Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:16][CH:15]=2)=O)=[O:9])=[CH:6][C:5]([Br:30])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.BrP(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CC#N>[NH2:1][C:2]1[C:7]([C:8]2[O:9][C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[CH:6][C:5]([Br:30])=[CH:4][N:3]=1
Reactant: CN(Cc1ccc(C(=O)NNC(=O)c2cc(Br)cnc2N)cc1)C(=O)OC(C)(C)C
Agent: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccc(-c2nnc(-c3cc(Br)cnc3N)o2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
tert-Butyl N-[[4-[[(2-amino-5-bromo-pyridine-3-carbonyl)amino]carbamoyl]phenyl]methyl]-N-methyl-carbamate (992.3 mg, 2.074 mmol) was dissolved in dry MeCN (15 mL) and cooled in an ice bath under a nitrogen atmosphere. DIPEA (804.2 mg, 1.084 mL, 6.222 mmol) was added via syringe followed by dibromo(triphenyl)phosphorane (1.185 g, 2.696 mmol) portionwise and the reaction allowed to warm to ambient temperature over 15 hours. A further portion of MeCN (15 mL) and dibromo(triphenyl)phosphorane (437.7 mg, 1.037 mmol) were added and the reaction mixture stirred at ambient temperature for a 10 minutes. The precipitate was isolated by filtration and the filtrate concentrated in vacuo. The filtrate was re-dissolved in MeCN (15 mL) and cooled to 0° C. DIPEA (804.2 mg, 1.084 mL, 6.222 mmol) was added followed by dibromo(triphenyl)phosphorane (437.7 mg, 1.037 mmol) and the reaction mixture stirred at 0° C. for 30 minutes. The reaction mixture was concentrated in vacuo and the resultant residue purified by column chromatography (ISCO Companion™, 40 g column, 0-50% EtOAc/Petroleum ether) and the product containing fractions concentrated in vacuo. The residue was combined with the previously obtained precipitate to give the sub-title product as a white solid (682 mg, 63% Yield corrected for residual OPPh3). 1H NMR (400.0 MHz, DMSO) δ 1.39-1.46 (d, 9H), 4.48 (d, J=10.5 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 8.22 (d, J=8.2 Hz, 2H), 8.32 (d, J=2.4 Hz, 1H) and 8.49 (d, J=2.4 Hz, 1H) ppm; MS (ES+) 462.1.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]1[CH:12]2[CH:13]3[CH:17]=[CH:16][CH:15]([CH:11]2[CH:10]=[CH:9]1)[CH2:14]3.[OH2:18]>>[C:1]([OH:6])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:18])=[O:5].[CH2:8]1[CH:12]2[CH:13]3[CH:17]=[CH:16][CH:15]([CH:11]2[CH:10]=[CH:9]1)[CH2:14]3
Reactant: O
Reactant: O=C1C=CC(=O)O1
Solvent: C1=CC2C3C=CC(C3)C2C1
Product: O=C(O)/C=C\C(=O)O

