Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.CS([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:30])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:18][CH:17]=3)=[C:13]([C:31]3[CH:36]=[CH:35][C:34]([O:37]S(C)(=O)=O)=[CH:33][CH:32]=3)[S:12][C:11]=2[CH:42]=1)(=O)=O.O1CCCC1.[OH-].[Na+]>CO>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:30])[C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:20][CH:21]=3)=[C:13]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)[S:12][C:11]=2[CH:42]=1
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(c1ccc(OCCN2CCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A 23.8 g. portion of the product of Example 3 above was added to 600 ml. of tetrahydrofuran, 240 ml. of methanol and 40 ml. of 5 N sodium hydroxide. The mixture was stirred at ambient temperature for 60 hours, and then it was evaporated under vacuum. The residue was diluted to 400 ml. with water, and the solution was continuously extracted with diethyl ether for 8 hours. The aqueous phase was then filtered, cooled to below 10°, and acidified to pH 2 with methanesulfonic acid. It was then diluted to about 7 liters with water, and was extracted with diethyl ether. The aqueous layer was degassed under vacuum and made basic with sodium bicarbonate. The solids which precipitated were collected and vacuum dried, and purified by column chromatography on a 4.5×60 cm. column of silica gel, using as eluant a gradient composed of 2 liters of 1% methanol in chloroform phasing to 2 liters of 25% methanol in chloroform. Twenty ml. fractions were collected, and fractions 33 through 150 gave 13.5 g. of product, m.p. 146°-147° after crystallization from acetone. Its UV spectrum showed an absorption maximum at 290 nm. (32,500). The IR spectrum showed a maximum at 1607 cm.-1 attributable to the conjugated eneone system.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N:10]=[O:11])=[CH:4][C:3]=2[O:2]1.[N:12]#[C:13][NH2:14].BrN1C(=O)CCC1=O>ClCCl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([N+:10](=[N:14][C:13]#[N:12])[O-:11])=[CH:4][C:3]=2[O:2]1
Reactant: N#CN
Reactant: O=Nc1ccc2c(c1)OCO2
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: N#CN=[N+]([O-])c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
3,4-Methylenedioxynitrosobenzene (1.05 g, 6.9 mmol) was dissolved in dichloromethane (20 ml). After the addition of cyanamide (0.42 g, 9.9 mmol) and N-bromosuccinimide (1.8 g, 9.9 mmol) the mixture was stirred at ambient temperature overnight. The resulting mixture was filtered and evaporated to dryness. Column chromatography on silica using 1:1 petroleum ether: ethyl acetate as eluant yielded 1.1 g 3,4-methylenedioxyphenyl-ONN-azoxycyanide as a yellow solid, m.pt. 145°-147° C. (Yield: 82.7% of theoretical).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:9]2[CH:16]=[C:15]([CH3:17])[C:12]([C:13]#[N:14])=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C(O[CH:34](N(C)C)[N:35]([CH3:37])[CH3:36])(C)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:9]2[CH:16]=[C:15](/[CH:17]=[CH:34]/[N:35]([CH3:37])[CH3:36])[C:12]([C:13]#[N:14])=[CH:11][N:10]=2)=[CH:27][CH:28]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(C)c(C#N)cn2)cc1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(/C=C/N(C)C)c(C#N)cn2)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 113.7 %

Procedure:
A mixture of 4-3 (7.20 g, 19.3 mmol), tert-butoxy bis(dimethylamino)methane (16.0 mL, 77.5 mmol), and N,N-dimethylformamide (5.40 mL) was stirred at 70° C. for 16 hours under an atmosphere of nitrogen gas. The reaction mixture was concentrated under reduced pressure to give 9.40 g of 4-4 as a brown oil. The crude product was used for next step without further purification.
Reaction SMILES: [C:1]([N:20]([CH2:27][CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[O:38][C:39]3[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=3[N:41]=2)=[CH:33][CH:32]=1)[CH2:21][CH2:22][O:23][CH2:24][C:25]#[CH:26])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1>C(N)CCC.[Cu]I.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>[C:1]([N:20]([CH2:27][CH2:28][O:29][CH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[O:38][C:39]3[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=3[N:41]=2)=[CH:35][CH:36]=1)[CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:47]1[CH:52]=[CH:51][C:50]([CH3:53])=[CH:49][CH:48]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CCOCCN(CCOCc1ccc(-c2nc3ccccc3o2)cc1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCN
Product: Cc1ccc(C#CCOCCN(CCOCc2ccc(-c3nc4ccccc4o3)cc2)C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 75 °C

