Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.O>O1CCCC1>[O:8]1[CH2:9][CH2:10][CH:5]([O:4][CH2:3][CH2:2][OH:1])[CH2:6][CH2:7]1
Reactant: C1CC2(CCO1)OCCO2
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Product: OCCOC1CCOCC1
Temperature: -50 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
1,4,8-Trioxaspiro[4.5]decane (0.43 g, 3.0 mmol) produced in Reference Example 13 (13a) was dissolved in tetrahydrofuran (1.0 mL), and the resulting mixture was cooled to −50° C. Subsequently, a 1.0M solution of borane-tetrahydrofuran complex in tetrahydrofuran (3.6 mL) and trimethylsilyl trifluoromethanesulfonate (33 mg, 0.15 mmol) were added. The resulting mixture was warmed to room temperature, followed by stirring for 18 hours. A small amount of water was added, and then the resulting mixture was purified by basic silica gel column chromatography (hexane:ethyl acetate, 100:0-0:100, V/V) to give the desired title compound (0.39 g, yield 88%).
Reaction SMILES: C(O[CH:5]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)(=O)C.[NH2:19][CH:20]1[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21]1>C1(C)C=CC=CC=1>[CH2:25]([N:22]1[CH2:23][CH2:24][CH:20]([NH:19][CH:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[O:12][C:13]3[C:18]2=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:21]1)[CH3:26]
Reactant: CCN1CCC(N)C1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: Cc1ccccc1
Product: CCN1CCC(NC2c3ccccc3Oc3ccccc32)C1

Procedure:
Refluxing 4.0 g. of 9-acetoxyxanthene and 2.05 g. of 3-amino-1-ethylpyrrolidine in 175 ml. of dry toluene for 24 hours, then working up as in Example 1 gives N-(N-ethyl-3-pyrrolidinyl)-9 -xanthenylamine.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[CH2:7]([C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)[C:13]2[CH:30]=[C:31]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:32]=[C:33]([CH3:34])[C:12]=2[N:11]=1)[CH2:8][CH3:9].O>CN(C)C=O>[CH2:7]([C:10]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:3]=[N:2][N:1]=3)=[CH:20][CH:21]=2)[C:13]2[CH:30]=[C:31]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:32]=[C:33]([CH3:34])[C:12]=2[N:11]=1)[CH2:8][CH3:9]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 140 °C
Reaction time: 24 h

Procedure:
4.3 g (66 mMol) of sodium azide and 3.5 g (66 mMol) of ammonium chloride are added to a solution of 1.60 g (3.3 mMol) of 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl in 50 ml of di-methylformamide and the mixture is stirred for 24 hours at 140° C. Then water is added and the precipitate is removed by suction filtering. The crude product thus obtained is purified by chromatography over silica gel (300 g of silica gel, methylene chloride +6% ethanol).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[N:12]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[N+:12]1([O-:9])[C:21]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1cnc2cccnc2c1
Solvent: ClCCl
Product: [O-][n+]1cccc2ncccc21
Yield: 84.2 %

Procedure:
m-CPBA (1.2 g, 6.91 mmol) was added in 3 portions (after every 3 h) to a solution of 1,5-naphthyridine (1.0 g, 7.68 mmol) in dry DCM (60 ml). After completion of the reaction, the mixture was concentrated in vacuo. The crude residue was purified by column chromatography with DCM/MeOH (98:2) as the eluent to get title compound (0.85 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([CH:20]=[N:21][CH:22]=4)[CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:23].FC1C=CC(C2C(C3C=NC(CN)=CC=3)=CC=CN=2)=CC=1C.C(O)=[O:47]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[N:18][C:17]([CH2:22][NH:21][CH:20]=[O:47])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: O=CO
Reactant: Cc1cc(-c2ncccc2-c2ccc3cncn3c2)ccc1F
Agent: Cc1cc(-c2ncccc2-c2ccc(CN)nc2)ccc1F
Product: Cc1cc(-c2ncccc2-c2ccc(CNC=O)nc2)ccc1F
Temperature: 100 °C
Reaction time: 72 h

