Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[CH:29]1[C:34](/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38])=[CH:33][CH:32]=[C:31]([OH:40])[CH:30]=1.C(OC(C)C)(C)C>CO>[CH:1]1[C:2]([CH2:10][C@@H:11]([NH2:28])[CH2:12][C:13]([N:15]2[CH2:27][C:19]3=[N:20][N:21]=[C:22]([C:23]([F:26])([F:25])[F:24])[N:18]3[CH2:17][CH2:16]2)=[O:14])=[C:3]([F:9])[CH:4]=[C:5]([F:8])[C:6]=1[F:7].[C:37]([O-:39])(=[O:38])/[CH:36]=[CH:35]/[C:34]1[CH:33]=[CH:32][C:31]([OH:40])=[CH:30][CH:29]=1
Reactant: O=C(O)/C=C/c1ccc(O)cc1
Agent: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Solvent: CO
Solvent: CC(C)OC(C)C
Product: O=C([O-])/C=C/c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Sitagliptin free base (2.0 gms) and coumaric acid (0.80 gms) were dissolved in methanol (12 ml) at 60° C. to 65° C. and the solution was cooled to room temperature. Isopropyl ether (240 ml) was added to the resultant clear solution and stirred for 14 hours. Precipitated solids were filtered and dried at 50° C. to 55° C. for 6 hours to obtain the title compound.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH2:32])[CH:29]=[N:30][CH:31]=1.C[Si](N[Si](C)(C)C)(C)C.[Li].CO>C1COCC1.C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:32][C:2]2[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][N:12]4[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:29]=[N:30][CH:31]=1
Reactant: COc1cncc(N)c1
Reactant: Cc1nc(-c2cccnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: COc1cncc(Nc2ncccc2-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
Argon was bubbled for 2 min through a glass microwave reaction vessel containing 6-(2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (100 mg, 0.319 mmol) and 5-methoxypyridin-3-amine (47.5 mg, 0.383 mmol, Astatech, Inc, Bristol, Pa.) in THF (5 mL), and the tube was sealed. The reaction mixture was cooled to 0° C. and lithium bis(trimethylsilyl)amine (1 N in THF, 1 mL, 0.957 mmol) was added dropwise. The red solution was stirred at 0° C. for 1 h and then warmed to room temperature. The mixture was quenched with saturated NH4Cl and extracted with EtOAc (3×).The combined organic extracts were washed with satd. NaCl and dried over Na2SO4. The solution was filtered and concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (25 g) eluting with a gradient of 2% to 5% 2 M NH3.MeOH in DCM to give N-(5-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (60 mg, 0.144 mmol, 45.0% yield) as an orange solid. m/z (ESI, +ve ion) 418 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl[C:18]1[N:19]=[N:20][C:21]([C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[CH:22][CH:23]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14]([C:18]3[N:19]=[N:20][C:21]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)=[CH:22][CH:23]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cnn(C3CCNCC3)c2c1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cn1cc(-c2ccc(N3CCC(n4ncc5ccc(F)cc54)CC3)nn2)cn1

Procedure:
6-Fluoro-1-(piperidin-4-yl)-1H-indazole (260 mg, 1.19 mmol), 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyridazine (230 mg, 1.19 mmol) and DIEA (269 uL) in DMSO (4 ml) under Ar were heated in a microwave reactor at 200° C. for 1 hour. After removal of most of the DMSO in vacuo, water (10 mL) was added and the aqueous layer extracted several times with CHCl3 (50 mL). The organic layer was washed with brine, dried (MgSO4), decolorized with NORITE, filtered and the solvent removed in vacuo. The resulting residue was purified via ISCO column chromatography (Amine “Redisep” 14 gram column eluded 0-100% EtOAc/hexane over 20 column volumes), then re-crystallized from DCM with heptanes to yield 6-fluoro-1-(1-(6-(1-methyl-1H-pyrazol-4-yl)pyridazin-3-yl)piperidin-4-yl)-1H-indazole.
Reaction SMILES: ClC1C=CC(C2C([C:12]3C=C[C:19]4[C:14](=[CH:15][CH:16]=[C:17](C(O)=O)[CH:18]=4)[N:13]=3)=CC(OC)=CC=2)=CC=1.C[N:30](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[N:30]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:13][CH:12]=1
Reactant: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(C(=O)O)ccc3n2)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound 525c (0.38 g, 0.97 mmol) was reacted with HBTU (0.444 g, 1.2 mmol) in anhydrous DMF (5 mL) in the presence of DIEA (0.41 mL, 2.35 mmol) for 30 min. The mixture was then transferred to a suspension of amine-resin in DMF (5 mL). The reaction mixture was shaken at room temperature overnight. The solution was drained and the resin was washed with DMF (5 mL×5), MeOH (5 mL×5), and CH2Cl2 (5 mL×5). The resin was dried under high vacuum.
Reaction SMILES: [CH2:1]([S:8]([C:11]1[N:12]([C:19]2[C:24]([CH2:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:27][CH3:28])[C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[CH2:1]([S:8]([C:11]1[N:12]([C:19]2[C:24]([CH2:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:27][CH3:28])[C:13]([C:16]([O-:18])=[O:17])=[CH:14][N:15]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2+:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCc1cccc(CC)c1-n1c(C(=O)O)cnc1S(=O)(=O)Cc1ccccc1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: C1CC[NH2+]CC1
Product: CCc1cccc(CC)c1-n1c(C(=O)[O-])cnc1S(=O)(=O)Cc1ccccc1
Yield: 89.2 %

