Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH:5]1[NH:9][C:8](=[O:10])[CH:7]=[CH:6]1)[CH2:2][CH3:3].[Li+].CCC[CH2-].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.CCCCCC>[C:16]1([S:22]([N:9]2[CH:5]([O:4][CH2:1][CH2:2][CH3:3])[CH:6]=[CH:7][C:8]2=[O:10])(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCCOC1C=CC(=O)N1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCOC1C=CC(=O)N1S(=O)(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
To a solution of 3 g of 1,5-dihydro-5-n-propyloxy-2H-pyrrol-2-one, in 80 cm3 of tetrahydrofuran, cooled to -45° C., there is added 13.25 cm3 of a 1.6M solution of N-butyllithium in n-hexane, while maintaining the temperature between -35° and -45° C. After 30 minutes, a solution of 3.74 g of benzenesulphonyl chloride in 12 cm3 of tetrahydrofuran is added at a temperature between -45° and -35° C., then the temperature is allowed to return to the ambient over two hours, followed by evaporating to dryness and chromatographing on silica (eluent: ethyl acetate-n-hexane, 1--1). 2.2 g of the expected product is recovered. m.p. 56°-58° C., crystallized from a mixture of ethyl ether-n-hexane, 1-2. By crystallizing from isopropanol, 1.4 g of the expected product is obtained, m.p. 66°-67° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:17])=[CH:5][C:6]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[C:7]([CH:12]=1)[C:8]([NH:10][NH2:11])=[O:9])#[N:2].C([O-])(O)=O.[Na+].Br[C:24]#[N:25]>O.O1CCOCC1.CCOC(C)=O>[NH2:25][C:24]1[O:9][C:8]([C:7]2[C:6]([CH:13]3[CH2:16][CH2:15][CH2:14]3)=[CH:5][C:4]([CH3:17])=[C:3]([CH:12]=2)[C:1]#[N:2])=[N:10][N:11]=1
Reactant: N#CBr
Reactant: Cc1cc(C2CCC2)c(C(=O)NN)cc1C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C2CCC2)c(-c2nnc(N)o2)cc1C#N
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-cyano-2-cyclobutyl-4-methylbenzohydrazide (compound 89.5, 0.5 g, 2.18 mmol) in H2O (10 mL) and dioxane (15 mL) was added NaHCO3 (0.55 g, 6.55 mmol). After the mixture was stirred at room temperature for 5 minutes, BrCN (1.3 mL, 5 M in CH3CN, 6.55 mmol) was added drop-wise. The mixture was stirred at room temperature for 30 minutes, where upon white solids formed. The mixture was diluted with EtOAc and washed with water, then brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexanes:EtOAc 1:1 to EtOAc) to yield 0.55 g (theoretical) of the title compound as a white solid. m/z (ES+) 255 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 7.93 (s, 1H), 7.45 (s, 1H), 5.10 (br, 2H), 4.38 (m, 1H), 2.61 (s, 3H), 2.48-2.34 (m, 2H), 2.17-1.98 (m, 3H), 1.91-1.79 (m, 1H).
Reaction SMILES: O.O.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:13])(=O)=[O:11])=[CH:6][CH:5]=1.[Na+].O.S(Cl)([Cl:18])=O.CN(C=O)C>C1(C)C=CC=CC=1>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([Cl:18])(=[O:13])=[O:11])=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=S(=O)(Cl)c1ccc(O)cc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
5 g (21.5 mmol) sodium 4-hydroxy-benzenesulfonate dihydrate were suspended in 50 ml toluene and refluxed for 2 hours using a Dean-Stark trap (a water separator used in chemical reactions). The solvent was evaporated, replaced by 12.8 g (108 mmol) thionyl chloride and 160 mg DMF and the mixture stirred for 4 hours at 60° C. and over night at room temperature. After evaporation, the residue was quenched with ice water, extracted thrice with dichloromethane and the extracts died and evaporated. Yield 4.78 g (quant.) raw product as white gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:29])[CH2:24][CH2:25][C:26](O)=[O:27].ClC(OCC(C)C)=O.C(N(CC)CC)C.C(O)(=O)C(O)=O.[CH2:51]([O:53][P:54]([CH2:59][NH2:60])(=[O:58])[O:55][CH2:56][CH3:57])[CH3:52]>C1COCC1>[CH2:51]([O:53][P:54]([CH2:59][NH:60][C:26](=[O:27])[CH2:25][CH2:24][C:23]([CH3:29])=[CH:22][CH2:21][C:4]1[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:18])[CH3:19])=[C:6]2[C:10](=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1])[CH2:9][O:8][C:7]2=[O:13])(=[O:58])[O:55][CH2:56][CH3:57])[CH3:52]
