Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:9]([O:17][C:18]1[C:26]2[CH:25]=[CH:24][S:23][C:22]=2[CH:21]=[CH:20][CH:19]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>ClCCl>[C:9]([O:17][C:18]1[C:26]2[CH:25]=[C:24]([C:1](=[O:3])[CH3:2])[S:23][C:22]=2[CH:21]=[CH:20][CH:19]=1)(=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Oc1cccc2sccc12)c1ccccc1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc2c(OC(=O)c3ccccc3)cccc2s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of acetyl chloride (0.25 ml) in dichloromethane (1.5 ml) was added dropwise under nitrogen at ambient temperature to a stirred suspension of anhydrous aluminium chloride (0.94 g) in dichloromethane (10 ml) and the mixture was stirred at ambient temperature for 15 minutes. A solution of benzo[b]thiophen-4-yl benzoate (0.6 g) in dichloromethane (4 ml) was added, the mixture was stirred at ambient temperature for 18 hours, then it was poured onto ice-water (60 ml). The product was extracted into dichloromethane (2×50 ml), the combined extracts were washed with water (50 ml), saturated aqueous sodium hydrogencarbonate solution (20 ml), water (2×50 ml) and saturated aqueous sodium chloride solution (40 ml), then they were dried (MgSO4) and the solvent was removed in vacuo. The residue was purified by flash chromatography over silica using a 7:3 mixture of dichloromethane and petroleum ether (b.p. 60-80° C.) as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-acetylbenzo[b]thiophen-4-yl benzoate (0.13 g) as a cream solid which was used without further purification.
Reaction SMILES: [H][H].[Na].C(=O)([O-])[O-].[Na+:8].[Na+].[O-2:10].[Ce+3].[O-2:12].[O-2].[Ce+3].[P:15]([O-:19])([O-:18])([O-:17])=[O:16].[Na+].[Na+].[Na+]>O>[P:15]([O-:19])([O-:18])([O-:17])=[O:16].[Na+:8].[Na+:8].[Na+:8].[O:10]=[O:12]
Reactant: [H][H]
Reactant: [O-2]
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Ce+3]
Solvent: O
Product: O=O

Procedure:
FIG. 1 depicts the cycle (a) in which hydrogen is the product and sodium is the alkali metal, and in which sodium carbonate is used in step 2. In the first step cerium oxide is reacted in the solid phase with dibasic sodium phosphate at about 750°-950° C. to provide sodium cerous phosphate, sodium phosphate, oxygen and water. The oxygen is recovered from the gaseous phase and the water removed from the reaction zone. The solid phase is conducted to reaction 2 wherein it is contacted with water and stream and sodium carbonate at 650°-950° C. The reaction produces ceric oxide plus sodium phosphate, carbon dioxide, and hydrogen. The hydrogen can be recovered separately as shown or can be passed directly to step 3 as hereinbefore described. In step 3 the cerium oxide and hydrogen do not participate in the reaction, wherein sodium phosphate is reacted with water and carbon dioxide to produce dibasic sodium phosphate and sodium bicarbonate. The preferred CO2 pressure for this step is about 1 atmosphere. It is preferred that the cerium oxide and sodium phosphate be contacted with carbon dioxide in the presence of only enough water to dissolve most of the sodium bicarbonate produced so that a solid mixture of cerium oxide dibasic sodium phosphate can be recycled directly to step 1 and only a small amount of water need be evaporated to recover the bicarbonate.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:35])[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([N+:24]([O-:26])=[O:25])[CH2:20][C@@H:19]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[CH3:34])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F-].[K+].[C:40]([O:48][CH3:49])(=[O:47])/[CH:41]=[CH:42]\[C:43]([O:45][CH3:46])=[O:44].O>CS(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOCC>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:35])[C:16]([N:18]2[CH2:23][CH2:22][C@@:21]([CH:42]([CH2:41][C:40]([O:48][CH3:49])=[O:47])[C:43]([O:45][CH3:46])=[O:44])([N+:24]([O-:26])=[O:25])[CH2:20][C@@H:19]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=2[CH3:34])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:8]=1
Reactant: Cc1cc(F)ccc1[C@H]1CC([N+](=O)[O-])CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)/C=C\C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: COC(=O)CC(C(=O)OC)[C@@]1([N+](=O)[O-])CCN(C(=O)N(C)[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.1 %

