Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.[CH2:64]([CH:66]1[CH2:71][CH2:70][CH2:69][CH2:68][NH:67]1)[CH3:65].CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:28][CH:29]=2)[CH:13]=[C:14]([N:67]2[CH2:68][CH2:69][CH2:70][CH2:71][CH:66]2[CH2:64][CH3:65])[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCC1CCCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(N2CCCCC2CC)c1
Temperature: 100 °C

Procedure:
To a solution of 4-methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester, 1g (250 mg, 0.49 mmol) in toluene (5 mL) in a sealed tube was added racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (59 mg, 0.15 mmol), Pd(OAc)2 (110 mg, 0.49 mmol), 2-ethyl-piperidine (83 mg, 0.73 mmol). The system was flushed with nitrogen. To this was added NaOtBu (70 mg, 0.73 mmol) and heated to 100° C. for 3 h. The system was cooled to room temperature and quenched by slow addition of water. The mixture was extracted with EtOAc (3×20 mL). The organic phase was washed with saturated NaHCO3 solution and brine. The organic fraction was dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by ISCO column chromatography to obtain 2-[5-(2-ethyl-piperidin-1-yl)-4′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid ethyl ester. Calcd for C28H36F3NO2 (M+H) 476.59, Found 476.38.
Reaction SMILES: [CH2:1]([N:3]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17](/[N:20]=[CH:21]/[C:22]4[O:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)=[CH:16][C:15]=3[F:30])[CH2:10][CH2:9]2)[O:5][C:4]1=[O:31])[CH3:2].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[CH2:1]([N:3]1[N:7]=[C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][CH2:21][C:22]4[O:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)=[CH:16][C:15]=3[F:30])[CH2:12][CH2:13]2)[O:5][C:4]1=[O:31])[CH3:2]
Reactant: CCn1nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)oc1=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCn1nc(C2CCN(c3ccc(NCc4ccc([N+](=O)[O-])o4)cc3F)CC2)oc1=O
Yield: 82.8 %

Procedure:
3-Ethyl-5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9 g, 0.43 g, 1 mmol) on reduction with sodiumcyanoborohydride (0.12 g, 2 mmol) in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 12 h. After completion of the reaction as indicated by TLC, the reaction mixture is neutralized with sodium bi carbonate and extracted into chloroform. The crude product thus obtained was purified by column chromatography using ethyl acetate-hexane (8:2) as eluant to obtain product 3-ethyl-5-[1-(2-fluoro-4-[(5-nitro-2-furyl)methyl]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadi azol-2-one (10g, 357 mg, 83%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].[C:18]([O:22][C:23]1[C:32]([CH:33]=O)=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[C:18]([O:22][C:23]1[C:32]([CH2:33][N:15]2[CH2:14][CH2:13][CH:12]([C:10](=[O:11])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[CH3:2])[CH2:17][CH2:16]2)=[N:31][C:30]2[C:25]([N:24]=1)=[CH:26][CH:27]=[CH:28][CH:29]=2)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccccc1CC(=O)C1CCNCC1
Reactant: CC(C)(C)Oc1nc2ccccc2nc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccccc1CC(=O)C1CCN(Cc2nc3ccccc3nc2OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 63 %

Procedure:
After suspending 183 mg of 2-(2-methylphenyl)-1-(piperidin-4-yl)ethanone hydrochloride in 3 ml of dichloromethane, 150 mg of 2-tert-butoxyquinoxaline-3-carboxaldehyde and 180 mg of sodium triacetoxyborohydride were added while stirring, and the stirring was continued overnight at room temperature. Aqueous sodium bicarbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain 1-[1-(3-tert-butoxy-2-quinoxalinylmethyl)piperidin-4-yl]-2-(2-methylphenyl)ethanone (177 mg, 63% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:9]#[N:10])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: N#Cc1c(Cl)nc(N)nc1OCc1ccccn1
Reactant: OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCc2ccccc2)nc(N)nc1OCc1ccccn1

