Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12](=[O:15])[S:13][CH:14]=2)=[CH:6][CH:5]=1.Cl.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].CC(CC(C)C)=O>[F:32][C:18]([F:17])([F:31])[C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([C:10]4[NH:11][C:12](=[O:15])[S:13][CH:14]=4)=[CH:6][CH:5]=3)[CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=c1[nH]c(-c2ccc(CCCl)cc2)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC(=O)CC(C)C
Product: O=c1[nH]c(-c2ccc(CCN3CCN(c4cccc(C(F)(F)F)c4)CC3)cc2)cs1
Yield: 23 %

Procedure:
To a 35 ml round-bottomed flask equipped with condenser and N2 inlet were added 1.89 g (7.89 mmol) of 4-(4-(2-chloroethyl)phenyl)thiazol-2-one, 2.10 g (7.89 mmol) of N-(3-trifluoromethylphenyl)piperazine hydrochloride, 2.20 ml (15.8 mmol) of triethylamine, 0.84 g (7.89 mmol) of sodium carbonate, 2 mg of sodium iodide, and 20 ml of methylisobutylketone. The reaction was heated at reflux for 6 days, cooled, and evaporated. The residue was taken up in ethyl acetate/water, the layers separated, and the ethyl acetate layer washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using ethyl acetate/methylene chloride as eluent. The product fractions were evaporated, and the residue triturated with ether, taken up in hot ethyl acetate, treated with ethyl acetate saturated with hydrochloride, precipitated with ether, filtered, washed with ether, and dried to give 0.787 g (20%) of a white solid, m.p. 285°-287° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:23][O:24][C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:26]=1[NH:40][C:41](=[O:43])[CH3:42]>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(#N)C>[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[N:3][C:2]([C:29]4[CH:28]=[CH:27][C:26]([NH:40][C:41](=[O:43])[CH3:42])=[C:25]([O:24][CH3:23])[CH:30]=4)=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:16][CH2:15]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(C)=O
Reactant: Clc1ccc(N2CCN(C3CC3)CC2)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2ccc(N3CCN(C4CC4)CC3)nn2)ccc1NC(C)=O

Procedure:
The title compound was prepared from 3-chloro-6-(4-cyclopropyl-piperazin-1-yl)-pyridazine (4.6 g, 19.3 mmol), 1 M sodium carbonate solution (50 mL, 100.5 mmol), acetonitrile (50 mL), bis(triphenylphosphine)palladium(II) chloride (0.68 g, 0.96 mmol) and N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (6.73 g, 23.1 mmol), yield 3.39 g (40%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.CCCC[Sn]([C:27]1[N:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(CCCC)CCCC>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][N:32]=2)[C:11]=1[CH3:12]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Cc1c(Cl)nc2ncccc2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2ncccc2c1Cl
Temperature: 25 °C

Procedure:
Prepared according to procedure E by using 2,4-dichloro-3-methyl-1,8-naphthyridine (540 mg, 2.53 mmol), 2-(1,1,1-tributylstannyl)pyridine (933 μL, 2.53 mmol), Pd(PPh3)4 (293 mg, 0.253 mmol) in toluene (10 mL) at reflux for 14 h. After this time the reaction was allowed to cool to rt and evaporated in vacuo. The resulting residue was triturated with hexanes and the solid was dried under vacuum to give 4-chloro-3-methyl-2-(pyridin-2-yl)-1,8-naphthyridine.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[N:12][C:13]([N+:16]([O-])=O)=[CH:14][CH:15]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>CCO.[Pd]>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12][CH:11]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)N1CCN(c2ccc(N)nc2)CC1
Reaction time: 18 h
Yield: 61.2 %

Procedure:
In a 250 mL round-bottomed flask, 1-isopropyl-4-(6-nitropyridin-3-yl)piperazine (788 mg, 3.15 mmol, Eq: 1.00) in EtOH (40 ml) was combined with palladium on carbon (DeGussa)(78.2 mg, 735 μmol, Eq: 0.233). The mixture was evacuated twice with hydrogen and then stirred under a hydrogen atmosphere for 18 h. The solution was filtered through celite, rinsing the celite with fresh ethanol. The solvent was evaporated under reduced pressure to give 5-(4-isopropylpiperazin-1-yl)pyridin-2-amine (425 mg, 61%). LC/MS-ESI observed [M+H]+ 221.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=1.[CH2:19](O)[CH3:20]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:10]=1
Reactant: CCO
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
The 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid (1.0 g, 4.0 mmol) was dissolved in ethanol (30 mL) and sulfuric acid (8 mL). The solution was stirred (80° C., 18 h) and then concentrated. The residue was dissolved in ethyl acetate and washed with water, brine and dried over MgSO4. Solvent evaporation afforded 1.0 g of ethyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate. Mass calculated for C15H12F2O3=278.25. found: [M+H]+=279.1.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].Br[CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O.CCOC(C)=O>[Cl:17][C:15]1[CH:16]=[C:11]([CH:12]=[C:13]([Cl:18])[CH:14]=1)[CH2:10][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: Clc1cc(Cl)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 60 °C
Yield: 91 %

