Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl/[C:2](/[N+]([O-])=O)=[CH:3]\[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][CH:5]=1.[OH:15][C:16]1[CH:21]=[C:20]([OH:22])[N:19]=[CH:18][N:17]=1.N12CCCN=C1CCCCC2>C(O)C>[CH2:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]2[C:21]3[C:20](=[O:22])[NH:19][CH:18]=[N:17][C:16]=3[O:15][CH:2]=2)=[CH:5][CH:6]=1)[CH3:11]
Reactant: Oc1cc(O)ncn1
Reactant: CCc1ccc(/C=C(\Cl)[N+](=O)[O-])cc1
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1ccc(-c2coc3nc[nH]c(=O)c23)cc1
Reaction time: 15 h

Procedure:
Analogously to the literature method [D. Dauzonne, Tetrahedron, 1992, 3069-3080], stir a suspension of 11.9 g (85% purity, 47.6 mmol) of 1-[(Z)-2-chloro-2-nitrovinyl]-4-ethylbenzene and 5.9 g (52.3 mmol) of 4,6-dihydroxypyrimidine in 200 ml of ethanol at 60-70° C. for 30 minutes. Then slowly add 14.4 ml (14.6 g, 96.1 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene. Stir the resulting reaction solution under reflux for six hours and then at 60° C. for 15 hours. After concentration under reduced pressure, take up the residue in dichloromethane and chromatograph it on silica gel (eluent: cyclohexane/ethyl acetate 1:1→1:5). Stir the resulting solid in diethyl ether and filter. 5.0 g (44% of theory) of the target compound are obtained.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][S:34][C:35]1[N:36]=[CH:37][N:38]2[CH:42]=[C:41]([Sn](CCCC)(CCCC)CCCC)[S:40][C:39]=12>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[O:13])=[C:8]([C:41]3[S:40][C:39]4=[C:35]([S:34][CH2:33][C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=5)[N:36]=[CH:37][N:38]4[CH:42]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(SCc3ccccn3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(SCc5ccccn5)c4s3)[C@H](C)[C@H]12
Yield: 11.3 %

Procedure:
The procedure of Example 1a) was repeated, except that 807 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 1.255 g of 7-(pyridin-2-yl)methylthio-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds. Thus, 149 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-2-yl)methylthioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was prepared.
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][N+:13]([O-])=[CH:12][CH:11]=1.C[Si](C#N)(C)C>C(#N)C>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:1]#[N:3])[CH:11]=1
Reactant: COc1cc[n+]([O-])cc1
Reactant: CCN(CC)CC
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Product: COc1ccnc(C#N)c1
Reaction time: 0.33 h

Procedure:
In an argon atmosphere, triethylamine (17.8 mL) was added to 4-methoxypyridine-N-oxide (8.0 g) in acetonitrile (160 mL) at room temperature. Trimethylsilyl cyanide (24.1 mL) was added dropwise to the mixture, followed by stirring for 20 minutes. Subsequently, the mixture was stirred at 95° C. for 14 hours, and then cooled in air. The solvent was evaporated under reduced pressure. The residue was partitioned between saturated aqueous solution of sodium hydrogencarbonate and ethyl acetate. The organic layer was dried over sodium hydrogensulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as a solid substance (1.57 g, 18%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:26](OCC)=[O:27]>O1CCCC1>[C:24]([C:23]([CH2:22][CH2:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:26][OH:27])#[N:25]
Reactant: CCOC=O
Reactant: N#CCCCCCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CC(=CO)CCCCc1ccccc1
Reaction time: 0.25 h
Yield: 83.8 %

Procedure:
A stirred solution of 2.2 mL (0.016 mole) of diisopropylamine in 200 mL of tetrahydrofuran was cooled to -80° C., and 6.4 mL (0.016 mole) of n-butyllithium (2.5 Molar in hexanes) was added dropwise during a 15 minute period. Upon completion of addition, the reaction mixture was stirred for an additional 15 minutes. While still maintaining the reaction mixture temperature at -80° C. to -75° C., a solution of 2.5 grams (0.016 mole) of 6-phenylhexanenitrile in 50 mL of tetrahydrofuran was added dropwise during a 30 minute period. Upon completion of addition, the reaction mixture was stirred at -80° C. for an additional 30 minutes. After this time, a solution of 1.3 mL (0.016 mole) of ethyl formate in 50 mL of tetrahydrofuran was added dropwise during a ten minute period. Upon completion of addition, the reaction mixture was stirred for two hours at -80° C. to -70° C. The reaction was quenched with 100 mL of water, and the mixture was acidified with 6N hydrochloric acid. The mixture was extracted with two 150 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography using silica gel. Elution was accomplished using 1% to 3% methanol in methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure, yielding 2.7 grams of 2-cyano-6-phenyl-1-hexen-1-ol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:29]([O:31][CH3:32])=[O:30])([CH2:26][CH:27]=C)[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:34].[Na+].O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@:9]([C:29]([O:31][CH3:32])=[O:30])([CH2:26][CH:27]=[O:34])[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])=[O:18])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@@](CC1CCN(C(=O)OCC[Si](C)(C)C)CC1)(NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@](CC=O)(CC1CCN(C(=O)OCC[Si](C)(C)C)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
750 mg of 2-trimethylsilanylethyl (S)-4-(2-tert-butoxycarbonylamino-2-methoxycarbonylpent-4-enyl)piperidine-1-carboxylate were dissolved in 30 ml of THF. 852 mg of sodium periodate and 10 ml of water were added. The mixture was then stirred at room temperature for 3 h and filtered through kieselguhr. The filter cake was washed twice with 10 ml of THF each time. The THF was removed in vacuo, and the residue was partitioned between 30 ml of water and 30 ml of ethyl acetate. The pH of the aqueous phase was adjusted to 2 with 1 N HCl solution. The phase were separated and the aqueous phase was extracted twice with 20 ml of ethyl acetate each time. The combined organic phases were dried with MgSO4. The solvents were removed in vacuo and the residue was chromatographed on silica gel.
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](B4OC(C)(C)C(C)(C)O4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:39][NH:40][C:41]([O:43][CH:44]([CH3:46])[CH3:45])=[O:42])([CH3:4])([CH3:3])[CH3:2].C(O)(=[O:50])C.OO.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:47])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][C:27]([OH:50])=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH2:39][NH:40][C:41]([O:43][CH:44]([CH3:45])[CH3:46])=[O:42])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1oc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Reactant: CC(=O)O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccc(O)cc2)nc1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CNC(=O)OC(C)C)c1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
According to the procedure in Organic Synthesis, vol. V, p. 918, a solution of 3-[2-(isopropoxycarbonylamino-methyl)-4-(2-{5-methyl-2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazol-4-yl}-ethoxy)-phenyl]-propionic acid tert-butyl ester (1.4 g, 2.16 mmol, Example 368, Step A) in THF (8 mL) was treated with glacial acetic acid (194 mg, 3.24 mmol) at 0° C. A solution of 30% H2O2 in water (4.75 mL) was diluted with H2O (1 mL) and added to the reaction mixture. The mixture was warmed to room temperature and treated with 1M aqueous Na2S2O3 solution (50 mL). The THF was removed under vacuum and the aqueous phase was extracted with ethyl acetate. The organic layer was washed with 1M Na2S2O3 (2×50 mL), dried (MgSO4), filtered, and concentrated to an oil containing (1.21 g). Purification using silica gel chromatography (1:1 ηεξανεσ:ετηψλ acetate) yielded the title compound as a white solid (1.10 g, 95%). 1H NMR (300 MHz CDCl3) δ 1.15 (d, 6H), 1.19 (s, 9H), 2.26 (s, 3H), 2.39 (t, 2H), 2.75 (t, 2H), 2.85 (t, 2H), 4.10 (t, 2H), 4.28 (d, 2H), 4.85 (m, 1H), 5.01 (br d, 1H), 6.63 (dd, 1H), 6.74 (m, 3H), 6.96 (d, 1 h), 7.70 (d, 2H); MS [EI+] m/z 539 (M+H).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][C:14]([NH2:16])=[NH:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:18][C:19](=O)/[C:20](/[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[C:21](\O)/[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C[O-].[Na+]>CO.ClCCl>[C:25]([O:24][C:22]([C:21]1[C:20]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:19]([OH:18])[N:16]=[C:14]([CH2:13][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[N:15]=1)=[O:23])([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)/C(OCc1ccccc1)=C(\O)C(=O)OC(C)(C)C
