Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[NH2:23]>>[O:11]([C:9]1[CH:8]=[CH:7][N:6]=[C:5]([NH:23][C:22]2[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:20]([O:19][CH3:18])[CH:21]=2)[N:10]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)c1nccc(Oc2ccccc2)n1
Reactant: COc1cc(N)cc(OC)c1OC
Product: COc1cc(Nc2nccc(Oc3ccccc3)n2)cc(OC)c1OC
Yield: 1.7 %

Procedure:
2-Methylsulphonyl-4-phenoxypyrimidine (0.76 g, 3.04 mmol) and 3,4,5-trimethoxyaniline (0.56 g, 4.0 mmol) were heated as a melt at 1400 for 2 h. On cooling the residue was partitioned between ethyl acetate (50 ml) and 2M hydrochloric acid (50 ml), and the organic layer was washed with water (50 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to column chromatography [silica 20% ethyl acetate-hexane] to give the title compound (18 mg) as a white solid m.p. 149° after recrystallisation from ethyl acetate. δH (CDCl3) 8.26 (1H, d, J 5.6 Hz), 7.39 (2H, m), 7.26 (1H,m), 7.18-7.15 (2H, m), 6.73 (2H, s), 6.31 (1H, d, J 5.6 Hz), 3.77 (3H, s) and 3.64 (6H, s). MS m/z 354 (M+H)+. The pyrimidine used as starting material was prepared by the addition of 50% 3-chloroperoxybenzoic acid (15.19 g, 88.0 mmol) to a solution of 4-phenoxy-2-thiomethylpyrimidine (5.0 g, 22.9 mmol) in CH2Cl2 (100 ml) at 0°. The resulting mixture was allowed to rise to room temperature over 12 h, and was then washed with 2M aqueous NaOH (2×100 ml), saturated aqueous sodium sulphite (2×100 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to column chromatography to give the desired product (0.81 g) as a colourless oil. δH (CDCl3) 8.49 (1H, d, J 5.5 Hz), 7.45 (2H, t, J 8.0 Hz), 7.33-7.26 (1H, m), 7.19-7.16 (2H, m), 6.85 (1H, d, J 5.5Hz) and 3.23 (3H, s). The 4-phenoxy-2-thiomethylpyrimidine used as starting material was prepared by heating a solution of 4-fluoro-2-thiomethylpyridine [N. Pleet al., J. Het. Chem. 31, 1311-1315 (1994)] (9.98 g, 69.3 mmol) and phenol (6.58 g, 70.0 mmol) in dry DMF (100 ml) in the presence of caesium carbonate (22.8 g, 70.0 mmol) at 400 for 6 h. The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was dried (MgSO4), concentrated under reduced pressure and the residue subjected to column chromatography [silica 40% ethyl acetate-hexane] to give the desired product (7.01 g) as a colourless oil. δH (CDCl3) 8.33 (1H, dd, J 4.7, 0.9 Hz), 7.40 (2H, dd, 8.0,1.1 Hz), 7.26 (1H, m), 7.23 (2H, m), 6.46 (1H, dd, J 4.7, 0.9Hz) and 2.37 (3H, s). MS m/z 219 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[N:10]=[C:9]([C:20]3[N:21]=[CH:22][N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=[O:14])[N:10]=[C:9]([C:20]3[N:21]=[CH:22][NH:23][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Cn1nc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1Cc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1nc(-c2c[nH]cn2)cc1Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of tert-butyl [5-(4-fluorobenzyl)-3-(1-trityl-1H-imidazol-4-yl)-1H-pyrazol-1-yl]acetate (0.5 g, 0.80 mmol) in CH2Cl2 (10 mL) was added dropwise TFA (10 mL) at 0° C. After the addition, the mixture was stirred at 0° C. for 2 hours. The solvent was removed in vacuo and the residue was washed with Et2O (3×10 mL) and dried in oven to yield the title compound (0.2 g, 80.0%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:15]1([CH:21]([NH2:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH:21]([NH:28][C:9]([CH2:8][NH:7][C:6](=[O:12])[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:14][CH:13]=1)=[O:11])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: NC(c1ccccc1)c1ccccc1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccccc1)c1ccccc1

