Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:14])=[CH:8][CH:7]=1)([CH3:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([P:40](=[O:51])([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])([F:39])[F:38])=[CH:33][CH:32]=1.C([O-])(=O)C.[NH4+]>C1COCC1>[C:47]([O:46][P:40]([C:37]([F:39])([F:38])[C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH:12]([C:9]2[CH:10]=[CH:11][C:6]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:22])=[CH:7][CH:8]=2)[C:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[O:14])=[CH:32][CH:33]=1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:51])([CH3:48])([CH3:49])[CH3:50]
Reactant: CC(C)(C)OP(=O)(OC(C)(C)C)C(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)OC(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1ccc(C(Cc2ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc2)C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of isopropyl-4-[2-(4-fluorophenyl)-2-oxoethyl]benzoate (0.130 g, 0.433 mmol), (Example 4, Step 1) 18-crown-6 (0.03 g) in THF (2.2 ml ) at −2020 C. was added a solution of potassium tert-butoxide 1 M in THF (0.475 ml). To the reaction mixture was added a solution of di(tert-butyl) [4-(bromomethyl)phenyl](difluoro)methylphosphonate (0.196 g, 0.475 mmol) in THF (5 ml). The reaction was stirred at room temperature for 1 hour, and then saturated ammonium acetate solution (20 ml) was added and the mixture was extracted with ethyl acetate (20 ml). The organic phase was washed with brine, dried over sodium sulfate, filtered, and evaporated to dryness. The residue was purified by flash chromatography using hexane/ethyl acetate 15% plus 1% triethylamine giving 0.05 g of the title compound.
Reaction SMILES: [CH3:1][C@@H:2]([C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:3](N1[C@@H](C(C)C)COC1=O)=[O:4].OO.O.[OH-].[Li+].S([O-])([O-])=[O:29].[Na+].[Na+]>O1CCCC1.O>[CH3:1][C@@H:2]([C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:3]([OH:4])=[O:29]
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](C)C(C)(C)c1ccccc1
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](C(=O)O)C(C)(C)c1ccccc1
Temperature: 25 °C
Yield: 72 %

Procedure:
To a 0° C. solution of (4S)-3-[(2S)-2,3-dimethyl-3-phenylbutanoyl]-4-isopropyl-1,3-oxazolidin-2-one (0.13 g, 0.43 mmol, from Reference Example 24) in tetrahydrofuran (6 mL) and water (2 mL) is added 30% aqueous hydrogen peroxide (2.4 mL). After one to two minutes of stirring, lithium hydroxide monohydrate (36 mg) is added and the reaction mixture is allowed to stir overnight while warming to room temperature. On the following day, the reaction mixture is cooled to 0° C. and aqueous sodium sulfite solution (1.5 M, 1.3 mL) is added. After stirring for an hour at room temperature, the reaction mixture is concentrated under reduced pressure. The aqueous residue is extracted twice with dichloromethane, then acidified to pH 1 with 10% aqueous hydrochloric acid solution. The acidified aqueous phase is then extracted thrice with ethyl acetate. The combined organic extracts are washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, decanted, and concentrated under reduced pressure to give a white crystalline solid (60 mg, 72%). Mp 69-72° C. MS (ES−): (M−H)=191.0
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]([NH2:12])=[CH:11][C:3]=2[O:2][CH3:1])[CH2:38][CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc(N)c([N+](=O)[O-])cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c([N+](=O)[O-])cc1C(=O)NC1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a solution of 2-methoxy-4-amino-5-nitrobenzoic acid (6.4 g; 0.03 moles) in N,N-dimethylformamide (175 ml) a solution of triethylamine (3 g; 0.03 moles) in N,N-dimethylformamide (5 ml) was added. The mixture was cooled to -5° to -10° C. and a solution of ethyl chloroformate (3.3 g; 0.03 moles) in N,N-dimethylformamide (5 ml) was added. The reaction mixture was stirred at the same temperature for 0.5 hours and then a solution of 1-benzyl-4-aminopiperidine (5.7 g; 0.03 moles) in N,N-dimethylformamide (15 ml) was added. After stirring for 1 hour at -5° to -10° C., the temperature was allowed to reach room temperature overnight. The solvent was removed in vacuo and the residue was poured into an aqueous sodium bicarbonate solution. The resulting solid was exhaustively extracted with methylene chloride, the organic layers washed with an aqueous sodium bicarbonate solution and then with water, dried (Na2SO4 ) and the solvent removed in vacuo. N-(1-Benzylpiperid-4-yl)-2-methoxy-4-amino-5-nitrobenzamide (9.3 g) was obtained and converted into its hydrochloride by treatment with a saturated solution of ethanolic hydrogen chloride; the hydrochloride melted at 218°-220° C. (dec).
Reaction SMILES: Br[C:2]1[S:25][C:5]2[CH2:6][CH2:7][C:8]3[CH:9]=[N:10][C:11]([NH:14][C:15]4[CH:16]=[C:17]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=4)=[N:12][C:13]=3[C:4]=2[CH:3]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].CCO.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.COCCOC>[C:26]1([C:2]2[S:25][C:5]3[CH2:6][CH2:7][C:8]4[CH:9]=[N:10][C:11]([NH:14][C:15]5[CH:16]=[C:17]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=5)=[N:12][C:13]=4[C:4]=3[CH:3]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NS(=O)(=O)c1cccc(Nc2ncc3c(n2)-c2cc(Br)sc2CC3)c1
Reactant: OB(O)c1ccccc1
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: CCO
Solvent: O
Solvent: COCCOC
Product: NS(=O)(=O)c1cccc(Nc2ncc3c(n2)-c2cc(-c4ccccc4)sc2CC3)c1

