Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S(C=C(SC)SC)(=O)=O)C=CC=CC=1.C[C:17]1[N:18]=CN[C:21]=1[CH2:22]SCCN.[C:27]1([S:33]([CH:36]=[C:37](SC)[NH:38][CH2:39][CH2:40][S:41][CH2:42][C:43]2[NH:47][CH:46]=[N:45][C:44]=2[CH3:48])(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N)C#C>>[C:27]1([S:33]([CH:36]=[C:37]([NH:18][CH2:17][C:21]#[CH:22])[NH:38][CH2:39][CH2:40][S:41][CH2:42][C:43]2[NH:47][CH:46]=[N:45][C:44]=2[CH3:48])(=[O:34])=[O:35])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CSC(=CS(=O)(=O)c1ccccc1)NCCSCc1[nH]cnc1C
Reactant: Cc1nc[nH]c1CSCCN
Agent: C#CCN
Agent: CSC(=CS(=O)(=O)c1ccccc1)SC
Product: C#CCNC(=CS(=O)(=O)c1ccccc1)NCCSCc1[nH]cnc1C

Procedure:
Reaction of methylphenylsulfone with carbon disulphide under strongly basic conditions and treatment of the product with methyl iodide yields 1-benzenesulphonyl-2,2-bis(methylthio)ethylene. When 1-benzenesulfonyl-2,2-bis(methylthio)ethylene is reacted with 2-[(4-methyl-1H-imidazol-5-yl)-methylthio]ethylamine according to the procedure of Example 6, Step A, the product is 1-benzenesulfonyl-2-methylthio-2-{2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamino}ethylene. Reaction of this methylthio compound with propargylamine by the procedure of Example 6, Step B, yields the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:26])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=3)[N:10]=2)[CH:8]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:26][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:30]([CH:27]2[CH2:29][CH2:28]2)=[O:31])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=2)[N:10]=1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc(-n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2nc(-c3cc(CNC(=O)C4CC4)ccc3Cl)[nH]c2=O)ccc1[N+](=O)[O-]

Procedure:
The title compound was prepared according to the procedure as described in step-2 Intermediate-30 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(3-methoxy-4-nitrophenyl)-1H-1,2,4-triazol-5(4H)-one (0.500 g, 1.33 mmol), cyclopropylcarbonyl chloride (0.207 g, 1.99 mmol), DIPEA (2.0 mL) and THF (30 mL) to afford 0.300 g of crude product which was triturated with methanol:DEE to afford 0.300 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 0.69 (s, 4H), 1.60 (m, 1H), 3.97 (s, 3H), 4.33 (d, J=5.4 Hz, 2H), 7.42-7.55 (m 3H), 7.70 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 8.12 (d, J=8.7 Hz, 1H), 8.69-8.71 (m, 1H), 12.83 (s, 1H); MS (m/z): 442.14 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)OCc2ccccc2)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(C(=O)O)cc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of benzyl 3-(benzyloxy)-4-methylbenzoate (4.30 g) in methanol (40 mL) and THF (40 mL) was added a solution of sodium hydroxide (2.60 g) in water (40 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and evaporated under reduced pressure. Water (20 mL) was added to the residue, and the mixture was adjusted with 1N hydrochloric acid to pH<4. The precipitated crystals were collected by filtration, and dried to give the title compound (2.80 g) as white crystals.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:7])C.O.[NH2:23][NH2:24]>C(O)C>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3([CH3:7])[CH2:5][C:4](=[O:3])[NH:24][NH:23]3)=[CH:9][CH:10]=2)=[CH:15][CH:16]=1
Reactant: NN
Reactant: CCOC(=O)C=C(C)c1ccc(-c2ccc(F)cc2)cc1
Solvent: CCO
Solvent: O
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
A solution of 28.4 g of 3-(4'-fluoro-4-biphenylyl)-2-butenoic acid ethyl ester [obtainable by dehydrating 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester employing p-toluenesulfonic acid] and 25 g of hydrazine hydrate (100% strength) in 400 ml of ethanol is boiled for 18 hours. The mixture is cooled, poured onto ice water and worked up in the usual manner to give 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([C:19]#[N:20])=[C:8]2[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1.[H-].[Na+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].O>CN(C)C=O>[C:19]([C:9]1[C:10]([CH2:15][CH:16]([CH3:18])[CH3:17])=[N:11][C:12]2[C:7]([C:8]=1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=[CH:6][C:5]([O:4][CH2:3][CH2:2][O:1][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:14][CH:13]=2)#[N:20]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(OCCO)cc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(OCCOCC(=O)OC(C)(C)C)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.7 %

