Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[C:5]([F:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[CH2:26])=[CH:21][CH:20]=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[C:4](/[CH:26]=[CH:25]/[C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: OB(O)c1cc(Br)cnc1F
Reactant: C=Cc1ccc(F)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Fc1ccc(/C=C/c2cc(Br)cnc2F)cc1
Temperature: 25 °C
Yield: 31.5 %

Procedure:
To a 15 mL round bottom flask was added 5-bromo-2-fluoropyridin-3-ylboronic acid (895 mg, 4.07 mmol), sodium carbonate (863 mg, 8.14 mmol) and 1-fluoro-4-vinylbenzene (647 mg, 5.29 mmol) in dimethylformamide (8 mL). The solution was stirred at room temperature and the flask was purged with oxygen for 3 min. To the purged flask was quickly added palladium(II) acetate (91 mg, 0.407 mmol) and the reaction flask was again sealed and purged with oxygen for 15 min. The reaction mixture was then stirred at room temperature overnight. The next day the reaction was quenched with water and diluted with ethylacetate. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude oil was purified by silica gel chromatography eluting with 0% EtOAc/100% hexanes to 15% EtOAc/85% hexanes affording (E)-5-bromo-2-fluoro-3-(4-fluorostyryl)pyridine (380 mg, 1.283 mmol, 31.5% yield) as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 8.15 (s, 1H), 8.09 (dd, J=8.0, 2.0, 1H), 7.55-7.52 (m, 2H), 7.22 (d, J=16.0, 1H), 7.13-7.09 (m, 2H), 7.00 (d, J=16.0, 1H), LC/Mass spec. (Analytical HPLC method 2): RT=2.31 min. Mass=296.08 (MH)+.
Reaction SMILES: CN(C)C(=CC=C(C1C=CC=CC=1)C(OCC)=O)C(OCC)=S.F[B-](F)(F)F.[CH3:29][N:30]([CH3:42])[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=[N+](C)C.CC[O-].[Na+].[O:47]([C:54]1[CH:55]=[C:56]([CH:65]=[CH:66][CH:67]=1)[CH2:57][S:58][CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C(O)C>[CH3:29][N:30]([CH3:42])[C:31](=[CH:32][CH:33]=[C:59]([S:58][CH2:57][C:56]1[CH:65]=[CH:66][CH:67]=[C:54]([O:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:55]=1)[C:60]([O:62][CH2:63][CH3:64])=[O:61])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)CSCc1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)SCc1cccc(Oc2ccccc2)c1
Yield: 77.1 %

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetraflouroborate (5.7 g), a 2M ethanolic solution of sodium ethylate (10 cc) and ethyl (3-phenoxybenzylthio)acetate (6.1 g) in ethanol (50 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluent, diethyl 2-dimethylamino-5-(3-phenoxybenzylthio)-2,4-hexadienedioate (7 g) is obtained in the form of a yellow oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [CH3:1]/[C:2](=[CH:9]\[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2)/[C:3]([NH:5][CH2:6][CH2:7][CH3:8])=[O:4].Br[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32].C(OCC)(=O)C>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:32][O:31][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][C:21]=1[CH2:20][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10](/[CH:9]=[C:2](/[C:3](=[O:4])[NH:5][CH2:6][CH2:7][CH3:8])\[CH3:1])[CH:11]=2)[NH:15][CH:14]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: CCCNC(=O)/C(C)=C/c1ccc2[nH]ccc2c1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCNC(=O)/C(C)=C/c1ccc2[nH]cc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Yield: 53.3 %