Reactant: N=C(N)CC1(c2ccccc2)CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccccc3)CCCCC2)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a mixture of HCl-salt of 2-(1-phenyl-cyclohexyl)-acetamidine (254) (2.0 g, 7.91 mmol) and (E)-2-benzyloxy-3-hydroxy-but-2-enedioic acid 4-tert-butyl ester 1-methyl ester (9) (3.66 g, 11.86 mmol) in methanol (50.0 mL) was added sodium methoxide (1.28 g, 23.73 mmol, 25% in methanol) at 0° C. Then the reaction mixture was allowed to warm up to room temperature and was stirred for 16 h. After completion of the reaction, the solvent was reduced and the crude product was dissolved in dichloromethane and the resultant mixture extracted with dichloromethane. The organic layer was washed with 1N HCl and with water and brine. It was then dried over Na2SO4 and concentrated. The crude product was purified by normal silica gel column chromatography (using 10% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclohexylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (255) (3.2 g, 85.0%) as a yellowish thick liquid which turned into a solid after storing at room temperature.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[N:6][CH:7]=1.[CH:13](O)=O>C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH3:13])[CH:5]=[N:6][CH:7]=1
Reactant: O=CO
Reactant: Brc1cncc(C2CCCN2)c1
Agent: C=O
Product: CN1CCCC1c1cncc(Br)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Enantiomerically enriched 5-bromo-3-(2-pyrrolidinyl)pyridine (1.82 g, 8 mmol) was dissolved in a mixture of 98% formic acid (16 mL) and 37% aqueous formaldehyde (8 mL). The solution was heated with stirring for 3 h at 80° C. After cooling to 25° C. the mixture was concentrated in vacuo and water (30 mL) added. The mixture was basified with solid NaOH to pH 12 and extracted with methylene chloride (3×40 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The crude material was chromatographed on silica gel with ethyl acetate:hexane (1:3) as eluant to afford 5-bromo-3-(1-methyl-2-pyrrolidinyl)pyridine as an oil, 1.63 g,84%. LRMS (EI) m/e 242 (C10H13N281Br), 241 (C10 H13N279Br--+H), 240 (C10H13 N279Br), 239 (C10H13N2Br--+H); 1H NMR (DMSO-d6, 300 MHz) δ 8.55 (d, J=2.1 Hz, 1H), 8.44 (d, J=1.9 Hz, 1H), 7.88 (t, J=1.9 Hz, 1H), 3.24 (b-dt, J=8.1 Hz, 1H), 3.10 (t, J=8.0 Hz, 1H), 2.36 (m, 1H), 2.18 (s, 3H), 1.95 (m, 1H), 1.85 (m, 1H), 1.70 (m, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)=[O:5])#[N:2].CO/[CH:17]=[CH:18]/[C:19](=O)[CH3:20].N12CCN(CC1)CC2.Cl>COCCOCCO>[F:14][C:9]1[CH:8]=[C:7]([N:6]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:3]([C:1]#[N:2])[C:4]2=[O:5])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: CO/C=C/C(C)=O
Reactant: N#CCC(=O)Nc1ccc(F)c(F)c1
Agent: C1CN2CCN1CC2
Agent: Cl
Solvent: COCCOCCO
Product: Cc1ccc(C#N)c(=O)n1-c1ccc(F)c(F)c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 49 %

Procedure:
A mixture of 2-cyano-N-(3,4-difluorophenyl)acetamide (6.0 g, 30.6 mmol), (3E)-4-methoxybut-3-en-2-one (4.29 g, 42.8 mmol) and 2-(2-methoxyethoxy)ethanol (60 mL) was stirred at 90° C. for 20 min. 1,4-Diazabicyclo[2.2.2]octane (3.77 g, 33.6 mmol) was added, and the mixture was stirred at 125° C. for 5 hr. After cooling to room temperature, the mixture was adjusted to pH 5 with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate/hexane (=1/1) and collected by filtration to give the title compound (3.69 g, 49%) as a pale-yellow solid.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][NH:15]1>C1(C)C=CC=CC=1>[NH:15]1[C:14]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:17][CH:16]1[CH2:4][C:5]1[C:9]2[C:8](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:7][CH:6]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: CN(C)Cc1c[nH]c2ccccc12
