Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([F:25])=[C:8]([C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:11])[CH:9]=1.[C:26](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([F:25])=[C:8]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:26])[CH2:14][C@@H:13]2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:11])[CH:9]=1
Reactant: O=C(c1cc(Br)ccc1F)N1CCNC[C@@H]1c1ccc(F)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(C(=O)c2cc(Br)ccc2F)[C@@H](c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
Formaldehyde (1.47 mL, 19.4 mmol of 37% aqueous solution) was added to (5-Bromo-2-fluoro-phenyl)-[(S)-2-(4-fluoro-phenyl)-piperazin-1-yl]-methanone (0.32 g, 0.65 mmol) in 10 mL of methanol. The mixture was stirred at ambient temperature for 1 h and then sodium triacetoxyborohydride (0.82 g, 3.9 mmol) was added and the resulting mixture was stirred overnight. The volatiles were removed in vacuo, and the residue was portioned between ethyl acetate and 1M sodium bicarbonate solution. The organic phase was washed with 1M sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated to leave 0.21 g of product. LC/MS: Retention time, 2.14 min; (M+H)=395/397.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N+:10]([O-:12])=[O:11])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1)c1ccccc1

Procedure:
To a solution of 0.75 g. of 5-amino-2-nitro-3-phenylbenzofuran in 5 ml. of pyridine is added 1 ml. of benzoyl chloride. The mixture is heated on a steam bath for about 1 hour, then decanted into 50 ml. of 2 N hydrochloric acid. A yellow residue forms which is recrystallized from a mixture of isopropanol, methanol and water to provide yellow crystals of 5-benzamido-2-nitro-3-phenylbenzofuran having the structure ##STR11##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[CH3:14][C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]2[CH:19]([CH2:20][NH:21][CH2:22]2)[C:18](=[O:24])[CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH3:14][C:15]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]2[CH:19]([CH2:20][N:21]([C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:22]2)[C:18](=[O:24])[CH2:17][CH2:16]1
Reactant: COc1ccccc1CC(=O)O
Reactant: CC1(c2ccccc2)CCC(=O)C2CNCC21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1CC2C(=O)CCC(C)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
To a solution of 1.66 g of 2-methoxyphenylacetic acid in 40 cm3 of dichloromethane are added, at 4° C., 1.62 g of N,N'-carbonyldiimidazole. Stirring for 30 minutes at room temperature is followed by dropwise addition of a solution containing 1.85 g of (3aRS,7SR,7aRS)-7-methyl-7-phenyl-4-perhydroisoindolone hydrochloride and 0.7 g of triethylamine in 30 cm3 of dichloromethane. After stirring for 2 hours, the reaction mixture is washed twice with 50 cm3 of water and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 3 cm, height 15 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (80/20 by volume) and collecting 50 cm3 fractions. Fractions 16 to 60 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). The residue is crystallized in 30 cm3 of ethyl acetate. 1.3 g of (3aRS,7SR,7aRS)-7-methyl-7-phenyl-2-[(2-methoxyphenyl)acetyl]-4-perhydroisoindolone are obtained, in the form of white crystals melting at 160° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7](O)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:22][CH3:23].[H][H]>S(=O)(=O)(O)O.[Pd].C(O)(=O)C>[Cl:1][C:2]1[C:10]2[O:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: [H][H]
Reactant: CCOC(=O)C1(C(=O)OCC)Oc2c(ccc(OC)c2Cl)C1O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)C1(C(=O)OCC)Cc2ccc(OC)c(Cl)c2O1
Yield: 82.5 %