Procedure:
A mixture of E-α-methyl-N-propylindol-5-acrylamide (1.75 g) and silver carbonate (1.99 g) in dry toluene (30 ml) was stirred and heated under reflux for 18 hr, under an atmosphere of nitrogen. The mixture was cooled to 80°, methyl 4-bromomethyl-3-methoxybenzoate (2.06 g) added, and the mixture stirred at 85° for 15 hours. The mixture was cooled, ethyl acetate (50 ml) added, the salts were removed by filtration through diatomaceous earth, the filter pad was washed with ethyl acetate, and the filtrate evaporated. The product was purified by flash chromatography, eluting with 5:2:3 hexane:methylene chloride:ethyl acetate, to give methyl E-3-methoxy-4-[5-[2-(propylcarbamoyl)-1-propenyl]indol-3-ylmethyl]benzoate (1.62 g, 53%) as a solid foam; mp 55°-60°; partial NMR (250 MHz, DMSO-d6): 0.87(t, 3H, CH2CH2CH3), 1.47(m, 2H, CH2CH2CH3), 1.99 (d, J=0.98 Hz, 3H, CCH3), 3.10(m, 2H, CH2CH2CH3), 3.82(s, 3H, OCH3), 3.91(s, 3H, OCH3), 4.05(s, 2H, ArCH2Ar'), 7.93(br t, NHCO), 11.0(br s, 1H, H1 -indole).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)=O.[C:22]([CH2:25][C:26](=O)[CH3:27])(=[O:24])[CH3:23].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:13]2[C:3]3[C:2](=[CH:7][CH:6]=[C:5]([O:8][C:9]([F:12])([F:11])[F:10])[CH:4]=3)[N:1]=[C:26]([CH3:27])[C:25]=2[C:22](=[O:24])[CH3:23])[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)c1cccc(Cl)c1
Reactant: CC(=O)CC(C)=O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(=O)c1c(C)nc2ccc(OC(F)(F)F)cc2c1-c1cccc(Cl)c1
Yield: 55 %

Procedure:
The title compound was prepared from (2-Amino-5-trifluoromethoxy-phenyl)-(3-chloro-phenyl)-methanone [example A7] and acetylacetone according to the procedure of example 1, except that the solvent was isopropanol, and heptane/ethyl acetate (1:2) was used. Yield: 55%; MS: m/z=380 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:9][CH2:8][CH2:7][O:6][C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: OCCOc1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(4-chlorophenoxy)ethanol (2.0 g, 11.6 mmol) in DCM (10 mL) was added Et3N (5 mL) and 4-methylbenzene-1-sulfonyl chloride (TsCl; 2.43 g, 12.8 mmol) sequentially. The reaction mixture was stirred at room temperature overnight and partitioned between water and ethyl acetate. The organic layer was washed with water, 5% sodium bicarbonate (NaHCO3), and brine and concentrated. The resulting residue was washed with hexane to afford the title compound quantitatively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:33])=[CH:27][CH:26]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1
Yield: 68 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) was dissolved in toluene (3 ml) with heat, 4-methoxyphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 30 minutes. The separated crystals were filtered and washed with toluene to obtain 54 mg of the title compound (yield: 68%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH:22]=O)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][O:25][CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].C(O)C>[CH3:24][O:25][CH2:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:22][C:16]1([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:15][CH:14]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: COC[C@@H]1CCCN1
Reactant: O=CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCO
Product: COC[C@@H]1CCCN1CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 71.8 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbaldehyde (350 mg, 1.103 mmol), (s)-(+)-2-(methoxymethyl)pyrrolidine (230 mg, 2.00 mmol), absolute ethanol (40 ml), activated 3 Å molecular sieves (350 mg), titanium (IV) isopropoxide (1.62 ml, 5.48 mmol) and STAB (2.09, 9.74 mmol) were reacted in accordance with the general procedure D. The isolated crude product was purified by column chromatography on silica eluting with DCM:MeOH:NH3 (98:1:1) to give the title compound as a white solid (330 mg, 72%). 1H NMR (400 MHz, CDCl3) δ7.18 (d, 2H), 6.86 (d, 2H), 4.02 (t, 2H), 3.84-3.70 (m, 2H), 3.59 (td, 1H), 3.45 (td, 1H), 3.27 (s, 3H), 3.10 (dd, 1H), 3.02 (dd, 1H), 2.94 (d, 1H), 2.63 (t, 2H), 2.59-2.45 (m, 5H), 2.39 (m, 1H), 2.21 (m, 1H), 2.06-1.34 (m, 15H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]([NH:22][NH2:23])=[O:21])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[C:24]([N:27]=[C:28]=[S:29])(=[O:26])[CH3:25]>ClCCCl>[NH2:1][C:2]1[C:3]([C:20]([NH:22][NH:23][C:28]([NH:27][C:24](=[O:26])[CH3:25])=[S:29])=[O:21])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:15])=[O:16])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Reactant: CC(=O)N=C=S
Solvent: ClCCCl
Product: CC(=O)NC(=S)NNC(=O)c1nc(-c2ccc(S(=O)(=O)C(C)C)cc2)cnc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-6-(4-isopropylsulfonylphenyl)pyrazine-2-carbohydrazide (100 mg, 0.2982 mmol), acetyl isothiocyanate (30.16 mg, 26.20 μL, 0.2982 mmol) and dry DCE (2.000 mL) were stirred at ambient temperature for 2 h and then concentrated in vacuo. Used directly in the next step without further purification; MS (ES+) 437.20
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][NH:14]2)=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[CH3:23])[N:9]=1.[Br:24]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:24][C:13]1[NH:14][C:15]2[C:11]([N:12]=1)=[C:10]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][C@H:18]1[CH3:23])[N:9]=[C:8]([N:3]1[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]1[CH3:1])[N:16]=2
Reactant: C[C@@H]1COCCN1c1nc(N2CCOC[C@@H]2C)nc2[nH]cnc12
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@@H]2C)nc2[nH]c(Br)nc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 46.4 %

