Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][CH2:28][C:23]=3[N:24]([CH3:27])[C:25]=2[CH:26]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]4[C:22]5[CH2:32][N:31]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:30][CH2:29][CH2:28][C:23]=5[N:24]([CH3:27])[C:25]=4[CH:26]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(Cl)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Temperature: 135 °C
Reaction time: 0.08 h
Yield: 49.3 %

Procedure:
A suspension of 4-(4-chlorobenzyloxy)pyridin-2(1H)-one (84 mg, 0.38 mmol), tert-butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (160 mg, 0.42 mmol), 8-hydroxyquinoline (11 mg, 0.076 mmol) and Cs2CO3 (137 mg, 0.42 mmol) in DMSO (10 mL) was degassed under reduced pressure for 40 min. CuI (87.0 mg, 0.42 mmol) was added to the above solution, and the reaction mixture was degassed under reduced pressure for 10 min. The reaction mixture was heated at 135° C. under nitrogen overnight. The suspension was cooled, 9:0.9:0.1 CH2Cl2/MeOH/NH4OH (10 mL) was added, and the resulting suspension was stirred at 25° C. for 5 min. Celite was added, and the resulting suspension was stirred for 5 min. The suspension was filtered through Celite, and the filtrate was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was dissolved in DCM and stirred with charcoal for 10 min. The suspension was filtered, concentrated and purified by prep-TLC (CH2Cl2/MeOH 95:5) to afford the title compound (0.10 g, 49%) as a light yellow solid and as a mixture of rotamers: 1H NMR (500 MHz, CDCl3) δ 7.63 (d, J=7.0 Hz, 0.3H), 7.53 (d, J=8.0 Hz, 0.7H), 7.39 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 7.35-7.27 (m, 2H), 6.99 (d, J=8.5 Hz, 1H), 6.05 (s, 1H), 6.03 (dd, J=7.5, 2.0 Hz, 1H), 5.02 (s, 2H), 4.71 (s, 0.7H), 4.63 (s, 1.3H), 3.76-3.65 (m, 2H), 3.65 (s, 3H), 2.99-2.97 (m, 2H), 2.05-2.00 (m, 2H), 1.44 (s, 3.3H), 1.37 (s, 5.7H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[S:11][C:10]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(O)C>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][C:7]1[S:11][C:10]([C:12]2[CH2:13][CH2:14][C:15](=[O:17])[N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:26]=2)=[CH:9][CH:8]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cc2ncc[nH]2)s1
Reactant: NNc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(Cc3ncc[nH]3)s2)=NN1c1ccccc1
Reaction time: 10 h

