Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:43])[C:9]=1[C:10](=[O:42])[CH2:11][N:12]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:13]([C:15]1[CH:16]=[N:17][N:18]([C@H:24]2[CH2:29][CH2:28][C@H:27]([C:30]([O:32]CC)=[O:31])[C:26]([CH3:36])([CH3:35])[CH2:25]2)[C:19]=1[C:20]([F:23])([F:22])[F:21])=[O:14].C1COCC1>CCO>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:43])[C:9]=1[C:10](=[O:42])[CH2:11][N:12]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[C:13]([C:15]1[CH:16]=[N:17][N:18]([C@H:24]2[CH2:29][CH2:28][C@H:27]([C:30]([OH:32])=[O:31])[C:26]([CH3:36])([CH3:35])[CH2:25]2)[C:19]=1[C:20]([F:23])([F:22])[F:21])=[O:14]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)cncc3Cl)CC(C)(C)C)c2C(F)(F)F)CC1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)CN(CC(=O)c1c(Cl)cncc1Cl)C(=O)c1cnn([C@H]2CC[C@H](C(=O)O)C(C)(C)C2)c1C(F)(F)F
Temperature: 60 °C
Reaction time: 40 h
Yield: 86.7 %

Procedure:
NaOH (1.6 mL of a 1.0 M aqueous solution, 1.6 mmol) was added to a stirring solution of ethyl (1S,4S)-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2,2-dimethylcyclohexanecarboxylate (0.098 g, 0.16 mmol, from Step 2), THF (1.6 mL), and EtOH (1.6 mL), and then the reaction mixture was heated at 60° C. After stirring for 40 h, the reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was dissolved with water (10 mL), concentrated hydrochloric acid (10 drops) was added to the solution, the resulting heterogeneous mixture was filtered, the filter cake washed with water, dissolved with Et2O, the solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved with DCM, the solution was filtered, and the filtrate was concentrated under reduced pressure to give (1S,4S)-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2,2-dimethylcyclohexanecarboxylic acid (0.082 g, 88% yield) as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6](O)=O)[CH3:2].C=O.N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[C:5](=[CH2:6])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH3:2]
Reactant: CCOC(=O)C(CCOCCCC1CCCCC1)C(=O)O
Agent: C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(CCOCCCC1CCCCC1)C(=O)OCC

Procedure:
82.3 g of 4-(3-cyclohexylpropyloxy)-2-methylenebutyric acid ethyl ester, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: chloroform), are obtained by the procedure described in Example (1b) from 103.6 g of 2-(3-cyclohexylpropyloxy)-ethylmalonic acid ethyl ester, 11 g of paraformaldehyde, 105 ml of pyridine and 2.9 g of piperidine.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6]P(OCC)(OCC)=O)=[O:5].[H-].[Na+].[C:17]1(=O)[CH2:20][CH2:19][CH2:18]1.O>C1COCC1>[C:17]1(=[CH:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:20][CH2:19][CH2:18]1
Reactant: O=C1CCC1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C1CCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of triethyl phosphono acetate (35.2 g) in 100 mL THF, at 0° C., was added slowly via a syringe a solution of NaH (6.2 g) in 60 mL THF. The mixture was stirred at 0° C. for 10 minutes, cyclobutanone (10 g) was added by a syringe, and the resulting mixture was stirred at room temperature for 2 hours, followed by addition of distilled water to quench the reaction. The aqueous solution was extracted by ethyl acetate (3×20 mL), the combined organic layers were dried over Na2SO4 and the solvent was removed by evaporation. The crude residue was eluted by column chromatography (10% ethyl acetate/hexane), to give ethyl 2-cyclobutylideneacetate (20 g). 1HNMR (300 MHz, CDCl3) δ=5.57 (s, 1H), 4.13 (q, 2H), 3.11 (m, 2H), 2.81 (m, 2H), 2.08(m, 2H), 1.26 (t) ppm. MS: m/z 370 (100, M+H)+
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:31][N:30]([C:32]3[CH:37]=[C:36]([CH:38]([CH3:40])[CH3:39])[CH:35]=[CH:34][C:33]=3[CH3:41])[CH2:29][CH2:28][C:4]=2[N:5]=[C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10]([CH3:27])=[CH:11][N:12]3[S:17]([C:20]2[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:7]=1.[CH3:42][C@H:43]1[NH:48][CH2:47][CH2:46][N:45]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:44]1.CCN(C(C)C)C(C)C>CN(C)C(=O)C.CCOC(C)=O>[CH:38]([C:36]1[CH:35]=[CH:34][C:33]([CH3:41])=[C:32]([N:30]2[CH2:29][CH2:28][C:4]3[N:5]=[C:6]([C:8]4[CH:16]=[CH:15][CH:14]=[C:13]5[C:9]=4[C:10]([CH3:27])=[CH:11][N:12]5[S:17]([C:20]4[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=4)(=[O:18])=[O:19])[N:7]=[C:2]([N:48]4[CH2:47][CH2:46][N:45]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:44][C@H:43]4[CH3:42])[C:3]=3[CH2:31]2)[CH:37]=1)([CH3:40])[CH3:39]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc(Cl)c5c(n4)CCN(c4cc(C(C)C)ccc4C)C5)cccc32)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(-c4nc5c(c(N6CCN(C(=O)OC(C)(C)C)C[C@H]6C)n4)CN(c4cc(C(C)C)ccc4C)CC5)cccc32)cc1
Temperature: 125 °C

