Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[N:13]=[CH:14][C:15]([NH:18]C(=O)OC(C)(C)C)=[N:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[N:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(OCCOCc2ccccc2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cnc(OCCOCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of tert-butyl {5-[2-(benzyloxy)ethoxy]pyrazin-2-yl}carbamate (614 mg) in dichloromethane (10 mL) was added trifluoroacetic acid (0.68 mL) at room temperature, followed by stirring at room temperature overnight. After concentration, saturated aqueous sodium bicarbonate was added thereto. After extraction with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by basic silica gel column chromatography (hexane:ethyl acetate=5:1-1:1) to obtain 5-[2-(benzyloxy)ethoxy]pyrazin-2-amine (269 mg) as a pale yellow solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]([N:7]2[C:13]([CH3:14])=[CH:12][C:11]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:10]=3[C:9]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[C:22]([CH3:29])[CH:21]=3)=[N:8]2)=[O:6])[CH2:3][CH2:2]1.O.NN>CO.ClCCl.[Ni]>[CH:1]1([NH:4][C:5]([N:7]2[C:13]([CH3:14])=[CH:12][C:11]3[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:10]=3[C:9]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([CH3:29])[CH:21]=3)=[N:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: CC1=Cc2ccc(Cl)cc2C(c2ccc([N+](=O)[O-])c(C)c2)=NN1C(=O)NC1CC1
Agent: [Ni]
Agent: NN
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC1=Cc2ccc(Cl)cc2C(c2ccc(N)c(C)c2)=NN1C(=O)NC1CC1
Reaction time: 1 h
Yield: 90.1 %

Procedure:
1.38 g (3.35 mmoles) of 8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3H-2,3-benzodiazepine-3-carboxylic acid cyclopropyl amide is dissolved in the mixture of 28 ml of methanol and 14 ml of dichloromethane, and about 1.0 g of wet Raney nickel catalyst and 0.42 ml (8.37 mmoles) of 98% hydrazine hydrate are subsequently added to it under vigorous stirring. The mixture is stirred for further 1 hour, the catalyst is filtered off, washed with dichloromethane, the filtrate is evaporated and the residue is solidified by rubbing with 10 ml of water. The crude product is recrystallized from ethanol. Thus 1.15 g (90%) of the desired compound melting at 233-236° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20](O)=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[F:23][C:9]1[CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:21])[CH:12]=[CH:13][C:8]=1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Reactant: C1CNCCN1
Product: Nc1cnc(-c2ccc(-c3ccccc3C(=O)N3CCNCC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and piperazine. MS (ESI): mass calcd. for C21H20FN5O, 377.17; m/z found, 378.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.64-8.56 (m, 1H), 8.11 (d, J=1.5, 1H), 8.04-7.93 (m, 1H), 7.53-7.40 (m, 4H), 7.37 (dd, J=8.1, 1.8, 1H), 7.30 (dd, J=12.2, 1.7, 1H), 4.77 (s, 2H), 3.72 (d, J=25.1, 2H), 3.14 (s, 1H), 2.92 (s, 2H), 2.65 (s, 2H), 2.05 (s, 1H).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11](=[O:21])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2]>S(Cl)(Cl)=O>[CH3:2][C:1]1[O:21][C:11]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:4]=1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)CCc1cccc(C)c1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1nc(C)oc1CCc1cccc(C)c1

Procedure:
Thionyl chloride (200 ml) was added dropwise over 15 min to the product from step (ii) (70 g) with cooling provided by an ice bath. The mixture was then set at reflux for 1 h. After cooling to room temperature the thionyl chloride was evaporated under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was collected, dried over magnesium sulphate and solvent removed under reduced pressure. Purification of the residue was performed by flash chromatography eluting with 2% ethanol in dichloromethane.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:4]1=[O:26].[C:27]([C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1)#[N:28].[BH3-]C#N.[Na+].C([O-])(O)=O.[Na+]>O.C(OCC)(=O)C.C(O)(=O)C.C1COCC1>[C:27]([C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:2][N:3]2[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=3)[N:5]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:4]2=[O:26])=[CH:31][CH:30]=1)#[N:28]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COc1ccc(CCN2C(=O)N(N)CC2c2ccc(C)c(C)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CCN2C(=O)N(NCc3ccc(C#N)cc3)CC2c2ccc(C)c(C)c2)cc1
Reaction time: 2 h
Yield: 39.5 %

