Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)#[CH:16]>>[C:11]([C:9]1[N:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1cccc(F)c1
Reactant: CC(C)(C)c1nc2ncc(Br)cn2n1
Product: CC(C)(C)c1nc2ncc(C#Cc3cccc(F)c3)cn2n1

Procedure:
The title compound, a light yellow solid, MS: m/e=295.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 42, step 1) and ethynyl-3-fluorobenzene.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[N:10][C:11]=2[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]([CH3:27])([CH3:26])[C:22]([NH:24][CH3:25])=[O:23]>>[CH3:26][C:21]([NH:20][C:17]([C:9]1[CH:8]=[CH:7][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:11]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16]2)[N:10]=1)=[O:19])([C:22](=[O:23])[NH:24][CH3:25])[CH3:27]
Reactant: O=C(O)c1ccc(C2CCCC2)c(OCC2CC2)n1
Reactant: CNC(=O)C(C)(C)N
Product: CNC(=O)C(C)(C)NC(=O)c1ccc(C2CCCC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39 b) and 2-amino-N,2-dimethyl-propanamide (CAN 106914-07-2) as starting materials, MS (LC/MS): 360.2 [M+H]+.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:18](=O)[C:17](=[O:20])[C:16]=2[O:21]C)[N:9]=1)[C:2]([NH2:4])=[NH:3].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1.CO>CN(C)C=O>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:21])[C:17](=[O:20])[C:18]=2[NH:23][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: NCc1ccncc1
Reactant: COc1c(NCCSCc2csc(NC(=N)N)n2)c(=O)c1=O
Solvent: CN(C)C=O
Solvent: CO
Product: N=C(N)Nc1nc(CSCCNc2c(NCc3ccncc3)c(=O)c2=O)cs1
Temperature: 25 °C
Reaction time: 168 h

Procedure:
A mixture of 1-[2-(2-guanidinothiazol-4-ylmethylthio)ethylamino]-2-methoxycyclobutene-3,4-dione (0.17 g), 4-aminomethylpyridine (0.054 g), methanol (5 ml) and dimethyl formamide (3 ml) was stirred at room temperature for seven days. Evaporation of the solution gave a yellow oil which crystallized on scratching; this was triturated with ethanol and filtered to give 1-[2-(2-guanidinothiazol-4-ylmethylthio)ethylamino]-2-(4-pyridylmethylamino)cyclobutene-3,4-dione, m.p. 172°-175°.
Reaction SMILES: [CH3:1][C@@H:2]1[C:7](=[O:8])[CH2:6][C@:5]2([CH:9]([CH3:11])[CH3:10])[C@H:3]1[CH2:4]2.[N:12]1[C:25]2[C:16](=[CH:17][CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH:15]=[CH:14][CH:13]=1>>[OH:8][C@@:7]1([C:22]2[CH:21]=[CH:20][C:19]3[C:24](=[C:25]4[C:16](=[CH:17][CH:18]=3)[CH:15]=[CH:14][CH:13]=[N:12]4)[N:23]=2)[C@@H:2]([CH3:1])[C@@H:3]2[C@@:5]([CH:9]([CH3:11])[CH3:10])([CH2:4]2)[CH2:6]1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: CC(C)[C@@]12CC(=O)[C@@H](C)[C@@H]1C2
Product: CC(C)[C@@]12C[C@@H]1[C@H](C)[C@@](O)(c1ccc3ccc4cccnc4c3n1)C2
Yield: 45 %