Procedure:
(2R)-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-nitro-1-piperidinecarboxamide (Intermediate 38, 500 mg, 0.934 mmol) was dissolved in Dimethyl Sulfoxide (DMSO) (6 ml) and to this solution were added potassium fluoride (271 mg, 4.67 mmol) and tetrabutylammonium iodide (345 mg, 0.934 mmol). The mixture was left stirring at rt for 10 min (pink mixture), then dimethyl maleate (0.584 ml, 4.67 mmol) was added. The mixture was left stirring at rt for 4 hrs and at 40° C. for 1 hr, then water and Et2O were added. The two phases were separated and the organic one was washed with 1N HCl. The organic phase was dried over Na2SO4 and evaporated to dryness. The crude was purified by flash chromatography (40M cartridge; eluting from 9:1 to 7:3 Cy:EtOAc) to give two batches of the title compound:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19](Cl)=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH3:22]>C(Cl)Cl>[C:19]([C:14]1[CH:13]=[C:12]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[Cl:18])(=[O:20])[NH2:22]
Reactant: N
Reactant: O=C(Cl)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 4.0 g of 3-chloro-2-(4-chloro-3-chloroformylphenyl)-5-trifluoromethylpyridine in 10 ml of methylene chloride was added dropwise to 100 ml of a 25% by weight aqueous ammonia solution cooled to 0° C. After 3 hours, the crystals which had formed were separated off, stirred with n-hexane, again separated off, washed with n-hexane and finally dried. Yield: 2.8 g (75%) of colorless crystals; melting point: 167°-168° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[C:18](=[O:46])[N:19](COCC[Si](C)(C)C)[CH:20]=[C:21]([C:23](=[O:37])[NH:24][C:25]2[CH:26]=[N:27][N:28]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:29]=2)[CH:22]=1)=O)(C)(C)C.NCCN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:30]([N:28]1[CH:29]=[C:25]([NH:24][C:23]([C:21]2[CH:22]=[C:17]([C:9]3[NH:8][C:16]4[C:11]([CH:10]=3)=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:18](=[O:46])[NH:19][CH:20]=2)=[O:37])[CH:26]=[N:27]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(C(=O)Nc3cnn(Cc4ccccc4)c3)cn(COCC[Si](C)(C)C)c2=O)cc2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: O=C(Nc1cnn(Cc2ccccc2)c1)c1c[nH]c(=O)c(-c2cc3ccccc3[nH]2)c1
Temperature: 25 °C

Procedure:
Intermediate (1d), 2-[5-(1-benzyl-1H-pyrazol-4-ylcarbamoyl)-2-oxo-1-(2-trimethylsilanyl-ethoxymethyl)-1,2-dihydro-pyridin-3-yl]indole-1-carboxylic acid tert-butyl ester (315 mg, 0.492 mmol) was stirred in tetrahydrofuran (15 mL) and 1,2-diaminoethane (89 mg, 98 ul, 1.48 mmol) was added followed by tetrabutylammonium fluoride solution 1.0M in tetrahydrofuran (2.46 mL, 2.46 mmol). The reaction mixture was heated at reflux for 18 hours, and cooled to ambient temperature. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and dichloromethane, and the organic layer was separated. The aqueous was extracted with a further portion of dichloromethane and the combined dichloromethane layers were washed with water (×3) dried (Na2SO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with dichloromethane—8% methanol/dichloromethane (gradient) to afford a solid. This solid was triturated with diethyl ether to afford the desired title compound as a yellow solid, 41 mg, 20%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23](O)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[N:28]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23]([N:36]4[CH2:37][CH2:38][CH:33]([N:28]5[CH2:32][CH2:31][CH2:30][CH2:29]5)[CH2:34][CH2:35]4)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)O
Product: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 2, 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-diethyl-1H-pyrazole-4-carboxylic acid (intermediate 1) and 4-pyrrolidin-1-yl-piperidine gave the title compound as colorless oil. MS: 517.3 (MH+, 1 Cl).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2.C(=O)(O)[O-].[K+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23](Cl)=[O:24].C1C2C(=CC=CC=2)CCN1>C1C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:23]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH3:12])[CH2:7]2)=[O:24]
Reactant: CN1CCc2c(N)cccc2C1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: O=C([O-])O
Agent: [K+]
Agent: c1ccc2c(c1)CCNC2
Solvent: c1ccccc1
Product: COc1ccc(C(=O)Nc2cccc3c2CCN(C)C3)cc1OC

