Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Sn]1(CCCC)[O:14][CH2:13][C:8]2([CH2:12][CH:11]=[CH:10][CH2:9]2)[CH2:7][O:6]1)CCC.[CH2:19]([C:21]1([CH2:28][CH3:29])[CH2:26][O:25][C:24](=S)[O:23][CH2:22]1)[CH3:20]>>[CH2:19]([C:21]1([CH2:28][CH3:29])[CH2:26][O:25][C:24]2([O:6][CH2:7][C:8]3([CH:9]=[CH:10][CH2:11][CH2:12]3)[CH2:13][O:14]2)[O:23][CH2:22]1)[CH3:20]
Reactant: CCCC[Sn]1(CCCC)OCC2(CC=CC2)CO1
Reactant: CCC1(CC)COC(=S)OC1
Product: CCC1(CC)COC2(OCC3(C=CCC3)CO2)OC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72 %

Procedure:
To the above solution of 8,8-dibutyl-7,9-dioxa-8-stannaspiro[4.5]dec-2-ene 4 was added 5,5-diethyl-1,3-dioxane-2-thione 1 (10.1 g, 60.3 mmol) in several small portions at room temperature over a period of 20 min. The resulting mixture was allowed to stir at room temperature for 24 hours. The reaction was monitored by TLC (silica gel, 25% ether/hexanes). The reaction mixture was then concentrated under reduced pressure and the residue taken up with ethyl ether (white suspension formed upon standing). The ether solution was filtered and concentrated under reduced pressure to give light yellowish oil. The crude material was purified by column chromatography (silica gel, 10-15% ethyl ether/hexanes). The desired 11,11-diethyl-7,9,13,14-tetraoxadispiro[4.2.5.2]pentadec-1-ene (DECP 5) was obtained as white solid in 72% yield. Mp (DSC) 95.19° C., 1H-NMR (CD13, 300 MHz) δ 5.60 (s, 2H), 3.80 (s, 4H), 3.69 (s, 4H), 2.27 (s, 4H), 1.45-1.37 (q, 4H, J=7.8 Hz), 0.82-0.77 (t, 6H, J−7.8 Hz); 13C-NMR (CD13, 300 MHz) δ 128.52, 114.39, 71.04, 69.48, 39.76, 34.33, 23.16, 7.12; FT-IR (Kbr pellet) (cm−1) 3053, 2968, 1619, 1457, 1360, 1266, 1212, 1178, 1001, 938; Anal. Calcd for C1H24O4: C, 67.14; H, 901; Found: C, 67.44; H, 9.22.
Reaction SMILES: CN(C)[C:3](=[O:28])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:14]([F:26])[C:13]=1[F:27].[OH-:30].[Na+]>CCO.O>[F:18][C:17]1[C:16]([F:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]([F:26])=[C:13]([F:27])[C:12]=1[NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH2:4][C:3]([OH:30])=[O:28]
Reactant: CN(C)C(=O)Cc1ccccc1Nc1c(F)c(F)c(-c2ccccc2)c(F)c1F
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccccc1Nc1c(F)c(F)c(-c2ccccc2)c(F)c1F

