Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][C:11]3[CH:14]=[N:15][NH:16][C:10]=3[CH:9]=2)[CH:5]=[N:4][CH:3]=1.Cl[C:18]1[N:23]=[C:22]([N:24]2[C:29](=[O:30])[CH2:28][CH2:27][C@H:26]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:25]2)[C:21]([CH3:39])=[CH:20][CH:19]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:39][C:21]1[C:22]([N:24]2[C:29](=[O:30])[CH2:28][CH2:27][C@H:26]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:25]2)=[N:23][C:18]([N:16]2[C:10]3[CH:9]=[C:8]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[N:13]=[CH:12][C:11]=3[CH:14]=[N:15]2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(Cl)nc1N1C[C@@H](NC(=O)OC(C)(C)C)CCC1=O
Reactant: Cc1cncc(-c2cc3[nH]ncc3cn2)n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C)c(N3C[C@@H](NC(=O)OC(C)(C)C)CCC3=O)n2)n1
Temperature: 110 °C
Yield: 20.5 %

Procedure:
A mixture of 6-(6-methylpyrazin-2-yl)-1H-pyrazolo[4,3-c]pyridine (150 mg, 0.710 mmol), tert-butyl N-[(3S)-1-(6-chloro-3-methyl-2-pyridyl)-6-oxo-3-piperidyl]carbamate (497 mg, 1.42 mmol), tris(dibenzylideneacetone)dipalladium(0) (65 mg, 0.071 mmol), xantphos (84 mg, 0.14 mmol), and sodium tert-butoxide (140 mg, 1.42 mmol) in toluene 3.0 mL was stirred at 110° C. 18 h. The reaction was filtered through celite. The crude product was purified by flash chromatography (EtOAc/Heptane then MeOH/DCM eluted at 10% MeOH) to give the desired product 75 mg 20% yield. MS (ESI) m/z: 515.1.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[O:18]1[CH2:17][CH:16]1[CH2:14][O:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1CO1
Reactant: O=C1CCCc2c(O)cccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O=C1CCCc2c(cccc2OCC2CO2)N1
Yield: 60 %

Procedure:
5.3 g (0.03 mole) of 6-hydroxy-2,3,4,5-tetrahydro-1H-benzazepin-2-one, 5 ml of epibromohydrin and 4.5 g of potassium carbonate in 250 ml of methyl isobutyl ketone are refluxed for 48 hours. After the mixture has cooled, it is filtered and the filtrate is concentrated under reduced pressure on a rotary evaporator. The residue is recrystallized from cyclohexane in the presence of animal charcoal. 4.2 g (60% yield) of 6-(2,3-epoxy-propoxy)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one, of melting point 121°-123° C., are obtained.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:20][CH2:19][CH2:18][NH:17][C:16]=12)=[O:10].CI.O>CN(C=O)C.CCOC(C)=O>[CH3:7][O:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[O:20][CH2:19][CH2:18][N:17]([CH3:1])[C:16]=12)=[O:10]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc2c1NCCO2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2c1N(C)CCO2
Temperature: 75 °C
Reaction time: 2 h

Procedure:
K2CO3 (1.79 mmol) is added to a solution of 3,4-dihydro-2H-benzo[1,4]oxazine-5-carboxylic acid methyl ester (0.78 mmol) in DMF (1.0 mL). After 30 min methyl iodide (1.55 mmol) is added and the mixture is stirred for 2 h at 75° C. Cold water and EtOAc are added, the layers are separated and the aq. layer is extracted with EtOAc. The combined organic layers are washed with water and brine, dried over MgSO4 and concentrated in vacuo to give a crude product which is used without further purification. LC-MS: tR=0.71 min; [M+H]+=208.1.
