Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC[C:3]([N:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH2:30][OH:31])[CH:25]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[S:11]([N:8]1[CH2:7][CH2:6][N:5]([C:3]([O:31][CH2:30][C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)=[O:4])[CH2:10][CH2:9]1)(=[O:13])=[O:12]
Reactant: OCc1cccnc1
Reactant: O=C(CCl)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(OCc1cccnc1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.3 %

Procedure:
To a stirred solution of 2-chloro-1-(4-(naphthalen-2-ylsulfonyl)piperazin-1-yl)ethanone (compound 4, 0.250 g, 0.905 mmol) and pyridin-3-yl-methanol (98 mg, 0.905 mmol) taken in dry DCM (10 mL), triphosgene (294 mg, 0.99 mmol) was added at 0° C. and allowed to stir at room temperature for 3 h. The mixture was then diluted with DCM washed with water (2×10 mL) & brine (2×10 mL). The organic extract was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography to yield the title compound (0.109 g, 30.27%) as a solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][CH2:3][C:4]([NH:16][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)[CH3:15])=[O:5]
Reactant: CC(N)c1ccc(Cl)cc1
Reactant: O=C(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)CCCl)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A solution of 3-chloropropionyl chloride (32.7 g) in methylene chloride (40 ml) was added dropwise to stirred solution of (±) 1-(4-chlorophenyl)ethylamine (40 g) in dichloromethane (260 ml) with triethylamine (28.4 g) over 45 minutes at 0°-5° C. The temperature was allowed to rise to 25° C. and the mixture stirred for a further 2 hours. The cooled reaction mixture was washed with saturated aqueous sodium bicarbonate (260 ml). The organic layer was separated, dried and filtered and the filtrate evaporated. The residue was triturated with petrol, collected by filtration and recrystallised from ethyl acetate to give 3-chloro-N-[1-(4-chlorophenyl)ethyl]propionamide, m.p. 86°-91° C. This product was obtained as a mixture with N-[1-(4-chlorophenyl)ethyl]acrylamide but was sufficiently pure for synthetic purposes. The acrylamide does not react and was removed on work-up in the next stage.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:18]([OH:20])=[O:19])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1.Cl.[CH3:22]O>>[CH3:22][O:19][C:18]([C:4]1[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=[C:2]([OH:1])[CH:3]=1)=[O:20]
Reactant: O=C(O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(O)cc2cc(-c3ccc(O)cc3)oc12
Yield: 47 %

Procedure:
A solution of carboxylic acid 24 (0.35 g , 1.3 mmol) in HCl/MeOH(10 ml) was refluxed for 2 hr. The reaction was then cooled, concentrated and the product was dissolved in EtOAc, washed with sat NaHCO3, separated dried, and concentrated to give a solid. The solid was triturated with CH2Cl2, filtered to give a solid (0.15 g, 47%): Mp=236–238° C.; 1NMR (DMSO-d6) δ 9.90 (s, 1 H), 9.57 (s, 1 H), 7.73 (d, 2 H, J=8.5Hz), 7.23 (d, 1 H, J=2.1 Hz), 7.17 (d. 1 H, J=2.1 Hz),7.12 (s, 1 H), 6.88 (d, 2 H, J=8.5 Hz), 3.94 (s, 3 H); MS 283 (M−H)−
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:14][C:13]([OH:15])=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[O:14][C:13]([OH:15])=[N:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(-c2nnc(O)o2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(-c2nnc(O)o2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a flask, is dissolved 5-(3-nitrophenyl)-1,3,4-oxadiazol-2-ol (369.90 mg; 1.79 mmol; 1.00 eq.) in MeOH (20.00 ml) under innert atmosphere. Palladium 10% on charcoal (190.03 mg; 0.18 mmol; 0.10 eq.) is added and the reaction mixture is stirred 5 minutes at RT. The mixture is then put under atmospheric pressure of hydrogen. The reaction is completed after 2 hours. The mixture is filtrated on celite and rinced with MeOH. The solvents are evaporated under vacuo, affording 5-(3-aminophenyl)-1,3,4-oxadiazol-2-ol as a white powder (283.30 mg; 89.55%). 1H NMR (DMSO-d6) δ: 5.43 (s, 2H), 6.70 (m, 1H), 6.89 (m, 1H), 7.08 (s, 1H), 7.14 (m, 1H), 12.44 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][N:47]=2)[CH:42]=[CH:41][C:40]=1[CH2:49]O.[OH-].[Na+]>O1CCOCC1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:49][C:40]3[CH:41]=[CH:42][C:43]4[C:48](=[N:47][CH:46]=[CH:45][CH:44]=4)[N:39]=3)=[CH:15][CH:14]=2)=[N:3]1
Reactant: OCc1ccc2cccnc2n1
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(O)cc2)n1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4cccnc4n3)cc2)n1
Temperature: 60 °C
Yield: 8.7 %