Procedure:
To a solution of 6-(2-hydroxyethoxy)-2-isobutyl-4-(4-methylphenyl)quinoline-3-carbonitrile (1.0 g, 2.8 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (60% in oil, 0.14 g, 3.4 mmol), and the mixture was stirred at room temperature for 1 hr. tert-Butyl bromoacetate (1 ml, 6.8 mmol) was added to the reaction mixture and the mixture was stirred at room temperature for 17 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl (2-{[3-cyano-2-isobutyl-4-(4-methylphenyl)quinolin-6-yl]oxy}ethoxy)acetate (0.9 g, yield 69%) as an oil.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[NH:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.CN(C=O)C.[H-].[Na+].I[CH2:25][CH3:26]>O>[CH2:25]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[NH:10][C:11](=[O:12])[C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2)[CH3:26]
Reactant: CCI
Reactant: O=C1Nc2ccccc2Nc2ncccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1c2ccccc2NC(=O)c2cccnc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A mixture of 15 g of 6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 150 ml DMF was heated to 50° C. To the slurry was added 7.5 g (2 equiv) of 50% sodium hydride in mineral oil dispersion, during which time the temperature rose to 65° C. The mixture was cooled to 40° C. and then 6.0 ml of iodoethane was added. The resulting mixture was stirred at room temperature overnight, then poured into 700 ml of water and extracted with 700 ml of ether. The ether phase was dried (MgSO4) and concentrated to dryness. The crude product was purified by column chromatography on basic alumina to yield 3.6 g (21% of theory) of 6,11-dihydro-11-ethyl-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one, m.p. 210°-220° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]([CH3:21])([CH3:20])[CH2:7][CH:8]([NH:12][C:13]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[O:14])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl[C:25]1[N:30]=[C:29]([NH:31][C:32]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:33]=2[C:34]([NH:36][CH3:37])=[O:35])[C:28]([Cl:43])=[CH:27][N:26]=1>>[Cl:43][C:28]1[C:29]([NH:31][C:32]2[C:33]([C:34](=[O:35])[NH:36][CH3:37])=[CH:38][CH:39]=[CH:40][C:41]=2[F:42])=[N:30][C:25]([NH:1][C:2]2[CH:23]=[CH:22][C:5]3[C:6]([CH3:20])([CH3:21])[CH2:7][CH:8]([NH:12][C:13]([N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)=[O:14])[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:26][CH:27]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CC(NC(=O)N2CCCC2)C(=O)Nc2cc(N)ccc21
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)N2CCCC2)CC3(C)C)ncc1Cl

Procedure:
Pyrrolidine-1-carboxylic acid {8-[5-chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl}-amide was prepared from Pyrrolidine-1-carboxylic acid (8-amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-amide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:18])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.CN(C=O)C.[H-].[Na+].[F:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1F.Cl.CCO>>[F:26][C:27]1[CH:32]=[C:31]([F:33])[C:30]([F:34])=[CH:29][C:28]=1[O:18][C@@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCC[C@@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cc(F)c(F)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCC[C@@H](Oc1cc(F)c(F)cc1F)[C@H]1CCNC1
Temperature: 90 °C

Procedure:
(S)-3-((R)-1-Hydroxypentyl)pyrrolidine-1-carboxylic acid t-butyl ester (40.0 mg, 155 μmmol) was dissolved in DMF (100 mL, 12.9 mmol). While stirring, 60% sodium hydride in oil (0.4:0.6, sodium hydride:mineral oil, 18.6 mg, 311 μmmol) was slowly added, and the mixture was stirred for 15 minutes. 1,2,4,5-Tetrafluorobenzene (52.1 μL, 466 μmmol) was added. The mixture was then heated at 90° C. for 3 hours. The reaction was quenched with MeOH (1 mL), and the solvent was removed under reduced pressure. 1.25M HCl in EtOH (2.0 mL, 2.5 mmol) was added, and the mixture was stirred overnight. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (19.2 mg, 97% purity). MS m/z: [M+H]+ calcd for C15H20F3NO, 288.15; found 288.2.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].C(#N)C.C(N(CC)CC)C.[CH3:34][S:35][C:36](SC)=[CH:37][N+:38]([O-:40])=[O:39]>>[CH3:34][S:35]/[C:36](/[N:7]1[CH2:8][CH2:9][C@H:10]([C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)=[O:12])[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)=[CH:37]\[N+:38]([O-:40])=[O:39]
Reactant: COC(=O)[C@H]1CNCC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H]1CN(/C(=C/[N+](=O)[O-])SC)CC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Temperature: 85 °C
Yield: 53.4 %