Reaction SMILES: CC1CCCO1.Cl.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:19]3[CH2:20][CH2:21][CH:16]2[CH2:17][CH2:18]3)=[CH:11][C:10]=1[C:22]([F:25])([F:24])[F:23].[O:26]=[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[C:37]([F:40])([F:39])[F:38])[NH:30][CH:29]=[C:28]1[C:41](O)=[O:42].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1>O>[CH:16]12[N:15]([C:12]3[CH:13]=[CH:14][C:9]([NH:8][C:41]([C:28]4[C:27](=[O:26])[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][C:35]=5[C:37]([F:40])([F:38])[F:39])[NH:30][CH:29]=4)=[O:42])=[C:10]([C:22]([F:25])([F:23])[F:24])[CH:11]=3)[CH:19]([CH2:18][CH2:17]1)[CH2:20][CH2:21]2
Reactant: Nc1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Reactant: O=C(O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC1CCCO1
Solvent: O
Product: O=C(Nc1ccc(N2C3CCC2CC3)cc1C(F)(F)F)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Temperature: 45 °C

Procedure:
2-Methyltetrahydrofuran (1 vol) was charged into a 30 L jacketed reactor vessel followed by the addition of the hydrochloride salt of 4-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline (11B) (1.2 eq) and 4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxylic acid (7) (573 g, 2.228 mol). An additional 2-methyltetrahydrofuran (9 vol) was charged into the vessel and stirring commenced. T3P in 2-methyltetrahydrofuran (2 eq) was added to the reaction mixture over a period of 15 min. Pyridine (3 eq) was added rapidly in a dropwise fashion using an addition funnel. Under stirring, the mixture was then heated to 45° C. over a period of about 30 min and this temperature was maintained for about 5 h. The mixture was cooled to room temperature. 2-Methyltetrahydrofuran (4 vol) was added, followed by the slow addition of water (6.9 vol), and the temperature of the reaction was kept below 30° C. The water layer was removed and the organic layer was washed twice with NaHCO3 saturated aqueous solution. The organic layer was then carefully washed with 10% w/w citric acid (5 vol) and water (7 vol), polished filtered, and then transferred into another dry vessel. 2-Methyltetrahydrofuran (10 vol) was added and stirring commenced. Heptane (10 vol) was rapidly added in a dropwise fashion with stirring. The mixture was stirred for a period of about 12 h, and then was vacuum filtered. The solid filter cake was introduced into another vessel. Water (15 vol) was charged into the vessel and the suspension was stirred vigorously for 48 h, and then filtered. The solid cake was washed with water (5 vol) and dried at 45° C. to constant weight to give Compound I, Form B.
Reaction SMILES: [CH2:1]([S:8][CH:9]1[NH:12][C:11](=[O:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:1]([S:8][CH:9]1[N:12]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11](=[O:13])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ICCCCc1ccccc1
Reactant: O=C1CC(SCc2ccccc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CC(SCc2ccccc2)N1CCCCc1ccccc1
Reaction time: 18 h
Yield: 14 %

Procedure:
A solution 4-(benzylthio)azetidin-2-one (1.1 g, 5.5 mmol) in dry THF (10 ml) was added dropwise over 10 minutes to a suspension of NaH (0.13 g, 5.6 mmol) in dry THF (5 ml) at -20° C. under a N2 atmosphere. A solution of 1-iodo-4-phenylbutane (1.4 g, 5.5 mmol) in dry THF (10 ml) was added dropwise over 10 minutes at -55° C. After stirring for 18 hours, the mixture was poured onto ice/water (50 g), filtered through hyflo, the THF evaporated under reduced pressure and the residue taken up in ethyl acetate. The solution was washed with brine (×2), dried (MgSO4), evaporated under reduced pressure to a yellow oil which was purified by flash chromatography on silica gel eluted with 5:1, 3:1 then 1:1 petroleun ether/ethyl acetate to give the product as a yellow oil (0.25 g, 14%). 1H NMR δ (CDCl3) 1.5 (4H, m, 2×CH2), 2.6 (2H, m, CH2Ph), 2.85, 3.2 (each 2H, m, H-3 & NCH2), 3.73 (2H, s, SCH2), 4.54 (1H, m, H-4), 7.2 (10H, m, 2×Ph--H)