Procedure:
2-((S)-3-Methyl-morpholin-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (786 mg, 2.47 mmol) were dissolved in CH2Cl2 (25 mL). Bromine (0.16 mL, 3.09 mmol) diluted in 2 mL of CH2Cl2 was added slowly within 2 minutes. The reaction mixture was stirred for 6 hours at room temperature. Aqueous Na2S2O3 (10 mL) was added to the reaction mixture, and stirring was continued for 15 minutes. The organic layer was washed with brine and aqueous NaHCO3. Drying over Na2SO4, filtering and concentration under reduced pressure gave a residue, which was purified by column chromatography (40 g SiO2, heptane/EtOAc in a gradient from 2/3 to 4/1) to give the product as a foam (455 mg, 46%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+:31]([C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH:36]=[O:37])([O-:33])=[O:32]>O1CCCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][CH:23]([CH:26]([CH:36]([OH:37])[C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[N+:31]([O-:33])=[O:32])[C:27]([O:29][CH3:30])=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CC1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C1CCN(Cc2ccccc2)CC1)C(O)c1ccccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Diisopropylamine (3.50 mL, 24.9 mmol) was dissolved in tetrahydrofuran (30 mL). The mixture was cooled to −78° C. Butyllithium (2.5 M in pentane, 9.8 mL, 24.5 mmol) was added to the mixture dropwise, and the reaction stirred at −78° C. for 15 min. A solution of methyl 2-(1-benzylpiperidin-4-yl)acetate (5.50 g, 22.2 mmol) in THF (8 mL) was then added to the mixture dropwise over 20 minutes. The reaction was stirred at −78° C. for 45 minutes. A solution of 2-nitrobenzaldehyde (3.70 g, 24.5 mmol) in THF (5 mL) was then added to the mixture dropwise over 15 minutes. The reaction was stirred at −78° C. for 30 minutes and quenched by the addition of saturated aqueous ammonium chloride. The resulting mixture was warmed to room temperature, extracted with ethyl acetate (2×). The combined organics were dried (magnesium sulfate), filtered, and concentrated. Silica gel chromatography afforded the desired product in 89% yield as light yellow foam. Mass spec.: 399.3 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4](F)[CH:3]=1.CN([CH:16]=[O:17])C.C[O-].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([O:17][CH3:16])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Product: COc1cc(Br)ccc1C(F)(F)F
Temperature: 0 °C
Yield: 45.5 %

