Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:12][S:13][C:14](SC)=[N:15][C:16]#[N:17]>N1C=CC=CC=1>[C:16]([N:15]=[C:14]([NH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[S:13][CH3:12])#[N:17]
Reactant: COC(=O)c1cccc(N)c1
Reactant: CSC(=NC#N)SC
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=NC#N)SC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture of methyl 3-aminobenzoate (6.04 g, 40 mmol) and dimethyl N-cyanodithioiminocarbonate (11.96 g, 80 mmol) in pyridine (70 mL) was heated at reflux for 2.5 hours. The reaction mixture was cooled to room temperature and upon standing overnight at room temperature the above compound (6.2 g) crystallized from the reaction mixture. The compound was used without further purification. 1H NMR was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.CS([O:25][CH2:26][C:27](=O)[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])(=O)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:27]([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:26][OH:25])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: COC(=O)CCCC(=O)COS(C)(=O)=O
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Solvent: C1CCOC1
Product: COC(=O)CCCC(CO)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 5-carbomethoxy-2-oxopentyl methanesulfonate under nitrogen to give 7-chloro-2-[[2-hydroxy-1-(3-carbomethoxypropyl)ethylidene]hydrazino] -5-phenyl-3H-1,4-benzodiazepine, methanesulfonate ester.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14](=[O:35])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[O:26])=[CH:19][CH:18]=2)[CH:11]=[CH:12][CH:13]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[O:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[O:28][NH:27][C:25](/[CH:24]=[CH:23]/[C:20]1[CH:21]=[CH:22][C:17](/[CH:16]=[CH:15]/[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])=[O:35])=[CH:18][CH:19]=1)=[O:26]
Reactant: O=C(/C=C/c1ccc(/C=C/C(=O)c2cccc(CO)c2)cc1)NOC1CCCCO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)(=O)OCc1cccc(C(=O)/C=C/c2ccc(/C=C/C(=O)NOC3CCCCO3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
Methanesulfonyl chloride (0.41 ml, 5.3 mmol) was added to a stirred solution of (E)-3-{4-[(E)-3-(3-hydroxymethyl-phenyl)-3-oxo-propenyl]-phenyl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (1.08 g, 2.68 mmol) and TEA (1.47 ml, 10.6 mmol) in DCM (18 ml) and DMF (12 ml). The mixture was stirred at room temperature for 30 min and then brought to basic conditions with 5% NaHCO3. The resulting slurry was extracted with Et2O and the organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: petroleum ether/AcOEt 1:1) to give 600 mg of a mixture of the title compound and (E)-3-{4-[(E)-3-(3-chloromethyl-phenyl)-3-oxo-propenyl]-phenyl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as the main product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[Cl:15])[CH2:10]Cl>C1COCC1>[NH2:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:10][C:9]1[CH:12]=[CH:13][C:14]([Cl:15])=[C:7]([Cl:6])[CH:8]=1
Reactant: NCCCN
Reactant: ClCc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: NCCCNCc1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h

