Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:12](=[O:22])[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH:20]=[O:21])[CH2:16][CH2:15]2)=[C:6]([Cl:23])[CH:5]=1)([O-])=O.S1C=CC=C1.[NH4+].[OH-]>CO.[Pt].C(Cl)Cl>[NH2:1][C:4]1[CH:5]=[C:6]([Cl:23])[C:7]([NH:11][C:12](=[O:22])[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH:20]=[O:21])[CH2:16][CH2:15]2)=[C:8]([Cl:10])[CH:9]=1
Reactant: O=CN1CCN(CC(=O)Nc2c(Cl)cc([N+](=O)[O-])cc2Cl)CC1
Agent: [Pt]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: c1ccsc1
Product: Nc1cc(Cl)c(NC(=O)CN2CCN(C=O)CC2)c(Cl)c1
Yield: 31.7 %

Procedure:
A mixture of N-(4-nitro-2,6-dichlorophenyl)-4-formyl-1-piperazineacetamide (1.79 g crude) was suspended in methanol (50 mL) containing 4% methanolic thiophene (0.5 mL) and 5% platinum on charcoal catalyst (900 mg). This was hydrogenated using a Parr apparatus for 30 minutes at 50° C. and 26 psi. After filtration and the removal of solvent in vacuo, the filtrate yielded 1.38 g of crude residue. This was subjected to flash chromatography on deactivated silica gel (from a slurry of 300 g of silica gel in methylene chloride containing 3.4 mL of conc. NH4OH). The product was eluted with CH2Cl2 :MeOH:NH4OH 98.8:1.0:0.2 yielding 590 mg of III an off-white solid. This was triturated in methylene chloride-ether to yield a white solid (520 mg, 39% yield).: m.p.>220° C. (dec.).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[C:4]([Cl:10])=[N:5][C:6](Cl)=[N:7][CH:8]=1.[F:13][C:14]([F:25])([F:24])[O:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:10][C:4]1[C:3]([C:2]([F:12])([F:11])[F:1])=[CH:8][N:7]=[C:6]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[O:15][C:14]([F:13])([F:24])[F:25])[N:5]=1
Reactant: NCc1ccccc1OC(F)(F)F
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccccc1CNc1ncc(C(F)(F)F)c(Cl)n1
Reaction time: 0.33 h
Yield: 51.5 %

Procedure:
To a solution of 5-(trifluoromethyl)-2,4-di-chloropyrimidine (0.5 g, 2.3 mmol) in DMF (8 mL) were added a solution of 2-(trifluoromethoxy)benzylamine (0.44g, 2.3 mmol) in DMF (2 mL) followed by DIPEA (0.44 mL, 2.3 mmol) at −20° C. The reaction mixture was stirred at that temperature for 20 min. When the starting material was all consumed, the mixture was diluted with EtOAc and washed with water (×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 100% CH2Cl2 as an eluent to afford 0.44 g (52%) of (4-chloro-5-trifluoromethyl-pyrimidin-2-yl)-(2-trifluoromethoxy-benzyl)-amine as a white foam.
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[CH:7]=[N:6][CH:5]=1.[C-:16]#[N:17].[K+]>C(=O)([O-])[O-].[K+].[K+].ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O.CCOCC>[ClH:2].[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH:7]=[N:6][CH:5]=[C:4]2[CH2:3][C:16]#[N:17]
Reactant: COc1ccc2cncc(CCl)c2c1
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCOCC
Product: COc1ccc2cncc(CC#N)c2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The hydrochloride of the compound obtained in Step C (0.60 g; 0.0024 mol) is dissolved in 10 ml of a saturated aqueous potassium carbonate solution and 40 ml of dichloromethane. Tetrabutylammonium bromide (2 g; 0.006 mol) and potassium cyanide (0.80 g; 0.012 mol) are then added to the preceding solution. The reaction mixture is stirred at ambient temperature for 24 hours. The solution is extracted with dichloromethane, and the organic phase is washed with water, dried over magnesium sulphate, filtered and evaporated. The oil obtained is taken up in acetone and in ether saturated with HCl(g). The precipitate formed is suction-filtered off and recrystallised from toluene/cyclohexane, 5/5, to yield the title compound in the form of a yellow solid.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:13]=[C:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.[CH:28]([S:30]([CH:33]=C)(=[O:32])=[O:31])=[CH2:29]>>[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[C:9]4[CH:26]=[CH:27][C:6]([CH:4]5[CH2:3][N:2]([CH2:29][CH2:28][S:30]([CH3:33])(=[O:32])=[O:31])[CH2:5]5)=[CH:7][C:8]=4[O:17][CH2:16][CH2:15][N:14]3[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:24])[CH3:25]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CNC3)cc1OCC2
Reactant: C=CS(=O)(=O)C=C
Agent: Cl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CN(CCS(C)(=O)=O)C3)cc1OCC2