Procedure:
A mixture of 2.64 g of 4-[5-(1-imidazolylmethyl)-thien-2-yl]-4-oxobutyric acid, 1.12 g phenylhydrazine, 40 ml water and 40 ml ethanol was stirred for 10 hours under reflux. After cooling the mixture was evaporated, the residue shaken with chloroform/dilute caustic soda solution, the chloroform phase washed with water, dried and evaporated. The residue was recrystallized from diisopropyl ether/ethyl acetate.
Reaction SMILES: [BH3-]C#N.[Na+].[CH2:5]([N:12]1[CH2:16][CH2:15][C:14]2([CH2:20][CH2:19][NH:18][CH2:17]2)[CH2:13]1)[C:6]1[CH:11]=CC=CC=1.C(O)(=O)C.C(C1(O[Si](C)(C)C)CC1)C.C(N)C1C=CC=CC=1.N#N>CO.CCO.[Pd]>[CH:5]1([N:12]2[CH2:16][CH2:15][C:14]3([CH2:20][CH2:19][NH:18][CH2:17]3)[CH2:13]2)[CH2:6][CH2:11]1
Reactant: c1ccc(CN2CCC3(CCNC3)C2)cc1
Agent: [Pd]
Agent: CCC1(O[Si](C)(C)C)CC1
Agent: N#N
Solvent: NCc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: C1CC2(CCN(C3CC3)C2)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaCNBH3 (654 mg, 10.4 mmol) was added to a solution of 2-benzyl-2,7-diaza-spiro[4.4]nonane (450 mg, 2.08 mmol), acetic acid (1.19 ml, 20.8 mmol), molecular sieve (3 Å, beads) and (1-ethylcyclopropyloxy) trimethylsilane (2.09 ml, 10.4 mmol) in MeOH (45 ml) and the mixture was then refluxed. After 4 h the reaction batch was cooled to RT and filtered. The residue was washed with MeOH (50 ml) and the combined organic phases were concentrated to dryness. The residue was taken up in water (5 ml) and NaOH solution (2 M, 10 ml) and extracted with DCM (2×40 ml). The combined organic phases were dried over Na2SO4 and concentrated to dryness. The crude product was used with no further purification. Yield: 440 mg, 82% 2. A solution of benzylamine (440 mg, 1.72 mmol) in absolute EtOH (10 ml) was gassed for 10 min with N2. Then Pd (10% on carbon, 183 mg, 172 μmol) was added and the mixture was again gassed for 10 min with N2. The reaction batch was stirred overnight at RT under an H2 atmosphere (3 bar). On completion of the reaction the mixture was filtered over celite and rewashed with DCM (30 ml) and MeOH (30 ml). The combined filtrates were concentrated to dryness. The product was used without further purification.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:10]=1[NH2:11].Cl[C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]>CN(C=O)C.[Cu]>[F:8][C:9]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:10]=1[NH:11][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Agent: [Cu]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Temperature: 85 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
A suspension of triethyl amine (15 ml, 0.11 mol), 2,4-difluoroaniline (25 ml, 0.24 mol), copper bronze (2.7 g., 0.04 mol), in hot DMF (25 ml) was treated with a solution of 2-chloro-4,5-difluorobenzoic acid (23 g., 0.12 mol) in 25 ml of DMF and the temperature was maintained at 85° C. for 8 hours. The reaction mixture was allowed to cool to room temperature and was then stirred overnight. The reaction mixture was evaporated in vacuo and the residue was partitioned between ether and aqueous ammonium chloride. The organic phase was washed with 2N HCl and saturated aqueous lithium chloride solution. The ether was dried over sodium sulfate, treated with darco and then filtered and evaporated. The residue was crystallized from hexane-ether to afford 21.6 g (62%) of 2-(2,4-difluorophenylamino)-4,5-difluorobenzoic acid; m.p.: 215°-216° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=O.C([O-])([O-])=O.[Na+].[Na+]>[N+]([O-])(O)=O>[C:1]1([C:7]2[NH:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1c[nH]c(-c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Product: O=Cc1c[nH]c(-c2ccccc2)n1
Temperature: 0 °C

Procedure:
A 17.4 gm. portion of 2-phenyl-4-imidazolemethanol and 13.4 ml. of concentrated HNO3 are heated on a steam bath for 21/2 hours. Three drops of fuming HNO3 are added to start the reaction.. The pH is adjusted to 8 with concentrated aqueous Na2CO3 and the mixture is cooled to 0° C. overnight. The solid is recovered, washed with water and recrystallized from a mixture of 70 ml. of ethyl acetate and 20 ml. of petroleum ether giving a yellow solid. Treatment of the mother liquor with petroleum ether gives an additional tacky substance which is triturated with isopropanol giving a second solid. These two solids are taken up in hot isopropanol and recrystallized as a yellow solid. This solid is recrystallized from ethanol:water (1:1) giving yellow crystals, m.p. 169°-171.5° C.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:38])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[C:31]([O:33]C(C)(C)C)=[O:32])=[O:25])=[CH:18][CH:17]=1)=[O:7])(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[C:31]([C@H:27]1[CH2:28][CH2:29][CH2:30][N:26]1[C:24](=[O:25])[CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][CH2:14][C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[C:6]([OH:7])=[O:5])=[O:38])=[CH:17][CH:18]=1)([OH:33])=[O:32]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)CNc1ccc(NCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)CNc1ccc(NCC(=O)N2CCC[C@@H]2C(=O)O)cc1
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of 168 mg (0.32 mmol) (R)-1-[[4-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethylamino]-phenylamino]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 2 ml trifluoroacetic acid was stirred for 4 h at room temperature. The solvent was removed, the residue suspended in toluene and the solvent removed again to eliminate excess trifluoroacetic acid. The residue was re-suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 160 mg (78%) of the title compound as a brown foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:16]1([CH:23]=[CH:22][CH:21]=[C:19]([OH:20])[CH:18]=1)[OH:17].C([O-])([O-])=O.[Na+].[Na+]>B(F)(F)F.CCOCC>[OH:17][C:16]1[CH:18]=[C:19]([OH:20])[CH:21]=[CH:22][C:23]=1[C:13](=[O:15])[CH2:12][CH:9]1[CH2:8][CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)C1CCC(CC(=O)O)CC1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C1CCC(CC(=O)c2ccc(O)cc2O)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of 2-(4-(ethoxycarbonyl)cyclohexyl)acetic acid (700 mg, 11.6 mmol) in BF3-Et2O (10 ml) was added resorcinol (1.5 g, 14.0 mmol). The solution was stirred at 85° C. overnight, poured into Na2CO3 solution (2N, 20 ml), extracted with EtOAc (30 ml×3), washed with brine, dried over Na2SO4, filtrated and concentrated to afford 3 g of yellow oil, which was purified by silica gel column (PE/EtOAc=3/1) to afford 400 mg of Intermediate C. MS (ESI): m/z 307.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C([O:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])C>>[F:16][C:15]([F:18])([F:17])[C:14](=[O:13])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C(F)(F)F
Product: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1

