Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35](S(C1C=CC=CC=1)(=O)=O)[C:34]([C:48]([O:50]CC)=O)=[C:33]2[S:53](Cl)(=[O:55])=[O:54].N1CCOCC1.FC(F)(F)C(O)=O.[NH:70]1[CH2:75][CH2:74][NH:73][CH2:72][C:71]1=[O:76]>>[Br:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]([C:48]([NH2:7])=[O:50])=[C:33]2[S:53]([N:73]1[CH2:74][CH2:75][NH:70][C:71](=[O:76])[CH2:72]1)(=[O:54])=[O:55]
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: O=C1CNCCN1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Solvent: C1COCCN1
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCNC(=O)C1

Procedure:
Following the procedures described in Steps D and E of Example 1, replacing in Step D ethyl 5-chloro-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and morpholine with piperazin-2-one trifluoroacetate, the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 402.1 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[S:13][C:14]([CH2:17][OH:18])=[CH:15][N:16]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[C:29]3[C:33](=[CH:34][CH:35]=2)[C:32](=[O:36])[NH:31][CH2:30]3)O1>>[OH:18][CH2:17][C:14]1[S:13][C:12]([NH:11][C:5]2[C:6]3[N:7]([CH:8]=[CH:9][N:10]=3)[C:2]([C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[C:32](=[O:36])[NH:31][CH2:30]4)=[CH:3][N:4]=2)=[N:16][CH:15]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CNC3=O)OC1(C)C
Reactant: OCc1cnc(Nc2ncc(Br)n3ccnc23)s1
Product: O=C1NCc2cc(-c3cnc(Nc4ncc(CO)s4)c4nccn34)ccc21

Procedure:
Prepared from the product of Step 2 and Intermediate 4 (5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-1-one) according to the procedure described in Example 1, Step 2. 1H-NMR (400 MHz, d6-DMSO) =4.52 (s, 2H, CH2), 4.67 (d, 2H, CH2), 5.40 (t, 1H, OH), 7.36 (s, 1H, Har), 7.71 (s, 1H, Har), 7.81 (s, 1H, Har), 7.89 (m, 2H, Har), 7.99 (s, 1H, Har), 8.09 (s, 1H, Har), 8.79 (s, 1H, H), 11.61 (s br, 1H, NH). LCMS: Rt 2.04 min (90.0%). MS (MH+, m/z) 379.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=2)[CH:17]=1.CN(C(O[N:36]1N=N[C:38]2C=CC=[CH:42][C:37]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(N)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:27])[C:12]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH:36][CH:37]([CH3:42])[CH3:38])=[O:23])=[CH:20][N:19]=2)[CH:17]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1nnc(-c2ccccc2Cl)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)N
Product: CC(C)NC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4Cl)nnn3C)c2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.5 %

Procedure:
To a solution of 6-(4-(4-(2-chlorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (74 mg, 0.194 mmol) and TBTU (69 mg, 0.214 mmol) in DMF (2.0 mL) was added DIPEA (170 μL, 0.972 mmol). Then isopropylamine (19 μL, 0.214 mmol) was added and the mixture was stirred at room temperature under Ar for 2 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (52 mg, 63%) as a white solid. MS: m/e=422.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>ClCCl.O.C(O)(=O)C>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: O=Cc1ccccc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COc1ccc(NCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 5-amino-2-methoxypyridine (1.00 g, 8.06 mmol) in dichloromethane (20.0 mL) was treated with benzaldehyde (0.080 mL, 8.06 mmol) followed by stirring at ambient temperature for 20 min. The mixture was then treated with sodium cyanoborohydride (1.79 g, 8.46 mmol) followed by acetic acid (0.460 mL, 8.06) and continued stirring for 2 h. The solution was treated with water and saturated sodium hydrogen carbonate, and then