Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([CH:10]1[O:12][CH2:11]1)Br.[OH-].[Na+]>O1CCOCC1>[C:1]1([S:7][CH2:8][CH:10]2[CH2:11][O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCC1CO1
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: c1ccc(SCC2CO2)cc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
A solution of 5.0 g of thiophenol in 30 ml of 1,4-dioxane was added dropwise at room temperature to a mixture of 6 ml of epibromohydrin, 5.45 g of sodium hydroxide and 30 ml of 1,4-dioxane, and then the mixture was stirred at room temperature for 36 hours. At the end of this time, insoluble solids were removed by filtration, the 1,4-dioxane was evaporated from the filtrate, water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extract by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a 1:10 by volume mixture of ethyl acetate and hexane as the eluent, to give 6.78 g of the title compound as a colorless oil having an Rf value of 0.60 (on silica gel thin layer chromatography, using a 1:10 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[CH:12]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][S:22]([CH2:25][CH2:26][NH:27][C:28]([C:30]2[S:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[O:29])(=[O:24])=[O:23])[CH2:17][CH2:16]1)([CH3:14])[CH3:13]>>[CH:12]([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:2][CH2:3][CH2:4][O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][O:7]2)[S:22]([CH2:25][CH2:26][NH:27][C:28]([C:30]2[S:31][C:32]([Cl:35])=[CH:33][CH:34]=2)=[O:29])(=[O:23])=[O:24])[CH2:17][CH2:16]1)([CH3:14])[CH3:13].[CH:6]([O-:7])=[O:5]
Reactant: CC(C)N1CCC(NS(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Reactant: ClCCCOC1CCCCO1
Product: CC(C)N1CCC(N(CCCOC2CCCCO2)S(=O)(=O)CCNC(=O)c2ccc(Cl)s2)CC1
Product: O=C[O-]

Procedure:
5-Chloro-thiophene-2-carboxylic acid (2-{(1-isopropyl-piperidin-4-yl)-[3-(tetrahydro-pyran-2-yloxy)-propyl]-sulfamoyl}-ethyl)-amide was prepared by an analogous procedure as described in example 15 starting from 245 mg (1.5 equiv.) 2-(3-chloro-propoxy)-tetrahydro-pyran and 360 mg (0.91 mmol) 5-chloro-thiophene-2-carboxylic acid [2-(1-isopropyl-piperidin-4-ylsulfamoyl)-ethyl]-amide. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 5-chloro-thiophene-2-carboxylic acid (2-{(1-isopropyl-piperidin-4-yl)-[3-(tetrahydro-pyran-2-yloxy)-propyl]-sulfamoyl}-ethyl)-amide as its formate.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.C(Cl)(Cl)Cl.[CH3:30][OH:31]>C(N)C1OC=CC=1>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:10][CH2:7][C:6]3[O:31][CH:30]=[CH:3][CH:4]=3)=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: CO
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Agent: NCc1ccco1
Solvent: ClC(Cl)Cl
Product: COC12C(CO)C3=C(C(=O)C(C)=C(NCc4ccco4)C3=O)N1CC1NC12
Product: NC(=O)O
Reaction time: 3 h
Yield: 42.7 %

Procedure:
To a solution of 60 mg (0.17 mmol) of mitomycin A in 8 ml of anhydrous methanol, 0.5 ml of furfurylamine was added with stirring. The progress of the reaction was periodically checked by TLC and the reaction appeared to be complete in 3 hours. The solvent was removed by evaporation under reduced pressure and the residue was chromatographed using silica-gel as adsorbent. The fraction obtained by eluting the column with ethyl acetate was evaporated. Recrystallization from a mixture of chloroform and here gave 30 mg (42.7% yield) of the desired product as colored crystals having a melting point of 62°-63° (decomposing) and providing the following analysis:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:36][N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22]C(C)C)=[C:18]([O:26]C(C)C)[CH:17]=1)=[CH:13][C:12]([O:30]C(C)C)=[C:11]([O:34][CH3:35])[CH:10]=2)=[O:5])[CH3:2].O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:36][N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:26])[CH:17]=1)=[CH:13][C:12]([OH:30])=[C:11]([O:34][CH3:35])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC(C)C)cc2c1-c1ccc(OC(C)C)c(OC(C)C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(O)cc2c1-c1ccc(O)c(O)c1
Reaction time: 10 h
Yield: 25.5 %

