Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][CH2:5][CH2:6][N:7]1[C:11](=[S:12])[NH:10][N:9]=[N:8]1)(=O)C.[ClH:13]>>[ClH:13].[NH2:4][CH2:5][CH2:6][N:7]1[C:11](=[S:12])[NH:10][N:9]=[N:8]1
Reactant: CC(=O)NCCn1nn[nH]c1=S
Agent: Cl
Product: NCCn1nn[nH]c1=S
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A mixture of 21.5 g. (11.4 mmol) of 1-[2-(acetylamino)ethyl]-1,4-dihydro-5H-tetrazole-5-thione in 300 ml. of 6N hydrochloric acid was heated at reflux for 3.5 hours. The mixture was filtered after cooling to room temperature. The filtrate was concentrated to small volume. The residual liquid was diluted with i-propanol. The solid which precipitated was filtered, washed and dried in vacuo to give 13.7 g. of 1-(2-aminoethyl)-1,4-dihydro-5H-tetrazole-5-thione, hydrochloride (66.1% yield) mp 232°-233.5° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:46]=1[Cl:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[C:49]([F:51])[CH:48]=[CH:47][C:46]=3[Cl:52])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Fc1ccc(Cl)c(CBr)c1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cc(F)ccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)-1-chloro-4-fluorobenzene and isolated as light-yellow gum (4.0 mg, 23%). MS (m/e): 425.3 (MH+).
Reaction SMILES: Br.C([O:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[O:15])=[CH:12][C:11]=1[O:25][CH3:26])C1C=CC=CC=1>C(O)(=O)C>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14](=[O:15])[C:13]1[CH:23]=[CH:24][C:10]([OH:9])=[C:11]([O:25][CH3:26])[CH:12]=1
Reactant: COc1cc(C(=O)c2ccccc2F)ccc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2ccccc2F)ccc1O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
170 ml of 33 percent hydrobromic acid in glacial acetic acid are added at 20°-25° within 20 minutes to 42.4 g of 4-(benzyloxy)-2'-fluoro-3-methoxybenzophenone (dissolved in 450 ml of methylene chloride). After stirring at 20° for 1.5 hours, the reaction mixture is poured into 750 ml of ice-water; the methylene chloride phase is separated and the aqueous phase is extracted twice more with 200 ml of methylene chloride. The combined methylene chloride phases are washed with 1200 ml of water, dried over sodium sulfate and evaporated. In order to remove the resulting benzyl bromide, the oily residue is treated with hexane and decanted off. There is obtained 2'-fluoro-4-hydroxy-3-methoxybenzophenone as a yellowish oil which can be used directly in the subsequent reaction step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CC([O-])(C)C.[K+].[C:18]([O:22][C:23](=O)[O:24]C(C)(C)C)([CH3:21])([CH3:20])[CH3:19].Cl>CN(C=O)C.O>[C:18]([O:22][C:23]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[C:10]([F:11])[CH:9]=2)[CH:5]=[CH:6]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: Fc1cc2[nH]ccc2cc1Br
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2cc(Br)c(F)cc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a solution of 2.1 g (9.81 mmol) 5-Bromo-6-fluoro-indole in 35 ml of DMF were added 1.54 g (13.76 mmol) KOtBu and 3.0 g (13.76 mmol) Di-tert.butylcarbonate, and the solution was stirred for 1 hr at room temperature and 30 min at 60° C. The mixture was poured into water, acidified with 2M aqueous HCl and extracted with Et2O. Drying of the organic layers with MgSO4, evaporation of the solvent, and chromatography on silica gel with hexane/EtOAc 49:1 gave 2.6 g (84%) 5-Bromo-6-fluoro-indole-1-carboxylic acid tert-butyl ester as a colorless liquid, MS: 313 (M, 1Br).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([Br:21])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(Br)cc2)CCN(Cc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Brc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A mixture of 121.6 g (0.35 mol) of 1-benzyl-4-(4-bromo-phenyl)-piperidin-4-ol and 121.6 g of p-toluenesulphonic acid monohydrate (0.64 mol) in 1200 ml of toluene was heated to reflux on a water separator for 4.5 hours. Subsequently, the reaction mixture was cooled to room temperature and adjusted to pH 10 with 3N sodium hydroxide solution. Thereafter, the mixture was extracted firstly with 200 ml and then with 500 ml of methylene chloride. The combined organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and then evaporated under reduced pressure. There were obtained 109.1 g (99% of theory) of 1-benzyl-4-(4-bromo-phenyl)-1,2,3,6-tetrahydro-pyridine as a yellowish solid; MS: 328, 330 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:22][C:23]([NH2:25])=[S:24].C([O-])(=O)C.[Na+].C(O)C>O>[NH2:25][C:23]1[S:24][CH:2]=[C:3]([C:4](=[N:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:22]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)C(=O)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NOCc1ccc(Cl)cc1Cl)c1csc(N)n1
Yield: 32.1 %

