Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12])[C:5]#[CH:6].CI.[C:15](O)(=O)C>C1COCC1.CO>[CH3:15][N:9]1[CH2:10][CH2:11][N:7]([CH:4]([CH3:3])[C:5]#[CH:6])[C:8]1=[O:12]
Reactant: C#CC(C)N1CCNC1=O
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: C1CCOC1
Product: C#CC(C)N1CCN(C)C1=O
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.2 g of 50% in oil) was added at 0° C. to a stirred solution of 1-(1-methyl-2-propynyl)-2-imidazolidinone (2.1 g) in dry THF (50 mL). After 15 min methyl iodide (3.0 mL) was added and the solution was stirred for an additional 30 min. Acetic acid (0.6 mL) and methanol (3 mL) were added and the solvent was removed under reduced pressure and the residual oil was partitioned between ethyl acetate and sodium hydroxide (10 mL of 2N). The ethyl acetate was removed and the crude product was chromatographed on silica gel to give 2.5 g of 1-methyl-3-(1-methyl-2-propynyl)-2-imidazolidinone as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:25][CH:26]([CH3:28])[CH3:27])=[N:4][CH:5]=[C:6]([C:8]2[S:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15](/[CH:19]=[CH:20]/[O:21]C)[C:14]=3[CH2:23][CH3:24])[N:9]=2)[CH:7]=1.Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][N:11]=[C:10]([C:13]3[C:14]([CH2:23][CH3:24])=[C:15]([CH2:19][CH:20]=[O:21])[CH:16]=[CH:17][CH:18]=3)[N:9]=2)[CH:5]=[N:4][C:3]=1[O:25][CH:26]([CH3:28])[CH3:27]
Reactant: CCc1c(/C=C/OC)cccc1-c1nsc(-c2cnc(OC(C)C)c(Cl)c2)n1
Agent: Cl
Solvent: C1CCOC1
Product: CCc1c(CC=O)cccc1-c1nsc(-c2cnc(OC(C)C)c(Cl)c2)n1
Temperature: 70 °C
Yield: 103.5 %

Procedure:
To a solution of 3-chloro-5-(3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]pyridine (D110) (2 g, 4.81 mmol) in Tetrahydrofuran (50 mL) was added HCl (4.81 mL, 9.62 mmol). The resulted solution was heated to 70° C. for 2 h. THF was removed in vacuo to afford [3-(5-{5-chloro-6-[(1-methylethyl)oxy]-3-pyridinyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]acetaldehyde (D111) (2 g, 4.98 mmol, 103% yield) as a crude product, which was used directly without further purification. MS (ES): C20H20ClN3O2S requires 401.0. found 402.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:29][CH3:30])=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:28])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)=[CH:13][CH:12]=1.[H-].[Na+].Cl[C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35]>C(COC)OC>[Cl:1][C:2]1[C:3]([CH2:29][CH3:30])=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([C:34]([O:36][CH2:37][CH:38]([CH3:40])[CH3:39])=[O:35])[C:9](=[O:28])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][N:19]=2)=[CH:15][CH:16]=1
Reactant: CCc1nccc(NC(=O)Cc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)c1Cl
Reactant: CC(C)COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1nccc(N(C(=O)Cc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)C(=O)OCC(C)C)c1Cl
Temperature: 25 °C
Yield: 32.4 %

Procedure:
1.0 g (2.3 mmol) of N-(3-chloro-2-ethylpyridin-4-yl)-4-[(5-trifluoromethylpyridin-2-yl)oxy]phenylacetamide was dissolved in 5 ml of dimethoxy ethane, and the solution was stirred at room temperature. Then, 0.067 g (2.8 mmol) of sodium hydride was gradually added thereto, and the mixture was further stirred for one hour at room temperature. Then, 2 ml of a 1,2-dimethoxyethane solution containing 0.38 g (2.8 mmol) of isobutyl chloroformate was dropwise added thereto at a temperature of from -5° to 0° C., and the mixture was stirred for 30 minutes at a temperature of from -5° to 0° C. and for one hour at room temperature. Then, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 0.4 g of the desired product as a yellow viscous substance (refractive index nD20 =1.3582).
Reaction SMILES: Cl.N[C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1.[C:33]([O:37][C:38]([NH:40][C@H:41]([C:46](O)=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])([CH3:36])([CH3:35])[CH3:34].F[P-](F)(F)(F)(F)F.N1C2C=CC=C(O[P+](N3CCCC3)(N3CCCC3)N3CCCC3)C=2N=N1.CCN(C(C)C)C(C)C>O1CCCC1>[C:33]([O:37][C:38](=[O:39])[NH:40][CH:41]([C:46]([C:3]1[N:11]=[CH:10][N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1)=[O:47])[CH2:42][CH:43]([CH3:44])[CH3:45])([CH3:34])([CH3:36])[CH3:35]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cc(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)c2nn[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.9 %

