Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]CCCCC.C([Li])(C)(C)C.[CH3:12][O:13][C:14]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18]([CH:28]=O)=[CH:19]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH3:12][O:13][C:14]1[C:23]([O:24][CH3:25])=[C:22]([O:26][CH3:27])[CH:21]=[C:20]2[C:15]=1[CH:16]=[CH:17][C:18]([CH:28]=[CH2:1])=[CH:19]2
Reactant: COc1cc2cc(C=O)ccc2c(OC)c1OC
Reactant: CCCCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=Cc1ccc2c(OC)c(OC)c(OC)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (2.8 g) was suspended in dry THF (10 mL) under an argon atmosphere, and a hexane solution (3.3 mL) of 1.7 M tert-butyllithium was added to the suspension at −20° C. After the reaction mixture was warmed to room temperature and stirred for 1 hour, it was cooled again to −20° C., a solution of 5,6,7-trimethoxynaphthalene-2-carboaldehyde (1.26 g) in dry THF (30 mL) was added dropwise thereto, and the mixture was stirred overnight at room temperature. The solvent was distilled off, and water was added to the residue to conduct extraction with ethyl acetate. The resultant organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:8) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[CH:18]=[O:19].CC(=CC)C.Cl([O-])=[O:28].[Na+].P(=O)(O)(O)O>O1CCOCC1>[CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:8])([CH3:9])[C:3]=1/[CH:10]=[CH:11]/[C:12](/[CH3:21])=[CH:13]/[CH:14]=[CH:15]/[C:16](/[CH3:20])=[CH:17]/[C:18]([OH:28])=[O:19]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)C(C)(C)CCC1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 55.9 %

Procedure:
A 1-liter three-necked flask was charged under an atmosphere of nitrogen with 54.9 g of vitamin A aldehyde (69.1% purity, 133.6 mmoles, ratio of all trans form: 98.5%), 250 g of 2-methyl-2-butene, 100 ml of dioxane and 53.2 g of a 25% aqueous sodium chlorite solution. The mixture was mechanically stirred vigorously and, while the internal temperature was maintained at 5° C., 170 g of a 8.5% aqueous phosphoric acid solution was added thereto dropwise over 1.5 hours. After completion of the addition, the mixture was further stirred vigorously at 5° C. for 40 minutes. After confirming exhaustion of the starting material vitamin A aldehyde by thin layer chromatography, yellow solid that precipitated was filtered through a glass filter and then washed several times with water. The yellow solid was transferred to a 500-ml flask, and 200 ml of a 5% aqueous potassium hydroxide solution and 100 ml of ethanol were added thereto. The mixture was refluxed with heating for 1.5 hours. After cooling, the reaction mixture was transferred to a 1-liter separating funnel. To the mixture 200 ml of hexane was added and the funnel was shaken sufficiently. The bottom layer was separated and acidified with a 10% aqueous sulfuric acid solution. The yellow solid that precipitated was extracted with 500 ml of isopropyl ether and the extract was washed with water until the bottom layer became neutral. The isopropyl ether was distilled off under reduced pressure and 400 ml of ethanol was added to the yellow residue and the mixture was heated. After confirmation of complete dissolution, the solution was gradually cooled with stirring to 0° C. The vitamin A acid crystal that precipitated was filtered through a glass filter and then washed with cold ethanol. The crystal was dried under reduced pressure, to give 22.3 g of vitamin A acid having a purity of at least 99%. The yield was 55.9%. The vitamin A acid thus obtained had a all trans form ratio of 99.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C=O)C.O>[CH2:36]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]2[N:12]=[C:13]3[C:19]([C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[CH:18][N:17]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[C:14]3=[N:15][CH:16]=2)=[N:7]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4ccccc4)c4cc(Cl)ccc34)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 247 μmol) was dissolved in DMF (1 mL) and cooled to 0° C. Sodium hydride (12.9 mg, 322 μmol) was added and the mixture was stirred for 30 min. Benzyl bromide (63.5 mg, 44.1 μL, 371 μmol) was added and the mixture was warmed to 20° C. After 15 h the mixture was diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica, 40 g Analogix column, 20-50% ethyl acetate in hexanes, 15 min gradient) to give 2-(1-benzyl-6-chloro-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (87 mg, 151 μmol, 61.1%) as a pale yellow powder. 1H NMR (CDCl3) δ: 9.29 (s, 1H), 8.48 (d, J=8.7 Hz, 1H), 8.38 (s, 1H), 8.20 (d, J=7.9 Hz, 1H), 7.43 (d, J=1.5 Hz, 1H), 7.20-7.39 (m, 6H), 5.73 (s, 2H), 5.68 (s, 2H), 4.38-4.55 (m, 1H), 3.52-3.64 (m, 2H), 1.42 (d, J=6.4 Hz, 6H), 0.86-1.00 (m, 2H), −0.03 (s, 9H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[CH:14]=[C:13]([C:15](=[O:42])[CH2:16][C@H:17]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[CH:12]=[CH:11][N:10]=1>ClCCl>[NH:33]1[CH2:34][CH:31]([C:28]2[CH:29]=[CH:30][C:25]([C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[CH2:16][C:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([CH3:8])[CH:14]=3)=[O:42])=[CH:26][CH:27]=2)[CH2:32]1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CN(C(=O)OC(C)(C)C)C3)cc2)c2ccccc2C)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C(=O)C[C@H](c2ccc(C3CNC3)cc2)c2ccccc2C)ccn1
Yield: 115.9 %

