Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[CH:3]=1.[CH2:16]([N:23]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.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>[CH2:16]([N:23]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH:13]([CH3:15])[CH3:14])[CH:3]=2)=[CH:28][CH:27]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(Br)cc1NC(C)C
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(B(O)O)cc1)Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(CCN(Cc3ccccc3)C(=O)OC(C)(C)C)cc2)cc1NC(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of methyl 4-bromo-2-(isopropylamino)benzoate (433 mg) in 1,2-dimethoxyethane (6.5 ml) were added [4-[2-[benzyl(tert-butoxycarbonyl)amino]ethyl]phenyl]boronic acid (848 mg), tetrakis(triphenylphosphine)palladium (184 mg) and aqueous solution of sodium carbonate (2M, 3.5 ml), and the mixture was stirred at 70° C. for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=17/3) to give methyl 4′-[2-[benzyl(tert-butoxycarbonyl)amino]ethyl]-3-(isopropylamino)-4-biphenylcarboxylate (768 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:12]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:12]([O:14][C:15]([N:17]1[CH2:18][CH2:19][N:20]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:21][CH2:22]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)N1CCNCC1
Reactant: BrCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)N1CCN(CCCCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A solution of 2.47 g of 1-bromo-4-phenylbutane in 5 ml of 2-butanone was added to a mixture of 1.93 g of 1-ethoxycarbonylpiperazine, 1.76 g of potassium carbonate and 15 ml of 2-butanone at room temperature. After stirring at 80° C. for 12 hours, the mixture was cooled and, after addition of water, extracted with ethyl acetate. The extract was washed with water and saturated aqueous solution of sodium chloride in that order and dried over anhydrous sodium sulfate. The residue obtained after concentration under reduced pressure was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give 1-ethoxycarbonyl-4-(4-phenylbutyl)piperazine. The compound obtained was dissolved in 20 ml of ethanol and 20 ml of 10% aqueous solution of sodium hydroxide, and the solution was stirred at 100° C. for 12 hours. After cooling, the reaction mixture was extracted with ethyl acetate, and the extract was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent:chloroform-methanol-25% aqueous ammonia=100:10:1) to give 1.5 g cf 1-(4-phenylbutyl)piperazine as an oil.
Reaction SMILES: [CH:1]1[C:6]([C:7](/[C:9](/Cl)=[N:10]/[OH:11])=[O:8])=[CH:5][CH:4]=[C:3]([Cl:13])[CH:2]=1.[F:14][C:15]([F:25])([F:24])[C:16]([C:20]([F:23])([F:22])[F:21])([OH:19])[C:17]#[CH:18].C(N(CC)CC)C>C1COCC1>[Cl:13][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[CH:18]=[C:17]([C:16]([OH:19])([C:15]([F:24])([F:14])[F:25])[C:20]([F:21])([F:23])[F:22])[O:11][N:10]=2)=[O:8])=[CH:1][CH:2]=1
Reactant: O=C(/C(Cl)=N/O)c1ccc(Cl)cc1
Reactant: C#CC(O)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1cc(C(O)(C(F)(F)F)C(F)(F)F)on1
Yield: 46.7 %

Procedure:
To a solution of commercially available 4-chlorophenyl glyoxylohydroxamyl chloride (109 mg, 0.5 mmol) in 1,1,1-trifluoro-2-trifluoromethyl-but-3-yn-2-ol from step 1 (about 1 mmol) was added a solution of triethylamine (60 mg, 0.6 mmol) in THF (10 ml) dropwise by syringe pump at r.t. over 30 h. The mixture was concentrated under reduced pressure and diluted with EtOAc. The organic layer was washed with 1N HCl, H2O and dried over MgSO4. Solvent was evaporated under reduced pressure and the residue was purified by preparative TLC (Hexanes: EtOAc, 5:1) to afford the title compound as a white solid (87.2 mg). 1H NMR (DMSO-d6) δ 7.37 (s, 1H), 7.60 (d, 2H), 8.14 (d, 2H), 9.92 (s, 1H); ESIMS: m/z 372 (M−H).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:16]#[N:17])=[N:11][C:12]([F:15])=[CH:13][N:14]=1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C1(C)C=CC=CC=1>[F:15][C:12]1[N:11]=[C:10]([C:16]#[N:17])[C:9](=[O:8])[NH:14][CH:13]=1
Reactant: N#Cc1nc(F)cnc1OCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1nc(F)c[nH]c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
In 10 mL of toluene was dissolved 1.0 g of 3-(benzyloxy)-6-fluoro-2-pyrazinecarbonitrile. Then, 0.64 g of aluminum chloride was added to the solution at an ice-cooled temperature, and the mixture thus formed was stirred at room temperature for 2 hours. Then, 10 mL of water was added to the reaction mixture, the aqueous layer was separated, and the organic layer was extracted with two 2 mL portions of water. The aqueous layers were united and extracted with two 5 mL portions of ethyl acetate. The organic layer thus obtained was washed with saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 0.51 g of 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was obtained as a yellow-colored solid product.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[F:16][C:17]([F:21])([F:20])[CH2:18][NH2:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+].CC(O)=O>[F:16][C:17]([F:21])([F:20])[CH2:18][NH:19][CH2:1][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: NCC(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(CNCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.2 %