Procedure:
To a 250 mL round-bottomed flask was added 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (12 mL, 50 mmol) and DMF (4.0 mL, 50 mmol). The solution was stirred at 0° C. and treated with sodium methoxide (4 g, 75 mmol). The reaction mixture was stirred at room temperature for 30 minutes and 60° C. for 2 hours. The resulting milky suspension was quenched with ice at 0° C. and the separated aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with saturated sodium chloride (1×25 mL), dried over Na2SO4, and concentrated to give the crude residue which was purified with flash column chromatography ((5%→20% EtOAc in hexane) to provide 4-bromo-2-methoxy-1-(trifluoromethyl)benzene (5.80 g, 46% yield) as a light yellow oil. m/z (%): 256.1.2 (100%, M++H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:20])[CH3:19])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br-:21].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:18](=[O:20])[CH2:19][Br:21])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)CBr)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1.40 g (5.09 mmol) 6-acetyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (preparation 29b) in 20 mL THF is added a solution of 2.45 g (5.09 mmol) tetrabutylammonium-tribromide in MeOH/THF at RT. The reaction mixture is stirred 30 min at RT and the solvent is evaporated. The residue is treated with water and 1 M aqueous HCl-solution and the aqueous phase is extracted with tert-butylmethylether. The organic phase is washed with water and 1 M aqueous HCl-solution, dried over MgSO4, filtered and the solvent is evaporated. The residue is purified by silica gel column chromatography with PE/EtOAc (7:3) as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:31])[C:18]([N:20]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[CH:26])=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:32][CH3:33].[OH-].[K+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:31])[C:18]([N:20]([C:27]([CH3:29])([CH3:30])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][C:25]#[CH:26])=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:32][CH3:33]
Reactant: C#CCCCCN(C(=O)C(=O)N1CCc2cc(OC)c(Br)cc2C1C(=O)OCC)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C#CCCCCN(C(=O)C(=O)N1CCc2cc(OC)c(Br)cc2C1C(=O)O)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A solution of 480 mg of 19b in 10 ml of dioxane was mixed with 200 mg of KOH in 2 ml of water. The mixture was stirred at rt for 3 h and then diluted with 40 ml of water and acidified to pH 3 with 0.5 N HCl. The product was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated, to provide 420 mg of 19c as white amorphous material; MS-ESI: [M+1] 495.19 and 493.18. NMR (CDCl3) δ 1.43 (m, 2, CH2), 1.53 (s, 9, tertC4H9), 1.68-1.90 (bm, 2, CH2), 1.92 (t, 1, CH), 2.16 (m, 2, CH2), 2.80-3.00 (bm, 2, CH2), 3.22-3.45 (bm, 2, CH2), 3.68 (m, 2, CH2), 3.88 (s, 3, OCH3), 5.74 (s, 1, CH), 6.65 (s, 1, ArH), 7.73 (s, 1, ArH).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][NH:4][C:3]1=[S:13].Br[CH2:15][CH2:16][CH2:17][Cl:18].C(O)(=O)C>C(O)C>[Cl:18][CH2:17][CH2:16][CH2:15][S:13][C:3]1[N:2]([CH3:1])[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]=1
Reactant: Cn1c(-c2cccnc2)n[nH]c1=S
Reactant: ClCCCBr
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c(SCCCCl)nnc1-c1cccnc1
Temperature: 90 °C

