Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:27](=[CH:28][CH:29]=1)[C:8]1=[N:9][O:10][C:11]([C:12]3[C:16]([C:17]([F:20])([F:19])[F:18])=[C:15]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[O:14][N:13]=3)=[C:7]1[CH2:6][CH2:5]2.C([O-])(=O)C.[K+].[CH:35]1([OH:40])[CH2:39][CH2:38][CH:37]=[CH:36]1>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[C:21]1([C:15]2[O:14][N:13]=[C:12]([C:11]3[O:10][N:9]=[C:8]4[C:27]5[C:4]([CH2:5][CH2:6][C:7]=34)=[CH:3][C:2]([CH:37]3[CH2:38][CH2:39][C:35](=[O:40])[CH2:36]3)=[CH:29][CH:28]=5)[C:16]=2[C:17]([F:19])([F:20])[F:18])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OC1C=CCC1
Reactant: FC(F)(F)c1c(-c2onc3c2CCc2cc(I)ccc2-3)noc1-c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=C1CCC(c2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Temperature: 75 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To a mixture of 7-iodo-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 121B, 370 mg, 0.728 mmol), tetrabutylammonium chloride (202 mg, 0.728 mmol), potassium acetate (214 mg, 2.184 mmol), and anhydrous DMF (2 mL) was bubbled with nitrogen for 3 min. before palladium (II) acetate (16.34 mg, 0.073 mmol) and cyclopent-2-enol (122 mg, 1.456 mmol) were added. The mixture was bubbled for 2 min. and sealed in a 2-dram vial. The mixture was stirred at 75° C. for 3 h. The mixture was cooled, diluted with water (30 ml) and extracted with ethyl acetate (3×10 mL). The combined ethyl acetate extracts were dried (sodium sulfate) and concentrated under reduced pressure. Flash chromatography purification (silica gel column, 5→50% ethyl acetate in n-heptane) afforded 3-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)cyclopentanone (230 mg, 0.495 mmol, 68.0% yield). The compound had an HPLC retention time=4.04 min. (condition C); LC/MS M+1=465.2.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[CH:4][CH:3]=1.[CH3:14][C:15]1([CH3:27])[C:24]2[C:19](=[CH:20][C:21]([NH2:25])=[CH:22][CH:23]=2)[C:18](=[O:26])[CH2:17][CH2:16]1.Cl>S(Cl)(Cl)=O.CN(C)C=O>[CH3:14][C:15]1([CH3:27])[CH2:16][CH2:17][C:18](=[O:26])[C:19]2[CH:20]=[C:21]([NH:25][C:6]([C:5]3[CH:4]=[CH:3][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:10][CH:9]=3)=[O:8])[CH:22]=[CH:23][C:24]1=2
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: CC1(C)CCC(=O)c2cc(N)ccc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of monomethyl terephthalate (VIIIa) (2.86 g, 15.89 mmoles) in thionylchloride (50 mL) with 2 drops of N,N-dimethylformamide was allowed to stir at room temperature. The mixture became homogeneous within 30 minutes and was then concentrated in vacuo. The residue was then taken up in 30 mL of anhydrous pyridine and treated with 4,4-dimethyl-7-amino-1-tetralone (3.00 g, 15.9 mmoles). After 16 hours at room temperature 1N HCl was added to the mixture. It was extracted with ethyl acetate, washed with 1N HCl (4×200 mL) and washed with saturated sodium bicarbonate (2×200 mL). The organic phase was then separated, dried over magnesium sulfate, and concentrated in vacuo to give 5.07 g (Y: 91%) of the title compound; 1H-NMR (CDCl3): δ 8.27 (dd, J=8.7, 2.5 Hz, 1H), 8.19 (bs, 1H), 8.14 (d, J=8.4 Hz, 2H), 7.95 (d, J=8.4 Hz, 2H), 7.91 (d, J=2.5 Hz, 1H), 7.46 (d, J=8.7 Hz, 1H), 3.94 (s, 3H), 2.70 (t, J=7.0 Hz, 3H), 2.00 (t, J=7.0 Hz, 3H), 1.38 (s, 6H); MS (DCI) m/e: 352 (MH+).
