (478.3 mmol) of cyclopropanecarbonyl chloride were added dropwise such that the reaction temperature did not exceed 50° C. (cooling required). After the addition has ended, the resultant suspension was stirred for another 30 min. After cooling, the reaction mixture was, under reduced pressure, concentrated to about one third of the original volume and then added to 2 liters of saturated aqueous ammonium chloride solution. The pH was adjusted to 8 by addition of saturated sodium bicarbonate solution and the mixture was then extracted three times with diethyl ether. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure without heating (cold water bath). The residue was distilled at a bath temperature of about 85° C. and 42 mbar. This gave 43.1 g (63.2% of theory) of the target compound as a clear liquid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[C:14]([C:22]#[N:23])=[C:13]2[N:24]1[CH2:25][CH2:26][N:27]([C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:28][CH2:29]1
Reactant: O=C(Cl)c1cccs1
Reactant: Cn1c(=O)c(C#N)c(N2CCNCC2)c2cc(Cl)ccc21
Solvent: c1ccncc1
Product: Cn1c(=O)c(C#N)c(N2CCN(C(=O)c3cccs3)CC2)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
2-Thiophene carbonyl chloride (160 μL, 1.5 mmol) was added to a stirred solution of Compound 73 (303 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 341 mg (83%) of white solids. M.P. 262° C. 1H NMR (DMSO-d6): δ 3.57 (s, 3H), 3.64 (m, 4H), 3.91 (m, 4H), 7.16 (m, 1H), 7.50 (d, J=3.2 Hz, 1H), 7.62 (d, J=9.0 Hz, 1H), 7.79 (m, 2H), 7.86 (s, 1H). EIMS m/z 414 (M+1). Anal. (C20H17ClN4O2S) C,H, N.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]([OH:15])[CH2:12][C:13]#[CH:14])([CH3:3])[CH3:2].Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>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.C(N(CC)CC)C>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]([OH:15])[CH2:12][C:13]#[C:14][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)([CH3:3])[CH3:2]
Reactant: C#CCC(O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C(O)CC#Cc1ccccn1
Temperature: 60 °C
Yield: 43.6 %

Procedure:
To a round bottom flask were added 1-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)but-3-yn-1-ol (0.47 g, 2.3 mmol), triethylamine (10 mL), 2-bromopyridine (0.28 mL, 2.7 mmol), bis(triphenylphosphine)palladium(II) dichloride (16 mg, 0.023 mmol) and copper(I) iodide (9 mg, 0.045 mmol). After this mixture was stirred with heating overnight at 60° C., it was allowed to cool to room temperature. The reaction was mixed directly with silica, concentrated and purified by silica chromatography to give the desired coupling product (286 mg).
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][C:17](=S)[C:12]=2[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:2][CH3:3].CC(C)=[O:24]>CI.O>[O:24]=[C:17]1[CH:16]=[C:15]([C:19]([OH:21])=[O:20])[O:14][C:13]2[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]3[C:10](=[CH:11][C:12]1=2)[CH2:9][CH2:8][CH2:7][CH2:6]3
Reactant: CCCc1c2c(cc3c(=S)cc(C(=O)O)oc13)CCCC2
Reactant: CC(C)=O
Solvent: CI
Solvent: O
Product: CCCc1c2c(cc3c(=O)cc(C(=O)O)oc13)CCCC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 10-propyl-6,7,8,9-tetrahydro-4-thioxo-4H-naphtho[2,3-b]pyran-2-carboxylic acid (0.025 g), methyl iodide (3 drops), acetone (10 ml) and water (4 drops) was stirred in the dark at ambient temperature for 2 days. Concentration of the reaction mixture in vacuo gave a brown solid which on crystallisation from acetone gave the title compound as a light-yellow solid, mp 245°-8°.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2C=C[C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\[OH:24].CC1OC(C=O)=CC=1>>[I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[O:24][C:17]([CH3:20])=[CH:16][CH:15]=2)[O:6][C:7]=1[CH3:8]
Reactant: CC(=O)/C(C)=N/O
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: Cc1ccc(C=O)o1
Product: Cc1ccc(-c2nc(CI)c(C)o2)o1

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 5-methylfuran-2-carbaldehyde gave 4-iodomethyl-5-methyl-2-(5-methylfuran-2-yl)oxazole.
Reaction SMILES: [C:1]([O:6]CCCC)(=O)[C:2]([CH3:4])=[CH2:3].[CH3:11][N:12]([CH3:19])[CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH2:16].OP(O)(O)=O.C1(C=CC(O)=CC=1)O>>[CH3:11][N:12]([CH3:19])[CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH:16][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3]
Reactant: CN(C)CC(C)(C)CN
Reactant: C=C(C)C(=O)OCCCC
Agent: O=P(O)(O)O
Agent: Oc1ccc(O)cc1
Product: C=C(C)C(=O)NCC(C)(C)CN(C)C
Yield: 60 %