Procedure:
In 15 ml of tetrahydrofuran, 300 mg (0.620 mmol) of 1-[4-(6-aminopurin-9-yl)phenyl]-3-(4-chloro-3-(trifluoromethyl)phenyl)urea hydrochloride was dissolved, and 771 mg (3.10 mmol) of tert-butoxycarbonyl-L-leucine, 1.60 g (3.10 mmol) of (benzotriazolyloxy)tripyrrolidino-phosphonium hexa-fluorophosphate (PyBOP) and 0.54 mL (3.10 mmol) of Hunig's base were added thereto and the mixture solution was stirred at room temperature for three days. The reaction solution was concentrated under reduced pressure, and then the residue was partitioned between ethyl acetate and water. The organic phase was washed with a saturated sodium chloride solution, dried, and then concentrated under reduced pressure. The residue was purified by Megabond Elute Silica Gel (10 g, ethyl acetate), to obtain 320 mg (78%) of [1-(9-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-9H-purin-6-ylcarbonyl)-3-methyl-butyl]carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:11]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[CH:12][C:13]([CH2:16][OH:17])=[N:14][CH:15]=1.[CH:23]1([CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34](O)[CH:33]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:25][CH2:24]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH:23]1([CH:26]([C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([O:17][CH2:16][C:13]3[CH:12]=[C:11]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])[C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[CH:15][N:14]=3)[CH:37]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:25]1
Reactant: COc1ccc(F)c(-c2cnc(CO)cc2OCC(C)C)c1
Reactant: COC(=O)CC(c1cccc(O)c1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)CC(c1cccc(OCc2cc(OCC(C)C)c(-c3cc(OC)ccc3F)cn2)c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Under a nitrogen atmosphere, to a solution of (5-(2-fluoro-5-methoxyphenyl)-4-isobutoxypyridin-2-yl)methanol (214 mg) and methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propanoate (155 mg) in toluene (10 mL) were added 1,1′-(azodicarbonyl)dipiperidine (283 mg) and tributylphosphine (280 μL), and the mixture was stirred at room temperature overnight. Hexane/ethyl acetate (1:1) was added to the reaction mixture, and the resulting precipitate was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (302 mg) as a colorless amorphous solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH:11]([CH:20]([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:31](Br)[CH:32]=[CH2:33]>CN(C)C=O>[CH2:33]([C:20]([CH:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:25]([O:27][CH3:28])=[O:26])[C:21]([O:23][CH3:24])=[O:22])[CH:32]=[CH2:31]
Reactant: COC(=O)C(C(=O)OC)C(Cc1ccccc1[N+](=O)[O-])c1ccc(OC)cc1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(C(=O)OC)(C(=O)OC)C(Cc1ccccc1[N+](=O)[O-])c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of [2-(2-nitrophenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (10 g, 25.81 mmol; see Example 15A) in 51 ml of dry dimethylformamide (0° C., argon) was treated with sodium hydride (6.19 g, 154.86 mmol of a 60% mineral oil dispersion); stirring at 0° C. was continued for 20 minutes. Allyl bromide* (11.17 ml, 129.05 mmol) was added and the reaction was carried out at room temperature for 1 hour, 10 minutes. The reaction was quenched by the slow addition of 1M hydrochloric acid (0° C. ice bath) followed by ethyl acetate. The aqueous layer was washed with ethyl acetate, the combined ethyl acetate layers were washed with 1M hydrochloric acid (3 times), saturated aqueous potassium carbonate solution (2 times), brine, dried over magnesium sulfate and evaporated in vacuo. The crude product was dissolved in dichloromethane and adsorbed onto Celite and filtered through a pad of silica gel (240-400 mesh, hexane, followed by 75/25 hexane/ethyl acetate). Evaporation in vacuo yielded 10.66 g of a viscous yellow-orange oil.
Reaction SMILES: [CH3:1][C:2]([O-:4])=[O:3].[CH3:5][C:6]([O-:8])=[O:7].[CH3:9][C:10]([O-:12])=[O:11].CC([O-])=O.[Pb+2:17].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH:28]2[CH2:30][CH2:29]2)=[C:23](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[C:2]([O-:4])(=[O:3])[CH3:1].[C:6]([O-:8])(=[O:7])[CH3:5].[C:10]([O-:12])(=[O:11])[CH3:9].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH:28]2[CH2:30][CH2:29]2)=[C:23]([Pb+3:17])[CH:24]=1
Reactant: OB(O)c1cc(Br)ccc1C1CC1
Reactant: [Pb+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Hg+2]
Solvent: ClC(Cl)Cl
Product: Brc1ccc(C2CC2)c([Pb+3])c1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of lead(IV)acetate (4.0 g, 0.0089 mol) and mercury(II)acetate (139 mg, 0.45 mmol) in chloroform (12 ml) at 50° C. is added 5-bromo-2-cyclopropylphenyl boronic acid (2.0 g, 0.0083 mol), and the solution is heated at this temperature for 5 hours. After cooling to room temperature the suspension is further cooled to 0° C. and anhydrous potassium carbonate (1.8 g) is added with rapid stirring for 2 minutes. The reaction mixture is then filtered (washing with additional chloroform), and the filtrate is concentrated to half its original volume and the crude product is precipitated with hexanes. Further concentration then filtration affords 5-bromo-2-cyclopropylphenyl lead triacetate as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.C1COCC1.[CH3:24][NH2:25]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH:25][CH3:24])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53 %