Procedure:
Ethyl 4-chloro-2-(2,4-dichlorobenzyloxyimino)-3-oxobutyrate (syn isomer, 37.3 g.), thiourea (8.1 g.), sodium acetate (8.7 g.), ethanol (100 ml.) and water (100 ml.) were treated in a similar manner to that of Example C-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-(2,4-dichlorobenzyloxyimino)acetate (syn isomer, 12.7 g.).
Reaction SMILES: [CH2:1]=O.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]4[CH:33]=[N:32][C:31]5[C:26](=[CH:27][C:28]([O:34][CH3:35])=[CH:29][CH:30]=5)[N:25]=4)[CH2:17][CH2:16]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1>>[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:15]3[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][S:23][C:24]4[CH:33]=[N:32][C:31]5[C:26](=[CH:27][C:28]([O:34][CH3:35])=[CH:29][CH:30]=5)[N:25]=4)[CH2:19][CH2:20]3)[CH3:1])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: C=O
Reactant: COc1ccc2ncc(SCCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)nc2c1
Product: COc1ccc2ncc(SCCN3CCC(N(C)Cc4ccc5c(c4)OCCO5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow foam (30 mg, 29% yield) following Scheme 3 and in analogy to Example 40 using paraformaldehyde (37 mg, 0.64 mmol 3.0 eq) and (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amine (100 mg, 0.22 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][C:20]#[N:21]>C(#N)C.O>[C:20]([CH2:19][C:13]1[C:12]2[C:16](=[CH:17][CH:18]=[C:10]([NH:9][C:7]([NH:6][C:4](=[O:5])[O:3][CH2:1][CH3:2])=[S:8])[CH:11]=2)[NH:15][CH:14]=1)#[N:21]
Reactant: N#CCc1c[nH]c2ccc(N)cc12
Reactant: CCOC(=O)N=C=S
Solvent: O
Solvent: CC#N
Product: CCOC(=O)NC(=S)Nc1ccc2[nH]cc(CC#N)c2c1
Reaction time: 0.33 h

Procedure:
Ethoxycarbonyl isothiocyanate (1.2 ml) was added dropwise to a stirred solution of 5-amino-1H-indole-3-acetonitrile (1.7 g) in dry acetonitrile (50 ml). After 10 min. the resulting suspension was diluted with water (40 ml) and stirred for 20 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[C:3]=1[CH3:22]>[Pt]=O.C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][C:12]2[N:13]=[C:14]3[C:19]([CH2:18][CH2:17][CH2:16][NH:15]3)=[CH:20][CH:21]=2)[C:3]=1[CH3:22]
Reactant: Cc1c(Cl)ncnc1OCCCc1ccc2cccnc2n1
Agent: O=[Pt]
Solvent: CCO
Product: Cc1c(Cl)ncnc1OCCCc1ccc2c(n1)NCCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.7 %

