Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[CH3:42][O:43][CH2:44][C:45](Cl)=[O:46]>C1COCC1.C(OCC)(=O)C>[F:32][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:45](=[O:46])[CH2:44][O:43][CH3:42])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1([C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:23])[CH2:21][CH2:20]1)=[O:18]
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: COCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCC(=O)Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (130 mg, 0.29 mmol) in 10 mL, of anhydrous tetrahydrofuran was added diisopropylethylamine (75 mg, 0.58 mmol). A solution of methoxyacetyl chloride (34.5 mg, 0.32 mmol) in THF (1 mL) was added drop wise at 0° C. The resultant reaction mixture was stirred at R.T. for 0.5 h. It was diluted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated. The residue was purified by prep-TLC to give N-(2,5-difluoro-4-((2-(2-methoxyacetamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (75 mg, 50% yield). 1H NMR (400 MHz, CDCl3): δ 9.79 (s, 1H), 8.89 (s, 1H), 8.53 (s, 1H), 8.30 (dd, J=12.0, 7.2 Hz, 1H), 8.17 (d, J=5.6 Hz, 1H), 7.83 (d, J=2.4 Hz, 1H), 7.49-7.45 (m, 2H), 7.07-6.99 (m, 3H), 6.64 (dd, J=5.6, 2.4 Hz 1H), 3.98 (s, 2H), 3.49 (s, 3H), 1.78-1.66 (m, 4H); MS (ESI): m/z 515.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)[CH:13]=[CH:12][C:11]=2[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:8])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:40][CH2:41][O:42][C:43](Cl)=[O:44]>ClCCl>[C:24]([O:23][C:22]([NH:21][C:11]1[CH:12]=[CH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[CH:15][C:10]=1[NH:9][C:7]([C:6]1[CH:29]=[CH:30][C:3]([CH2:2][NH:1][C:43](=[O:44])[O:42][CH2:41][Cl:40])=[CH:4][CH:5]=1)=[O:8])=[O:28])([CH3:25])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CN)cc1
Reactant: O=C(Cl)OCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CNC(=O)OCCl)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
tert-butyl [2-{[4-(aminomethyl)benzoyl]amino}-4-(2-thienyl)phenyl]carbamate (2.0 g, 4.72 mmol) was suspended in dichloromethane (50 ml). Hunig's Base (1 ml, 5.73 mmol) was added. The solution was cooled to 0° C. Chlorocarbonic acid chloromethyl ester (0.5 ml, 5.68 mmol) was added slowly. The reaction was stirred for approximately 1-2 h. The mixture, while cold, was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc/hexane. MS: calc'd 417 (MH+-Boc), exp 417 (MH+-Boc).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:9]2[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=3[F:1])=[N:8]2)=[C:26]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:27]=1
Reactant: Clc1ccc(CBr)c(OCc2ccccc2)c1
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccn(Cc2ccc(Cl)cc2OCc2ccccc2)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
To a mixture of 2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for as preparation see Intermediate 9) (76 mg, 0.340 mmol) and potassium carbonate (96 mg, 0.692 mmol) was added a solution of 1-(bromomethyl)-4-chloro-2-[(phenylmethyl)oxy]benzene (0.106 g, 0.340 mmol) in DMF (1 ml). The reaction was stirred overnight, at ambient temperature and under nitrogen. The suspension was filtered using a hydrophobic frit and the residue washed with methanol (1 ml). The filtrate was purified by MDAP (supelcosil ABZ+Plus column) eluting with solvents A/B (A: Water+0.1% Formic acid, B: MeCN:Water 95:5+0.05% Formic acid) (Method A). The solvent was evaporated in vacuo to give the title compound as a white solid (27 mg); LCMS: (System 1) MH+=454, tRET=3.68 min.
Reaction SMILES: [K].[SH:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[C:25]([O:26][CH3:27])=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=[CH:22][N:21]=1>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:29]([O:28][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([CH2:19][S:2][C:3]2[NH:4][C:5]3[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[C:25]=1[O:26][CH3:27])[CH3:30]
Reactant: CCOc1ccnc(CBr)c1OC
Reactant: Sc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOc1ccnc(CSc2nc3ccccc3[nH]2)c1OC
Yield: 68.3 %

