Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:23]([O-])=O)[C:5]([OH:22])=[C:6]([CH:21]=1)[CH:7]=[C:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.C(=O)([O-])O.[Na+].Cl[CH2:32][C:33](Cl)=[O:34]>CO.[Pd].CC(=O)CC>[O:34]=[C:33]1[NH:23][C:4]2[CH:3]=[CH:2][CH:21]=[C:6]([CH2:7][CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[C:5]=2[O:22][CH2:32]1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cc(Br)cc([N+](=O)[O-])c2O)CC1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc3c2OCC(=O)N3)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
A solution of tert-butyl 4-(5-bromo-2-hydroxy-3-nitrobenzylidene)piperidine-1-carboxylate (2.1 g, 4.9 mmol) in methanol (150 mL) was stirred under atmospheric hydrogen in the presence of 10% palladium on charcoal (0.5 g) for 4 h. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to give a crude oil (1.8 g) which was taken up in 2-butanone (30 mL) and aqueous sodium hydrogen carbonate (1.3 g in water 20 mL). Chloroacetyl chloride (0.78 g) was added dropwise at 0° C. The mixture was stirred at 0° C. for further 2 h and then at 80° C. for 4 h. It was partitioned between water (50 mL) and ethyl acetate (100 mL). The organic layer was evaporated in vacuo. Silica gel chromatography of the resulting residue eluting with ethyl acetate in petroleum ether (20–30%) gave the title compound (1.5 g) as an oil.
Reaction SMILES: O.[CH3:2][CH:3]([OH:10])[CH2:4][NH:5][CH2:6][CH:7]([OH:9])[CH3:8].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[C:12]1([CH:11]2[N:5]([CH2:6][CH:7]([OH:9])[CH3:8])[CH2:4][CH:3]([CH3:2])[O:10]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(O)CNCC(C)O
Reactant: O=Cc1ccccc1
Solvent: O
Solvent: c1ccccc1
Product: CC(O)CN1CC(C)OC1c1ccccc1
Yield: 96.8 %

Procedure:
A reaction vessel equipped with a thermometer, a dropping funnel, a stirrer and a condenser having a water separator was charged with 133 g of diisopropanolamine and 100 g of benzene, to which 107 g of benzaldehyde was added dropwise at room temperature for one hour. The content was heated to reflux and, after removing water produced during reacting, reacted for another 5 hours. Benzene was removed under a reduced pressure and then distilled at 125° to 127° C./1 mmHg to obtain 214 g of 2-phenyl-3-(2-hydroxypropyl)-5-methyloxazolidine.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[Cl:19][CH2:20][S:21](Cl)(=[O:23])=[O:22].Cl>ClCCl>[Cl:19][CH2:20][S:21]([NH:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])(=[O:23])=[O:22]
Reactant: O=S(=O)(Cl)CCl
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNS(=O)(=O)CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
2-Aminoacetophenone hydrochloride (4.56 g, 26.6 mmol) was dissolved in dichloromethane (250 mL). To the solution was added triethylamine (9.30 mL, 66.7 mmol), and the mixture was stirred at room temperature for 10 minutes. After the reaction mixture was cooled to 0° C., chloromethanesulfonyl chloride (purity 90%, 3.60 mL, 36.3 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 2 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added diethyl ether, and the deposited crystals were collected by filtration and dried to give 2-(chloromethylsulfonylamino)acetophenone (5.00 g, 76%).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)Cl>[F:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:3]([O:4][CH3:5])[CH3:2])=[O:12])=[CH:9][CH:8]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
In a volumetric flask N,O-dimethylhydroxylamine hydrochloride (25.54 g, 261.8 mmol) and CH2Cl2 (443 mL) were introduced under argon atmosphere at 0° C. 4-Fluorobenzoyl chloride (34.59 g, 218.2 mmol) was added followed by the slow addition of triethylamine (48.13 g, 475.6 mmol). The reaction was stirred for 30 min at 5° C. and allowed to reach room temperature. It was washed with 5% aqueous citric acid (180 mL) and with 5% aqueous NaHCO3 (180 mL). The aqueous phase was extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated to dryness, to afford 20.23 g of the desired compound (yield: 88%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C>[N:20]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1
Temperature: 60 °C

