Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]1[CH:13]=[C:14]([C:21]2([CH3:26])[O:25][CH2:24][CH2:23][O:22]2)[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19].[CH3:27]I>CN(C)C=O>[CH3:27][N:11]([C:12]1[CH:13]=[C:14]([C:21]2([CH3:26])[O:22][CH2:23][CH2:24][O:25]2)[CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:5]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=1[F:3]
Reactant: CI
Reactant: CC1(c2ccc([N+](=O)[O-])c(Nc3ccc(F)cc3F)c2)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc(F)cc1F)c1cc(C2(C)OCCO2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
Sodium hydride (60%; 0.14 g) was added portionwise to an ice-cooled solution of 2-[3-(2,4-difluorophenylamino)-4-nitrophenyl]-2-methyl-1,3-dioxolane (1 g) in N,N-dimethylformamide. To the resulting mixture as added methyl iodide (1.7 g). The mixture was stirred at 0° C. for 30 minutes, poured into ice-water (50 ml) and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The oily residue was purified by column chromatography on silica gel (30 g) eluting with toluene to give an oil of 2-{3-[N-methyl-N-(2,4-difluorophenyl)amino]-4-nitrophenyl}-2-methyl-1,3-dioxolane (0.88 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[C:19]([F:22])([F:21])[F:20].[OH-].[Na+]>CS(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([F:20])([F:21])[F:22])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Oc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)c(C(F)(F)F)c1
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
To a solution containing 64.2 g (0.5 mole) of 4-chlorophenol and 112.7 g (0.5 mole) of 2-chloro-5-nitrobenzotrifluoride in 400 ml of DMSO was added dropwise with stirring at 30°-35° C. a solution containing 20 g (0.5 mole) of sodium hydroxide in 20 ml of water. After 1.5 hours, the reaction mixture was poured into cold water and extracted with 800 ml of ether. The ether solution was dried and concentrated under reduced pressure to give 158 g (99%) of product that crystallized on standing; melting point, 46°-48° C. (from hexane).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[C:11]3[C:28]([O:30]CC)=[O:29])=[CH:4][C:3]=2[O:2]1.C1OC2C=CC(C3(O)C4C(=CC=CC=4)C(C4C=CC5OCOC=5C=4)=C3C(OCC)=O)=CC=2O1.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([OH:30])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
Ethyl(RS)-1,3-Di-(3,4-methylenedioxyphenyl)indene-2-carboxylate. To a solution of ethyl (1RS)-1,3-di-(3,4-methylenedioxyphenyl)-1-hydroxyindene-2-carboxylate (0.29 g, 0.65 mmol) in CH2Cl2 (3 ml) at 0° C. under an argon atmosphere was added triethylsilane (91 mg, 0.78 mmol), followed by boron trifluoride etherate (0.3 ml, 2.4 mmol). The reaction mixture was stirred for 10 min, at which time was added ice-cold 1M HCl, and the mixture was extracted with EtOAc. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo, and the residue was placed on a small pad of silica gel, eluting with CH2CL2 to provide the title compound (257 mg, 92%).
Reaction SMILES: [CH:1]([CH:3]1[CH2:7][CH:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:5]([OH:15])[CH:4]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=O.[C:24]([CH:31]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH:4]1[CH:3]([CH:1]=[CH:31][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH:6]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[CH:5]1[OH:15]
Reactant: CCCCCC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CC(OC2CCCCO2)C(O)C1CCCCCCCO
Solvent: C1CCOC1
Product: CCCCCC(=O)C=CC1CC(OC2CCCCO2)C(O)C1CCCCCCCO
Yield: 57.3 %

Procedure:
A mixture of 3-formyl-2-(7-hydroxyheptyl)-5-(2-tetrahydropyranyloxy)cyclopentanol [5.4 g.; prepared as described above in Example 2(e)] and hexanoylmethylene triphenylphosphorane (5.6g.) in dry tetrahydrofuran (60 ml.) was heated under reflux under nitrogen for 24 hours. The solvent was then removed in vacuo and the resulting residue was chromatographed on silica gel. Elution with diethyl ether gave 2-(7-hydroxyheptyl)-3-(3-oxooct-1-enyl)-5-(2-tetrahydropyranyloxy)cyclopentanol (3.64g.), νmax 3450 cm-1, 1670 cm-1, 1630 cm-1, 985 cm-1.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][N:13]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(N(CC)C(C)C)(C)C>CN1C(=O)CCC1>[CH3:12][N:13]([CH:21]1[CH2:22][CH2:23][N:24]([C:2]2[C:3]3[C:10]([CH3:11])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:25][CH2:26]1)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18]
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1c[nH]c2ncnc(N3CCC(N(C)C(=O)OC(C)(C)C)CC3)c12
Temperature: 150 °C

