Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](I)[CH:13]=2)[O:9][N:8]=1.C(N(CC)CC)C.[CH2:28]([OH:31])[C:29]#[CH:30]>CN(C)C=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.[Cu]I>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([C:30]#[C:29][CH2:28][OH:31])[CH:13]=2)[O:9][N:8]=1
Reactant: C#CCO
Reactant: N#Cc1cc(I)cc(-c2nc(-c3ccccn3)no2)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cc(C#CCO)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
A mixture of the 3-(2-pyridyl)-5-(5-cyano-3-iodophenyl)-1,2,4-oxadiazole (140 mg, 0.374 mmol), Pd(PPh3)4 (10 mg, 0.009), and CuI (30 mg, 0.158 mmol) in N,N-dimethylformamide (3 mL) was treated with triethylamine (1 mL, 726 mg, 7 mmol). The reaction mixture was cooled to 0° C. and treated with propargyl alcohol (56 mg, 1 mmol). The mixture was stirred at ambient temperature 5 hours and then filtered through a short plug of silica gel, washing with ethyl acetate. The organic solution was concentrated in vacuo. Silica gel chromatography afforded 20 mg (18%) of 3-(2-pyridyl)-5-(5-cyano-3-[3-hydroxypropyn-1-yl]phenyl)-1,2,4-oxadiazole: 1H-NMR (MeOH-d4), δ ppm: 8.80 (d, 1H), 8.60 (s, 1H), 8.58 (s, 1H), 8.30 (d, 1H), 8.10 (m, 2H), 7.60 (m, 1H), 4.5 (s, 2H).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]2[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH:16]=[CH:15][CH2:14]2)=[CH:7][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH:13]2[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH:16]=[CH:15][CH2:14]2)=[CH:9][CH:10]=1
Reactant: COCOc1ccc(CCC2CC=CC(=O)CCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=CCC(CCc2ccc(O)cc2)CCC1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
0.17 g of 5-[2-(4-methoxymethoxyphenyl)ethyl]-2-cyclooctene-1-one prepared in Example 12 was dissolved in 10 ml of 50% aqueous solution of trifluoroacetic acid. The resulting solution was stirred at room temperature for forty minutes. The reaction solution was cooled in an ice bath, and to the solution was added slowly 30 ml of a saturated sodium carbonate aqueous solution. Then, the reaction solution was extracted with ether. The extract was washed with a saturated sodium bicarbonate aqueous solution six times, and dried over anhydrous sodium sulfate. The solvent was evaporated. The residue was purified on silica gel column, and the eluate with ethyl acetate-hexane (1:6) was collected, to afford 0.077 g of the title compound above as colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=[N:58][C:53]2[CH:54]=[CH:55][CH:56]=[CH:57]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(N)CCCC1>CN(C=O)C>[CH:53]1([NH:58][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([C:18]3[C:13]4[CH:12]=[CH:11][C:10](=[O:42])[N:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[C:14]=4[N:15]=[C:16]([N:29]4[CH2:34][CH2:33][CH:32]([N:35]5[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]5)[CH2:31][CH2:30]4)[N:17]=3)[CH:20]=2)[CH2:54][CH2:55][CH2:56][CH2:57]1
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CCCC2)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and cyclopentanamine (8.15 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (16.9 mg, 48%). LC-MS m/z 641 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=34)[C:19]3[C:32](=[O:42])[N:33](C(OC(C)(C)C)=O)[CH2:34][C:18]=3[C:17]=2[F:43])[CH2:13][CH2:12][O:11][CH2:10]1)=O)(C)(C)C.[ClH:44]>C(O)(C)C>[ClH:44].