extracted twice with dichloromethane. The combined organic portions were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was swirled in hexanes, and a solid was filtered. The filtrate was concentrated and the title compound was obtained as a light pink solid (0.340 g, 20%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (d, J=2.5 Hz, 1H), 7.28-7.41 (m, 5H), 7.01 (dd, J=8.8, 3.0 Hz, 1H), 6.62 (d, J=9.3 Hz, 1H), 4.30 (s, 2H), 3.87 (s, 3H). MS(ES+) m/e 215 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH:12][CH:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(N)C(=O)O
Reactant: O=[N+]([O-])c1c(F)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCC(Nc1cccc(Cl)c1[N+](=O)[O-])C(=O)O
Temperature: 80 °C
Yield: 96.7 %

Procedure:
A mixture of 1-chloro-3-fluoro-2-nitrobenzene (2.00 Kg, 11.4 mol), 2-aminobutyric acid (1.22 kg, 11.8 mol) and K2CO3 (1.58 Kg, 11.4 mol) in anhydrous DMSO (4.2 L) was heated at 80° C. for 16 h (after the reaction initiated, the internal temperature went up to 110° C.). At this time LC-MS analysis showed that the reaction was complete. After cooling to rt, the reaction mixture was carefully poured into water (10 L) with vigorous stirring. The aq. layer was washed with methyl tert-butyl ether (2×5 L) to remove organic impurities. The aq. layer was then acidified to pH ˜1.5 with cond HCl to give an orange solid. The orange solid was collected by filtration, washed with water (2×4 L) and air-dried to give 2-((3-chloro-2-nitrophenyl)amino)butanoic acid (2.85 Kg), which was used as such in the next step. 1H NMR (DMSO-d6) δ ppm 7.35 (t, J=8.3 Hz, 1H), 6.82-6.91 (m, 2H), 6.25 (d, J=7.6 Hz, 1H), 4.14 (td, J=7.4, 5.4 Hz, 1H), 3.4 (br. s., 1H), 1.74-1.92 (m, 2H), 0.88 (t, J=7.4 Hz, 3H). Mass Spectrum (ESI) m/z=259.2 (M+1).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[C:16]1[C:20]([C:21](Cl)=[O:22])=[C:19]([CH3:24])[O:18][N:17]=1.[CH3:25][O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH2:35])[CH2:30]1)=[O:28]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:25][O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH:31]([NH:35][C:21]([C:20]2[C:16]([C:10]3[C:11]([F:15])=[CH:12][CH:13]=[CH:14][C:9]=3[Cl:8])=[N:17][O:18][C:19]=2[CH3:24])=[O:22])[CH2:30]1)=[O:28]
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: COC(=O)N1CCCC(N)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CCCC(NC(=O)c2c(-c3c(F)cccc3Cl)noc2C)C1
Yield: 89.5 %

Procedure:
Add 4-dimethylamino-pyridine (0.19 g, 1.5 mmol), triethylamine (3.2 mL, 23.2 mmol), and 3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl chloride (5.53 g, 20.1 mmol) to a solution of 3-amino-piperidine-1-carboxylic acid methyl ester (2.45 g, 15.5 mmol) in dichloromethane (100 mL). Stir the reaction at room temperature under nitrogen overnight. Wash the reaction with 1N HCl, saturated aqueous sodium bicarbonate solution, and brine; dry over magnesium sulfate; and concentrate. Purify by flash chromatography on silica gel (eluting with 0.75% methanol/chloroform) to give 5.49 g of the title compound as a yellow foam, 90% yield. 1H NMR: consistent with structure. MS (ion spray) 396 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][C:36](=C)[CH2:37]O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][C:36]([CH3:37])=[CH2:35])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: C=C(C)CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)COC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 55.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-methyl-2-propen-1-ol (19 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (37 mg, yield 47%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:1]([O:3][C:4]([CH:6]1[C:14]2[N:13]=[CH:12][N:11]([C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCc2[nH]cnc21
