Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C@H]1OC(=O)[C@H]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)N(C)C(=O)[C@H](C)NC(=O)C([C@H](C(C)C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2N(C[C@H](O)C2)C(=O)[C@@H](CC(C)C)NC(=O)[C@H]1NC(C1N=CC=CC=1O)=O.CC1[O:96][C:94](=[O:95])[CH:93](C2C=CC=CC=2)[N:92](C)[C:90](=O)C(C)NC(=O)C(C(C(C)C)C)N(C)C(=O)CN(C)C(=O)C2N(CC(O)C2)C(=O)C(CC(C)C)NC(=O)C1NC(C1N=CC=CC=1O)=O.C[C@H]1OC(=O)[C@H]2CSC(C(NCC=CC=C[C@@H](O)C[C@@H](O)CC3OC=C(C(N2)=O)N=3)=O)=CC1>>[C:34]1([N:92]([CH2:93][C:94]([OH:96])=[O:95])[CH3:90])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)C[C@H]1NC(=O)[C@@H](NC(=O)c2ncccc2O)[C@@H](C)OC(=O)[C@H](c2ccccc2)N(C)C(=O)[C@H](C)NC(=O)C([C@@H](C)C(C)C)N(C)C(=O)CN(C)C(=O)[C@H]2C[C@@H](O)CN2C1=O
Reactant: CC(C)CC1NC(=O)C(NC(=O)c2ncccc2O)C(C)OC(=O)C(c2ccccc2)N(C)C(=O)C(C)NC(=O)C(C(C)C(C)C)N(C)C(=O)CN(C)C(=O)C2CC(O)CN2C1=O
Agent: C[C@@H]1C/C=C2\SC[C@@H](NC(=O)c3coc(n3)C[C@H](O)C[C@H](O)/C=C\C=C/CNC2=O)C(=O)O1
Agent: C[C@@H]1CC=C2SC[C@@H](NC(=O)c3coc(n3)C[C@H](O)C[C@H](O)C=CC=CCNC2=O)C(=O)O1
Product: CN(CC(=O)O)c1ccccc1

Procedure:
In addition the identity of neoviridogrisein IV with viridogrisein was further confirmed by IR, UV, NMR and mass spectrometry, thin layer chromatography, hydrolysate analysis and antimicrobial spectrometry. On the other hand, the griseoviridin preparation obtained in Example 5 was crystallized in warm methanol to yield needle crystals. Then a part of the needle crystals were compared and identified with an authentic preparation of griseoviridin by IR, UV, NMR and mass spectrometry, thin layer chromatography, elementary analysis and other physico-chemical properties.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.[C:11]1([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[CH2:24]=O>C(O)C>[C:4]1([C:1](=[O:3])[CH2:2][CH2:24][N:20]2[CH2:21][CH2:22][N:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:18][CH2:19]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: O=C(CCN1CCN(c2ccccc2)CC1)c1ccccc1
Yield: 80.4 %

Procedure:
A well-stirred mixture of acetophenone (17) (3.40 mL, 29.0 mmol), 1-phenylpiperazine hydrochloride (18) (4.48 g, 22.5 mmol), and 0.05 mL of concentrated HCl in absolute ethanol (35 mL) was heated under N2 at reflux conditions. Paraformaldehyde (1.00 g, 33.3 mmol) was added in four equal portions over 40 minutes. The reaction mixture was further refluxed for 6 hours. The solution was then cooled and poured onto crushed ice. The solid was separated by filtration, dried, and re-crystallized using a small amount of aqueous ethanol (<10 mL). The solution was allowed to cool overnight and yielded 5.32 g the desired product 19 (18.1 mmol, 62%) as a white, yellow crystal. 1H-NMR (CDCl3): δ 8.03 (2 H, d, J=7.24 Hz), 7.63 (1 H, t, J=7.37, 7.42 Hz), 7.50 (2H, t, J=7.87, 7.35 Hz), 7.31 (2H, m), 6.97 (3H, m), 3.89 (2H, t, J=6.89, 6.72 Hz), 3.62 (8H, m), 3.10 (2H, m). 13C-NMR (CDCl3): δ 195.99, 149.27, 135.41, 134.24, 129.51, 128.37, 122.00, 117.43, 52.36, 51.97, 46.91, 33.14. Melting Point: 182-185° C.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]1([CH2:26][C:27](O)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]1([CH2:26][C:27]([N:12]2[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Reactant: O=C(O)CC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CC1CCCCC1)C2
Reaction time: 0.5 h