Procedure:
To 4-methyl-5-(3-pyridinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.4 g, preparation reported in WO 02/40471) in ethanol (6 ml) sodium ethanolate (0.85 ml) was carefully added with stirring followed by 1-bromo-3-chloropropane (0.31 ml). The mixture was heated at 90° C. for 1 h. Acetic acid was added at room temperature until pH=4. After elimination of the solvent under reduced pressure the residue was partitioned between aqueous NaHCO3 (saturated) and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated and submitted to column chromatography (EtOAc—acetone gradient) to provide the title compound as white solid (0.360 g).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]#[C:6][C:7]([CH3:10])([CH3:9])[CH3:8].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[OH:24].C1(O)C=CC=CC=1>[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:3]=1[O:4][C:5]([O:24][C:18]1[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:17]=1[Cl:16])=[CH:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)C#COc1ccc(Cl)cc1Cl
Reactant: Oc1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Oc1ccccc1
Product: CC(C)(C)C=C(Oc1ccc(Cl)cc1Cl)Oc1ccc(Cl)cc1Cl
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
24.3 g (0.1 mole) of 1-(2,4-dichlorophenoxy)-3,3-dimethylbut-1-yne were initially taken together with 16.3 g (0.1 mole) of 2,4-dichlorophenol and 1.4 g (0.01 mole) of zinc chloride, and the stirred mixture was heated at 160° C. After 30 minutes, the phenol had reacted quantitatively with the phenoxyalkyne to give 1,1-bis-(2,4-dichlorophenoxy)-3,3-dimethylbut-1-ene.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:4].Cl.[NH2:31][OH:32].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:32][NH:31][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:11][CH2:12][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)(=[O:17])=[O:18])[CH2:14][CH2:15]2)=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)s1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NO)c1cnc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound (12d) (125 mg, 0.276 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (191 mg, 2.76 mmol) and a freshly prepared solution of sodium methoxide in methanol (95 mg, 4.14 mmol of sodium dissolved in 1 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethyl acetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethyl acetate (5 mL) and the combined organic layers were dried on sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13d as a solid. HPLC: =92% (Rt=14.16 min).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH:18]=[C:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].O1CCOC[CH2:23]1.COC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[CH3:23][O:20][C:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10](=[CH:9][CH2:8][C@@H:7]3[C:17]2=[CH:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C:3]2=[O:21])[CH:11]=1
Reactant: C1COCCO1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: c1ccncc1
Product: COC1=CC2=CC[C@@H]3C(=CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Reaction time: 48 h

Procedure:
11.5 g of 4,9(11)-androstadiene-3,17-dione [U.S. Pat. No. 3,441,559 (1969)]in 200 ml of dioxane is reacted with 20 ml of orthoformic acid trimethyl ester and 100 mg of p-toluenesulfonic acid. After 48 hours, 5 ml of pyridine is added to the solution, the latter is concentrated under vacuum, the residue taken up in ethyl acetate, washed with water, and dried over sodium sulfate. After chromatography of the crude product with a hexane-ethyl acetate gradient on silica gel containing 2% triethylamine, 9.2 g of 3-methoxy-3,5,9(11)-androstatrien-17-one is isolated; mp 153.4° C.
Reaction SMILES: [CH:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:13][CH2:14][C:15](=[O:19])[NH:16][C:17]=2[N:18]=1)=CC1C=CC=CC=1.BrC1C=CC2[O:25]CC(=O)NC=2N=1.C1(/C=C/B(O)O)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=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>[O:19]=[C:15]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]([CH:1]=[O:25])=[N:18][C:17]=2[NH:16]1
Reactant: O=C1COc2ccc(Br)nc2N1
Reactant: O=C1COc2ccc(C=Cc3ccccc3)nc2N1
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: OB(O)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc2c(n1)NC(=O)CO2
Temperature: 25 °C
Yield: 43 %

Procedure:
6-Styryl-4H-pyrido[3,2-b][1,4]oxazin-3-one. To a solution of 6-bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (3.2 g, 14 mmol) in 1,4-dioxane (80 mL) was added trans-2-phenylvinylboronic acid (2.1 g, 14 mmol). After the reaction mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium(0) (0.129 g, 0.112 mmol) and a solution of K2CO3 (3.7 g, 27 mmol) in H2O (10.7 mL) were added. The reaction was heated at reflux for 17 h, then cooled to RT, and diluted with EtOAc (300 mL). The organic layer was separated, washed with H2O (300 mL), brine (300 mL), dried (Na2SO4), and concentrated. The solid residue was purified on SiO2 (5-10% EtOAc/CHCl3) to provide 1.5 g (43%) of the title compound as a solid. MS (ESI): exact mass calculated for C15H12N2O2, 252.09; m/z found, 253.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.53-7.00 (m, 9H), 4.66 (d, J=6.9, 2H).