Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:38]=[C:37]([F:39])[C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][C:18]4[C:23]([F:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=4)[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:4]([F:40])[CH:3]=1.[F:41][CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(P(C(C)(C)C)C(C)(C)C)(C)C.CC(P(C(C)(C)C)C(C)(C)C)(C)C.[Pd].C1(C)C=CC=CC=1>[F:40][C:4]1[CH:3]=[C:2]([N:45]2[CH2:46][CH2:47][CH:42]([F:41])[CH2:43][CH2:44]2)[CH:38]=[C:37]([F:39])[C:5]=1[CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([O:16][CH2:17][C:18]3[C:23]([F:24])=[CH:22][C:21]([CH3:25])=[CH:20][N:19]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]1[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1c1nc2ccc(OCc3ncc(C)cc3F)cc2n1Cc1c(F)cc(Br)cc1F
Reactant: FC1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CCCC[C@@H]1c1nc2ccc(OCc3ncc(C)cc3F)cc2n1Cc1c(F)cc(N2CCC(F)CC2)cc1F
Temperature: 110 °C

Procedure:
To a 5 mL vial were added racemic cis-ethyl 2-(1-(4-bromo-2,6-difluorobenzyl)-6-((3-fluoro-5-methylpyridin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylate (150 mg, 0.24 mmol), Pd(t-Bu3P)2 (12 mg, 0.024 mmol), 4-fluoropiperidine (28 mg, 0.27 mmol), Cs2CO3 (238 mg, 0.73 mmol) and toluene (1 mL). The mixture was heated at 110° Celsius for 1 h. The mixture was cooled to RT, concentrated to dryness and purified by FCC to afford racemic cis-ethyl 2-(1-(2,6-difluoro-4-(4-fluoropiperidin-1-yl)benzyl)-6-((3-fluoro-5-methylpyridin-2-yl)methoxy)-1H-benzo[d]imidazol-2-yl)cyclohexanecarboxylate. To the resulting ethyl ester, in a 5 mL vial, was added HCl (5 mL, 6 N). The mixture was heated at 100° Celsius for 16 h. The mixture was cooled to RT then concentrated to dryness. The residue was purified using FCC to provide the title compound. MS (ESI): mass calcd. for C33H34F4N4O3, 610.26; m/z found, 611.3 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 6.71 (s, 1H), 6.00-5.97 (m, 1H), 5.95 (d, J=8.8 Hz, 1H), 5.59 (d, J=2.3 Hz, 1H), 5.38 (dd, J=8.8, 2.3 Hz, 1H), 5.07-4.97 (m, 2H), 3.96 (d, J=15.9 Hz, 1H), 3.80 (d, J=15.9 Hz, 1H), 3.68-3.59 (m, 2H), 3.22-3.16 (m, 1H), 2.21-2.15 (m, 1H), 1.93-1.83 (m, 2H), 1.74-1.66 (m, 2H), 1.35-1.28 (m, 1H), 0.87 (s, 3H), 0.83-0.72 (m, 1H), 0.50-0.35 (m, 5H), 0.32-0.14 (m, 4H), 0.01-0.14 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.[C:27]([O-])(=[O:30])[CH2:28][OH:29].[Na+].[Na]>C(O)CO>[OH:29][CH2:28][CH2:27][O:30][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1
Reactant: O=C([O-])CO
Reactant: COc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C)cc2)cc1
Agent: [Na+]
Agent: [Na]
Solvent: OCCO
Product: COc1ccc(-c2c(NS(=O)(=O)c3ccc(C)cc3)ncnc2OCCO)cc1

Procedure:
190 mg of N-[6-chloro-5-(p-methoxyphenyl)-4-pyrimidinyl]-p-toluenesulfonamide were added to a sodium glycolate solution from 46 mg of sodium in 1 ml of ethylene glycol. After a reaction period of 5 hours at 100° C., the reaction mixture was evaporated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase was washed neutral, dried and evaporated under reduced pressure. The residue was chromatographed on silica gel with methylene chloride and ethyl acetate (4:1 v/v). There were obtained 175 mg of N-[6-(2-hydroxy-ethoxy)-5-(p-methoxyphenyl)-4-pyrimidinyl]-p-toluenesulfon-amide, melting point 147°-149° C. (from methylene chloride/hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[S:11])[CH:5]=[CH:6][C:7]=1[OH:8].Cl[C:24]1[N:29]=[C:28]([Cl:30])[N:27]=[C:26]2[N:31]([CH3:34])[N:32]=[CH:33][C:25]=12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:30][C:28]1[N:27]=[C:26]2[N:31]([CH3:34])[N:32]=[CH:33][C:25]2=[C:24]([O:8][C:7]2[CH:6]=[CH:5][C:4]([NH:9][C:10]([NH:12][C:13](=[O:22])[CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)=[S:11])=[CH:3][C:2]=2[F:1])[N:29]=1
