Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:17][NH2:18]>O>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:17][N:18]=2)[CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1ccc(C(=O)CCC(=O)O)cc1O
Reactant: NN
Solvent: O
Product: Cc1ccc(C2=NNC(=O)CC2)cc1O

Procedure:
A stirred suspension of 3-(3-hydroxy-4-methylbenzoyl)propionic acid (6.75 g, 0.032 mole) in water (40 ml) was treated with hydrazine hydrate (2.4 ml, 0.048 mole) and heated under reflux for one hour. The mixture was diluted with water (50 ml) and cooled. The product (6.36 g, 96%, m.p. 215°-218° C) was collected, washed with water and crystallised from ethanol to give pure 6-(3-hydroxy-4-methylphenyl)-4,5-dihydro-3(2H)-pyridazinone, m.p. 216°-218° C. (Found: C, 64.80; H, 5.94; N, 13.52; M+, 204. C11H12N2O2 requires: C, 64.69; H, 5.92; N, 13.72%; M, 204).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[C:15]([CH2:23][C:24](=O)[CH3:25])(=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:23]=[C:24]([CH3:25])[N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: CC(=O)CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(-c2ccccc2)nc2nc(SCc3ccccc3)nn12
Yield: 14.5 %

Procedure:
A solution of 20.6 g (100 mmol) of 3-amino-5-benzylthio-1,2,4-triazole and 16.2 g (100 mmol) of benzoyl acetone in 100 ml of glacial acetic acid was heated at reflux for 14 hours. The solvent was removed by evaporation at reduced pressure and the residue was chromatographed on silica gel (HPLC) eluting with EtOAc-hexane (3:7, v/v) to afford 4.81 g (14%) of 2-benzylthio-7-methyl-5-phenyl-1,2,4-triazolo[1,5-a]pyrimidine as a pale yellow wolid, m.p. 154°-155° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:24]([O:25][CH3:26])=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[C:11]([N+:27]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O.[OH-].[Na+]>C(#N)C>[NH2:27][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:24]([O:25][CH3:26])=[CH:23][C:12]=1[C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14]
Reactant: COc1cc(C(=O)OCc2ccccc2)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: COc1cc(C(=O)OCc2ccccc2)c(N)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Benzyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (77 g) was dissolved in acetonitrile (882 ml). Sodium dithionite (160.5 g) was added to the solution and the temperature adjusted to 25° C. Water (588 ml) was then added, maintaining the temperature at 25° C. The pH was maintained at 6 using 8.8 M sodium hydroxide during the reduction. The slurry was then heated to 65° C. and the lower aqueous phase was removed. Concentrated hydrochloric acid (35% w/w, 7.25 ml) was then added. The slurry was allowed to cool to 40° C. and then to 20° C. Sodium hydroxide solution (47% w/w, 12.4 ml) was added and the slurry cooled to 0° C. The product (benzyl 2-amino-4-(benzyloxy)-5-methoxybenzoate) was isolated by filtration, washed with water (2×196 ml) and then dried at 40° C. under vacuum. Yield: 66.2 g, 92.4%;
Reaction SMILES: C[Sn](C)(C)[C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]2[O:12][CH2:13][O:14][C:5]=2[CH:4]=1.[C:17]([O:20][CH2:21][CH3:22])(=O)C>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:13]1[O:14][C:5]2[C:6](=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([C:3]3[CH:4]=[C:5]4[C:6](=[CH:7][CH:8]=3)[CH:22]=[C:21]([O:20][CH3:17])[C:21]([O:20][CH3:17])=[CH:22]4)[CH:4]=2)[O:12]1