Reaction SMILES: C[SiH](C)C1C=CC=CC=1[SiH](C)C.[CH2:13]([N:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[CH2:13]([N:20]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCCCCN1Cc1ccccc1
Agent: C[SiH](C)c1ccccc1[SiH](C)C
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCCCCC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A 20-mL eggplant flask equipped with a three-way cock and a magnetic stirrer was heat dried while pumping to a vacuum of 5 Pa before its interior was purged with argon atmosphere. Into the flask, iron complex A (1.0 mg, 0.002 mmol) was admitted as catalyst and dissolved in toluene (0.5 mL). To the solution, 1,2-bis(dimethylsilyl)benzene (475 μL) was added through a syringe, and N-benzyl-ε-caprolactam (203 mg, 1.0 mmol) was added. The solution was stirred at 100° C. for 30 minutes. Toluene was distilled off in vacuum. The crude product was purified by silica gel-packed column chromatography using hexane/ethyl acetate (10/1) as developing solvent, obtaining 1-benzylazepane (169 mg, 0.89 mmol, 89%). The results are shown as Entry 5 in Table 5. The resulting amine was identified for geometry by 1H and 13C-NMR spectroscopy and IR spectroscopy.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([CH2:19]Cl)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:46]([SH:49])[CH:47]=[CH2:48].[Cl-].[Na+]>CN(C)C=O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:21]([O:23][CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[C:15]([CH2:19][S:49][CH2:46][CH:47]=[CH2:48])[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12
Reactant: C=CCS
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCSCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S(=O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of benzhydryl 7-(2-phenylacetamido)-3-chloromethyl-3-cephem-4-carboxylate-1-oxide (25 g) in N,N-dimethylformamide (150 ml) were added triethylamine (6.42 ml) and 2-propene-1-thiol (8.0 ml), and the mixture was stirred at 25° C. for 3 hours. The reaction mixture was poured into a saturated aqueous solution of sodium chloride (1.5 l), followed by collecting the precipitated solid by filtration, which was washed with water and diisopropyl ether, and then dried to give benzhydryl 7-(2-phenylacetamido)-3-allylthiomethyl-3-cephem-4-carboxylate-1-oxide (24.2 g).
Reaction SMILES: C([O:4][C:5]([CH3:50])([CH3:49])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:20]=[C:19]3[N:21]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5([NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:39][CH2:38]5)=[CH:33][CH:32]=4)[C:22]([C:24]4[C:25]([NH2:30])=[N:26][CH:27]=[CH:28][CH:29]=4)=[N:23][C:18]3=[CH:17][CH:16]=2)[CH:10]=1)=[O:7])(=O)C.C(=O)([O-])[O-]>CO>[NH2:30][C:25]1[C:24]([C:22]2[N:21]([C:31]3[CH:32]=[CH:33][C:34]([C:37]4([NH:41][C:42](=[O:43])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:39][CH2:40]4)=[CH:35][CH:36]=3)[C:19]3=[N:20][C:15]([C:11]4[CH:12]=[CH:13][CH:14]=[C:9]([NH:8][C:6](=[O:7])[C:5]([OH:4])([CH3:50])[CH3:49])[CH:10]=4)=[CH:16][CH:17]=[C:18]3[N:23]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: CC(=O)OC(C)(C)C(=O)Nc1cccc(-c2ccc3nc(-c4cccnc4N)n(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c3n2)c1
Agent: O=C([O-])[O-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-n3c(-c4cccnc4N)nc4ccc(-c5cccc(NC(=O)C(C)(C)O)c5)nc43)cc2)CCC1
Temperature: 40 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
To a solution of 2-({3-[2-(2-aminopyridin-3-yl)-3-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3H-imidazo[4,5-b]pyridin-5-yl]phenyl}amino)-1,1-dimethyl-2-oxoethyl acetate (24 mg) in methanol (6 mL) was added MP-carbonate (Argonaout technologies 2.91 mmol/g, 200 mg) at room temperature. After being stirred at 40° C. for 4 h, the reaction mixture was filtered and concentrated under reduced pressure. Purification by column chromatography (0-10% methanol in chloroform) gave the product (20 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH:14](C(OCC)=O)[C:15]([O:17][CH2:18]C)=[O:16])=[CH:12][N:11]=[C:10]1[S:25][CH2:26][CH2:27][CH3:28].ClC1C=CC=CC=1CN1C(CC(O)=O)=CN=C1SCCC>CO.Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:12][N:11]=[C:10]1[S:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCSc1ncc(C(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Agent: Cl
Solvent: CO
Product: CCCSc1ncc(CC(=O)OC)n1Cc1ccccc1Cl

Procedure:
Diethyl [1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]malonate was converted to 2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]acetic acid by the method described in Example 15. The methyl ester was prepared in methanol/hydrochloric acid to give methyl 2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5yl]acetate hydro- chloride; mp 158°-159° C.
