Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH:2]1[CH:3]=[CH:4][C:5]2[C:6](=[CH:8][CH:9]=[CH:10][C:11]=2O)[CH:7]=1.CS([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[C:27]([CH2:34][CH2:35][NH:36][C:37](=[O:39])[CH3:38])[CH:28]=[CH:29][CH:30]=2)[CH:25]=1)(=O)=O.Cl>O.CO>[C:37]([NH:36][CH2:35][CH2:34][C:11]1[CH:10]=[CH:9][CH:8]=[C:6]2[C:5]=1[CH:4]=[C:3]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[C:26]3[C:31]([CH:30]=[CH:29][CH:28]=[C:27]3[CH2:34][CH2:35][NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:33]=1)[CH:2]=[CH:7]2)(=[O:39])[CH3:38]
Reactant: CC(=O)NCCc1cccc2ccc(OCCCCCOS(C)(=O)=O)cc12
Reactant: Oc1cccc2ccccc12
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CO
Product: CC(=O)NCCc1cccc2ccc(OCCCCCOc3ccc4cccc(CCNC(C)=O)c4c3)cc12

Procedure:
In a 100 ml round-bottomed flask containing 30 ml of methanol, add sodium (0.07 g 0.0030 at. g.) in small portions. When the sodium has been completely used up, add naphthol (0.82 g, 3.6 mmol). Stir using a magnetic stirrer for 20 minutes. Remove the methanol by evaporation under reduced pressure. Take up the resulting residue in 15 ml of dimethylformamide. Add the compound obtained in Step C (1.2 g, 3 mmol) and heat at reflux for 12 hours. Allow the reaction mixture to cool and pour it into a mixture of 100 ml of water and 10 ml of 3M hydrochloric acid. Extract the aqueous phase twice with ethyl acetate. Wash the organic phase with an aqueous 10% sodium hydroxide solution and then with water. Dry over magnesium sulphate and remove the ethyl acetate by evaporation under reduced pressure. Recrystallise the resulting solid residue from acetonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1ccccc1C1CCN(C(=O)c2cn(CC(=O)N(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([C:28]([CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:29])[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[CH2:16][CH2:15]1)=[O:4].[OH2:36].[OH-].[Li+].[ClH:39]>C1COCC1.O>[OH2:2].[OH2:36].[ClH:39].[CH:30]1([C:28]([N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:3]([OH:4])=[O:2])[CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[CH2:18][CH2:19]2)=[O:29])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COC(=O)c1ccccc1N(CCN1CCN(c2ccccc2OC)CC1)C(=O)C1CCCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1N1CCN(CCN(C(=O)C2CCCCC2)c2ccccc2C(=O)O)CC1
Yield: 84 %

Procedure:
A solution of 0.33 g of the compound of example 18 and 0.06 g of lithium hydroxide monohydrate in 5 mL of THF and 1 mL of H2O was stirred at 70° C. for 9 h. The solution was added with 2 N aq. HCl to pH≡1 and evaporated to dryness. The residue was taken up with 10 mL of boiling Me2CO and filtered to give 0.32 g (84%) of the title compound as a white solid.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:27]=[CH:26][S:25][C:24]=1[CH:28]=[O:29])([O-:16])=[O:15].C(O)(C)C>CC(C)=O>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([OH:3])=[O:29])([O-:16])=[O:15]
Reactant: CC(C)=O
Reactant: O=Cc1sccc1-c1ccccc1[N+](=O)[O-]
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Product: O=C(O)c1sccc1-c1ccccc1[N+](=O)[O-]
Reaction time: 18 h
Yield: 66 %