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CC(Cc1c[nH]c3ccccc13)N2
Yield: 52.7 %

Procedure:
To gramine (731 mgs, 4.2 mmol) in dry PhMe (20 ml) was added 1,2-dihydroisoindole (prepared as in Org. Syn., Coll. Vol. V, p. 406) (500 mgs, 4.2 mmol) and the reaction refluxed for 6 h. The solvent was evaporated, the residue triturated with PhMe and the resultant solid recrystallised from PhMe to yield the title compound (550 mgs, 52%). M.p. 168°-170° C.; (Found: C, 80.44; H, 6.46; N, 10.98. C17H16N2.0.25H2O) requires C, 80.76; H, 6.38; N, 11.08%). δH (CDCl3) 4.00 (4H, s, 2×isoindolinyl CH2), 4.11 (2H, s, NCH2Ar), 7.08-7.23 (7H, m, ArH), 7.36 (1H, d, J 7.9 Hz, ArH), 7.77 (1H, d, J 7.9 Hz, ArH), 8.18 (1H, brs, NH); m/z (CI+, NH3) 249 (M+1)+.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C([Li])CCC.[CH3:14][C:15](N(C)C)=[O:16].[Cl-].[NH4+]>C1COCC1>[CH:1]([N:4]1[C:8]([C:15](=[O:16])[CH3:14])=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1cncn1
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1ncnn1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of 1-isopropyl-1H-[1,2,4]triazole (33 g, 300 mmol) in THF at −10° C. was added n-butyllithium (145 mL, 2.5M, 360 mmol) dropwise over 45 min, and then the mixture stirred at 0° C. for 30 min. DMA (35 mL) was added, the mixture allowed to warm to RT and stirred for 1 h. The resultant suspension was treated with saturated aqueous ammonium chloride (300 mL). The aqueous phase was extracted with ethyl acetate and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to give 1-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone as a pale orange oil (40.1 g, 87%). 1H NMR δ (ppm) (CDCl3): 7.93 (1H, s), 5.58-5.46 (1H, m), 2.72 (3H, d, J=0.78 Hz), 1.49 (6H, dd, J=6.61, 0.78 Hz).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:18][CH3:19])[C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][CH2:31][CH2:32][NH2:33].C(N(CC)CC)C>CS(C)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:18][CH3:19])[C:10]([F:17])=[C:11]([NH:33][CH2:32][CH2:31][NH:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[C:12]=3[O:14][CH3:15])[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: NCCNc1ccccn1
Reactant: CNc1c(F)c(F)c(OC)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CNc1c(F)c(NCCNc2ccccn2)c(OC)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-methylamino-4-oxoquinoline-3-carboxylic acid (500 mg, 1.54 mmol), N-2-pyridyl-1,2-ethanediamine (423 mg, 3.03 mmol) and triethylamine (0.430 mL, 3.09 mmol) in anhydrous DMSO (8 mL) was stirred at 100° C. for 3 h. After cooling, the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, washed with water, dried over Na2SO4, and evaporated. The residue was purified by column chromatography (hexane: EtOAc 1:1→EtOAc) to give 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-5-methylamino-7-[2-(2-pyridylamino)ethylamino]-4-oxoquinoline-3-carboxylic acid (373 mg, 55%) as a yellow solid.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1.Cl>O1CCCC1.O>[F:30][C:27]([F:28])([F:29])[C:24]1[CH:23]=[CH:22][C:21]([C:20]2[O:19][N:18]=[CH:17][C:16]=2[CH2:3][CH2:2][C:1]([OH:9])=[O:8])=[CH:26][CH:25]=1
Reactant: FC(F)(F)c1ccc(-c2oncc2CCl)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCc1cnoc1-c1ccc(C(F)(F)F)cc1
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
