Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([N:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][OH:12])[CH3:7].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([O:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:13][CH3:14])[CH2:6][CH3:7])=[CH:18][C:17]=1[N+:23]([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: CCN(CC)CCCO
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)CCCOc1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
MsCl (6.0 mmol) was added dropwise at 0° C. to a stirred solution of 3-diethylamino-1-propanol (6.0 mmol), TEA (6.0 mmol) in anhydrous DCM (6 mL), and the mixture was stirred at the same temperature for 10 min, and at room temperature for additional 1 h. After the removal of the solvent in vacuo, the solid residue was mixed with 4-chloro-3-nitrophenol (5.0 mmol), and K2CO3 (10 mmol) in anhydrous DMF (10 mL), following the general procedure III (Step A). The crude product is purified using silica gel column chromatography 5% MeOH/DCM as eluent to yield 2-chloro-5-(3-diethylamino-1-propoxy)nitrobenzene (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: COC(=O)C1CC(Cl)=NN1c1cccnc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)nn1-c1cccnc1
Reaction time: 4 h
Yield: 36.2 %

Procedure:
Methyl 3-chloro-1-(pyridine-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (0.500 g, 2.09 mmol) was stirred in acetone (10 mL). potassium permanganate (0.330 g, 2.09 mmol) was added in one portion and the reaction was stirred at room temperature overnight, at which point thin layer chromatography analysis (70% ethyl acetate/hexanes) indicated that the reaction was <50% complete. Additional potassium permanganate (520 mg, 3.29 mmol) was added and the reaction was stirred for an additional 4 hours. The mixture was filtered and concentrated and the residue was partitioned between ethyl acetate and water. The organic portion was dried over sodium sulfate, filtered, and concentrated. The residue was purified flash column chromatography using 80-100% ethyl acetate/hexanes as eluent to provide the desired product as a white solid (180 mg 36%).
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH:3]=[CH2:4].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[C:8]=1I.C(=O)([O-])O.[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[C:8]=1/[CH:4]=[CH:3]/[C:2](=[O:5])[CH3:1]
Reactant: Clc1cc(Cl)c(I)c(Cl)c1
Reactant: C=CC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CC(=O)/C=C/c1c(Cl)cc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 24 h
Yield: 62.9 %

Procedure:
A round bottom flask equipped with magnetic stirrer and nitrogen inlet was charged with but-3-en-2-one (1.14 g, 16.25 mmol), 1,3,5-trichloro-2-iodo-benzene (2.0 g, 6.5 mmol), Pd(OAc)2 (125 mg, 0.65 mmol), sodium hydrogen carbonate (1.64 g, 19.5 mmol) and tetrabutylammonium chloride (2.17 g, 7.8 mmol) in DMF (20 ml). The mixture was stirred at 50° C. for 24 hours. The reaction mixture was poured onto water (100 ml) and extracted with ether (3×50 ml). Combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel (150 g) (eluent: n-hexane/ethyl acetate 1:20) to afford 1.02 g (63% of theory) of (E)-4-(2,4,6-trichloro-phenyl)-but-3-en-2-one in form of an oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH2:15]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1nccn1Cc1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 96.2 %

Procedure:
To a solution of 1H-imidazole-2-carbaldehyde (240 mg, 2.4 mmol) and potassium carbonate (662 mg, 4.8 mmol) in acetonitrile (5 mL) at 0° C. was added dropwise (bromomethyl)benzene (493 mg, 2.88 mmol). The mixture was stirred at 40° C. for 4 hr. Then the mixture was filtrated, evaporated to remove the acetonitrile from the filtrate, added EtOAc to extract the residues, and washed the extract with brine and water. The organic layer was dried with anhydrous Na2SO4, concentrated, and chromatographed on a silica gel column (EtOAc:hexane=1:9) to obtain the title compound (430 mg, yield 95%). LC-MS (ESI) m/z: 187 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH2:13][CH2:14][O:15][C:16](=[O:18])[CH3:17])=[CH:5][C:6]=1[C:7](OCC)=[O:8].C([O-])(=O)C.[NH4+].[CH:24]([NH2:26])=O>O>[C:16]([O:15][CH2:14][CH2:13][CH2:12][C:4]1[S:3][C:2]2[N:1]=[CH:24][NH:26][C:7](=[O:8])[C:6]=2[CH:5]=1)(=[O:18])[CH3:17]
Reactant: CCOC(=O)c1cc(CCCOC(C)=O)sc1N
Reactant: NC=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CC(=O)OCCCc1cc2c(=O)[nH]cnc2s1
Temperature: 145 °C
Yield: 73.6 %