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(O)c(F)c1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1ncc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
To a mixture of 1-(3-fluoro-4-hydroxyphenyl)-3-(2-(4-fluorophenyl)acetyl)thiourea (24 mg, 0.075 mmol), 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (15.3 mg, 0.075 mmol, preparation: J. Org. Chem. 1958, 23, 852, the disclosure of which is herein incorporated by reference) and K2CO3 (10 mg, 0.075 mmol) was added DMF (2 mL). The reaction was stirred at RT for 24 h. The reaction was quenched with water (2 mL) and CH2Cl2 (5 mL). The organic layer was separated, dried with sodium sulfate, concentrated in vacuo and purified by reverse phase preparative HPLC to give the title compound (22.9 mg, 60%) as a white solid. MS(ESI+) m/z 457 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH3:7])[CH:4]=[O:5])[CH3:2].[C:8](#[N:11])[CH:9]=[CH2:10].[OH-].[K+]>>[C:8]([CH2:9][CH2:10][C:3]([CH2:6][CH3:7])([CH2:1][CH3:2])[CH:4]=[O:5])#[N:11]
Reactant: CCC(C=O)CC
Reactant: C=CC#N
Agent: [K+]
Agent: [OH-]
Product: CCC(C=O)(CC)CCC#N
Yield: 76.6 %

Procedure:
In the presence of alkaline catalysts, acrylonitrile reacts with aldehydes, the α-carbon atoms of which possess one or two hydrogen atoms, forming 3-substituted propionitriles (U.S. Pat. No. 2,353,687). This so-called "cyanoethylation" reaction also occurs with other compounds which have an active hydrogen atom. For example, 2-ethyl butyraldehyde and acrylonitrile react in the presence of catalytic amounts of 50 percent caustic potash solution forming 2-(β-cyanoethyl)-2-ethyl butyraldehyde. A yield of 76.6 percent results after a reaction period of 4.5 hours. (H. A. Bruson, Th. W. Riener, J. Am. Chem. Soc., 66, 57 [1944]). The reaction is strongly exothermal. Acetaldehyde reacts with acrylonitrile in the presence of a 50 percent caustic soda solution forming γ-formylpimelonitrile. For a yield of 40-50%, the reaction period amounts to 2-3 hours. Under the same conditions, propionaldehyde forms 4.9 percent 2-methyl-4-cyanobutyraldehyde (U.S. Pat. No. 2,409,086). 2,2-dimethyl-4-cyano-butyraldehyde is formed in up to 60 percent yield from the reaction between isobutyraldehyde and acrylonitrile.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][C@H:33]1[CH:38]=O)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])O.[Na+]>ClCCl>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][C@H:33]1[CH:38]=[C:20]([Br:24])[Br:21])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1C=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1C=C(Br)Br
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Triphenylphosphine (7.31 g) was added to a solution of carbon tetrabromide (4.62 g) in dichloromethane (15 ml) at 0° C. and the mixture was stirred at 0° C. for 15 minutes. A solution of (3S)-4-tert-butoxycarbonyl-3-formylmorpholine (1.5 g) in dichloromethane (15 ml) was added dropwise to the solution over 10 minutes at 0° C. and stirred for 3 hours, and the mixture was added saturated sodium hydrogen carbonate solution. The organic layer was separated and the aqueous layer was extracted with ethyl acetate three times. The combined organic layer was washed with brine, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and n-hexane (4:6) to give (3R)-4-tert-butoxycarbonyl-3-(2,2-dibromoethenyl)morpholine as an oil.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH3:10][Si:11]([C:14]#[C:15][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)([CH3:13])[CH3:12]