Procedure:
To 4-(6-(bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.5 g) in DMF (11 mL) was added sodium azide (2 eq). The reaction was heated at 60° C. for 1 hour and then extracted with ethyl acetate and brine. The organic layer was dried (Mg2SO4), filtered and concentrated to afford 0.437 g of crude 4-(6-(azidomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine. This intermediate was then suspended in THF (4 mL), triphenylphosphine (2 eq) was added and the reaction was stirred at room temperature for 1.5 hours. Water (0.1 mL) was added to the reaction mixture which was then loaded onto a 10 g biotage isolute scx-2 cartridge then eluted with 2M ammonia in methanol then purified by flash column chromatography to yield 0.27 g (2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methanamine.
Reaction SMILES: [H-].[Na+].C1COCC1.[CH2:8]([N:15]1[C@@H:20]2[CH2:21][CH2:22][C@@:16]1([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C@H:17]([OH:23])[CH2:18][CH2:19]2)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:31][C:32]([F:46])([F:45])[C:33]1[CH:34]=[C:35]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:36]Br>CCCC(C)C.O>[CH2:8]([N:15]1[C@@H:20]2[CH2:21][CH2:22][C@@:16]1([C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[C@H:17]([O:23][CH2:36][C:35]1[CH:38]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:40]=[C:33]([C:32]([F:31])([F:45])[F:46])[CH:34]=1)[CH2:18][CH2:19]2)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccc(F)cc1)N2Cc1ccccc1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCC(C)C
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc([C@]23CC[C@H](CC[C@H]2OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)N3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
Sodium hydride (320 mg, 60% in oil, 7.98 mmol) was washed with iso-hexane (×3) then THF (8 ml) and (1R*,2R*,5R*)-8-benzyl-1-(4-fluorophenyl)-8-azabicyclo[3.2.1]octan-2-ol (Description 15; 1.24 g, 3.99 mmol) added and the mixture stirred at room temperature for 10 minutes then 3,5-bis(trifluoromethyl) benzyl bromide added and the reaction mixture stirred at 60° C. overnight. The reaction mixture was poured into water and extracted with ethyl acetate (×3), dried (MgSO4) and concentrated in vacuo to give a yellow oil. This was purified by flash column chromatography [5% ethyl acetate in iso-hexane] to give the title compound (1.51 g, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[O:16][CH:17]=[N:18][N:19]=3)[CH:10]=2)=[CH:7][C:6]([CH:20]=[O:21])=[CH:5][CH:4]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1.[NH4+].[Cl-]>C1COCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:20]([C:6]2[CH:7]=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]4[O:16][CH:17]=[N:18][N:19]=4)[CH:10]=3)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[OH:21])=[CH:25][CH:24]=1
Reactant: COc1ccc(C=O)cc1-c1cccc(-c2nnco2)c1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccc(F)cc2)cc1-c1cccc(-c2nnco2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of the above aldehyde, 6-Methoxy-3′-[1,3,4]oxadiazol-2-yl-biphenyl3-carbaldehyde (86 mg, 0.307 mmol) in anhydrous THF (1 mL) was added dropwise a solution of 4-fluorophenyl magnesium bromide in THF (0.46 ml, 1M) at −78° C. After the addition was complete, the resulting mixture was allowed to warm to room temperature and stirred for 40 minutes. Then saturated NH4Cl aq. was added. The mixture was extracted with EtOAc (2×10 ml). The combined organic layers were washed with water and dried over Na2SO4. Removal of solvent gave a residue, which was purified by chromatography on silica gel to give 112 mg of the product (P-117). 1H NMR (400 MHz, CDCl3) δ ppm 3.82 (s, 3H), 5.85 (s, 1H), 6.97 (d, J=8.4 Hz, 1H), 6.98-7.05 (m, 2H), 7.31-7.39 (m, 4H), 7.54 (t, 1H), 7.67-7.7 (m, 1H), 8.01-8.04 (m, 1H), 8.23 (s, 1H), 8.46 (s, 1H) ppm; LCMS (ESI+): 377 (M+1).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:32])=[C:15]([CH:31]=3)[C:16]([NH:18][C:19]3[C:20]([CH3:30])=[C:21]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:22]([O:24][CH3:25])=[O:23])=[O:17])[CH2:7][CH2:6]2)[O:4]CC1.Cl>C1COCC1>[CH3:30][C:20]1[C:19]([NH:18][C:16](=[O:17])[C:15]2[CH:31]=[C:11]([N:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[CH:12]=[CH:13][C:14]=2[CH3:32])=[C:28]([CH3:29])[CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC4(CC3)OCCO4)ccc2C)c1C
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(=O)CC3)ccc2C)c1C
Temperature: 25 °C
Reaction time: 22 h
Yield: 53.4 %

