Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]=[N:4][C:5]1[CH:6]=[CH:7][C:8]([C:15]([O:17][CH3:18])=[O:16])=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:10]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([NH:30][C:31](OC2C=CC=CC=2)=[O:32])[N:23]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH3:29][O:28][C:26]1[CH:27]=[C:22]([O:21][CH3:20])[N:23]=[C:24]([NH:30][C:31]([NH:14][S:11]([C:9]2[CH:10]=[C:5]([N:4]=[CH:3][N:2]([CH3:19])[CH3:1])[CH:6]=[CH:7][C:8]=2[C:15]([O:17][CH3:18])=[O:16])(=[O:13])=[O:12])=[O:32])[N:25]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: COC(=O)c1ccc(N=CN(C)C)cc1S(N)(=O)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)c1ccc(N=CN(C)C)cc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 0 °C

Procedure:
A suspension of 1.50 g of 5-(2-dimethylamino-1-azaethenyl)-2-methoxycarbonylbenzenesulfonamide, 1.61 g of 4,6-dimethoxy-2-phenoxycarbonylaminopyrimidine, 32 ml of acetonitrile and 0.83 ml of DBU is stirred initially at 0° C. and then at room temperature until the reaction has ended. The reaction mixture is then concentrated under reduced pressure. The residue is taken up in water and washed with diethyl ether. The aqueous phase is carefully acidified with conc. hydrochloric acid (pH 6) and the sulfonylurea precipitate is separated off, washed with diisopropyl ether and water and dried. This affords 1.89 g of the desired sulfonylurea, melting point 73-75° C.;
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:12]=1[C:13]([O:15]C)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCOCC1.CO>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:12]=1[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(I)cc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1ccc(I)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (4.1 mL) was added to a solution mixture of methyl 2-(benzyloxy)-4-iodobenzoate (1.0 g) in dioxane (5.0 mL) and methanol (5.0 mL), followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and water was added to the residue. After adjusting the pH to 2.5 with 6.0 mol/L hydrochloric acid under ice-cooling, ethyl acetate was added. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue, and the resulting solid substance was collected by filtration to obtain 0.93 g of 2-(benzyloxy)-4-iodobenzoic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17]3[C:16]4[CH:15]=[N:14][CH:13]=[CH:12][C:11]=4[C:10](=[O:18])[C:9]=3[C:8](OS(C3C=CC(C)=CC=3)(=O)=O)=[N:7][C:6]=2[CH:30]=1.[NH2:31][CH2:32][CH2:33][N:34]([CH3:43])[CH2:35][CH2:36][CH2:37][N:38]([CH2:40][CH2:41][NH2:42])[CH3:39]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17]3[C:16]4[CH:15]=[N:14][CH:13]=[CH:12][C:11]=4[C:10](=[O:18])[C:9]=3[C:8]([NH:42][CH2:41][CH2:40][N:38]([CH2:37][CH2:36][CH2:35][N:34]([CH2:33][CH2:32][NH:31][C:8]3[C:9]4[C:10](=[O:18])[C:11]5[CH:12]=[CH:13][N:14]=[CH:15][C:16]=5[C:17]=4[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:30][C:6]=4[N:7]=3)[CH3:43])[CH3:39])=[N:7][C:6]=2[CH:30]=1
Reactant: CN(CCN)CCCN(C)CCN
Reactant: Cc1ccc(S(=O)(=O)Oc2nc3cc(Cl)ccc3c3c2C(=O)c2ccncc2-3)cc1
Product: CN(CCCN(C)CCNc1nc2cc(Cl)ccc2c2c1C(=O)c1ccncc1-2)CCNc1nc2cc(Cl)ccc2c2c1C(=O)c1ccncc1-2

Procedure:
In a similar manner to Example 4, this compound was obtained starting from toluene-4-sulfonic acid 3-chloro-7-oxo-7H-5,10-diaza-benzo[c]fluoren-6-yl ester (the compound of Reference Example 7c-1) and N,N′-bis-(2-amino-ethyl)-N,N′-dimethyl-propane-1,3-diamine. The desired product was obtained as a reddish powder.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=2)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:29](OC1C=CC(C(OC)=O)=CC=1)CCCCCCCCC=C.[OH-].[K+].C(Cl)(=O)C(Cl)=O.OC1C=CC(C=O)=CC=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C>[CH2:1]([O:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=2)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:29]
Reactant: C=CCCCCCCCCCOc1ccc(C(=O)OC)cc1
Reactant: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=Cc1ccc(O)cc1
Solvent: CCN(CC)CC
Product: C=CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1

