Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[Cl-].[OH:19][NH3+:20].C([O-])(=O)C.[Na+].O>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[N:20][OH:19])=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: O=C1CCc2cc(N3CCOCC3)c(F)cc21
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: ON=C1CCc2cc(N3CCOCC3)c(F)cc21
Yield: 102.5 %

Procedure:
A solution of 6-fluoro-5-morpholin-4-ylindan-1-one (200 mg), hydroxylammonium chloride (102 mg) and sodium acetate (241 mg) in ethanol (5.0 mL) was heated to reflux for 1 hour. After confirming that the raw materials disappeared, water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 218 mg of 6-fluoro-5-morpholin-4-ylindan-1-one oxime. Next, 10% palladium-carbon (water content: 48%, 200 mg) was added to a solution of the resulting 6-fluoro-5-morpholin-4-ylindan-1-one oxime (218 mg) in ethanol (5.0 mL), and the reaction solution was stirred in a hydrogen atmosphere (0.4 MPa) at room temperature for 9 hours. The reaction solution was filtered on a celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 56.0 mg of the title compound. The physical properties of the compound are as follows.
Reaction SMILES: [H-].[K+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.C([Li])(C)(C)C.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>O1CCCC1>[CH3:19][N:16]1[CH2:17][CH2:18][CH:13]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([B:25]([OH:30])[OH:26])[CH:5]=3)[NH:9][CH:8]=2)[CH2:14][CH2:15]1
Reactant: CN1CCC(c2c[nH]c3ccc(Br)cc23)CC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [H-]
Agent: [K+]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(B(O)O)cc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
To a slurry of potassium hydride (20% suspension in mineral oil, 0.72 g, 3.58 mmol) in 7 mL of anhydrous tetrahydrofuran at 0° C. was slowly added dropwise 5-bromo-3-(1-methylpiperidin-4-yl)-1H-indole (1.0 g, 3.41 mmol) in 7 mL of anhydrous tetrahydrofuran. After stirring at 0° C. for 30 minutes, the mixture was cooled to −78° C., and tert-butyl lithium (1.7M in pentane, 7.51 mmol, 4.42 mL) was added dropwise. After 15 minutes, a solution of triisopropyl borate (6.82 mmol, 2.0 eq, 1.57 mL) in 2 mL of anhydrous tetrahydrofuran was added dropwise. The stirred mixture was allowed to warm to room temperature, and was quenched with 5N aqueous hydrochloric acid. The aqueous phase was extracted with diethyl ether, and the ether extracts were separated, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a crude white solid which was treated with hexanes, sonicated for 30 minutes, filtered and dried to give 0.252 g (29%) of the title compound as an amorphous white material which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[C:13]2=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]2[CH:11]=[CH:10][CH:9]=1>C1COCC1.CO.[C].[Pd].[C].[Rh]>[F:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[CH:8]1[C:13]2=[N:14][S:15](=[O:19])(=[O:18])[CH2:16][CH2:17][N:12]2[CH2:11][CH2:10][CH2:9]1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(-c4ccccc4)cc3F)C2=N1
Agent: [Pd]
Agent: [Rh]
Solvent: C1CCOC1
Solvent: CO
Product: O=S1(=O)CCN2CCCC(c3ccc(-c4ccccc4)cc3F)C2=N1
Temperature: 50 °C
Reaction time: 24 h
Yield: 76.3 %

Procedure:
To a solution of 9-(3-fluorobiphenyl-4-yl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (200 mg) in THF/methanol (30 ml/30 mL) was added 10% palladium carbon (50 mg). The reaction mixture was stirred under a hydrogen atmosphere at 50° C. for 1 day. 5% Rhodium carbon (100 mg) was added, and the reaction mixture was stirred under a hydrogen atmosphere at room temperature for 7 hr, and insoluble material was filtered off through celite. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by recrystallization (methanol-THF/diisopropyl ether) to give the title compound (154.4 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[I:19]Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:7]=1[I:19]
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: ClI
Solvent: CC(=O)O
Product: COc1ccc2nc(-c3ccc(N)c(I)c3)sc2c1
Yield: 56.1 %