Procedure:
6.5 g (0.016 mol) of 2-benzylsulfonyl-1-(2,6-diethylphenyl)-imidazole-5-carboxylic acid were stirred with 1.6 g (0.019 mol) of piperidine in 50 ml of methylene chloride until the carboxylic acid had dissolved. The solution was evaporated down, the residue was brought to crystallization with ether, and the solid was filtered off under suction and dried to give 6.9 g (87% of theory) of piperidinium 2-benzylsulfonyl-1-(2,6-diethylphenyl)-imidazole-5-carboxylate, a colorless solid of melting point 167°-170° C.
Reaction SMILES: C([Cl:4])(=O)C.S(Cl)(Cl)=O.[CH3:9][O:10][CH:11](OC)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[CH:11]([Cl:4])[O:10][CH3:9]
Reactant: CC(=O)Cl
Reactant: COC(OC)c1ccc(Cl)c(Cl)c1
Solvent: O=S(Cl)Cl
Product: COC(Cl)c1ccc(Cl)c(Cl)c1
Reaction time: 22 h
Yield: 99.8 %

Procedure:
A mixture of acetyl chloride (77 g) and thionyl chloride (0.8 ml) was added, with stirring, to 3,4-dichlorobenzaldehyde dimethyl acetal (110 g). The mixture was kept at laboratory temperature (about 27° C.) for 22 hours and then evaporated at 30° C. under reduced pressure (0.15 mm Hg) for about 4 hours until constant in weight. 3,4-Dichloro-α-methoxybenzyl chloride (112 g) was thus obtained as an oil, which was used without further purification as a starting material in the above preparations.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH2:22][CH2:21]1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])=[O:6].C(N(CC)CC)C.[S:40]1[CH:44]=[CH:43][C:42]([C:45](O)=[O:46])=[CH:41]1>C(Cl)Cl>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH2:10][CH2:9][CH2:8][NH:7][C:5]([C:4]1[CH:17]=[CH:18][C:19]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[CH2:22][CH2:21]2)=[C:2]([NH:1][C:45]([C:42]2[CH:43]=[CH:44][S:40][CH:41]=2)=[O:46])[CH:3]=1)=[O:6]
Reactant: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Reactant: O=C(O)c1ccsc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1N1CCN(c2ccc(C(=O)NCCCN3CCCC3=O)cc2NC(=O)c2ccsc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 272.1 %

Procedure:
To a suspension of 3-amino-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-4-(4-o-tolyl-piperazin-1-yl)-benzamide (0.1 g, 0.229 mmol) in methylene dichloride (5 ml), triethylamine (0.069 g, 0.489 mmol), thiophene-3-carboxylic acid (0.044 g, 0.344 mmol) and 1-propane phosphonic cyclic anhydride (0.21 g, 0.489 mmol) were added. The reaction mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated and extracted with dichloromethane (10 ml×1). The organic layer was washed with water (10 ml×2) and dried over anhydrous sodium sulphate. The organic layer was concentrated and the crude product obtained was purified by flash chromatography using silica gel column to get (0.34 g, 34%) of the titled compound as a brown solid.
Reaction SMILES: [NH2:1][CH2:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8].[C:9](Cl)(Cl)=[S:10].C(N(CC)CC)C.[NH2:20][CH2:21][N:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:29]>C(Cl)Cl>[O:29]=[C:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:22]1[CH2:21][NH:20][C:9]([NH:1][CH2:2][N:3]1[CH2:7][CH2:6][CH2:5][C:4]1=[O:8])=[S:10]
Reactant: S=C(Cl)Cl
Reactant: NCN1CCCC1=O
Reactant: NCN1CCCCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCCCN1CNC(=S)NCN1CCCC1=O
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 395.4 %

