Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:35])[CH2:33][CH3:34]>C1C=CC=CC=1>[C:32]([N:14]([CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:35])[CH2:33][CH3:34]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)CCCNC(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CCOC(=O)CCCN(C(=O)CC)C(c1ccccc1)c1ccccc1
Yield: 92.6 %

Procedure:
Analogously to Example 19, 9.0 g of ethyl 4-benzhydrylaminobutyrate and 4.3 g of diisopropylethylamine in 100 ml of benzene are reacted with 3.1 g of propionyl chloride. The reaction product is recrystallized from ethyl acetate/ligroin (1:1) to obtain 9.9 g (92.5% of theory) of ethyl N-propionyl-4-benzhydrylaminobutyrate (M.P. 83° to 85°).
Reaction SMILES: Cl.C([N:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([C:18]([O:20][CH3:21])=[O:19])[N:11]=[C:10]1[CH2:22][O:23][CH3:24])C1C=CC=CC=1>O1CCOCC1.CO.[Pd]>[CH3:24][O:23][CH2:22][C:10]1[NH:11][C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([C:14]([O:16][CH3:17])=[O:15])[N:9]=1
Reactant: COCc1nc(C(=O)OC)c(C(=O)OC)n1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COCc1nc(C(=O)OC)c(C(=O)OC)[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
650 mg of 10% w/w palladium-on-carbon and 6.1 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 6.5 g of dimethyl 1-benzyl-2-methoxymethylimidazole-4,5-dicarboxylate [prepared as described in step (iii) above] in 65 ml of methanol. The mixture was then stirred at room temperature for 1.5 hours under a hydrogen atmosphere. At the end of this time, the catalyst was filtered off and the filtrate was concentrated by evaporation under reduced pressure, to give a crystalline compound. This crystalline compound was washed with ethyl acetate, no give 5.13 g of the hydrochloride of the title compound, melting at 108°-111° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.C(#N)C.C[Si]([CH:20]=[N+:21]=[N-:22])(C)C.C(OCC)C>C1COCC1>[N+:21](=[CH:20][C:10](=[O:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[N-:22]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc(CC(=O)C=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under an argon atmosphere, 4-methoxyphenylacetyl chloride (61) (952 mg, 5.16 mmol) was dissolved in THF (2.5 mL) and acetonitrile (2.5 mL) and cooled to 0° C. To this was slowly added a solution of trimethylsilyldiazomethane in diethyl ether (2.0 M, 5.00 mL, 10.0 mmol), which was stirred overnight (15 hours) after warming up to room temperature. After concentrating under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/diethyl ether=1/1) to give 1-diazo-3-(4-methoxyphenyl)propan-2-one (62) as a pale yellow oily substance (692 mg, 3.64 mmol, 70.6%).
Reaction SMILES: N1C=CC=CC=1.S(Cl)([Cl:9])=O.[CH:11]([C:14]1[C:19]([C:20](OCC)=O)=[C:18]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:17]([CH2:32][OH:33])=[C:16]([CH:34]([CH3:36])[CH3:35])[N:15]=1)([CH3:13])[CH3:12].[C:37]([O:40]CC)(=O)[CH3:38]>O1CCCC1>[Cl:9][CH2:20][C:19]1[C:18]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[C:17]([C:32]([O:40][CH2:37][CH3:38])=[O:33])[C:16]([CH:34]([CH3:36])[CH3:35])=[N:15][C:14]=1[CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(C)=O
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CCl)c1-c1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
1.69 ml (20.9 mmol) of pyridine and 1.5 ml (20.9 mmol) of thionyl chloride are added successively at -5°0 C. to 5 g (13.9 mmol) of the compound from Example 4 dissolved in 100 m of dry tetrahydrofuran and the mixture is stirred for 15 minutes at the same temperature. The mixture is diluted using ethyl acetate and extracted several times using saturated sodium hydrogen carbonate solution, and the organic phases are dried over magnesium sulphate and concentrated in vacuo. The residue is chromatographed on a column (silica gel 70-230 mesh, in petroleum ether/ethyl acetate 95:5).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:14]([C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([C:10]([F:9])([F:20])[F:21])[CH:12]=2)=[O:15])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.081 g), commercially available 3-(trifluoromethyl)benzoyl chloride (2.086 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. overnight. The reaction mixture was treated in the same manner as described in Example 120 to obtain 719 mg of the title compound (yield: 26%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][C:6](=O)[CH2:5][CH2:4][S:3]1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28]([Br:35])[CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2)=[O:25].[SiH](CC)(CC)CC>C(Cl)Cl>[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28]([Br:35])[CH:29]=[C:30]2[C:34]=1[NH:33][CH:32]=[C:31]2[CH:6]1[CH2:5][CH2:4][S:3][C:2]([CH3:9])([CH3:1])[CH2:7]1)=[O:25]
Reactant: COC(=O)c1cc(Br)cc2cc[nH]c12
Reactant: CC1(C)CC(=O)CCS1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc(Br)cc2c(C3CCSC(C)(C)C3)c[nH]c12
Reaction time: 2 h
Yield: 52.1 %