Procedure:
5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (12.9 g) prepared as in Example 4 was dissolved in dry benzene (100 ml) and 0.5 g of dry potassium bicarbonate was added. A 0.1 mole excess of 3,4-dimethoxybenzoyl chloride was dissolved in dry benzene (100 ml) and this solution was added to the solution of the tetrahydroisoquinoline. A precipitate formed immediately and the mixture was refluxed for 1 hour. The precipitate was collected by filtration and washed with 10% sodium carbonate solution followed by water. The washings were discarded and the remaining residue was recrystallized from ethanol to yield 12.0 g of the desired product as a white powder, m.p. 160°-161.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[C:10]([C:12]([O:14]C)=[O:13])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C1COCC1.CO.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:8]2[CH:9]=[C:10]([C:12]([OH:14])=[O:13])[O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc2c(OC)cccc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc2oc(C(=O)O)cc12
Yield: 96 %

Procedure:
To a suspension of methyl 4-methoxy-benzofuran-2-ylcarboxylate (206 mg, 1.0 mmol) in THF/methanol/water (6 ml, 1/1/1) was added 2M aqueous NaOH (1.0 ml) and refluxed until saponification was completed (˜3 h). The reaction mixture was acidified with 1M aqueous HCl (10 ml) and diluted with ethyl acetate (30 ml). The separated organic layer was washed with 1M aqueous HCl (30 ml), brine (30 ml), dried over sodium sulfate, and concentrated in vacuo to provide 4-methoxy-benzofuran-2-ylcarboxylic acid as a white solid (189 mg, 0.96 mmol), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][O:20][NH2:21])=[CH:17][CH:16]=1.[CH3:24][C:25]([CH3:39])([C:31](=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(O)(=O)C.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC.O.C(O)C>[CH3:39][C:25]([CH3:24])(/[C:31](=[N:21]\[O:20][CH2:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:23][CH:22]=1)/[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CON)cc1
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(C)(C)/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Temperature: 25 °C
Yield: 27.5 %

Procedure:
After a mixture of 4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyamine (600 mg), ethyl 2,2-dimethyl-3-oxo-3-phenylpropionate (468 mg), acetic acid (0.331 ml), sodium acetate (317 mg) and ethanol (20 ml) was heated to reflux for 5 days, the mixture was cooled to room temperature. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to silica gel chromatography to obtain ethyl Z-2,2-dimethyl-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionate (273 mg, yield 28%) as a colorless oil from an ethyl acetate-hexane (2:9, v/v)-eluted fraction.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]2[C@H:13]([NH:16][C:17](=[O:29])[C@@H:18]([N:23]3[CH2:28][CH2:27]O[CH2:25][CH2:24]3)[CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:14][CH2:15][C@H:10]2[CH2:9]1)C1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].FC(F)(F)C1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:21][CH:20]([CH3:22])[CH2:19][C@H:18]([N:23]1[CH2:28][CH2:27][CH2:25][CH2:24]1)[C:17]([NH:16][C@H:13]1[C@H:11]2[C@H:10]([CH2:9][N:8]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:12]2)[CH2:15][CH2:14]1)=[O:29]
Reactant: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(Cc3ccccc3)C[C@H]21)N1CCOCC1
Reactant: CS(=O)(=O)Cl
Agent: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CC(C)C[C@@H](C(=O)N[C@@H]1CC[C@H]2CN(S(C)(=O)=O)C[C@H]21)N1CCCC1