Procedure:
196 parts maleic anhydride, 278 parts (95% pure) dicyclopentadiene and 36 parts demineralized water were placed into a four-necked flask, and addition reaction was performed under nitrogen stream at 130° C. for 3 hours to obtain an addition product of maleic acid to dicyclopentadiene. Next, 118 parts phthalic anhydride and 124 parts ethylene glycol were added and mixed. Then the mixture was dehydrated and condensed in a widely-used manner under nitrogen stream at 200° C. for 8 hours to obtain a dicyclopentenyl-group-containing unsaturated polyester having an acid value of 25 mgKOH/g and a dicyclopentenyl group ratio of 38 percent by weight. This dicyclopentenyl-group-containing unsaturated polyester was dissolved at 80° C. in a solution in which 0.1 parts hydroquinone is dissolved in 310 parts styrene monomer. A dicyclopentenyl-group-containing unsaturated polyester resin (I) of a viscosity of 3.0 stokes/25° C. was thus obtained.
Reaction SMILES: [C:1]([N:20]1[N:24]=[N:23][C:22]([CH2:25][C:26]#[N:27])=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C=O)CCCCC1.[OH-].[Na+].[I-].C[S+](C)(C)=O.[H-].[Na+].[CH:46]1([CH:52]=[C:53](C2N=NN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C#N)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C1C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CCOC(C)=O>[CH:46]1([CH:52]2[CH2:53][C:25]2([C:22]2[N:23]=[N:24][N:20]([C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:21]=2)[C:26]#[N:27])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: N#CCc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N#CC(=CC1CCCCC1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[S+](C)(C)=O
Agent: O=CC1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: N#CC1(c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CC1C1CCCCC1
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of (2-trityl-2H-tetrazol-5-yl)-acetonitrile (1.0 g, 2.85 mmol) in 15 mL benzene was added cyclohexanecarboxaldehyde (0.38 mL, 3.13 mmol), 10 mL 10% NaOH (aq), and tetrabutylammonium bromide (50 mg). The mixture was stirred for 1 h, then poured into EtOAc. The phases were separated, and the organic phase dried (MgSO4) and concentrated. Meanwhile, to trimethylsulfoxonium iodide (0.75 g, 3.42 mmol) in 7.0 mL DMF was added sodium hydride (60% dispersion in mineral oil, 0.14 g, 3.42 mmol). The mixture was stirred for 30 min at which time a solution of crude 3-cyclohexyl-2-(2-trityl-2H-tetrazol-5-yl)-acrylonitrile 2 (ca. 2.8 mmol) in 5.0 mL DMF was added quickly dropwise. The orange solution was stirred overnight, partitioned between EtOAc and H2O, and the phases separated. The organic phase was washed with brine, dried (MgSO4) and concentrated. Flash chromatography of the residue (15→20% EtOAc/hexanes) provided 1.15 g (88%, two steps) of 2-cyclohexyl-1-(2-trityl-2H-tetrazol-5-yl)-cyclopropanecarbonitrile as a colorless foam. 1H NMR (CDCl3) δ 7.33 (m, 9H), 7.07 (m, 6H), 1.88 (dd, J=4.9, 8.8 Hz, 1H, cyclopropyl —CHH), 1.66-1.84 (m, 4H), 1.57 (dd, J=4.9, 7.7 Hz, 1H, cyclopropyl —CHH), 1.25 (m, 8H).
Reaction SMILES: [S:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([NH2:10])=[C:4]2[N:3]=[N:2]1.C1C(=O)N([Br:18])C(=O)C1>C1COCC1>[Br:18][C:6]1[CH:7]=[CH:8][C:9]([NH2:10])=[C:4]2[C:5]=1[S:1][N:2]=[N:3]2
Reactant: Nc1cccc2snnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: Nc1ccc(Br)c2snnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
A mixture of 1,2,3-benzothiadiazol-4-amine (200.0 mg, 1.323 mmol) and NBS (341.4 mg, 1.918 mmol) in THF (10 mL) was stirred at RT overnight. The solution was adsorbed onto silica gel and purified by ISCO chromatography (10 to 30% EtOAc:heptane) to afford 80 mg (30%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 6.74 (d, J=8.3 Hz, 1 H), 6.97 (s, 2 H), 7.60 (d, J=8.3 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15](F)=[N:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:24][NH2:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[C:15]([NH:25][CH3:24])=[N:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:20]([CH3:23])=[N:21][O:22][C:11]=3[CH2:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1noc2c1-c1ccnc(F)c1C(c1ccc(Cl)cc1)=NC2
Product: CNc1nccc2c1C(c1ccc(Cl)cc1)=NCc1onc(C)c1-2
Temperature: 80 °C