Procedure:
To a suspension of potassium salt of 2-mercaptobenzimidazole (1.3 g) and potassium carbonate (1.0 g) in dimethylformamide (15 ml) was added with stirring, a solution of 2-bromomethyl-4-ethoxy-3-methoxy-pyridine (1.6 g) in dimethylformamide (5 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with chloroform (50 ml), washed with water, 1N-sodium hydroxide, and water in this order, dried, and evaporated. The residue was purified by column chromatography on silica gel (chloroform-methanol (50:1)), to give 2-[(4-ethoxy-3-methoxypyrid-2-yl)methylthio]benzimidazole (1.4 g) as a light yellow oil.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]1[C@H:14](OS(C)(=O)=O)[CH2:13][CH2:12][N:11]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:10]1)=[O:7])(C)(C)C>N1C=CC=CC=1>[O:7]=[C:6]1[NH:8][C@@H:9]2[CH2:10][N:11]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:12][CH2:13][C@@H:14]2[O:5]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1OS(C)(=O)=O
Solvent: c1ccncc1
Product: O=C1N[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@@H]2O1

Procedure:
A solution of (3R,4R)-benzyl 3-(tert-butoxycarbonylamino)-4-(methylsulfonyloxy)piperidine-1-carboxylate in pyridine (0.16 M) was heated to 120° C. in the microwave for 10 minutes. The solution was then concentrated to almost dryness and the forming solid was filtered to give the desired product. The filtrate was further purified via silica gel column chromatography eluting with ethyl acetate (100%) to give the product in 75% combined yield. LCMS (m/z): 277.1 (MH+), LC Rt=2.33 min.
Reaction SMILES: O[CH2:2][CH:3]1C(CO)CC=CC1.Cl[C:12]1C=CC=C(C(OO)=O)[CH:13]=1.[OH:22][CH2:23][CH:24]1[CH:29]([CH2:30][OH:31])[CH2:28][CH:27]2[O:32][CH:26]2[CH2:25]1.C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)CC.C(OC=C)(=O)C>C1(C)C=CC=CC=1>[CH:2]([O:22][CH2:23][CH:24]1[CH:29]([CH2:30][O:31][CH:12]=[CH2:13])[CH2:28][CH:27]2[O:32][CH:26]2[CH2:25]1)=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OCC1CC2OC2CC1CO
Reactant: OCC1CC=CCC1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCC(=O)O
Solvent: Cc1ccccc1
Solvent: C=COC(C)=O
Product: C=COCC1CC2OC2CC1COC=C
Reaction time: 1 h
Yield: 82 %

Procedure:
4,5-di(hydroxymethyl)cyclohexene was epoxidized with m-chloroperbenzoic acid and thereby yielded 4,5-di(hydroxymethyl)cyclohexene oxide (cis-trans mixture). A mixture (280 mL) of sodium carbonate 24.9 g (0.23 mol) and toluene was heated to 95° C., and 1.4 g of propionic acid was added to the mixture. Maintaining the temperature of the reaction mixture, the mixture was combined with 19 g of vinyl acetate added dropwise, and fifteen minutes later, further combined with 1.27 g (1.9 mmol) of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2. Next, 30 g (0.19 mol) of 4,5-di(hydroxymethyl)cyclohexene oxide (cis-trans mixture) was added dropwise for three hours, and a reaction was carried out in a nitrogen atmosphere while adding dropwise 62 g of vinyl acetate and holding the reaction temperature at 95° C. After the completion of dropwise addition, the mixture was stirred for one hour. As the result of gas chromatography analysis of the mixture, it is confirmed that there were produced 4,5-di(vinyloxymethyl)cyclohexene oxide (cis-trans mixture) represented by following Formula (12) in a yield of 82% and 4-vinyloxymethyl-5-hydroxymethyl cyclohexene oxide (cis-trans mixture) in a yield of 4%. Purification of the reaction mixture by distillation yielded 31 g of 4,5-di-(vinyloxymethyl)cyclohexene oxide (cis-trans mixture) with a purity of 98%.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.C([O-])([O-])=O.[Na+].[Na+]>CO>[O:6]=[C:1]1[CH2:5][CH2:4][CH:3]([N:11]2[C:7](=[O:17])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10]2=[O:12])[CH2:2]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1C=CCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: O=C1CCC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70889.1 %