Procedure:
Triethylamine 0.84 ml was added in a methylene chloride 20 ml solution of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 0.95 g, and stirred at o@C for 30 min. Cyclohexyl acetic acid 0.72 g and WSC 1.35 g were added therein, then the reaction mixture was gradually changed to room temperature and stirred for 25 hours. The reaction mixture was washed with saturated sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-cyclohexylacetyl-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 30 ml solution of lithium aluminum hydride 0.38 g and refluxed for 1 hour. The reaction mixture was cooled, then added 6N hydrochloric acid and 1N sodium hydroxide thereto, and filtered the insoluble material. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of silica gel column chromatography (Wako gel, C200, chloroform acetone methanol=10:1:0.1) to obtain the product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][C:5]=1Cl.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][C:5]=1[CH:14]=[CH2:15]
Reactant: COC(=O)c1ccc(OC)nc1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1nc(OC)ccc1C(=O)OC
Temperature: 80 °C
Reaction time: 16 h
Yield: 53.2 %

Procedure:
A mixture of 2-chloro-6-methoxy-nicotinic acid methyl ester (10 g, 49.8 mmol), tributyl(vinyl)tin (15.8 g, 49.8 mmol), 2,6-di-tert-butyl-4-methylphenol (0.3 g, 1.36 mmol) and trans-bis(triphenylphosphine)palladium(II) chloride (0.5 g, 0.71 mmol) was added to DMF (50 mL) under nitrogen. The mixture was stirred at 80° C. for 16 h. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; petroleum ether/EtOAc 50/1). The desired fractions were collected and the solvents evaporated in vacuo to yield 6-methoxy-2-vinyl-nicotinic acid methyl ester (5.12 g, 54%) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](SC)=[N:6][C:5](=[O:10])[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[N:3]1.[Na].[CH3:19][OH:20]>>[CH3:1][N:2]1[C:7]([O:20][CH3:19])=[N:6][C:5](=[O:10])[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[N:3]1
Reactant: CSc1nc(=O)c(-c2ccc(C)cc2)nn1C
Reactant: CO
Agent: [Na]
Product: COc1nc(=O)c(-c2ccc(C)cc2)nn1C
Yield: 86 %

Procedure:
2-Methyl-3-methylthio-6-(p-methylphenyl)-5-oxo-2,5-dihydro-1,2,4-triazine (1.0 g) was added in a solution of metallic sodium (0.1 g) in methanol (10 ml), and the resultant mixture was stirred at room temperature for 2 hours. After stirring, the resulting mixture was evaporated to dryness to give a crude product. Recrystallization of the crude product from acetone gave 0.8 g of 2-methyl-3-methoxy-6-(p-methylphenyl)-5-oxo-2,5-dihydro-1,2,4-triazine in 86% yield. M.P., 159° 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[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42][C:43](=[O:49])OC(Cl)(Cl)Cl)Cl.[C:51]([C:55]1[CH:60]=[CH:59][C:58]([S:61][CH2:62][CH2:63]CO)=[CH:57][CH:56]=1)([CH3:54])([CH3:53])[CH3:52]>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[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:42][CH2:40][CH2:63][CH2:62][S:61][C:58]2[CH:59]=[CH:60][C:55]([C:51]([CH3:52])([CH3:54])[CH3:53])=[CH:56][CH:57]=2)=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CC(C)(C)c1ccc(SCCCO)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OCCCSc4ccc(C(C)(C)C)cc4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 77.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (82 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 (122 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-[4-(tert-butyl)phenyl]sulfanyl-1-propanol (80 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, followed 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 (113 mg, yield 73%).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:10][O:11][C:7]=2[C:6]([O:20]C(=O)C(C)(C)C)=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:4]=1.[NH:32]1[CH:36]=[CH:35][CH:34]=[N:33]1.C1(C)C=CC=CC=1>CCOC(C)=O>[N:32]1([CH2:2][C:3]2[C:8]3[C:9]([C:12]4[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=4)=[N:10][O:11][C:7]=3[C:6]([OH:20])=[C:5]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:4]=2)[CH:36]=[CH:35][CH:34]=[N:33]1
Reactant: c1cn[nH]c1
Reactant: CCOC(=O)c1nc(CBr)c2c(-c3ccc(OC)cc3)noc2c1OC(=O)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nc(Cn2cccn2)c2c(-c3ccc(OC)cc3)noc2c1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.8 %