To a solution of diethyl malonate (4.71 g) in tetrahydrofuran (40 ml) was gradually added sodium hydride (60%, oil, 1.07 g) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(4-trifluoromethylphenyl)isoxazole (3.50 g) in tetrahydrofuran (40 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was dissolved in a mixture of 6N hydrochloric acid (40 ml) and acetic acid (60 ml) and heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated, dried and recrystallized from ethyl acetate to give a colorless prism (3.00 g, yield 79%) of 3-[5-(4-trifluoromethylphenyl)-4-isoxazolyl]propionic acid. melting point: 171–172° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][O:8][C:9](=[O:29])[C@@H:10]2[CH2:14][C@@H:13]([OH:15])[CH2:12][N:11]2[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:29])[C@@H:10]2[CH2:14][C@@H:13]([O:15][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:12][N:11]2[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)=[O:17])=[CH:30][CH:31]=1
Reactant: COc1ccc(COC(=O)[C@@H]2C[C@@H](O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)[C@@H]2C[C@@H](OC(=O)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C

Procedure:
Trans-1-(p-Nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzyl ester (49 g) was dissolved in 300 ml of dry tetrahydrofuran, and 33 ml of triethylamine, 9.59 g of 4-dimethylaminopyridine and 33.2 g of benzoyl chloride were added thereto, followed by stirring under reflux for 5 hours. The reaction mixture was cooled down to room temperature and distilled to remove the solvent. The residue was diluted with ethyl acetate, washed successively with water, dilute hydrochloric acid, water, a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to remove the solvent. Recrystallization of the residue from diethyl ether gave trans-1-(p-nitrobenzyloxycarbonyl)-4-benzoyloxy-L-proline p-methoxybenzyl ester.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([OH:13])=O)=[CH:7][CH:8]=2)[NH:3]1.[NH2:14][C:15]1[CH:16]=[C:17]([NH:21][C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:19][CH:20]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:22]([NH:21][C:17]1[CH:16]=[C:15]([NH:14][C:11]([C:6]2[CH:5]=[C:4]3[C:9]([CH2:10][C:2](=[O:1])[NH:3]3)=[CH:8][CH:7]=2)=[O:13])[CH:20]=[CH:19][CH:18]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(NC(=O)c2ccccc2)c1
Reactant: O=C1Cc2ccc(C(=O)O)cc2N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Cc2ccc(C(=O)Nc3cccc(NC(=O)c4ccccc4)c3)cc2N1
Reaction time: 20 h

Procedure:
To a solution of 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (0.20 g, 1.1 mmol) in DMF (1 ml) is added N-(3-amino-phenyl)-benzamide (0.26 g, 1.2 mmol), N,N-diisopropylethylamine (0.44 g, 3.4 mmol) and HATU (0.47 g, 1.24 mmol). The reaction is stirred for 20 hours and concentrated. The residue is purified by HPLC (C18 column, eluted with CH3CN—H2O containing 0.05% TFA) to give 2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid (3-benzoylamino-phenyl)-amide as off-white solid. This amide (15 mg, 0.04 mmol) is then heated with 1H-pyrrole-2-carbaldehyde (6.0 mg, 0.06 mmol) in ethanol (2 ml) in the presence of 2 drops of piperidine at 80° C. for 20 hours. The mixture is concentrated and the desired compound is obtained after HPLC purification: 1H NMR (DMSO-d6) δ 6.41 (s, 1H), 6.93 (s, 1H), 7.31 (t, 1H, J=7.8 Hz), 7.44 (s, 1H), 7.48-7.51 (m, 3H), 7.54 (t, 2H, J=7.2 Hz), 7.59 (d, 1H, J=6.6 Hz), 7.70 (d, 1H, J=8.4 Hz), 7.78 (d, 1H, J=8.4 Hz), 7.92 (s, 1H), 7.98 (d, 2H, J=7.2 Hz), 8.33 (s, 1H), 10.27 (s, 1H), 10.31 (s, 1H), 11.13 (s, 1H), 13.38 (s, 1H); LC-MS: 449.1 (MH+).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][O:15][CH2:16][CH:17]([CH3:27])[O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.[OH-].[K+]>C(O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH:17]([CH3:27])[CH2:16][O:15][CH3:14])=[CH:26][CH:25]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Reactant: COCC(C)Oc1ccc(CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COCC(C)Oc1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
In 30 ml of 95% ethanol were dissolved 1.5 g of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone and 1.8 g of 4-(2-methoxy-1-methylethoxy)-benzyl bromide, and thereto was added 0.48 g of powdery potassium hydroxide. The reaction mixture was stirred overnight at room temperature. Then, similarly to the procedures in Preparation Example 3, there was obtained 1.2 g of the aimed product, m.p. 51.0°~52.0° C.