Procedure:
A mixture of 4-chloro-6-(5-isopropyl-2-methylphenyl)-2-(3-methyl-1-tosyl-1H-indol-4-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (Example 17-E) (0.274 g, 0.468 mmol), (R)-tert-butyl 3-methylpiperazine-1-carboxylate (0.375 g, 1.87 mmol) and DIEA (0.33 mL, 1.87 mmol) in N,N-dimethylacetamide (3 mL) was heated at 125° C. for 15 h. Reaction mixture was diluted with EtOAc, washed with sat aq NaHCO3 and brine. The organic layer was then dried over Na2SO4, concentrated, purified via FCC (0-40% EtOAc/heptane) to provide the title compound. MS (ESI+) m/z 749.4 (M+H)+.
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][Si](C(C)(C)C)(C)C)[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCCCCCC.C(OCC)(=O)C>[C:1]([N:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:6](=[O:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(=O)N(CCCCCCO[Si](C)(C)C(C)(C)C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)N(CCCCCCO)C(C)(C)C
Reaction time: 1 h

Procedure:
A solution of 2g of 16e in 20 ml of THF was treated with 11 ml of 1M tetra-n-butyl ammonium fluoride in THF at 55° C. After stirring for 1 hr the mixture was concentrated, diluted with 50 ml of 5% aq. NH4Cl and 10 ml of sat. NaCl and extracted with ethyl acetate. The organic layer was concentrated to give an oil. This was passed trough a silica pad using a gradient of heptane/ethyl acetate as eluent, to provide 1.5 g of 16f as a colorless oil, which was used without further purification in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:16]([NH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].S(Cl)(Cl)=O.[Cl-].[Na+]>CC(C)=O.C(OCC)(=O)C.C(Cl)Cl.C(COC)OC.CC(N(C)C)=O.O>[CH2:16]([NH:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[O:38])=[CH:40][CH:41]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A solution of 40.4 g. of p-nitrobenzenesulfonamide in 250 ml. of dry dimethylacetamide is added dropwise, over 30 minutes, to a stirred and cooled (water bath) suspension of 5.5 g. of sodium hydride in 100 ml. of dry dimethylacetamide. The resulting dark solution is stirred for a further 30 minutes at room temperature. In the meantime, a mixture of 36.2 g. of p-hexadecylaminobenzoic acid in 1200 ml. of methylene chloride, 300 ml. of dimethoxyethane, and 40 ml. of thionyl chloride is refluxed for 1 hour and 15 minutes. The solution is evaporated to an oil which is co-evaporated twice with added dioxane to remove excess thionyl chloride. The resulting amber oil is dissolved in 75 ml. of dry dimethylacetamide and the solution is added, over approximately 3 minutes, to the previously prepared solution of sodium p-nitrobenzenesulfonamide and cooled in an ice bath. After the addition, the ice bath is removed and the solution is stirred at room temperature for one hour. The solution is filtered through a bed of diatomaceous earth and the filtrate is poured into 2.1 of water to give a suspension. Saturated sodium chloride solution (250 ml.) followed by sodium chloride crystals (100 g.) is added to produce a finely divided precipitate. The mixture is filtered through a bed of diatomaceous earth. The product is washed with water and partially dried on the filter to give a yellow paste. The paste is dissolved in a mixture of 250 ml. of methylene chloride, 250 ml. of ethyl acetate, and 250 ml. of acetone. The solution is filtered through a bed of diatomaceous earth, a small aqueous layer separated, and the organic phase dried over anhydrous sodium sulfate. The solution is filtered and the filtrate is evaporated to an amber glass which is crystallized from 150 ml. of 1:1 ether:hexane. The product was recrystallized three times from absolute ethanol to provide 14.75 g. of the title compound as bright yellow crystals, melting point 129.5°-131° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:8]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:37][CH3:38])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1>>[CH3:22][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH2:37][CH3:38])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:8]=1
Reactant: COc1cc(O)ccc1CC(=O)Nc1ccc(N(C)C)cn1
Reactant: CCOc1cc2ncnc(Cl)c2cc1OC
Product: CCOc1cc2ncnc(Oc3ccc(CC(=O)Nc4ccc(N(C)C)cn4)c(OC)c3)c2cc1OC
Yield: 67 %