Procedure:
Mix cyclopentenone (100 g, 1.2 mol) and phthalimide (170 g, 1.2 mmol) in MeOH (900 mL) and stir for 18 h at ambient temperature. Stir vigorously with a mechanical stirrer and add 2 M aqueous Na2CO3 (80 mL). After approximately 2 h, a thick white precipitate will form. Stir at room temperature for 48 h. Collect the white solid by vacuum filtration and rinse with methanol. Suspend the solid in water (300 mL) and stir for 3 h. Collect the solid and dry in a vacuum oven at 40° C. overnight to give 195 g (71%) of the title compound as a white solid. 1H NMR (DMSO-d6) δ 7.85-7.77 (m, 4H), 4.90 (m, 1H), 2.67 (ddd, 1H, J=18.5, 6.2, 1.3 Hz), 2.54 (dd, 1H, J=18.5, 9.2 Hz), 2.45 (m, 1H), 2.32-2.21 (m, 3H); MS (m/z): 230 (M+1, weak).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1.C(N(CC)CC)C.[CH:22]([N:25]([CH:29]([CH3:31])[CH3:30])[C:26](Cl)=[O:27])([CH3:24])[CH3:23]>C1C=CC=CC=1>[CH:22]([N:25]([CH:29]([CH3:31])[CH3:30])[C:26]([N:5]([CH2:4][CH2:3][N:2]([CH3:14])[CH3:1])[C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:27])([CH3:24])[CH3:23]
Reactant: Cc1cc(C)nc(NCCN(C)C)c1
Reactant: CC(C)N(C(=O)Cl)C(C)C
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1cc(C)nc(N(CCN(C)C)C(=O)N(C(C)C)C(C)C)c1
Yield: 24.1 %

Procedure:
A solution of 5.80 g (30.0 mmoles) of 2-(2-dimethylaminoethylamino)-4,6-dimethylpyridine (from Example 1, B) and 2.20 ml (30.0 mmoles) of triethylamine in 50 ml of benzene is dried by azeotropic distillation. After adding 4.91 g (30.0 mmoles) of diisopropylcarbamoyl chloride, the reaction mixture is heated at reflux for 24 hours. The crude product, after removal of solvent, is chromatographed on silica gel using 5% methanol in chloroform as eluant. Appropriate fractions are combined, the solvent removed and product distilled through a short path still to give 2.32 g (24.1% yield) of N,N-diisopropyl-N'-(2-dimethylaminoethyl)-N'-(4,6-dimethyl-2-pyridyl)urea as a colorless oil boiling at 148°/0.35 mm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[C:4]([Br:11])[N:3]=1.[Na+].[C:13]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)(=[O:15])[CH3:14].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]([S:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][C:13](=[O:15])[CH3:14])=[CH:22][CH:21]=2)(=[O:25])=[O:24])[CH:5]=[C:4]([Br:11])[N:3]=1
Reactant: O=[N+]([O-])c1cc(Br)nc(Br)c1
Reactant: CC(=O)Nc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)c2cc(Br)nc(Br)c2)cc1
Temperature: 15 °C
Reaction time: 3.5 h
Yield: 68.6 %

Procedure:
To a solution of 63.7 g (0.226 Mol) 2,6-dibromo-4-nitropyridine in dimethylformamide (600 ml) at -15° C. were slowly added 50.0 g (0.226 Mol) 4-acetamido-benzenesulfinic acid sodium salt. The mixture was stirred at 15° C. for 3.5 h. Then 2.0 l water were added. It was stirred for another hour, filtered and the residue on the filter was washed with water (150 ml). It was then dissolved in aceton (hot, 700 ml) and evaporated. The residue was suspended in toluene (700 ml) and evaporated, again suspended in toluene and filtered. The residue on the filter was washed with toluene (200 ml) and dried in a high vacuum. It was obtained 67.3 g (69%) N-[4-(2,6-dibromo-pyridine-4-sulfonyl)-phenyl]-acetamide as a bright beige powder; mp.: 211° C.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH:23]=[CH:24][N:25]4[CH2:30][C:31](O)=[O:32])[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][C@@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:48][S:49]([NH2:52])(=[O:51])=[O:50].O>CN(C=O)C>[CH3:48][S:49]([NH:52][C:31](=[O:32])[CH2:30][N:25]1[C:26]2[C:22](=[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][C@@H:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])=[C:3]([C:2]([F:34])([F:1])[F:35])[CH:4]=4)[O:20][N:19]=3)[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1)(=[O:51])=[O:50]
Reactant: CS(N)(=O)=O
Reactant: C[C@H](Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(=O)O)no2)cc1C(F)(F)F)C(F)(F)F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](Oc1ccc(-c2nc(-c3cccc4c3ccn4CC(=O)NS(C)(=O)=O)no2)cc1C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.9 %