Procedure:
To a solution of 4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenol (72 mg) in dioxane 1.5 ml, was added triphenyl phosphine (121 mg), [1,8]Naphthyridin-2-yl-methanol (69 mg) and di-t-butyl-diazacarboxalate (106 mg) and the reaction mixture heated at 60° C. for 24 h. The reaction mixture was poured into 1 N NaOH, extracted with methylene chloride, dried magnesium sulfate and concentrated. Purification via Prep TLC eluting with 15% methanol/70%ethyl acetate/15% hexanes provided the title compound (9.8 mg). 1H NMR (400 MHz, CDCl3) δ 9.13 (dd, J=4.2, 1.7 Hz, 1H), 8.45 (d, J=5.8 Hz, 2H), 8.23 (d, J=8.3 Hz, 1H), 7.21 (dd, J=8.5, 2.1 Hz, 1 H), 7.79 (d, J=8.7 Hz, 1H), 7.57 (s, 1H), 7.52 (m, 1H), 7.37(d, J=9.1 Hz, 2 H), 7.16 (d, J=6.2 Hz, 2H), 7.01 (d, J=8.7 Hz, 2 H), 5.47 (s, 2H), 3.94 (s, 3 H); MS: (M+H m/z=394.0).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:19]1[S:20][CH:21]=[CH:22][N:23]=1)CCC>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[S:20]1[CH:21]=[CH:22][N:23]=[C:19]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: N#Cc1ccc(Br)cc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2nccs2)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
A solution of 4-bromo-2-(trifluoromethyl)benzonitrile (0.5 g, 2 mmol) in DMF (5 mL) was purged with argon and 2-(tributylstannyl)thiazole (1.12 g/0.9 mL, 3 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (0.14 g, 0.2 mmol) added. The reaction mixture was purged with argon for 5 min and retained in microwave for 30 min at 100° C. The reaction mixture was diluted with ice cold water (10 mL) and extracted with ethyl acetate (200 mL). The organic solvent was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to obtain crude product. The crude product was purified by silica gel chromatography (100-200 mesh; 8% ethyl acetate in hexane) to give 4-(thiazol-2-yl)-2-(trifluoromethyl)benzonitrile (0.42 g, 84% yield) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.42-8.39 (m, 2H), 8.27 (d, 1H), 8.08 (d, 1H), 8.03 (d, 1H). LC-MS m/z calculated for [M+H]+ 255.01, found 255.0.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]([OH:22])=[C:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:12])[N:10]=1.Cl>C1COCC1>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:11]([C:9]2[N:10]=[C:5]([CH2:4][CH:3]=[O:2])[N:6]([CH3:24])[C:7](=[O:23])[C:8]=2[OH:22])=[O:12])=[CH:20][CH:19]=1
Reactant: COC(Cc1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C)OC
Agent: Cl
Solvent: C1CCOC1
Product: Cn1c(CC=O)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O

