Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][C:15]1[S:23][C:22]2[CH2:21][CH2:20][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][C:17]=2[CH:16]=1>C(Cl)Cl>[CH3:8][S:9]([O:13][CH2:14][C:15]1[S:23][C:22]2[CH2:21][CH2:20][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][C:17]=2[CH:16]=1)(=[O:11])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(CO)cc2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2sc(COS(C)(=O)=O)cc2C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Triethylamine (21.2 mmol) and methanesulfonyl chloride (7.95 mmol) were added to a 0° C. cold solution of tert-butyl 2-(hydroxymethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (5.3 mmol) in methylene chloride (22 ml). The reaction mixture obtained was stirred at 0° C. for 2 hours. The course of the reaction was monitored by thin layer chromatography. The reaction mixture was then diluted with methylene chloride and washed successively with water and saturated sodium chloride solution. After the organic phase had been dried over sodium sulfate, the solvent was removed under reduced pressure. The crude product obtained was employed in the next stage without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C>[CH2:18]([O:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[CH2:10][CH3:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCc1cc(Br)cc(C)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc(Br)cc(C)c1OCc1ccccc1
Temperature: 25 °C

Procedure:
A suspension of 39.8 g (185 mmol) 4-bromo-2-ethyl-6-methyl-phenol, 63.9 g (0.46 mmol) K2CO3 and 22.0 mL (185 mmol) benzyl bromide in 450 mL acetonitrile was refluxed for 3 h, cooled to RT and concentrated by evaporation i.vac. The residue was combined with EtOAc, the organic phase was washed with water and saturated NaCl solution, dried on Na2SO4 and concentrated by evaporation i.vac.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17]C(=O)C)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1>Cl.O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Yield: 53 %

Procedure:
N-[4-(4-methylpiperazine-1-sulfonyl)phenyl]acetamide (2 g, 6.7 mmol) was dissolved in 3 N HCl (50 mL) and 1,4-dioxane (12 mL). The reaction mixture was refluxed for 1 h, evaporated under vacuum, and the resulting mixture made basic with 30% NH4OH. The desired product was extracted with CH2Cl2, dried (Na2SO4), filtered, and evaporated under reduced pressure to obtain 4-(4-methylpiperazin-1-sulfonyl)aniline as a white solid. MP: 210° C.; Yield 53%; 1H NMR (DMSO d6): δ 2.22 (s, 3H), 2.50 (m, 4H), 2.82 (m, 4H), 6.10 (bs, 2H), 6.62-6.67 (d, 2H, J=10 Hz), 7.32-7.36 (d, 2H, J=8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][C:3]=1[O:11][CH2:12][CH3:13].C([O:16][C:17](=O)[CH:18]=[C:19]([NH2:23])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:23][C:19]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([O:11][CH2:12][CH3:13])[CH:4]=2)[C:17](=[O:16])[CH:18]=1
Reactant: CCOc1cc(CNN)ccc1Cl
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOc1cc(Cn2[nH]c(N)cc2=O)ccc1Cl
Reaction time: 8 h

Procedure:
45.5 g of 4-chloro-3-ethoxybenzylhydrazine were added, under nitrogen, to a solution of 35 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 200 ml of ethanol. After stirring overnight, the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 143°, 15.2 g (26%).
Reaction SMILES: [O:1]1[C:11]2([CH3:12])[CH:2]1[CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:13]([OH:15])=[O:14])=[CH:9][C:10]=12.[K].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.N1C=CN=C1.[K]>CN(C=O)C>[OH:1][C:11]1([CH3:12])[C:10]2[CH:9]=[C:8]([C:13]([OH:15])=[O:14])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH:2]1[N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1
Reactant: CC12OC1CCc1ccc(C(=O)O)cc12
Reactant: c1c[nH]cn1
Agent: [K]
Solvent: CN(C)C=O
Product: CC1(O)c2cc(C(=O)O)ccc2CCC1n1ccnc1
Temperature: 130 °C

