Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1Cl.CC(C)([O-])C.[K+].CN(C)C(=O)C.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([NH:37][C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([OH:48])[CH:46]=3)[N:41]=[CH:40][N:39]=2)=[N:33]1>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH3:13])(=[O:11])=[O:10])[CH:5]=[N:6][C:7]=1[O:48][C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[N:41]=[CH:40][N:39]=[C:38]2[NH:37][C:34]1[CH:35]=[CH:36][N:32]([CH3:31])[N:33]=1
Reactant: CN(C)CCN(C)S(=O)(=O)c1cnc(Cl)c(Cl)c1
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)CCN(C)S(=O)(=O)c1cnc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)c(Cl)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 59.9 %

Procedure:
5,6-Dichloro-N-[2-(dimethylamino)ethyl]-N-methylpyridine-3-sulfonamide (104 mg, 0.33 mmol) and potassium tert-butoxide (58 mg, 0.52 mmol) were added to an N,N-dimethylacetamide solution (1 ml) of 4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (50 mg, 0.21 mmol), and stirred under a nitrogen atmosphere at 100° C. for 2.5 hours. The reaction solution was cooled with ice, saline water was added, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by amine-type silica gel column chromatography (Biotage NH, hexane:ethyl acetate:chloroform=2:5:1 to 2:5:2) to obtain the entitled compound (65 mg, yield: 61%) as a pale orange amorphous solid.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1F.[NH2:15][CH2:16][CH:17]([NH2:19])[CH3:18].C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:18][CH:17]1[CH2:16][NH:15][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=2[C:3](=[O:14])[NH:19]1
Reactant: CC(N)CN
Reactant: COC(=O)c1c(F)cccc1[N+](=O)[O-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CNc2cccc([N+](=O)[O-])c2C(=O)N1
Yield: 66.6 %

Procedure:
A solution of 2-fluoro-6-nitrobenzoic acid methyl ester (500 mg, 2.51 mmol) in 1,4-dioxane (3 mL) was treated with 1,2-diaminopropane (0.186 mL, 2.51 mmol) and diisopropylethylamine (0.874 mL, 2.51 mmol). The reaction was irradiated at 140° C. for 20 minutes. The reaction mixture was then reduced en vacuo and purified by flash column chromatography (0% ethyl acetate/hexanes—100% ethyl acetate/hexanes) to afford 370 mg of 3-Methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one and 2-Methyl-6-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (mixture of regioisomers) as a yellow oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH3:14])[C:12]=1[NH2:13])=[O:7])[CH3:4].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].OS([O-])(=O)=O.[K+]>C1COCC1.CCOC(C)=O>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH3:14])[C:12]=1[NH:13][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])=[O:7])[CH3:4]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCOC(=O)c1cnn(C)c1N
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 57.3 %

Procedure:
Sodium hydride (60% dispersion in oil, 7.0 g, 170 mmol) was added portionwise to a suspension of 5-amino-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (21.1 g, 125 mmol) in anhydrous THF (300 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred for 0.75 h then cooled to 0° C. 1-fluoro-2-nitrobenzene (17.6 g, 125 mmol) was added and the resultant suspension was stirred at room temperature for 18 h. EtOAc and 0.3M KHSO4 were added and separated. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant 50% hexanes/50% ethyl acetate) to yield the title compound (20.8 g, 58%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:3]=1[CH3:19].[CH:20](=[O:23])[CH2:21][CH3:22]>C1COCC1>[CH3:19][C:3]1[C:4]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[N:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH:20]([OH:23])[CH2:21][CH3:22]
Reactant: Cc1cc(C)c(Oc2nc(C)cc(Br)c2C)c(C)c1
Reactant: CCC=O
Solvent: C1CCOC1
Product: CCC(O)c1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Reaction time: 0.33 h

Procedure:
To a −78° C. solution of 4-bromo-3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)pyridine in dry THF was added nBuli and stirred at that temperature for 20 minutes. Excess propionaldehyde was added and stirred for 2 hours at −78° C. The mixture was quenched with water, extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated. After column chromatography, an off-white solid was obtained, mp. 119-120° C. 1H NMR(CDCl3) d 6.86(s,3H), 4.90(m,1H), 2.281(s,3H), 2.28(s,3H), 2.21(s,3H), 2.02(s,6H), 1.65-1.8(m,2H), 1.00(t,3H) ppm.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:36])([CH3:35])[O:6][C@H:7]1[CH2:12][C@@H:11]([CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:10][N:9]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:8]1)([CH3:4])[CH3:3].NN>CCO>[NH2:14][CH2:13][C@H:11]1[CH2:12][C@@H:7]([O:6][Si:5]([C:2]([CH3:1])([CH3:4])[CH3:3])([CH3:36])[CH3:35])[CH2:8][N:9]([C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[CH2:10]1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)CN(C(=O)OCc2ccccc2)C1
Agent: NN
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@H](CN)CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 91.4 %

