Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:24]1([NH:30]N)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)[N:8]=[C:7]1[C:5]1[N:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:2]=[CH:3][CH:4]=1
Reactant: NNc1ccccc1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(C(N)=O)cc2)ccc1=O
Solvent: CO
Product: NC(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)cc1
Yield: 6 %

Procedure:
To a solution of 4-{3-[3-(dimethylamino)prop-2-enoyl]-4-oxopyridazin-1(4H)-yl}benzamide (crude 682 mg, 2.19 mmol) in 20 mL of methanol was added phenylhydrazine (946 mg, 8.76 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 4-[4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]benzamide (50 mg, 6% for two steps) as a yellow solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]([O:10][C:11]([NH:13][C@@H:14]1[C@@H:19]([OH:20])[CH2:18][CH2:17][O:16][CH2:15]1)=[O:12])([CH3:9])[CH3:8].C(N(CC)CC)C>C(Cl)Cl>[CH3:9][C:7]([O:10][C:11]([NH:13][C@@H:14]1[C@@H:19]([O:20][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:18][CH2:17][O:16][CH2:15]1)=[O:12])([CH3:6])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@@H]1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (30 ml) in DCM (100 ml) was added dropwise to a solution of 1,5-an hydro-2,4-dideoxy-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-L-threo-pentitol (75 g) and triethylamine (58 ml) in DCM (900 ml) at 0° C., maintaining the temperature below 3° C. during the addition. The mixture was stirred for 30 min, warmed to 25° C. and stirred for 2 h. The reaction mixture was washed with water (2×1.4 l), the organic phase dried and the solvent evaporated to give 1,5-anhydro-2,4-dideoxy-2-({[(1,1-dimethylethy)oxy]carbonyl}amino)-3-O-(methylsulfonyl)-L-threo-pentitol (103.1 g).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH:11][C:12]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=O)=[C:9]([C:21]#[N:22])[C:8]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:30]O.[OH-].[Na+]>C(O)C.O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:22][C:21](=[O:30])[C:9]3=[C:8]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1c(Cc2ccccc2)nn(C2CCCC2)c1NC(=O)Cc1ccccc1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=c1nc(Cc2ccccc2)nc2n(C3CCCC3)[nH]c(Cc3ccccc3)c1-2
Temperature: 0 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
To an ice-cooled solution of 1-cyclopentyl-3-phenylmethyl-4-cyano-5-(phenylmethylcarbonylamino)-1H-pyrazole (1.1 g, 2.8 mmol) in ethanol (30 ml) was added 30% H2O2 (2.5 ml), followed by NaOH (100 mg) dissolved in water (5 ml). The reaction mixture was stirred a such for 1 hour, then at room temperature for 1 hour, then it was heated on a steam bath for 3.5 hours and finally it was stirred at room temperature overnight. The reaction mixture was concentrated to dryness, and partitioned between water (25 ml) and CHCl3 (50 ml). The organic layer was separated, and concentrated in vacuo and the oily residue was crystallized from isopropanol to afford 234 mg (22%) of 1-cyclopentyl-3-phenylmethyl-6-(phenylmethyl)-pyrazolo[3,4-d]pyrimidin-4-one, as a white solid, m.p. 204°-206° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1([CH3:18])[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:10]=2[O:9]1.[C:19](Cl)([Cl:21])=[O:20]>C1C=CC=CC=1>[Cl:21][C:19]([O:17][C:16]1[C:10]2[O:9][C:8]([CH3:18])([CH3:7])[CH2:12][C:11]=2[CH:13]=[CH:14][CH:15]=1)=[O:20]
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(C)Cc2cccc(OC(=O)Cl)c2O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 7.9 g. (0.1 mol) sample of pyridine was added dropwise to a solution of 16.4 g. (0.1 mol) 2,3-dihydro-2,2-dimethyl-7-benzofuranol and 9.9 g. (0.1 mol) phosgene in 100 ml. benzene at about 25° C. The reaction mixture was stirred at 25° C for 2 hours, filtered and evaporated under reduced pressure. The solid residue was washed with hexane and dried to give the product, m.p. 85°-87.5° C. Elemental analysis for C11H11O3Cl showed:
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:19][C:18](=O)[C:17]2[C:12](=[CH:13][C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=2)[N:11]=1)[CH3:2].P(Cl)(Cl)([Cl:27])=O.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:27][C:18]1[C:17]2[C:12](=[CH:13][C:14]([C:21]([F:24])([F:23])[F:22])=[CH:15][CH:16]=2)[N:11]=[C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][CH2:1][CH3:2])[N:19]=1
Reactant: CCSc1ccccc1-c1nc2cc(C(F)(F)F)ccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCSc1ccccc1-c1nc(Cl)c2ccc(C(F)(F)F)cc2n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1.29 g of 2-(2-ethylsulfanylphenyl)-7-trifluoromethyl-3H-quinazolin-4-one, 0.38 ml of phosphorus oxychloride, 523 mg of N,N-diisopropylethylamine and 20 ml of toluene was stirred at 90° C. for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the cooled reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate, then concentrated under reduced pressure to obtain 1.23 g of 4-chloro-2-(2-ethylsulfanylphenyl)-7-trifluoromethylquinazoline (Compound of Present Invention 4).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=2)[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[F:22][CH2:23][C:24]([CH2:30][F:31])([CH:28]=[CH2:29])[C:25]([OH:27])=[O:26].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([NH:7][C@@H:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][C:14](/[CH:29]=[CH:28]/[C:24]([CH2:30][F:31])([CH2:23][F:22])[C:25]([OH:27])=[O:26])=[CH:15][CH:16]=2)[N:11]=1)[CH3:9])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(Br)cc2n1
Reactant: C=CC(CF)(CF)C(=O)O
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(/C=C/C(CF)(CF)C(=O)O)cc2n1
Temperature: 60 °C
Yield: 100 %