Procedure:
A mixture of N,N-dimethyl-2-(2′,3′,5′,6′-tetrafluoro-4′-phenylanilino)phenylacetamide (2.7 g, 6.7 mmol) and NaOH (3.0 g, 72 mmol) in EtOH (100 mL) and water (20 mL) is heated at reflux temperature for 14 hours. After cooling to room temperature, most of the ethanol is removed by rotary evaporator. Ice water (250 mL) and ice cold Et2O (250 mL) are added and the organic phase is separated and washed with ice cold 1 N HCl (200 mL) and then brine (100 mL). The organic solution is dried (MgSO4) and evaporated by rotary evaporator taking care not to warm above 50° C. The title compound is obtained by trituration of the residue with hexane (m.p. 180–181° C.).
Reaction SMILES: [N:1]([C:4]1[C:11]([F:12])=[C:10]([F:13])[C:7]([CH:8]=O)=[C:6]([F:14])[C:5]=1[F:15])=[N+:2]=[N-:3].[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1.[OH-].[Na+]>CO.O>[N:1]([C:4]1[C:11]([F:12])=[C:10]([F:13])[C:7]([CH:8]=[C:19]2[C:20](=[O:23])[C:21](=[CH:8][C:7]3[C:6]([F:14])=[C:5]([F:15])[C:4]([N:1]=[N+:2]=[N-:3])=[C:11]([F:12])[C:10]=3[F:13])[CH2:22][N:17]([CH3:16])[CH2:18]2)=[C:6]([F:14])[C:5]=1[F:15])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)c(F)c(C=O)c(F)c1F
Reactant: CN1CCC(=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CC(=Cc2c(F)c(F)c(N=[N+]=[N-])c(F)c2F)C(=O)C(=Cc2c(F)c(F)c(N=[N+]=[N-])c(F)c2F)C1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a stirred solution of 4-azido-2,3,5,6-tetrafluorobenzaldehyde (23), 0.140 g, 0.640 mmol) and 1-methylpiperidine-4-one (0.040 mL, 0.32 mmol) in MeOH (1.5 mL), 1N aq. NaOH (0.650 mL, 0.650 mmol) was added dropwise. Yellow suspension resulted within minutes which was stirred at rt for forty-five minutes and diluted with water (3 mL). Yellow solid was collected by vacuum filtration, washed with water until the filtrate was neutral to pH paper. The yellow solid was dried further in vacuo to give 0.139 g (83%) 3,5-bis(4'-azido-2',3',5',6'-tetrafluorophenylmethylene)-1-methyl piperidine-4-one (22) as bright yellow powder; mp 153° C. (violent decomposition). 1HNMR(CDCL3 δ 2.37 (s, 3H), 3.42 (s, 4H), 7.55 (s,2H). ##STR28##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26].CCCCCC.C(OCC)(=O)C>C(OCC)(=O)C>[CH2:28]([O:27][C:25](=[O:26])[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([F:18])[CH:11]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(Nc1ccc(OCc2ccccc2)c(F)c1)OCc1ccccc1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of 34.9 g 1-benzyloxy-2-fluoro-4-nitro-benzene (WO03064413) (MW: 247.28, 141 mmol) and 340 mg platine 5% on activated carbon in 350 ml ethyl acetate was stirred under hydrogen at rt and normal pressure. The reaction was monitored by HPLC and was complete after twenty hours. The catalyst was filtered over a glass fibre filter, and the filtrate evaporated under reduced pressure to dryness. The oily residue was dissolved in 500 ml acetone and treated with 250 ml of a saturated solution of sodium bicarbonate and 17.5 g of sodium bicarbonate (MW: 84.01, 208 mmol). The mixture was cooled to 5° C. and treated drop wise with 26.08 g of benzyl chloroformate (MW: 170.59, 152 mmol). The reaction was allowed to stirred at room temperature for two hours and monitored by TLC (hexane/ethyl acetate 3:1). The acetone was evaporated, the residue diluted with 500 ml water, and the solid filtered off. The crystals were washed with 500 ml water and dried. Yield: 48.05 g, 95.8%. MS: 352.5 (M+H)+, 350.8, (M−H)−. Method ESI+, ESI−.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[S:17])=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:18][N:19]([C:21](=[O:23])[CH3:22])[NH2:20].C(O)(C)C.CCOCC>CCOCC>[CH3:18][N:19]([C:21](=[O:23])[CH3:22])[NH:20][C:16]([NH:15][C:12]1[CH:11]=[CH:10][C:9]([N:2]([CH3:1])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:14][CH:13]=1)=[S:17]
Reactant: CC(=O)N(C)N
Reactant: CCOC(=O)CN(C)c1ccc(N=C=S)cc1
Solvent: CC(C)O
Solvent: CCOCC
Product: CCOC(=O)CN(C)c1ccc(NC(=S)NN(C)C(C)=O)cc1