Procedure:
To cis-phenylmethyl (3RS,5RS)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1-piperidinecarboxylate (660 mg; 1.3 mmol) in EtOH (20 ml) was added anhydrous hydrazine (0.2 ml; 6.5 mmol). The reaction was allowed to stir at room temperature under nitrogen for 14 hours, and the reaction was filtered through a pad of Celite®. The filtrate was partitioned between EtOAc (150 ml) and water (50 ml), the layers were separated, and the organic layer was washed with brine and dried with Na2SO4. The solvents were removed to give the desired compound (450 mg; 92%) as a pale yellow oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH:5]=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[CH:16][C:15]=1[F:21].[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>O>[F:21][C:15]1[CH:16]=[N+:17]([O-:20])[CH:18]=[CH:19][C:14]=1[C:3]1[N:4]=[CH:5][C:6]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[N:7][C:2]=1[C:24]1[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C(Nc1cnc(-c2cc[n+]([O-])cc2F)c(Cl)n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1cnc(-c2cc[n+]([O-])cc2F)c(-c2cccnc2)n1)C1CC1
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 55.6 %

Procedure:
In a sealed tube three cycles of vacuum and argon were applied to a mixture of the N-[6-chloro-5-(3-fluoro-1-oxidopyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide (2.23 g, 7.22 mmol), pyridin-3-ylboronic acid (1.15 g, 9.39 mmol) and Cs2CO3 (7.06 g, 21.66 mmol). A solution of 1,4-dioxane:H2O (64 mL, 9:1) was added and argon was bubbled for 5 min, after which, PdCl2dppfCH2Cl2 (0.59 g, 0.72 mmol) was added and argon was again bubbled other 5 min. The reaction mixture was heated at 90° C. for 1 h. Upon the reaction completion the 1,4-dioxane was concentrated in vaccuo, and the obtained residue was adsorbed onto silica gel with 10% MeOH/THF (150 mL) and purified by column chromatography on silica gel eluting with a MeOH/EtOAc gradient (0→20%). The green solid obtained was precipitated with 1% MeOH/CH2Cl2 (5 mL), and washed with 1% MeOH/CH2Cl2 (3×3 mL), CH2Cl2 (3×5 mL), 1% MeOH/Et2O (3×5 mL) and Et2O (4×5 mL) to yield the title compound as a white powder (1.41 g, 56%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH2:7]O.C(N(CC)CC)C.CS([Cl:30])(=O)=O>ClCCl>[Cl:30][CH2:7][C:6]1[S:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:3][C:2]=1[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.0 g of [4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-yl]-methanol were dissolved in 50 ml dichloromethane, 3.0 ml of triethylamine were added followed by the addition of 1.36 ml of methanesulfonylchloride. The reaction mixture was stirred at room temperature for two hours. 100 ml dichloromethane were added and the mixture washed with saturated sodium hydrogen carbonate solution, water and brine. The organic layer was dried over MgSO4. The solvent was removed in vacuo to obtain 3.3 g of crude 5-Chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C:18]3([OH:32])[CH2:23][CH:22]4[CH2:24][CH2:25][CH:19]3[CH:20]=[C:21]4[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[C:41](Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>C(Cl)Cl.C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:33])[CH2:16][CH2:17][C@:18]3([O:32][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:23][C@H:22]4[CH2:24][CH2:25][C@@H:19]3[CH:20]=[C:21]4[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cccc2[nH]c(CCCN(C)CCC3(O)CC4CCC3C=C4c3ccccc3)nc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2[nH]c(CCCN(C)CC[C@]3(OC(=O)C(C)(C)C)C[C@H]4CC[C@@H]3C=C4c3ccccc3)nc12
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 150 mg of rac-(1R*,2R*,4R*)-2-(2-{[3-(4-methoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol in 2 mL DCM and 2 mL THF were added 0.21 mL of NEt3 and 41 mg of DMAP. The reaction mixture was cooled to 0° C., 0.17 mL of pivaloyl chloride were added and it was then stirred at 65° C. for 24 h. During the next 4 days further 0.52 mL of NEt3 and 0.41 mL of pivaloyl chloride were added in small aliquots. The reaction was quenched with sat. aq. NaHCO3, extracted with DCM, dried and concentrated in vacuo. Purification by CC using DCM-MeOH (10:1) yielded 40 mg of rac-2,2-dimethyl propionic acid (1R*,2R*,4R*)-2-(2-{[3-(4-methoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amino}-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl ester as brownish foam.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[OH:9][C:10]1[C:18]2[S:17][C:16]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[N:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>C(#N)C.C(OCC)C>[OH:9][C:10]1[C:18]2[S:17][C:16]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[N:15][C:14]=2[CH:13]=[CH:12][C:11]=1[N+:7]([O-:8])=[O:6]
Reactant: O=[N+]=O
Reactant: CCNC(=O)Nc1nc2cccc(O)c2s1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOCC
Product: CCNC(=O)Nc1nc2ccc([N+](=O)[O-])c(O)c2s1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 10.4 %