Reaction SMILES: [CH3:1][C:2]([Mg]Br)=[CH:3][CH3:4].[F:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)[C:11]([N+:24]([O-])=O)=[CH:10][CH:9]=1.[Cl-].[NH4+]>O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]2[C:3]([CH3:4])=[C:2]([CH3:1])[NH:24][C:11]2=[C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)[N:13]=1
Reactant: CC=C(C)[Mg]Br
Reactant: O=[N+]([O-])c1ccc(F)nc1N1CCc2ccccc2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(F)cc2c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
1-Methyl-1-propenyl magnesium bromide (0.5M in tetrahydrofuran solution; 138 ml, 68.9 mmol) was slowly added at −78° C. to a solution of 2-(6-fluoro-3-nitropyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline (5.38 g, 19.7 mmol) prepared in Step 2 in anhydrous tetrahydrofuran (150 ml). The reaction mixture was stirred for 1 hour at the same temperature, slowly warmed to room temperature, and then stirred overnight. 20% (w/v) Ammonium chloride solution was added to the reaction mixture, which was then extracted with ethyl acetate. The resulting organic layer was dried on anhydrous magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography. The resulting product was crystallized with ethyl ether to give the titled compound as red oil. (Yield: 32%)
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]([O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:9][C:10]=1[C:11]1[CH:27]=[CH:26][C:14]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([C:23](O)=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].[ClH:36].[CH3:37][NH:38][CH3:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>CN(C=O)C.O.CCOC(C)=O.C(O)(=O)C.C(Cl)Cl.CCOCC>[ClH:36].[ClH:36].[CH3:37][N:38]([CH3:39])[C:23]([CH:20]1[CH2:21][CH2:22][CH:17]([CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:10]3[CH:9]=[C:8]([O:28][CH:29]4[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]4)[N:7]=[N:6][C:5]=3[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:27][CH:26]=2)[CH2:18][CH2:19]1)=[O:24]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OCC2CCC(C(=O)O)CC2)cc1
Reactant: CNC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OCC2CCC(C(=O)N(C)C)CC2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
To a solution of 4-{4-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-phenoxymethyl}-cyclohexanecarboxylic acid (0.2 mmol, 97 mg) in DMF (1 mL) was added dimethylamine hydrochloride (0.3 mmol, 25 mg), HBTU (0.4 mmol, 152 mg), DIEA (0.4 mmol, 70 μL). The mixture was stirred at 100° C. for 2 hours. The mixture was then diluted with water/EtOAc and neutralized with acetic acid. The organic layers were combined, dried, and condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1 mL), 2N HCl in ether (1 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (89 mg). LCMS: m/z 510 [M+1]. 1H NMR (400 MHz, CD3OD): δ 7.64 and 7.76 (1H, s), 7.45-7.51 (2H, m), 7.13-7.17 (2H, m), 5.37-5.54 (1H, m), 4.30 (2H, d), 3.35-3.69 (3H, m), 3.08-3.30 (4H, m), 2.94 (3H, s), 2.81 (6H, s), 2.21-2.74 (5H, m), 1.86-2.98 (2H, m), 1.25-1.54 (10H, m), 0.82 (3H, t).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26]I)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[N+:41]([C:44]1[N:45]=[CH:46][NH:47][CH:48]=1)([O-:43])=[O:42].O>CN(C=O)C>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:47]3[CH:48]=[C:44]([N+:41]([O-:43])=[O:42])[N:45]=[CH:46]3)=[CH:16][CH:15]=2)=[O:12])[N:7]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1c[nH]cn1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCI)c3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCn3cnc([N+](=O)[O-])c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.8 %

Procedure:
A mixture of 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(4-(2-iodoethoxy)naphthalen-1-yl)urea (J. Med. Chem., 2003, 46, 4676-4686) (400 mg, 0.704 mmol), potassium carbonate (292 mg, 2.111 mmol) and 4-nitroimidazole (88 mg, 0.774 mmol) in DMF (2.0 mL) was placed in a pre-heated oil bath at 50° C. and stirred for 16 hr. The mixture was cooled to RT, poured into water (5.0 mL) and extracted with EtOAc (5.0 mL×2). The combined organic layers were dried, filtered and evaporated and the resulting residue was subjected to column chromatography (40 g), eluting with EtOAc to give 1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(4-(2-(4-nitro-1H-imidazol-1-yl)ethoxy)naphthalen-1-yl)urea (35) as a brown solid (276 mg, 60%): m/z 554 (M+H)+ (ES+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][C:8](=[O:21])[C:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[C:14]([I:20])[CH:13]=1)([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[N+]([O-])=O.C(OCC)(=O)C>CN1C(=O)CCC1>[C:1]([O:5][C:6]([C:7]1[C:30]2[CH:31]=[CH:32][C:33]([C:34]#[N:35])=[CH:36][C:37]=2[O:21][C:8]=1[C:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[C:14]([I:20])[CH:13]=1)([CH3:11])[CH3:10])=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1ccc(C(C)(C)C(=O)CC(=O)OC(C)(C)C)cc1I
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCc1ccc(C(C)(C)c2oc3cc(C#N)ccc3c2C(=O)OC(C)(C)C)cc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25.9 %

Procedure:
4-(4-Ethyl-3-iodo-phenyl)-4-methyl-3-oxo-pentanoic acid tert-butyl ester (1.00 g, 2.40 mmol) was dissolved in NMP (4 ml), added with cesium carbonate (1.56 g, 4.80 mmol, 2.0 eq.), and the mixture was stirred for 5 min. The NMP solution (2 ml) of 4-chloro-3-nitro-benzonitrile (542 mg, 2.88 mmol, 1.2 eq.) was added thereto, and the mixture was stirred at 50° C. for 64 hrs under nitrogen atmosphere. After cooling to room temperature, ethyl acetate (20 ml) was added and the organic layer was washed with saturated aqueous solution of ammonium chloride (20 ml). The organic layer was further washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (white amorphous, 320 mg, 26%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NS(=O)(=O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cnc(Nc2ccccc2)c(Br)c1
Temperature: 60 °C
Yield: 57.9 %

Procedure:
A mixture of Example 86a (0.136 g, 0.5 mmol), aniline (0.186 g, 2.0 mmol), and 60% sodium hydride (0.12 g, 3.0 mmol) in dioxane (2 mL) was stirred and heated at 60° C. for 16 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was neutralized with 10% HCl and extracted with additional ethyl acetate twice. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (2:3 ethyl acetate/hexanes) to give 0.095 g of the title product.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:36])([F:35])[C:21]1[CH:22]=[C:23]([C:27]2[S:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][S:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:36])([F:19])[F:35])[CH:22]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)c1ncsc1-c1cccc(C(F)(F)F)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncsc3-c3cccc(C(F)(F)F)c3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-trifluoromethyl-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]3)[CH:13]=[CH:12]2)=[C:4](Cl)[N:3]=1.[C:24]1([CH:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:31][NH2:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][OH:22])[CH:18]=[N:17]3)[CH:13]=[CH:12]2)=[C:4]([NH:32][CH2:31][CH:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:3]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: OCc1cnn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: OCc1cnn([C@@H]2C=C[C@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C2)c1

