Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:15])[CH:12]=2)[CH2:7][N:6]1[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[OH:24])=[O:4].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][CH2:39][CH3:40]>CCOC(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Br:15])[CH:12]=2)[CH2:7][N:6]1[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[O:24][CH2:38][CH2:39][CH3:40])=[O:4]
Reactant: COC(=O)C1Cc2cc(Br)ccc2CN1C(=O)c1cccc(C)c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1c(C)cccc1C(=O)N1Cc2ccc(Br)cc2CC1C(=O)OC
Temperature: 79 °C
Reaction time: 16 h
Yield: 101 %

Procedure:
A 100 mL round bottom flask which contains 6-bromo-(2-hydroxoxy-3-methyl-benzoylamino)-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid methyl ester (373, 0.39 g, 0.932 mmol) and a stirring bar is charged with dry DMF (10 mL). Stirring is initiated. K2SO4 (0.258 g, 1.86 mmol), KI (1 mg, 6 μM), and 1-bromopropane (0.2 mL, 2.24 mmol) are added in turn. The reaction flask is immersed in an oil bath and fitted with a reflux condenser. The oil bath is heated to 79° C. The reaction is stirred for 2 h at this temperature then the oil bath is turned off. After 16 h at ambient temperature, heating is reinitiated at 53° C. for an additional hour. Analysis by ttlc (silica, 1:1 EtOAc:Heptanes), indicates consumption of starting material and appearance of a spot with a slightly lower Rf. The reaction is again allowed to cool to ambient temperature and filtered through a bed of Celite. The resulting solution is diluted with EtOAc (60 mL) and washed repeatedly with brine (4×40 mL), and then dried over MgSO4, filtered and evaporated by pumping to a constant weight yields light yellow oil (0.42 g, 98%).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[O:7]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:28]3[C:27]([NH2:29])=[N:26][CH:25]=[N:24][C:23]=3[NH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C)C=O>N1C=CC=CC=1>[C:1]([N:22]1[C:23]2[N:24]=[CH:25][N:26]=[C:27]([NH2:29])[C:28]=2[C:20]([C:17]2[CH:16]=[CH:15][C:14]([O:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:19][CH:18]=2)=[CH:21]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)C(=O)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21
Temperature: 20 °C

Procedure:
Isobutyryl chloride (1.8 g) was added dropwise to a mixture of 5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (4.32 g), dry dimethyl-formamide (200 ml) and dry pyridine (2 ml) with stirring under nitrogen at 20° C. The mixture was stirred at ambient temperature for 1 hour and evaporated under vacuum. The residue was partitioned between water and ethyl acetate. The ethyl acetate was separated, dried and evaporated and the residue obtained was recrystallised from toluene to give 7-isobutyryl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 160.5-161° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[C:26](Cl)(=[O:28])[CH3:27].O>ClC(Cl)C>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:26](=[O:28])[CH3:27])[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=1
Reactant: Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Solvent: O
Product: CC(=O)Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Reaction time: 0.17 h

Procedure:
To 0.2 g of (3-amino-5-bromo-phenyl)-pyridin-3-yl-methanone in 10 mL of dichloroethane was added 0.126 mL of diisopropyl ethyl amine and 0.051 mL of acetyl chloride. The reaction mixture was stirred for 10 minutes then poured into water and extracted twice with CH2Cl2. The organic phase was dried over sodium sulfate, filtered and and concentrated to give 154 mg of N-[3-bromo-5-(pyridine-3-carbonyl)-phenyl]-acetamide, which was used without further purification. 1H NMR (400 MHz, methanol-d4/CDCl3): δ 8.89 (d, J=2.0 Hz, 1H), 8.76 (dd, J=4.9, 1.6 Hz, 1H), 8.17 (dt, J=4.9, 2.7 Hz, 1H), 8.11 (t, J=1.8 Hz, 1H), 7.90 (t, J=1.6 Hz, 1H), 7.61-7.55 (m, 2H), 2.11 (s, 3H).
Reaction SMILES: [N:1]1[N:5]2[C:6]3[C:11]([C:12](O)=[CH:13][C:4]2=[N:3][N:2]=1)=[CH:10][CH:9]=[CH:8][N:7]=3.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:12]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[N:1]=[N:2][N:3]=[C:4]2[CH:13]=1
Reactant: Oc1cc2nnnn2c2ncccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc2nnnn2c2ncccc12