Procedure:
Prepared in analogy to example 1.1 from p-fluoro-hippuric acid (CA [366-79-0]) and C,C-diphenylmethylamine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([N:11]=[C:12]=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:14][C:15]1[NH:19][N:18]=[C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[N+:31]([O-:33])=[O:32])[CH:16]=1.Cl>CN(C=O)C>[C:7]([NH:11][C:12]([N:19]1[C:15]([CH3:14])=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[N+:31]([O-:33])=[O:32])=[N:18]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: Cc1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])n[nH]1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])nn1C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.8 %

Procedure:
Potassium carbonate (0.83 g, 6.0 mmol) and tert-butyl isocyanate (0.59 g, 6.0 mmol) were added to a solution of 5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)pyrazole (1.15 g, 4.0 mmol) in DMF (10 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a white solid of N-tert-butyl-5-methyl-3-(2-nitro-4-trifluoromethylphenyloxy)-pyrazole-1-carboxamide (0.80 g, yield: 51.8%). mp: 104-106° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.41 (s, 9H), 2.61 (s, 3H), 5.82 (s, 1H), 6.65-6.90 (br s, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.82 (dd, J=2.1 and 8.7 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[OH:18].Cl[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][N:21]=1.O>CS(C)=O>[N+:26]([C:23]1[CH:22]=[N:21][C:20]([O:18][C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][C:8]=2[Cl:7])=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1ccc(C(F)(F)F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)nc1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
7.6 g of anhydrous sodium carbonate and 9.8 g of 2-chloro-4-trifluoromethylphenol were added to 20 ml of dimethyl sulfoxide, and a solution having 7.9 g of 2-chloro-5-nitropyridine dissolved in 10 ml of dimethyl sulfoxide was added dropwise thereto at room temperature (i.e., about 20° to 30° C.) while stirring. After completion of the dropwise addition, the mixture was allowed to react at 50° C. for 30 minutes. After completion of the reaction, the reaction product was poured into water, followed by extracting with methylene chloride. The extracted phase was washed with water and dried, and the solvent was then distilled off to obtain 13 g of a crystal. The thus obtained crystal was recrystallized from n-hexane to obtain 9.8 g of a titled compound having a melting point of 69° to 72° C.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH:6]([OH:8])[CH2:5][CH:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[Cl:16])[C:3]1=[O:17].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([N:31]=[C:32]=[S:33])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[CH:4]1[CH2:5][CH:6]([OH:8])[CH2:7][N:2]([NH:1][C:32](=[S:33])[NH:31][CH:28]2[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:24])[CH2:30][CH2:29]2)[C:3]1=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCC(N=C=S)CC1
Reactant: NN1CC(O)CC(c2ccc(F)cc2Cl)C1=O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=S)NN2CC(O)CC(c3ccc(F)cc3Cl)C2=O)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of (3SR,5SR)-1-amino-3-(2-chloro-4-fluorophenyl)-5-hydroxypiperidin-2-one (0.8 g, 2.9 mmol) in dimethylacetamide (1 mL) was added 4-isothiocyanatopiperidine-1-carboxylic acid tert-butyl ester (0.8 g, 3.2 mmol, US2006/14958A1) and the reaction stirred for 2 hours at 80° C. The reaction was diluted with ethyl acetate, washed with water, brine, dried with sodium sulfate and the solvent was evaporated in vacuo. The product was triturated from dichloromethane by addition of heptane to afford the title compound as a colourless powder (1.2 g, 83%). MS ISP (m/e): 501.2 [(M+H)+].
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1I.Cl[C:19]1[S:23][N:22]=[C:21]([S:24][CH3:25])[N:20]=1>[Zn].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCCC1>[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:19]1[S:23][N:22]=[C:21]([S:24][CH3:25])[N:20]=1
Reactant: CC1CCCCC1I
Reactant: CSc1nsc(Cl)n1
Agent: [Fe+2]
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CSc1nsc(C2CCCCC2C)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 27.6 %

