Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(CC2C=C3C(C(O)=C(C(OCC)=O)C(=[O:24])N3CCCSC)=NC=2)=CC=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]2[CH:48]=[C:47]3[C:42]([C:43]([OH:61])=[C:44]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[C:45](=[O:55])[N:46]3[CH2:49][CH2:50][CH2:51][S:52]([CH3:54])=[O:53])=[N:41][CH:40]=2)=[CH:34][CH:33]=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]2[CH:48]=[C:47]3[C:42]([C:43]([OH:61])=[C:44]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[C:45](=[O:55])[N:46]3[CH2:49][CH2:50][CH2:51][S:52]([CH3:54])(=[O:24])=[O:53])=[N:41][CH:40]=2)=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCSC)c1=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)=O)c1=O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)(=O)=O)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cold (0° C.) solution of 30% ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methylthio)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 70% ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methylsulfinyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (269 mg, 0.611 mmol) in dichloromethane (10 mL) was added m-chloroperoxybenzoic acid (158 mg, 0.915 mmol). The reaction mixture was warmed to room temperature and stirred 3 hours. The reaction mixture was diluted with dichloromethane and washed with water and brine, then dried over sodium sulfate. Filtration and concentration provided ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methylsulfonyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1 H), 7.66 (s, 1 H), 7.22 (dd, J=8.5, 5.5 Hz, 2 H), 7.03 (t, J=8.5 Hz, 2 H), 4.52 (q, J=7.1 Hz, 2 H), 4.39 (t, J=7.8 Hz, 2 H), 4.13 (s, 2 H), 3.16 (t, J=6.9 Hz, 2 H), 2.95 (s, 3 H), 2.22 (m, 2 H), 1.48 (t, J=7.0 Hz, 3 H); MS m/z 461 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[N:6]=[N:7][N:8]([CH2:10][C@H:11]([N:18]2[CH2:23][C:22]3[CH:24]=[C:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[CH:27][C:21]=3[N:20]=[C:19]2[NH2:35])[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:43][O:44][CH2:45][C:46](Cl)=[O:47]>C(Cl)Cl>[C:1]([C:5]1[N:6]=[N:7][N:8]([CH2:10][C@@H:11]([N:18]2[CH2:23][C:22]3[CH:24]=[C:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]=[CH:27][C:21]=3[N:20]=[C:19]2[NH:35][C:46](=[O:47])[CH2:45][O:44][CH3:43])[CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cn(C[C@@H](C2CCCCC2)N2Cc3cc(Oc4ccccc4)ncc3N=C2N)nn1
Reactant: COCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)NC1=Nc2cnc(Oc3ccccc3)cc2CN1[C@H](Cn1cc(C(C)(C)C)nn1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound #152 (0.115 g, 0.24 mmol), prepared, for example, as described in Example 44 above, was taken up into DCM (5 mL) and then triethylamine (34 μL, 0.24 mmol) was added. Methoxy-acetyl chloride (22 μL, 0.24 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified using normal phase chromatography (heptanes:EtOAc) to yield the title compound as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:13][CH2:14][O:15][CH2:16][CH2:17]Br.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]([OH:11])[CH3:10])=[CH:3][C:2]=1[N:1]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: BrCCOCCBr
Reactant: CC(O)c1ccc(F)c(N)c1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)c1ccc(F)c(N2CCOCC2)c1
Yield: 88.4 %

Procedure:
A mixture of 1-(3-amino-4-fluoro-phenyl)ethanol (3.1 g), bromoethyl ether (5.413 g), and i-Pr2NEt (6.1921 g) in toluene (15 mL) was refluxed for 4 hours. After cooling, the reaction mixture was quenched with water. The aqueous layer was extracted with dichloromethane, and the combined organic layers were dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography (33% ethyl acetate in hexane) to give 3.98 g of the title compound as an oil.
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][C:14]([OH:16])=[O:15])=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=[CH:8][CH:7]=2)([CH3:3])[CH3:2].OS(O)(=O)=O.[CH3:25][CH2:26]O>>[CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][C:14]([O:16][CH2:25][CH3:26])=[O:15])=[C:10]([N+:17]([O-:19])=[O:18])[CH:9]=[CH:8][CH:7]=2)([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)c1[nH]c2cccc([N+](=O)[O-])c2c1CC(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1c(C(C)C)[nH]c2cccc([N+](=O)[O-])c12