Procedure:
Following the procedure for 152, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene hydrochloride (Example 65) was reacted with vinyl sulfone to give 191 as a white solid. 1H NMR δ (ppm) (CDCl3): 8.44 (1 H, d, J=8.28 Hz), 7.84 (1 H, s), 7.60 (1 H, s), 7.05 (1 H, dd, J=8.32, 1.83 Hz), 6.94 (1 H, d, J=1.78 Hz), 5.99-5.89 (1 H, m), 4.48-4.39 (4 H, m), 3.78-3.70 (2 H, m), 3.71-3.62 (1 H, m), 3.25-3.18 (2 H, m), 3.04 (3 H, s), 3.02-2.95 (4 H, m), 1.56 (6 H, d, J=6.64 Hz). LCMS: RT=5.58 min, M+H+=457
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]([CH2:7][C:8]1[S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)#[N:6]>O.C(O)(=O)C>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:7](=[N:1][OH:3])[C:5]#[N:6]
Reactant: N#CCc1nc2ccccc2s1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(=NO)c1nc2ccccc2s1

Procedure:
A solution of 7.8 g (0.1 mol) of NaNO2 in 20 ml of water is added dropwise at room temperature to 17.4 g (0.1 mol) of 2-cyanomethyl-benzthiazole in 50 ml of glacial acetic acid. The end product is filtered off after 2 hours and washed with water: 19.5 g (96% of theory), melting point >170° (decomposition).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[O:19][CH2:20][CH3:21])/[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][C:11]=1I)[CH2:2][CH2:3][CH3:4].[CH3:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:13]=[C:14](\[O:19][CH2:20][CH3:21])/[C:15]([O:17][CH3:18])=[O:16])[CH:9]=[CH:10][C:11]=1[C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([NH:23][CH3:22])[CH:25]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(/C=C(\OCC)C(=O)OC)ccc1I
Reactant: CNc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCCCOc1cc(/C=C(\OCC)C(=O)OC)ccc1-c1cccc(NC)c1
Temperature: 80 °C
Yield: 52.2 %

Procedure:
To a solution of 0.4 g (1 mmol) of methyl (Z)-3-(3-butoxy-4-iodophenyl)-2-ethoxyacrylate in 8 mL of ethylene glycol dimethyl ether placed under nitrogen, 0.25 g (1.1 mmol) of methyl[3-(4,4,5,5-tetramethyl[1.3.2]dioxaborolan-2-yl)phenyl]amine (prepared as in Example 10a), 1.5 mL (3 mmol) of aqueous 2 M potassium phosphate solution, 2 mg (0.01 mmol) of palladium (II) acetate and 7 mg (0.02 mmol) of dicyclohexyl-o-biphenylphosphine are added. The reaction medium is then heated at 80° C. for 20 hours. After addition of water, the reaction medium is extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with an 85/15 heptane/ethyl acetate mixture. 0.2 g (63%) of methyl (Z)-3-(2-butoxy-3′-methylaminobiphenyl-4-yl)-2-ethoxyacrylate are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]([F:24])([F:23])[F:22])=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[Br:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([C:33](C(OCC)=O)=[N:34][N:35]=2)[CH:32]=1.O.[OH-].[Li+].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C.C1COCC1.O>[Br:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([C:33]([C:14]([N:11]3[CH2:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=4[C:21]([F:23])([F:24])[F:22])[CH2:13][CH2:12]3)=[O:15])=[N:34][N:35]=2)[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(Cl)c2C(F)(F)F)CC1
Reactant: CCOC(=O)c1nnc2ccc(Br)cn12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cccc(Cl)c2C(F)(F)F)CC1
Reaction time: 3 h
Yield: 49.3 %

