Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.CS(O[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=O)=O.CN(C)P(N(C)C)(N(C)C)=O>O>[C:29]1([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CS(=O)(=O)OCCCCCCCCCCCc1ccccc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)c1ccc(NCCCCCCCCCCCc2ccccc2)cc1

Procedure:
A mixture of 16.5 g. of ethyl p-aminobenzoate, 16.3 g. of 11-phenylundecanol O-methanesulfonate (prepared as described in Example 7) and 50 ml. of hexamethylphosphoramide are heated in an oil bath at 120° C. for 20 hours. The mixture is poured into ice and water and extracted with chloroform. The extracts are washed with water, 0.1 N NaOH, saturated sodium chloride solution and water. After drying over magnesium sulfate the extract is filtered through silica gel and the silica gel is washed with chloroform. The filtrate is concentrated in vacuo to an oil which is combined with 200 ml. of ethanol-water (9:1), 15 g. of potassium hydroxide and the mixture is refluxed for 3.5 hours. The mixture is acidified with concentrated hydrochloric acid, diluted with 50 ml. of water and chilled. Dilution with 100 ml. of ethanol and 25 ml. of water and filtration gives a gummy solid which is washed with water. The solid is dissolved in hexane:ether:ethyl acetate:acetic acid (40:5:5:2) and filtered through silica gel G. The support is washed with the same solvent (2 fractions). The first fraction is concentrated in vacuo to an oil which is crystallized from hexane to give pale yellow crystals, m.p. 50°-52° C. Recrystallization from ether-hexane (1:1) gives white crystals, m.p. 53°-55° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:13]([CH2:23][C:24]([O:26]C)=[O:25])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:13]([CH2:23][C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CN(CCCc1ccccc1)C(=O)CCCCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)CN(CCCc1ccccc1)C(=O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
Methyl 2-(5-phenyl-N-(3-phenylpropyl)pentanamido)acetate (34.2 mg, 0.0931 mmol) was dissolved in 0.5 mL of methanol and then 100 μL of 20% aqueous sodium hydroxide solution was added. The reaction mixture was then stirred for 2 hours at room temperature. Upon completion of the reaction, the reaction solution was diluted with 3 mL of ethyl acetate and neutralized by adding 200 μL of 10% aqueous hydrogen chloride solution. After removing water with anhydrous magnesium sulfate and filtering out the precipitate, the resulting solution was concentrated by distillation under reduced pressure and purified by column chromatography to obtain 26.2 mg (0.0741 mmol, 80%) of the desired compound.
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:20])=[C:10]2[C:18]([CH3:19])=[N:17][S:16][C:11]2=[C:12]([CH2:14][CH3:15])[N:13]=1)=[O:7])CCC.[NH2:21][CH2:22][C:23]([OH:25])=[O:24]>>[CH2:14]([C:12]1[N:13]=[C:8]([C:6]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:7])[C:9]([OH:20])=[C:10]2[C:18]([CH3:19])=[N:17][S:16][C:11]=12)[CH3:15]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(CC)c2snc(C)c2c1O
Product: CCc1nc(C(=O)NCC(=O)O)c(O)c2c(C)nsc12

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-Ethyl-4-hydroxy-3-methyl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and glycine: MS (m/z) 296.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1([C:11]([OH:13])=O)[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:4][NH:3]1.C(N(CC)CC)C.N1C(F)=NC(F)=NC=1[F:23]>ClCCl>[Cl:1][C:2]1([C:11]([F:23])=[O:13])[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[CH:5]=[CH:4][NH:3]1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CCNC1=NC(Cl)(C(=O)O)NC=C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC1=NC(Cl)(C(=O)F)NC=C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
