Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)c1ccccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A solution of [tert-Butoxycarbonylmethyl-(2-hydroxy-phenyl)-amino]-acetic acid tert-butyl ester (11) (7.4 g, 21.9 mmol) in dry THF (50 mL) was treated with sodium hydride (0.81 g, 33.8 mmol) at 0° C. under an Ar atmosphere. After stirring at 0° C. for 30 min, benzyl bromide (3.9 mL, 32.7 mmol) was added. The mixture was stirred at 0° C. for another 30 min and then warmed to room temperature overnight. The reaction mixture was quenched with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash column chromatography, eluting with CH2Cl2/hexane/EtOAc=1:4:0.2 to yield 6.3 g (67%) of the desired product 12 as a colorless oil. Rf=0.33 (in CH2Cl2/hexane/EtOAc=1:4:0.2); 1H NMR (300 MHz, CDCl3) δ 7.45-7.28 (m, 5H), 6.84 (m, 4H), 5.12 (s, 2H), 4.08 (s, 4H), 1.40 (s, 18H); 13C NMR (75 MHz, CDCl3) δ 170.5, 150.5, 139.6, 137.5, 128.4, 127.6, 127.2, 121.9, 121.4, 119.4, 114.7, 81.0, 70.9, 54.6, 28.0; mass spectrum, calculated for C25H33NO5 (MH+) 428.2, Found 427.9.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][C@@H:8]([CH2:16][OH:17])[CH2:9][C@H:10]([CH3:15])[CH2:11][CH2:12][CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:18])[CH2:7][C@@H:8]([CH2:16][O:17][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)(=[O:27])=[O:26])[CH2:9][C@H:10]([CH3:15])[CH2:11][CH2:12][CH2:13][CH3:14])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC[C@@H](C)C[C@H](COS(=O)(=O)c1ccc(C)cc1)CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To alcohol 140 (6.14 mmol) in 30 mL CH2Cl2 at 0° C. was added DMAP (0.1 g), p-toluenesulfonyl chloride (1.37 g, 7.2 mmol), and then triethylamine (1.8 mL, 13 mmol) was added quickly dropwise. The mixture was warmed immediately to ambient temperature following addition and stirred overnight, and did not proceed to completion. The mixture was partitioned between Et2O and 1N HCl (aq), the phases were separated, and the organic phase washed with sat. NaHCO3 (aq), dried (MgSO4), and concentrated to provide tosylate 141. The product was used without further purification.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CS(C)=O>[O:19]1[CH2:20][CH2:21][N:16]([C:2]2[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=2)[CH2:17][CH2:18]1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: CCOC(=O)c1sc(N2CCOCC2)nc1C(F)(F)F
Yield: 95.8 %

Procedure:
Add ethyl 2-chloro-4-(trifluoromethyl)thiazole-5-carboxylate (4.00 g, 15.4 mmol) to a solution of morpholine (4.03 g, 46.2 mmol) in DMSO (10 mL). Stir the reaction at ambient temperature overnight. Add CH2Cl2, and wash the mixture with H2O. Dry the organic phase over Na2SO4, filter, and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (20:5:1 hexanes:EtOAc:2 M NH3/MeOH) to yield the title compound (4.58 g, 96%). ES/MS m/z 311.0 (M+1).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])C1C=CC=CC=1.[Br:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31]CN)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:1][NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH:16][C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[O:10])=[CH:29][CH:28]=1
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Reactant: NCCc1ccc(Br)cc1
Product: O=C(NCCc1ccc(Br)cc1)c1sccc1Nc1ncnc2[nH]ccc12
Yield: 20 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide using 4-bromophenethylamine instead of benzylamine and obtained in 20% yield (HPLC: 60%, RT: 6.81 min). 1H NMR (DMSO-d6) 11.98 (br s, 1H), 11.37 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.38 (s, 1H), 8.32 (t, J=5.5 Hz, 1H), 7.75 (d, J=5.1 Hz, 1H), 7.50-7.47 (m, 2H), 7.37 (dd, J=3.3, 2.2 Hz, 1H), 7.25-7.21 (m, 2H), 6.45 (dd, J=3.6, 1.8 Hz, 1H), 3.54-3.47 (m, 2H), 2.85 (t, J=7.0 Hz, 2H); MS (m/z) 442 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([NH2:9])=[C:4]([F:10])[CH:3]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([F:10])[CH:3]=1)[NH:9][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:18]2
Reactant: C#Cc1ccccc1
Reactant: Nc1c(F)cc(Cl)cc1I
Product: Fc1cc(Cl)cc2cc(-c3ccccc3)[nH]c12
Yield: 92 %