Procedure:
To the 3-(8-Bromo-5,6-dihydro-thieno[2,3-h]quinazolin-2-ylamino)-benzenesulfonamide (200 mg, 0.46 mmol) in a 10 mL microwave reaction tube was added Phenyl boronic acid (56 mg, 0.46 mmol), 2M Na2CO3(aq) (920 μL, 1.84 mmol), Pd(PPh3)4 (5.3 mg, 0.0046 mmol), 3:4 EtOH/H2O (1.5 mL) and DME (2.5 mL).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17]>S1(CCCC1)(=O)=O>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CNc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: O=S1(=O)CCCC1
Product: CNc1nc(Nc2ccc(Cl)c(Cl)c2)ncc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
6.47 g of 2-chloro-4-methylamino-5-nitro-pyrimidine and 11.7 g of 3,4-dichloro-aniline are heated to 160° C. in 60 ml of sulpholane within 45 minutes in an oil bath. After 40 minutes stirring at this temperature the reaction mixture is cooled and added to 600 ml of ice water. The precipitate is suction filtered, washed repeatedly with water and dried. The residue is stirred for one hour with 100 ml of ethyl acetate, the precipitate is suction filtered, washed with ethyl acetate and dried.
Reaction SMILES: FC(F)(F)C([O:5][CH2:6][CH:7]([O:16][C:17]([C:19]1([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)=[C:24]([F:36])[CH:23]=2)[CH2:21][CH2:20]1)=[O:18])[CH2:8][O:9]C(=O)C(F)(F)F)=O.N1C=CC=CC=1.CO>CCCCC.C(Cl)Cl>[OH:5][CH2:6][CH:7]([O:16][C:17]([C:19]1([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)=[C:24]([F:36])[CH:23]=2)[CH2:21][CH2:20]1)=[O:18])[CH2:8][OH:9]
Reactant: O=C(OCC(COC(=O)C(F)(F)F)OC(=O)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1)C(F)(F)F
Solvent: ClCCl
Solvent: CCCCC
Solvent: c1ccncc1
Product: O=C(OC(CO)CO)C1(c2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)CC1
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 100.4 %