Reactant: CCOP(=O)(CN)OCC
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CCC(=O)O)C(=O)OC2
Agent: CC(C)COC(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOP(=O)(CNC(=O)CCC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
To a solution of 6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid (50 mg, 0.12 mmol) in THF (1 mL) was added isobutyl chloroformate (17 μL, 0.13 mmol) and triethylamine (50 μL, 0.36 mmol) at 0° C. After stirring at 0° C. for 2 hours, diethyl(aminomethyl)phosphonate oxalate (62 mg, 0.26 mmol) was added and stirring was continued at room temperature for 20 minutes. After removal of solvent, the residue was purified by preparative reverse-phase HPLC to afford 54.8 mg (81%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 9H), 1.15-1.22 (m, 2H), 1.31 (t, 6H), 1.81 (s, 3H), 2.18 (s, 3H), 2.30 (m, 4H), 3.41 (d, 2H, J=7 Hz), 3.65 (dd, 2H, J=6, 12 Hz), 3.77 (s, 3H), 3.77-4.16 (m, 4H), 4.26-4.32 (m,2H), 5.12 (s, 2H), 5.17-5.19 (m, 1H), 5.86 (bs, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 23.01 ppm; MS (m/z) 568 [M−H]−, 592 [M+Na]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](Br)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:24][O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH3:24][O:25][C:26](=[O:27])[C:28]1[CH:33]=[CH:32][C:31]([C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH:14]([CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[CH2:18][C:17]=3[CH:19]=2)=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2ccc3c(c2)CC(C2CCNCC2)O3)cc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a mixture of 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.00 g) and 4-(methoxycarbonyl)phenyl boronic acid (565 mg) in N,N-dimethylformamide (50 mL) a 2 M aqueous Na2CO3 solution (3.27 mL) is added. The mixture is sparged with argon for 10 min and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene].CH2Cl2 complex (213 mg) is added. The resulting mixture is stirred for 5 h at 90° C. After cooling to room temperature water (50 mL) and ethyl acetate (100 mL) are added and the aqueous phase is extracted with ethyl acetate. The organic phase is washed with water and brine, dried over MgSO4, and the solvent is evaporated. The residue is mixed with trifluoroacetic acid (1.4 mL), dichloromethane (1.4 mL), and water (0.15 mL) and stirred for 3 h. The solvents are evaporated and the residue is mixed with diethyl ether. The title compound is collected by filtration as the trifluoroacetic acid salt. LC (method 8): tR=1.19 min; Mass spectrum (ESI+): m/z=338 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[N:33]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:38][C:36]1[CH:37]=[C:32]([CH3:31])[N:33]=[C:34]([C:39]2([NH:42][C:24]([C:23]3[CH:27]=[CH:28][C:29]([CH3:30])=[C:21]([C:18]4[CH:19]=[CH:20][C:10]5[O:9][C:8]([C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)=[C:12]([C:13]([NH:14][CH3:15])=[O:16])[C:11]=5[CH:17]=4)[CH:22]=3)=[O:25])[CH2:40][CH2:41]2)[N:35]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: Cc1cc(C)nc(C2(N)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nc(C)cc(C)n5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.5 mmol, 1 eq), 1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (0.203 g, 1.2 mmol, 2.5 eq) (60% purity), HOBT (0.068 g, 0.5 mmol, 1.1 eq), EDC.HCl (0.105 g, 0.55 mmol, 1.1 eq) in DCM at ambient temperature under a nitrogen atmosphere was added diisopropylehtylamine (0.194 g, 1.5 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally purified by preparative HPLC. Yield: 0.15 g (14%). 1H NMR (400 MHz, DMSO-d6): δ 1.24-1.27 (m, 2H), 1.53-1.56 (m, 2H), 2.30 (s, 3H), 2.32 (s, 6H), 2.82 (d, J=4.8 Hz, 3H), 7.00 (s, 1H), 7.38-7.44 (m, 4H), 7.59 (d, J=1.2 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.82-7.84 (s and d, 2H), 7.98-8.02 (m, 2H), 8.47-8.50 (m, 1H), 9.14 (s, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]#[N:10])[C@H:4]([CH2:11][OH:12])[CH2:3]1.C(N(CC)[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C>>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][CH2:8][C:9]2[NH:10][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[C@H:4]([CH2:11][OH:12])[CH2:3]1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Reactant: N#CCCN1C[C@H](O)C[C@H]1CO
