Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:25](=S)=[S:26]>N1C=CC=CC=1.C(N(CC)CC)C>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]=[C:25]=[S:26])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cc(Br)ccc1N=C=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 800 ml of pyridine were dissolved 275 ml of carbon disulfide and 93 ml of triethylamine. To the solution was added 125 g of 4-bromo-2-methylaniline. The mixture was stirred at room temperature overnight. Thereto was added 138.5 g of 1,3-dicyclohexylcarbodiimide (DCC). The mixture was stirred overnight. Pyridine was removed by distillation. To the residue was added n-hexane. The resulting precipitate (DC-thiourea) was removed by filtration. The filtrate was concentrated and the residue was purified by a silica gel column chromatography (eluant: n-hexane) to obtain 138 g of 4-bromo-2-methylphenyl isothiocyanate.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH:14]=[C:13]([C:27]([F:30])([F:29])[F:28])[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][CH:48]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:21][CH:22]=4)[CH:14]=[C:13]([C:27]([F:29])([F:28])[F:30])[N:12]=3)[CH:10]=2)=[N:49][CH:48]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3cc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-4-(4-trifluoromethyl-phenyl)-pyridine (Example G.12) (0.570 g, 0.88 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.265 g, 0.99 mmol), tetrakis(triphenyl-phosphine)palladium (0.061 g, 0.046 mmol) in toluene (6 mL) was heated under reflux conditions for 16 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (220 mg, 43%). MS (ISP) 576.3 [(M+H)+]; mp 252° C.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][OH:9].C(=O)([O-])[O-].[K+].[K+].[Si:16](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ClCCl.CO>CN(C)C=O>[Si:16]([O:9][CH2:8][C:7]1[NH:6][CH:5]=[N:4][C:3]=1[CH3:2])([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc[nH]c1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 3 h
Yield: 25.5 %

Procedure:
To 2.0 g(13.5 mmol) of 4-methyl-5-imidazolemethanol hydrochloride and 1.95 g(14.17 mmol) of potassium carbonate in 20 ml of dimethylformamide was added 3.88 g(14.17 mmol) of t-butyldiphenylsilylchloride was added dropwise thereto, and the resulting mixture was stirred for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in 20 ml of ethylacetate. The organic layer was washed with 20 ml of saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography(eluent: dichloromethane/methanol=95/5, v/v) to give 1.22 g(3.44 mmol, Yield 26%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[NH:3]1.Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[F:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:3]2[C:2](=[O:1])[C:7]([CH2:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]4[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]3[N:26]=[CH:27][N:28]=[C:4]23)=[CH:32][CH:33]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2ncnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(Cc2ccc(F)cc2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A mixture of 4′-[(5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 1-(bromomethyl)-4-fluorobenzene (0.2 mL), potassium carbonate (0.38 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.58 g, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH2:9]([O:11][C:12](=[O:17])[C:13](=O)[CH2:14]Br)[CH3:10]>C1(C)C=CC=CC=1.O>[CH2:9]([O:11][C:12]([C:13]1[N:8]=[C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]2[CH:14]=1)=[O:17])[CH3:10]
Reactant: Nc1cc(Br)ccn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cn2ccc(Br)cc2n1
Temperature: 115 °C
Yield: 104.5 %

