Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH:25]([CH3:27])[CH3:26])[CH:18]=1)=[C:10]([Cl:28])[CH:9]=2)=[O:5])C.[H-].[Na+].I[CH3:32]>CN(C)C=O>[CH3:1][O:3][C:4]([C:6]1[N:7]([CH3:32])[C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[C:11]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH:25]([CH3:26])[CH3:27])[CH:18]=1)=[C:10]([Cl:28])[CH:9]=2)=[O:5]
Reactant: CCOC(=O)c1cc2c(Cl)c(Oc3ccc(OC)c(C(C)C)c3)c(Cl)cc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Cl)c(Oc3ccc(OC)c(C(C)C)c3)c(Cl)cc2n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a solution of 4,6-dichloro-5-(3-isopropyl-4-methoxy-phenoxy)-1H-indole-2-carboxylic acid ethyl ester (50 mg, 0.12 mmol) in N,N-dimethylformamide (1 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 4.3 mg, 0.18 mmol) and the mixture was stirred at 0° C. for 30 minutes. To which at 0° C. was added iodomethane (15 μL, 0.24 mmol). The solution was warmed to room temperature, stirred for 19 hours, quenched with 1M hydrochloric acid (15 mL) and extracted with ethyl acetate (15 mL). The organic extract was washed with 1M hydrochloric acid (4 times 20 mL), brine (20 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by preparative thin layer chromatography (50% CH2Cl2 in hexane) to afford the title compound (46 mg). 1H NMR (400 MHz, CDCl3) δ7.42 (s, 1H), 7.33 (s, 1H), 6.85 (d, 1H), 6.65 (d, 1H), 6.42-6.39 (dd, 1H), 4.05 (s, 3H), 3.91 (s, 3H), 3.91 (s, 3H), 3.74 (s, 3H), 3.27-3.23 (m, 1H), 1.15 (d, 6H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][C:19]1[NH:20][C:21]([CH3:26])=[CH:22][C:23](=[O:25])[N:24]=1)=[O:17].[N:27]1[C:34]([Cl:35])=[N:33][C:31](Cl)=[N:30][C:28]=1[Cl:29]>C(#N)C>[Cl:29][C:28]1[N:27]=[C:34]([Cl:35])[N:33]=[C:31]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][C:19]2[NH:20][C:21]([CH3:26])=[CH:22][C:23](=[O:25])[N:24]=2)=[O:17])[N:30]=1
Reactant: Cc1cc(=O)nc(NC(=O)NCCCCN)[nH]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cc(=O)nc(NC(=O)NCCCCNc2nc(Cl)nc(Cl)n2)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.2 %

Procedure:
An aqueous solution (40 ml) containing 6 ml of diisopropylethylamine and 5 g (0.018 mol) of 1-(4-aminobutyl)-3-(6-methyl-4-oxo-1,4-dihydropyrimidin-2-yl)urea, prepared beforehand, was added, dropwise, to 5 g (0.018 mol) of cyanuryl chloride suspended in 80 ml of acetonitrile, at a temperature of −20° C. The reaction medium was stirred for 12 hours at ambient temperature and then poured into 200 ml of ice-cold water. The precipitate formed was filtered off and then dried under vacuum, so as to give 6.8 g (0.0175 mol) of a yellow powder with a yield of 97%.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:31](=[N:34]O)([NH2:33])[CH3:32]>CN(C=O)C.C(OCC)(=O)C>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]1[O:5][N:34]=[C:31]([CH3:32])[N:33]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(N)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc([C@@H]2CCCN2C(=O)OCc2ccccc2)n1
Temperature: 115 °C
Reaction time: 5 h