Procedure:
The title compound was prepared by substituting (2S)-N-[(3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl]-4-methyl-2-pyrrolidin-1-ylpentanamide from Example 250 for (S)-N-((3aS,4R,6aR)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-4-methyl-2-morpholinopentanamide and methanesulfonyl chloride for 3-(trifluoromethyl)benzene-1-sulfonyl chloride in the procedures described in Example 319: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.24-8.26 (m, 1H), 4.35 (p, J=6.8 Hz, 1H), 3.79 (dd, J=9.9, 2.6 Hz, 1H), 3.50 (dd, J=9.9, 7.0 Hz, 1H), 3.35 (dd, J=9.6, 7.0 Hz, 1H), 3.17-3.21 (m, 2H), 3.04 (s, 3H), 2.67-2.75 (m, 4H), 2.60-2.63 (m, 2H), 1.99-2.07 (m, 1H), 1.78-1.95 (m, 3H), 1.58-1.68 (m, 6H), 1.32-1.39 (m, 1H), 0.99 (d, J=6.2 Hz, 3H), 0.92 (d, J=6.3 Hz, 3H); MS (ESI+) m/z 372 (M+H)+.
Reaction SMILES: [Li]C(CC)C.C1CCCCC1.[CH2:12]([NH:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[CH3:13].[CH3:24][Si:25](Cl)([CH3:27])[CH3:26]>C1COCC1.CCOCC.O>[CH2:12]([NH:14][C:15](=[O:23])[C:16]1[C:21]([Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[CH3:13]
Reactant: CCNC(=O)c1ccccc1F
Reactant: C[Si](C)(C)Cl
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CCNC(=O)c1c(F)cccc1[Si](C)(C)C
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
A solution of 1.3M s-BuLi in cyclohexane (20.3 mL, 26.4 mmol) was added to an ether/liquid nitrogen cooled solution of N-ethyl-2-fluorobenzamide (2.00 g, 11.98 mmol) in THF (75 mL) and ether (75 mL), maintaining the internal reaction temperature ≤-95° C. The resulting mixture was stirred at this temperature for 30 min, then TMSCl (1.43 g, 13.2 mmol) was added and the mixture warmed to -60° C. After 2 h, the reaction was poured into water (200 mL). The organic layer was dried (MgSO4), concentrated, and purified by silica gel chromatography, eluted with 3:7 ethyl acetate/hexanes, to afford 0.45 g of the title compound as a white solid, a 16% yield. m.p. 86-87° C.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.[CH3:10][O:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14](O)=[O:15].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[CH3:10][O:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)=[O:15]
Reactant: NC(=O)C1CCNCC1
Reactant: COCC(C)(C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(C)(C)C(=O)N1CCC(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of isonipecotamide (1.0 g, 8.0 mmol), 3-methoxy-2,2-dimethylpropanoic acid (Bulletin of the Chemical Society of Japan 2001, 74, 1695–1702, 1.1 g, 8.0 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU, 3.3 g, 8.8 mmol) and N,N-diisopropylethylamine (1.5 mL, 8.8 mmol) in N,N-dimethylformamide (8 mL) was stirred at room temperature for 18 h. Water (8 mL) was added and the mixture was extracted with ethyl acetate (20 mL×6). Removal of solvent gave a crude of 1-(3-methoxy-2,2-dimethylpropanoyl)piperidine-4-carboxamide as a brown oil, which was dissolved in tetrahydrofuran (15 mL) and added to a suspension of lithium aluminum hydride (2.26 g, 47.7 mmol) in tetrahydrofuran (15 mL) at 0° C. The mixture was stirred at 40° C. for 3 h and quenched with sodium sulfate decahydrate and potassium fluoride. Filtration through a pad of Celite and concentration of the filtrate gave 925 mg (54%) of the title compound as a colorless oil.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:27][C@@H:28]2[C:34](=[O:35])[N:33]([CH2:36][C:37]([O:39]CC3C=CC=CC=3)=[O:38])[C:32]3[CH:47]=[CH:48][CH:49]=[CH:50][C:31]=3[O:30][CH2:29]2)[C:22]([O:24]CC)=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[C:22]([C@@H:21]([NH:27][C@@H:28]1[C:34](=[O:35])[N:33]([CH2:36][C:37]([OH:39])=[O:38])[C:32]2[CH:47]=[CH:48][CH:49]=[CH:50][C:31]=2[O:30][CH2:29]1)[CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:24])=[O:23]
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCC2CCNCC2)C(=O)O)COc2ccccc21
Reaction time: 0.5 h
Yield: 73 %