Procedure:
A solution of 6.27 g (0.055 mole) of 1-aminomethyl-2-pyrrolidinone in 50 ml of methylene chloride is added slowly and with vigorous stirring to a solution of 3.8 ml (0.05 mole) of thiophosgene and 10.1 g (0.1 mole) of triethylamine in 50 ml of methylene chloride kept at -70° C. After the addition, the reaction mixture is allowed to return to ambient temperature and 7.8 g (0.005 mole) of 1-aminomethyl-hexahydro-2H-azepin-2-one are added slowly. Stirring is continued for 15 minutes and the reaction mixture is then cooled to -50° C. in order to precipitate the triethylamine hydrochloride. It is filtered and the filtrate is evaporated to dryness. The residue obtained is purified by chromatograhy on silica (eluent: chloroform). 5.9 g of 1-[(hexahydro-2-oxo-1H-azepin-1-yl)methyl]-3-[(2-oxo-pyrrolidino)methyl]-2-thiourea are obtained. Yield: 39% of theory; M.P. 147°-148° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:6]([C:7]([NH:9][CH3:10])=[O:8])=[CH:5][N:4]=1.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([N:33]=[C:34]=[S:35])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>O1CCOCC1.C(Cl)Cl>[CH2:14]([O:13][C:11]1[C:6]([C:7](=[O:8])[NH:9][CH3:10])=[CH:5][N:4]=[C:3]([CH2:2][NH:1][C:34]([NH:33][C:31]([O:30][CH2:29][CH:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:28]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:32])=[S:35])[CH:12]=1)[CH3:15]
Reactant: CCOc1cc(CN)ncc1C(=O)NC
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOc1cc(CNC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)ncc1C(=O)NC
Reaction time: 1 h
Yield: 74.6 %

