Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.[OH-].[Na+].[CH2:9]([OH:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[Br:16][C:17]([CH2:19]Br)=[CH2:18]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:16][C:17]([CH2:19][O:15][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH2:18]
Reactant: C=C(Br)CBr
Reactant: CCCCCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: C=C(Br)COCCCCCC
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To a three neck round bottom flask equipped with an addition funnel and an overhead stirrer was added 35 ml of hexane, 42 g of 50% sodium hydroxide and 0.50 g of tetra-n-butylammonium bromide. A mixture of 6.74 g of hexanol (66 mmol) and 20 g (100 mmol) of 2,3-dibromopropene were fed to the well-stirred reaction mixture over a 20 minute period. The reaction was stirred an additional 1 hour, then water was added, and the phases were separated. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and stripped. The product was fractionally distilled under reduced pressure to give 6.1 g of 95% pure 2-bromo-3-hexyloxypropene.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+].C(=O)([O-])O.[Na+]>CO.O1CCOCC1.O.Cl>[NH2:24][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][O:18]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CCC3CCCO3)c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CCC3CCCO3)c2n1
Reaction time: 4 h

Procedure:
N2-Butyl-8-methoxy-9-[2-(tetrahydrofuran-2-yl)ethyl]-9H-purine-2,6-diamine (107 mg) was dissolved in methanol (2 ml) and 4N hydrogen chloride in dioxan (1 ml) added. After 4 h the solvents were stripped and the residue taken up in water and basified with 2N sodium hydroxide. A few drops of 2N hydrochloric acid were added and the pH adjusted to 7-8 by addition of saturated sodium hydrogen carbonate. The resulting solid was filtered, washed and dried to give the title compound as a solid, yield 101 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][C:16](=[O:18])[NH:15][C:14]([CH3:19])=[C:13]1[C:20]([OH:22])=O.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([Cl:33])[CH:32]=1)[NH:29][N:28]=[CH:27]2.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:33][C:31]1[CH:32]=[C:24]([NH:23][C:20]([C:13]2[CH:12]([C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[F:1])[CH2:17][C:16](=[O:18])[NH:15][C:14]=2[CH3:19])=[O:22])[CH:25]=[C:26]2[C:30]=1[NH:29][N:28]=[CH:27]2
Reactant: Nc1cc(Cl)c2[nH]ncc2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC1=C(C(=O)Nc2cc(Cl)c3[nH]ncc3c2)C(c2ccc(C(F)(F)F)cc2F)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.4 %

Procedure:
The product of Example 21, Step 2 (200 mg, 0.63 mmol, 1.00 equiv), 5-amino-7-chloroindazole (106 mg, 0.63 mmol, 1.0 equiv), and EDC (145 mg, 0.757 mmol, 1.20 equiv) were suspended in 1.5 mL DMF. Et3N (0.106 mL, 0.757 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) and further purified by reverse-phase HPLC (10-80% CH3CN/H2O—NH4OH to pH 10 over 18 minutes, retention time 12.41 min) to provide 60 mg (20%) of the title compound as a white solid. MS (ES+) m/e 467 [M+H]+
Reaction SMILES: [Br-:1].C([N+](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:28][CH2:27][C:26](=[O:29])[N:25]([CH3:30])[C:24]=2[CH:31]=1>C(Cl)Cl.CO>[NH2:19][C:20]1[C:21]([Br:1])=[CH:22][C:23]2[O:28][CH2:27][C:26](=[O:29])[N:25]([CH3:30])[C:24]=2[CH:31]=1
Reactant: [Br-]
Reactant: CN1C(=O)COc2ccc(N)cc21
Agent: CC(C)(C)[N+](C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: CN1C(=O)COc2cc(Br)c(N)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 36 %

