Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6])#[N:2].[Br:16][C:17]1[C:18](I)=[N:19][C:20]([I:23])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:16][C:17]1[C:18]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6])=[CH:8][CH:9]=2)=[N:19][C:20]([I:23])=[N:21][CH:22]=1
Reactant: Brc1cnc(I)nc1I
Reactant: N#CCNC(=O)c1ccc(B(O)O)cc1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCNC(=O)c1ccc(-c2nc(I)ncc2Br)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 50.2 %

Procedure:
To a mixture of 4-(cyanomethylcarbamoyl)phenylboronic acid (see example 3) (185 mg, 0.9 mmol) and 5-bromo-2,4-diiodopyrimidine (410 mg, 1.0 mmol) in 1,4-dioxane (10 mL), was added 2M aqueous potassium carbonate (100 μL). The resulting mixture was stirred under nitrogen for 5 minutes then tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.045 mmol) was added under a nitrogen atmosphere. The mixture was heated at 80° C. overnight. The cooled reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with water then brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as a brown solid. The crude material was purified by flash chromatography, eluting with 50% ethyl acetate/petroleum spirit to give 4-(5-bromo-2-iodopyrimidin-4-yl)-N-(cyanomethyl)benzamide (200 mg, 35% over 2 steps). LC-ESI-MS (method B): rt 6.2 min.; m/z 443.0/445.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:9]2[CH2:14][CH2:13][N:12](CC3C=CC(OC)=CC=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.ClC(OC(Cl)C)=O.Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC2)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Temperature: 27.5 °C
Reaction time: 12 h
Yield: 63.7 %

Procedure:
35 ml tetrahydrofuran was added to 10 gms (0.02463 moles) of compound obtained from Example 3 followed by slow addition of 4 gms (0.02797 moles) 1-chloroethyl chloroformate in 10 ml of tetrahydrofuran. The reaction mass was heated at reflux temperature for about 3 hours and concentrated to an oil. To the oil 50 ml of methanol was added, heated to reflux for about 16 hours and concentrated to get a residue. The residue was further treated with 50 ml of aqueous HCl and washed with dichloromethane (3×30 ml). To the aqueous layer 2 ml of n-Heptane was added and then treated with sodium hydroxide solution at 25-30° C. The reaction mass was stirred at 25-30° C. for about 12 hours. After completion of the reaction the product obtained was filtered and dried under vacuum at 50-55° C. to obtain the title compound (4.5 gms).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH3:24])=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][C:14]([C:19](OCC)=[O:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][NH:26][O:27][CH3:28].Cl.C([Mg]Cl)(C)C>C1COCC1>[CH2:1]([C:8]1[C:9]([CH3:24])=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][C:14]([C:19]([N:26]([O:27][CH3:28])[CH3:25])=[O:20])=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc2nc(C)c(Cc3ccccc3)c(C)c2c1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc2nc(C)c(Cc3ccccc3)c(C)c2c1
Temperature: 0 °C

Procedure:
A slurry of ethyl 3-benzyl-2,4-dimethylquinoline-6-carboxylate (99.5 mg, 0.312 mmol, Intermediate 34: step b) and N,O-dimethylhydroxylamine.HCl (42.2 mg, 0.433 mmol) in THF (1 mL) was stirred at 0° C. under argon while iPrMgCl (2.01 M in THF, 0.43 mL, 0.864 mmol) was added dropwise. The resulting dark solution was stirred at 0° C. overnight while the ice bath expired. It was then quenched with 5 M aqueous NH4Cl (4 mL) and extracted with EtOAc (2×3 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated, and the residue was flash chromatographed with a heptane to 100% EtOAc gradient to yield the title compound as an amber oil.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10](Cl)[S:9][N:8]=2)=[CH:3][CH:2]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1.O=O>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:10]2[S:9][N:8]=[C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:13])=[CH:2][CH:3]=3)[N:11]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2nsc(Cl)n2)cc1
Reactant: Fc1ccc([Mg]Br)cc1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: O=O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nsc(-c3ccc(F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.2 %