Procedure:
A solution of [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-carbamic acid tert-butyl ester (105 mg, 0.3 mmol), 2,2-bis-fluoromethyl-but-3-enoic acid (50 mg, 0.33 mmol), tri(o-tolyl)phosphine (18 mg, 0.06 mmol) and triethylamine (91 mg, 0.13 mL, 0.9 mmol) in 1,4-dioxane (3 mL) was degassed with nitrogen for 15 min. Tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.03 mmol) was added and the reaction mixture was heated to 60° C. for 1 h. The reaction mixture was cooled to room temperature and the mixture was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude (E)-4-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-2,2-bis-fluoromethyl-but-3-enoic acid (0.3 mmol) as a yellow gum. LCMS (m/z) 421.1 [M+H], Tr=2.27 min. A solution of crude (E)-4-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-2,2-bis-fluoromethyl-but-3-enoic acid (0.3 mmol), N,N-diisopropylethylamine (96 mg, 0.13 mL, 0.75 mmol), 4-(dimethylamino)-pyridine (73 mg, 0.6 mmol) and 2-methyl-6-nitrobenzoic anhydride (193 mg, 0.56 mmol) in anhydrous dichloromethane (5 mL) was stirred at 0° C. under nitrogen. A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (142 mg, 0.33 mmol) in dichloromethane (2 mL) was added and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 18 h. The reaction mixture was diluted with dichloromethane and the solution was washed with ice-cold saturated sodium hydrogen carbonate solution, water, ice-cold hydrochloric acid (1 M), water and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 2:1 to 0:1 to afford the partially purified title compound (26 mg, 10%) as a yellow gum. LCMS (m/z) 834.3, 836.2 [M+H], Tr=3.39 min.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[NH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a stirring solution of (S)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (1.5 g, 7.5 mmol) in 25 mL CH2Cl2 was added triethylamine (2.1 mL, 15 mmol) at 0° C., followed by the dropwise addition of benzyl chloroformate (1.58 mL, 11.2 mmol). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was quenched with water, and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 3% MeOH in CH2Cl2 gave benzyl((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (1.5 g, 60%). LC/MS: m/z: 335.5 (M+H)+ at 3.01 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:42]N1C(=O)CCC1=O>C(Cl)Cl>[Br:42][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[CH3:22]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(CO)c(C)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C#Cc2ccc(CBr)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of ethyl 4-(4-hydroxymethyl-3-methyl-phenylethynyl)-benzoate (Compound 117, 130.0 mg, 0.44 mmol) and triphenylphosphine (150.0 mg, 0.57 mmol) in 5 mL CH2Cl2 was cooled to 0° C. and N-bromosuccinimide (101.0 mg, 0.57 mmol) was added in 5 portions over 20 minutes. The solution was warmed to 25° C. and stirred for 17 hours. The reaction was quenched by the addition of dilute aqueous NaHCO3. The resulting mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. The title compound, 120.0 mg (76%), was isolated by column chromatography (2-5% EtOAc-hexanes) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[N:40]1([C:46](Cl)=[O:47])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([NH:23][C:46]([N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[O:47])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([C:24](=[O:27])[CH2:25][CH3:26])=[C:5]2[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(Cl)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(=O)(=O)NC(=O)N2CCCCC2)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(6-bromo-1-oxo-4-phenyl-3-propionyl-1H-isoquinolin-2-ylmethyl)benzenesulfonamide (0.10 g), potassium carbonate (0.11 mg), 1-piperidinecarbonyl chloride (29 μl) and DMF (2.0 ml) was stirred at 50° C. for 18 hrs. After the completion of the reaction, the reaction mixture was concentrated, and the residue was diluted with dichloromethane. Then, this solution was washed with 1N hydrochloric acid, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=4/1-1/1) to give the title compound (38 mg) as a colorless powder. HPLC analysis: purity 91.6% (retention time: 4.78 min). MS (ESI+): 636 (M+H), 638.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl.N1C=CC=CC=1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([S:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][S:28]([C:20]2[O:19][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH:21]=2)(=[O:29])=[O:30])(=[O:11])=[O:10])=[CH:17][CH:16]=1
Reactant: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccccc1NS(=O)(=O)c1cc2ccccc2o1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
To a solution of N-(2-aminophenyl)-4-chlorobenzenesulfonamide (0.5 mmol, prepared as in Example 11) in DCM (1 mL) and pyridine (1 mL), benzofuran-2-sulfonyl chloride (0.55 mmol), prepared as above, was added at RT and the reaction mixture was then allowed to stir at RT overnight or until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% aqueous HCl (5 mL), water (5 mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to afford 92 mg benzofuran-2-sulfonic acid [2-(4-chlorobenzenesulfonylamino)phenyl]-amide. LC: Tr 1.13 min, MS: 464.0 (M+1)+.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH3:14].S(Cl)([Cl:19])(=O)=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Cl:19][CH2:14][C:5]1[C:6]([C:10]([F:13])([F:12])[F:11])=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1c(C(F)(F)F)nn(C)c1OC(F)F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(C(F)(F)F)c(CCl)c1OC(F)F
Yield: 36.3 %