Procedure:
A mixture of ethyl 2-amino-5-(3-acetyloxypropyl)-thiophene-3-carboxylate (2.6 g, 9.7 mmole), ammonium acetate (0.74 g, 9.7 mmole) and formamide (8.64 ml, 19.2 mmole), was stirred under reflux at 145° C. for 12 hours. It was then cooled, diluted with water (20 ml), extracted with ethyl acetate (3×25 ml), dried, concentrated and purified by column chromatography to obtain the pure 6-(3-Acetoxypropyl)-thieno[2,3-d]pyrimidin-4(3H)-one of Formula (4-A26) (1.8 gm, 75%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([O:17]C)[CH:6]=1)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N-]=[N+]=[N-]>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([OH:17])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: COc1cc(CN=[N+]=[N-])ccc1-c1ccccc1
Agent: [N-]=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(-c2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
4-Azidomethyl-2-methoxy-biphenyl (100 mg, 0.42 mmol) is dissolved in THF (5 mL) and H2O (0.5 mL) and to which PPh3 (100 mg, 0.38 mmol) is added. The mixture is allowed to stir at room temperature overnight. After analysis of TLC suggested the disappearance of the starting azide, the reaction is stopped and THF evaporated. The residue is purified through chromatography to provide the title compound (84 mg, 100%).
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[N:9]2[N:10]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH:24]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:20][CH2:19]3)[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:37]([CH3:44])([CH3:43])[C:38]([O:40]CC)=[O:39].[OH-].[Na+]>CC(O)C>[Cl:4][C:5]1[N:9]2[N:10]=[C:11]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:19][CH2:20][N:21]([CH:24]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:22][CH2:23]3)[CH:12]=[CH:13][C:8]2=[N:7][C:6]=1[C:37]([CH3:44])([CH3:43])[C:38]([OH:40])=[O:39]
Reactant: CCOC(=O)C(C)(C)c1nc2ccc(OCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)(C(=O)O)c1nc2ccc(OCCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)nn2c1Cl
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 34.1 %

Procedure:
458 mg of ethyl 2-[3-chloro-6-[3-[4-(diphenylmethyl)piperazino]propoxy]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate trihydrochloride was dissolved in 4 ml of 2-propanol; 1.34 ml of a 2 N aqueous solution of sodium hydroxide was added, followed by stirring at 80° C. for 1.5 hours, after which 0.3 ml of a 2 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 2 hours. After cooling, the mixture was concentrated under reduced pressure; the residue was diluted with water and washed with ethyl acetate; the water layer was ajusted to pH 4 by the addition of 1 N hydrochloric acid, followed by extraction with ethyl acetate; the extract was dried with sodium sulfate. The dry product was concentrated under reduced pressure and crystallized by the addition of ethyl acetate-ethyl ether-hexane (2:5:1), collected by filtration, washed with ethyl ether and dried to yield 125 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:16])[CH2:9][C:10]([NH:12][CH2:13][CH2:14][CH3:15])=[O:11].CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:16])[C:9](=[CH:19][N:20]([CH3:22])[CH3:21])[C:10]([NH:12][CH2:13][CH2:14][CH3:15])=[O:11]
Reactant: COC(OC)N(C)C
Reactant: CCCNC(=O)CC(=O)c1ccccc1Cl
Solvent: ClCCl
Product: CCCNC(=O)C(=CN(C)C)C(=O)c1ccccc1Cl
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of 789 mg (3.29 mmol) of 2-chloro-β-oxo-N-propyl-benzenepropanamide in 5 mL of CH2Cl2 was treated with neat N,N-dimethylformamide dimethylacetal (450 μL, 402 mg, 3.38 mmol) added dropwise via syringe. The reaction was allowed to stir overnight and then concentrated in vacuo. Flash chromatography (11 cm in a 5 cm column) eluting with 2% MeOH/CH2Cl2 afforded 756 mg (79%) of the title compound as a yellow foam. Trituration with hexanes gave a yellow solid, mp 76-78° C.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:12][C:13]1[N:14]=[CH:15][C:16]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)=[CH:17][CH:18]=1
Reactant: OB(O)c1ccc(F)nc1
Reactant: COC(=O)c1cc(Br)oc1C
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: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(F)nc2)oc1C
Yield: 89.5 %

