Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:16][C:15]2[CH:14]=[N:13][CH:12]=[N:11][C:10]=2[C:9]=1[C:17]#[N:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[S:31][C:30]([CH2:32]OS(C)(=O)=O)=[N:29][N:28]=2)=[C:23]([C:38]([F:41])([F:40])[F:39])[CH:22]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:17]#[N:18])=[C:10]2[C:15]([N:16]=1)=[CH:14][N:13]([CH2:32][C:30]1[S:31][C:27]([C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][C:23]=3[C:38]([F:41])([F:39])[F:40])=[N:28][N:29]=1)[CH:12]=[N:11]2
Reactant: N#Cc1c(-c2ccccc2F)[nH]c2cncnc12
Reactant: COc1ccc(-c2nnc(COS(C)(=O)=O)s2)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nnc(Cn3cnc4c(C#N)c(-c5ccccc5F)nc-4c3)s2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 8.5 %

Procedure:
To a solution of 6-(2-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carbonitrile (29 mg) and methanesulfonic acid 5-(4-methoxy-2-trifluoromethylphenyl)-[1,3,4]thiadiazol-2-ylmethyl ester (49 mg) in DMF was added NaH (5 mg). The reaction was stirred for 14 h at rt. The reaction was quenched by slow addition of AcOH (glacial), filtered, and purified by HPLC (10-70% MeCN/H2O with 1% formic acid) then lyophilized to give 5.3 mg of the titled compound (8%). 1H NMR (DMSO-d6): 9.40 (s, 1 h), 9.18 (s, 1 h), 7.85 (t, 1 h), 7.73 (d, 1H), 7.56-7.64 (m, 1H), 7.35-7.47 (m, 4H), 6.30 (s, 2H), 3.93 (s, 3H). LC-MS calculated for C24H14F4N6OS 510.5, found 511.00 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH:12]=[CH:13][C:14]=1[CH:15]=[CH:16][C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:38]=[O:39].O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([N:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH:12]=[CH:13][C:14]=1[CH:15]=[CH:16][C:17]1[S:18][C:19]([CH:38]=[O:39])=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CCCCN(CCCC)c1ccc(C=Cc2cccs2)c(OCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Temperature: -72.5 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
In a stream of argon, in 35 ml of tetrahydrofuran was dissolved 2.6 g (6.2 mmol) of [3-benzyloxy-4-[2-(thiophene-2-yl)vinyl]phenyl]dibutylamine, and 5.8 ml of n-butyllithium (1.6 mol solution in hexane) (9.28 mmol) was added dropwise thereto under cooling at −71 to −74° C. The mixture was stirred for 1 hour. Next, 0.59 g (8.07 mmol) of N,N-dimethylformamide was added dropwise. The reaction mixture was stirred for 1 hour and the temperature was allowed to rise. To this mixture, 10 ml of water was added dropwise. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was dissolved in 300 ml of ether and 130 mg of iodine pieces were added thereto. After stirred at room temperature, the mixture was washed with a 5% sodium bisulfite solution and then with a saturated saline solution. After drying over anhydrous magnesium sulfate and concentration, the residue was crystallized from ethyl acetate/hexane (⅙) and the precipitate was separated by filtration to give 1.76 g of a reddish orange crystal. Further, the mother liquor was purified by silica gel column chromatography and the residue was crystallized in the same manner as described above to further give 0.12 g of the crystal (In total: 1.88 g; yield: 67.