Procedure:
8N Jones' reagent (ca. 30 ml) was added dropwise to a solution of 3-(2-nitrophenyl)-thiophen-2-aldehyde (8) (4.4 g, 3.1 mmol) in 32 ml of acetone, until an orange colour persisted. The mixture was left at room temperature for 18 hrs with stirring. Isopropanol (20 ml) was added to remove the excess Jones' reagent and the mixture was then filtered, the organic solvents were removed under vacuum and extracted with ethyl acetate (4×100 ml). The combined organic layer was washed with a saturated solution of NaCl, dried (Na2SO4), and evaporated under reduced pressure. The mixture was then chromatographed using 95/5 chloroform/methanol, thus giving the compound (9) (3.6 g, 66% yield).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22]([C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[N:30]=[CH:29][CH:28]=[CH:27]3)=[O:23])[CH:20]=1>C(N(CC)CC)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:34])=[C:19]([NH:21][C:22]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[CH:29][CH:28]=[CH:27]4)=[O:23])[CH:20]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(N)cc1NC(=O)c1ccc2ncccc2c1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(C(F)(F)F)cc2)cc1NC(=O)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
Using an analogous procedure to that described in Example 4, 4-trifluoromethylbenzoyl chloride was reacted with N-(5-amino-2methylphenyl)-quinoline-6-carboxamide in the presence of triethylamine. The reaction mixture was stirred at ambient temperature for 18 hours and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. There was thus obtained the title compound in 52% yield; Mass Spectrum: M+H+ 450.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OCC)(=[O:21])[CH2:17][C:18]([CH3:20])=O.C(O)C>O.Cl.[Cl-].[Zn+2].[Cl-]>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:12]([C:18]([CH3:20])=[CH:17][C:16](=[O:21])[O:15]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(NCc2ccccc2)c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCO
Product: Cc1cc(=O)oc2cc(NCc3ccccc3)ccc12

Procedure:
7-Benzylamino-4-methylcoumarin was synthesized from 3-benzylaminophenol and ethyl acetoacetate by the usual Peckmann reaction (anhydrous zinc chloride, absolute ethanol). Recrystallization from ethanol gave flat needles, m.p. 174.5°-175.5° C. The fluorescence maximum in water was 455 nm (excited 355 nm), in 10-2N HCl 458 nm. 1H nmr (60 MHz, CDCl3), δ2.36 (s, 3H, C--CH3), 4.45 (d, 2H, --CH2NH--, J=~5.5 Hz, collapses to a singlet when D2O added), 4.7-5 (1H, NH), 6.03 (s, 1H, H3), 6.57 (d, 1H H8), 6.63 (dd, 1H, H6, J56 =~9 Hz, J68 =~2 Hz), 7.45 (s, 5H, C6H5), 7.45 (d, 1H, H5, J56 =~9 Hz).
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5](=O)[C:6]2[CH:11]=[CH:10][S:9][C:7]=2[N:8]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:5]1[C:6]2[CH:11]=[CH:10][S:9][C:7]=2[N:8]=[C:3]([S:2][CH3:1])[N:4]=1
Reactant: CSc1nc2sccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1nc(Cl)c2ccsc2n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Methylsulfanyl-3H-thieno[2,3-d]pyrimidin-4-one (12 g, 60.5 mmol) was combined with POCl3 (56 mL), and the resulting mixture was heated to reflux for about 1 hour. The reaction mixture was concentrated under reduced pressure at 50° C. The residue was diluted with ethyl acetate (700 mL) at 0° C. Saturated sodium bicarbonate solution (600 mL) was added slowly. The resulting mixture was stirred vigorously at 0° C. for one hour and the layers were separated. Saturated sodium bicarbonate solution (600 mL) was added to the organic layer at 0° C., and the mixture was stirred vigorously for 20 minutes. The layers were separated. Brine (600 mL) was added to the organic layer and stirred vigorously for 5 minutes, and the layers were again separated. The organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (10.7 g) as a dark tan powder (M+=216, M.P.=105.0-107.4° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C@@H:5]([O:14][CH2:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[O:19]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][CH2:32][CH2:33]Br)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[C@@H:5]([O:14][CH2:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:33][CH2:32][CH2:31][O:30][C:29]2[CH:35]=[CH:36][C:26]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:27][CH:28]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCCO[C@@H](Cc1ccc(O)cc1)C(=O)OCC
Reactant: BrCCCOc1ccc(Oc2ccccc2)cc1
Product: CCCO[C@@H](Cc1ccc(OCCCOc2ccc(Oc3ccccc3)cc2)cc1)C(=O)OCC