Procedure:
To a solution of 2,2-Dimethyl-tetrahydro-thiopyran-4-one (7.9 g, 55.1 mmol) in DCM (100 mL) was added TMSOTf (10 mL, 55.1 mmol) and 5-Bromo-1H-indole-7-carboxylic acid methyl ester (7.0 g, 27.6 mmol) at 0° C. After 2 hours, Et3SiH (15 mL, 110 mmol) was added at 0° C., then the mixture was stirred for 18 hours. The reaction mixture was quenched with sat. Sodium bicarbonate solution, extracted with DCM (3×100 mL). The combined organic layer was dried over MgSO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE:EA=50:1 to 30:1) to give the title compound as a light yellow solid (5.5 g, 52%).
Reaction SMILES: Cl.[C@@H:2]12[N:10]([CH2:11][CH:12]([C:14]3[CH:21]=[C:20]([O:22][CH3:23])[C:17]([C:18]#[N:19])=[CH:16][N:15]=3)[OH:13])[C@@H:6]([CH2:7][NH:8][CH2:9]1)[CH2:5][O:4][CH2:3]2.[CH3:24][C:25]1[C:33]2[CH2:32][O:31][C:30](=[O:34])[C:29]=2[CH:28]=[CH:27][C:26]=1[C@@H:35]1[CH2:37][O:36]1>>[OH:13][C@@H:12]([C:14]1[CH:21]=[C:20]([O:22][CH3:23])[C:17]([C:18]#[N:19])=[CH:16][N:15]=1)[CH2:11][N:10]1[CH:6]2[CH2:7][N:8]([CH2:37][CH:35]([OH:36])[C:26]3[C:25]([CH3:24])=[C:33]4[C:29](=[CH:28][CH:27]=3)[C:30](=[O:34])[O:31][CH2:32]4)[CH2:9][CH:2]1[CH2:3][O:4][CH2:5]2
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: COc1cc(C(O)CN2[C@@H]3CNC[C@H]2COC3)ncc1C#N
Agent: Cl
Product: COc1cc([C@H](O)CN2C3COCC2CN(CC(O)c2ccc4c(c2C)COC4=O)C3)ncc1C#N

Procedure:
(R)-6-(1-Hydroxy-2-(7-(2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)ethyl)-4-methoxynicotinonitrile was prepared in a similar fashion to that described for the synthesis of EXAMPLE 1 starting from 6-(2-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl)-1-hydroxyethyl)-4-methoxynicotinonitrile hydrochloride (INTERMEDIATE 25) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1 (3H)-one [INTERMEDIATE 2].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:32])[NH2:31])=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:12](O)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:33][N:34](C=O)[CH3:35].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CNC>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30](=[O:32])[NH2:31])=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)[C:12]([N:34]([CH3:35])[CH3:33])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)C=O
Reactant: NC(=O)CCc1ccc(Oc2ccc(C(=Cc3ccc4c(c3)OCO4)C(=O)O)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Product: CN(C)C(=O)C(=Cc1ccc2c(c1)OCO2)c1ccc(Oc2ccc(CCC(N)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-benzo[1,3]dioxol-5-yl-2-{4-[4-(2-carbamoylethyl)-phenoxy]-phenyl}-acrylic acid, 78, (2.00 g, 4.6 mmol) in DMF (10 mL) triethylamine (0.96 mL, 6.9 mmol) and BOP reagent (2.21 g, 5.0 mmol) were added and stirred at room temperature for 15 min. Dimethylamine (2.0 M in THF, 6.90 mL, 1.8 mmol) was added and stirred for another 15 min. Reaction mixture was poured into ice cold water (100 mL) and extracted with ethyl acetate (4×50 mL). Combined organic layer was washed with saturated aqueous sodium bicarbonate solution (30 mL), water (3×50 mL), brine (2×50 mL), dried on anhydrous magnesium sulfate. Crude product was purified by silica gel chromatography and product was eluted with chloroform-methanol (19:1). Yield: 1.91 g (90.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[Mg].C1O[C:13]2([CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[O:12]C1>O1CCCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:16]1[CH2:17][CH2:18][C:13](=[O:12])[CH2:14][CH:15]=1
Reactant: Clc1ccccc1I
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Mg]
Solvent: C1CCOC1
Product: Cl
Product: O=C1CC=C(c2ccccc2Cl)CC1
Yield: 10 %