Procedure:
N-trityl-N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-(prop-2-ynyloxy)ethanamine (0.517 g; 0.87 mmol), 4-iodotoluene (0.262 g; 1.2 mmol) and copper (I) iodide (3.5 mg; 2%/wt) are dissolved in BuNH2 (4 ml) in an inert atmosphere (argon). To this is added (PPh3)2PdCl2, [bis(triphenylphosphine)palladium chloride], (6 mg; 1%/wt) and the reaction is heated at 75° C. for 1 hour. The mixture is then concentrated in vacuo and purified by column chromatography using 10 Et3N/10 CH2Cl2 /PE to obtain N-trityl-N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-2-[3-(4-methylphenyl)prop-2-ynyloxy]ethanamine which is used directly in Step G.
Reaction SMILES: O[C:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:4]([CH3:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[OH:21][N:20]=[C:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:4]([CH3:13])[CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: NO
Reactant: CCCCCN1C(=O)C(O)=C(C(=O)OCC)C1C
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCN1C(=O)C(=NO)C(C(=O)OCC)C1C
Reaction time: 120 h
Yield: 59.5 %

Procedure:
To the title compound of Example J (21.6 g, 0.085 mol) in pyridine (150 ml) was added hydroxylamine hydrochloride (10.6 g, 0.17 mol) and the solution was stirred for 5 days. The solvent was removed in vacuo to give an orange oil which was chromatographed on silica gel eluting with 2% EtOH/CH2Cl2 to give the title compound (13.67 g, 59%) as an oil. Calculated C13H22N2O4 1/2H2O: C, 55.90; H, 8.30; N, 10.02. Found: C, 55.99; M, 8.38; N, 10.00. MS calcd for C13H22N2O4 270, found 270.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[N+:15]([O-])([OH:17])=[O:16].O>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:14])[CH:5]([C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-(4-hydroxy-phenyl)-propionic acid ethyl ester (9.02 g) in acetic acid (75 mL) was added nitric acid (60%, 5.24 g in AcOH) at room temperature. The reaction mixture was stirred for 30 minutes at room temperature and added water. The mixture was extracted with EtOAc and the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel (n-Hex:EtOAc=10:1) to afford the product as yellow oil. (9.71 g)
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]1[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]1)[C:14](=[O:28])[NH:15][C:16]1[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=1.[F:36]C1C=C(S)C=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[F:36][C:8]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][N:13]([C@H:29]2[CH2:34][CH2:33][C@H:32]([CH3:35])[CH2:31][CH2:30]2)[C:14](=[O:28])[NH:15][C:16]2[S:17][C:18]([S:21][C:22]([CH3:27])([CH3:26])[C:23]([OH:25])=[O:24])=[CH:19][N:20]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1SCCCN(C(=O)Nc1ncc(SC(C)(C)C(=O)O)s1)[C@H]1CC[C@H](C)CC1
Reactant: Fc1cccc(S)c1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCCSc2cccc(F)c2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-{2-[3-[3-(2-methoxy-phenylsulfanyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2-methyl-propionic acid using 3-fluoro-thiophenol and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)=[CH:4][CH:5]=[C:6]2[C:15]=1[CH2:14][CH2:13][C:12]1[CH:11]=[C:10]([CH2:16][CH2:17][CH3:18])[CH:9]=[CH:8][C:7]2=1.BrN1C(=O)CCC1=O.O>C1C=CC=CC=1>[F:1][C:2]1[C:3]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)=[CH:4][CH:5]=[C:6]2[C:15]=1[CH:14]=[CH:13][C:12]1[CH:11]=[C:10]([CH2:16][CH2:17][CH3:18])[CH:9]=[CH:8][C:7]2=1
Reactant: CCCc1ccc2c(c1)CCc1c-2ccc(-c2cc(F)c(F)c(F)c2)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: c1ccccc1
Solvent: O
Product: CCCc1ccc2c(ccc3c(F)c(-c4cc(F)c(F)c(F)c4)ccc32)c1