Procedure:
The general procedure was used to convert 4-Chloro-2-fluoro-6-iodo-phenylamine and phenylacetylene to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 92% yield. 1H NMR (300 MHz, DMSO) δ 12.13 (s, 1H), 7.98-7.95 (d, J=7.72, 2H), 7.51-7.46 (t, J=7.53, 2H), 7.44 (s, 1H), 7.40-7.35 (t, J=7.72, 1H), 7.11-7.07 (d, J=10.92, 1H), 6.96 (s, 1H). 13C NMR (75 MHz, DMSO) δ 150.98, 147.70, 141.53, 133.51, 132.04, 129.73, 129.04, 126.54, 124.59, 124.10, 116.44, 108.27, 100.39. Anal. Calcd. for C14H9ClFN: C, 68.44; H, 3.69; Cl, 14.43; F, 7.73; N, 5.70. Found C, 68.26; H, 3.76; Cl, 14.70; F, 7.5; N, 5.72. m.p.: 153-155° C.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=2[N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CS(C)=O>O>[N:15]1([C:2]2[NH:6][C:5]3[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:4]=3[N:3]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: C1CNCCN1
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1ccc2nc(N3CCNCC3)[nH]c2c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2-chloro-6-trifluoromethyl-1H-benzoimidazole (221 mg, 1 mmol, Example 1c), piperazine (172 mg, 2 mmol, Aldrich) and DMSO (2 mL) was stirred at 80° C. for 24 h. The mixture was cooled to room temperature, water (10 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic phases were washed with water (2×5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 10% MeOH/CH2Cl2+1% ammonia (30% in water) to give the title compound. MS (ESI, pos. ion) m/z: 271 (M+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:11]1([C:14]2[CH:51]=[CH:50][CH:49]=[CH:48][C:15]=2[CH2:16][CH2:17][C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][N:21]=[C:20]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([CH:35]4[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37][CH2:36]4)=[N:33][CH:34]=3)[N:19]=2)[CH2:13][CH2:12]1)(=[O:10])[NH2:9]>C(Cl)Cl>[NH:38]1[CH2:37][CH2:36][CH:35]([C:32]2[N:33]=[CH:34][C:29]([NH:28][C:20]3[N:19]=[C:18]([CH2:17][CH2:16][C:15]4[CH:48]=[CH:49][CH:50]=[CH:51][C:14]=4[C:11]4([C:8]([NH2:9])=[O:10])[CH2:12][CH2:13]4)[C:23]([C:24]([F:26])([F:25])[F:27])=[CH:22][N:21]=3)=[CH:30][CH:31]=2)[CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCNCC4)nc3)ncc2C(F)(F)F)CC1
Reaction time: 4 h