To a solution containing 7.0 g (34.72 mmol) of acid prepared in step 2.4 and 5.32 mL (38.19 mmol) of triethylamine in 98 mL of dichloromethane are added 5.89 mL (69.79 mmol) of cyanuric fluoride. The mixture is stirred for 3 hours and the solution is diluted with 590 mL of CH2Cl2 and 190 mL of ice-cold aqueous NaHCO3. The organic phase is washed twice with 190 mL of ice-cold aqueous NaHCO3 and dried over MgSO4. The solvent is then evaporated off under reduced pressure. 7.0 g of expected product are obtained in the form of a red oil that solidifies slowly, and that is used as obtained in the following step. Quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[CH2:21]([NH:23][CH2:24][CH:25]1[CH:29]([CH3:30])[CH2:28][NH:27][CH2:26]1)[CH3:22].C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[C:3]([N:27]2[CH2:28][CH:29]([CH3:30])[CH:25]([CH2:24][NH:23][CH2:21][CH3:22])[CH2:26]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: CCNCC1CNCC1C
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCNCC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2Cl)CC1C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.5 g), anhydrous acetonitrile (5 ml), 3-ethylaminomethyl-4-methylpyrrolidine (0.36 g) and DBU (0.25 g) was refluxed for 2 hours and allowed to stand overnight at room temperature. The resulting precipitate was collected by filtration, washed with acetonitrile and ether successively and recrystallized from chloroform-methanol-concentrated aqueous ammonia to give the title compound (0.56 g) as pale yellow powder, mp 254°-257° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C:28]4(OC)[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.B(F)(F)F>C(#N)C.ClC(Cl)C>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH2:18][C:19]3[CH:20]=[C:21]([C@H:28]4[C@H:33]([OH:34])[C@@H:32]([OH:35])[C@H:31]([OH:36])[C@@H:30]([CH2:37][OH:38])[O:29]4)[CH:22]=[CH:23][C:24]=3[CH:25]([CH3:27])[CH3:26])[CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1(c2ccc(C(C)C)c(Cc3ccc4c(c3)N(Cc3ccccc3)CCO4)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: CC(Cl)Cl
Product: CC(C)c1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCO2
Temperature: 0 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
To a stirred solution of (3R,4S,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol (600 mg, 1.09 mmol) in acetonitrile-dichloroethane mixture (1:1 mixture, 10 mL) was added triethylsilane (0.7 mL, 4.4 mmol) and boron trifluoride diethyletharate complex (0.27 mL, 2.18 mmol) at −20° C. After stirring for 4 h at 0° C., the reaction was quenched with aq. saturated NaHCO3 solution (8 mL). The volatiles were evaporated under reduced pressure; the resulting mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined and washed with brine (5 mL), dried over sodium sulphate, concentrated to a residuer which was purified by column chromatography to furnish (2S,3R,4R,5S,6R)-2-[3-(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-4-isopropyl-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (520 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][NH:14][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([Br:15])=[CH:17][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1CNC(=O)c1ccc(Br)cc1
Reaction time: 3 h
Yield: 100 %

Procedure:
To 2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.00 g, 4.97 mmol) and 4-bromo-benzoic acid (996 mg, 4.97 mmol) in DMF (25 mL) was added N-methylmorpholine (655 μl, 5.96 mmol) and HATU (1.89 g, 4.97 mmol). After stirring for 3 hours the reaction was concentrated then diluted with EtOAc and washed with 1N HCl, saturated NaHCO3, and brine. The organic phase was then dried over Na2SO4 and concentrated. The crude material was purified by silica gel chromatography (20-50% EtOAc-hexanes gradient) to afford 2-[(4-bromo-benzoylamino)-methyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.91 g, 4.97 mmol, quantitative yield). LCMS-ESI+: calc'd for C17H24BrN2O3: 383.1 (M+H+). Found: 383.6 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:18])[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32]>>[O:32]=[C:27]1[NH:28][C:29](=[O:31])[C:30](=[CH:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:18])[CH:10]=3)=[CH:7][CH:8]=2)[S:26]1
Reactant: O=Cc1ccc(-c2cccc(CNC(=O)Nc3ccccc3)c2)cc1
Reactant: O=C1CSC(=O)N1
Product: O=C(NCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1)Nc1ccccc1
