Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl(O)(=O)(=O)=[O:2].[CH3:6][C:7]1[N:11]([CH2:12][CH:13]2[C:26](=[O:27])[C:17]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[N:24]([CH3:25])[C:16]=3[CH2:15][CH2:14]2)[CH:10]=[CH:9][N:8]=1.[C:28]([OH:31])(=[O:30])[CH3:29]>>[CH3:25][N:24]1[C:16]2[CH2:15][CH2:14][CH:13]([CH2:12][N:11]3[CH:10]=[CH:9][N:8]=[C:7]3[CH3:6])[C:26](=[O:27])[C:17]=2[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2.[C:28]([OH:31])(=[O:30])[CH:29]=[O:2]
Reactant: [O-][Cl+3]([O-])([O-])O
Reactant: CC(=O)O
Agent: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Product: O=CC(=O)O

Procedure:
A mixture containing 2.83 g (0.01 mole) of 3-hydroxymethyl-9-methyl-1,2,3,9-tetrahydro-4H-carbazol-4-one-3-glyoxylic acid lactone [compound of the formula (Ic)] and 1.64 g (0.02 mole) of 2-methylimidazole in 6.0 ml of sulfolane (tetramethylenesulfone) is heated in an oil bath of 150 to 160° C. for 15 minutes while stirring. After cooling down and diluting with 60 ml of acetone the precipitate is filtered off, washed with acetone and dried to give 0.95 g of the title compound, m.p.: 190°-200° C. (with decomposition). The active agent content of this product measured by titration with perchloric acid in glacial acetic acid was found to be 96%. In the combined filtrate of the reaction, ondansetron could be detected by thin layer chromatography. The most important characteristics of the title product are as follows:
Reaction SMILES: [C:1]12([CH2:9][CH:8](NC(NC3SC4C=C(F)C=CC=4N=3)=O)[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[O:5]1)[CH2:4][CH2:3][CH2:2]2.IC.[C:30](=O)([O-])[O-:31].[K+].[K+].CN(C)C=[O:39]>>[CH3:30][O:31][C:25]1[CH:26]=[CH:27][C:6]2[O:5][C:1]3([CH2:2][CH2:3][CH2:4]3)[CH2:9][C:8](=[O:39])[C:7]=2[CH:24]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1nc2ccc(F)cc2s1)NC1CC2(CCC2)Oc2ccccc21
Reactant: CN(C)C=O
Agent: [K+]
Solvent: CI
Product: COc1ccc2c(c1)C(=O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3,4-Dihydro-6-hydroxy-4-oxo-spiro[2H-1-benzopyran-2,1′-cyclobutane] (Example 12) (10 mmol) in dimethylformamide, iodomethane (12 mmol) and potassium carbonate (12 mmol) was added and the reaction mixture was stirred at rt for 12 h. Solvent was then evaporated and the residue was dissolved in ethyl acetate. Organic layer was washed with water, brine and separated. It was then dried on anhydrous Na2SO4 and concentrated to afford the desired product as oil.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]([CH3:13])=[N:7]1.[C:14]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].ClCCl>C(#N)C.O>[C:14]1([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:11](=[O:12])[CH:10]=[CH:9][C:8]([CH3:13])=[N:7]3)[CH2:26][CH2:25]2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: Cc1ccc(=O)n(CCCCBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(=O)n(CCCCN2CCN(c3cccc4ccccc34)CC2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.7 %

Procedure:
A mixture of 2-(4-bromobutyl)-6-methyl-3(2H)-pyridazinone (2.3 g, 9.5 mmol), 1-naphthylpiperazine (1.7 g, 8 mmol), K2CO3 (1.12 g, 8 mmol), and KI (10 mg) in acetonitrile (50 mL) was stirred at room temperature for 48 hours. Thereafter, the solvent was eliminated at reduced pressure and the residue distributed between dichloromethane and water; the aqueous phase was extracted with dichloromethane (twice). The organic extracts were collected, dried over anhydrous Na2SO4 and concentrated to dryness. The obtained residue was purified by flash chromatography (CH2Cl2/MeOH 96:4), yielding 2-[4-(4-naphthylpiperazine-1-yl)-butyl]-6-methyl-3(2H)-pyridazinone (2.4 g). The product was dissolved in ethanol and by adding hydrochloric acid concentrated up to a pH=1 yielded a white solid, which was re-crystallised in methanol, yielding the hydrochloride of the title compound, presenting a M.P. higher than 260° 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][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33].CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[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][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])=[O:33])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1ccccc1N=C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 75 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinazoline (100 mg) was dissolved in toluene (10 ml) with heat, 2-methoxyphenyl isocyanate (0.36 ml) was added, and the admixture was refluxed with heat for 40 minutes. After removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with chloroform/methanol (100/1) and then with chloroform/acetone (5/1) to obtain 112 mg of the title compound (yield: 75%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1)[CH3:3].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[C:21](=[N:27]O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1>N1C=CC=CC=1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[NH:12][C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:3])[CH3:1])=[CH:6][CH:7]=3)=[N:27][C:21]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1
Reactant: CN(C)Cc1ccc(CN)cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)c1nc(-c2ccc(CN(C)C)cc2)[nH]c1-c1ccc(Cl)cc1
Yield: 39.7 %

