Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=O.[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([NH2:21])=[C:16]([NH2:22])[CH:15]=1.N>S1(CCCC1)(=O)=O>[CH3:11][C:9]1[CH:8]=[C:7]([CH3:12])[C:3]2[C:4](=[O:6])[NH:22][C:16]3[CH:15]=[C:14]([CH3:13])[C:19]([CH3:20])=[CH:18][C:17]=3[NH:21][C:2]=2[N:10]=1
Reactant: Cc1cc(C)c(C(=O)O)c(Cl)n1
Reactant: Cc1cc(N)c(N)cc1C
Agent: N
Solvent: O=S1(=O)CCCC1
Product: Cc1cc(C)c2c(n1)Nc1cc(C)c(C)cc1NC2=O
Temperature: 220 °C
Reaction time: 0.75 h

Procedure:
A mixture consisting of 52.0 gm of 2-chloro-4,6-dimethyl-nicotinic acid, 38.0 gm of 4,5-dimethyl-o-phenylenediamine and 150 ml of sulfolane was heated on an oil bath at 220° C. After 45 minutes the mixture was allowed to cool to 100° C. and was then poured over ice. After neutralization with ammonia and standing for several hours the precipitate which had formed was suction-filtered off and admixed with dilute acetic acid. The mixture was suction-filtered after one hour, and the filter cake was recrystallized from aqueous 80% acetic acid, yielding 34% of theory of the compound named in the heading, which had a melting point of 264°-268° C.
Reaction SMILES: ClCCCC([O:11]C(=O)C)CCCCC.ClCCCC(OC(=O)C)CCCCC(F)(F)F.C([O:35][CH:36]([CH2:54][CH2:55][CH2:56][CH2:57][C:58](F)(F)F)[CH2:37][CH2:38][CH2:39][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51]CC)=[O:50])[C:41]#[N:42])(=O)C>>[OH:35][C@H:36]([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[C:37]#[C:38][CH2:39][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])[C:41]#[N:42].[OH:35][C@H:36]([CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[C:37]#[C:38][CH2:39][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])[C:41]([NH2:42])=[O:11]
Reactant: CCOC(=O)CCCCCCN(C#N)CCCC(CCCCC(F)(F)F)OC(C)=O
Reactant: CCCCCC(CCCCl)OC(C)=O
Agent: CC(=O)OC(CCCCl)CCCCC(F)(F)F
Product: CCCCC[C@@H](O)C#CCN(C#N)CCCCCCC(=O)O
Product: CCCCC[C@@H](O)C#CCN(CCCCCCC(=O)O)C(N)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the 1-chloro-4-acetoxynonane is replaced by an equimolar amount of 1-chloro-4-acetoxy-9,9,9trifluorononane (Example E). The product of Step A is thus ethyl 7-[N-(4-acetoxy-9,9,9-trifluorononyl)cyanamido]heptanoate. The subsequent steps yield 7-[N-(4-hydroxy-9,9,9-trifluorononyl)cyanamido]heptanoic acid (B) and 7-[1-(4-hydroxy-9,9,9-trifluorononyl)-ureido]heptanoic acid (C).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18]([O:20][CH3:21])=[O:19])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CC(C)=O>[CH3:33][O:32][C:30](=[O:31])[CH2:29][O:1][C:2]1[C:3]([C:18]([O:20][CH3:21])=[O:19])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: COC(=O)CCc1ncc(O)c(C(=O)OC)c1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCc1ncc(OCC(=O)OC)c(C(=O)OC)c1C(=O)OC
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
To a mixture of dimethyl 5-hydroxy-2-(3-methoxy-3-oxopropyl)pyridine-3,4-dicarboxylate (5.10 g, 17.2 mmol) and potassium carbonate (12.3 g, 69.0 mmol) in acetone (100 mL) was added methyl bromoacetate (3.26 mL, 34.4 mmol) at room temperature, and the mixture was stirred for 30 min. The solvent was evaporated under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (5.14 g, yield 81%).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C@@H:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])[CH2:4][C@H:3]1[NH:14]C(=O)OC(C)(C)C.CCN(CC)CC>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:14][C@@H:3]1[CH2:4][C@H:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])[C:2]1([CH3:22])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)N2CCOCC2)C1(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)[C@H](N)C[C@@H]1C(=O)N1CCOCC1
Reaction time: 1 h