Procedure:
To 1,3-diaminopropane (42 ml) in dry THF (200 ml) at 60° C. was added dropwise a solution of 3,4-dichlorobenzylchloride (13.9 ml, 100 mmol) in 90 ml dry THF over 3 h. The mixture was kept at 60° C. for an additional 15 min and then kept at 25° C. for 3 days. The precipitate was removed by filtration and the mother liquor concentrated in vacuo. The residue was partitioned between water and t-butyl methyl ether (TBME). To the organic layer was added aq. HCl (2 M) and the mixture was filtered. The layers were separated and NaOH was added to the aqueous layer with stirring. The resulting mixture was extracted with TBME and the organic extract was dried (Na2CO3), filtered, and the solvent evaporated to give the title compound as a slightly cloudy oil, (18.2 g, 78%). δH (CDCl3) 1.20 (br, s, ca. 3H), 1.58-1.71 (m, 2H), 2.67 (t, J=6.9, 2H), 2.78 (t, J=6.8, 2H), 3.74 (s, 2H), 7.15 (dd, J=8.2, 2.0, 1H), 7.37 (d, J=8.2, 1H), 7.43 (d, J=1.9, 1H); MS (ES+) 233 (MH+, 13%), 159 (100).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:26])[C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[CH:14][CH:13]=3)=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=3)[S:8][C:7]=2[CH:35]=1.C(S)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:26])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[CH:16][CH:17]=3)=[C:9]([C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[S:8][C:7]=2[CH:35]=1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCN(C)CC3)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CN1CCC(Oc2ccc(C(=O)c3c(-c4ccc(O)cc4)sc4cc(O)ccc34)cc2)CC1
Yield: 63.9 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-[1-methylpiperidin-4-oxy]benzoyl)benzo[b]thiophene (749 mg, 1.54 mmol) was dissolved in 30 mL of methylene chloride. This solution was stirred and ethane thiol (7.68 mmol) and aluminum chloride (1.23 g, 9.22 mmol) were added. The reaction mixture was stirred vigorously for 30 minutes and then quenched with brine and saturated sodium bicarbonate. Any resulting residue was dissolved by the addition of methanol and ethyl acetate. The pH was adjusted to make it slightly basic and the mixture was diluted with 150 mL of ethyl acetate. After separation of the aqueous layer, the organic layer was washed with 75 mL of aqeous potassium sodium tartrate. The organic layer was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by rotary chromatography (4 mm. Plate, eluting solvent 4:1 ethyl acetate:methanol) to give 452 mg (64%) of the title compound as a yellow solid. MS(FD) 459(M+). IR (CHCl3) ν max 3221, 2960, 1598, 1467, 1241, 1166.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)[CH2:23][CH2:24][CH3:25]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:22][CH2:23][CH2:24][CH3:25])=[CH:31][CH:30]=1)[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([N:40]([CH3:42])[CH3:41])=[CH:38][CH:39]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: CCCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CCCCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cc1
Yield: 92 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.66 g) and (4-butylphenyl)[(4-dimethylaminophenyl)methyl]amine (0.55 g) as starting materials, 5-benzyloxy-N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.98 g) was obtained. By the reaction and treatment in the same manner as in Example 17 using this compound, N-(4-butylphenyl)-N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.44 g) was obtained. melting point: 138° C.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH:11]1([CH2:14][OH:15])[CH2:13][CH2:12]1.[OH-].[K+]>CS(C)=O>[CH:11]1([CH2:14][O:15][C:2]2[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH2:13][CH2:12]1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: OCC1CC1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)c1cnc(OCC2CC2)cn1
Temperature: 80 °C
Yield: 34 %

Procedure:
A solution of 5-chloro-pyrazine-2-carboxylic acid (1.50 g, 9.46 mmol) in dry dimethylsulfoxide (5 ml) was treated at 25° C. with cyclopropyl-methanol (1.02 g, 14.1 mmol) and powdered potassium hydroxide (2.12 g, 37.4 mmol). The mixture was heated in a microwave oven at 80° C. for 90 minutes. For the workup, the reaction mixture was quenched with an aqueous solution of citric acid (10%), then extracted with ethyl acetate (5×30 ml), followed by the extraction with a 4:1-mixture of dichloromethane and methanol. The combined organic layers were washed with brine (200 ml), dried and evaporated ate reduced pressure. After lyophilization the 5-cyclopropylmethoxy-pyrazine-2-carboxylic acid (34% yield) was obtained as a white solid. MS (ISP): m/z=195.0 [M+H]+.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl.[CH3:25][C:26]1[C:27]([Si:35]([CH3:43])([CH3:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:28]([C:31]([CH3:34])=[CH:32][CH:33]=1)[CH2:29][OH:30]>C(OCC)C>[CH3:25][C:26]1[C:27]([Si:35]([CH3:43])([CH3:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:28]([C:31]([CH3:34])=[CH:32][CH:33]=1)[CH:29]=[O:30]
Reactant: Cc1ccc(C)c([Si](C)(C)c2ccccc2)c1CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1ccc(C)c([Si](C)(C)c2ccccc2)c1C=O
Reaction time: 24 h