Procedure:
Trifluoroacetic acid (1.37 g, 927 μl, 12.0 mmol) was added at 0° C. to a solution of (R)-tert-butyl 3-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)azetidine-1-carboxylate (283 mg, 601 μmol, Eq: 1.00) in dichloromethane (2 mL). The ice bath was removed, then after 2 h the reaction mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated to afford the title compound (258 mg, purity ca. 85%), which was used for the next step without purification. Off-white foam, MS (ESI+): m/z=371.0 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[S:12]1[C:16](B(O)O)=[CH:15][C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]1=2.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C.[Pd].O>[S:12]1[C:16]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=2)=[CH:15][C:14]2[CH:20]=[CH:21][CH:22]=[CH:23][C:13]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(-c2cc3ccccc3s2)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of methyl 4-bromobenzoate (430 mg, 2.00 mmol), 2-benzo[b]thiopheneboronic acid (392 mg, 2.20 mmol), palladium(0) acetate (2.2 mg, 0.010 mmol), potassium carbonate (691 mg, 5.00 mmol), tetrabutylammonium bromide (645 mg, 2.00 mmol) and water (2.2 mL) was stirred in a nitrogen atmosphere at 70° C. for 1 hour. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified through silica gel column chromatography to obtain the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][C:4](=O)[CH2:5][C:6]1[C:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=1.O.O.[NH2:20][NH2:21].C(O)(=O)C>C(O)C>[CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][C:4]1[N:21]=[N:20][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=1
Reactant: NN
Reactant: CC(C)(C)CC(=O)CC1=CCCCCCC1=O
Agent: CC(C)(C)CC(=O)C/C1=C/CCCCCC1=O
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)Cc1cc2c(nn1)CCCCCC2
Temperature: 105 °C

Procedure:
A solution of (Z)-2-(4,4-Dimethyl-2-oxo-pentyl)-cyclooct-2-enone (0.07 g) in ethanol (6 ml) was treated at RT with water (1.5 ml), hydrazine monohydrate (0.07 ml) and acetic acid (1.5 ml), and the mixture was then heated to reflux for 12 h (oil bath temperature: 105° C.). The reaction mixture was partitioned between water and AcOEt. The combined organic layers were washed with 2M aqueous KHCO3, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (heptane/AcOEt 100% to 85%) to give 3-(2,2-dimethyl-propyl)-5,6,7,8,9,10-hexahydro-cycloocta[c]pyridazine, (0.018 g) as an amorphous white solid. MS (ESI): 233.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1.C(O)(=O)C.[O-:27][C:28]#[N:29].[K+]>O>[CH2:17]([C:10]1[N:9]=[C:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([NH2:29])=[O:27])[CH:3]=[CH:4][C:5]=2[O:19][CH2:20][CH2:21][CH3:22])[NH:13][C:12](=[O:14])[C:11]=1[CH2:15][CH3:16])[CH3:18]
Reactant: CCCOc1ccc(N)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCOc1ccc(NC(N)=O)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reaction time: 2 h
Yield: 101.6 %