Procedure:
Tert-butyl (1R,3S)-2,2-dimethyl-3-(morpholine-4-carbonyl)cyclobutylcarbamate (Step 1, 0.260 g, 0.833 mmol) was taken in TFA:DCM (1:4) (3 ml) at 0° C.-room temperature and stirred for 1 hour. After completion of the reaction the solvent was evaporated and the crude dissolved in DCM and basified with Et3N (0.7 ml, 5.0 mmol). The resulting solution as such used for next reaction immediately. Wt: 0.176 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.O.[NH2:12][NH2:13]>COCCOC>[Cl:1][C:2]1[C:7]2[CH:8]=[N:12][NH:13][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: NN
Reactant: O=Cc1c(Cl)ccnc1Cl
Solvent: O
Solvent: COCCOC
Product: Clc1nccc2[nH]ncc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a solution of 2,4-dichloropyridine-3-carbaldehyde (7.0 g) in DME (70 mL) was added hydrazine monohydrate (8.0 g) at room temperature. The reaction mixture was stirred overnight at 75° C., and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (4.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Product: CCS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with ethanethiol to afford 2-chloro-4-(ethylthio)benzonitrile. 2 g of 2-chloro-4-(ethylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(ethylthio)benzoic acid. 1.5 g of 2-chloro-4-(ethylthio)benzoic acid was reacted via Procedure R to yield 2-chloro-4-(ethylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)benzamide. MS (Q1) 435.1 (M)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][NH:17][CH2:18]2.C(N(CC)CC)C.[S:30](Cl)([Cl:33])(=[O:32])=[O:31]>C(Cl)Cl>[Br:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][N:17]([S:30]([Cl:33])(=[O:32])=[O:31])[CH2:18]2
Reactant: FC(F)(F)c1ccc(-c2cccc3c2CCNC3)c(Br)c1
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Cl)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Reaction time: 2 h
Yield: 76.1 %

Procedure:
A 15-mL round-bottom flask was charged with 5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate D, 287.2 mg, 0.731 mmol) and triethylamine (224 μl, 1.609 mmol) in DCM (3.8 mL) to give a brown solution. The flask was cooled in an ice-bath for 10 min, then sulfuryl chloride (125 μl, 1.536 mmol) was added dropwise. Stirring was continued for 2 hours at which time the mixture was quenched with water, then extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on a 40 g silica gel column with 0 to 40% EtOAc/Heptane to give 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonyl chloride (253.01 mg, 0.556 mmol) as a clear, very viscous oil that was immediately used in the next step. A vial was charged with 5-(2-bromo-4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonyl chloride (40.045 mg, 0.088 mmol), pyrimidin-4-amine (41.9 mg, 0.440 mmol), chloroform (587 μl), and pyridine (71.2 μl, 0.881 mmol) and was placed into a 50° C. bath. The mixture was heated overnight before being allowed to cool to rt. The mixture was concentrated under a vacuum, and the residue was chromatographed on a 12 g silica gel column with 0 to 6% MeOH/DCM to give 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (29.77 mg, 0.058 mmol) as a yellow solid. [M+H]+=513.0. 