Procedure:
A sufficient quantity of ethanol to solubilize the product, and 15 mg of platinum oxide are added to 300 mg (0.953 mmoles) of 2-[3-(6-chloro-5-methyl-pyrimidin-4-yloxy)-propyl]-[1,8]naphthyridine. The reaction mixture is then purged under vacuum and surmounted on a balloon flask containing hydrogen. The reaction medium is left under stirring and at ambient temperature for 6 hours then overnight. The reaction mixture is then filtered on Clarcel and concentrated to dryness under reduced pressure (2 kPa). Then 300 mg of expected product is obtained.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[NH:17][C:18](=O)[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(C)(C)C>C(O)(=O)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]2[N:8]([CH2:7][C:6]([OH:5])=[O:28])[C:18]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][C:10]=2[CH:11]=1)#[N:16]
Reactant: CC(C)(C)OC(=O)CNc1ccc(C#N)cc1NC(=O)COc1ccccc1
Solvent: CC(=O)O
Product: N#Cc1ccc2c(c1)nc(COc1ccccc1)n2CC(=O)O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A solution of N-(4-cyano-2-phenoxyacetamidophenyl)glycine tert-butyl ester (6.61 g) in acetic acid (250 ml) was stirred at 80° C. for 12 hours. After completion of the reaction, the solvent was evaporated and to the obtained residue was added trifluoroacetic acid (60 ml), and the mixture was stirred at 50° C. for 30 min. After completion of the reaction, the solvent was evaporated. To the obtained residue were added chloroform and acetone and the resultant solid was collected by filtration and dried under reduced pressure to give the title compound (5.0 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:28][CH2:27][C:5]2[N:6]([CH2:14][CH:15](OS(C)(=O)=O)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:29]([NH2:31])[CH3:30]>O>[CH3:1][N:2]1[CH2:28][CH2:27][C:5]2[N:6]([CH2:14][CH:15]([NH:31][CH2:29][CH3:30])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Reactant: CCN
Solvent: O
Product: CCNC(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C

Procedure:
Methanesulfonicacid-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester (300 mg, 0.75 mmol) in 70% ethylamine in water (15 mL) was heated at 100° C. for 18 h. The reaction mixture was cooled to RT and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (2×20 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by reverse phase chromatography to obtain 55 mg of [2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-ethyl-amine. 1H NMR (DMSO, TFA salt): δ (ppm): 8.5 (d, 2H), 7.3 (d, 1H), 7.2 (m, 3H), 6.9 (d, 1H), 4.7 (m, 2H), 4.43 (m, 2H), 4.1 (d, 1H), 3.3 (m, 1H), 3.0 (m, 2H), 2.85 (d, 6H), 2.8 (m, 1H), 2.5 (m, 2H), 2.3 (s, 3H), 1.22 (s, 3H). Chiral HPLC separates the racemate into enantiomers II-8a-b.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@@H:3]([NH:2][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:21])=[CH:30][CH:29]=3)=[O:32])[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]2)=[O:5])=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Product: O=C(N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
(R)-2-Amino-3-(4-fluoro-phenyl)-1-(4-hydroxy-piperidin-1-yl)-propan-1-one hydrochloride (0.6 mmol) and 5-chloro-1H-indole-2-carboxylic acid (0.6 mmol) were coupled according to Procedure A and the crude product purified by chromatography on silica gel eluted with 50, 75 and 100% ethyl acetate in hexanes. Yield 171 mg, 765%; HPLC (60/40) 4.23 minutes (97%); MS 444/446 (MH+, 100%); TSPMS 444/446 (MH+, 100%);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].[N+](C1C=CC=CC=1)([O-])=O.[C:27](Cl)(=[O:29])[CH3:28].Cl>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:27](=[O:29])[CH3:28])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: Fc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4′-Fluoro-biphenyl (0.03 mol) was added to 1 M AlCl3 in nitrobenzene (40 mL, 0.04 mol) with chilling in an ice bath. Acetyl chloride (0.06 mol) was added dropwise and the mixture stirred overnight at room temperature. The dark solution was poured into a mixture of crushed ice (150 mL), water (25 mL) and HCl (50 mL). The aqueous phase was separated and the nitrobenzene removed by steam distillation to give a dark low melting solid. The solid was recrystallised from aqueous methanol to give the title compound. δC (CDCl3, 62.9 MHz): 26.7, 115.9 (d, J 21.5), 127.1, 129.0 (d, J=7.8), 135.8, 136.0 (d, J 2.9), 144.7, 163.0 (d, J 248.0) and 197.8.
Reaction SMILES: [CH:1]1([O:7][CH2:8][C:9]2[N:14]=[C:13]([S:15][CH3:16])[NH:12][C:11](=O)[CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:20])=O>ClCCl.CN(C)C=O>[Cl:20][C:11]1[CH:10]=[C:9]([CH2:8][O:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:14]=[C:13]([S:15][CH3:16])[N:12]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1nc(COC2CCCCC2)cc(=O)[nH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CSc1nc(Cl)cc(COC2CCCCC2)n1