Procedure:
A solution of 1.25 g (5.0 mmol) of ethyl N-methyl-N-(4-isothiocyanatophenyl)glycinate and 0.44 g (5.0 mmol) of 1-methyl-1-acetylhydrazine in 40 ml of 1/1 isoproply alcohol/ether was left uncovered so the ether could evaporate over a 24 hr period. The product was collected and washed with isopropyl alcohol to give 1.32 g (3.9 mmol, 78%), mp 162° dec. Anal. C15H22N4O3S (338): Calcd.: C,53.24; H,6.55; N,16.56; S,9.48. Found: C,53.12; H, 6.45; N,17.05; S,8.90. MS(FD) m/z 338. 1H NMR(DMSO-d6)δ: 9.76,s,2H,NH; 7.11,d,2H,ArH; 6.58,d,2H,ArH; 4.15,s,2H,CH2—N; 4.05,q,2H,CH2—O; 2.93,s,3H,CH3—N; 1.92,s,3H,CH3CO; 1.14,t,3H,CH3—C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:14]1[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([NH2:21])[N:15]=1>CN(C=O)C>[Cl:20][C:19]1[C:14]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=3)[CH:6]=[N:7]2)=[N:15][C:16]([NH2:21])=[N:17][CH:18]=1
Reactant: Nc1ncc(Cl)c(Cl)n1
Reactant: Ic1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc(Cl)c(-n2ncc3ccc(I)cc32)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 6-iodo-1H-indazole (100 mg, 0.41 mmol) in DMF (3 mL) was added NaH (60% oil dispersion, 32 mg, 0.82 mmol) at 0° C. The mixture was stirred at 0° C. to RT for 10 min before addition of 4,5-dichloropyrimidin-2-amine (134.4 mg, 0.82 mmol). The mixture was stirred at 50° C. for 2 hr, then quenched with water and extracted with DCM (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. LC-MS (Method B) indicated a mixture of title compound [67%, Retention time=2.11 min, m/z=+371.9/373.9 (M+H)+] and an isomeric by-product [10%, Retention time=2.07 min, m/z=+371.9/373.9 (M+H)+]. Purification by flash chromatography (Isolute column, 50% EtOAc in heptane) afforded the title compound: 1H NMR (500 MHz, DMSO) δ 7.31 (2H, br. s.), 7.65 (1H, dd, J=8.51, 1.26 Hz), 7.71 (1H, d, J=8.20 Hz), 8.45-8.48 (1H, m), 8.56-8.71 (1H, m), 8.61 (1H, s); LC-MS: m/z=+371.9 (M+H)+.
Reaction SMILES: OS(O)(=O)=O.C[O-].[Na+].[SH:9][CH:10]([C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:11]([CH3:13])[CH3:12].[CH3:20][O:21][C:22](=[O:25])[CH2:23]Cl>CO.O>[CH3:20][O:21][C:22]([CH2:23][S:9][CH:10]([C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:11]([CH3:13])[CH3:12])=[O:25]
Reactant: CC(C)CC(=O)C(S)C(C)C
Reactant: COC(=O)CCl
Agent: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CSC(C(=O)CC(C)C)C(C)C
Temperature: 24 °C
Reaction time: 0.02 h

Procedure:
Into a 50 ml, round-bottom, three-necked flask equipped with magnetic stirrer, pot thermometer, "Y" tube, nitrogen inlet tube, reflux condenser with cotton plug, H2SO4 bubbler for nitrogen, and cold water bath is added a solution of 0.65 grams of sodium methoxide dissolved in 10 ml anhydrous methanol. At a reaction mass temperature of 25°-28° C and over a period of one minute, with stirring, is added a solution of 2.1 grams of 3-mercapto-2,6--dimethyl-4-heptanone dissolved in 2 ml anhydrous methanol. After stirring 8 minutes, 1.30 grams of methylchloroacetate (0.012 moles) is added over a period of 2 minutes to the reaction mass; the temperature of the reaction mass rising to 38° C. The reaction mass is allowed to cool to 24° C and is stirred for a period of 2 hours.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9](OS(C(F)(F)F)(=O)=O)=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][NH:35][CH3:36]>>[C:1]([O:5][C:6]([C:8]1[C:9]([N:35]([CH3:36])[CH3:34])=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1)=[CH:15][C:14]([Cl:25])=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)c1c(OS(=O)(=O)C(F)(F)F)nc2ccc(Cl)cc2c1-c1cccc(Cl)c1
Product: CN(C)c1nc2ccc(Cl)cc2c(-c2cccc(Cl)c2)c1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared in analogy to example 91 step D from 6-chloro-4-(3-chloro-phenyl)-2-trifluoromethanesulfonyloxy-quinoline-3-carboxylic acid tert-butyl ester (prepared as described in example 91 step C, 150 mg, 0.29 mmol) and dimethylamine (2M solution in THF, 1 ml, 2 mmol). Pale yellow solid (85 mg, 71%). LC-MS (ESI): 417 (M+H)+.
Reaction SMILES: N(OCCC(C)C)=O.CS[S:11][CH3:12].[Br:13][C:14]1[CH:20]=[CH:19][C:17](N)=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=1>>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([S:11][CH3:12])=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:15]=1
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: CSSC
Agent: CC(C)CCON=O
Product: CSc1ccc(Br)cc1C(F)(F)F
Temperature: 85 °C
Yield: 87.2 %