Procedure:
Using an analogous procedure to that described in Example 15, N-(5-dimethylaminopyridin-2-yl)-2-(4-hydroxy-2-methoxyphenyl)acetamide was reacted with 4-chloro-7-ethoxy-6-methoxyquinazoline. There was thus obtained the title compound in 67% yield; 1H NMR: (CDCl3) 1.59 (t, 3H), 2.92 (s, 6H), 3.75 (s, 2H), 3.91 (s, 3H), 4.07 (s, 3H), 4.29 (d, 1H), 4.32 (d, 1H), 6.85 (s, 1H), 6.87 (m, 1H), 7.11 (m, 1H), 7.32 (s, 1H), 7.4 (d, 1H), 7.54 (s, 1H), 7.72 (d, 1H), 8.09 (d, 1H), 8.20 (br s, 1H), 8.63 (s, 1H); Mass Spectrum: M+H+ 504.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([N:24]=[C:25]([C:27]4[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=4)[N:26]=3)[CH:23]=2)=[CH:12][CH:11]=1)[C:7]#[C:8][CH3:9])[CH3:2].Br[CH2:36][CH2:37][C:38]([CH3:41])([OH:40])[CH3:39].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][C@@H:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[N:22]([N:24]=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH2:36][CH2:37][C:38]([OH:40])([CH3:41])[CH3:39])=[CH:31][CH:32]=4)[N:26]=3)[CH:23]=2)=[CH:12][CH:11]=1)[C:7]#[C:8][CH3:9])[CH3:2]
Reactant: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(O)cc4)nn3c2)cc1
Reactant: CC(C)(O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC#C[C@@H](CC(=O)OCC)c1ccc(OCc2ccc3nc(-c4ccc(OCCC(C)(C)O)cc4)nn3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a stirred solution of (S)-3-{4-[2-(4-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylmethoxy]-phenyl}-hex-4-ynoic acid ethyl ester (0.2 g, 0.43 mmol) in acetonitrile (20 mL) is added 4-bromo-2-methyl-butan-2-ol (0.14 g, 0.87 mmol) and cesium carbonate (0.41 g, 1.2 mmol) and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is filtered and evaporated to dryness. The crude material is purified by silica gel chromatography (combiflash purifier 24 g redisep column) and is eluted with 15-20% EtOAc in hexane to give the title compound (0.23 g, 100%). LCMS m/z 542 (M+H)+.
Reaction SMILES: C([O:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[O:11])C1C=CC=CC=1>CO>[OH:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=1)=[O:11]
Reactant: O=C(COCc1ccccc1)Nc1cccc(C(F)(F)F)c1
Solvent: CO
Product: O=C(CO)Nc1cccc(C(F)(F)F)c1
Reaction time: 2.5 h
Yield: 84 %