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C@H:14]3[CH2:18][CH2:17][C@@H:16]([C:19]([NH:21][C:22]4[CH2:29][CH2:28][C:25]5([CH2:27][CH2:26]5)[CH2:24][C:23]=4[C:30]([O:32]CC)=[O:31])=[O:20])[CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C@H:14]3[CH2:18][CH2:17][C@@H:16]([C:19]([NH:21][C:22]4[CH2:29][CH2:28][C:25]5([CH2:27][CH2:26]5)[CH2:24][C:23]=4[C:30]([OH:32])=[O:31])=[O:20])[CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1.[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C@H:14]3[CH2:18][CH2:17][C@H:16]([C:19]([NH:21][C:22]4[CH2:29][CH2:28][C:25]5([CH2:27][CH2:26]5)[CH2:24][C:23]=4[C:30]([OH:32])=[O:31])=[O:20])[CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1=C(NC(=O)[C@@H]2CC[C@H](N3CCN(c4ccc(Cl)cc4)CC3)C2)CCC2(CC2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1=C(NC(=O)[C@@H]2CC[C@H](N3CCN(c4ccc(Cl)cc4)CC3)C2)CCC2(CC2)C1
Product: O=C(O)C1=C(NC(=O)[C@H]2CC[C@H](N3CCN(c4ccc(Cl)cc4)CC3)C2)CCC2(CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 6-((1R,3S)-3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopentane carboxamido)spiro[2.5]oct-5-ene-5-carboxylate (0.3 g, 0.62 mmol) was dissolved in 10 ml of tetrahudrofuran/methanol/water (3:1:1). To this solution was added lithium hydroxide (0.12 g, 2.8 mmol). The mixture was stirred at room temperature overnight, concentrated, and acidified using 1 N hydrochloric acid to pH 6. To the resulting white slurry was added water (20 ml). The mixture was extracted with dichloromethane (2×50 ml). The organic layer was dried over sodium sulfate and concentrated to afford the title compound 6-((1R,3S)-3-(4-(4-chlorophenyl)piperazin-1-yl)cyclopentane carboxamido)spiro[2.5]oct-5-ene-5-carboxylic acid along with its corresponding diastereomer 6-((1S,3S)-3-(4-(4-chlorophenyl) piperazin-1-yl)cyclopentanecarboxamido)spiro[2.5]oct-5-ene-5-carboxylic acid as observed on the HPLC column.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[N:3]=[C:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]12[CH3:6])[C:18]1[CH:17]=[CH:16][C:15]([OH:22])=[CH:14][C:13]=1[CH2:12][CH2:11]3.N1C=CN=C1.[CH3:29][C:30]([Si:33](Cl)([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C=O)C.CCOCC>[CH3:23][N:2]([CH3:1])[N:3]=[C:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:5]12[CH3:6])[C:18]1[CH:17]=[CH:16][C:15]([O:22][Si:33]([C:30]([CH3:32])([CH3:31])[CH3:29])([CH3:35])[CH3:34])=[CH:14][C:13]=1[CH2:12][CH2:11]3
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)N=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)N=C1CC[C@H]2[C@@H]3CCc4cc(O[Si](C)(C)C(C)(C)C)ccc4[C@H]3CC[C@]12C
Reaction time: 16 h

Procedure:
To a solution of 15.5 gr. of 3-hydroxyestra-1,3,5(10)-trien-17-one dimethylhydrazone (34) in 200 ml of DMF was added 13 gr. of imidazole, followed by dropwise addition of 15 gr. of TBDMSCl in 20 ml of ether. After stirring for an additional 16 hr the reaction mixture was poured onto 2 liters of water and the resulting mixture was stirred for an additional 10 minutes. The precipitate was filtered and dried in vacuo, to provide 20 g of 35, M.p. 100-103° C.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=C[O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH2:32](N(CC)CC)C.Cl.[CH3:40][O:41][C:42]1[CH:47]=[CH:46][C:45]([N:48]2[CH2:53][CH2:52][N:51]([CH2:54][CH2:55][CH2:56][NH:57][CH3:58])[CH2:50][CH2:49]2)=[CH:44][CH:43]=1>C(Cl)Cl>[OH:19][C:20]1[C:21](=[O:22])[C:13]2[CH:8]3[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]3)[CH2:6][CH:5]([O:4][C:2](=[O:3])[CH3:1])[C:14]=2[C:15]2([CH3:30])[C:16]=1[C:17](=[CH:58][N:57]([CH2:56][CH2:55][CH2:54][N:51]1[CH2:50][CH2:49][N:48]([C:45]3[CH:44]=[CH:43][C:42]([O:41][CH3:40])=[CH:47][CH:46]=3)[CH2:53][CH2:52]1)[CH3:32])[C:23](=[O:24])[O:25][CH:26]2[CH2:27][O:28][CH3:29]
