Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:13]([CH3:29])=[CH:14][C:15]([F:28])=[C:16]([NH:18][C:19]([NH:21][CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH:17]=3)[C:9]([CH3:30])=[N:8][C:6]=2[N:7]=1.CN(C1C=CC=CN=1)C.[C:40](OC(=O)C)(=[O:42])[CH3:41].C([O-])([O-])=O.[Na+].[Na+]>N1C=CC=CC=1.O.CO>[CH3:27][C:24]([CH3:25])([CH3:26])[CH2:23][CH2:22][NH:21][C:19](=[O:20])[NH:18][C:16]1[C:15]([F:28])=[CH:14][C:13]([CH3:29])=[C:12]([C:10]2[C:9]([CH3:30])=[N:8][C:6]3[N:7]=[C:2]([NH:1][C:40](=[O:42])[CH3:41])[N:3]=[CH:4][C:5]=3[CH:11]=2)[CH:17]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(F)c(NC(=O)NCCC(C)(C)C)cc1-c1cc2cnc(N)nc2nc1C
Agent: CN(C)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CO
Product: CC(=O)Nc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C)c(F)cc3C)c(C)nc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
Treat a cooled solution (0° C.) of 1-(5-(2-amino-7-methylpyrido[2,3-d]pyrimidin-6-yl)-2-fluoro-4-methylphenyl)-3-(3,3-dimethylbutyl)urea (0.167 g, 0.407 mmol) and catalytic dimethylaminopyridine (0.005 g, 0.041 mmol) in pyridine (4 mL) with acetic anhydride (0.269 ml, 2.85 mmol) and stir at RT overnight. Add saturated. Na2CO3 and MeOH and heat at 45° C. overnight. Treat the mixture with water, extract with 4:1 EtOAc/THF (3×), wash the combined organics with saturated. Na2CO3, then brine, dry over MgSO4, concentrate to dryness and purify via silica gel chromatography (15-100% EtOAc/Hexanes). Dissolve the resulting material in acetonitrile/H2O, freeze and lyophilize to afford the title compound as an off-white solid (55 mg, 30% yield). MS (m/z): 453.2 (M+1).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][CH2:21][OH:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.C(OCC)C>[Si:1]([O:18][CH2:19][CH2:20][CH:21]=[O:22])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCCCO)(c1ccccc1)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)[Si](OCCC=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-(tert-butyl-diphenylsilyloxy)-1-propanol (1 mmole) in methylene chloride (7 mL) was treated with powder molecular sieves (4 A, 0.5 equiv. wt/wt) and pyridinium chlorochromate (1.5 mmole) at 0° C. The resulting mixture was stirred at room temperature for 2 h, and diluted with diethyl ether (7 mL) and stirred at room temperature for another 30 min. Filtration, evaporation and chromatography gave 3-(tert-butyldiphenylsilyloxy)-1-propanal as a clear oil.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].[C:14](Cl)([N:16]=[C:17]=[O:18])=[O:15].N#N.Cl>CCOC(C)=O>[CH3:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]2[O:7][C:17](=[O:18])[NH:16][C:14](=[O:15])[C:4]=2[CH2:5][CH2:6]1
Reactant: CC1(c2ccccc2)CCCC1=O
Reactant: O=C=NC(=O)Cl
Agent: Cl
Agent: N#N
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)CCc2c1oc(=O)[nH]c2=O
Temperature: 58 °C
Reaction time: 1.75 h
Yield: 43 %

