Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[CH3:7][C:8]1([CH3:30])[C:28]2[C:11](=[CH:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[O:25][CH3:26])=[N:15][C:14]=3[CH:27]=2)[NH:10][C:9]1=[O:29].C(N(CC)CC)C>CN(C)C=O>[CH3:7][C:8]1([CH3:30])[C:28]2[C:11](=[CH:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH:24][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:20][C:19]=4[O:25][CH3:26])=[N:15][C:14]=3[CH:27]=2)[NH:10][C:9]1=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(N)ccc1-c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.26 g. (11 mmol) methanesulphonyl chloride were slowly added dropwise to a solution of 3.6 g. (10 mmol) 7,7-dimethyl-2-(2-methoxy-4-aminophenyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one hydrochloride and 2.2 g. (22 mmol) triethylamine in 50 ml. dimethylformamide. After stirring for 2 hours at 25° C., the dimethylformamide was distilled off under a high vacuum. The residue was worked up with water and filtered off with suction. Subsequently, it was recrystallised from ethanol to give 2.9 g. (72.5% of theory) of the title compound; m.p. >300° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=[O:17])[CH2:15]Cl.O>CC(C)CC(=O)C>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=[O:17])[CH2:15][N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=C(CCl)c1ccc(F)cc1F
Reactant: c1cn[nH]c1
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C(Cn1cccn1)c1ccc(F)cc1F
Yield: 77.9 %

Procedure:
A mixture of 1H-pyrazole (1.3 mol) in 4-methyl-2-pentanone (500 ml) was stirred and refluxed. 1-(2,4-difluorophenyl)-2-chloroethanone (0.26 mol) dissolved in 4-methyl-2-pentanone (500 ml) was added dropwise and the mixture was stirred and refluxed for 3 h. The mixture was cooled, poured into water and separated. The organic layer was evaporated. The residue was stirred up in HCl/water, filtered off and washed with water. The precipitate was stirred up in hexane, filtered off and dried in vacuo at 45° C., yielding 45 g (78%) of 1-(2,4-difluorophenyl)-2-(1H-pyrazol-1-yl)ethanone; mp. 76.4° C. (interm. 12).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([OH:15])=O)=[CH:4][N:3]=1.[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]1>>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[C:5]([C:13]([NH:23][CH2:22][CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)=[O:15])=[CH:4][N:3]=1
Reactant: Cc1cccc2c(Cl)ncc(C(=O)O)c12
Reactant: NCC1CCOCC1
Product: Cc1cccc2c(Cl)ncc(C(=O)NCC3CCOCC3)c12

Procedure:
The title compound was prepared by using 1-chloro-5-methylisoquinolin-4-carboxylic acid (Intermediate-10) and (tetrahydro-2H-pyran-4-yl)methanamine by following the similar procedure as described for Intermediate-11a.
Reaction SMILES: C([O:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]([NH:13][CH3:14])=[C:7]([NH2:15])[C:6]=1[CH3:16])(=O)C.CO[C:19]([CH2:21][O:22][C:23]1[CH:36]=[CH:35][C:26]([CH2:27][CH:28]2[S:32][C:31](=[O:33])[NH:30][C:29]2=[O:34])=[CH:25][CH:24]=1)=O.Cl.C(=O)([O-])O.[Na+]>C(OCC)C.O1CCOCC1>[OH:4][C:5]1[C:10]([CH3:11])=[C:9]([CH3:12])[C:8]2[N:13]([CH3:14])[C:19]([CH2:21][O:22][C:23]3[CH:24]=[CH:25][C:26]([CH2:27][CH:28]4[S:32][C:31](=[O:33])[NH:30][C:29]4=[O:34])=[CH:35][CH:36]=3)=[N:15][C:7]=2[C:6]=1[CH3:16]
Reactant: CNc1c(C)c(C)c(OC(C)=O)c(C)c1N
Reactant: COC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1c(O)c(C)c2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)n(C)c2c1C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 27.2 %