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C1CCCc2c1ncn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of 4,5,6,7-tetrahydro-1H-benzimidazole-4-carboxylic acid ethyl ester (18.9 g, 97 mmol, J. Am. Chem. Soc., 1996, 98, 984) in acetonitrile (250 ml) were added triethylamine (27 ml, 194 mmol) and a solution of trityl chloride (40.6 g, 146 mmol) in acetonitrile (500 ml). The resulting mixture was stirred at 20° C. overnight. The mixture was concentrated under reduced pressure and the residue was redissolved in ethyl acetate, washed with water (2×) and brine (1×), and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate/heptane, to yield 20.8 g (49%) of 1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole-4-carboxylic acid ethyl ester as a colourless solid. From the mother liquor more product (10.3 g, 24%) was isolated by column chromatography (silica gel, gradient elution with heptane/ethyl acetate 9:1 to 1:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:19]2[N:20]=[C:21]([CH2:26][CH3:27])[C:22]([N+:23]([O-])=O)=[C:18]2[CH:17]=[CH:16][CH:15]=1.C(O)C.O>[Zn].C(O)(=O)C>[CH3:13][O:12][C:5]1[CH:6]=[C:7]([CH2:9][O:10][CH3:11])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:14]1[N:19]2[N:20]=[C:21]([CH2:26][CH3:27])[C:22]([NH2:23])=[C:18]2[CH:17]=[CH:16][CH:15]=1
Reactant: CCc1nn2c(-c3c(OC)cc(COC)cc3OC)cccc2c1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1nn2c(-c3c(OC)cc(COC)cc3OC)cccc2c1N
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
A suspension of 7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (0.7 g) in a mixed solvent of ethanol (35 mL), water (18 mL) and acetic acid (3.5 mL) was added zinc powder (0.7 g) at room temperature, and the reaction mixture was heated and stirred for 30 minutes at 60° C. The reaction mixture was filtered through celite to remove insoluble residue, water was added to the filtrate and extraction was performed with ethyl acetate. The obtained organic extract was washed with brine, saturated aqueous sodium bicarbonate and then brine and dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the title compound (0.48 g) was obtained as a yellow oil from the n-hexane:ethyl acetate (4:1) fraction.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[I:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([OH:17])[CH:16]=1.Cl[CH2:20][O:21][CH3:22]>ClCCl.CCOCC>[I:10][C:11]1[CH:12]=[CH:13][C:14]([CH3:18])=[C:15]([O:17][CH2:20][O:21][CH3:22])[CH:16]=1
Reactant: Cc1ccc(I)cc1O
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: COCOc1cc(I)ccc1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N,N-Diisopropylethylamine (8.3 mL, 47.4 mmol) (Aldrich) was added to a suspension of 5-iodo-2-methyl-phenol (10.1 g, 43.1 mmol) (from Example 17 supra) in dichloromethane (40 mL) with cooling in an ice-water bath. Chloromethyl-methyl ether (6.5 mL, 86.1 mmol) (Aldrich) was added dropwise and the mixture stirred at room temperature for 5 hours. The mixture was then diluted with ether (200 mL) and washed with water (200 mL), followed by 0.1 N HCl (2×200 mL) and brine (200 mL). Aqueous layers were back washed with ether (200 mL). Organic solutions were combined, dried (MgSO4), filtered and concentrated. Residue was filtered through silica gel (Biotage 40 L) eluting with dichloromethane-hexenaes (1:4 V/v). Fractions were combined and concentrated to give 4-iodo-2-methoxymethoxy-1-methyl-benzene as colorless oil. (Yield 9.05 g, 75.6%).