Procedure:
Combined 2-methyl-2-phenylcyclopentanone (Intermediate V(1) (705.5 mg, 4.05 mmol) and carbonisocyanatidic chloride (1700 mg, 8.06 mmol), flushed with N2, and sealed in a sealed tube. Heated at 58° C. for 1 h, then 130° C. for 1.75 h. Let cool to rt. Carefully opened the tube (HCl), and dissolved the residue in EtOAc. Partitioned with NaHCO3 (aq), and extracted 3 times into EtOAc. Washed combined organic layers with brine, dried over MgSO4, filtered, and concentrated in vacuo. Loaded the residue onto Silica gel and eluted with an EtOAc/Hexane gradient to afford 7-methyl-7-phenyl-6,7-dihydrocyclopenta[e][1,3]oxazine-2,4(3H,5H)-dione (43% yield)LC-MS (M+H)+=244.1. 1H NMR (500 MHz, CDCl3) δ ppm 8.12 (1 H, br. s.), 7.32-7.38 (2 H, m), 7.26-7.30 (3 H, m), 2.69-2.75 (2 H, m), 2.43-2.52 (1 H, m), 2.21-2.29 (1 H, m), 1.68 (3 H, s).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15](Cl)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2].CS(C)=O.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1.[NH4+].[OH-]>O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(Cl)c3ccccc3nc21
Reactant: NCc1ccncc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCn1ncc2c(NCc3ccncc3)c3ccccc3nc21
Yield: 34.5 %

Procedure:
A mixture of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline (1.0 g, 4.3 mmol), DMSO (3 ml) and 4-(aminomethyl)pyridine (0.92 ml, 9 mmol) was heated at 80°-90° C. overnight. The reaction mixture was poured into water (200 ml)/NH4OH (1 ml) and the mixture was extracted with CH2Cl2 (3×100 ml). The CH2Cl2 layers were combined, dried over MgSO4 and evaporated. The residue was crystallized from ethyl acetate and recrystallized from ethyl acetate to afford 450 mg of 1-ethyl-N-(4-pyridinylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 191°-192° C.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5](=[O:16])[C:4]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[NH:22]1[CH:26]=[CH:25][CH:24]=[N:23]1.[OH-].[K+].CCOC(C)=O>C1COCC1.O>[N:22]1([CH2:2][C:3]2[N:7]([CH3:8])[N:6]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[C:5](=[O:16])[C:4]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:26]=[CH:25][CH:24]=[N:23]1
Reactant: CCOC(=O)c1c(CBr)n(C)n(-c2ccc(F)cc2)c1=O
Reactant: c1cn[nH]c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cn2cccn2)n(C)n(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of ethyl 5-(bromomethyl)-2-(4-fluorophenyl)-1-methyl-3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (1.3 g, 3.6 mmol) and 1H-pyrazole (0.25 g, 3.6 mmol) in THF (50 mL) and H2O (1 mL) cooled in an ice-water bath is added solid KOH (0.2 g, 3.6 mmol) in three portions. After the reaction mixture is stirred at RT overnight, the solvent is removed. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (4:1) to give the product (0.87 g, 70% yield). MS (m/z): 345.1 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[CH:5]=1.[Cl:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]2[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=2)[CH:31]=1>>[ClH:28].[ClH:28].[ClH:28].[ClH:28].[CH3:1][N:2]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([C:36]3[CH:41]=[C:40]([O:42][CH3:43])[C:39]([O:44][CH3:45])=[C:38]([O:46][CH3:47])[CH:37]=3)[CH:31]=2)[CH2:24][CH2:23]1)[CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:11]=[C:12]([O:20][CH3:21])[C:13]([O:18][CH3:19])=[C:14]([O:16][CH3:17])[CH:15]=2)[CH:5]=1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cc(CN(C)C3CCNCC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(N(C)Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
4-[N-methyl-N-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]amino]piperidine (73 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (58 mg) were condensed in the same manner as described in Example 2. The title compound was obtained after converting a free base to a tetrahydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:25])[C:11](C(OCC)=O)=[C:12]([C:16]([F:19])([F:18])[F:17])[N:13]([CH3:15])[CH:14]=1.B(Br)(Br)Br.N1C2C(=CC=CC=2)C=CC=1.O>ClCCl.[Cu]>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:25])[CH:11]=[C:12]([C:16]([F:19])([F:17])[F:18])[N:13]([CH3:15])[CH:14]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)n(C)cc(-c2ccc(Cl)cc2Cl)c1=O
Agent: [Cu]
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: Cn1cc(-c2ccc(Cl)cc2Cl)c(=O)cc1C(F)(F)F
Temperature: -60 °C
Reaction time: 3 h
Yield: 26.9 %