Procedure:
A mixture of 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine D4 (1 g), 1,1-dimethylethyl methyl(4-piperidinyl)carbamate (1.918 g, 8.95 mmol, commercially available from e.g. Fluorochem, Apollo or Butt Park) and N,N-diisopropylethylamine (2.61 mL, 14.92 mmol) was heated at 150° C. for 20 minutes. LC/MS showed incomplete reaction. Further NMP (2 mL) and DIPEA (1.3 mL) was added. The mixture was heated at 150° C. for 20 minutes. The mixture was partitioned between ethyl acetate (70 mL) and water (60 mL) and the organic phase washed with water (2×60 mL) and brine (50 mL). It was dried (MgSO4), filtered and the solvent removed in vacuo. The crude material was purified by silica chromatography, eluting 50-100% EtOAc in isohexane. The desired fractions collected and the solvent has been evaporated to give the desired product D22 in 0.793 g as a white solid. LCMS [M+H]+345.87@0.88 min (2 min run)
Reaction SMILES: [CH2:1]([N:4]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:5]1)[CH2:2][CH3:3].[F:15][CH:16]([F:29])[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH3:18]>C(Cl)Cl.N1C=CC=CC=1>[F:29][CH:16]([F:15])[CH:17]([C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:14][C:11]2[CH:10]=[CH:9][C:8]([CH:6]3[CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:7]3)=[CH:13][CH:12]=2)(=[O:27])=[O:26])=[CH:23][CH:24]=1)[CH3:18]
Reactant: CCCN1CC(c2ccc(N)cc2)C1
Reactant: CC(c1ccc(S(=O)(=O)Cl)cc1)C(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCN1CC(c2ccc(NS(=O)(=O)c3ccc(C(C)C(F)F)cc3)cc2)C1
Yield: 12.6 %

Procedure:
Following the same procedure as described in example 55, 4-(1-propyl-azetidin-3-yl)phenylamine (150 mg, 0.78 mmol) in CH2Cl2/pyridine 1:1 (12 ml) was treated with 4-(2,2-difluoro-1-methyl-ethyl)-benzenesulfonyl chloride (321 mg, 1.26 mmol). Purification of the crude product by flash column chromatography (CH2Cl2:methanol, 95:5) provided the title compound (40 mg, 18%) as a colourless gum.
Reaction SMILES: [OH:1][N:2]=[C:3]1[S:7][C:6](=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:9]#[N:10])[CH:5]=[CH:4]1.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21].C(N(CC)CC)C>C1COCC1>[Cl:18][C:19]([Cl:24])([Cl:23])[C:20]([O:1][N:2]=[C:3]1[S:7][C:6](=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[C:9]#[N:10])[CH:5]=[CH:4]1)=[O:21]
Reactant: Cc1ccccc1C(C#N)=C1C=CC(=NO)S1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(C#N)=C1C=CC(=NOC(=O)C(Cl)(Cl)Cl)S1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
1.0 g (4.1 mmol) of (5-Hydroxyimino-5H-thiophen-2-ylidene)-(2-methylphenyl)-acetonitrile, prepared as described in example 7.1, are dissolved in 11 ml of THF and cooled in an ice bath. After adding 0.83 g (4.5 mmol) of trichloroacetyl chloride to the solution, 0.63 g (6.2 mmol) of triethylamine are added dropwise, keeping the temperature below 5° C. While the reaction mixture is stirred at 5° C. for 20 min, a precipitate is formed. The precipitate is filtered off and washed with THF. The filtrate is concentrated by a rotary evaporator. The residue is diluted with 2-PrOH and stirred at room temperature for 15 min. After cooling the mixture in an ice bath, the solid is isolated by filtration and washed with 2-PrOH. The product is obtained in the form of a yellow solid, 165° C.(Dec). The structure is confirmed by the 1H-NMR spectrum (CDCl3). δ [ppm]: 2.39 (s, 3H), 6.23 (d, 1H), 6.86 (d, 1H), 7.19-7.4 (m, 4H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4](=[CH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:11][CH:10]=2)[S:3]1.[Br:27]Br>C(O)(=O)C>[Br:27][C:11]1[CH:10]=[C:9]([CH:8]=[C:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: O=C(O)CCCCOc1ccc(C=C2SC(=O)NC2=O)c2ccccc12
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)CCCCOc1c(Br)cc(C=C2SC(=O)NC2=O)c2ccccc12
Temperature: 25 °C
Reaction time: 336 h