Procedure:
To a stirred solution of (3R,4S)-4-((R)-3-phenyl-pyrrolidine-1-carbonyl)-piperidine-3-carboxylic acid methyl ester (3.10E2 mg, 0.000980 mol) in anhydrous acetonitrile (9.8 mL, 0.19 mol) at rt was added triethylamine (274 uL, 0.00196 mol) and 1,1-bis(methylthio)-2-nitroethylene (248 mg, 0.00147 mol). The reaction mixture was heated to reflux (oil bath temperature: 85° C.) for 19 h. The reaction mixture was concentrated in vacuo. The residue was purified by Combiflash with 40-95% EtOAc/Hex to give the product as a yellow viscous oil (227 mg, 53% in yield). MS (ESI): (M+H)+=434.1.
Reaction SMILES: [Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH2:4].[OH-].[Na+].[Cl-].[C:16]([NH3+])(C)(C)C.S(OC)(OC)(=O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-:12])=[O:11])[C:3]=1[NH:4][CH3:16]
Reactant: Nc1c([N+](=O)[O-])ccc(Cl)c1Cl
Reactant: CC(C)(C)[NH3+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Product: CNc1c([N+](=O)[O-])ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,3-dichloro-6-nitroaniline (1.026 g, 5 mmole), was suspended in toluene (10 ml). To this vigorously stirred suspension was added 50% aqueous sodium hydroxide solution (1.7 g), tertiary-butyl ammonium chloride (0.07 g, 0.25 mmole) and dimethyl sulfate (0.51 ml, 5.4 mmole). After 4 hr stirring at room temperature the intense red solution was washed with water, brine, dried with magnesium sulfate, filtered, evaporated in vacuo. Weight=1.03 g, m.p.=82° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([CH2:9][OH:10])[CH:8]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25]Br>C1COCC1>[CH3:20][O:21][C:22](=[O:27])[CH2:23][CH2:24][CH2:25][O:11][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[C:7]([CH2:9][OH:10])[CH:6]=1
Reactant: COC(=O)CCCBr
Reactant: OCc1cc(O)cc(CO)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCCOc1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3,5-bis-hydroxymethylphenol (Felder, D.; Gutiérrez Nava, M.; del Pilar Carreon, M.; Eckert, J. F.; Luccisano, M.; Schell, C.; Masson, P.; Gallani, J. L.; Heinrich, B.; Guillon, D.; Nierengarten, J. F. Helv. Chimica Acta 2002, 85, 288) (200 mg), potassium iodide (50 mg) and potassium carbonate (540 mg) in THF (2.5 mL) was added 4-bromo-butyric acid methyl ester (400 μL). The reaction mixture was stirred for 20 h at room temperature then the unsoluble part was filtered off. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (Merck SuperVarioFlash 30 g column, Si60 15-40 μm), using gradient elution with a mixture of MeOH (A)/DMC (B), (gradient: 100% B down to 5% A: 95% B) to give 4-(3,5-bis-hydroxymethyl-phenoxy)-butyric acid methyl ester (53.5 mg): LC/MS (Method A2: ES: m/z=255 MH+; m/z=237 (M+H−H2O)+; RT=2.5 min; 1H N.M.R. (400 MHz, DMSO-d6, δ in ppm): δ=1.96 (m, 2H); 2.47 (t, J=6.5 Hz, 2H); 3.61 (s, 3H); 3.96 (t, J=6.5 Hz, 2H); 4.43 (d, J=6.0 Hz, 4H); 5.11 (t, J=6.0 Hz, 2H); 6.71 (s, 2H); 6.82 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C@:27]([OH:31])([C:29]#[CH:30])[CH3:28])[N:23]=1>N1CCCCC1.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.[Cu]I>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:30]#[C:29][C@@:27]([OH:31])([C:24]4[N:23]=[C:22]([CH3:21])[O:26][N:25]=4)[CH3:28])[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: Nc1nccc(-n2nc(C(=O)O)c3ccc(I)cc32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(C(=O)O)nn(-c4ccnc(N)n4)c3c2)no1
Temperature: 35 °C