Reactant: CNCCCN1CCN(c2ccc(OC)cc2)CC1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(C)CCCN2CCN(c3ccc(OC)cc3)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added {3-[4-(4-methoxy-phenyl)-piperazin-1-yl]-propyl}-methyl-amine hydrochloride (123 mg). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 695 (M+H).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:8][N:9]=1)(=O)C.C(N)(=O)C.CC(NC1SC(S(N)(=O)=O)=NN=1)=O.Cl>CO>[NH2:4][C:5]1[S:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:8][N:9]=1
Reactant: CC(=O)Nc1nnc(S(N)(=O)=O)s1
Agent: CC(N)=O
Agent: Cl
Solvent: CO
Product: Nc1nnc(S(N)(=O)=O)s1
Reaction time: 6 h
Yield: 85 %

Procedure:
This is prepared by hydrolysis of the acetamide 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide (acetazolamide). A slurry of 0.2 mol of acetazolamide in 600 mL of methanol is treated with 60 mL 12N HCl. This mixture is heated with stirring to reflux for 6 hours. Reaction progress is monitored using liquid chromatography. If reaction is not completed after 6 hours, another 30 mL of 12N HCl is added, and the mixture held at reflux for 2 hours. Methanol is then removed under reduced pressure. Product is recovered after raising the pH of the suspension to 7 by addition of NaOH at 0° C.-4° C., followed by filtration. Yield is between 85% and 98% of theoretical with 99% purity. KI =40 nM.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH3:19])[CH:17]=2)[N:6]=[CH:5][CH:4]=1)#[N:2].OO.NC(N)=[O:24].FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(#N)C.C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[CH:5][N+:6]([O-:24])=[C:7]([C:13]2[CH:14]=[N:15][N:16]([CH2:18][CH3:19])[CH:17]=2)[C:8]=1[C:9]([O:11][CH3:12])=[O:10])#[N:2]
Reactant: NC(N)=O
Reactant: CCn1cc(-c2nccc(C#N)c2C(=O)OC)cn1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCn1cc(-c2c(C(=O)OC)c(C#N)cc[n+]2[O-])cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-cyano-2-(1-ethyl-1H-pyrazol-4-yl)nicotinate (207 mg, 0.808 mmol) in ACN (2 mL) was added urea hydrogen peroxide (380 mg, 4.04 mmol) and trifluoroacetic anhydride (0.456 mL, 3.23 mmol) at 0° C. The resulting mixture was stirred at RT overnight. Next, saturated aq NaHCO3 solution and chloroform were added. The aqueous phase was extracted with chloroform (3×200 mL). The organic layers were combined and washed with brine, dried over MgSO4, and evaporated to give the title compound which was used without further purification (210 mg, 95%). [M+H] calc'd for C13H12N4O3, 273.5; found, 273.5.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28](=[O:37])[NH:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>ClC(Cl)C>[F:36][C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:28]([O:27][C:24]2[CH:23]=[CH:22][C:21]([C:18]3[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:7]([CH:8]([CH3:10])[CH3:9])[C:6]([OH:38])=[O:5])(=[O:14])=[O:13])=[CH:16][CH:17]=3)=[CH:26][CH:25]=2)=[O:37])=[CH:35][CH:34]=1
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)Nc3ccc(F)cc3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: CC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)Nc3ccc(F)cc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