Procedure:
4-(Dimethylaminomethyl)phenylmethylamine (11.7 g) and ethyl 3-(4-chlorophenyl)-2-hydroxyimino-3-oxopropionate (15.1 g) were dissolved in pyridine (220 ml) and the solution was refluxed under heating for 12 hr. The solvent was concentrated under reduced pressure and the obtained residue was subjected to silica gel column chromatography to give the objective ethyl 5-(4-chlorophenyl)-2-[4-(dimethylaminomethyl)phenyl]imidazole-4-carboxylate (9.0 g), melting point 175-176° C.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[CH:9]=[CH:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:35])[C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:26])[CH:19]=1)[CH3:4]>O1CCCC1.CO>[CH2:3]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:9]=[CH:8][C:7]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]([CH3:35])[C:25]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:26])[CH:19]=1)[CH3:4]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCC)c1
Yield: 78 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10.0 mmol, 4.8 eq) of sodium hydroxide and methyl 3-[2-ethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate, obtained in the preceding step, in 10 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane/isopropyl ether, 246 mg of 3-[2-ethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=64° C.). Yield=78% over the two steps
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH:30]=O>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:30][C:26]1[O:25][CH:29]=[CH:28][CH:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccco1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1ccco1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Mix carbon tetrabromide (49.8 g, 150 mmol) and methylene chloride (75 mL) and cool to 0° C. Add, by dropwise addition, a solution of triphenylphosphine (78.6 g, 300 mmol) in methylene chloride (75 mL). Stir at 0° C. for 30 minutes. Add, by dropwise addition, a solution of 2-furan-carboxaldehyde (7.57 g, 78.8 mmol) in methylene chloride (75 mL). Remove the cooling bath and stir at room temperature until the reaction is complete. Pour onto ethyl ether and water, separate the organic layer and dry (MgSO4). Filter and evaporate the solvent in vacuo. Purify by silica gel chromatography to yield the title compound.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[CH2:19]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[CH2:19]([C:26]1[CH:27]=[C:28]([NH:29][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:30]=[CH:31][CH:32]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Reactant: Nc1cccc(Cc2ccccc2)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Nc1cccc(Cc2ccccc2)c1)c1ccn2c1CSC2c1cccnc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 30.8 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (5.7 g) is added, at a temperature between 60° and 65° C., to a solution of 3-benzylaniline (3.5 g) and triethylamine (3.9 g) in dioxane (100 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 25 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (250 cc). The solution obtained is washed twice with distilled water (160 cc in total), twice with an aqueous 1N sodium hydroxide solution (200 cc in total) and 5 times with distilled water (500 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (5 g) is thereby obtained, which is dissolved in boiling acetonitrile (50 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 4° C. for 1 hour. The crystals formed are separated by filtration, washed with acetonitrile cooled to a temperature in the vicinity of 4° C. (10 cc) and twice with diethyl ether (20 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(3-benzylphenyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole-7-carboxamide (2.4 g) in the form of white crystals, m.p. 139.5° C., is thereby obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]([F:32])([F:31])[C:24]1[N:25]=[C:26]([CH2:29]O)[S:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:29][C:26]5[S:27][CH:28]=[C:24]([C:23]([F:32])([F:31])[F:22])[N:25]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: OCc1nc(C(F)(F)F)cs1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4nc(C(F)(F)F)cs4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.4 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (4-(trifluoromethyl)-1,3-thiazol-2-yl)methanol (65.1 mg) and triphenylphosphine (140 mg) in THF (5 ml) was added bis(2-methoxyethyl) azodicarboxylate (125 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-hexane to give the title compound (26.5 mg) as a white solid.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14]C=1C([O-])=O>C(Cl)Cl.CN(C=O)C>[CH3:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COCCCc1sc(-c2ccccc2)nc1C(=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COCCCc1sc(-c2ccccc2)nc1C(=O)Cl
Reaction time: 0.33 h
Yield: 99.6 %

