Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.I[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:44])[C:36](=[O:45])[CH:35]=1>CN(C=O)C>[C:1]1([O:7][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37](=[O:44])[C:36](=[O:45])[CH:35]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1C=C(OCCCCCCI)c2ccccc2C1=O
Reactant: Oc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C1C=C(OCCCCCCOc2ccccc2)c2ccccc2C1=O
Reaction time: 48 h
Yield: 42.8 %

Procedure:
Phenol (28 mg, 0.3 mmol) was treated with tetrabutylammonium hydroxide (0.3 mL of 1.0 M solution in methanol) and the reaction mixture was concentrated to dryness in vacuo. Iodonaphtoquinone 505 (115 mg, 0.3 mmol) in DMF (3 mL) was added to the tetrabutylammonium salt, stirred for 48 h and quenched with H2O (10 mL). The product was extracted with CHCl3, the extract was washed with H2O, then brine, dried (Na2SO4), and purified by chromatography (5% EtOAc in benzene) to give 512 as a yellow solid (45 mg, 43%) 1H NMR (CDCl3) 8.13 (d, J=7.4 Hz, 1H), 7.86 (d, J=7.4 Hz, 1H), 7.67 (t, J=7.6 Hz, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.15-7.40 (m, 2H), 6.85-7.10 (m, 3H), 5.96 (s, 1H), 4.17 (t, J=6.5 Hz, 2H), 3.99 (t, J=6.2 Hz), 1.70-2.10 (m, 4H), 1.35-1.70 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:11](=O)[CH3:12].[BH3-]C#N.[Na+].C(NCC)C>C1(C)C=CC=CC=1.CO>[CH2:11]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[CH3:12]
Reactant: CC=O
Reactant: NCCc1ccc(O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCNCC
Solvent: CO
Solvent: Cc1ccccc1
Product: CCNCCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
To a stifling solution of tyramine (1 mM, 137 mg) and MeOH (5 mL) was added acetaldehyde in excess. Then excess NaBH3CN (1 mM, 62.8 mg) was added and the mixture stirred for 2 hours at r.t. After evaporating the solvent, methylene chloride (5 mL) was added and mixture was washed with H2O (3×5 mL). The mixture was dried over MgSO4, filtered, and evaporated to give the product in 72% yield as an orange oil. TLC (toluene:diethylamine, 4:1 v/v): RF=0.5. 1H NMR, δ: 9.48 (s, 1H), 7.14 (d, 2H), 6.70 (d, 2H), 2.85 (m, 2H), 2.60 (t, 2H), 250 (q, 2H), 2.1 (s, 1H), 1.1 (t, 3H). 13C NMR, δ: 167.5, 134.3, 130.2, 115.6, 48.2, 44.4, 35.6, 15.6. Anal. calcd for C10H15NO: C, 72.69; H, 9.15; N, 8.48%. Found; C, 72.50; H, 9.20; N, 8.50%.
Reaction SMILES: F[C:2]1[CH:27]=[CH:26][C:5]2[S:6][CH:7]=[C:8]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[C:23]([O:24][CH3:25])=[CH:22][N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[C:4]=2[CH:3]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.OCCCC1C2C=C([C:52]([NH2:54])=[O:53])C=CC=2SC=1.COC1C(N2CCNCC2)=NC=NC=1>>[NH2:54][C:52]([C:2]1[CH:27]=[CH:26][C:5]2[S:6][CH:7]=[C:8]([CH2:9][CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[C:23]([O:24][CH3:25])=[CH:22][N:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[C:4]=2[CH:3]=1)=[O:53]
Reactant: NC(=O)c1ccc2scc(CCCO)c2c1
Reactant: COc1cncnc1N1CCN(CCCc2csc3ccc(F)cc23)CC1
Agent: COc1cncnc1N1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: COc1cncnc1N1CCN(CCCc2csc3ccc(C(N)=O)cc23)CC1