Reactant: O=Cc1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
As shown in the following Reaction 6, 500 mg (2.15 mmol) of 4-iodobenzaldehyde was melted in 2.7 mL of tetrahydrofuran, and 0.45 mL (3.22 mmol, 1.5 eq) of trimethylsilylacetylene, 0.6 mL (3.44 mmol, 1.6 eq) of diisopropylethylamine (DIEA), 7 mg (0.01 mmol, 0.5 mol %) of dichlorobis-(triphenylphosphine)palladium(II), and 3 mg (0.02 mmol, 1 mol %) of copper iodide was added thereto, and then the reaction solution was stirred under nitrogen atmosphere for 12 hours at room temperature. Next, the reaction solution was filtered with ether, and then was extracted with 1M sodium chloride aqueous solution 1 time. The organic solvent layer was dehydrated with magnesium sulfate, filtered, and then distilled under reduced pressure. The compound distilled under reduced pressure was purified with a column chromatography (mobile phase volume ratio; ethylacetate:n-hexane=1:10) to obtain 420 mg of 4-trimethylsilylethynyl benzaldehyde with the yield of 98%. NMR data of the obtained compound is as follows. [1H NMR (400 MHz, CDCl3): δ 9.81 (s, 1H), 7.63 (d, 2H), 7.42 (d, 2H), 0.13 (s, 9H)].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[SH:15])=[O:6].[H-].[Na+].Cl[C:28]1[N:33]=[N:32][C:31]([CH:34]([C:37]2[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=2[Cl:44])[C:35]#[N:36])=[CH:30][CH:29]=1>CN(C=O)C>[C:35]([CH:34]([C:37]1[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][C:38]=1[Cl:44])[C:31]1[N:32]=[N:33][C:28]([S:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][NH:7][C:5](=[O:6])[C:4]2[CH:16]=[C:17]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH:18]=[C:2]([F:1])[CH:3]=2)=[CH:29][CH:30]=1)#[N:36]
Reactant: O=C(NCc1ccccc1S)c1cc(F)cc(N2CCOCC2)c1
Reactant: N#CC(c1ccc(Cl)nn1)c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(c1ccc(Sc2ccccc2CNC(=O)c2cc(F)cc(N3CCOCC3)c2)nn1)c1c(Cl)cccc1Cl
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 25 %

Procedure:
A solution of 3-fluoro-5-(morpholin-4-yl)-N-(2-sulfanylbenzyl)benzamide (80 mg, 0.23 mmol) in DMF (3 mL) was treated with sodium hydride (60% in mineral oil, 8.8 mg, 0.22 mmol). The mixture was stirred for 5 min and treated with a solution of (6-chloro-pyridazin-3-yl)-(2,6-dichloro-phenyl)-acetonitrile (63 mg, 0.21 mmol) in DMF (1 mL). The reaction mixture was heated at 100° C. for 45 min, cooled to RT and partitioned between aqueous saturated NaHCO3 and EtOAc. The aqueous layer was extracted with EtOAc, the combined organic layers were dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. Purification by reverse phase preparative HPLC (water/acetonitrile+0.1% HCO2H 50% isocratic), afforded the title compound (32 mg, 25%) as a yellow oil. LCMS (Method 3): Rt 11.77 min, m/z 608 [MH+]. 1H NMR (400 MHz, CDCl3): 7.67-7.58 (2H, m), 7.53-7.47 (1H, m), 7.45-7.32 (4H, m), 7.31-7.20 (2H, m), 7.09 (1H, t, J 1.7), 6.75 (1H, br t, J 5.6), 6.71-6.61 (2H, m), 6.33 (1H, s), 4.76 (2H, m), 3.86 (4H, t, J 4.8), 3.21 (4H, t, J 4.8).