Procedure:
Ethyl 4-(bromomethyl)-3-(4-methoxyphenyl)-7-(pivaloyloxy)isoxazolo[4,5-c]pyridine-6-carboxylate (34 mg, 0.069 mmol) and pyrazole (9.4 mg, 0.138 mmol) were added to 1 mL of toluene, and the mixture was stirred at room temperature for 48 h. An additional equiv. of pyrazole was added, and the mixture was stirred at room temperature for 16 h and then at 45° C. for 16 h. The mixture was diluted with EtOAc (20 mL) and washed with 1M hydrochloric acid. The organic layer was dried over MgSO4 and concentrated, and the residue was purified by flash chromatography (0-100% EtOAc/hexanes) to give 19 mg of the title compound. MS: (+) m/z 395.29 (M+1).
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:28][CH2:27][C:10]2[C:11]3[C:16]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:26][C:9]=2[CH2:8]1)=[O:6].[NH:29]1[CH2:32][CH2:31][CH2:30]1>CN(C=O)C.C(OC)(C)(C)C>[N:29]1([CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]2[CH2:28][CH2:27][C:10]3[C:11]4[C:16]([NH:17][C:18]5[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=5)=[N:15][CH:14]=[N:13][C:12]=4[S:26][C:9]=3[CH2:8]2)=[O:6])[CH2:32][CH2:31][CH2:30]1
Reactant: C1CNC1
Reactant: O=C(/C=C/CCl)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: O=C(/C=C/CN1CCC1)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Temperature: 50 °C
Yield: 13.1 %

Procedure:
To a suspension of Example 59A (100 mg, 0.20 mmol) in DMF (2 mL) was added azetidine (23 mg, 0.40 mmol), and the mixture was heated to 50° C. for 1 h. It was then diluted with methyl tert-butyl ether, washed with water and dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified by preparative HPLC to yield 12.4 mg (13%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16](O)=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2.S(Cl)([Cl:26])=O.CN(C)C=O>ClCCl>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:19])/[CH2:14][CH2:15][C:16]([Cl:26])=[O:17])=[C:9]([O:20][CH3:21])[C:8]([CH3:22])=[C:7]2[C:3]=1[C:4](=[O:23])[O:5][CH2:6]2
Reactant: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)CCC(=O)Cl)C(=O)OC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid (mycophenolic acid) (32.0 g) was dissolved in dichloromethane (250 ml), followed by the addition of thionyl chloride (25.9 ml) and dimethylformamide (0.3 ml). The reaction mixture was stirred at room temperature for 3 hours, after which the volatile components were removed under vacuum to afford E-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid chloride as an oil.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH:9](=O)[CH2:10][CH2:11]CC.[OH-].C(C([NH+](C(CCCC)(CCCC)C)CCCCCC[NH3+])(CCCC)C)CCC.[OH-].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>O>[CH3:9][CH2:10][CH2:11][CH2:8][CH:7]1[O:6][C:1](=[O:5])[CH2:2][CH:3]1[CH3:4]
Reactant: C/C=C/C(=O)OCC
Reactant: CCCCC=O
Agent: CCCCC(C)(CCCC)[NH+](CCCCCC[NH3+])C(C)(CCCC)CCCC
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [OH-]
Solvent: O
Product: CCCCC1OC(=O)CC1C