Procedure:
To a solution of 11.5 g (50.0 mmol) of 5-difluoromethoxy-1,4-dimethyl-3-trifluoromethyl-1H-pyrazole in 50 ml of carbon tetrachloride were added 10.1 g (75.0 mmol) of sulfuryl chloride and 0.8 (5.0 mmol) of α,α′-azobisisobutyronitrile, followed by heating and refluxing under stirring. The reaction solution was externally irradiated with a light for 11 hours. After the completion of the reaction was confirmed, the reaction solution was poured into water and extracted with chloroform. The resulting organic layer was washed with water and saline, successively, and then dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure and the residue was purified by silica gel column chromatography to obtain 4.8 g (purity: 83.4%, yield: 30.3%) of 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole as a colorless transparent liquid.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:18]([C:23]2[N:24]=[N:25][N:26]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[N:27]=2)[CH:19]=[CH:20][CH:21]=[O:22])=[CH:13][CH:12]=1>O1CCCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:18]([C:23]2[N:24]=[N:25][N:26]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[N:27]=2)[CH:19]=[CH:20][CH:21]([OH:22])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:13][CH:12]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COCCOCn1nnc(C(C=CC=O)=C(c2ccc(F)cc2)c2ccc(F)cc2)n1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(COCCOC)n1
Reaction time: 1 h

Procedure:
Ethyl acetoacetate dianion (2.1 mL of freshly prepared 1M solution as described in Example 10) was added to a solution of 5,5-bis(4-fluorophenyl)-4-[2-(2-methoxyethoxy)methyl-2H-tetrazol-5-yl]-2,4-pentadienal (0.9 g, 2.0 mmoles) in 15 mL of tetrahydrofuran at -50 ° C. After stirring for 1 hours, another 1 mL of dianion solution was added and the mixture stirred for an additional 30 minutes. The reaction mixture was quenched with 1N HCl and then extracted with methylene chloride. The organic extracts were dried (MgSo4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 1% (v/v) methanol in methylene chloride to give 0.55 g of the title compound. MS (CI): m/e=557 for M+H)+ ;
Reaction SMILES: C[O-].[Na+].Br[CH2:5][CH2:6][OH:7].[N:8]1[CH:13]=[CH:12][C:11]([CH2:14][SH:15])=[CH:10][CH:9]=1>C(O)C>[OH:7][CH2:6][CH2:5][S:15][CH2:14][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1
Reactant: OCCBr
Reactant: SCc1ccncc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCSCc1ccncc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 18.1 %

