Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][C:21]([C:27](O)=[O:28])=[CH:20][C:19]=3[CH:30]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH2:31][C:32]1[CH:45]=[CH:44][C:35]([CH2:36][P:37]2(=[O:43])[O:42][CH2:41][CH2:40][CH2:39][O:38]2)=[CH:34][CH:33]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[S:24](=[O:25])(=[O:26])[CH2:23][CH2:22][C:21]([C:27]([NH:31][C:32]4[CH:45]=[CH:44][C:35]([CH2:36][P:37]5(=[O:43])[O:38][CH2:39][CH2:40][CH2:41][O:42]5)=[CH:34][CH:33]=4)=[O:28])=[CH:20][C:19]=3[CH:30]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccc(CP2(=O)OCCCO2)cc1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CP4(=O)OCCCO4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
In DMF (8 ml) were dissolved 7-(4-(2-butoxyethoxy)phenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (0.4 g), 2-(4-aminobenzyl)-1,3,2-dioxaphosphorinane-2-oxide (0.22 g) and 1-hydroxybenzotriazole (0.13 g), and to the solution were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.36 g) and triethylamine (0.4 ml). Under nitrogen atmosphere, the mixture was stirred at room temperature overnight, poured into water and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated to give crude crystals, which were recrystallized from ethanol to give 2-(4-(7-(4-(2-butoxyethoxy)phenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carbonylamino) benzyl)-1,3,2-dioxaphosphorinane-2-oxide (Compound 156) (0.40 g) as colorless crystals.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[S:13]([Cl:17])(=[O:16])(=[O:15])[NH2:14].ClS(N=C=O)(=O)=O.C(N(CC)CC)C>C(#N)C>[ClH:17].[N:1]1([C:6]2[CH:7]=[C:8]([O:12][S:13](=[O:16])(=[O:15])[NH2:14])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NS(=O)(=O)Cl
Reactant: Oc1cccc(-n2ccnc2)c1
Agent: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cl
Product: NS(=O)(=O)Oc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(1H-imidazol-1-yl)phenol (8 g, 0.05 mole) in acetonitrile was treated in an ice bath with sulfamoyl chloride generated from 0.075 mole of chlorosulfonyl isocyanate followed by 0.075 mole of triethylamine. After stirring overnight at room temperature, TLC, and 1H NMR of a sample showed starting material still present. The reaction was then treated with another 0.075 mole each of sulfamoyl chloride and triethylamine for another night.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])[CH2:7][C@@H:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]([C:41]([OH:44])([CH3:43])[CH3:42])[CH:38]=[CH:39][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O>[OH:44][C:41]([C:37]1[CH:36]=[C:35]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH2:12][C:13]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:14])[CH2:7][C@@H:6]4[CH2:23][O:24][CH2:25][CH2:26][N:5]4[C:4]=3[N:3]=2)[CH:40]=[CH:39][CH:38]=1)([CH3:43])[CH3:42]
Reactant: CC(C)(O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)c1cccc(-c2ncc3c(n2)N2CCOC[C@H]2CN3CC(=O)NCC2CCOCC2)c1
Temperature: 120 °C
Yield: 68.7 %

Procedure:
A mixture of (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (PREPARATION x26, 50 mg, 0.131 mmol), 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol (51.5 mg, 0.196 mmol), tetrakis(triphenylphospine)palladium (0) (15.13 mg, 0.013 mmol) and sodium carbonate (27.8 mg, 0.262 mmol) in 1,4-dioxane (0.5 mL) and H2O (0.25 mL) was heated to 120° C. in a microwave for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (amine-functionalized silica, 0-10% MeOH gradient in CHCl3) to afford the title compound as an off-white solid (43.4 mg, 0.090 mmol, 68.8%). 