Procedure:
2-Chloro-4-morpholinothieno[3,2-c]pyrimidine-6-carbaldehyde 10 (2.0 g) was dissolved in 50 mL toluene and 50 mL THF followed by the addition of 20 mL of 40% methylamine in H2O. The reaction mixture was stirred at room temp under N2 for 24 hours. The solvents were removed in vacuo and the residue was dissolved in 50 mL methanol and 50 mL THF and the NaBH4 added portion-wise. This reaction mixture was stirred at room temp under N2 for 24 hours and complete reaction was confirmed by LCMS. The solvents were removed in vacuo and the crude product purified by flash chromatography (EtOAc/EtOH) to give 1.12 g 35 (53% yield). MS (Q1) 300 (M+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([O:19][C:20]([CH2:22][O:23][N:24]=[C:25]([C:29]1[N:30]=[C:31]([NH:34][CH:35]=[O:36])[S:32][CH:33]=1)[C:26]([OH:28])=O)=[O:21])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[NH2:38][CH:39]1[C:64](=[O:65])[N:41]2[C:42]([C:48]([O:50][CH:51]([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[O:49])=[C:43]([CH:46]=[CH2:47])[CH2:44][S:45][C@H:40]12.C[Si](CC(N)=O)(C)C>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[CH:6]([O:19][C:20]([CH2:22][O:23][N:24]=[C:25]([C:29]1[N:30]=[C:31]([NH:34][CH:35]=[O:36])[S:32][CH:33]=1)[C:26]([NH:38][CH:39]1[C:64](=[O:65])[N:41]2[C:42]([C:48]([O:50][CH:51]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:49])=[C:43]([CH:46]=[CH2:47])[CH2:44][S:45][C@H:40]12)=[O:28])=[O:21])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=CNc1nc(C(=NOCC(=O)OC(c2ccccc2)c2ccccc2)C(=O)O)cs1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(NC=O)n3)[C@H]2SC1
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
Vilsmeir reagent was prepared from phosphorus oxychloride (1.28 ml) and N,N-dimethylformamide (1.06 ml) in tetrahydrofuran (35 ml) in a usual manner. To the resultant suspension was added 2-benzhydryloxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetic acid (syn isomer) (5 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes to prepare the activated acid solution. This solution was added at a time to a solution of benzhydryl 7-amino-3-vinyl-3-cephem-4-carboxylate hydrochloride (4.89 g) and trimethylsilylacetamide (9.2 g) in ethyl acetate (40 ml) at -20° C., followed by stirring at -20° to -10° C. for an hour. After water and ethyl acetate were added to the reaction mixture, the separated organic layer was washed with 5% aqueous sodium carbonate and an aqueous sodium chloride, followed by drying over magnesium sulfate. Removal of the solvent gave benzhydryl 7-[2-benzhydryloxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (8.7 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C:14](O)([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]2[C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]=[C:12]2[C:21]2[CH:29]=[CH:28][C:24]3[O:25][CH2:26][O:27][C:23]=3[CH:22]=2)=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc3c(c2)OCO3)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc3c(c2)OCO3)cc1
Yield: 79 %