Procedure:
The compound (200 mg, 0.6 mmol) of example 42 was suspended in a mixed solution of water (5 ml) and acetic acid (5 ml), added with potassium cyanate (81 mg, 1 mmol), and heated to reflux and stirred for 2 h. The cooled reaction mixture was poured into water to generate a white solid, which was washed with water (10 ml×3) and dried to give the title compound (210 mg, yield: 91%). 1H NMR (DMSO-d6) δ: 11.76 (1H, br), 8.56 (1H, br), 7.76 (1H, d), 7.59 (1H, dd), 7.06 (1H, d), 5.78 (1H, br), 4.00 (2H, t), 2.56 (2H, q), 2.46 (2H, q), 1.74 (2H, m), 1.19 (3H, t), 1.04 (3H, t), 0.97 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:25]=[CH:26]/[C:27](OCC)=[O:28])[CH:5]=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[O:16])[CH2:11][CH2:10]1.[OH-].[Na+].Cl.ClC1C=C(C=CC(O)=O)C=NC=1NC1CCN(C(=O)NC2C=CC(Cl)=CC=2)CC1.[O:64]1[CH2:69][CH2:68][CH2:67][CH2:66][CH:65]1[O:70][NH2:71].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CO.CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:5]=[C:4](/[CH:25]=[CH:26]/[C:27](=[O:28])[NH:71][O:70][CH:65]2[CH2:66][CH2:67][CH2:68][CH2:69][O:64]2)[CH:3]=1
Reactant: CCOC(=O)/C=C/c1cnc(NC2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)c(Cl)c1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C=Cc1cnc(NC2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C(/C=C/c1cnc(NC2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)c(Cl)c1)NOC1CCCCO1
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of ethyl (2E)-3-{5-chloro-6-[(1-{[(4-chlorophenyl)amino]carbonyl}-4-piperidyl) amino]-3-pyridyl}acrylate (363 mg) in THF (3 ml) and MeOH (3 ml) was added 1N NaOH aq (2.35 ml), the mixture was stirred at 80° C. for 1 hour. The pH of the mixture was adjusted to ca. 4.5 with 1N HCl aq. The solution was evaporated under reduced pressure to give crude 3-{5-Chloro-6-[1-(4-chloro-phenylcarbamoyl)-piperidin-4-ylamino]-pyridin-3-yl}-acrylic acid. To a suspension of crude 3-{5-Chloro-6-[1-(4-chloro-phenylcarbamoyl)-piperidin-4-ylamino]-pyridin-3-yl}-acrylic acid (247 mg) in DMF (3 ml) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (73.1 mg), EDCI (96.9 mg), HOBt (84.3 mg,), the mixture was stirred at 23° C. for 8 hours. The mixed solution was poured into a mixture of water (20 ml) and AcOEt (20 ml). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give 4-[(3-chloro-5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)amino]-N-(4-chlorophenyl)-1-piperidinecarboxamide (246 mg).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>C(Cl)Cl>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][NH:24][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1
Reactant: NCc1ccccn1
Reactant: OCCCSc1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(CNCCCSc2ccncc2)nc1
Temperature: 80 °C
Yield: 24.4 %