Procedure:
To a solution of 2-methylpyridone (0.020 mL, 0.20 mmol, 1.2 eq) in anhydrous acetonitrile (0.5 mL), nitronium tetrafluoroborate (0.045 g, 0.32 mmol, 1.9 eq) was added. The suspension was stirred at about 20° C. for about 5 minutes to get an orange solution. The solution was then transferred to a suspension of 1-(7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 8 (0.040 g, 0.17 mmol) in acetonitrile (0.5 mL). The reaction mixture was stirred at about 20° C. for about 15 minutes, then taken up in diethyl ether (8 mL), and neutralized by washing with saturated sodium bicarbonate solution (1.5 mL). The organic extract was concentrated and dissolved in methanol (2 mL). LC/MS purification was followed by flash chromatography purification on silica (methylene chloride/methanol=40/1) to afford 0.005 g (10%) of the desired compound 17. 1H NMR (DMSO) δ 11.20 (br s, 1H, NH), 8.02 (d, 1H, J=9.0 Hz, ArH), 7.23 (d, 1H, J=7.5 Hz, ArH), 6.78 (br s, 1H, NH), 3.20 (m, 2H, CH2), 1.10 (t, 3H, J=7.2 Hz, CH3). LC/MS 283 (MH+); RP-HPLC RT 2.74 minutes.
Reaction SMILES: [OH-].[Na+].[P:3]([O:7][CH2:8][C@@H:9]([OH:18])[C@H:10]([OH:17])[C@H:11]([OH:16])[C@@H:12]([OH:15])[CH:13]=[O:14])([O-:6])([O-:5])=[O:4].[Ba+2].[N+]([O-])(O)=O>O>[P:3]([O:7][CH2:8][C@@H:9]([OH:18])[C@H:10]([OH:17])[C@H:11]([OH:16])[C@@H:12]([OH:15])[CH:13]=[O:14])([OH:5])([OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)COP(=O)([O-])[O-]
Agent: [Ba+2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)COP(=O)(O)O
Reaction time: 504 h

Procedure:
The pH of an 11.3-ml aqueous solution of 0.67M cis-[Pt(NH3)2 (H2O)2 ](NO3)2 was adjusted with sodium hydroxide to 4. Then, 3.0 grams of barium D-galactose-6-phosphate dissolved in 30 ml water were added. The pH of the resulting solution was adjusted to 5.0 with 2 M nitric acid. After stoppering the solution with a porous plug and stirring for 21 days, the above-identified complex which had formed during that time period was recovered as a water-insoluble blue precipitate by the method described in Example 5.
Reaction SMILES: C([NH:8][CH2:9][C:10]([OH:12])=[O:11])(OC(C)(C)C)=O.[CH2:13]([OH:20])[C:14]([NH2:19])([CH2:17][OH:18])[CH2:15][OH:16].[OH:21][C:22]([CH:24]([C:26]1[CH:39]=[CH:38][CH:37]=[C:28]([C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:30])[CH:27]=1)[CH3:25])=[O:23].[ClH:40].C(OCC)(=O)C.C(OCC)C>CCCCCC>[NH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH2:13]([OH:20])[C:14]([NH2:19])([CH2:17][OH:18])[CH2:15][OH:16].[ClH:40].[OH:23][C:22]([CH:24]([C:26]1[CH:39]=[CH:38][CH:37]=[C:28]([C:29]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:30])[CH:27]=1)[CH3:25])=[O:21]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: NCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 361 mg (0.37 mmol) of the Boc-glycine-tris(hydroxymethyl)aminomethane-ketoprofen obtained above, 2 ml of 4 M hydrochloric acid/ethyl acetate was added under ice-cooling and stirred at room temperature for 2 hours. After confirming disappearance of Boc-glycine-tris(hydroxymethyl)aminomethane-ketoprofen by TLC, diethyl ether and hexane were added thereto for decantation. Thereafter, the precipitate was dried under reduced pressure to give the titled compound quantitatively with the yield of 336 mg. The structure was identified by 1H-NMR (CDCl3).
Reaction SMILES: [C:1]1([CH2:6][NH:7][C:8]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:9]=2[CH:10](O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:5][CH:4]=[CH:3][CH:2]=1.[C:25](=O)([O:27]CC)[NH2:26]>C(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[C:1]1([CH2:6][N:7]2[C:8]3[C:9](=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)[CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:26][C:25]2=[O:27])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(N)=O
Reactant: O=[N+]([O-])c1ccc(NCc2cccs2)c(C(O)c2ccccc2)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClC(Cl)Cl
Product: O=C1NC(c2ccccc2)c2cc([N+](=O)[O-])ccc2N1Cc1cccs1
Temperature: 180 °C