Procedure:
To a solution of 2-nitroimidazole and 1-bromomethyl-3,5-dichloro-benzene in anhydrous DMSO was added Na2CO3. The reaction mixture was heated to 60° C. for 6 h. The reaction mixture was then diluted with EtOAc and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 98:2 CH2Cl2:MeOH to afford 1-(3,5-dichloro-benzyl)-2-nitro-1H-imidazole (0.66 g, 91%).
Reaction SMILES: [CH2:1]([S:7][CH2:8][C:9]([O:11]C1C=CC([N+]([O-])=O)=CC=1)=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.OCC1C=C(C=CC=1)OCCC[NH2:30]>O1CCCC1>[CH2:1]([S:7][CH2:8][C:9]([NH2:30])=[O:11])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CSCc1ccco1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCOc1cccc(CO)c1
Solvent: C1CCOC1
Product: NC(=O)CSCc1ccco1
Reaction time: 18 h

Procedure:
p-Nitrophenyl 2-(furfurylthio)acetate (6.5 g) was dissolved in 200 ml of tetrahydrofuran, and under ice cooling, 75 ml of a tetrahydrofuran solution of 4 g of 3-(3-hydroxymethylphenoxy)propylamine was added dropwise to the solution. One hour later, the temperature was returned to room temperature, and the mixture was stirred for 18 hours. The solvent was concentrated, and the concentrate was taken into ethyl acetate, washed with a 1N aqueous solution of sodium hydroxide and water, and dried. The solvent was evaporated to give 7.02 g (94.9%) of N-3-(3-hydroxymethylphenoxy)propyl]-2-(furfurylthio)acetamide.
Reaction SMILES: [N+:1]([C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:12])([O-:3])=[O:2].C(=O)(O)[O-].[Na+].[I:18]I>>[I:18][C:6]1[C:5]([OH:12])=[C:4]([N+:1]([O-:3])=[O:2])[C:9]([O:10][CH3:11])=[CH:8][CH:7]=1
Reactant: COc1cccc(O)c1[N+](=O)[O-]
Reactant: II
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(I)c(O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A mixture of 1.36 g (8 mmol) of the product of Step 1 and 0.68 g (8 mmol) of sodium bicarbonate was sonicated at room temperature until it become homogenous. The resulting mixture was cooled to 0° C. and 2.04 g (8 mmol) of iodine was added. After stirring for 1 h at room temperature the precipitate formed was filtered off, dried and recrystallized from ethyl ether to give 2.28 g (96% yield of pure title compound as an orange crystals; 1H NMR (CDCl3) 3.92 (s, 3H, OMe); 6.41 (d, 1H, CH J=9 Hz); 7.82 (d, 1H, J=9 Hz); 10.37 (s, 1H, OH).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]#[N:14])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Br[CH2:18][CH2:19]Br>CS(C)=O>[Cl:1][C:2]1[C:11]([C:12]2([C:13]#[N:14])[CH2:19][CH2:18]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrCCBr
Reactant: COC(=O)c1cccc(CC#N)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CC2)c1Cl
Yield: 35 %