Procedure:
A mixture of 1.0 g of 4-acetoxy-N-methyl-3,5,6-trimethyl-1,2-phenylenediamine (prepared as described in Preparation 19), 2.7 g of 5-(4-methoxycarbonylmethoxybenzyl)thiazolidine-2,4-dione (prepared as described in Preparation 21), 5 ml of 1,4-dioxane and 25 ml of concentrated aqueous hydrochloric acid was heated under reflux for 2 days. At the end of this time, the reaction mixture was added to ice-water and the resulting mixture was neutralized by the addition of sodium hydrogencarbonate. It was then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, after which the residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent. Fractions containing the title compound were collected and the solvent was removed by distillation under reduced pressure, to give a red residual oil. 150 ml of diethyl ether were added to the oil, and the mixture was agitated ultrasonically for 5 minutes. The precipitate which separated out was collected by filtration and dissolved in 300 ml of tetrahydrofuran. The resulting solution was concentrated to a volume of between about 10 ml and 20 ml by evaporation under reduced pressure. 200 ml of ethyl acetate were added to the concentrate, and the mixture was agitated ultrasonically for 20 minutes. The precipitate which separated out was collected by filtration, to give 0.52 g of the title compound, melting at 240°-244° C. and having an Rf value=0.44 (on thin layer chromatography on silica gel; developing solvent: ethyl acetate).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[CH:13][C:14]=1[Br:15].[CH2:17](Br)[CH:18]=[CH2:19]>>[Br:15][C:14]1[CH:13]=[CH:12][C:11]([O:16][CH2:19][CH:18]=[CH2:17])=[CH:10][C:9]=1[O:8][CH3:7]
Reactant: C=CCBr
Reactant: COc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCOc1ccc(Br)c(OC)c1
Reaction time: 8 h

Procedure:
To a stirred mixture of K2CO3 (3.45 g, 0.025 mol), and 3-methoxy-4-bromo-phenol (6.09 g, 0.030 mol) at ambient temperature under argon is added allyl bromide (3.60 g, 0.030 mol). The resulting mixture is heated and stirred overnight. The mixture is filtered and the filtrate is concentrated on the rotovap. The residue is partitioned between Et2O and H2O. The Et2O layer is separated and extracted with 2×70 ml 5% NaOH, washed with brine, dried (MgSO4) and filtered. Evaporation on the rotovap followed by flash chromatography (EtOAc-hexane 1:9) gives 5.93 (81%) of the title compound. Rf-0.41 (EtOAc-hexane 25:75) HNMR (CDCl3) d 7.38 (d, 1H), 6.38 (dd, 1H) 6.1-5.9 (m, 1H), 5.41 (d, 1H), 5.29 (d, 1H), 4.51-4.48 (m, 2H), 3.84 (s, 3H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:19]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:17])=[C:11]([C:34](=[O:38])[N:35]([CH3:37])[CH3:36])[CH:10]=1)C1C=CC=CC=1>CO.C1COCC1.[C].[Pd]>[CH3:36][N:35]([CH3:37])[C:34]([C:11]1[CH:10]=[C:9]([OH:8])[CH:14]=[CH:13][C:12]=1[NH:15][C:16]([C:18]1[C:19]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:17])=[O:38]
Reactant: CN(C)C(=O)c1cc(OCc2ccccc2)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reaction time: 5 h
Yield: 105.9 %

Procedure:
4′-Trifluoromethylbiphenyl-2-carboxylic acid (4-benzyloxy-2-dimethylcarbamoylphenyl)amide (1.2 g) was dissolved in MeOH (25 mL)-THF (25 mL), and thereto was added 7.5% palladium carbon (250 mg). The mixture was stirred for 5 hours under hydrogen atmosphere. The reaction solution was filtered through a Celite and the filtrate was concentrated to give 4′-trifluoromethylbiphenyl-2-carboxylic acid (2-dimethylcarbamoyl-4-hydroxyphenyl)amide (1.05 g).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][N:7]([C:9]3[C:10]4[CH:17]=[CH:16][NH:15][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:6][CH2:5][NH:4]2)[CH2:2]1.[S:18](N)([NH2:21])(=[O:20])=[O:19]>O1CCOCC1>[N:12]1[C:11]2[NH:15][CH:16]=[CH:17][C:10]=2[C:9]([N:7]2[CH2:8][C:3]3([CH2:1][CH2:2]3)[N:4]([S:18]([NH2:21])(=[O:20])=[O:19])[CH2:5][CH2:6]2)=[N:14][CH:13]=1
Reactant: NS(N)(=O)=O
Reactant: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2

