Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][N:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2=[N:4][CH:3]=1.[Cl:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([Sn](CCCC)(CCCC)CCCC)=[N:29][NH:30]2)=[CH:26][CH:25]=1>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.[Cu]I>[Cl:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([C:2]3[N:7]=[C:6]4[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][N:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]4=[N:4][CH:3]=3)=[N:29][NH:30]2)=[CH:26][CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)ccc12
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Temperature: 90 °C
Yield: 85.7 %

Procedure:
A mixture of methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (0.26 g, 0.7 mmol), 6-chloro-3-(tributylstannyl)-1H-indazole (0.31 g, 0.7 mmol), Pd(PPh3)4 (81 mg, 0.07 mmol) and CuI (27 mg, 0.14 mmol) in dry DMF (3 mL) was heated to 90° C. for 3 hours. Product was extracted with ethyl acetate (60 mL), and organic phase washed with water (3×10 mL) and brine (2×10 mL), dried over Na2SO4, filtered and concentrated to afford methyl 2-(6-chloro-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (265 mg, crude) as a brown oil. LCMS: (M+H)+=442.
Reaction SMILES: [OH-].[Na+:2].CC1C=CC(CC(=O)C(O)=O)=CC=1.CI.Cl.[O:19]=[C:20]([CH:24]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[CH3:25])[C:21]([OH:23])=[O:22]>CO>[O:19]=[C:20]([CH:24]([C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)[CH3:25])[C:21]([O-:23])=[O:22].[Na+:2]
Reactant: Cc1ccc(C(C)C(=O)C(=O)O)cc1
Agent: Cc1ccc(CC(=O)C(=O)O)cc1
Agent: Cl
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: Cc1ccc(C(C)C(=O)C(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 80 %

Procedure:
A 3N aqueous solution of sodium hydroxide (4.0 ml, 12 mmoles) and 10 ml of methanol were added to 0.53 g (3.0 mmoles) of p-methylphenylpyruvic acid to form a solution. Then, 1.0 ml of methyl iodide was added, and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with three 30 ml portions of ether. The ether layers were dried over magnesium sulfate, and concentrated under reduced pressure to give a pale brown oil. Its NMR spectral analysis led to the determination that 2-oxo-3-(p-methylphenyl)butanoic acid was formed in a yield of 80 %. To this product was added 3 ml of a 3N aqueous solution of sodium hydroxide, and the mixture was concentrated under reduced pressure. Ether was added to the resulting semi-solid mixture, and the precipitated sodium 2-oxo-3-(p-methylphenyl)butanoate was isolated by filtration as a white solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.C([SnH2][C:27]([O:29][CH2:30][CH3:31])=[CH2:28])CCC>C(#N)C.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.[Cu]I>[CH2:30]([O:29][C:27]([C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1)=[CH2:28])[CH3:31]
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: C=C(OCC)[SnH2]CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: C=C(OCC)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 55 %

Procedure:
To a solution of 6-(6-bromo-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl)-quinoline (2 g, 5.86 mmol) in ACN (47 mL) (degassed 3 times with nitrogen) was added Pd(PPh3)2Cl2 (205 mg, 0.293 mmol), CuI (167 mg, 0.879 mmol), and butyl-(1-ethoxy-vinyl)-stannane (5.9 mL, 17.59 mmol). The reaction was refluxed for 4 hours until the LC-MS showed complete product. The reaction was filtered over a celite pad and washed with ether (100 mL). The solution was washed with water (1×50 mL), dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography with EtOAc:Hexanes to give 1.05 g of the product 6-[6-(1-ethoxy-vinyl)-[1,2,3]triazolo[4,5-b]pyrazin-1-ylmethyl]-quinoline (55% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[C:13](Cl)(=[O:15])[CH3:14]>C1C=CC=CC=1>[C:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: CCNc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: CCN(C(C)=O)c1ccc([N+](=O)[O-])cc1