Procedure:
A solution of (15h) (2.67 g., 0.008 mol) and 3 drops of concentrated sulfuric acid in 100 ml. of glacial acetic acid was treated with 0.3 g. of 20% palladium on carbon in a Parr apparatus under 3 atmospheres of hydrogen for 2 hours at room temperature. The solvent was evaporated under reduced pressure and the residue was dissolved in chloroform. This solution was washed with aqueous sodium bicarbonate and brine solutions, dried over anhydrous sodium sulfate, and evaporated. There resulted an 82.5% yield of diethyl 7-chloro-2,3-dihydro-6-methoxybenzofuran-2,2-dicarboxylate, m.p. 97°-99° C. Analysis (C15H17ClO6) C,H.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(C(O)CCc2ccc(F)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(C(Cl)CCc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(4-cyanophenyl)-3-(4-fluorophenyl)-1-propanol (3.43 g, 13 mmol) is dissolved in dichloromethane (20 ml). Thionylchloride (1.2 ml, 16 mmol) is added dropwise to the cooled solution and the mixture is stirred in room temperature for 2 hours. The mixture is washed with water, dried and the solvent is evaporated. The residue is used for the next step without further purification.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])C.[OH-].[Na+]>CO.O>[C:21]([O:20][C:18]([NH:17][C@H:6]([CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([F:15])=[CH:10][C:9]=1[F:16])[CH2:5][C:4]([OH:25])=[O:3])=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)CC(Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)c(F)cc1F
Temperature: 42.5 °C
Reaction time: 1.25 h
Yield: 99.6 %

Procedure:
Refer to the common known method Tetrahedron Asymmetry, 2006, 17(2), 205-209. 3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid ethyl ester 1e (10 g, 27.7 mmol) and sodium hydroxide (3.32 g, 83.1 mmol) were dissolved in 150 mL of the mixture of methanol and water (v:v=1:1). The reaction mixture was stirred at 40-45° C. for 1-1.5 hours, then part of the solution was evaporated under reduced pressure. The residues were added with a little of water, then the pH was adjusted to 2-3 with 1 M hydrochloric acid in an ice-water bath. The mixture was extracted with ethyl acetate (200 mL×3), and the combined organic phase was washed with 200 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and then the residues were recrystallized from ethyl acetate/n-hexane to obtain the title compound (R)-3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyric acid 1f (9.2 g) as a white solid, which was directly used in the next step. MS m/z (ESI): 332.3 [M−1].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][C:8]1[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:24][C:25]([N:27]([CH:36]([CH3:38])[CH3:37])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:26]>CN(C=O)C>[CH:36]([N:27]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:25](=[O:26])[CH2:24][NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:37])[CH3:38]
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Reactant: Nc1ccccc1Nc1ncccn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CNc2ccccc2Nc2ncccn2)C(C)C)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of N-pyrimidin-2-yl-benzene-1,2-diamine (82 mg, 0.441 mmol) in DMF (2 mL) was added potassium carbonate (61 mg, 0.441 mmol), potassium iodide (7 mg, 0.044 mmol), and 2-Bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (126 mg, 0.441 mmol). The resultant reaction mixture was stirred overnight at 60° C. The solvent was removed in vacuo and the crude material partitioned between CH2Cl2 (35 mL) and water (15 mL). The organic phase was separated, dried with MgSO4, filtered and concentrated to a yellow oil which upon trituration with EtOH (6 mL) and filtration gave the title compound (96.7 mg, 0.247 mmol) as yellow crystals: 1H NMR (CDCl3, 300 MHz): 8.36 (d, 2H, J=4.9 Hz), 7.38 (dd, 1H, J=1.2, 7.8 Hz), 7.06-6.90 (m, 6H), 6.75 (t, 1H), 6.66 (t, 1H), 6.36 (dd, 1H, J=1.2, 7.8 Hz), 4.97 (m, 1H), 3.87 (s, 3H), 3.43 (s, 2H), 1.04 (d, 6H, J=6.8 Hz); TLC (EtOAc): Rf =0.62; MS (FAB) m/z 392.0 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([CH2:10][C:11](OCC)=[O:12])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:8][C:6]1([CH3:9])[CH2:7][C:2]([CH3:1])([CH3:16])[CH2:3][CH:4]([CH2:10][CH2:11][OH:12])[CH2:5]1
Reactant: CCOC(=O)CC1CC(C)(C)CC(C)(C)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1(C)CC(CCO)CC(C)(C)C1
Yield: 81.4 %