Procedure:
Synthesized as described above for compound 10. Quantities: 4 (10.10 g, 33 mmol), KOH (2.46, 45 mmol), oxalyl chloride (13 mL, 148 mmol), p-hydroxybenzaldehyde (4.6 g, 38 mmol), triethylamine (33.7 mL, 0.24 mol), DMAP (0.20 g, 1.6 mmol). Yield 8.9 g (71%). 1HNMR: δH (CDCl3; 300 MHz): 1.24-1.52 (12 H, m, CH2), 1.83 (2 H, m, O—CH2—CH2), 2.04 (2 H, m, CH2═CH—CH2), 4.05 (2 H, t, 3J=6.5 Hz, O—CH2), 4.95 (2 H, m, CH2═CH), 5.82 (1 H, m, CH2═CH), 6.99 (2 H, d, 3J=9.0 Hz, Ar—H), 7.40 (2 H, d, 3J=8.5 Hz, Ar—H), 7.96 (2 H, d, 3J=8.6 Hz, Ar—H), 8.14 (2 H, d, 3J=9.0 Hz, Ar—H), 10.0 (1 H, s, COH). 13C NMR: δC (CDCl3; 75 MHz): 26.4, 29.3, 29.5, 29.5, 29.7, 29.8, 29.9, 34.2, 68.8, 114.6, 114.8, 121.2, 123.0, 131.6, 132.8, 134.3, 139.6, 156.3, 164.3, 164.6, 191.4.
Reaction SMILES: C1N2CN3CN(C2)C[N:2]1C3.[I-].[Na+].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH2:27]Cl)[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>ClCCl.CO.C(OCC)C>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][NH2:2])[CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: ClCc1cc(OCc2ccccc2)ccn1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: NCc1cc(OCc2ccccc2)ccn1

Procedure:
1.5 g (10.78 mmol) of hexamethylenetetramine and then 1.3 g of sodium iodide are added to 2.1 g (8.99 mmol) of 4-(benzyloxy)-2-(chloromethyl)pyridine (described in stage A) in 60 ml of dichloromethane. The reaction medium is heated at reflux for 12 hours and then concentrated under reduced pressure. The residue obtained is taken up in 45 ml of methanol. 7.5 ml (89.90 mmol) of a 12N hydrochloric acid solution are added. The reaction medium is heated at reflux for 16 hours. After addition of ethyl ether, the precipitate obtained is filtered off and then taken up in a saturated aqueous sodium carbonate solution. The aqueous phase is extracted with ethyl acetate, dried over sodium sulfate and then concentrated under reduced pressure. 1.1 g of a beige oil are collected. Mass spectrometry (ES+Mode): MH+=215
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([CH3:10])[CH2:7][CH2:8][OH:9])[CH:2]=[CH2:3].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1COCC1.[OH-].[Na+]>>[CH2:11]([O:9][CH2:8][CH2:7][C:6](=[N:5][O:4][CH2:1][CH:2]=[CH2:3])[CH3:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: C=CCON=C(C)CCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCON=C(C)CCOCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A reactor was charged with 0.1 mole of 3-allyloxyiminobutanol, 0.12 mole of benzyl chloride and 2 moles of THF. The mixture was cooled to 0° C., and 0.11 mole of sodium hydroxide was added little by little. The temperature of the mixture was returned to room temperature, and it was stirred for 2 hours. After the reaction, the product was isolated in a customary manner to give 3-allyloxyiminobutyl benzyl ether in a yield of 95 mole %.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([S:2][CH3:1])[O:4][C:5]=2[CH:11]=1
Reactant: CSc1nc2ccccc2o1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CSc1nc2ccc(Br)cc2o1
Reaction time: 0.75 h

Procedure:
2-(Methylthio)benzoxazole (5.8 g, see (a) above) was dissolved in chloroform (75 ml) and a solution of bromine (6.0 g) in chloroform (30 ml) was added dropwise, with stirring, over a period of 45 minutes. The mixture was allowed to stand overnight at room temperature and the solvent removed by distillation under reduced pressure to give a brown oil. The oil was washed with aqueous sodium metabisulfite and crystallised from ethanol/water to give the title compound as pink platelets (2.0 g), mp 95°-96° C.
Reaction SMILES: COS([O:6][CH3:7])(=O)=O.[I:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17]O)=[CH:11][CH:10]=1.[OH-].[Na+].[OH-].[NH4+]>>[I:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][O:6][CH3:7])=[CH:11][CH:10]=1
Reactant: COS(=O)(=O)OC
Reactant: OCC#Cc1ccc(I)cc1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Product: COCC#Cc1ccc(I)cc1
Reaction time: 2.5 h
Yield: 92 %