Procedure:
Tetrazolo[1,5-a][1,8]naphthyridin-5-ol (0.5 g, 2.67 mmole) was suspended in phosphorous oxychloride (10 mL) and heated at reflux for 4 hours. The reaction mixture was concentrated under vacuum and the residue was poured into water. Dichloromethane was added and the aqueous layer was made basic with sodium bicarbonate. The dichloromethane layer was separated, dried over magnesium sulfate, filtered and then concentrated under vacuum. The resulting solid was recrystallized from toluene to provide 0.3 g of 5-chlorotetrazolo[1,5-a][1,8]naphthyridine as a solid, m.p. 229-230° C. (decomposition). Analysis: Calculated for C8H4ClN5: %C, 46.73; %H, 1.96; %N, 34.06; Found: %C, 46.87; %H 1.54; %N, 33.93.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]>C(O)C>[Cl-:13].[N+:20]([C:17]1[CH:16]=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=[CH:19][C:18]=1[N+:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][NH+:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1)([O-:22])=[O:21].[Cl-:13]
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: c1cc(-c2ccncc2)ccn1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-[n+]2ccc(-c3cc[nH+]cc3)cc2)c([N+](=O)[O-])c1
Product: [Cl-]
Yield: 136.3 %

Procedure:
4,4′-Bipyridine (10 g, 0.065 moles) and chloro-2,4-dinitrobenzene (13 g, 0.065 moles) in ethanol (150 ml) in a 250 ml flask were refluxed for fifteen hours and allowed to cool. The ethanol was removed under vacuum and acetone (200 ml) was added and the mixture was stirred. The suspension was filtered and dried under vacuum to yield 1-(2,4-dinitrophenyl)-4,4′-bipyridinium chloride (17.5 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([OH:24])[CH:6]=1)(=[O:3])[CH3:2].[C:25](=O)([O-])[O-].[K+].[K+].[F:31][C:32]([F:55])([F:54])[C:33]([F:53])([F:52])[C:34]([F:51])([F:50])[C:35]([F:49])([F:48])S(OCC(F)(F)C(F)(F)F)(=O)=O>CS(C)=O>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:19])([F:20])[F:21])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][CH2:25][C:35]([F:48])([F:49])[C:34]([F:50])([F:51])[C:33]([F:52])([F:53])[C:32]([F:31])([F:54])[F:55])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(=O)Nc1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(=O)Nc1cc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.1 %

Procedure:
0.5 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole was dissolved in 10 mL of dimethylsulfoxide, and 0.23 g of potassium carbonate was added, followed by stirring at room temperature for 5 minutes. To this solution, 0.79 g of 2,2,3,3,3-pentafluoropropyl nonafluorobutanesulfonate was added, followed by stirring at room temperature for 12 hours. Then, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.55 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,4,4,5,5,5-nonafluoropentyloxy)pyrazole.
Reaction SMILES: [BH4-].[Na+].[ClH:3].[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[N:15]=[CH:16][CH:17]=[C:18]2[C:22]([CH:23]=[O:24])=[C:21]([CH3:25])[N:20]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[C:19]=12.O>CO>[ClH:3].[CH2:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:14]1[N:15]=[CH:16][CH:17]=[C:18]2[C:22]([CH2:23][OH:24])=[C:21]([CH3:25])[N:20]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[C:19]=12
Reactant: Cc1c(C=O)c2ccnc(N3CCc4ccccc4C3)c2n1Cc1cccc(F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1c(CO)c2ccnc(N3CCc4ccccc4C3)c2n1Cc1cccc(F)c1
Reaction time: 1 h
Yield: 31.9 %

