Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13]>N1C=CC=CC=1>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NCCCCN
Reactant: Brc1ccccn1
Solvent: c1ccncc1
Product: NCCCCNc1ccccn1
Yield: 67 %

Procedure:
2-Bromopyridine (10 g), 1,4-diaminobutane (35 ml) and pyridine (7 ml) were heated together under reflux for 4 hr. The mixture was stripped to remove the excess of diaminobutane and the residue taken up in water. The solution was extracted with chloroform at pH 7 and 13. After drying (K2CO3) the latter extract was stripped and the residue distilled at reduced pressure to give 2-(4-amino-butylamino) pyridine 7.0 g (67%) bp 136°-38° C., 2 mm Hg. (ii) A mixture of sodium hydride (0.78 g) and 2-(4-aminobutylamino) pyridine (4.9 g) in DMSO (45 ml) was heated slowly to 85° C. under nitrogen. After the evolution of hydrogen had ceased the solution was cooled to room temperature and methyl iodide (2.1 ml) in DMSO (10 ml) added dropwise below 25° C. After a further 1.5 hr the mixture was poured into water (150 l) and extracted with dichloromethane. The volume of the extract was reduced and washed with 2N hydrochloric acid. Partitioning between water, ether and dichloromethane at pH 1 and 13 gave, on stripping the final basic extract, 2-[N-(4-aminobutyl)-N-methylamino]pyridine (3.22 g) as an oil which was used without further purification. (iii) 2-[N-(4-aminobutyl)-N-methylamino]pyridine (0.81 g) and 2-methylthio-5-(4-chlorobenzyl)pyrimid-4-one (1.0 g) were heated together under reflux in pyridine (2.5 ml) for 23 hr. After stripping, the residue was crystallised twice from ethanol/water to give 2-[4-(N-methyl-N-pyrid-2-ylamino)butylamino]-5-(4-chlorobenzyl)pyrimid-4-one 1.5H2O, 0.98 g (62%) mp softens 72-75 melts 133°-35° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH2:26])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:35](=[O:37])[CH3:36])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)4-)-4-[4-[5-(aminomethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 8, 9.45 g) in dry methylene chloride (96 mL) under N2 is treated with pyridine (5.82 mL) and acetic anhydride (3.40 mL), and the resulting mixture is stirred at ambient temperature for four hours, diluted with methylene chloride (25 mL), washed with water (25 mL), saturated aqueous sodium bicarbonate (25 mL) and saline (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is then chromatographed on silica gel (230-400 mesh, 350 g), eluting with a gradient of methanol/chloroform (2.5/97.5-7.5/92.5). Pooling and concentration of those fractions with an Rf=0.51 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 144-146° C.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][N:14]1[C:18]([CH2:23][CH:24]([CH3:26])[CH3:25])([CH2:19][C:20](O)=[O:21])[C:17](=[O:27])[N:16]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:15]1=[O:36].Cl.[CH2:38]([O:45][NH2:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CN1CCOCC1>C(Cl)Cl>[CH2:38]([O:45][NH:46][C:20](=[O:21])[CH2:19][C:18]1([CH2:23][CH:24]([CH3:25])[CH3:26])[C:17](=[O:27])[N:16]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:15](=[O:36])[N:14]1[CH3:13])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)CC1(CC(=O)O)C(=O)N(CCc2ccccc2)C(=O)N1C
Reactant: NOCc1ccccc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CC1(CC(=O)NOCc2ccccc2)C(=O)N(CCc2ccccc2)C(=O)N1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
CDI (57.0 mg, 0.352 mmol) is added to a solution of 3-methyl-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetic acid (113 mg, 0.340 mmol) and CH2Cl2 (2.5 mL). The solution is stirred for 1 hour at room temperature and then O-benzyl hydroxylaminehydrochloride (67.0 mg, 0.420 mmol) and N-methylmorpholine (46 μL, 0.42 mmol) are added. The solution is stirred for 60 hours at room temperature. Basic workup (CH2Cl2, NaHCO3, MgSO4) and purification by flash chromatography (1:1 hexane:EtOAc) provides 94.8 mg (64%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.ClC(Cl)(Cl)C(=N)O[C:15]([CH3:18])([CH3:17])[CH3:16].[Cl-].[Na+].C(OCC)(=O)C>O1CCCC1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:9])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Reactant: Cc1cnc(C(=O)O)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cnc(C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A boron trifluoride-diethyl ether complex (91.7 μL) was added dropwise to a suspension of 2-methylpyrazine-5-carboxylic acid (1 g) and tert-butyl 2,2,2-trichloroacetimidate (4.75 g) in tetrahydrofuran (20 mL) under ice-cooling. The reaction solution was warmed to room temperature, followed by stirring for two hours. A saturated sodium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the insoluble matter was separated by filtration. The filtrate was concentrated and purified by silica gel column chromatography to obtain the title compound (1.4 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([CH3:27])([CH2:25][CH3:26])[C:22]([OH:24])=[O:23].N(C(OCC)=O)=NC(OCC)=O.[C:40]([CH:44]([O:66][SiH:67]([CH3:69])[CH3:68])[C:45]1[C:46]([CH:63]([CH3:65])[CH3:64])=[N:47][C:48]([CH:60]([CH3:62])[CH3:61])=[C:49]([CH2:58]O)[C:50]=1[C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=1)([CH3:43])([CH3:42])[CH3:41]>O1CCCC1>[C:40]([CH:44]([O:66][SiH:67]([CH3:69])[CH3:68])[C:45]1[C:46]([CH:63]([CH3:64])[CH3:65])=[N:47][C:48]([CH:60]([CH3:61])[CH3:62])=[C:49]([CH2:58][O:23][C:22](=[O:24])[C:21]([CH3:27])([CH3:20])[CH2:25][CH3:26])[C:50]=1[C:51]1[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CCC(C)(C)C(=O)O
Reactant: CC(C)c1nc(C(C)C)c(C(O[SiH](C)C)C(C)(C)C)c(-c2ccc(F)cc2)c1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)OCc1c(C(C)C)nc(C(C)C)c(C(O[SiH](C)C)C(C)(C)C)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
865 mg (3.3 mmol) of triphenylphosphine, 0.41 ml (3.3 mmol) of 2,2-dimethylbutyric acid and 0.52 ml (3.3 mmol) of diethyl azodicarboxylate are added successively at 0° C. to 1.29 g of the compound from Example 6 in 50 ml of absolute tetrahydrofuran and the mixture is stirred overnight at room temperature. The mixture is concentrated in vacuo and t he residue is chromatographed on a column (silica gel 70-230 mesh, using ethyl acetate/petroleum ether 1:9).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31](Cl)(=O)C.C[Mg]Br.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.C(OCC)(=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C@H:11]1[CH2:24][C:25]1[CH:26]=[CH:27][N:28]=[C:29]([CH3:31])[CH:30]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccncc2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CC(=O)Cl
Agent: C[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C[C@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)ccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(pyridin-4-ylmethyl)oxazolidine-3-carboxylate (0.150 g, 0.344 mmol) was dissolved in THF (3.5 mL) and cooled to 0° C. Acetyl chloride (0.0256 ml, 0.361 mmol) was added and the reaction was stirred 30 minutes before METHYLMAGNESIUM BROMIDE (0.294 ml, 0.412 mmol) was added. The reaction was stirred 1 hr. at 0° C. and then warmed to RT and quenched with saturated ammonium chloride and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with a 9:1 aqueous solution of saturated ammonium chloride/ammonium hydroxide, water, brine, and dried over sodium sulfate. The crude product was dissolved in isopropylacetate (4 mL) and heated to 50° C. before DDQ (0.117 g, 0.515 mmol) was added. After 30 minutes the reaction was cooled and diluted with ethyl acetate and washed twice with saturated sodium bicarbonate, once with water, brine, and dried over sodium sulfate. The mixture was passed through a plug of silica gel with 2:1 Hexanes/EtOAc and concentrated to afford the title compound, MS m/z: 451.3 (100%, M+1)).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14].[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[CH3:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.2 %