Procedure:
5-[4-(2,4-Dioxothiazolidin-5-ylidenemethyl)-naphthalen-1-yloxy]pentanoic acid (example 292, 185 mg, 0.5 mmol) was treated with an equimolar amount of bromine in acetic acid (10 mL). Stirring at RT for 14 days followed by evaporation to dryness afforded a mixture of the brominated compound and unchanged starting material. Purification by preparative HPLC on a C18 column using acetonitrile and water as eluent afforded 8 mg of the title compound.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][CH:7]([CH3:20])[CH2:8][CH:9](C(OCC)=O)[C:10]([O:12]CC)=[O:11])[CH2:4][CH3:5].S(=O)(=O)(O)O.C1C=CC=CC=1>O>[CH2:3]([O:6][CH:7]([CH3:20])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH2:4][CH3:5]
Reactant: CCCOC(C)CC(C(=O)OCC)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCOC(C)CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
Then, 87 g of 85% KOH was dissolved in 87 ml of water, and 100 g of the above ethyl 4-propoxy-2-ethoxycarbonylvalerate was added at 15°-25° C. in 45 min. The mixture was stirred at 90°-96° C. for 2 hours, and then cooled. While keeping the temperature below 20° C., a solution of 138 g of conc. sulfuric acid in 194 ml of water was added dropwise in 30 min. The mixture was stirred at 90°-95° C. for 3 hours, cooled to room temperature and then subjected to extraction with ether. The ether layer was washed with saturated saline water and then ether was distilled off, followed by vacuum distillation to obtain 47 g of a fraction of 100°-130° C./5 mmHg. Benzene was added to the fraction, and the mixture was washed with 5% NaOH aqueous solution. The aqueous layer was acidified to pH 1 with 6N-hydrochloric acid and subjected to extraction with ether. The ether extract was washed with saturated saline water, and ether was distilled off to obtain 38 g of 4-propoxyvaleric acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C@@H:4]([C:5]#[C:6][C:7](=[O:13])[O:8][CH2:9][CH:10]([F:12])[F:11])[C@H:3]1[C:14]([O:16]C(C)(C)C)=[O:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:21])[C@@H:4]([C:5]#[C:6][C:7](=[O:13])[O:8][CH2:9][CH:10]([F:11])[F:12])[C@H:3]1[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(F)F)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(F)F
Yield: 96.8 %

Procedure:
A mixture of 5.2 g of the product of Step B and 500 mg of p-toluene sulfonic acid in 40 ml of toluene was refluxed for 25 mintues and after cooling, 400 ml of ether were added thereto. The mixture was washed with water and the organic phase was dried and evaporated to dryness to obtain 4.1 g of (1R,cis) 2,2-dimethyl-3-[3-oxo-3-(2,2-difluoroethoxy)-1-propynyl]-cyclopropane-carboxylic acid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=2)=[CH:3][CH:4]=1)=[O:13]
Reactant: O=Cc1ccc(O)c2ccccc12
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)nc1
Temperature: 80 °C

Procedure:
To a solution of 4-hydroxynaphthaldehyde (1.24 g, 7.2 mmol) in DMSO (8 mL) was added 2-chloro-5-cyanopyridine (1.0 g, 7.2 mmol) and K2CO3 (2.0 g, 14.5 mmol). The reaction was heated at 80° C. for 4 h. The reaction was cooled to rt and poured into water (100 mL). The resulting solid was filtered, washed with water, ether and air dried to give the title compound: RT=3.54 min; m/z (ES+)=275.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH2:13][CH3:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.C(OCC)C>C1(C)C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH:12]=[CH:11][N:10]=[C:9]3[CH2:13][CH3:14])=[CH:6][CH:7]=2)=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCc1nccn1-c1ccc(N)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCc1nccn1-c1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Reaction time: 7 h
Yield: 75.6 %