Procedure:
Sodium borohydride (4.7 mg, 0.124 mmol) was added to a solution of 7-(3,4-dihydro-1H-isoquinolin-2-yl)-1-(3-fluorobenzyl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-3-carbaldehyde hydrochloride (25 mg) prepared in Example 616 in methanol (2 ml). The reaction mixture was stirred for 1 hour and water was added thereto. The reaction mixture was extracted with ethyl acetate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/1, v/v). The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 8 mg of the titled compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]([O:24]CC)=[O:23])=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>C(O)C.O1CCCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][C:11]([C:22]([OH:24])=[O:23])=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)c1cc(-c2ccc(SC)cc2)n(-c2ccc(C#N)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CSc1ccc(-c2cc(C(=O)O)nn2-c2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A mixture of ethyl 1-(4-cyanophenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylate (2.8 g) and 1N sodium hydroxide (10 ml) in ethanol (150 ml) and tetrahydrofuran (20 ml) was stirred at ambient temperature for 3 hours. The solvent was evaporated, and the residue was dissolved in water, acidified with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried, and evaporated to give 1-(4-cyanophenyl)-5-[4-(methylthio)phenyl]pyrazole-3-carboxylic acid (2.5 g).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C[O-].[Na+].[C:9]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:14]=[CH:13][C:12]([C:15]([OH:27])([CH2:25]Cl)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[CH:11][CH:10]=1>CO.CN(C)C=O>[C:9]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:10]=[CH:11][C:12]([C:15]([OH:27])([CH2:25][N:4]2[CH:3]=[N:2][N:1]=[CH:5]2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])=[CH:13][CH:14]=1
Reactant: OC(CCl)(Cc1ccc(Cl)cc1Cl)c1ccc(-c2ccccc2)cc1
Reactant: c1nc[nH]n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: OC(Cc1ccc(Cl)cc1Cl)(Cn1cnnc1)c1ccc(-c2ccccc2)cc1
Temperature: 70 °C
Yield: 10.4 %

Procedure:
7.6 g (0.11 mol) of 1,2,4-triazole are added to a solution of 3.5 g (0.065 mol) of a sodium methylate in 18 ml of methyl alcohol; a solution of 19.5 g (0.05 mol) of 2-(4-biphenylyl)-3-chloro-1-(2,4-dichlorophenyl)-propan-2-ol in 38 ml of dimethylformamide is then added dropwise and the mixture is heated to 70° C. for 90 minutes. The solvent is removed in vacuo in a rotary evaporator and the residue is stirred with water. The resulting crystals are washed with diethyl ether and recrystallised from acetonitrile. 2.2 g of 2-(4-biphenylyl)-1-(2,4-dichlorophenyl)-3-(1,3,4-triazol-1-yl)-propan-2-ol of melting point 260° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH2:11][C:10]([OH:13])([CH3:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:30][N:31]([CH:33](OC)OC)[CH3:32]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([C:14]2[CH:15]=[CH:16][C:17]([C:20](=[O:28])[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:30][N:31]([CH3:33])[CH3:32])=[CH:18][CH:19]=2)[CH2:9][C:10]([OH:13])([CH3:12])[CH2:11]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1(O)CC(NC(=O)OC(C)(C)C)(c2ccc(C(=O)Cc3ccccc3)cc2)C1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C(C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CC(C)(O)C2)cc1)c1ccccc1

Procedure:
To a solution of compound 2-3 (3.96 g, 10 mmol) in toluene (20 mL) was added DMFDMA (9.2 g, 35 mmol) and the mixture was heated at reflux for 4 hours. The mixture was cooled and the formed white solid was collected. After washed by PE, the solid was dried in vacuum to get the product 2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]([CH2:8][Cl:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4]([Cl:10])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: ClCc1ccc(Cl)nc1Cl
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(CCl)c(Cl)nc1Cl
Temperature: 110 °C