Procedure:
A solution of (2-isopropyl-4-nitro-1H-indol-3-yl)acetic acid from Step D (500 mg, 1.91 mmol) and conc. H2SO4 (0.5 mL) in EtOH (100 mL) was heated at reflux for 1 h. The cooled mixture was partially concentrated in vacuo, made basic by addition of saturated aqueous NaHCO3 and washed with CHCl3 (4×30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound, which was of sufficient purity for use in the next step. MS: m/z=291 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=O)=O)=[CH:4][C:3]=1[Cl:12].CN(C=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[Cl:12]
Reactant: O=S(=O)(Cl)c1ccc(Br)c(Cl)c1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Sc1ccc(Br)c(Cl)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 32.3 %

Procedure:
4-Bromo-3-chloro-benzenesulfonyl chloride (3.78 g, 13.0 mmol) was dissolved in dichloromethane (40 ml) and DMF (1.0 ml) was added. The mixture was cooled to 0° C. under argon and triphenylphosphine (10.26 g, 39.0 mmol) was added slowly, then the mixture was allowed to return to room temperature with stirring over 16 h. Hydrochloric acid (1 M, 75 ml) was added and the layers were separated. The organic layer was concentrated and the residue suspended in 1 M aqueous sodium hydroxide (75 ml) and filtered. The filtrate was extracted with Et2O (×2), then neutralised (1 M HCl, 75 ml). The mixture was then extracted (Et2O×3) and the combined organic layers were dried (Na2SO4) and concentrated to afford the title compound as a colourless oil (0.94 g, 32%). 1H NMR (CDCl3 400 MHz) 3.49 (1H, s), 7.02 (1H, dd, J=8.35, 2.24 Hz), 7.38 (1H, d, J=2.18 Hz), 7.45 (1H, d, J=8.35 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:26])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[O:22][CH2:23][CH2:24][F:25])[CH:5]=[CH:6][C:7]=1[F:8].C1COCC1.[Cl:32][C:33]1[C:46]([N:47]=[C:48]=S)=[C:45]([Cl:50])[CH:44]=[CH:43][C:34]=1[CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39].CC(C)N=C=NC(C)C>CC#N.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:11]2[C:12]([O:22][CH2:23][CH2:24][F:25])=[CH:13][C:14]3[N:20]([CH3:21])[C:48]([NH:47][C:46]4[C:45]([Cl:50])=[CH:44][CH:43]=[C:34]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[C:33]=4[Cl:32])=[N:17][C:15]=3[CH:16]=2)=[O:26])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CNc1cc(OCCF)c(C(=O)Nc2ccc(F)c(Cl)c2)cc1[N+](=O)[O-]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: [Pd]
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Solvent: CC#N
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)Nc3ccc(F)c(Cl)c3)c(OCCF)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(3-chloro-4-fluorophenyl)-2-(2-fluoroethoxy)-4-methylamino-5-nitro-benzamide (67.9 mg, 0.176 mmol), Pd/C (15 mg) and 10 mL THF is stirred under a H2-atmosphere (3 bar) for 8 h. The crude mixture is filtered into a flask charged with N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (59 mg, 0.185 mmol) and concentrated to ˜5 mL. The mixture is stirred for 2 h at rt and concentrated i. vac. The mixture is diluted with MeCN (2.0 mL), DIC (29 μl, 0.186 mmol) is added and it is stirred overnight at rt and 2 h at 60° C. The mixture is cooled to rt and the resulting precipitate is filtered off, washed with MeCN, redissolved in dioxane/MeCN and a few drops of HCOOH and lyophilized.
Reaction SMILES: NC1C=C([C:8]2C3C(=CC(OC)=C(OC)C=3)N=[C:10](CN)[N:9]=2)C=CC=1.Cl.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[C:32]([NH:39][CH3:40])[N:31]=[C:30]2[C:41]1[CH:42]=[C:43]([NH:47][C:48](=[O:58])[C:49]2[CH:57]=[CH:56][C:52]([C:53]([OH:55])=O)=[CH:51][CH:50]=2)[CH:44]=[CH:45][CH:46]=1>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[C:32]([NH:39][CH3:40])[N:31]=[C:30]2[C:41]1[CH:42]=[C:43]([NH:47][C:48](=[O:58])[C:49]2[CH:57]=[CH:56][C:52]([C:53]([N:9]([CH3:10])[CH3:8])=[O:55])=[CH:51][CH:50]=2)[CH:44]=[CH:45][CH:46]=1
Reactant: COc1cc2nc(CN)nc(-c3cccc(N)c3)c2cc1OC
Reactant: CNc1nc(-c2cccc(NC(=O)c3ccc(C(=O)O)cc3)c2)c2cc(OC)c(OC)cc2n1
Agent: Cl
Product: CNc1nc(-c2cccc(NC(=O)c3ccc(C(=O)N(C)C)cc3)c2)c2cc(OC)c(OC)cc2n1