Procedure:
Triethylamine (2.91 g, 28.86 mmol) was added to the stirred solution of 4-methoxy-1-butanol (1.00 g, 9.62 mmol) in dichloromethane (15 mL) at 0° C. and stirred for 15 min. p-Toluene sulfonyl chloride (1.83 g, 9.62 mmol) was added and the mixture was warmed to ambient temperature and stirred for 2 h. The reaction mixture was quenched with ice-water and the organic layer was separated. The aqueous layer was extracted with dichloromethane (3×5 mL) and the combined organic layers were washed with saturated sodium bicarbonate, water, and brine; dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product was purified by column chromatography over silica gel (60-120 mesh) with 0% to 20% ethyl acetate in petroleum ether as eluent to afford 4-methoxybutyl-4-methylbenzenesulfonate (800 mg, 32%) as a liquid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C:7]([CH3:31])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][C:18]([C:20]2[CH:21]=[N:22][N:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:24]=2)=O)[N:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CO>O1CCCC1>[C:1]([O:5][C:6](=[O:32])[C:7]([CH3:8])([S:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][CH2:16][NH:17][CH2:18][C:20]2[CH:21]=[N:22][N:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:24]=2)[N:14]=1)[CH3:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNC(=O)c2cnn(-c3ccccc3)c2)cs1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNCc2cnn(-c3ccccc3)c2)cs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.4 %