Procedure:
Oxalyl chloride (67.2 mmol, 5.9 mL) was slowly added to a room temperature solution of 5-(3-methoxypropyl)-2-phenylthiazole-4-carboxylate (22.4 mmol, 6.2 g) in CH2Cl2 (100 mL). 3 drops of DMF were added and the reaction became homogeneous over ˜20 min. The reaction was stirred for 3 h, then concentrated under reduced pressure. The crude product was dissolved in CH2Cl2 (150 mL) and concentrated under reduced pressure. The crude product was dissolved in EtOAc (150 mL), washed with brine (2×100 mL), dried (MgSO4), and concentrated under reduced pressure to give 5-(3-methoxypropyl)-2-phenylthiazole-4-carbonyl chloride as a tan solid (6.6 g, 99% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CO.CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]4[CH:30]=[CH:29][CH:28]=[C:27]5[C:23]=4[CH:24]=[CH:25][NH:26]5)[CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Fc1ccc2c(C3CCNCC3)c[nH]c2c1
Solvent: CS(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2c[nH]c3cc(F)ccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 6-fluoro-3-(piperidin-4-yl)-1H-indole (1.00 g, 4.6 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.91 g, 4.8 mmol). The product was isolated as a white foam. Yield 0.75 g (40%). mp 94°-97° C. FDMS m/e=407 (M+ of free base). α[D]589 =+7.97 (c=1.00, methanol/dimethylsulfoxide).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].O.[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([S:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.[Na+].O.CCOC(C)=O>CN(C=O)C.[Cu]I>[CH3:13][O:12][C:5]1[C:4]([O:14][CH3:15])=[CH:3][C:2]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:26])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(I)cc(OC)c1OC
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Temperature: 110 °C
Reaction time: 14 h

Procedure:
To a solution of methyl 5-iodo-2,3-dimethoxy-benzoate (2.25 g, 7.0 mmol) in 20 mL DMF, sodium p-toluenesulfinate hydrate (2.21 g, 11.26 mmol, 1.6 eq.) and CuI (2.22 g, 11.6 mmol, 1.66 eq.) were added and light green solution was stirred at 110° C. for 14 h. H2O and EtOAc were then added to the mixture and the phases were separated. The organic layer was washed with saturated NaCl solution, dried over MgSO4 and evaporated under reduced pressure. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc 8:2→3:2) to yield the desired product as a colorless solid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C(C)=CC=CC=1>[C:9]1([C:8]2[O:7][CH2:6][CH:2]([CH:3]([CH3:5])[CH3:4])[N:1]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)[C@H](N)CO
Solvent: Cc1ccccc1C
Product: CC(C)C1COC(c2ccccc2)=N1
Temperature: 150 °C
Reaction time: 67 h

Procedure:
L-Valinol (206 mg, 2 mmol), benzaldehyde (0.205 ml, 2 mmol), 250 mg of an oxidation catalyst and 4 ml of xylene as solvent were charged into a 100 ml three-neck flask, and were stirred at 150° C. for 67 hours under an oxygen atmosphere. The reaction mixture was filtered through a cotton plug, and then the oxidation catalyst was washed with ethyl acetate. After the filtrate was condensed with a rotary evaporator, the product was separated by silica gel column chromatography. A resulting colorless liquid was weighed and the yield thereof was defined as a reaction yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[OH:29])[CH:24]=O)[CH3:19].[NH2:33][C:34]([NH2:36])=[O:35].Cl>CCO.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:36][C:34](=[O:35])[NH:33][CH:24]([C:23]3[CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[C:28]([OH:29])=[C:21]([O:20][CH2:18][CH3:19])[CH:22]=3)[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(Cc1ccccc1)c1cc(F)cc(Cl)c1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cc(C2NC(=O)NC(c3cc(F)cc(Cl)c3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 58.2 %