Procedure:
426 g (3 mols) of butyl methacrylate, 390 g (3 mols) of N,N,2,2-tetramethylpropane-1,3-diamine, 29.4 g (0.3 mol) of H3PO4, and 2 g of hydroquinone were warmed for 2 hours at 220° C. N-(3-dimethylamino-2,2-dimethylpropyl)-methacrylic acid amide was formed in this way. Yield: 60% (selectivity: 94% calculated on the reacted butyl methacrylate).
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)(Cl)=O.Cl[CH:19](Cl)C>>[Cl:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][CH3:19])=[O:10])=[CH:12][CH:13]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
4-Chlorosulfonyl benzoic acid (5 g, 23 mmol) and thionyl chloride (20 mL) in dichloroethane (10 mL) was heated to 80° C. for 2 hr. The reaction mixture was concentrated via rotary evaporation to give a brownish solid. The solid was chilled on ice for 5 minutes and ice-cold methanol (40 mL) was added with stirring at 0° C. for 5 minutes. The reaction mixture was allowed to warm to ambient temperature and stirred an additional 10 min. The addition of ice-cold water (40 mL), produced a white solid that was collected by filtration and dried under vacuum to afford pure methyl 4-(chlorosulfonyl)benzoate (4.5 g, 84%). NMR (400 MHz, DMSO-d6): δ, ppm: 3.84 (s, 3H), 7.70 (d, 2H, J=8.4 Hz), 7.93 (d, 2H, J=8.4 Hz).
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[N:13]=[CH:14][NH:15][CH:16]=3)=[C:10]([CH2:17][O:18][CH3:19])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>>[CH3:19][O:18][CH2:17][C:10]1[O:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:11]=1[C:12]1[N:13]=[CH:14][N:15]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[CH:16]=1
Reactant: COCc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: N#Cc1ccc(F)cc1
Product: COCc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C#N)cc2)cn1
Yield: 42 %

Procedure:
As described for Example 1f, 3-phenyl-4-(1H-imidazol-4-yl)-5-methoxymethyl-isoxazole (128 mg, 0.50 mmol) was converted, using 4-fluorobenzonitrile instead of 1-(4-fluorophenyl)-ethanone, to the title compound (75 mg, 42%) which was obtained as an off-white solid. MS: m/e=357.0[M+H]+.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=3)[CH:12]=[C:11]([CH2:25][OH:26])[CH:10]=2)[CH:6]=[CH:5][N:4]=1)[NH2:2].[C:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[C:36]([CH3:38])=O)(O)=[O:28]>C(O)CO>[CH3:38][C:36]1[C:31]2[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27](=[O:28])[N:1]([C:3]2[CH:8]=[C:7]([C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:22][CH2:23][CH3:24])=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=4)[CH:12]=[C:11]([CH2:25][OH:26])[CH:10]=3)[CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: CC(=O)c1ccccc1C(=O)O
Reactant: CCOc1cc2cc(CO)cc(-c3ccnc(NN)c3)c2cc1OCC
Solvent: OCCO
Product: CCOc1cc2cc(CO)cc(-c3ccnc(-n4nc(C)c5ccccc5c4=O)c3)c2cc1OCC
Yield: 87.5 %

Procedure:
1-(2-Hydrazino-4-pyridyl)-3-hydroxymethyl-6,7-diethoxynaphthalene (177 mg), 1-carboxy-2-methylcarbonylbenzene (86 mg) and ethylene glycol (1 ml) are treated in the same manner as in Example 104-(3) to give 1-{2-(4-methyl-1(2H)-phthalazinon-2-yl)-4-pyridyl}-3-hydroxymethyl-6,7-diethoxynaphthalene (211 mg), which is listed in Table 14.
Reaction SMILES: C[Si](C)(C)C1C=C(C=CC=1)N.Cl[C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=1.[CH3:23][C@@H:24]1[CH2:29][NH:28][CH2:27][CH2:26][NH:25]1>>[CH3:23][CH:24]1[NH:25][CH2:26][CH2:27][N:28]([C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:29]1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: C[C@@H]1CNCCN1
Agent: C[Si](C)(C)c1cccc(N)c1
Product: CC1CN(c2ncccc2C(F)(F)F)CCN1
Yield: 92.6 %

Procedure:
Compound A-03 can be synthesized according to method 1. Just of Scheme 1, R1 is —CF3; R2 is -Me; R3 is p-SiMe3. More specifically, compound 1 is 2-chloro-3-(trifluoromethyl)-pyridine (2 g); compound 2 is (R)-2-methylpiperazine; the synthesized compound 3 is 3-methyl-1-(3-trifluoromethyl-2-pyridyl)piperazine (2.5 g, yield about 92.6%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[CH2:21][OH:22])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:6]1([C:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[CH2:21][O:22][S:2]([CH3:1])(=[O:4])=[O:3])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1oc2ccccc2c1-c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1oc2ccccc2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.3 %