Procedure:
A solution of ethyl 3,3,5,5-tetramethylcyclohexylacetate 8 (1.8 g, 8.0 mmol) in ether (30 ml) was added dropwise to a stirred suspension of lithium aluminum hydride (0.9 g, 24.0 mmol) in ether (30 ml), which was cooled in an ice bath. The reaction mixture was refluxed for 3 h, cooled and residual lithium aluminum hydride was destroyed with water. The aqueous layer was separated and twice extracted with ether. The combined ether phases were washed with saline, dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate mixture (4:1) to give 1.2 g (79%) of 11 as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]2[CH:20]=[CH:19]N=C[CH:16]=2)[C:3]=1[O:4][CH2:5][C:6]([NH:8][NH2:9])=[O:7].CC1C=C(C)C=C(C2C=C[N:37]=[CH:36]C=2)C=1OCC([O-])=O.O.NN>CCO>[CH3:1][C:2]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([C:15]2[CH:16]=[N:37][CH:36]=[CH:19][CH:20]=2)[C:3]=1[O:4][CH2:5][C:6]([NH:8][NH2:9])=[O:7]
Reactant: Cc1cc(C)c(OCC(=O)NN)c(-c2ccncc2)c1
Reactant: Cc1cc(C)c(OCC(=O)[O-])c(-c2ccncc2)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(OCC(=O)NN)c(-c2cccnc2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
Synthesis of 2-(2,4-dimethyl-6-(pyridin-4-yl)phenoxy)acetohydrazide: 2-(2,4-dimethyl-6-(pyridin-4-yl)phenoxy)acetate (0.1 g, 0.37 mmol) was dissolved in EtOH. Hydrazine monohydrate (0.13 g, 2.63 mmol) was added thereto, followed by stirring at 100° C. for 16 hours under reflux. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and purified by column chromatography to obtain 2-(2,4-dimethyl-6-(pyridin-3-yl)phenoxy)acetohydrazide (0.1 g, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(OCC)(=O)C>[CH2:19]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:16]([CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][C:11]2[N:15]=[CH:14][NH:13][CH:12]=2)=[O:18])[CH2:28][CH2:29]1)=[O:23])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CCOC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)C(Cc2c[nH]cn2)NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of N-t-butoxycarbonylhistidine (2 g, 7.05 mmol) in THF (30 mL) was added 1-ethoxycarbonylpiperazine (1.36 mL, 1.3 eq.), EDCl (1.65 g, 1.2 eq.), HOBt (1.2 g, 1.1 eq.) and the reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 2%–6% MeOH in CH2Cl2 afforded 4-ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (820 mg). 4-Ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (200 mg, 0.5 mmol) was treated with trifluoroacetic acid/methylene chloride (1:1, 2.0 mL) with stirring at ambient temperture for 1 hour. Evaporation gave 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, which was treated with methylene chloride and triethylamine (0.5 mL), and the solvents evaporated to again afford 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine. To a solution of 2-carboxy-4-methoxyquinoline (124 mg, 0.61 mmol) in THF (4 mL) was added a mixture of 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, THF (2 mL), and triethylamine (0.1 mL), followed by addition of EDCl (136 mg, 1.4 eq.), HOBt (98 mg, 1.4 eq.). The resulting mixture was stirred overnight. The crude product (245 mg, foam) was isolated from the reaction mixture by the same methods employed above. Flash column chromatography with 25%–6% MeOH in methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(imidazol-4-yl)ethyl]aminocarbonyl-4-methoxyquinoline; NMR (CDCl3) 1.25 (t, 3), 3.10–3.30 (m, 2), 3.20–3.65 (m, 9), 4.10 (m, 5), 5.40 (m, 1), 6.90 (s, 1), 7.55–7.60 (m, 3), 7.70 (t, 1), 8.02 (d, 1), 8.20 (d, 1), 9.0 (d, 1) ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23[CH2:21][CH2:20][N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)=[O:11])=C1.[NH:22]1C2C(=CC=CC=2)C(C(Cl)=O)=N1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]23[CH2:21][CH2:20][N:17]([CH2:18][CH2:19]2)[CH2:16][CH2:15]3)=[O:11])=[N:22]1
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Reactant: O=C(Cl)c1n[nH]c2ccccc12
Product: O=C(OCC12CCN(CC1)CC2)c1n[nH]c2ccccc12