Procedure:
583 mg of zinc powder and 83 mg of 1,2-dibromoethane was added into 9 ml of tetrahydrofurane under nitrogen atmosphere and the mixture was refluxed for 1 minute. After cooling to room temperature, 49 mg of trimethylsilyl chloride and 3.0 g of 2-methylcyclohexyl iodide were added to the mixture, and the mixture was stirred for 6 hours at room temperature. Further, 1.49 g of 5-chloro-3-methylthio-1,2,4-thiadiazole and 109 mg of {1,1′-bis(diphenylphosphino)ferrocene} dichloro palladium(II) dichloromethane complex were added in the mixture, and the reaction mixture was stirred for 15 hours at room temperature and refluxed for 5 hours. The reaction mixture was concentrated, and the residue subjected to silica gel column chromatography to give 564 mg of 5-(2-methylcyclohexyl)-3-methylthio-1,2,4-thiadiazole.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1>CC1C=CC=CC=1C>[CH3:12][CH:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: Cc1cccc2c(C)cccc12
Solvent: Cc1ccccc1C
Product: Cc1cccc2c1CCCC2C
Yield: 88 %

Procedure:
In Example 1, a hydrocarbon feed of 5:1 (wt:wt) o-xylene: 1,5-dimethylnaphthalene was hydrogenated in a reactor with a PtS/Boron-SSZ-33 catalyst (0.5 g) at 400° F. and 200 psig. The hydrogenation products including the solvent o-xylene were collected and then dehydrogenated by being fed to PtS/Na-ZSM-5 in a reactor at 850° F., 100 psig, 0.5 ml/hr feed, 23 ml/min H2 and 0.5 g catalyst. The feed (hydrogenation products of 1,5-DMN) is shown in chromatographic form in FIG. 15b in comparison to 1,5-DMN (used as feed for hydrogenation in Example 1) in FIG. 15a. The result of the dehydrogenation is shown in chromatographic form in FIG. 15c. As described in Example 1, in the hydrogenation step, 96% of 1,5-DMN was converted, yielding 88% 1,5-DMT and 8% DMD's and other C12's. No other DMT isomers were observed. In the dehydrogenation step of this example, the resulting dehydrogenation product has the following composition: ~0% DMD's and other C12's, 0.9% 1,5-DMT, 1.3% other DMT's, 96.5% 1,5-DMN, 1.3% 1,6/1,7-DMN. No MN's were detected. The detailed GC peak identification is demonstrated in FIGS. 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 10a and 10b. Since PtS/Na-ZSM-5 works for the "bulky" 1,5-isomers as demonstrated in this example, this catalyst apparently also works for the dehydrogenation of other DMN isomers.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([N:10]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13](=[O:22])[C:12]([CH3:23])=[C:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:8][CH:9]=1.[CH2:30](Br)[C:31]#[CH:32]>CS(C)=O>[CH3:23][C:12]1[C:13](=[O:22])[CH:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:32][C:31]#[CH:30])[CH:5]=2)[C:11]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cc1c(-c2ccccc2)n(-c2cccc(O)c2)c(-c2ccccc2)cc1=O
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CCOc1cccc(-n2c(-c3ccccc3)cc(=O)c(C)c2-c2ccccc2)c1
Temperature: 0 °C
Yield: 38.3 %

Procedure:
To 50 ml of a suspension of 0.72 g (0.03 mole) of sodium hydride in DMSO, 3.5 g (0.01 mole) of 1-(3-hydroxyphenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone was added, followed by further dropwise addition of 1.4 g (0.012 mole) of propargyl bromide. The reaction mixture was thereafter poured into ice water, followed by extraction with chloroform. After washing the organic layer (the extract) with water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off, followed by recrystallization from a 2:1 mixed solvent of acetone and hexane to obtain 1.5 g of 3-methyl-2,6-diphenyl-1-(3-propargyloxyphenyl)-4-(1H)-pyridinone having a melting point of 166°-169° C.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:10]2[C:5](=[N:6][C:7]([C:12]3[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=34)=[N:8][CH:9]=2)[N:4]1[C@H:23]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1.[C:29]([CH2:31][C:32](ON1C(=O)CCC1=O)=[O:33])#[N:30]>CN(C=O)C>[C:29]([CH2:31][C:32]([N:25]1[CH2:26][CH2:27][CH2:28][C@H:23]([N:4]2[C:3](=[O:2])[NH:11][C:10]3[C:5]2=[N:6][C:7]([C:12]2[CH:13]=[N:14][N:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=24)=[N:8][CH:9]=3)[CH2:24]1)=[O:33])#[N:30]
Reactant: N#CCC(=O)ON1C(=O)CCC1=O
Reactant: N#Cc1ccn2ncc(-c3ncc4[nH]c(=O)n([C@H]5CCCNC5)c4n3)c2c1
Agent: Cl
Solvent: CN(C)C=O
Product: N#CCC(=O)N1CCC[C@H](n2c(=O)[nH]c3cnc(-c4cnn5ccc(C#N)cc45)nc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.8 %