Procedure:
The product of Step 1 was treated with a mixture HCl 1N/THF for 1 hour at 40° C. Organics were removed in vacuo and residue extracted in DCM, dried over Na2SO4 and concentrated to give the title compound as a foam which was immediately reacted in the following reductive amination.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)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].O1CCOCC1>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[C:9]([NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[CH:7]=1)=[O:18]
Reactant: Nc1nccs1
Reactant: O=C(Nc1ccnc(Br)c1)c1c(Cl)cccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=C(Nc1ccnc(Nc2nccs2)c1)c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 25.3 %

Procedure:
A 25 mL microwave tube containing N-(2-bromopyridin-4-yl)-2,6-dichlorobenzamide (0.21 g, 0.61 mmol), 2-aminothiazole (92 mg, 0.92 mmol), Pd2(dba)3 (56 mg, 0.061 mmol), Cs2CO3 (0.4 g, 1.22 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 71 mg, 0.122 mmol), and dioxane (8 mL) was degassed and then charged with N2 (3×). The resulting mixture was heated at 80° C. overnight. After cooling, the mixture was diluted with dioxane (20 mL) and filtered through celite. The filtrate was concentrated under reduced pressure and the residue was purified by reverse-phase HPLC (Gemini, 200 mm×25 mm, gradient: CH3CN/0.05% NH3.H2O, 50-80, 10 min) to afford the desired product (56.4 mg, yield: 25%). 1HNMR: (DMSO-d6, 400 MHz): 611.26 (s, 1H), 11.13 (s, 1H), 8.21 (d, J=6.0 Hz, 1H), 7.61-7.50 (m, 4H), 7.36 (d, J=3.6 Hz, 1H), 7.11 (q, J=1.6, 6.0 Hz, 1H), 6.98 (d, J=3.6 Hz, 1H). LCMS (ESI) m/z: 364.8 [M+H+]
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]2[NH:7][C:8]3[N:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([C:20]([F:23])([F:22])[F:21])([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[C:5]=2[CH:4]=1)#[N:2].C1C(=O)N([Br:33])C(=O)C1.CCOC(C)=O.CCCCCC>C(#N)C>[Br:33][C:11]1[CH:10]=[N:9][C:8]2[NH:7][C:6]3[CH:24]=[CH:25][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[C:14]([C:20]([F:21])([F:22])[F:23])([CH2:15][O:16][CH:17]([CH3:19])[CH3:18])[C:13]=2[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)OCC1(C(F)(F)F)c2cc(C#N)ccc2Nc2ncccc21
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)OCC1(C(F)(F)F)c2cc(C#N)ccc2Nc2ncc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a stirred solution of 7-cyano-5-trifluoromethyl-5-isopropoxymethyl-5,10-dihydrobenzo[b][1,8]naphthyridine (14)(61 mg, 0.176 mmol) in anhydrous acetonitrile (2 mL) at room temperature was added NBS (38 mg, 0.211 mmol). The reaction mixture was stirred at room temperature for 1 h 30 min. The reaction was quenched with 1:1 saturated aqueous NaHCO3/water (20 mL), and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (20%-30% EtOAc-Hexane) furnished 15 (73 mg, 97% yield) as an off-white solid: m.p. 76-77° C.; low resolution mass spectrum (ESI) m/z 426.2 [(M+H)+ calcd for C18H16BrF3N3O: 426.05].
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].[Na+]>CN(C)C=O>[C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:15])[NH:9]2)(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 80.6 %

Procedure:
To the product from step (b) (37.7 g, 186 mmol) was added N,N-dimethylformamide (200 mL) and potassium carbonate (34.5 g, 250 mmol) followed by benzyl bromide (31.8 g, 186 mmol). The mixture was stirred at room temperature for 2.25 hour and then poured into saturated sodium chloride (3.5 L) at 0° C. and stirred for 1 hour. The product was collected and dried on a Buchner funnel for 1 hour, and the resulting solids were dissolved in dichloromethane (2 L) and this mixture was dried over sodium sulfate. The solution was filtered through a pad of Celite which was then washed with dichloromethane (5×200 mL). The combined filtrate was then concentrated to dryness and the resulting solids were triturated with ether (500 mL) for 2 h. The product was collected on a Buchner funnel, washed with ether (2×250 mL) and dried under reduced pressure to give the title compound (44 g) as a powder.
Reaction SMILES: [CH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:9]=[CH2:10]>>[CH2:9]=[CH:10][CH2:1][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2]
Reactant: C1=CCCCCCC1
Reactant: C=C
Product: C=CCCCCCCC=C