Procedure:
A mixture of 3-(p-tolyl)-5-chloro-1,2,4-thiadiazole (0.50 g, 2.37 mmol) and [1,3-bis(diphenylphosphino)propane]nickel(II) chloride catalyst (1.41 g, 2.61 mmol) in anhydrous THF (20 ml) is cooled in an ice-water bath. To this mixture is added slowly 4-fluorophenyl-magnesium bromide (1.0M in THF, 2.5 ml, 2.49 mmol) with exclusion of both moisture and oxygen. The mixture is allowed to warm to room temperature and stirred for 18 hours under N2. The mixture is filtered through celite and concentrated. The residue is taken up in CHCl3 (50 ml) and washed with brine (50 ml×2). The organic layer is dried over magnesium sulfate and concentrated. The residue is purified on a silica gel column, eluting with 3:7 CHCl3:hexanes to yield 5-(4′-fluorophenyl)-3-(p-tolyl)-1,2,4-thiadiazole (0.20 g, 31%).
Reaction SMILES: S[C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.ClCC(O)=[O:18].Cl>O>[OH:18][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Oc1cc(-c2ccccc2)nc(S)n1
Reactant: O=C(O)CCl
Agent: Cl
Solvent: O
Product: Oc1cc(-c2ccccc2)nc(O)n1
Yield: 83.5 %

Procedure:
2-Mercapto-4-hydroxy-6-phenylpyrimidine (8.6 g, 42 mmol) and chloroacetic acid (8.5 g, 90 mmol) were slurried in water (100 mL). After refluxing the mixture for 24 hours, hydrochloric acid was added and the precipitate was isolated by filtration. The solid was dried in a vacuum oven to give 6.6 g (83%) of 2,4-dihydroxy-6-phenylpyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1.N#N.[C:24](O)(=[O:26])[CH3:25]>[Pd]>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][N:11]([C:24](=[O:26])[CH3:25])[N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1
Reactant: CC(=O)O
Agent: [Pd]
Agent: N#N
Product: COc1ccc2c(c1)CN(C(C)=O)N=C2Cc1c(Cl)cncc1Cl
Yield: 50 %

Procedure:
A solution of 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (1 g, 3.12 mmoles), prepared as described in example 5, in glacial acetic acid (30 ml) under stirring and N2 was added with 10% Pd/C in catalytic amount, and the solution was put in a hydrogenator at 4 atmospheres. After 2 days the mixture was filtered and brought to dryness. The residue was flash chromatographed (eluent: hexane/ethyl acetate 3:7) to give 0.5 g of the title compound (yield: 50%). m.p.: 186-188° C.
Reaction SMILES: [O:1]1[C:5]2[C:6]([CH2:10][OH:11])=[CH:7][CH:8]=[CH:9][C:4]=2[O:3][CH2:2]1.[N:12]1([C:17](N2C=CN=C2)=[O:18])[CH:16]=[CH:15][N:14]=[CH:13]1>C(Cl)Cl>[N:12]1([C:17]([O:11][CH2:10][C:6]2[C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=[CH:8][CH:7]=2)=[O:18])[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: OCc1cccc2c1OCO2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(OCc1cccc2c1OCO2)n1ccnc1
Yield: 86.5 %

Procedure:
A solution of (benzo[d][1,3]dioxol-7-yl)methanol (2 g, 13.14 mmol) and di(1H-imidazol-1-yl)methanone (4.26 g, 26.28 mmol) in 20 mL CH2Cl2 was heated overnight at 50° C. The reaction was quenched with water, extracted with CH2Cl2, dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 10-70% EtOAc in CH2Cl2 gave (benzo[d][1,3]dioxol-7-yl)methyl 1H-imidazole-1-carboxylate (2.8 g, 86%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:17])=O>>[CH3:2][C:3]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:4]=1[C:5]([Cl:17])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Agent: Cl
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)Cl