Procedure:
TFA (0.50 mL, 6.5 mmol) was added to a mixture of tert-Butyl 4-(5-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A79 (0.080 g, 0.13 mmol) in DCM (5 mL) and the mixture stirred for 4 hours. The mixture was concentrated under reduced pressure and quenched with 25% aqueous NaOH (20 mL) before extracting with EtOAc (3×20 mL). The combined organic extracts were concentrated under reduced pressure and the above procedure repeated with DCM (1.5 mL) and TFA (0.2 mL) for 3 hours. The mixture was concentrated under reduced pressure and quenched with 25% aqueous NaOH (20 mL) before extracting with EtOAc (3×20 mL). The combined organic residues were dried (phase separation cartridge) and concentrated under reduced pressure to give the title compound 68 (0.069 g, quantitative). LCMS-A: rt 4.783 min; m/z 511.3 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH:9]([C:30]#[N:31])[CH2:10][C@H:11]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-:33].[K+].[K+].OO>CS(C)=O.O>[CH2:1]([NH:8][CH:9]([C:30](=[O:33])[NH2:31])[CH2:10][C@H:11]1[N:15]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:14]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:13][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](CC(C#N)NCc2ccccc2)N1C(=O)OC(C)(C)C
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](CC(NCc2ccccc2)C(N)=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2.6 g of di-tert-butyl (2S,5S)-5-(2-benzylamino-2-cyanoethyl)pyrrolidine-1,2-dicarboxylate were dissolved in 6.5 ml of dimethyl sulfoxide. 373 mg of finely ground potassium carbonate and 1.08 ml of a 30% strength hydrogen peroxide solution were added thereto. The mixture was stirred at room temperature for 14 h and was then heated at 35° C. for 30 min. The solution was diluted with 60 ml of water and extracted 3 times with 100 ml of ethyl acetate each time. The combined organic phases were washed once with 120 ml of a saturated sodium chloride solution and dried with sodium sulfate. The solvents were removed in vacuo, and the residue was chromatographed on silica gel.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([C:8]([CH2:19][C:20]4[N:25]=[C:24]([C:26](OCC5C=CC=CC=5)=[O:27])[CH:23]=[CH:22][CH:21]=4)=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:10]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[NH3:36]>CO>[CH:1]1([C:4]2[CH:12]=[C:11]3[C:7]([C:8]([CH2:19][C:20]4[N:25]=[C:24]([C:26]([NH2:36])=[O:27])[CH:23]=[CH:22][CH:21]=4)=[C:9]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[NH:10]3)=[CH:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: N
Reactant: O=C(OCc1ccccc1)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(C4CC4)ccc23)n1
Solvent: CO
Product: NC(=O)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(C4CC4)ccc23)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Benzyl 6-(6-cyclopropyl-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (200 mg) was dissolved in a solution of ammonia in methanol (about 7 mol/L, 3.3 mL). This solution was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (138 mg). 1H-NMR (CDCl3) δ ppm: 0.69-0.77 (2H, m), 0.92-1.02 (2H, m), 1.97-2.06 (1H, m), 4.42 (2H, s), 5.38-5.59 (1H, br), 6.86 (1H, dd, J=1.4, 8.2 Hz), 7.11-7.15 (1H, m), 7.24-7.29 (1H, m), 7.32-7.48 (4H, m), 7.51-7.58 (2H, m), 7.63-7.71 (1H, m), 7.76-7.96 (1H, br), 7.97-8.03 (1H, m), 8.08 (1H, br).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1.CCN=C=NCCCN(C)C.Cl.[Br:25][CH2:26][C:27]([OH:29])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[Br:25][CH2:26][C:27]([N:2]([CH3:1])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[O:9][C:5]=2[CH:4]=1)=[O:29]
Reactant: CNc1ccc2nc(C)oc2c1
Reactant: O=C(O)CBr
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1nc2ccc(N(C)C(=O)CBr)cc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
To a solution of N,2-dimethylbenzo[d]oxazol-6-amine (9.4 g, 58.0 mmol) in DCM (100 mL) was added EDC.HCl (26.6 g, 139 mmol), DMAP (0.354 g, 2.9 mmol) and bromoacetic acid (18.5 g, 133.0 mmol) at 0° C. under N2. The reaction mixture was stirred at rt overnight, then diluted with water (200 mL). The product was extracted with DCM (3×100 mL) and the organics were washed with brine, dried over Na2SO4 and concentrated to obtain 2-bromo-N-methyl-N-(2-methylbenzo[d]oxazol-6-yl)acetamide (10.0 g, 61%), (MS: ESI +ve, 283.1 [M+H]); 1H NMR: (400 MHz, DMSO) δ: 2.59 (s, 3H), 3.23 (s, 3H), 4.04 (s, 2H), 6.76-6.74 (d, J=8.8, 1H), 7.38-7.30 (dd, J=8.8, 1H), 7.73-7.71 (d, J=8, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]2)[OH:9])=[CH:4][CH:3]=1.[CH2:16]([N:23]1[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[CH2:16]([N:23]1[CH2:28][CH2:27][C:26]2([N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]3[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[O:9]2)[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC(c1ccc(Cl)cc1)C1CCCCN1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: Clc1ccc(C2OC3(CCN(Cc4ccccc4)CC3)N3CCCCC23)cc1