Procedure:
To a solution of 4-(3,4-diisopropoxyphenyl)-6-isopropoxy-7-methoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (96.0 mg) in dichloromethane (1.0 ml), titanium tetrachloride (TiCl4) (316 mg) was added at 0° C., followed by stirring at the same temperature for 10 hours. The reaction mixture was poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed by sequential additions of a saturated aqueous sodium hydrogen carbonate solution and water and then dried (MgSO4), after which the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (10:1, v/v) to yield 4-(3,4-dihydroxyphenyl)-6-hydroxy-7-methoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (19.0 mg, 26%) having a melting point of 264° to 266° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]=1[C:18]([F:21])([F:20])[F:19].[OH-].[Na+]>CCO.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[C:18]([F:19])([F:20])[F:21]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2′-methyl-2-(trifluoromethyl)biphenyl-4-carboxylate (5.0 g, 17.0 mmol) in EtOH (150 mL) at RT was treated with a 5N aqueous solution of sodium hydroxide (10.2 mL, 51 mmol). The reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated to give a brown solid which was taken up in water (300 mL) and the aqueous phase was washed twice with EtOAc. The aqueous phase was acidified with a concentrated aqueous solution of HCl (pH-2), then it was concentrated until precipitation (half of the volume). The suspension was filtered affording the title compound as a beige solid. 1H NMR (DMSO-d6, 300 MHz) δ 13.55 (br s, 1H), 8.31 (s, 1H), 8.25 (d, J=7.9 Hz, 1H), 7.50 (d, J=7.9 Hz, 1H), 7.37-7.12 (m, 4H), 1.99 (s, 3H). LC/MS (Method A): 278.9 (M−H)−. HPLC (Method A) Rt 4.57 min (Purity: 98.7%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:15]2[C:10]3=[C:11]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=3)[CH:12]=[CH:13][CH:14]=2.C1C(=O)N([Br:30])C(=O)C1.O>C(Cl)Cl.C(#N)C>[Br:30][C:13]1[CH:14]=[C:15]2[C:10]3=[C:11]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[N:9]3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:2]2([CH3:22])[CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)c2ccccc2-n2c3ccccc3c3cccc1c32
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: CC1(C)c2ccccc2-n2c3ccccc3c3cc(Br)cc1c32
Reaction time: 4 h

Procedure:
6.3 g (22.2 mmol) of 8,8-dimethylindolo[3,2,1-de]acridine are initially introduced in 150 ml of CH2Cl2. A solution of 8 g (45.1 mmol) of NBS in 100 ml of acetonitrile is subsequently added dropwise at −15° C. with exclusion of light, and the mixture is allowed to come to room temperature and is stirred at this temperature for a further 4 h. 150 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot hexane and filtered off with suction. Yield: 4.5 g (12 mmol), 57% of theory, purity according to 1H-NMR about 97%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([CH3:17])([CH3:16])[CH2:9][CH:10](O)[CH2:11][N+:12]([O-:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]([CH3:17])([CH3:16])[CH2:9][CH:10]=[CH:11][N+:12]([O-:14])=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(CC(O)C[N+](=O)[O-])NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CC=C[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 57.6 %