Procedure:
By using the general procedure above, (−)-thujone (0.186 g, 1.22 mmol) was reacted with 1,10-phenanthroline to provide 0.083 g (45% yield) of the title compound as a colorless oil: 1H NMR (300 MHz, CDCl3) δ9.16 (dd, J=4.50, 1.80 Hz, Hp9), 8.27 (d, J=8.40 Hz, Hp4), 8.24 (dd, J=8.10, 1.80 Hz, Hp7) 7.82 and 7.76 (two d, J=8.80 Hz, Hp5 and Hp6), 7.72 (d, J=8.40 Hz, Hp3), 7.62 (dd, J=8.10, 4.50 Hz, Hp8), 6.38 (br s, OH), 2.75 (dq, J=6.6, 4.5 Hz, CHCH3), 2.50 (dd, J=13.5, 1.2 Hz, C(OH)CHH), 2.21 (d, J=13.5 Hz, C(OH)CHH), 1.53 (sep, 6.9 Hz, CH(CH3)2), 1.37 (t, J=3.9 Hz, cyclopropyl H), 1.31 (dd, J=4.2, 8.4 Hz, cyclopropyl H), 1.07 (d, J=6.9 Hz, CH3), 0.95 (d, J=6.9 Hz, CH3), 0.89 (d, J=6.9 Hz, CH3), 0.37 (dd, J=4.5, 9.0 Hz, cyclopropyl H); 13C NMR (75 MHz) δ165.09, 150.16, 145.56, 142.86, 137.10, 136.05, 128.98, 127.17, 126.29, 126.05, 122.87, 119.72, 81.85, 48.66, 46.71, 33.01, 32.70, 29.53, 20.10, 19.94, 13.12, 11.60; IR (CHCl3) 3381 (OH), 2957 (C—H Ar), 2928 (CH), 850 (C—H Ar) cm−1; HRMS m/e Calcd for C22H25N2O (MH+): 333.1967, found: 333.1943.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:21]=[CH:20][C:14]([C:15](OCC)=[O:16])=[CH:13][CH:12]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][C:15]([C:14]2[CH:20]=[CH:21][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[O:16])[CH:3]=1
Reactant: CCOC(=O)c1ccc(OC)cc1
Reactant: Cc1cc(Cl)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2cc(Cl)ccn2)cc1
Temperature: 45 °C

Procedure:
To a cold (0° C.) solution of 4-chloro-2-picoline (10 g, 78.4 mmol) and ethyl 4-methoxybenzoate (14.1 g, 78.4 mmol) in tetrahydrofuran (100 mL) was added lithium bis(trimethylsilyl)amide (157 mL, 1.0 M in tetrahydrofuran, 157 mmol) dropwise via a pressure equalizing funnel over half an hour. Upon complete addition, the ice bath was removed and the resulting solution was heated at 45° C. for 15 hours. The mixture was cooled to room temperature, and the solution was concentrated. Methanol was added to quench the reaction, resulting in the formation of a yellow precipitate. The precipitate was collected by filtration and dried to give the product as a mixture of enol and ketone tautomers. MS m/z 262 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:21][N:6]2[C:7]3[C:12]([C:13]([CH2:14][C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[C:5]2[CH2:4][CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH3:22]C(OC(OC(OC(C)(C)C)=O)=O)(C)C>CO>[CH3:22][NH:1][C@H:2]1[CH2:21][N:6]2[C:7]3[C:12]([C:13]([CH2:14][C:15]([O:17][CH2:18][CH2:19][CH3:20])=[O:16])=[C:5]2[CH2:4][CH2:3]1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](N)CC2
Solvent: CO
Product: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reaction time: 2 h

Procedure:
Propyl [(7R)-7-amino-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate (2.5 g) and TEA (1.4 mL) were dissolved in 87 mL MeOH. Boc2O (2.1 g) was added in 10 mL MeOH, and the mixture was stirred for 2 h. The solvent was removed and propyl {(7R)-7-[(tert-butoxycarbonyl)amino]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetate was purified on silica gel (ethyl acetate/hexanes). Propyl {(7R)-7-[(tert-butoxycarbonyl)amino]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetate (3.15 g) was dissolved in DMF (81 mL). The mixture was cooled in an ice bath and MeI (3.47 g) was added followed by NaH (342 mg, 60% w/w in mineral oil). The ice bath was removed after 0.5 h, and the mixture was stirred for 1 h at RT. The reaction was quenched with ½ (sat.) aqueous ammonium chloride. Work up consisted of extraction of the aqueous layer with ether (2×). The combined organic fractions were washed with water and brine, then dried (MgSO4). The solvent was evaporated under reduced pressure and propyl {(7R)-7-[(tert-butoxycarbonyl)(methyl)amino]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetate was purified on silica gel (ethyl acetate/hexanes). {(7R)-7-[(tert-butoxycarbonyl)-(methyl)amino]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl}acetate and anisole (2.2 g) were dissolved in 66 mL DCM. 66 mL of TFA was added and the mixture was stirred for 1 h. The mixture was then stripped several times with toluene. Work up consisted of extraction with dichloromethane (3×) from aqueous sodium carbonate. The combined organic fractions were washed with brine and dried (MgSO4). The solvent was evaporated under reduced pressure and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate was obtained after purification on silica gel. (MeOH/DCM).
Reaction SMILES: C(O[CH:5]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)C.[H][H]>[C].[Pd].CO>[CH2:5]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc(C(OC(C)=O)c2ccccc2)ccn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cc(Cc2ccccc2)ccn1
Yield: 84.2 %