Procedure:
A mixture of 1-(3-chloro-5-fluorophenyl)-2-phenylethanone (Intermediate 60) (150 mg, 0.60 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (116 mg, 0.55 mmol), urea (99 mg, 1.65 mmol), concentrated HCl (0.05 mL, 0.55 mmol) in EtOH (5 mL) was refluxed overnight. Followed standard aqueous/EtOAc workup and purified by preparative HPLC to give Compound 121 (155 mg, yield 58%). 1H NMR (DMSO-d6 400 MHz): δ 10.27 (brs, 1H), 8.85 (s, 1H), 7.58 (s, 1H), 7.40 (d, J=1.6 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.25 (s, 1H), 7.12 (d, J=6.4 Hz, 2H), 7.08 (d, J=7.6 Hz, 2H), 7.01 (d, J=7.2 Hz, 1H), 6.88 (d, J=7.2 Hz, 2H), 5.27 (d, J=2.4 Hz, 1H), 4.09-3.99 (m, 2H), 1.32 (t, J=7.2 Hz, 3H); MS (ESI): m/z 484.1 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([C:27](O)=[O:28])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[CH:33]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.[CH2:50]([NH:54][CH2:55][CH:56]([CH3:58])[CH3:57])[CH:51]([CH3:53])[CH3:52].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([C:27](=[O:28])[N:54]([CH2:55][CH:56]([CH3:58])[CH3:57])[CH2:50][CH:51]([CH3:53])[CH3:52])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[CH:33]=[C:34]([CH3:39])[CH:35]=[C:36]([CH3:38])[CH:37]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C(=O)O)c(Cl)cc3[nH]c2=O)c1
Reactant: CC(C)CNCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(C(=O)N(CC(C)C)CC(C)C)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a solution of 4-[2-(1-tert-butoxycarbonyl-piperidin-2-yl)-ethoxy]-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinoline-6-carboxylic acid (48 mg in 0.50 mL methylene chloride) was added 12 mg 1-hydroxybenzotriazole (HOBt) followed by 0.020 mL diisobutylamine, 0.025 mL triethylamine and 33 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and the mixture stirred at room temperature. After 22 hours, the mixture was diluted with methylene chloride and washed with 10% aqueous sodium bisulfate and brine. The organics were dried over sodium sulfate and the concentrate purified by flash chromatography on silica gel (chloroform:methanol, 97.5:2.5) to give the title compound (37 mg).
Reaction SMILES: [CH2:1]([CH:4]1[C:10]([Cl:12])([Cl:11])[CH2:9][CH2:8][CH:7]2[C:5]1(Cl)[O:6]2)[CH:2]=[CH2:3].N1C=CC=CC=1.[ClH:20]>>[CH2:1]([C:4]1([Cl:20])[C:10]([Cl:12])([Cl:11])[CH2:9][CH2:8][CH2:7][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: Cl
Reactant: C=CCC1C(Cl)(Cl)CCC2OC21Cl
Solvent: c1ccncc1
Product: C=CCC1(Cl)C(=O)CCCC1(Cl)Cl

Procedure:
1.60 g (6.62 mmol) of epoxide 2j and 2 cm3 (25 mmol) of pyridine were heated to reflux for 24 h. After cooling, the mixture was acidified to pH=1 with 3N HCl, extracted with ether (3×30 cm3), dried over MgSO4 filtered and evaporated down. The crude product was purified by flash chromatography on silica (eluent: ether/petroleum ether=1/99). The following were isolated (in the order of elution): starting epoxide 2j, 0.40 g of transposition ketone 6a (Yld=40%), traces of 2-allyl-2,3-dichloro-3-cyclohexenone 7 (evidence based on GC/mass) and phenol 4f.
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:31])(=[O:30])=[O:29])=[O:19])[C:15]([OH:32])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.C(O)C.[OH-].[Na+:38]>CC(C)=O>[O:33]=[S:2]1(=[O:1])[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH3:31])(=[O:30])=[O:29])=[O:19])[C:15]([O-:32])=[C:14]2[C:9]=1[CH:10]=[CH:11][CH:12]=[N:13]2.[Na+:38]
Reactant: CS(=O)(=O)c1ccccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccccc1CNC(=O)c1nc(N2CCCCS2(=O)=O)c2cccnc2c1[O-]

Procedure:
5-(1,1-dioxido-1,2-thiazinan-2-yl)-8-hydroxy-N-[2-(methylsulfonyl)benzyl]-1,6-naphthyridine-7-carboxamide (53 mg, 0.108 mmol) was suspended in a 1:1 mixture of ethanol and acetone (1 mL each). NaOH (130 uL, 1 M) was added and the starting material dissolved. After 1 hour the sodium salt precipitated. The sample was concentrated in vacuo to afford the desired material as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[Br:23]Br>CO>[NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[Br:23]
Reactant: COC(=O)c1ccc(-c2ccc(N)nn2)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(Br)c(N)nn2)cc1
Reaction time: 16 h
Yield: 43.6 %

Procedure:
In a 250 mL round bottom flask was placed methyl 4-(6-aminopyridazin-3-yl)benzoate (2.8 g, 12.2 mmol), NaHCO3 (2.05 g, 22.4 mmol) and methanol (100 mL) and to this suspension was added Br2 (1.95 g, 12.2 mmol) drop wise over about 30 minutes at room temperature. The mixture was stirred for 16 h, then filtered and concentrated in vacuo. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=2:1) to give methyl 4-(6-amino-5-bromopyridazin-3-yl)benzoate (1.64 g, 43.6%) as a light orange solid. LC-MS: [M+H]+, 309.9, tR=1.397 min.