Procedure:
A mixture of 17 g alpha-(4-chlorophenyl)-2-piperidinemethanol, 15 g of N-benzyl-4-piperidone, and 0.3 g of p-toluenesulfonic acid in 150 ml of xylene is stirred under reflux for 48 hours in a vessel provided with a Dean-Stark water separator. The cooled mixture is filtered and evaporated in vacuo. The residue is crystallized from methanol to provide the product, hexahydro-1'-benzyl-1-(4-chlorophenyl)spiro[3H-oxazolo[3,4-a]pyridine-3,4'-piperidine]; mp 134°-136° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]2[C:17]3[CH:16]=[CH:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[N:11]=[CH:10]2)=[CH:3][C:2]=1[C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccnc1
Reactant: Cn1ccc2c(ncn2-c2ccc(F)c(Br)c2)c1=O
Product: Cn1ccc2c(ncn2-c2ccc(F)c(-c3cccnc3)c2)c1=O
Yield: 32 %

Procedure:
1-(3-Bromo-4-fluorophenyl)-5-methyl-1,5-dihydroimidazo[4,5-c]pyridin-4-one was coupled to 3-pyridylboronic acid, in the same way as in Example 1, to give 1-[4-fluoro-3-(pyridin-3-yl)phenyl]-5-methyl-1,5-dihydro-imidazo[4,5-c]pyridin-4-one as an off-white solid (50 mg, 32%): δH (400 MHz, CDCl3) 3.69 (3H, s), 6.38 (1H, d, J 7), 7.22 (1H, d, J 7), 7.40-7.49 (3H, m), 7.54 (1H, dd, J 7 and 3), 7.90-7.94 (2H, m), 8.70 (1H, dd, J 5 and 2), 8.84 (1H, s); m/z (ES+) 321 [MH+].
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]([O:11]CC)=O)=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][C:18]3[O:22][CH:21]=[CH:20][CH:19]=3)[N:15]=[CH:16][C:4]=12)[NH2:2].C([N:25]1[C:29]2=NC=[C:32](C(OCC)=O)[C:33](NN)=[C:28]2C=N1)C>>[CH2:17]([N:14]1[C:5]2[N:6]=[CH:7][C:8]3[C:9](=[O:11])[NH:25][C:29]4[N:1]([N:2]=[C:33]([CH3:32])[CH:28]=4)[C:3]=3[C:4]=2[CH:16]=[N:15]1)[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1NN
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NN
Product: Cc1cc2[nH]c(=O)c3cnc4c(cnn4Cc4ccco4)c3n2n1

Procedure:
By substituting 4-hydrazino-1-furfurylpyrazolo-[3,4-b]pyridine-5-carboxylic acid, ethyl ester for the 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester in Example 1 a and proceeding as in parts a and b, 8-furfuryl-2-methyl-4H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is obtained. This compound is now processed as in Example 1, part c, substituting bromobenzene for the methyl iodide. A small amount of copper catalyst is added to obtain 1-furfuryl-1-methyl-4-phenyl-4H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido-[3,4-e]pyrimidin-5(8H)-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]2)[CH:2]=1.[Br:21]N1C(=O)CCC1=O.O>C(#N)C>[Br:21][C:6]1[N:1]=[CH:2][C:3]([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9][CH2:8]2)=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccnc2)CC1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(Br)nc2)CC1
Temperature: 0 °C

Procedure:
1-(3-Pyridyl)-4-tert-butoxycarbonyl homopiperazine (25.0 g, 90.1 mmol) was solved in acetonitrile (400 ml) and cooled to 0° C. N-Bromosuccinimide (19.3 g, 108.2 mmol) was added during 10 min. Water (400 ml) was added and the mixture was extracted twice with diethyl ether (200 ml). Chromatography on silica gel with a mixture of petroleum:ethyl acetate (1:1) gave the title compound as free base. Yield 18.7 g, 58%.
Reaction SMILES: [C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](N1C2C(=CC=CC=2)C(=O)C1=O)CCC>>[C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:19][CH2:20][CH2:21][CH3:23])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN1C(=O)C(=O)c2ccccc21
Reactant: CCCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21
Product: CCCCN1C(=O)C(OC(=O)c2ccccc2)c2ccccc21