Procedure:
To 6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine (0.020 g, 0.061 mmol) was added a solution of methylamine (33% in EtOH) (4 mL) at room temperature. The reaction was heated to 80° C. for 22 h before silica gel was added. The solvent was removed under vacuum, the dry silica gel was packed and the adsorbed product was purified by flash chromatography (hexane/EtOAc 8:2 to 2:8) to give 6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-amine as a white solid (0.014 g). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J=5.26 Hz, 1H), 7.35 (td, J=2.30, 8.93 Hz, 2H), 7.30 (td, J=2.30, 8.93 Hz, 2H), 6.93 (d, J=5.26 Hz, 1H), 5.87 (q, J=4.35 Hz, 1H), 5.22 (d, J=12.82 Hz, 1H), 4.03 (s, 1H), 2.61 (d, J=4.58 Hz, 3H), 2.50 (s, 3H); LC/MS m/z 339 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[N:13]=[N:12][C:11]([N:14]([CH2:22][C:23]3([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:26][CH2:25][CH2:24]3)C(=O)OC(C)(C)C)=[CH:10][CH:9]=2)[CH:4]=1)#[N:2].C(=O)([O-])[O-:35].[K+].[K+].CS(C)=O.OO>C(OCC)(=O)C>[F:33][C:32]1[C:27]([C:23]2([CH2:22][NH:14][C:11]3[N:12]=[N:13][C:8]([N:5]4[CH:6]=[CH:7][C:3]([C:1]([NH2:2])=[O:35])=[CH:4]4)=[CH:9][CH:10]=3)[CH2:26][CH2:25][CH2:24]2)=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(-n2ccc(C#N)c2)nn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: NC(=O)c1ccn(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.6 %

Procedure:
t-butyl 6-(3-cyano-1H-pyrrol-1-yl)pyridazin-3-yl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)carbamate (120 mg, 267 μmol), potassium carbonate (147 mg, 1.1 mmol), and DMSO (3 mL) were combined in a vial and cooled to 0° C. Hydrogen peroxide (700 uL) was added dropwise, and the reaction was warmed to rt and stirred for 1 h. The reaction was then poured into ethyl acetate (50 mL), washed with water (3×20 mL), and the organic layer was separated, dried over Na2SO4, filtered, and concentrated. The crude solid was dissolved in 50% TFA/CH2Cl2 (2 mL) and stirred for 30 min. The reaction was then concentrated and purified using reverse phase chromatography to give 29 mg of 1-(6((1-(3-fluoropyridin-2-yl)cyclobutyl)methylamino)pyridazin-3-yl)-1H-pyrrole-3-carboxamide as a tan solid (M+H=367.1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[I-:11].[Na+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu](I)I>[I:11][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2
Reactant: [I-]
Reactant: Brc1ccc2[nH]ncc2c1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: Ic1ccc2[nH]ncc2c1
Yield: 98.1 %

Procedure:
5-Bromo-1H-indazole (2.0 g, 10.15 mmol) was dissolved in dioxane (50 ml) and stirred under N2 atmosphere. Copper iodide (97 mg, 0.51 mmol), sodium iodide (3.04 g, 20.3 mmol) and trans-1,2-bis-(methylamino)-cyclohexane (147 mg, 1.02 mmol) was added and the reaction mixture was stirred for 68 hours at 110° C. The cooled solution was filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in DCM (20 mL) and extracted with aqueous ammonia (1M, 5×10 mL). The organic phase was then washed three times with an aqueous Na2S2O3 solution, dried over MgSO4, filtered and concentrated under reduced pressure to give the product as a white solid (2.43 g, 100%).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:6].[N:20]1([C:24]([C:26]2[CH:31]=[N:30][C:29](Cl)=[CH:28][N:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[N:20]1([C:24]([C:26]2[N:27]=[CH:28][C:29]([O:18][C:16]3[CH:15]=[C:10]([CH:9]=[C:8]([O:7][C@@H:5]([CH3:6])[CH2:4][O:3][CH:2]([F:19])[F:1])[CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])=[N:30][CH:31]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)COC(F)F)c1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@@H](C)COC(F)F)c1
Temperature: 140 °C
Reaction time: 5 h
Yield: 74.7 %