Procedure:
To a suspension of N-ethyl 4-nitroaniline (1.5 g, 9.026 mmol) in benzene (15 ml), is added acetylchloride (10 ml) and the mixture refluxed for 40 minutes. The solvent is removed by evaporation. The residue is dissolved in ethyl acetate prior to washing with 2N sodium bicarbonate and water, drying (MgSO4) and evaporation. The product is dried under vacuum; ES+ (M+1) 208.57.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[N:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][N:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:29]=[C:28]([C:30]([F:32])([F:33])[F:31])[S:27][C:17]=2[N:18]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[C:21]1([CH2:27][CH2:28][CH2:29][CH2:30]O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:30][CH2:29][CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCCCc1ccccc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCCCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 4-phenylbutanol (1.37 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The material was purified by HPLC (dichloromethane-hexane; 2:1) to provide 0.64 g of 4-[(4-phenybutyl)oxy]-alpha-oxobenzeneacetic acid methyl ester as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]([O:29]CC)=[O:28])[CH:22]=[N:21]2)=[CH:17][CH:16]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][N:20]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]([OH:29])=[O:28])[CH:22]=[N:21]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)/C=C/c1cnn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(Cn2cc(/C=C/C(=O)O)cn2)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 80.9 %

Procedure:
A mixture of ethyl(E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazole-4-yl]propenoate (887 mg), 1 N aqueous sodium hydroxide solution (4 ml), ethanol (8 ml), and tetrahydrofuran (8 ml) was stirred at 40° C. for 3 hours. After the reaction mixture was acidified with 1 N hydrochloric acid, the obtained crystals were collected by filtration, and (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propenoic acid (672 mg, yield: 81%) was obtained. This was recrystallized from ethanol. Melting point: 186–187° C.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)[N:4]=1.[CH:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1>>[F:21][C:2]([F:1])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][NH:19][S:25]([CH:22]3[CH2:24][CH2:23]3)(=[O:27])=[O:26])=[CH:14][CH:13]=2)[N:4]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Product: O=S(=O)(NCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)C1CC1

Procedure:
The title compound was prepared from ({4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methyl)amine and cyclopropanesulphonyl chloride using a similar procedure to that described for Example 88.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[C@H:23]([CH2:34][O:35][CH3:36])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>C(Cl)(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([O:20][C@H:21]4[CH2:26][CH2:25][NH:24][C@H:23]([CH2:34][O:35][CH3:36])[CH2:22]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: COC[C@@H]1C[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC[C@@H]1C[C@@H](Oc2cccc3ccc(-c4nnc5ccccn45)nc23)CCN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product from Step B (0.070 g, 0.14 mmol) was dissolved in CHCl3 (1.4 mL). Then HCl (1.4 mL, 5.7 mmol, 4.0M in dioxane) was added and the mixture stirred at ambient temperature for 5.0 hours. The mixture was filtered directly and the solid washed with CH2Cl2 followed by Et2O and dried. The crude solid was purified by preparative TLC (1 mm, 8% MeOH/DCM with 1% NH3). This provided 0.031 g (56%) of the product as a pale orange solid. MS ESI (+) m/z 390.2 (M+1) detected.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14].[N+:24]([C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[CH:29][CH:28]=1)([O-:26])=[O:25]
Reactant: COc1ccccc1C(=C/C=C/C(=O)O)c1ccccc1OC
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccccc1C(=C/C=C/C(=O)Oc1ccc([N+](=O)[O-])cc1)c1ccccc1OC
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
As in Example 115. (E)-5.5-bis(2-methoxyphenyl)-2,4-pentadienoic acid (5 g) and 4-nitrophenol (2.7 g) in dichloromethane (35 mL) was treated with 1,3-dicyclohexylcarbodiimide (3.34 g). The mixture was stirred at 0°-5° C. for 30 minutes and then at room temperature for 18 hours. After the usual work up. the crude Product was crystallized from 2-propanol to give 6.1 g of (E)-5,5-bis(2-methoxyphenyl)2,4-pentadienoic acid 4-nitrophenyl ester. mp 141.5°-143° C. A portion from the 2-propanol to yield the analytical sample, mp 142°-143° C.
Reaction SMILES: [OH-].[Na+].C1C=CC=CC=1.[C:9]([N:13]1[C:18](=[O:19])[C:17]([Cl:20])=[C:16](Cl)[CH:15]=[N:14]1)([CH3:12])([CH3:11])[CH3:10].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][SH:28])=[CH:25][CH:24]=1>O.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[C:9]([N:13]1[C:18](=[O:19])[C:17]([Cl:20])=[C:16]([S:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=2)[CH:15]=[N:14]1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: SCc1ccc(Cl)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C)(C)n1ncc(SCc2ccc(Cl)cc2)c(Cl)c1=O
Reaction time: 15 h
Yield: 64.4 %