Procedure:
Was prepared in a method analogous to 2-oxo-1-propylindolin-3-yl benzoate using 1-butylindoline-2,3-dione. 1H-NMR δ 8.11 (d, 2H), 7.58 (m, 1H), 7.49-7.34 (m, 4H), 7.05 (dd, 1H), 6.89 (d, 1H), 6.19 (s, 1H), 3.75 (m, 2H), 1.73 (m, 2H), 1.44 (m, 2H), 0.99 (t, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=2[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[C:6]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:5][N:4]=1.[BH4-].[Na+]>C(O)C>[C:12]1([CH:10]2[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[N:7]3[C:6]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[N:5][N:4]=[C:3]3[CH2:2][O:1]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCCCCCCCCc1nnc(CO)n1-c1ccccc1C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCCCCCc1nnc2n1-c1ccccc1C(c1ccccc1)OC2
Yield: 38.5 %

Procedure:
2-(3-Hydroxymethyl-5-undecyl1,2,4-triazol-4-yl)benzophenone (2.7 g) obtained in Example 23 was dissolved in ethanol (30 ml). Thereto was added sodium borohydride (240 mg) with stirring and the mixture was stirred at room temperature for 2 hours. After the ethanol was distilled away, 5% aqueous sodium hydrogencarbonate was added thereto and the liberated oily substance was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and toluene (150 ml) was added to the residue. The mixture was refluxed under heating with stirring and sulfuric acid was gradually added dropwise until the reaction ended. After cooling, 5% aqueous sodium hydrogencarbonate was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromotography. The oily substance obtained was crystallized from hexane to give 1 g of 6-phenyl-1-undecyl-4H,6H-[1,2,4]triazolo[4,3-a][4,1]benzoxazepine, melting point 83°-84° C.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([C:16]([NH2:18])=O)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH:11]1[C:12]2[C:13]3([C:16]#[N:18])[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: NC(=O)C12CC(c3ccccc31)c1ccccc12
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: N#CC12CC(c3ccccc31)c1ccccc12

Procedure:
A solution of 9,10-dihydro-9,10-methanoanthracene-9-carboxamide (30 mg) and thionyl chloride (0.15 ml) in toluene (1 ml) was refluxed for 18 hours. Evaporation of toluene and excess thionyl chloride gave 9,10-dihydro-9,10-methanoanthracene-9-carbonitrile. M.P. 120°-123° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](F)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.[H-].[Na+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)([O-:3])=[O:2]
Reactant: CN1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Reaction time: 1 h

Procedure:
3,4-Dinitrofluorobenzene (1.86 g, 10 mmol) and 4-hydroxy-1-methylpiperidine (1.38 g, 12 mmol) were dissolved in THF (20 ml) and stirred at ambient temperature while sodium hydride (60% dispersion in mineral oil, 0.40 g, 10 mmol) was added in several small portions. The reaction mixture was stirred for one hour and then reduced in vacuo, partitioned between ethyl acetate and water, and the organic phase washed with brine, dried (MgSO4) and reduced in vacuo. The resulting residue was subject to column chromatography, eluting with 5% MeOH/DCM to give a yellow solid (1.76 g, 2:1 ratio of 4-(3,4-dinitro-phenoxy)-1-methyl-piperidine and a 4-(4-fluoro-2-nitro-phenoxy)-1-methyl-piperidine).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:30]([C:34]1[CH:39]=[CH:38][C:37](OB=O)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:30]([C:34]1[CH:39]=[CH:38][C:37]([O:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[CH:36][CH:35]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: COc1cc2nccc(Oc3ccc(O)cc3)c2cc1OC
Reactant: CC(C)(C)c1ccc(OB=O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(Oc4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 96 h
Yield: 57.7 %

Procedure:
4-(6,7-Dimethoxy-4-quinolyloxy)phenol (starting compound 8) (24 mg) was dissolved in chloroform (2 ml) to prepare a solution. Triethylamine (0.3 ml), 4-tert-butylphenylboranic acid (50 mg), and copper(II) acetate (90 mg) were added to the solution, and the mixture was stirred at room temperature for 4 days. The insolubles were removed by filtration, and the solvent was then removed by evaporation under the reduced pressure. The residue was purified by thin-layer chromatography on silica gel using chloroform/acetone for development to give the title compound (20 mg, yield 58%).