Procedure:
The following compounds of Examples 4 to 10 were synthesized by methods similar to Example 3, using the compound of Example 2 as a starting substance, and also using the corresponding alcohol or amine.
Reaction SMILES: [CH:1](=O)[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH:8]1[CH2:12][CH:11]=[CH:10][CH:9]=1>C(NCC)C.CO>[O:6]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:1]1[C:9](=[CH2:10])[CH:8]=[CH:12][CH:11]=1
Reactant: C1=CCC=C1
Reactant: O=Cc1ccco1
Solvent: CCNCC
Solvent: CO
Product: C=C1C=CC=C1c1ccco1

Procedure:
About equal molar amounts of furfural and cyclopentadiene are reacted in the presence of diethylamine catalyst and about 33% methanol solvent according to the method suggested by C. Schmidt, Chem, Ber., Volume 90, p. 1352, 1957. A viscous dark material is separated from the water layer.
Reaction SMILES: [O:1]1[C:12]2[C:4](=[CH:5][C:6](=[CH:10][CH:11]=2)[CH2:7][CH:8]=[CH2:9])[O:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:18]>C(Cl)Cl>[O:1]1[C:12]2[C:4](=[CH:5][C:6](=[CH:10][CH:11]=2)[CH2:7][CH:8]2[O:18][CH2:9]2)[O:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1ccc2c(c1)OCO2
Solvent: ClCCl
Product: c1cc2c(cc1CC1CO1)OCO2

Procedure:
Safrole oxide was prepared by stirring a solution of safrole (1.48 mL, 10 mmol) and m-chloroperoxybenzoic acid (2.70 g, 11 mmol) in methylene dichloride (25 mL) overnight. The reaction was quenched by pouring into water (50 mL). The aqueous was extracted with ether (3×25 mL). The organic layers were combined and washed with 10% aqueous sodium sulfate (2×25 mL), saturated aqueous sodium bicarbonate (3×25 mL), and brine (25 mL). The organic phase was dried over magnesium sulfate and the solvents were removed in vacuo. The resulting yellow oil was used without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[CH:11]=[CH:12][C:13]([C:15]1[NH:16][CH:17]=[CH:18][CH:19]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[O:1]([C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][C:13]([C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[O:14])[CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1cccc(Oc2ccccc2)c1)c1ccc[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(CCc1cccc(Oc2ccccc2)c1)c1ccc[nH]1
Yield: 99.3 %