Procedure:
Sodium hydroxide 0.7 g was dissolved in 15 ml of water, and thereto were added 100 ml of benzene, 3.3 g of 2-tert.-butyl-4,5-dichloro-3(2H)-pyridazinone and 0.15 g of triethylbenzylammonium chloride. The resulting solution was incorporated with 2.4 g of 4-chlorobenzyl mercaptan at room temperature and then stirred for 15 hours. After completion of the reaction, only the organic layer was separated therefrom, washed with a 5% aqueous solution of sodium hydroxide and then with water, and dried over anhydrous sodium sulfate. Solvent was distilled away therefrom under reduced pressure. The resulting oily residue was incorporated with hexane to give crystals. The crystals were filtered off to obtain 3.3 g of the intended compound (yield: 64%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[NH:15]1[C:23]2[C:18](=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.CC(O)C.C(=O)(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[NH:15]1[C:23]2[C:18](=[C:19]([C:2]3[CH:10]=[C:9]4[C:5]([CH:6]=[N:7][N:8]4[CH3:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=3)[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: Cn1ncc2c([N+](=O)[O-])cc(Br)cc21
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cn1ncc2c([N+](=O)[O-])cc(-c3cccc4[nH]ccc34)cc21
Temperature: 150 °C
Yield: 43 %

Procedure:
6-Bromo-1-methyl-4-nitro-1H-indazole (100 mg, 0.39 mmol), Pd(dppf)Cl2 (32 mg, 0.04 mmol) and 1H-indol-4-ylboronic acid (94 mg, 0.59 mmol) were treated with a 4:1 mixture of propan-2-ol and saturated sodium bicarbonate solution (3 ml) and the reaction was heated in a microwave at 150° C. for 10 mins. Ethyl acetate was added, a solid was filtered off and the filtrate was partitioned between ethyl acetate and water. The water was washed twice with ethyl acetate and the combined organics were washed with brine, dried over magnesium sulphate, filtered and evaporated. The residue was purified by silica chromatography, eluting with 0-25% ethyl acetate in cyclohexane. Appropriate fractions were combined and evaporated to give the title compound (49 mg) as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH2:10][C:11](O)([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:13]([F:15])([F:16])[F:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)cc1
Yield: 54 %

Procedure:
A mixture of 2-(4-methylphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-4,5-dihydro-1H-imidazole (Step 2) (0.9 g, 2.3 mmol) and p-toluenesulfonic acid monohydrate (150 mg) in toluene (100 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 was purified by chromatography on silica gel using toluene/ethyl acetate (1/1) to give pure 2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole (462. mg, 54%) as a white solid: mp (DSC) 190° C. Anal. Calc'd for C18H15N2F3SO2: C, 56.84; H, 3.97; N, 7.36; S, 8.43. Found: C, 56.66; H, 3.82; N, 7.23; S, 8.45.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:26]#[N:27].C(=O)(O)[O-].[Na+].[O:33]=[S:34]1(=[O:44])[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][CH2:42][OH:43])[CH2:36][CH2:35]1>>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:4]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:43][CH2:42][CH2:41][CH2:40][N:37]3[CH2:36][CH2:35][S:34](=[O:44])(=[O:33])[CH2:39][CH2:38]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:26]#[N:27]
Reactant: O=S1(=O)CCN(CCCO)CC1
Reactant: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1F
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Product: COc1cc(Nc2c(C#N)cnc3cc(OCCCN4CCS(=O)(=O)CC4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 100 °C