Procedure:
To 4-(4,7-diaza-spiro[2.5]oct-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (1 g, 4.4 mmol) (intermediate 21) in dry dioxane (20 mL) was added sulfamide (419 mg, 4.4 mmol). The reaction mixture was heated to reflux for 6 hours. After evaporation of the solvent in vacuo the crude mixture was purified by flash chromatography on silica using heptane→EtOAc:MeOH (9:1) as eluent.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([C:26]2[N:30]([CH3:31])[CH:29]=[N:28][N:27]=2)[CH2:21][C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=1.[Li+].[OH-]>C1COCC1.CCO>[F:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([C:26]2[N:30]([CH3:31])[CH:29]=[N:28][N:27]=2)[CH2:21][C:22]([OH:24])=[O:23])=[CH:16][CH:15]=1
Reactant: COC(=O)C[C@@H](c1ccc(OCc2ccc3c(c2F)CCCC3)cc1)c1nncn1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1cnnc1[C@@H](CC(=O)O)c1ccc(OCc2ccc3c(c2F)CCCC3)cc1
Temperature: 23 °C

Procedure:
To a stirred solution of 47.9 (100 mg, 0.24 mmol) in THF/EtOH (6 mL, 3/1, v/v) is added 1N LiOH (aq) (2 mL). The reaction mixture is stirred at 23° C. until TLC confirms consumption of the starting material. The organic solvent is removed in vacuo. 1N HCl is added to neutralize the mixture to pH 7. The mixture is extracted with EtOAc (2×10 mL), concentrated in vacuo. The residue is purified by column chromatography (silica, MeOH/DCM), to afford acid 47.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][C:14]2([CH3:18])[CH:16]([OH:17])[C:10]([CH3:26])([CH2:11][N:12](CC3C=CC=CC=3)[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([N:8]1[CH2:9][C:10]2([CH3:26])[CH:16]([OH:17])[C:14]([CH3:18])([CH2:13][NH:12][CH2:11]2)[CH2:15]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC12CN(Cc3ccccc3)CC(C)(CN(Cc3ccccc3)C1)C2O
Agent: [Pd]
Solvent: CCO
Product: CC12CNCC(C)(CN(Cc3ccccc3)C1)C2O

Procedure:
A solution of 3,7-dibenzyl-1,5-dimethyl-9-hydroxy-3,7-diazabicyclo-[3.3.1]nonane (from step (i) above; 2.71 g, 7.74 mmol) in aqueous ethanol (20 mL; 95%) was hydrogenated over 5% Pd/C at 1 atm. until tlc indicated that the reaction was complete. The catalyst was removed by filtration through a pad of Celite®, and the filtrate concentrated to give the sub-title compound in a quantitative yield.
Reaction SMILES: [CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH2:15])=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2.[Cl-].[C:17]([O:28][CH3:29])(=[O:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-])=[O:23])=[CH:20][CH:19]=1.Cl>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH:15][C:22]([C:21]4[CH:25]=[CH:26][C:18]([C:17]([O:28][CH3:29])=[O:27])=[CH:19][CH:20]=4)=[O:23])=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2
Reactant: CC12CCCc3cc(N)cc(c31)CCC2
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Agent: Cl
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(C(=O)Nc2cc3c4c(c2)CCCC4(C)CCC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
A solution of 6a-methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenylamine (0.138 g) in anhydrous benzene (5 ml) and pyridine (2 ml) was added with monomethyl terephthalate chloride (0.177 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with 2 N aqueous hydrochloric acid and thereby made acidic, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water, 10% aqueous sodium carbonate, water and saturated brine, and then dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from chloroform-n-hexane to obtain the title compound (0.205 g, yield: 82%) as colorless needles (melting point: 217-218° C.).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1.C(OCC)C>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:7]([C:8]#[N:9])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:26]
Reactant: CCOC(=O)CBr
Reactant: N#CCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Combine phenylacetonitrile (5.85 g, 50.0 mmol) and tetrahydrofuran (140 mL). Cool to about 5° C. Add dropwise, a solution of sodium bis(trimethylsilyl)amide (800 mL, 1 M in tetrahydrofuran, 800 mmol). When the addition is complete, warm the reaction mixture to ambient temperature and allow to stir for 1 hour. Transfer the above solution via cannula into a cooled (−8° C.) solution of ethyl bromoacetate (84.5 mL, 762 mmol) in tetrahydrofuran (500 mL) at such a rate that the temperature of the reaction mixture does not rise above about 20° C. Allow to stir at ambient temperature. After 18 hours, dilute with diethyl ether (1.5 L) and extract with saturated aqueous solution of ammonium chloride, then water, and then saturated aqueous solution of sodium chloride. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to obtain a residue. Distill the residue by bulb-to-bulb distillation to give the title compound: bp; 140-150° C. at 0.2 mm Hg.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[O:12][C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31]Cl)[CH3:27]>>[CH2:26]([N:28]([CH2:33][CH3:34])[CH2:29][CH2:30][CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[O:12][C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1)[CH3:27]
Reactant: CCN(CC)CCCCl
Reactant: O=S(=O)(c1ccc(O)cc1)c1oc2ccccc2c1-c1ccccc1
Product: CCN(CC)CCCOc1ccc(S(=O)(=O)c2oc3ccccc3c2-c2ccccc2)cc1