Procedure:
A mixture of methyl 5-bromo-2-methyl-3-furancarboxylate (2.6 g), 2-fluoropyridine-5-boronic acid (2.1 g), tetrakis(triphenylphosphine)palladium(0) (0.7 g), 2N aqueous sodium carbonate solution (15 mL) and 1,2-dimethoxyethane (20 mL) was stirred under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (2.5 g, 87%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NCc1ccncc1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCc1ccncc1

Procedure:
Using the general method of Example 11, 6.8 g of 2,4-dichloro-3-nitroquinoline was reacted with 4-(aminomethyl)pyridine to provide 7.8 g of crude 2-chloro-3-nitro-N-(4-pyridylmethyl)-4-quinolinamine. This material was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[OH-].[K+].[CH3:13]I>CO.C(OCC)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:13])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Brc1ccc2cn[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: Cn1ncc2ccc(Br)cc21

Procedure:
6-Bromoindazole (400 mg) was dissolved in methanol (10 mL). To this solution, potassium hydroxide (450 mg) was added followed by methyl iodide (0.50 mL) and the mixture was refluxed for 2.5 h. The reaction was cooled, diluted with diethyl ether, washed with water, brine, dried and concentrated. The product 6-bromo-1-methylindazole (160 mg) was separated from its isomer by Combiflash.
Reaction SMILES: [CH2:1]([CH:3]1[O:8][C:7]([CH3:11])([CH:9]=[CH2:10])[CH2:6][CH2:5][CH:4]1[C:12]([CH3:14])=[CH2:13])[CH3:2].[H][H]>[Pd]>[CH2:9]([C:7]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:12]([CH3:13])[CH3:14])[CH:3]([CH2:1][CH3:2])[O:8]1)[CH3:10]
Reactant: [H][H]
Reactant: C=CC1(C)CCC(C(=C)C)C(CC)O1
Agent: [Pd]
Product: CCC1OC(C)(CC)CCC1C(C)C
Temperature: 90 °C
Reaction time: 0.58 h
Yield: 63.5 %

Procedure:
The hydrogenation was carried out in a hydrogenation autoclave. 202 g of 6-ethyl-5-isopropenyl-2-methyl-2-vinyltetrahydropyran (from stage 1) were filled along with 8 g of Pd/active charcoal (Pd content: 5%) in the autoclave in the autoclave and hydrogenated at 30 bar hydrogen pressure. The reaction took place exothermically from 20° C. to approximately 50° C., after which heating to 90° C. was carried out. The H2 absorption was complete after 35 minutes. 107% of theoretical H2 was absorbed. The catalyst was filtered off and this was then rinsed with ethanol. The material obtained in this way was distilled via a 120 cm column. 131 g of 2,6-diethyl-5-isopropyl-2-methyl-tetrahydropyran (purity >97%) were obtained (73% of theoretical yield).
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]([OH:22])=[C:15]([I:23])[CH:14]=1.[CH3:24]O>>[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1[CH:21]=[C:17]([C:18]([O:20][CH3:24])=[O:19])[C:16]([OH:22])=[C:15]([I:23])[CH:14]=1
Reactant: CO
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)cc(I)c1O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(-c2ccc(F)cc2F)cc(I)c1O
Reaction time: 0.25 h