Procedure:
500 mg (2.39 mmol) of 6-aminomethyl-4-ethoxy-N-methylnicotinamide (Example 12f) were dissolved in 25 ml of dioxane and treated at RT with 672.4 mg (2.39 mmol) of fluoren-9-ylmethyloxycarbonyl isothiocyanate. After one hour, the mixture was freed from the solvent and the residue was taken up in DCM. It was washed three times with aqueous LiCl solution and once with water. After drying with MgSO4, the mixture was concentrated and the crude product (875 mg) thus obtained was reacted further without further purification.
Reaction SMILES: C(OC(C)C)(=O)C.[C:8]([O:12][C:13]([N:15]1[C@H:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:18][C:17](=[CH2:33])[C:16]1=[O:34])=[O:14])([CH3:11])([CH3:10])[CH3:9].[H][H]>>[C:8]([O:12][C:13]([N:15]1[C@H:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[CH2:18][C@@H:17]([CH3:33])[C:16]1=[O:34])=[O:14])([CH3:11])([CH3:9])[CH3:10].[C:8]([O:12][C:13]([N:15]1[C@H:19]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)[CH2:18][C@H:17]([CH3:33])[C:16]1=[O:34])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Reactant: [H][H]
Solvent: CC(=O)OC(C)C
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Product: C[C@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Isopropyl acetate (1 ml) is added to a mixture of 100 mg (R)-5-biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (4-a, R1=Boc) and 10% platinium on carbon (10 mg). Hydrogen gas (ambient pressure) is applied to the mixture. The mixture is stirred at ambient temperature and pressure for 4 h. The mixture is then filtered over Celite® and washed with isopropyl acetate (2×0.5 ml). The mixture is then concentrated in vacuo to give (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-a, R1=Boc) and (3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 33:67 (3-a, R1=Boc:3-b, R1=Boc) as determined by hplc. Spectroscopic data in described in WO/2008/083967, for example, Examples 14 and 18.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:9].C([Li])CCC.Cl[Si](C)(C)CC[Si](Cl)(C)C.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27].Cl>O1CCCC1>[CH2:29]([O:28][C:26](=[O:27])[C:7]1[C:6]([F:8])=[CH:5][CH:4]=[C:3]([NH2:9])[C:2]=1[F:1])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: C[Si](C)(Cl)CC[Si](C)(C)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1ccc(F)c(C(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To 2,4-difluoro-phenylamine (1, 5.11 mL, 50.7 mmol) in 250 mL of tetrahydrofuran, cooled with dry ice/acetone bath under an atmosphere of nitrogen, n-butyllithium (1.60 M in hexane, 34.0 mL, 54.4 mmol) was added slowly. After 30 minutes, 1,2-bis-(chloro-dimethyl-silanyl)-ethane (11.5 g, 53.4 mmol) dissolved in 40.0 mL of tetrahydrofuran was added slowly. After 1 hour, n-butyllithium (1.60 M in hexane, 31.9 mL, 51.1 mmol) was added slowly. The reaction was stirred at −78° C. for 30 minutes and then allowed to warm to room temperature over 40 minutes. The reaction was cooled to −78° C. and n-butyllithium (1.60 M in hexane, 35.1 mL, 56.1 mmol) was added slowly. After 70 minutes, benzyl chloroformate (2, 7.97 mL, 55.8 mmol) was added to the reaction. The reaction mixture was stirred at −78° C. overnight followed by addition of 120 mL of 2 N aqueous hydrochloric acid. The reaction was allowed to warm to room temperature for 2 hours. The organic layer was separated. The aqueous layer was basified with potassium carbonate and extracted with ethyl acetate. The organic layers were combined and washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The desired compound was isolated by silica gel column chromatography (ethyl acetate/hexane 20%) to give a colorless oil (3, 10.6 g, 79.7%). MS(ESI) [M+H+]+=264.1.
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[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[C:35]([C:39]1C=[CH:43][CH:42]=[CH:41][C:40]=1O)([CH3:38])([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[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[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][C:24]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4C(C)(C)C)cc3)c2cc1OC
Yield: 80.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-(tert-butyl)phenol (39 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (64 mg, yield 74%).
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]=[CH:5][C:4]3=[CH:3][CH:2]=1.[CH:21](=[O:28])C1C=CC=CC=1.C(C1C2=C3C(C4C5C(=CC=CC2=5)C=CC=4)=CC=CC3=CC=1)#C.BrC1C=C(C=C(Br)C=1)C=O>[Cu]I>[C:16]1([CH:21]=[O:28])[C:17]2=[C:20]3[C:9]([C:8]4[C:19]5[C:4](=[CH:3][CH:2]=[CH:1][C:18]2=5)[CH:5]=[CH:6][CH:7]=4)=[CH:10][CH:11]=[CH:12][C:13]3=[CH:14][CH:15]=1
Reactant: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54
Reactant: O=Cc1ccccc1
Agent: [Cu]I
Agent: C#Cc1ccc2cccc3c4cccc5cccc(c1c23)c54
Agent: O=Cc1cc(Br)cc(Br)c1
Product: O=Cc1ccc2cccc3c4cccc5cccc(c1c23)c54
Yield: 31 %

Procedure:
The first route employs bromoperylene PMI-12 and 3,5-diethynylbenzaldehyde (16) as the starting materials. The reaction under copper-free conditions, similar to those employed for the Sonogashira coupling of two porphyrins (Wagner, R. W. et al., Chem. Mater. 1999, 11, 2974-2983) afforded only a small amount (8.9%) of perylene-aldehyde 18 (entry 1, Table 1). The same reaction in the presence of CuI failed to produce perylene-aldehyde 18 (entry 2). We next examined the reaction with the reverse ethyne/bromo substitution pattern on the perylene and benzaldehyde. The reaction of ethynylperylene PMI-12′ and 3,5-dibromobenzaldehyde (14) (2:1 ratio) with CuI cocatalysis afforded 18 in 31% yield (entry 3). A further increase in the amount of perylene PMI-12′ (2.4:1 ratio) gave 18 in 66% yield (entry 4). Repetition of this reaction furnished 18 in 83% yield. While of limited scope, the survey of the Sonogashira reaction of perylene PMI-12 or PMI-12′ with aldehyde 14 or 16 revealed important reactivity differences between a bromoperylene and an ethynylperylene. Unlike perylene-aldehyde 15, compound 18 proved to be very soluble, thereby enabling subsequent porphyrin-forming reactions.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][CH:13]2[CH:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([O:18]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])(=[O:3])[CH3:2].C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][CH:13]2[CH:10]([C:11](=[O:15])[CH2:12]2)[C:9]=1[C:16]([OH:18])=[O:17])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCSC1=C(C(=O)OC(c2ccccc2)c2ccccc2)C2C(=O)CC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(=O)NCCSC1=C(C(=O)O)C2C(=O)CC2C1
Yield: 91.6 %