Procedure:
A solution of 1.9 g of 5,6-dihydro-7,8-epoxy-8-methyl-2-naphthalenecarboxylic acid (prepared by epoxidation of 5,6-dihydro-8-methyl-2-naphthalenecarboxylic acid, m.p. 150°-153° C.) in anhydrous DMF is added to a solution of imidazole potassium salt, prepared from prepared from 3.16 g of imidazole and 1.81 g of potassium, in anhydrous DMF (100 ml) and heated at 130° C., with vigorous stirring, for 6 hours. The solvent is evaporated under reduced pressure and the residue is taken up with water and ethyl acetate. The aqueous layer is separated and acidified to pH=5 with acetic acid. The water is evaporated under vacuum and the residue is chromatographed on silica gel (eluent CHCl3 :CH3OH, 70:30) giving 1.6 g of 5,6,7,8-tetrahydro-8-hydroxy-8-methyl-7-(1H-imidazol-1-yl)-2-naphthalenecarboxylic acid.
Reaction SMILES: [OH:1][C:2]1([C:9]2[O:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:20])[CH2:15]1>>[OH:1][C:2]1([C:9]2[O:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][CH:5]([N:14]2[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)=[O:20])[CH2:15]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2ncco2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3ncco3)CC2)C1

Procedure:
The title compound was prepared as a white solid from reductive amination of 4-hydroxy-4-oxazol-2-yl-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][CH:2]([C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]#[N:4].[NH2:13][NH2:14].CCO.CO>C(Cl)Cl>[CH3:1][C:2]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[N:14][NH:13][C:3]=1[NH2:4]
Reactant: NN
Reactant: CC(C#N)C(=O)c1ccccc1
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: Cc1c(-c2ccccc2)n[nH]c1N

Procedure:
A vial was charged with 2-Methyl-3-oxo-3-phenyl-propionitrile (1.0 g, 6.28 mmol), hydrazine (0.2 mL) and EtOH (1 mL), and subject to microwave irradiation at 100° C. for 50 min. Flach chromatography of the crude product using 3%-5% MeOH in CH2Cl2 gave the pyrazolylamine as a yellow oil (0.21 g). LC/MS (10% MeOH, 90% H20, 0.2% H3PO4 to 90% MeOH, 10% H20, 0.2% H3PO4, 2 minute gradient with an Exterra C18 S-5 column 4.6×30 mm): [M+H]+ m/z=174.10; retention time=1.02 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([OH:11])[CH:5]=1.[C:13](Cl)(=O)[CH3:14].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(N(CC)CC)C>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]=[C:13]([CH3:14])[O:11][C:6]=2[CH:5]=1)=[O:12]
Reactant: COC(=O)c1ccc(N)c(O)c1
Reactant: CC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)c1ccc2nc(C)oc2c1
Reaction time: 8.5 h
Yield: 80.3 %

Procedure:
To a solution of 4-amino-3-hydroxy-benzoic acid methyl ester (2085 mg, 12.47 mmmol) in xylene (200 mL) were added acetyl chloride (1.06 mL, 14.96 mmol), pyridinium p-toluenesulfonate (940 mg, 3.74 mmol) and triethylamine (2.09 mL, 14.96 mmol), and the solution was stirred for 8.5 hours under reflux. Ethyl acetate was added to the reaction mixture, which was then washed with water, dried over anhydrous magnesium sulfate, then, evaporated in vacuo, the resulting residue was purified by silica gel chromatography (hexane-ethyl acetate), and the title compound (1917 mg, 10.02 mmol, 80.4%) was obtained.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[CH3:20])[NH2:16]>ClCCl>[CH3:12][C:13]1[CH:14]=[C:15]([NH:16][C:2]2[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])[CH:17]=[CH:18][C:19]=1[CH3:20]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Cc1ccc(N)cc1C
Solvent: ClCCl
Product: Cc1ccc(Nc2cc(O)ccc2[N+](=O)[O-])cc1C
Temperature: 150 °C
Reaction time: 2 h

Procedure:
3 g of 3-fluoro-4-nitrophenol and 6.9 goof 3,4-dimethylaniline were mixed and stirred for 2 hours at 150° C. After cooling, it was dissolved in dichloromethane and extracted six times with 1N aqueous hydrochloric acid. The organic phase was discarded, and the combined aqueous phases were extracted three times with chloroform. The combined extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(=O)([O-])[O-].[Ag+2]>[CH2:13]([O:8][C:5]1[CH:4]=[C:3]([C:2]([Br:1])=[CH:7][N:6]=1)[C:9]([O:11][CH3:12])=[O:10])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cc(=O)[nH]cc1Br
Reactant: BrCc1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Product: COC(=O)c1cc(OCc2ccccc2)ncc1Br
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To 2 mL of methyl 5-bromo-2-oxo-1,2-dihydropyridine-4-carboxylate (232 mg, 1.00 mmol)(commercially available from Combi-Blocks) was added benzyl bromide (205 mg, 1.20 mmol) and silver carbonate (413 mg, 1.50 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA). The resulting mixture was stirred at 50° C. overnight. After reaction completion, the mixture was loaded onto a solid silica gel cartridge and purified by chromatography with 10% EtOAc/hexane to afford the desired product H6.1 (293 mg, 91%). MS ESI (pos.) m/e: 322.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:14]([NH:16][C:17]([NH:19][C:20]1[S:21][C:22]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:27][C:26](B(O)O)=[CH:25][C:23]=2[N:24]=1)=[O:18])[CH3:15]>C1COCC1.O>[Cl:1][C:2]1[N:6]=[C:5]([C:26]2[CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:22]3[S:21][C:20]([NH:19][C:17]([NH:16][CH2:14][CH3:15])=[O:18])=[N:24][C:23]=3[CH:25]=2)[S:4][N:3]=1
Reactant: Clc1nsc(Cl)n1
Reactant: CCNC(=O)Nc1nc2cc(B(O)O)cc(-c3ccccn3)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc2cc(-c3nc(Cl)ns3)cc(-c3ccccn3)c2s1
Temperature: 110 °C