Procedure:
Tetra-tert-butyl ammonium bromide (6.77 g, 14.04 mmol) was added to a solution of 6-amino-4-methyl-4H-benzo[1,4]oxazin-3-one (2.5 g, 14.04 mmol) in methylene chloride (100 ml) and MeOH (50 ml). The mixture was stirred at room temperature for 20 minutes, then quenched with aqueous sodium bisulfite solution. The mixture was extracted with methylene chloride, and the combined organic extracts were dried over MgSO4, filtered, concentrated under reduced pressure and purified via column chromatography to give 1.30 g of 6-amino-7-bromo-4-methyl-4H-benzo[1,4]oxazin-3-one as a light yellow solid, 40%.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:53][C:54]([O:56][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:55])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].CCCCCC>C(O)(=O)C>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:30]=[N:31][N:32]=3)=[CH:20][CH:21]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:53][C:54]([O:56][CH2:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:55])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(NC(=O)OCc3ccccc3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCCCc1nc2ccc(NC(=O)OCc3ccccc3)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 55 %

Procedure:
The product of Example 44 was deprotected in the manner described in Example 69. The product was purified by MPLC over a silica Lobar A column eluting with 40:59:1 EtOAc:hexane:acetic acid to give a 55% yield of a white solid. 1H-NMR (CDCl3, 300 MHz): 0.87 (t, 3H, J=7.4 Hz), 1.32 (m, 2H), 1.69 (m, 2H), 2.65 (3 line m, 2H, J=7.3 Hz), 5.15 (s, 2H), 5.29 (bs, 2H), 6.95 and 7.04 (AB, 4H, J=8.2 Hz), 7.30-7.42 (m, 5H), 7.49-7.59 (m, 3H), 7.72(bs, 1H), 7.98 (d, 1H), 8.06 (s, 1H), 8.12 (bd, 1H). FABMS m/e: 586 (M+ +1) calc. for C34H31N7O3
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([CH:10](C(OCC)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[C:6]([F:21])[C:5]([F:22])=[C:4]([F:23])[C:3]=1[F:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:1][C:2]1[C:7]([C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[C:6]([F:21])[C:5]([F:22])=[C:4]([F:23])[C:3]=1[F:24]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1c(C)c(F)c(F)c(F)c1F
Yield: 70.8 %

Procedure:
To diethyl 6-methyl-2,3,4,5-tetrafluorobenzoyl-malonate (8 g) are added water (20 ml) and p-toluenesulfonic acid (80 mg) and the mixture is refluxed for 2.5 hours. After cooling, the resultant is extracted with diethyl ether, and the extract is dried over magnesium sulfate and concentrated to give ethyl 6-methyl-2,3,4,5-tetrafluorobenzoylacetate (4.5 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:21])[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[NH2:6].[Br:23][C:24]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:25]=1[C:26](O)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:2][O:3][C:4](=[O:22])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:21])[N:16]([CH3:20])[CH:17]=[CH:18][CH:19]=2)=[CH:12][CH:13]=1)[NH:6][C:26]([C:25]1[CH:29]=[C:30]([O:33][CH3:34])[CH:31]=[CH:32][C:24]=1[Br:23])=[O:27]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2cccn(C)c2=O)cc1
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cccn(C)c2=O)cc1)NC(=O)c1cc(OC)ccc1Br
Yield: 67.6 %

Procedure:
A solution of 4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride (52 mg, 0.16 mmol), 2-bromo-5-methoxybenzoic acid (45 mg, 0.19 mmol), DIEA (140 μL, 0.80 mmol) and HBTU (85 mg, 0.22 mmol) in DMF (3 mL) was stirred at room temperature for 18 hr. The mixture was concentrated, the residue was dissolved in ethyl acetate (15 mL), was washed with 0.5 N HCl (1×5 mL), sat. NaHCO3 (1×5 mL), brine (1×5 mL) and was dried (MgSO4). The residue obtained upon evaporation (85 mg) was chromatographed on 25 g of silica gel, eluting with ethyl acetate to give N-[(2-bromo-5-methoxyphenyl)carbonyl]-4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (54 mg, 68%). HRMS: Obs. Mass 499.0872. Calcd. Mass 499.0869 (M+H)
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[CH:16]=[CH2:17]>CN(C=O)C>[CH2:17]([O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH:16]=[CH2:15]
Reactant: Oc1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(O)cc1
Reaction time: 8 h