Reactant: C[Sn](C)(C)c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: CCOC(C)=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2ccc(-c3cc4c(cc3[N+](=O)[O-])OCO4)cc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (40 mg) and cuprous bromide (8 mg) were added to a solution of 6,7-dimethoxy-2-naphthalenetriflate (160 mg, 0.48 mmol) and trimethyl(3,4-methylenedioxy-6-nitrophenyl)stannane (8, 187 mg, 0.57 mmol) in THF (20 mL). The mixture was stirred at room temperature for 0.5 h., and then refluxed under nitrogen for 18 h. After Cooling, THF was rotaevaporated and ethyl acetate (50 ml) was added to the residue. the solution was washed with water (30 mL). The organic layer was separated and passed through a celite bed to remove suspended particles. The organic layer was then washed with brine, dried (anhydrous Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel using 70:30 hexanes:ethyl acetate to give a mixture of two compounds with same Rf value. The mixture can be separated after the hydrogenation step.
Reaction SMILES: [F:1][CH:2]([F:13])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[N:6]=[C:5]1[CH3:12].[NH2:14][C@@H:15]([CH3:32])[CH2:16][N:17]1[CH:21]=[CH:20][C:19]([C:22]2[CH:29]=[C:28]([F:30])[C:25]([C:26]#[N:27])=[C:24]([Cl:31])[CH:23]=2)=[N:18]1.C1C=CC2N(O)N=NC=2C=1.CN(C=O)C>O>[Cl:31][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][N:17]([CH2:16][C@@H:15]([NH:14][C:9]([C:7]3[N:6]=[C:5]([CH3:12])[N:4]([CH2:3][CH:2]([F:1])[F:13])[CH:8]=3)=[O:11])[CH3:32])[N:18]=2)[CH:29]=[C:28]([F:30])[C:25]=1[C:26]#[N:27]
Reactant: Cc1nc(C(=O)O)cn1CC(F)F
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1CC(F)F
Yield: 5.6 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) using 1-(2,2-difluoro-ethyl)-2-methyl-1H-imidazole-4-carboxylic acid (0.926 mmol, 176 mg), (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (0.617 mmol, 172 mg) and only a catalytic amount of HOBt (0.062 mmol, 8.34 mg). DMF was used as the solvent. Water was added to the reaction mixture and the mixture was extracted it three times with DCM. The combined organics were washed twice with water. The organic phase was evaporated and the residue was purified by flash chromatography and preparative HPLC, respectively. 15.5 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.07 (d, 3H), 2.36 (s, 3H), 4.23-4.55 (m, 5H), 6.19-6.51 (m, 1H), 7.02 (d, 1H), 7.53 (s, 1H), 7.86 (d, 1H), 7.90-7.95 (m, 1H), 8.00 (s, 1H), 8.12 (d, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1([CH3:31])[CH:12]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:11]2[C:18]([CH3:30])=[C:19]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:20]([CH3:23])=[C:21]([CH3:22])[C:10]=2[O:9]1.CS(O[CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=1)(=O)=O.[ClH:47]>C(#N)C.C(OCC)(=O)C>[ClH:47].[ClH:47].[CH3:46][O:45][C:41]1[CH:40]=[C:39]([CH2:38][CH2:37][N:27]2[CH2:26][CH2:25][N:24]([C:19]3[C:20]([CH3:23])=[C:21]([CH3:22])[C:10]4[O:9][C:8]([CH3:31])([CH3:7])[CH:12]([N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[C:11]=4[C:18]=3[CH3:30])[CH2:29][CH2:28]2)[CH:44]=[CH:43][CH:42]=1
Reactant: COc1cccc(CCOS(C)(=O)=O)c1
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cccc(CCN2CCN(c3c(C)c(C)c4c(c3C)C(N3CCCC3)C(C)(C)O4)CC2)c1
Reaction time: 16 h
Yield: 25 %