Procedure:
Using Methyl 2-chloro-3-(cyanomethyl)benzoate (2.00 g, 9.54 mmol), sodium hydride (60% in oil, 1.14 g, 28.6 mmol), 1,2-dibromoethane (1.18 mL, 14.3 mmol) and dimethyl sulfoxide (20 mL) as starting materials, and in the same manner as in Example A1(ii), the title compound (787 mg, 35%) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:3]1.NN>CO.[Ni]>[CH3:8][CH:6]1[NH:7][CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5]1
Reactant: CC1CN(c2ccc([N+](=O)[O-])cc2)CC(C)N1
Agent: [Ni]
Agent: NN
Solvent: CO
Product: CC1CN(c2ccc(N)cc2)CC(C)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
3,5-Dimethyl-1-(4-nitro-phenyl)-piperazine (1.40 g, 5.90 mmol) is dissolved in 20 ml of methanol with ˜1 g of Raney nickel suspension. Hydrazine (0.576 g, 14.9 mmol) is dissolved in 20 ml of methanol and added dropwise to the reaction mixture over 20 minutes. Mixture is stirred at room temperature for 3 hours. Mixture is filtered through celite and reduced on rotovap to afford the product as a black solid (1.05 g, 67%); 1H NMR (DMSO-d6) δ 0.94 (d, J=6.3 Hz, 6H), 1.93-2.00 (m, 2H), 2.65-2.85 (m, 3H), 3.13-3.20 (m, 2H), 4.45 (bs, 2H), 6.43 (d, J=8.5 Hz, 2H), 6.61 (d, J=8.5 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:3]1=[CH2:4].[N:14]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[OH:26])=O>C(O)C>[CH3:12][N:5]1[C:3]2([O:26][C:17]3[CH:18]=[CH:19][C:20]4[C:25]([C:16]=3[N:14]=[CH:4]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:2]([CH3:13])([CH3:1])[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: O=Nc1c(O)ccc2ccccc12
Reactant: C=C1N(C)c2ccccc2C1(C)C
Solvent: CCO
Product: CN1c2ccccc2C(C)(C)C12C=Nc1c(ccc3ccccc13)O2

Procedure:
A mixture 1,3-dihydro-1,3,3-trimethyl-2-methyleneindoline (3.62 g; 0.021 mol) and 1-nitroso-2-naphthol (3.46 g; 0.02 mol) in ethanol (80.0 ml) was heated under reflux for 2 h. The solution was evaporated and the residue flash-chromatographed over silica (dichloromethane) to give 1,3-Dihydro-1,3,3-trimethylspiro[2H-indole-2,3'-3H-naphtho[2,1-b][1,4]oxazine] as a pale yellow solid (3-96 g; 60%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[C:7]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)#[N:8].N1C=CC=CC=1>C(Cl)Cl>[C:7]([C:9]1[CH:15]=[CH:14][C:12]([NH:13][C:4](=[O:5])[CH2:3][CH2:2][Cl:1])=[CH:11][CH:10]=1)#[N:8]
Reactant: O=C(Cl)CCCl
Reactant: N#Cc1ccc(N)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(NC(=O)CCCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
3-Chloropropionylchloride (1.08 g; 8.5 mmol) was added to a cooled (10° C.) solution of 4-cyanoaniline (1.0 g; 8.5 mmol) and pyridine (0.69 mL; 8.5 mnol) in DCM (40 mL), and the reaction mixture was stirred at rt. for 1 h. The reaction mixture was extracted with HCl (2N), washed with water, dried and concentrated to give the sub-title compound in a 81% yield.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][C:14]1[O:19][CH2:18][N:17]([C:20]([CH3:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:16](=[O:29])[C:15]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCOCC>ClCCl>[CH:13]([C:14]1[O:19][CH2:18][N:17]([C:20]([CH3:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:16](=[O:29])[C:15]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:12]
Reactant: CC(C)(c1ccccc1)N1COC(CO)=C(c2ccccc2)C1=O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(c1ccccc1)N1COC(C=O)=C(c2ccccc2)C1=O
Reaction time: 9 h
Yield: 95.7 %