Procedure:
To a solution of tert-butyl 4-formylpiperidine-1-carboxylate (1 g, 4.69 mmol) in DCM (25 mL) was added 2,2,2-trifluoroethanamine (0.464 g, 4.69 mmol) and AcOH (0.05 mL). The reaction was stirred at RT for 3 hours and then sodium triacetoxyborohydride (1.292 g, 6.10 mmol) was added, and the reaction was stirred at RT for 16 hours. The reaction was diluted with DCM and saturated aqueous NaHCO3. The aqueous layer was adjusted to a pH of approximately 10 with 1 N aqueous NaOH, and extracted with DCM. The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to generate tert-butyl 4-((2,2,2-trifluoroethylamino)methyl)piperidine-1-carboxylate as a colorless oil (1.49 g, 107% yield).
Reaction SMILES: [C:1]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:10])[CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4].[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[Na]>C(O)CCC>[CH2:16]([C:2]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])([C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])[C:1]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCOC(=O)CC(=O)OCCCC
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: [Na]
Solvent: CCCCO
Product: CCCCCCCCCCCCCCCCCCC(CCCCCCCCCCCCCCCCCC)(C(=O)OCCCC)C(=O)OCCCC

Procedure:
62 m mol of dibutyl malonate, 63 m mol of stearyl bromide, and 69 m mol of sodium were made to react in butanol in the presence of 2 m mol of a crown ether, thereby forming 30 m mol of dibutyl distearylmalonate. Dibutyl distearylmalonate, 15 m mol, was first hydrolyzed, and was then heated in vacuum to be decarboxylated, whereby obtaining 10 m mol of 2-octadecyl eicosanoic acid. This acid, 8 m mol, was converted into its acid chloride. The acid chloride was allowed to react with 10 m mol of p-amino-methlylsulfonylanilide in pyridine, thereby obtaining 7 m mol of p-methylsulfonamide-3-heptadecyleicosanoylanilide. The eicosanoylanilide, 5 m mol, was allowed to react with lead tetraacetate in toluene, thus forming 3.2 m mol of N-(2-octadecyleicosanoyl)-N'methylsulfonyl-p-quinonediimine which is represented by the following formula: ##STR29##
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:15]1([CH2:21][CH2:22]O)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:22][CH2:21][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OCCN1CCOCC1
Reactant: COc1cc2c(Cl)ncnc2cc1O
Product: COc1cc2c(Cl)ncnc2cc1OCCN1CCOCC1

Procedure:
The compound was synthesised according to GP 4 from 4-chloro-7-hydroxy-6-methoxy-quinazoline and 2-Morpholin-4-yl-ethanol. LC/ESI-MS: m/z=324 [M+H].
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([NH:18][C:19]2[C:28]3[C:23](=[N:24][C:25]([CH3:29])=[CH:26][CH:27]=3)[N:22]=[CH:21][CH:20]=2)[CH:6]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:29][C:25]1[N:24]=[C:23]2[C:28]([C:19]([NH:18][C:7]3[CH:6]=[C:5]([CH2:4][OH:3])[CH:10]=[CH:9][C:8]=3[S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:20][CH:21]=[N:22]2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1ccc(Sc2ccccc2)c(Nc2ccnc3nc(C)ccc23)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(Nc3cc(CO)ccc3Sc3ccccc3)ccnc2n1

