Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:28])/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[C:18]([O:26]C)[CH:17]=2)[CH:9]=[CH:10][CH:11]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:28])/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[C:18]([OH:26])[CH:17]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc(/C=C/C(=O)Nc2cccc(Cl)c2)ccc1S(N)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(/C=C/C(=O)Nc2cccc(Cl)c2)cc1O
Temperature: 0 °C
Yield: 30.7 %

Procedure:
BBr3 (0.680 mL, 0.68 mmol) was added to a suspension of (E)-N-(3-chloro-phenyl)-3-(3-methoxy-4-sulfamoyl-phenyl)-acrylamide (0.045 g, 0.12 mmol) in dry DCM (12 mL) at 0° and under nitrogen atmosphere. The resulting mixture was allowed to reach RT, stirred at reflux temperature for 4 hrs and then poured into ice/water. The aqueous phase was concentrated under reduced pressure and the resulting residue was triturated with water, filtered and dried to give 13 mg of the title (E)-N-(3-chloro-phenyl)-3-(3-hydroxy-4-sulfamoyl-phenyl)-acrylamide as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([C:12]2[C:13]([F:22])=[CH:14][C:15]([Cl:21])=[C:16]([CH:20]=2)[C:17]([OH:19])=[O:18])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[H-].[Na+].[CH2:25]([Li])CCC.CI>C1COCC1>[Cl:21][C:15]1[CH:14]=[C:13]([F:22])[C:12]([C:3]2[C:2]([CH3:25])=[C:6]([C:7]([F:10])([F:9])[F:8])[N:5]([CH3:11])[N:4]=2)=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]
Reactant: [Li]CCCC
Reactant: Cn1nc(-c2cc(C(=O)O)c(Cl)cc2F)c(Br)c1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(-c2cc(C(=O)O)c(Cl)cc2F)nn(C)c1C(F)(F)F
Temperature: 60 °C

Procedure:
A solution of 30 g of 5-[4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2-chloro-4-fluorobenzoic acid in 800 mL of anhydrous THF was stirred with a mechanical stirrer and treated with 3.36 g of 80% NaH. The stirred mixture was kept under a nitrogen atmosphere and heated to 60° C. for one hour. After formation of the sodium carboxylate salt, the mixture was cooled to -110° C. and 32.3 mL of 2.5M n-butyllithium in hexanes was added never allowing the temperature to exceed -100° C. The reaction was stirred at -110° C. for ten minutes, subsequently treated with 9.3 mL of methyl iodide and allowed to warm to room temperature. The mixture was quenched with 3N HCl and the volatiles removed. A precipitate formed which was collected and recrystallized from ethanol/water to give 24.5 g of a white solid: mp 155.0° C.; 1HNMR (CDCl3) δ 2.06 (m, 3H), 4.01 (s, 3H), 7.27 (d, 1H, J=9.6 Hz), 8.17 (d, 1H, J=7.6 Hz). Anal. Calcd for C13H9O2Cl1N2F4 : C, 46.38; H, 2.69; N, 8.32. Found: C, 46.46; H, 2.65; N, 8.33.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:18]=1.CN(C)C=O.[F:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][C:30]=1[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][N:8]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:18]=1
Reactant: OB(O)c1ccncc1F
Reactant: Brc1ccc2c(c1)C(c1ccccc1)=NCCN2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cnccc1-c1ccc2c(c1)C(c1ccccc1)=NCCN2
Temperature: 150 °C