Procedure:
11.5 ml of methanol and 2.9 ml of thionyl chloride (SOCl2) were placed in a flask under an inert atmosphere. It was stirred for 15 min and 1.67 g (4.56 mmol) of 5-(2,4-difluorophenyl)-3-iodo-salicylic acid was added. It was stirred continuously at room temperature until no evolution was observed by HPLC. The solvent was evaporated at low pressure and extraction was carried out with ethyl acetate. A crude of 97% purity was obtained and then purified by chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3(O)[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[S:7][C:6]=2[CH:24]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=3)[S:7][C:6]=2[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc3ccc(Cl)cc3s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc2cc(C3=CCNCC3)sc2c1
Temperature: 23 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
A solution of 6-chloro-2-(4-hydroxy-N-t-butoxycarbonyl-piperidin-4-yl)benzo[b]thiophene (1.04 g, 2.83 mmol) in methylene chloride (30.0 ml) was treated with 4.36 ml of trifluoroacetic acid and stirred at 23° C. for 4 hours. The reaction was concentrated to a foam under reduced pressure and the residue chromatographed (silica gel, CHCl3 /MeOH 95:5) to give 0.640 g (90%) of a tan powder. FDMS m/e=250 (M+ of free base)
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:24])[NH:5][C:6]([C:11]2[CH:16]=[C:15]([NH:17][CH2:18][CH3:19])[CH:14]=[CH:13][C:12]=2[O:20][CH2:21][CH2:22][CH3:23])=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>C(O)C>[CH2:18]([N:17]([C:15]1[CH:14]=[CH:13][C:12]([O:20][CH2:21][CH2:22][CH3:23])=[C:11]([C:6]2[NH:5][C:4](=[O:24])[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH3:10])[N:7]=2)[CH:16]=1)[C:28]([NH:27][CH2:25][CH3:26])=[O:29])[CH3:19]
Reactant: CCCOc1ccc(NCC)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reactant: CCN=C=O
Solvent: CCO
Product: CCCOc1ccc(N(CC)C(=O)NCC)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Yield: 79.9 %

Procedure:
The compound (0.33 g, 1 mmol) of example 195 was dissolved in ethanol (10 ml), and added with ethyl isocyanate (0.8 g, 1.1 mmol). After refluxed for 1 h, the reaction mixture was concentrated to dryness. The resultant solid was recrystallized from ethyl acetate-petroleum ether to obtain the title compound (0.32 g, yield: 80%). 1H NMR (DMSO-d6) δ: 11.81 (1H, br), 7.58 (1H, d), 7.30 (1H, dd), 7.19 (1H, d), 5.65 (1H, t), 4.07 (2H, t), 3.55 (2H, q), 3.00 (2H, m), 2.56 (2H, q), 2.46 (2H, q), 1.77 (2H, m), 1.18 (3H, t), 1.04 (3H, t), 0.99 (3H, t), 0.98 (3H, t), 0.95 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20](O)=[O:21])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:21])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)N3CCOCC3)c2)=C(C)C1=O
Yield: 37 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid (90 mg, 0.27 mmol) obtained in Example 57 and morpholine (0.035 ml, 0.41 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (41 mg, 0.10 mmol, yield 37%).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][N:11]([CH2:15][CH:16]=[CH2:17])[C:10]=2[C:9](=[O:18])[NH:8][C:7]1=[O:19])[CH2:2][CH2:3][CH2:4][CH3:5].[C:20](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:20][N:8]1[C:9](=[O:18])[C:10]2[N:11]([CH2:15][CH:16]=[CH2:17])[CH:12]=[N:13][C:14]=2[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]1=[O:19]
Reactant: O=C([O-])[O-]
Reactant: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCCC
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=CCn1cnc2c1c(=O)n(C)c(=O)n2CCCCC
Yield: 100 %