Procedure:
To a solution of methyl 3-[[5-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-2-methyl-benzoyl]amino]-2,4-dimethyl-benzoate (250 mg, 570.09 μmoles) in THF (2 ml) is added 4M HCl (1 ml) and stirred at ambient temperature. The mixture is concentrated under reduced pressure and re-dissolved in acetone (5 ml) followed by the addition of 5N HCl (1 ml). After 22 hours at 60° C., the mixture is cooled to ambient temperature and diluted with 2M NaOH to pH 6 and extracted twice with ethyl acetate. The combined organic layers are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using 0-50% ethyl acetate in hexane to afford the title compound as an off-white foam (0.12 g, 53.36%). Mass spectrum (m/z): 395.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.C(O)(=[O:23])C.OO.[OH-].[Na+]>CO.O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].O.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([OH:23])=[N:6]2
Reactant: COc1ccc(-c2cc(Cl)c3cnc(SC)nn23)cn1
Reactant: CC(=O)O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2cc(Cl)c3cnc(O)nn23)cn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
5-Chloro-7-(6-methoxy-pyridin-3-yl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (114 mg, 0.372 mmol) was dissolved in Methanol (12.0 mL): Tetrahydrofuran (8.0 mL), Acetic acid (0.200 mL, 3.52 mmol) was added followed by Sodium Tungstate Dihydrate (7.0 mg, 0.021 mmol) and 50% Hydrogen Peroxide (0.100 mL, 1.76 mmol) and the mixture was heated at 60-80° C. overnight in a vial. LCMS shows conversion to a mixture of sulfoxide and sulfone. The mixture was cooled, added portionwise to stirring water (60 mL) and let stand. The solids were collected, washing with water. The crude 5-Chloro-2-methanesulfonyl-7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazine was suspended in 1,4-Dioxane (3.00 mL): 5.0 M of Sodium hydroxide in Water (0.50 mL, 2.5 mmol) and heated at 60° C. for 2 h, then cooled and treated with Acetic acid (0.200 mL, 3.52 mmol) and water (1 mL). The solids were let stand 1 h, then collected. Product was also in the aq. layer, which was extr. with DCM (3×20 mL), comb. with the solids and conc. in vacuo onto 3 g silica gel. Purification (ISCO, 0-80% EtOAc:Hex) afforded 5-Chloro-7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (31 mg; Yield=30%) as yellow solids.
Reaction SMILES: COC1C=CC(CO)=CC=1.CC1(C)C2(C)C(O)CC1CC2.C(O)C1C=CC=CC=1.[Cl:30][C:31]([Cl:35])([Cl:34])[CH2:32][OH:33].COC1C=CC(C[O:43][C:44]([NH:46][CH:47]2[C:50](=[O:51])[N:49]([CH2:52][C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=3[O:61][CH3:62])[CH:48]2[C:63]([O:65][CH3:66])=[O:64])=O)=CC=1.C(OC(NC1C(=O)N(CC2C=CC(OC)=CC=2OC)C1C(OC)=O)=O)C1C=CC=CC=1>C(O)(C)(C)C>[Cl:30][C:31]([Cl:35])([Cl:34])[CH2:32][O:33][C:44]([NH:46][CH:47]1[C:50](=[O:51])[N:49]([CH2:52][C:53]2[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[CH:55][C:54]=2[O:61][CH3:62])[CH:48]1[C:63]([O:65][CH3:66])=[O:64])=[O:43]
Reactant: COC(=O)C1C(NC(=O)OCc2ccc(OC)cc2)C(=O)N1Cc1ccc(OC)cc1OC
Reactant: OCC(Cl)(Cl)Cl
Agent: CC1(C)C2CCC1(C)C(O)C2
Agent: COC(=O)C1C(NC(=O)OCc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Agent: COc1ccc(CO)cc1
Solvent: OCc1ccccc1
Solvent: CC(C)(C)O
Product: COC(=O)C1C(NC(=O)OCC(Cl)(Cl)Cl)C(=O)N1Cc1ccc(OC)cc1OC