Procedure:
To a mixture of 6-cyclohexyloxymethyl-2-methylsulfanyl-3H-pyrimidin-4-one (20 mg) in dichloromethane (2 mL) and dimethylformamide (catalytic amount) was added thionyl chloride (47 mg). The mixture was heated at reflux for 1.5 h. The solvent was removed under vacuum to give 4-chloro-6-cyclohexyloxymethyl-2-methylsulfanylpyrimidine, which was used in the next reaction without further purification.
Reaction SMILES: I[C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:12](/B(O)O)=[CH:13]\[CH3:14].C([O-])([O-])=O.[K+].[K+]>CCO.[Pd]>[CH3:11][C:10]1[C:2](/[CH:12]=[CH:13]/[CH3:14])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: C/C=C/B(O)O
Reactant: Cc1cccc(C(=O)O)c1I
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C/C=C/c1c(C)cccc1C(=O)O
Yield: 105.1 %

Procedure:
To a solution of 2-iodo-3-methyl-benzoic acid (708 mg, 2.70 mmol) and trans-1-propen-1-ylboronic acid (526 mg, 6.12 mmol) in EtOH (10 mL) is added palladium anchored homogeneous catalyst, FibreCatPd(0) (4.84% Pd, 235 mg, 0.15 mmol) and 2M aqueous solution of K2SO4 (3.06 mL, 6.12 mmol). The resulting reaction mixture is covered with argon and run in a microwave reaction: 110° C., 7 h. After concentration in vacuo, the residue is purified by HPLC to give a pure product (162) as a pale yellow solid (500 mg, 93%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][O:5][C:4]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17]CC)=O)[C:3]1=2.[NH2:20][CH2:21][CH:22]([OH:34])[CH2:23][N:24]1[CH2:33][CH2:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25]1>CCO>[CH2:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:33][N:24]1[CH2:23][CH:22]([OH:34])[CH2:21][NH:20][C:15](=[O:17])[CH2:14][O:13][C:12]1[C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH2:6][O:5][C:4]=2[CH:9]=[CH:10][CH:11]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COc1cccc2c1N(C)C(=O)CO2
Solvent: CCO
Product: CN1C(=O)COc2cccc(OCC(=O)NCC(O)CN3CCc4ccccc4C3)c21
Yield: 27.9 %

Procedure:
A reaction vessel containing a mixture of ethyl 2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yloxy)acetate (43.0 mg, 0.162 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl) propan-2-ol (33.0 mg, 0.163 mmol) and EtOH (0.5 mL) was placed in a microwave reactor and the mixture irradiated at external temperature of 120° C. for 1 h. The reaction mixture was purified in two steps by preparative TLC followed by preparative HPLC to render the title product (19.2 mg, 19% yield)
Reaction SMILES: [CH2:1]1[O:12][C:11]2[C:3](=[C:4]([C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[O:2]1.C(OCC)(OCC)O[CH2:18][CH3:19]>>[CH2:1]1[O:12][C:11]2[C:3](=[C:4]([C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=2)[C:5]([O:7][CH2:18][CH3:19])=[O:6])[O:2]1
Reactant: O=C(O)c1c([N+](=O)[O-])ccc2c1OCO2
Reactant: CCOC(OCC)OCC
Product: CCOC(=O)c1c([N+](=O)[O-])ccc2c1OCO2
Yield: 67 %