Procedure:
The title compound was prepared from (S)-3-(4-hydroxy-phenyl)-2-propoxy-propionic acid ethyl ester and 3-(4-phenoxy-phenoxy)-propyl bromide (Example 244) using the Standard Procedure L. The product was purified by column chromatography on silica gel using 9/1 Hexan/Ethyl acetate mixture as eluent to afford the title product. MS(ES) for C29H34O6 [M+NH4]+: 496.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=[O:15])[C:3]=1[CH:16]=[N:17]O.P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17]
Reactant: O=c1c(C=NO)c(Cl)ccn1-c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1c(Cl)ccn(-c2ccccc2Cl)c1=O
Temperature: 90 °C
Yield: 98.3 %

Procedure:
To a solution of 4-chloro-1-(2-chlorophenyl)-3-((hydroxyimino)methyl)pyridin-2(1H)-one obtained in Step C (968 mg) in acetonitrile (6.80 mL) was added phosphorus oxychloride (0.319 mL) at room temperature. The reaction mixture was heated at 90° C. for 1 hr, cooled to room temperature, and poured into ice water, and the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution under ice-cooling. The aqueous layer was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (891 mg). 1H NMR (400 MHz, CDCl3) δ 6.47 (1H, d, J=7.6 Hz), 7.35 (1H, dd, J=7.6, 1.6 Hz), 7.39 (1H, d, J=7.6 Hz), 7.42-7.50 (2H, m), 7.60 (1H, dd, J=7.6, 1.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.O.[NH2:10][NH2:11]>C(O)(C)C>[F:1][C:2]1[N:3]=[C:4]([NH:10][NH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: Fc1cccc(F)n1
Solvent: O
Solvent: CC(C)O
Product: NNc1cccc(F)n1
Yield: 76.8 %

Procedure:
2,6-Difluoropyridine (25 g), isopropyl alcohol (100 ml) and hydrazine hydrate (40 ml) were mixed and refluxed with heating for 3 hours. The isopropyl alcohol was evaporated under reduced pressure, and the residue was added with water. The deposited crystals were collected by filtration, washed with water and dried to obtain 6-fluoro-2-hydrazinopyridine (21.2 g, yield: 76.8%). Coloration was observed during drying, and accordingly, the product was used for the next reaction immediately after the drying.
Reaction SMILES: C(OC([C:8]1([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:14][CH2:13][C:12]([CH3:15])=[CH:11][CH:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]1=[O:23])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:23]=[C:9]1[CH:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=[C:12]([CH3:15])[CH2:13][CH2:14][CH:8]1[CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CC1(C(=O)OC(C)(C)C)CCC(C)=CC(Cc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CC1CCC(C)=CC(Cc2ccccc2)C1=O
Reaction time: 0.75 h

Procedure:
To a stirred solution of the above di-ester (22) (1.35 g) in CH2Cl2 (20 mL) was added trifluoroacetic acid (80 mL). After stirring for 45 min the reaction was evaporated to dryness and re-evaporated twice with fresh toluene to remove any residual TFA. The oil which remained was then taken up in toluene (100 mL) and refluxed under Ar for 1 h. The product (23) was obtained after evaporation and purification by flash chromatography on silica gel eluted with 10% ethyl acetate in n-hexane (0.85 g, 85%).
Reaction SMILES: [Cl:1][C:2](=[N:10][OH:11])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[Cl:1][C:2](=[N:10][O:11][C:12](=[O:14])[CH3:13])[C:3]1[CH:4]=[CH:5][C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: ON=C(Cl)c1ccc(Cl)cc1
Solvent: O
Product: CC(=O)ON=C(Cl)c1ccc(Cl)cc1
Yield: 77.6 %