Procedure:
To a solution of 1-amino-3-[2-(4-methoxy-phenyl)ethyl]-4-(3,4-dimethylphenyl)-2-imidazolidinone hydrochloride (350 mg, 0.93 mmol), THF (4.5 mL), and 4-cyanobenzaldehyde (131 mg, 1.0 mmol) is stirred at 50° C. for 30 minutes, then cooled in an ice bath and glacial acetic acid (3.5 mL) is added. To the resulting mixture is added NaCNBH3 (183 mg, 2.9 mmol). The reaction is stirred in the cold for 2 hours and ethyl acetate and H2O are added. The mixture is made basic with solid NaHCO3, and the organic phase is washed with 10% aqueous NaHCO3 and brine. The organic phase is dried (Na2SO4) and concentrated under reduced pressure. The residue is purified over silica (45% ethyl acetate/hexanes) to afford 167 mg (40% yield) of the desired product. 1H NMR (CDCl3) δ 7.65 (m, 2H), 7.56 (d, J=8.4 Hz, 2H), 7.12 (d, J=7.8 Hz, 1H), 7.05 (m, 2H), 6.89 (m, 2H), 6.84 (m, 2H), 4.20 (m, 3H), 3.82 (s, 3H), 3.67 (m, 1H), 3.48 (t, J n=8.4 Hz, 1H), 3.06 (t, J=8.1 Hz, 1H), 2.91 (m, 1H), 2.76 (m, 1H), 2.67 (m, 1H), 2.29 (s, 3H), 2.26 (s, 3H). MS 455 (MH+). Anal. Calcd. For C28H30N4O2: C, 73.98; H, 6.65; N, 12.33. Found: C, 73.68; H, 6.65; N, 12.08.
Reaction SMILES: [CH2:1]([N:8]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20]C=1)=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[Li+].[Cl-].[CH2:40]([C@@H:47]1[CH2:51][O:50][C:49](=[O:52])[NH:48]1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C1COCC1>[C:17]1([O:16][C:14](=[O:15])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][C:11]([N:48]2[C@H:47]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:51][O:50][C:49]2=[O:52])=[O:13])[CH:18]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)CCN(Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1ccccc1)N(CCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1)Cc1ccccc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3-{benzyl[(benzyloxy)cabonyl]amino}propanoic acid (13.80 g, 44.04 mmol) and triethylamine (18.5 mL, 132.1 mmol) in anhydrous THF (220 mL) at −25° C. was slowly added pivaloyl chloride (6.03 mL, 48.44 mmol) to immediately form a white precipitate. The reaction mixture was stirred at −20° C. for 1 h, prior to the sequential addition of LiCl and (R)-(+)-4-benzyl-2-oxazolidinone. After stirring the reaction mixture at rt for 16 h, the reaction was quenched with saturated aqueous NaHCO3 (80 mL) and water (80 mL). The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by Combiflash (20-40% EtOAc/hexane) to give benzyl-{3-[(4R)-benzyl-2-oxo-1,3-oxazolidin-3-yl)-3-oxo-propyl]-carbamic acid phenyl ester as a colorless semi-solid (17.00 g, 82% in yield). MS (ESI): 473.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[Cl:8][CH2:9][C:10](=O)[CH2:11][C:12](OCC)=[O:13]>>[Cl:8][CH2:9][C:10]1[N:1]=[C:2]2[S:3][CH:4]=[C:5]([CH3:7])[N:6]2[C:12](=[O:13])[CH:11]=1
Reactant: Cc1csc(N)n1
Reactant: CCOC(=O)CC(=O)CCl
Product: Cc1csc2nc(CCl)cc(=O)n12
Yield: 85.3 %