Procedure:
1-(3′,4′-Dichloro-2-fluorobiphenyl-4-yl)cyclopropane carboxylic acid oxiranylmethyl ester (1.0 g, 2.62 mmol) was dissolved in dry DCM (25 mL), and the solution was cooled at −20° C. To this solution 2,2,2-trifluoroacetic anhydride (1.46 mL, 10.49 mmol) in dry DCM (25 mL) was added, and the reaction mixture was kept at r.t. for 2 hours. All the volatile components were removed under reduced pressure, and traces of trifluoroacetic anhydride were removed by co-evaporation with toluene (2×100 mL) to afford crude 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid 2-(2,2,2-trifluoro-acetoxy)-1-(2,2,2-trifluoro-acetoxymethyl)ethyl ester (1.4 g, 2.368 mmol) as a colourless oil. 1-(3′,4′-Dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid 2-(2,2,2-trifluoro-acetoxy)-1-(2,2,2-trifluoro-acetoxymethyl)ethyl ester (0.9 g, 1.522 mmol) was dissolved in a mixture of pentane/CH2Cl2 (3/1 v/v; 10 mL), and the solution was cooled at −20° C. To this solution, pyridine (1.231 mL, 15.22 mmol) and methanol (0.925 mL, 22.83 mmol) dissolved in a mixture of pentane/DCM (3/1 v/v; 10 mL) were added. The reaction mixture was allowed to warm to r.t. and stirred at r.t. for 1 hour and 45 minutes. The solvent was removed under reduced pressure, and the residue was dried under vacuum for 1 hour to obtain crude 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropane carboxylic acid 2-hydroxy-1-hydroxymethylethyl ester (0.61 g, quantitative yield) which was used as such in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([OH:26])([C:5]2[C:6]3[O:10][CH:9]=[CH:8][C:7]=3[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:22]([CH3:27])[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc(Br)c2occc2c1
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Product: COc1cc(C2(O)CCN(Cc3ccccc3)CC2C)c2occc2c1
Yield: 53.8 %

Procedure:
Beginning with 4.0 gm (17.6 mMol) 5-methoxy-7-bromobenzofuran and 3.94 gm (19.4 mMol) 1-benzyl-3-methyl-4-oxo-piperidine, 3.33 gm (54%) of the desired compound were recovered essentially as described in EXAMPLE 3.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]([NH:8][C:9]1[S:10][C:11]([S:15](Cl)(=[O:17])=[O:16])=[C:12]([CH3:14])[N:13]=1)(=[O:7])[CH3:6].C(N(CC)CC)C>O1CCOCC1>[OH:2][CH2:1][CH2:3][NH:4][S:15]([C:11]1[S:10][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[N:13][C:12]=1[CH3:14])(=[O:16])=[O:17]
Reactant: NCCO
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)NCCO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.8 %

Procedure:
To a stirred solution of ethanolamine (1.08 g, 17.7 mmol) in dioxane (20 ml) was added at 0° C. (ice water bath) commercially available 2-acetamido-4-methylthiazole-5-sulfonyl chloride (1.5 g, 5.89 mmol) and triethylamine (0.9 ml, 6 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by flash chromatography on silica gel (ethyl acetate/MeOH) and subsequent crystallization (dichloromethane/MeOH/hexane) to yield 2-acetamido-4-methyl-thiazole-5-sulfonic acid (2-hydroxy-ethyl)-amide (1.0 g, 61%) as a white solid. MS (ISP) 278.0 [(M−H)−]; mp 211° C.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:35])[C@@H:24]([NH:25]C(=O)CC4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][CH:18]2OS(C2C=CC(C)=CC=2)(=O)=O)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C>ClCCl.CO>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:35])[CH:24]([NH2:25])[C@H:21]3[S:20][CH2:19][CH:18]=2)=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)OC(c2ccccc2)c2ccccc2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 0 °C
Reaction time: 4 h
Yield: 57.9 %