Procedure:
To a mixture of potassium carbonate (207 mg, 1.1 mmol) and (2,2,4,6,7-pentamethyl-3-pyrrolidinyl-2,3-dihydro-1-benzofuran-5-yl)piperazine obtained in Example 134 in acetonitrile (5 ml) was added 3-methoxyphenethyl methanesulfonate (253 mg) at room temperature. After the mixture was stirred for 16 hours, the resulting mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic extract was washed saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate/hexane=4/1) to obtain 186 mg as a free base. The free base was treated with 4N hydrogenchloride in ethyl acetate (10 mL) to obtain 137 mg (yield 25%) of the title compound. mp. 183–185° C. (decomposition) (ethanol-ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:11]1[C:12](=[O:33])[N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=2)[C:14]2[C:19]([C:20]=1O)=[CH:18][CH:17]=[CH:16][N:15]=2)=O.O.[NH2:35][NH2:36].C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[C:11]2[C:12](=[O:33])[N:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:30])[F:31])[CH:23]=3)[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:20]=2[NH:36][N:35]=1
Reactant: O=C(Cc1ccccc1Cl)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3ccccc3Cl)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 115 °C
Reaction time: 3 h

Procedure:
To a suspension of 3-(2-chlorophenylacetyl)-4-hydroxy-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridine-2(1H)-one (622 mg, 1.3 mmol) produced in Synthesis Example 29 in DMF (6 mL) was added hydrazine monohydrate (purity of 80%, 210 μL), and the mixture was stirred at 110 to 120° C. for 3 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-(2-chlorobenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (579 mg, yield 94%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=O.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[N:10]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:8]=[C:12]2[CH2:13][CH2:14][N:10]=[CH:11]2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=Cc1cnccc1Cl
Reactant: C1CCNC1
Solvent: CCO
Product: C1=NCCC1=Cc1cnccc1N1CCCC1

Procedure:
A mixture of 4-chloropyridine-3-carboxaldehyde (10 g, prepared according to the method described in J. Het. Chem, 25, 81), pyrrolidine (25 ml) and ethanol (100 ml) was heated under reflux for 5 hours, then concentrated. The residue was purified by flash column chromatography (grade II alumina) eluting first with dichloromethane and then with methanol/dichloromethane (1:200) to give 3-[[4-(pyrrolidin-1-yl)pyridin-3-yl]methylidene]-1-pyrroline (900 mg) as a white solid. NMR (d6DMSO): δ1.8(4H,m); 2.5(2H,m); 3.3(4H,m); 3.95(2H,m); 6.6(1H,d); 7.0(1H,t), 7.9(1H,t), 8.0(1H,d); 8.15(1H,s); m/e 228(M+H)+ ; calculated for C14H17N3 : C, 74.0; H, 7.5; N, 18.5; found C, 74.1; H, 7.7; N, 18.4%.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:8]=[C:9]([CH3:26])[C:10]2[O:16][C:15]3[C:17]([Cl:22])=[CH:18][C:19]([NH2:21])=[CH:20][C:14]=3[CH2:13][S:12](=[O:24])(=[O:23])[C:11]=2[CH:25]=1)=[O:6]>O.CO>[NH2:21][C:19]1[CH:18]=[C:17]([Cl:22])[C:15]2[O:16][C:10]3[C:9]([CH3:26])=[CH:8][C:7]([C:5]([OH:6])=[O:4])=[CH:25][C:11]=3[S:12](=[O:23])(=[O:24])[CH2:13][C:14]=2[CH:20]=1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N)cc1CS2(=O)=O
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A solution of sodium hydroxide (0.32 g, 7.13 mmol) in water (5 mL) was added to a solution of Example 1 (1 g, 2.71 mmol) in methanol (30 mL). The reaction mixture was stirred at 60° C. for 1.5 h, the solvent was removed under vacuum and water (20 mL) was added. The reaction mixture was acidified to pH 3 using 10% aqueous hydrochloric acid. The precipitate was filtered and washed with water, dried to obtain the title compound. Yield: 0.85 g, (89%); 1H NMR (DMSO-d6, 300 MHz): δ 2.61 (s, 3H, CH3), 5.66 (s, 2H, CH2), 6.64 (d, 2H, Ar), 8.03 (s, 1H, Ar), 8.12 (s, 1H, Ar); MS: m/e (ES−) 352 (M−1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][C:22]([CH:25]=[O:26])=[N:23][CH:24]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.Br[C:28]([F:35])([F:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1COCC1.[Zn]>[F:34][C:28]([F:35])([CH:25]([OH:26])[C:22]1[CH:21]=[CH:20][C:19]([C:4]2[CH:5]=[C:6]([NH:8][C:9]3[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=3)[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:24][N:23]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc(C=O)nc2)c1
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(F)(F)C(O)c1ccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 25 °C

Procedure:
A flask fitted with a stirring bar was charged with zinc (64.9 mg, 0.992 mmol) and anhydrous THF (5.00 mL) under a nitrogen atmosphere. Then, a solution of 5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-carbaldehyde (250 mg, 0.698 mmol) in THF (5.00 mL) was added to the flask and the mixture was brought to reflux. Ethyl bromodifluoroacetate (135 μL, 1.048 mmol) was slowly added via syringe to the reaction mixture and refluxed for 1 hour. The reaction mixture was cooled to room temperature, quenched by the addition of saturated aqueous sodium thiosulfate (3.00 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3:7 ethyl acetate:hexanes) to afford ethyl 2,2-difluoro-3-hydroxy-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]propanoate. MS APCI C22H20F5N4O3 [M+H]+ 483. found 483. 1H NMR (500 MHz, CDCl3) δ 8.84 (d, J=1.7 Hz, 1H), 8.66 (d, J=4.8 Hz, 1H), 7.98 (dd, J=2.2 Hz, 8.1 Hz, 1H), 7.89 (s, 1H), 7.52 (d, J=9.1 Hz, 2H), 7.38 (s, 1H), 7.14 (s, 1H), 7.06 (d, J=4.9 Hz, 1H), 5.26 (dd, J=4.9 Hz, 17.5 Hz, 1H), 4.47-4.29 (m, 2H), 2.45 (s, 3H), 1.36 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[S:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:13][CH2:14][C:15](OCC)=[O:16]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:15](=[O:16])[CH2:14][NH:13][C:10]2=[S:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)CN
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: O=C1CNC(=S)N1c1cc(Cl)cc(Cl)c1
Reaction time: 60 h
Yield: 82.8 %