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 7, using 9.5 grams (0.040 mole) of 1-chloro-2-iodobenzene, 1.1 grams (0.044 mole) of magnesium turnings, 6.2 grams (0.040 mole) of 1,4-cyclohexanedione mono-ethylene ketal, and about 1 00 mL of aqueous 10% hydrochloric acid in about 95 mL of tetrahydrofuran, yielding 1-(2-chlorophenyl)-1-cyclohexen-4-one.
Reaction SMILES: [Cl:1][C:2]1[C:7](OS(C(F)(F)F)(=O)=O)=[N:6][C:5]2[N:16]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:18][C:4]=2[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[CH3:27][C:28]1([CH3:45])[CH2:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][C:30]([CH3:44])([CH3:43])[NH:29]1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([C:32]2[CH2:31][C:30]([CH3:44])([CH3:43])[NH:29][C:28]([CH3:45])([CH3:27])[CH:33]=2)=[N:6][C:5]2[N:16]([CH:19]([CH3:21])[CH3:20])[N:17]=[CH:18][C:4]=2[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Reactant: CCOC(=O)c1c(Cl)c(OS(=O)(=O)C(F)(F)F)nc2c1cnn2C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1c(Cl)c(C2=CC(C)(C)NC(C)(C)C2)nc2c1cnn2C(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
A solution of ethyl 5-chloro-1-isopropyl-6-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.2 g, 0.481 mmol), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (0.127 g, 0.481 mmol) and Pd(PPh3)4 (0.027 g, 0.024 mmol) in 1,4-dioxane (3 mL) was purged with argon for 10 min. Then, 2M Na2CO3 solution (0.183 g, 1.734 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using 10% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (0.09 g, 45.6%).
Reaction SMILES: NCC[CH2:4][CH:5]([C:7]1[CH:21]=[CH:20][C:10]2[N:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[NH:13][C:9]=2[CH:8]=1)[CH3:6].ClCCl.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28].[CH2:31]([N:33](CC)CC)C>>[CH3:25][N:26]([CH3:30])[C:27]([NH:33][CH2:31][C:5]([C:7]1[CH:21]=[CH:20][C:10]2[N:11]=[C:12]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[NH:13][C:9]=2[CH:8]=1)([CH3:6])[CH3:4])=[O:28]
Reactant: CCN(CC)CC
Reactant: CN(C)C(=O)Cl
Reactant: CC(CCCN)c1ccc2nc(-c3ccncc3)[nH]c2c1
Solvent: ClCCl
Product: CN(C)C(=O)NCC(C)(C)c1ccc2nc(-c3ccncc3)[nH]c2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To 0.25 g. 5-(2-aminoethylpropan-2-yl)-2-(4-pyridinyl)-benzimidazole (prepared in Example 1) in 6 ml. dichloromethane is added, with ice cooling, 0.13 ml. triethylamine and 0.1 g. N,N-dimethylcarbamic acid chloride. The reaction mixture is stirred for 20 hours at ambient temperature, the solvent is then removed in a vacuum, the residue is digested with water and the product is filtered off with suction and purified by filtration over a short column of silica gel (elution agent dichloromethane containing 5% methanol). The eluate is evaporated to dryness and the residue is crystallised from ethyl acetate. There is obtained 0.15 g. of the title compound; m.p. 136°-138° C.
Reaction SMILES: [OH:1][CH:2]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=[O:11])[C:5]([CH3:12])=[CH:4][CH:3]1[O:13][CH3:14].[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[C:21](O)=[O:22])([O-:17])=[O:16]>>[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[N+:27]([O-:29])=[O:28])[C:21]([O:1][CH:2]1[C:8]([CH3:9])([CH3:10])[CH2:7][C:6](=[O:11])[C:5]([CH3:12])=[CH:4][CH:3]1[O:13][CH3:14])=[O:22])([O-:17])=[O:16]
Reactant: COC1C=C(C)C(=O)CC(C)(C)C1O
Reactant: O=C(O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Product: COC1C=C(C)C(=O)CC(C)(C)C1OC(=O)c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Yield: 85 %