Procedure:
To a solution of 122 mg Z-Pro-OH in 4 ml DMF was added a solution of 325 mg 1,1′-carbonyldiimidazole in 5 ml DMF and the solution was stirred for 30 minutes at RT before a solution of 148 mg acetamide oxime in 3 ml DMF was added. The reaction mixture was stirred for 12 h before 325 mg 1,1′-carbonyldiimidazole were added and the mixture stirred at 115° C. for 5 h. Then, the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4% w/w), saturated aqueous NaHCO3 and 0.1 M HCl. The crude product obtained after evaporation of the solvent was used in the next reaction step without further purification. Yield: 337 mg.
Reaction SMILES: [O:1]([C:8]1[C:17]2[N:18]=[CH:19][N:20]([CH2:21][CH2:22][OH:23])[C:16]=2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][C:26]1[C:27]([CH3:32])=[N:28][O:29][C:30]=1[CH3:31]>>[CH3:32][C:27]1[C:26]([CH2:25][O:23][CH2:22][CH2:21][N:20]2[C:16]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:17]=3[N:18]=[CH:19]2)=[C:30]([CH3:31])[O:29][N:28]=1
Reactant: OCCn1cnc2c(Oc3ccccc3)nc3ccccc3c21
Reactant: Cc1noc(C)c1CCl
Product: Cc1noc(C)c1COCCn1cnc2c(Oc3ccccc3)nc3ccccc3c21
Yield: 52.9 %

Procedure:
Using the general method of Example 13 Part F, 2-(4-phenoxy-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (0.82 g, 2.69 mmol) was reacted with 4-(chloromethyl)-3,5-dimethylisoxazole (0.43 g, 2.95 mmol) and purified to provide 0.59 g of 1-{2-[(3,5-dimethylisoxazol-4-yl)methoxy]ethyl}-4-phenoxy-1H-imidazo[4,5-c]quinoline as a white foamy solid.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31]1([C:37]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[N:38]2[CH:42]=[C:41]([CH2:43][CH2:44]O)[N:40]=[CH:39]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:52]1([C:37]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[N:38]2[CH:42]=[C:41]([CH2:43][CH2:44][O:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=3)[N:40]=[CH:39]2)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(OCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 0.08 h

Procedure:
15 ml of freshly distilled tetrahydrofuran, 340 mg (2.1 mmol) of 4-trifluoromethylphenol and 550 mg (2.1 mmol) of triphenylphosphine are added under nitrogen to 708 g (2 mmol) of 1-triphenylmethyl-4-(2-hydroxyethyl)-1H-imidazole. The resulting mixture is cooled and stirred for 5 min. 66 mg (2.1 mmol) of diethyl azodicarboxylate in 10 ml of tetrahydrofuran are then slowly added. Stirring is continued at room temperature for 2 hours under nitrogen. The solvent is then evaporated under reduced pressure and the residue is chromatographed on a column of silica gel, using diethyl ether as the eluent, to give 1-triphenylmethyl-4-[2-(4-trifluoromethylphenoxy)ethyl]-1H-imidazole.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>CO.ClCCl.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(c2ccc(N)cc2)CC1
Yield: 63.6 %

Procedure:
1-Methyl-4-(4-nitro-phenyl)-piperazine (200 mg) was hydrogenated over 10% Pd—C (20 mg) in methanol (20 ml) at atmospheric pressure until no further gas uptake was observed. The reaction mixture was then filtered over celite and concentrated to give a crude solid. Column chromatography over silica gel using 4% methanol in dichloromethane gave 4-(4-methyl-piperazin-1-yl)-phenylamine (110 mg, 64%) as solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](Cl)=[O:15])[CH2:10][CH2:9]1)(=[O:7])[CH3:6].[C:17]1([S:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:15])[C:20]2[CH:21]=[CH:22][C:17]([S:23][CH3:24])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: CSc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CSc1ccc(C(=O)C2CCN(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.4 %