Procedure:
The product from Example 53c (2.30 g, 5.54 mmol) in 60 mL of THF was reacted with the LiAlH4 (420 mg, 11.0 mmol) for 18 h followed quenching with dilute HCl. Adjusted to pH 10 with NH4OH. Extracted with CH2Cl2, dried over MgSO4 filtered and concentrated under vacuum giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (325 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.76 (s, 3H) 3.99 (br. s, 1H) 4.58 (s, 2H) 6.31 (d, J=7.35 Hz, 1H) 7.25 (s, 5H) 7.40 (m, 2H) 7.46 (s, 1H) 7.78 (d, J=8.82 Hz, 1H) 8.42 (d, J=6.99 Hz, 1H) 8.95 (d, J=8.46 Hz, 1H) 11.06 (br. s., 1H) 14.44 (br. s., 1H); MS (ESI+) m/z 374 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:6]([C:7]#[N:8])[N:5]2[C:9](=[O:12])[C@H:10](Br)[C@H:4]2[S:3]1.O1CCCCC1OC1C=CC(C=O)=CC=1.P([O-])([O-])([O-])=O>O1CCCC1.[Zn]>[CH3:1][C:2]1([CH3:13])[C@H:6]([C:7]#[N:8])[N:5]2[C:9](=[O:12])[CH2:10][C@H:4]2[S:3]1
Reactant: CC1(C)S[C@@H]2[C@@H](Br)C(=O)N2[C@H]1C#N
Agent: O=Cc1ccc(OC2CCCCO2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Zn]
Solvent: C1CCOC1
Product: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C#N
Reaction time: 3 h

Procedure:
Activated mossy zinc (500 mg) and zinc dust (100 mg) are added to a solution of 2,2-dimethyl-3α-cyano-6α-bromopenam (522 mg, 2 mmol) and p-(2-tetrahydropyranyloxy)benzaldehyde (750 mg, 3.75 mmol) prepared according to E. Piers, W. deWaal and R. W. Britton, J. Am. Chem. Soc., 93, 5113 (1971) in 1 ml of dry tetrahydrofuran. After stirring vigorously at 50° for 3 hrs., the mixture is allowed to cool and 1 ml of pH 5 phosphate buffer is added. After standing for 10 min., the solids are removed by filtration and washed thoroughly with ethyl acetate. The filtrate is extracted with ethyl acetate. The combined extracts are washed with phosphate buffer and saturated sodium chloride, dried with sodium sulfate and the solvents removed by evaporation. The crude material is purified by chromatography on 60 g of silica gel using 40% acetone/chloroform as eluant to afford 2,2-dimethyl-3α-cyanopenam as a by-product melting at 73°- 75° C. and a mixture of 2,2-dimethyl-3α-cyano-6α-[p-(2-tetrahydropyranyloxy)-α-hydroxybenzyl]penam and 2,2-dimethyl-3α-cyano-6β-[p-(2-tetrahydropyranyloxy)-α-hydroxybenzy]-penam. Separation of the 6α-and 6β-compounds is effected by PLC (10% acetone/toluene; two developments) providing the individual 6α- and 6β-compounds.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[SH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[S:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(C)c1ccc(S)cc1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C(=O)O)c1ccc(Sc2nccs2)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A mixture of 2-bromothiazole (3.9 g) and ethyl 2-(4-mercaptophenyl)propionate (4.56 g), potassium carbonate powder (4.9 g) and dimethylformamide (50 ml) is stirred at 85° C. overnight. The reaction mixture is treated in the same manner as in Example 6 to give 2-[4-(2-thiazolylthio)phenyl]propionic acid melting at 85°-87° C.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8]([C:19]([O:21]CC)=[O:20])([C:14]([O:16]CC)=[O:15])[CH2:9]2)[CH3:3]>[OH-].[K+]>[CH3:3][CH:2]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][C:8]([C:19]([OH:21])=[O:20])([C:14]([OH:16])=[O:15])[CH2:9]2)[CH3:1]
Reactant: CCOC(=O)C1(C(=O)OCC)Cc2cccc(OC(C)C)c2C1
Agent: [K+]
Agent: [OH-]
Product: CC(C)Oc1cccc2c1CC(C(=O)O)(C(=O)O)C2
Temperature: 25 °C
Yield: 89.6 %