Procedure:
3,5-dichloro-1,2,4-thiadiazole (50 mg, 0.32 mmol), Cesium carbonate (285.6 mg, 0.88 mmol), Pd(dppf)2C12 (20 mg, 0.03 mmol) and {2-[(ethylcarbamoyl)amino]-7-(pyridin-2-yl)-1,3-benzothiazol-5-yl}boronic acid (100 mg, 0.29 mmol) was suspended in a mixture of THF (9 mL) and water (1 mL) and heated in the microwave at 110° C. for 50 min. The reaction mixture was concentrated in vacuo and the residue partitioned between 10% IPA/DCM (10 mL) and water (10 mL). The organic layer was separated and the aqueous extracted with further 10% IPA/DCM (3×10 mL), the organic layers were combined, dried (MgSO4), filtered and concentrated, then pre-absorbed onto silica and purified by flash column chromatography (Biotage SP4 12 g, 2% MeoH/DCM-5% MeoH/DCM-8% MeOH/DCM) to give 1-[5-(3-chloro-1,2,4-thiadiazol-5-yl)-7-(pyridin-2-yl)-1,3-benzothiazol-2-yl]-3-ethylurea as a brown solid. (100 mg, 81%) MS: 416.92 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.I[CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14].[I-].[Na+]>>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(C)CCI
Agent: [I-]
Agent: [Na+]
Product: CC(C)CCOc1ccc(C=O)cc1
Yield: 92.6 %

Procedure:
The compound was synthesized as in Example 24.1, using 4-hydroxybenzaldehyde (200 mg, 1.64 mmol) and 1-iodo-3-methylbutane (649 mg, 1.97 mmol) in place of 1-chloro-3,3-dimethylbutane (no sodium iodide was used) to give 4-(isopentyloxy)benzaldehyde (292 mg, quant. crude) as a dark yellow oil that was used without further purification or characterization.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=O.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1.C([OH:24])C>>[OH:24][C:16]1[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=1[N:14]=[CH:12][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:2]=1
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: CCO
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(N=Cc2cccc3ccccc23)c(O)c1
Temperature: 70 °C