Procedure:
The title compound was prepared (0.20 g, 37%, mp 169°-170° C.) in a manner analogous to the preparation of 1-[3-(5-fluorobenzo[b]thien-3-yl)propyl]-4-(5-methoxy-4-pyrimidinyl)piperazine (Example 52) by the reaction of 3-(3-hydroxypropyl)benzo[b]thiene-5-carboxamide tosylate with 1-(5-methoxy-4-pyrimidinyl)piperazine.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])O)[OH:11])[OH:9])[OH:7].OCCNC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O>>[CH2:5]1[N:4]([CH2:3][CH2:2][OH:1])[CH:12]([CH2:14][OH:15])[CH:10]([OH:11])[CH:8]([OH:9])[CH:6]1[OH:7]
Reactant: OCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: OCCNC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O
Product: OCCN1CC(O)C(O)C(O)C1CO
Reaction time: 24 h
Yield: 95 %

Procedure:
N-(2-hydroxyethyl)glucamine is microbially oxidized in substantial accordance with the teaching of Example 26, except N-(2-hydroxyethyl)glucamine is used in place of N-ethylglucamine and N-(2-hydroxyethyl)-1-deoxynojirimycin is obtained instead of N-ethyl-1-deoxynojirimycin. HPLC analysis after 24 hours indicates that 79% of the initial charge of N-(2-hydroxyethyl)glucamine has been converted to 6-(2-hydroxyethyl)amino-6-deoxy-α-L-sorbofuranose. After 48 hours, at least 90% of the initial charge has been converted. After 72 hours, the supernatant is separated from the cells and sterile filtered. The pH of an aliquot (10 mL) is adjusted to pH 9.0 with concentrated NH4OH, chilled in an ice bath, and 100 mg NaBH4 is added. After standing in the ice bath overnight, the samples are acetylated and assayed by gas chromatography mass spectroscopy (GC-MS). GC-MS indicates a 95% yield of N-(2-hydroxyethyl)-1-deoxynojirimycin from 6-(2-hydroxyethyl)amino-6-deoxy-α-L-sorbofuranose (chemical ionization mass spectroscopy of the acetylated product indicated the GC peak corresponding to the reduced, cyclized product has a parent peak mass of 418 (M+H) corresponding to the penta-acetylated N-2hydroxyethyl-1-deoxynojirimycin.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[C@@H:10]([C@H:31]([CH3:33])O)[NH:11][C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)(=O)=O.C(OC(=O)C)C>C1(C)C=CC=CC=1>[C:12]([N:11]1[C@@H:31]([CH3:33])[C@@H:10]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:34])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[C@H](O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OCc1ccccc1
Solvent: O=S(=O)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@H]1[C@H](C(=O)OCc2ccccc2)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
N-Trityl-D-threonine benzyl ester (2.5 g, 5.5 mmol), TEA (2.8 ml, 20 mmol) were dissolved in 100 ml of dry toluene at −50° C. A solution of sulfuryl chloride (800 ul, 8 mmol) in toluene (20 ml) was added in 15 min. The reaction was allowed to warm up to r.t. Ethylacetate (100 ml) was added and this was washed with sat. NaCl, dried over Na2SO4. The product was crystallized in MeOH (10 ml) to give benzyl N-trityl-3(S)-methylaziridine-2(R)-carboylate. NMR (500 MHz, CDCl3) δ: 1.37 (d, 3H), 1.64 (m, 1H), 1.95 (d, 1H), 5.15(d, J=12 Hz, 1H), 5.28(d, J=12 Hz, 1H), 7.19˜7.28 (m, 12H), 7.33˜7.36 (m, 1H), 7.36˜7.39 (m, 3H), 7.51˜7.54 (m, 4H).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[CH:9]=2)[CH:2]=1.I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].C(=O)([O-])[O-].[K+].[K+]>[N+](C1C=CC=CC=1)([O-])=O.[Cu]>[C:1]1([CH3:22])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([C:3]2[CH:2]=[C:1]([CH3:22])[CH:6]=[CH:5][CH:4]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([C:29]3[CH:24]=[C:25]([CH3:30])[CH:26]=[CH:27][CH:28]=3)[C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[CH:9]=2)[CH:2]=1
Reactant: Cc1ccccc1I
Reactant: Cc1cccc(Nc2cccc(Nc3cccc(C)c3)c2)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cccc(N(c2cccc(C)c2)c2cccc(N(c3cccc(C)c3)c3cccc(C)c3)c2)c1