Procedure:
To a solution of 5.26 g (31.1 mmol) of 4-(3-hydroxypropylthio)pyridine and 5.20 ml (37.3 mmol) of triethylamine in 150 ml of methylene chloride, 2.90 ml (37.3 mmol) of methanesulfonyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and then the solvent was distilled off. To 6.33 g of the residue was added 2.64 ml (25.6 mmol) of 2-aminomethylpyridine. The resulting mixture was heated at 80° C. for 3 hours. After cooling, the mixture was purified by column chromatography (eluent: chloroform/methanol=25:1) to obtain 1.62 g of the desired compound (yield: 25.4%, yellow oil).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:50]=[CH:49][C:16]([C:17]([O:19][C:20]2[CH:27]=[CH:26][C:25]([O:28][C:29](=[O:48])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:43][C:44](=[O:47])[CH:45]=[CH2:46])=[CH:32][CH:31]=3)=[CH:24][C:21]=2[CH:22]=[O:23])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3].CC(C)=[O:53]>>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:50]=[CH:49][C:16]([C:17]([O:19][C:20]2[CH:27]=[CH:26][C:25]([O:28][C:29](=[O:48])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][O:43][C:44](=[O:47])[CH:45]=[CH2:46])=[CH:32][CH:31]=3)=[CH:24][C:21]=2[C:22]([OH:53])=[O:23])=[O:18])=[CH:15][CH:14]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(C)=O
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(OCCCCCCOC(=O)C=C)cc3)c(C=O)c2)cc1
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(OCCCCCCOC(=O)C=C)cc3)c(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Jones oxidant (CrO3/H2SO4/H2O) (48 ml) was added to a ice-cooled solution of 2,5-di-[4-(6-acryloyloxyhexyloxy)benzoyloxy]benzaldehyde (8.24 g, 12 mmol) in acetone (300 ml) in a dropwise fashion over a period of 30 min. The reaction mixture was stirred overnight at room temperature. The resulting green-orange mixture was filtered off to leave a green precipitate that was washed with 600 ml of ether. The combined organic solutions were washed with water until the orange coloration disappeared (6×250 ml). The colourless organic solution obtained was washed with saturated NaCl solution (2×300 ml), dried over MgSO4 and filtered. Removal of the solvent gave pure 2,5-di-[4-(6-acryloyloxyhexyloxy)benzoyloxy]benzoic acid as a white crystalline material. Yield 8.5 g.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[C:11](=[CH:16][CH:17]=1)[C:12]([O:14][CH3:15])=[O:13].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42](O)=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]>CN(C=O)C.CCOC(C)=O>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH2:41][C:42]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][O:7][C:8]2[CH:9]=[C:10]([C:18]([O:20][CH3:21])=[O:19])[C:11](=[CH:16][CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])=[O:43])[CH:27]=[CH:28][C:29]=1[NH:30][C:31]([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40])=[O:32]
Reactant: COC(=O)c1ccc(OC[C@@H]2CCCN2)cc1C(=O)OC
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1C(=O)OC
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To a stirred solution of dimethyl (S)-4-(2-pyrrolidinylmethoxy)phthalate (212 mg, 0.72 mmol) in DMF (8 mL) was added pentafluorophenyl ester of the 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (346 mg, 0.72 mmol) and Et3 N (120 ml, 0.86 mmol), and the mixture was stirred overnight. The resulting mixture was diluted with EtOAc, washed with 1 N HCl, sat. NaHCO3, brine, and dried over MgSO4. The solvent was evaporated off in vacuo to give 413 mg (97%) dimethyl (S)-4-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinylmethoxy]phthalate as an oil. 1H-NMR (CDCl3) δ 1.92–2.12 (m, 4 H), 2.29 (br s, 3 H), 3.51–3.64 (m, 7 H), 3.87 (s, 3 H), 3.89 (s, 3 H), 4.10–4.19 (m, 2 H), 4.44 (m, 1 H), 6.73–8.02 (series of m, total 12 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21]C)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([OH:23])[CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([OH:21])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([OH:23])[CH:3]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3O)c12

Procedure:
Intermediate III (333 mg), sodium hydroxide solution 1M (5 ml) in 10 ml methanol and 10 ml THF were stirred at rt overnight. Then the mixture was acidified with hydrochloric acid and filtrated.
Reaction SMILES: [CH2:1]([CH:11]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([NH:25][C:26](=[O:50])[CH:27]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:24]=1)[C:18]([O:20]C)=[O:19])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[K+].CO.O>C(OCC)C>[CH2:1]([CH:11]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH:22]=[C:23]([NH:25][C:26](=[O:50])[CH:27]([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:24]=1)[C:18]([OH:20])=[O:19])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Nc1cc(NC(=O)C(CCCCCCCCCC)CCCCCCCCCCCC)cc(C(=O)OC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Nc1cc(NC(=O)C(CCCCCCCCCC)CCCCCCCCCCCC)cc(C(=O)O)c1
Temperature: 25 °C