Procedure:
A mixture of 5-[1-[4-(methylsulfonyl)phenyl]-4-hydroxy-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]-1,3-benzodioxole from Step 2 (1.26 g, 2.9 mmol) and p-toluenesulfonic acid monohydrate (200 mg) in toluene (50 mL) was heated to reflux for 72 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture (1.34 g) was purified by chromatography on silica gel using toluene/ethyl acetate 1/1 to give pure 5-(1-(4-(methylsulfonyl)phenyl)-4-(trifluoromethyl)-1H-imidazol-2-yl]-1,3-benzodioxole (940 mg, 80%) as a white solid: mp (DSC) 165° C. Anal Calc'd. for C18H13N2SO4F3: C, 52.68; H, 3.19; No 6.83. Found: C, 53.05; H, 3.19; N, 6.65.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)c1oc2cccc(N)c2c1C
Product: CCOC(=O)c1oc2cccc(NS(=O)(=O)c3ccccc3)c2c1C
Yield: 83 %

Procedure:
4-Benzenesulfonylamino-3-methyl-benzofuran-2-carboxylic acid ethyl ester was prepared from 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 60, Step 1), and benzenesulfonyl chloride according to the procedure of Example 68, Step 1. Yield: 83%. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.2 Hz, 3 H) 2.6 (s, 3 H) 4.4 (q, J=7.1 Hz, 2 H) 6.6 (d, J=7.8 Hz, 1 H) 7.3 (m, 1 H) 7.6 (t, J=7.8 Hz, 3 H) 7.7 (m, 3 H) 10.1 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[NH2:15][C:16]1[C:17]([F:26])=[CH:18][C:19]2[CH2:23][O:22][B:21]([OH:24])[C:20]=2[CH:25]=1.N1C=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[S:11]([NH:15][C:16]1[C:17]([F:26])=[CH:18][C:19]2[CH2:23][O:22][B:21]([OH:24])[C:20]=2[CH:25]=1)(=[O:13])=[O:12]
Reactant: Nc1cc2c(cc1F)COB2O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c(F)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2cc3c(cc2F)COB3O)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
To a stirred solution of 2-fluoro-4-nitrobenzene-1-sulfonyl chloride (1.336 g, 5.57 mmol) and 6-amino-5-fluorobenzo[c][1,2]oxaborol-1(3H)-ol (0.93 g, 5.57 mmol) in 20 mL of ACN was added pyridine (900 uL, 11.14 mmol) dropwise. The reaction mixture was stirred at room temperature for 16 hours. After quenched with water, the solvent was removed in vacuo. The residue was extracted with ethyl acetate three times, and washed with water and brine. The organic layer was dried over Na2SO4, and concentrated to give 1.84 g of the title compound as a yellow residue. MS calcd for (C13H9BF2N2O6S): 370.0. MS found (ESI negative): (M−H)−=368.9
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:25])=[C:7]([C:16]([I:24])=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[C:18]=1[I:19])[C:8]([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])=[O:9])(=[O:3])[CH3:2].[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1O)([O-:28])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>>[N+:26]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:14][C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[C:7]1[C:6]([I:25])=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[C:18]([I:19])=[C:17]([NH:20][C:21](=[O:23])[CH3:22])[C:16]=1[I:24])([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)N[C@@H](C)C(=O)O)c1I
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(=O)Nc1c(I)c(NC(C)=O)c(I)c(C(=O)N[C@@H](C)C(=O)Oc2ccccc2[N+](=O)[O-])c1I

