Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C:6]1[N:11]=[C:10]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:34])[C:21]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)([OH:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:15][CH2:14]2)[CH:9]=[CH:8][CH:7]=1)=O)C.[ClH:35].C1(P([N:50]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl.O1CCOCC1>CO.[OH-].[Na+].C(O)(C)(C)C.C(N(CC)CC)C>[ClH:35].[ClH:35].[NH2:50][C:6]1[N:11]=[C:10]([CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20](=[O:34])[C:21]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)([OH:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:18]2)[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cccc(CN2CCC(NC(=O)C(O)(c3ccccc3)C3CCCC3)CC2)n1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Nc1cccc(CN2CCC(NC(=O)C(O)(c3ccccc3)C3CCCC3)CC2)n1
Reaction time: 15 h

Procedure:
To a solution of 40 mg of N-[1-(6-ethoxycarbonyl-2-pyridylmethyl)piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide in 1 ml of methanol, 0.5 ml of 1N sodium hydroxide solution was added at room temperature, followed by 15 hours' stirring at the same temperature. The reaction mixture was made weakly acidic with 1N hydrochloric acid and concentrated under reduced pressure. The residue was dissolved in ethanol, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase ODS column chromatography (acetonitrile/water=2/1) to provide 27 mg of an oily substance. The product was dissolved in 1 ml of t-butanol. After addition of 20 mg of diphenylphosphoryl azide and 27 μl of triethylamine, the solution was refluxed for 18 hours. The solvent was distilled off, and the residue was purified by preparative thin layer chromatography [Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol=10/1] to give 14 mg of an oily substance. The product was dissolved in 0.5 ml of methanol, and to which 4N hydrogen chloride/dioxane was added at room temperature, followed by an overnight stirring. The reaction mixture was solidified by drying under reduced pressure to give 13 mg of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH:12]2[CH2:17][N:16]([CH3:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[O:13]2)[CH:3]=1.[C:23]([C:26]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)([CH3:28])[CH3:27])([OH:25])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:6]1[N:7]=[C:2]([C:31]2[CH:30]=[C:29]([C:26]([CH3:28])([CH3:27])[C:23]([OH:25])=[O:24])[CH:34]=[CH:33][CH:32]=2)[CH:3]=[C:4]([NH:10][CH2:11][CH:12]2[CH2:17][N:16]([CH3:18])[C:15]3[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=3[O:13]2)[N:5]=1
Reactant: COc1nc(Cl)cc(NCC2CN(C)c3ccccc3O2)n1
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCC2CN(C)c3ccccc3O2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 85 °C
Yield: 68.3 %

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-amine (200 mg, 0.62 mmol), 3-(1-carboxy-1-methyl-ethyl)-phenyl-boronic acid (190 mg, 0.94 mmol), and Cs2CO3 (0.51 g, 1.6 mmol) in ethylene glycol dimethyl ether (10 mL) and water (2 mL) is degassed by bubbling with Ar gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium(0) (36 mg, 0.03 mmol) at room temperature. The mixture is heated at 85° C. for 6 h. The mixture is diluted with H2O (20 mL), and extracted with EtOAc (20 mL). The aqueous layer is separated, acidified to pH 3 with 1M HCl solution, and extracted with EtOAc (2×30 mL). The extracts are dried (MgSO4), filtered, and concentrated. The residue is chromatographed on SiO2 (70% EtOAc in heptane) to afford 2-(3-{2-methoxy-6-[(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-amino]-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid (190 mg, Example 92). LCMS: RT=2.59 minutes; MS: 449 (M+H). IC50=278 nM
Reaction SMILES: CS(C)=O.C(Cl)(C(Cl)=O)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][OH:26])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(Cl)Cl>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][N:21]([CH:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:25]=[O:26])[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCN(C(CO)c2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(C=O)c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
To DMSO (2.19 mL) in MeCl2 (40 mL) at −78° C. was added (COCl)2 (1.29 mL, ×mmol) dropwise. The reaction mixture was allowed to stir at −78° C. for 15 minutes and then 4-(2-Hydroxy-1-phenyl-ethyl)piperazine-1-carboxylic acid tert-butyl ester (364) (3.78 g, 12.34 mmol) in MeCl2 (8 mL) was added. The reaction mixture was allowed to stir at −78° C. for 1 h and then TEA (8.6 mL) amine added. The reaction mixture was allowed to stir at −78° C. for another 3 h and then allowed to warm to room temperature and stirred for 18 h. The reaction mixture is then quenched with sat. NH4Cl (55 mL). The desired product is extracted into EtOAc (100 mL). The organic phase is dried over MgSO4 and concentrated to dryness. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 30% EtOAc in hexanes) yielding 2.37 g (63%) pure product.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@@:21]3([NH:25][CH:24]([C:26]([O:28]C)=O)[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CO.[NH3:45]>>[F:10][C:9]([F:12])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([N:15]([CH3:40])[C:16]([N:18]2[CH2:31][CH2:30][C@@:21]3([NH:25][CH:24]([C:26]([NH2:45])=[O:28])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=2[CH3:39])=[O:17])[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:8]=1
Reactant: COC(=O)C1CC[C@]2(CCN(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reactant: N
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCC(C(N)=O)N2)CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 48 h
Yield: 84 %