Procedure:
Part A. A 1-L flask equipped with a reflux condenser and a nitrogen sweep to an HCl gas scrubber was charged with 2-methyl-5-nitrobenzoic acid (200 g, 1.10 mol). The reaction vessel was cooled in an ice bath and thionyl chloride (307 mL, 4.20 mol) was added in one portion. The ice bath was removed, and the reaction mixture was refluxed overnight. The excess thionyl chloride and the SO2 and HCl reaction side-products were removed by vacuum distillation to afford 2-methyl-5-nitrobenzoyl chloride as a solid residue, which was used without further purification. This material was immediately dissolved in methylene chloride (100 mL) and added dropwise with stirring to a commercial 40% dimethylamine solution (500 mL, 4.45 mol) which was maintained at 0° to 12° by periodic immersion in a dry ice-acetone bath. After complete addition, the reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was diluted with water and extracted with methylene chloride. The combined organic extracts were washed with water, dried, and concentrated. The resulting material was distilled under vacuum to afford 5-nitro-N,N,2-trimethylbenzamide (189.9 g, 0.91 mol, 83% yield) as a solid: mp 98°-99°; bp 156°-170° (0.5 torr); MS m/e 209(M+ +H); 1H NMR(CDCl3) δ 8.00-8.17(m,2H), 7.40(d,J=8 Hz,1H), 3.17(s,3H), 2.88 (s,3H), 2.41(s,3H). Anal. Calcd for C10H12N2O3 : C,57.69; H,5.81; N,13.45. Found: C,57.72; H,5.84; N,13.49.
Reaction SMILES: [CH3:1][N:2]([CH3:4])O.[H-].[Na+].[N+:7]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[C:20]([CH2:23]Cl)=[N:21][N:22]=[C:18]3[CH2:17][N:16]=[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:14]=2[CH:32]=1)([O-:9])=[O:8]>CN(C)C=O>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]2[N:19]3[C:20]([CH2:23][N:2]([CH3:4])[CH3:1])=[N:21][N:22]=[C:18]3[CH2:17][N:16]=[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])[C:14]=2[CH:32]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: CN(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 16, a solution of N,N-dimethylhydroxylamine in dimethylformamide is treated with sodium hydride, suspended in mineral oil, and the mixture is treated with 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-nitro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1>>[N+:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][OH:23])=[CH:17][CH:16]=1)([O-:13])=[O:12]
Reactant: Nc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=[N+]([O-])c1ccc(Nc2ccc(CCO)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2-chloro-1,5-dinitrobenzene and 4-aminophenylethyl alcohol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[C:5]([C:11]([OH:13])=[O:12])=[C:4]([CH3:14])[CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>[OH-].[Na+]>[CH2:9]([S:8][C:6]1[C:5]([C:11]([OH:13])=[O:12])=[C:4]([CH3:14])[CH:3]=[C:2]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:7]=1)[CH3:10]
Reactant: CCSc1nc(Cl)cc(C)c1C(=O)O
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Product: CCSc1nc(N2CCOCC2)cc(C)c1C(=O)O
Temperature: 105 °C
Yield: 48.9 %

Procedure:
A mixture of 12.0 g (51.7 mmol) 6-chloro-2-ethylsulfanyl-4-methyl-pyridine-3-carboxylic acid and 33.7 g (387 mmol) morpholine was heated to 105° C. for 5 d. After cooling to RT a 2M aq. NaOH sol. (200 ml) was added, followed by washing with ether (3×200 ml). The aqueous layer was then acidified with a 2M aq. HCl to pH 5 and extracted with EtOAc. In the same manner pH 4 was adjusted followed by extraction with EtOAc. The combined EtOAc extracts were dried over MgSO4 and concentrated in vacuo. Crystallisation (DCM/hexane) of the residue yielded 7.2 g (25.3 mmol, 49%) 2-ethylsulfanyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16](N5CCNCC5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1>>[OH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:30]1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: OCC1CCCNC1
Product: O=c1c2c[nH]c3ccc(N4CCCC(CO)C4)nc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following the procedure described for 6a using 3-hydroxymethylpiperidine instead of piperazine. 1H-NMR (DMSO-d6) δ (ppm): 1.75 (4H, brm), 2.87 (1H, dd, J=12.91, 9.89 Hz), 3.05 (1H, m), 3.13 (1H, d, J=5.22 Hz), 3.54 (2H, brm), 3.88 (2H, brd, J=2.91 Hz), 7.14 (1H, dt, J=7.42, 1.10 Hz), 7.19 (1H, d, J=9.34 Hz), 7.42 (2H, ddd, J=7.41, 2.20, 1.92 Hz), 7.79 (1H, d, J=9.34 Hz), 8.21 (2H, ddd, J=7.69, 1.92, 1.10 Hz), 8.52 (1H, s). m/z 361.4 (MH+).
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([CH:21]=[O:22])[CH2:17][CH2:16]1>CN(C)C=O>[N+:1]([C:4]1[N:5]([CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([CH:21]=[O:22])[CH2:19][CH2:20]2)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: O=CN1CCC(CCCBr)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=CN1CCC(CCCn2ccnc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The mixture of 2-nitroimidazole (11.3 g, 0.1M) and 50% by weight NaH in mineral oil (4.8 g, 0.1M) in dimethylformamide (50 ml) was stirred at room temperature for 1/2 hr. The solution of 4(3-bromo-propyl)-1-piperidine carboxaldehyde (23.4, 0.1M) in dimethylformamide (20 ml) was added to the above mixture and heated at 110° C. for 15 min. After the reaction, the solvent was removed in vacuo wand water (100 ml) was added and the mixture was extracted with ethylacetate (72×100 ml). The extracts, dried over Na2SO4, were concentrated and purified on silica gel columns, eluted with 5% by volume MeOH--95% by volume CH2Cl2 to give 4-[3-(2-nitro-1H-imidazol-1-yl)propyl]-piperidinecarboxaldehyde (22.8 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])=O.C(=O)(O)[O-].[Na+]>O>[C:8]([C:7]1[O:12][C:3]([CH2:2][Cl:1])=[N:5][N:6]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)C(=O)NNC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1nnc(CCl)o1
Temperature: 90 °C
Reaction time: 10 h
Yield: 92.2 %