Procedure:
5 g of 10% palladium carbon and 500 ml of methanol were added to 112 g of 4-(α-acetoxybenzyl)-2-methoxypyridine, followed by conducting hydrocracking in a hydrogen atmosphere. The catalyst was filtered off and the filtrate was evaporated. Then, the residue was neutralized by an aqueous saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was removed, to give 73 g of the target compound.
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[NH2:10][C:11]1[C:16](Br)=[N:15][C:14]([Br:18])=[CH:13][N:12]=1>CS(C)=O>[Br:18][C:14]1[N:15]=[C:16]([O:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: OCC1CCCC1
Reactant: Nc1ncc(Br)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1ncc(Br)nc1OCC1CCCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 70.6 %

Procedure:
To a solution of 4.24 g (0.042 mol) cyclopentanmethanol in 40 mL DMSO was added 1.74 g sodium hydride 55% in oil and the mixture was stirred at room temperature for 45 min. To the resulting solution was added 5.06 g (0.020 mol) 2-amino-3,5-dibromopyrazine and the mixture was stirred at room temperature for 20 h. To the resulting solution was added 1.0 g (0.011 mol) cyclopentanemethanol and the mixture was stirred at room temperature for 20 h. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase washed with water (3×) and brine, dried over magnesium sulfate, evaporated and the residue was purified by chromatography on silica gel with heptane:ethyl acetate=9:1 to 3:1 to yield 3.845 g of the title compound as yellow orange crystals melting at 78-79° C.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:21])[C:4]2[C:9]([O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:8]1[NH:18][N:19]=[CH:20][C:7]1=[CH:6][CH:5]=2.[Cl:22][O-].[Na+]>CCO>[Cl:22][C:20]1[C:7]2=[CH:6][CH:5]=[C:4]3[C:9]([O:10][C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([I:1])[C:3]3=[O:21])=[C:8]2[NH:18][N:19]=1
Reactant: [O-]Cl
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccc1cn[nH]c12
Agent: [Na+]
Solvent: CCO
Product: O=c1c(I)c(-c2ccccc2)oc2c1ccc1c(Cl)n[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a stirred solution of 7-iodo-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one (73 mg, 0.188 mmol) in EtOH (10 mL), with cooling in a 10° C. water bath, was added sodium hypochlorite (10% aqueous solution, 9 mL). After 15 minutes, the temperature was allowed to increase to RT. After a further 30 minutes, the reaction mixture was concentrated in vacuo and the remaining reside was partitioned between EtOAc and water. The resulting biphasic mixture was separated, the aqueous phase was further extracted with EtOAc, the combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and evaporated in vacuo to afford the title compound (44 mg, 55%) as a cream solid. LCMS (Method H): RT=3.75 min, [M+H]+=423/425.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:12]1[O:29][C@H:28]([CH2:30][O:31]C(=O)C)[C@@H:23]([O:24]C(=O)C)[C@H:18]([O:19]C(=O)C)[C@H:13]1[O:14]C(=O)C.[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([C:44](Cl)=O)[CH:42]=[CH:43][C:36]1=2>>[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([CH2:44][C:4]3[C:3]4[C:7](=[CH:8][CH:9]=[C:10]([F:11])[C:2]=4[Cl:1])[N:6]([C@@H:12]4[O:29][C@H:28]([CH2:30][OH:31])[C@@H:23]([OH:24])[C@H:18]([OH:19])[C@H:13]4[OH:14])[CH:5]=3)[CH:42]=[CH:43][C:36]1=2
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)c(F)ccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc2occc2c1
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc4occc4c3)c3c(Cl)c(F)ccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The above 4-chloro-5-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole and benzo[b]furan-5-carbonyl chloride were treated in a manner similar to Example 27 to give the titled compound, 3-(benzo[b]furan-5-yl-methyl)-4-chloro-5-fluoro-1-(β-D-glucopyranosyl)indole as a colorless powder. APCI-Mass m/Z 462/464 (M+H). 1H-NMR (DMSO-d6) δ 3.15-3.45 (m, 4H), 3.65 (m, 2H), 4.35 (s, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.11 (d, J=5.3 Hz, 1H), 5.17 (d, J=5.0 Hz, 1H), 5.24 (d, J=5.8 Hz, 1H), 5.40 (d, J=9.0 Hz, 1H), 6.87 (d, J=1.4 Hz, 1H), 7.16 (t, J=9.2 Hz, 1H), 7.21 (dd, J=8.4, 1.0 Hz, 1H), 7.37 (s, 1H), 7.44 (s, 1H), 7.49 (d, J=8.5 Hz, 1H), 7.57 (dd, J=9.0, 4.0 Hz, 1H), 7.93 (d, J=1.9 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][N:19]=1>>[N:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:20]3[C:21]4[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=4[C:18]([C:17]([F:16])([F:28])[F:27])=[N:19]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: O=S(=O)(c1ccc(I)cc1)N1CCCC1
Product: O=S(=O)(c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCC1