2-[4′-(4-Fluoro-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (223 mg) was dissolved in dichloroethane (7.5 mL) and added with TFA (2.5 mL). The mixture was stirred at room temperature for 5 hrs and TLC indicated the reaction was complete. Regular work-up and column chromatography to give 2-[4′-(4-Fluoro-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid in 89% yield (178 mg).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8](Cl)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].C(O)C[OH:18].Cl>O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([OH:18])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCO
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1c(O)cnn(C(C)(C)C)c1=O
Temperature: 130 °C
Reaction time: 4 h

Procedure:
(Method A): A mixture of 2.0 g (0.01 mol) of 2-tert.-butyl-5-chloro-4-methyl-3(2H)-pyridazinone and 2.8 g (0.05 mol) of potassium hydroxide was added to 30 ml of ethylene glycol and stirred at 130° C. for 4 hours. After allowing to cool, the reaction liquid was poured into 200 ml of water and added with 20 ml of 6N hydrochloric acid. The crystals thus precipitated were collected by filtration. After drying, the crystals were washed with 30 ml of hot isopropyl ether to give 1.7 g of 2-tert.-butyl-5-hydroxy-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.C([O:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[N:43][C:44]=1[C:45]([F:48])([F:47])[F:46])C1C=CC=CC=1.Cl.[H][H]>CC(O)C.[Pd]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16](=[O:30])[C:17]4[C:22]([C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH3:13])[N:9]=[C:10]([C:41]3[CH:42]=[N:43][C:44]([C:45]([F:47])([F:48])[F:46])=[C:39]([OH:38])[CH:40]=3)[C:3]=12
Reactant: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Reactant: OB(O)c1cnc(C(F)(F)F)c(OCc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(-c2cnc(C(F)(F)F)c(O)c2)c2c(N)ncnc21
Yield: 18.9 %

Procedure:
The title compound was made in a similar way as that of example 68, using 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (intermediate D2a, 100 mg, 0.196 mmol) and (5-(benzyloxy)-6-(trifluoromethyl)pyridin-3-yl)boronic acid (Intermediate G25, 87 mg, 0.295 mmol). The resulting crude material was reacted in 2-Propanol (10 ml) with 1 N aqueous HCl (1 ml), palladium on carbon 5% wet (0.071 mmol) and hydrogen (1 atm). Then, catalyst was filtered off over celite pad and solvent was removed. Target product was purified by purified by C18 flash chromatography (Snap 30 g chromatography ((H2O/ACN)) 95:5+0.1% HCOOH}:{(ACN/H2O) 95:5+HCOOH 0.1%} from 100:0 to 0:100 affording the title compound (20 mg, 0.037 mmol, 51.8% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:17])=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].[H][H].[C:20]1([CH2:26]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.C(OCC)C>[C:20]1([CH2:26][O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[C:4]([F:17])[F:3])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [H][H]
Reactant: OCCCCCCCCCCC=C(F)F
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: FC(F)=CCCCCCCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