Procedure:
Claisen reaction of the commercially available p-methyl-acetophenone and trifluoroacetic acid ethyl ester gave 4,4,4-trifluoro-1-(4-methylphenyl)-butane-1,3-dione in good yield. The latter was further reacted with the commercially available p-hydrazino-benzenesulfonic acid in an inert solvent in the presence of hydrochloric acid to give the new 4-(5-p-methyl-phenyl)-3-trifluoromethyl-pyrazol-1-yl)-benzenesulfonic acid of formula (III) (yield over 80%),
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6]([OH:8])=[O:7].Br[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH:19]1([CH2:18][O:3][CH2:4][C@H:5]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6]([OH:8])=[O:7])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: BrCC1CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](COCC1CCCCC1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Undercooling with ice, sodium hydride (60%, 3.95 g) was added to a solution of (2S)-3-hydroxy-2-t-butoxycarbonylaminopropanoic acid (10.11 g) in dimethylformamide (200 ml, hereinafter abbreviated as DMF). The mixture was stirred for 30 minutes at 0° C. Under cooling with ice, (bromomethyl)cyclohexane (9.0 ml) was added dropwise to the reaction mixture and tetrabutylammonium iodide (910 mg) was added thereto. The mixture was stirred for 23 hours at room temperature. Further, (bromomethyl)cyclohexane (2.1 ml) was added dropwise to the reaction mixture. The mixture was stirred for 4 hours. (Bromomethyl)cyclohexane (2.1 ml) was added dropwise to reaciton mixture again. The mixture was stirred for 25 hours at room temperature. The reaction mixture was concentrated and the residue was diluted with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, successively, dried over anhydrous magnesium sulfate. The organic layer was concentrated and the residue was purified by silica gel column chromatography (chloroform:methanol=97:3) to give the title compound (2.52 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[CH:12][CH2:13][NH2:14])=[CH:5][CH:4]=1.[C:15](Cl)(=[O:19])[CH2:16][CH2:17][CH3:18]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6](=[CH:5][CH:4]=1)[CH2:7][CH:8]=[C:9]2[CH2:12][CH2:13][NH:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC(=O)Cl
Reactant: COc1ccc2c(c1)C(=CCN)CC2
Product: CCCC(=O)NCCC1=CCc2ccc(OC)cc21

Procedure:
Starting with 2-(6-methoxyindan-1-ylidene)ethylamine (hydrochloride) and butyryl chloride, the title compound was synthesized in otherwise the same manner as Example 15 (yield 65%).
Reaction SMILES: [CH2:1]([CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[O:11][CH2:10][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:12][O:13]2)=[CH:17][CH:16]=1
Reactant: CCCCCCCCC(CO)CO
Reactant: O=Cc1ccc(Br)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCC1COC(c2ccc(Br)cc2)OC1

Procedure:
Quantities: compound from Example 9 (48.3 g, 0.26 mol), 4-bromobenzaldehyde (46.5 g, 0.25 mol) and 4-toluenesulphonic acid (150 mg). The experimental procedure was as described in Example 11.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)CCC>O1CCOCC1.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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5ccccn5)cc34)cc2)cc1
Yield: 55.5 %