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:19](=[O:26])[CH2:20][C:21](OCC)=[O:22])=[C:10]([C:15]([O:17][CH3:18])=[O:16])[N:11]2[CH3:14])=[CH:7][CH:6]=1>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Cl:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:19](=[O:26])[CH2:20][C:21]([N:2]([CH3:3])[CH3:1])=[O:22])=[C:10]([C:15]([O:17][CH3:18])=[O:16])[N:11]2[CH3:14])=[CH:7][CH:6]=1
Reactant: CNC
Reactant: CCOC(=O)CC(=O)c1c(C(=O)OC)n(C)c2cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C(=O)CC(=O)N(C)C)c2ccc(Cl)cc2n1C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A stream of gaseous dimethylamine is passed into a mixture of 15 g (44.4 mmol) of ethyl 3-[6-chloro-2-(methoxycarbonyl)-1-methyl-1H-indol-3-yl]-3-oxo-propanoate, obtained in step 2.1., and 0.2 g (1.63 mmol) of 4-(N,N-dimethyl)aminopyridine in 100 ml of toluene. Immediately a condenser, surmounted by a balloon flask, is fitted and the solution is stirred at 100° C. under low pressure for 20 h. The mixture is cooled to ambient temperature and concentrated under reduced pressure and the residue is chromatographed on a silica gel column (eluent: cyclohexane/dichloromethane: 50/50, then dichloromethane/ethyl acetate: 100/0 to 0/100). This gives 3.8 g of a yellow solid which is recrystallized from a dichloromethane/ethyl acetate mixture.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH3:17])[C:11]([CH:18]([CH3:20])[CH3:19])=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>CO.O>[OH:3][C:4]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH3:17])[C:11]([CH:18]([CH3:20])[CH3:19])=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COCOc1cc(O)c(C(=O)OC)cc1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCOc1cc(O)c(C(=O)O)cc1C(C)C
Temperature: 25 °C
Yield: 83.2 %

Procedure:
Aqueous potassium hydroxide (50% w/v, 1 ml) was added to a mixture of methyl 2-hydroxy-5-isopropyl-4-(methoxymethyloxy)benzoate (508 mg, 2.0 mmol) in methanol (10 ml) and water (4 ml) and the mixture was stirred and held at reflux for 6 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (30 ml). The solid material was collected by suction filtration, rinsed with water (2×20 ml) and sucked dry under reduced pressure to afford 2-hydroxy-5-isopropyl-4-(methoxymethyloxy)benzoic acid (400 mg, 83%) as a colourless solid. 1H NMR (DMSO-d6) 13.60 (1H, br s), 11.30 (1H, br s), 7.58 (1H, s), 6.58 (1H, s), 5.30 (2H, s), 3.42 (3H, s), 3.15 (1H, m), 1.18 (6H, d). MS: [M+H]+ 241.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:14]=[C:13]([C:15]3[CH:19]=[CH:18][O:17][C:16]=3[CH3:20])[CH:12]=[CH:11][N:10]=2)[CH2:3]1.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.O>[Br:21][C:12]1[C:13]([C:15]2[CH:19]=[CH:18][O:17][C:16]=2[CH3:20])=[N:14][C:9]([N:4]2[CH2:3][C@H:2]([CH3:1])[O:7][C@H:6]([CH3:8])[CH2:5]2)=[N:10][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1occc1-c1ccnc(N2CC(C)OC(C)C2)n1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1occc1-c1nc(N2C[C@@H](C)O[C@@H](C)C2)ncc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