Procedure:
To a stirred solution of 4-Bromo-pyridin-2-ylamine (4 g, 23.12 mmol) in toluene (40 mL) is added 3-Bromo-2-oxo-propionic acid ethyl ester (4.5 g, 23.12 mmol). The reaction mixture is heated at 115° C. for 16 hours. Reaction mixture is cooled to 0° C. then diluted with water and extract with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo to afford the title compound (6.5 g). 1H-NMR (400 MHz, DMSO-d6) δ: 1.31 (t, J=7.2 Hz, 3H), 4.26-4.33 (q, J=7.2 Hz, 2H), 7.18-7.20 (dd, J1=1.92 Hz, J2=7.16 Hz, 1H), 7.98 (s, 1H), 8.53 (d, J=7.32 Hz, 1H), 8.57 (s, 1H). LC-MS (m/z): [M+H]=271.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)C(O)=O.Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH2:32].CN([C:36]([O:40]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH:32][C:36](=[O:40])[C:13]1[CH:14]=[CH:15][C:7]([O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:8][CH:9]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: COc1cccc(Oc2cccc(C(=O)O)c2)c1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Oc2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)c1
Yield: 28.7 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(3-methoxyphenoxy)benzamide was prepared according to method A with 3-(3-methoxyphenoxy)benzoic acid (0.080 g, 0.347 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.077 g; 0.331 mmol), HATU (0.190 g; 0.365 mmol) and N,N-diisopropylethylamine (0.142 mL; 0.829 mmol) in DMF (3 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.040 g (29%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11]O)=[CH:7][C:6]=1[C:13]([F:16])([F:15])[F:14])([CH3:3])[CH3:2].S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[Cl:19][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)Oc1ccc(CO)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(CCl)cc1C(F)(F)F
Temperature: 75 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a solution of (4-isopropoxy-3-(trifluoromethyl)phenyl)methanol (11.27 mmol) in toluene (20 mL) was added thionyl chloride (67.7 mmol). The reaction was stirred at 75° C. for 3 h. The mixture was diluted with hexanes, washed with water (twice), saturated NaHCO3, dried over MgSO4, and filtered. The solvent was removed under vacuum to give the title compound as an oil (10.4 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (d, J=6.06 Hz, 6H), 4.75-4.85 (m, 3H), 7.30 (d, J=8.46 Hz, 1H), 7.63-7.70 (m, 2H).
Reaction SMILES: C(N1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=O.[N:13]1([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]1.[NH2:30][C@H:31]1[CH2:36][C:35]2[C:37]([N:41]3[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]3)=[CH:38][CH:39]=[CH:40][C:34]=2[O:33][CH2:32]1.C(Cl)(Cl)Cl>CN(C)C=O.C(O)C>[C:25]([O:27][CH2:11][CH3:12])(=[O:26])[CH3:24].[CH3:47][N:44]1[CH2:45][CH2:46][N:41]([C:37]2[C:35]3[CH2:36][C@H:31]([NH:30][C:25](=[O:27])[C:24]4[CH:23]=[CH:22][C:21]([N:13]5[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]5)=[CH:29][CH:28]=4)[CH2:32][O:33][C:34]=3[CH:40]=[CH:39][CH:38]=2)[CH2:42][CH2:43]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CCN1
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(C)=O
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(N4CCNC(=O)CC4)cc2)CO3)CC1
Temperature: 25 °C
Reaction time: 336 h
Yield: 204.2 %

Procedure:
A solution of 1,1′-carbonyldiimidazole (151 mg, 0.934 mmol) and 4-(hexahydro-1,4-diazepin-5-on-1-yl)benzoic acid (219 mg, 0.934 mmol) in anhydrous N,N-dimethylformamide (7 mL) was stirred at 75° C. for 55 min. The mixture was allowed to cool, and a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (210 mg, 0.85 mmol) in N,N-dimethylformamide (3.5 mL) was added. The reaction mixture was stirred at room temperature for 14 days. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica (eluent: chloroform/ethanol, 90:10+1% conc. NH3). The product was crystallized from a mixture of chloroform, ethanol, and ethyl acetate affording 84 mg (21% yield) of the title compound as white crystals: mp 244-247° C. (decomposes); [α]21D−148° (c 0.50, chloroform); TSPMS (70 eV) m/z 464 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:39])[CH:15]([C:30]2[CH:35]=[CH:34][C:33]3[O:36][CH2:37][O:38][C:32]=3[CH:31]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:18]=2[CH2:27][CH2:28][CH3:29])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:40][Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].IC>C1COCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14](=[O:39])[C:15]([C:30]2[CH:35]=[CH:34][C:33]3[O:36][CH2:37][O:38][C:32]=3[CH:31]=2)([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][C:18]=2[CH2:27][CH2:28][CH3:29])[CH3:40])(=[O:12])=[O:11])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[NH-]
Reactant: CCCc1cc(C(=O)OC)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCc1cc(C(=O)OC)ccc1OC(C)(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 0.516 g (0.93 mmol) of the product of Example 57 dissolved in 1.0 mL of anhydrous THF was added 2.80 mL (2.80 mmol) of a 1.0M solution of lithim bis(trimethylsilylamide) in THF at -78° C. under a nitrogen atmosphere. The reaction mixture was magnetically stirred at -78° C. for 1 hour, then 174 μL (2.80 mmol) of iodomethane was added via syringe. The reaction was allowed to warm to room temperature and was stirred an additional 14 hours. The reaction was next quenched with excess 10% aqueous NaHSO4 and partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaCl, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with CHCl3 --MeOH--NH4OH (90:10:1). Evaporation of the purified fractions and drying in vacuo afforded 0.293 g (55%) of the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[N+:16]([O-])=O)[O:6][N:5]=1.S.[Na].[Na]>O1CCOCC1.O.ClCCl>[CH3:19][N:2]([CH2:3][C:4]1[N:8]=[C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[NH2:16])[O:6][N:5]=1)[CH3:1]
Reactant: Cc1ccc([N+](=O)[O-])c(-c2nc(CN(C)C)no2)c1
Agent: S
Agent: [Na]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(N)c(-c2nc(CN(C)C)no2)c1
Temperature: 80 °C
Yield: 83.2 %