Procedure:
The (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (200 mg, 0.49 mmol), 2-(tributylstannyl)pyridine (200 mg, 0.53 mmol) and bis(triphenylphosphine)palladium(II) chloride (catalytic) were dissolved in dioxan (3 ml) and heated at reflux under nitrogen for 9 hr. The cooled reaction mixture was absorbed onto silica and purified by flash column chromatography (silica gel, eluting with an ethyl acetate/iso-hexane gradient). The resulting solid was triturated with iso-hexane/ethyl acetate to give the product (110 mg, 56%) as a pale yellow solid; δH [2H6]-DMSO 9.99 (1H, b, NH), 9.18 (1H, s, 5-H), 8.76 (1H, d, pyridine-H), 8.60 (1H, d, 7-H), 8.54 (1H, s, 2-H), 8.23 (1H, d, pyridine-H), 8.00 (1H, t, pyridine-H), 7.87 (1H, d, 8-H), 7.70 (2H, d, 2′-H, 6′-H), 7.53-7.31 (6H, m, 5×Ph-H, pyridine-H), 7.09 (2H, d, 3′-H, 5′-H), 5.14 (2H, s, CH2); m/z 405 (M+1)+.
Reaction SMILES: [CH3:1][CH2:2][C:3]1(O)[CH:26]([C:27]([O:29][CH3:30])=[O:28])[C:8]2[C:9]([OH:25])=[C:10]3[C:23](=[O:24])[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([OH:22])[C:16]=4[C:14](=[O:15])[C:11]3=[C:12]([OH:13])[C:7]=2[C:5](=[O:6])[CH2:4]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:6])[C:7]2[C:12]([OH:13])=[C:11]3[C:14]([C:16]4[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:17]=4[C:23](=[O:24])[C:10]3=[C:9]([OH:25])[C:8]=2[C:26]=1[C:27]([O:29][CH3:30])=[O:28])=[O:15]
Reactant: CCC1(O)CC(=O)c2c(O)c3c(c(O)c2C1C(=O)OC)C(=O)c1cccc(O)c1C3=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCc1cc(O)c2c(O)c3c(c(O)c2c1C(=O)OC)C(=O)c1cccc(O)c1C3=O
Yield: 84 %

Procedure:
When maggiemycin was refluxed with p-toluene sulfonic acid in benzene for 4 hours, anhydromaggiemycin, at a yield of 84%, was obtained that was identical to the natural product in all physicochemical properties. The preparation of these compounds is summarized in FIG. 10.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[S:5][C:6]=1[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1.[Br:16]N1C(=O)CCC1=O>C(#N)C>[Br:16][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[C:6]1[S:5][C:4]([NH:12][C:13](=[O:15])[CH3:14])=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1nc(C)c(-c2ccsc2)s1
Solvent: CC#N
Product: CC(=O)Nc1nc(C)c(-c2ccsc2Br)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
N-[4-methyl-5-(3-thienyl)-1,3-thiazol-2-yl]acetamide obtained in Step I as described above (3880 mg; 16.3 mmol; 1 eq) is dissolved in ACN (375 ml). N-bromosuccinimide (2898 mg; 16.3 mmol; 1 eq) is added and the resulting solution is stirred at room temperature for 30 minutes. Solvents are concentrated. Water is added and the desired product is extracted with EtOAc (3 times). Organic phases are washed with water (3 times) and dried over MgSO4, affording the title compound (5000 mg; 97%).
Reaction SMILES: I[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14]C1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Sn](C)(C)(C)C.CCN(CC)CC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:14][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Reactant: O=[N+]([O-])c1cc(I)c2occc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Sn](C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cc2ccoc12
Temperature: 100 °C
Reaction time: 0.05 h