Procedure:
To a solution of [4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetic acid (100 mg) in DMF (1 ml) was added CDI (39 mg), and after 30 min, methanesulfonamide (23 mg) and 2,3,4,6,7,8,9,10-octahydropyrimide[1,2-a]azepine (37 mg) were added thereto, followed by stirring at room temperature for 15 hours. The reaction mixture was added with water to complete the reaction. It was extracted with EtOAc, the obtained organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 90:10) to obtain N-(methylsulfonyl)-2-[4-(5-{3-(trifluoromethyl)-4-[(1S)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetamide (56.4 mg) as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C:6]([NH:8][CH:9]([C:13]1[S:14][CH:15]=[CH:16][CH:17]=1)[C:10]([OH:12])=[O:11])=O.CCOCC>C(#N)C>[ClH:3].[NH2:5][C:6]1[O:11][C:10](=[O:12])[CH:9]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[N:8]=1
Reactant: NC(=O)NC(C(=O)O)c1cccs1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CC#N
Product: Cl
Product: NC1=NC(c2cccs2)C(=O)O1
Reaction time: 0.17 h
Yield: 91.5 %

Procedure:
Thionyl chloride (0.87 g, 7.3 mmol) was added to a suspension of 2-[(aminocarbonyl)amino]-2-(thien-2-yl) acetic acid (0.60 g, 3 mmol) in dry acetonitrile (17 ml) at 0°-5° C. under a nitrogen atmosphere. After 5 minutes dry ether (29 ml) was added and the resulting slurry was stirred for 10 minutes. The precipitate was then filtered under nitrogen, and washed well with ether. The product was dried in vacuo to afford 2-amino-4-(thien2-yl)-4H-oxazol-5-one hydrochloride (0.60 g, 92%) as a salmon pink powder; νmax (Nujol) 1878, 1745, 1725 cm-1.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[C:4]([Br:16])[CH:5]=[CH:6]3)[CH:2]=1)=O.[CH2:17]([NH2:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>C(O)(=O)C>[Br:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:15])[N:23]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:11](=[O:13])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: CCCCCCN
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCN1C(=O)c2cccc3c(Br)ccc(c23)C1=O
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A mixture of 4-bromo-1,8-naphthalic anhydride (21.40 g, 77.2 mmol), n-hexylamine (13.1 mL, 100 mmol), toluene (200 mL), and chloroform (200 mL) was heated to boil for 1 hour. Precipitate formed making stirring difficult. The mixture was acidified with acetic acid, and heating was continued at 90° C. with distillation of chloroform. After all precipitate dissolved, the reaction mixture was poured onto crushed ice (300 g) and acidified with concentrated HCl to pH 1. After the ice melted, the solid was filtered off and dried. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate 2:1) to give 6-bromo-2-hexyl-1H-benzo[de]isoquinoline-1,3(2H)-dione (20.66 g, 74%).
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:13])=[N:7]2.[CH2:14](OCC)C.C[Mg]Cl>[Ni+2].ClC(Cl)(CP(C1C=CC=CC=1)C1C=CC=CC=1)CP(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:13][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[C:11]([F:12])[C:2]=2[CH3:14])[N:7]=1
Reactant: CCOCC
Reactant: Cc1ccc2c(Br)c(F)ccc2n1
Agent: [Ni+2]
Agent: C[Mg]Cl
Agent: ClC(Cl)(CP(c1ccccc1)c1ccccc1)CP(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc2c(C)c(F)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 24.0 g (0.1 mole) of 5-bromo-6-fluoro-2-methylquinoline, 2.8 g (0.005 mole) of dichloro[1,3-bisdiphenylphosphinopropane] nickel (II) catalyst, and 380 ml of diethyl ether were combined. 44 ml of 3.17M methylmagnesium chloride in tetrahydrofuran was added dropwise at a rapid rate. The reaction was allowed to stir at room temperature overnight. The ether solution was decanted off into 200 ml of 3N hydrochloric acid in an ice bath, accompanied by vigorous stirring. The aqueous and organic layers were then separated. The aqueous layer was extracted with 100 ml of ethyl acetate and cooled in an ice bath, and the pH was adjusted to pH 10 with concentrated ammonium hydroxide. This was extracted twice with 100 ml of portions of ethyl acetate. The extracts were combined and washed with 30 ml of brine, dried over magnesium sulfate, and filtered and evaporated to give 14.9 g of 2,5-dimethyl-6-fluoroquinoline of 94.4% purity as determined by gas chromatography analysis.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([S:10]SCC)[CH3:9].C(S)C>C(O)CC.CCCO.CCCO.CCCO.CCCO.[Zr].[Zr]>[CH2:8]([S:10][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH3:9]
Reactant: CCSSCC
Reactant: Oc1ccccc1
Agent: [Zr]
Solvent: CCCO
Solvent: CCS
Product: CCSc1ccccc1O
Temperature: 200 °C
Yield: 41.2 %