Procedure:
2-Methyl-2-{[4-(2-{[(1-phenyl-1H-pyrazol-4-yl)carbonyl]amino}ethyl)-1,3-thiazol-2-yl]thio}propionic acid tert-butyl ester (16.2 g) obtained in Example 451-1 was dissolved in tetrahydrofuran (20 mL), 1 mol/L-borane/tetrahydrofuran complex (160 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was ice-cooled, and methanol (200 mL) was added dropwise. After warming to room temperature, the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, piperidine (60 mL) was added, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; dichloromethane:methanol=20:1 to 10:1) to give the title compound (9.5 g) as a slightly yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12](=[O:25])[NH:13][CH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.C(Cl)Cl>C(O)(C(F)(F)F)=O>[NH2:7][C@H:8]([CH:9]([CH3:11])[CH3:10])[C:12]([NH:13][CH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)=[O:25]
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=O)NCCc1ccc2c(c1)OCO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@@H](N)C(=O)NCCc1ccc2c(c1)OCO2
Yield: 83.3 %

Procedure:
[1-(2-Benzo[1,3]dioxol-5-yl-ethylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester (447.1 mg, 1.23 mmol) was dissolved in 1:1 TFA:DCM (6 mL) and stirred at room temperature for 3 hours. After this time, the solvent was removed by vacuum. The crude material was dissolved in DCM (75 mL) and washed with 1M NaOH (aq) (75 mL) to afford the crude product as the freebase. The product was purified by Flash Chromatography (0-10% methanol/DCM gradient) to afford 270.7 mg (83.5%) of the pure product, 2-amino-N-(2-benzo[1,3]dioxol-5-yl-ethyl)-3-methyl-butyramide. [M+H]+ 265.1
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([CH3:33])[CH:24]=[CH:23][C:22]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])=[CH:21][CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30]([C:26]3[N:27]=[CH:28][O:29][C:25]=3[C:22]3[CH:23]=[CH:24][C:19]([CH3:33])=[CH:20][CH:21]=3)=[O:31])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1ccc(-c2ocnc2C(=O)O)cc1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccc(C)cc3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-p-tolyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.04 min; [M+H]+=391.15.
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35].C(N(C(C)C)C(C)C)C.[CH3:46][N:47]([CH3:52])[CH2:48][CH2:49][CH2:50][NH2:51]>CN(C)C=O>[F:1][C:2]1([F:36])[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH:51][CH2:50][CH2:49][CH2:48][N:47]([CH3:52])[CH3:46])=[O:29])=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35]
Reactant: CN(C)CCCN
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCCCN(C)C)ccc1Nc1ncc2c(n1)N(CCCc1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
To a mixture of 0.05 g (0.10 mmole) of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-281), 0.07 mL (0.40 mmole) of ethyldiisopropyl amine and 0.0074 g (0.11 mmole) of N,N-dimethyl-propane-1,3-diamine in 2.0 mL of dimethylformamide was added 0.048 g (0.11 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-40:60) gave 0.020 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(3-phenyl-propyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-285) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[N:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:38]3[CH2:39][CH2:40][CH:35]([C:32]4[CH:31]=[CH:30][N:29]=[CH:34][CH:33]=4)[CH2:36][CH2:37]3)=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: c1cc(C2CCNCC2)ccn1
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCC(c3ccncc3)CC2)no1
Yield: 60.1 %