Procedure:
A solution of hydroquinone (33.00g, 0.30 mol) and potassium carbonate (45.6 g, 0.33 mol) in dry DMF ( 250 mL) was stirred at 40° C. for 30 minutes. Allyl bromide (5.20 mL, 0.06 mol) was added and the reaction was stirred overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic layer was washed twice with water, then dried over sodium sulfate. The organic layer was filtered and evaporated to an oil which was chromatographed over silica gel with hexane/ethyl acetate (4:1) to afford 4-allyloxyphenol.
Reaction SMILES: [C:1]1([C:7]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[O:21][C:22]2[CH:29]=[CH:28][C:25](C=O)=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:30]([OH:36])(=[O:35])[CH2:31][C:32](O)=O.Cl>N1C=CC=CC=1.N1CCCCC1>[C:1]1([C:7]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[O:21][C:22]2[CH:23]=[CH:24][C:25](/[CH:32]=[CH:31]/[C:30]([OH:36])=[O:35])=[CH:28][CH:29]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(Oc2c(-c3ccccc3)c(C(F)(F)F)cc3ccccc23)cc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(C(F)(F)F)cc3ccccc23)cc1
Temperature: 85 °C
Yield: 79.6 %

Procedure:
4-{[2-Phenyl-3-(trifluoromethyl)-1-naphthalenyl]oxy}benzaldehyde (183) (92 mg, 0.24 mmol) was dissolved in pyridine (3 mL). To this solution was added malonic acid (74 mg, 0.70 mmol) and 1 drop of piperidine. The reaction mixture was heated at 85° C. overnight, cooled and poured into 5 N HCl (20 mL). The mixture was extracted with EtOAc. The combined organic extract was washed with 5 N HCl, water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a light brown viscous oil, which upon trituration with 1% MeOH in hexanes, yielded 83 mg (81%) of the title compound (184) as a white solid. mp 210-211° C. 1H NMR (400 MHz, CH3OH-d4): δ 6.28 (d, J=15.9 Hz, 1H), 6.56 (d, J=8.8 Hz, 2H), 7.10-7.30 (m, 5H), 7.37 (d, J=8.7 Hz, 2H), 7.53 (d, J=16.0 Hz, 1H), 7.60-7.72 (m, 2H), 7.89 (d, J=8.1 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 8.36 (s, 1H). LCMS (APCI): m/z 435 (M+H)+, m/z 433 (M−H)−. Anal. Calc for C26H17F3O3.⅙H2O: C, 71.39; H, 3.99. Found: C, 71.50; H, 3.94.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]([CH2:13][CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:16][CH2:15][CH2:14][CH2:13][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCOc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCOc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Methanesulphonyl chloride (16.15 g) was added dropwise to a stirred solution of 3-phenoxy-1-propanol (17.81 g) and triethylamine (23.78 g) in dry dichloromethane (120 ml) at 0° C. under nitrogen. The mixture was stirred at room temperature for 1 h and then washed successively with 2N hydrochloric acid (100 ml), water (100 ml), 8% sodium bicarbonate solution (100 ml) and brine (100 ml). The solution was dried and evaporated in vacuo to give an oil which solidified on standing to give the title compound (25.88 g) as a waxy solid. T.l.c. (diethyl ether) Rf 0.50.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1)([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[N+:12]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:5]2[C:1](=[O:11])[C:2]3=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]3[C:4]2=[O:6])=[CH:17][CH:16]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
A mixture of phthalimide (4 g), p-nitrophenylmethylchloride (4,7 g), potassium carbonate (4 g) and DMF (20 ml) was stirred at 150° C. for 1.5 h. After cooling, the mixture was diluted with water. The precipitate was filtered and the crude product (I) was recrystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:7][C:6]2=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:7][C:6]2=[S:30]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc2c(c1)c(=O)nc(-c1ccccc1)n2C
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)c(=S)nc(-c1ccccc1)n2C
Reaction time: 3 h