Procedure:
A mixture of cyclooctene and ethylene was contacted with catalyst and adjuvant as in Examples IX and X at room temperature and 25 psi pressure to yield 13 weight percent 1,9-decadiene. This shows that ethylene and a cyclic olefin are converted to an acyclic polyene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:12]2[CH2:17][CH2:16][CH2:15]/[C:14](=[CH:18]\[C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)=[C:21]([O:31][CH3:32])[CH:20]=3)/[C:13]2=[O:33])[C@H:9]([OH:11])[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].CI.O.[C:39](=O)(O)[O-].[Na+]>C(OCC)(=O)C.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:12]2[CH2:17][CH2:16][CH2:15]/[C:14](=[CH:18]\[C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]4)=[C:21]([O:31][CH3:32])[CH:20]=3)/[C:13]2=[O:33])[C@H:9]([O:11][CH3:39])[CH3:10])=[CH:4][CH:3]=1
Reactant: COc1cc(/C=C2\CCCN([C@H](c3ccc(F)cc3)[C@@H](C)O)C2=O)ccc1-n1cnc(C)c1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CCCN([C@H](c3ccc(F)cc3)[C@@H](C)OC)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a THF (1 mL) solution of (E)-1-(1-(4-fluorophenyl)-(1R,2R)-2-hydroxy propyl)-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidin-2-one (4 mg) obtained in Example 1119, sodium hydride (40% mineral oil content, 0.5 mg) was added, and the reaction solution was agitated at room temperature for 30 minutes. Methyl iodide (2 mg) was added to the reaction solution, and the reaction solution was agitated at room temperature for 2 hours. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer obtained was dried over magnesium sulfate and concentrated under reduced pressure. By purifying the residue with silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: ethyl acetate->ethyl acetate:methanol 9:1), 3 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[O:17][CH2:16][CH2:15][N:14]([C:18]4[S:19][C:20]5[C:21](=[O:29])[NH:22][C:23]([CH3:28])([CH3:27])[CH2:24][C:25]=5[N:26]=4)[C:13]=3[CH:30]=2)[CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.CC(P(C(C)(C)C)C1[CH-]C=CC=1)(C)C.[Cl-].[Cl-].[Fe+2].[Pd+2]>[CH3:27][C:23]1([CH3:28])[NH:22][C:21](=[O:29])[C:20]2[S:19][C:18]([N:14]3[C:13]4[CH:30]=[C:9]([O:8][C:6]5[CH:5]=[CH:4][CH:3]=[C:2]([N:31]6[CH2:35][CH2:34][CH2:33][CH2:32]6)[N:7]=5)[CH:10]=[CH:11][C:12]=4[O:17][CH2:16][CH2:15]3)=[N:26][C:25]=2[CH2:24]1
Reactant: C1CCNC1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(Oc5cccc(Br)n5)cc43)sc2C(=O)N1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc[cH-]1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC1(C)Cc2nc(N3CCOc4ccc(Oc5cccc(N6CCCC6)n5)cc43)sc2C(=O)N1
Temperature: 140 °C
Yield: 34.6 %