Reaction SMILES: [N:1]([C:4]1[C:21](=[O:22])[CH:20]=[CH:19][C@@:18]2([CH3:23])[C:5]=1[C:6](=[CH2:25])[CH2:7][C@@H:8]1[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]1[CH2:10][CH2:11][C:12]2=[O:24])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1.O>O1CCCC1>[NH2:1][C:4]1[C:21](=[O:22])[CH:20]=[CH:19][C@@:18]2([CH3:23])[C:5]=1[C:6](=[CH2:25])[CH2:7][C@@H:8]1[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]1[CH2:10][CH2:11][C:12]2=[O:24]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C(N=[N+]=[N-])=C12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C(N)=C12
Temperature: 35 °C
Reaction time: 2.5 h
Yield: 30 %

Procedure:
To a stirred solution of 4-azido-6-methylenandrosta-1,4-diene-3,17-dione (3.374 g, 10 mmol) in tetrahydrofuran (25 ml) was added portionwise triphenylphosphine (2.823 g, 10 mmol). During the reaction, which lasted about 2.5 h, the temperature raised to about 35° C. and there was nitrogen evolution. Then dioxane (100 ml) and water (10 ml) was added and the mixture was refluxed for 10 h. Finally the mixture was poured onto water and the raw product extracted with ethyl acetate. The organic phase was extracted 4× with 2N hydrochloric acid, the aqueous phase was separated and the product precipitated by alkalinization with sodium hydroxide solution. Thus almost pure 4-amino-6-methylen-androsta-1,4-diene-3,17dione was obtained in about 30% yield (0.934 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[C:18]([C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])[NH2:23])#[CH:19]>C(O)(C)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:23][C:22]1[CH:24]=[CH:25][C:26]([F:27])=[C:20]([C:18]#[CH:19])[CH:21]=1)(=[O:3])[CH3:2]
Reactant: C#Cc1cc(N)ccc1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Solvent: CC(C)O
Product: C#Cc1cc(Nc2ncnc3cc(OC)c(OC(C)=O)cc23)ccc1F
Temperature: 83 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
A suspension of 4-chloro-7-methoxyquinazolin-6-yl acetate (4.31 g), 3-ethynyl-4-fluoroaniline (2.77 g) and isopropanol (65 mL) was stirred at 83° C. overnight. The reaction mixture was cooled to room temperature and filtered, the residue was washed with 100 mL of isopropanol and dried to afford the desired compound as a solid (5.29 g, 88.30%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:25][S:26]([O:8][C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([C:4]([F:6])([F:5])[F:7])[C:2]([F:16])([F:17])[F:1])(=[O:28])=[O:27]
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 5 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
5.16 g (20 mmol) of 1,1,1,3,3,3-hexafluoro-2-p-tolylpropan-2-ol were dissolved in 50 ml of methylene chloride, and 2.8 g (28 mmol) of triethylamine were added. 3.2 g (22 mmol) of methanesulfonyl chloride were added dropwise, while stirring, to the solution cooled to 5° C. After warming up to room temperature, the mixture was allowed to stand overnight. The precipitated salt was filtered off and the organic solution was evaporated down. The subsequent chromatography (silica gel/methylene chloride) gave 4.8 g of 2-methanesulfonyloxy-2-p-tolyl-1,1,1,3,3,3-hexafluoropropane (pale yellow oil).
Reaction SMILES: [CH2:1]([CH:8]([C:22](=[O:34])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][CH3:33])[CH:26]=1)[C:9](=[O:21])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(OCC)(=O)C>[CH2:1]([CH:8]([C:9](=[O:21])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1)[C:22](=[O:34])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([O:32][CH3:33])[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C=CC(=O)C(Cc2ccccc2)C(=O)C=Cc2ccc(O)c(OC)c2)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(CCC(=O)C(Cc2ccccc2)C(=O)CCc2ccc(O)c(OC)c2)ccc1O
Yield: 51.9 %

Procedure:
4-Benzyl-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (9a, 0.25 g, 0.5 mmol) and palladium on activated carbon (0.20 g, 10%) were combined in ethyl acetate (45 ml). The mixture was placed under a hydrogen atmosphere (60 psi) on a Parr apparatus for 2 hr at room temperature. The resulting mixture was filtered through celite and the filtrate was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford an oil. The crude oil was twice chromatographed on silica gel with ethyl acetate/hexane to give 0.12 g (48%) of a pale yellow oil; 1H NMR: δ enol form: 2.66 (m, 8H), 3.53 (s, 2H), 3.77 (s, 6H), 5.55 (s, 2H), 6.56 (m, 4H), 6.77 (d, 2H, J=7.6 Hz), 7.06 (m, 6H), 7.20 (m, 2H); keto form: 2.66 (m, 8H), 3.08 (d, 2H, J=7.3 Hz), 3.82 (s, 6H), 3.92 (t, 1H, J=8.3 Hz), 5.55 (s, 2H), 6.56 (m, 4H), 6.77 (d, 2H, J=7.6 Hz), 7.06 (m, 6H), 7.20 (m, 2H); 13C NMR: δ 29.0, 31.1, 31.8, 34.3, 37.7, 44.6, 55.8, 69.2, 111.0, 114.2, 120.7, 120.8, 126.6, 127.4, 128.5, 128.6, 132.3, 132.6, 137.9, 143.8, 146.3, 193.4, 204.5; Exact mass calcd for C28H30O6: 462.2042, observed (M+H) 463.2073.