Procedure:
A mixture of 9 g (31.1 mmol) of 2-(3-phenoxycinnamoyl)pyrrole, 3, and 2 g of 10% Pd/C in 200 ml of ethanol was stirred and hydrogen gas was passed over the reaction mixture for 2 hours and 15 minutes. The mixture was dried and concentrated on a rotary evaporator to give 9 g of solid product. The crude reaction product was chromatographed on silica gel (for dry column chromatography), eluting with ethyl acetate/hexane (1:4). The chromatographed material was recrystallized twice from isopropanol yielding analytically pure light yellow solid material, m.p. 75°-76° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C:7]2=[N:6][C:5]1=[O:15].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(#N)C>[CH3:23][S:24]([O:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C:7]2=[N:6][C:5]1=[O:15])(=[O:26])=[O:25]
Reactant: O=c1nc2n(c(=O)n1CCO)CCCC2
Reactant: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCn1c(=O)nc2n(c1=O)CCCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To an ice-cooled solution of 1.80 g of 3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-2H-pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione prepared in Reference Example 27 and 1.20 g of triethylamine in 25 ml of acetonitrile, 1.17 g of methanesufonyl chloride was added dropwise. After stirring for 30 minutes, the mixture was concentrated to dryness, and the residue was extracted with chloroform. Concentration of the chloroform solution gave 2.34 g of the entitled compound as an yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:24]=[CH:23][C:12]2[C@:13]3([CH3:22])[C@@H:18]([CH2:19][CH2:20][C:11]=2[CH:10]=1)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)#[N:2].[C:25](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:25][N:17]1[C@H:18]2[C@@:13]([CH3:22])([C:12]3[CH:23]=[CH:24][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[CH:10][C:11]=3[CH2:20][CH2:19]2)[CH2:14][CH2:15][C:16]1=[O:21]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccccc3C#N)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccccc4C#N)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-cyanophenyl)-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (55 mg, 0.17 mmol), 0.4 mL of t-butanol, and potassium t-butoxide (58 mg, 0.51 mmol). Methyl iodide (0.034 mL, 0.54 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 50 mg (87%) of the title compound as a white solid. mp 54°-55°. FDMS: m/e=330. α[D]589 =+74.33 (c=0.36, chloroform).
Reaction SMILES: [N+](C1C=CC(COC([NH:12][S:13]([NH:16][CH2:17][CH2:18]O)(=[O:15])=[O:14])=O)=CC=1)([O-])=O.[OH:22][C@@H:23]([C@H:25]1[C:61](=[O:62])[N:27]2[C:28]([C:48]([O:50]CC3C=CC([N+]([O-])=O)=CC=3)=[O:49])=[C:29]([C:32]3[S:36][C:35]4=[C:37]([C:40]([C:42]5[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=5)=[O:41])[N:38]=[CH:39][N:34]4[CH:33]=3)[C@H:30]([CH3:31])[C@H:26]12)[CH3:24]>>[OH:22][C@@H:23]([C@H:25]1[C:61](=[O:62])[N:27]2[C:28]([C:48]([O-:50])=[O:49])=[C:29]([C:32]3[S:36][C:35]4=[C:37]([C:40]([C:42]5[CH:43]=[N+:44]([CH2:18][CH2:17][NH:16][S:13](=[O:15])(=[O:14])[NH2:12])[CH:45]=[CH:46][CH:47]=5)=[O:41])[N:38]=[CH:39][N:34]4[CH:33]=3)[C@H:30]([CH3:31])[C@H:26]12)[CH3:24]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cccnc5)c4s3)[C@H](C)[C@H]12
Reactant: O=C(NS(=O)(=O)NCCO)OCc1ccc([N+](=O)[O-])cc1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(C(=O)c5ccc[n+](CCNS(N)(=O)=O)c5)c4s3)[C@H](C)[C@H]12
Yield: 17.7 %

Procedure:
The title compound (101 mg) was prepared in the same manner as in steps a) and b) of Example 4, except that 572 mg of 2-(4-nitrobenzyloxycarbonylaminosulfonyl)aminoethanol was used instead of 3-azido-1-propanol in step a) of Example 4 and 585 mg of 4-nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate was used as the starting compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](O)=[O:23])=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:22](=[O:23])[CH2:21][C:18]2[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(O)Cc1ccc(F)cc1
Product: COc1ccc(CCNC(=O)Cc2ccc(F)cc2)cc1OC

Procedure:
prepared by reaction of 3,4-dimethoxyphenylethylamine and 4-fluorophenyl-acetic acid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl.[N:30]1([CH2:36][CH2:37][O:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]([C:49](O)=O)=[CH:41][CH:40]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH2:1]([N:3]([CH2:49][C:42]1[C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:39]([O:38][CH2:37][CH2:36][N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:40][CH:41]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c2ccccc12
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCC2)c2ccccc12)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 87.8 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (60 mg) and 4-(2-piperidin-1-ylethoxy)naphthalene-1-carboxylic acid hydrochloride (100 mg) according to an analogous synthetic method to Example 152, the title compound (78 mg) was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH2:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH2:12][CH2:13][CH3:14]>>[CH2:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:20][CH:21]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCc1ccc(N)cc1
Reactant: CSc1ccc(C#N)cc1
Product: CCCCc1ccc(NC(=N)c2ccc(SC)cc2)cc1