Product: Cc1cccc2c(=O)[nH]c(CCN3C[C@H](O)C[C@H]3CO)cc12

Procedure:
In the same manner as in Example 10b (a) and using (3R,5S)-5-hydroxymethylpyrrolidin-3-ol described in Collect. Czech. Chem. Commun., vol. 61, pp. S234–S237 (1996), 3-[(2S,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile is obtained. In the same manner as in Example 1b (e) and using 3-[(2S,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-{2-[(2S,4R)-4-hydroxy-2-hydroxymethylpyrrolidin-1-yl]ethyl}-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[Mg]Br.C[C:12]1[CH:17]=[C:16](C)[CH:15]=[CH:14]C=1Br.[Mg].C1(=O)CCCC1.OS(O)(=O)=O>CCOCC.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:14]1[CH2:15][CH2:16][CH2:17][CH:12]=1
Reactant: Cc1ccc(Br)c(C)c1
Reactant: Cc1ccc([Mg]Br)c(C)c1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: O=C1CCCC1
Solvent: O
Product: Cc1ccc(C2=CCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.8 %

Procedure:
To a 5° C. solution of 2,4-dimethylphenylmagnesium bromide (prepared from 18.5 g (100 mmol) of 2,4-dimethylbromobenzene and 2.5 g (105 mmol) of magnesium turnings) in 100 mL of ether, was added cyclopentanone (8.4 g, 100 mmol) in 25 mL of ether. The mixture was stirred at room temperature for 1 hour and was then heated under reflux for 0.5 hours. The solution was cooled in an ice bath, 60 mL of 30% aqueous H2SO4 was carefully added, and the resulting mixture was heated under reflux for 2 hours. Water was added and the mixture was extracted with ether. The ether extract was washed with aqueous sodium bisulfite solution, aqueous sodium bicarbonate, and brine, dried, and evaporated. Purification of the residue by flash chromatography (hexane) afforded 6 g of 1-(2,4-dimethyl-phenyl)cyclopentene.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][CH:16]([F:26])[O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:23]([CH2:22][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH:16]([F:15])[F:26])=[CH:25][CH:24]=1)[CH2:12]2
Reactant: NCc1ccc(OC(F)F)cc1
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2c(Cl)cc(Cl)cc2CN1Cc1ccc(OC(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
A mixture of 2-Bromomethyl-4,6-dichloro-benzoic acid methyl ester (0.150 g, 0.5 mmol), 4-difluoromethoxy-benzyl amine (0.101 g, 0.6 mmol), and K2CO3 (0.138 g, 1.0 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography of the product using 30% ethyl acetate in hexane afforded 5,7-dichloro-2-(4-difluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.036 g, 20%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.22 (s, 2H), 4.74 (s, 214), 6.49 (t, 1H) 7.11 (d, 2H), 7.26-7.32 (m, 3H), 7.42 (s, 1H). GC-MS: m/z 357 (M)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8].C(O[Si](C)(C)C)(=O)[CH2:16][C:17]([O:19][Si](C)(C)C)=[O:18].[Li+].[Br-].OS(O)(=O)=O.[C:37]([O:40][C:41]([CH3:43])=[CH2:42])(=[O:39])[CH3:38]>CC#N.CCN(CC)CC>[O:8]=[C:7]([C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=1)[CH2:16][C:17]([OH:19])=[O:18].[CH3:42][C:41]1([CH3:43])[O:40][C:37](=[O:39])[CH:38]=[C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=2)[O:8]1
Reactant: C[Si](C)(C)OC(=O)CC(=O)O[Si](C)(C)C
Reactant: O=C(Cl)c1cccc(OC(F)(F)F)c1
Reactant: C=C(C)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1(C)OC(=O)C=C(c2cccc(OC(F)(F)F)c2)O1
Product: O=C(O)CC(=O)c1cccc(OC(F)(F)F)c1

Procedure:
The 3-oxo-3-(3-trifluoromethoxy-phenyl)-propionic acid was prepared from 3-trifluoromethoxybenzoyl chloride and bis(trimethylsilyl) malonate with Et3N and LiBr in CH3CN at 0° C. according to general procedure H (method c1). The crude material was transformed into the title compound by stirring in isopropenyl acetate and conc. H2SO4 according to general procedure J (method a). Obtained as an orange solid (2.27 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:19])[F:18])[N:12]([CH3:20])[N:11]=2)=[N:4][C:5]([OH:9])=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].[CH2:23](I)[CH3:24].CCCCCC.C(OCC)(=O)C>CS(C)=O>[CH2:23]([N:4]1[C:3]([C:10]2[C:14]([Cl:15])=[C:13]([O:16][CH:17]([F:18])[F:19])[N:12]([CH3:20])[N:11]=2)=[C:2]([F:1])[CH:7]=[C:6]([Cl:8])[C:5]1=[O:9])[CH3:24]
Reactant: Cn1nc(-c2nc(O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCn1c(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc(Cl)c1=O

Procedure:
1.5 g of 3-(3-fluoro-5-chloro-6-hydroxy-2-pyridyl)-4-chloro-5-difluoromethoxy-1-methyl-[1H]-pyrazole (Example P27) are introduced into 6 ml of dimethyl sulfoxide (DMSO). 2.5 ml of a 2N aqueous sodium hydroxide solution are added thereto. 0.78 g of ethyl iodide in 2 ml of DMSO is then added dropwise, with stirring, and the mixture is further stirred overnight at 70° C. The next day, the reaction mixture is partitioned between dilute hydrochloric acid and diethyl ether. After extraction by shaking, and separation of the phases, the ethereal phase is washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Finally, the residue is purified over a flash chromatography column (silica gel; elution gradient: n-hexane/ethyl acetate 4/1 to 1/1 (v/v)). 0.54 g of the desired target compound is obtained in the form of a yellow oil having an Rf value of 0.17 on silica gel 60 F254 (eluant: n-hexane/-ethyl acetate 2/1 (v/v)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]=[C:9]2[CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[C:9]2[CH2:18][CH2:19][CH3:20])=[CH:6][CH:7]=1
Reactant: CCCc1nc(C(=O)OCC)cn1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc(C(=O)O)cn1-c1ccc(Cl)cc1
Temperature: 55 °C
Reaction time: 12 h
Yield: 64 %

Procedure:
To a solution of ethyl 1-(4-chlorophenyl)-2-propyl-1H-imidazole-4-carboxylate (compound 5, 1.28 g, 4.37 mmol) in THF/water (20/20 mL) was added lithium hydroxide monohydrate at room temperature. The reaction mixture was stirred at 55° C. for 12 hrs. The mixture was washed with CH2Cl2, the aqueous layer was acidified with 1N-HCl solution (pH≈6), extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The obtained product was washed with hexane to provide the title compound (740 mg, 64%) as a pale brown solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30]CC)=[CH2:29])CCC.Cl.O>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([C:28](=[O:30])[CH3:29])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Agent: [Pd]
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
To a flask loaded with tetrakis-(triphenylphosphine)-palladium (1.7 g, 1.48 mmol) under nitrogen was added a solution of 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (5.8 g, 18.55 mmol) in DMF (150 mL). The system was purged with nitrogen three times and then tributyl-(1-ethoxy-vinyl)-stannane (6.59 mL, 19.47 mmol) was added. The temperature was increased to 100° C. and stirred overnight. After cooling, 20 mL of 3N HCl was added and the mixture was stirred for additional 2 h. Water was added and the product was then extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography to afford 4.8 g (79%) of the title compound as a dark yellow solid. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.82 (dd, 1H), 8.31 (d, 1H), 8.10 (d, 1H), 7.98 (d, 1H), 7.85 (s, 1H), 7.78 (d, 1H), 7.72 (d, 1H), 7.50 (q, 1H), 4.72 (s, 2H), 2.68 (S, 3H). LCMS (method A): [MH]+=321, tR=5.07 min.