Procedure:
To a suspension of Example 382 (50 mg, 0.103 mmol) in toluene (4 mL) was added pyrrolidine (0.025 ml, 0.308 mmol), sodium tert-butoxide (20 mg, 0.206 mmol) and [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (10 mg, 20% wt). The reaction was heated to 140° C. under microwave irradiation for 90 minutes then cooled to room temperature. The mixture was partitioned between DCM (50 mL) and water (50 mL); the organic phase was washed with brine (50 mL), dried (MgSO4), and concentrated in vacuo. The residue was purified by preparative HPLC (Method 6) to give the title compound (17 mg, 35%) as an off-white solid. δH (CDCl3) 7.91 (1H, d, J 2.4 Hz), 7.39 (1H, t, J 7.9 Hz), 6.93 (1H, d, J 8.9 Hz), 6.88 (1H, dd, J 8.9 and 2.4 Hz), 6.02 (1H, d, J 8.1 Hz), 5.91 (1H, d, J 7.7 Hz), 5.29 (1H, s), 4.38-4.29 (2H, m), 4.15-4.06 (2H, m), 3.45-3.37 (4H, m), 2.85 (2H, s), 2.01-1.92 (4H, m), 1.37 (6H, s). LCMS (ES+) 478.0 (M+H)+, RT 3.96 minutes (Method 1).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[CH:9][C:10]([NH:17][C:18](=[O:20])[CH3:19])=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[H-].[Na+].CI.[CH:25](Cl)(Cl)Cl>C1COCC1>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([S:6][C:7]3[CH:8]=[CH:9][C:10]([N:17]([CH3:25])[C:18](=[O:20])[CH3:19])=[CH:11][C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: CC(=O)Nc1ccc2sc3ccc(Br)cc3c(=O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc2sc3ccc(Br)cc3c(=O)c2c1
Reaction time: 0.25 h
Yield: 97 %

Procedure:
To a stirred solution of 1.1 g (3.2 mmol) acetamide 23 in 20 mL of THF was added 0.17 g (4.2 mmol) of NaH (60%) under N2. The mixture was stirred for 15 min followed by the dropwise addition of 0.70 g (4.9 mmol) of methyl iodide. The reaction mixture was stirred at room temperature for 48 h and then concentrated in vacuo to obtain a solid residue. To the residue was added CHCl3, followed by filtration and concentration of the filtrate in vacuo to obtain 1.1 g (97% yield) of methyl amide (25) as a yellow solid, mp 240-241° C. 1H-NMR (400 MHz, CDCl3): 1.93 (3H, s), 3.34 (3H, s), 7.46-7.54 (2H, m), 7.66 (1H, d, J=8.7 Hz), 7.76 (1H, d, J=8.7 Hz), 8.45 (1H, s), 8.75 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[H-].[Na+].Br[CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Br)ccc1O
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(Br)ccc1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.1 %

Procedure:
A solution of 5-bromo-2-hydroxybenzonitrile (1 g, 5.05 mmol) in DMF was treated with 95% NaH (242 mg, 9.6 mmol) for 20 min at room temperature. 2-(2-Bromoethoxy)tetrahydro-2H-pyran (0.839 ml, 5.56 mmol) was then added to the reaction and the mixture was stirred at room temperature for 5 hrs. The reaction was then diluted with DCM and washed with water. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness to provide the crude title compound, 5-bromo-2-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)benzonitrile (1.6 g, 9.75% yield) which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:41])[C@H:4]([O:18][C:19]1[C:24]([Br:25])=[CH:23][C:22]([C:26]2[C:34]3[C:33]4[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=4[S:31][C:30]=3[CH:29]=[CH:28][C:27]=2[Br:39])=[CH:21][C:20]=1[Br:40])[CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[I-].[Li+]>N1C=CC=CC=1>[Br:25][C:24]1[CH:23]=[C:22]([C:26]2[C:34]3[C:33]4[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=4[S:31][C:30]=3[CH:29]=[CH:28][C:27]=2[Br:39])[CH:21]=[C:20]([Br:40])[C:19]=1[O:18][C@H:4]([CH2:5][CH2:6][N:7]1[C:8](=[O:17])[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]1=[O:16])[C:3]([OH:41])=[O:2]
Reactant: COC(=O)[C@@H](CCN1C(=O)c2ccccc2C1=O)Oc1c(Br)cc(-c2c(Br)ccc3sc4ccccc4c23)cc1Br
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)[C@@H](CCN1C(=O)c2ccccc2C1=O)Oc1c(Br)cc(-c2c(Br)ccc3sc4ccccc4c23)cc1Br
Reaction time: 48 h
Yield: 63 %