Procedure:
Dimethylsulphate (2.2 g) was added dropwise over 5 min to a vigorously stirred mixture of the product of stage (i) (3.0 g), TAB (0.15 g) 50% w/v aqueous sodium hydroxide (2.8 ml) in H (10 ml) and MC (5 ml) and stirring was continued for a further 2.5 h. Concentrated ammonium hydroxide solution (5 ml) was added and the mixture was stirred for 30 min to destroy the excess dimethylsulphate. Water (50 ml) was added, the mixture extracted with ER (2×35 ml), the organic layer dried and concentrated in vacuo at 35° to afford a brown oil. This was purified by FCC eluting with ER-CX (1:10) yielding the title compound as a cream crystalline solid (2.91 g) m.p. ca20°. T.l.c. (ER-H 1:8) Rf 0.44.
Reaction SMILES: C1(C([N:14]2[C:22]3[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=3)[C:16]3([C:27]4=[CH:28][C:29]5[O:33][CH2:32][O:31][C:30]=5[CH:34]=[C:26]4[O:25][CH2:24]3)[C:15]2=[O:35])C2C=CC=CC=2)C=CC=CC=1>[OH-].[Pd+2].[OH-].C(O)(=O)C>[CH3:23][C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[NH:14][C:15](=[O:35])[C:16]12[C:27]2=[CH:28][C:29]3[O:33][CH2:32][O:31][C:30]=3[CH:34]=[C:26]2[O:25][CH2:24]1
Reactant: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCO4)C(=O)N2C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C1(COc3cc4c(cc31)OCO4)C(=O)N2
Temperature: 60 °C
Reaction time: 96 h
Yield: 43.4 %

Procedure:
A stainless steel hydrogenating vessel was successively charged with (diphenylmethyl)-5′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.90 g, 1.95 mmol), glacial acetic acid (50.0 mL) and palladium hydroxide (0.10 g, 1.35 mmol, 20 wt % on carbon). The vessel was flushed with nitrogen, sealed then heated to 60° C. and placed under 120 Psi of H2. After 4 days of stirring, the reaction mixture was diluted with ethyl acetate and passed through a bed of celite. The filtrate was washed with water (6×100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexane (40-50%) to afford the title compound (0.25 g, 43%): mp 269-271° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.00 (d, 1H), 6.87 (s, 1H), 6.76 (d, 1H), 6.63 (s, 1H), 6.21 (s, 1H), 5.87 (d, 2H), 4.64 (ABq, 2H), 2.17 (s, 3H); MS (ES+) m/z 296.28 (M+1).
Reaction SMILES: C[Zn]C.[CH2:4]([O:6][C:7]([C:9]1[C:10](Br)=[CH:11][N:12]2[CH:16]=[CH:15][S:14][C:13]=12)=[O:8])[CH3:5].CO.[CH3:20]C(OC)(C)C>C1(C)C=CC=CC=1.O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:4]([O:6][C:7]([C:9]1[C:10]([CH3:20])=[CH:11][N:12]2[CH:16]=[CH:15][S:14][C:13]=12)=[O:8])[CH3:5]
Reactant: COC(C)(C)C
Reactant: CCOC(=O)c1c(Br)cn2ccsc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Zn]C
Solvent: Cc1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)cn2ccsc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under nitrogen atmosphere a solution of dimethylzinc in toluene (1.2 M, 19.1 mL) is added to a mixture of 6-bromo-pyrrolo[2,1-b]thiazole-7-carboxylic acid ethyl ester (11.4 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.23 mmol, complex with CH2Cl2) in dioxane (35 mL). The mixture is heated to reflux for 2 h, stirred at RT for 12 h and diluted by addition of MeOH (2.3 mL) and TBME. The mixture is washed with hydrochloric acid (1.0 M) and water, dried over MgSO4, concentrated in vacuo and purified by flash chromatography (gradient: heptane to heptane/EtOAc 8/2) to give the desired product. LC-MS: tR=0.91 min; [M+H]+=210.0.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](Cl)=[O:13])=[CH:4][CH:3]=1.[Si]([CH:19]=[N+:20]=[N-:21])(C)(C)C>ClCCl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12](=[O:13])[CH:19]=[N+:20]=[N-:21])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)c2ccccc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Product: [N-]=[N+]=CC(=O)c1ccc(Br)c2ccccc12
Temperature: 0 °C
Reaction time: 18 h