Procedure:
6-(2-(4-Fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine (Compound 269) can be prepared via the reactions shown in the first two steps of Scheme 20: (2′-(4-Fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methanamine (2.18 g) and formic acid (15 mL) were stirred and heated under nitrogen atmosphere at 100° C. After 72 h, the reaction mixture was concentrated and partitioned between CH2Cl2/aq. NaHCO3. Usual work-up and purification by flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g and 50-100% EtOAC/hexanes as elutant) provided 630 mg of N-((2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methyl)formamide as an off white solid. N-((2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methyl)formamide (630 mg) and POCl3 (3 mL) were stirred and heated in benzene (20 mL) overnight at 75° C. The reaction mixture was cooled to room temperature and concentrated. Subsequently, ice/water solution was added to the crude residue followed by CH2Cl2 and aq. NaHCO3. Upon allowing the solution warm to room temperature, organic layer was separated, stirred over Na2SO4, filtered and concentrated. Purification of the crude residue by flash column chromatography (Combiflash® companion System® with RediSep® silica gel column 40 g and 2-8% MeOH/CH2Cl2 as an eluting solvent) provided 320 mg of 6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridine as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[N:11]=[C:10]2[S:12][C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])=[N:14][C:9]2=[CH:8][CH:7]=1.[N:25]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)=[C:26]=[O:27]>N1C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[F:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[N:11]=[C:10]3[S:12][C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])=[N:14][C:9]3=[CH:8][CH:7]=2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[NH:25][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:37])[F:36])[CH:29]=1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3n2)ccc1F
Temperature: 90 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.436 mmol) produced in Example 16(vi) in pyridine (4 mL) was added 1-isocyanato-3-(trifluoromethyl)benzene (120 μL, 0.871 mmol), and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate (15 mL)/tetrahydrofuran (5 mL), and washed successively with aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was washed with acetone (15 mL) to give the title compound (69 mg, 37%) as a white solid.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[I:9]I>C1COCC1>[I:9]/[CH:1]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C#CCCCCCC
Reactant: II
Solvent: C1CCOC1
Product: CCCCCC/C=C/I
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
To a solution of oct-1-yne (113 mg, 1 mmol, available from Lancaster, Pelham, N.H., USA) and Cp2ZrCl2 (413 mg, 1.4 mmol, 1.4 eq.) in THF (4 mL) at RT was rapidly added a 1 M THF solution of LiAlH(Ot-Bu)3 (1.4 mL, 1.4 mmol, 1.4 eq.). A resulting dark red solution was stirred at RT for 15 min. Then, a solution of iodine (355 mg, 1.4 mmol, 1.4 eq., Aldrich) in THF (2 mL) was added. After additional stirring at RT for 15 min., the reaction mixture was quenched with 1 N HCl, and extracted with diethyl ether (3×10 mL). The organic extracts were combined and washed successively with saturated Na2SO3, H2O, and brine. The organic residue was then dried over MgSO4 and concentrated via evaporation under reduced pressure. Purification of the residue was performed using a short silica gel column (silica gel 60, 230-400 mesh) with EtOAc/hexanes as eluent. (E)-1-iodooct-1-ene (217 mg, 91% yield) was obtained as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm: 6.51 (dt, J=14.30, 7.12 Hz, 1H), 5.97 (d, J=14.31 Hz, 1H), 2.05 (dt, J=7.01, 6.96 Hz, 2H), 1.45-1.34 (m, 2H), 1.33-1.18 (m, 6H), 0.88 (t, J=6.66 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ ppm: 146.78, 74.21, 36.03, 31.56, 28.58, 28.32, 22.54, 14.04. The physical and spectral data are consistent with those previously reported (see Ren, H.; Krasovskiy, A.; Knochel, P. Org. Lett. 2004, 6, 4215-4217).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([CH3:14])(=[N:10][N+:11]([O-:13])=[O:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Br:15][C:16]1[C:17]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])=[N:18][C:19](Cl)=[N:20][CH:21]=1.Cl.C([O-])(O)=O.[Na+]>C(#N)C.O1CCOCC1>[Br:15][C:16]1[C:17]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])=[N:18][C:19]([NH:1][C:2]2[CH:3]=[C:4]([S:8]([CH3:14])(=[N:10][N+:11]([O-:13])=[O:12])=[O:9])[CH:5]=[CH:6][CH:7]=2)=[N:20][CH:21]=1
Reactant: CS(=O)(=N[N+](=O)[O-])c1cccc(N)c1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC#N
Product: C[C@H](CO)Nc1nc(Nc2cccc(S(C)(=O)=N[N+](=O)[O-])c2)ncc1Br