Procedure:
8-fluoro-2-propyl-7-(3,4,5-trifluorophenyl)-9,10-dihydrophenanthrene produced in Example 1 was dissolved in benzene, NBS (N-bromosuccinimide) and AIBN (2,2-azobis isobutyronitrile) were added, and the temperature was gradually raised to benzene reflux temperature. Stirring was then continued for a further 2 hours, before water was added and the reaction halted, and the organic layer was then separated. The aqueous layer was extracted with toluene and this extract was combined with the organic layer, which was then washed with water and a saturated aqueous solution of sodium chloride, before being dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the whole crude product was dissolved in ethyl acetate, and 5% palladium/carbon (wet) was then added, and the mixture was stirred in an autoclave under a hydrogen pressure of 4 Kg/cm2. After 5 hours stirring at room temperature, the catalyst was removed by filtration through celite, and the solvent was then removed by evaporation. The crude product was purified by silica gel column chromatography (hexane) and then recrystallized 3 times from ethanol to yield 8-fluoro-2-propyl-7-(3,4,5-trifluorophenyl)phenanthrene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[O:5][CH2:6][CH2:7]Br.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>O>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][CH2:7][CH2:6][O:5][C:4]2[CH:9]=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:25][CH:24]=1
Reactant: Clc1ccc(OCCBr)cc1Cl
Reactant: NCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1ccc(CNCCOc2ccc(Cl)c(Cl)c2)cc1

Procedure:
2.70 Grams (10.0 mmol) of 2-(3,4dichlorophenoxy)ethyl bromide was dissolvedin 30 ml of ethanol, followed by the addition of 1.06 g (10.0 mmol) of anhydrous sodium carbonate and 4.25 g (30.0 mmol) of 4-chlorobenzylamine. The mixture was heated and refluxed on an oil bath for 7 hours. After cooling, the reaction mixture was poured into 100 ml of water and was extracted with chloroform (20 ml×3).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:6].[Br:19][CH2:20][C:21](Br)=[O:22].C(OCC)C>C(OCC)(=O)C>[CH3:1][N:2]([C:21](=[O:22])[CH2:20][Br:19])[C:3]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:4]=1[C:5](=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13]
Reactant: O=C(Br)CBr
Reactant: CNc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CN(C(=O)CBr)c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 56 g of 2-methylamino-2', 5-dichlorobenzophenone in 400 cc of ethyl acetate there are added an equal volume of ice and then 23 cc of bromoacetylbromide. After stirring overnight at room temperature, 300 cc of ethyl ether are added. The solvent layer is decanted, washed with 2 N caustic soda, and then washed with water until neutral. It is then dried over sodium sulfate, filtered, and evaporated to dryness. The residue is treated with petroleum ether and then recrystallized from ethyl acetate. In this way there are obtained 65 g of crystals; yield: 81%.
Reaction SMILES: Br[C:2]1[C:3]([F:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OC([C:17]2[CH2:18][CH2:19][O:20][CH2:21][CH:22]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:8][C:3]1[C:2]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Fc1ncccc1Br
Reactant: CC1(C)OC(C2=CCOCC2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Fc1ncccc1C1CCOCC1
Yield: 51.1 %

Procedure:
A mixture of 3-bromo-2-fluoro-pyridine (500 mg, 2.84 mmol), 4-(4,4,5,5-Tetramethyl-[1,3]dioxolan-2-yl)-3,6-dihydro-2H-pyran (656 mg, 3.12 mmol), K3PO4 (1.2 g, 5.68 mmol), and Pd (dppf)Cl2 (208 mg, 0.284 mmol) in 1,4-Dioxane/H2O (5:1) (30 mL) was heated to reflux overnight under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated and purification by prep-TLC to give 2-fluoro-3-(tetrahydro-pyran-4-yl)-pyridine (260 mg, 1.45 mmol, 51.2%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].C([Li])CCC.CCCCCC.[CH2:22]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[CH2:22]([N:29]1[CH2:34][CH2:33][C:32]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][OH:10])([OH:35])[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: OCCc1ccccc1Br
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCCc1ccccc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 76.9 %