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:27]=[C:26]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:25]=2)=[CH:20][CH:19]=1>CN(C=O)C>[Si:6]([O:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:28]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[N:27]=[C:26]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:25]=2)=[CH:22][CH:23]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CCOC(=O)c1cc(-c2ccc(OCCO)cc2)n(-c2ccc(OC)cc2)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(OCCO[Si](C)(C)C(C)(C)C)cc2)n(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Imidazole (680 mg) and t-butyldimethylsilyl chloride (903 mg) was added successively to a solution of ethyl 5-[4-{2-(hydroxy)ethoxy}phenyl]-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (1.91 g) in DMF (15 ml) under cooling in an ice bath. After stirring at ambient temperature for 2 hours, the mixture was partitioned between AcOEt and H2O. The oreganic layer was washed with H2O, saturated aqueous sodium chloride solution, dried over MgSO4, concentrated in vacuo. The residual crystals were collected and washed with n-hexane to give ethyl 5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-phenyl]-1-(4-methoxyphenyl)-1H-pyrazole-3-carboxylate (2.34 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([O:12]CC)=[O:11])=[CH:8][CH:7]=[N:6]1.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=[N:6]1
Reactant: CCOC(=O)c1ccnn1CCOC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCCn1nccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
Ethyl 1-(2-methoxyethyl)-1H-pyrazole-5-carboxylate (Preparation 28, 710 mg, 3.6 mmol) was dissolved in ethanol (10 ml), a solution of sodium hydroxide (160 mg, 4.0 mmol) in water (5 ml) was added and the solution was stirred at room temperature for 2 hours. The ethanol was removed in vacuo and the residue was acidified with 2M HCl (approximately 2 ml) and extracted with dichloromethane (40 ml). The organic layers were dried over anhydrous Na2SO4, filtered and the dichloromethane removed in vacuo to give 590 mg of a pale yellow foam.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:12]([F:13])=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[F:14].[ClH:15].C(OC([N:23]1[CH2:30][CH:29]2[O:31][CH:25]([CH2:26][NH:27][CH2:28]2)[CH2:24]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[ClH:15].[F:14][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([F:13])[C:5]=1[O:4][CH2:3][CH2:2][N:27]1[CH2:26][CH:25]2[O:31][CH:29]([CH2:30][NH:23][CH2:24]2)[CH2:28]1)[C:9]#[N:10]
Reactant: N#Cc1cc(F)c(OCCBr)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1cc(F)c(OCCN2CC3CNCC(C2)O3)c(F)c1
Temperature: 60 °C
Reaction time: 120 h
Yield: 83.4 %

Procedure:
A suspension of 4-(2-bromoethoxy)-3,5-difluorobenzonitrile (12 g, 45.8 mmol; see step (i) above), 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester HCl-salt (11.5 g, 0.0435 mol; see WO 01/28992) and dry K2CO3 (25.32 g, 0.183 mol) in 140 mL of dry acetonitrile was stirred at 60° C. for five days under a nitrogen atmosphere. The reaction mixture was filtered through Celite® and the filtrate was then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel, using 20% ethyl acetate in petroleum ether as eluent, to yield 12.55 g of the sub-title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:15](OS(C(F)(F)F)(=O)=O)=[C:14]2[C:26]2[CH:31]=[CH:30][C:29]([CH:32]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:28][CH:27]=2)=[CH:8][CH:9]=1)=[O:4].[C-:48]#[N:49].[Na+]>CC#N.[Cu]I.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]2[CH2:17][CH2:16][C:15]([C:48]#[N:49])=[C:14]2[C:26]2[CH:27]=[CH:28][C:29]([CH:32]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:30][CH:31]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C(OS(=O)(=O)C(F)(F)F)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Reactant: [C-]#N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CC#N
Product: CCCCCC(OCc1ccc(OC)cc1)c1ccc(C2=C(C#N)CC[C@@H]2CCCc2ccc(C(=O)OC)s2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A solution of vinyl triflate 48 (61 mg, 0.088 mmol) in 1 mL CH3CN was cannula transferred to a flask containing NaCN (21 mg, 0.42 mmol, dried under vacuum at 105° C. over 3 days), CuI (13 mg, 0.069 mmol), and (Ph3P)4Pd (8 mg, 0.0066 mmol), rinsing with 1 mL CH3CN. The reaction was stirred at 90° C. for 2 h, cooled to room temperature and then filtered through Celite, washing with ethyl acetate. The filterate was washed with 20 mL water and 20 mL brine and then was dried (Na2SO4), filtered and evaporated. The residue was purified on a Combiflash unit by Teledyne Isco (4 g silica gel column, 0%→50% ethyl acetate/hexanes) to give the title compound (41 mg, 88%).