Procedure:
4-Bromo-naphthalene-1-carbonyl chloride (13.8 g) was dissolved in dichloromethane (130 mL) and cooled to 0° C. TMS diazomethane solution (40 mL, 2 M in DCM) was added, and ice bath was removed. Reaction mixture was stirred for 18 hours and evaporated under vacuum, giving 1-(4-bromonaphthalen-1-yl)-2-diazoethanone (13.8 g, crude) as a brown oil.
Reaction SMILES: [CH:1]1([C@@H:4]([N:7]2[CH:12]=[C:11]([Cl:13])[N:10]=[C:9](Cl)[C:8]2=[O:15])[CH2:5][CH3:6])[CH2:3][CH2:2]1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[NH:22][CH2:21][CH2:20]2>>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([Cl:26])[CH:25]=1)[N:22]([C:9]1[C:8](=[O:15])[N:7]([C@H:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:5][CH3:6])[CH:12]=[C:11]([Cl:13])[N:10]=1)[CH2:21][CH2:20]2
Reactant: Clc1cc(Br)cc2c1NCC2
Reactant: CC[C@@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Product: CC[C@@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(Br)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 1-[(1S)-1-cyclopropylpropyl]-3,5-dichloro-2(1H)-pyrazinone and 5-bromo-7-chloroindoline as the starting materials. mp 126-127° C.; 1H NMR (300 MHz, CDCl3): δ 7.31 (d, J=1.9 Hz, 1 H), 7.24 (d, J=1.4 Hz, 1 H), 7.01 (s, 1H), 4.32 (t, J=7.9 Hz, 2 H), 4.08-4.02 (m, 1 H), 3.14 (t, J=8.1 Hz, 2 H), 1.94-1.78 (m, 2 H), 1.05-1.00 (m, 1 H), 0.94 (t, J=7.3 Hz, 3 H), 0.81-0.77 (m, 1 H), 0.54-0.48 (m, 2 H), 0.34-0.30 (m, 1 H); HRMS (ESI) calcd for C18H19N3OBrCl2 (M+H)+: 442.0089; Found m/z 442.0093.
Reaction SMILES: [CH2:1]([C@@:3]12[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][C@@H:9]1[CH2:8][CH2:7][CH2:6][C:5]1[CH:15]=[C:16]([O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])[CH:17]=[CH:18][C:4]2=1)[CH3:2].C([C@]12CC[C:37](=[O:40])[CH2:36][C@H]1CCCC1C=C(OS(C(F)(F)F)(=O)=O)C=CC2=1)C.C(O)CO.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>CCOC(C)=O.C1(C)C=CC=CC=1>[F:25][C:23]([F:26])([F:24])[S:20]([O:19][C:16]1[CH:17]=[CH:18][C:4]2[C:3]3([CH2:1][CH3:2])[CH2:13][CH2:12][C:11]4([O:40][CH2:37][CH2:36][O:14]4)[CH2:10][CH:9]3[CH2:8][CH2:7][CH2:6][C:5]=2[CH:15]=1)(=[O:21])=[O:22]
Reactant: CC[C@@]12CCC(=O)C[C@@H]1CCCc1cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: CC[C@]12CCC(=O)C[C@H]1CCCc1cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCC12CCC3(CC1CCCc1cc(OS(=O)(=O)C(F)(F)F)ccc12)OCCO3
Temperature: 25 °C
Yield: 89.9 %