Yield: 50.9 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 2.1 g (6.4 mmol) of 1-(4′-formylbiphenyl-3-ylmethyl)-3-phenylurea with 750 mg (6.4 mmol) of 2,4-thiazolidine dione, 1.4 g (53%) of the expected product are obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(O)[CH:10]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:38])([CH3:37])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:26][C:25]=2[O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:10]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:37])([CH3:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:26][C:25]=2[O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CN(Cc3ccccc3)CCC2(O)CCCc2ccccc2)c(OCc2ccccc2)c1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCCCCC(C)(C)c1ccc(C2=C(CCCc3ccccc3)CCN(Cc3ccccc3)C2)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a -5° C. solution of 3.0 g. (4.85 mmols.) of 1-benzyl-3-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-phenylpropyl)-4-piperidinol in 5 ml. of pyridine is slowly added 2.89 g. (24.3 mmols.) of thionyl chloride. The reaction mixture is then allowed to slowly warm to 25° C. and is stirred 12 hours longers. The reaction mixture is quenched by slow addition to 200 ml. of cold 20% potassium carbonate. The quenched mixture is extracted with 250 ml. of ether, the extract washed once with 200 ml. 20% potassium carbonate, dried over magnesium sulfate and evaporated. THe residue is purified via column chromatography on 300 g. silica gel eluted with 50% ether-cyclohexane to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:2]=2[F:1])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Reactant: Nc1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cc1)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
A solution of 2-fluoro-4-(trifluoromethyl)benzoyl chloride (5.05 g, 0.0223 mol) and 4-bromoaniline (3.83 g, 0.0223 mol) in anhydrous dichloromethane (150 mL) was cooled to 0° C. and N,N-diisopropylethylamine (4.26 mL, 0.0245 mol) was added under nitrogen atmosphere dropwise. The resulting mixture was stirred at ambient temperature for 24 hours, concentrated and the residue was partitioned between ethyl acetate (120 mL) and water (100 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated. The residue was suspended in cold n-heptane (50 mL) and the precipitate was collected by filtration and dried to yield N1-(4-bromophenyl)-2-fluoro-4-(trifluoromethyl)benzamide (7.1 g, 0.0196 mol) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.74 (s, 1H), 7.90 (m, 2H), 7.74 (d, 1H), 7.68 (d, 2H), 7.56 (d, 2H).
Reaction SMILES: C([O:8][C:9]1[C:10]([NH2:21])=[N:11][CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:14]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[NH2:21][C:10]1[C:9]([OH:8])=[CH:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12][N:11]=1
Reactant: Nc1ncc(-c2ccccc2)cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Nc1ncc(-c2ccccc2)cc1O
Reaction time: 5 h
Yield: 93 %

Procedure:
To a solution of 3-benzyloxy-5-phenyl-pyridin-2-ylamine (Example I-87, 3.27 g, 11.8 mmol) in methanol (30 mL) was added Pd(OH)2 (2.5 g, 2.37 mmol). The mixture was degassed and charged with hydrogen three times, and then stirred under hydrogen balloon for 5 hr. The reaction was filtered through a celite pad, washed with methanol, and condensed. After high vacuum dry, 2-amino-5-phenyl-pyridin-3-ol was obtained (2.04 g, 93% yield). MS m/z 187 [M+1].
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.[F:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[CH:21]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:28][CH:27]=1)[C:22]([NH2:24])=[S:23].C(=O)([O-])O.[Na+]>ClCCl>[CH3:6][S:23][C:22](=[NH:24])[CH:21]([C:12]1[CH:13]=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:11]=1[F:10])[NH:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:36]=[C:35]([CH3:37])[O:34][N:33]=2)=[CH:30][CH:31]=1
Reactant: COc1cc(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc1OC
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
After adding 3.62 g of trimethyloxonium tetrafluoroborate (hereinafter, “Me3O+BR4−”) to a solution of 8.59 g of 2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetamide in 400 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with dichloromethane. After washing the organic layer with saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (8.89 g, crude product) as an oil.