Procedure:
Methanesulfonyl chloride (160 μL, 2.05 mmol) was added dropwise to a solution of (3-phenylbenzofuran-2-yl)methanol (367 mg, 1.64 mmol) and DIPEA (343 μL, 1.97 mmol) in anhydrous DCM (10 mL) at 0° C. Stirring at 0° C. was continued for 15 min, then the mixture slowly warmed to RT. After 2 h at RT, additional amounts of methanesulfonyl chloride (80 μL, 1.03 mmol) and DIPEA (172 μL, 0.99 mmol) were added and stirring continued for 1.5 h. The reaction mixture was diluted with DCM and the organic fraction washed with water, dried (Na2SO4) and concentrated in vacuo affording the title compound as an oil (443 mg, 89%). 1H NMR (DMSO-d6, 400 MHz): δ 7.71-7.64 (2H, m), 7.62-7.56 (4H, m), 7.52-7.41 (2H, m), 7.37-7.32 (1H, m), 4.98 (2H, s), 3.89 (3H, s)
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-n2ccnc2)cc1
Temperature: 25 °C

Procedure:
Heat 101.6 g (0.65 mol) of methyl 4-fluorobenzoate, 66.65 g (0.98 mol) of imidazole, and 182.0 g (1.31 mol) of potassium carbonate in dimethylsulfoxide at ca. 120° C. for about 3 hr. Cool the solution to room temperature and pour into 500 mL of cold water. Filter to obtain crystals of the title compound.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[CH3:20][N:21]([CH:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][C:23]=1[C:29]([F:32])([F:31])[F:30]>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([NH:28][C:25]3[CH:26]=[CH:27][C:22]([N:21]([CH3:20])[CH:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)=[O:19])=[CH:14][CH:15]=2)[CH:2]=1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: CN1CCC(N(C)c2ccc(N)cc2C(F)(F)F)CC1
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(N(C)c2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 7.1) and 4-[methyl-(1-methyl-piperidin-4-yl)-amino]-3-trifluoromethyl-phenylamine. Title compound: ES-MS: 523.0 [M+H]+; single peak at tR=3.33 min (System 1); Rf=0.18 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C:13]=1[O:14][CH3:15])[CH2:10][C:9]([CH3:26])=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1.[Li]CCCC.[Cl:39][Si:40](Cl)([CH3:42])[CH3:41]>C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]2[C:11]([CH:10]=[C:9]([CH3:26])[CH:8]2[Si:40]([Cl:39])([CH3:42])[CH3:41])=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:13]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(Cl)Cl
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccc(C(C)(C)C)cc1)CC(C)=C2
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccc(C(C)(C)C)cc1)C=C(C)C2[Si](C)(C)Cl
Temperature: -20 °C
Reaction time: 10 h
Yield: 99.7 %

Procedure:
To a solution of 10.5 g (30.0 mmol) of 5-tert-butyl-7-(4-tert-butylphenyl)-6-methoxy-2-methyl-1H-indene in 200 ml of toluene 12.0 ml (30.0 mmol) of 2.5 M nBuLi in hexanes was added at room temperature. The resulting viscous solution was stirred for 10 h, and then 10 ml of THF was added. The formed mixture was stirred for 2 h at 60° C., then cooled to −20° C., and 19.4 g (150 mmol, 5 eq.) of dichlorodimethylsilane was added in one portion. The resulting solution was warmed to room temperature, refluxed for 1 h, and then filtered through glass frit (G3). The precipitate was additionally washed by 2×10 ml of toluene. The combined filtrate was evaporated to dryness to give 13.2 g (99%) of the title product as a yellowish oil which was further used without an additional purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].C1([PH2](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:31]([CH2:38][C:39](=[O:41])[CH3:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:40][C:39](=[O:41])[CH2:38][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(=O)COc1ccccc1
Agent: c1ccc([PH2](c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(C=CC(=O)COc2ccccc2)ccc1O
Reaction time: 3 h
Yield: 76.5 %

Procedure:
4-Hydroxy-3-methoxybenzaldehyde (2.1 g, 13.8 mMol) and 3-phenoxypropane-2-one triphenylphosphorane (2.8 g, 6.9 mMol) (prepared as described by LeCorre: C. R. Acad. Sci. Paris, 273 81 (1971)) are dissolved in 100 ml of toluene and warmed to reflux. After three hours, the solvent is evaporated and the residue is taken up in tHF. Sodium bisulfite (10.0 g) is dissolved in 100 ml of water and stirred with the solution for one hour. The THF is evaporated and the water is extracted with chloroform. Drying over magnesium sulfate and evaporation of the chloroform gives a yellow oil. Flash chromatography in ethyl acetate on silica gel gives 1.5 g (65%) of 1-(4'-hydroxy,3'-methoxyphenyl)-4-phenoxy-1-butene-3-one; mp=85°-87° C. C, H analysis: Calcd for C17H16O4 (71.81, 5.68); Found (71.85, 5.50).