Procedure:
1.9 g of 1-(4-aminophenyl)-2-ethylimidazole was added to a solution of 2.6 g of p-chlorobenzoyl chloride in 50 ml of toluene, and the mixture was refluxed with stirring for 7 hours. The reaction mixture was naturally cooled and diethyl ether was then added thereto. The precipitated crystal was recovered by filtration, washed sufficiently with ethyl ether and recrystallized from ethanol and then from water to obtain 2.5 g of the intended compound in the form of a hydrochloride. The melting point was 265° to 267° C. Elementary analysis values as C18H16ClN3O.HCl.1/2H2O were as follows.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][O:23][CH2:24][C:25]#[C:26][CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][O:23][CH2:24][C:25]#[C:26][CH2:27][N:28]1[C@@H:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1C=O
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCC#CCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
Sodium hydride (60% dispersion in oil, 41 mg, 1.03 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (247 mg, 1.02 mmol) in THF (4 mL) at 0° C. After 1 h at 0° C., a solution of [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-but-2-ynyloxy]-acetic acid methyl ester (1.23 mmol, crude, prepared as in Example 69, step 4) in THF (3 mL) was added via cannula. The reaction was allowed to warm to rt. After 18 h at rt, the reaction was quenched with aqueous acetic acid (50%, 30 mL) and extracted with EtOAc (3×40 mL). The combined organic phase was washed with brine (50 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (30% →50% EtOAc/CH2Cl2, gradient) afforded 122 mg (31%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br)=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].Cl>CO.CCC(C(OCCN1C(C)C(C2C=CC=CC=2)OCC1)=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:18][CH3:17])=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: BrCCCCCCCSc1ccc(Br)cc1
Agent: CCC(C(=O)OCCN1CCOC(c2ccccc2)C1C)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCCCCCCCSc1ccc(Br)cc1

Procedure:
To a solution of 1-bromo-4-(7-bromoheptylthio)benzene (5 g) in methanol (25 ml) was added 28% sodium mehtylate in nethanol (7.9 g) and the mixture was stirred under refluxing for 2 hours. The residue was adjusted to pH 2 with dilute HCl aq. and extracted with ethyl acetate. The organic layer was seperated, wahsed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (50:1) to give 1-bromo-4-(7-methoxyheptylthio)benzene (3.59 g).
Reaction SMILES: [CH2:1]([O:8]CCOC1C=C(C2OC(=O)NCC2)C=CC=1OC)C1C=CC=CC=1.[CH:27]1([O:32][C:33]2[CH:34]=[C:35]([CH:41]([OH:47])[C:42]([CH3:46])([CH3:45])[C:43]#[N:44])[CH:36]=[CH:37][C:38]=2[O:39][CH3:40])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([O:32][C:33]2[CH:34]=[C:35]([CH:41]3[O:47][C:1](=[O:8])[NH:44][CH2:43][C:42]3([CH3:45])[CH3:46])[CH:36]=[CH:37][C:38]=2[O:39][CH3:40])[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(C2CCNC(=O)O2)cc1OCCOCc1ccccc1
Reactant: COc1ccc(C(O)C(C)(C)C#N)cc1OC1CCCC1
Product: COc1ccc(C2OC(=O)NCC2(C)C)cc1OC1CCCC1
Yield: 54.3 %