Reaction SMILES: C1(C2C=CN=[N:6][C:5]=2[C:10]2N=CO[N:11]=2)CC1.[CH:15]1([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:28]=[CH:27]N=NC=3)[N:19]=2)[CH2:17]C1>>[CH:23]1([C:20]2[N:19]=[C:18]([C:15]3[CH:17]=[N:11][CH:10]=[CH:5][N:6]=3)[O:22][N:21]=2)[CH2:28][CH2:27]1
Reactant: c1cc(C2CC2)c(-c2ncon2)nn1
Reactant: c1cc(-c2noc(C3CC3)n2)cnn1
Product: c1cnc(-c2nc(C3CC3)no2)cn1

Procedure:
The cyclopropyl-1,2,4-oxadiazolylpyridazine according to claim 1: 4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-pyridazine.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:28]=[CH:29][N:30]=[CH:31][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:41]([O:44][CH2:45][C:46](Cl)=[O:47])(=[O:43])[CH3:42]>CN(C=O)C>[C:41]([O:44][CH2:45][C:46]([N:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:18]=[N:17][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[C:8]5[CH:28]=[CH:29][N:30]=[CH:31][C:7]=5[N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:10]=4[N:11]=3)=[CH:21][CH:20]=2)[CH2:23][CH2:24]1)=[O:47])(=[O:43])[CH3:42]
Reactant: CC(=O)OCC(=O)Cl
Reactant: c1cc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c2cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)N1CCN(c2ccc(Nc3ncc4c5ccncc5n(C5CCCC5)c4n3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 7 (207 mg, 0.50 mmol) in DMF (5 mL) were added N,N-diisopropylethylamine (174 uL, 1.0 mmol) and acetoxyacetyl chloride (65 uL, 0.60 mmol) and the resulted mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated to give compound 189 as a yellow solid which was used in next step without further purification. LCMS-ESI (POS), M/Z, M+1: Found 514.2, Calculated 514.2.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]12([OH:17])[CH2:14][C:9]3([OH:15])[CH2:10][CH:11]([CH2:13][C:7]([OH:16])([CH2:8]3)[CH2:6]1)[CH2:12]2>CN(C=O)C>[C:1]([O:17][C:5]12[CH2:14][C:9]3([O:15][C:9](=[O:15])[CH3:8])[CH2:10][CH:11]([CH2:13][C:7]([O:16][C:7](=[O:16])[CH3:6])([CH2:8]3)[CH2:6]1)[CH2:12]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Solvent: CN(C)C=O
Product: CC(=O)OC12CC3CC(OC(C)=O)(C1)CC(OC(C)=O)(C3)C2
Temperature: 40 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3,5-adamantanetriol obtained by the method of Example 32 and 36 mmole of triethylamine were dissolved in 10 mL of DMF. To the mixture, 33 mmole of acetyl chloride was added dropwise over 30 minutes at 40° C. The mixture was stirred for another 3 hours at 40° C. As a result, the conversion of 1,3,5-adamantanetriol was 99%, and 1,3,5-tris(acetyloxy)adamantane (yield 95%) was formed.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].[Cl:13][C:14]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:15]=1[C:16]([N:18]=[C:19]=[O:20])=[O:17]>C(#N)C>[Cl:13][C:14]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:15]=1[C:16]([NH:18][C:19](=[O:20])[NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6])=[O:17]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: O=C=NC(=O)c1ccc(Cl)cc1Cl
Solvent: CC#N
Product: COc1ccc(C(=O)O)cc1NC(=O)NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 95.7 %

Procedure:
20 g (120 mmol) of 3-amino-4-methoxybenzoic acid were made to react with 36 g (168 mmol) of 2,4-dichlorobenzoyl isocyanate from step a in 400 ml of acetonitrile and left to react therewith at reflux for 2 hours. After the mixture has cooled down to room temperature, the precipitate is filtered off with suction, washed twice with in each case 20 ml of acetonitrile, sucked dry and dried under high vacuum. 44 g (96%) of the desired product are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:14][S:15][C:16](S(C)=O)=[CH:17][N+:18]([O-:20])=[O:19]>CO>[CH3:14][S:15][C:16]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][N:7]=1)=[CH:17][N+:18]([O-:20])=[O:19]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: COc1cccnc1CSCCN
Solvent: CO
Product: COc1cccnc1CSCCNC(=C[N+](=O)[O-])SC
Yield: 56.9 %

Procedure:
A solution of 2-[2-aminoethylthiomethyl]-3-methoxypyridine (2.1 g) in methanol (33 ml) was added over 25 minutes to a stirred solution of 1-methylthio-1-methylsulphinyl-2-nitroethylene (2.1 g) in methanol (75 ml) at 30°. After standing for an hour the solution was concentrated to give a yellow-brown oil which was crystallised from ethanol/ether to yield 1-methylthio-1-[2-((3-methoxy-2-pyridyl)methylthio)ethylamino]-2-nitroethylene (1.9 g), m.p. 87.5°-88.5°.