Procedure:
2-(4'-Aminophenyl)-6-methoxybenzothiazole (0.22 g, 0.84 mmol) was treated with iodine monochloride (0.21 g, 1.3 mmol) in acetic acid according to the above-described general procedure for iodination. Crude product was purified by flash chromatography on silica gel, using ethyl acetate-hexane (1:3) as eluent, to give brown small crystals (0.18 g, 54.9%), m.p. 179.2-181.1° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[C:22]([CH2:24][OH:25])[N:21]=[C:20]([CH2:26][OH:27])[CH:19]=1)=[N+:12]=[N-:13].C(N(CC)CC)C>C(Cl)Cl>[N:11]([CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[C:22]([CH:24]=[O:25])[N:21]=[C:20]([CH:26]=[O:27])[CH:19]=1)=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=NCCCOc1cc(CO)nc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: [N-]=[N+]=NCCCOc1cc(C=O)nc(C=O)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
DMSO (1.21 mL, 17.1 mmol) was diluted with CH2Cl2 (approximately 25 mL) and cooled to −78° C. Oxalyl chloride (0.745 mL, 8.45 mmol) was added dropwise and the reaction mixture was stirred for 15 minutes. 4-(3-azidopropoxy)-2,6-dihydroxymethylpyridine (1 g, 4.27 mmol) dissolved in CH2Cl2 (10 mL) was added slowly to the cooled reaction mixture. After 0.5 hour triethylamine (2.77 mL, 19.70 mmol) was added dropwise to the reaction mixture. The dry ice/acetone bath was removed and the reaction mixture was warmed to room temperature for approximately 40 minutes. The reaction mixture was partitioned between CH2Cl2 and water and extracted several times with CH2Cl2. The CH2Cl2 layers were combined, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by silica gel flash column chromatography to give the title compound. 1H NMR (DMSO) δ 2.02 (m, 2H, CH2), 3.52 (t, 2H, CH2), 4.31 (t, 2H, CH2), 7.64 (s, 2H, 2x Ar), 10.01 (s, 2H, CHO). 13C NMR (DMSO) δ 27.61 (CH2), 47.40 (CH2), 66.22 (CH2), 111.58 (Ar), 154.40 (quaternary, Ar), 166,50 (quaternary, Ar), 192.44 (CHO).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3](=[O:21])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:9]=1)([CH3:7])[CH3:6].CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>ClCCl>[CH3:26][N:27]([CH3:29])/[CH:28]=[N:20]/[S:17]([C:10]1[CH:9]=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C:3](=[O:21])[C:2]([F:1])([F:22])[F:23])[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=1)(=[O:19])=[O:18]
Reactant: COC(OC)N(C)C
Reactant: CC(C)(CC(=O)C(F)(F)F)c1cc(S(N)(=O)=O)cc2c1OCC2
Solvent: ClCCl
Product: CN(C)/C=N/S(=O)(=O)c1cc2c(c(C(C)(C)CC(=O)C(F)(F)F)c1)OCC2
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
A solution of 7-(4,4,4-trifluoro-1,1-dimethyl-3-oxobutyl)-2,3-dihydrobenzofuran-5-sulfonic acid amide (870 mg, 2.47 mmol) in 30 mL of dichloromethane was reacted with N,N-dimethylforamide dimethyl acetal (580 mg, 4.86 mmol). After 30 minutes, the mixture was concentrated in vacuo to dryness. The resulting solid was triturated with diethyl ether and collected to afford 950 mg of the title compound (94% yield).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)=O.[N:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=2)[C:3](/[CH:1]=[CH:20]/[C:17]2[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=2)=[N:4]1)(=[O:23])[CH3:22]
Reactant: Cc1ccncc1
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc2c(C=O)n[nH]c2c1
Product: CC(=O)n1nc(/C=C/c2ccncc2)c2ccc(C#N)cc21
Temperature: 25 °C