Procedure:
A mixture of 1.34 g of N′-(chloroacetyl)-2,2-dimethylpropanohydrazide and 6.6 g of polyphosphoric acid was stirred at 90° C. for 10 hours. The reaction mixture was cooled to room temperature. After 200 ml of water and then sodium bicarbonate were added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 1.12 g of 2-t-butyl-5-(chloromethyl)-1,3,4-oxadiazole.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][N:12](CC1C=CC=CC=1)[CH2:13][CH2:14][CH2:15][NH:16][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1.CO.[ClH:32].[H][H]>[Pd].CC(O)C>[ClH:32].[ClH:32].[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH2:3][CH:2]1[CH2:11][NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[NH:22][CH2:21][CH2:20][CH2:19][N:18]=1
Reactant: [H][H]
Reactant: c1ccc(CN(CCCNc2ncccn2)CC2CCc3ccccc3O2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: c1ccc2c(c1)CCC(CNCCCNC1=NCCCN1)O2
Yield: 38 %

Procedure:
A mixture of 7.8 g of N-(3,4-dihydro-2H-1-benzopyran-2-yl)methyl-N-phenylmethyl-N'-(2-pyrimidinyl)-1,3-propanediamine, 200 ml methanol and 10 ml of 2-propanol saturated with HCl was hydrogenated in the presence of 2 g of palladium-on-charcoal catalyst (5%). After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was converted into the dihydrochloride salt in 2-propanol by adding 2-propanol saturated with hydrochloric acid. The salt was filtered off and dried, yielding 2.9 g (38.0%) of (±)-N-[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3-propanediamine dihydrochloride; mp. 227.0° C. (comp. 95).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:15])[CH2:12]3)[C:9]=2[C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:40])C=1>C(Cl)Cl>[C:1]1([S:7]([C:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:15])[CH2:12]3)[C:9]=2[C:16]([O:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])=[O:40])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccccc2)CC2CC(=O)C12
Solvent: ClCCl
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(S(=O)c2ccccc2)CC2CC(=O)C12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 150 mg of 3-phenylthio-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester in 7 mL of methylene chloride at -50° under argon was added 75 mg of 85% m-chloroperbenzoic acid in methylene chloride solution. The resulting solution was stirred between -40° and -35° for 30 min and then allowed to warm to room temperature over approximately 30 min. The solution was diluted with methylene chloride, washed successively with aqueous sodium sulfite and aqueous sodium bicarbonate, and then dried over sodium sulfate. Evaporation of the solvent afforded a crude product mixture which was purified by preparative thin layer chromatography on a 20×20×0.2 cm silica gel plate eluted with ether. The most prominent band, which was in the center of the plate, contained 115 mg (73.9%) of 3-phenylsulfinyl-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmethyl ester, as a colorless solid [an approximately 3:1 mixture of diastereoisomers at sulfur (by NMR)]. IR (neat): 1785, 1710, 1720, 1605 cm-1 : NMR (220 MHz; CDCl3): δ 2.32 (1H, m), 2.55 (1H, dd, J=18, 4), 2.7-3.0 (1H, m), 3.0-3.3 (1H, m), 3.36 (1H, m), 4.57 (1/4H, m, from minor isomer), 4.70 (3/4H, m, from major isomer), 6.86 (1H, broad s), and 7.1-7.6 (15H, m).
Reaction SMILES: O[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH:4]=[CH:5][C:6]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])=[O:7]>O>[C:10]1([C:9]2[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2([CH:5]=[CH:4][C:3]3[C:17](=[CH:18][CH:19]=[CH:20][CH:2]=3)[O:7]2)[O:12]1)=[O:11]
Reactant: O=C(O)c1ccccc1C(=O)C=Cc1ccccc1O
Solvent: O
Product: O=C1OC2(C=Cc3ccccc3O2)c2ccccc21
Yield: 90.3 %