Procedure:
To (3-Hydroxy-1,1-dimethyl-4-nitro-butyl)-carbamic acid tert-butyl ester (2.00 g, 7.6 mmol) and triethylamine (2.73 g, 27.0 mmol) in 50 mL CH2Cl2 at −10° C. was added dropwise over 5 min. methanesulfonyl chloride. The mixture was warmed to rt for 1 h, and then was diluted with water and extracted with CH2Cl2 (3×30 mL). The extracts were washed sequentially with 1% HCl, water and brine and were dried over MgSO4 and concentrated. Silica gel chromatography (10:1 hexane/EtOAc) gave 1.07 g (60%) of a colorless oil: 1H NMR (300 MHz, CD3OD) d 7.1–7.4 (comp, 2H), 2.72 (d, 2H, J 7.5 Hz), 1.46(s, 9H), 1.31 (s, 6H).
Reaction SMILES: [CH3:1][C@H:2]([NH:6]C(OC(C)(C)C)=O)[C:3](O)=[O:4].[ClH:14].N[CH:16]1[CH2:22][C:21]([CH3:24])([CH3:23])[CH:20]=[N:19][C:18]2[CH:25]=[CH:26][CH:27]([CH3:30])[C:28](=[O:29])[C:17]1=2.Cl.[NH2:32][C@H](C(NC1CC(C)(C)C=NC2C=CC(C)C(=O)C1=2)=O)C>>[ClH:14].[NH2:6][C@H:2]([C:3]([CH:16]1[CH2:22][C:21]([CH3:24])([CH3:23])[C:20]([NH2:32])=[N:19][C:18]2[CH:25]=[CH:26][CH:27]([CH3:30])[C:28](=[O:29])[C:17]1=2)=[O:4])[CH3:1]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1C=CC2=C(C1=O)C(N)CC(C)(C)C=N2
Reactant: CC1C=CC2=C(C1=O)C(NC(=O)[C@H](C)N)CC(C)(C)C=N2
Agent: Cl
Product: CC1C=CC2=C(C1=O)C(C(=O)[C@H](C)N)CC(C)(C)C(N)=N2

Procedure:
Following the General Procedure H and using N-t-Boc-L-alanine and 5-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride (Example 1-C), 5-(N-t-Boc-L-alaninyl)amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepine-6-one was prepared. Following the General Procedure (Example 1-C, Step B) and using 5-(N-t-Boc-L-alaninyl)amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one, 5-(L-alaninyl)amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride was prepared.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][CH2:17][C:18]1[CH:19]=[C:20]([CH2:26][CH:27]([O:33][CH:34]([CH3:36])[CH3:35])[C:28]([O:30]CC)=[O:29])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>>[CH:34]([O:33][CH:27]([CH2:26][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([CH2:17][NH:16][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)[CH:19]=1)[C:28]([OH:30])=[O:29])([CH3:36])[CH3:35]
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using 4-phenylbenzoic acid and ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 2-isopropoxy-3-(4-methoxy-3-[(4-phenylbenzoyl)amino]methylphenyl)propanoic acid was obtained in the same method as in Example 19d) and then in Example 19e).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([OH:21])[CH:13]=[CH:14][C:15]=3[OH:20])[C:10](=[O:22])[C:9]=2[C:8]([NH:23][CH2:24][CH2:25][NH2:26])=[CH:7][CH:6]=1.C1C=CC=CC=1.[CH:33](=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[NH2:26][CH2:25][CH2:24][NH:23][C:8]1[C:9]2[C:10](=[O:22])[C:11]3[C:16](=[C:15]([OH:20])[CH:14]=[CH:13][C:12]=3[OH:21])[C:17](=[O:19])[C:18]=2[C:5]([NH:4][CH2:3][CH2:2][N:1]=[CH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: NCCNc1ccc(NCCN)c2c1C(=O)c1c(O)ccc(O)c1C2=O
Solvent: c1ccccc1
Product: NCCNc1ccc(NCCN=Cc2ccccc2)c2c1C(=O)c1c(O)ccc(O)c1C2=O

Procedure:
A suspension of 0.0057 mole of the free base, 1,4-bis[(2-aminoethyl)amino]-5,8-dihydroxyanthraquinone (prepared as described in Example 1) in 60 ml of benzene containing 0.0057 mole of benzaldehyde is refluxed and treated as described in the general procedure for Examples 3-20, to give the desired product.
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.S(=O)(=O)(O)O.N.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>CO.C(Cl)Cl.C(C(C)=O)C>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[CH3:34][O:11][CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=2)[CH2:17][CH2:16]1
Reactant: O=C1c2ccccc2C(O)N1CCCN1CCN(c2ccc(O)cc2)CC1
Agent: N
Agent: O=C(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CCC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COC1c2ccccc2C(=O)N1CCCN1CCN(c2ccc(O)cc2)CC1
Reaction time: 5 h
Yield: 66.8 %