Procedure:
To a stirred suspension of aluminum chloride (16.66 g, 125 mmol) in dichloromethane (100 mL) was added 1-acetyl-4-piperidinecarbonyl chloride (12.33 g, 65.0 mmol) at −10° C. Thioanisole (6.21 g, 50.0 mmol) was added dropwise at −10° C., the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was poured into ice water (80 g), the organic layer was separated and the aqueous layer was extracted with dichloromethane (40 mL) The combined organic layers were washed with 1N aqueous sodium hydroxide (2×40 mL), brine (40 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. Ethyl acetate and diethyl ether was added to the residue, the resulting precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to afford the title compound (11.43 g, 41.2 mmol, 82%) as a white solid.
Reaction SMILES: [CH:1]([N:4]([CH:23]([CH3:25])[CH3:24])[C:5](=[O:22])[CH:6]([CH3:21])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].[OH-:26].[Na+]>O1CCCC1>[CH:23]([N:4]([CH:1]([CH3:2])[CH3:3])[C:5](=[O:22])[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([OH:26])=[O:20])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)[CH3:21])([CH3:25])[CH3:24]
Reactant: CC(C(=O)N(C(C)C)C(C)C)c1ccc(-c2ccc(C=O)cc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C(=O)N(C(C)C)C(C)C)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
18.04 ml of IN sodium hydroxide and 3.14 g of Ag2O were added to a solution of 380 mg of the product of Stage A in 8 ml of tetrahydrofuran and the mixture was stirred for 24 hours at ambient temperature. After adding 6N hydrochloric acid, extraction was carried out with ethyl acetate to obtain 380 mg of the expected product which is recrystallized from isopropanol to obtain a Rf=0.11 (ethyl acetate/cyclohexane 1/1).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][CH2:2]1.Cl[C:6]1[N:11]=[C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][N:20]=2)[C:16]#[N:17])[CH:9]=[C:8]([CH:21]2[CH2:26][CH2:25][N:24]([CH:27]3[CH2:30][O:29][CH2:28]3)[CH2:23][CH2:22]2)[CH:7]=1>>[N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][N:20]=3)[C:16]#[N:17])[CH:9]=[C:8]([CH:21]3[CH2:22][CH2:23][N:24]([CH:27]4[CH2:30][O:29][CH2:28]4)[CH2:25][CH2:26]3)[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccnc(Nc2cc(C3CCN(C4COC4)CC3)cc(Cl)n2)c1
Reactant: C1CNC1
Product: N#Cc1ccnc(Nc2cc(C3CCN(C4COC4)CC3)cc(N3CCC3)n2)c1
Yield: 47 %

Procedure:
Reaction of azetidine with 2-((6-chloro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-yl)amino)isonicotinonitrile (40 mg, 0.11 mmol) following general Buchwald-Hartwig procedure described above afforded the target compound as a colorless solid (19.8 mg, 47%); 1H NMR (400 MHz, DMSO) δ 9.76 (br s, 1H), 8.51 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 7.18 (d, J=5.1 Hz, 1H), 6.59 (s, 1H), 5.80 (s, 1H), 4.57-4.49 (m, 2H), 4.49-4.40 (m, 2H), 4.00-3.92 (m, 4H), 3.43-3.35 (m, 1H), 2.82-2.73 (m, 2H), 2.40-2.27 (m, 3H), 1.88-1.78 (m, 2H), 1.77-1.68 (m, 2H), 1.68-1.51 (m, 2H); ESI-LRMS m/z [M+1]+=391.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)[CH:57]=2)[CH:52]=[CH:51]1>CN(C=O)C>[NH:50]1[C:58]2[C:53](=[CH:54][CH:55]=[C:56]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)[CH:57]=2)[CH:52]=[CH:51]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccc3cc[nH]c3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc5cc[nH]c5c4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 52.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-indol-6-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.014 g of product in 53% yield: LCMS (ESI) m/z 411 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([NH:16][NH2:17])=[O:12])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNc1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CNc1ccc(Cl)cc1
Yield: 58.4 %

Procedure:
Ethyl 2-(4-chlorophenylamino)acetate (A) (25.6 g, 120 mmol) and hydrazine monohydrate (7.0 mL, 144 mmol) were heated to reflux in ethanol (120 mL) for 22 hours. After concentration in vacuo, the solid obtained was recrystallised from ethanol to yield the title compound (14.0 g, 59%) as a pale brown powder. 1H NMR (400 MHz, CDCl3) δ 3.85 (2H, d), 4.18 (2H, br), 6.53 (2H, d), 7.16 (2H, d), 7.60 (1H, br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[S:9][CH3:10].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:15]=[CH:16][C:17]=1Cl.[OH-].[Na+]>CS(C)=O>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]([F:20])([F:21])[F:22])[CH:15]=[CH:16][C:17]=1[O:8][C:5]1[CH:4]=[C:3]([S:9][CH3:10])[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CSc1cc(O)ccc1Cl
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CSc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 80.1 %