Procedure:
Pyridinium dichromate (9.24 g, 1.8 equivalents) was added to a methylene chloride solution of the benzyl alcohol product of step (q), above, at room temperature. The reaction was stirred for 24 hours, then diluted with diethyl ether and filtered. The filtrate was concentrated on a rotary evaporator and the residual oil was taken up in MTBE and washed with 2N hydrochloric acid, aqueous NaHCO3, brine, treated with charcoal, dried and concentrated on a rotary evaporator to give the product of this step as a pale yellow oil. The product was distilled under reduced pressure (~0.5 mm Hg) using a Kugelrohr apparatus to give 3.3 g of refined product as a clear oil.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C@@H:28](O)[CH3:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:18][CH2:17][C:16]([F:19])([F:20])[CH2:15]2)[C:8]2[NH:13][N:12]([C@@H:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[Cl:21])[CH3:29])[NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](O)c1ccccc1Cl
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1Cl)N1Nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.7 %

Procedure:
To a solution of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (41.3 μmol), (S)-1-(2-chlorophenyl)ethanol (12.9 mg, 82.6 μmol) and PPh3 (21.7 mg, 82.6 μmol) in THF (250 μL) was added DEAD (13.1 μL, 82.6 μmol) at 0° C. After being stirred at the room temperature for 2 h, the reaction mixture was directly purified by preparative HPLC (column: Gemini Sum C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 50:50% to 5:95%. WL: 300 nm Flow: 30 mL/min.) to afford the title compound as light-yellow gum (3.1 mg, 17%). MS (m/e): 421.4 (MH+).
Reaction SMILES: Br.[CH:2]([C:5]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]2[CH:16]=1)([CH3:4])[CH3:3].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([NH:13][C:10]3[CH:11]=[CH:12][C:7]4[N:8]([CH:16]=[C:5]([CH:2]([CH3:4])[CH3:3])[N:6]=4)[CH:9]=3)=[O:31])=[CH:26][CH:25]=2)=[CH:22][CH:23]=1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CC(C)c1cn2cc([N+](=O)[O-])ccc2n1
Agent: Br
Product: CC(C)c1cn2cc(NC(=O)c3ccc(-c4ccc(F)cc4)cc3)ccc2n1

Procedure:
Conducting the operations similar to those of Example 1 using 2-isopropyl-6-nitroimidazo[1,2-a]pyridine hydrobromide and 4′-fluoro[1,1′-biphenyl]-4-carboxylic acid, the title compound was obtained as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.S(=O)(=O)(O)[OH:22]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Reactant: O=S(=O)(O)O
Agent: OO
Solvent: CO
Product: COc1ccc(O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a cooled (0° C.), stirred solution of 3-benzyloxy-4-methoxybenzaldehyde (10 g) in MeOH (100 mL) was added hydrogen peroxide (5.5 mL of 30% aqueous) dropwise. After having been warmed to RT, concentrated sulfuric acid (1 mL) was added and the resulting solution was allowed to stir for 1.5 h. The reaction mixture was partitioned between ethyl ether/saturated aqueous sodium bicarbonate, another organic layer was dried over sodium sulfate and concentrated in vacuo to afford an oil. Flash chromatography (20% ethyl acetate/hexanes) afforded 3-benzyloxy-4-methoxyphenol (5.8 g).
Reaction SMILES: [CH3:1][C:2]([CH3:40])([CH3:39])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:15]=[C:16]([CH:23]=[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:25]=3)[C:17]([NH:19][CH2:20][CH2:21][OH:22])=[O:18])[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4]>C(Cl)Cl.CO>[CH3:1][C:2]([CH3:40])([CH3:39])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:15]=[C:16]([CH:23]=[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:25]=3)[C:17]([NH:19][CH2:20][CH2:21][OH:22])=[O:18])[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc(C(=O)NCCO)cc(N4CCCC4)c3)nc12
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cc(C(=O)NCCO)cc(N4CCCC4)c3)nc12
Yield: 83 %