Procedure:
The same procedure is followed as in Example 2, but starting from an agitated solution of 3-hydroxy-2-[3-(4-(4-hydroxyphenyl)-1-piperazinyl)propyl]-1-isoindolinone (4.6 g) in methanol (115 cc), to which 22.7 cc of concentrated sulphuric acid is added in the course of 15 minutes and at a temperature close to 20° C. Agitation is continued for 5 hours at a temperature close to 65° C. After cooling the solution to a temperature close to 0° C., 57 cc of a 33% aqueous solution of ammonia is added in the course of 1 hour. The precipitate formed is filtered and washed with methanol (50 cc). The filtrate is diluted with distilled water (200 cc) and a 33% aqueous solution of ammonia (50 cc) and extracted with methylene chloride (4×100 cc). The organic extracts are combined, dried over anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue obtained is dissolved in methylene chloride (20 cc) and the solution is poured onto silica (500 g) contained in a column of 6 cm diameter. Elution is carried out with a mixture of methylene chloride and methanol (97-3 by volume). The first 800 cc are eliminated and the next 3000 cc are evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 50° C. The residue obtained is dissolved in methyl ethyl ketone (35 cc). A solution of oxalic acid (0.8 g) in methyl ethyl ketone (20 cc) is added, and agitation continued for 1 hour at a temperature close to 20° C. The precipitate formed is separated by filtration and recrystallized from boiling acetonitrile (200 cc). 1.4 g of 3-methoxy-2-[3-(4-(4-hydroxyphenyl)-1-piperazinyl)propyl]-1-isoindolinone oxalate are thus obtained, melting at 147° C.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Cl:8][C:9]1[CH:25]=[CH:24][C:23]([N:26]2[C:31](=[O:32])[CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[NH:28][C:27]2=[O:37])=[CH:22][C:10]=1[C:11]([O:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12].[CH2:38](Br)[CH:39]=[CH2:40]>O>[Cl:8][C:9]1[CH:25]=[CH:24][C:23]([N:26]2[C:31](=[O:32])[CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[N:28]([CH2:40][CH:39]=[CH2:38])[C:27]2=[O:37])=[CH:22][C:10]=1[C:11]([O:13][C:14]([CH3:20])([CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12]
Reactant: C=CCBr
Reactant: CCOC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C(=O)OC(C)(C)C(=O)OCC)c2)c1=O