Procedure:
1.20 g (4.51 mmol) 6-Methoxy-1-methyl-2-phenyl-1H-quinazolin-4-one and 1.82 g (4.50 mmol) Lawesson's reagent (C14H14O2P2S4, Fluka) were dissolved in 20 ml toluene. The reaction mixture was boiled for 3 h. After evaporation the residue was further purified by column chromatography with silica, eluent dichloromethane/acetone 95/5.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([OH:17])[CH2:4][C:5]1([CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[O:8][CH2:7][CH2:6]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[F:19][C:2]([F:1])([F:18])[C:3](=[O:17])[CH2:4][C:5]1([CH3:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[O:8][CH2:7][CH2:6]1
Reactant: CC1(CC(O)C(F)(F)F)CCOc2ccc(F)cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1(CC(=O)C(F)(F)F)CCOc2ccc(F)cc21
Reaction time: 18 h
Yield: 44.1 %

Procedure:
To a solution of 2.4 g (8.62 mmol) of 1,1,1-trifluoro-3-(6-fluoro-4-methylchroman-4-yl)propan-2-ol in 20 mL of dichloromethane was added 11.8 mmol of Dess-Martin periodinane. After 18 hours, the mixture was adsorbed onto silica gel and passed through a pad of silica gel, washing with EtOAc-hexanes (1:9) to afford 1.05 g (44%) of the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH:21]=[C:20]([CH2:23]O)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:10]([N:17]1[CH2:18][CH:19]=[C:20]([CH2:23][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[I:9])[CH2:21][CH2:22]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCC1=CCN(Cc2ccccc2)CC1
Reactant: Oc1ccc(Cl)cc1I
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OCC2=CCN(Cc3ccccc3)CC2)c(I)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-iodo-phenol 4b (20.32 g, 0.08 mol), (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol (20.5 g, 0.08 mol) and triphenylphosphine (23.58 g, 0.09 mol) in dry THF (150 mL) was added DEAD (17.4 g, 0.09 mol) at 0° C. under nitrogen atmosphere. After addition, the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness and the residue was basified by Na2CO3 solution (10% 100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with water (100 mL×2) and brine (200 mL), dried over Na2SO4, concentrated to dryness. The residue was purified by column on silica gel to afford 1-benzyl-4-(4-chloro-2-iodo-phenoxymethyl)-1,2,3,6-tetrahydro-pyridine 4c. 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J=2.4 Hz, 1H), 7.22-7.38 (m, 6H), 6.70 (d, J=8.8 Hz, 1H), 5.82 (s, 1H), 4.43 (s, 2H), 3.63 (s, 2H), 3.05 (s, 2H), 2.67 (t, J=5.6 Hz, 2H), 2.28 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:13]([CH3:18])=[N:14][O:15][C:16]=3[CH3:17])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[C:22]([C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH2:28])([CH3:25])([CH3:24])[CH3:23]>CC#N>[C:22]([C:26]1[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:13]([CH3:18])=[N:14][O:15][C:16]=3[CH3:17])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1noc(C)c1-c1ccc2c(Cl)c([N+](=O)[O-])cnc2c1
Reactant: CC(C)(C)c1ccccc1N
Solvent: CC#N
Product: Cc1noc(C)c1-c1ccc2c(Nc3ccccc3C(C)(C)C)c([N+](=O)[O-])cnc2c1
Yield: 80 %

Procedure:
A mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-3-nitroquinoline (for a preparation see Intermediate 16) (2.2 g, 7.2 mmol) and 2-tert-butylaniline (1.2 g, 8 mmol) in CH3CN (20 ml) was refluxed for 1 h. The solvent was evaporated in vacuo and the residue treated with an aqueous solution of sodium hydroxide N, extracted with DCM, washed with water and dried over Na2SO4. The residue was purified by chromatography on silica gel eluting with DCM/MeOH (99:1) to give the title compound as a yellow solid (2.4 g, 80%). [APCI-MS] m/z: 417 MH+, Rt 3.73 min. NMR (300 MHz, DMSO-d6, ppm) δ: 9.87 (brs, 1H), 8.92 (s, 1H), 8.34 (d, J=8.7 Hz, 1H), 7.82 (s, 1H), 7.50 (d, J=8.9 Hz, 1H), 7.25-6.91 (m, 4H), 2.32 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Si:12]([O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:7][CH:6]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)[Si](OCCCc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Yield: 94.2 %