Procedure:
A flask equipped with a Dean-Stark apparatus was charged with trifluoro-methanesulfonic acid (7aR,11aS)-11a-ethyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cyclohepten-3-yl ester; compound with trifluoro-methanesulfonic acid (7 aS,11aR)-11a-ethyl-9-oxo-6,7,7a,8,9,10,11,11a-octahydro-5H-dibenzo[a,c]cyclohepten-3-yl ester (19, R2=Ethyl) (2.2 g, 5.63 mmol), ethane-1,2-diol (1.571 mL, 28.2 mmol), pTSA (0.107 g, 0.563 mmol) and toluene (44 mL). The mixture was heated to reflux for about 21 h. The mixture was cooled to rt, EtOAc (20 mL), sat. aq. NaHCO3 (10 mL) were added and the layers were separated. The organic layer was washed with brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (12 g) using a gradient of 0-40% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to yield rac-(4aR,11bS)-11b-ethyl-1,2,4,4a,5,6,7,11b-octahydrospiro[dibenzo[a,c][7]annulene-3,2′-[1,3]dioxolan]-9-yl trifluoromethanesulfonate (20, R2=Ethyl) (2.2 g, 90%); LC/MS, method 3, Rt=3.05 min, MS m/z 435 (M+H)+. 1H NMR (400 MHz, DMSO) δ 7.42-7.35 (m, 1H), 7.26-7.22 (m, 2H), 3.91-3.69 (m, 4H), 3.04-2.77 (m, 2H), 2.43-2.37 (m, 1H), 2.22-2.13 (m, 1H), 2.11-1.94 (m, 2H), 1.71-1.62 (m, 2H), 1.61-1.54 (m, 2H), 1.52-1.35 (m, 3H), 1.32-1.17 (m, 2H), 0.59 (t, J=7.4 Hz, 3H).
Reaction SMILES: C(O)=O.[CH2:4]([O:6][C:7](=[O:54])[C@H:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3[N:33]([CH2:44][CH2:45][O:46]CC3C=CC=CC=3)[CH2:34][CH2:35][O:36]CC3C=CC=CC=3)[CH:24]=2)[CH:18]=1)[NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH3:5]>[OH-].[Pd+2].[OH-].C(O)C>[CH2:4]([O:6][C:7](=[O:54])[C@H:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3[N:33]([CH2:44][CH2:45][OH:46])[CH2:34][CH2:35][OH:36])[CH:24]=2)[CH:18]=1)[NH:9][C:10](=[O:15])[C:11]([F:13])([F:14])[F:12])[CH3:5]
Reactant: CCOC(=O)[C@H](Cc1cccc(-c2ccc3c(N(CCOCc4ccccc4)CCOCc4ccccc4)cccc3c2)c1)NC(=O)C(F)(F)F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=CO
Product: CCOC(=O)[C@H](Cc1cccc(-c2ccc3c(N(CCO)CCO)cccc3c2)c1)NC(=O)C(F)(F)F
Temperature: 25 °C
Yield: 74 %

Procedure:
Ethanol (10 ml), formic acid (1.94 ml, 52 mmol) and 20% palladium hydroxide (145 mg) were added to 3-[5-bis[2-(benzyloxy)ethyl]amino-naphth-2-yl]-N-trifluoroacetyl-L-phenylalanine ethyl ester (739 mg, 1.03 mmol) and the mixture was heated under reflux for 3 days. After the mixture was cooled to room temperature, the catalyst was filtered off and the solvent of the filtrate was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/chloroform=1 and 2) to give 3-[5-bis[2-(hydroxy)ethyl]amino-naphth-2-yl]-N-trifluoroacetyl-L-phenylalanine ethyl ester (395 mg, 71%) as a dark yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:10]2[O:17][CH2:16][C@H:15]3[C@@H:11]2[CH2:12][O:13][C@H:14]3[C:18]2[CH:19]=[CH:20][C:21]([OH:26])=[C:22]([O:24][CH3:25])[CH:23]=2)[CH:6]=[CH:7][C:8]=1[OH:9].Br[C:28]([C@@H:30]([C@H:32]([C@@H:34]([C@@H:36]([CH2:38][OH:39])[OH:37])[OH:35])[OH:33])[OH:31])=O>N1C2C(=CC=CC=2)C=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:10]2[O:17][CH2:16][C@H:15]3[C@@H:11]2[CH2:12][O:13][C@@H:14]3[C:18]2[CH:19]=[CH:20][C:21]([O:26][C@@H:28]3[O:37][C@H:36]([CH2:38][OH:39])[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@H:30]3[OH:31])=[C:22]([O:24][CH3:25])[CH:23]=2)[CH:6]=[CH:7][C:8]=1[O:9][C@@H:28]1[O:37][C@H:36]([CH2:38][OH:39])[C@@H:34]([OH:35])[C@H:32]([OH:33])[C@H:30]1[OH:31]
Reactant: COc1cc([C@H]2OC[C@H]3[C@@H]2CO[C@H]3c2ccc(O)c(OC)c2)ccc1O
Reactant: O=C(Br)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: c1ccc2ncccc2c1
Product: COc1cc([C@H]2OC[C@H]3[C@@H]2CO[C@@H]3c2ccc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(OC)c2)ccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
Pinoresinol-diglucoside - Silver oxide (2.24 g, 9.65 mmol) was added to a stirred reaction mixture of pinoresinol (358 mg, 1 mmol) and aceto-α bromo glucose (2.24 g, 5.45 mmol) in 6 ml of dry quinoline over a period of 15 min. After stirring the reaction mixture for 16 hours at 25° C., the reaction mixture was extracted with 20 ml of ether. The organic ethereal layer was successively washed with water (2 × 10 ml), 1 N HCl (5 × 5 ml), dilute NaHCO3 (3 × 5 ml) and dried over Na2SO4. After evaporation of the organic solvent in vacuo, the residue was dissolved in 20 ml of methanol containing 1 ml of 5 N NaOH and the mixture was stirred for 2 hours at 0° C. After acidification to pH 4.5 with 2N HCl, this mixture was evaporated to dryness. The residue was dissolved in 5 ml of water and chromatographed over an Amberlite XAD-2 column (1.9 × 38 cm). The column was washed with 150 ml of water to remove salts. The diglucoside was then eluted off the column with 250 ml of 20% aqueous acetone. The combined acetone fractions were evaporated to dryness and the residue was chromatographed over a silica-gel column (3.5 × 44 cm). Elution of the column with solvent system, CHCl3 :CH3OH:H2O (65:30:10) gave 230 mg (34%) of pure pinoresinol diglucoside, m.p. 238-250°; uv (H2O) 276 nm (ε6,600) and 226 (ε21,900); [α]D25 -15.3° (c, 0.4, H2O); IR (KBr) 1600, 1515, 1414, 1275, 1260, 1230, 1080, 1050, 1030, 993 810 cm-1. Anal calcd for C32H42O16.4H2O: C, 50.92; H, 6.68. Found: C, 50.70; H, 6.70.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:26])[CH:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1.Cl>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N:12]([CH3:26])[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: COc1ccc([N+](=O)[O-])cc1N(C)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc([N+](=O)[O-])cc1N(C)C1CCNCC1
Temperature: 42.5 °C
Reaction time: 0.17 h
Yield: 114.8 %