Procedure:
To a solution of N,N-dimethyl-1-[5-(5-methyl-2-nitro-phenyl)-1,2,4-oxadiazol-3-yl]methanamine (38 mg, 0.15 mmol) in dioxane (1 mL) at 80° C. was added a hot solution (80° C.) of disodium sulfur dihydride anion nonahydrate (70 mg, 0.29 mmol) in water (1 mL). The reaction was heated at 80° C. for 30 min then cooled to room temperature. The reaction was diluted with dichloromethane, washed with 50% saturated sodium bicarbonate solution (2×20 mL), and brine. The solution was dried over Na2SO4, filtered, and concentrated in vacuo to provide 2-(3-((dimethylamino)methyl)-1,2,4-oxadiazol-5-yl)-4-methylaniline (29 mg, 86% yield). LC/MS m/z 233.2 [M+H]+.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([Si:7](Cl)([CH2:9]Cl)[CH3:8])=[CH:3][CH:2]=1.[Na].[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.[CH3:24][OH:25]>CN(C)C=O.O>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([SiH:7]([CH2:9][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[CH2:8][O:25][CH3:24])=[CH:3][CH:2]=1
Reactant: c1c[nH]cn1
Reactant: C[Si](Cl)(CCl)c1ccc(-c2ccccc2)cc1
Reactant: CO
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: COC[SiH](Cn1ccnc1)c1ccc(-c2ccccc2)cc1
Reaction time: 1 h

Procedure:
A mixture of (1,1'-biphenyl-4-yl)chloro(chloromethyl)methylsilane and two equivalents of imidazole sodium salt in dimethylformamide is warmed to 80°-90° C. for 2 hours. Ten equivalents of methanol is then added, and the mixture is held at 70° for 1 hour, cooled, diluted with water, and quickly extracted with ether. Washing the ether solution with water and brine, drying over magnesium sulfate, and evaporation leaves the title compound.
Reaction SMILES: [H-].[Na+].[CH2:3]([PH:7](=[O:11])[O:8][CH2:9][CH3:10])[CH2:4][CH2:5][CH3:6].[CH3:12]I.O>O1CCCC1.ClCCl>[CH2:3]([P:7]([CH3:12])(=[O:11])[O:8][CH2:9][CH3:10])[CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCC[PH](=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCP(C)(=O)OCC

Procedure:
A suspension of 8.0 g of sodium hydride (55% dispersion in oil) in 35 ml of anhydrous tetrahydrofuran under an inert atmosphere is treated with 35 ml of an anhydrous tetrahydrofuran solution of 25 g of ethyl n-butylphosphinate. The resulting suspension is stirred at room temperature for 1 hour before dropwise addition of 32 ml of methyl iodide. After 3 hours stirring at room temperature 10 ml of water are carefully added followed by 200 ml of dichloromethane. Separation of the organic layer, drying over anhydrous magnesium sulphate and removal of the solvent in vacuo affords an oil. Kugelrohrdistillation at 90° and 10-1 mbar affords ethyl n-butyl-(methyl)phosphinate.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:11][N:12]1[CH:16]=[CH:15][C:14]([NH2:17])=[N:13]1.C1(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C1(C)C=CC=CC=1>[Br:8][C:6]1[CH:7]=[C:2]([NH:17][C:14]2[CH:15]=[CH:16][N:12]([CH3:11])[N:13]=2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1ccc(N)n1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2cccc3ccccc23)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1ccc(Nc2cc(Br)cn(C)c2=O)n1
Temperature: 130 °C
Yield: 54.4 %