Procedure:
Methyl 3,5-bis(2′-decyltetradecanamido)benzoate from Step 2, potassium hydroxide (0.38 g, 5.77 mmol), and methanol (20 mL) were added to a 50 mL vessel and heated to reflux. Deionized water (10 mL) was then added and the reaction was held at reflux overnight. The reaction was then cooled to room temperature, which resulted in the formation of an oil phase. Diethyl ether (20 mL) was added and the aqueous phase was removed. The organic phase was then washed successively with 1 Molar hydrochloric acid (30 mL), 0.1 Molar hydrochloric acid (30 mL), and deionized water twice (30 mL each), before concentrating the ether layer by rotary evaporation and drying in vacuo to give 3,5-bis(2′-decyltetradecanamido)benzoic acid as a light brown waxy solid (1.33 g, 99%). The product was identified by 1H and 13C NMR spectroscopy and ESI-MS and was of satisfactory purity. The product was believed to be of the formula
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([NH2:10])=[O:9])=[O:5])[CH3:3]>CO>[NH:1]([C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])[C@@H:2]([C:4]([NH:6][CH2:7][C:8]([NH2:10])=[O:9])=[O:5])[CH2:3][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(N)=O
Solvent: CO
Product: NC(=O)CNC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1

Procedure:
Z-D-Ala-Gly-NH2 (21) (Richman et al., Int. Peptide Protein Res., 25:648-662 (1985), which is hereby incorporated by reference): 1H and 13C NMR data are identical to (8). HRMS (FAB+) MH+ calcd 280.1297 found 280.1298; [α]27D+10.5 (c 0.72, MeOH); lit. [α]D=+10.5.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:26])[NH:17][CH2:18][C:19]1([CH2:24][OH:25])[CH2:23][CH2:22][CH2:21][CH2:20]1)([CH3:14])([CH3:13])[CH3:12].O>C(Cl)Cl>[C:11]([O:15][C:16](=[O:26])[NH:17][CH2:18][C:19]1([CH:24]=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC1(CO)CCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1(C=O)CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
To a solution of oxalyl chloride (456 μL, 5.38 mmol) in DCM (30.0 mL) at −78° C. was added DMSO (637 μL, 8.97 mmol) and the resulting mixture was stirred for 5 minutes. tert-Butyl[1-(hydroxymethyl)cyclopentyl]methylcarbamate (1.03 g, 4.48 mmol) in DCM (10.0 mL) was added and the resulting mixture was stirred for 30 minutes at −78° C. TEA (2.50 mL, 17.9 mmol) was added and the resulting mixture was allowed to warm to ambient temperature over 30 minutes. Water was added. The organic phase was washed sequentially with 0.1 N HCl, water, saturated sodium bicarbonate solution, and brine, and then dried over sodium sulfate and the solvent was removed in vacuo to afford the product (957 mg, 94%). 1H NMR (300 MHz, CDCl3): δ 9.39 (s, 1H), 4.94 (br s, 1H), 3.25 (d, 2H), 1.89-1.46 (m, 8H), 1.41 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=12)=[O:7].[C:14](O)(=O)CC(O)=O.C(N(CC)CC)C.C(=O)=O>O>[OH:7][C:6]1([CH3:14])[C:5]2[C:4](=[C:3]([O:2][CH3:1])[CH:13]=[CH:12][CH:11]=2)[C:9](=[O:10])[O:8]1
Reactant: O=C(O)CC(=O)O
Reactant: COc1cccc2c1C(=O)OC2=O
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cccc2c1C(=O)OC2(C)O
Temperature: 73 °C

Procedure:
5.4 g of 3-methoxy-phthalic acid anhydride [see A. V. R. Rao et al., Indian J. Chew. 20B, 248 ff. (1981)], 4.7 g of malonic acid and 9 ml of triethylamine are heated slowly. The suspension becomes stirrable at 55° C. and, from 68° C., moderately vigorous CO2 evolution occurs. The internal temperature is maintained at 73° C. until gas evolution ceases (about 1 hour) and the reaction mixture is then heated at reflux temperature (internal temperature 85° C.) for a further 4 hours. When it has cooled, the reaction mixture is treated with water and extracted with ethyl acetate. The aqueous phase is then adjusted to pH 1.7 and extracted three times with fresh ethyl acetate, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. Fractional crystallisation (ethyl acetate/n-hexane) yields 3-hydroxy-7-methoxy-3-methyl-phthalide, m.p. 156°-158° C.; IR spectrum (CHCl3): C=O 1772 cm-1.