1H NMR (400 MHz, DMSO-d6) δ ppm=9.55 (br. s., 1H), 9.07 (br. s., 1H), 8.57 (br. s., 1H), 8.13 (d, J=1.3 Hz, 1H), 7.99 (br. s., 1H), 7.83 (dd, J=1.1, 8.0 Hz, 1H), 7.55-7.44 (m, 1H), 7.35-7.21 (m, 2H), 7.02 (dd, J=2.0, 6.8 Hz, 1H), 4.71 (d, J=6.4 Hz, 1H), 4.32-4.17 (m, 2H), 3.24-3.07 (m, 2H), 2.45 (br. s., 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]#N)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[C:13](Cl)(=[O:15])[CH3:14].C(Cl)Cl.C([O-])(O)=[O:21].[Na+]>CCO>[CH2:13]([O:15][C:11](=[O:21])[CH2:10][C:4]1[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([Br:1])[CH:3]=1)[CH3:14]
Reactant: COc1ncc(CC#N)cc1Br
Reactant: CC(=O)Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)Cc1cnc(OC)c(Br)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To (5-bromo-6-methoxy-pyridin-3-yl)-acetonitrile (1.139 g, 5.02 mmol) in EtOH (11 ml) was added acetyl chloride (3.6 mL, 50.54 mmol), and the reaction was stirred at 50° C. for 24 hours, and at room temperature for 2 days. The reaction was worked up with CH2Cl2 and saturated aqueous NaHCO3, and then reacidified and extracted with CH2Cl2. The combined organic layers were dried, filtered, and concentrated to give (5-bromo-6-methoxy-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O.O.CCCCCC>[CH2:15]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
A solution of 4-bromophenol (17.3 g) in dimethylformamide (200 mL) was treated with potassium carbonate (15.2 g) followed by benzyl bromide (17.1 g 11.9 mL). After stirring for 16 hours at ambient temperature, the reaction mixture was diluted with water and hexane. The aqueous layer was extracted with hexane:ether (5:1). The organic extracts were washed (water, 1N sodium hydroxide, brine), dried and evaporated to give the bromobenzene as a white solid (23.4 g); NMR (CDCl3): 5.03 (s, 2), 6.85 (dd, 2, J1 =5, J2 =2), 7.3-7.4 (m, 7); MS: m/z=263(M+1). This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][NH:5][CH2:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:9]=1[OH:15].[CH3:18][O:19][C:20]1[C:21](=O)[C:22](=[O:26])[C:23]=1[O:24]C>>[OH:15][C:9]1[C:10]([NH:14][C:21]2[C:22](=[O:26])[C:23](=[O:24])[C:20]=2[O:19][CH3:18])=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([CH2:6][NH:5][CH2:4][C:3]([O:2][CH3:1])=[O:17])=[O:16]
Reactant: COc1c(OC)c(=O)c1=O
Reactant: COC(=O)CNCC(=O)c1cccc(N)c1O
Product: COC(=O)CNCC(=O)c1cccc(Nc2c(OC)c(=O)c2=O)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.1 %