Procedure:
117.5 g (0.6 mol) of 2,6-dichloro-3-chloromethylpyridine are dissoled in a mixture of 540 ml of concentrated sulphuric acid and 600 ml of 100% strength fuming nitric acid. The reaction mixture is then heated at 110°C in an oil bath for 5 hours. After cooling to approx. 20°C, the reaction mixture is poured onto ice. The resulting crystals are filtered off and are purified by being well ground with water in a mortar and then filtered off with suction and rinsed with water on the filter. After drying the crude product in vacuo at 25°C over diphosphorus pentoxide. crude 2,6-dichloro-3-chloromethyl-5-nitropyridine is obtained in the form of pale yellow crystals, which can be recrystallised from methanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].[Li]CCCC.Cl[Si:16]([CH3:28])([CH3:27])[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:25]=1[CH2:24][C:23]([CH3:26])=[CH:22]2>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][Si:16]([CH3:27])([CH3:28])[C:17]2[CH:18]=[CH:19][CH2:20][C:21]3[C:25]=2[CH:24]=[C:23]([CH3:26])[CH:22]=3)[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: Cc1cc(C)cc(N)c1
Reactant: CC1=Cc2cccc([Si](C)(C)Cl)c2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=CC2=C([Si](C)(C)Nc3cc(C)cc(C)c3)C=CCC2=C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4.54 g (37.5 mmol) of 3,5-dimethylaniline in 110 mL of THF 15.0 mL (37.5 mmol) of 2.5 M nBuLi in hexanes was added at 0° C. This mixture was additionally stirred for 4 hours at room temperature, then cooled to −40° C., and a solution of 8.35 g (37.5 mmol) of chloro(dimethyl)(2-methyl-1H-inden-7-yl)silane in 70 mL of THF was added in one portion. The resulting mixture was stirred for 12 hours at room temperature and then evaporated to dryness. To the residue 100 mL of ether was added, and the obtained suspension was stirred for 20 minutes, and then filtered through glass frit (G3). The precipitate was additionally washed with 2×100 mL of ether. The combined filtrate was evaporated to dryness, and the residue was washed with 3×7 mL of cold hexanes and then dried in vacuum. Yield 7.26 g (63%) of white solid. 1H NMR (C6D6): δ 7.50 (dd, J=6.5 Hz, J=2.1 Hz, 1H, 6-H in indenyl), 7.24-7.30 (m, 2H, 4,5-H in indenyl), 6.35 (m, 2H, 3-H in indenyl and 4-H in 3,5-Me2C6H3), 6.27 (s, 2H, 2,6-H in 3,5-Me2C6H3), 3.27 (s, 2H, 1,1′-H in indenyl), 3.24 (s, 1H, NH), 2.08 (s, 6H, 3,5-Me in 3,5-Me2C6H3), 1.83 (s, 3H, 2-Me in indenyl), 0.45 (s, 6H, SiMe2). Anal. Calc. for C20H25NSi: C, 78.12; H, 8.19; N, 4.55%. Found: C, 78.41; H, 8.00; N, 4.38%.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[C:6]([C:9]1[CH:10]=[C:11](/[CH:14]=[C:15]2\[C:16](=[O:26])[NH:17][C:18]3[C:23]\2=[C:22](I)[C:21]([F:25])=[CH:20][CH:19]=3)[NH:12][CH:13]=1)(=[O:8])[CH3:7]>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.CN(C=O)C.CCN(CC)CC>[C:6]([C:9]1[CH:10]=[C:11](/[CH:14]=[C:15]2\[C:16](=[O:26])[NH:17][C:18]3[C:23]\2=[C:22]([C:5]#[C:4][CH2:3][NH:2][CH3:1])[C:21]([F:25])=[CH:20][CH:19]=3)[NH:12][CH:13]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Reactant: C#CCNC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1cc(C(C)=O)c[nH]1)C(=O)N2