Procedure:
A solution of Methyl (5R,7R)-8-{[{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (diastereoisomer 2) (Intermediate 8, 18 mg, 0.030 mmol) in 7N Ammonia in MeOH (5 mL, 35.0 mmol) was stirred at 25° C. for 1 day and then it was left still for 2 days. The solvent was evaporated to dryness and the crude was purified by SCX and silica cartridges (from 1:0 to 97.5:2.5 DCM/0.5 M NH3 in MeOH) to give two batches of the title compound as colourless oil (total amount: 14.9 mg, 0.025 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.90-8.08 (m, 1H) 7.62-7.77 (m, 2H) 7.26-7.46 (m, 1H) 7.04-7.23 (m, 2H) 6.84-6.96 (m, 1H) 6.69-6.80 (m, 1H) 5.24-5.41 (m, 1H) 4.31-4.49 (m, 1H) 3.49-3.65 (m, 1H) 3.10-3.25 (m, 1H) 2.94-3.08 (m, 1H) 2.61-2.87 (m, 3H) 2.35 (s, 3H) 1.92-2.10 (m, 1H) 1.62-1.84 (m, 2H) 1.38-1.60 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O.I[C:23]1[CH:24]=[C:25]([CH:29]([N:31]([O:43][CH3:44])[C:32]([C:34]2[C:35]([CH:40]([F:42])[F:41])=[N:36][N:37]([CH3:39])[CH:38]=2)=[O:33])[CH3:30])[CH:26]=[CH:27][CH:28]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:23]2[CH:24]=[C:25]([CH:29]([N:31]([O:43][CH3:44])[C:32]([C:34]3[C:35]([CH:40]([F:41])[F:42])=[N:36][N:37]([CH3:39])[CH:38]=3)=[O:33])[CH3:30])[CH:26]=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CON(C(=O)c1cn(C)nc1C(F)F)C(C)c1cccc(I)c1
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)c1cccc(Oc2ccc(Cl)cc2)c1
Yield: 22.9 %

Procedure:
A mixture of 4-chlorophenol (0.2 g, 0.86 mmol) in DMF (2 ml), cesium carbonate (0.7 g, 1.14 mmol), N,N-dimethylglycine (0.01 g, 0.057 mmol), 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [1-(3-iodo-phenyl)-ethyl]methoxy-amide (0.25 g, 0.57 mmol), prepared as described in example P2, and Cul (0.09 g, 0.024 mmol) was subjected to microwave irradiation at 90° C. for 20 minutes. Reaction mass was diluted with water and extracted with ethyl acetate (3×60 ml), washed with water, brine and dried over anhydrous sodium sulfate. The crude mass was purified by chromatography to yield 0.057 g (28% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid {1-[3-(4-chloro-phenoxy)-phenyl]-ethyl}-methoxy-amide in form of a resin.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[Cl:22][C:23]1[S:27][C:26]([S:28]([NH:31][C@H:32]([CH2:38][OH:39])[CH:33]([CH2:36][CH3:37])[CH2:34][CH3:35])(=[O:30])=[O:29])=[CH:25][CH:24]=1>C(Cl)Cl>[Cl:22][C:23]1[S:27][C:26]([S:28]([NH:31][C@H:32]([CH:38]=[O:39])[CH:33]([CH2:34][CH3:35])[CH2:36][CH3:37])(=[O:30])=[O:29])=[CH:25][CH:24]=1
Reactant: CCC(CC)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCC(CC)[C@@H](C=O)NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 18 h
Yield: 61.1 %