Procedure:
Reaction of 2-(4-hydroxyphenylsulfonyl)-3-phenylbenzofuran with 3-diethylaminopropyl chloride according to the procedure of Example 1 gives the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[CH3:8][NH:9][C:10]([NH:12][NH2:13])=[S:11].C(O)(=O)C>CO>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:9]([CH3:8])[C:10](=[S:11])[NH:12][N:13]=1
Reactant: O=C1CCCCO1
Reactant: CNC(=S)NN
Solvent: CC(=O)O
Solvent: CO
Product: Cn1c(CCCCO)n[nH]c1=S
Temperature: 120 °C

Procedure:
Tetrahydro-2H-pyran-2-one (2 ml), N-methylhydrazinecarbothioamide (3.4 g) and acetic acid (0.3 ml) were suspended in methanol (10 ml). The reaction was heated in microwave oven at 120° C. for 20′ followed by further 10′ at 110° C. Acetic acid was added (0.3 ml) and reaction was heated in a microwave oven at 140° C. for 20′, further acetic acid (0.3 ml) was added and the reaction was in a microwave oven at 140° C. for 20′. The solvent was removed under reduced pressure, DCM was added to the crude and solid filtered-off. Solvent was removed under reduced pressure to give a crude product that was purified by flash chromatography on silica gel (DCM/MeOH from 0 to 10%) to give the title compound as a white solid (1 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([O:26]C)[CH:19]=3)=[N:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br>C(O)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([OH:26])[CH:19]=3)=[N:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc3ncn(Cc4ccccc4)c3c(=O)[nH]2)cc1OC
Agent: Br
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(O)c(O)c2)nc2ncn(Cc3ccccc3)c12
Yield: 100.1 %

Procedure:
0.92 g of 7-benzyl-2-(3,4-dimethoxyphenyl)hypoxanthine obtained in Example 2 was dissolved in 18 ml of acetic acid and 3 ml of 48% aqueous solution of hydrogen bromide, and the resulting solution was stirred for 16 hours at 120° C. After removing acetic acid by evaporation under vacuum, water was added and the mixture was stirred for a while. The solid precipitate produced was separated by filtration, washed with water, and dried under reduced pressure. The crude product was purified by silica gel column chromatography and dried under reduced pressure to obtain 0.85 g of 7-benzyl-2-(3,4-dihydroxyphenyl)hypoxanthine (yield 53%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[Na].[CH3:10][NH:11][NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>CO>[CH3:10][N:11]1[C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[N:2][C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:12]1
Reactant: N#Cc1cccnc1
Reactant: CNNC(=O)c1ccc(Cl)cc1
Agent: [Na]
Solvent: CO
Product: Cn1nc(-c2ccc(Cl)cc2)nc1-c1cccnc1
Reaction time: 0.5 h
Yield: 3.8 %

Procedure:
To 3-cyanopyridine (2 g.) in methanol (30 ml.) is added sodium (0.1 g.). The solution is allowed to stand 0.5 hours at ambient temperature and is then added to a solution of 1-methyl-2-(p-chlorobenzoyl)hydrazine (3.6 g.) in methanol (40 ml.). The reaction mixture is heated at reflux for 5 hours and is then concentrated to an oil which solidifies. After recrystallization from isopropanol, yielding 0.2 g of 1-methyl-3-(p-chlorophenyl)-5-(3-pyridyl)-1,2,4-triazole, m.p. 157°-158°C. is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[NH:19]1[CH:23]=[N:22][N:21]=[N:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:16][C:15]([CH3:18])([CH3:17])[CH2:14][N:13]1[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:2][N:19]1[CH:23]=[N:22][N:21]=[N:20]1
Reactant: c1nnn[nH]1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(Cn2cnnn2)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 45 %