Procedure:
3,5-Dibromo-1-methyl-1H-pyridin-2-one (469 mg, 1.76 mmol), 1-Methyl-1H-pyrazol-3-ylamine (205 mg, 2.11 mmol), tris(dibenzylidineacetone)dipalladium(0) (80 mg, 0.087 mmol), 2,2′-bis(diphenylphosphino-1,1′-binaphthalene (82 mg, 0.13 mmol), and cesium carbonate (801 mg, 2.46 mmol) were deposited in a sealed vial with 10 mL toluene. This was heated at 130° C. for 18 hours. The resulting mixture was poured into 50 mL water. This was extracted with ethylacetate. The ethylacetate layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (eluted with ethylacete/hexanes) to yield 5-Bromo-1-methyl-3-(1-methyl-1H-pyrazol-3-ylamino)-1H-pyridin-2-one (271 mg, 0.957 mmol). MS (ESI) 284.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([OH:16])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N+:7]([O-:25])=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([OH:16])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccccc1Oc1nnc(Cl)cc1O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1Oc1n[n+]([O-])c(Cl)cc1O
Reaction time: 48 h
Yield: 22.6 %

Procedure:
135 mg (0.572 mmol) of 6-chloro-3-(2-methylphenoxy)-4-pyridazinol (Compound No. 128) obtained in Example 1 and methylene chloride (6 mL) were mixed, 247 mg (purity 80%, 1.14 mmol) of m-chloroperbenzoic acid was added to the mixture and the resulting mixture was refluxed for 16 hours with stirring. The mixture was allowed to stand at room temperature for 2 days, the reaction mixture was poured in a saturated aqueous sodium-sulfite solution, and washed with methylene chloride. The aqueous layer was made acidic with hydrochloric acid, extracted with methylene chloride, then washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (YMC GEL, SIL60, 350/250 mesh, eluted with ethyl acetate) to obtain 32.6 mg (0.129 mmol, Yield: 22.6%) of 6-chloro-3-(2-methylphenoxy)-4-pyridazinol 1-oxide (Compound No. 129).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[Br:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[NH:23][C:24]([NH2:26])=[S:25]>>[BrH:1].[Br:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[NH:23][C:24]1[S:25][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=2[CH3:10])[N:26]=1
Reactant: Cc1ccc(NC(N)=S)c(Br)c1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Product: Br
Product: COC(=S)c1cc(-c2csc(Nc3ccc(C)cc3Br)n2)c(C)s1
Yield: 62.7 %

Procedure:
Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was allowed to react with 2-bromo-4-methylphenyl thiourea (47 mg) as described in Example 154, step (a) to give 62 mg (61% yield) of methyl 4-{2-[(2-bromo-4-methylphenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ2.28 (s, 3H), 3.82 (s, 3H), 7.19-7.23 (m, 1H), 7.27 (s, 1H), 7.48 (m, 1H), 8.14, 8.17 (s, 1H rotomer), 9.52, 9.72 (bs, 1H rotomer); Mass Spectrum (ESI) m/z calcd. for C17H15BrN2O2S3, 455.42 (M+H), found 455.0, 457.0.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].N12CCC(CC1)CN2.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([NH2:23])(=[O:22])=[O:21]>C1(C)C=CC=CC=1>[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([N:23]=[C:2]=[O:3])(=[O:22])=[O:21]
Reactant: NS(=O)(=O)c1ccco1
Reactant: O=C(Cl)C(=O)Cl
Agent: C1CN2CCC1CN2
Solvent: Cc1ccccc1
Product: O=C=NS(=O)(=O)c1ccco1
Reaction time: 2 h