Procedure:
Following the procedure employed in Example 15, condensation of 2,3-methylenedioxy 6-nitrobenzoic acid (10 g) with 40 ml of triethyl orthoformate gives the title compound in 67% yield after ethanol crystallization.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14]S(C)(=O)=O)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[O:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][O:31][CH2:32][CH2:33][N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[C:43]([CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44]>>[CH3:1][N:2]([CH2:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][CH2:14][N:48]1[CH2:47][CH2:46][CH:45]([C:43]([C:35]2[N:34]([CH2:33][CH2:32][O:31][CH2:30][C:26]3[O:25][CH:29]=[CH:28][CH:27]=3)[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=2)=[O:44])[CH2:50][CH2:49]1)[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(CC(CCS(C)(=O)=O)c1ccccc1)C(=O)c1ccccc1
Reactant: O=C(c1nc2ccccc2n1CCOCc1ccco1)C1CCNCC1
Product: CN(CC(CCN1CCC(C(=O)c2nc3ccccc3n2CCOCc2ccco2)CC1)c1ccccc1)C(=O)c1ccccc1

Procedure:
Prepare by the method of Example 1.7 using N-methyl-N-(2-phenyl-4-methanesulfonylbutyl)benzamide and 4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[NH:6][CH:7]=[N:8]2)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22]Cl>CN(C)C(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22][N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][CH:11]=[N:12][C:4]=2[NH:3][CH2:1][CH3:2]
Reactant: CCNc1ncnc2nc[nH]c12
Reactant: Fc1cccc(Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCNc1ncnc2c1ncn2Cc1c(F)cccc1Cl
Yield: 34.1 %

Procedure:
In a procedure analogous to that of Example 9, by using 1.63 g of 6-ethylaminopurine, 1.38 g of potassium carbonate, 50 ml of N,N-dimethylacetamide and 3.58 g of 2-chloro-6-fluorobenzyl chloride, there was obtained 1.04 g of 9-(2-chloro-6-fluorobenzyl)-6-ethylaminopurine as colorless needles (yield: 34%), m.p. 175°-176° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:26][C:25](=[O:27])[C:24]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][N:22]=5)[CH:17]=[CH:16][C:15]=4[N:14]=3)=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:32](#[N:34])C.O.CN>[Cl-].[Na+].O>[CH3:32][NH:34][C:25]([C:24]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:28]([F:30])([F:31])[F:29])[CH:11]=2)=[O:26])=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)=[O:27]
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3cccnc3c12
Reactant: CC#N
Agent: CN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CNC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2cccnc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a suspension of 140 mg (0.28 mmol) of the above 2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-oxa-1,5-diaza-phenanthren-4-one in 5.60 mL of a mixture acetonitrile: H2O 4:1 (v/v) is added 74 μL (0.85 mmol) of methylamine (solution 40% in water). The reaction mixture is stirred for 6 hours at ambient temperature. Brine is then added to the mixture and the product is extracted with ethyl acetate (3 times). The regrouped organic phases are dried on Na2SO4, filtrated and evaporated. The purification of the residue by flash chromatography (SiO2, heptane and ethyl acetate as eluants) affords 84 mg (62%) of a white solid; LC/MS:475/477 (M+H)+, m.p.: 219-220° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][CH:10]=[C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:12]=1[CH3:13])=[O:7])C>O1CCOCC1.O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][C:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[NH:9][CH:10]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1[nH]cc(CCc2ccc(Cl)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(CCc2ccc(Cl)cc2)c[nH]c1C(=O)O
Temperature: 80 °C
Yield: 66 %

Procedure:
Freshly prepared aq. NaOH (1M in H2O, 10 equivalents) was added at room temperature to a stirred solution of 86 (1 equivalent) in a mixture of 1,4-dioxane and H2O (v/v 3:1). The reaction was heated to 80° C. until the reaction was judged complete by TLC. The product was extracted with Et2O, then the aqueous layer was made acid (pH=1) with the dropwise addition of 10% aq. HCl. The solid was filtered off and washed with water. The solid was dried under vacuum overnight to obtain 87. Yield: 66%. 1H-NMR (400 MHz, CD3OD): δ 2.19 (s, 3H), 2.69 (m, 2H), 2.78 (m, 2H), 6.58 (d, 1H), 7.11 (d, 2H), 7.22 (d, 2H) ppm. LC/MS: 100%, m/z=263. HPLC (200-400 nm): 95.93%