Procedure:
3.44 g (20.0 mmol) of 2-hydroxy-1-naphthaldehyde was dissolved in 50 ml ethanol under heating, and 2.14 g (20.0 mmol) of p-toluidine was added. After stirring under reflux at 70° C. for 1 hour, completion of the reaction was confirmed by TLC. Upon concentration of the solution with an evaporator to about 40 ml, a crystal was formed, which was filtered by Kiriyama funnel. Drying under reduced pressure at 25° C. for 24 hours gave 2-hydroxy-1-naphthylmethylidene-4-methylaniline (hereinafter, also referred to as “HNPT”) as a yellow crystal (4.70 g, 90%). 1.06 g (4.00 mmol) of HNPT was dissolved in a mixed solvent of 20 ml tetrahydrofuran and 30 ml ethanol, and 50 ml of an ethanol solution of 0.40 g (2.00 mmol) of copper acetate monohydrate was added with stirring. Upon stirring under reflux at 70° C. for 1 hour, a crystal was deposited. Completion of the reaction was confirmed by TLC. The resulting crystal was filtered by Kiriyama funnel, and washed sufficiently with ethanol. Drying under reduced pressure at 25° C. for 24 hours gave a crude product of a complex compound NPTCu of the following formula as a red-brown crystal (1.17 g, 94%). A part of the resulting crystal was dissolved in tetrahydrofuran, and ethanol having a 4-fold volume thereof was added to deposit a crystal. This crystal was filtered, and dried under reduced pressure to give a purified product of the complex compound NPTCu.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH:10]([Mg]Cl)([CH3:12])[CH3:11].CON(C)[C:18](=[O:46])[CH2:19][O:20][CH2:21][C:22]1[N:23]=[CH:24][N:25]([C:27](C2C=CC=CC=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)C2C=CC=CC=2)[CH:26]=1>O1CCCC1>[C:27]([N:25]1[CH:26]=[C:22]([CH2:21][O:20][CH2:19][C:18]([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)=[O:46])[N:23]=[CH:24]1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:10]1[CH:12]=[CH:26][CH:22]=[CH:21][CH:11]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: N#Cc1ccc(I)cc1
Reactant: CC(C)[Mg]Cl
Reactant: CON(C)C(=O)COCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)COCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 14 mmol of 4-iodobenzonitrile [3058-39-7] in 20 ml of tetrahydrofuran is cooled to −30° C., and 14.80 mmol of i-propylmagnesium chloride (2M in tetrahydrofuran) are added. The mixture is stirred at −30° C. for 60 minutes and a solution, precooled to −30° C., of 10.0 mmol of N-methoxy-N-methyl-2-(1-trityl-1H-imidazol-4-ylmethoxy)acetamide in 30 ml of tetrahydrofuran is added. The mixture is stirred at −30° C. for 30 minutes, and then the reaction mixture is warmed to room temperature and quenched with saturated aqueous ammonium chloride solution. The phases are separated, and the aqueous phase is extracted with ethyl acetate (3×). The combined organic phases are washed with brine, dried with magnesium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60 F).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:23])=[O:22])=[CH:17][CH:16]=1)[C:9]([CH3:24])=[C:8]2[CH2:25][C:26]([OH:28])=[O:27].C(=O)(O)[O-:30].[Na+].OO.[H][H]>CO.C(#N)C>[F:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:23])(=[O:30])=[O:22])=[CH:17][CH:16]=1)[C:9]([CH3:24])=[C:8]2[CH2:25][C:26]([OH:28])=[O:27]
Reactant: O=C([O-])O
Reactant: CC1=C(CC(=O)O)c2cc(F)ccc2C1=Cc1ccc(S(C)=O)cc1
Reactant: [H][H]
Agent: C[O-]
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC1=C(CC(=O)O)c2cc(F)ccc2C1=Cc1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Yield: 89 %

Procedure:
5-fluoro-2-methyl-1-(p-methylsulfonylbenzylidene)-3-indenyl acetic acid is prepared by adding sodium methoxide (4.4M in MeOH, 68.5 ml, 0.3 mol) dropwise to a stirred, cooled mixture of 5-fluoro-2-methyl-1-(p-methylsulfinylbenzylidene)-3-indenyl acetic acid (100 g, 0.281 mol) in methanol (250 ml) and acetonitrile (500 ml). Sodium bicarbonate (0.56 mol) and hydrogen peroxide (30% in water, 0.56 mol) are added and allowed to react for 18 hours at -10° C. Excess sodium bicarbonate is filtered off, and cooled filtrate (0° C.) neutralized dropwise to pH 7 with 1M hydrochloric acid (350 ml). The resulting product is then filtered and washed with methanol. A thin layer chromatography system to check for purity utilizes chloroform:methyl isobutyl ketone (8:2); the Rf value is 0.21. A tetrahydrofuran/diisopropyl ether combination can be used for product recrystallization. Reaction yield is 89%. (R1 =5-fluoro; R2 =CH3 ; R3 =hydrogen; R4 =COOH; R5 =CH3SO2 ; n=1).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[N:5]=1)[CH3:2].C(N(CC)CC)C.[F:25][C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[C:27]=1[C:28](Cl)=[O:29]>C1COCC1>[F:25][C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[C:27]=1[C:28]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)[N:5]=1)=[O:29]
Reactant: CCNc1cccc(OC2CCN(C)CC2)n1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(C(=O)c1c(F)cc(F)cc1F)c1cccc(OC2CCN(C)CC2)n1
Temperature: 55 °C
Yield: 81.7 %