Procedure:
The title compound was prepared from 1-[(4-iodophenyl)sulfonyl]pyrrolidine and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 87.
Reaction SMILES: C(N(C(C)C)C(C)C)C.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:37])=[C:15]([C@:17]23[CH2:25][O:24][C@H:23]([CH3:26])[C@H:22]2[C:21](=[O:27])[N:20]([CH3:28])[C:19]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[N:18]3)[CH:16]=1.[CH3:38][O:39][C:40]1[N:41]=[CH:42][C:43]([C:46](O)=[O:47])=[N:44][CH:45]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[F:37][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:46]([C:43]2[CH:42]=[N:41][C:40]([O:39][CH3:38])=[CH:45][N:44]=2)=[O:47])=[CH:16][C:15]=1[C@:17]12[CH2:25][O:24][C@H:23]([CH3:26])[C@H:22]1[C:21](=[O:27])[N:20]([CH3:28])[C:19]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[N:18]2
Reactant: C[C@H]1OC[C@]2(c3cc(N)ccc3F)N=C(NC(=O)OC(C)(C)C)N(C)C(=O)[C@H]12
Reactant: COc1cnc(C(=O)O)cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C)[C@H]3C(=O)N(C)C(NC(=O)OC(C)(C)C)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.1 %

Procedure:
N-Ethyl-N-(propan-2-yl)propan-2-amine (0.33 mL, 1.9 mmol) was added to a stirred mixture of tert-butyl ((4aS,5R,7aS)-7a-(5-amino-2-fluorophenyl)-3,5-dimethyl-4-oxo-3,4,4a,5,7,7a-hexahydrofuro[3,4-d]pyrimidin-2-yl)carbamate (150 mg, 0.38 mmol), 5-methoxypyrazine-2-carboxylic acid (89 mg, 0.57 mmol) and (1H-benzotriazol-1-yloxy)(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (300 mg, 0.57 mmol) in dry DCM (2 mL). The mixture was stirred at RT overnight. The reaction mixture was partitioned between DCM and NaHCO3 (aq). The aqueous layer was extracted with DCM (×2). The combined extracts were dried by passing through a hydrophobic frit and then evaporated. The residue was purified by column chromatography (normal phase, 10 g, Biotage SNAP cartridge KP-Sil, 12 mL per min, gradient 5% to 30% EtOAc in n-hexane) to give the title compound (213 mg, foam). 1H NMR (400 MHz, CDCl3) δ ppm 1.52 (d, J=6.06 Hz, 3H) 1.56 (s, 9H) 3.31 (s, 3H) 3.44 (dd, J=9.09, 1.77 Hz, 1H) 4.08 (s, 3H) 4.31 (d, J=9.85 Hz, 1H) 4.37-4.47 (m, 2H) 7.16 (dd, J=10.74, 8.97 Hz, 1H) 7.54 (dd, J=6.82, 2.53 Hz, 1H) 7.84 (ddd, J=8.78, 4.23, 2.65 Hz, 1H) 8.15 (d, J=1.26 Hz, 1H) 9.01 (d, J=1.26 Hz, 1H) 9.49 (s, 1H) 10.60 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.CN.C(C1NC=CN=1)([C:15]1[NH:16]C=CN=1)=O>>[CH3:15][NH:16][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)=[O:10]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)c1cccc(Br)n1
Agent: CN
Product: CNC(=O)c1cccc(Br)n1