Procedure:
Ethyl crotonate (6.9% by weight) and pentanal (5.2% by weight) were emulsified in an aqueous electrolyte (0.16% by weight of bis(dibutylethyl)hexamethylenediammonium hydroxide (bisquat), 0.38% by weight of EDTA, 0.14% by weight of TEA, 1.45% by weight of Na2B4O7 and 5.84% by weight of Na2HPO4 in water at a pH of 10) (all % by weight based on the total aqueous reaction electrolyte) and subjected to galvanostatic electrolysis at a current density of 2.23 A/dm2 and a temperature of 25° C. in a frame electrolysis cell. The current throughput was 2 F/mol of ester. A steel anode and a lead cathode were used as electrodes (electrode area of 0.1 dm2 and spacing of 1 cm). To monitor the reaction, the MTBE extract of a sample of the electrolysis output is analyzed by gas chromatography. A yield of 3-methyl-4-butylbutyrolactone (whiskey lactone) of 68.5% and a yield of the corresponding ethyl γ-hydroxycarboxylate of 24.2% were achieved. This corresponded to a total yield of target products of 92.7% of the theoretical yield.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:32])[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:21](=[O:31])[C:22](=[O:30])[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)=[O:13].C([Sn](CCCC)(CCCC)[C:40]1[CH:45]=[N:44][CH:43]=[CH:42][N:41]=1)CCC>O1CCOCC1.CCOC(C)=O.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>[N:41]1[CH:42]=[CH:43][N:44]=[CH:45][C:40]=1[C:2]1[N:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11](=[O:32])[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[C:21](=[O:31])[C:22](=[O:30])[C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:16][CH2:15]1)=[O:13]
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCN(c4c(-c5ccccc5)c(=O)c4=O)CC3)c12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cnc(-c2cnccn2)c2[nH]cc(C(=O)C(=O)N3CCN(c4c(-c5ccccc5)c(=O)c4=O)CC3)c12
Temperature: 90 °C
Yield: 6.7 %

Procedure:
A solution of 3-[4-[2-(7-bromo-4-methoxy-6-azaindol-3-yl)-2-oxoacetyl]piperazin-1-yl]-4-phenyl-cyclobut-3-ene-1,2-dione (0.030 g, 0.057 mmol) and 2-tributylstannylpyrazine (0.025 g, 0.069 mmol) in dioxane (3 mL) was purged with Ar and then Pd(PPh3)4 (0.020 g, 0.017 mmol) was added, the reactor was sealed and the mixture was heated at 90° C. for 16 h. The cooled reaction mixture was diluted with EtOAc, washed (1M aqueous KF, brine), dried (Na2SO4) and evaporated to give a solid. Purification of this material by preparative HPLC (C-18/10-90% MeCN-5 mmolar aqueous NH4OAc) gave the title compound (0.002 g, 7%) as a yellow solid:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3cccc(F)c3)nc12

Procedure:
From 3-fluorobenzoic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+31.0° (c=0.70, CHCl3), ES-MS m/e (%): 389 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH3:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[O:21][CH3:22])[CH3:23])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CI
Reactant: COc1ccc(OC)c(Nc2nc(Cl)nc3ccccc23)c1
Product: COc1ccc(OC)c(N(C)c2nc(Cl)nc3ccccc23)c1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(2,5-dimethoxy-phenyl)-amine and methyl iodide by a procedure similar to example 36 (78% yield). 1H NMR (CDCl3): 7.72-7.75 (m, 1H), 7.56 (ddd, J=8.4, 5.7 and 2.1 Hz, 1H), 6.98-7.00 (m, 2H), 6.92-6.92 (m, 2H), 6.78-6.79 (m, 1H), 3.75 (s, 3H), 3.58 (s, 3H), 3.56 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH:26]1[C:35]2[N:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:29][CH2:28][CH2:27]1)[CH2:23][CH2:24][NH2:25]>C1COCC1.ClCCl.CCN(CC)CC>[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[CH2:21][N:22]([CH:26]1[C:35]2[N:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:29][CH2:28][CH2:27]1)[CH2:23][CH2:24][NH:25][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:10][N:9]=[CH:8][C:7]=1[Cl:11]
Reactant: O=C(Cl)c1c(Cl)cncc1Cl
Reactant: NCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1c(Cl)cncc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35.6 %