Procedure:
A solution of 3(4-hydroxyphenyl)-1-(tert-butyldiphenylsilyloxy)propane (3.91 g, 10.0 mmol) and methyl bromoacetate (3.0 g, 19.7 mmol) in acetonitrile (100 ml) was treated with powdered anhydrous potassium carbonate (10 g) and the resulting mixture was heated under reflux for 1 hour. The cooled mixture was filtered and the filtrate was concentrated in vacuo. Chromatography of the residue on silica gel (elution toluene-ethyl acetate, 98:2) gave 4.36 g (94%) of the title material as clear oil.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH:4]([C:13]([OH:15])=O)[CH2:3]1.CC[N:18]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH:4]([C:13]([NH2:18])=[O:15])[CH2:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C1CC(=O)N(c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: NC(=O)C1CC(=O)N(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A 10 ml portion of a DMF solution of 500 mg of 5-oxo-1-phenylpyrrolidine-3-carboxylic acid was mixed with 935 mg of WSC hydrochloride, 396 mg of HOBt and 500 mg of(1R)-1-naphthylethylamine and stirred at room temperature for 3 days. After completion of the reaction, 100 ml of saturated sodium bicarbonate aqueous solution was added thereto, and the thus formed solid was collected by filtration to obtain 1.01 g of N-(1R)-1-(1-naphthyl)ethyl]-5-oxo-1-phenylpyrrolidine-3-carboxamide as a colorless solid. EP: 359.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30][S:39]([CH3:38])(=[O:41])=[O:40])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(CN(CCCCCCO)C(=O)Nc2ccc(Cl)cc2C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2ccc(Cl)cc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a cooled solution (0°-5° C.) of 5.24 g of 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-(6-hydroxyhexyl)urea and 4.0 ml of triethylamine in 65 ml of dichloromethane was added dropwise a solution of 1.2 ml of methanesulfonyl chloride in 10 ml of dichloromethane. The resulting solution was gradually warmed to room temperature, then was stirred for 16 hours. The procedure of Example 515 was continued and gave 6.0 g of the desired product as a light brown oil in 97% yield.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:8]=2)[CH:3]=1.[Mg].[C:18](=[S:20])=[S:19]>>[CH2:13]([S:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:18]([SH:20])=[S:19])[CH:11]=[CH:10]2)[CH2:14][CH2:15][CH3:16]
Reactant: S=C=S
Reactant: CCCCSc1ccc2cc(Br)ccc2c1
Agent: [Mg]
Product: CCCCSc1ccc2cc(C(=S)S)ccc2c1

Procedure:
Compound 12 (3.71 g, 0.013 mol), magnesium turnings (0.94 g, 0.039 mol), carbon disulphide (1.09 g, 0.014 mol). A purple solid was obtained.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:14]([C:15](OCC)=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([CH3:21])=[C:10]1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[F:29][C:30]([F:47])([F:46])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38](Cl)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[CH3:21][C:11]1[NH:12][C:13]2[CH:20]=[C:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[C:30]([F:47])([F:46])[F:29])[C:15](=[O:16])[C:14]=2[CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:28])([F:1])[F:27])[C:10]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: FC(F)(F)c1ccccc1N=C(Cl)c1ccccc1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1C(F)(F)F
Product: CCOC(=O)C1=C(C)Nc2cc(-c3ccccc3)n(-c3ccccc3C(F)(F)F)c(=O)c2C1c1ccccc1C(F)(F)F

Procedure:
This product is obtained using the procedure of Example 1 from diethyl 1,4-dihydro-4-(2-trifluoromethylphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate and N-(2-trifluoromethylphenyl)-benzimidoyl chloride (4.7 g, 15.5%).