Procedure:
Quinuclidin-4-ylmethyl 1H-indazole-3-carboxylate was prepared in a similar manner to (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate, substituting 1H-indazole-3-carbonyl chloride as the electrophile.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]3[CH:13]=[C:14]([C@H:20]4[C@H:25]([OH:26])[C@@H:24]([OH:27])[C@H:23]([OH:28])[C@@H:22]([CH2:29][OH:30])[O:21]4)[CH:15]=[CH:16][C:17]=3[CH2:18][CH3:19])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:31]([O:33][P:34](Cl)([O:36][CH2:37][CH3:38])=[O:35])[CH3:32]>N1C=CC=CC=1>[CH2:31]([O:33][P:34](=[O:35])([O:36][CH2:37][CH3:38])[O:30][CH2:29][C@@H:22]1[C@@H:23]([OH:28])[C@H:24]([OH:27])[C@@H:25]([OH:26])[C@H:20]([C:14]2[CH:15]=[CH:16][C:17]([CH2:18][CH3:19])=[C:12]([CH2:11][C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:13]=2)[O:21]1)[CH3:32]
Reactant: CCc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)OCCO2
Reactant: CCOP(=O)(Cl)OCC
Solvent: c1ccncc1
Product: CCOP(=O)(OCC)OC[C@H]1O[C@@H](c2ccc(CC)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reaction time: 1 h
Yield: 33.2 %

Procedure:
To a stirred solution of (2S,3R,4R,5S,6R)-2-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (Intermediate 2, 500 mg, 1.2 mmol) in pyridine (5 ml) was added diethylchlorophosphate (0.27 ml, 1.9 mmol) at −40° C. After stirring for 1 h at same temperature, reaction was quenched with the addition of 1N HCl and extracted with ethyl acetate (2×10 ml). Combined organic layers were washed with brine (10 ml), dried over sodium sulfate, concentrated and purified by preparative HPLC to give 220 mg of phosphoric acid (2R,3S,4R,5R,6S)-6-[3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-ethyl-phenyl]-3,4,5-trihydroxy-tetrahydro-pyran-2-ylmethyl ester diethyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.S(=O)(=O)(O)O.C(OCC)(=O)C>O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[C:21]2[CH:22]=[CH:23][C:18](=[O:17])[NH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: Oc1ccccn1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1ccc(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)c[nH]1
Temperature: 200 °C

Procedure:
Combine 50.6 g. (0.2 mole) of 4,4'-dichlorobenzhydrol with 57.1 g. (0.6 mole) of 2-hydroxy pyridine, with stirring heat to 200° C. and add dropwise 1.0 ml. of concentrated sulfuric acid. Increase the reaction temperature to 240°-250° C. and maintain at that temperature range while collecting water emanating from the reaction. Cool the reaction mixture, add a mixture of ethyl acetate and water with stirring and separate the liquid phases. Dry the organic phase, reduce the volume of ethyl acetate, cool to precipitate the crude product, yield 43 g. Crystallization from ethanol affords the product of this step, m.p. 211°-215° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]Cl)[CH2:10][CH:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>CC(C)=O>[Cl:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[CH2:10][CH:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1
Reactant: ClCCN1CCN(Cc2ccc(Cl)cc2)C(c2ccccc2)C1
Reactant: CCNCC
Agent: Cl
Solvent: CC(C)=O
Product: CCN(CC)CCN1CCN(Cc2ccc(Cl)cc2)C(c2ccccc2)C1