Procedure:
More specifically, resorcinol of formula (A) is reacted with m-toluidine of formula (B) in the presence of iodine in a nitrogen current to obtain N,N'-di(3-tolyl)-1,3-phenylenediamine of formula (C). Then, N,N'-di(3-tolyl)-1,3-phenylenediamine is reacted with iodotoluene of formula (D) in the presence of potassium carbonate and powdery copper under reflux in nitrobenzene to obtain N,N,N',N'-tetra(3-tolyl)-1,3-phenylenediamine of formula (E).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(=O)(O)[O-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C1(C)C=CC=CC=1>C1C=CC=CC=1>[C:13]([N:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1=CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)N1CC=CCC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
83.1 g (1 mol) of 1,2,5,6-tetrahydropyridine are dissolved in 300 ml of benzene. 83 g of sodium bicarbonate are introduced into this solution and the mixture is cooled to 0° under a nitrogen atmosphere and, at this temperature, treated dropwise in the course of one hour with 332 ml of a 50% strength solution of benzyl chloroformate in toluene (1 mol). The reaction mixture is stirred at 0° for a further 21/2 hours and then poured into 1.5 liters of ice-water. The benzene phase is separated off and the aqueous phase is extracted by shaking 3 times with 250 ml of methylene chloride; subsequently the combined organic phases are washed with 1 N hydrochloric acid and then with a saturated solution of sodium chloride, dried over sodium sulphate and evaporated under a water pump vacuum. The oily residue is distilled under a high vacuum and gives 1-carbobenzyloxy-1,2,5,6-tetrahydropyridine with a boiling point of 102°-113°/0.01 mm Hg.
Reaction SMILES: [C:1]([C:4]1[C:8]([NH:9][C:10](=O)[C:11]2[CH:16]=[C:15](S(N3CCN(CC)CC3)(=O)=O)[CH:14]=[N:13][C:12]=2[O:28][CH2:29][CH3:30])=[C:7]([CH2:32][CH3:33])[N:6]([CH2:34][CH2:35][O:36][CH3:37])[N:5]=1)(=[O:3])[NH2:2].[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40].[C:44](#N)[CH3:45]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:29]([O:28][C:12]1[C:11]([C:10]2[NH:2][C:1](=[O:3])[C:4]3[C:8](=[C:7]([CH2:32][CH3:33])[N:6]([CH2:34][CH2:35][O:36][CH3:37])[N:5]=3)[N:9]=2)=[CH:16][C:15]([C:43]#[C:42][Si:39]([CH3:41])([CH3:40])[CH3:38])=[CH:14][N:13]=1)[CH2:30][CH2:44][CH3:45]
Reactant: CC#N
Reactant: C#C[Si](C)(C)C
Reactant: CCOc1ncc(S(=O)(=O)N2CCN(CC)CC2)cc1C(=O)Nc1c(C(N)=O)nn(CCOC)c1CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCOc1ncc(C#C[Si](C)(C)C)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Reaction time: 2 h