Procedure:
To a solution of 3-p-toluenesulfonyloxy-7beta-phenylacetylaminocepham-4-carboxylic acid diphenylmethyl ester (3d) in dichloromethane (7 parts) cooling at -15° to -10° C. are added pyridine (2 equivalents) and phosphorus pentachloride (1.7 equivalents). After stirring at -15° to -10° C. for 4 hours, the mixture is diluted with methanol (12 parts) cooled at -40° to -30° C. and then stirred at -30° C. for 30 minutes and at 0° to 5° C. for 2.5 hours. The mixture is cooled to -40° to -30° C., mixed dropwise with triethylamine (8 equivalents), and the mixture is stirred at 0° to 5° C. for 2 hours and let stand overnight. The mixture is diluted with dichloromethane and ice-water and stirred for 20 minutes at 0° to 5° C. The formed organic layer is taken, washed with hydrochloric acid, water, aqueous sodium hydrogen carbonate, and water, dried, and concentrated. The residue is crystallized from ethyl acetate to give 7beta-amino-3-cephem-4-carboxylic acid diphenylmethyl ester (5). Yield: 57.9%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:24]([O:34][CH3:35])[CH:23]=3)[N:13]3[CH2:18][CH2:17][NH:16][C:15](=[O:19])[C:14]=23)=[CH:6][CH:5]=1.CI.O.[C:39](=O)(O)[O-].[Na+]>C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:24]([O:34][CH3:35])[CH:23]=3)[N:13]3[CH2:18][CH2:17][N:16]([CH3:39])[C:15](=[O:19])[C:14]=23)=[CH:8][CH:9]=1
Reactant: COc1cc(/C=C/c2nc(-c3ccc(F)cc3)c3n2CCNC3=O)ccc1-n1cnc(C)c1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/c2nc(-c3ccc(F)cc3)c3n2CCN(C)C3=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (containing mineral oil at 60%, 8 mg) was added to a solution of 1-(4-fluorophenyl)-3-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-6,7-dihydro-5H-imidazo[1,5-a]pyrazin-8-one (42 mg) in THE (3 mL), and the reaction solution was stirred at room temperature for 20 minutes. Methyl iodide (20 mg) was added to the reaction solution, and the reaction solution was stirred at room temperature for two hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: ethyl acetate→ethyl acetate:methanol=5:1) to obtain 10 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][OH:8])=[NH:6].[C:12]1(=O)[O:17][C:15](=[O:16])[CH2:14][CH2:13]1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[N:6]=[C:12]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[O:8][N:7]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: N=C(NO)c1cccc(Cl)c1
Reactant: O=C1CCC(=O)O1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)CCc1nc(-c2cccc(Cl)c2)no1
Yield: 59.7 %