Procedure:
50 g of 4-chloro-3-methylmercaptophenol, 62 g of 3,4-dichlorobenzotrifluoride and 12 g of sodium hydroxide are stirred in 150 ml of dimethyl sulphoxide for 6 hours at 142° C. The reaction mixture is then poured onto ice and extracted with toluene. Distillation of the organic phase yields 81 g of 3-(2'-chloro-4-trifluoromethylphenoxy)-6-chlorothioanisole with a boiling point of 158° C./0.4 mbar.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[O-:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>[Cu]>[CH3:9][O:8][C:5]1[C:4](=[CH:3][C:2]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[O:10][CH3:11]
Reactant: COc1ccc(I)cc1OC
Reactant: [O-]c1ccccc1
Agent: [Cu]
Agent: [Na+]
Product: COc1ccc(Oc2ccccc2)cc1OC

Procedure:
R = 4-phenoxy. Heating a mixture of 4-iodoveratrol (Janssen et al., J. Org. Chem. 20, 1326 (1955)), sodium phenoxide and a catalytic amount of copper powder at about 200° C. for about 4 hours, then pouring the mixture over ice, extracting the mixture with an organic solvent such as ether, drying the extract, stripping the solvent and distilling the residue to give 4-phenoxycatechol dimethyl ether. Treating this product with an anhydrous aluminum chloride/sodium chloride melt (Janssen et al., supra), pouring the resulting mixture into ice-hydrochloric acid, extracting the mixture with an organic solvent, stripping the solvent under reduced pressure and fractionally distilling the residue gives the desired 4-phenoxycatechol.
Reaction SMILES: [C:1]([CH2:13][C:14]([O:16]CC)=O)(=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[NH2:19][C:20]([NH2:22])=[O:21]>Cl.C(O)C>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([C:1]2[NH:22][C:20](=[O:21])[NH:19][C:14](=[O:16])[CH:13]=2)[CH:11]=[CH:10][C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)CC(=O)c1ccc(OC)c(OC)c1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: COc1ccc(-c2cc(=O)[nH]c(=O)[nH]2)cc1OC
Temperature: 120 °C
Yield: 27.6 %

Procedure:
To a mixture of ethyl veratroylacetate (45 g) and urea (11.7 g) were added conc. hydrochloric acid (5 drops) and ethanol (5 ml). The mixture was heated at 120° C. for 16 hours under reduced pressure. To the residue was added another conc. hydrochloric acid (5 drops) and ethanol (5 ml) and the mixture was heated again at 150° C. for 2 hours under reduced pressure. The resulting residue was washed successively with ethyl acetate, ethanol and isopropyl ether to give 6-(3,4-dimethoxyphenyl)-2,4(1H,3H)-pyrimidinedione (12.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:4]([F:28])[CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:40])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:40])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[C:4]([F:28])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3F)c[nH]c12
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3)c3ccc(Cl)cc3F)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
70 mg (0.17 mmol) of the compound from Example 104 were introduced into 10 ml of dichloromethane at 0° C., 42 mg (0.17 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 76 mg (99% of theory) of the title compound were obtained as mixture of diastereomers.
Reaction SMILES: [C@@H:1]1([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.F[C:21](F)(F)C(OC(=O)C(F)(F)F)=O.C[O-].[Na+].Cl.N1C=CC=CC=1>N1C=CC=CC=1.CO>[NH2:17][C:16]1[N:18]=[C:19]2[C:12]([N:11]=[CH:10][N:9]2[C@@H:1]2[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)=[C:13]([O:14][CH3:21])[N:15]=1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: COc1nc(N)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 0 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To 2 mmol of deoxyguanosine, dried by evaporation of pyridine and suspended in 10 mL of dry pyridine was added dropwise 2.3 mL (16 mmol) of trifluoroacetic anhydride, with cooling in an ice both. After ten minutes a suspension of 4.3 g of sodium methoxide in 300 mL of methanol was added dropwise. After a further 24 hrs, the mixture was treated with a solution of pyridine hydrochloride (12 mL of pyridine/4 mL conc HCl). The excess acid was destroyed by addition of 2 g of sodium bicarbonate and the mixture was evaporated to dryness. The residue was dissolved in water and purified on a Dynamax reversed-phase hplc column using a gradient of 2-5% acetonitrile in water in 45 min at a flow rate of 6 mL/min. Evaporation of appropriate fractions gave 0.36 g (60%) of pure 2-amino-6-methoxy-9-(2-deoxy-Beta-D-erythro-pentofuranosyl)purine. A crystalline sample was obtained by crystallization from water, mp 155°-7°. UVmax (MeOH) 281 nm; UVmin 281 nm; 1H NMR (DMSO-d6) delta (ppm) 8.07 (s, 1,H8), 6.43 (br s, 2, NH2), 6.20("t", 1, Japp =6.9 Hz, H1'), 5.27 (d, 1, J=3.8 Hz, 3'-OH), 4.98 (t, 1, J=5.5 Hz, 5'-OH) , 4.35 (m,1,H3'), 4.00 (s, 3, OCH3), 3.82 (m, 1, H4'), 3.53 (m, 2, H5',5'), 2.57 & 2.22 (m & m, 1 & 1, H2' & H2"). Anal. Calcd. for C11H15N5O4.H2O: C, 44.15; H, 5.72; N, 23.40. Found: C, 44.15; H, 5.83; N, 23.43.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14][C:15]([OH:17])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.ClC1C=CC=CC=1[NH2:27]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]1([C:7]2([CH2:13][CH2:14][C:15]([NH2:27])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)CCC1(c2ccccc2)CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: NC(=O)CCC1(c2ccccc2)CCCCC1
Temperature: 0 °C
Yield: 92 %