Procedure:
A solution of 37 mg (0.17 mmol) of (RS)-S-(3-aminophenyl)-S-methyl-N-nitrosulfoximide in 3 ml of acetonitrile is mixed with 91 mg (0.34 mmol) of (R)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]propan-1-ol and 0.06 ml of a 4 molar solution of hydrochloric acid in dioxane, and it is stirred under reflux overnight. Another 0.05 ml of the 4 molar solution of hydrochloric acid in dioxane is added, and it is refluxed for another 6 hours. After TLC monitoring, it is mixed again with 92 mg (0.34 mmol) of (R)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]propan-1-ol and refluxed overnight. After cooling, the batch is made basic with saturated NaHCO3 solution and extracted from ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The residue that is obtained is purified by chromatography (DCM/EtOH 95:5). 24 mg (0.05 mmol, corresponding to 32% of theory) of the product is obtained (diastereomers A/B 1:1).
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][C:18]2=[O:21])=[CH:14][C:13]=1[Cl:22])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23]Br>C(O)(=O)C>[CH2:1]([NH:8][S:9]([C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH:17]([Br:23])[C:18]2=[O:21])=[CH:14][C:13]=1[Cl:22])(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCc2cc(Cl)c(S(=O)(=O)NCc3ccccc3)cc21
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C1c2cc(S(=O)(=O)NCc3ccccc3)c(Cl)cc2CC1Br

Procedure:
According to Example 1 e), 10.05 g (30 mmoles) of 6-benzylsulfamoyl-5-chloro-1-indanone and 4.8 g (30 mmoles) of bromine in a total of 110 ml of glacial acetic acid yield the substance having a melting point of from 159° to 161° C. which after reprecipitation from a mixture of ethyl acetate and petroleum ether has a melting point in the range of from 176° to 178° C.
Reaction SMILES: CC#N.[OH2:4].[CH2:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(Cl)Cl.OF>CC#N>[CH2:7]([CH:6]1[CH2:5][O:4]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O
Reactant: C=CCCCCCCCCCC
Agent: OF
Solvent: ClCCl
Solvent: CC#N
Product: CCCCCCCCCCC1CO1
Yield: 85 %

Procedure:
Under a flow of F2 (10% in N2) of 8.9 ml min−1 (1.49 mmol h−1) fed through conduit 12, MeCN:H2O (4:1, 5.50 ml) was added to conduit 16 at a rate of 5.50 ml −1 (60.4 mmol h−1). A solution of dodec-1-ene 24 (0.25 g, 1.49 mmol) (in a 1:1 mixture of DCM:MeCN) was added to pot reactor 22 prior to reaction. The HOF.MeCN thus generated was passed via conduit 20 into the pot reactor 22. Following reaction and purging with nitrogen, the reaction mixture was then transferred from pot reactor 22 to a vessel containing 100 ml of sodium bicarbonate solution, washed with DCM (3×75 ml), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield 2-decyloxirane (0.233 g, 1.27 mmol, 85%) as a pale yellow oil, with no further purification required.
Reaction SMILES: [O:1]([CH2:19][C:20]1[NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([NH:31][C:32]3[CH:63]=[CH:62][C:35]([C:36]([N:38]([CH3:61])[C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][C:40]=4[O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]([N:54]4[CH2:59][CH2:58][N:57]([CH3:60])[CH2:56][CH2:55]4)=[O:53])=[O:37])=[CH:34][C:33]=3[O:64][CH3:65])=[O:30])[C:22]=2[N:21]=1)[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:1][CH2:19][C:20]1[NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:28]([C:29]([NH:31][C:32]3[CH:63]=[CH:62][C:35]([C:36]([N:38]([CH3:61])[C:39]4[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][C:40]=4[O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][C:52]([N:54]4[CH2:55][CH2:56][N:57]([CH3:60])[CH2:58][CH2:59]4)=[O:53])=[O:37])=[CH:34][C:33]=3[O:64][CH3:65])=[O:30])[C:22]=2[N:21]=1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CO)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.1 %