Procedure:
When p-methoxybenzyl alcohol, isoborneol, benzyl alcohol, or 2,2,2-trichloroethanol is substituted for t-butanol in Example 3, methyl 3-(p-methoxybenzyloxycarbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, methyl 3-(isobornyloxycarbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, methyl 3-(benzyloxycarbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate, or methyl 3-(2,2,2-trichloroethoxycarbonylamino)-1-(2,4-dimethoxybenzyl)-4-oxoazetidine-2-carboxylate is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([O:20]C)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:22][CH3:23])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:22][CH3:23])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1Cc2ccc(OC)cc2CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc2c(c1)CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Methyl 2-(t-butyloxycarbonyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline-3(S)-carboxylate (0.58 g, 1.81 mmol) in MeOH:H2O 1:1 (20 mL) was added 1 N NaOH (2.7 mL, 2.72 mmol) and the resulting solution was stirred at 25° C. for 18 hr. The methanol was evaporated in vacuo and the remaining aqueous portion was acidified to pH=3 with 1 N HCl and then extracted two times with EtOAc. The organic layers were washed with saturated NaCl (30 mL) and dried (MgSO4). Filtration and evaporation in vacuo gave the title compound.
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21]([O:23][C:24](=[O:25])[C:3](=[C:4]23)[CH:2]=1)=[O:22].[OH-:26].[K+]>C(O)(C)(C)C>[CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]([C:21]([OH:23])=[O:22])[C:4]3=[C:3]([C:24]([OH:25])=[O:26])[CH:2]=1
Reactant: O=C1OC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc2c3cccc4cccc(c5ccc(C(=O)O)c1c25)c43
Yield: 50 %

Procedure:
At a yield of 50% in the reaction in the autoclave, monoimide 2b is a suitable starting material for preparing perylene-3,4-dicarboxylic anhydride 4. To this end, 2b is reacted, for example, with KOH in tert-butyl alcohol, followed by hydrolysis to give the monoamide of perylene-3,4-dicarboxylic acid. Acidification of the alkaline solution of the monoamide thus obtained results in further hydrolysis of a portion thereof to give the desired perylene-3,4-dicarboxylic anhydride (4) (while the other portion reverts to the starting material 2b). A particularly suitable acid is 50 per cent acetic acid, which gives yields of more than 60% of 4; based on conversion, the isolated yield of 4 is even more than 90%. The remaining portion of the cyclization product 2b can be separated off without any difficulty by dissolution with hot potassium carbonate solution, filtration and precipitation with acetic acid, so that the anhydride 4 is obtained in high purity.
Reaction SMILES: C([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[CH2:6]1)(=O)C.[ClH:20]>>[ClH:20].[NH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:11]=2)[CH2:6]1
Reactant: COC(=O)COc1ccc2c(c1)CC(NC(C)=O)C2
Agent: Cl
Product: COC(=O)COc1ccc2c(c1)CC(N)C2
Reaction time: 13 h
Yield: 91 %

Procedure:
To 0.735 g of methyl (2-acetylaminoindan-5-yl)oxyacetate are added 6 ml of aqueous 10% hydrochloric acid solution, and the mixture is refluxed under stirring for 13 hours. The reaction mixture is evaporated to remove solvent and 10 ml of methanol are added to the residue. The mixture is refluxed for 1.5 hours and evaporated to remove methanol. The residue is recrystallized from methanol-diethyl ether to give 0.655 g of methyl (2-aminoindan-5-yl)oxyacetate hydrochloride as yellow prisms. Yield: 91%
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](N)=[O:10])=[C:4]([F:12])[CH:3]=1.[OH-:13].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:13])=[O:10])=[C:4]([F:12])[CH:3]=1
Reactant: [OH-]
Reactant: NC(=O)Cc1ccc(Br)cc1F
Agent: [Na+]
Product: O=C(O)Cc1ccc(Br)cc1F
Temperature: 25 °C
Yield: 38 %