Procedure:
To a mixture of 3-formyl-1H-indazole-6-carbonitrile (1.14 g, 6.67 mmol) and 4-picoline (2 mL) was added acetic anhydride (2 mL). The resulting mixture was stirred to make a homogeneous solution and then irradiated 10 min at 100° C. by microwave. After cooling to rt, the mixture was poured onto ice/H2O (50 mL) and stirred for 10 min, sonicated for 2 min, then stirred for 10 min and suction filtered to give the crude (E)-1-acetyl-3-(2-(pyridin-4-yl)vinyl)-1H-indazole-6-carbonitrile as a dark brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH:3]=1.C([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)#N.C([O-])([O-])=[O:33].[Cs+].[Cs+]>O.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][NH:10][C:4]2[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:23]3[CH:24]=[C:25]([OH:33])[CH:26]=[CH:27][CH:28]=3)[CH:3]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: COc1nc(Cl)cc(NCCc2ccc(F)c(F)c2)n1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(NCCc2ccc(F)c(F)c2)cc(-c2cccc(O)c2)n1
Yield: 57.7 %

Procedure:
A solution of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(3,4-difluoro-phenyl)-ethyl]-amine (1.6 g), 3-cyano-phenylboronic acid (1.5 g), Cs2CO3 (8.3 g) and tetrakis(triphenylphosphine)palladium (0) (45 mg) in water (8 mL) and DME (32 mL) is heated at 90° C. for 16 hours. The solution is poured into water and extracted with EtOAc (2×200 mL). The combined extract is dried over sodium sulfate, filtered, evaporated in vacuo and chromatographed on silica gel eluting with EtOAc to afford 3-{6-[2-(3,4-difluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenol (1.1 g). MS: 379 (M+H); 1H NMR (300 MHz, CDCl3), □8.3 (1H, s); 8.2 (1H, d, J=5.1 Hz); 7.9 (1H, d (J=5.1 Hz)); 7.6 (1H, t); 7-7.2 (4H, m); 6.4 (1H, s); 5 (1H, m); 3.95 (3H, s); 3.7 (2H, t); 3 (2H, t).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][O:5][C:4](=[O:8])[C:3]=1[CH3:9].[CH2:10](O)[CH3:11]>P([O-])([O-])([O-])=O>[O:5]1[C:6]2[CH:7]=[CH:2][CH:10]=[CH:11][C:9]=2[CH2:3][C:4]1=[O:8]
Reactant: CCO
Reactant: Cc1c(O)ccoc1=O
Agent: O=P([O-])([O-])[O-]
Product: O=C1Cc2ccccc2O1

Procedure:
0.40 g of the compound (7.4) are dissolved together with 0.175 g of 4-hydroxy-methyl-pyranone (Fluka) in 40 mL of phosphate buffer (0.2M, pH=5) at room temperature, and 20.0 mg of laccase (Trametes versicolor (Fluka)) are added. For better solubility, 1 mL of ethanol is also added. The mixture is stirred in an open vessel until the starting materials can no longer be detected (about 2 days). The mixture is concentrated and the residue is taken up in methanol and centrifuged. The desired product (211 mg) is obtained in the form of a brownish-beige solid. The product can be purified further by reprecipitation from ether/methanol mixtures.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=3[S:15]2)[N:10]([CH3:24])[C:9]1=S)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(OC)(=O)=O)=CC=1.[NH2:38][C:39]1[CH:40]=[C:41]([C:48](=[O:50])[CH3:49])[CH:42]=[CH:43][C:44]=1[NH:45][CH2:46][CH3:47]>>[C:48]([C:41]1[CH:42]=[CH:43][C:44]([NH:45][CH2:46][CH3:47])=[C:39]([N:38]=[C:9]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:12](=[O:13])[C:11](=[C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[S:15]3)[N:10]2[CH3:24])[CH:40]=1)(=[O:50])[CH3:49]
Reactant: CN1C(=S)N(Cc2ccccc2)C(=O)C1=C1Sc2ccccc2N1C
Reactant: CCNc1ccc(C(C)=O)cc1N
Agent: COS(=O)(=O)c1ccc(C)cc1
Product: CCNc1ccc(C(C)=O)cc1N=C1N(C)C(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 1, intermediate 3-benzyl-1-methyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-thioxoimidazolidin-4-one was alkylated with methyl p-toluenesulfonate and condensed with 3′-amino-4′-ethylaminoacetophenone to yield the title compound. 1H-NMR (CDCl3): δ 8.11 (1H, d), 7.84 (1H, dd), 7.51 (1H, dd), 7.31 (1H, m), 7.16 (1H, m), 6.95-7.12 (7H, m), 6.08 (1H, br t), 4.46 (2H, hs m), 3.99 (2H, m), 3.78 (3H, s), 3.50 (3H, s), 2.65 (3H, s), 1.06 (3H, t); MS(ESI): 512 (MH+).
Reaction SMILES: [CH:1]1[C:14]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:25]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[O:24]=[C:15]([C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[CH:13][C:14]=2[CH:1]=1)[CH2:16][CH:17]([CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:25]([O:33][CH2:34][CH3:35])=[O:32])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(C=Cc1ccccc1)c1ccc2c(ccc3ccccc32)c1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc2c(ccc3ccccc32)c1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1-(2-phenanthrenyl)-3-phenylprop-2-en-1-one and diethyl malonate, diethyl 2-[3-oxo-3-(2-phenanthrenyl)-1-phenylpropyl]malonate was obtained as colourless solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]([CH2:38][C:39]([O:41]CC)=[O:40])[CH2:32][C:33]([O:35]CC)=[O:34])(=[O:30])=[O:29])(=[O:21])=[O:20])[CH:6]=[C:7]([CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][O:12][NH:13][C:14]([NH2:16])=[NH:15].C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[CH3:2][C:3]1[CH:4]=[C:5]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]([CH2:32][C:33]([OH:35])=[O:34])[CH2:38][C:39]([OH:41])=[O:40])(=[O:30])=[O:29])(=[O:20])=[O:21])[CH:6]=[C:7]([CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][O:12][NH:13][C:14]([NH2:16])=[NH:15]
Reactant: CCOC(=O)CN(CC(=O)OCC)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(CC(=O)O)CC(=O)O)c1
Yield: 87 %