Procedure:
To a solution of 4-(2-tert-butyldiphenylsiloxymethyl-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (296 mg) in dry tetrahydrofuran (10 ml) was added tetrabutylammonium fluoride (173 mg) in ice water bath under nitrogen and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform. The solution was washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 4-(2-hydroxymethyl-1H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg) as a powder.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[N:8]1.[CH3:13][C:14]1[CH:25]=[CH:24][C:17]2[C:18](=O)[O:19]C(=O)[NH:21][C:16]=2[CH:15]=1>CCCCCC.O1CCCC1>[NH2:21][C:16]1[CH:15]=[C:14]([CH3:13])[CH:25]=[CH:24][C:17]=1[C:18](=[O:19])[CH2:12][C:11]1[N:7]([CH3:6])[N:8]=[N:9][N:10]=1
Reactant: Cc1ccc2c(=O)oc(=O)[nH]c2c1
Reactant: Cc1nnnn1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C(=O)Cc2nnnn2C)c(N)c1
Reaction time: 0.5 h

Procedure:
A solution of butyl lithium in hexane (2.5M, 20 ml) was added slowly to a stirred solution of 1,5-dimethyltetrazole (4.9 g) in dry tetrahydrofuran (100 ml) at -5° to 0° under nitrogen. After stirring for 0.5 hour, 7-methyl-1H-3,1-benzoxazine-2,4-dione (2.6 g) was added and stirring continued for 1.5 hours at room temperature and for 3 hours at 40°. The solvent was evaporated under reduced pressure at 40°-50°, water (100 ml) was added to the residue, followed by 5N hydrochloric acid dropwise until neutral to Universal pH paper. The mixture was extracted with ethyl acetate (3×50 ml) and the combined extracts were washed with 10% aqueous potassium carbonate solution (50 ml), dried over anhydrous magnesium sulphate and then evaporated under reduced pressure at 50°. The residue was triturated with ether to give a solid product which was collected by filtration and recrystallised from ethyl acetate to give the novel compound 1-(2-amino-4-methylphenyl)-2-(1-methyl-1H-tetrazol-5-yl)ethanone, m.p. 155°-6°.
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].[Br:23][C:24]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:25]=1[C:26](OC)=O.[H-].[Na+]>CN(C=O)C>[Br:23][C:24]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:25]=1[C:26]1[O:1][C:2]2[C:3]([C:20](=[O:22])[CH:21]=1)=[C:4]([O:18][CH3:19])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=2[C@@H:8]1[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]1[CH2:14][OH:15]
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Reactant: COC(=O)c1cc(OC)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(-c2cc(=O)c3c(OC)cc(OC)c([C@@H]4CCN(C)[C@H]4CO)c3o2)c1

Procedure:
Compound of example 6 (1.5 g, 4.85 mmol) in dry DMF (25 mL) was reacted with methyl 2-bromo-5-methoxybenzoate (3.11 g, 12.69 mmol) in the presence of NaH (50%, 1.16 g, 24.17 mmol) as described in example 16, to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Cu](C#N)[C:15]#[N:16]>C(OCC)(=O)C>[CH3:10][O:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:15]#[N:16])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1C
Reactant: N#C[Cu]C#N
Solvent: CCOC(C)=O
Product: COc1cc([N+](=O)[O-])c(C#N)cc1C
Yield: 41.6 %

Procedure:
A mixture compound 108 (20 g, 100 mmol) and copper cyanide (11.25 g, 125 mmol) in n-methyl-pyrrolidone-2 (60 ml) was stirred for 20 h at 140-150° C. The mixture was diluted with ethyl acetate filtered and washed four times with water. The organic phase was dried with sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with hexane-ethyl acetate which gave the title compound (8 g, 41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]([CH2:13][CH:14]3[CH2:17][N:16]([CH3:18])[CH2:15]3)[CH:12]=2)=[CH:4][C:3]=1[CH3:25].[Cl:26][C:27]1[C:28]([NH2:34])=[N:29][CH:30]=[N:31][C:32]=1Cl>>[Cl:26][C:27]1[C:28]([NH2:34])=[N:29][CH:30]=[N:31][C:32]=1[N:22]1[CH2:21][CH2:20][CH:19]([C:10]2[N:11]([CH2:13][CH:14]3[CH2:15][N:16]([CH3:18])[CH2:17]3)[CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:25])[CH:4]=3)[N:9]=2)[CH2:24][CH2:23]1
Reactant: Cc1cc(-c2cn(CC3CN(C)C3)c(C3CCNCC3)n2)ccc1F
Reactant: Nc1ncnc(Cl)c1Cl
Product: Cc1cc(-c2cn(CC3CN(C)C3)c(C3CCN(c4ncnc(N)c4Cl)CC3)n2)ccc1F