Procedure:
To a solution of 2-bromophenyl ethyl alcohol (1.9 g, 9.6 mmol) in tetrahydrofuran (25 ml) was added 1.6 M n-butyl lithium solution in n-hexane (14 ml, 23 mmol) at −60° C. After stirring for 30 min a solution of 1-benzyl-4-piperidone (2.6 g, 14 mmol) in tetrahydrofuran (10 ml) was added over a period of 15 min at −40° C. The cooling bath was removed and the reaction mixture was stirred for 72 h at room temperature. The mixture was quenched with saturated aqueous ammonium chloride solution (30 ml). Basification to pH 11 with 2 M aqueous sodium carbonate solution (50 ml) was followed by extraction with three 100-ml portions of tert-butyl methyl ether. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Volatile impurities were removed by kugelrohrdistillation at 170° C. and 1-2 mbar. Flash chromatography of the residual crude product with dichloromethane/methanol as eluent gave the title compound (2.3 g, 53%) as dark brown oil. MS m/e: 312 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:11])[N:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:2]2[C:7]3[CH:8]=[CH:9][S:10][C:6]=3[CH:5]=[C:4]([CH3:11])[N:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cc2sccc2c(Cl)n1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(C)cc3sccc23)cc1
Temperature: 170 °C
Reaction time: 4 h

Procedure:
A mixture of 7.0 g of 4-chloro-6-methylthieno[3,2-c]pyridine and 28 ml of 4-methoxybenzylamine was stirred at 170° C. for 4 hours. After being cooled, the reaction mixture was diluted with 400 ml of chloroform, washed with water and saturated saline, dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 10 g of the title compound as a yellow oily material.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1)[CH3:2].ClN1C(=O)CCC1=O.[F:20][C:21]([F:39])([F:38])[C:22]1[CH:23]=[C:24]([C:32]([C:34]([F:37])([F:36])[F:35])=[CH2:33])[CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1.C(=O)([O-])O.[K+]>CN(C)C=O.O>[F:20][C:21]([F:38])([F:39])[C:22]1[CH:23]=[C:24]([C:32]2([C:34]([F:37])([F:36])[F:35])[O:9][N:8]=[C:7]([C:6]3[CH:10]=[CH:11][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)[CH2:33]2)[CH:25]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:27]=1
Reactant: C=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(F)(F)F
Reactant: CCc1ccc(C=NO)cc1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(C2=NOC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1
Reaction time: 14 h

Procedure:
To a solution of 1.49 g of 4-ethylbenzaldoxime in 10 mL of N,N-dimethylformamide, 1.60 g of N-chlorosuccinimide was added and the resultant mixture was stirred at room temperature for 2 hours. Next, to the reaction mixture, 3.00 g of 3,5-bis(trifluoromethyl)-1-(1-trifluoromethylethenyl)benzene and 3.00 g of potassium hydrogen carbonate were added and the stirring of the resultant reaction mixture was continued at room temperature further for 14 hours. After the completion of the reaction, 10 mL of water was added to the reaction mixture and the resultant reaction mixture was extracted with ethyl acetate (50 mL×1). The organic phase was washed with 20 mL of water and then dehydrated and dried over saturated saline and anhydrous sodium sulfate in this order, and the solvent was distilled off under reduced pressure. To the resultant residue, hexane was added and a deposited crystal was filtered off to obtain 3.00 g of the objective substance as a white crystal.
Reaction SMILES: FC(F)(F)C1C=C(C2C(C(O)=O)=NC=C(C3C=CC=C(C(F)(F)F)C=3)C=2)C=CC=1.C[O:31][C:32]([C:34]1[C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)=[CH:38][C:37]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:59])([F:58])[F:57])[CH:51]=2)=[CH:36][N:35]=1)=O.CC1C(C(O)=O)=NC=C(C2C=CC=C(C(F)(F)F)C=2)C=1.[N:80]1([CH:85]2[CH2:90][CH2:89][NH:88][CH2:87][CH2:86]2)[CH2:84][CH2:83][CH2:82][CH2:81]1>>[F:47][C:46]([F:49])([F:48])[C:42]1[CH:41]=[C:40]([C:39]2[C:34]([C:32]([N:88]3[CH2:89][CH2:90][CH:85]([N:80]4[CH2:84][CH2:83][CH2:82][CH2:81]4)[CH2:86][CH2:87]3)=[O:31])=[N:35][CH:36]=[C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[C:52]([C:56]([F:58])([F:59])[F:57])[CH:51]=3)[CH:38]=2)[CH:45]=[CH:44][CH:43]=1
Reactant: COC(=O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1-c1cccc(C(F)(F)F)c1
Reactant: C1CCN(C2CCNCC2)C1
Agent: Cc1cc(-c2cccc(C(F)(F)F)c2)cnc1C(=O)O
Agent: O=C(O)c1ncc(-c2cccc(C(F)(F)F)c2)cc1-c1cccc(C(F)(F)F)c1
Product: O=C(c1ncc(-c2cccc(C(F)(F)F)c2)cc1-c1cccc(C(F)(F)F)c1)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, 3,5-bis-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid [prepared from 3,5-bis-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid methyl ester (intermediate 8) by saponification in analogy to the procedure described for intermediate 1B] was reacted with 4-pyrrolidin-1-yl-piperidine to give the title compound as light yellow oil. MS: 548.3 (MH+).
Reaction SMILES: C([O:5][C@@H](C1C(C2C=CC(Cl)=CC=2)=C2C(=CC=1C)N=C(CN(C)C)C=C2)C(O)=O)(C)(C)C.[C:32]([O:36][C@@H:37]([C:43]1[C:44]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)=[C:45]2[C:50](=[CH:51][C:52]=1[CH3:53])[N:49]=[C:48]([CH2:54][OH:55])[CH:47]=[CH:46]2)[C:38]([O:40][CH2:41][CH3:42])=[O:39])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C@@H:37]([C:43]1[C:44]([C:56]2[CH:61]=[CH:60][C:59]([Cl:62])=[CH:58][CH:57]=2)=[C:45]2[C:50](=[CH:51][C:52]=1[CH3:53])[N:49]=[C:48]([C:54]([OH:5])=[O:55])[CH:47]=[CH:46]2)[C:38]([O:40][CH2:41][CH3:42])=[O:39])([CH3:33])([CH3:34])[CH3:35]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(CO)ccc2c1-c1ccc(Cl)cc1
Reactant: Cc1cc2nc(CN(C)C)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(C(=O)O)ccc2c1-c1ccc(Cl)cc1