[NH2:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=34)[C:19]3[C:32](=[O:42])[NH:33][CH2:34][C:18]=3[C:17]=2[F:43])[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: Cc1ccn2ncc(-c3nc(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)c2c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccn2ncc(-c3nc(N[C@@H]4CCOC[C@@H]4N)c(F)c4c3C(=O)NC4)c2c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a solution of tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(5-methylpyrazolo[1,5-a]pyridin-3-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (45 mg, 0.075 mmol) in isopropanol (5 mL) at 65° C. was added concentrated HCl (0.268 mL, 3.21 mmol) dropwise. The reaction mixture was stirred at 65° C. overnight and then slowly cooled. The solids were filtered and dried to give an HCl salt of the title compound as a pale yellow solid (30 mg, 92%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.84 (d, J=9.88 Hz, 1H), 2.08-2.22 (m, 1H), 2.46 (s, 3H), 3.55-3.67 (m, 2H), 3.94-4.09 (m, 2H), 4.35-4.47 (m, 2H), 6.88 (dd, J=7.08, 1.83 Hz, 1H), 7.12 (d, J=5.98 Hz, 1H), 8.03 (d, J=3.97 Hz, 2H), 8.15 (s, 1H), 8.39 (s, 1H), 8.66 (d, J=7.08 Hz, 1H), 9.24 (s, 1H). [M+H] calc'd for C20H21FN6O2, 397. found, 397.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.Cl[C:25]1[CH:26]=[C:27]([F:32])[C:28]([F:31])=[N:29][CH:30]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[F:31][C:28]1[C:27]([F:32])=[CH:26][C:25]([C:13]2[CH:12]=[N:11][N:10]([CH2:9][CH2:8][O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:14]=2)=[CH:30][N:29]=1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: Fc1cc(Cl)cnc1F
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1cc(-c2cnn(CCOC3CCCCO3)c2)cnc1F
Temperature: 100 °C
Yield: 60.5 %

Procedure:
A 48 mL tube was charged with 1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.4 g, 19.9 mmol), 5-chloro-2,3-difluoropyridine (1.7 mL, 16.6 mmol), X-Phos (1.6 g, 3.3 mmol), Potassium phosphate (3.5 g, 16.6 mmol), PdOAc2 (0.4 g, 1.7 mmol), 1,4-dioxane (50 mL), and water (5.0 mL), flushed with argon, sealed, then heated at 100° C. for 3 hours. The mixture was concentrated and purified by MPLC, eluting with 2.5% MeOH/DCM over 40 minutes to afford 2,3-difluoro-5-(1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-pyrazol-4-yl)pyridine as a clear oil which solidified upon standing at room temperature (3.1 g, 60.5% yield). LC/MS shows the product as the free alcohol. However, the structure of the product is as drawn above. MS m/z=226.2 [M+1]+. Calc'd for C15H17F2N3O2: 309.3
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:40])[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]2[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=2)=[CH:26][CH:25]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([N:23]([CH3:22])[CH3:40])=[CH:29][CH:28]=1)[C:32]1[CH:33]=[N:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(NCc2ccc(N(C)C)cc2)cn1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Product: COc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 73.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.0 g) and [(4-dimethylaminophenyl)methyl](6-methoxypyridin-3-yl)amine (0.91 g) as starting materials, 5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.35 g) was obtained. By the reaction and treatment in the same manner as in Example 105 using this compound, N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(6-methoxypyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.34 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17](O)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:35]=[CH:34][C:29]2[NH:30][C:31](=[O:33])[NH:32][C:28]=2[CH:27]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:35]=[CH:34][C:29]4[NH:30][C:31](=[O:33])[NH:32][C:28]=4[CH:27]=3)=[O:18])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Product: CCC(C(=O)Nc1ccc2[nH]c(=O)[nH]c2c1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
71 mg (0.20 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 33 mg (0.22 mmol, 1.1 eq.) of 5-amino-1,3-dihydro-2H-benzimidazol-2-one were reacted according to General Method 1. Yield: 74 mg (76% of theory)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[NH:12][N:11]=[C:10]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:9]=2[CH2:18][CH2:19][NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:5]=[CH:4][N:3]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN1CCCC1=O>[N:35]1([C:2]2[CH:7]=[C:6]([C:8]3[NH:12][N:11]=[C:10]([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:9]=3[CH2:18][CH2:19][NH:20][S:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:28][CH:29]=3)(=[O:23])=[O:22])[CH:5]=[CH:4][N:3]=2)[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: C1COCCN1