Procedure:
3-Pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.20 g, 0.76 mmol), potassium carbonate (0.4 g, 2.9 mmol) and methyl iodide (0.5 ml, 4.9 mmol) were stirred and heated at 50° C. in DMF (5 ml) for 3 h. The solution was allowed to cool and separated between ethyl acetate and brine. The organics were isolated, dried (MgSO4) and concentrated to provide the title compound (0.21 g, 100%). m/z 277[MH+]
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([N:19]1[N:23]=[N:22][C:21]([C:24]([F:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25]([OH:27])=O)=[N:20]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:35]([C:38]1[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]([CH3:47])[CH3:46])[C:39]=1[NH2:40])([CH3:37])[CH3:36].CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:47][CH:45]([C:41]1[CH:42]=[CH:43][CH:44]=[C:38]([CH:35]([CH3:37])[CH3:36])[C:39]=1[NH:40][C:25](=[O:27])[C:24]([F:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:21]1[N:22]=[N:23][N:19]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:20]=1)[CH3:46]
Reactant: CCCCCCCCCCCCn1nnc(C(F)(C(=O)O)c2ccccc2)n1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCn1nnc(C(F)(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 0 %

Procedure:
Oxalyl chloride (0.08 mL, 0.92 mole) was added to a stirred solution of 2-dodecyl-α-fluoro-α-phenyl-2H-tetrazole-5-acetic acid (0.24 g, 0.61 mole) in 5 mL of CH2Cl2 at room temperature. The mixture was stirred 60 minutes, the one drop of DMF was added (immediate gas evolution). The solution was stirred overnight, concentrated (rotovap), toluene was added, and the solution concentrated again. The residue was dissolved in CH2Cl2 (3 mL) and added to a stirred solution of 2,6-diisopropylaniline (0.12 mL, 0.61 mole) and Et3N (0.14 mL, 1.0 mole) in CH2Cl2 (2 mL) cooled to 0° C. under dry nitrogen. After 20 minutes, the ice bath was removed and the solution allowed to warm to room temperature and stirred for 3 days. The mixture was then diluted with ethyl acetate (150 mL) and washed with dilute HCl (50 mL), bicarbonate (50 mL), brine (50 mL), and dried. Filtration and concentration afforded an oil which was flash chromatographed (silica gel, 10:1 hexanes-ethyl acetate) to produce 150 mg of the title compound as an oil which solidified on standing.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:20][N:19]=2)[CH3:13])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.CO.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:20][N:19]=2)[CH3:13])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CN(CCCOc1nsc(-c2ccccc2)n1)CCc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Solvent: CCO
Product: CN(CCCOc1nsc(-c2ccccc2)n1)CCc1ccc(N)cc1
Yield: 56.6 %

Procedure:
2.1 g of 3-(3-[N-(2-(4-nitrophenyl)-ethyl)-N-methylamino]-propyloxy)-5-phenyl-1,2,4-thiadiazole (for) preparation, see Example 8)), were dissolved in a mixture of 75 ml ethanol and 75 ml methanol and reacted with a catalytic quantity of Raney nickel. The reaction mixture was then hydrogenated for 2.5 hours at room temperature with hydrogen at a hydrogen pressure of 5 bars. The catalyst was filtered off and the filtrate concentrated to dryness. The oily crude title compound obtained was purified by medium-pressure chromatography over fine-grained silica gel (Lichroprep Si 60®) using 95:5 ethyl acetate/methanol as the eluent. 1.1 g of the title compound were obtained as an oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][OH:16])=[C:13]([CH3:17])[N:12]=[N:11]2)=[CH:6][CH:5]=1.[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>C1COCC1>[Cl:18][C:19]1[N:20]=[N:21][C:22]([O:16][CH2:15][C:14]2[N:10]([C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=3)[N:11]=[N:12][C:13]=2[CH3:17])=[CH:23][CH:24]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1CO
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nnn(-c2ccc(F)cc2)c1COc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
To a suspension of sodium hydride (55%, 106 mg, 2.41 mmol) in THF (4 mL) a solution of [3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-methanol (500 mg, 2.41 mmol) in THF (6 mL) was added under ice cooling. After the addition was complete the mixture was allowed to warm up to room temperature and stirred for 30 min. Again under ice cooling a solution of 3,6-dichloropyridazine (358 mg, 2.41 mmol) in THF (6 mL) was added and the reaction mixture stirred at room temperature for 16 h. The mixture was then poured into ice water and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 50% ethyl acetate in heptane) afforded the title compound (735 mg, 95%) as a colourless gun. MS: m/e=3020.1 [M+H]+.