Procedure:
This compound was synthesized from 2-amino-4-methyl thiazole (5.0 g, 43.710 mmol) and ethyl chloroacetoacetate (9.893 g, 59.561 mmol) in polyphosphoric acid (40.0 g) according to the procedure described in Step 1, Intermediate 2 to afford 8.0 g of the desired compound as a black solid; 1H NMR (300 MHz, DMSO-d6) δ 2.67 (s, 3H), 4.53 (s, 2H), 6.27 (s, 1H), 7.05 (s, 1H); ESI-MS (m/z) 215.39 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH:13]=[CH2:14]>CCOC(C)=O.[Pd]>[OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14]
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1cc(C(=O)OC)ccc1O
Reaction time: 24 h

Procedure:
To 22-3 (6.0 g, 33.2 mmol) in 50 mL of EtOAc was added 60 mg of 5% Pd on carbon and the whole was hydrogenated at atmospheric pressure for 24 h. Hydrogen was removed from the reaction mixture and the solution was filtered through Celite. Evaporation of the solvent afforded product 22-4 as a white solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][CH:12]=[C:11]([C:14](=[N:16][NH:17][C:18]([C:20]3[S:24][C:23]([C:25]([O:27]C)=[O:26])=[CH:22][CH:21]=3)=[O:19])[CH3:15])[C:10]=2[OH:29])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C(O)(C)(C)C>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][CH:12]=[C:11]([C:14](=[N:16][NH:17][C:18]([C:20]3[S:24][C:23]([C:25]([OH:27])=[O:26])=[CH:22][CH:21]=3)=[O:19])[CH3:15])[C:10]=2[OH:29])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(F)(F)F)cc3)c2O)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CC(=NNC(=O)c1ccc(C(=O)O)s1)c1csc(-c2ccc(C(F)(F)F)cc2)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.3 %

Procedure:
To a suspension of methyl 5-[(2-{1-[5-(4-trifluoromethylphenyl)-4-hydroxy-3-thienyl]ethylidene}hydrazino)carbonyl]-2-thiophenecarboxylate (56.2 mg, 0.12 mmol) in t-butanol (1.2 mL), 0.2 M sodium hydroxide aqueous solution (1.26 mL, 0.25 mmol) was added, and the mixture was stirred at room temperature for 4 hours. After completion of the stirring, 1 M hydrochloric acid (252 μL) was added, and the precipitated solid was filtered and washed with methanol to obtain 14.9 mg of the desired product as an orange solid (yield 27%).
Reaction SMILES: FC1C=C(F)C(F)=CC=1C(O)=[O:5].N1C2C(=CC=CC=2)C=CC1=O.[Cl:24][C:25]1[C:26](Cl)=[C:27]([Cl:37])[C:28]([Cl:36])=[C:29]2[C:34](=[O:35])[O:33][C:31](=[O:32])[C:30]=12>[OH-].[Na+].[Zn]>[Cl:36][C:28]1[C:27]([Cl:37])=[CH:26][C:25]([Cl:24])=[C:30]([C:31]([OH:32])=[O:5])[C:29]=1[C:34]([OH:33])=[O:35]
Reactant: O=C(O)c1cc(F)c(F)cc1F
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: O=c1ccc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1c(Cl)cc(Cl)c(Cl)c1C(=O)O

Procedure:
2,4,5-Trifluorobenzoic acid (2,4,5--TiFBA) is used as an intermediate in preparing quinolone antibacterials. It is prepared by a process that begins with tetrachlorophthalic anhydride. Tetrachlorophthalic anhydride is first hydrodechlorinated in NaOH/Zn to produce 3,4,6-trichlorophthalic acid, followed by imidization using methylamine to form 3,4,6-trichloro-N-methylphthalimide. That product is fluorinated by KF to form 3,4,6-trifluoro-N-methyl phthalimide, which is hydrolyzed to produce 3,4,6-trifluorophthalic acid. Decarboxylation results in a solution of 2,4,5-TiFBA in an organic decarboxylating solvent such as N-methylpyrrolidone (NMP).
Reaction SMILES: C([NH:14][CH2:15][CH2:16][C:17]1[C:18]([O:36][CH3:37])=[N:19][C:20]([C:32]([F:35])([F:34])[F:33])=[CH:21][C:22]=1[CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])(C1C=CC=CC=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[Si:25]([O:24][CH2:23][C:22]1[CH:21]=[C:20]([C:32]([F:35])([F:34])[F:33])[N:19]=[C:18]([O:36][CH3:37])[C:17]=1[CH2:16][CH2:15][NH2:14])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: [H][H]
Reactant: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1CCNC(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1CCN