Procedure:
3,5-Dichlorophenylisothiocyanate (5 g, 24.5 mmol) was added by portion to a suspension of the HCl salt of ethyl glycinate (3.4 g, 24.5 mmol) in a mixture of TEA (7.5 ml, 53.9 mmol) and dry DCM (40 ml) while cooling the flask in a water bath. After 60 h at RT, the solution was concentrated to dryness and partitioned between EtOAc and aqueous HCl. The organic layer was washed with water and concentrated. The obtained amorphous solid was washed with Et2O to yield 3-(3,5-dichlorophenyl)-2-thioxoimidazolidin-4-one as an orange solid (5.3 g). 1H NMR (CDCl3): 7.45 (1H, m), 7.25 (2H, m), 4.44 (2H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]([C:29]3[N:33]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([C:41]([O:43]C)=[O:42])=[CH:37][CH:36]=4)[C:32]4[CH:45]=[CH:46][CH:47]=[CH:48][C:31]=4[N:30]=3)=[O:28])[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].O.[OH-].[Li+].O1CCCC1.O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:49]=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([C:27]([C:29]3[N:33]([CH2:34][C:35]4[CH:36]=[CH:37][C:38]([C:41]([OH:43])=[O:42])=[CH:39][CH:40]=4)[C:32]4[CH:45]=[CH:46][CH:47]=[CH:48][C:31]=4[N:30]=3)=[O:28])[CH2:25][CH2:26]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7]
Reactant: COC(=O)c1ccc(Cn2c(C(=O)C3CCN(CCC4(c5ccccc5)CCN(C(=O)c5cc(OC)c(OC)c(OC)c5)C4)CC3)nc3ccccc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(C(=O)O)cc4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reaction time: 72 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-[2-[4-[1-(4-methoxycarbonyl-benzyl)-1 H-benzoimidazole-2-carbonyl]-piperidin-1-yl]-ethyl]-3-phenyl-pyrrolidine (0.68 g, 0.92 mmol) and lithium hydroxide hydrate (0.12 g, 2.75 mmol) in 4/1 tetrahydrofuran/water (45 mL). After 72 hours, dilute the reaction mixture with water and evaporate in vacuo to remove most of the tetrahydrofuran. Acidify to pH 2 using 1 M hydrochloric acid solution to obtain a solid. Collect the solid by filtration. Suspend the solid in diethyl ether (150 mL) and stir. Collect the solid by filtration and dry to give the title compound: mp; 173.0-190.0° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]1([C:19]2[C:20]3[N:21]([CH2:36][CH2:37][N:38]=3)[C:22]3[C:27]([N+:28]=2[O-:29])=[CH:26][CH:25]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:23]=3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[CH3:1][S:2]([N:33]1[CH2:34][CH2:35][N:30]([C:24]2[CH:23]=[C:22]3[C:27]([N+:28]([O-:29])=[C:19]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:20]4[N:21]3[CH2:36][CH2:37][N:38]=4)=[CH:26][CH:25]=2)[CH2:31][CH2:32]1)(=[O:4])=[O:3]
Reactant: [O-][N+]1=C(c2ccccc2)C2=NCCN2c2cc(N3CCNCC3)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc3c(c2)N2CCN=C2C(c2ccccc2)=[N+]3[O-])CC1
Temperature: 25 °C
Yield: 62.7 %