Reactant: CCCCCc1ccc(S(=O)(=O)NCCc2c(-c3cccs3)n[nH]c2-c2ccnc(Cl)c2)cc1
Solvent: CN1CCCC1=O
Product: CCCCCc1ccc(S(=O)(=O)NCCc2c(-c3cccs3)n[nH]c2-c2ccnc(N3CCOCC3)c2)cc1
Temperature: 190 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
A mixture of N- {2-[5-(2-Chloro-pyridin-4-yl)-3-thiophen-2-yl-1H-pyrazol-4-yl]-ethyl}-4-pentyl-benzenesulfonamide (10 mg, 19.4 μmol) and morpholine (17 μl, 194 μmol) in 1-methyl-2-pyrrolidinone (500 μL) was stirred at 190° C. in a seal tube for 3 h. The reaction mixture was concentrated to 2 ml. The crude product was purified by Prep-HPLC. Removal of the solvent in vacuo provided the title compound (8.3 mg, 76% yield). MS m/e 566; HPLC retention time 3.35 min (Method A).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[Si:10]([C:14]#[CH:15])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1.[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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:11][Si:10]([C:14]#[C:15][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1)([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(Br)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(C=O)nc1
Yield: 92.8 %

Procedure:
A solution of 5-bromopicolinaldehyde (1 g, 5.3 mmol), TMS-acetylene (1.04 g, 10.6 mmol) and triethylamine (4 mL) in THF (10 mL) was purged with argon for 10 min Copper iodide (76 mg, 0.4 mmol), Pd(PPh3)2Cl2 (141 mg, 0.4 mmol) and triphenylphosphine (0.1 g, 0.4 mmol) was added and the mixture was heated to 100° C. under microwave irradiation for 10 min Ethyl acetate (200 mL) was added at the solution was washed with water (2×25 mL), dried over MgSO4 and concentrated to dryness. The residue was filtered through silica gel with CH2Cl2 to give the title compound as a yellow oil (1 g, 95%). 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.82 (s, 1H), 7.91 (s, 2H), 0.29 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]([NH:18]C(OCC1C=CC=CC=1)=O)=[CH:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][CH:10]=[C:9]2[C:16]#[N:17]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:29])[CH:4]([NH2:18])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][CH:10]=[C:9]2[C:16]#[N:17]
Reactant: COC(=O)C(=Cc1cc(C)c2[nH]cc(C#N)c2c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(N)Cc1cc(C)c2[nH]cc(C#N)c2c1
Reaction time: 8 h
Yield: 89.7 %

Procedure:
2-Benzyloxycarbonylamino-3-(3-cyano-7-methyl-1H-indol-5-yl)-acrylic acid methyl ester (0.1 g, 0.26 mmol) in methanol (2.5 mL) was flushed with nitrogen, and treated with palladium on charcoal (10%, 10 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated. Column chromatography gave 60 mg (90%) of the desired material. LC/MS: tR=0.93 min, 258.22 (MH)+.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:14])[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1.I[CH3:16]>CC(C)=O>[CH3:16][O:1][C:2]1[C:3](=[O:14])[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:6][CH:7]=1
Reactant: CI
Reactant: O=c1cc(-c2ccccc2)occ1O
Solvent: CC(C)=O
Product: COc1coc(-c2ccccc2)cc1=O
Temperature: 60 °C
Yield: 93 %

Procedure:
To a solution of 4-oxo-6-phenyl-4H-pyran-3-yl acetate (100 mg, 0.4 mmol) in MeOH (10.9 mL) is added K2CO3 (180 mg, 1.3 mmol) and the reaction was stirred for 15 min at room temperature. The reaction mixture was concentrated under reduced pressure to provide 5-hydroxy-2-phenyl-4H-pyran-4-one which was used in the subsequent step without further purification. To a solution of crude 5-hydroxy-2-phenyl-4H-pyran-4-one (0.4 mmol) in acetone (10.9 mL) is added iodomethane (0.7 mL, 11.3 mmol) and the reaction mixture was heated at 60° C. for 2 h. After being cooled to room temperature, the reaction was concentrated under reduced pressure and diluted with CHCl3 (10 mL) and water (10 mL). The layers were separated and the organic fraction washed with sat. aq. NaCl, dried (Na2SO4), and concentrated under reduced pressure to provide (93%) of 5-methoxy-2-phenyl-4H-pyran-4-one as tan crystals which were used in the subsequent step without further purification. LC/MS (M+H)+ 203.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Na+].[I-].Cl[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:17].[CH3:25][CH:26]([CH3:42])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:31]=1)=[O:28]>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][N:39]2[CH2:40][CH2:41][CH:36]([C:32]3[CH:31]=[C:30]([NH:29][C:27](=[O:28])[CH:26]([CH3:25])[CH3:42])[CH:35]=[CH:34][CH:33]=3)[CH2:37][CH2:38]2)=[CH:19][CH:20]=1
Reactant: O=C(CCCCCCCl)c1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme E using K2CO3 instead of Na2CO3 and NaI instead of KI and 7-chloro-1-(4-chlorophenyl)-1-heptanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 469.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:14](=O)[CH2:15][C:16](=O)[C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].[NH2:23][C:24]1[C:28]([Br:29])=[CH:27][NH:26][N:25]=1>>[Br:29][C:28]1[CH:27]=[N:26][N:25]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]([C:6]3[CH:7]=[CH:8][C:9]([C:10]([F:13])([F:12])[F:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)=[N:23][C:24]=12
Reactant: CCOc1cc(C(=O)CC(=O)C(F)(F)F)ccc1C(F)(F)F
Reactant: Nc1n[nH]cc1Br
Product: CCOc1cc(-c2cc(C(F)(F)F)n3ncc(Br)c3n2)ccc1C(F)(F)F
Yield: 92.8 %

Procedure:
Prepared from 1-(3-ethoxy-4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (example C.3 step 1) (8.00 g, 24 mmol) and commercially available 3-amino-4-bromopyrazole (4.03 g, 24 mmol) as described in example C.1 step 2a to give the 3-bromo-5-(3-ethoxy-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (10.12 g, 91%) as a yellow solid. MS (ISP) 454.0 [(M+H)+] and 456.0 [(M+2+H)+].
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=3)[C:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].BrC1C=CC=CC=1.CO>C1(C)C=CC=CC=1.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].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.O>[CH2:24]([C:5]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]2[CH:3]=[CH:2][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: Brc1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccccc21
Temperature: 60 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a mixture of 9,9-di-n-octylfluorene-2,7-di(ethyleneboronate) (monomer (1)), R=n-octyl, 15.8 g, 29.49 mmol), 2,7-dibromo-9,9-di-n-octylfluorene (16.18 g, 29.49 mmol, (monomer (2)), R=n-octyl) in toluene (130 mL) under nitrogen is added Aliquat® 336 (1.5 g, 3.7 mmol), tetrakis(triphenylphosphine)palladium (0.18 g, 0.15 mmol), and 2M aqueous sodium carbonate (50 mL, 100 mmol). The mixture is stirred vigorously and heated at gentle reflux for 2 hours when a viscous reaction mixture is observed. An additional 50 mL of toluene is added and the reaction continued for another 15 hours. Sixty mL of toluene is then added to the very viscous reaction mixture and the heating and stirring are continued for 9 more hours. At the end of this period, the polymer is capped by adding 2 g of phenyl ethyleneboronate followed by heating for 15 hours, and one gram of bromobenzene followed by heating for 5 hours. The reaction mixture is cooled to about 60° C. and is added slowly to a stirred solution of 3 L of methanol and 300 mL of deionized water. The fibrous polymer is collected by filtration and is washed successively with methanol (500 mL), deionized water (200mL), and methanol (800 mL), and then dried in vacuum at 60° C. for 10 hours. The polymer weighed 23 g (100% yield). The inherent viscosity of the polymer is 1.50 dL/g. Molecular weight measurement by gel permeation chromatography shows a Mw of 148,00 g/mole, Mn of 47,980 g/mole relative to polystyrene standards. The spectral characteristics of the polymer are consistent with the structure: ##STR7##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:4]=1[OH:10].Br[CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+].O>OCC(CO)O.[Cu]>[CH3:1][O:2][C:3]1[C:4]2[O:10][CH2:13][CH2:12][O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc(O)c1O