Procedure:
From 2-amino-4-chloro-6-(pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile, benzyl alcohol and DBU in DME. ES-MS m/e (%): 356 (MNa+, 50), 334 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[N:18]2.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[N:18]3)[C:9]1=[O:13]
Reactant: Brc1ccc2nccnc2c1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3nccnc3c2)C1=O
Yield: 67.7 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84650 mmol) was reacted with 6-bromo-quinoxaline (176.9 mg, 0.84650 mmol), 1,4-dioxane (20 mL), copper iodide (16 mg, 0.084650 mmol), trans-1,2-diamino cyclohexane (29 mg, 0.2539 mmol) and potassium phosphate (538 mg, 2.539 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in DCM) afforded 175 mg of the product (67.8% yield).
Reaction SMILES: [Na+].[I-:2].[N:3]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12]Cl)=[O:10])[CH2:5][CH2:4]1>C(#N)C>[N:3]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH:6]([C:9]([O:11][CH2:12][I:2])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCCl)CC1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCI)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94 %

Procedure:
To a solution of NaI (1.6 g, 11.09 mmol) in dry acetonitrile (8 mL) was added dropwise 1-tert-butyl 4-chloromethyl piperidine-1,4-dicarboxylate (2.8 g, 10.08 mmol) in 2 mL of acetonitrile. The mixture turned dark orange and was stirred at rt in the dark for 24 h. The reaction mixture was filtered to remove NaCl and the filtrate was concentrated in vacuo. The remaining residue was partitioned between DCM and 5% aq NaHSO3 solution. The organic layer was washed with water and brine, dried (Na2SO4), and concentrated in vacuo to give 1-tert-butyl 4-iodomethyl piperidine-1,4-dicarboxylate as a pale yellow oil (3.5 g, 94%). Attempts to characterize by NMR in DMSO-d6 resulted in rapid decomposition. The material was stored in the dark at −20° C. to minimize decomposition before further use. LCMS: MH=370.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[CH:12][N:11]=1>C(O)CCC>[Cl:9][C:10]1[N:11]=[CH:12][N:13]=[C:14]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=2)[CH:15]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1cccc(N)n1
Solvent: CCCCO
Product: Nc1cccc(Nc2cc(Cl)ncn2)n1
Temperature: 100 °C
Yield: 32.7 %

Procedure:
A mixture of 2,6-diaminopyridine (1.530 g, 14.020 mmol) and 4,6-dichloropyrimidine (2.610 g, 17.519 mmol) in 15 mL of n-butanol in a sealed vial was heated at 100° C. for 72 h. The dark brown sample was cooled and was concentrated at reduced pressure to remove most of the n-butanol. The residue was then partitioned between EtOAc and saturated. NaHCO3 solution. An emulsion formed, the sample was filtered through a pad of Celite and the layers were separated. The organic extract was washed with sat. KH2PO4 and brine solutions, dried (MgSO4), filtered and concentrated to brown oily-solid. The sample was suspended into ˜50 mL of CH2Cl2, cooled and filtered to give 1.017 g (36%) of N-(6-chloro-pyrimidin-4-yl) -pyridine-2,6-diamine as yellow-orange solid. MS: m/z 222/224 (M+1, 100/63%). To a solution of N-(6-chloro-pyrimidin-4-yl)-pyridine-2,6-diamine (100 mg, 0.45 mmol) in DMF (1 mL) was added 3-methylphenol (88 mg, 0.8 mmol) and anhydrous K2CO3 (93 mg, 0.6 mmol). The reaction mixture was heated at 145° C. for 16 h. It was then cooled and DMF was removed under reduced pressure to get a yellow gummy residue. The residue was taken in EtOAc (20 mL), was washed sequentially with water (5 mL) and brine (5 mL) and was dried over Na2SO4. Filtration followed by concentration under reduced pressure afforded a yellow gum which was further purified by column chromatography (SiO2, 60-120, EtOAc/hexane, 5/5) to give 100 mg of 2-[6-(3-methylphenoxy)-pyrimidin-4-yl]amino-6-aminopyridine (IR-12) as a pale yellow solid. MS: m/z 294 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]3C(=O)C(=O)O[C:9]32[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]=[C:9]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: O=C1OC2(C3CCCCC3)c3cc(Cl)ccc3CCN2C1=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: Clc1ccc2c(c1)C(C1CCCCC1)=NCC2
Yield: 96.9 %