Procedure:
The title compound from Example 1 of PCT application IB00/1430 (127 mg, 0.25 mmol) was suspended in triethylamine (2 mL) and trimethylsilylacetylene (38 mg, 0.39 mmol) and acetonitrile (2 mL). Pd(PPh3)2Cl2 (5 mg, 0.006 mmol) and cuprous iodide (1.2 mg, 0.006 mmol) were added and the reaction mixture stirred. After 1 h a further portion of trimethylsilylacetylene (19 mg, 0.19 mmol) was added and stirring continued for 2 h. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organics were washed with brine, dried (MgSO4) and concentrated to give a brown foam. Purification by flash column chromatography (gradient elution from 100% dichloromethane to 99% dichloromethane/methanol) gave the title compound as a light brown solid (108 mg).
Reaction SMILES: [S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[OH:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][N:11]=[C:10]1SC.[NH2:16][NH2:17]>C(O)C.COC(C)(C)C>[S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[OH:6][CH2:7][CH2:8][N:9]1[CH2:13][CH2:12][N:11]=[C:10]1[NH:16][NH2:17]
Reactant: NN
Reactant: CSC1=NCCN1CCO
Agent: CS(=O)(=O)O
Solvent: COC(C)(C)C
Solvent: CCO
Product: NNC1=NCCN1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-Hydroxyethyl)-2-methylthioimidazoline mesylate (35 g, 0.136 mole) is suspended in ethyl alcohol (80 ml) and treated with anhydrous hydrazine (9.3 ml, 0.296 mole). The mixture became clear immediately. The solution is stirred at room temperature overnight and then diluted with t-butyl methyl ether (1 liter). On storage of the mixture in the freezer at -20° C., crystals separated, which are filtered, washed well with t-butyl methyl ether and dried. Recrystallization from isopropyl alcohol and t-butyl methyl ether gives 1-(2-hydroxyethyl)-2-hydrazinoimidazoline mesylate, melting point 85°-88° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:32]([OH:34])[CH3:33]>>[CH2:32]([O:34][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1)[CH3:33]
Reactant: CCO
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOc1nc(Nc2ccc(OC)c(Cl)c2)nc(NC2CCCCCC2)n1

Procedure:
A portion of 6-chloro-N-(3-chloro-4-methoxyphenyl)-N′-cycloheptyl-[1,3,5] triazine-2,4-diamine (5 g) was refluxed in ethanol in presence of K2CO3 (3.2g) for about 8–10 h. TLC was monitored. After the completion of the reaction, the reaction mass was filtered through vacuum and the filtrate was evaporated to yield the title compound. (Wt. 4.6 g Y: 90%).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][CH:8]2[CH:4]([CH2:5][CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7]2)[CH2:3]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C[Si](C)([O:30][CH2:31][CH2:32]O[Si](C)(C)C)C>C(Cl)Cl>[CH2:3]1[CH:4]2[CH:8]([CH2:7][CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5]2)[CH2:9][C:2]21[O:30][CH2:31][CH2:32][O:1]2
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Reactant: CCOC(=O)C1CC2CC(=O)CC2C1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CC2CC3(CC2C1)OCCO3
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 5-oxooctahydropentalene-2-carboxylate (210 mg) in DCM (5 mL) cooled to −78° C. were added slowly trimethylsilyl trifluoromethanesulfonate (11.89 mg, 0.054 mmol) and 2,2,7,7-tetramethyl-3,6-dioxa-2,7-disilaoctane (287 mg, 1.391 mmol) under nitrogen. After stirring at −78° C. for 30 min, the reaction mixture was warmed to rt and stirred at rt for 16 h. The reaction was quenched with anhydrous pyridine at −78° C. followed by sat. NaHCO3, and then extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography to afford ethyl hexahydro-1′H-spiro[[1,3]dioxolane-2,2′-pentalene]-5′-carboxylate (a mixture of endo/exo isomers) as a clear oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]#[C:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20].[H][H]>CN(C=O)C.[Pd]>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20]
Reactant: O=C1c2ccccc2C(=O)N1CC#Cc1cnccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCc1cnccn1
Yield: 65.9 %