Procedure:
A solution of 150 mg of 3-(2'-acetamidoethylthio)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, and 130 mg of anisole in 1 mL of trifluoroacetic acid was stirred at ambient temperature for 15 min. The solvent was then removed by a stream of nitrogen leaving a residue which was crystallized from ether to afford 85 mg (92%) of 3-(2'-acetamidoethylthio)-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid as colorless crystals, mp 150° to 152°. IR (Nujol): 1640, 1660, 1785, 3150 cm-1 ; NMR (CDCl3 /DMSO-d6): δ 1.93 (3H, s), 2.8-3.0 (5H, m), 3.1-3.4 (4H, m), 4.43 (1H, m), and 7.43 (1H, m). HRMS: The molecular ion (m/z 269) was not observed; however, a major fragment corresponding to loss of ketene from the molecular ion was mass measured: Calcd for C10H13O3NS, 227.0615; found, 227.0616.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]3[CH:16]=[C:17]([CH2:19][CH2:20][CH3:21])[S:18][C:12]=3[NH:11][C:10]2=[O:22])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:37]2[N:41]=[C:40](C(Cl)(Cl)Cl)[O:39][N:38]=2)=[CH:27][CH:26]=1.C(=O)([O-])[O-:47].[K+].[K+]>C(#N)C>[N:1]1([CH2:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]3[CH:16]=[C:17]([CH2:19][CH2:20][CH3:21])[S:18][C:12]=3[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]4[NH:41][C:40](=[O:47])[O:39][N:38]=4)=[CH:27][CH:26]=3)[C:10]2=[O:22])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: CCCc1cc2c(=O)n(CCN3CCOCC3)c(=O)[nH]c2s1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Agent: [K+]
Solvent: CC#N
Product: CCCc1cc2c(=O)n(CCN3CCOCC3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
A mixture of 3-(2-morpholin-4-ylethyl)-6-propylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.5 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (0.83 g), potassium carbonate (0.43 g) and acetonitrile (20 mL) was stirred at room temperature for 2 hr. Insoluble material was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (4 mL) and methanol (4 mL). 1N Aqueous sodium hydroxide solution (4 ml) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 4 with water and 1N hydrochloric acid, and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.29 g, 32%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:21])(=O)=O)=CC=1.C(O[B:35]1[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:43])([CH3:42])[O:36]1)(C)C>C1COCC1>[F:21][C:5]1[S:1][C:2]([B:35]2[O:39][C:38]([CH3:41])([CH3:40])[C:37]([CH3:43])([CH3:42])[O:36]2)=[CH:3][CH:4]=1
Reactant: c1ccsc1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(F)s2)OC1(C)C
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 21 %

Procedure:
To a solution of thiophene (252 mg, 2.99 mmol) in THF (3.5 mL) at −78° C. was added n-butyllithium (2.5M, 1.3 mL, 3.2 mmol) dropwise to keep the temperature below −70° C. The solution was stirred for 40 minutes at −78° C. A solution of N-fluorobenzenesulfonimide (987 mg, 3.1 mmol) in THF (5 mL) was added over a period of 20 minutes. The temperature of the mixture was allowed to rise to −10° C. and was subsequently cooled to −78° C. To the mixture was added n-butyllithium (2.5M, 1.3 mL, 3.2 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (580 mg, 3.1 mmol) in THF (2 mL). The reaction was allowed to continue at −78° C. for 30 min and then quenched with saturated aqueous ammonium chloride (10 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (3×15 mL). The organic layers were combined and dried over sodium sulfate. After removal of solvent, the residue was purified by flash chromatography (petroleum ether/ethyl acetate=20:1) to give the title compound (143 mg, 21%). 1H NMR (400 MHz, CDCl3) δ ppm 1.32 (s, 12H), 6.55 (d, J=3.6 Hz, 1H), 7.27 (d, J=3.6 Hz, 1H).