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “1” by using 4-[4-(4-fluoro-3-methyl-phenyl)-1-(1-methyl-azetidin-3-ylmethyl)-1H-imidazol-2-yl]-piperidine and 5,6-Dichloro-pyrimidin-4-ylamine. LC-MS (M+H=471, obsd=471).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([CH:15]2[CH2:17][CH2:16]2)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[BH3-]C#[N:25].[Na+]>CO>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([NH2:25])[CH:15]2[CH2:17][CH2:16]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C1CC1)C1CCN(Cc2ccccc2)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC(C1CC1)C1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 1 g sample of the compound from step 470b, 3.37 g of ammonium acetate and 274 mg of NaBH3CN were dissolved in 15 mL of methanol, 1.2 g of 4 Å molecular sieves were added, and the mixture was stirred at room temperature under N2 for 16 hours. The mixture was filtered, the sieves washed with methanol, the wash and filtrate combined, and concentrated. The residue was dissolved in 100 mL of methylene chloride, and 30 mL of 15% NaOH was added. The organic phase and a second wash of the aqueous phase were combined and washed with water and brine, then dried over MgSO4. The solvent was removed, and the residue was chromatographed on silica gel to give 460 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21](=O)[CH2:22]Br.[C:25]([NH2:28])(=[S:27])[CH3:26]>C(O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[N:28]=[C:25]([CH3:26])[S:27][CH:22]=1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C(=O)CBr
Reactant: CC(N)=S
Solvent: CCO
Product: Cc1nc(-c2c(C#N)nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2N)cs1

Procedure:
To a solution of 5-amino-4-bromoacetyl-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (0.1 g) in ethanol (5 ml) was added thioacetamide (0.0375 g). After 1 hour at room temperature the mixture was evaporated and the residue was purified by column chromatography on silica gel (10 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 226-8° C.
Reaction SMILES: [OH:1]/[N:2]=[C:3]1\[CH2:4][C@@H:5]2[C@@H:14]([C@:15]3([CH3:22])[C:20]\1=[CH:19][C:18](=O)[CH2:17][CH2:16]3)[CH2:13][CH2:12][C@@:10]1([CH3:11])[C@H:6]2[CH2:7][CH2:8][C:9]1=[O:23].Cl.Cl.[NH:26]1[CH2:30][CH2:29][C@H:28]([O:31][NH2:32])[CH2:27]1>>[NH:26]1[CH2:30][CH2:29][C@H:28]([O:31][N:32]=[C:18]2[CH2:17][CH2:16][C@@:15]3([CH3:22])[C:20](/[C:3](=[N:2]/[OH:1])/[CH2:4][C@@H:5]4[C@@H:14]3[CH2:13][CH2:12][C@@:10]3([CH3:11])[C@H:6]4[CH2:7][CH2:8][C:9]3=[O:23])=[CH:19]2)[CH2:27]1
Reactant: NO[C@H]1CCNC1
Reactant: C[C@]12CCC(=O)C=C1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: Cl
Product: C[C@]12CCC(=NO[C@H]3CCNC3)C=C1/C(=N/O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 65 %

Procedure:
The title compound I-dw was obtained following the procedure described in Example 100 and starting from 6-(E)-hydroxyiminoandrost-4-ene-3,17-dione (II-bw, Prepn. 63, 200 mg) and 3-(S)-pyrrolidinyloxyamine dihydrochloride (III-d, Prepn. 4) (110 mg). The crude product (1/1 ratio of the E/Z isomers) was purified by flash chromatography (SiO2, CH2Cl2/MeOH/26% NH4OH 90/10/1). The less polar fractions were evaporated to dryness to give the title compound I-dw in 65% yield. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 10.72 (1H, bs), 6.16 (1H, bs), 4.69 (1H, m), 3.36-3.10 (7H, m), 2.60-1.10 (16H, m), 0.96 (3H, s), 0.83 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14]([OH:16])=O)=[C:12]([CH3:17])[NH:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:23]1([CH2:22][CH2:21][CH2:20][NH:19][C:14]([C:13]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:9][C:10](=[O:18])[NH:11][C:12]=2[CH3:17])=[O:16])[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)NC(=O)N1
Reactant: NCCCn1ccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCCCn2ccnc2)C(c2cccc(Cl)c2)NC(=O)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.750 mmol) of 4-(3-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 113 mg (0.900 mmol) of 1-(3-aminopropyl)imidazole were dissolved in 10 ml of DMF. 216 mg (1.13 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1 to 10/1) to obtain the title compound.