Procedure:
4.1 g (10.4 mmol) of 5-(2,4-dichlorophenyl)-3-ethoxycarbonyl-1-methyl-2-trifluoromethyl-4(1H)-pyridone was dissolved in 100 ml of dichloromethane, and 10 ml of a dichloromethane solution of 3N boron tribromide was dropwise added thereto under cooling to −60° C. After stirring at room temperature for 3 hours, the reaction solution was poured into ice water, and precipitated crystals were collected by filtration and washed with water. They were dried under reduced pressure to obtain crude crystals. To 50 ml of quinoline, the crude crystals and 0.04 g (0.6 mmol) of copper were added, followed by stirring at 170° C. for 1 hour. This reaction solution was poured into water, and precipitated crude crystals were collected by filtration. The crude crystals were dissolved in a small amount of DMF, and insoluble matters were filtered off. Then, the filtrate was poured into water, and precipitated crystals were collected by filtration. The crystals were washed with water and then dried to obtain 0.9 g (yield: 26%) of the desired product. Melting point: 205-206° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[N:7]2.[Se](=O)=[O:19]>C1C2C(=CC=CC=2)C=CC=1.C(Cl)Cl>[C:12]1([C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[N:10][CH:11]=[C:2]([CH:1]=[O:19])[C:3]=3[CH:4]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=[Se]=O
Reactant: Cc1cncc2ncc(-c3ccccc3)cc12
Solvent: ClCCl
Solvent: c1ccc2ccccc2c1
Product: O=Cc1cncc2ncc(-c3ccccc3)cc12
Temperature: 200 °C
Reaction time: 5 h

Procedure:
36.2 g (164 mmol) of the compound from Example III are well stirred with 27.4 g of selenium dioxide in 130 g of naphthalene at 180° C. After 5 h, a further 3.65 g of SeO2 are added and the mixture is stirred for a further 3 h at 200° C. It is allowed to cool and is dissolved in CH2Cl2 and the solution is concentrated on a rotary evaporator after addition of 200 g of silica gel. The residue is applied to a large silica gel column and chromatographed (toluene→ethyl acetate). Yield: 18 g (47%) M.p.: 148° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C@@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl.[CH3:18]O>>[NH2:5][C@@H:6]([C:14]([O:16][CH3:18])=[O:15])[CH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[ClH:3]
Reactant: CO
Reactant: N[C@H](CC1CCCCC1)C(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Product: COC(=O)[C@H](N)CC1CCCCC1

Procedure:
To cold (-20° C.) and dry methanol (195 ml) was added dropwise thionylchloride (28 ml). H-D-Cha-OH.HCl (40 g) was added and the reaction mixture was heated under reflux for 5 h. The mixture was concentrated in vacuo and coevaporated with methanol (3 times). The residue was crystallized from methanol/diethylether yielding H-D-Cha-OMe.HCl as a crystalline powder (40.9 g).
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH:8]([C:11]([O:13]CC)=O)[C:6](=[O:7])[N:5]([CH3:16])[C:3]1=[O:4].[CH3:17][N:18]1[C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[N:21][C:20]([C:31]([F:34])([F:33])[F:32])=[N:19]1>C1(C)C=CC=CC=1>[CH3:16][N:5]1[C:6](=[O:7])[CH:8]([C:11](=[O:13])[NH:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][C:22]3[N:18]([CH3:17])[N:19]=[C:20]([C:31]([F:34])([F:33])[F:32])[N:21]=3)=[CH:25][CH:26]=2)[C:9](=[O:10])[N:2]([CH3:1])[C:3]1=[O:4]
Reactant: Cn1nc(C(F)(F)F)nc1Oc1ccc(N)cc1
Reactant: CCOC(=O)C1C(=O)N(C)C(=O)N(C)C1=O
Solvent: Cc1ccccc1
Product: CN1C(=O)C(C(=O)Nc2ccc(Oc3nc(C(F)(F)F)nn3C)cc2)C(=O)N(C)C1=O
Temperature: 25 °C