Procedure:
A 5 mL microwave tube was charged with 7-bromo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine (50 mg), dimethylformamide (3.5 mL), 3-fluoro-4-pyridylboronic acid (2 equiv), potassium carbonate (2 equiv), bis(triphenylphosphine)-palladiumdichloride (10 mol %), and water (0.7 mL). The mixture was heated in a microwave at 150° C. for 5 min, then cooled and concentrated to dryness. The residue was taken up in ethyl acetate and filtered through a Celite pad. The filtrate was concentrated to dryness and the residue was triturated in diethyl ether. The resulting solids were collected on filter then purified using preparative thin-layer chromatography. The plates were eluted with 12.5% methanol in chloroform, and the desired band was collected to provide 7-(3-fluoropyridin-4-yl)-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine as a yellow powder. H1 NMR (d6-dmso): 8.45 (d, 1H), 8.32 (d, 1H), 7.52 (d, 1H), 7.46 (m, 2H), 7.36-7.42 (m, 4H), 7.21 (s, 1H), 6.91 (d, 1H), 6.78 (brt, 1H), 3.96 (m, 2H), 3.60 (m, 2H).
Reaction SMILES: O.[O:2]([CH2:9][C:10]([NH:12][CH:13]1[C:35](=[O:36])[N:15]2[CH:16]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C:17]([CH3:21])([CH3:20])[S:18](=[O:19])[C@H:14]12)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:37]N1C(=O)C2=CC=CC=C2C1=O>C1(C)C=CC=CC=1>[CH3:20][C:17](=[CH2:21])[CH:16]([N:15]1[C:35](=[O:36])[CH:13]([NH:12][C:10](=[O:11])[CH2:9][O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:14]1[S:18]([Cl:37])=[O:19])[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)=[O:23]
Reactant: O=C1c2ccccc2C(=O)N1Cl
Reactant: CC1(C)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2S1=O
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1S(=O)Cl

Procedure:
Toluene (425 ml.) was heated in equipment containing a Dean-Stark water trap to azeotropically remove any moisture which may be present, and 25 ml. of toluene were removed thereby. To the remaining toluene were added 10.0 g. (20 mmol.) of p-nitrobenzyl 6-phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide, the toluene being maintained at a temperature slightly below reflux. Toluene (200 ml.) was separately distilled, and 4.0 g. (22 mmol.) of N-chlorophthalimide were added. The resulting solution (warm) was added dropwise to the solution of the penicillin sulfoxide ester over a period of 30 minutes. The mixture remained a light yellow solution throughout addition. The mixture then was refluxed for 55 minutes after which time a sample was removed, and nmr (CDCl3) analysis of the sample indicated virtually entire conversion of the penicillin sulfoxide ester to the title compound.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]([Br:18])=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:19])[NH:13]2)=[O:5])C.O.[OH-].[K+]>C(O)C>[C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]([Br:18])=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:19])[NH:13]2)([OH:5])=[O:3]
Reactant: CCOC(=O)COc1ccc(Br)c2c1CCC(=O)N2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)COc1ccc(Br)c2c1CCC(=O)N2

Procedure:
3.6 Grams of 5-ethoxycarbonylmethoxy-8-bromo-3,4-dihydrocarbostyril is dissolved in 150 ml of ethanol, and to this solution is added a 50 ml water solution of 5 g of potassium hydroxide, and the mixture is refluxed for 5 hours. The solvent is distilled off and the residue is dissolved in water and then made acidic with hydrochloric acid. The precipitate is filtered out and recrystallized from aqueous ethanol to obtain 2.5 g of 5-carboxymethoxy-8-bromo-3,4-dihydrocarbostyril in the form of colorless needle-like crystals, m.p., 255°-256° C. (decomposed).
Reaction SMILES: [CH:1]1[C:2]([I:10])=[CH:3][C:4]([I:9])=[C:5]([OH:8])[C:6]=1[I:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH3:25].O>CN(C)C=O>[I:7][C:6]1[CH:1]=[C:2]([I:10])[CH:3]=[C:4]([I:9])[C:5]=1[O:8][CH2:18][CH2:19][C:20]#[C:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Oc1c(I)cc(I)cc1I
Reactant: CCCCC#CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC#CCCOc1c(I)cc(I)cc1I
Temperature: 70 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A mixture of triiodophenol (1.0 g, 2.1 mmol) and potassium carbonate (0.35 g, 2.54 mmol, 1.2 eq) in 4 ml of dimethylformamide was heated at 70° C. for 1 hr and then cooled to room temperature. 1-bromo-3-octyne was added in a single portion and the mixture was stirred for 1 hr. The reaction mixture was poured into water and the precipitated solids were collected by filtration. The collected solid was recrystallized from methanol to give 0.39 g (32%) of desired product. Mp 45° C.-49° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].C(N(C(C)C)CC)(C)C>ClCCl>[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[C:14]([F:16])([F:15])[F:17])[CH2:9][CH2:10]1)(=[O:27])=[O:26]
Reactant: Fc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1Cl)N1CCN(c2ccc(F)cc2C(F)(F)F)CC1
Yield: 73.3 %