Procedure:
4-Bromo-2-fluoro-phenylacetamide (1.3 gm) was suspended in 100 ml of 30% NaOH, heating at reflux temperature for 24 hrs, cooled to room temperature, washed with DCM and ethyl acetate. The aqueous layer was acidified with conc. HCl, extracted with ethyl acetate, evaporated; the residue was crystallized from isopropanol-water to give needle crystals (0.5 gm, 38%) H1-NMR INOVA-500 (DMSO d6) δ 3.619 (s, 2H), 7.316 (t, J=8.0 Hz, 1H), 7.379 (dd, J=8.0, 1.5 Hz, 1H), 7.516 (dd, J=8.0, 1.5 Hz, 1H), 12.555 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([C:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[S:7][CH:8]=1)[CH3:3].C([Li])CCC.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.[Cl-].[Na+].O>[OH:31][C:28]1([C:8]2[S:7][C:6]3[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=3[C:4]=2[CH:2]([OH:1])[CH3:3])[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CC(O)c1csc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1c(C2(O)CCN(C(=O)OC(C)(C)C)CC2)sc2ccccc12
Temperature: 0 °C
Reaction time: 6 h
Yield: 87.1 %

Procedure:
Scheme IA, Step A: To a solution of 3-(1-hydroxyethyl)benzo[b]thiophene (2.036 g, 11.4 mmol) in tetrahydrofuran (75 mL) at −78° C. was added a solution of n-butyllithium (15.7 mL, 25.1 mmol, 1.6 M in hexanes). The solution was warmed to 0° C. for one hour then recooled to −78° C. A solution of 1-t-butyloxycarbonyl-4-piperidone (2.503 g, 12.6 mmol) in tetrahydrofuran was added dropwise and the mixture was warmed to 20° C. After stirring for 6 hours at 20° C. the mixture was diluted with brine and extracted 3 times with ethyl acetate. The combined organics were dried over sodium sulfate then filtered and evaporated. The residue was purified using silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent) to give 3.75 g (87%) of the intermediate title compound as a yellow amorphous solid. FDMS m/e=378 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][C:10]2[CH2:14][CH2:13][CH2:12][CH:11]=2)[C:3]=1[OH:15]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[O:15][C:10]3([CH2:14][CH2:13][CH2:12][CH2:11]3)[CH2:9][C:4]=2[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1c(Br)cc(Cl)cc1CC1=CCCC1
Solvent: Cc1ccccc1
Product: Clc1cc(Br)c2c(c1)CC1(CCCC1)O2
Temperature: 80 °C
Yield: 94.8 %

Procedure:
The mixture of 2-bromo-4-chloro-6-(cyclopentenylmethyl)phenol (518) (5.7 g, 19.8 mmol) and Amberlyst® 15 ion-exchange resin (5.2 g) in toluene (100 mL) was heated at 80° C. for 3 hours. Subsequently, the Amberlyst 15 resin was filtered off and the filtrate was concentrated in vacuo to give 7-bromo-5-chloro-3H-spiro[benzofuran-2,1′-cyclopentane] (519) (5.4 g, 94.9%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]([N:6]=[C:7]=[O:8])=[C:3]([Cl:5])[Cl:4].[OH:9][C:10]1[N:14]=[C:13]([O:15][CH2:16][CH3:17])[S:12][N:11]=1>C1C=CC=CC=1>[Cl:1][C:2]([NH:6][C:7]([N:11]1[C:10](=[O:9])[N:14]=[C:13]([O:15][CH2:16][CH3:17])[S:12]1)=[O:8])=[C:3]([Cl:5])[Cl:4]
Reactant: CCOc1nc(O)ns1
Reactant: O=C=NC(Cl)=C(Cl)Cl
Solvent: c1ccccc1
Product: CCOc1nc(=O)n(C(=O)NC(Cl)=C(Cl)Cl)s1
Temperature: 20 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
51.7 g of trichlorovinyl isocyanate were added dropwise to a solution of 21.9 g of 3-hydroxy-5-ethoxy-1,2,4-thiadiazole in 300 ml of benzene and after stirring the mixture for 16 hours at 20° C, the mixture was filtered. The filtrate was evaporated to dryness and the product was eluted with 7-3 benzene-ethyl acetate mixture and crystallized from isopropyl ether to obtain 22 g of 2-(N-trichlorovinylcarbamoyl)-5-ethoxy-1,2,4-thiadiazole-3-one melting at 123° C.