Reaction SMILES: C1(P(=[CH:20][C:21]#[N:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:23]1[CH:24]=[CH:25][C:26]([CH:31]=O)=[C:27]([CH:29]=[O:30])[CH:28]=1>ClCCl>[CH:29]([C:27]1[CH:28]=[CH:23][CH:24]=[CH:25][C:26]=1[CH:31]=[CH:20][C:21]#[N:22])=[O:30]
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1C=O
Solvent: ClCCl
Product: N#CC=Cc1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
A solution of triphenylphosphoranylidene acetonitrile (13 g) in dry dichloromethane (20 ml) was added to a solution of ortho phthalaldehyde (5.4 g) in dry dichloromethane (20 ml), at 0°. The solution was stirred at room temperature for 1 h, then the solvent evaporated and the oil taken up with diethyl ether. The solid was filtered, washed with ether and the solution evaporated to dryness to give a yellow oil, which was eluted on a silica gel column (gradient petrol ether/diethyl ether, 1:1) to give the (E)-isomer of the title compound (0.9 g) and the (Z)-isomer of the title compound (2 g) (eluted first) as white solids which were recrystallized from petrol ether/diethyl ether (9:1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:15][C:16]([OH:18])=[O:17]>CN(C)C(=O)C>[CH2:3]([O:10][CH2:11][CH2:12][O:13][CH2:15][C:16]([OH:18])=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)CCl
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=C(O)COCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.4 %

Procedure:
Sixty % sodium hydride in oil (6.80 g) is suspended in N,N-dimethylacetamide (80 ml) and a solution of 2-(benzyloxy)ethanol (12.9 g) in N,N-dimethylacetamide (50 ml) is added dropwise to the mixture over 10 minutes under ice-cooling. After stirring at room temperature for 15 minutes, the reaction solution is cooled with ice, and thereto is added chloroacetic acid (8.13 g) in small portions. The mixture is then stirred at room temperature for 11 hours. The reaction solution is concentrated under reduced pressure, and to the resulting residue is added aqueous sodium hydrogen carbonate solution and the mixture is washed with diethyl ether. The aqueous layer is acidified with conc. hydrochloric acid, and then extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove solvent under reduced pressure to give [2-(benzyloxy)ethoxy]acetic acid (18.24 g).
Reaction SMILES: C(O[C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:29][CH2:28][CH2:27][C@H:17]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])=[O:15])[CH3:13])=[O:10])C1C=CC=CC=1.[CH3:30][CH2:31]OCC.C(OC(=O)CC)(=O)CC>Br.C(O)(=O)C>[C:9]([NH:11][C@H:12]([C:14]([N:16]1[CH2:29][CH2:28][CH2:27][C@H:17]1[C:18]([NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19])=[O:15])[CH3:13])(=[O:10])[CH2:30][CH3:31]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Reactant: CCOCC
Agent: Br
Agent: CCC(=O)OC(=O)CC
Solvent: CC(=O)O
Product: CCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8.7 g (0.022 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline anilide were dissolved in 40 ml of 4-N hydrogen bromide in acetic acid and the solution was stirred at room temperature for 1 hour. Upon addition of 300 ml of dry ether a white solid separated. It was allowed to settle. The solution was decanted off and the solid washed with two 150 ml portions of ether, dried on a rotary evaporator and dissolved in 120 ml of dry pyridine. 5.73 ml (0.044 mol) of propionic anhydride were added and the mixture was stirred at room temperature for 1 hour and then evaporated. The residue was dissolved in 250 ml of chloroform and the solution washed with 100 ml of 1-N hydrochloric acid, 100 ml of water and 100 ml of 5% sodium bicarbonate solution, dried over magnesium sulphate and evaporated to an oil. This oil crystallised from ethyl acetate/ether to yield 3.5 g of N-propionyl-L-alanyl-L-proline anilide. A second crop (1.5 g) was obtained from the mother liquor on allowing same to stand. The two crops were combined and chromatographed on 200 g of silica gel. 2% methanol/chloroform was used for the elution and 15 ml fractions were collected. Fractions 35-90 were combined and evaporated. The residue was recrystallised from ethyl acetate/petroleum ether to give 3.24 g (46%) of N-propionyl-L-alanyl-L-proline anilide of melting point 156°-157° C.; [α]D20 =-188.7° (c=1.034% in methanol).