Procedure:
Sulfonylation of 1-(4-fluoro-2-(trifluoromethyl)phenyl)piperazine (386 mg, 1.55 mmol) with 2-chlorobenzene-1-sulfonyl chloride (382.2 mg, 1.555 mmol) was carried out according to a similar to the representative sulfonation procedure described in Example 1 using anhydrous dichloromethane (3 mL) as solvent and diisopropylethylamine (1.35 mL, 7.775 mmol) as base. 1-[(2-chlorophenyl)sulfonyl]-4-[4-fluoro-2-(trifluoromethyl)phenyl]piperazine was obtained in 73.3% yield (481.8 mg) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[F:8].S(Cl)([Cl:15])=O>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([Cl:15])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=C(Cl)Cc1ccc(F)c(F)c1
Yield: 100 %

Procedure:
To (3,4-difluoro-phenyl)-acetic acid (2.0 g) dissolved in 1,2-dichloroethane (5 mL) was added thionyl chloride (5 mL) and the mixture was refluxed for 16 hours under argon. The crude mixture was concentrated in vacuo to furnish 2.2 g (100%) of the title compound as a yellow oil. 1H NMR (500 MHz, CDCl3): 4.10 (s, 2H), 7.00 (m, 1H), 7.11 (m, 1H), 7.17 (m, 1H).
Reaction SMILES: S(O)(O)(=O)=O.C1O[C:17]2[CH:16]=[CH:15][C:10]([CH2:11][CH2:12]NN)=[CH:9][C:8]=2O1.[Na].C1OC2C=CC(C[CH2:26][NH:27][N:28]=[C:29]([CH3:33])[C:30]([O-:32])=[O:31])=CC=2O1.[Na+:38]>>[C:10]1([CH2:11][CH2:12][CH2:26][NH:27][N:28]=[C:29]([CH3:33])[C:30]([O-:32])=[O:31])[CH:9]=[CH:8][CH:17]=[CH:16][CH:15]=1.[Na+:38]
Reactant: CC(=NNCCc1ccc2c(c1)OCO2)C(=O)[O-]
Reactant: NNCCc1ccc2c(c1)OCO2
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [Na]
Product: CC(=NNCCCc1ccccc1)C(=O)[O-]

Procedure:
3,4-methylenedioxy-phenethylhydrazine sulphate (m.p. 138°-140° C. (decomp.)) and subsequent preparation of the sodium salt: sodium 2-(3,4-methylenedioxy-phenethylhydrazono)-propionate; m.p. 175°-177° C. (decomp.), after recrystallization from ethanol.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][C:24]=3[F:32])[CH:14]=2)=[N:11][CH:12]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=3[F:32])[CH:14]=2)=[N:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Yield: 103 %