Procedure:
N-[3-(2-Pyrazinyl)-2-propynyl]phthalimide (780 mg, 2.96 mmol) was dissolved in DMF (30 mL) followed by addition of 10% palladium on carbon (500 mg, 50% water), and then the mixture was stirred in a hydrogen atmosphere at room temperature for 5.5 hours. The reaction mixture was filtered through Celite, and the resulting filtrate was concentrated to give N-[3-(2-pyrazinyl)propyl]phthalimide (521 mg; yield 66%).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[F:10][C:11]1[CH:16]=[C:15]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28]O)=[CH:24][CH:23]=3)[N:18]=2)[CH:14]=[CH:13][C:12]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[Cl:3][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[N:18]=[C:17]([C:15]3[CH:14]=[CH:13][C:12]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:11]([F:10])[CH:16]=3)[O:21][N:20]=2)=[CH:23][CH:24]=1
Reactant: OCc1ccc(-c2noc(-c3ccc(-c4ccccc4)c(F)c3)n2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Fc1cc(-c2nc(-c3ccc(CCl)cc3)no2)ccc1-c1ccccc1
Temperature: 80 °C

Procedure:
Thionyl chloride (20 mL, 0.274 mol) and N,N-dimethylformamide (2 mL) are added to a stirred solution of 4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole-3-yl]phenylmethanol (32 g, 0.092 mol) in dichloromethane (150 mL) at 0° C. The reaction mixture is heated at 80° C. for 1 hour and then concentrated under reduced pressure. The residue is neutralized with a saturated aqueous sodium bicarbonate solution (150 mL) to furnish a solid which is filtered and washed with n-hexane (150 mL) to give 3-(4-chloromethylphenyl)-5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.C(OC([NH:30][CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:33]2[CH2:34][CH2:35][CH:31]([NH2:30])[CH2:32]2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1c(N2CCC(N)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 32.1 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (90 mg), 3-t-butoxycarbonylaminopyrrolidine (115 mg), DBU (50 mg) and anhydrous acetonitrile (4 ml) was refluxed for 20 hours. After cooling, the resulting precipitate was collected by filtration and added to concentrated hydrochloric acid-methanol (1:1, 2 ml). The mixture was stirred for 10 minutes at room temperature, then neutralized with concentrated aqueous ammonia, and the precipitate was collected by filtration. A solution of the precipitate in cold water was acidified with concentrated hydrochloric acid below pH 1 and allowed to stand in a refrigerator. The resulting precipitate was collected by filtration and washed with cold diluted aqueous hydrochloric acid to give the title compound (35 mg) as yellow needles, mp 254°-257° C. (decompd.).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=1.[CH2:14]([O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1)[CH3:15]>>[F:12][C:2]([F:1])([F:13])[C:3]1[N:4]=[CH:5][C:6]([C:7]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([O:16][CH2:14][CH3:15])=[CH:18][C:19]=2[N+:24]([O-:26])=[O:25])=[O:9])=[CH:10][CH:11]=1
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Product: CCOc1ccc(NC(=O)c2ccc(C(F)(F)F)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-trifluoromethylnicotinic acid and 4-ethoxy-2-nitroaniline as a yellow solid as described in Example 15. 1H NMR (CDCl3): 11.23 (s, 1H), 9.32 (d, J=3.6, 1H), 8.83 (d, J=9.3, 1H), 8.47-8.43 (m, 1H), 7.88 (d, J=8.1, 1H), 7.76 (d, J=3.0, 1H), 7.35-7.31 (m, 1H), 4.12 (q, J=6.9, 2H), 1.47 (t, J=6.9, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH3:16][N:17]([CH3:25])[NH:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[S:20]>>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:20][C:19](=[N:21][CH:22]([CH3:24])[CH3:23])[N:18]2[N:17]([CH3:25])[CH3:16])=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: CC(C)NC(=S)NN(C)C
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Product: Br
Product: CC(C)N=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1N(C)C