Procedure:
To a solution of the compound obtained in example 6 (45 mg, 0.095 mmol) in anhydrous DMF (3 mL), 2,5-dioxopyrrolidin-1-yl 2-cyanoacetate (69 mg, 0.38 mmol) and anhydrous TEA (0.09 mL, 0.665 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, and the solvent was concentrated off. It was quenched with saturated NaHCO3 aqueous solution (15 mL) and extracted with EtOAc (3×15 mL). The combined organic phases were dried over anhydrous Mg2SO4, filtered and concentrated. The crude residue was flash chromatographed on a silica gel flash system (ISCO Rf) using hexanes/acetone mixtures of increasing polarity as eluent to afford 11.7 mg of the desired compound (29% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH2:14][CH2:15][C:16]([OH:18])=O)(=[O:12])=[O:11])([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>O1CCCC1>[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:16](=[O:18])[CH2:15][CH2:14][NH:13][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:11])=[O:12])[CH2:34][CH2:33]1
Reactant: CN1CCNCC1
Reactant: O=C(O)CCNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)CCNS(=O)(=O)c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a solution of methyl 3-(2-nitrobenzenesulfonylamino)propionate (6.15 g) in ethanol (20 mL)-methanol (5 mL) was added 5 mol/L aqueous sodium hydroxide solution (20 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was acidified by addition of 2 mol/L hydrochloric acid (55 mL), and the resulting mixture was extracted with ethylacetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with n-hexane and ethylacetate. The precipitated crystals were collected by filtration, washed with n-hexane and dried under reduced pressure to give 3-(2-nitrobenzenesulfonylamino)propionic acid (5.83 g). To a solution of the obtained 3-(2-nitrobenzenesulfonylamino)propionic acid (0.5 g) in tetrahydrofuran (5 mL) was added 1,1′-carbonylbis-1H-imidazole (0.35 g), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1-methylpiperazine (0.46 g), and the mixture was stirred at 50° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on aminopropylated silica gel (eluent: dichloromethane/methanol 40/1) to give the title compound (0.61 g).
Reaction SMILES: Br[CH2:2][CH:3]([C:12]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:30])[NH:17]2)[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1>CS(C)=O.C(OCC)(=O)C>[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH:40][CH2:2][C@@H:3]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16](=[O:30])[NH:17]3)[O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6])=[CH:34][CH:33]=1
Reactant: CC(C)(C)[Si](C)(C)OC(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: NCCc1ccc(N)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(N)cc1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 100 °C
Yield: 91.6 %