Procedure:
Pyridinium chlorochromate (4.70 g) was suspended in dichloromethane (20 ml), and a dichloromethane solution (27 ml) of 6-hydroxymethyl-3-(1-methyl-1-phenylethyl)-5-phenyl-2,3-dihydro-4H-1,3-oxazin-4-one (Compound No. 53, 4.70 g) was added thereto at room temperature. After stirring for about 9 hours, a large amount of ether was added and separated by decantation. The organic layer was dried with magnesium sulfate and the solvent was evaporated. The crude product was purified by silica gel chromatography to afford the captioned compound (4.47 g, yield 96%).
Reaction SMILES: C1(=O)O[CH:4]=[CH:3]O1.[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([C:13]([NH2:15])=[O:14])=[CH:9][CH:8]=1>O>[CH3:16][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][CH:3]=[CH:4][N:15]=2)=[CH:9][CH:8]=1
Reactant: O=c1occo1
Reactant: Cc1ccc(C(N)=O)cc1
Solvent: O
Product: Cc1ccc(-c2ncco2)cc1
Temperature: 170 °C
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
Polyphosphoric acid (20 g), vinylene carbonate (5.73 mL, 90.0 mmol) and p-toluamide (12.2 g, 90.0 mmol) were combined and heated at 170° C. for 2 h. The reaction mixture was allowed to cool to ˜80° C., water (˜100 mL) was carefully added, and stirred for ˜10 min. This mixture was extracted three times with ethyl acetate, combined organic extracts were dried with Na2SO4, and concentrated in vacuo. Purification by medium pressure liquid chromatography (SiO2, 97:3 hexanes/acetone) gave 6.41 g (45%) of the title compound. MS 160 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([Cl:34])[CH:33]=1)[CH2:30][C:29](=O)[CH2:28][CH2:27]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:29]2[CH2:28][CH2:27][C:26]3[C:31](=[C:32]([Cl:34])[CH:33]=[C:24]([Cl:23])[CH:25]=3)[CH2:30]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: O=C1CCc2cc(Cl)cc(Cl)c2C1
Product: CCCC(NC1CCc2cc(Cl)cc(Cl)c2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6,8-dichloro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.5, 19.6, 24.3, 26.6, 26.6, 26.7, 28.5, 29.5, 34.0, 34.7, 36.6, 52.5, 53.2, 56.0, 59.1, 59.2, 60.1, 60.8, 67.3, 104.8, 126.7, 127.2, 127.3, 131.1, 131.5, 131.7, 131.8, 131.9, 135.3, 137.3, 139.7, 140.0, 172.2, 172.4; MS m/z 506.4, 508.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:20])[CH:14]=[C:15]([NH2:19])[O:16][CH2:17][CH3:18])[CH3:11]>>[CH2:10]([O:12][C:13]([C:14]1[CH:6]([C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:14]([C:13]([O:12][CH2:10][CH3:11])=[O:20])[C:15]([O:16][CH2:17][CH3:18])=[N:19][C:15]=1[NH2:19])=[O:20])[CH3:11]
Reactant: CCOC(=O)C=C(N)OCC
Reactant: O=Cc1ccc(Cl)cc1
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1ccc(Cl)cc1
Yield: 56 %

Procedure:
Boiling a solution of 7.1 g of 4-chlorobenzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 50 ml of alcohol for 8 hours yields 2-amino-4-(4-chlorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 130°-132° C (ethyl acetate/petroleum ether). Yield: 56% of theory.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:13][C:14]1[S:18][C:17]([Sn](CCCC)(CCCC)CCCC)=[N:16][CH:15]=1.O.CCOC(C)=O>C1COCC1.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>[CH3:13][C:14]1[S:18][C:17]([C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N:16][CH:15]=1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncc(C)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(-c2ncc(C)s2)c1
Temperature: 75 °C

Procedure:
A mixture of commercially available ethyl 3-iodobenzoate (485 mg; 1.75 mmol), 5-methyl-2-(tributylstannyl)thiazole (685 mg; 1.76 mmol), and PdCl2(PPh3)2 (123 mg; 0.17 mmol) in anh. THF (10 ml) was heated to 75° C., under nitrogen, for 18 h. In order to complete this reaction, the resulting reaction mixture was then heated to 85° C. for 8 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded ethyl 3-(5-methylthiazol-2-yl)benzoate as an orange oil. LC-MS (conditions A): tR=0.88 min.; [M+H]+: 247.98 g/mol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[N:6][CH:7]=1.[F:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>>[F:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:32])[C:11]3[CH:16]=[CH:15][C:14]([CH2:17][N:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]4)=[CH:13][CH:12]=3)=[O:9])=[N:6][CH:7]=2)=[CH:36][CH:35]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Br)cn3)cc2)CCN1C(=O)OC(C)(C)C
Reactant: Nc1ccc(F)cc1
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Nc4ccc(F)cc4)cn3)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
The title compound was prepared 1,1-dimethylethyl (2S)-4-({4-[[(5-bromo-2-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D72) and 4-fluoroaniline using a method similar to that described for D58 in Description 58 although the reaction time was 18 h. MS (ES): MH+ 534.2.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].CCN(CC)CC.[C:17](Cl)(=[O:19])[CH3:18].NC1C=CC=CC=1>O.ClCCl>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:17](=[O:19])[CH3:18])[CH3:2]
Reactant: CCc1ccccc1N
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: Nc1ccccc1
Product: CCc1ccccc1NC(C)=O
Temperature: 0 °C
Yield: 57.9 %