Procedure:
To a suspension of 30 (10 g, 22.05 mmol) in EtOH (216 ml) and water (108 ml) was added iron powder (10.47 g, 187 mmol) and ammonium chloride (1.015 g, 18.97 mmol). The mixture was heated to reflux for 30 min, filtered while hot and the solids were washed with ether (200 mL). The filtrate and washings were combined and concentrated to afford intermediate 31 (9.62 g, 99% yield) as a beige solid. This material was used in the next step (Scheme 9) without additional purification. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.64 (d, J=2.0 Hz, 1H), 8.51 (dd, J=5.6, 2.0 Hz, 1H), 8.34 (s, 1H), 8.28 (dd, J=8.0, 0.8 Hz, 1H), 7.93 (dd, J=8.4, 2.0 Hz, 1H), 7.13 (t, J=9.0 Hz, 1H), 6.61 (dd, J=5.4, 0.6 Hz, 1H), 6.54 (dd, J=13.2, 2.4 Hz, 1H), 6.46 (ddd, J=8.8, 2.8, 0.6 Hz, 1H), 5.67 (s, 1H), 5.56 (s, 2H), 4.19 (dd, J=10.6, 5.0 Hz, 2H), 3.98 (td, J=12.0, 2.5 Hz, 2H), 2.09-1.99 (m, 1H), 1.49 (dt, J=13.2, 1.3 Hz, 1H). MS (m/z): 424.1 (M+H).
Reaction SMILES: [NH2:1][OH:2].[CH3:3][O:4][C:5]1[CH:29]=[CH:28][C:8]([CH2:9][CH2:10][N:11]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=2)(=[O:20])=[O:19])[CH2:12][CH2:13][C:14](OC)=[O:15])=[CH:7][CH:6]=1>>[OH:2][NH:1][C:14](=[O:15])[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:29][CH:28]=1)[S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1)(=[O:20])=[O:19]
Reactant: COC(=O)CCN(CCc1ccc(OC)cc1)S(=O)(=O)c1cccc(N)c1
Reactant: NO
Product: COc1ccc(CCN(CCC(=O)NO)S(=O)(=O)c2cccc(N)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.6 %

Procedure:
Freshly prepared NH2OH solution (1 M in MeOH) (0.6 mL, 0.6 mmol)) was added to methyl 3-[(4-methoxyphenethyl)-(3-aminobenzenesulfonyl)amino]propionate (110 mg, 0.28 mmol). After stirring at room temperature for 18 h, the reaction mixture was concentrated and taken up with 10 mL of water. The mixture was acidified to pH 3-4 by 1 N HCl solution and extracted with ethyl acetate (2×20 mL). Combined organic layers was washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (10/1 methylene chloride/methanol) to give N-hydroxy-3-[(4-methoxyphenethyl)-(3-aminobenzene-sulfonyl)amino]-propionamide (33 mg, 0.08 mmol). NMR (360 MHz, DMSO-d6) δ 10.44 (s, 1H), 8.72 (br s, 1H), 7.23-6.25 (m, 8H), 5.57 (br s, 2H), 3.70 (s, 3H), 3.33 (t, 2H), 3.24 (t, 2H), 2.65 (t, 2H), 2.24 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11](=O)[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11](=[CH:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Yield: 99.8 %

Procedure:
To a solution of (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone (29b) (2.00 g, 8.21 mmol) in toluene (40 mL) was added ethyl 2-triphenylphosphoranylideneacetate (4.29 g, 12.31 mmol). The reaction was refluxed overnight then concentrated in vacuo and purified by silica gel chromatography (Hexanes:EtOAc). The desired product eluted at 15% ethyl acetate. Clean fractions were combined and concentrated to give 2.57 g of 62a. LCMS+: 314.18 at 3.75 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[CH2:9]([O:11][C:12](=[O:26])[CH:13]([CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:14](=O)[CH3:15])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C.C(Cl)Cl>[CH2:9]([O:11][C:12]([C:13]1[CH:17]=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:1]([C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)[C:14]=1[CH3:15])=[O:26])[CH3:10]
Reactant: Cc1cccc(N)c1
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2cccc(C)c2)c1C

Procedure:
m-Toluidine (5 mmol, 0.5 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in methylene chloride, then washed with water, 5% sodium bicarbonate, and brine. The organic layer was dried over NaSO4, then the solids were separated and the solvents evaporated under vacuum. The crude product was recrystallized from ethanol to yield the named product (m.p. 103° C.-104.5° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][NH:10][C:11](=[O:12])[C:3]=12.I[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:16].CCN(CC)CC.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[S:9][N:10]=[C:11]([O:12][CH2:14][C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]3)=[O:16])[C:3]=12
Reactant: CCOC(=O)N1CCN(C(=O)CI)CC1
Reactant: Cc1cc(C)c2c(=O)[nH]sc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)COc2nsc3nc(C)cc(C)c23)CC1
Yield: 10.8 %