Procedure:
Pyridinium dichromate (2.4 g, 6.4 mmol) was added to a solution of 5-chloro-N-[(S)-2-ethyl-1-(hydroxymethyl)butyl]-2-thiophenesulfonamide (0.5 g, 1.6 mmol) in CH2Cl2 (20 mL). After 18 h, the reaction mixture was filtered through a plug of Celite. The filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (eluant: 1:4 EtOAc-hexane) to give 5-chloro-N-[(S)-2-ethyl-1-formylbutyl]thiophene-2-sulfonamide as a white solid (303 mg, 61%). [α]D25=+136.76° (c=1% SOLUTION, CHCl3). Mass Spectrum (−ESI): 308 (M−H)−. Anal. Calc'd for C11H16ClNO3S2: C, 42.64; H, 5.21; N, 4.52. Found: C, 42.57; H, 5.24; N, 4.52.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[N:10]=[C:11]=[O:12])([O:3][CH3:4])=[O:2].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[O:6][C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[NH:10][C:11]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)=[O:12])([O:3][CH3:4])=[O:2]
Reactant: Cc1ccc(N)cc1
Reactant: COC(=O)c1oc(C(C)(C)C)cc1N=C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1oc(C(C)(C)C)cc1NC(=O)Nc1ccc(C)cc1
Reaction time: 1 h

Procedure:
The 2-carbomethoxy-5-tert-butyl-3-furyl isocyanate prepared in Step 3 was dissolved in anh. toluene (40 mL), p-toluidine (2.05 g, 6.02 mmol, 1.0 equiv) was added, and the resulting solution was stirred at room temp. for 1 h. The toluene mixture was concentrated under reduced pressure, then diluted with CHCl3 (150 mL). The organic solution was washed with a 1N HCl solution (2×100 mL) and a saturated NaCl solution (100 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (100 g SiO2, gradient from hexane to 10% EtOAc/hexane) to give N-(2-carbomethoxy-5-tert-butyl-3-furyl)-N′-(4-methylphenyl)urea as a yellow solid (0.71 g, 35): mp 78-9° C.; TLC (20% EtOAc/hexane) Rf0.46; 1H NMR δ1.28 (s, 9H), 2.33 (s, 3H), 3.80 (s, 3H), 7.03 (s, 1H), 7.10 (br s, 1H), 7.15 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.5 Hz, 2H) 8.60 (brs, 1H); 13C NMR δ20.8, 28.5 (3C), 33.2, 51.3, 100.3, 121.7 (br s, 2C), 126.2, 129.8 (br s, 2C), 134.3 (br s), 135.0, 137.5 (br s), 152.6, 160.8, 168.5; FAB-LRMS m/z (rel abundance) 331 (M+H, 64%).
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[CH2:5]([N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=O)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:13][CH2:14]1
Reactant: CON
Reactant: O=C1CCN(Cc2ccccc2)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CCN(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methoxyl amine hydrochloride (0.74 g, 8.9 mmol) was added to a solution of Example 15C (1.92 g, 8.1 mmol) in pyridine (20 mL) and stirred overnight at ambient temperature. The mixture was concentrate under reduced pressure, ethyl acetate (200 mL) was added, and the organic layer was washed twice with water (200 mL) and brine, dried over sodium sulfate, filtered, and concentrate under reduced pressure. The residue was chromatographed on silica gel eluting with 0-20% ethyl acetate in hexane to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 2.88 (t, J=6.44 Hz, 2H), 3.29 (t, J=6.44 Hz, 2H), 3.97 (s, 3H), 4.47 (s, 2H), 6.65 (d, J=8.14 Hz, 1H), 6.70 (t, J=7.46 Hz, 1H), 7.13 (td, J=7.80, 1.70 Hz, 1H), 7.31 (m, 5H), 7.92 (dd, J=7.80, 1.70 Hz, 1H). MS (DCI) m/z 267.11 (M+H)+.
Reaction SMILES: BrBr.[Cl:3]Cl.[CH3:5][O:6][C:7](=[O:14])[CH2:8][CH2:9][C:10]([CH2:12]Br)=[O:11]>>[CH3:5][O:6][C:7](=[O:14])[CH2:8][CH2:9][C:10]([CH2:12][Cl:3])=[O:11]
Reactant: ClCl
Reactant: COC(=O)CCC(=O)CBr
Agent: BrBr
Product: COC(=O)CCC(=O)CCl
Yield: 35 %