Procedure:
To a solution of 1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic acid (150 mg, 0.39 mmol) in piperidine (1.5 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (45.5 mg, 0.04 mmol), copper(I) iodide (7.4 mg, 0.04 mmol) and (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (120 mg, 0.79 mmol). The reaction was warmed to 35° C. for 1 hr. After cooling to RT, the reaction mixture was concentrated in vacuo and the residue purified by silica gel flash column chromatography (eluent: DCM containing a 1-15% MeOH gradient followed by 85:15 DCM:7M ammonia in methanol). The partially purified product was suspended in 2M aqueous citric acid (3 mL) and extracted with 3:1 chloroform/isopropanol (5×5 mL). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo to furnish the title compound as a yellow-brown solid: 1H NMR (500 MHz, DMSO) delta 1.91 (3H, s), 2.64 (3H, s), 6.81 (1H, s), 7.27 (1H, d, J=5.9 Hz), 7.54 (1H, dd, J=8.4, 1.2 Hz), 7.80 (2H, s), 8.22 (1H, d, J=8.3 Hz), 8.42 (1H, d, J=6.0 Hz), 8.97 (1H, s), 13.92 (1H, s); LC-MS: m/z=+406.00 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1.N#N.[Br-].[CH2:16]([Zn+])[CH2:17][CH3:18]>C1COCC1.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>[CH2:16]([C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1)[CH2:17][CH3:18]
Reactant: CCC[Zn+]
Reactant: CCOC(=O)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCc1cccc(C(=O)OCC)n1
Temperature: 25 °C

Procedure:
A solution of ethyl 6-bromopicolinate (8 g, 34.8 mmol, purchased from AK Scientific, Inc., Union City, Calif.) in THF (200 mL) was sparged with N2 at 0° C. for 20 min. To the mixture under N2 atmosphere was added Pd(PPh3)4 (3.21 g, 2.78 mmol) and a solution of propylzinc bromide (100 mL, 0.5 M in THF, 50.0 mmol) dropwise over 30 min. The mixture was removed from the ice bath and heated to reflux for 18 h. After that time the solution was cooled to rt, poured into saturated aqueous NH4Cl solution (18 mL), diluted with water (30 mL), and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water and sat. aq. NaCl solution and were dried over Na2SO4. After removal of the organic solvents under reduced pressure, purification of the residue by flash chromatography on silica gel with 0 to 50% EtOAc/hexanes provided the title compound. Mass Spectrum (ESI) m/z=194.0 (M+1).
Reaction SMILES: C(OC([O:7][CH2:8][CH3:9])C=O)C.[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2C=1C=[N:18][CH:17]=[CH:16]2>>[Br:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:9]=1[C:8](=[O:7])[NH:18][CH:17]=[CH:16]2
Reactant: CCOC(C=O)OCC
Reactant: Brc1cccc2ccncc12
Product: O=c1[nH]ccc2cccc(Br)c12