1H NMR (400 MHz, DMSO-d6) δ 1.06-1.26 (m, 2H), 1.45 (s, 6H), 1.48-1.71 (m, 3H), 2.91-3.05 (m, 3H), 3.11-3.36 (m, 5H), 3.50-3.67 (m, 2H), 3.73-3.93 (m, 4H), 3.96-4.09 (m, 2H), 4.56 (d, J=11.87 Hz, 1H), 5.04 (s, 1H), 7.31 (t, J=7.71 Hz, 1H), 7.40-7.47 (m, 1H), 7.51 (s, 1H), 7.99-8.12 (m, 2H), 8.34 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C26H35N5O4, 481.27. found 482.4.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=2)=[N:13][C:14]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[O:16].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.ON1C2C=CC=CC=2N=N1.[CH3:65][O:66][CH2:67][C@@H:68]([NH2:70])[CH3:69].C(Cl)[Cl:72].CO>>[ClH:72].[NH2:8][C:9]1[C:14]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:16])=[N:13][C:12]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH:70][C@@H:68]([CH3:69])[CH2:67][O:66][CH3:65])=[O:30])=[CH:26][CH:25]=2)=[CH:11][N:10]=1
Reactant: Nc1ncc(-c2ccc(C(=O)O)cc2)nc1C(=O)Nc1cccnc1
Reactant: ClCCl
Reactant: COC[C@H](C)N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CO
Product: COC[C@H](C)NC(=O)c1ccc(-c2cnc(N)c(C(=O)Nc3cccnc3)n2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29 %

Procedure:
Triethylamine (0.12 mL, 0.89 mmol) was added to a mixture of 4-{5-amino-6-[(pyridin-3-ylamino)carbonyl]pyrazin-2-yl}benzoic acid (100 mg, 0.30 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.105 g, 0.33 mmol) and 1-hydroxybenzotriazole (44 mg, 0.33 mmol) in methylene chloride/methanol (9:1, 10 mL) at room temperature. (S)-(+)-1-methoxy-2-propylamine was added dropwise and the resulting mixture was stirred at room temperature for 1.5 h. The mixture was evaporated onto silica and purified by chromatography on silica using toluene/acetonitrile, (2:1 to 0:1) as the eluent. The formed yellow solid was dissolved in methylene chloride. Hydrochloride acid in diethyl ether (0.4 mL, 1 M) was added and the mixture was stirred at room temperature. The precipitated product was filtrated off and dried in vacuo at 40° C. giving 39 mg (29% yield) of the product as a yellow solid. 1H NMR (DMSO-d6) δ 9.38 (m, 1H), 9.08 (s, 1H), 8.85 (d, J=9 Hz, 1H), 8.67 (d, J=5 Hz, 1H), 8.36 (d, J=8 Hz, 2H), 8.32 (d, J=8 Hz, 2H), 8.03 (m, J=6 Hz, 1H), 7.99 (d, J=8 Hz, 2H), 7.80 (br s, 1H), 4.23 (m, 1H), 3.45 (m, 1H), 3.32 (m, 1H), 3.29 (s, 3H), 1.17 (d, J=7 Hz, 3H); 13C NMR (D2O) δ 165.8, 165.5, 154.9, 146.3, 138.2, 138.1, 137.5, 135.6, 134.3, 128.0, 126.9, 125.6, 123.0, 75.3, 58.4, 44.8, 17.6; MS (ESP) m/z 407 (M++1).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1.[CH2:13](Br)[C:14]#[CH:15].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[CH3:1][N:2]([CH2:15][C:14]#[CH:13])[CH:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: CNC1CCCc2cccnc21
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCN(C)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-methyl-5,6,7,8-tetrahydroquinolin-8-amine, 5, (0.50 g, 3.08 mmol) in THF (15 mL) was added propargyl bromide (0.28 mL, 3.08 mmol), sodium iodide (0.05 g, 0.31 mmol) and sodium carbonate (0.98 g, 9.24 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was diluted with water, extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude solid was used without further purification: 1H NMR (d6-DMSO) δ 8.30 (d, J=4.4 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 7.13 (dd, J=8.0, 5.2 Hz, 1H), 3.74 (dd, J=4.8, 4.8 Hz, 1H), 3.47 (ddd, J=16.8, 2.4, 2.4 Hz, 2H), 3.06 (s, 1H), 2.80-2.60 (m, 2H), 2.12 (s, 3H), 2.12-1.87 (m, 2H), 1.74-1.68 (m, 1H), 1.62-1.55 (m, 1H); ESI+ MS: m/z (rel intensity) 201.1 (100, [M+H]+).