Procedure:
A solution of methanesulfonyl chloride (0.33 g, 0.003 mol) in dichloromethane (20 ml) was cooled in an ice-bath. To this solution was added dropwise with stirring, a solution of triethylamine (0.29 g, 0.003 mol) and 1,2-dihydro-4-phenyl-8-piperazinylimidazo[1,2-a]quinoxaline 5-oxide (1 g, 0.003 mol) in dichloromethane (10 ml). The reaction mixture was stirred for an additional 15 minutes and then was allowed to warm to room temperature. The reaction mixture was washed with water, dried over anhydrous magnesium sulphate and then evaporated to dryness under reduced pressure to yield a yellow solid. Recrystallization from ethyl acetate yielded 1,2-dihydro-8-(4-(methylsulphonyl)piperazinyl)-4-phenylimidazo[1,2-a]quinoxaline 5-oxide (0.8 g), as yellow crystals, m.p. 252°-253° C. (Found: C,59.19; H,5.35; N,16.33%; C21H23N5O3S requires C,59.29; H,5.41; N,16.47%) having the formula: ##STR31##
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=2)[N:3]=1.[H-].[Na+].CN(C)C=O.[CH2:35](I)[CH3:36]>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[C:4]([N:13]([C:14]2[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:26][CH:27]=2)[CH2:35][CH3:36])[N:3]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Nc2cc3ccc(Cl)cc3c(Cl)n2)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(N(CC)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 103.9 %

Procedure:
A mixture of ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)amino]phenoxy}propionate (0.36 g), sodium hydride (0.05 g, 60%) and dimethylformamide (10 ml) was stirred at room temperature for 15 minutes. Ethyl iodide (0.17 g) was added and stirring was continued for a further 15 minutes. The mixture was then poured into ethyl acetate and washed with water, dried (MgSO4) and evaporated. Purification by column chromatography over silica gel gave ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-ethylamino]phenoxy}propionate as a yellow oil (0.40 g).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH3:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH2:7][CH:8]([CH3:18])[CH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[C:16]#[N:17]
Reactant: CC(Cc1cccc(C#N)c1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)Cc1cccc(C#N)c1

Procedure:
A solution of [2-(3-Cyano-phenyl) -1-methyl-ethyl]-carbamic acid tert-butyl ester (180 mg, 0.69 mmol) in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was stirred for 15 min at room temperature. Solvents removed under vacuum, and residue was partitioned between dichloromethane and 1 N sodium hydroxide. Organic dried over magnesium sulfate and reduced to an oil under vacuum. M+1=161.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:5]([CH3:7])[CH:6]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:7][N:5]1[CH:6]=[C:2]([C:22]2[CH:23]=[CH:24][S:20][CH:21]=2)[N:3]=[C:4]1[CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: Cn1cc(Br)nc1CCc1ccc2ccccc2n1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccsc2)nc1CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
A suspension of 2-(2-(4-bromo-1-methyl-1H-imidazol-2-yl)ethyl)quinoline (0.31 g, 0.980 mmol), thiophen-3-ylboronic acid (0.25 g, 1.960 mmol), and Pd(PPh3)4 (0.022 g, 0.441 mmol) in 1,4-dioxane (6 mL) under N2 was stirred at room temperature for 0.5 h and then Na2CO3 (0.3105 g, 2.94 mmol) in water (1 mL) was added. The mixture was refluxed overnight. The mixture was then cooled to room temperature and partitioned between water and ethyl acetate (EtOAc). The separated organic layer was dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 55.6 mg of the desired compound. LC-MS: m/z 320 (M+H+).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9](OCC)=[O:10])=[CH:7][N:6]=[C:5]2[N:14]([CH2:17][CH3:18])[N:15]=[CH:16][C:4]=12)#[N:2].[NH2:19][NH2:20]>C(O)C>[NH2:2][C:1]1[C:3]2[C:4]3[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:5]=3[N:6]=[CH:7][C:8]=2[C:9](=[O:10])[NH:19][N:20]=1
Reactant: NN
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1C#N
Solvent: CCO
Product: CCn1ncc2c3c(N)n[nH]c(=O)c3cnc21
Temperature: 80 °C
Yield: 60 %

Procedure:
To a suspension of 4-cyano-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid, ethyl ester (10.0 g, 40.1 mmol) in ethanol (100 mL) was added anhydrous hydrazine (5 eq). This suspension was then heated at 80° C. until starting material was consumed. The reaction was allowed to cool to rt and diluted with water (200 mL). The resulting solid was filtered and washed thoroughly with water until the filtrate was colorless. The solid was dried under vacuum to afford the title compound as a yellow solid (5.5 g, 60%). This material was >90% pure as judged by HPLC and was used directly.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][C:25]1[N:26]=[CH:27][S:28][C:29]=1[C:30](O)=[O:31]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:30]([C:29]3[S:28][CH:27]=[N:26][C:25]=3[CH3:24])=[O:31])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: Cc1ncsc1C(=O)O
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cc1ncsc1C(=O)NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 4-methyl-thiazole-5-carboxylic acid. LC-MS (basic): tR=0.73 min; [M+H]+=457.8.