Procedure:
22.8 g of 1,3-dimethyl-5-ethoxycarbonylbarbituric acid and 25.8 g of 1-methyl-3-trifluoromethyl-5-(4-aminophenoxy)-1H-1,2,4-triazole are heated under reflux in 200 ml of toluene for 4 hours. The crude product, which precipitates on cooling to room temperature, is isolated by filtration, washed with diethyl ether and dried. Yield: 39.2 g (89% of theory). Melting point: 202°-204° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23](Cl)[N:24]=1)[C:19]([NH2:21])=[O:20].CN(C(C(C)C)C)C.O>CCOC(C)=O>[NH2:21][C:19]([C:18]1[CH:17]=[C:16]([Cl:15])[N:24]=[C:23]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]2)[CH:22]=1)=[O:20]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: NC(=O)c1cc(Cl)nc(Cl)c1
Agent: CC(C)C(C)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=O)cc(Cl)n2)CC1

Procedure:
tert-Butyl piperidin-4-ylcarbamate (500 mg, 2.62 mmol), was dissolved in anhydrous N,N′-dimethyl acetamide (4 ml). 2,6-Dichloroisonicotinamide (522 mg, 2.62 mmol) was added, followed by N,N-dimethyl isopropylethylamine (465 μl, 2.62 mmol). Using a Smith Microwave Synthesizer, the mixture was subjected to single-mode microwave at 150° C. for 20 minutes. H2O (50 ml) and EtOAc (100 ml) were added, the EtOAc layer was washed (4×50 ml), dried over Na2SO4 and concentrated in vacuo to give the title product as a brown solid. (760 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16]OS(C)(=O)=O)[C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([CH3:32])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][C:29](=[O:31])[CH3:30].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:16][CH:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH3:32])[C:29](=[O:31])[CH3:30])[C:10]([O:12][CH:13]([CH3:14])[CH3:15])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)OC(=O)C(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cc1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC(=O)C(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)C)c1ccccc1C
Reaction time: 30 h
Yield: 65.6 %

Procedure:
To a solution of 2 (181.2 g, 0.557 mol) in THF (1 L) was added TEA (84.6 g, 0.836 mol) in portions at 15-20° C. The mixture was stirred for 30 h. After the reaction was complete, the solution was concentrated to give crude 7. To a solution of 35 (82.5 g, 0.557 mol) and Cs2CO3 (91 g, 0.279 mol) in DMSO (1 L) was added slowly crude 7 in DMSO (500 mL) over 30 min at 15-20° C. The mixture was stirred for 1 h. After the reaction was complete, the mixture was partitioned with water and MTBE (5 L), and extracted with MTBE twice. The combined organic layer was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (5-10% EtOAc/PE) to give 36 (138 g, 65% yield).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4](/[C:8](=[N:10]\O)/[CH3:9])[CH:5]=[CH:6][CH:7]=1>C(O)(=O)C.CO.[Zn]>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C/C(=N/O)c1cccc(Cl)c1C
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(Cl)cccc1C(C)N
Temperature: 40 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To (1Z)-1-(3-chloro-2-methylphenyl)ethanone oxime (383 mg, 2.08 mmol) in acetic acid (10 ml) was added zinc dust (2.72 g, 41.6 mmol) and the resulting mixture was stirred at 40° C. for 3 hours. The reaction mixture was diluted with methanol and filtered. The filtrate was concentrated in vacuo and the obtained residue was partitioned between 1 N hydrochloric acid and ethyl acetate. The aqueous portion was neutralized with sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to give 1-(3-chloro-2-methylphenyl)ethanamine as a clear oil (290 mg, 1.7 mmol, 82% yield). 1H NMR (400 MHz, CDCl3): 8.98 (s, 1H), 7.11-7.44 (m, 3H), 2.37 (s, 3H), 1.81 (s, 3H); MS (EI) for C9H12ClN: 170 (MH+).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:21])[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1O)=[CH:11][CH:10]=[CH:9][N:8]=2)(=O)[CH3:2].Cl.Cl.[CH2:24]([NH:31][NH2:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(O)(=O)C>[CH2:24]([N:31]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[N:8][C:7]=3[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:5](=[O:21])[C:4]=2[C:1]([CH3:2])=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1nn(Cc2ccccc2)c2c1c(=O)n(-c1ccccc1)c1ncccc21
Temperature: 25 °C
Yield: 61.5 %