Procedure:
A mixture of methyl 3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxybenzoate (0.28 g, 1.01 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (201 mg, 1.01 mmol) and potassium carbonate (280 mg, 2.03 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 5 hours. The reaction mixture was reduced in vacuo, ethyl acetate (50 mL) added and the organics washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 20 to 70% ethyl acetate in isohexane, to give the desired compound as a colourless oil (330 mg). 1H NMR δ (CDCl3): 1.38 (d, 3H), 2.37 (quin, 2H), 3.90 (s, 3H), 3.93-4.04 (m, 2H), 4.26 (d, 2H), 4.61-4.70 (m, 3H), 6.25 (t, 1H), 6.95 (t, 1H), 7.43-7.44 (m, 1H), 7.49-7.50 (m, 1H), 8.32 (d, 1H), 8.85 (d, 1H); m/z 438 (M+H)+
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([C:13]([CH2:17][CH3:18])(O)[CH2:14][CH3:15])=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([C:3]1[S:4][C:5]([CH:13]([CH2:17][CH3:18])[CH2:14][CH3:15])=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: CCOC(=O)c1cc(C(O)(CC)CC)sc1CC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(C(CC)CC)sc1CC
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a solution of ethyl 2-ethyl-5-(1-ethyl-1-hydroxypropyl)thiophene-3-carboxylate (3.71 g) synthesized above in trifluoroacetic acid (35 mL) was added triethylsilane (6.61 mL), and the mixture was stirred at room temperature for 2 hr and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane alone) to give the title compound (2.28 g, 65%) as a colorless oil.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3][C:2]1=[S:11].Cl[CH2:13][C:14](O)=[O:15].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[S:11]1[C:2]2=[N:1][C:10]3[C:5]([CH2:4][N:3]2[C:14](=[O:15])[CH2:13]1)=[CH:6][CH:7]=[CH:8][CH:9]=3
Reactant: S=C1NCc2ccccc2N1
Reactant: O=C(O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CSC2=Nc3ccccc3CN12
Temperature: 90 °C

Procedure:
A mixture of 1.0 g (0.006 mol) 3,4-dihydro-2(1H)-quinazolinethione (compound II), 0.57 g (0.006 mol) chloroacetic acid, and 0.54 g (0.0065 mol) sodium bicarbonate is mixed in 31.25 ml water, and heated overnight at 90° C. Then, 12.5 ml of dimethylformamide is added, and the reaction mixture is refluxed for 61/2 hours. After cooling, 5H-thiazolo[2,3-b]quinazolin-3(2H)-one, as the precipitated solid, is filtered off and recrystallized from anhydrous ethanol. Replacement of 3,4-dihydro-2(1H)-quinazolinethione by a derivative thereof in which a nuclear hydrogen of the benzene ring has been substituted with lower alkyl, alkoxy, halogen, trifluoromethyl, NO2 or NH2, results in the corresponding derivative of 5H-thiazolo[2,3-b]quinazolin-3(2H)-one.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14]CC)=O.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>CCCCCC>[CH2:20]([O:19][C:17]([C:11]1[CH:10]=[N:9][C:4]2[C:5]([C:12]=1[OH:14])=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:1])([F:22])[F:23])=[O:18])[CH3:21]
Reactant: CCOC(=O)C(=CNc1ccccc1C(F)(F)F)C(=O)OCC
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1O
Temperature: 250 °C
Yield: 91.7 %