Procedure:
3-Chloro-N-hydroxy-benzamidine 4.52 g, 26.5 mmol) was heated with succinic anhydride (2.65 mg, 26.5 mmol) in DMF (5 ml) at 150° C. for an h. The reaction mixture was cooled down and diluted with ethyl acetate. The organic solution was washed with water and brine, concentrated by vacuum. The residue was triturated with 20% ethyl acetate in hexanes to give 4.0 g (60%) of 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid as white solid. ). 1H-NMR(CDCl3) d(ppm): 8.08 (s, 1H), 7.96 (d, 1H), 7.49 (d, 1H), 7.42 (t, 1H), 3.28 (t, 2H) and 3.04 (t, 2H). Step 2: 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid hydrazide: This acid was reacted with iodoethane (1.6 g, 10.5 mmol) and K2CO3 (1.46 10.5 mmol) in DMF (5 ml) for 5 min to form 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid ethyl ester. The ethyl ester was then treated with 37% hydrazine (2 ml) in ethanol (5 ml) at 80° C for2 h to give 595 mg (65% in 3 steps) of 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid hydrazide as off-white solid 1H-NMR (CDCl3) d(ppm): 8.07 (s, 1H), 7.96 (d, 1H), 7.49 (d, 1H), 7.43 (t, 1H), 7.00 (w, 1H), 3.95 (w, 2H), 3.34 (t, 2H) and 2.79 (t, 2H).
Reaction SMILES: [Na].[CH3:2][NH:3][C:4]([NH2:6])=[S:5].[C:7]([CH:9]([CH2:15][CH:16](OCC)OCC)[C:10](OCC)=[O:11])#[N:8]>C(O)C>[CH3:2][N:3]1[C:7]2[NH:8][CH:16]=[CH:15][C:9]=2[C:10](=[O:11])[N:6]=[C:4]1[SH:5]
Reactant: CNC(N)=S
Reactant: CCOC(=O)C(C#N)CC(OCC)OCC
Agent: [Na]
Solvent: CCO
Product: Cn1c(S)nc(=O)c2cc[nH]c21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Sodium metal (1.21 g) was dissolved in anhydrous ethanol (50 ml) followed by addition of N-methylthiourea (4.96 g), and the mixture was stirred for dissolution at 50° C. for 30 minutes. Then, a solution of ethyl 2-cyano-4,4-diethoxybutyrate (11.47 g) in ethanol (10 ml) was added and the mixture was refluxed at 100° C. for 5 hours. The solvent was then distilled off under reduced pressure and the residue was-dissolved by adding water (20 ml). Then, 10% hydrochloric acid (75 ml) was added and the mixture was stirred overnight. The resulting precipitate was collected by filtration, washed serially with water, ethanol and ether, and dried to provide the title compound (6.8 g). 1H-NMR (DMSO-d6) δ: 3.82(3H,s), 6.41-6.44(1H,m), 6.92-6.95(1H,s), 12.02(1H,s), 12.06(1H,s).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]3[C:20](=O)[C:19](=[O:22])[C:18]=3[O:23]C)[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:25][NH2:26]>CO.C(Cl)(Cl)Cl.C(O)C>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH:12]([NH:16][C:17]3[C:18](=[O:23])[C:19](=[O:22])[C:20]=3[NH:26][CH3:25])[CH2:11]2)[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: COc1c(NC2CCCC(c3csc(NC(=N)N)n3)C2)c(=O)c1=O
Reactant: CN
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: CO
Product: CNc1c(NC2CCCC(c3csc(NC(=N)N)n3)C2)c(=O)c1=O
Reaction time: 2 h

Procedure:
A solution of 1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-2-methoxycyclobutene-3,4-dione (0.25 g.) in warm methanol/chloroform (50:50 v/v) (50 ml.) was treated with 14 ml. of a solution of methylamine in ethanol (33% w/v) and the resulting solution allowed to stand at room temperature for 2 hours. Concentration of the reaction mixture gave a crystalline solid (0.21 g.) which was collected and washed with a small volume of methanol to give 1-[3-(2-guanidinothiazol-4-yl)cyclohexylamino]-2-methylaminocyclobutene-3,4-dione, obtained as the hemihydrate, m.p. 263°-268° (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9](=[O:13])[NH:10][CH2:11]Cl.[Cl:14][C:15]1[CH:25]=[C:24]([Cl:26])[C:23]([Cl:27])=[CH:22][C:16]=1[O:17][CH2:18][C:19]([O-:21])=[O:20].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([NH:10][CH2:11][O:21][C:19](=[O:20])[CH2:18][O:17][C:16]1[CH:22]=[C:23]([Cl:27])[C:24]([Cl:26])=[CH:25][C:15]=1[Cl:14])=[O:13]
Reactant: O=C([O-])COc1cc(Cl)c(Cl)cc1Cl
Reactant: O=C(NCCl)Oc1ccccc1Cl
Agent: [Na+]
Solvent: CC#N
Product: O=C(COc1cc(Cl)c(Cl)cc1Cl)OCNC(=O)Oc1ccccc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.6 %