Procedure:
The title compound was prepared in 87% yield from 3-[5-methyl-3-(2-(N,N-bis(ethoxycarbonylmethyl)aminosulfonyl)phenylsulfonyloxy)phenoxy]propoxy guanidine hydrochloride, as prepared in step b of Example 57, in a manner analogous to Example 27. 1H-NMR (300 MHz, DMSO-d6) δ 8.29 (d, J=7.0 Hz, 1H), 8.10 (d, J=7.6 Hz, 1H), 7.97 (t, J=7.6 Hz, 1H), 7.84 (t, J=7.6 Hz, 1H), 7.63 (br s, 4H), 6.72 (s, 1H), 6.58 (s, 1H), 6.49 (s, 1H), 4.13 (s, 4H), 3.97 (t, J=6.3 Hz, 2H), 3.90 (t, J=6.3 Hz, 2H), 2.23 (s, 3H), 2.03 (pentet, J=6.2 Hz, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C21H26N4O11S2: 575.1 (M+H), 597.1 (M+Na), 613.1 (M+K). Found: 575.1, 597.0, 613.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:15])[N:6]([CH3:14])[C:7](=[O:13])[NH:8]2.[H-].[Na+].Br[CH2:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22]>CN(C)C=O.O>[CH2:4]([CH:3]([CH2:12][CH3:11])[CH2:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=[O:15])[N:6]([CH3:14])[C:7](=[O:13])[N:8]2[CH2:19][CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:5]
Reactant: CCC(CC)CBr
Reactant: COc1cccc2[nH]c(=O)n(C)c(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC)COc1cccc2c1c(=O)n(C)c(=O)n2CC(CC)CC
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 33.2 %

Procedure:
To a solution of 5-methoxy-3-methylquinazoline-2,4(1H,3H)-dione (47 mg, 0.228 mmol) [example 5] in N,N-dimethylformamide (1 ml) was added sodium hydride (8.6 mg, 0.342 mmol). The mixture was stirred at 80° C. for 15 min and 1-bromo-2-ethylbutane (0.064 ml, 0.0753 mmol) was added. The resulting mixture was stirred at 80° C. for 18 h and diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting 50% ethyl acetate/n-hexane to afford 20 mg (32%) of 1-(2-ethylbutyl)-5-hydroxy-3-methyl-2,4(1H,3H)-dione (A) and 9 mg (11%) of 5-(2-ethylbutoxy)-1-(2-ethylbutyl)-3-methylquinazoline-2,4(1H,3H)-dione (B).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[CH2:17]1>CCOCC>[ClH:11].[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][CH2:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[CH2:17]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1ccccc1OC1CCN(CCCN)C1
Solvent: CCOCC
Product: COc1ccccc1OC1CCN(CCCNS(=O)(=O)c2ccc(F)cc2)C1
Product: Cl
Reaction time: 2 h
Yield: 61.8 %