Procedure:
(S)-6-(1-tert-Butoxy-2-ethoxy-2-oxoethyl)-5-(4-chlorophenyl)-7-methylquinoline-2-carboxylic acid was prepared following the procedure used to prepare compound (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)acetic acid of Example 9, except that (S)-ethyl 2-tert-butoxy-2-(5-(4-chlorophenyl)-2-(hydroxymethyl)-7-methylquinolin-6-yl)acetate was used instead of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-((dimethylamino)methyl)-7-methylquinolin-6-yl)ethanol. LCMS-ESI+ (m/z): 456.2, 458.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1C(O)=O.S(Cl)(Cl)=O.[N-:16]=[N+]=[N-].[Na+]>O>[CH3:1][C:2]1[C:3]([NH2:16])=[C:7]([CH3:11])[CH:8]=[CH:9][N:10]=1
Reactant: Cc1ccnc(C)c1C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: Cc1ccnc(C)c1N
Temperature: 60 °C
Yield: 73.7 %

Procedure:
A mixture of 1a (0.98 g, 6.5 mmol) and thionyl chloride (5 ml) was heated to 60° C. for 1 hour. The mixture was concentrated to dryness. The mixture was then dissolved in acetone (10 ml) prior to the addition of NaN3 (0.65 g, 10 mmol) and water (5 ml). The solution was heated to 70° C. for 1 hour. Acetone was evaporated from the reaction mixture which was washed with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, concentrated and chromatographed to yield 1b (0.585 g, 4.79 mmol, 74%).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].[CH2:18]([NH2:20])[CH3:19]>O>[N+:1]([CH:4]=[C:5]([NH:20][CH2:18][CH3:19])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2]
Reactant: CCN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1nccs1
Solvent: O
Product: CCNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene (see Example 55(i)) with ethylamine by the procedure of Example 8(ii) gives the title product, m.p. 115°-116° (from water).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C@H:14]([CH:18]([CH3:20])[CH3:19])[C:15](O)=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1.Cl.[CH2:29]([O:36][NH2:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl.C(ON)(C)(C)C>>[CH2:29]([O:36][NH:37][C:15](=[O:16])[C@H:14]([N:13]([S:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)(=[O:11])=[O:12])[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)[CH:18]([CH3:20])[CH3:19])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)O)C(C)C)cc1
Agent: CC(C)(C)ON
Agent: Cl
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NOCc2ccccc2)C(C)C)cc1

Procedure:
2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanoic acid hydrochloride is reacted with O-benzylhydroxylamine hydrochloride under conditions described for reaction with O-t-butylhydroxylamine hydrochloride to yield N-(benzyloxy)-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methyl-butanamide, m.p. 74.5°-76° C.