Procedure:
To a solution of the compound from Step I above (1.25 g, 2.36 mmol) in absolute ethanol (100 mL) was added 10% palladium on carbon (480 mg). The reaction mixture was placed in a Parr apparatus and shaken under 50 psi of hydrogen for 4 hours. The solution was filtered through a pad of Celite and concentrated in vacuo to yield the title compound. LC/MS: 365 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[O:13])=[CH:8][CH:7]=1.[C:25]([C:27]1[CH:28]=[C:29]([CH:44]=[CH:45][CH:46]=1)[O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:32]=1)#[CH:26].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCCC>[O:37]([C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=1)[O:30][C:29]1[CH:28]=[C:27]([C:25]#[C:26][C:2]2[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=2)[O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[O:13])=[CH:8][CH:7]=2)[CH:46]=[CH:45][CH:44]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: C#Cc1cccc(Oc2cccc(Oc3ccccc3)c2)c1
Reactant: O=C(C(=O)c1ccc(Oc2cccc(Br)c2)cc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C(C(=O)c1ccc(Oc2cccc(C#Cc3cccc(Oc4cccc(Oc5ccccc5)c4)c3)c2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.1 %

Procedure:
To a 250 ml flask fitted with a reflux condenser, nitrogen inlet and thermometer were added 4(3-bromophenoxy)benzil (11.08 g, 29.08 mmol), 1-(3-ethynylphenoxy)-3-phenoxybenzene (21.64 g, 75.66 mmol), triethylamine (150 ml), and triphenylphosphine (0.40 g). After stirring at room temperature under a nitrogen atmosphere for 10 minutes, cuprous iodide (Alfa 98%, 0.20 g) and dichlorobis (triphenylphosphine) palladium (II) (0.20 g) were added. The flask was heated to an internal temperature of 90° C. and maintained by oil bath heating under nitrogen until TLC indicated reaction completion (4 hr). The triethylamine was distilled from the residue and the residue was suspended in toluene. The toluene was washed with 15% HCl (560 ml) twice and separated. The organic layer was washed with ethylenediamine (20 ml) by adding the ethylenediamine at room temperature, heating to 60° C. for 0.5 h and cooling. Water (250 ml) was added and the toluene was separated from the aqueous layer. The ethylenediamine wash was repeated once more. After washing with water (3×500 ml), the organic layer was dried over anhydrous magnesium sulfate (3.00 g) and the toluene distilled by rotary evaporation at reduced pressure to give a dark brown oil. The oil was dissolved in 4:1 hexane:methylene chloride and chromatographed on a silica gel column (Woelm DCC, 230 g, 5 cm dia×25 cm H) using 4:1 hexane:methylene chloride as the eluent. The product was dried in a 70° C. oven under reduced pressure to afford a light brown tacky oil (7.52 g, 44%).
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[Na+]>O.CN(C=O)C>[O:18]=[C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[C:10]([Cl:16])[C:9]=2[Cl:17])[CH2:14][C:6]1([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH3:19]
Reactant: CCOC(=O)CCCBr
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C2CCCC2)Cc2cc(OCCCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
By following the procedure described in Example 5, Step G, using as the reactants 2-cyclopentyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (30.9 g., 0.1 mole), potassium carbonate (15.2 g., 0.11 mole), DMF (200 ml.), ethyl 4-bromobutyrate (23.5 g., 0.11 mole), water (200 ml.) and 10 N sodium hydroxide (40 ml.), there is obtained 4-(1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)butyric acid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:14]1[CH:30]=[CH:29][C:17]([CH:18]=[CH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)=[O:13].C(O)(=[O:33])C.OO>ClCCl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][S:12]([C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[CH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)=[CH:29][CH:30]=1)(=[O:33])=[O:13]
Reactant: CC(=O)O
Reactant: O=C(O)c1ccc(C=Cc2ccc(S(=O)Cc3ccc4ccccc4n3)cc2)cc1
Agent: OO
Solvent: ClCCl
Product: O=C(O)c1ccc(C=Cc2ccc(S(=O)(=O)Cc3ccc4ccccc4n3)cc2)cc1
Temperature: 25 °C