Procedure:
A solution of (R)-2-[2,6-dibromo-4-(2-bromo-dibenzothiophen-1-yl)-phenoxy]-4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyric acid methyl ester (0.514 g, 0.68 mmol) and lithium iodide (0.915 g, 6.8 mmol) in pyridine (20 mL) was stirred at 110° C. After 2 days, the mixture was quenched with 10% aqueous HCl and further diluted with water (150 mL). Aqueous mixture was extracted with dichloromethane (150 mL). The dichloromethane extract was washed with water, dried with brine. Silica gel was added. Solvent was removed and the adsorbate was flash chromatographed (eluent 7:3 petroleum ether:ethyl acetate) to provide the title compound as a white solid (0.319 g, 63%): mp 130-132° C.: NMR (CDCl3): δ 7.86 (dd, J=8, 1 Hz, 2H), 7.81 (d, J=8 Hz, 1H), 7.77-7.70 (m, 4 H), 7.52 (d, J=1 Hz, 2H), 7.39 (ddd, J=8, 7, 1 Hz, 1H), 7.18 (ddd, J=8, 7, 1 Hz, 1H), 6.77 (d, J=8 Hz, 1H), 5.24 (t, J=7 Hz, 1H), 4.21-4.05 (m, 2 H), 2.67-2.55 (m, 2H); MS (+EI): [M+], 3 bromine isotope pattern, 741, 743, 745, 747; Anal. Calc. for C3OH18Br3NO5S: C 48.86, H, 2.74, N, 1.83. Found: C 48.90, H, 2.82, N, 1.18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[C:8](=[O:15])[N:7]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:6]2=[O:21].C(OCC)(=O)C>CO.C(Cl)Cl.[Pd]>[NH2:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C:6](=[O:21])[N:7]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:8]2=[O:15]
Reactant: COC(=O)CN1C(=O)c2cc(OC)c([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)c2cc(N)c(OC)cc2C1=O
Yield: 99.9 %

Procedure:
A mixture of methyl 2-(5-methoxy-6-nitro-1,3-dioxoisoindolin-2-yl)acetate (0.225 g, 0.765 mmol) and 10% w/w Pd/C (a catalytic amount) in MeOH (20 ml) and ethyl acetate (10 ml) was hydrogenated in a Parr apparatus at 15 psi for 1 hour. The mixture was diluted with DCM till complete dissolution of the yellow precipitate, the catalyst was filtered off and the filtrate was evaporate to dryness affording methyl 2-(5-amino-6-methoxy-1,3-dioxoisoindolin-2-yl)acetate (0.202 g, 0.764 mmol, 100% yield). MS/ESI+ 265.0 [MH]+.
Reaction SMILES: C[Mg]Cl.[CH3:4][C:5]([CH:9]([CH3:11])[CH3:10])=[CH:6][CH:7]=[O:8].[C:12](O)(=O)C>O1CCCC1>[CH3:4][CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:6][CH:7]([OH:8])[CH3:12]
Reactant: CC(=O)O
Reactant: CC(=CC=O)C(C)C
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)CC(C)C(C)C
Temperature: 17.5 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
Methylmagnesium chloride (CH3MgCl) in tetrahydrofuran (THF) (3 M, 1.8 L) was charged into a flame-dried 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a condenser, and a dropping funnel. The reaction flask was cooled with an external bath to about 15-20° C. 3,4-Dimethyl-pentenal (prepared as above) (422 g) was fed over about 2-3 hours to allow the exotherm temperature at about 30-35° C. After the feeding was completed, the reaction mass was aged for about 2 hours. GC analysis determined a conversion rate of about 96%. The reaction mixture was poured into a mixture of ice and acetic acid (300 g). The organic layer was separated and washed sequentially with brine (500 mL) and sodium carbonate (5%, 300 mL), and further fractional distilled to provide 4,5-dimethyl-hexan-2-ol (410 g) with a boiling point of 114° C. at 90 mmHg.