2,6-Dimethyl-4-[4-(2-methyl-3-furanyl)-2-pyrimidinyl]morpholine (737 mg, 2.70 mmol) was dissolved in chloroform (13 mL), cooled in an ice bath and treated with N-bromosuccinimide (480 mg, 2.70 mmol). The resulting mixture was stirred at 0° C. for 1 hour. The reaction mixture was diluted with water and extracted with ethyl acetate (×2). The ethyl acetate layers were combined, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by SP4 Biotage column chromatography eluting with a gradient of 0-20% ethyl acetate in iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound (719 mg, 2.041 mmol, 76% yield) as a white solid. LC/MS [M+H]+=352/354.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:3]=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)[CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1Cc2cc(C3CCCC3)cc(Br)c2O1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C4CCCC4)cc(Br)c3O2)cc1
Yield: 85.7 %

Procedure:
To a solution of 4-cyclopentylphenol (3.0 g, 18.0 mmol) in acetonitrile (30 mL) cooled to 0° C. was slowly added N-bromosuccinimide (3.29 g, 18 mmol) generally according to the procedure described for Example 309 afforded 3.75 g (84%) of 2-bromo-4-cyclopentylphenol Treatment of 2-bromo-4-cyclopentylphenol (3.75 g, 16.0 mmol) with potassium carbonate (5.4.0 g, 40 mmol) and allyl bromide (2.38 g, 20.8 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-bromo-4-cyclopentylphenol. Treatment of 2-allyl-6-bromo-4-cyclopentylphenol (3.0 g, 10.0 mmol) with 3-chloroperoxybenzoic acid (3.49 g, 12.0 mmol, 77%) followed by potassium carbonate (3.7 g, 25.0 mmol) generally according to the procedure described for Intermediate 9 afforded 1.68 g, (53%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methanol (1.68 g, 4.6 mmol) with p-toluenesulfonyl chloride (0.96 g, 5.0 mmol) generally according to the procedure described for Intermediate 10 gave 1.78 g (70%) of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of (±)-(7-bromo-5-cyclopentyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.5 g, 1.1 mmol) and 2-methylphenylboronic acid (0.45 g, 3.3 mmol) generally according to the procedure described for Intermediate 35 afforded 0.51 g, (99%) of (5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.239 g, 3.67 mmol) generally according to the procedure described for Intermediate 98 afforded 0.16 g (65%) of (±)-2-(azidomethyl)-5-isopropyl-7-phenyl-2,3-dihydro-1-benzofuran. Treatment of (±)-2-(azidomethyl)-5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran with polymer-supported triphenylphosphine (0.24 g, 0.48 mmol) according to the procedure described in Example 154 afforded 0.126 g (50%) of (±)-[(5-cyclopentyl-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl]amine as a white solid, hydrochloride salt. mp 190-193° C. (dec).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[SH:9].[CH2:10](Cl)[C:11](=[CH2:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:10][CH:11]([CH2:13][S:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:12]
Reactant: C=C(C)CCl
Reactant: Cc1ccc(C)c(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C)c(SCC(C)C)c1
Yield: 88.5 %

Procedure:
A 100-ml eggplant type flask was charged with 6.9 g (50 mmol) of 2,5-dimethylthiophenol, 5.5 g (60 mmol, 1.2 equivalents) of methallyl chloride which was a halogenated olefin, 6.9 g (50 mmol, 1 equivalent) of potassium carbonate and 30 ml of acetone, and the mixture was refluxed under heat for 1 hour. The reaction mixture was allowed to cool, insolubles were removed by filtration, and the acetone was distilled off. The resultant residue was re-dispersed in n-hexane and washed with a saturated sodium chloride aqueous solution. An organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off to give 8.6 g (yield 89%) of 2-methyl-3-(2,5-dimethylphenylthio)-propane.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH:14]([CH3:19])[C:15](OC)=[O:16].Cl>CCOCC>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH:14]([CH3:19])[CH2:15][OH:16]