Procedure:
A solution of isoamyl nitrite (4.02 mL, 30 mmol) in dimethyl disulfide (19.8 mL, 220 mmol) at 25° C. was slowly treated with 4-bromo-2-(trifluoromethyl)aniline (4.8 g, 20 mmol). The reaction was exothermic with gas evolution. The resulting brown reaction mixture was heated to 80-90° C. for 2 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to 25° C. and then concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (200 mL). The organic layer was washed successively with a 1 N aqueous hydrochloric acid solution (1×200 mL) and a saturated aqueous sodium chloride solution (1×200 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 8/1 hexanes/ethyl acetate) afforded 4-bromo-1-methylsulfanyl-2-trifluoromethyl-benzene (4.73 g, 87%) as a brown oil: EI-HRMS m/e calcd for C8H6BrF3S (M+) 269.9326, found 269.9327.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][C:13](=O)[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([Cl:21])[CH:12]=[CH:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccc2c([nH]1)CCN(Cc1ccccc1)C2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc2c(n1)CCN(Cc1ccccc1)C2
Temperature: 100 °C

Procedure:
To POCl3 (20 mL) is added 6-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one (1.21 g, 5.04 mmol) and the mixture is heated at 100° C. for 6 hr. Solvent is removed and the thick oil is poured onto crashed ice (60 g). Upon stirring, solid Na2CO3 is added to the suspension until pH>7. EtOAc (60 ml) is added and the layers are separated. The aqueous layer is extracted with EtOAc (30 ml) and the combined extracts are dried and evaporated. The residue is purified by flash silica gel column eluting with hexane/EtOAc (4:1) to give the title compound as a light yellow solid. MS (M+1): 259.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.O.O1CCOCC1.Cl[CH:19]([F:21])[F:20]>[OH-].[K+].C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:19]([F:21])[F:20])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: CSc1nc(O)cc(Cl)n1
Reactant: FC(F)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CSc1nc(Cl)cc(OC(F)F)n1
Temperature: 40 °C
Yield: 84.6 %

Procedure:
6.8 g (0.036 mole) of 4-chloro-6-hydroxy-2-methylthiopyrimidine are suspended in 25 ml 50% potassium hydroxide solution, 25 ml of water and 100 ml of dioxane. After the addition of 0.5 g of 18-crown-6, the reaction mixture is heated to 40° C., and 10 g of chlorodifluoromethane are subsequently introduced over 3 hours. The mixture is then cooled to room temperature, the phases are separated and the organic phase is evaporated to dryness. The residue is crystallised from methanol/water, affording 6.9 g (84.4% of theory) of 4-chloro-6-difluoromethoxy-2-methylthiopyrimidine with a melting point of 36°-37° C. The substance has a boiling point of 76°-78° C. at 0.15 mbar.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9](F)=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1>C(O)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH:4][CH:1]([CH3:3])[CH3:2])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Solvent: CCO
Product: CC(C)Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isopropylamine (3 mL) is added to a solution of 4-bromo-1-fluoro-2-nitrobenzene (700 mg, 3.18 mmol) in ethanol. The reaction may be stirred for an appropriate time at an appropriate temperature, such as room temperature for overnight and concentrated. The residue may be purified by any appropriate method such as Biotage column chromatography to give 4-bromo-N-isopropyl-2-nitroaniline (770 mg).
Reaction SMILES: [CH:1]1([C@@H:4]2[O:13][CH2:12][C:7]3=[N:8][O:9][C@@H:10]([CH3:11])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1.C1([C@@H]2OC[C@]3([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])NOC[C@@H]3C2)CC1>>[CH:1]1([C@@H:4]2[O:13][CH2:12][C@:7]3([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=4[F:33])[NH:8][O:9][C@@H:10]([CH3:11])[C@@H:6]3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: Fc1ccc([C@]23CO[C@@H](C4CC4)C[C@H]2CON3)c(F)c1
Reactant: C[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Product: C[C@@H]1ON[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@@H]12