Procedure:
In connection with this it is remarkable, that the 5-chlorolevulinic acid methyl ester can be also selectively produced by means of low temperature crystallisation from the chlorination mixture, which you get from the bromination mixture of levulinic acid or levulinic acid methyl ester in methanol and the subsequent bromine/chlorine exchange, in a gentle manner as already described for the 5-bromolevulinic acid methyl ester. As in the case of the 5-bromolevulinic methyl ester you proceed in the same way by using the same solvents and solvent mixtures and temperatures between −20° C. and −40° C. You get the 5-chlorolevulinic acid methyl ester in 35–38% yield and >98 purity. Impurities are the 3-chlorolevulinic acid methyl ester and the unconverted levulinic acid methyl ester. The 5-chlorolevulinic acid esters of the alcohols with chain lengths of C2–C4 can not be produced by low-temperature crystallisation because no crystallisation occurs under these conditions. The same is valid for the corresponding bromination mixtures of the 5-bromolevulinic acid esters which are produced from alcohols with chain lengths of C2–C4.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:21][OH:22])([CH2:19][OH:20])[C:7](=[O:18])[N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.O.[CH3:24][C:25]1C=CC(S(O)(=O)=O)=C[CH:26]=1.COC(OC)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:19][O:20][C:25]([CH3:26])([CH3:24])[O:22][CH2:21]3)[C:7](=[O:18])[N:8]2[C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(CO)(CO)c2ccc(Br)cc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COC(C)(C)OC
Product: CC(C)(C)OC(=O)N1C(=O)C2(COC(C)(C)OC2)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution or tert-butyl 6-bromo-3,3-bis(hydroxymethyl)-2-oxoindoline-1-carboxylate (1.00 g, 2.69 mmol) and 4-methylbenzenesulfonic acid hydrate (0.026 g, 0.134 mmol) in DMF (27 mL) was added 2,2-dimethoxypropane (0.49 mL, 4.03 mmol). The solution was stirred at rt overnight followed by the addition of additional 2,2-dimethoxypropane (0.49 mL, 4.03 mmol) and 4-methylbenzenesulfonic acid hydrate (0.026 g, 0.134 mmol). After stirring at 60° C. for 5 h, the solution was poured into saturated aqueous NaHCO3 and extracted with DCM. The combined organic extracts were purified by column chromatography (eluting with a gradient of 0-30% EtOAc in hexanes) to give tert-butyl 6′-bromo-2,2-dimethyl-2′-oxospiro[[1,3]dioxane-5,3′-indoline]-1′-carboxylate as a white solid. Mass Spectrum (ESI) m/e=434.0 [(M+Na+) (79Br)] and 436.0 [(M+Na+) (81Br)].
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(N(C)C)(N(C)C)=O>O>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)=[CH:18][CH:17]=1
Reactant: Clc1ccc(CCCCCCCCCCCCCBr)cc1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCOC(=O)C=Cc1ccc(NCCCCCCCCCCCCCc2ccc(Cl)cc2)cc1

Procedure:
A mixture of ethyl p-aminocinnamate, 5.9 g. 13-(4-chlorophenyl)tridecyl bromide and one equivalent of anhydrous powdered potassium carbonate in 50 ml. hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated. Crystallization from acetonitrile provides the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[C@H:10]([C:21]([O:23]C)=[O:22])[CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].OS([O-])(=O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[C@H:10]([C:21]([OH:23])=[O:22])[CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CN(c2cccc(Cl)n2)C[C@H]1c1ccc(F)cc1F
Agent: O=S(=O)([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CN(c2cccc(Cl)n2)C[C@H]1c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The product from step A (41 mg, 0.116 mmol) in THF (2.0 ml) was treated with 1M aqueous LiOH (0.349 ml, 0.349 mmol) at rt. The mixture was stirred at rt for 12 h, poured into 2M aq NaHSO4 and extracted with MTBE. The combined organics were dried with anhydrous Na2SO4, filtered and concentrated to afford the title compound which was used without further purification. HPLC/MS: 339.1/340.9 (M+1); Rt=1.16 min (LC2).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH:12]=[N:13][OH:14].[O-]Cl.[Na+]>C(Cl)Cl.O>[O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]#[N+:13][O-:14]
Reactant: O=C1NCCN1CCOc1ccccc1C=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: ClCCl
Product: O=C1NCCN1CCOc1ccccc1C#[N+][O-]
Temperature: -18 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 2-[2-(2-oxoimidazolidin-1-yl)ethoxy]benzaldehyde oxime (20.2 g, 0.081 mol) in CH2Cl2 (400 mL) at −1° C. is added, dropwise over 10 minutes, an aqueous NaOCl solution in water (157 mL, Aldrich, >4% of active chlorine). The reaction medium is then stirred for 20 minutes. The aqueous and organic phases are separated and the aqueous phase is extracted with CH2Cl2 (twice 75 mL). The combined organic phases are washed with water (3 times 10 mL) and dried over Na2SO4. The phases are concentrated to 100 mL under reduced pressure at room temperature. 50 mL of petroleum ether are added. The solution is cooled to −18° C. (3 hours). The precipitate is filtered, washed with CH2Cl2/petroleum ether (5 mL/10 mL; then 5 mL/20 mL; then 0 mL/20 mL) and then dried under atmospheric pressure at room temperature.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([NH:16][NH:17][C:18](=[O:20])[CH3:19])=O)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.N(C(OCC)=O)=NC(OCC)=O>ClCCCl>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]3[O:20][C:18]([CH3:19])=[N:17][N:16]=3)[S:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COCOc1cccc2sc(C(=O)NNC(C)=O)cc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COCOc1cccc2sc(-c3nnc(C)o3)cc12
Temperature: 0 °C
Yield: 62.1 %