Procedure:
To a solution of tert-butyl 4-(3-chloro-2-(trifluoromethyl)phenyl)piperidine-1-carboxylate (0.115 g, 0.316 mmol) in dichloromethane (3 mL) was added HCl (2 M in ether, 3 mL). The mixture was stirred for 3 h and evaporated to afford a solid that was dissolved in DMF (3 mL). In a separate flask, to a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (0.094 g, 0.348 mmol) in THF (3 mL) was added a solution of lithium hydroxide hydrate (0.015 g, 0.348 mmol) in water (1 mL). The mixture was stirred for 20 min, acidified with 2 N HCl to PH 6 and evaporated. To the residue were added benzotriazole-1-yl-oxy-tris(dimethylamino)phosphonium hexa-fluorophosphate (0.210 g, 0.474 mmol), N,N-diisopropylethylamine (0.163 g, 1.26 mmol), and the DMF solution obtained from the first reaction. The mixture was stirred at ambient temperature for 16 h and poured into water. The mixture was extracted with ethyl acetate and the organic layer was washed with brine for three times, dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (0-60% EtOAc in hexanes) to give (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(3-chloro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a solid (0.076 g, 49%): 1H NMR (300 MHz, CDCl3) δ9.36 (m, 1H), 7.78 (dd, J=9.6, 0.9 Hz, 1H), 7.50-7.34 (m, 4H), 5.73-5.68 (m, 1H), 5.00-4.94 (m, 1H), 3.52-3.28 (m, 2H), 2.97 (m, 1H), 2.01-1.74 (m, 4H); MS (ESI+) m/z 489 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[H-].[Na+].Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br.[NH4+].[Cl-]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]2([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:5]=[C:6]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2cc(Cl)c(OCC(F)(F)F)c(-c3ccc(C(F)(F)F)cc3)c2)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
Ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.5 g, 1.13 mmol) was dissolved in anhydrous DMF (30 mL), NaH (60% wt. in paraffin oil, 0.113 g, 2.8 mmol) was added at 0° C. The reaction mixture was stirred for 30 min at room temperature and 1,5-dibromopentane (0.19 g, 1.24 mmol) was added drop wise at 0° C. The reaction mixture was stirred an additional 1 h at 0° C. and saturated NH4Cl solution (10 mL) was added. The reaction mixture was extracted with EtOAc (3×20 mL) and the combined organic phases were washed with water (3×20 mL) and brine (20 mL), and dried over MgSO4. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to yield compound ethyl 1-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)-cyclohexanecarboxylate (0.37 g) as a thick liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:7][C:6](=[O:8])[C:5](=[C:9]([NH:11][C@@H:12]2[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@@H:16]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[O:15][C@@H:13]2[OH:14])[CH3:10])[C:4](=[O:32])[CH2:3]1.[Cl:34][C:35]([Cl:39])([Cl:38])[C:36]#[N:37].N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:34][C:35]([Cl:39])([Cl:38])[C:36](=[NH:37])[O:14][CH:13]1[O:15][C@H:16]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:12]1[NH:11][C:9](=[C:5]1[C:4](=[O:32])[CH2:3][C:2]([CH3:33])([CH3:1])[CH2:7][C:6]1=[O:8])[CH3:10]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(=O)OC[C@H]1O[C@H](O)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)OC[C@H]1OC(OC(=N)C(Cl)(Cl)Cl)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
A mixture of 2-Deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-3,4,6-tri-O-acetyl-α-D-glucopyranose (100 mg, 0.21 mmol) and trichloroacetonitrile in CH2Cl2 was cooled to 0° C. and 1,8-diazabicyclo(5.4.0)undec-7-en (2 mg) added. The reaction mixture was stirred at 0° C. for 1.5 h and at room temperature for 2 h. The solution was evaporated, and the residue chromatographed using CHCl3/EtOAc 1:1 as the mobile phase to give 2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethylamino]-3,4,6-tri-O-acetyl-α,β-D-glucopyranosyl trichloroacetimidate (13) (71 mg, 55%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])OC(C)(C)C)[CH2:2]1.[CH:13](N(CC)C(C)C)(C)C.C(Cl)(=O)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C(Cl)Cl.C(OCC)(=O)C>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[CH3:13])[CH2:2]1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Product: CC(=O)NC1CNC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
100 mg of t-butyl azetidin-3-ylcarbamate was dissolved in 5 ml of methylene chloride, and 225 mg of N,N-diisopropylethylamine was added. Under ice-cooling, the reaction mixture was added with 68 mg of acetyl chloride, and stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with 5% citric acid aqueous solution and brine in turn, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 146 mg of a brown oily matter. The obtained residue was dissolved in 2.5 ml of methylene chloride, and 1 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and then 66 mg of N-(azetidin-3-yl)acetamide trifluoroacetate was obtained. Subsequently, 33 mg of N-(azetidin-3-yl)acetamide trifluoroacetate, 148 mg of triethylamine, 100 mg of (S)-6-chloro-N2-[1-(4-fluorophenyl)ethyl]-N4-(pyrazin-2-yl)pyrimidine-2,4-diamine, 28 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 56 mg of sodium t-butoxide and 30 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 3 ml of degassed 1,4-dioxane, and the mixture was stirred at 90° C. for 2 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 17 mg of the objective compound as bright golden yellow powder.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=[O:2].[N:14]1([CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[NH:27][C:26]([CH:31]=O)=[CH:25]3)[CH2:18][CH2:17][CH2:16][CH2:15]1.N1CCCCC1>C(O)C>[O:13]=[C:8]1[C:7](=[CH:31][C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([CH2:21][CH2:20][CH2:19][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:30][CH:29]=3)[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)[NH:9]1
Reactant: O=Cc1cc2cc(CCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(C(=O)O)cc2C1=Cc1cc2cc(CCCN3CCCC3)ccc2[nH]1
Temperature: 80 °C