Procedure:
To a 1 L pressure vessel was added crude 2-Benzyloxy-N-(3-trifluoromethyl-phenyl)-acetamide (˜10 g) and methanol (400 mL). The solution was purged with N2. 10% Pd/C (1.1 g) was added. The vessel was placed under H2 atmosphere at 50 psi for 2.5 h. LC/MS analysis shows only partial hydrogenolysis of the benzyl ether, so Pd(OH)2H2O (2 g) was added and the vessel is placed again under H2 atmosphere at 50 psi for 2.5 h. The reaction mixture was filtered through a pad of Celite and concentrated to give a brown oil. The crude material was purified via flash chromatography (1:1 EtOAc/Hexanes) to give 2-hydroxy-N-(3-trifluoromethyl-phenyl)-acetamide as a white solid (5.27 g, 84% yield, two steps). LC/MSD (HP Series 1100 MSD) Expected MW: 219.05, Observed M+H, 220.0, Retention time: 1.22. 1H-NMR, DMSO-d6, Varian 400 MHz δ 10.07 (s, 1H), 8.22 (s, 1H), 7.97 (dd, 1H), 7.55 (t, 1H), 7.41 (m, 1H), 5.76 (t, 1H), 4.03 (d, 2H) ppm.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][N:21]([CH2:52]C)[C:22](=[O:51])[CH2:23][C@@H:24]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](=[O:43])(=[O:42])[NH2:41])=[CH:36][C:35]=1[S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])[CH2:25][S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(SC[C@H](NC2C=CC(S(=O)(=O)N)=CC=2S(C(F)(F)F)(=O)=O)CC(O)=O)C=CC=CC=1.[Si](OCCNC)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[Si:1]([O:18][CH2:19][CH2:20][N:21]([CH3:52])[C:22](=[O:51])[CH2:23][C@@H:24]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](=[O:42])(=[O:43])[NH2:41])=[CH:36][C:35]=1[S:44]([C:47]([F:50])([F:48])[F:49])(=[O:46])=[O:45])[CH2:25][S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: CNCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: NS(=O)(=O)c1ccc(N[C@@H](CSc2ccccc2)CC(=O)O)c(S(=O)(=O)C(F)(F)F)c1
Product: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Yield: 93 %

Procedure:
The title product (590 mg, yield: 93%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 24 utilizing (R)-4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butanoic acid (INTERMEDIATE 8, 400 mg, 0.8 mmol) and 2-(tert-butyldiphenylsilyloxy)-N-methylethanamine (INTERMEDIATE 26, 251 mg, 0.8 mmol) as starting materials. The title product was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→100% EtOAc/hexanes).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[N:17]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])[C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[N:15][C:14]=3[C:33]([NH:35][C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=3)[C:39]([OH:41])=[O:40])=[O:34])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[C:1]12([CH2:11][CH2:12][C:13]3[N:17]([CH2:18][C:19]([OH:21])=[O:20])[C:16]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[N:15][C:14]=3[C:33]([NH:35][C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=3)[C:39]([OH:41])=[O:40])=[O:34])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Cc1ccccc1-c1nc(C(=O)Nc2cccc(C(=O)O)c2)c(CCC23CC4CC(CC(C4)C2)C3)n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1-c1nc(C(=O)Nc2cccc(C(=O)O)c2)c(CCC23CC4CC(CC(C4)C2)C3)n1CC(=O)O

Procedure:
A solution of the product of step d (217 mg, 0.36 mmol) in trifluoroacetic acid was stirred at room temperature for 16 h. The trifluoroacetic acid was removed in vacuum, the residue was dissolved in chloroform (15 ml) and the solvent was evaporated to afford the triflouoroacetic acid salt. 1H NMR (300 MHz, d6-DMSO) 9.91 (1H, s), 8.52 (1H, d), 7.96 (1H, d), 7.63 (1H, d), 7.45-7.27 (5H, m), 5.00 (2H, br s), 2.93 (2H, m), 2.17 (3H, s), 1.96 (3H, br s), 1.71-1.54 (12H, m), 1.31 (2H, m). Found: C, 62.33; H, 5.73; N, 6.27%. C34H36F3N3O7 requires: C, 62.28; H, 5.53; N, 6.41%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>>[Cl:12][C:13]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:14]=1[C:15]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=1)=[O:16]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)c1ccc(Cl)cc1Cl