Reaction SMILES: O[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=O)[C:3]=1C.[CH:10](OC)(OC)[O:11][CH3:12].S(=O)(=O)(O)O.S(O)(O)(=O)=O.[NH2:27][OH:28].C(=O)(O)[O-].[Na+]>CO>[CH3:12][O:11][C:10]1[CH2:6][CH2:5][CH2:4][C:3](=[N:27][OH:28])[C:2]=1[CH3:7]
Reactant: CC1=C(O)CCCC1=O
Reactant: COC(OC)OC
Reactant: NO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC1=C(C)C(=NO)CCC1
Temperature: 40 °C
Reaction time: 2.25 h
Yield: 91.1 %

Procedure:
3-Hydroxy-2-methyl-cyclohex-2-enone (500 g, 3.96 mol) is added to a mechanically stirred reactor. To this is added methanol (1.35 L) followed by trimethyl orthoformate (1.65 L, 15.85 mol, 4 eq) and sulfuric acid (15 mL). The resulting mixture is stirred for 2 h until completion and hydroxylamine sulfate (275 g, 3.96 mol, 1 eq) is added as a solid. The mixture is heated to 40° C. and stirred at that temperature until complete conversion (2-2.5 h). The solution is then cooled to 5° C. and the pH is adjusted to 7 with saturated sodium bicarbonate (˜3 L). The precipitate formed is collected by filtration (filter 10 cm diameter, 1.5 cm cake thickness, <3 min total filtration time), rinsed with heptane (400 mL) and dried under nitrogen flow for 4-6 h to provide 560 g (92% yield) of 3-methoxy-2-methyl-cyclohex-2-enone oxime.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl.[CH3:26][C:27]1[N:28]=[C:29]([CH3:56])[N:30]2[C:35]=1[C:34]([O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[C:40]([O:45][CH3:46])=[C:39]([O:47][CH3:48])[CH:38]=1)=[N:33][C:32]([C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][CH:50]=1)=[N:31]2>ClCCl>[CH3:26][C:27]1[N:28]=[C:29]([CH3:56])[N:30]2[C:35]=1[C:34]([O:36][C:37]1[CH:38]=[C:39]([O:47][CH3:48])[C:40]([O:45][CH3:46])=[C:41]([O:43][CH3:44])[CH:42]=1)=[N:33][C:32]([C:49]1[CH:50]=[CH:51][C:52]([NH:53][C:1](=[O:4])[CH3:2])=[CH:54][CH:55]=1)=[N:31]2
Reactant: COc1cc(Oc2nc(-c3ccc(N)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Reactant: CC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COc1cc(Oc2nc(-c3ccc(NC(C)=O)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 10 mg (0.09 mmol) of acetic acid in dichloromethane is treated with 10 mg (0.09 mmol) of HOBt and 20 mg (0.21 mmol) of 4-methylmorpholine. The mixture is cooled to −20° C. and treated with 20 mg (0.09 mmol) of EDC. It is stirred for 30 min. Subsequently, 30 mg (0.07 mmol) of 4-[5,7-dimethyl-4-(3,4,5-tri-methoxyphenoxy)imidazo[5,1-f][1,2,4]triazin-2-yl]aniline from example 1 are added thereto at −20° C., and the mixture is stirred for 5 h at 20° C. The solution is then washed with aqueous 1 N potassium hydrogensulfate solution and saturated aqueous sodium hydrogencarbonate solution. The organic phase is dried and concentrated under reduced pressure. The residue is purified by flash chromatography (eluent:dichloromethane/methanol 100:1-80:1-60:1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6](NC)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:13]([N:16](C(C)C)CC)(C)C.