Procedure:
To a 250 mL three neck round bottom flask, added 2-Methoxy-5-nitro-N-methyl-N-(1-Boc piperidine-4-yl)phenyl amine (3 grams, 8.21 mmol) obtained at step (II), followed by the addition of isopropyl alcohol (20 mL) and allowed to stir for 10 minutes. The reaction mass was heated to 40-45° C. and stirred for 5 minutes to get a clear solution. Isopropanolic hydrogenchloride, (20%) solution (15.99 mL, 65.75 mmol) was added to the above reaction mass, drop-wise over a period of 10 minutes. Further the reaction mass was heated at 60-63° C. for 2 hours. The solids that separated were filtered and taken into water (20 mL), basified with ammonia solution and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine solution (20 mL), dried over sodium sulfate and solvent was removed under reduced pressure to obtain 2.5 grams of the title product.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9]Br.O.O.OC[S:15]([O-:17])=[O:16].[Na+].O>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)C>[CH2:9]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2][S:15](=[O:16])[O:17]1
Reactant: BrCc1ccccc1CBr
Reactant: O=S([O-])CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: O=S1Cc2ccccc2CO1
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To a stirred solution of 1,2-bis(bromomethyl)benzene (15 g, 56.8 mmol) in N,N-dimethylformamide (100 mL) at 0° C. was added tetrabutylammonium bromide (3.66 g, 11.4 mmol), followed by sodium hydroxymethane sulfinate dihydrate (17.5 g, 113.6 mmol) in one portion. The resulting suspension was stirred at 0° C. for 7 h under nitrogen and then at room temperature for 10 h. Water (250 mL) was added and after 30 min the reaction mixture was diluted with diethyl ether. The organic layer was washed with water twice. The aqueous layer was extracted with diethyl ether twice more. The combined organic layers were dried over anhydrous magnesium sulfate and evaporated under vacuum to yield the title compound (purity 80%). 13C NMR (400 MHz, CDCl3) δ 133.8, 130.0, 128.6, 127.9, 125.9, 125.7, 63.0, 57.0. 1H NMR (400 MHz, CDCl3) δ 7.20-7.41 (m, 4H), 5.31 (d, J=13.6 Hz, 1H), 4.97 (d, J=13.6 Hz, 1H), 4.42 (d, J=15.4 Hz, 1H), 3.56 (d, J=15.4 Hz, 1H). MS [M+H]+, 169.