Procedure:
6-Bromopicolinic acid (Aldrich) was coupled with methyl amine using carbonyl diimidazole (CDI) as coupling reagent to afford 6-bromopyridine-2-carboxylic acid methylamide. The 6-bromopyridine-2-carboxylic acid methylamide underwent Suzuki coupling with 4-phenoxyphenylboronic acid, in the presence of tetrakis(triphenylphosphine)palladium as catalyst to give 6-(4-phenoxyphenyl)pyridine-2-carboxylic acid methylamide as a solid. 1H NMR (CDCl3): δ 8.12 (d, J=7.8 Hz, 1H), 7.98 (d, J=8.7 Hz, 2H), 7.90 (t, J=7.8 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.38 (t, J=8.4 Hz, 2H), 7.18-7.06 (m, 5H), 3.08 (d, J=5.4 Hz, 3H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[C:20]([CH3:22])[N:19]=[C:18](Cl)[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:24][CH3:25])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:26]1[CH:30]=[CH:29][N:28]=[CH:27]1>CN1CCCC1=O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([N:26]5[CH:30]=[CH:29][N:28]=[CH:27]5)[CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:24][CH3:25])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(-c3cc(C)nc(Cl)c3)nc(=O)c1-2
Reactant: c1c[nH]cn1
Solvent: CN1CCCC1=O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3cc(C)nc(-n4ccnc4)c3)nc(=O)c1-2
Temperature: 25 °C
Yield: 5.5 %

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-6-(2-chloro-6-methyl-4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-one (0.30 g, 0.84 mmol), imidazole (0.06 g, 0.9 mmol) and N-methyl-2-pyrrolidinone (10 ml) was refluxed for 60 hours. The mixture was cooled to room temperature, filtered through a plug of celite and the plug was rinsed with methanol. The solvent was removed in vacuo and the residue was washed with ethanol and the solution was filtered. The filtrate was treated with charcoal, filtered, and the solvent was removed in vacuo. The residue was triturated with ether and a dark solid was collected by filtration. The product was recrystallized from ether/methanol to afford 0.018 g (10%) of 1-cyclopentyl-3-ethyl-6-[2-(1-imidazolyl)-6-methyl-4-pyridyl]pyrazolo[3,4-d]pyrimidin-4-one. 1/4 hydrate as a beige powder, m.p. 277°-278° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4](Cl)[N:3]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]2)=[C:4]([NH:23][CH:20]2[CH2:22][CH2:21]2)[N:3]=1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1
Reactant: NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(NC2CC2)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1

Procedure:
(+)-(1S, 2R, 4R)-4-(2-Amino-6chloro-9H-purin-9-yl)-2-(hydroxymethyl)cyclopentanol (425 mg, 1.5 mmol), cyclopropylamine (Aldrich, 1.4 mL), and ethanol (4 mL) were refluxed for 3 hours. To the cooled solution was added 1N sodium hydroxide (1.5 mL). The residual oil left on evaporation of volatiles under vacuum was chromatographed on silica gel. Title compound was eluted with methanol: ethyl acetate/15:85 as a white solid foam which solidified to white powder in methanol-acetonitrile (309 mg, 68%); m.p. 174°-176° C.; mass spectrum (Cl, CH4) 305 (M+1); 1H-NMR (DMSO-d6) δ: 7.79 (s, 1, H-8); 7.25 (d, J=2.9 Hz, 1, NH), 5.79 (s, 2, NH2), 4.90-4.75 (m, 1, CH--N), 4.73 (d, J=4.0 Hz, 1, OH), 4.63 (t, J=5.3 Hz, 1, CHOH), 4.08-4.00 (m, 1, CHO), 3.58-3.38 (m, 2, CH2O), 3.05-2.95 (m, 1, CH--NH), 2.35-2.20 (m. 1, CH), 2.18-2.0 (m, 1, 1/2CH2), 2.0-1.9 (m, 2, methylene), 1.7-1.5 (m, 1, 1/2CH2), 0.70-0.50 (m, 4, 2CH2 of cyclopropyl); [α]20589 +7.72°, [α]20578 +7.87°, [α]20546 +8.77°, [α]20436 +14.4°, [α]20365 +20.1° (c=0.66, methanol).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]=[CH:9][C:8]([C:15]([O:17]CC)=[O:16])=[C:7]2[NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH3:2].[OH-].[Na+].Cl>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[N:12][C:13]=1[CH3:14])[N:10]=[CH:9][C:8]([C:15]([OH:17])=[O:16])=[C:7]2[NH:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH3:2]
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Nc1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1cc2c(Nc3ccc(OC)cc3)c(C(=O)O)cnc2nc1C