Procedure:
Pyridinothiazolone 4 (300 mg, 1.66 mmol) was treated with ethyl 4-(2-iodoacetyl)piperazine-1-carboxylate (541 mg, 1.66 mmol), Et3N (840 mg, 8.30 mmol) and Cs2CO3 (500 mg, 1.54 mmol) in anhydrous CH2Cl2 (25 mL) at room temperature for 24 h, and then washed with H2O. The organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (EtOAc/hexane (1:1)) to give the title compound (68 mg, 11% yield) in addition to the main N-alkylation product 21 (YMU1, 60%). The purity of product 28 was 99.5% as shown by HPLC on an HC-C18 column (Agilent, 4.6×250 mm, 5 μM), tR=4.9 min (gradients of 40-90% aqueous CH3CN in 15 min).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[C:11]([Si:13]([CH3:16])([CH3:15])[CH3:14])#[CH:12].C(N(C(C)C)CC)(C)C>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][Si:13]([C:11]#[C:12][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1)([CH3:16])[CH3:15]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc2cnccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cnc2cnccn12
Temperature: 50 °C
Yield: 91.7 %

Procedure:
A mixture of 3-bromoimidazo[1,2-a]pyrazine (0.15 g, 0.76 mmol; prepared according to J. Bradac, et al. J. Org. Chem. (1977), 42, 4197-4201), 0.09 g (0.91 mmol) of ethynyltrimethylsilane, 0.044 g (0.038 mmol) of Pd(PPh3)4, 0.014 g (0.076 mmol) of Cul, and 0.26 mL (1.52 mmol) of diisopropylethylamine in 3.8 mL of DMF was heated at 50° C. overnight under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 50% EtOAc/hexanes) to provide 0.15 g of product: 216 m/z (M+H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([OH:21])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][O:29]2)[CH2:25][CH2:24]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([Br:18])=[C:13]2[N:12]=[CH:11][C:10]=1[C:19]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][O:29]2)[CH2:25][CH2:24]1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc2c(c1)COC21CCNCC1
Reactant: O=C(O)c1cnc2c(Br)cnn2c1NCc1ccccc1
Agent: Cl
Product: O=C(c1cnc2c(Br)cnn2c1NCc1ccccc1)N1CCC2(CC1)OCc1ccccc12
Yield: 94 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-bromopyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.754 g, 2.18 mmol) obtained in Example 22, step 3 and 3H-spiro[isobenzofuran-1,4′-piperidine]hydrochloride (Journal of Organic Chemistry, 1976, vol. 15, item 2628, 0.491 g, 0.218 mmol), the title compound (0.484 g, 94%) was obtained.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:11]=1[C:12]#[N:13].[C:20](=[O:22])=[O:21]>C1COCC1>[C:12]([C:11]1[C:10]([F:9])=[C:17]([CH:16]=[CH:15][C:14]=1[O:18][CH3:19])[C:20]([OH:22])=[O:21])#[N:13]
Reactant: O=C=O
Reactant: COc1cccc(F)c1C#N
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)c(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred lithium diisopropylamide solution (1.8M in heptane/THF/ethylbenzene, 44.1 mL, 79.4 mmol) at −50° C. was added a solution of 2-fluoro-6-methoxybenzonitrile (10 g, 66.16 mmol) in THF (80 mL) slowly and stirring was continued at that temperature for 1 h. The reaction mixture was poured onto a stirred slurry of dry ice in dry THF (100 mL). After the mixture had warmed up to room temperature, it was concentrated to about 50 mL, diluted with 6 N HCl (200 mL), extracted with dichloromethane, dried with sodium sulfate, concentrated, and dried in vacuo to give 3-cyano2-fluoro-4-methoxybenzoic acid (12.9 g, 100%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH:20]C(=O)C)=[CH:12][CH:11]=1)(=[O:9])=[O:8]>C[O-].[Na+]>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([NH2:20])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2nccs2)c2ccccc12
Agent: C[O-]
Agent: [Na+]
Product: Nc1ccc(S(=O)(=O)Nc2nccs2)c2ccccc12
Temperature: 70 °C
Yield: 73.6 %