Procedure:
According to the same procedure as in Example 1(2) to (3), using 3-(3-cyclopentyloxy-4-methoxyphenyl)-2,2-dimethyl-3-hydroxypropiononitrile instead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-described compound (yield 54.3%) was obtained as a colorless oil.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([C:13]2([OH:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:4]=1)=[O:2].CC(=CC)C.P([O-])(O)(O)=[O:33].[Na+].Cl([O-])=O.[Na+]>CC(O)(C)C.O>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][C:13]([C:5]2[CH:4]=[C:3]([C:1]([OH:33])=[O:2])[C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)([OH:26])[CH2:14][CH2:15]1)=[O:20])([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C=O)c3ccccc3c2)CC1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc(C(=O)O)c3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.5 g (4.2 mmol) of tert-butyl 4-(4-formyl-2-naphthyl)-4-hydroxypiperidine-1-carboxylate in 25 mL of 2-methyl-2-propanol was added 2.3 mL (21 mmol) of 2-methyl-2-butene followed by dropwise addition of a solution of 1.00 g (8.45 mmol) of sodium dihydrogen phosphate and 877 mg (59.7 mmol) of sodium chlorite in 15 mL of water. The resulting mixture was stirred at ambient temperature for 2 h then evaporated in vacuo to remove all volatiles. The residue was diluted with water (5 mL) and an aqueous 2 N HCl solution was then added dropwise to the stirred mixture until a pH of 4 was achieved. The aqueous phase was then extracted with ethyl acetate (3×5 mL) and the combined organic layers were washed with brine (25 mL), dried over magnesium sulfate, filtered and evaporated in vacuo to yield the crude title compound as a colorless oil. LC/MS 394.2 (M+23).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:51])[CH2:4][CH2:5][NH:6][CH2:7][CH2:8][NH:9][C:10]([C@:12]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:44])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)=[O:11].I[CH2:53][CH3:54].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O1CCOCC1>[CH2:53]([N:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:51])[CH2:7][CH2:8][NH:9][C:10]([C@:12]12[CH2:47][CH2:46][C@@H:45]([C:48]([CH3:50])=[CH2:49])[C@@H:13]1[C@@H:14]1[C@@:27]([CH3:30])([CH2:28][CH2:29]2)[C@@:26]2([CH3:31])[C@@H:17]([C@:18]3([CH3:44])[C@@H:23]([CH2:24][CH2:25]2)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=2)=[CH:20][CH2:19]3)[CH2:16][CH2:15]1)=[O:11])[CH3:54]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCNCCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(CC)CCC(=O)OC)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 75.7 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(3-methoxy-3-oxopropylamino)ethylcarbamoyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (20 mg, 0.029 mmol), iodoethane (0.019 mL, 0.228 mmol) and potassium carbonate (7.89 mg, 0.057 mmol) in acetonitrile (2 mL) and dioxane (2 mL) was refluxed for 8 hours. LCMS indicated the formation of desired product and consumption of starting material. The reaction mixture was quenched with distilled water, extracted with DCM (3×3 mL). All the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as white solid (16 mg, 77%). LCMS: m/e 729.45 (M+H)+, 2.76 min (method 1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[N+:8]([O-])=O.C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][S:2][C:3]1[N:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[S:6][C:7]=1[NH2:8]
Reactant: [H][H]
Reactant: CSc1nc(-c2cccnc2)sc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CSc1nc(-c2cccnc2)sc1N
Reaction time: 2 h

Procedure:
To a nitrogen-purged solution of 4-(methylthio)-5-nitro-2-(pyridin-3-yl)thiazole (253 mg, 1 mmol) in ethyl acetate (50 mL) in a Parr bottle were added glacial acetic acid (601 mg, 10 mmol), followed by Pd on carbon (35 mg, 10% (w)). Hydrogen was added and the mixture was shaken in a Parr shaker for 2 hours and filtered through a bed of Celite®. The filtrate was concentrated under vacuum to give 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine as a pale yellow solid, which was placed under high vacuum to remove residual acetic acid. This crude was found to be 95% pure by GC-MS. The crude 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine was used without further purification to prepare 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide. To a solution of 4-(methylthio)-2-(pyridin-3-yl)thiazol-5-amine (100 mg, 0.45 mmol) in methylene chloride (2 mL) were added dimethylaminopyridine (137 mg, 1.12 mmol) followed by 3-(methylthio)propanoyl chloride (68 mg, 0.49 mmol). The mixture was stirred at room temperature for 30 min. The mixture was diluted with dichloromethane (10 mL) and water (5 mL). The organic phase was separated, rinsed with brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. This solid was purified by silica gel chromatography (methylene chloride-methanol) to give 3-(methylthio)-N-(4-(methylthio)-2-(pyridin-3-yl)thiazol-5-yl)propanamide as a yellow solid (32 mg, 22%): mp 72-74° C., 1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.08 (m, 1H), 8.64 (d, J=4.8 Hz, 1H), 8.32 (d, J=9.0 Hz, 1H), 7.57 (dd, J=5.1 Hz, 8.4 Hz, 1H), 3.25 (s, 3H), 2.85 (m, 2H), 2.73 (m, 2H), 2.07 (s, 3H); ESIMS m/z 326.1(M+1), 324.1 (M-1).