Under a nitrogen atmosphere a stirred mixture of 0.18 gram (0.0075 mole) of sodium hydride in 25 ml of tetrahydrofuran was cooled in an ice-bath, and 1.5 grams (0.0068 mole) of 12,12-difluoro-11-dodecen-1-ol (prepared in Example 5) was added dropwise. Upon completion of addition and when the evolution of hydrogen ceased, a solution of 1.2 grams (0.0068 mole) of phenylmethyl bromide in 5 ml of tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 18 hours. After this time the reaction mixture was taken up in 150 ml of diethyl ether and was washed with 50 ml of water and then with 50 ml of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure yielding 0.8 gram of 12,12-difluoro-11-dodecenyl phenylmethyl ether. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)[C:2]#[CH:3].I[C:22]1[N:23]=[C:24]([NH2:40])[C:25]2[N:26]=[CH:27][N:28]([C:38]=2[N:39]=1)[C@@H:29]1[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]1[OH:31]>>[CH3:20][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[CH3:19])[O:12][C:10]([N:7]1[CH2:6][CH2:5][CH:4]([CH2:1][C:2]#[C:3][C:22]2[N:23]=[C:24]([NH2:40])[C:25]3[N:26]=[CH:27][N:28]([C:38]=3[N:39]=2)[C@@H:29]2[O:37][C@H:34]([CH2:35][OH:36])[C@@H:32]([OH:33])[C@H:30]2[OH:31])[CH2:9][CH2:8]1)=[O:11]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C#CCC1CCN(C(=O)Oc2ccc(C)c(C)c2)CC1
Product: Cc1ccc(OC(=O)N2CCC(CC#Cc3nc(N)c4ncn([C@@H]5O[C@H](CO)[C@@H](O)[C@H]5O)c4n3)CC2)cc1C

Procedure:
3,4-Dimethylphenyl 4-(prop-2-ynyl)piperidine-1-carboxylate (1.430 g, 5.27 mmol) was added to a solution of 2-iodoadenosine (0.620 g, 1.577 mmol) according to general procedure 2: yield 252 mg, 30%. 1H NMR (CD3OD) δ 8.30 (s, 1H), 7.08 (d 1H, J=8.2 Hz), 6.84 (d, 1H, J=2.3 Hz), 6.78 (dd, 1H, J=2.4, J=8.1 Hz), 5.93 (d, 1H, J=6.5 Hz), 4.71 (dd, 1H, J=5.1 Hz, J=6.5 Hz), 4.38-4.27 (m, 2H), 4.25-4.14 (m, 2H), 3.89 (dd, 1H, J=2.3 Hz, J=12.6 Hz), 3.74 (dd, 1H, J=2.6, J=12.6 Hz), 3.04, 2.90 (2×br t, 2H), 2.46 (d, 2H, J=6.2 Hz), 2.23, 2.22 (2×s, 6H), 2.02-1.79, 1.52-1.26 (2×m, 5H). 13C NMR (CD3OD) δ 157.3, 155.8, 150.8, 150.2, 147.5, 142.6, 138.8, 134.7, 131.1, 123.7, 120.5, 119.9, 91.4, 88.3, 86.7, 82.3, 75.5, 72.6, 63.5, 45.5, 36.5, 32.5, 26.5, 19.8, 19.1. LRMS ESI (M+H+) 537.2. HPLC rt=10.9 min.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[C:9]=1[C:10]([C:12]1[CH:17]=[C:16]([Br:18])[C:15]([OH:19])=[C:14]([Br:20])[CH:13]=1)=[O:11])[CH2:2][CH2:3][CH3:4].Br[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28]>>[Br:18][C:16]1[CH:17]=[C:12]([C:10]([C:9]2[C:8]3[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=3[O:6][C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[O:11])[CH:13]=[C:14]([Br:20])[C:15]=1[O:19][CH2:26][C:27]([OH:29])=[O:28]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCc1oc2ccccc2c1C(=O)c1cc(Br)c(O)c(Br)c1
Product: CCCCc1oc2ccccc2c1C(=O)c1cc(Br)c(OCC(=O)O)c(Br)c1

Procedure:
This compound was prepared from (2-butyl-benzofuran-3-yl)-(3,5-dibromo-4-hydroxy-phenyl)-methanone and tert-butyl bromoacetate in substantially the same manner, as described in Example 2, and was obtained as an off-white solid, mp 92-94° C.; MS m/e 508 (M+); Analysis for: C21H18Br2O5 Calc'd: C, 49.44; H, 3.56 Found: C, 47.24; H, 3.59
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:9])[CH3:8].CC[C@H:13](O)[C@@H:14]([C:16]1[O:22][C@@H:21]([CH3:23])[C@@H:20]([CH3:24])[C:18](=[O:19])[C:17]=1[CH3:25])[CH3:15].CN(C)C=[O:30]>>[CH3:23][CH:21]1[CH:20]([CH3:24])[C:18](=[O:19])[C:17]([CH3:25])=[C:16]([C:14]([CH3:13])([O:30][C:7](=[O:9])[CH3:8])[CH3:15])[O:22]1
Reactant: CC(=O)Cl
Reactant: CN(C)C=O
Reactant: CC[C@H](O)[C@H](C)C1=C(C)C(=O)[C@H](C)[C@H](C)O1
Solvent: c1ccncc1
Product: CC(=O)OC(C)(C)C1=C(C)C(=O)C(C)C(C)O1
Temperature: 25 °C
Reaction time: 10 h
Yield: 90 %

Procedure:
After adding 7.9 g (0.1 moles) of pyridine and 7.8 g (0.1 moles) of acetyl chloride to 100 ml of dehydrated dimethylformamide and cooling the mixture with ice, 11.3 g (0.05 moles) of stegobiol were dripped and agitated at 20° at 25° C. for 10 hours to provide 12.1 g of 2,3-dihydro-2,3,5-trimethyl-6-(1-methyl-1-acetoxyethyl)-4H-pyran-4-on. The yield was 90%.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([C:11](C1C=C(C(C)C)C(OC)=CC=1OC)=[O:12])[CH2:5]2.C([O-])([O-])=O.[Na+].[Na+].[C:32]1(C)C=CC=C[CH:33]=1>CO.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>[CH:32]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([CH:11]=[O:12])[CH2:5]2)=[CH2:33]
Reactant: COc1cc(OC)c(C(C)C)cc1C(=O)N1Cc2ccc(Br)cc2C1
Reactant: Cc1ccccc1
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: [Na+]
Solvent: O
Solvent: CO
Product: C=Cc1ccc2c(c1)CN(C=O)C2
Temperature: 80 °C

Procedure:
To (5-bromo-1,3-dihydro-isoindol-2-yl)-(5-isopropyl-2,4-dimethoxyphenyl)methanone (2.2 g, 5.44 mmol), and 2-vinyl-4,4,5,5-tetramethyl-1,3,2-dioxaboralane (1.2 ml, 6.53 mmol) in MeOH (25 ml) and toluene (25 ml) was added Na2CO3 in water (25 ml). The reaction was degassed, Pd(PPh3)4 (0.38 g, 0.05 mmol) added then heated at 80° C. overnight. The reaction was worked up by adding water and extracting with EtOAc (×3). The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness then purified by flash column chromatography, gradient elution (ether:petrol) to yield 5-isopropyl-2,4-dimethoxy-phenyl)-(5-vinyl-1,3-dihydro-isoindol-2-yl)-methanone as a yellow oil (1.6 g). 1H NMR (Me-d3-OD) 7.47-7.15 (3H, m), 7.15 (1H, s), 6.82-6.72 (1H, m), 6.71 (1H, s), 5.79 (1H, dd), 5.24 (1H, dd), 4.90 (2H, d), 4.64 (2H, d), 3.93 (3H, s), 3.91 (3H, s), 3.27 (1H, sept), 1.23 (6H, d). MS: [M+H]+ 352.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:17])[CH2:15][CH2:14][C:13](=O)[CH:12]=[CH:11]1.[Cl-].[NH4+].C([OH:23])(C)C>O1CCCC1>[CH3:9][C:10]1([CH3:17])[CH2:15][CH2:14][C:13]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)=[CH:12][C:11]1=[O:23]
Reactant: CC(C)O
Reactant: Fc1ccc(Br)cc1
Reactant: CC1(C)C=CC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CCC(c2ccc(F)cc2)=CC1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
1-bromo-4-fluorobenzene (7.06 g, 40 mmole) was dissolved in 20 ml of tetrahydrofuran, then the resulting solution was stirred at -78° C. in an argon gas stream. N-butyl lithium (25.2 ml, 1.6 mole solution) was added slowly and the solution was allowed to stand for 15 minutes. A solution of 5 g (40 mmole) of 4,4-dimethyl-2-cyclohexene-1-one in 20 ml of tetrahydrofuran was slowly added to the above solution, and then, the resulting solution was allowed to stand for 30 minutes. Thereafter, a saturated aqueous solution of ammonium chloride was added, the whole solution was poured into ice water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate to remove the solvent. 20 ml of acetone was added to the residue, until the Jone's reagent previously prepared no longer changed color (until it no longer became green). After 30 minutes, the reaction was ceased by adding isopropyl alcohol. The whole was poured into ice water, and the crude product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate to the solvent was removed by evaporation. The residue was purified by column chromatography (10% ethyl acetate/hexane) to obtain the above-titled compound [V-1] (7.8 g).