Procedure:
12.7 g of o-(o-hydroxycinnamoyl)benzoic acid was heated in 100 ml of N-dimethylformamide under agitation for 6 hours. Then, the liquid reaction mixture was poured into 400 ml of water to form a white crystal. The crystal was recovered by filtration and recrystallized from ethyl alcohol to obtain 10.7 g of 2H-chromene-2-spiro-3'-phthalide (compound (1)) as a colorless needle. (yield = 90%). Physical properties of the product are as follows:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]([NH:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[F:29])=[O:16])=[CH:4][CH:3]=1.[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)[CH2:37][CH2:36]1)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1([C:38]2[CH:43]=[CH:42][C:41]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]([NH:17][CH2:18][C:19]4[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=4[F:29])=[O:16])=[CH:4][CH:3]=3)=[CH:40][CH:39]=2)[CH2:36][CH2:37]1)=[O:34])[CH3:31]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NCc1cc(C(F)(F)F)ccc1F
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)NCc4cc(C(F)(F)F)ccc4F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-(2-fluoro-5-trifluoromethyl-benzyl)-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]([C:9](=[S:11])[NH2:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([C:39](=O)[CH2:40]Br)[CH:25]=[C:26]([N+:36]([O-:38])=[O:37])[C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([C:39]2[N:10]=[C:9]([C:8]3[C:3]([C:2]([F:1])([F:12])[F:13])=[N:4][CH:5]=[CH:6][CH:7]=3)[S:11][CH:40]=2)[CH:25]=[C:26]([N+:36]([O-:38])=[O:37])[C:27]=1[O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(CBr)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: NC(=S)c1cccnc1C(F)(F)F
Solvent: CCO
Product: O=[N+]([O-])c1cc(-c2csc(-c3cccnc3C(F)(F)F)n2)cc(OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 2-(trifluoromethyl)pyridine-3-carbothioamide (0.227 g, 1.10 mmol) and 1-[3,4-bis(benzyloxy)-5-nitrophenyl]-2-bromoethanone (0.50 g, 1.10 mmol) were refluxed overnight in absolute ethanol (5 mL). After cooling to room temperature, the reaction mixture was poured onto water (50 mL). The resulting precipitate was filtered off, washed with water (25 mL) and dried. Recrystallisation from dichloromethane/isopropanol afforded 4-(3,4-bis(benzyloxy)-5-nitrophenyl)-2-(2-(trifluoromethyl)pyridin-3-yl)thiazole, 0.539 g (87%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[CH2:3][N:4]=[C:5]([NH2:23])[NH:6][C:7]1[S:11][N:10]=[C:9]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:17](=[N:20][C:21]#[N:22])SC)[N:8]=1.[CH3:26][NH2:27]>C(O)C>[F:25][C:2]([F:1])([F:24])[CH2:3][N:4]=[C:5]([NH2:23])[NH:6][C:7]1[S:11][N:10]=[C:9]([CH2:12][S:13][CH2:14][CH2:15][NH:16][C:17]([NH:27][CH3:26])=[N:20][C:21]#[N:22])[N:8]=1
Reactant: CN
Reactant: CSC(=NC#N)NCCSCc1nsc(NC(N)=NCC(F)(F)F)n1
Solvent: CCO
Product: CNC(=NC#N)NCCSCc1nsc(NC(N)=NCC(F)(F)F)n1
Reaction time: 18 h

Procedure:
A solution of 5-[2-(2,2,2-trifluoroethyl)guanidino]-3-[2-(3-cyano-2-methylisothioureido)ethylthiomethyl]-1,2,4-thiadiazole in 33% w/v methylamine in ethanol (4 ml.) was kept at 20° for 18 hours. Volatile material was evaporated in vacuo and the crude material was fractionated on a silica column (26 cm.×1 cm. diameter) eluted with a methanol/ethyl acetate 1:50 v/v to give 5-[2-(2,2,2-trifluoroethyl)guanidino]-3-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]-1,2,4-thiadiazole. The n.m.r. spectrum in d6 dimethylsulphoxide using tetramethyl silane as an internal standard (δ=0) had the following resonances (δ): 4.2 (2H, quartet); 3.8 (2H, singlet); 3.3 (2H, multiplet); 2.7 (2H, triplet).