Procedure:
To phenol (35.3 g, 0.37 moles) was added 10.6 g of zirconium n-propoxide in n-propanol consisting of 21.6% zirconium (0.025 mole) and 10.8% free n-propanol. The mixture was distilled at atmospheric pressure removing n-propanol. Ethyl disulfide (30.6 g, 0.25 moles) was added, and the mixture was heated under nitrogen while ethyl mercaptan was removed continuously by distillation. Heating was continued for a total of 6.5 hours during which temperature slowly increased to 200° C. Distillation of the mixture at 0.5 mm mercury to a maximum head temperature of 84° C. yielded 31.7 g of distillate. GC analysis indicated the distillate contained 12.4 g of phenol (35% recovered) and 15.9 g of ortho-(ethylthio)phenol (41% yield).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:24]([O:27][C:28](Cl)=[O:29])[CH2:25][CH3:26]>ClCCl>[CH2:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:28]([O:27][CH2:24][CH2:25][CH3:26])=[O:29])[CH2:3][CH2:2]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: CCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 15.0 g benzyl 1-piperazinecarboxylate in 100 ml dichloromethane were added 20.7 ml triethylamine. The solution was cooled to 0° C. and 8.4 ml propylchloroformate added dropwise at this temperature. After stirring for 1 h the reaction mixture was diluted with dichloromethane and washed with 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using an ethyl acetate/heptane gradient. Yield: 19.3 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CC(=O)CC>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:6]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=1
Reactant: CCCCCCCCCCBr
Reactant: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCOc1ccc(C(=O)OC)cc1C(C)(C)C
Yield: 105.2 %

Procedure:
A mixture of 12.0 g of 3-(1,1-dimethylethyl)-4-hydroxybenzoic acid methyl ester, 11.15 g of 1-bromodecane, 9.95 g of potassium carbonate, 0.797 g of potassium iodide and 100 ml of 2-butanone is heated at reflux temperature for 40 hours. The reaction is cooled, filtered and the filtrate concentrated in vacuo. The residue is purified by chromatography (silica gel: 0-3% ethyl acetate/hexane) to give 18.49 g of the desired product as a light yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.C1(C)C=C(C)C=C(C)C=1S(O[NH2:22])(=O)=O.[CH3:24][O:25][C:26]1[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1>>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]2[N:22]=[C:31]([C:29]3[S:30][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[N:9]=[C:4]2[CH:3]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: COc1ccc(C=O)s1
Reactant: Nc1cc(Br)cc(N)n1
Product: COc1ccc(-c2nc3cc(Br)cc(N)n3n2)s1

Procedure:
The title compound, MS m/e (%): 325 (M+, 100), was prepared in accordance with the general method of example 63 from 4-bromo-pyridine-2,6-diamine, O-mesitylene-sulfonylhydroxylamine, and 5-methoxy-thiophene-2-carbaldehyde. The purification was performed with reversed phase HPLC eluting with an acetonitrile/water gradient.
Reaction SMILES: [CH3:1][C:2]1[N:3]2[CH:9]=[C:8]([CH2:10]O)[N:7]=[C:4]2[S:5][CH:6]=1.CCOCC.O=S(Cl)[Cl:19]>>[ClH:19].[CH3:1][C:2]1[N:3]2[CH:9]=[C:8]([CH2:10][Cl:19])[N:7]=[C:4]2[S:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1csc2nc(CO)cn12
Solvent: CCOCC
Product: Cc1csc2nc(CCl)cn12
Product: Cl

Procedure:
10 g of 3-methyl-6-hydroxymethyl-imidazo-(2,1-b)thiazole prepared as described in one of the methods in Example 26, is refluxed for 2 hours in 100 ml of SOCl2. The solution is then cooled, 50 ml of ether are added to yield 11 g of 3-methyl-6-chloromethyl-imidazo-(2,1-b)thiazole hydrochloride; m.p. 280°.