Procedure:
Diethyl 2-({[2-(trifluoromethyl)phenyl]amino}methylene)malonate (compound of formula (IV)), 69.73 g, 210.5 mmol) was taken into Dowtherm A (350 mL) and brought to reflux (˜250° C.) with the removal of ethanol that was formed during the reaction for 45 min. The reaction was allowed to cool to approximately 100° C. then carefully poured into hexane (1 L) and allowed to cool overnight. A white solid precipitated which was filtered and dried to afford the title compound as a white solid (55.04 g, 91.7%). MS ESI (m/z) 286 ([M+H]+); MS ESI (m/z) 284 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:31])[C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=3[Cl:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:31])[C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=3[Cl:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:34])([F:35])[F:33]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cc(C)ccc1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(Cl)c(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(2-chloro-5-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (50 mg, 0.088 mmol) in 4N HCl in dioxane (4 mL) and water (1 mL) was stirred at 100° C. for overnight. The reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified via column chromatography to afford 4-chloro-N-[5-chloro-2-(2-chloro-5-methyl-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzene sulfonamide (29.5 mg) in 64% yield. ESMS m/z (relative intensity): 522.9 (M+H)+ (30), 544.9 (M+Na)+ (50).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:37][C:36]([C:38]3[CH:43]=[CH:42][C:41]([CH2:44][OH:45])=[CH:40][CH:39]=3)=[N:35][N:34]=2)=[CH:29][CH:28]=1)[CH:24]([CH3:26])[CH3:25]>ClCCl>[CH2:23]([C:27]1[CH:28]=[CH:29][C:30]([C:33]2[O:37][C:36]([C:38]3[CH:39]=[CH:40][C:41]([CH:44]=[O:45])=[CH:42][CH:43]=3)=[N:35][N:34]=2)=[CH:31][CH:32]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)Cc1ccc(-c2nnc(-c3ccc(CO)cc3)o2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)Cc1ccc(-c2nnc(-c3ccc(C=O)cc3)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
Dess-Martin periodinane (0.576 g, 21.4 mmol) was added to a solution of {4-[5-(4-isobutylphenyl)-1,3,4-oxadiazol-2-yl]phenyl}methanol (0.322 g, 1.04 mmol) and dichloromethane (10 mL) and stirred at room temperature for 1 hour. The reaction mixture was quenched with 1M NaOH (10 mL), stirred for 15 minutes then additional 1N NaOH (5 mL) was added. The layers were separated and the aqueous phase was extracted with ethyl acetate (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (0.322 g, 88% yield) as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.C(OC(C1C(C2C=CN=CC=2)=NOC=1C)=O)C>>[CH3:11][C:10]1[O:9][N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1c(-c2ccccn2)noc1C
Agent: CCOC(=O)c1c(-c2ccncc2)noc1C
Product: Cc1onc(-c2ccccn2)c1CO
Yield: 96.4 %

Procedure:
As described for example 67b, 5-methyl-3-pyridin-2-yl-isoxazole-4-carboxylic acid ethyl ester (25 g, 108 mmol) was converted, instead of 5-methyl-3-pyridin-4-yl-isoxazole-4-carboxylic acid ethyl ester, to the title compound (19.8 g, 97%) which was obtained as a light yellow solid. MS: m/e=191.3 [M+H]+.
Reaction SMILES: [Cl:1][Pd:2][Cl:3].[C:4]12[CH2:10][C:7]([CH2:8][CH2:9]1)=[CH:6][CH:5]=2.[CH3:11][O-:12].[Na+]>CO>[Pd:2]([Cl:3])[Cl:1].[CH3:11][O:12][C:4]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]=[CH:5]2
Reactant: C1=C2CCC(=C1)C2
Reactant: C[O-]
Agent: Cl[Pd]Cl
Agent: [Na+]
Solvent: CO
Product: COC12C=CC(CC1)C2

Procedure:
The above-prepared norbornadiene dichloropalladium (1.40 g) was added to 20 mL of methanol in a flask made of glass where inner air was substituted with highly pure argon and then the inner temperature was made −40° C. using a dry ice bath. Into this was dropped 1.5 mL of a 28% methanolic solution of sodium methoxide (manufactured by Wako Pure Chemical Industry). The mixture was made to react for 1 hour and returned to room temperature. The resulting yellow solid was sucked and washed with methanol to give 1.22 g of methoxynorbornene palladium chloride dimer.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:5][N:4]=1.[NH:17]([C:21]1[S:22][CH:23]=[C:24]([CH2:26][S:27][CH2:28][CH2:29][NH2:30])[N:25]=1)[C:18]([NH2:20])=[NH:19]>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][C:6]2[C:7](=[O:9])[NH:8][C:3]([NH:30][CH2:29][CH2:28][S:27][CH2:26][C:24]3[N:25]=[C:21]([NH:17][C:18]([NH2:20])=[NH:19])[S:22][CH:23]=3)=[N:4][N:5]=2)[CH:12]=1
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Reactant: CSc1nnc(Cc2cccnc2)c(=O)[nH]1
Product: N=C(N)Nc1nc(CSCCNc2nnc(Cc3cccnc3)c(=O)[nH]2)cs1
Temperature: 140 °C
Yield: 19.5 %