Reactant: COC(=O)C(C)OC1CCCCO1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CC(CO)OC1CCCCO1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
25.0 g of lithium aluminum hydride was suspended in anhydrous ether, and 36.7 g of the compound (5a) was added thereto, followed by stirring for 1 hour at 0° C. and 2 hours at room temperature and neutralization by addition of aqueous HCl solution at 0° C. The reaction mixture was subjected to extraction with ether and reduced pressure-distillation (60° C./0.3 mmHg) to obtain 28.0 g of the product. (Yield: 90.2 %)
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[C:12]1[C:17]([CH:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:29])[N:15]=[C:14]2[S:30][C:31]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=3[C:13]=12)C=C.CN1C(=O)CC(=O)N(C)C1=O>ClCCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:25]([O:24][CH:18]([C:17]1[C:12]([C:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[OH:4])=[C:13]2[C:32]3[CH2:33][CH2:34][CH2:35][CH2:36][C:31]=3[S:30][C:14]2=[N:15][C:16]=1[CH3:29])[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:26])[CH3:27]
Reactant: C=CCOc1cc(C)ccc1-c1c(C(OC(C)(C)C)C(=O)OCC)c(C)nc2sc3c(c12)CCCC3
Agent: [Pd]
Agent: CN1C(=O)CC(=O)N(C)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1O)CCCC3
Yield: 63 %

Procedure:
To a stirred solution of ethyl {4-[2-(allyloxy)-4-methylphenyl]-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl}(tert-butoxy)acetate (Step 8, 370 mg, 729 μmol) in dichloromethane (10 mL) was added 1,3-dimethylbarbituric acid (569 mg, 3.64 mmol), and the reaction was evacuated and filled with nitrogen. Palladium tetrakis(triphenylphosphine) (17 mg, 15 μmol) was added and the reaction was heated to reflux for 16 hours. Further palladium tetrakis(triphenylphosphine) (17 mg, 15 μmol) was added and the reaction was heated to reflux for a further 4 hours. The reaction was concentrated in vacuo and preabsorbed onto silica. The residue was purified using ISCO Companion with a Redisep silica gel 12 g cartridge and a gradient of heptane and ethyl acetate (0% to 20%). Product containing fractions were concentrated in vacuo to give the title compound as a pair of diastereoisomers as a colourless oil, 214 mg, in a 63% yield. The other pair of minor diastereoisomers co-eluted with unreacted starting material and were not isolated. LC-MS (12 min acidic) 6.89 mins 100% pure by UV, ES+/APCI+ 468, ES−/APCI− 466 1H NMR (400 MHz, CDCl3) δ ppm 1.01 (s, 9H) 1.20 (t, 3H) 1.62-1.85 (m, 4H) 2.02-2.14 (m, 2H) 2.41 (s, 3H) 2.74 (s, 3H) 2.78-2.85 (m, 2H) 4.08-4.18 (m, 2H) 5.14 (s, 1H) 6.78 (s, 1H) 6.82 (d, 1H) 7.17 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[S:20]([O:27]S(C(F)(F)F)(=O)=O)([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21]>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:24][C:23]([F:26])([F:25])[S:20]([OH:27])(=[O:22])=[O:21].[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: Oc1cccc(-c2ccncc2)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=S(=O)(O)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2.5 g (0.015 mol) of 4-(3-hydroxyphenyl)pyridine and 40 ml of pyridine and 2.3 g of 4-(dimethylamino)pyridine (DMAP) are cooled to 0° C. 3.2 ml of triflic anhydride are added thereto dropwise. The mixture is stirred at 0° C. for one hour and at ambient temperature overnight. It is poured into a water/ice mixture, extraction is carried out with ethyl acetate, the organic phase is dried and the solvent is evaporated under reduced pressure. The crude product is purified by chromatography on a column of silica gel, elution being carried out with a cyclohexane/ethyl acetate=8/2 mixture. 