Procedure:
3-[7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-N-(2-hydroxy-ethyl)-5-pyrrolidin-1-yl-benzamide was prepared following the same procedure but using 3-[7-(2,2-dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-N-(2-hydroxy-ethyl)-5-pyrrolidin-1-yl-benzamide as starting material. The product was obtained in 83% yield after SiO2 chromatography (DCM/MeOH 0-5% MeOH).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH:21]([Sn](CCCC)(CCCC)CCCC)=[CH2:22]>CN(C=O)C.CC#N.CC#N.Cl[Pd]Cl>[CH:21]([C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])=[CH2:22]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: C=Cc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 2-iodoadenosine (1.585 g, 4.03 mmol) and bis(acetonitrile)palladium chloride (0.053 g, 0.20 mmol) in DMF (20 ml) was added vinyltributyltin (1.24 ml, 4.23 mmol), and the mixture stirred at 100° C. for 1 h. The reaction mixture was cooled and filtered. The solvent was evaporated and the residue was purified through silica gel with chloroform and 10% methanol/chloroform to give 1.099 g (92%) of 2-vinyladenosine: 1H NMR (Me2SO-d6) δ3.66 (m, 2H), 3.98 (m, 1H), 4.16 (m, 1H), 4.65 (m, 1H), 5.18 (d, 1H), 5.38-5.62 (m, 3H), 5.89 (d, 1H), 6.41 (dd, 1H), 6.59 (dd, 1H), 7.27 (br.s, 2H), 8.32 (s, 1H); UV (EtOH) λmax 293 nm, 271 nm, 265 nm.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:22]([NH:24][N:25]1[C:30](=[O:31])[CH2:29][N:28](C(OCC2C=CC=CC=2)=O)[CH2:27][C:26]1=[O:42])=[O:23])[CH2:12][CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]>C(O)(C)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:43][CH:44]([CH3:46])[CH3:45])[C:22]([NH:24][N:25]1[C:26](=[O:42])[CH2:27][NH:28][CH2:29][C:30]1=[O:31])=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CN(C(=O)OCc2ccccc2)CC1=O)[C@H](CC=Cc1ccccc1)C(=O)NOC1CCCCO1
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CNCC1=O)[C@H](CCCc1ccccc1)C(=O)NOC1CCCCO1
Yield: 51.1 %

Procedure:
A solution of 0.178 g of 2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-4-methyl-N-(4-benzyloxycarbonyl-2,6-dioxo-1-piperazinyl)valeramide in 5 ml of isopropyl alcohol was hydrogenated for 4 hours in the presence of 0.020 g of 10% palladium-on-carbon. The catalyst was removed by filtration and the solvent was evaporated to give 0.072 g of 2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenylbutyl]-4-methyl-N-(2,6-dioxo-1-piperazinyl)valeramide in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH2:4]Br.[P:11]([O:18]CC)([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>>[CH2:13]([O:12][P:11]([CH2:4][C:3]1[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:10])(=[O:18])[O:15][CH2:16][CH3:17])[CH3:14]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1c(Cl)cccc1Cl)OCC
Temperature: 150 °C

Procedure:
2,6-Dichlorobenzyl bromide (1.20 g, 5 mmol) was mixed with triethyl phosphite (1.66 g, 10 mmol) and heated at 150° C. for 2 h. The resulting mixture was then distilled at 160° C. under reduced pressure (10 mm Hg) to remove the excess triethyl phosphite. (2,6-Dichloro-benzyl)-phosphonic acid diethyl ester was obtained as a colorless liquid (1.46 g, 100%). 1H NMR (300 MHz, CDCl3) δ 7.33-7.28 (m, 2H), 7.15-7.07 (m, 1H), 4.14-4.02 (m, 4H), 3.60 (d, 2H, J=22.4 Hz), 1.27 (t, 6H, J=7.0 Hz).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)#[CH:2].[NH2:11][C:12]1([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C:27]3=[O:32])=[C:22]([CH3:33])[CH:21]=2)=[O:18])[CH2:16][CH2:15][O:14][CH2:13]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:1]([C:3]1[S:7][C:6]([C:8]([NH:11][C:12]2([C:17](=[O:18])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C:27]4=[O:32])=[C:22]([CH3:33])[CH:21]=3)[CH2:16][CH2:15][O:14][CH2:13]2)=[O:10])=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc(C(=O)O)s1
Reactant: Cc1cc(NC(=O)C2(N)CCOC2)ccc1N1CCOCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C#Cc1ccc(C(=O)NC2(C(=O)Nc3ccc(N4CCOCC4=O)c(C)c3)CCOC2)s1