Procedure:
A solution/suspension of diethyl 4-(2-propyl)oxyindan-2,2-dicarboxylate (11.5 g) in potassium hydroxide solution (50 ml, 3 M) was heated at reflux for 18 hours. The solution was cooled to room temperature and was extracted with ether. The aqueous was acidified to pH<1 with aqueous hydrochloric acid (3 M) and was extracted with ethyl acetate. The standard workup afforded 4-(2-propyl)oxyindan-2,2-dicarboxylic acid (8.5 g) as a brown solid, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:14]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:13](=[O:30])[C:12]([CH3:31])=[C:11]3[NH:32][C:33](=[O:35])[CH3:34])=[CH:4][CH:3]=1.I[CH3:37]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:14]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:13](=[O:30])[C:12]([CH3:31])=[C:11]3[N:32]([CH3:37])[C:33](=[O:35])[CH3:34])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(=O)Nc1c(C)c(=O)n(CC(C)C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Product: CC(=O)N(C)c1c(C)c(=O)n(CC(C)C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
Using the general procedure of EXAMPLE 12 the product of EXAMPLE 43 was reacted with iodomethane to afford the title compound. HPLC/MS: 542.2 (M+1), 544.2 (M+3); Rt=4.40 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH2:20]Br.[CH3:23][O-:24].[Na+]>CO>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[N:6][C:5]=1[CH2:20][O:24][CH3:23]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Agent: [Na+]
Solvent: CO
Product: COCc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 0.401 g (1.072 mmol) of the above prepared 2-bromomethyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester, dissolved in 4.0 ml of abs. MeOH, was added 0.116 g (2.15 mmol) of sodium methoxide and the mixture stirred for 4 h at ambient temperature, when TLC indicated the complete disappearance of starting material. Pouring onto crashed ice/NH4Cl-solution, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=9/1), produced 0.279 g of pure title compound as white solid.
Reaction SMILES: F[O:2][C:3]([C:12]([F:15])([F:14])[F:13])([C:8]([F:11])([F:10])[F:9])[C:4]([F:7])([F:6])[F:5].FN(F)N(F)F>>[F:5][C:4]([F:7])([F:6])[C:3]([O:2][O:2][C:3]([C:4]([F:5])([F:6])[F:7])([C:12]([F:13])([F:15])[F:14])[C:8]([F:11])([F:10])[F:9])([C:12]([F:15])([F:14])[F:13])[C:8]([F:11])([F:10])[F:9]
Reactant: FOC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Agent: FN(F)N(F)F
Product: FC(F)(F)C(OOC(C(F)(F)F)(C(F)(F)F)C(F)(F)F)(C(F)(F)F)C(F)(F)F

Procedure:
In accordance with this invention, it has been found that the above-described objects can be accomplished by effecting a photolytic reaction between equimolar amounts of perfluoro-t-butyl hypofluorite and tetrafluorohydrazine. The resulting volatile reaction product, NF3, is evacuated at -90° C leaving a pure bis(perfluoro-t-butyl) peroxide residue.
Reaction SMILES: [C:1]1([C:7]23[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:11][N:10](CC2C=CC=CC=2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[C:1]1([C:7]23[CH2:15][CH2:14][CH2:13][CH:12]2[CH2:11][NH:10][CH2:9][CH2:8]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CN2CCC3(c4ccccc4)CCCC3C2)cc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(C23CCCC2CNCC3)cc1
Temperature: 60 °C

Procedure:
A solution of 21 g. of 4a-phenyl-2-benzyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine in 172 ml. of ethanol was stirred while 7 g. of 5 percent palladium suspended on carbon was added in one portion. The reaction mixture was stirred under a hydrogen gas atmosphere at 60 psi and heated at 60° C. for three hours. The reaction mixture was cooled to room temperature, filtered, and the solvent was removed by evaporation under reduced pressure to provide 13.3 g. of the product as an oil. The oil was distilled to afford 4a-phenyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine.
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][C:6]1([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:41])[CH2:23][C:24]3[CH:40]=[CH:39][C:27]4[N:28]=[C:29]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[CH3:38])[O:30][C:26]=4[CH:25]=3)=[CH:17][CH:16]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)C.[OH-].[Na+]>C(O)C>[C:33]1([CH3:38])[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[NH:31][C:29]1[O:30][C:26]2[CH:25]=[C:24]([CH2:23][C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([C:6]4([CH2:5][C:4]([OH:42])=[O:3])[CH2:14][C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[CH2:7]4)=[CH:16][CH:17]=3)=[O:41])[CH:40]=[CH:39][C:27]=2[N:28]=1
Reactant: CCOC(=O)CC1(c2ccc(NC(=O)Cc3ccc4nc(Nc5ccccc5C)oc4c3)cc2)Cc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)Nc3ccc(C4(CC(=O)O)Cc5ccccc5C4)cc3)cc2o1
Reaction time: 8 h
Yield: 24.8 %