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (1 g, 6.7 mmol) and 4-n-butylaniline (1 g, 6.7 mmol) by following the procedure described in preparation 10 (1.27 g, yield 63.66%). 1H-NMR (CDCl3):δ 0.91-0.95 (t, 3H), 1.33-1.39 (m, 2H), 1.56-1.63 (m, 2H), 2.52 (s, 3H), 2.56-2.6 (m, 2H), 4.8 (bs, 2H, D2O exchangeable), 6.88-6.9 (d, 2H), 7.15-7.17 (d, 2H), 7.27-7.29 (m, 2H), 7.79-7.81 (d, 2H). MS m/z:299.3 (M+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1.[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br.[Cl-].[NH4+]>C1COCC1>[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][C:13]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]1
Reactant: BrCc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(Cc2cccc(Br)c2)CC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Under argon, 14.8 ml (105.48 mmol) of diisopropylamine were initially charged in 66 ml of dry THF, and the mixture was cooled to −40° C. 42.2 ml (105.48 mmol) of n-butyllithium solution (2.5 M in hexane) were slowly added dropwise and the mixture was stirred for 30 min. The reaction solution was then cooled to −78° C., and a solution of 10.0 g (70.32 mmol) of tert-butyl cyclopropanecarboxylate in 17 ml of THF was added. After 4 h of stirring at −78° C., a solution of 19.34 g (77.36 mmol) of 3-bromobenzyl bromide in 17 ml THF was added. The reaction mixture was slowly warmed to RT overnight, and aqueous ammonium chloride solution was then added carefully and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on 750 g of silica gel (mobile phase cyclohexane/dichloromethane 50:1, then 5:1). This gave 13.3 g (60.7% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[NH2:18][C@@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:18][C@@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Yield: 82.9 %

Procedure:
Following general procedure B, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (200 mg, 0.640 mmol) was reacted with tert-butyl cis-4-aminocyclohexylcarbamate (164 mg, 0.767 mmol) to afford the desired product (259 mg, 83%) as a brown solid: ESI MS m/z 489 [C24H30BrN3O3+H]+.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.O.[NH2:30][NH2:31]>C(O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:30][N:31]=[C:19]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: O=C(CCc1ccncc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Solvent: CCO
Solvent: O
Product: O=c1c2c(CCc3ccncc3)n[nH]c2c2cccnc2n1-c1ccccc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(pyridin-4-yl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (50 mg, 0.13 mmol, prepared in Synthetic Example 1) in ethanol (1 ml) was added hydrazine monohydrate (80%, 20 μl, 0.50 mmol, 3.7 eq.) and the resultant mixture was heated under reflux overnight. The liquid reaction mixture was cooled to room temperature, and then filtered to give precipitates which were dried to obtain 5-phenyl-3-[2-(pyridin-4-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (40 mg, 81%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:14])[N:4]([CH:11]([CH3:13])[CH3:12])[C:5]([S:9][CH3:10])=[N:6][C:7]=1[OH:8].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:14])[N:4]([CH:11]([CH3:12])[CH3:13])[C:5]([S:9][CH3:10])=[N:6][C:7]=1[O:8][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([Cl:15])=[CH:17][CH:18]=1
Reactant: CSc1nc(O)c(Br)c(=O)n1C(C)C
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(OCc2ccc(Cl)cc2)c(Br)c(=O)n1C(C)C
Yield: 55.3 %

Procedure:
In 20 ml of N,N-dimethylformamide were dissolved 1.0 g of 5-bromo-6-hydroxy-2-methylthio-3-i-propyl-4(3H)-pyrimidinone and 0.74 g of 4-chlorobenzylbromide, and then 1 g of potassium carbonate was added thereto. The mixture was subjected to a reaction at 80° C. for 3 hours. After allowing to cool in air, the resulting solution was poured into 50 ml of water and then extracted twice with 30 ml of ethyl ether. The ethyl ether layer was washed with water, dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure to give 1.25 g of a crude product. The product was purified by means of column chromatography (on silica gel, eluting with benzene) to give 0.8 g of the intended product as an oil.