Procedure:
2-ethylaniline (12.4 mL, 100 mmol) and NEt3 (15.4 mL, 110 mmol) were added to 100 mL of dichloromethane and cooled to 0° C. Acetyl chloride (7.10 mL 100 mmol) was added dropwise to the cooled aniline solution, affording a peach colored suspension after complete addition. The slurry was warmed to room temperature and heated to reflux overnight. The suspension was taken to dryness and the solid was treated with 200 mL of water. The solid was collected by filtration, washed with 200 mL of diethylether and dried in vacuo, yielding 9.45 g (58%) of white solid. 1H NMR (400 MHz, CDCl3): 7.68 (d, 1H), 7.26-7.11 (m, 4H), 2.59 (q, 2H), 2.18 (s, 3H), 1.22 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1B(O)O>>[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Reactant: OB(O)c1ccc(F)cc1F
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4ccc(F)cc4F)n3)cnc2n1

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidine (250 mg, 0.62 mmol) and 2,4-difluorobenzeneboronic acid (196 mg, 1.24 mmol) were reacted together as described in Example 61. Purification by column chromatography on silica using 2.5% MeOH/CH2Cl2 gave 3-[2-(2,4-difluorophenyl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine: m/z (ES+) 482 (M+H+).
Reaction SMILES: [C:1]1([C:11]([C:14]2[N:15]=[CH:16][N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=2)(O)[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)(=O)C.O>[C:1]1([C:11]([C:14]2[N:15]=[CH:16][NH:17][CH:18]=2)=[CH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(O)(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: C=C(c1c[nH]cn1)c1cccc2ccccc12

Procedure:
1-Naphthalen-1-yl-1-(1-trityl-1H-imidazol-4-yl)-ethanol (Intermediate H1) in acetic acid:water (˜2:1) was heated to 100° C. for 1 h. The mixture was basified with 1 M NaOH and extracted (6×) with CHCl3:iPrOH (3:1). The organic solution was dried over MgSO4, filtered, and concentrated onto silica gel. The material was eluted from a column of silica with 5% NH3-MeOH:CH2Cl2 to give 4-(1-naphthalen-1-yl-vinyl)-1H-imidazole.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[NH2:11][C:12]1[CH:13]=[C:14]([C:18](=[O:20])[CH3:19])[CH:15]=[CH:16][CH:17]=1.C(N(C(C)C)CC)(C)C>ClCCl>[C:18]([C:14]1[CH:13]=[C:12]([NH:11][CH:8]=[O:10])[CH:17]=[CH:16][CH:15]=1)(=[O:20])[CH3:19]
Reactant: O=CO
Reactant: CC(=O)c1cccc(N)c1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cccc(NC=O)c1
Temperature: 50 °C

Procedure:
A 25 ml portion of acetic anhydride was cooled at 0° C. in an ice bath. A 12.5 ml portion of formic acid was added, the mixture was heated at 50° C. for 15 minutes then cooled to 0° C., giving 9.69 g of crude mixed formicacetic anhydride. This anhydride was reacted with 13.52 g of m-aminoacetophenone, 14.21 g of diisopropylethylamine and 800 ml of dichloromethane as described in Example 1, giving 13.27 g of N-(3-acetylphenyl)formamide, mp 100°-102° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=12)=[O:5])[CH3:2].[CH3:20]I>CN(C=O)C.[Ag]=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:20])[C:11](=[O:19])[C:10]=12)=[O:5])[CH3:2]
Reactant: CI
Reactant: CCOC(=O)c1ncn2c1c(=O)[nH]c1ccccc12
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn2c1c(=O)n(C)c1ccccc12
Yield: 62.7 %

Procedure:
To a solution of 4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline 3-carboxylic acid ethyl ester (12.4 g) and methyl iodide (98 g) in DMF (1 liter) was added silver oxide (65 g) with stirring. The reaction mixture was stirred at room temperature for 18 hours. After removal of insoluble material the solution was evaporated under oil pump vacuum to dryness. The residue was extracted with chloroform several times. The combined chloroform extracts were washed with water, dried by magnesium sulfate, then evaporated under water aspirator vacuum to give the product as a white solid (8.2 g, 63% yield). Recrystallized from acetonitrile, m.p. 233°-236° C.