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][CH2:16][N:15]([C:18]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][N:27]=3)[CH2:22][CH2:21]2)=[O:19])[CH2:14][CH2:13]1)C1C=CC=CC=1>[Pd].CO>[N:29]1[CH:30]=[CH:31][C:26]([N:23]2[CH2:22][CH2:21][CH:20]([C:18]([N:15]3[CH2:14][CH2:13][NH:12][CH2:17][CH2:16]3)=[O:19])[CH2:25][CH2:24]2)=[N:27][CH:28]=1
Reactant: O=C(C1CCN(c2ccncn2)CC1)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(C1CCN(c2ccncn2)CC1)N1CCNCC1
Yield: 94.3 %

Procedure:
Ammonium formate (1.88 g) was added to a mixture of 1-benzyl-4-[1-(4-pyrimidinyl) -4-piperidylcarbonyl]piperazine (2.73 g) and 10% palladium on carbon catalyst (0.55 g) in methanol (70 ml) under an atmosphere of argon. The mixture was stirred under reflux for 1 hour. The cooled mixture was filtered through diatomaceous earth and the filtercake was well washed with methanol. The filtrate and washings were combined and evaporated. The residual oil was suspended in saturated aqueous sodium carbonate solution (30 ml) and the mixture was extracted with dichloromethane (4×100 ml). The dichloromethane extracts were combined, dried (Na2SO4) and evaporated to give 1-[1-(4-pyrimidinyl)-4-piperidylcarbonyl]piperazine (1.94 g, 94%) as an off-white solid; NMR (CDCl3): 1.75-1.95 (m, 4H), 2.7-3.15 (m, 8H), 3.4-3.7 (m, 4H), 4.3-4.47 (m, 2H), 6.45-6.55 (d, 1H), 8.12-8.23 (d, 1H) and 8.52-8.63 (s, 1H); m/z 276 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[C:14](=[O:16])[NH2:15])C.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=O>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:17])=[C:8]([C:14]2[O:16][CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:15]=2)[CH:9]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)COc1ccc(Br)cc1C(N)=O
Product: O=C(O)COc1ccc(Br)cc1-c1nc(-c2ccccc2)co1

Procedure:
Title compound was prepared from (4-bromo-2-carbamoylphenoxy)acetic acid ethyl ester and 2-bromoacetophenone according to GP7: LC/MS (an 10p8) Rt 2.32 min, m/z 374/376 [M+H]+.
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][C:18](OCC)=[O:19])[N:12]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:11]2=[O:27].[Br:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33](=[O:48])[N:34]([CH2:44][CH:45]([CH3:47])[CH3:46])[CH:35]2[CH2:38][C:39](OCC)=[O:40])=[CH:31][CH:30]=1>C(O)C.O.C(OCC)C>[Br:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33](=[O:48])[N:34]([CH2:44][CH:45]([CH3:46])[CH3:47])[CH:35]2[CH2:38][C:39]([NH:5][C:4]([NH2:6])=[NH:3])=[O:40])=[CH:31][CH:30]=1.[Br:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][C:18]([NH:5][C:4]([NH2:6])=[NH:3])=[O:19])[N:12]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:11]2=[O:27]
Reactant: CCOC(=O)CC1c2cc(Br)ccc2C(=O)N1CC(C)C
Reactant: CCOC(=O)CC1c2ccc(Br)cc2C(=O)N1CC(C)C
Reactant: NC(N)=[NH2+]
Agent: [Cl-]
Agent: [Na]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: CC(C)CN1C(=O)c2cc(Br)ccc2C1CC(=O)NC(=N)N
Product: CC(C)CN1C(=O)c2ccc(Br)cc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 16 h

Procedure:
N-[(5-Bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine and N-[(6-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine are prepared as described in Example 9, starting with 30 cm3 of absolute ethanol, 0.36 g of sodium, 1.5 g of guanidinium chloride and 3.7 g of ethyl (5-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate and ethyl (6-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate in 20 cm3 of absolute ethanol. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in a mixture of 100 cm3 of water and 200 cm3 of ethyl acetate. The organic phase is washed with 100 cm3 of water and then with 150 cm3 of saturated sodium chloride solution. This organic phase is dried over magnesium sulfate and concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. A white solid is thus obtained, which is then taken up again and stirred in a mixture of 15 cm3 of water and 50 cm3 of diethyl ether for 1.5 hours at a temperature in the region of 20° C. The white solid thus obtained is filtered off, washed with twice 50 cm3 of diethyl ether and dried in a desiccator under reduced pressure (2 Pa) at a temperature in the region of 35° C. 0.92 g of N-[(5-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine and N-[(6-bromo-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine are thus obtained in the form of a white powder. (Analysis: C15 H19 Br N4 O2, % calculated C, 49.06; H, 5.21; Br, 21.76; N, 15.26; O, 8.71%. found C, 48.97; H, 5.34; Cl, 14.72; N, 21.52). Mass spectrum: EI: m/e 366 (M+), m/e 279, m/e 86 (base peak).