[C:22]([O:26][C:27](=[O:47])[NH:28][CH:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH:36][C:37]2[C:42]([N+:43]([O-:45])=[O:44])=[CH:41][N:40]=[C:39](Cl)[N:38]=2)[CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23]>CN(C=O)C.C(#N)C.C(OCC)(=O)C>[C:22]([O:26][C:27](=[O:47])[NH:28][CH:29]1[CH2:34][CH2:33][CH:32]([CH2:35][NH:36][C:37]2[C:42]([N+:43]([O-:45])=[O:44])=[CH:41][N:40]=[C:39]([NH:16][CH2:13][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][CH:2]=[N:1]4)[N:38]=2)[CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CNc1cccc2ncccc12
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(Cl)ncc2[N+](=O)[O-])CC1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3cccc4ncccc34)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.5 %

Procedure:
To a solution of quinolin-5-yl-methylamine 100 mg, 0.39 mmol) and diisopropylethylamine (140 μL, 0.78 mmol) in a mixture of DMF (2 mL) and acetonitrile (2 mL) was added {4-[(2-chloro-5-nitro-pyrimidin-4-ylamino)-methyl]-cyclohexyl}-carbamic acid tert-butyl ester (150 mg, 0.39 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water (×2). The combined organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 95:5 CH2Cl2:MeOH as an eluent to afford 197 mg of [4-({5-nitro-2-[(quinolin-5-ylmethyl)-amino]-pyrimidin-4-ylamino}-methyl)-cyclohexyl]-carbamic acid tert-butyl ester as a light yellow solid (100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])=[N:10][C:9]=2[C:19](N(OC)C)=[O:20])[CH:5]=[CH:6][CH:7]=1.[CH3:25][Mg]Br>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH3:18])=[N:10][C:9]=2[C:19](=[O:20])[CH3:25])[CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)c1nc(C)c2ccccc2c1-c1cccc(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1nc(C)c2ccccc2c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of 4-(3-fluorophenyl)-N-methoxy-N,1-dimethylisoquinoline-3-carboxamide (257 mg, 0.792 mmol) in tetrahydrofuran (1 mL) was added 1.4 M methylmagnesium bromide in tetrahydrofuran (3.4 mL, 4.8 mmol). The reaction was stirred at room temperature overnight, quenched with sat. ammonium chloride, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated to dryness to afford the desired product (0.221 g, 100%). LCMS calculated for C18H15FNO (M+H)+: m/z=280.1; Found: 280.1.