Procedure:
7-Iodo-5-nitro-benzofuran (6.5 g, 22.1 mmol), Pd(OAc)2 (1 g, 3.9 mmol), P(o-tolyl)3, Me4Sn, Et3N were dissolved in DMF (40 mL) and portioned out in 13 tubes and heated at 100° C. for 10 min each using controlled microwave energy. The reaction mixtures were combined and filtered and the solvent was evaporated. The crude material was purified using flash chromatography (using a gradient of isohexane—10% EtOAc in isohexane). Yield: 2.82 g (70%) of 7-methyl-5-nitro-1-benzofuran. 1H NMR (400 MHz, CDCl3) δ ppm 2.51-2.64 (m, 3H) 6.90 (d, J=2.3 Hz, 1H) 7.77 (d, J=2.3 Hz, 1H) 8.04 (d, J=1.3 Hz, 1H) 8.37 (d, J=2.3 Hz, 1H); HPLC 96% Rt=2.31 min (System A; 10-97% in 3 min ACE column). MS (ESI+) for C9H7NO3 m/z 178 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[S:17][C:10]=12.[C:29]1([CH2:35][C:36]([N:38]=[C:39]=[S:40])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[S:40])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:23]=3)[S:17][C:10]=12
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Reactant: O=C(Cc1ccccc1)N=C=S
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To a solution of 49 (46.7 mg, 0.1 mmol) in dry THF (5 mL), 2-phenylacetyl isothiocyanate (40 mg, 0.2 mmol) was added and the reaction was allowed to stir for 30 minutes. The THF was removed under reduced pressure and the resultant product was purified by column chromatography on silica gel, eluent hexane/EtOAc (1:1), to afford the title compound 50 (35.4 mg, 53% yield). 1HNMR (DMSO) δ (ppm): 12.49 (s, 1H), 11.85 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.30 (s, 1H), 8.17 (d, J=8.4 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H), 7.63-7.52 (m, 5H), 7.34 (d, J=4.1 Hz, 2H), 6.71 (d, J=5.3 Hz, 1H), 3.82 (brs, 2H), 3.27 (s, 3H) MS (m/z) 592.0 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Br[C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[N:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[N+:18]([C:15]1[CH:14]=[CH:13][C:12]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:17][N:16]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Oc2ccc([N+](=O)[O-])nc2)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 33 %

Procedure:
A mixture of 3-nitrophenol (7.76 g, 55.8 mmol), 5-bromo-2-nitropyridine (10.3 g, 50.7 mmol), cesium carbonate (24.8 g, 76.1 mmol) and N,N-dimethylformamide (150 mL) was stirred at 50° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (NH silica gel, hexane/ethyl acetate=100/0→0/100) to give the title compound (4.37 g, 33%) as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>O1CCCC1>[NH2:2][CH2:1][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5]1
Reactant: N#CCN1CCN(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCCN1CCN(c2ccccc2)CC1
Yield: 76.8 %

Procedure:
A solution of 600 g 1-Cyanomethyl-4-phenylpiperazine in 1525 ml tetrahydrofuran was added dropwise to a suspension of 181 g LiAlH4 in 4.5 liters tetrahydrofuran. The mixture was refluxed 18 hours, cooled and added 181 ml water, 181 ml 15% NaOH, and 543 ml water. The mixture was filtered and concentrated to dryness on the rotovap and the residue distilled to give 470 g product, b0.1 117°-24°,m.50°-7°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[C:10]1[NH:15][C:14](=[O:16])[N:13]2[N:17]=[C:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=[C:12]2[CH:11]=1.Br[CH2:27][CH:28]1[CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:2].[CH:28]1([CH2:27][N:23]2[CH2:24][CH2:25][CH:20]([C:18]3[N:19]=[C:12]4[N:13]([C:14](=[O:16])[NH:15][C:10]([C:4]5[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=5[Cl:2])=[CH:11]4)[N:17]=3)[CH2:21][CH2:22]2)[CH2:30][CH2:29]1
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cc2nc(C3CCNCC3)nn12
Reactant: BrCC1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cc2nc(C3CCN(CC4CC4)CC3)nn12
Temperature: 80 °C
Reaction time: 16 h

Procedure:
1.00 g (2.50 mmol) of 7-(2,4-dichlorophenyl)-2-(piperidin-4-yl)[1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one hydrochloride were initially charged in DMF (6 ml), and 268 μl (2.75 mmol) of 1-bromomethylcyclopropane and 759 mg (5.49 mmol) of potassium carbonate were added. The reaction mixture was stirred at 80° C. for 16 h, the solution was then filtered and ethyl acetate (100 ml) and water (75 ml) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (two times 15 ml). The combined organic phases were washed with saturated aqueous sodium chloride solution, dried (magnesium sulfate) and concentrated. The product was taken up in acetonitrile and purified by preparative RP-HPLC (Method 11). This gave 413 mg (39% of theory) of the product.