Procedure:
A mixture comprising {1-[(1S,4R)-4-(2,6-dichloro purin-9-yl)-cyclopent-2-enyl]-1H-pyrazol-4-yl}-methanol (0.675 g, 1.92 mmol), diphenylethylamine (0.398 g, 2.02 mmol) and DIPEA (0.298 g, 2.31 mmol) in dry THF (20 mL) is stirred at 35 C for 3 days. The solvent is removed in vacuo and the resulting crude residue is partitioned between DCM and 0.1 M HCl. The organic portion is separated, washed with water, brine, dried (MgSO4) and concentrated in vacuo to afford the title product.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]3(CC3)[CH2:9][NH:10][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C=O.[CH3:18][C:19]([CH3:21])=O>>[CH:19]([N:10]1[CH2:9][CH2:8][C:7]2[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11]1)([CH3:21])[CH3:18]
Reactant: CC(C)=O
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC21CC1
Agent: C=O
Product: CC(C)N1CCc2ccc([N+](=O)[O-])cc2C1

Procedure:
870 mg of the entitled compound was obtained as a colorless solid according to the same method as in Production Example 10-6), for which, however, the compound obtained in Production Example 22-1) was used in place of 7′-nitro-1′,2′-dihydro-3′H-spiro[cyclopropane-1,4′-isoquinoline] used in Production Example 10-6), and acetone was used in place of aqueous formaldehyde solution.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].[NH2:25][C@H:26]([C:28]([OH:30])=[O:29])[CH3:27]>C[O-].[Na+].CO>[C:23]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:25][C@@H:26]([CH3:27])[C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:24]
Reactant: COC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](NC(=O)c1nc(C#N)c2c(Oc3ccccc3)cccc2c1O)C(=O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 1-cyano-4-hydroxy-8-phenoxy-isoquinoline-3-carboxylic acid methyl ester (101 mg, 0.31 mmol) and L-Alanine (561 mg, 6.29 mmol) in 0.5 M sodium methoxide/methanol (12 mL) was refluxed for four days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water (20 mL) and extracted with methyl t-butyl ether (2×30 mL). The remaining aqueous layer was acidified to pH=3 with 1N HCl (8 mL). The resulting white suspension was extracted with ethyl acetate (30 mL), dried and concentrated in vacuo to give the title compound as a white solid (117 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.52 (bs, 1H), 10.11 (br s, 1H), 8.30 (d, 1H), 8.07 (m, 1H), 7.67 (t, J=8 Hz, 1H), 7.42 (m, 2H), 7.17 (m, 3H), 4.83 (q, 1H), 1.68 (d, J=7.4 Hz); MS: (+) m/z 378.29 (M+1).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].CC[O-].[Na+].[CH2:20]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35]I)=[CH:30][CH:29]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>C(O)C.O1CCCC1>[C:1]([NH:4][C:5]([CH2:35][CH2:34][C:31]1[CH:30]=[CH:29][C:28]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:33][CH:32]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCCCCCCCc1ccc(CCI)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(CCC(NC(C)=O)(C(=O)OCC)C(=O)OCC)cc1

Procedure:
To a solution of diethyl acetamidomalonate (277 g) and sodium ethylate (86.6 g) in anhydrous ethanol (850 ml) is added a solution of 2-(4-octylphenyl)ethyl iodide (7) (146 g) in anhydrous tetrahydrofuran (533 ml), and the mixture is refluxed under heating for 6 hr. The reaction mixture is concentrated and partitioned between water and hexane, and the hexane layer is washed three times with water. The obtained hexane layer is dried over anhydrous magnesium sulfate and concentrated. The residue is recrystallized from hexane to give the title compound (8) as colorless crystals. The resulting Compound (8) has the same physico-chemical characteristics as indicated in Example 7.