Procedure:
Following the procedure of example 33, the desired compound is synthesized from 13.7 g (20 mMol) N-(3,5-diacetamido-2,4,6-triiodobenzoyl)-L-alanine, 3,5 g (25 mMol)-o-nitrophenol and 5 g (24 mMol) N,N'-dicyclohexylcarbodiimide.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10])=[N+]=[N-].[H][H]>C(OCC)(=O)C.O=[Pt]=O>[CH3:10][C:9]1[O:8][C:7]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[N:6][C:5]=1[CH2:4][NH2:1]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CN=[N+]=[N-]
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CN
Yield: 84.2 %

Procedure:
A mixture of 4-azidomethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (1.70 g) and PtO2 (0.106 g) in ethyl acetate (50 mL) at room temperature under 60 psi of hydrogen for 5 hrs, the reaction mixture is filtered through celite and filtrate is concentrated giving the title compound (1.3 g, 84.2% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]2[C:12]=1[N:11]([CH3:13])[C:10](=[O:14])[CH:9]=[CH:8]2>[C].[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:15][CH:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]2[C:12]=1[N:11]([CH3:13])[C:10](=[O:14])[CH:9]=[CH:8]2
Reactant: CCOC(=O)C(=Cc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(OC)c2c1ccc(=O)n2C)C(=O)OCC
Reaction time: 6 h
Yield: 81.3 %

Procedure:
Diethyl 2-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethylene)malonate (16.62 g) and 10% palladium carbon (1.6 g) were added to 300 ml of ethanol, followed by catalytic hydrogenation at room temperature and atmospheric pressure for 6 hours. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:1) to thereby obtain 13.59 g (yield: 81%) of diethyl 2-(8-methoxy-1-methyl-2-oxo-1,2-dihydroquinolin-5-ylmethyl)malonate as a light yellow oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:4]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1COCC1>[CH2:16]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([O:14][CH3:15])=[O:13])=[N:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1n[nH]c2ccccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nn(Cc2ccccc2)c2ccccc12
Temperature: 0 °C
Yield: 77 %

Procedure:
To a suspension of sodium hydride (60% in oil, 55 mg, 1.22 mM) in dry THF (10 ml) stirring at 0° C. was added a solution of methyl indazole-3-carboxylate (von Auwers et al, Ber., 52, pg 1345 (1919), 210 mg, 1.22 mM) in dry THF (10 ml). After 10 min benzyl bromide (0.15 ml, 1.22 mM) was added and the solution left stirring at room temperature overnight. Water (2 ml) was added and the solvent removed in vacuo. The residue was partitioned between water and ethyl acetate and the combined organic dried over magnesium sulfate and evaporated. Column chromatography (ethyl acetate/cyclohexane 1:4) provided methyl 1 benzyl-indazole-3-carboxylate as a yellow powder (250 mg, 77%). M.pt. 181° C.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([F:14])=[CH:11][C:12]=2[F:13])=[CH:5][C:4]([C:15]([OH:17])=[O:16])=[C:3]([OH:18])[CH:2]=1.Cl.CN(C)[CH2:22][CH2:23]CN=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)C>CN(C)C=O.O>[F:13][C:12]1[CH:11]=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[C:6]1[CH:5]=[C:4]([C:15]([O:17][CH2:22][CH3:23])=[O:16])[C:3]([OH:18])=[CH:2][CH:1]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
Diflunisal (250 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (382 mg), 1-hydroxybenzotriazole hydrate (306 mg), and ethanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give ethyl 5-(2,4-difluorophenyl)salicylate (188 mg, yield 34%).