Procedure:
9-chloro-10b-cyclohexyl-6,10b-dihydro-5H-[1,3]oxazolo[2,3-a]isoquinoline-2,3-dione (2.37 g) was dissolved in MeOH (16 mL), and a solution of sulfuric acid (8 mL) in MeOH (24 mL) was added thereto, followed by stirring under heating at reflux for 18 hours. The reaction mixture was left to cool and then the solvent was evaporated. The reaction mixture was neutralized by an aqueous 1 M sodium hydroxide solution, extracted with chloroform, washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and then the resulting residue was dried to obtain 7-chloro-1-cyclohexyl-3,4-dihydroisoquinoline (1.78 g).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:19].ON1C2C=CC=CC=2N=N1.[C:30]([C:33]1[N:34]=[CH:35][C:36]2[NH:37][C:38]3[C:43]([C:44]=2[CH:45]=1)=[CH:42][CH:41]=[CH:40][CH:39]=3)(O)=[O:31].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[CH:35]1[C:36]2[NH:37][C:38]3[C:43]([C:44]=2[CH:45]=[C:33]([C:30]([C:2]2([NH2:1])[CH2:8][CH2:7][C:6]4[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=4[N:4]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:3]2=[O:19])=[O:31])[N:34]=1)=[CH:42][CH:41]=[CH:40][CH:39]=3
Reactant: NC1CCc2ccccc2N(c2ccccc2)C1=O
Reactant: O=C(O)c1cc2c(cn1)[nH]c1ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC1(C(=O)c2cc3c(cn2)[nH]c2ccccc23)CCc2ccccc2N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
In 15 ml of dimethylformamide were dissolved 0.252 g of 3-amino-1-phenyl-2,3,4,5-tetrahydro-1-benzoazepin-2(1H)-one, 0.127 g of 1-hydroxybenzotriazole, 0.223 g of 3-carboxy-β-carboline and 0.2 g of 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride and 0.5 ml of triethylamine was added to the solution, and the mixture was stirred at room temperature for one day. After the solvent was removed under reduced pressure, a 10% aqueous citric acid and chloroform were added to the residue and the mixture was stirred. Thereafter, the chloroform layer was separated, washed with a 10% sodium hydroxide aqueous solution and then with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and ethyl acetate was added to the residue. The precipitates were collected by filtration to obtain 0.312 g of the title compound as crystals. Melting point: 302° to 304° C., IR (Nujol) (cm-1): 3360, 3290, 1730, 1670, 1650, 1625, MS (m/z): 446 (M+), 264 (base)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[CH:6]=[CH:7]/[C:8]1[O:9][C:10]2[C:11](=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][CH:16]=2)[N:12]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[CH:6]=[CH:7]/[C:8]1[O:9][C:10]2[C:11](=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][CH:16]=2)[N:12]=1
Reactant: COC(=O)c1cccc2oc(/C=C/c3ccc(OC)c(OC)c3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(/C=C/c2nc3c(C(=O)O)cccc3o2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a stirred solution of (E)-methyl 2-(3,4-dimethoxystyryl)benzo[d]oxazole-4-carboxylate (240 mg, 0.71 mmol) in THF (10 mL) and MeOH (5 mL) was added 2 N NaOH solution (1.77 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for two hours then quenched with a 1N HCl solution. The mixture was then extracted with DCM and the organic phase was washed with saturated aqueous NaCl solution and dried over sodium sulfate. The solvent was then removed under reduced pressure to give (E)-2-(3,4-Dimethoxystyryl)benzo[d]oxazole-4-carboxylic acid (170 mg, 74%). 