Procedure:
A mixture of 3.42 g of 2-(2-thenylamino)-5-nitrobenzhydrol, 6 g of ethyl carbamate and 0.5 g of zinc chloride was heated at 180° C. (bath temperature) for 2 hours. After cooling, the reaction mixture was dissolved in chloroform and the chloroform solution was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give 1-(2-thenyl)-4-phenyl-6-nitro-3,4-dihydro-2(1H)-quinazolinone.
Reaction SMILES: [C:1]1([CH2:14][OH:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:16]([Li])CCC.IC.C(OCC)(=O)C>C1COCC1.CCCCCC>[CH3:16][O:15][CH2:14][C:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: OCc1cccc2c1Cc1ccccc1-2
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CCCCCC
Product: COCc1cccc2c1Cc1ccccc1-2
Yield: 83.6 %

Procedure:
A solution of 1-fluorenemethanol (5.0 g, 25.6 mmol) in 50 mL of THF was charged with butyl lithium solution (11.0 mL, 26.0 mmol) at -78° C. After 15 min of stirring iodomethane (25.1 g, 176.1 mmol) was introduced. The reaction mixture was stirrer for 3 days at room temperature. The reaction was monitored by TLC (silica, 25% ethyl acetate in hexane). As soon as no more starting material was detected the reaction was quenched with water (30 mL). The organic layer was separated, washed with water, brine, dried over magnesium sulfate and evaporated. A short path chromatography of the residual oil (silica, 5% ethyl acetate in hexane) afforded 4.5 g (70.0%) of 1-methoxymethylfluorene.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH:9]=1.FC(F)(F)C(O)=O.[NH:24]1[CH2:27][CH:26]([OH:28])[CH2:25]1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.C(OCC)(=O)C.O>[S:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][CH2:2][N:24]2[CH2:27][CH:26]([OH:28])[CH2:25]2)=[CH:9]1
Reactant: ClCCCOCCc1csc2ccccc12
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: OC1CN(CCCOCCc2csc3ccccc23)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
In 5 mL of dimethyl sulfoxide was dissolved 1.00 g of 3-[2-(3-chloropropoxy)ethyl]-1-benzothiophene, and 1.10 g of 3-azetidinol trifluoroacetate and 1.63 g of potassium carbonate were added to the solution, after which the resulting mixture was stirred at 70° C. for 2 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the pH was adjusted to 1 with 6 mol/L hydrochloric acid, and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer and the pH was adjusted to 10 with a 2 mol/L aqueous sodium hydroxide solution, after which the organic layer was separated. The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform:methanol=30:1 to 10:1) to obtain 0.55 g of 1-{3-[2-(1-benzothiophen-3-yl)ethoxy]propyl}-3-azetidinol as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH:10]12[O:22][CH:13]([CH2:14][CH:15]1[S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17])[CH:12]=[CH:11]2.CCCCCC>ClCCl>[CH3:9][C:4]1[CH:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:20]([NH:19][S:16]([CH:15]2[CH:10]3[O:22][CH:13]([CH:12]=[CH:11]3)[CH2:14]2)(=[O:17])=[O:18])=[O:21])[N:3]=1
Reactant: O=C=NS(=O)(=O)C1CC2C=CC1O2
Reactant: Cc1cc(C)nc(N)n1
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)C2CC3C=CC2O3)n1
Temperature: 0 °C
Yield: 90.8 %