Procedure:
To a stirred mixture of 20 parts of aluminium chloride and 100 parts of fluorobenzene are added dropwise 20.5 parts of 2,4-dichlorobenzoyl chloride. Upon completion, the mixture is heated to reflux and stirred at reflux temperature for 5 minutes. The reaction mixture is poured onto crushed ice and the product is extracted with 1,1'-oxybisethane. The extract is dried and evaporated, yielding 30 parts of (2,4-dichlorophenyl)(4-fluorophenyl) methanone as an oily residue.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2].[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[CH:32]=[O:33]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[C:24]([CH:32]=[O:33])[CH:25]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])([O-:3])=[O:2]
Reactant: COc1ccc(-c2nc3cc(Br)ccc3o2)cc1[N+](=O)[O-]
Reactant: O=Cc1cc(B(O)O)ccc1F
Product: COc1ccc(-c2nc3cc(-c4ccc(F)c(C=O)c4)ccc3o2)cc1[N+](=O)[O-]

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-methoxyphenyl)-5-bromobenzoxazole (200 mg, 0.57 mmol) and 4-fluoro-3-formylphenylboronic acid (143 mg, 0.85 mmol) the subtitle compound was obtained (146 mg, 44%). MS 393 m/z (M+H)+.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.Cl.[CH2:16](O)[CH3:17]>O1CCOCC1>[CH2:16]([O:9][C:8](=[O:10])[CH2:7][C:4]1[CH:3]=[CH:2][C:1]([CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)[CH3:17]
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(CC(=O)O)cc1

Procedure:
A solution of the diester from preparation 9 (11.8 g,•47.0 mmol) and 2,2′-(1,4-phenylene)diacetic acid (15.73 g, 81.0 mmol) in ethanol (6.14 ml) and dioxan (75 ml) was treated dropwise with 12M hydrochloric acid (1.57 ml, 18.8 mmol). The reaction mixture was stirred at reflux for 18 hours before being allowed to cool and concentrated to low volume. The reaction mixture was diluted with toluene (125 ml) and the resulting slurry filtered. The filtrate was concentrated in vacuo and the residue taken up in water and basified with sodium bicarbonate until pH neutral. The mixture was diluted with ethyl acetate (200 ml) and the organic layer was separated and washed with sodium bicarbonate solution (5×30 ml) and sat. aq. sodium chloride (50 ml). The combined aqueous extracts were acidified to pH 3 with 6M hydrochloric acid and extracted with ether (3×30 ml). The organics were combined, dried (magnesium sulphate) and concentrated in vacuo. The residue was triturated with pentane giving the title compound as a colourless solid 10.8 g.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:12][C:11](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:13]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C.[N+:69]([CH3:72])([O-:71])=[O:70]>>[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([CH:21]([CH2:72][N+:69]([O-:71])=[O:70])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:13]([O:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/C1(C(=O)OCCC(C)C)CC(OCc2ccccc2)C1
Reactant: C[N+](=O)[O-]
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C[N+](=O)[O-])C1(C(=O)OCCC(C)C)CC(OCc2ccccc2)C1

Procedure:
A 9.46 g (25.3 mmol) portion of ethyl (E)-3-[1-benzyloxy-3-(isoamyloxycarbonyl)cyclobutan-3-yl]acrylate was dissolved in 50 ml of nitromethane to which, while cooling in an ice bath and stirring, was subsequently added dropwise 3.78 ml (25.3 mmol) of diazabicycloundecene. After 10 minutes of stirring, the reaction mixture was further stirred at room temperature for 1 hour. While cooling in an ice bath and stirring, the reaction solution was acidified by gradually adding 10% citric acid aqueous solution and then mixed with ethyl acetate to effect separation of layers. The resulting organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure to give 11.45 g (25.26 mmol) of the title compound. The thus obtained compound was used in the following reaction without purification.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9](OCCC2C=CC=CC=2)[CH2:8][CH2:7]1)=[O:5])C>[OH-].[Na+]>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:3])=[O:5])[CH2:11][CH2:10][N:9]([CH2:32][CH2:31][O:30][C:27]3[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=3)[CH2:8][CH2:7]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(OCCc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCOc3ccccc3)CC2)cc1

Procedure:
4-(4-n-Butoxy-benzenesulfonyl)-1-(2-phenoxy-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-n-butoxy-benzenesulfonyl)-1-(2-phenyl-ethoxy)-piperidine-4-carboxylic acid ethyl ester (2.5 g, 5.76 mmol) dissolved in TBF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.5 g (56%); off white powder, mp 204° C.; MS: 462.5 (M+H)+.