Procedure:
To a suspension of 3,5-dichloro-isonicotinoyl chloride (0.34 mmol) in THF (3 mL) at 0° C. was added a solution of N1-(1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-ethane-1,2-diamine (0.100 g, 0.312 mmol) in dichloromethane (3 mL), THF (1 mL) and Et3N (0.087 mL). After stirring at 0° C. for 5 min., the mixture was warmed to room temperature and stirred for 2.5 h. The solvents were evaporated and the residue was taken into saturated aqueous NaHCO3 (30 mL). The mixture was extracted with chloroform (3×20 mL). The extracts were dried over Na2SO4 and concentrated. Purification of the crude material by column chromatography on silica gel (200:1:1 CH2Cl2—CH3OH—NH4OH) provided 55 mg (44%) of COMPOUND 152 as a pale yellow solid 1H NMR (CDCl3) δ 1.55-1.70 (m, 1H), 1.78-1.85 (m, 1H), 2.03 (m, 1H), 2.29 (m, 1H), 2.66-2.82 (m, 3H), 3.20 (d, J=13.5 Hz, 1H), 3.39 (m, 1H), 3.55 (m, 1H), 3.90 (dd, J=10.8 Hz, 5.7 Hz, 1H), 4.12 (d, J=16.7 Hz, 1H), 4.30 (d, J=16.7 Hz, 1H), 6.99 (dd, 1H, J=7.8 Hz, 4.8 Hz, 1H), 7.15-7.21 (m, 2H), 7.27 (m, 1H), 7.41 (d, J=7.8 Hz, 1H), 7.54 (d, J=4.2 Hz, 1H), 7.63 (d, J=4.2 Hz, 1H), 8.40 (m, 1H), 8.56 (s, 2 H); 13C NMR (CDCl3) δ 21.79, 23.08, 29.32, 38.68, 48.54, 49.25, 61.63, 119.35, 122.24, 122.69, 123.19, 129.64, 133.76, 135.76, 138.70, 143.50, 144.39, 146.46, 148.03, 154.85, 157.38, 162.22; ES-MS m/z 496 (M+H). Anal. Calcd. for C25H24N6Cl2O.0.9CH2Cl2: C, 54.40; H, 4.55; N, 14.70; Cl, 23.56. Found: C, 54.64; H, 4.53; N, 14.62 Cl, 23.41.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([Cl:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[S:12](=[O:15])(=[O:14])=[O:13]>ClCCl.ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([S:12]([OH:15])(=[O:14])=[O:13])[C:9]([Cl:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)=O
Reactant: O=C(Cl)Cc1cccc(Cl)c1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)C(c1cccc(Cl)c1)S(=O)(=O)O
Temperature: 25 °C

Procedure:
A solution of 3-chlorophenylacetyl chloride (1.89 g, 10 mmole) in dichloromethane (20 ml) was treated with a suspension of sulphur trioxide--dioxane complex (15 mmole) in dichloroethane at 0° C. The mixture was stirred at room temperature for eighteen hours and evaporated, νmax. (CH2Cl2) 1790 cm-1.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[C:35]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)(=[O:37])[CH3:36]>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:41]2[CH:42]=[CH:43][C:38]([C:35](=[O:37])[CH3:36])=[CH:39][CH:40]=2)=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(C(C)=O)cc3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 4-acetylphenylboronic acid (97 mg) under an argon atmosphere, and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (26 mg, yield 52%).
Reaction SMILES: C([O:5][C:6](=[O:24])/[CH:7]=[CH:8]/[C:9]1[CH:13]=[CH:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=2)(=[O:16])=[O:15])[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Br:23][C:19]1[CH:18]=[C:17]([S:14]([N:11]2[CH:12]=[CH:13][C:9](/[CH:8]=[CH:7]/[C:6]([OH:24])=[O:5])=[CH:10]2)(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1ccn(S(=O)(=O)c2cccc(Br)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.6 %

Procedure:
A mixture of 2.0 g (E)-3-[1-(3-bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tert-butyl ester with 60 ml dichloromethane and 6.0 ml TFA is stirred at ambient temperature for 24 h. The dichloromethane and TFA is evaporated and the residue is coevaporated with toluene for a few times. By this method 0.77 g brown solid is obtained.