Procedure:
0.78 g (4.0 mmol) of 4-fluorophenylsulphonyl chloride in 15 ml of ether were added dropwise to a solution of 1.0 g (4.0 mmol) of 1-(3-aminopropyl)-3-(2-methoxyphenoxy)-pyrrolidine in 20 ml of anhydrous ether at 0° C. After 2 hours at room temperature, the mixture was freed from solvent in vacuo and the remaining oily residue was brought to crystallization by trituration with diethyl ether/hexane. In this manner, 1.1 g (62%) of title compound were obtained as a slightly reddish, hygroscopic solid. It melted from 50° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40][C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[CH3:49][C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][C:51]=1[S:57][CH2:58]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:40][CH2:38][CH2:58][S:57][C:51]2[CH:52]=[C:53]([CH3:56])[CH:54]=[CH:55][C:50]=2[CH3:49])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C)c(SCCO)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCSc4cc(C)ccc4C)cc3)c2cc1OC
Temperature: 25 °C
Yield: 80.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (77 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (105 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-[(2,5-dimethylphenyl)sulfanyl]-1-ethanol (78 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, follow by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (105 mg, yield 74%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[C:29]([N+:36]([O-:38])=[O:37])[CH:30]=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[C:29]([N+:36]([O-:38])=[O:37])[CH:30]=[CH:31][CH:32]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: O=[N+]([O-])c1cccc2ccc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ccc5cccc([N+](=O)[O-])c5n4)cc3CC[C@@H]12
Yield: 54.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-8-nitro- quinoline (96 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 48 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80-100% ethyl acetate/hexanes eluent) to give 90 mg (55%) of the title compound as a solid. mp 199°-200°. FDMS: m/e=433. α[D]589 =+76.80 (c=0.42, chloroform).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:22])[NH:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.C(O)C.[OH-].[K+].Cl>O>[C:16]1([C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][C:7](=[O:22])[C:6]=2[C:4]([OH:5])=[O:3])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1c(-c2ccccc2)c2ccccc2[nH]c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1c(-c2ccccc2)c2ccccc2[nH]c1=O
Yield: 93.1 %

Procedure:
A mixture of 1,2-dihydro-4-phenyl-2-oxo-3-quinoline carboxylic acid ethyl ester (5 g, 17 mmol), ethanol (20 ml), water (40 ml) and potassium hydroxide (5 g, mmol) was refluxed with heat for 1.5 hours. To the reaction mixture was added 60 ml of 2N-HCl to acidify the mixture to obtain a precipitated crystal by filtration. The crystal obtained was recrystallized from ethanol to give 4.2 g (yield: 92.9%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6]O[C:4]([C:8]([OH:10])=[O:9])=[C:3]1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][NH2:23]>C(O)C>[CH3:19][O:20][CH:21]([O:24][CH3:25])[CH2:22][N:23]1[CH:6]=[CH:7][C:2](=[O:1])[C:3]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1occc(=O)c1OCc1ccccc1
Reactant: COC(CN)OC
Solvent: CCO
Product: COC(Cn1ccc(=O)c(OCc2ccccc2)c1C(=O)O)OC
Reaction time: 18 h

Procedure:
To a flask (1 L) charged with 500 mL of anhydrous ethanol was added 49.2 g (0.2 mol) of 4-oxo-3-[(phenylmethyl)oxy]-4H-pyran-2-carboxylic acid 5. The suspension was slowly heated to 55-60° C. before addition of 2-amino-acetaldehyde-dimethylacetal (84.1 g, 0.8 mole). The reaction was then brought up to 65° C. and further stirred for 18 hours. The solvent was removed under reduced pressure to produce 1-[2,2-Bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid 22 (crude) as brown oil, which was used for the next step directly.