Procedure:
To 19 g (0.1 mol) of α-chloro-4-chlorobenzaldoxime prepared above was added 20.6 g (2.0 mol) of acetic anhydride followed by heating on a water bath at a temperature of from 80° to 90° C for about 2 hours. After completion of the reaction, the reaction mixture was poured into water to give pale yellow crystals. The product thus obtained was filtered, dried and recrystallized from ligroin to give 18 g of the desired product as white crystals having a melting point of 76°-77° C. Yield, 77%.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([NH:25][CH2:26][CH2:27][N:28]1[C@@H:33]([CH3:34])[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][C@H:29]1[CH3:42])=[O:24]>ClCCl>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[C:23]([NH:25][CH2:26][CH2:27][N:28]1[C@H:33]([CH3:34])[CH2:32][NH:31][CH2:30][C@@H:29]1[CH3:42])=[O:24]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CNC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.2 %

Procedure:
Trifluoroacetic acid (10 ml) was added to a solution of tert-butyl (cis)-4-[2-([(2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinyl]carbonylamino)ethyl]-3,5-dimethyl-1-piperazinecarboxylate (0.95 g) [see Preparation 8] in dichloromethane (10 ml) at 0° C. The reaction mixture was then stirred at room temperature for 1.5 hours, after which time the solvent was removed under reduced pressure and the residue partitioned between saturated potassium carbonate solution and ethyl acetate. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The product was azeotroped several times with dichloromethane to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2 -2-[(cis)-2,6-dimethyl-1-piperazinyl]ethyl-2-piperidinecarboxamide (0.65 g) as a white foam.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=1.C([O-])(O)=O.[Na+].O=P(Cl)(Cl)[Cl:29]>C(Cl)Cl>[Cl:29][C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(O)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)n2nc(C)c(-c3c(C)cc(Cl)cc3C)c2n1
Reaction time: 2 h

Procedure:
Slurry 7-hydroxy-2,5-dimethyl-3-(4-chloro-2,6-dimethylphenyl)-pyrazolo[1,5-a] pyrimidine in 10 mL POCl3 and reflux at 130° C. under N2. After 2 h, monitoring by TLC (alcohol Rf=0.5, chloride Rf=1.0; EtOAc as eluent), quench the reaction carefully at ambient temperature by diluting with 50 mL CH2Cl2 and pouring slowlyj into non-stirring saturated NaHCO3. Adjust stirring speed to control rate of quenching of residual POCl3 and stir until gas evolution ceases. Separate the layers and extract the aqueous layer with CH2Cl2 (2×50 mL). Pool the organic layers and dry over Na2SO4. Filter and evaporate to yellow oil, which is used directly without further purification.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH2:32])([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:21][CH:20]=4)[CH:14]=3)[CH:9]=2)[CH2:4][O:3]1.CO.Cl.O>>[NH2:32][C:5]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[CH:14]=2)[CH:9]=1)([CH2:4][OH:3])[CH2:6][OH:7]
Reactant: CC1(C)OCC(N)(c2ccc3cc(Oc4ccc(Oc5ccccc5)cc4)ccc3c2)CO1
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(CO)(CO)c1ccc2cc(Oc3ccc(Oc4ccccc4)cc3)ccc2c1
Temperature: 90 °C
Yield: 78.2 %