4-(3-Hydroxyphenyl)pyridine trifluoromethanesulfonate is obtained in the form of an oil. 2.26 g of this product are mixed with 112 ml of anhydrous dimethylformamide, 38 g of palladium acetate, 2.5 ml of anhydrous triethylamine and 2 g of N,N-dimethylethanolamine vinyl ether. The mixture is heated at 80° C. for 48 hours. The solvent is evaporated under reduced pressure. The residue is purified by flash chromatography on a column of silica gel, elution being carried out with ethyl acetate, to remove the first product, and subsequently with an ethyl acetate/methanol=1/1 mixture. 2-[2-[3-(4-Pyridyl)-phenyl)ethenyl)oxy)]-N,N-dimethyl-1-ethanamine is obtained. 0.53 g of this product, dissolved in 35 ml of methanol, is treated with 20 ml of water and 5 ml of 96% sulfuric acid. The mixture is heated at 60° C. for 6 hours and is poured into ice, a saturated aqueous NaHCO3 solution is added thereto and extraction is carried out with ethyl acetate. The organic phase is dried and the solvent is evaporated under reduced pressure. 3-(4-Pyridyl)phenylacetaldehyde dimethyl acetal is obtained. Its N-oxide derivative is prepared by reaction with m-chloroperbenzoic acid in methylene chloride and the aldehyde is subsequently released by reaction with a mixture of trifluoroacetic acid, water and methylene chloride. The title compound is thus obtained.
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH3:12])=[N:10][N:9]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:8]=2[NH2:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(N=[C:22]=[O:23])C.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:16][N:15]([CH3:17])[CH2:14][CH2:13][N:9]1[C:8]2[NH:18][C:22](=[O:23])[C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=3[C:7]=2[C:11]([CH3:12])=[N:10]1
Reactant: CCN=C=O
Reactant: Cc1nn(CCN(C)C)c(N)c1C1=CCCCC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1nn(CCN(C)C)c2[nH]c(=O)c3c(c12)CCCC3
Yield: 68.5 %

Procedure:
To a solution of EXAMPLE 8A (1.05 g, 4.22 mmol) in pyridine (10 mL) was added ethyl isocyanate (1.0 mL, 12.68 mmol) and the solution heated at reflux overnight. The mixture was cooled, stirred with 15 mL ethyl acetate at ambient temperature for 5 minutes and the solid collected by filtration, washed with ethyl acetate and dried to give 793 mg of the title compound. The mother liquor was concentrated and the residue recrystallized from ethyl acetate to give an additional 300 mg of the title compound (94% overall yield). 1H NMR (DMSO-d6) 1.64-1.75 (m, 4H), 2.16 (s, 6H), 2.34-2.39 (m, 5H), 2.59 (t, J=6.4 Hz, 2H), 2.83-2.87 (m, 2H), 4.18 (t, J=6.6 Hz, 2H).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]([CH3:10])[CH3:9])=[O:7])=[CH:4][C:3]=1[CH3:13].[CH:14]([B-](F)(F)F)=[CH2:15].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].N#N>C1COCC1.Cl[Pd]Cl.O>[CH3:13][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:2]=1[CH:14]=[CH2:15])[C:6]([N:8]([CH3:10])[CH3:9])=[O:7]
Reactant: C=C[B-](F)(F)F
Reactant: Cc1cc(C(=O)N(C)C)ccc1Br
Agent: Cl[Pd]Cl
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(C(=O)N(C)C)cc1C
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A mixture of 4-bromo-3,N,N-trimethyl-benzamide (798 mg, 3.30 mmol), potassium vinyltrifluoroborate (579 mg, 4.32 mmol), PdCl2 (59.0 mg, 0.333 mmol), PPh3 (265 mg, 1.01 mmol) and Cs2CO3 (3.22 g, 9.90 mmol) in THF (6.5 ml)-H2O (0.65 ml) was heated with stirring at 85° C. for 21 hours in a sealed test tube in an N2 atmosphere. The reaction mixture was cooled to room temperature and then extracted with ether. The organic layer was washed with water, and then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 3,N,N-trimethyl-4-vinyl-benzamide (565 mg, 90%).