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:3])[CH3:2].[OH-].[Na+].Cl[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.ICCCCCOC1C=CC(C#N)=CC=1>C(OC(=O)C)C.CN(C)C=O>[CH:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]#[N:31])=[CH:32][CH:33]=2)=[CH:14][CH:15]=1)([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(OCCCCCCl)cc1
Reactant: Cc1nc(-c2ccc(O)cc2)c(C(C)C)s1
Agent: N#Cc1ccc(OCCCCCI)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(OCCCCCOc3ccc(C#N)cc3)cc2)c(C(C)C)s1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
While 72.6 g of 4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenol (6) prepared in Example 4 were added to 850 ml of dimethylformamide and stirred, 15.0 g of sodium hydroxide were added. The reaction temperature was gradually increased and stirring was continued at 50-55° C. for 30 min. Thereafter, 70.0 g of 4-(5-chloro-pentoxy)-benzonitrile (8), prepared in Example 5, or 95.3 g of 4-(5-iodo-pentoxy)-benzonitrile (9), prepared in Example 6, were added. The reaction temperature was gradually increased and stirring was continued at 80-90° C. for 3 hr. After the reaction was completed, the temperature was decreased to room temperature, and the resultant reaction mixture was added with 850 ml of ethylacetate, and then washed with water and brine. Subsequently, the ethylacetate layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residual solution was crystallized with ethylacetate and n-hexane, thus obtaining 114 g (yield: 90%) of a title compound as a light yellow solid through the reaction with the compound (8), or 119.6 g (yield: 94%) of a title compound as a light yellow solid through the reaction with the compound (9).
Reaction SMILES: [CH:1]1[N:2]=[C:3]([NH2:22])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@@H:13]4[CH2:15][O:16][P:17]([OH:20])([O:19][C@H:12]4[C@H:11]3[OH:21])=[O:18])[C:5]=2[N:6]=1.[CH:23]1[N:27]([C@@H:28]2[O:32][C@@H:31]3[CH2:33][O:34][P:35]([OH:38])([O:37][C@H:30]3[C@H:29]2[OH:39])=[O:36])[C:26]2[NH:40][C:41]([NH2:45])=[N:42][C:43](=[O:44])[C:25]=2[N:24]=1>>[CH:1]1[N:2]=[C:3]([NH2:22])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][P:17]([OH:20])([OH:19])=[O:18])[C@@H:12]([OH:32])[C@H:11]3[OH:21])[C:5]=2[N:6]=1.[CH:23]1[N:27]([C@@H:28]2[O:32][C@H:31]([CH2:33][O:34][P:35]([OH:38])([OH:37])=[O:36])[C@@H:30]([OH:14])[C@H:29]2[OH:39])[C:26]2[NH:40][C:41]([NH2:45])=[N:42][C:43](=[O:44])[C:25]=2[N:24]=1
Reactant: Nc1nc(=O)c2ncn([C@@H]3O[C@@H]4COP(=O)(O)O[C@H]4[C@H]3O)c2[nH]1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Product: Nc1nc(=O)c2ncn([C@@H]3O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]3O)c2[nH]1
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
The enzyme of the present invention isolated and purified from rat cerebral cortex in Example was acted on [8-3H] cAMP and [8-3H] cGMP as substrates to form [8-3H] 5'-AMP and [8-3H] 5'-GMP, respectively. The products were reacted with 5'-nucleotidase to form [8-3H] adenosine and [8-3H] guanosine, respectively. These products were separated from each other on a cation exchange resin column (AG50 W-X4, Bio-Rad) to assay for the radioactivity. The assay was carried out in a manner similar to that of the enzymatic activity described in Example.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]([CH3:24])=[CH2:23])[CH:17]=[CH:16][C:15]=1[S:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][CH:27]=1>C(O)C>[CH3:24][C:22](=[CH2:23])[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:35])[CH3:34])=[CH:28][CH:27]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: C=C(C)COc1ccc(Sc2ccc(NC(C)=O)cc2)c(N)c1
Solvent: CCO
Product: C=C(C)COc1ccc(Sc2ccc(NC(C)=O)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 mL) with the product from Example 234a (55 mg, 0.17 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (12 mg, 25%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.76 (s, 3H) 2.02 (s, 3H), 2.75 (s, 3H), 4.52 (s, 2H), 4.98 (s, 1H), 5.05 (s, 1H), 6.30 (d, J=7.35 Hz, 1H), 7.04-7.19 (m, 4H), 7.36 (s, 1H), 7.41 (d, J=8.46 Hz, 2H) 7.78 (d, J=8.82 Hz, 1H), 8.37 (d, J=6.99 Hz, 1H), 8.94 (d, J=8.46 Hz, 1H) 9.97 (s, 1H, ) 10.99 (s, 1H), 14.33 (s, 1H); MS (ESI+) m/z 471 (M+H)+.