Procedure:
5-Hydroxy-4-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU154) obtained in Example 4 (25.0 g, 126 mM) was treated with 3,4-dinitrobenzoic acid according to the procedures described in Example 20, and crystallized from methanol to obtain 42.1 g (85%) of 5-(3,4-dinitrobenzoyloxy)-4-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one (AU409) as light yellow needles. Melting point: 103° to 104° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:12])=[CH:5][C:6](=O)[C:7]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([CH3:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(=O)c([N+](=O)[O-])c(C)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)c([N+](=O)[O-])c(C)n1
Yield: 79 %

Procedure:
By the method of Yakugaku Zasshi, 87, 387 (1967), 2,6-dimethyl-3-nitro-4(1H)-pyridone (see part (a)) (11.23 g, 66.8 mmol) and phosphorus oxychloride (57 ml) were heated together at reflux for 1.5 hours. The excess reagent was removed under reduced pressure, and the residue dissolved in dichloromethane (150 ml). This solution was treated with dilute aqueous sodium bicarbonate until the aqueous layer was at pH7, then the organic phase was separated, dried (MgSO4) and concentrated under reduced pressure to give the title compound as a pale yellow solid, (9.8 g, 79%). Caution: this compound is a potential skin irritant.
Reaction SMILES: O1CCCC1.[N+:6]([C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)([O-:8])=[O:7].[CH3:18][N:19]1[C:24]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][OH:33])[CH2:27][CH2:26]2)=[CH:23][C:22](=[O:34])[N:21]([CH3:35])[C:20]1=[O:36]>C(N(CC)CC)C>[CH3:18][N:19]1[C:24]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][O:33][C:13](=[O:14])[C:12]3[CH:11]=[CH:10][C:9]([N+:6]([O-:8])=[O:7])=[CH:17][CH:16]=3)[CH2:27][CH2:26]2)=[CH:23][C:22](=[O:34])[N:21]([CH3:35])[C:20]1=[O:36]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cn1c(N2CCN(CCO)CC2)cc(=O)n(C)c1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN(CCOC(=O)c3ccc([N+](=O)[O-])cc3)CC2)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5 ml of tetrahydrofuran were added 0.5 g of 4-nitrobenzoyl chloride, 0.47 g of 1,3-dimethyl-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione (compound 41) and 1.5 ml of triethylamine, and the resulting mixture was stirred at room temperature overnight. Afterward, the used solvent was distilled off under reduced pressure, and the residue was then dissolved in chloroform. The resulting chloroform solution was washed with water, then dried over anhydrous sodium sulfate, and concentrated to dryness, thereby obtaining a crude product. The latter was then purified through a silica gel column chromatograph (chloroform/methanol=40/1 in terms of volume ratio) in order to obtain 1,3-dimethyl-6-{4-[2-(4-nitrobenzoyloxy)ethyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione. Next, this pyrimidinedione derivative was treated with an oxalic acid/methanol solution in a usual manner to prepare 0.84 g of 1,3-dimethyl-6-{4-[2-(4-nitrobenzoyloxy)ethyl]piperazine-1-yl}-2,4(1H,3H)-pyrimidinedione oxalate (compound 40).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:13][C:12]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=3[N:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CCN(CC)CC.[CH2:26]([NH:29][C:30]([NH2:32])=[O:31])[C:27]#[CH:28]>CN(C=O)C.I[Cu].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:28]#[C:27][CH2:26][NH:29][C:30]([NH2:32])=[O:31])=[N:3][C:4]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:11]=2[N:10]=1
Reactant: Cc1ccc2nc(-c3nc(Br)cnc3N)[nH]c2c1
Reactant: C#CCNC(N)=O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2nc(-c3nc(C#CCNC(N)=O)cnc3N)[nH]c2c1
Yield: 82 %