Reaction SMILES: [CH2:1]([SH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:12]([C:14]1OCC[N:18]=1)C.[ClH:19]>[Cl-].[Zn+2].[Cl-]>[ClH:19].[CH2:1]([S:11][CH2:12][CH2:14][NH2:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCS
Reactant: CCC1=NCCO1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: CCCCCCCCCCSCCN
Temperature: 140 °C

Procedure:
Approximately 225 pounds of decylmercaptan are loaded into a jacketed reactor equipped with an agitator. 1.25 pounds of zinc chloride catalyst are added through the manhole. The system is heated to approximately 140° C. and 130 pounds of 2-ethyl-2-oxazoline are added at the rate of 3 lbs/min in about 45 minutes. About 30 minutes are allowed for the reaction to be completed, the reactor cooled to approximately 120° C. and 155 pounds of 32 weight percent hydrochloric acid are then added to the reaction mixture. The reactor is heated to 150°-160° C., at which time the vapor pressure of the system is approximately 60 psi. The temperature is maintained near 150° C. for 2 hours to complete the hydrolysis.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([S:8][CH:9]([C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])C=3)[CH:14]=[C:13]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:12]=2)C)=[N:5][N:4]=1)[CH3:2].C(Br)C1C=CC=CC=1.ClCC1[N:53]=C(C(OCC)=O)C=CC=1>>[CH2:1]([C:3]1[S:7][C:6]([S:8][CH2:9][C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26]([O:28][CH2:29][CH:30]=[CH2:31])=[O:27])[N:53]=3)[CH:14]=[C:13]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)[CH:12]=2)=[N:5][N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(CCl)n1
Reactant: C=CCOC(=O)Nc1cccc(CNc2cc(N3CCOCC3)cc(C(C)Sc3nnc(CC)s3)n2)c1
Agent: BrCc1ccccc1
Product: C=CCOC(=O)Nc1cccc(CNc2cc(N3CCOCC3)cc(CSc3nnc(CC)s3)n2)n1

Procedure:
The above identified compound was obtained as a pale yellow solid in the same manner as in Example 1-(6), Example 4-(2) and (3) and Example 1-(7) except that benzyl bromide was changed to ethyl 6-chloromethylpyridine-2-carboxylate.
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:27])[C@:4]1([O:24]C=O)[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.C(=O)(O)[O-].[K+]>CO.O.C(OCC)(=O)C>[Br:1][CH2:2][C:3](=[O:27])[C@:4]1([OH:24])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(OC=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CBr
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Under argon, 4.0 g of 21-bromo-17-formyloxy-1,4-pregnadiene-3,20-dione is agitated in a mixture of 150 ml of methanol and 24 ml of water with 1.3 g of potassium bicarbonate at room temperature. After one hour, the reaction mixture is introduced into ice water, the precipitated product is suctioned off, dissolved in ethyl acetate, washed with water, and dried over sodium sulfate, yielding 3.2 g of 21-bromo-17-hydroxy-1,4-pregnadiene-3,20-dione, mp 189.9° C. (decomposition).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(=O)C)=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].[C:15](OCC)(=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].[O-]CC.[Na+].Cl>C(O)C.O>[NH2:10][C:7]1[CH:6]=[C:5]2[C:4]([C:1](=[O:3])[CH:2]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:14]2)=[CH:9][CH:8]=1
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2ccc(N)cc2o1
Temperature: 25 °C
Yield: 61 %

Procedure:
A solution of N-(4-acetyl-3-hydroxyphenyl)acetamide (4.00 g., 21 mmol) and diethyl oxalate (7.3 mL, 54 mmol) in absolute ethanol is added dropwise to a solution of sodium ethoxide (0.1 mol) in absolute ethanol. The mixture is heated at reflux temperature for 1.5 h, cooled to ambient temperature, poured into water, acidified to pH 3 with 6N HCl and extracted with ethyl acetate. The extracts are combined and concentrated in vacuo to afford an oily residue. The residue is dissolved in ethanol, treated with concentrated HCl heated at reflux temperature overnight, cooled to 0° C. for several hours and filtered. The filtercake is dried to afford the title compound as an orange solid, 2.95 g (61% yield), mp 195°-198° C., identified by NMR and mass spectral analyses.