Procedure:
A solution of 220 g (1 mole) of N-chloromethylcarbamic acid 2-chlorophenyl ester in 1 liter of anhydrous acetonitrile was added dropwise to a suspension of 277.5 g (1 mole) of sodium 2,4,5-trichlorophenoxyacetate in 2 liters of anhydrous acetonitrile. After the exothermic reaction had subsided, the mixture was stirred for a further 15 hours at room temperature. It was then filtered and the filtrate was concentrated in vacuo by distilling off the solvent. The residue was recrystallised from ether/benzine. 354 g (80.6% of theory) of 2-(2,4,5-trichlorophenoxy)-acetic acid 2-chlorophenoxycarbonylaminomethyl ester were obtained in the form of white crystals of melting point 119° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:19])([F:18])[C:12]([F:17])([F:16])C([O-])=O.[Na+]>CN(C=O)C.O.CCOCC.[Cu]I>[F:16][C:12]([F:17])([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:11]([F:19])([F:18])[F:10]
Reactant: N#Cc1ccc(Br)cc1
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)C(F)(F)F)cc1
Reaction time: 0.08 h

Procedure:
4-Bromobenzonitrile (10 g, 54.9 mmol), sodium pentafluoropropionate (26.5 g, 0.143 mol) and copper (I) iodide (27.1 g, 0.142 mol) were heated to 150° C. in dry DMF (130 ml) for 4 h. The reaction mixture was diluted with water and Et2O and kieselgur filter aid was added. This bi-phasic mixture was stirred for 5 min, filtered and separated. The aqueous phase was extracted with Et2O. The combined organic phases were washed with water and aq. NH3, then dried over MgSO4, filtered and concentrated under reduced pressure to give the crude product as a brown oil. This was purified by flash chromatography (silica gel, 20-30% DCM in iso-hexanes) to give the title compound, 7.5 g (62%). 1H NMR (500 MHz, CDCl3): δ 7.75 (2H, d, J 8.3), 7.83 (2H, d, J 8.6), 19F NMR (470 MHz, CDCl3): δ −84.5, −116.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.N1C=CC=CC=1.Cl[C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:15][C:12]1[CH:11]=[CH:10][C:9]2[C:3]3[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=3[NH:1][C:23](=[O:25])[C:14]=2[CH:13]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1nn(C)c(N)c1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nn(C)c2[nH]c(=O)c3cc(F)ccc3c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 146 %

Procedure:
A solution of 5-amino-4-(4-fluorophenyl)-1,3-dimethylpyrazole (20.0 g) and pyridine (23.6 mL) in dichloromethane (150 mL) was added dropwise over 30 min to a solution of triphosgene (11.6 g) in dichloromethane (100 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. The reaction solution was added dropwise to a solution of aluminum chloride (97.5 g) in dichloromethane under ice-cooling, and the mixture was stirred at room temperature for 2 days. After the completion of the reaction, the reaction solution was poured into ice-water. The precipitated crystals were collected by filtration and washed with water to give 7-fluoro-1,3-dimethyl-3H-pyrazolo[3,4-c]isoquinolin-5(4H)-one (13.2 g).
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(O)=O.S(=O)(=O)(O)O.[NH:24]=[N+]=[N-]>C(Cl)CCl>[NH2:24][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: [N-]=[N+]=N
Reactant: O=C(O)c1ccc(C2CCCc3cncn32)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: Nc1ccc(C2CCCc3cncn32)cc1

Procedure:
A solution of 2.42 g of 5-(p-carboxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in 100 ml of ethylene dichloride is treated with 6 ml of concentrated sulfuric acid. The reaction mixture is heated to 40° and 6 ml of hydrazoic acid (2M is ethylene dichloride) is added dropwise. When gas evolution has ceased, the reaction mixture is evaporated. The residue is redissolved in water and adjusted to pH 10. The aqueous phase is extracted with methylene chloride (3×30 ml). The organic extracts are dried over potassium carbonate and evaporated to yield the title compound.