Procedure:
2,2-Dimethyl-5-[6-(4-phenoxy-phenoxy)-naphthalen-2-yl]-1,3-dioxinan-5-ylamine (0.1241 g, 0.0002811 mol) was dissolved in methanol (3 mL, 0.07 mol) and a solution of 1 M of hydrogen chloride in water (5 mL, 0.005 mol) in a 40 mL reaction vial equipped with a magnetic stir bar. The vial was capped and heated at 90° C. overnight. TLC analysis showed that the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure. The resulting solid was dissolved in methylene chloride (5 mL) and washed with water then aqueous sodium carbonate. The combined organic layer was dried over magnesium sulfate, then concentrated under vacuum and purified by HPLC to give 88.3 mg of the title compound (78% yield). MS: m/z=424.45 [M+Na+]. 1H NMR (DMSO-d6) δ: 8.00 (s, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 7.62-7.68 (m, 1H), 7.39-7.44 (m, 2H), 7.35-7.39 (m, 2H), 7.30 (dd, J=8.9, 2.5 Hz, 1H), 7.00-7.17 (m, 6H), 3.73 (d, J=3.8 Hz, 4H)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][C:8](=[O:32])[N:9]2[C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[F:28])[C:15]([O:29][CH3:30])=[CH:14][C:13]=2[Cl:31])=[C:5]([O:33][CH3:34])[N:4]=1.N1C=CC=CC=1.[C:41](OC(=O)C)(=[O:43])[CH3:42].Cl>C(Cl)Cl>[C:41]([NH:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][C:8](=[O:32])[N:9]2[C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]3[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=3[F:28])[C:15]([O:29][CH3:30])=[CH:14][C:13]=2[Cl:31])=[C:5]([O:33][CH3:34])[N:4]=1)(=[O:43])[CH3:42]
Reactant: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CN)nc32)cc1OCc1c(F)cccc1OC
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(Cl)c(-n2c(=O)[nH]c3c(OC)nc(CNC(C)=O)nc32)cc1OCc1c(F)cccc1OC
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a mixture of 2-aminomethyl-9-[2-chloro-5-(2-fluoro-6-methoxybenzyloxy)-4-methoxyphenyl]-6-methoxy-7,9-dihydro-8H-purin-8-one (94 mg) and pyridine (0.1 mL) in methylene chloride (3 mL) was added acetic anhydride (0.055 mL), and the mixture was stirred at room temperature for 5 days. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−ethyl acetate). The obtained product was suspended in diethyl ether, and collected by filtration. The collected material was dried under reduced pressure to give the title compound (44 mg).
Reaction SMILES: [C-:1]#[N:2].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1)=[O:10]>CS(C)=O>[C:5]1([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:1]#[N:2])=[CH:13][CH:12]=2)=[O:10])[S:4][CH:8]=[CH:7][CH:6]=1
Reactant: [C-]#N
Reactant: O=C(c1ccc(CBr)cc1)c1cccs1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc(C(=O)c2cccs2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 5.9 parts of sodium cyanide in 40 parts of dimethyl sulfoxide is heated to 60° C and there are added at once 11.3 parts of α-bromo-p-tolyl 2-thienyl ketone (exothermic reaction: temperature rises to 100° C). The whole is stirred for 2 hours at 60° C. After cooling, the reaction mixture is poured onto water and the product is extracted three times with 450 parts of chloroform. The combined extracts are washed twice with 200 parts of water, dried and evaporated. The dark-coloured residual tar is extracted several times with ether. The combined ether extracts are stirred with activated charcoal, filtered and evaporated. The residue is triturated in petroleumether (solid carbon dioxide) and the whole is evaporated, yielding 2-[p-(2-thenoyl)phenyl]acetonitrile as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42](O)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]>C(Cl)Cl>[CH3:25][O:26][C:27]1[C:28](=[O:51])[C:29]([CH3:50])=[C:30]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:46][C:47](=[O:49])[CH3:48])=[C:41]([CH:45]=2)[C:42]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:43])[C:31](=[O:35])[C:32]=1[O:33][CH3:34]
Reactant: Nc1ccc(Cl)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(Cl)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
4-Chloroaniline (0.150 g, 1.18 mmol), triethylamine (0.119 g, 1.18 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.199 g, 1.18 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) to obtain the titled compound (0.115 g, 0.238 mmol, 44%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:21]=[CH:22]/[C:23]([NH:25][CH3:26])=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1>C(O)C.C1COCC1.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:21][CH2:22][C:23]([NH:25][CH3:26])=[O:24])[CH:6]=[C:7]([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=3)[CH:10]=2)[CH:8]=1
Reactant: CNC(=O)/C=C/c1cc(OC)cc(-c2ccc3cc(OC)ccc3c2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)CCc1cc(OC)cc(-c2ccc3cc(OC)ccc3c2)c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A suspension of (E)-3-[3-methoxy-5-(6-methoxynaphthalene-2-yl)phenyl]-N-methylacrylic amide (100 mg, 0.30 mmol, 1 eq) and Pd(OH)2 (2.82 mg) in ethanol (1 ml) and THF (0.4 ml) is stirred for 19 h at RT under a hydrogen atmosphere. Filtration and concentration of the reaction mixture on a rotary evaporator yields the desired product in quantitative yield.