Procedure:
Dissolve ethyl-[6-(1-methyl-piperidin-4-yloxy)-pyridin-2-yl]-amine (preparation 74, 110 mg, 0.47 mmol) in THF (6 mL), add triethylamine (95 mg, 0.94 mmol) and 2,4,6-trifluorobenzoyl chloride (136 mg, 0.70 mmol) sequentially, heat at 55° C. overnight. Quench the reaction with 0.1N NaOH, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 3.5% 2M NH3-methanol in methylene dichloride provides 151 mg (82%) of the title compound as an oil: mass spectrum (ion spray): m/z=394.1 (M+1); 1H NMR (CDCl3, ppm): 7.43 (t, 1H), 6.52 (m, 4H), 4.82 (m, 1H), 4.03 (q, 2H), 2.73 (m, 2H), 2.33 (s, 3H), 2.26 (m, 2H), 1.95 (m, 2H), 1.75 (m, 2H), 1.31 (t, 3H). Mono-hydrochloride salt: Anal calcd for C20H22F3N3O2.HCl.H2O: C, 53.63; H, 5.63; N, 9.38. Found: C, 53.66; H, 5.12; N, 9.29.
Reaction SMILES: O[Li:2].O.[CH:4]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[CH:4]([S:12]([O-:15])(=[O:13])=[O:14])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Li+:2]
Reactant: [Li]O
Reactant: O=S(=O)(O)C=Cc1ccccc1
Solvent: O
Product: O=S(=O)([O-])C=Cc1ccccc1
Product: [Li+]

Procedure:
Purolite C-100E, C-120E, C-145 or C150 (The Purolite Co., Bala Cynwyd, Pa.,USA). The yield from the ion exchange column is about one liter of hydrogen styrene sulfonate, which is then neutralized by addition of LiOH.H2O powder (approximately 33 g) until the pH of the solution is about 7. The resulting solution of lithium styrene sulfonate in water is dried. A yield of about 143 g lithium styrene sulfonate (a white or grey powder) with a water content of about 9.9% is obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:15]=[N:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>C1CCCCC1.O1CCCC1>[Cl:13][C:14]1[N:15]=[N:16][C:17]([O:20][CH3:21])=[C:18]([Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=1
Reactant: COc1ccc(Cl)nn1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1nnc(Cl)cc1[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
In a 2-necked round bottom flask under argon placed 4.0476 g of distilled diisopropylamine and 60 mL of tetrahydrofuran (Aldrich, anhydrous, no stabilizer). The mixture was cooled to −78° C., then ca 20 mL of 2.0 M butyl lithium in cyclohexane was added. The mixture was set in an ice bath for 20 minutes, then cooled to −78° C. and a solution of 2.8912 g of 3-chloro-6-methoxy-pyridazine and 3.05 mL of chlorotrimethyl silane in 12 mL of tetrahydrofuran was added over 15 minutes. The mixture was stirred for 2 hours (a deep red color formed, then faded to yellow), then quenched by the addition of 10 mL of saturated sodium dihydrogen phosphate solution. The mixture was taken up in 350 mL of ethyl acetate, washed 1×75 mL brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
Reaction SMILES: O=C1C(C2C=CC=CC=2)(C2C=CC=CC=2)CCN1CC(O)=O.F[C:24]1[CH:29]=[CH:28][C:27]([C:30]2([C:40]3[CH:45]=[CH:44][C:43](F)=[CH:42][CH:41]=3)[CH2:34][CH2:33][N:32]([CH2:35][C:36]([OH:38])=O)[C:31]2=[O:39])=[CH:26][CH:25]=1.[C:47]([C:51]1[CH:61]=[CH:60][C:54](/[C:55](=[N:58]/[H])/[NH:56]O)=[CH:53][CH:52]=1)([CH3:50])([CH3:49])[CH3:48].ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[C:47]([C:51]1[CH:61]=[CH:60][C:54]([C:55]2[N:56]=[C:36]([CH2:35][N:32]3[CH2:33][CH2:34][C:30]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:27]4[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=4)[C:31]3=[O:39])[O:38][N:58]=2)=[CH:53][CH:52]=1)([CH3:50])([CH3:48])[CH3:49]
Reactant: [H]/N=C(\NO)c1ccc(C(C)(C)C)cc1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: CC(C)(C)c1ccc(-c2noc(CN3CCC(c4ccccc4)(c4ccccc4)C3=O)n2)cc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)-4-tert-butyl-N-hydroxybenzimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 7.99-7.91 (m, 2H), 7.51-7.46 (m, 2H), 7.42-7.27 (m, 9H), 6.95-6.89 (m, 1H), 4.89 (s, 2H), 3.55 (t, J=6.5, 2H), 2.88 (t, J=6.5, 2H), 1.36 (s, 9H); MS (DCI) m/z 452.2 (M+H)+.