Procedure:
To 3 mmol of the sulfinyl compound from Step A in acetic acid (40 mmol) is added 30% hydrogen peroxide (2 ml). The mixture is stirred at ambient temperature and assayed by TLC. Upon disappearance of the sulfinyl starting compound, the reaction mixture is diluted with dichloromethane, washed with dilute aqueous sodium bisulfite and water, dried and evaporated to give 4-(4-(2-quinolinylmethylsulfonyl)-styryl)benzoic acid.
Reaction SMILES: [K].S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:13][C:14]1[CH:19]=[C:18]([C:20](=[N:22]O)[CH3:21])[CH:17]=[CH:16][N:15]=1.[N:24]#[C:25][NH2:26].[OH-].[Na+].[OH-].[NH4+]>CCOCC.C(O)C>[CH3:13][C:14]1[CH:19]=[C:18]([C:20]2[N:22]=[C:25]([NH2:26])[NH:24][CH:21]=2)[CH:17]=[CH:16][N:15]=1
Reactant: CC(=NO)c1ccnc(C)c1
Reactant: N#CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOCC
Product: Cc1cc(-c2c[nH]c(N)n2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 210 mg. of potassium metal dissolved in 10 ml. of absolute ethanol was added a suspension of 1.46 (4.8 mmoles) of 2-methyl-4-acetylpyridine oxime tosylate in 10 ml. of dry ethanol, and the mixture allowed to stir at room temperature for one hour. Ether (200 ml.) was added, the potassium tosylate filtered, and the filtrate extracted with (3×20 ml.) 1 N hydrochloric acid. The combined acid extracts were concentrated to a yellow solid, which was then dissolved in 30 ml. of water. Cyanamide (600 mg., 14.2 mmoles) was dissolved in the aqueous solution and the pH adjusted to 4.5 by the addition of 2 N sodium hydroxide. The solution was heated on a steam bath for one hour, cooled in an ice bath and made basic with concentrated ammonium hydroxide. The mixture was concentrated, and the residue triturated with 15 ml. of ethanol. The solids were filtered and the filtrate was treated with ether. The resulting precipitate was filtered and dried in vacuo, 755 mg. (90%), m.p. 226°-228° C.
Reaction SMILES: C[O:2][C:3]1[N:4]=[N:5][C:6]([S:9]([C:12]2[O:13][C:14]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:15]=3[C:16]=2[CH2:17][CH3:18])(=[O:11])=[O:10])=[CH:7][CH:8]=1.Cl>O1CCOCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:14]2[O:13][C:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3](=[O:2])[NH:4][N:5]=3)(=[O:11])=[O:10])=[C:16]([CH2:17][CH3:18])[C:15]=2[CH:19]=1
Reactant: CCc1c(S(=O)(=O)c2ccc(OC)nn2)oc2ccc(Cl)cc12
Agent: Cl
Solvent: C1COCCO1
Product: CCc1c(S(=O)(=O)c2ccc(=O)[nH]n2)oc2ccc(Cl)cc12
Temperature: 100 °C