Reaction SMILES: [OH:1]O.[OH-].[Na+].[C:5]([C:8]1[N:12]([CH3:13])[N:11]=[C:10]([CH2:14][CH2:15][CH3:16])[C:9]=1[NH:17][C:18](=O)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=1)(=[O:7])[NH2:6]>O.O1CCOCC1>[OH:1][CH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:18]2[NH:6][C:5](=[O:7])[C:8]3[N:12]([CH3:13])[N:11]=[C:10]([CH2:14][CH2:15][CH3:16])[C:9]=3[N:17]=2)=[CH:21][CH:22]=1
Reactant: CCCc1nn(C)c(C(N)=O)c1NC(=O)Cc1ccc(CBr)cc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(CO)cc3)nc12
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Aqueous hydrogen peroxide (0.24 ml, 30% w/w, 0.0021 mol) was added to a solution of sodium hydroxide (180 mg, 0.0045 mol) in water (10 ml). A solution of N-(5-carbamoyl-1-methyl-3-propyl-1H-pyrazolyl)-2-(4-bromomethylphenyl)acetamide (400 mg, 0.001 mol) in dioxan (5 ml) was then added and the mixture stirred at 90° C. for 4 hours. On cooling, the reaction mixture was concentrated under reduced pressure, the residue dissolved in water (10 ml) and acidified to pH 5 with 1N aqueous hydrochloric acid. This solution was then extracted with dichloromethane (2×20 ml), the combined organic extracts dried (MgSO4), filtered and evaporated under reduced pressure.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23](O)=[O:24])=[CH:13][CH:12]=2)[C:8]2[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl>C1C=CC=CC=1>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH2:23][OH:24])=[CH:13][CH:12]=2)[C:8]2[CH:26]=[CH:27][CH:28]=[CH:29][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Agent: Cl
Solvent: c1ccccc1
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.4 %

Procedure:
A stirred solution of 2-butyl-1-[(2'-carboxy-biphenyl-4-yl)methyl]benzimidazole (1.50 g.) in benzene (30 ml) was added dropwise to sodium dihydro-bis(2-methoxyethoxy)aluminate (70% toluene solution). The mixture was stirred for one hour at room temperature, and then heated for 10 minutes under reflux. The reaction mixture was cooled and poured into 2N-HCl, followed by extraction with dichloromethane. The extract was washed with water and dried (MgSO4), and the solvent was evaporated in vacuo. The residue was purified by silica gel (80 g) column chromatography to give the title compound (0.67 g, 46%) as an oil, which was crystallized from ethyl acetate-ether to afford pale yellow prisms, m.p.162°-163° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=2)[C:10]#N)[CH:5]=[CH:6][C:7]=1[F:8].O=[CH:24][C:25](=C)[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19](=[O:22])(=[O:21])[NH2:20])=[CH:15][CH:14]=3)[CH:24]=[C:25]([CH3:26])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#CC(Nc1ccc(S(N)(=O)=O)cc1)c1ccc(F)c(F)c1
Reactant: C=C(C)C=O
Product: Cc1cc(-c2ccc(F)c(F)c2)n(-c2ccc(S(N)(=O)=O)cc2)c1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(3,4-difluorophenyl)-α-(4-sulfamoylanilino)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a pale yellow powder (yield 51%), melting at 177-1 79° C.