Procedure:
(3S,3aR,5R)-5-Cyclopropyl-3-methyl-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C27) was converted to the product according to the method described for synthesis of rel-(3aR,5R,7aS)-5-cyclopropyl-7a-(2,4-difluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C19) in Example 2. The product was obtained as a gum. Yield: 60 mg, 0.20 mmol, 40%. 1H NMR (400 MHz, CDCl3) δ 7.99 (ddd, J=9.2, 9.0, 6.8 Hz, 1H), 6.90 (dddd, J=8.9, 7.9, 2.6, 1.0 Hz, 1H), 6.79 (ddd, J=11.9, 8.7, 2.5 Hz, 1H), 6.31 (br s, 1H), 4.03-4.10 (m, 1H), 3.89 (dd, half of ABX pattern, J=12.8, 2.0 Hz, 1H), 3.80 (br dd, half of ABX pattern, J=12.8, 1.5 Hz, 1H), 2.79-2.91 (m, 2H), 2.16 (ddd, J=14.3, 7.5, 2.5 Hz, 1H), 1.64 (dddd, J=14.2, 10.7, 10.7, 1.7 Hz, 1H), 0.90-0.99 (m, 1H), 0.79 (d, J=6.5 Hz, 3H), 0.52-0.64 (m, 2H), 0.39-0.45 (m, 1H), 0.24-0.31 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][CH2:4][NH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[NH:8][CH:9]=[N:10]2.[Br:16][CH2:17][CH2:18]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CS(C)=O>[CH3:1][C:2]([CH3:15])=[CH:3][CH2:4][NH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:18][CH2:17][Br:16]
Reactant: BrCCBr
Reactant: CC(C)=CCNc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)=CCNc1ncnc2c1ncn2CCBr
Yield: 70 %

Procedure:
Mixture of 6-[(3-methylbut-2-en-1-yl)amino]purine (2 g, 9.8 mmol), 1,2-dibromoethane (12.94 g, 6 ml, 69 mmol) and K2CO3 (2.5 g, 24 mmol) was stirred in 50 ml DMSO for 12 h. Reaction mixture was poured onto drift ice and after ice dissolution 30 ml ethyl acetate was added. Ethyl acetate layer was purified by charcoal and SiO2 and then it was evaporated in vacuo. The pure product was recrystallised from methanol; yellow solid was obtained. Yield: 70%. 1H NMR (DMSO-d6): 1.75 (3H, s), 1.59 (3H, s), 4.12 (2H, t, J=5.76), 4.10 (2H, s (br)), 4.6 (2H, t, J=5.76), 5.3 (1H, t, J=6.57), 8.1 (1H, s (br)), 8.3 (1H, s).
Reaction SMILES: CC(C)(O)[C:3]#[N:4].[C-]#N.[K+].[CH3:10][C@:11]12[CH2:28][CH:27]=[C:26]3[C@@H:16]([CH2:17][CH2:18][C:19]4[C@:24]3([CH3:25])[CH2:23][CH2:22][C:21](=[O:29])[CH:20]=4)[C@@H:15]1[CH2:14][CH2:13][C:12]2=[O:30].CO>O>[C:3]([C@@:12]1([OH:30])[CH2:13][CH2:14][C@H:15]2[C@H:16]3[C:26](=[CH:27][CH2:28][C@:11]12[CH3:10])[C@:24]1([CH3:25])[C:19](=[CH:20][C:21](=[O:29])[CH2:22][CH2:23]1)[CH2:18][CH2:17]3)#[N:4]
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(C)(O)C#N
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C#N
Reaction time: 3.5 h