Procedure:
Prepared analogously to Example 1a from 5-ethynylthiophene-2-carboxylic acid and 3-amino-N-[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]tetrahydro-furan-3-carboxamide with TBTU and NMM in DMF.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:36])([CH3:35])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:42])[CH3:41])(=[O:39])=[O:38])=[N:4][C:5]([NH:8][C:9]2SC(N3CCN(C4C=CC=CN=4)CC3)=NN=2)=[N:6][CH:7]=1.[N:43]1([C:49]2[S:50][CH:51]=[C:52](CN)[N:53]=2)[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>>[Cl:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([P:33]([CH3:35])([CH3:36])=[O:34])=[CH:29][C:28]=2[S:37]([CH:40]([CH3:42])[CH3:41])(=[O:38])=[O:39])=[N:4][C:5]([NH:8][CH2:9][C:52]2[N:53]=[C:49]([N:43]3[CH2:44][CH2:45][O:46][CH2:47][CH2:48]3)[S:50][CH:51]=2)=[N:6][CH:7]=1
Reactant: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(Nc2nnc(N3CCN(c4ccccn4)CC3)s2)ncc1Cl
Reactant: NCc1csc(N2CCOCC2)n1
Product: CC(C)S(=O)(=O)c1cc(P(C)(C)=O)ccc1Nc1nc(NCc2csc(N3CCOCC3)n2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[4-(dimethylphosphoryl)-2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as described in Example 53) with 1-[2-(morpholin-4-yl)-1,3-thiazol-4-yl]methanamine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([O:21]C)=O)=[CH:15][CH:16]=1)=[O:11])([CH3:4])([CH3:3])[CH3:2].[NH2:35][C:36]([NH2:38])=[NH:37]>O1CCCC1>[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:8][NH:9][C:10]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](=[O:21])[NH:37][C:36]([NH2:38])=[NH:35])=[CH:15][CH:16]=1)=[O:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)s1
Reactant: N=C(N)N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(CCC(=O)NC(=N)N)s1)NC(=O)OCc1ccccc1
Yield: 10.5 %

Procedure:
0.272 g (0.55 mmol) of the product obtained in step c) were suspended in 30 ml of dry tetrahydrofuran. 0.168 g (2.75 mmol) of guanidine (free base) were added. The resulting suspension was heated under reflux for 2.5 hours. The solvents were removed in vacuo and the residue was dissolved in 200 ml dichloromethane. The resulting solution was washed four times with 30 ml each of water. The organic phase was then dried with dry magnesium sulfate, filtered off and evaporated. 30 mg of a resinous material were obtained which was sufficiently pure for use in the subsequent step.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:13])[NH:10][C:9](=[O:11])[CH2:8][C:7]1=[O:12].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:12][C:7]1[C:6]([CH3:13])([CH3:5])[NH:10][C:9](=[O:11])[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC1(C)NC(=O)CC1=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1=CC(=O)NC1(C)C
Reaction time: 24 h
Yield: 18.7 %

Procedure:
At 0 to 5° C., a solution of 4.08 g of acetyl chloride in 20 of methylene chloride is added dropwise to a solution of 6.36 g of 5,5-dimethylpyrrolidine-2,4-dione and 5.57 g of triethylamine in 50 ml of methylene chloride. The mixture is then left to reach room temperature over the course of approximately one hour and then stirred for a further 24 hours. The reaction mixture is then diluted with 50 ml of methylene chloride, and extracted by shaking twice with in each case 50 ml of water, twice with in each case 25 ml of 5% strength sodium hydroxide solution and once with 50 ml of saturated aqueous NaCl solution. Drying and concentration by evaporation gives 1.58 g of the title compound in a purity according to HPLC of 97%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: OCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. ES-MS m/e (%): 294 (M+H+, 100).