Procedure:
N′-(4-(Methoxymethyloxy)benzo(b)thiophen-2-ylcarbonyl)acetohydrazide (2.4 g) was dissolved in 1,2-dichloroethane (50 ml) and triphenylphosphine (3.2 g) and triethylamine (2 ml) were added. The mixture was stirred under ice-cooling. Diethyl azodicarboxylate (40% toluene solution) (5.2 g) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title product (1.4 g) as pale-yellow crystals.
Reaction SMILES: O[C:2]([C:14]1[CH:15]=[C:16]([CH3:46])[C:17]([O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39]C2CCCCO2)=[C:18]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26]C2CCCCO2)[CH:19]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[H][H]>C(O)C.[Pd]>[C:8]1([CH:2]([C:14]2[CH:15]=[C:16]([CH3:46])[C:17]([O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][OH:39])=[C:18]([O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][OH:26])[CH:19]=2)[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: Cc1cc(C(O)(CC(C)(C)C)c2ccccc2)cc(OCCOCCOC2CCCCO2)c1OCCOCCOC1CCCCO1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C(CC(C)(C)C)c2ccccc2)cc(OCCOCCO)c1OCCOCCO
Reaction time: 2 h
Yield: 94.2 %

Procedure:
5-(1-Hydroxy-1-phenyl-3,3-dimethyl-1-butyl)-3-methyl-1,2-di(2-[2-(2-tetrahydropyranyloxy)ethoxy]ethoxy)benzene (3.0 g, 0.005 mole) was dissolved in absolute ethanol (100 ml) with 10% Pd/C catalyst (0.4 g). This mixture was shaken in a Parr hydrogenator at 50 psi hydrogen pressure for 18 hours. The solution was filtered and 1N HCl (10 ml) was added to the filtrate. After 2 hours, the alcohol was evaporated in vacuo, the residual oil was dissolved in methylene chloride (50 ml) and washed with water (25 ml), brine (25 ml) and dried over MgSO4. Evaporation gave the title compound as a colorless oil (2.17 g, 95% yield).
Reaction SMILES: COC[O:4][C:5]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:6]=1[CH:7]=[O:8].C[C:15]1[CH:22]=[CH:21][CH:20]=[C:19](C)[C:16]=1[CH:17]=O.Cl>O1CCCC1>[C:5]1([C:17]([C:16]2[CH:15]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:17][C:16]2[CH:19]=[CH:20][C:21]([C:7]([C:6]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:5]=3[OH:4])=[O:8])=[CH:22][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:6]=1
Reactant: Cc1cccc(C)c1C=O
Reactant: COCOc1ccc(C)cc1C=O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(O)c(C(=O)c2ccc(C=C(c3ccccc3)c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 211.5 %

Procedure:
An intermediate compound was prepared by the same method described in Example 6 except that 2-methoxymethoxy-5-methylbenzaldehyde (1.3 g) synthesized in the above-described Synthesis Example 3 was used instead of 2,6-dimethylbenzaldehyde (0.65 g). A 6 N hydrochloric acid solution (1 mL) was added to a tetrahydrofuran solution (30 mL) of the intermediate compound, and the mixture was stirred at 25° C. for 12 hours. After confirmation of the degree of reaction progress by TLC, the reaction was quenched with an aqueous solution of sodium hydrogen carbonate, and the organic phase was extracted with ethyl acetate. The resulting organic phase was dried over anhydrous magnesium sulfate, concentrated, and recrystallized to obtain 2.0 g (yield: 84%) of [4-(2,2-diphenylvinyl)phenyl]-(2-hydroxy-5-methylphenyl)methanone (12) as white crystals. The structure of Product 12 was confirmed by 1H-NMR. Table 1 shows optical characteristics and practical utility of Product 12.