Procedure:
6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.33 mmol) and 1H-tetrazole (0.65 mmol) are dissolved in DMF (3 ml). To the solution, K2CO3 (0.98 mmol) is added and the mixture is stirred at room temperature under nitrogen atmosphere for 23 h. The reaction mixture is diluted with water and extracted with AcOEt. The organic layer is washed with brine, dried over sodium sulfate, and concentrated. The crude product is purified by silica gel column chromatography to give A in 45% yield and B in 48% yield in the order of elution.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[N:12]([CH3:21])[C:11]2=[O:22])=[C:4]([F:23])[CH:3]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[N:12]([CH3:21])[C:11]2=[O:22])=[C:4]([F:23])[CH:3]=1
Reactant: COc1cc(Cl)cc(F)c1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2c(O)cc(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
5.7 g (16 mmol) of 3-(4-chloro-2-fluoro-6-methoxyphenyl)-1-methyl-6-trifluoromethyluracil was dissolved in 100 ml of dichloromethane, and 27 ml (80 mmol) of boron tribromide (3.0M dichloromethane solution) was dropwise added at 0° C. After stirring at room temperature for 3 hours, the reaction solution was poured into ice water and neutralized with sodium hydrogencarbonate. It was extracted with dichloromethane. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained crude crystals were washed with isopropyl ether to obtain 5.4 g (yield: 98.2%) of the desired product as white crystals. Melting point: 143-144° C.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[C:21]([NH:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)(=[O:24])[CH2:22][CH3:23]>CN(C=O)C.O>[C:21]([NH:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30]/[C:4](=[C:11]2\[C:12](=[O:20])[NH:13][C:14]3[C:19]\2=[CH:18][CH:17]=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:28][CH:27]=1)(=[O:24])[CH2:22][CH3:23]
Reactant: CCC(=O)Nc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccccc21)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
265 mg (1 mmol) of 3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone are dissolved in 5 ml of DMF and after the addition of 300 mg (1.8 mmol) of 4-propionylamino-aniline stirred for 8 hours at 150° C. After cooling, it is diluted with water, the crystalline product is suction filtered, washed and dried.
Reaction SMILES: [CH2:1]([C@H:8]([NH:11][C:12]1[N:20]=[C:19](Cl)[N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[C@@H:22]1[CH2:26][C@H:25]([NH:27][C:28](=[O:31])[CH2:29][OH:30])[C@@H:24]([OH:32])[C@H:23]1[OH:33])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:34]([C:37]1[N:41]=[CH:40][NH:39][N:38]=1)([O-:36])=[O:35]>>[OH:32][C@H:24]1[C@@H:23]([OH:33])[C@H:22]([N:16]2[CH:15]=[N:14][C:13]3[C:17]2=[N:18][C:19]([N:39]2[CH:40]=[N:41][C:37]([N+:34]([O-:36])=[O:35])=[N:38]2)=[N:20][C:12]=3[NH:11][C@H:8]([CH2:9][OH:10])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:26][C@@H:25]1[NH:27][C:28](=[O:31])[CH2:29][OH:30]
Reactant: O=[N+]([O-])c1nc[nH]n1
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(-n4cnc([N+](=O)[O-])n4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound can be prepared from N-{(1S,2R,3S,4R)-4-[6-((S)-1-benzyl-2-hydroxy-ethylamino)-2-chloro-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate GC) and 3-nitro-1,2,4-triazole, as described for N-{(1S,2R,3S,4R)-4-[6-(2,2-diphenyl-ethylamino)-2-(4-nitro-pyrazol-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate QD).
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].CN(C)[CH:10]=[C:11]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C>[C:13]1([C:12]2[C:11]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)=[CH:10][N:7]=[CH:5][N:6]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CN(C)C=C(C(=O)c1ccccc1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N=CN
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2cncnc2-c2ccccc2)CC1
Temperature: 140 °C

Procedure:
To a stirred solution of formamidine acetate (2.8 g) in triethylamine (6 ml) in a sealed tube, was added tert-butyl 4-(1-(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)piperazine-1-carboxylate (1.0 g) and the reaction mixture was heated at 140° C. for 6 h. The reaction mixture was brought to room temperature and triethylamine was removed under reduced pressure. Water (10 ml) was added to the residue and the organic compound was extracted into ethylacetate (4×20 ml). Combined organic layers were dried (Na2SO4) and concentrated. The crude material was purified by column chromatography using methanol/chloroform (1:9) to give tert-butyl 4-(4-phenylpyrimidin-5-yl)piperazine-1-carboxylate.