1H-NMR (400 MHz, DMSO-d6) δ 3.81 (s, 3H), 3.85 (s, 3H), 7.03 (d, J=8.0 Hz, 1H), 7.33-7.39 (m, 2H), 7.46 (app t, J=8.0 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.80 (d, J=16.0 Hz, 1H), 7.87 (dd, J=8.0, 1.2 Hz, 1H), 7.93 (dd, J=8.0, 1.2 Hz, 1H); LC-MS (ES-API): rt 8.88 min; m/z calculated for C18H15NO5 [M−H]− 324.1, found 324.1.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([C:12]1[C:20]2[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=2)[NH:14][CH:13]=1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.[C-:25]#[N:26].[K+]>CS(C)=O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH:4]([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23][CH3:24])[CH:17]=[C:18]([F:21])[CH:19]=3)[NH:14][CH:13]=2)[CH2:3][CH2:2][C:25]#[N:26])=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: CSCc1cc(F)cc2c(C(CCCl)c3ccc(Cl)cc3)c[nH]c12
Agent: [K+]
Solvent: CS(C)=O
Product: CSCc1cc(F)cc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
180 mg (0.47 mmol) of 3-[3-chloro-1-(4-chlorophenyl)propyl]-5-fluoro-7-[(methylsulfanyl)methyl]-1H-indole and 61.3 mg (0.94 mmol) of potassium cyanide were dissolved in 11 ml of DMSO and stirred at 120° C. overnight. The mixture was concentrated, and the residue was taken up in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in a further 140 mg (80% of theory) of the title compound and thus in an overall yield of the title compound of 242 mg (64% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][C:22]([O:24]CC)=[O:23])[CH:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1.[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]=[C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:21][C:22]([OH:24])=[O:23])[CH:17]=3)[O:13][N:12]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)Cn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cn1ccc(-c2nc(N3CCC(Oc4cc(F)ccc4Br)CC3)no2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl (3-{3-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]-1,2,4-oxadiazol-5-yl}-1H-pyrrol-1-yl)acetate (35 mg, 0.071 mmol) in THF (236 μL) and MeOH (118 μL) was added 1N NaOH (142 μL, 0.142 mmol). The mixture was stirred at RT for 10 min. The THF and MeOH were removed by evaporation under diminished pressure and the aqueous layer was washed with Et2O (2×2 mL). The aqueous layer was acidified to pH 1 with 1N HCl and extracted with EtOAc (3×2 mL). The combined organic fractions were dried over Na2SO4 and the solvent was evaporated to afford the title compound.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[N:16]=2)[CH2:11][CH:10]1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:35].[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([CH:10]2[CH2:11][N:12]([C:15]3[N:20]([CH3:21])[C:19](=[O:22])[CH:18]=[C:17]([C:23]4[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=4)[N:16]=3)[CH2:13][CH2:14][NH:9]2)=[CH:34][CH:33]=1
Reactant: Cn1c(N2CCN(C(=O)OC(C)(C)C)C(c3ccc(Cl)cc3)C2)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: Cn1c(N2CCNC(c3ccc(Cl)cc3)C2)nc(-c2ccncc2)cc1=O
Yield: 178.3 %