Procedure:
Sodium methoxide (361 mg., 6.7 mmoles) was dissolved in 15 ml. of ethanol and cooled in an ice-water bath. 2-Bromoethanol (760 mg., 6.08 mmoles) was added dropwise over 5 minutes, followed by the dropwise addition of 4-picolyl mercaptan (760 mg., 6.08 mmoles) in 5 ml. of ethanol. The reaction mixture was warmed to room temperature and stirred for 20 hours. Precipitated salts were removed by filtration and the filtrate evaporated to crude product, which was chromatographed on 20 g. of silica gel with chloroform and then 1% methanol in chloroform as eluant. The column was monitored by tlc (9:1 chloroform:ethanol, Rf 0.25). Clean product fractions were combined and evaporated to yield clear title product as an oil (186 mg.), having m/e 269 and pnmr/CDCl3 /TMS/delta: 8.63-8.42 (m, 2H), 7.38-7.18 (m, 2H), 3.73 (t, 2H), 3.72 (s, 2H), 2.89 (s, broad, 1 H) and 2.63 (t, 2H) ppm.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[N:15][CH:16]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[I:35])[NH2:31].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[C:30]([NH:31][CH2:2][C:3]2[CH:8]=[C:7]([F:9])[C:6]([F:10])=[CH:5][C:4]=2[C:11]2[CH:12]=[CH:13][C:14]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[N:15][CH:16]=2)[CH:32]=[CH:33][C:34]=1[I:35]
Reactant: Nc1ccc(I)c(Cl)c1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CBr)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)c(F)cc2CNc2ccc(I)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
Ethyl 3-(5-(2-(bromomethyl)-4,5-difluorophenyl)picolinamido)propanoate (1.0 g, 2.3 mmol), 3-chloro-4-iodoaniline (1.2 g, 4.7 mmol), and K2CO3 (647 mg, 4.7 mmol) were diluted with DMF (2.4 mL) and the resulting mixture was stirred at room temperature. After 2 h the resulting mixture directly purified via column chromatography to yield the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12][C:11](=[O:13])O[C:8](=[O:9])[C:7]=12.[NH:14]([CH2:16]C(O)=O)[CH3:15].CS(C)=O>O>[F:1][C:2]1[C:7]2[C:8](=[O:9])[N:14]([CH3:16])[CH2:15][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Reactant: CNCC(=O)O
Solvent: O
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2cccc(F)c2C1=O
Temperature: 100 °C

Procedure:
7.2 g (0.04 mol) of 6-fluoroisatoic acid anhydride and 3.9 g (0.044 mol) of sarcosine are added to 10 ml of dimethyl sulphoxide and the mixture is heated at 100° C. for 30 minutes. After cooling and diluting with 15 ml of water, the separated substance is filtered off. After drying, there is obtained 6-fluoro-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione of melting point 214°-217° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]([CH:25]=3)[C:21]([O:23][CH3:24])=[O:22])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[C:27](N1C=CN=C1)(N1C=CN=C1)=[S:28].C1COCC1>C(OCC)(=O)C>[Cl:26][C:19]1[CH:18]=[CH:17][C:16]([NH:15][S:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([N:1]=[C:27]=[S:28])=[CH:3][CH:4]=3)[CH:9]=2)(=[O:14])=[O:13])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(N)cc3c2)ccc1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(N=C=S)cc3c2)ccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.8 %

Procedure:
To 4.5 g (11.5 mmol) of compound 134 and 9.01 g (50.6 mmol) of 1,1′-thiocarbonyldiimidazole was added 50 mL of THF. The solution was allowed to stir at ambient temperature for 1.5 hours. Then, the reaction was poured into 300 mL of ethyl acetate and extracted with 1N HCl, water, and brine. The organic layer was dried (MgSO4), filtered, and the volatiles removed by rotary evaporation to yield 4.77 g of compound 135.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14]C1SC(C(COC(=O)COC(=O)C)(C)C)=NN=1>C1(C)C=CC=CC=1.CCCCC>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5]([NH2:14])=[O:6]
Reactant: COc1cccc(OC)c1C(=O)Cl
Reactant: CC(=O)OCC(=O)OCC(C)(C)c1nnc(N)s1
Solvent: Cc1ccccc1
Solvent: CCCCC
Product: COc1cccc(OC)c1C(N)=O
Temperature: 25 °C
Yield: 3 %

Procedure:
A solution of 300 mg of 2,6-dimethoxybenzoyl chloride in 20 ml of toluene containing 300 mg of 2-amino-5-[(2-acetoxy-1-acetoxymethyl)-1-methylethyl]-1,3,4-thiadiazole was heated at reflux for eighteen hours. The reaction mixture was cooled to room temperature and diluted with pentane. A solid precipitate which formed was collected by filtration and air dried to give N-[5-(2-acetoxy-1-acetoxymethyl)-1-methylethyl)-1,3,4-thiadiazol-2-yl]-2,6-dimethoxybenzamide in 3% yield.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:18][CH:19]=1
Reactant: COc1ccc(-c2nc(Sc3ccccc3OC)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccccc3OC)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.19 g of 4,5-bis(4-methoxyphenyl)-2-(2-methoxyphenylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus producing 3.86 g of 4,5-bis(4-methoxyphenyl)-2-(2-methoxyphenylsulfinyl)imidazole as an amorphous foam.