Procedure:
A mixture of 3-methylthio-6-(3-pyridylmethyl)-1,2,4-triazin-5-one (0.23 g) and 2-guanidino-4-[(2-aminoethyl)thiomethyl]thiazole (0.23 g) was heated at 140° C. for 2 hours and then allowed to cool to room temperature. The black solid mass was triturated with a mixture of methanol (10 ml) and dimethylformamide (2 ml) and the resulting pale brown solid was filtered off. This was purified by preparative TLC using Merck Kieselgel GF 254 2 mm preparative plates in chloroform/methanol/ammonia (s.g. 0.880) 8:2:0.3 v/v/v as eluant to give 6-(3-pyridylmethyl)-3-[2-(2-guanidinothiazol-4-ylmethylthio)-ethylamino]-1,2,4-triazin-5-one (0.08 g). The n.m.r. spectrum of the product in d6 dimethyl sulphoxide using tetramethylsilane as an internal standard (δ=0) had the following resonances: 2.7 (2H, triplet); 3.4 (2H, broad multiplet); 3.6 (2H, sharp singlet); 3.8-4.1 (8H, broad multiplet--contains H2O); 6.6 (1H, sharp singlet); 6.9 (4H, broad singlet); 7.3 (1H, multiplet); 7.7 (1H, double triplet); 8.5 (2H, multiplet).
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH3:15])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl.O>[CH3:1][O:2][N:3]([CH:4]([CH3:15])[CH2:5][C:6]1[C:7]([Cl:14])=[CH:8][C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: CONC(C)Cc1c(Cl)cc(Cl)cc1Cl
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.8 %

Procedure:
To a solution of O-Methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (0.65 g, 2.4 mmol) prepared as described in example P15d, in dichloromethane (5 ml) was added triethylamine (0.844 ml, 6.0 mmol) followed by drop wise addition of a solution 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.519 g, 2.67 mmol) in dichloromethane at 0° C. After complete addition of acid chloride the mixture was stirred 18 hours at ambient temperature. When the TLC confirmed completion of the reaction, the reaction mass was diluted with water and extracted with dichloromethane (3×60 ml). The combined dichloromethane layer were washed with 2N HCl, followed by saturated NaHCO3, then with water and finally with brine solution before drying over sodium sulfate and evaporation of the solvent. The resulting crude mass was purified by column chromatography using 60-120μ mesh silica gel and product collected at 30% ethyl acetate in hexane as eluent to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-amide (0.51 g, 49%) as off white solid. m.p: 110-112° C.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH2:12][OH:13])[N:3]=1.[CH2:14]([CH2:16][NH2:17])[OH:15].O>C(O)C>[Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5]([NH:17][CH2:16][CH2:14][OH:15])[N:4]([CH2:11][CH2:12][OH:13])[N:3]=1
Reactant: O=[N+]([O-])c1c(Br)nn(CCO)c1Br
Reactant: NCCO
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1c(Br)nn(CCO)c1NCCO
Yield: 73.4 %

Procedure:
1.5 g (4.8 mmoles) of 3,5-dibromo-1-(2'-hydroxyethyl)-4-nitropyrazole are heated in a solution of 0.58 g (9.6 mmoles) ethanolamine in 30 ml ethanol for 15 hours at 80° C. After cooling, 50 ml of water are added to the reaction mixture which is then extracted three times with 70 ml of acetic acid ethyl ester. 200 ml n-hexane are added to the purified extraction solutions and the solvent mixture is vacuum distilled to a third of its original amount. Once again, n-hexane is added until the solution becomes cloudy. The crystallized product is then collected by filtration and washed with n-hexane (10 to 20 ml). 1.04 g (74 percent of theory) of 3-bromo-1-(2'-hydroxyethyl)-5-(2'-hydroxyethyl)amino-4-nitropyrazole are obtained in the form of bright yellow crystals with a melting point of 132° to 134° C.