Reaction SMILES: C([O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([I:18])=[CH:16][C:15]([CH2:19][CH3:20])=[CH:14][C:13]=1[CH:21]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C1C=CC=CC=1.I[Si](C)(C)C.C(O)C>ClCCl>[C:34]([C:31]1[CH:32]=[CH:33][C:28]([NH:27][CH:21]([C:13]2[CH:14]=[C:15]([CH2:19][CH3:20])[CH:16]=[C:17]([I:18])[C:12]=2[O:11][CH2:10][CH2:9][OH:8])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:29][CH:30]=1)#[N:35]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(I)c1OCCOCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(CC)cc(I)c1OCCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
A solution of 7.1 g of ethyl (RS)-[2-(2-benzyloxy-ethoxy)-5-ethyl-3-iodo-phenyl]-(4-cyano-phenylamino)-acetate in 50 ml of dichloromethane was treated with 7.29 g of iodotrimethylsilane. After 12 hours at room temperature the same amount of iodotrimethylsilane was added and the mixture was stirred for 18 hours at room temperature. Then, ethanol was added. The reaction mixture was concentrated, poured on to ice/aqueous sodium bisulphite solution and extracted with ethyl acetate. The organic phases were washed with aqueous sodium hydrogen carbonate solution and ice-water, dried over sodium sulphate and concentrated. Crystallization of the residue gave 3.8 g of ethyl (RS)-(4-cyano-phenylamino)-[5-ethyl-2-(2-hydroxy-ethoxy)-3-iodo-phenyl]-acetate. Chromatography of the mother liquor on silica gel gave an additional 1.83 g of product; MS (ISP) m/z 495 (M+H)+, 517 (M+Na)+.
Reaction SMILES: C1(C(C)C)C=CC=CC=1.[Na].[O-]O.C1(C(C)C)C=CC=CC=1.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[C:30]1([CH2:36][CH2:37][C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH3:40])[CH3:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CO>[C:24]1([CH2:23][CH2:22][CH:36]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:37][C:38]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)([CH3:40])[CH3:39])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(CCc1ccccc1)c1ccccc1
Reactant: C=Cc1ccccc1
Agent: [Na]
Agent: [O-]O
Solvent: CO
Solvent: CC(C)c1ccccc1
Product: CC(C)(CC(CCc1ccccc1)c1ccccc1)c1ccccc1
Temperature: 135 °C
Reaction time: 2 h
Yield: 35.5 %

Procedure:
A one-liter glass flask equipped with a stirrer, a dropping funnel with a gas introduction conduit, a reflux condenser with a calcium chloride tube, and a thermometer was charged with 240 grams (2.0 moles) of purified cumene, 4.0 grams (0.17 mole) of metallic sodium, and 3.6 grams (0.02 mole) of 80% cumene hydroperoxide while introducing argon gas through the gas introduction conduit, and the resulting mixture was heated to 135° C. A mixture of 69 grams (0.66 mole) of purified styrene and 60 grams (0.50 mole) of purified cumene was dropped thereto with stirring over 2 hours while maintaining the temperature of the reaction system at 135°-140° C. After dropwise addition was completed, the reaction mixture was further stirred while heating for 1 hour and then cooled to room temperature. An excess of metallic sodium was decomposed by dropping methanol in small portions while stirring. Introduction of argon gas was stopped, and the contents were transferred to a separating funnel and washed with water. The aqueous layer was removed, and the remaining oily layer was analyzed by gas chromatography. This gas chromatographic analysis showed that 67.6 grams (0.31 mole) of 1,3-diphenyl-3-methylbutane and 36.5 grams of (0.11 mole) of 1,3,5-triphenyl-5-methylhexane were formed. The total yield (per styrene) was 80 mole %.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:20](C(Cl)=O)=[CH:21][CH:22]=[CH:23][CH:24]=1.[CH2:34]([C:36]1[S:40][C:39]([NH2:41])=[N:38][N:37]=1)[CH3:35]>>[C:28]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:29]=[CH:30][C:31]([C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]2[C:16]([NH:41][C:39]2[S:40][C:36]([CH2:34][CH3:35])=[N:37][N:38]=2)=[O:18])=[O:7])=[CH:32][CH:33]=1
Reactant: CCc1nnc(N)s1
Reactant: O=C(Cl)c1ccccc1-c1ccccc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCc1nnc(NC(=O)[C@@H]2CC(=NOC)CN2C(=O)c2ccc(-c3ccccc3)cc2)s1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]carbonyl chloride, and 5-ethyl-1,3,4-thiadiazol-2-amine the title compound was obtained in 89% purity by LC/MS. MS(ESI+): m/z=450.2.