Procedure:
A mixture of 3.92 g (16.4 mmol, 1 eq) of methyl[(3-amino-2-hydroxybenzoyl)methylamino]acetate and 4.68 g (32.9 mmol, 1 eq) of 3,4-dimethoxy-3-cyclobutene-1.2-dione was stirred at ambient temperature for 24 hours. The solvent was evaporated off and the residue was chromatographed on silica gel (200 g prepacked column, eluent 20/80 then 0/100 heptane/ethyl acetate). 3.49 g of methyl {[2-hydroxy-3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)benzoyl]methylamino}acetate were obtained in the form of a white solid. Yield=61%.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[Li]CCCC.[Br:10][C:11]1[CH:12]=[C:13]([CH:22]=[C:23]([F:25])[CH:24]=1)/[CH:14]=[N:15]/[S@:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17]>C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([C@H:14]([NH:15][S@:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])[CH2:4][N+:1]([O-:3])=[O:2])[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: CC(C)(C)[S@](=O)/N=C/c1cc(F)cc(Br)c1
Reactant: C[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@H](C[N+](=O)[O-])c1cc(F)cc(Br)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 38.7 %

Procedure:
Nitromethane (1.0 mL, 17.20 mmol) was dissolved in THF (34.4 mL), then BuLi (2.5 M in hexanes) (7.22 mL, 18.06 mmol) was added at −78° C. The reaction mixture was stirred at −78° C. for 10 min, then warmed up to room temperature for 20 min. After cooling down to −78° C., (S,E)-N-(3-bromo-5-fluorobenzylidene)-2-methylpropane-2-sulfinamide (4.74 g, 15.48 mmol) in THF (6 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 20 min, warmed up to room temperature, and stirred at room temperature for 5 h. The reaction mixture was quenched by sat NH4Cl, and extracted by EtOAc. The organic was dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (0-40%-100% EtOAC/heptane). Pure fractions were combined to yield (S)—N—((S)-1-(3-bromo-5-fluorophenyl)-2-nitroethyl)-2-methylpropane-2-sulfinamide (2.2 g, 5.99 mmol, 38.7% yield). LCMS (m/z): 367.1/369.1 (MH+), 0.89 min; 1H NMR (400 MHz, CDCl3) δ ppm 7.31 (s, 1H), 7.03 (d, J=9.0 Hz, 1H), 5.03 (q, J=5.7 Hz, 1H), 4.87-4.78 (m, 2H), 4.48 (d, J=5.1 Hz, 1H), 1.33-1.25 (m, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[CH:27][C:28]=4[F:30])[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH:41]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[NH:16][CH:15]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:14]3([C:29]4[C:24](=[CH:25][C:26]([Cl:31])=[CH:27][C:28]=4[F:30])[NH:23][C:22]3=[O:32])[CH:13]2[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=2[F:40])=[O:11])=[CH:7][CH:8]=1)(=[O:41])[NH2:2]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide (0.2 g, 0.34 mmol) prepared in Example 72 in DMSO (15 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.39 g, 3.4 mmol), then aqueous solution (1N) of NaOH (1.7 mL, 1.7 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in dichloromethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-carbamoyl-phenyl)-amide as a white solid (Yield 0.18 g, 87%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:4]=1[O:5][CH2:6][C:7](Cl)=[O:8].COC1C=CC([N+]([O-])=O)=CC=1OCC(O)=O.S(Cl)(Cl)=O.[CH:37]1([NH:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>ClCCl>[CH:44]1([N:43]([CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[C:7](=[O:8])[CH2:6][O:5][C:4]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:3]=2[O:2][CH3:1])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: COc1ccc([N+](=O)[O-])cc1OCC(=O)Cl
Agent: COc1ccc([N+](=O)[O-])cc1OCC(=O)O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([N+](=O)[O-])cc1OCC(=O)N(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Yield: 45.5 %

Procedure:
A solution of 2-methoxy-5-nitro-phenoxyacetyl chloride (0.22 g, 0.9 mmol), prepared from 2-methoxy-5-nitro-phenoxyacetic acid (Brown et al., J. Chem. Soc. 1955, 3681) and thionyl chloride, in dichloromethane (10 mL) was added to a mixture of dicyclohexylamine (0.16 g, 0.9 mmol) and diisopropylethylamine (0.23 g, 1.76 mmol) in dichloromethane (20 mL), maintained at RT for 16 h, washed with water (2×20 mL), dried (Na2SO4), and concentrated in vacuo. The residue was recrystallized from methanol to afford the title compound (0.16 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:20][C:21]([N:23]=[C:24](SC)SC)=O.O.[NH2:30][NH2:31]>O1CCCC1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:24]2[NH:31][NH:30][C:21](=[O:20])[N:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: COC(=O)N=C(SC)SC
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: O=c1nc(NCCCOc2cccc(CN3CCCCC3)c2)[nH][nH]1
Reaction time: 6 h
Yield: 10.6 %

Procedure:
A solution of 3-[3-(1-piperidinylmethyl)phenoxy]propanamine (1.76 g) in tetrahydrofuran (70 ml) was treated with dimethyl N-methoxycarbonylcarbonimidodithioate (1.27 g) at room temperature, and the mixture was stirred for 6 h. Hydrazine hydrate (2 g) was added, and the mixture was heated under reflux for 18 h. The solution was evaporated, and the residue was chromatographed to give the title compound (250 mg) as a colourless oil. tlc. System B, Rf 0.5. Nmr (D2O) 2.5,t, (1H); 2.8-3.0,m,(3H); 5.72,s,(1H); 5.8,t, (3H); 6.5,m, (2H); 6.65,t, (2H); 7.05,br.t, (2H); 7.7-8.6,m, (8H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccc3ccccc3n2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccc3ccccc3n2)c2ccccc12
Reaction time: 18 h
Yield: 111.9 %