Procedure:
A mixture of sodium (48 mg, 2.1 mmol) in 2 mL of 3-(1,1-dioxothiomorpholinyl)-1-propanol (WO 20047212) is heated at 100° C. for 1 hour. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-fluoro-6-methoxy-3-quinolinecarbonitrile (200 mg, 0.51 mmol) is added and the reaction mixture is heated at 100° C. for 4 hours, then cooled to room temperature. The reaction mixture is poured into saturated sodium bicarbonate and the solids are collected by filtration. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane to provide 88 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-[3-(1,1-dioxido-4-thiomorpholinyl)propoxy]-6-methoxy-3-quinolinecarbonitrile, mp 118-120° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:21])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=1.C(OC(C1C=C(N)N(C2C=CC=CC=2[F:39])N=1)=O)C>>[O:21]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:39])[N:10]=[C:9]([C:18]([OH:20])=[O:19])[CH:8]=1
Reactant: O=C(O)c1cc(N2CCCS2(=O)=O)n(-c2ccccc2)n1
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2F)n1
Product: O=C(O)c1cc(N2CCCS2(=O)=O)n(-c2ccccc2F)n1

Procedure:
According to this procedure 5-(1,1-Dioxo-1lambda*6*-isothiazolidin-2-yl)-1-phenyl-1H-pyrazole-3-carboxylic acid is prepared starting from 5-Amino-1-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:14]=2)=[CH:8][C:7]=1[CH3:34].[OH-].[Na+].Cl>CO.O>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]([CH3:34])[CH:8]=2)=[C:21]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(Cl)cc3Oc3ccccc3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(Oc2cccc(Oc3ccc(Cl)cc3Oc3ccccc3)c2)ccc1CCC(=O)O
Yield: 107.1 %

Procedure:
A solution of 3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester (0.221, 0.452 mmol) in methanol (7 mL) is treated with 5 N NaOH (2 mL) and heated to reflux until saponification is completed. The mixture is cooled, and the solvent is removed in vacuo to afford a residue that is acidified with 1 N HCl. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried (Na2SO4), and the solvent removed in vacuo to afford 0.230 g (100%) of the title compound. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C28H23O5Cl 474, found 475 and 477 (M+1 and M+3, 100%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH2:35][C:36]([O:38]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:37])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH2:35][C:36]([OH:38])=[O:37])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)OCC(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CC(C)OC(C)C
Product: C=CC1=C(C(=O)OCC(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Yield: 81.3 %

Procedure:
A solution of tert-butoxycarbonylmethyl 7-[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.0 g) in trifluoroacetic acid (10 ml) and anisole (5 ml) was stirred at 25° to 30° C. for an hour. The reaction mixture was poured into diisopropyl ether (150 ml), and the precipitates were collected by filtration and dissolved in 5% aqueous sodium bicarbonate (50 ml). The aqueous solution was washed with ethyl acetate and then adjusted to pH 2.3 with 10% hydrochloric acid. The precipitated substance was collected by filtration and washed with water to give carboxymethyl 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([C:6]([NH:8][CH:9]([CH3:35])[CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH:18]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH3:30])[C:25]=4[O:28][CH3:29])[CH:20]([CH2:31][NH:32]C=O)[O:19]3)[CH2:14][CH2:13]2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[NH2:32][CH2:31][C@H:20]1[C:21]2[C:26](=[C:25]([O:28][CH3:29])[C:24]([CH3:30])=[CH:23][CH:22]=2)[CH2:27][C@@H:18]([CH:15]2[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[C:5]3[CH:36]=[CH:37][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH3:35])[CH2:13][CH2:14]2)[O:19]1
Reactant: COc1c(C)ccc2c1CC(C1CCN(CCC(C)NC(=O)c3ccc(Cl)cc3)CC1)OC2CNC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C)ccc2c1C[C@@H](C1CCN(CCC(C)NC(=O)c3ccc(Cl)cc3)CC1)O[C@H]2CN

Procedure:
Stir and heat at 70° C. a solution of 4-chloro-N-{3-[4-(1-formylaminomethyl-5-methoxy-6-methyl-isochroman-3-yl)-piperidin-1-yl]-1-methylpropyl}-benzamide in CH3OH/THF (10 mL of 1:1 solution) and of 15% NaOH solution (2 mL) for 4 hours. Concentrate the reaction mixture, and extract three times with EtOAc (2 mL). Wash the combined organic phase sequentially with H2O (2 mL), brine (2 mL), and then dry over MgSO4. Concentrate and purify the crude product on a 2 g SCX column.