Procedure:
A mixture of 5-carboxy-2-oxindole (35 mg, 0.2 mmol), 5-(3-pyrrolidin-1-yl-propyl)-1H-indole-2-carbaldehyde (51 mg, 0.2 mmol) and piperidine (0.2 mL) in ethanol (1 mL) was heated in a sealed tube at 80° C. for 6 hours. The reaction mixture was concentrated and the residue was dissolved in methanol, made acidic with 1 N hydrochloric acid until solid was formed. The precipitate was filtered, washed with 1 N hydrochloric acid, water, ethanol and dried to give the title compound.
Reaction SMILES: Cl[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].Cl>CN(C=O)C.O>[F:14][C:15]1[CH:20]=[C:19]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]
Reactant: CCOC(=O)C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 44.4 %

Procedure:
9.8 g of potassium tert.butylate were dissolved in 90 ml of DMF and cooled to −45° C. For this purpose, a mix of ethyl 2-chloro-2-phenylacetate (43.8 mmol, 8.7 g) and 1-fluoro-2-nitrobenzene (43.8 mmol, 4.6 ml) was carefully added dropwise and the mixture was stirred for a further 20 minutes. The reaction mix was set to pH 4 using 16% HCl, diluted with 25 ml of water and extracted with EtOAc (3×50 ml). Once combined, the organic phases were washed with water and sat. aq. NaCl sol., dried over MgSO4 and concentrated under vacuum. The resulting residue was purified by column chromatography (silica gel: mesh 100-200, eluent: 10% EtOAc in cyclohexane) and produced 5.9 g (44.9%) of product.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[Cl:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([O:24][CH2:25][CH:26]([OH:29])[CH2:27]O)=[CH:16][CH:15]=1.CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>O.C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=2[Cl:12])[O:29][CH:26]([CH2:25][O:24][C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([Cl:13])=[CH:15][CH:16]=2)[CH2:27][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: OCC(O)COc1ccc(Cl)c2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: c1ccccc1
Solvent: O
Product: Clc1ccc(C2(CBr)OCC(COc3ccc(Cl)c4ccccc34)O2)c(Cl)c1