Procedure:
Compound 102 obtained in Example 2, 3.0 g (10.7 millimoles), was suspended in 20 ml of glacial-- acetic acid, and 3.1 g (16.1 millimoles) of benzylhydrazine dihydrochloride and 9.0 ml (64.2 millimoles) of triethylamine were added to the suspension. The mixture was heated under reflux for 10 hours. The reaction solution was cooled to room temperature, and the precipitate was collected by filtration and recrystallized from DMF-water to give 2.4 g (61.5%) of Compound 5.
Reaction SMILES: [CH3:1][S:2][C:3](=[N:5][N+:6]([O-:8])=[O:7])[NH2:4].[H-].[Na+].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][N:13]=1>CS(C)=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:4][C:3](=[N:5][N+:6]([O-:8])=[O:7])[S:2][CH3:1])=[CH:14][N:13]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CSC(N)=N[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CSC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Reaction time: 1 h
Yield: 6.9 %

Procedure:
To a solution of 2-methyl-3-nitroisothiourea (15.0 g) in dimethylsulfoxide (100 ml) was gradually added sodium hydride (oil free 2.9 g) at 5° C., while being stirred for one hour. Thereafter, 2-chloro-5-chloromethyl pyridine (18.0 g) was added to the solution at a temperature in the range of from 5° to 10° C., followed by overnight stirring thereof at room temperature. After the dimethylsulfoxide in the solution was distilled off under reduced pressure, the resulting residue was purified on a chromatographic column (the eluent was a mixture of ethanol and chloroform), so as to obtain the desired 1-(2-chloro-5-pyridylmethyl)-2-methyl-3-nitroisothiourea (2.0 g) having a melting point in the range of from 141° to 143° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1.[H-].[Na+].Cl.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29]Cl)[CH2:24][CH2:23]1.Cl>O1CCOCC1.C(O)C>[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:9]=2)[CH2:24][CH2:23]1
Reactant: ClCCN1CCOCC1
Reactant: Oc1ccccc1-c1nc(-c2ccccc2)no1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: c1ccc(-c2noc(-c3ccccc3OCCN3CCOCC3)n2)cc1
Temperature: 27.5 °C
Reaction time: 0.25 h

Procedure:
2.38 g of 5-(2-hydroxyphenyl)-3-phenyl-1,2,4-oxadiazole are dissolved in 100 ml of anhydrous dioxane and stirred with 0.3 g of 80% sodium hydride suspension in oil for 15 minutes at 25-30° C. To this solution is added 75 ml of absolute dioxane, mixed with 3.72 g of 2-(morpholino)ethylchloride hydrochloride and 0.6 g of 80% sodium hydride suspension in oil. This solution is also stirred for 15 minutes at 25-30° C. The combined solutions are heated to 100° C. for 6 hours and then concentrated by evaporation in vacuo. The residue is mixed with water and 20 ml of 1N sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, the solvent is distilled off in vacuo and the residue is chromatographed on silica gel with ethyl acetate/isopropanol (70:30, mixed with 1.5% of a 25% ammonia solution). The base thus obtained is dissolved in anhydrous ethanol, acidified with ethereal HCl and precipitated with diethyl ether. The residue is recrystallised from anhydrous ethanol and diethylether. Yield: 1.9 g (49% of theory). m.p.: 194-195° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH2:22])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[CH2:23]([N:25]1[C:29]2=[N:30][C:31]([CH2:54][CH3:55])=[C:32]([CH2:41][NH:42][C:43]([C:45]3[CH:46]=[C:47]([CH:51]=[CH:52][CH:53]=3)[C:48](O)=[O:49])=[O:44])[C:33]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:28]2[CH:27]=[N:26]1)[CH3:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:23]([N:25]1[C:29]2=[N:30][C:31]([CH2:54][CH3:55])=[C:32]([CH2:41][NH:42][C:43]([C:45]3[CH:53]=[CH:52][CH:51]=[C:47]([C:48]([NH:22][CH2:21][C:17]4[CH:16]=[C:15]([C:11]5[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][CH:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)[CH:10]=5)[CH:20]=[CH:19][CH:18]=4)=[O:49])[CH:46]=3)=[O:44])[C:33]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:28]2[CH:27]=[N:26]1)[CH3:24]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)c1
Reactant: CN1CCC(Cc2cccc(-c3cccc(CN)c3)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CC4CCN(C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 59.3 %