Procedure:
4N Hydrogen chloride in ethyl acetate was added to the solution of 2-(1-(tert-butoxycarbonyl)-2-(4-chlorophenyl)-piperazine-4-yl)-3-methyl-6-(4-pyridyl)pyrimidin-4-one (500 mg, 1.0 mmol) in ethyl acetate and stirred. Filtration and successive dryness gave the title compound (373 mg, 79%).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]=[CH:3][CH:2]=1.[OH-].[K+].I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)C=O>[CH2:34]([N:7]([C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][N:4]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:13]=1)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17]
Reactant: c1ccc(Nc2ccccn2)nc1
Reactant: CCCCCCCCCCCCCCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCN(c1ccccn1)c1ccccn1
Reaction time: 1 h

Procedure:
To a flask were added 1.0 g 2,2′-dipyridylamine, 1.0 g of pulverized potassium hydroxide and 15 ml of N,N-dimethylformamide. After stirring for 1 hour under nitrogen, the mixture was cooled to 5 C and 2.2 g of 1-iodooctadecane were added. The mixture was allowed to warm to 22 C and stirred for 16 hours, then heated to 40 C for 2 hours. After quenching with 25 ml water and cooling to 22 C, the product was filtered and washed with water. The product was dissolved in 25 ml hot ethanol with 100 mg activated carbon, stirred for 30 minutes and filtered through celite. After adding 25 ml water and cooling to 5 C, the product was filtered, washed with water and dried leaving 2.1 g light yellow solid.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.Br[CH:18]([CH3:27])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20]>C(O)C>[ClH:3].[ClH:1].[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:18]([C:19](=[O:20])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:27])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: Clc1ccc(CN2CCNCC2)cc1
Agent: Cl
Solvent: CCO
Product: CC(C(=O)c1ccccc1)N1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 146.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)piperazine dihydrochloride (5 g, 20 mmol), anhydrous KHCO3 (70 mmol) and 2-bromo-1-phenylpropan-1-one (3.96 ml, 26 mmol) in 40 ml of anhydrous ethanol was refluxed for 8 hours, and then treated according to general preparation 2 to give 6.1 g of compound (IV-2), yield 59.51%, mp 260-262° C. M+ 342.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:10]2[CH2:14][O:13][C:12](=[O:15])[C:11]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].BrCC(C1C=CC(OC)=C(C=1)[C:43]#[N:44])=O>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[CH2:14][O:13][C:12](=[O:15])[C:11]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:3][C:2]=1[C:43]#[N:44]
Reactant: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2)cc1Cl
Reactant: COc1ccc(C(=O)CBr)cc1C#N
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2)cc1C#N

Procedure:
Following the procedure for the preparation of 4-(3-chloro-4-methoxyphenyl)-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one-using 5-(2-bromoacetyl)-2-methoxybenzonitrile provided the title compound. 1H NMR (500 MHz, d6-DMSO): δ 8.32-8.28 (m, 1H), 8.06-7.95 (m, 2H), 7.81-7.76 (m, 2H), 7.62-7.56 (m, 1H), 7.49-7.39 (m, 2H), 7.26-7.18 (m, 3H), 7.12-7.05 (m, 2H), 5.41 (s, 2H), 5.33 (s, 2H), 3.89 (s, 3H). MS: M+H: m/z=449.0. HPLC: 91%, (Condition-H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1nc2cc(Br)ccc2cc1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)(C)O
Product: CCOC(=O)c1nc2cc(N3CCOCC3)ccc2cc1NC(=O)OCc1ccccc1
Temperature: 100 °C
Yield: 98.4 %

Procedure:
A mixture of ethyl 3-{[(benzyloxy)carbonyl]amino}-7-bromoquinoline-2-carboxylate (300 mg, 0.7 mmol), morpholine (120 mg, 1.4 mmol), Pd(OAc)2 (20 mg), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (49 mg, 0.10 mmol), and K3PO4 (580 mg, 2.8 mmol) in tert-butanol (10 mL) in a sealed vial was purged with nitrogen then heated at 100° C. for 1 h. The solution was allowed to cool then and diluted with EtOAc, and the mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography on 40 g of silica gel, eluting with 0-100% EtOAc in hexanes, to give the sub-title compound (0.3 g, 20%). LCMS (ESI) calc. for C24H26N3O5 [M+H]+: m/z=436.2. found: 436.1.