Procedure:
0.35 g of sodium hydride (50% dispersion in white oil) is added to 40 ml of dimethylformamide while stirring. 2.9 g of ethyl 2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-benzoyloxy}-2-methyl-propionate [sic] are added portionwise as the solid. After completion of the addition the mixture is stirred at room temperature for a further hour. 1.2 g of allyl bromide are now added in one portion. The reaction mixture is stirred at room temperature for 18 hours and thereafter introduced into 100 ml of water at 0° C. The mixture is extracted twice with 150 ml of ethyl acetate each time. The organic phases are washed once with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel with ethyl acetate/n-hexane (1:4). There is obtained ethyl 2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-3-(2-propenyl)-4 -trifluoromethyl-1(2H)-pyrimidinyl]-benzoyloxy}-2-methyl-propionate as an oil;
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]([C:24]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)#[N:23]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:27]4[CH2:26][CH2:25][C:24]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)([C:22]#[N:23])[CH2:29][CH2:28]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: N#CC1(c2ccccc2)CCN(C[C@@H](O)COc2ccc(-c3noc4cc(F)ccc34)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-cyano-4-phenylpiperidine in ethanol, essentially as described above in Example 70. Purity by LC/MS=<100%, [M+H]+=472.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11](C3C=CC=CC=3)=O)=[CH:4][C:3]=2[O:2]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[C:29]3[N:33]([C:34]=2[CH:35]=O)[CH:32]=[CH:31][S:30]3)=[CH:23][CH:22]=1.[OH-:37].[Na+]>C(O)C.C(OCC)(=O)C.CCCCCC>[O:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:10](=[O:37])/[CH:11]=[CH:35]/[C:34]3[N:33]4[C:29]([S:30][CH:31]=[CH:32]4)=[N:28][C:27]=3[C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=3)=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: COc1ccc(-c2nc3sccn3c2C=O)cc1
Reactant: O=C(Cc1ccc2c(c1)OCO2)c1ccccc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc3sccn3c2/C=C/C(=O)c2ccc3c(c2)OCO3)cc1
Temperature: 27 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a stirred solution 3,4-methylenedioxy phenyl acetophenone (164 mg, 1.0 mmol) and a 6-(4-methoxyphenyl)imidazo[2,1-b]thiazol-5-carbaldehyde (258 mg, 1.0 mmol) in ethanol (20 ml) 10% aqueous solution of NaOH was added (5 ml). The reaction mixture was stirred at room temperature 27° C. for 4 h and the reaction was monitored by TLC using ethyl acetate-hexane (3:7) as a solvent system. The solvent was evaporated under vacuum then the residue was dissolved in ethylacetate/water. The organic layer was washed with brine and evaporated. This was further purified by column chromatography using ethyl acetate:hexane (2:8) as a solvent system to obtain the pure product (11a) as yellow solid (323 mg, 80% yield). Mp: 189-191° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[C:3]1[CH3:11].C(N(CC)CC)C.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[CH3:21][Si:20]([CH3:23])([CH3:22])[O:1][C@H:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][C:9]#[CH:10])=[C:3]1[CH3:11]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC1=C(C)[C@@H](O)CC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCC1=C(C)[C@@H](O[Si](C)(C)C)CC1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
1 To a solution of (S)-4-hydroxy-3-methyl-2(2-propynyl)-cyclopent-2-ene-1-one (12.88 g) and triethylamine (13.2 g) in tetrahydrofuran (200ml) was added dropwise chlorotrimethylsilane (10.4 g) for 5 minutes under ice-water cooling, then the solution was stirred for 2 hours under ice-water cooling, and 13 hours at room temperature. Then this solution was poured into ice-water and extracted twice with diethyl ether. The ether layers were combined and washed twice with brine. The separated organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resultant residue was subjected to column chromatography over florisil (eluent; n-hexane:ethyl acetate=20:1) to afford (S)-4-trimethylsilyloxy-3-methyl-2-(2-propynyl )-cyclopent-2-ene-1-one (18.0 g, yield 79.1% ) as a pale yellow oil.
Reaction SMILES: CO.S([O:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([OH:18])[CH3:17])[C:11]([O:19][CH3:20])=[CH:10][C:9]=1[CH3:21])(=O)(=O)C.[OH-].[Na+].C(O)(=O)C>O>[CH3:21][C:9]1[CH:10]=[C:11]([O:19][CH3:20])[C:12]([NH:14][CH2:15][CH:16]([OH:18])[CH3:17])=[CH:13][C:8]=1[OH:7]
Reactant: COc1cc(C)c(OS(C)(=O)=O)cc1NCC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: COc1cc(C)c(O)cc1NCC(C)O
Yield: 83.2 %

Procedure:
Into 100 ml of methanol was added 2.0 g (13.1 mmol) of 2-methyl-4-methoxy-5-(2-hydroxypropyl)aminophenyl mesylate. After conducting nitrogen substitution at room temperature, 40 ml of 7.5N aqueous solution of sodium hydroxide was added to the mixture and the resulting mixture was heated under reflux for 7 hours with blowing nitrogen gas thereinto. After allowing to cool, the mixture was neutralized with acetic acid and poured into 400 ml of water. The resulting solution was extracted with 400 ml of ethyl acetate. The organic layer was washed with a saturated aqueous solution of common salt and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily matter. The oily matter was crystallized from the solvent mixture of hexane/ethyl acetate (1:1 by volume) to give 2.30 g (10.9 mmol) of 2-methyl-4-methoxy-5-(2-hydroxypropyl)aminophenol. The yield was 49%.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[CH2:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1.CN1C(=O)N(C)CC1>[CH2:19]([NH:26][C:27]([NH:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=NCc1ccccc1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CN1CCN(C)C1=O
Solvent: C1COCCO1
Product: O=C(NCc1ccccc1)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With the exclusion of moisture, 261 mg (1.00 mmol) of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) are dissolved in 2.5 ml of dioxane and 1 ml of DMEU; 138 μl (1.1 mmol) of benzyl isocyanate are added and the reaction mixture is stirred at RT overnight. The dioxane is evaporated off from the reaction mixture in a rotary evaporator. The resulting yellow solution is poured into 75 ml of water and the product that precipitates is filtered off. Stirring in boiling ethyl acetate yields 3-(benzylamino-carbonylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine; HPLC:tRet(grad20-100)=9.5; FAB-MS: (M+H)+=394.