Procedure:
0.390 g (9.3 mmol) of lithium hydroxide monohydrate and 45 cm3 of water are added at 25° C. to 0.935 g (3.1 mmol) of 3-methoxycarbonyl-1-(quinol-2-yl)-1H-indole dissolved in 45 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 18 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm3 of water and then triturated with 9.3 cm3 of N hydrochloric acid. After filtering off and drying under reduced pressure (2.7 kPa) at 40° C., 1 g of 3-carboxy-1-(quinol-2-yl)-1H-indole is obtained in the form of a white solid. Mass spectrum (DCI): m/e 289 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:33])[CH2:22][N:23]([C:25]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[O:26])[CH3:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:34]1[CH2:36][C@@H:35]1[CH2:37][O:38][C:39]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[N:44]2>C(O)C>[C:14]1([CH2:13][CH2:12][CH2:11][CH:10]([NH:20][C:21](=[O:33])[CH2:22][N:23]([C:25]([CH:27]2[CH2:28][CH2:29][N:30]([CH2:36][C@@H:35]([OH:34])[CH2:37][O:38][C:39]3[CH:48]=[CH:47][CH:46]=[C:45]4[C:40]=3[CH:41]=[CH:42][CH:43]=[N:44]4)[CH2:31][CH2:32]2)=[O:26])[CH3:24])[CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)C1CCNCC1
Solvent: CCO
Product: CN(CC(=O)NC(CCCc1ccccc1)CCCc1ccccc1)C(=O)C1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1
Temperature: 25 °C
Yield: 34 %

Procedure:
N-(Piperidine-4-carbonyl)-(N-methyl)-2-aminoacetic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (68) (223.5 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 15.5 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (110 mg) as a white solid. ESMS:MH+ 651.6
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8](C)=[C:7]([NH2:12])[CH:6]=1)[C:2](C)=[O:3].[NH2:13]C1C=CC=CC=1OC>>[NH2:12][C:7]1[CH:6]=[C:5]([NH:1][C:2]([NH2:13])=[O:3])[CH:10]=[CH:9][CH:8]=1
Reactant: CC(=O)Nc1ccc(C)c(N)c1
Reactant: COc1ccccc1N
Product: NC(=O)Nc1cccc(N)c1

Procedure:
4-acetamino-2-aminotoluene or 2-aminoanisole;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:17][C:11]3([CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:10](=[O:18])[CH2:9][C:8]=2[CH:19]=1)([O-:3])=[O:2].[CH3:20][N:21]=[C:22]=[S:23].CC(C)([O-])C.[K+]>CN(C)C=O>[OH:18][C:10]1[C:11]2([CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[O:17][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:19][C:8]=2[C:9]=1[C:22](=[S:23])[NH:21][CH3:20]
Reactant: CN=C=S
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2OC12CCOCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=S)C1=C(O)C2(CCOCC2)Oc2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 62 %

Procedure:
To a mixture of 4.8 g of 3,4-dihydro-6-nitrospiro[2H-1-benzopyran-2,4'-tetrahydropyran]-3-one and 60 ml of dried N,N-dimethylformamide was added 1.65 g of methyl isothiocyanate under nitrogen stream. Then, 2.39 g of potassium tertiary butoxide was added therein with stirring under ice-cooling and the mixture was stirred for 1 hour and then stirred at 5° C. for 17 hours. Ice water was added to the reaction solution and it was washed with ether. A water layer was acidified to be hydrochloric acid and extracted with ether. An organic layer was washed with water and dried, and the solvent was distilled. The obtained residue was recrystallized by a mixed solvent of ethyl acetate and hexane to obtain 3.8 g of 3-hydroxy-N-methyl-6-nitrospiro-[2H-1-benzopyran-2,4'-tetrahydropyran]-4-carbothioamide with a melting point of 217°-218° C.
Reaction SMILES: [CH3:1][C:2]1([OH:29])[CH2:7][CH2:6][CH:5]([CH3:8])[CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[C:22](=[O:28])[CH:21]=[CH:20]4)[CH:10]=2)[CH2:3]1.[CH3:30]I>>[CH3:1][C:2]1([O:29][CH3:30])[CH2:7][CH2:6][CH:5]([CH3:8])[CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[C:22](=[O:28])[CH:21]=[CH:20]4)[CH:10]=2)[CH2:3]1
Reactant: CI
Reactant: CC1CCC(C)(O)CC1c1cccc(OCc2ccc3c(ccc(=O)n3C)c2)c1
Product: COC1(C)CCC(C)C(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)C1
Yield: 41 %

Procedure:
Using an analogous procedure to that described in Example 2, (1RS,3RS,4SR)-1,4-dimethyl-1-hydroxy-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]cyclohexane was reacted with methyl iodide to give (1RS,3RS,4SR)-1,4-dimethyl-1-methoxy-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]cyclohexane as an oil in 41% yield.