Procedure:
Dry toluene (150 ml), 25 ml oxalyl chloride (295), and a trace of DABCO (diaza-bicyclo[2.2.2]octane) were heated to 90°. Ten g of 2-furansulfonamide was added over a 15 minute period and the mixture was held at 95° for 2 hours. After filtering, the solvent was removed under vacuum to yield 2.1 g of an oil showing the characteristic isocyanate absorption in the infrared (2280 cm-1).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[N:13]=[N:12][CH:11]=[N:10]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C>[C].[Pd].O1CCCC1>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][N:9]2[N:13]=[N:12][CH:11]=[N:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cn2ncnn2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc(Cn2ncnn2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
A mixture of 2-(4-nitrobenzyl)-2H-tetrazole (5 g), 10% palladium carbon (500 mg), ethanol (100 ml) and tetrahydrofuran (100 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. Recrystallization of the residue from ethyl acetate-hexane gave 2-(4-aminobenzyl)-2H-tetrazole (2.83 g, 66%) as yellow prism crystals. melting point: 86-87° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.C[C:18]1[CH:22]=[CH:21][NH:20][N:19]=1.[OH-].[Na+].[CH3:25]S(C)=O>CCOC(C)=O>[CH3:25][C:22]1[CH:18]=[N:19][N:20]([C:2]2[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[CH:7]=2)[CH:21]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1N1CCCCC1
Reactant: Cc1cc[nH]n1
Reactant: CS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cnn(-c2ccc([N+](=O)[O-])c(N3CCCCC3)c2)c1
Yield: 95 %

Procedure:
A solution of 1-(5-fluoro-2-nitro-phenyl)-piperidine (98 mg, 0.43 mmol, as prepared in Example 22, step (a), 3-methylpyrazole (49.2 mg, 0.6 mmol), and NaOH (22.4 mg, 0.56 mmol) were heated in 3 mL of DMSO at 90° C. overnight. The reaction was diluted with EtOAc (50 mL), washed with water (2×50 mL), dried (Na2SO4) and concentrated in vacuo to afford 117 mg (95%) the title compound as a yellow solid. Mass spectrum (ESI, m/z): Calcd. for C15H18N4O2 287.1 (M+H), found 287.1.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@H:4]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:5]([CH2:7][C:8]1[S:9][C:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:11][CH:12]=1)[CH3:6].[OH-].[Li+:26]>CO.O1CCCC1>[Li+:26].[C:16]([O:15][C:13]([C:10]1[S:9][C:8]([CH2:7][N:5]([CH3:6])[C@H:4]([C:3]([O-:24])=[O:2])[CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:12][CH:11]=1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@H](CC(C)C)N(C)Cc1ccc(C(=O)OC(C)(C)C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C[C@@H](C(=O)[O-])N(C)Cc1ccc(C(=O)OC(C)(C)C)s1
Reaction time: 8 h

Procedure:
The compound (0.87 g, 2.4 mmol) obtained in step 1 was dissolved in methanol (2.7 mL) and tetrahydrofuran (5.4 mL), 1N aqueous lithium hydroxide solution (2.7 mL) was added, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was lyophilized to give the title compound (0.83 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][N:16]=2)=[C:11]([F:22])[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].N1C=CC=CC=1.[C:29](Cl)(=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:29](=[O:38])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:17][N:16]=2)=[C:11]([F:22])[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCCC(=O)Cl
Reactant: CCCCCCCOc1ccc(-c2ccc(O)cn2)c(F)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCC(=O)Oc1ccc(-c2ccc(OCCCCCCC)cc2F)nc1
Reaction time: 12 h

Procedure:
0.1 mol of 2-(4-heptyloxy-2-fluorophenyl)-5-hydroxypyridine (prepared from 4-heptyloxy-2-fluoroacetophenone in accordance with Example 1) is dissolved together with 0.12 mol of pyridine in toluene and 0.1 mol of nonanoyl chloride is then added at room temperature. Stirring is then carried out for 12 hours and standard working-up is carried out. 2-(4-Heptyloxy-2-fluorophenyl)5-nonanoyloxypyridine is obtained.