Procedure:
5-Bromo-3-(6-methyl-1H-benzimidazol-2-yl)pyrazin-2-amine (50 mg, 0.1644 mmol), Et3N (166.4 mg, 229.2 μL, 1.644 mmol), iodocopper (31.3 mg, 0.1644 mmol), Pd(PPh3)4 (9.5 mg, 0.0082 mmol) and the relevant prop-2-ynylurea (24.2 mg, 0.2466 mmol) in DMF (2 mL) were heated at 100° C. for 30 minutes under microwave conditions. The reaction mixture was purified directly by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as an yellow solid (43.3 mg, 82% Yield). 1H NMR (400.0 MHz, DMSO) δ 2.45 (3H, s), 4.7 (2H, s), 6.1 (1H, s), 7.1-7.15 (1H, m), 7.4 (1H, vbr s), 7.6 (1H, vbr s), 7.85 (2H, s), 8.65 (1H, s), 9.5-9.7 (2H, m), 10.6 (1H, br s); MS (ES+) 332.
Reaction SMILES: [Cl:1][C:2]1[NH:3]/[C:4](=[N:17]\[NH2:18])/[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:9]=2[N:10]=1.[CH:19]([O-])([O-])OCC>>[Cl:1][C:2]1[N:3]2[CH:19]=[N:18][N:17]=[C:4]2[C:5]2[N:6]=[CH:7][N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[C:9]=2[N:10]=1
Reactant: N/N=c1\[nH]c(Cl)nc2c1ncn2C1CCCCO1
Reactant: CCOC([O-])[O-]
Agent: NNc1nc(Cl)nc2c1ncn2C1CCCCO1
Product: Clc1nc2c(ncn2C2CCCCO2)c2nncn12

Procedure:
A mixture of (6Z)-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-1,9-dihydro-6H-purin-6-one hydrazone [which is a tautomeric form of 2-chloro-6-hydrazino-9-(tetrahydro-2H-pyran-2-yl)-9H-purine; 0.1 g, 0.5 mmol] and ethyl orthoformate (3 g, 20 mmol) was stirred at 98° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to provide the product. LCMS calculated for C11H12ClN6O (M+H): 279.1; found: 279.0.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9](Br)=[N:10][CH:11]=[CH:12][CH:13]=1)(=O)C.[F:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[O:7]([C:8]1[C:9]([C:31]2[CH:32]=[N:33][C:28]([F:27])=[CH:29][CH:30]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1Br
Reactant: OB(O)c1ccc(F)nc1
Product: O[C@@H]1[C@@H](O)[C@H](Oc2cccnc2-c2ccc(F)nc2)SC[C@H]1O

Procedure:
By carrying out the operation analogously to example 239, starting from 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation III, and 6-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of a white powder (yield=14%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=O)=[CH:6][CH:5]=1)([O-])=O.O.Cl>C(O)C.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1
Reactant: O=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CCCC2
Reaction time: 18 h

Procedure:
7-Nitrotetralone (Formula 10) is dissolved in a solvent, such as ethanol or methanol, preferably ethanol (about 4 L/mole). To this solution is added water (about 400 ml/mmol), concentrated HCl (about 95 ml/mmol) and 10% palladium on carbon (about 40 g/mmol). The reaction mixture is hydrogenated at a pressure of about 30-40 psi for a period of about 12 to 24 hours, preferably about 18 hours. When the reaction is substantially compete, 2-amino-5,6,7,8-tetrahydronaphthalene of Formula 11 is isolated and purified by conventional means, preferably by preparative TLC or flash column chromatography.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CN1CCNCC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Br)c2)[C@H](c2ccccc2)C1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CN1CCN(c2cccc([C@H]3CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)C[C@H]3c3ccccc3)c2)CC1
Yield: 37.9 %

Procedure:
To a solution of rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(3-bromo-phenyl)-3-phenyl-piperidin-1-yl]-methanone (500 mg, 0.899 mmol) in 5 mL dry toluene was added 1-methyl-piperazine (0.123 mL, 1.08 mmol), sodium tert.-butoxide (125 mg, 1.26 mmol), bis(dibenzylidenacetone)palladium (2.1 mg, 0.002 mmol) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (4.3 mg, 0.007 mmol) and than refluxed overnight. The reaction mixture was diluted with 10 mL water and extracted three times with 20 mL ethyl acetate. Organic phases were pooled, dried with magnesium sulfate and evaporated. Flash chromatography on silica gel with hexane/ethyl acetate/triethyl amine 10:10:1 gave the desired product (196 mg, 38%), MS: m/e=576.1 (M+H+).