Procedure:
A solution of (2-(4-(2-(2-o-tolylamino-benzoxazol-6-yl)-acetylamino)-phenyl)-indan-2-yl)-acetic acid ethyl ester [0.297 g, Reference Example 9(a)] in ethanol (10 mL) was treated with aqueous sodium hydroxide (1.61 mL, 1N) and the mixture was heated at reflux temperature for 6 hours and then left at room temperature overnight and then evaporated. The residue was treated with water (30 mL) and the resulting mixture was acidified to pH 1 by addition of hydrochloric acid (1N) then extracted with ethyl acetate. The ethyl acetate extract was dried over magnesium sulfate and then evaporated. The residue was dissolved in hot acetonitrile and the solution was treated with charcoal then filtered. The filtrate was evaporated to give the title compound (0.07 g) as a biscuit coloured solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([S:14]([N:17]([C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])[C:18]3[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=3)(=[O:16])=[O:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:34]([O:38][CH3:39])(=[O:37])[CH:35]=[CH2:36].C(N(CC)CC)C>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:30]([O:29][C:27]([N:17]([C:18]1[C:23]([O:24][CH3:25])=[N:22][C:21]([CH3:26])=[CH:20][N:19]=1)[S:14]([C:13]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH:36]=[CH:35][C:34]([O:38][CH3:39])=[O:37])=[CH:3][CH:4]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)(=[O:16])=[O:15])=[O:28])[CH:31]([CH3:33])[CH3:32]
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(I)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C=Cc1ccc(-c2ncccc2S(=O)(=O)N(C(=O)OCC(C)C)c2ncc(C)nc2OC)cc1

Procedure:
A solution of 2-(4-iodophenyl)-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (1.5 g), methyl acrylate (0.25 ml), palladium acetate (58 mg) and triethylamine (1.79 ml) in dimethyl formamide (45 ml) and water (5 ml) was heated at 100° C. for 1 hour. Volatile material was removed by evaporation and water (50 ml) was added to the residue. The mixture was acidfied to pH 3 with 1M hydrochloric acid and extracted with ethyl acetate (2×50 ml). The extracts were washed with water (50 ml) and saturated sodium chloride solution (50 ml), treated with charcoal and dried (MgSO4). The solvent was removed by evaporation and the residue was triturated with ether/hexane (1:1 v/v) to give N-isobutoxycarbonyl-2-[4-(2-[methoxycarbonyl]vinyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (0.99 g), m.p. 149°-151° C.; microanalysis found: C, 57.7; H, 5.2; N, 10.6%; C26H28N4O7S requires: C, 57.8; H, 5.2; N, 10.4%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1.C(Cl)(Cl)Cl.CO>[Cl:1][CH2:2][CH2:3][CH:4]=[CH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2
Reactant: O=C1CCc2cc(C=CCCCl)ccc2N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=c1ccc2cc(C=CCCCl)ccc2[nH]1

Procedure:
2.5 Grams of 6-(4-chloro-1-butenyl)-3,4-dihydrocarbostyril and 2.3 g of DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) were mixed in 160 ml of dioxane and the mixture was refluxed by heating for 6 hours. Further, 1.1 of DDQ was added to the reaction mixture and the mixture was refluxed by heating for 3 hours. The reaction mixture was cooled and the precipitates thus formed were removed by filtration and the mother liquor was concentrated under a reduced pressure to obtain a residue. The residue was dissolved in a mixture of 100 ml of chloroform with 5 ml of methanol and the solution was padded through a silica gel column for removing the unreacted DDQ. The residue was recrystallized from methanol to obtain 1.6 g of 6-(4-chloro-1-butenyl)carbostyril in yellow needle-like crystals. Melting point: 215°-128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:18]=1)=[O:5]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccc(Cl)cc2Cl)cc1
Yield: 6.6 %

Procedure:
In a manner similar to that described in Example 3, 2,4-dichloro-benzoyl chloride (0.070 g, 0.00033 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.006 g of 4-[4-(2,4-dichloro-benzoylamino)-phenyl]-4-oxo-butyric acid as a yellow solid; MS-(AP+) MH+366.