Procedure:
A solution of 3-phenyl-3-cyclohexanepropanoic acid (0.5 g, 2.15 mmol) and oxalyl chloride (0.3 ml, 3.01 mmol) in 5 ml of toluene was stirred for 3 hours at 35-40° C. and then at room temperature overnight. The mixture was then concentrated in vacuo to provide a yellow oil which was dissolved in 5 ml of CH2Cl2, cooled to 0° C. and treated with 2-chloroaniline. The resultant mixture was stirred at 0° C. for 2 hours and filtered. The filtrate was then washed sequentially with 1.0N HCl, NaHCO3 and brine, dried over Na2SO4, filtered and then concentrated in vacuo to provide a white solid (0.66 g, 92%). A portion of this solid was recrystallized (hexanes/CH2Cl2) to provide a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=3)[O:10][C:3]=12.[CH3:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:31][C:30]3[C:22]([CH3:21])=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][CH:25]=[CH:24]4)[CH:8]=2)[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: Cc1c(N)ccc2[nH]ccc12
Reactant: COc1ccc(-c2cc3nccc(Cl)c3o2)cc1OC
Product: COc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)cc1OC

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(3,4-dimethoxyphenyl)furo[3,2-b]pyridine (29.50 mg; 0.10 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (15.63 mg; 0.11 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (23 mg, 57%). (HPLC (method F): 92%, RT: 3.82 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.13 (s, 1H), 8.50 (s, 1H), 7.94 (d, J=5.5, 1H), 7.52 (dd, J=8.4, 1.8, 1H), 7.38 (dd, J=10.5, 7.8, 2H), 7.31 (t, J=4.1, 2H), 7.06 (d, J=8.5, 1H), 7.01 (d, J=8.5, 1H), 6.52 (s, 1H), 6.12 (d, J=5.5, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 2.37 (s, 3H); MS (m/z) 400 [M+H]+, RT: 3.6 min.
Reaction SMILES: Cl.[CH3:2][C:3]1([NH2:13])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]([CH3:12])([CH3:11])[CH2:4]1.Br[CH2:15][CH2:16][CH2:17][C:18]#[N:19].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1>[C:18]([CH2:17][CH2:16][CH2:15][NH:13][C:3]1([CH3:2])[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][C:5]([CH3:12])([CH3:11])[CH2:4]1)#[N:19]
Reactant: CC1(C)CC(C)(C)CC(C)(N)C1
Reactant: N#CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CC(C)(C)CC(C)(NCCCC#N)C1
Yield: 78.7 %

Procedure:
A mixture of 1,3,3,5,5-pentamethylcyclohexylamine hydrochloride (1) (2-06 g, 10 mmol) 4-bromobutyronitrile (1.55 g. 10.5 mmol) and sodium carbonate (3.18 g, 30 mmol) in tetrahydrofuran (50 ml) was refluxed for 85 h, the poured into water (100 ml) and extracted with ether (3*30 ml). The combined organic phases were washed with brine (20 ml) and dried over K2CO3. The solution was filtered and evaporated and the crude product was purified by chromatography on silica gel, eluting with hexane-ether (10:1), (6:1), (4:1) to give product 2 (1.86 g, 86%) as an colorless oil.