Reactant: BrCCBr
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: OCC(O)CO
Product: COc1cccc2c1OCCO2
Temperature: 110 °C

Procedure:
A heterogeneous mixture containing 1.42 mol of 3-methoxycatechol, 1.57 mol of 1,2-dibromoethane, 1.42 mol of potassium carbonate and 4 g of copper powder in 150 ml of glycerol is heated at 110° C. for 15 hours. After cooling, the mixture is poured into 1 l of water. The aqueous phase is extracted with ethyl ether. The ether phases are then washed with 1N sodium hydroxide, dried and evaporated, and give the expected product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=1>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]([CH:8]=[O:9])=[CH:6][N:7]=1
Reactant: OCc1cnc(Cl)cc1Nc1ccccc1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cnc(Cl)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
MnO2 (39 g, 448 mmol) was added to a solution of (6-chloro-4-phenylamino-pyridin-3-yl)-methanol (13 g, 56 mmol) in CH2Cl2 (100 ml) and the mixture was stirred at RT overnight. The solids was removed by filtration and the filtrate was concentrated to give 6-chloro-4-(phenylamino)nicotinaldehyde (11 g, 86% yield). 1H-NMR (400 MHz, DMSO-d6): δ 10.18 (s, 1H), 9.99 (s, 1 H), 8.62 (s, 1 H), 7.49-7.31 (m, 5 H), 6.80 (s, 1 H).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:12][CH:13]=[CH2:14])=O)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[F:17][C:16]([F:18])([F:19])[C:15]([N:11]([CH2:12][CH:13]=[CH2:14])[CH2:10][CH2:9][NH2:8])=[O:20]
Reactant: C=CCN(CCNC(=O)OC(C)(C)C)C(=O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCN(CCN)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolve N-(t-butyloxycarbonyl)-N'-(trifluoroacetyl)-N'-(allyl)-ethylenediamine (1.95 mmol) in methylene chloride (7 mL) and add trifluoroacetic acid (2.6 mL). Stir at room temperature for 1 hour then evaporate the solvent in vacuo to give N'-(trifluoroacetyl)-N'-(allyl)-ethylenediamine trifluoroacetate
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:12]([NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)C1C=CC=CC=1.CO.[H][H]>[Pd].CCOC(C)=O>[C:32]([NH:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:23][C:12]2[C:11]([NH2:10])=[CH:16][CH:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:13]=2)=[O:35])=[CH:26][CH:27]=1)(=[O:34])[CH3:33]
Reactant: [H][H]
Reactant: CC(=O)Nc1ccc(C(=O)Nc2nc(-c3ccccc3)ccc2NC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)Nc1ccc(C(=O)Nc2nc(-c3ccccc3)ccc2N)cc1

Procedure:
A solution of benzyl(2-{[4-(acetylamino)benzoyl]amino}-6-phenylpyridin-3-yl)carbamate from the previous step (30 mg theoretical, 0.0626 mmol) and MeOH (100 uL) were treated with 10% palladium on carbon (cat) and the reaction was fitted with a hydrogen balloon. After one hour the reaction was diluted with EtOAc, filtered through celite and concentrated to a residue purified via reversed phase HPLC (30-70% MeCN in water with 0.05% TFA) to afford fractions concentrated via sublimation to afford the title compound as a light yellow solid and a TFA salt. 1H NMR (MeOH-d4, 600 MHz) δ 8.04 (d, J=8.8 Hz, 2H), 7.87 (d, J=7.3 Hz, 2H), 7.76 (t, 8.2 Hz, 3H), 7.62 (d, J=8.5 Hz, 1H), 7.51 (t, J=7.6 Hz, 2H), 7.45 (d, J=7.3 Hz, 1H), 2.18 (s, 3H); MS cal'd (M+H)+, exp 347 (M+H)+. The in vitro HDAC1 IC50 of this compound is 86 nM. The IC50 of this compound in HCT-116 cells is 2050 nM.