Procedure:
20 g. of 1-(4'-chloro benzyl)-2-phenyl-4-(β-chloro ethyl) piperazine hydrochloride, 14 g. of diethylamine and 200 cc. of acetone are boiled under reflux for 12 hours. After cooling, the precipitated diethylamine hydrochloride is filtered off with suction and the solvent of the filtrate is evaporated in a vacuum. The residue is distilled in a vacuum. 15 g. of a light yellow oil having a boiling point of 190° C./0.06 mm. Hg are obtained. This product is identical with the product as obtained according to Example 2 B).
Reaction SMILES: [C:1]([Si:5]([CH3:55])([CH3:54])[O:6][C@@H:7]1[C@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[O:9][C@H:8]1[N:29]1[C:38]2[N:37]=[CH:36][N:35]=[C:33]([NH2:34])[C:32]=2[N:31]=[C:30]1[NH:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[CH:43][C:42]=1[OH:53])([CH3:4])([CH3:3])[CH3:2].O[CH2:57][CH2:58][NH:59][C:60](=[O:69])[O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:62]([O:61][C:60]([NH:59][CH2:58][CH2:57][O:53][C:42]1[CH:43]=[C:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:45]=[CH:46][C:41]=1[CH2:40][NH:39][C:30]1[N:29]([C:38]2[N:37]=[CH:36][N:35]=[C:33]([NH2:34])[C:32]=2[N:31]=1)[C@@H:8]1[O:9][C@H:10]([CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[C@@H:11]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@H:7]1[O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:55])[CH3:54])=[O:69])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4ccccc4)cc3O)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(NCCO)OCc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(NCc3ccc(-c4ccccc4)cc3OCCNC(=O)OCc3ccccc3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A mixture of 2′,3′,5′-tris-O-(tert-butyldimethyl-silyl)-8-(3-hydroxybiphenyl-4-ylmethylamino)adenosine (0.175 g), benzyl N-(2-hydroxyethyl)carbamate (0.065 g), triphenylphosphine (0.074 g) in tetrahydrofuran (1.1 mL) was stirred at 50° C. for 30 minutes. Diisopropyl azodicarboxylate (40% toluene solution, 0.143 g) was added dropwise, and the resulting mixture was stirred at 50° C. for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2 to 1/1) to give 8-[3-(2-benzyloxycarbonylaminoethoxy)biphenyl-4-ylmethyl-amino]-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)adenosine (0.146 g). To a solution of 8-[3-(2-benzyloxycarbonyl-aminoethoxy)biphenyl-4-ylmethylamino]-2′,3′,5′-tris-O-(tert-butyldimethylsilyl)adenosine (0.143 g) in methanol (1.5 mL) was added ammonium fluoride (0.323 g), and the resulting mixture was stirred at 60° C. for 13.5 hours. The reaction mixture was cooled to room temperature. Dichloromethane (7.5 mL) was added, and the insoluble material was filtered out. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on aminopropylated silica gel (eluent: dichloromethane/methanol=15/1) to give the title compound (0.077 g).
Reaction SMILES: [CH2:1]([N:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:13]=[C:12]([CH:14]=O)[O:11][C:10]=2[CH:16]=1)[CH2:4][CH3:5])[CH3:2].[C:17]([CH:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:22][O:21][C:20]1=[O:30])#[N:18].[NH4+].[Cl-]>N1C=CC=CC=1>[C:17]([C:19]1[C:20](=[O:30])[O:21][C:22](=[CH:14][C:12]2[O:11][C:10]3[CH:16]=[C:6]([N:3]([CH:1]=[CH2:2])[CH:4]=[CH2:5])[CH:7]=[CH:8][C:9]=3[CH:13]=2)[C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)#[N:18]
Reactant: N#CC1C(=O)OC=C1c1ccccc1
Reactant: CCN(CC)c1ccc2cc(C=O)oc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Product: C=CN(C=C)c1ccc2cc(C=C3OC(=O)C(C#N)=C3c3ccccc3)oc2c1
Temperature: 80 °C

Procedure:
To 5 mL of pyridine in a 15 mL round bottom flask was added 217 mg (1 mmol) of the compound of Example 2 and 172 mg (1 mmol) of 3-cyano-4-phenyl-2-furanone. The solution was heated at 80° C. for one hour, cooled and poured into 20 mL dilute NH4Cl. The resulting mixture was extracted 2X with 20 mL 3:2 hexanes Et2O and the combined organic extracts were washed once with 10 mL of water, The organic phase was dried (MgSO4) and the solvent removed by rotary evaporation. The resulting solid was purified by flash chromatography (7:2 cyclohexane/EtOA; SiO2, 1×12") to yield 292 mg of dye. Anal. calcd. for C24H20N2O3 : C, 74.2; H, 5.4; N, 7.5. Found: C, 74.0; H, 5.2; N, 6.9.
Reaction SMILES: [CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.[CH3:16]O>S(=O)(=O)(O)O.CCOC(C)=O>[CH:1]1([CH:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH2:5][C:6]([O:8][CH3:16])=[O:7])[CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)CC(c1ccc(O)cc1)C1CC1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: COC(=O)CC(c1ccc(O)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of 21.3 (2.4 g, 12 mmol) in MeOH (25 mL) was added five drops of sulfuric acid. The mixture was stirred overnight at reflux, cooled to room temperature, diluted with EtOAc, washed with water and brine, dried over MgSO4, filtered, and concentrated. The crude product was chromatographed on silica gel (0-25% EtOAc/hexane) to afford 21.4 (2.2 g, 84%) as a colorless oil.