Procedure:
A solution of ethyl 5-{(1R)-1 -[2-(tert-butoxy)-2-oxoethyl]4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (0.50 g, 1.27 mmol) in ethanol (10 ml) was treated with 4-(4-pyridinyl)piperidine (Monatsh.Chem.; 3; 1882; 867) (0.41 g, 2.54 mmol) and the resulting mixture was heated under reflux under a nitrogen atmosphere for 72 hours. Further 4-(4-pyridinyl)piperidine (0.21 g, 1.27 mmol) was added and the mixture heated under reflux for 24 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organic layers were washed sequentially with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99:1) gradually changing to dichloromethane:methanol (95:5) to afford the title compound as a pale yellow oil (0.39 g).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>CC(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[N:3]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CC(C)O
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(Cl)nc21
Reaction time: 8 h

Procedure:
2,6-dichloro-9-isopropyl-9H-purine (1.1 mmol) was mixed with tyramine (1.16 mmol) dissolved in i-PrOH (6 ml) and the mixture was stirred overnight. The reaction mixture was concentrated, and the residue purified by column chromatography on silica gel, eluting with hexane/EtOAc (5:1 to 1:2) to afford the title compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 9.21 (br, 1H), 8.49 (s, 1H), 7.80 (s, 1H), 7.10 (d, 2H), 6.73 (d, 2H), 4.87 (m, 1H), 4.03 (t, 2H), 3.01 (t, 2H), 1.68 (d, 6H); HRMS (EI) calcd for C16H18ClN5O (M+H±) 332.1273, found 332.1278.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]2[C:7]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])=[C:8]([C:10]3[CH:11]=[N:12][NH:13][CH:14]=3)[O:9][C:5]=2[CH:4]=1.ClCCl.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.O=O>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]2[C:7]([C:15]([C:17]3[CH:18]=[C:19]([O:27][CH3:28])[C:20]([O:25][CH3:26])=[C:21]([O:23][CH3:24])[CH:22]=3)=[O:16])=[C:8]([C:10]3[CH:14]=[N:13][N:12]([C:39]4[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=4)[CH:11]=3)[O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c(-c3cn[nH]c3)oc2c1
Reactant: COc1ccc(B(O)O)cc1
Agent: O=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2cc(-c3oc4cc(OC)ccc4c3C(=O)c3cc(OC)c(OC)c(OC)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14.4 %

Procedure:
To an 8 mL screw cap glass vial was added [6-methoxy-2-(1H-pyrazol-4-yl)-benzofuran-3-yl]-(3,4,5-trimethoxyphenyl)-methanone (11 mg, 0.027 mmol), 3 Å molecular sieves, dichloromethane (0.5 mL), cupric acetate (10 mg, 0.054 mmol), 4-methoxy-phenyl boronic acid (9 mg, 0.059 mmol) and pyridine (15 μl, excess) and the capped vial was shaken at room temperature for two days with occasional removal of the cap to expose the mixture to atmospheric oxygen. After this time the reaction mixture was filtered through celite and the filtrate was concentrated and purified by silica-gel flash chromatography (eluent=hexane:ethyl acetate, 3:1) to afford the product as a yellow solid (2 mg, 15% yield). 1H-NMR (CDCl3) δ 8.56 (s, 1H), 8.17 (s, 1H), 7.60 (d, J=8.9 Hz, 2H), 7.15 (s, 2 H), 7.14 (d, J=8.7 Hz, 1H), 7.07 (d, J=2.0 Hz, 1H), 6.96 (d, J=8.9 Hz, 2H), 6.81 (dd, J=8.7, 2.0 Hz, 1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.84 (s, 3H), 3.78 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)(=O)C>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(CC(F)(F)F)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=280.1 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2,2,2-trifluoroethyl mesylate.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][NH:6][NH2:7].C([O:13][C:14](=O)[CH:15]=[C:16]([NH2:20])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:20][C:16]1[NH:7][N:6]([CH2:5][C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[C:14](=[O:13])[CH:15]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1cccc(I)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2cccc(I)c2)[nH]1
Reaction time: 8 h

Procedure:
A solution of 45 g of m-iodobenzylhydrazine in 70 ml of ethanol was added dropwise to a solution of 28.6 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulphonic acid in 350 ml of ethanol. After stirring overnight, the compound identified above had separated out as a precipitate and was filtered off and recrystallised from ethanol. Melting point: 186°, 16 g (28%).