Procedure:
A mixture ethyl 6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridine-3-carboxylate (6.38 g), water (40 ml), sodium hydroxide solution (120 ml, 0.6M) was boiled and stirred under reflux for 2 hours and then allowed to cool. The mixture was acidified with 5M hydrochloric acid (100 ml) and filtered. The filtrate was extracted with dichloromethane to give a residue which was washed with 5M hydrochloric acid and filtered to give 6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridine-3-carboxylic acid, m.p. 259°-263° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][C:29]([C:32]([O:34]CC2C=CC([N+]([O-])=O)=CC=2)=[O:33])([CH3:31])[CH3:30])/[C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:20]3[C@@H:12]2[CH2:13][S:14][C@H:15]2[C@@:19]3([C:23]([O-:25])=[O:24])[O:18][C:17](=[O:26])[CH2:16]2)=[O:9])[N:6]=1.[Na+:45].P([O-])([O-])([O-])=O.C(O)C.[H][H]>O.[C].[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][C:29]([C:32]([OH:34])=[O:33])([CH3:31])[CH3:30])/[C:8]([NH:10][C@@H:11]2[C:21](=[O:22])[N:20]3[C@@H:12]2[CH2:13][S:14][C@H:15]2[C@@:19]3([C:23]([O-:25])=[O:24])[O:18][C:17](=[O:26])[CH2:16]2)=[O:9])[N:6]=1.[Na+:45]
Reactant: [H][H]
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2[C@@H]1CS[C@@H]1CC(=O)O[C@]12C(=O)[O-])c1csc(N)n1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2[C@@H]1CS[C@@H]1CC(=O)O[C@]12C(=O)[O-])c1csc(N)n1)C(=O)O
Yield: 77 %

Procedure:
In 5 ml of water was dissolved 0.148 g of the compound obtained in Example 7. To this solution were added 5 ml of a 0.1M phosphate buffer solution, 5 ml of ethanol and 0.075 g of 10% palladium-carbon. Into the mixture was introduced hydrogen gas while stirring under ice-cooling. In 1.5 hour after starting of the reaction, 0.04 g of 10% palladium-carbon was added to the reaction system, followed by stirring for further one hour. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to a volume of about 5 ml. The residue was subjected to a Amberlite XAD-2 column chromatography. Fractions eluted with water were combined and freeze-dried to give 0.091 g of the subject compound as powders.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[C:15](/[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)\[CH3:16])=[CH:8][CH:7]=1)C.C(O)C>[OH-].[Na+].Cl.C(OCC)(=O)C>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:19]=[CH:18][C:17](/[C:15](/[CH3:16])=[CH:14]/[CH2:13][O:12][C:9]3[CH:8]=[CH:7][C:6]([CH2:5][C:4]([OH:30])=[O:3])=[CH:11][CH:10]=3)=[CH:22][CH:21]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(Br)cc3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C/C(=C\COc1ccc(CC(=O)O)cc1)c1ccc(-c2ccc(Br)cc2)cc1
Yield: 55.6 %

Procedure:
(E)-{4-[3-(4′-Bromo-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-acetic acid ethyl ester (example 24) (210 mg, 0.58 mmol) was suspended in 1N NaOH (1.16 mL) and ethanol (5 mL) and stirred for 24 h at room temperature. The mixture was diluted with 1N HCl (1.16 mL) and ethyl acetate (10 mL). The aqueous layer was separated and extracted with ethyl acetate (30 L) The organic layers were combined, washed with brine, dried (MgSO4) and evaporated to give 141 mg (55%) of the title compound.