Procedure:
The isoquinolin-8-yl system can be prepared from the appropriately substituted benzylamine by cyclocondensation with diethoxy-acetaldehyde (see, for example, K. Kido and Y. Watanabe, Chemical & Pharmaceutical Bulletin, 35(12), 4964-6; 1987). Alternatively 8-bromo-isoquinoline (prepared by the method of F. T. Tyson, J.A.C.S., 1939, 61, N. Briet et al., Tetrahedron (2002), 58(29), 5761-5766 or W. D. Brown, et al., Synthesis (2002), (1), 83-86. 183 can be subjected to N-oxidation and rearrangement to give 8-bromo-2H-isoquinolin-1-one. This can be N-methylated to give 8-bromo-2-methyl-2H-isoquinolin-1-one, an appropriate intermediate for the 2-methyl-1-oxo-1,2-dihydroisoquinolin-8-yl system.
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][N:6]1[CH:11]([CH3:12])[CH2:10][N:9]([C:13]2[C:22]([O:23][CH3:24])=[C:21]3[C:16]([C:17](=[O:42])[C:18]([C:30]([NH:32][CH2:33][C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=4[Cl:41])=[O:31])=[CH:19][N:20]3[CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:15][C:14]=2[F:43])[CH2:8][CH:7]1[CH3:44])C.[OH-].[Li+].CS(C)=O>O1CCOCC1>[Cl:41][C:35]1[CH:36]=[C:37]([Cl:40])[CH:38]=[CH:39][C:34]=1[CH2:33][NH:32][C:30]([C:18]1[C:17](=[O:42])[C:16]2[C:21](=[C:22]([O:23][CH3:24])[C:13]([N:9]3[CH2:8][CH:7]([CH3:44])[N:6]([CH2:5][C:4]([OH:45])=[O:3])[CH:11]([CH3:12])[CH2:10]3)=[C:14]([F:43])[CH:15]=2)[N:20]([CH2:25][C:26]([F:27])([F:28])[F:29])[CH:19]=1)=[O:31]
Reactant: CCOC(=O)CN1C(C)CN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4Cl)cn(CC(F)(F)F)c3c2OC)CC1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: COc1c(N2CC(C)N(CC(=O)O)C(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(CC(F)(F)F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
45.0 mg (0.06 mmol) of the compound from Example 1 are dissolved in 1 ml of dioxane, and 0.31 ml (0.31 mmol) of a 1M lithium hydroxide solution are subsequently added and the mixture is stirred at room temperature overnight. For the work-up, the solvent is removed on a rotary evaporator, the residue is taken up in water and acidified (pH 3) using 1M hydrochloric acid, and the precipitate formed is dissolved with a little dimethyl sulfoxide. After fine purification via preparative RP-HPLC (method 5), 38 mg of the target compound are obtained from the solution.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=[CH:12][C:13]=1[O:14]C1CCCCO1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(N(CC)CC)C>[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: CCCCC=Cc1ccc(OC2CCCCO2)c(OC2CCCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCC=Cc1ccc(O)c(O)c1
Reaction time: 2 h
Yield: 57.8 %

Procedure:
In 10 ml of absolute methanol was dissolved 198 mg of 1-(3',4'-bistetrahydropyranyloxy-phenyl)-1-hexene obtained in Example 17-(1), and a catalytic amount of p-toluenesulfonic acid was added to the solution at 0° C. The mixture was stirred for 2 hours at the same temperature. After reaction, one drop of triethylamine was added to the reaction mixture and the mixture was concentrated to give crude product. By purification of the crude product by means of column chromatography [silica gel/ether:hexane (1:2)], 61 mg of pure product was obtained.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[CH:9][C:8]=1[F:22])([CH3:4])([CH3:3])[CH3:2].[Li]C(CC)C.B(OC)(OC)[O:31]C.C(O)(=O)C.OO.O>C1COCC1>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[C:8]([F:22])=[C:9]([OH:31])[CH:10]=[C:11]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COB(OC)OC
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: OO
Agent: [Li]C(C)CC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)c1cc(O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
To a solution of 2-(tert-butyl-dimethyl-silanyloxy)-4-(tert-butyl-dimethyl-silanyloxymethyl)-1-fluoro-benzene (23.70 g, 63.9 mmol, 1.0 equiv) in anhydrous THF (130 mL) was added at −78° C. under Ar a solution of sec-BuLi (54.5 mL, 71.6 mmol, 1.1 equiv; 1.3 M solution in hexane) within 30 min. Then a solution of trimethyl borate (7.13 mL, 6.64 g, 63.9 mmol, 1.0 equiv) in anhydrous THF (30 mL) was added slowly within 30 min and the cooling bath removed. A solution of conc. acetic acid (5.49 mL, 5.76 g, 95.9 mmol, 1.5 equiv) was slowly added followed by addition of a solution of 35% hydrogen peroxide in water (6.2 mL, 6.83 g, 70.3 mmol, 1.1 equiv) and the reaction mixture kept at 0° C. for 30 min. After stirring at rt for an additional 4 h, the reaction was extracted with diethyl ether (2×100 mL) and the combined organic phases washed with a solution of 10% NaOH (2×100 mL) and a sat. solution of NaCl (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (19:1) providing 15.80 g (64%) of the title compound. 1H NMR (400 MHz, CDCl3): δ0.00 (s, 6H), 0.10 (s, 6H), 0.85 (s, 9H), 0.91 (s, 9H), 4.50 (s, 2H), 4.93 (br s, 1H), 6.37 (d, J=5.6 Hz, 1H), 6.47 (d, J=5.6 Hz, 1H). MS (EI): 329.2 [M-tert-Bu]+.