Procedure:
A mixture of 3-methoxy-6-(5-chloro-3-ethyl-benzofuran-2-sulfonyl)-pyridazine, without further purification, (1.04 mmol, 352 mg), conc. HCl (1.5 mL), and dioxane (3 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled and evaporated to dryness. Water (10 mL) was added to the residue and the resulting solid, 6-(5-chloro-3-ethyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one, was collected. (46%, 155 mg); mp 209° C.-210° C.
Reaction SMILES: [OH-].[Na+].[ClH:3].C[O:5][C:6](=[O:38])[CH:7]([NH:20][C:21](=[O:37])[CH2:22][NH:23][S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25])[CH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([NH2:19])=[N:14][CH:13]=[CH:12]2>O1CCOCC1.O>[ClH:3].[NH2:19][C:15]1[C:16]2[C:11](=[CH:10][C:9]([CH2:8][CH:7]([NH:20][C:21](=[O:37])[CH2:22][NH:23][S:24]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)(=[O:26])=[O:25])[C:6]([OH:38])=[O:5])=[CH:18][CH:17]=2)[CH:12]=[CH:13][N:14]=1
Reactant: COC(=O)C(Cc1ccc2c(N)nccc2c1)NC(=O)CNS(=O)(=O)c1ccc2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nccc2cc(CC(NC(=O)CNS(=O)(=O)c3ccc4ccccc4c3)C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.7 %

Procedure:
0.16 mL of aqueous 2N NaOH was added to a solution of 47 mg of 1k in 1.0 mL of dioxane and 0.5 mL water. After stirring at room temperature for one hour, the reaction mixture was made acidic (pH 2) and extracted with a mixture of n-butanol and dichloromethane. Evaporation of the organic solvents yielded 47 mg of acid 2a. 1H-NMR 200 MHz (CDCl3/CD3 OD=3/1) δ: 3.20-3.65 (4H, m), 4.87 (1H, dd, J=7 Hz and J=5 Hz), 7.10 (1H, d, J=7 Hz), 7.41 (1H, d, J=7 Hz), 7.58-8.03 (8H, m), 8.29 (1H, d, 7 Hz), 8.41 (1H, d, 2 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[N:16]=[C:15]([C:26]([OH:28])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:50]3[CH2:54][C:53](=[O:55])[NH:52][CH2:51]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[N:16]=[C:15]([C:26]([N:50]3[CH2:54][C:53](=[O:55])[NH:52][CH2:51]3)=[O:28])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:10])[F:11])[CH:7]=1
Reactant: COc1cc(-n2nc(C(=O)O)cc2-c2cc(Br)cc(OC(F)(F)F)c2)ccn1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: COc1cc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2cc(Br)cc(OC(F)(F)F)c2)ccn1

Procedure:
18 mg (0.04 mmol) of the compound of Example 49A is reacted analogously to the synthesis of the compound of Example 1 with 5 mg (0.04 mmol) of 4-imidazolinone-hydrochloride. 4 mg (14% of theory, 82% purity) of the title compound is obtained.
Reaction SMILES: CC[O-].[Na+].[Na].[C:6]1([CH2:12][O:13][C:14]([NH:16][CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:28](Br)[C:29]#[CH:30]>C(O)C.C1(C)C=CC=CC=1>[C:6]1([CH2:12][O:13][C:14]([NH:16][C:17]([C:28]#[C:29][CH3:30])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCBr
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC#CC(NC(=O)OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Yield: 41.9 %

Procedure:
A solution of sodium ethylate previously prepared from 500 mg of sodium in 20 ml of ethanol is added to 6 g of diethyl 2-[[(phenylmethoxy)carbonyl]amino]-propanedioate (prepared according to Bladon. C. M. J.Chem. Soc. Perkin. Trans I 9, 1151-1158 (1990) in 30 ml of ethanol then, after 30 minutes, 3 g of propargyl bromide at 80% in toluene is added and the reaction mixture is heated under reflux for 1 hour. The reaction mixture is then brought back to ambient temperature followed by evaporation under reduced pressure, taking up in dichloromethane, washing and drying. After evaporation under reduced pressure 6 g of the expected product is obtained which is purified by chromatography, eluting with a Cyclohexane/Ethyl acetate mixture 85/15. 2.82 g of purified product is obtained.