Procedure:
A solution of benzyl 3(S)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.65 g) in ethanol (40 ml) is subjected to catalytic hydrogenolysis over 10% palladium carbon (1 g, 50% wet) at ambient temperature and pressure until the absorption of hydrogen ceases. After removal of the catalyst by filtration, the filtrate is concentrated. To the residue is added 5N hydrogen chloride-ethyl acetate solution (2 ml), and the resulting mixture is diluted with ethyl ether (50 ml) to deposit 3(S)-[1(S)-ethoxycarbonyl-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.45 g) as a colorless precipitate. This acid is dissolved in 1N sodium hydroxide solution (15 ml), and the resulting solution is allowed to stand for 30 minutes at room temperature. After addition of acetic acid (3 ml), the mixture is subjected to MCI gel column chromatography using water-methanol (2:1) as an eluent. The eluate is concentrated in vacuo and lyophilized to yield 3(S)-[1(S)-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.3 g) as colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C[O:11][C:12](=[O:27])[CH:13]([O:25][CH3:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23]Br)[CH:16]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:26][O:25][CH:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:16]=1)[C:12]([OH:11])=[O:27]
Reactant: COc1cccc(O)c1
Reactant: COC(=O)C(Cc1cccc(OCCBr)c1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COc1cccc(OCCOc2cccc(CC(OC)C(=O)O)c2)c1

Procedure:
The title compound was prepared from 3-methoxy-phenol and 3-[3-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 351, Step 1) via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC. MS (ES) for C19H22O6 [M−H]31: 345.1.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4](=[CH2:13])/[CH:5]=[CH:6]/[CH2:7][C:8]([O:10]CC)=[O:9]>CO.O1CCCC1.O>[CH3:13][C:4](=[CH2:3])/[CH:5]=[CH:6]/[CH2:7][C:8]([OH:10])=[O:9]
Reactant: C=C(C)/C=C/CC(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=C(C)/C=C/CC(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 69.1 %

Procedure:
2.5 g (0.1 mol) of lithium hydroxide are added at 0° C. to 10 g (0.07 mol) of ethyl trans-4-methyl-2,4-pentadienecarboxylate, dissolved in a solvent mixture of 75 ml of methanol, 17 ml of tetrahydrofuran and 2.5 ml of water, and the mixture is stirred for 20 hours at room temperature. After the mixture has been diluted with 200 ml of water, it is extracted once using diethyl ether, and a pH of 1 is established in the aqueous phase at 0° C. using concentrated hydrochloric acid. The mixture is extracted using diethyl ether, the combined organic phases are washed several times with water and saturated sodium chloride solution, and, after drying and concentrating, 6.1 g (76% of theory) of trans-4-methyl-2,4-pentadienecarboxylic acid are obtained. ##STR207##
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[N:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:35]2=[O:50].O>CN(C)C=O>[O:49]=[C:43]1[CH:42]([N:36]2[C:35](=[O:50])[C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:10]([C:7]4[N:8]=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=4)=[O:12])[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: CCOc1ccc(C(=O)O)nn1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)nn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
A stirred mixture of 6-ethoxy-pyridazine-3-carboxylic acid (0.50 g, 3.00 mmol) and CDI (0.54 g, 3.30 mmol) in N,N-dimethylformamide (20 mL) was heated to 40° C. under nitrogen. After 1 h, 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione methane sulfonate (1.15 g, 3.00 mmol) was added and the mixture was heated at 40° C. for 1.5 h. The mixture was cooled to rt and water (40 mL) was added. After 1 h, the product was isolated by filtration, washed with water (10 mL) and dried in vacuo to give 6-ethoxy-pyridazine-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (1.15 g, 88% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 6.89 min (98.61%); mp: 238-240° C.; 1H NMR (DMSO-d6) δ 1.42 (t, J=7.1 Hz, 3H, CH3), 1.96-2.14 (m, 1H, CHH), 2.42-2.69 (m, 2H, CHH, CHH), 2.78-3.01 (m, 1H, CHH), 4.58 (q, J=7.0 Hz, 2H, CH2), 4.68 (d, J=6.2 Hz, 2H, CH2), 5.14 (dd, J=5.4, 12.9 Hz, 1H, CH), 7.35 (d, J=9.1 Hz, 1H, Ar), 7.76-7.95 (m, 3H, Ar), 8.09 (d, J=9.1 Hz, 1H, Ar), 9.85 (t, J=6.2 Hz, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.28, 21.99, 30.93, 42.39, 48.99, 63.47, 117.91, 122.10, 123.53, 128.83, 129.82, 131.59, 133.57, 147.30, 149.11, 162.93, 165.86, 166.99, 167.13, 169.83, 172.75; LCMS: MH=438; Anal Calcd for C21H19N5O6: C, 57.66; H, 4.38; N, 16.01. Found: C, 57.32; H, 4.16; N, 15.80.