Procedure:
N-[4-(Thiazol-2-ylsulfamoyl)-naphthalen-1-yl]-acetamide (0.48 g, 1.38 mmol) was dissolved in 0.5 M NaOMe (20 ml) and heated at 70° C. for 16 h. After the solvents were evaporated, a 2:1 EtOH:H2O mixture (6 ml) and a few drops of AcOH were added. While stirring the mixture, a precipitate formed which was filtered and dried under vacuum to give 4-amino-naphthalene-1-sulfonic acid thiazol-2-ylamide (0.31 g, 73%). LC/MS (10-99% CH3CN), M/Z: M+1 obs=306.0; tR=2.04 min.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:8][C@@H:9]([O:10]S(C3C=CC(C)=CC=3)(=O)=O)[C@H:5]2[O:4][CH2:3]1.[O-][CH2:29][CH3:30].[Na+]>C(O)C.C(=O)([O-])O.[Na+]>[CH2:29]([O:10][C@H:9]1[CH2:8][N:7]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C@@H:6]2[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]12)[CH3:30]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reactant: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCO[C@H]1CN(C(=O)OC(C)(C)C)[C@H]2[C@@H]1OC[C@@H]2O
Temperature: 80 °C
Yield: 7 %

Procedure:
A stirred mixture of tosylate (35b) (20 mg, 0.05 mmol), ethanol (1 mL) and sodium ethoxide solution in ethanol (21% wt, 94 μL, 0.25 mmol) was heated under an atmosphere of argon at 80° C. for 16 hours. The mixture was diluted with aqueous saturated sodium hydrogen carbonate solution (10 mL) then extracted with tert-butyl methyl ether (3×5 mL). The organic phase was dried (MgSO4), filtered and reduced in vacuo to leave an oil. Flash chromatography over silica, eluting with diethyl ether:pentane mixtures 65:35 to 83:17 gave ethoxyalcohol (59) as a pale yellow solid (1 mg, 7%). TLC (Rf=0.50, Et2O); analytical HPLC main peak, Rt=15.35 min., HPLC-MS 218.1 [M+2H−tBu]+, 296.1 [M+Na]+, 569.3 [2M+Na]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11](SC)=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:21][C:22]([NH2:26])([CH3:25])[CH2:23][CH3:24]>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([NH:26][C:22]([CH3:25])([CH3:21])[CH2:23][CH3:24])=[C:12]([S:15]([CH3:18])(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CSC(Nc1ccc2c(c1)OCO2)=C(C#N)S(C)(=O)=O
Reactant: CCC(C)(C)N
Solvent: CC#N
Product: CCC(C)(C)NC(Nc1ccc2c(c1)OCO2)=C(C#N)S(C)(=O)=O

Procedure:
A mixture of 3-(benzo[1,3]dioxol-5-ylamino)-2-methanesulfonyl-3-methylsulfanyl-2-propenenitrile(0.800 g, 2.5 mmol) and 1,1-dimethylpropylamine (2.92 ml) in 10 ml of acetonitrile was stirred and refluxed for one week under nitrogen. The reaction mixture was concentrated and the residue dissolved in dichloromethane, washed twice with 1N aqueous HCl, once with brine, and trice with water. The organic phase was dried (sodium sulphate) and evaporated to afford the title compound as white crystals. Mp 86-88° C. 1H NMR (200 MHz, DMSO-d6): δ=0.90 (t, 3H), 1.34 (s, 6H), 1.70 (q, 2H), 3.04 (s, 3H), 6.66 (dd, 1H), 6.74 (d, 1H), 6.88 (d, 1H), 7.21 (s, 1H), 8.19 (s, 1H).