Procedure:
To a solution of ({3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)amine (0.0294 g, 0.10 mmol) in DCM (1 mL) was added 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]benzoic acid (0.0452 g, 0.10 mmol), HBTU (0.0417 g, 0.11 mmol), and TEA (0.0303 mL, 0.20 mmol) and was stirred at room temperature for 17 h. The reaction was quenched with H2O (1 drop), concentrated by Glas-Col evaporator and re-dissolved in MeOH/DMSO (0.5/0.1 mL). The resultant mixture was purified using a Gilson HPLC (with 0.1% TFA), concentrated by GeneVac EZ-2 evaporator and basified with an amine cartridge to afford the title compound 0.0432 g (59.34%). LC-MS m/z 728 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.37-1.44 (m, 3 H) 1.46-1.54 (m, J=7.28, 7.28 Hz, 5 H) 1.81-1.98 (m, 5 H) 2.05-2.13 (m, J=12.55 Hz, 2 H) 2.68 (d, J=6.53 Hz, 2 H) 2.78-2.86 (m, 3 H) 2.88-2.97 (m, 2 H) 3.15 (q, J=7.61 Hz, 2 H) 3.43-3.51 (m, J=12.30 Hz, 2 H) 3.67 (t, J=11.54 Hz, 2 H) 4.03 (d, J=11.80 Hz, 2 H) 4.30-4.41 (m, 1 H) 4.47 (q, J=7.19 Hz, 2 H) 4.65 (s, 2 H) 4.71 (s, 2 H) 7.17 (d, J=7.53 Hz, 1 H) 7.33-7.53 (m, 6 H) 7.59-7.66 (m, 2 H) 8.05 (dd, J=7.91, 1.63 Hz, 2 H) 8.29 (s, 1 H) 8.39 (s, 1 H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].Br[CH2:23][CH2:24][CH:25]=[CH2:26]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH:23]=[CH:24][CH2:25][CH3:26])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: C=CCCBr
Reactant: O=S(=O)(NCCCCO)c1ccc(-c2ccccc2)cc1
Product: CCC=CN(CCCCO)S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using a method analogous to that described in Example 4, with biphenyl-4-sulfonic acid-(4-hydroxybutyl)-amide and 4-bromobutene, reacted at 60° C. for 3 hours, the title compound was obtained as a white powder. δC (CDCl3, 62.9 MHz): 25.2, 29.6, 33.4, 47.8, 48.3, 62.4, 117.2, 127.3, 127.6, 127.7, 128.5, 129.1, 134.6, 138.4, 139.3 and 145.3. δH (CDCl3, 250 MHz): 1.58 (4H, m), 2.34 (3H, m), 3.21 (4H, m), 3.66 (2H, t, J 6.1), 5.04 (2H, m), 5.69 (1H, m), 7.46 (3H, m), 7.60 (2H, d, J 7.3), 7.70 (2H, d, J 8.2) and 7.86 (2H, d, J 8.2)