Procedure:
4.7 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 2.4 g of 1,1-dimethyl-4-isopropylthiosemicarbazide were reacted according to the prescription of Example 23 and the crystalline end product was filtered off. Colorless crystals: melting point: 189° C (decomposition).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:3]=1.[F:14][C:15]1[C:22]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:21][C:20]([O:34][CH3:35])=[CH:19][C:16]=1[CH:17]=O.C[Si]([C:40]#[N:41])(C)C.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3]>ClCCl.C(OCC)(=O)C>[F:14][C:15]1[C:22]([O:23][Si:24]([CH:31]([CH3:32])[CH3:33])([CH:28]([CH3:29])[CH3:30])[CH:25]([CH3:27])[CH3:26])=[CH:21][C:20]([O:34][CH3:35])=[CH:19][C:16]=1[CH:17]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:3]=[C:2]([CH3:1])[O:6][N:5]=2)=[CH:8][CH:9]=1)[C:40]#[N:41]
Reactant: COc1cc(C=O)c(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(C#N)Nc2ccc(-c3noc(C)n3)cc2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
After adding 5.47 g of 4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamine, 10.2 g of 2-fluoro-5-methoxy-3-triisopropylsilanyloxybenzaldehyde, 10 g of MS3A and 6.2 ml of trimethylsilyl cyanide to a solution of 1.94 g of Yb(OTf)3 in 100 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred for 3 days at room temperature. Ethyl acetate was added to the reaction mixture, and washing was performed with water. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (9.01 g) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[NH2:16][C:17]1[C:18](=[O:37])[N:19]([CH3:36])[C:20]2[C:25]([C:26]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33])=[CH:24][C:23]([CH3:34])=[CH:22][C:21]=2[CH3:35].N1C=CC=CC=1.C1COCC1>O>[OH2:2].[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]1[C:25]2[C:20](=[C:21]([CH3:35])[CH:22]=[C:23]([CH3:34])[CH:24]=2)[N:19]([CH3:36])[C:18](=[O:37])[C:17]=1[NH:16][C:8](=[O:9])[CH:7]=[CH:6][C:5]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: Cc1cc(C)c2c(c1)c(-c1ccccc1Cl)c(N)c(=O)n2C
Reactant: COc1ccc(C=CC(=O)Cl)cc1OC
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C=CC(=O)Nc2c(-c3ccccc3Cl)c3cc(C)cc(C)c3n(C)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 96 h
Yield: 65.4 %

Procedure:
A mixture of 3,4-dimethoxycinnamoyl chloride (678 mg), 3-amino-4-(2-chlorophenyl)-1,6,8-trimethyl-2(1H)-quinolone (511 mg), pyridine (0.28 ml) and THF (10 ml) was stirred at room temperature for four days. Then, the mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was removed and the residue was purified by a silica gel chromatography with benzene-acetone (4:1) to give crystals of 4-(2-chlorophenyl)-3-(3,4-dimethoxycinnamoylamino)-1,6,8-trimethyl-2(1H)-quinolone hydrate (510 mg, 65.6%). The crystals were recrystallized from ethanol to afford colorless prisms.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:14])[C:12](=[O:15])[CH:11]([CH3:16])[N:10]=[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[C:8]=2[CH:24]=1)(=O)[CH3:2].Cl.[NH2:26][OH:27]>N1C=CC=CC=1>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:9]1[C:8]2[CH:24]=[C:4]([C:1](=[N:26][OH:27])[CH3:2])[CH:5]=[CH:6][C:7]=2[N:13]([CH3:14])[C:12](=[O:15])[CH:11]([CH3:16])[N:10]=1
Reactant: CC(=O)c1ccc2c(c1)C(c1ccccc1F)=NC(C)C(=O)N2C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccc2c(c1)C(c1ccccc1F)=NC(C)C(=O)N2C

Procedure:
A solution of 4.41 g (13.60 mmol) of 7-acetyl-5-(o-fluorophenyl)-1,3-dihydro-1,3-dimethyl-2H-1,4-benzodiazepin-2-one and 4.41 g (63.46 mmol) of hydroxylamine hydrochloride in 250 ml of pyridine is stirred at room temperature for 19 hours, subsequently poured on to ice and extracted with chloroform. The organic extracts are washed successively with 2 N hydrochloric acid and water, dried and evaporated. After chromatography of the residue on 250 g of silica gel using chloroform/ethanol (98:2) as the elution agent, there is obtained 5-(o-fluorophenyl)-1,3-dihydro-7-[1-(hydroxyimino)ethyl]-1,3-dimethyl-2H-1,4-benzodiazepin-2-one of melting point 101°-103°.