Procedure:
30.7 g (0.25 mole) of 2-amino-4,6-dimethylpyrimidine were dissolved in 350 ml of dichloromethane and a solution of 52 g (0.26 mole) of 7-oxabicyclo[2.2.1]hept-2-en-6-ylsulfonyl isocyanate (Diels-Alder adduct of vinylsulfonyl isocyanate and furan) in 100 ml of dichloromethane was added at 0° C. with stirring. The mixture was stirred a further 12 hours at room temperature, cooled to 0° C. and n-hexane was added. The precipitated reaction product was filtered off with suction, washed with n-hexane and dried. 73.6 g (90.8% of theory) of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-7-oxabicyclo[2.2.1]hept-2-en-6-ylsulfonamide having a melting point of 125°-145° C. were obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][N:7]1[C:11]([I:12])=[C:10]([CH:13]=[O:14])[CH:9]=[C:8]1[C:15]([O:17][CH3:18])=[O:16].N1C2C(=CC=CC=2)C(CCCC[OH:35])=C1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH:13]([C:10]1[CH:9]=[C:8]([C:15]([O:17][CH3:18])=[O:16])[N:7]([CH2:6][C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([CH2:2][OH:35])[CH:4]=2)[C:11]=1[I:12])=[O:14]
Reactant: OCCCCc1c[nH]c2ccccc12
Reactant: COC(=O)c1cc(C=O)c(I)n1Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C=O)c(I)n1Cc1cccc(CO)c1
Temperature: 65 °C
Yield: 93.2 %

Procedure:
To a stirred solution of 1 (0.20 g, 0.43 mmol) in DMF (2.5 mL) was added 4-(1H-Indol-3-yl)butan-1-ol (82 mg, 0.43 mmol) and K2CO3 (60 mg, 0.43 mmol) at room temperature. The resulting mixture was heated at 65° C. for 18 hours. After cooling to room temperature water (3 mL) was added, extracted with EtOAc, washed with brine, dried over MgSO4, and then purified by MPLC (gradient: Hex to EtOAc) to give 0.16 g of the titled compound as an inseparable mixture with 4-(1H-Indol-3-yl)butan-1-ol. It was intended to obtain an ether, but the reaction converted the Br to OH; 1H NMR (400 MHz, CDCl3) δ 9.70 (s, 1H), 7.54 (s, 1H), 7.27-7.2 (m, 2H), 7.04 (s, 1H), 6.87 (d, J=7.0 Hz, 1H), 5.79 (s, 2H), 4.65 (s, 2H), and 3.77 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:12]([O-])=O)[C:7]=1[NH:8][CH:9]1[CH2:11][CH2:10]1>C(O)(=O)C.[Fe]>[Br:1][C:2]1[C:7]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[C:6]([NH2:12])[CH:5]=[N:4][CH:3]=1
Reactant: O=[N+]([O-])c1cncc(Br)c1NC1CC1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cncc(Br)c1NC1CC1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of the product obtained from Step 3 (2.95 g, 11.4 mmol) in glacial acetic acid (50 ml) was added iron dust (3.35 g, 60 mmol). The resulting mixture was stirred at 80° C. for 90 minutes, after which it was filtered through Celite and the liquor concentrated under vacuum. The crude product was re-dissolved in ethyl acetate, basified with sodium bicarbonate and refiltered. Th organic phase was washed with water three times, followed by twice with brine before concentrating under vacuum to give the product. Passed through a silica plug affording product as an oil, 1.65 g (63%); MS (ES+) m/e 228/230 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>>[CH2:30]([CH:24]1[C:25](=[O:26])[O:27][CH:21]([CH2:20][CH2:19][CH:14]2[CH:13]3[C:12](=[CH:11][CH:10]([CH3:29])[CH2:9][CH:8]3[O:7][C:5](=[O:6])[CH:3]([CH3:4])[CH2:2][CH3:1])[CH:17]=[CH:16][CH:15]2[CH3:18])[CH2:22][CH:23]1[OH:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Reactant: BrCc1ccccc1
Agent: Cl
Product: CCC(C)C(=O)OC1CC(C)C=C2C=CC(C)C(CCC3CC(O)C(Cc4ccccc4)C(=O)O3)C21
Reaction time: 0.25 h

Procedure:
After 15 minutes, 202 mg (0.50 mmol) of mevinolin are added and the reaction mixture is kept at −77° C. for 30 minutes. Then 171 mg (1.0 mmol) benzyl bromide are added. After 2 hours the reaction is let come to room temperature and poured onto 0.1 N aqueous HCl. The phases are separated and the aqueous phase is extracted twice with ethyl acetate. The organic phases are combined, washed with brine and dried over sodium sulfate. The solvent is evaporated and the crude product is purified by silica gel chromatography (diethyl ether/hexane 2/1) to afford the desired product as a colorless oil.