Procedure:
Using Method C above, N-methylpropargyl amine (43.6 mg, 0.66 mmol) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (100 mg, 0.25 mmol) (Example 90B) using (Ph3P)4Pd (30.1 mg) and Cul (6.0 mg) as catalyst in DMF (6 mL) and Et3N (6 mL) as solvent at 89° C. for 5 h to yield (Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C@@H:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)[O:16][CH3:17].N1CCCCC1.[S:32]1[CH2:36][C:35](=[O:37])[NH:34][C:33]1=[O:38]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C@@H:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[C:36]2[S:32][C:33](=[O:38])[NH:34][C:35]2=[O:37])=[CH:20][CH:19]=1)[O:16][CH3:17]
Reactant: CO[C@@H](CCc1nc(-c2ccccc2)oc1C)c1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CO[C@@H](CCc1nc(-c2ccccc2)oc1C)c1ccc(C=C2SC(=O)NC2=O)cc1
Yield: 86.6 %

Procedure:
The title compound of Example 16 (580 mg, 1.7 mmol), piperidine (30 mg, 0.34 mmol) and 2,4thiazolidinedione (405 mg, 3.4 mmol) were combined in ethanol (20 mL) and the resulting solution was refluxed overnight. The solvent was removed in vacuo and the residue was purified on silica gel, eluting with hexane/ethyl acetate (3/1) plus 5% acetic acid, to afford the title compound as a solid (640 mg, 87%). mp 205-206° C. 1HNMR (300 MHz, DMSO-d6): δ2.0 (m, 2H), 2.3 (s, 3H), 2.4 (t, 2H), 3.1 (s, 3H), 4.2 (dd, 1H), 7.4 (m, 5H), 7.6 (d, 2H), 7.7 (s, 1H), 7.9 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=O.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.[CH3:25][C:26]1[C:31]([CH3:32])=[C:30]([OH:33])[CH:29]=[CH:28][C:27]=1[CH2:34][CH2:35]C(OCC)=O>>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:13])([F:12])[F:1])=[C:4]2[CH2:8][O:10][C:11]2[CH:35]=[CH:34][C:27]([CH2:28][CH2:29][CH2:30][OH:33])=[C:26]([CH3:25])[C:31]=2[CH3:32])=[CH:18][CH:17]=1
Reactant: CCOC(=O)CCc1ccc(O)c(C)c1C
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-n2ccc(C(F)(F)F)c2COc2ccc(CCCO)c(C)c2C)cc1

Procedure:
The title compound was prepared by (a) reacting the product prepared in Step B of Example 1 and 4-methoxyphenylboronic acid according to the procedure described in Example 1, Step C, (b) then reacting the resulting product according to the procedure in Example 1, Step D, (c) then reacting the resulting product with ethyl 3-(2,3-dimethyl-4-hydroxyphenyl)propanoate according to the procedure in Example 1, Step E, and Example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[CH:6]=[CH:7][CH:8]=1.O.[CH2:15]=O.[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>O1CCOCC1.C(O)(=O)C>[CH2:17]([N:19]([CH2:20][CH3:21])[CH2:15][C:13]#[C:12][CH2:11][CH2:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:18]
Reactant: C=O
Reactant: CCNCC
Reactant: C#CCCCc1cccc(OC)c1
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)CC#CCCCc1cccc(OC)c1