Procedure:
Acetone cyanohydrin (5 ml) and sufficient potassium cyanide to adjust the pH to 9.9 is added to a slurry of androst-4,9(11)-dien-3,17-dione (0,5 g), methanol (40 ml) and water (2.5 g) at 40°. The reaction becomes homogeneous followed by precipitation of the product. After 3.5 hours, water (7.5 ml) is added dropwise and the reaction is allowed slowly to stir at 20°-25° overnight. The slurry is cooled on an ice bath, filtered, the solids washed with methanol/water (1/1) and dried under reduced pressure to give the title compound (4.54 g); [α]D (c=1, CHCl3)=+118°; MS=311, 296 and 284 m/e; NMR (CDCl3)=0.97, 1.37, 2.9, 5.5 and 5.70 δ.
Reaction SMILES: C([CH:8]([NH2:32])[C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=4[C:21](=[O:29])[N:20]4[CH2:30][CH2:31][C@H:19]4[C:18]=23)[N:10]=1)(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[NH2:32][CH2:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[CH:16][N:17]3[C:23]4[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=4[C:21](=[O:29])[N:20]4[CH2:30][CH2:31][C@H:19]4[C:18]=23)[N:10]=1
Reactant: CC(C)(C)OC(=O)C(N)c1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)no1
Solvent: O=C(O)C(F)(F)F
Product: NCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)no1
Yield: 81.4 %

Procedure:
4.40 g (10 mmol) of (S)-1-[5-(BOC-aminomethyl)-1,2,4-oxadiazol-3-yl]-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred for 2 hours in 20 ml of trifluoroacetic acid. The solution was concentrated, the residue was taken up in water and the aqueous solution was washed twice with methylene chloride. The aqueous phase was made alkaline with 25% ammonia and extracted seven times with methylene chloride. After drying and evaporating the combined organic phases there were obtained 2.77 g (81%) of (S)-1-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 195°-198°, which was converted into the hydrochloride of m.p. 275°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:14])=[C:7]([C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[CH:8]=1)#[N:2].C(OCC)C.CO[C:22](OC)([CH3:24])[CH3:23]>S(=O)(=O)(O)O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:14][C:22]([CH3:24])([CH3:23])[O:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:7]=2[CH:8]=1)#[N:2]
Reactant: CC(C)(CO)c1cc(C#N)ccc1O
Reactant: COC(C)(C)OC
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC1(C)OCC(C)(C)c2cc(C#N)ccc2O1
Reaction time: 1 h

Procedure:
A suspension of 2-(5-cyano-2-hydroxyphenyl)-2-methyl-1-propanol (5 g), prepared as in Example 26, in 2,2-dimethoxypropane was treated with 2 drops sulphuric acid at 10° C. After 1 hour at ambient temperature, diethyl ether was added, and the solution was washed with sodium hydroxide solution and water (twice). It was then dried over magnesium sulphate and run down, yielding 2.4 g of an oil which solidified on standing. The solid was dissolved in petroleum ether (bp 40°-60° C.) and the solution was cooled in an ice/salt bath. The resulting crystalline solid was separated off by filtration, yielding 1.9 g of product, mp 55°-56° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[NH:28][S:27](=[O:30])(=[O:29])[CH2:26][C:25]=2[CH:31]=1>>[O:29]=[S:27]1(=[O:30])[CH2:26][C:25]2[CH:31]=[C:21]([NH:20][C:14](=[O:16])[C:13]([N:10]3[CH2:9][CH2:8][CH:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:19][CH:18]=4)[CH2:12][CH2:11]3)=[O:17])[CH:22]=[CH:23][C:24]=2[NH:28]1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2c(c1)CS(=O)(=O)N2
Product: O=C(Nc1ccc2c(c1)CS(=O)(=O)N2)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl) piperidin-1-yl]-oxo-acetic acid (Example 1a) and 5-amino-1,3-dihydro-2,1-benzisothiazole-2,2-dioxide according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 183-184° C. (isopropanol)
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([F:12])=[CH:7][CH:6]=2)[CH3:2].[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.[OH-].[Na+]>C(O)(=O)C.P(=O)(O)(O)O>[CH2:1]([C:3]1[NH:4][C:5]2[C:10]([C:11]=1[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1)=[CH:9][C:8]([F:12])=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1cc2cc(F)ccc2[nH]1
Reactant: O=C1CCNCC1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1[nH]c2ccc(F)cc2c1C1=CCNCC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
2.83 g 2-ethyl-5-fluoro-1H-indole are suspended in 50 ml acetic acid and heated to 90° C. A suspension of 6.66 g 4-piperidone in 15 ml phosphoric acid 2N is added. The reaction mixture is stirred for 3 hours at 90° C., combined with sodium hydroxide solution and the product is extracted with ethyl acetate. 2.85 g product are obtained as a solid.