Procedure:
A mixture of 5-(2-bromo-1-(tert-butyl-dimethyl-silanyloxy)-ethyl)-8-benzyloxy-1H-quinolin-2-one (5.0 g, 1.0 equiv) and 2-(4-aminophenyl)ethylamine (2.8 g, 2.0 equiv) in dimethylsulfoxide (10 mL) was heated at 100° C. for 12 h. The reaction mixture was cooled to 20° C., and the resulting red oil was diluted with ethyl acetate (200 mL) and extracted with two portions water (200 mL). The organic layer was washed with two portions of (1:1 10% aqueous acetic acid and saturated aqueous sodium chloride (200 mL). The organic layer was basified by carefully extracting with two portions of saturated sodium bicarbonate (200 mL), followed by saturated sodium chloride (200 mL). The resulting organic solution was treated with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to afford the title intermediate (5.1 g) which was used without further purification.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[S:23][C:17]=2[N:16]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:15]1=[O:39].[C:40](=[O:42])=[O:41].[OH-].[Na+]>O1CCCC1>[CH3:13][N:14]1[C:19](=[O:20])[C:18]2[C:21]([C:40]([OH:42])=[O:41])=[C:22]([CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[S:23][C:17]=2[N:16]([CH2:35][CH:36]([CH3:37])[CH3:38])[C:15]1=[O:39]
Reactant: O=C=O
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cc(Cc3cccc4ccccc34)sc21
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3cccc4ccccc34)sc21
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
n-Butyllithium (2.0M solution in hexanes, 1.90 ml) was added dropwise to a solution of diisopropylamine (0.069 ml) in anhydrous tetrahydrofuran (30 ml) at 0° C., under nitrogen. The solution was stirred for 5 minutes then cooled to −78° C. and a solution of 3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (1.50 g) in anhydrous tetrahydrofuran (15 ml) was added dropwise. After 15 minutes, the flask was transferred to a sealed bomb containing carbon dioxide pellets (2 g) and heated to 50° C. for 18 hours. The reaction mixture was cooled to room temperature then added to aqueous sodium hydroxide solution (0.25M, 75 ml) and washed with ether (2×75 ml). The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ether (2×75 ml). The organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with isohexane:ethyl acetate (3:1) containing 1% acetic acid, to give the subtitle compound (0.337 g) as a solid.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:34]([O:41][CH2:42][C@H:43]([C:45]1[C:53]2[C:48](=[N:49][CH:50]=[C:51]([C:54]([CH3:59])([CH3:58])[C:55](O)=[O:56])[CH:52]=2)[NH:47][C:46]=1[C:60]1[CH:65]=[C:64]([CH3:66])[CH:63]=[C:62]([CH3:67])[CH:61]=1)[CH3:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH2:68]([NH:72][CH2:73][CH:74]([CH3:76])[CH3:75])[CH:69]([CH3:71])[CH3:70].C(N(CC)CC)C>C(Cl)Cl>[CH2:68]([N:72]([C:55](=[O:56])[C:54]([C:51]1[CH:52]=[C:53]2[C:45]([C@H:43]([CH3:44])[CH2:42][O:41][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:46]([C:60]3[CH:65]=[C:64]([CH3:66])[CH:63]=[C:62]([CH3:67])[CH:61]=3)[NH:47][C:48]2=[N:49][CH:50]=1)([CH3:59])[CH3:58])[CH2:73][CH:74]([CH3:76])[CH3:75])[CH:69]([CH3:71])[CH3:70]
Reactant: Cc1cc(C)cc(-c2[nH]c3ncc(C(C)(C)C(=O)O)cc3c2[C@H](C)COCc2ccccc2)c1
Reactant: CC(C)CNCC(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(-c2[nH]c3ncc(C(C)(C)C(=O)N(CC(C)C)CC(C)C)cc3c2[C@H](C)COCc2ccccc2)c1
Reaction time: 12 h

Procedure:
PyBOP is added to a stirred mixture of (S)-2-[3-(2-benzyloxy-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-pyrrolo-[2,3-b]pyridin-5-yl]-2-methylpropanoic acid, diisobutylamine and triethylamine in CH2Cl2 at ambient temperature. After approximately 12 h, the reaction mixture is poured into waterlbrine (1:1) and extracted with ethyl acetate. The combined organic extract is washed with brine, dried (MgSO4) and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (gradient elution; 60-75% ethyl acetate/hexanes as eluent) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Br)c2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Br)c2)CC1
Yield: 94.4 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(3-bromophenyl)methylidene]-1-piperidine-carboxylate (201 mg, 0.571 mmol) in THF (1 mL) was applied onto an H-Cube hydrogenation device (H-Cube, LLC, Dallas, Tex., USA; http://www.h-cubeinc.com/) 10% PD/C at a flow rate of 1 mL/min and 1 atm H2. The mixture was concentrated to afford the title compound 0.1909 g (94%). LC-MS m/z 354 (M+H)+.