Procedure:
A mixture of 13.6 parts of 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone, 15.2 parts of 3-(4-chloro-1-naphthalenyloxy)-1,2-propanediol, 3 parts of 4-methylbenzenesulfonic acid, 80 parts of butanol and 180 parts of benzene is stirred and refluxed for 24 hours with water-separator. The reaction mixture is evaporated and the residue is triturated in 2-propanol. The product is filtered off and crystallized from butanol, yielding A + B 2-(bromomethyl)-4-(4-chloro-1-naphthalenyloxymethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolane; mp. 122.7° C.
Reaction SMILES: IC.[C:3](=O)([O-])[O-].[Cs+].[Cs+].[F:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([OH:24])=[C:12]([CH2:25][OH:26])[CH:11]=1.O>CN(C=O)C>[F:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:13]([O:24][CH3:3])=[C:12]([CH2:25][OH:26])[CH:11]=1
Reactant: OCc1cc(F)cc(OCc2ccccc2)c1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(CO)cc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
Iodomethane (24 mL, 382 mmol) and cesium carbonate (25 g, 76.4 mmol) were added to a solution of 4-fluoro-2-(hydroxymethyl)-6-[(phenylmethyl)oxy]phenol (9.5 g, 38.2 mmol) in DMF (125 mL). The mixture was stirred for 1 h at rt, and then water was added. The resulting aqueous mixture was extracted twice with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (70% hexanes, 30% ethyl acetate) to provide {5-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]phenyl}methanol as a yellow solid (7.9 g, 30.2 mmol, 79% yield). 1H NMR (400 MHz, CDCl3): δ 7.44-7.32 (m, 5H), 6.69-6.63 (m, 2H), 5.08 (s, 2H), 4.67 (d, 2H), 3.86 (s, 3H).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[Br:18]Br.C([O-])(=O)C.[Na+]>CCCCCC.C(O)(=O)C.O>[Br:18][C:10]1[CH:9]=[CH:8][C:7]2[O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]=2[CH:11]=1
Reactant: BrBr
Reactant: c1ccc2c(c1)OCCCO2
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)OCCCO2
Reaction time: 24 h

Procedure:
To a mixture of 3,4-dihydro-2H-1,5-benzodioxepine (8.86 g) and sodium carbonate (9.4 g) in hexane (100 ml) was added dropwise at room temperature a solution of bromine. (3.0 ml) in hexane (30 ml) for 2.5 hours, and the mixture was stirred for 24 hours. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give orange oil. To the obtained oil (13.39 g) in acetic acid (50 ml) was added sodium acetate (4.1 g), and then was added dropwise a solution of bromine (1.3 ml) in acetic acid (25 ml) for 1 hour. The mixture was stirred for 24 hours and concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate/hexane=1:4) to give orange oil of 7-bromo-3,4-dihydro-2H-1,5-benzodioxepine (13.17 g).
Reaction SMILES: N.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][N:11]2[C:15]3[CH:16]([CH2:21][C:22]([OH:24])=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[N:13]=[C:12]2[CH:25]([CH3:27])[CH3:26])[CH:6]=[CH:7][C:8]=1[Cl:9].[CH2:28](O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl.CN(C)CCCN=C=NCC>ClCCl.CN(C)C1C=CN=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][N:11]2[C:15]3[CH:16]([CH2:21][C:22]([O:24][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[N:13]=[C:12]2[CH:25]([CH3:27])[CH3:26])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: OCc1ccccc1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(CC(=O)O)CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)c(Cl)c1)C(CC(=O)OCc1ccccc1)CCCC2
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of Example 3 (180 mg) in dichloromethane (5 mL) at 0° C. was added benzyl alcohol (0.095 mL), 4-dimethylamino pyridine (10 mg) and N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (100 mg) sequentially. The reaction was stirred at 0° C. under an atmosphere for 1.5 hr. The reaction was allowed to achieve ambient temperature and stirred for a further 18 hr. The reaction mixture was partitioned between dichloromethane (10 mL) and water (10 mL). The aqueous phase was back extracted with dichloromethane (10 mL). The combined organics were dried (hydrophobic frit) and concentrated in vacuo to give 274 mg of product. The sample was purified on silica using 0-100% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound (159 mg). LC/MS MH+ 485, 487, Rt 2.28 min (5 minute run).