Procedure:
Referring now to FIG. 1, wherein the compounds are assigned Roman numerals for identification schematically, the sequence of reactions involved in the synthesis of a specific embodiment, namely, 13β,17α-diethyl-17β-hydroxygon-4-en-3-one, is illustrated. 3-(m-Methoxyphenyl)propanol (I) is heated with phosphorus tribromide in benzene after dropwise addition in the cold to form 3-(m-methoxyphenyl)propyl bromide (II). This halogen compound (II) dissolved in tetrahydrofuran is condensed with sodium acetylide in liquid ammonia to obtain 5-(m-methoxyphenyl)-1-pentyne (III). Compound III is allowed to stand under nitrogen with water, 30% formalin, acetic acid, diethylamine, dioxan, and cuprous chloride a 70°C for about 12 hours, whereby there is obtained 1-diethylamino-6-(m-methoxyphenyl)-2-hexyne (IV), which is in turn hydrated in the presence of a mercury salt and sulfuric acid to form 1-diethylamino-6-(m-methoxyphenyl)-3-hexanone (V). The ketamine (V) may eliminate diethylamine on distillation to give the vinyl ketone 6-m-methoxyphenyl)-1-hexen-3-one (VI). Either the ketamine (V) or the ketone (VI), or mixtures thereof, is then reacted with 2-ethyl-1,3-cyclopentanedione (VII) under Michael condensation conditions, e.g. refluxing in methanolic potassium hydroxide to form 2-ethyl-2-[6-(m-methoxyphenyl)-3-oxohexyl]-1,3-cyclopentanedione (VIII).
Reaction SMILES: IN1C(=O)CCC1=O.[CH3:9][O:10][CH2:11][CH2:12][N:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18](=O)[CH2:19][C:20]([O:22][CH3:23])=[O:21].[NH2:25][C:26]([NH2:28])=[S:27]>CCOC(C)=O>[NH2:28][C:26]1[S:27][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([C:14]2[N:13]([CH2:12][CH2:11][O:10][CH3:9])[CH:17]=[CH:16][N:15]=2)[N:25]=1
Reactant: COCCn1ccnc1C(=O)CC(=O)OC
Reactant: NC(N)=S
Agent: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Product: COCCn1ccnc1-c1nc(N)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
N-Iodosuccinimide (9.3 g, 41 mmol) was added to a mixture of 7.52 g (41 mmol) methyl 3-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-3-oxopropanoate (Intermediate 56) and 7.5 g Amberlyst-15 resin in 400 ml EtOAc followed by stirring for 1 hour at room temperature. The resin was filtered off and rinsed with EtOAc. Solvent was removed from the filtrate and the residue was taken up in diethyl ether. Insoluble material was filtered off and rinsed with additional ether. Solvent was removed from the filtrate and the residue was dissolved in 200 ml MeOH before added 4.7 g (62 mmol) thiourea. The mixture was heated at reflux for 1 hour. Then the solvent was removed and the residue was taken up in aqueous Na2CO3. Insoluble material was collected by filtration and rinsed well with water. The solids were dried in vacuo affording 4.51 g of the title compound: MS (ES) (M+H)+: 283 for C11H14N4O3S; NMR: 3.22 (s, 3H), 3.61 (m, 2H), 3.69 (s, 3H), 4.32 (m, 2H), 7.91 (s, 2H), 8.41 (s, 2H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][O:25][CH3:26])[CH:20]=[CH:19][C:18]=1[CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH2:33])[CH2:28]1>ClCCl>[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH2:24][O:25][CH3:26])[CH:20]=[CH:19][C:18]=1[CH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([NH:33][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:28]1
Reactant: COCOc1ccc(C2CCCC(N)C2)c(OCOC)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc(C2CCCC(NS(C)(=O)=O)C2)c(OCOC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.014 ml) and methanesulfonyl chloride (8 μl) were added to a solution of (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexylamine (27 mg) in dichloromethane (1 ml), and the mixture was stirred under argon at ambient temperature. After 1 hr, the mixture was partitioned between ethyl acetate (20 ml) and sodium hydrogen carbonate (20 ml of a saturated aqueous solution). The aqueous layer was extracted with ethyl acetate (2×20 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo to furnish the title compound as an oil and a mixture of diastereoisomers; m/z (ES+) 374 (M+H)+.