Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:20][CH:19](I)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[Cl:22][C:23]1[CH:28]=[C:27](I)[CH:26]=[C:25]([Cl:30])[N:24]=1>CN(C)C(=O)C.CCOC(C)=O.[Zn].C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].[Cu]I>[Cl:22][C:23]1[CH:28]=[C:27]([CH:19]2[CH2:20][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:18]2)[CH:26]=[C:25]([Cl:30])[N:24]=1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Clc1cc(I)cc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe]
Solvent: BrCCBr
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(c2cc(Cl)nc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
Under a nitrogen atmosphere, zinc dust (6.91 g, 105 mmol) was suspended in N,N-dimethylacetamide (10 mL) and 1,2-dibromoethane (1.08 mL, 12.4 mmol) was added, followed by careful addition of trimethylsilylchloride (1.61 mL, 12.4 mmol) and was added cautiously over 5 min while the flask sat on a bed of ice. The bath was removed, and after stirring for a further 15 min, a solution of N-(tert-butoxycarbonyl)-3-iodoazetidine (25.1 g, 86.9 mmol) in N,N-dimethylacetamide (30 mL) was added over 30 min and stirring was continued for an additional 30 min. In the open atmosphere, this mixture was filtered through Celite as quickly as possible, rinsing with N,N-dimethylacetamide (100 mL). The resulting yellow solution was injected into a separately prepared, nitrogen flushed vessel containing [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.56 g, 3.10 mmol), copper(I) iodide (1.18 g, 6.21 mmol) and 2,6-dichloro-4-iodopyridine (17.0 g, 62.1 mmol) and this mixture was stirred at 80° C. for 19.5 h. After cooling to rt, the mixture was diluted with EtOAc and washed with water (3×). On the third time, filtration through Celite was necessary to break the emulsion, following which, the organics were washed with brine and then dried over MgSO4. After being freed of volatiles, the resultant residue was purified by flash column chromatography (100:0-70:30 heptanes/EtOAc) to afford tert-butyl 3-(2,6-dichloropyridin-4-yl)azetidine-1-carboxylate as a white solid (10.98 g, 58%); 1H NMR (400 MHz, CDCl3) δ 7.22 (s, 2H), 4.35 (dd, J=8.7, 5.6 Hz, 2H), 3.92 (dd, J=8.7, 5.6 Hz, 2H), 3.73-3.61 (m, 1H), 1.47 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[C:4]([CH:10]=[C:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[C:12]=1[C:13]([F:16])([F:15])[F:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].O.[CH:38]([B-](F)(F)F)=[CH2:39].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.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>[Cl:1][C:2]1[C:3]([CH:38]=[CH2:39])=[C:4]([CH:10]=[C:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[C:12]=1[C:13]([F:15])([F:14])[F:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c(Cl)c1OS(=O)(=O)C(F)(F)F
Reactant: C=C[B-](F)(F)F
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: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1c(C(=O)OCC)cc(Cc2ccc(-n3cccn3)cc2)c(C(F)(F)F)c1Cl
Temperature: 80 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
To a solution of ethyl 3-chloro-5-[4-(1H-pyrazol-1-yl)benzyl]-4-(trifluoromethyl)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (0.25 g) in THF (8.00 mL)-water (5.00 mL) were added potassium vinyltrifluoroborate (0.13 g), cesium carbonate (0.46 g) and tetrakis(triphenylphosphine)palladium(0) (0.03 g), and the mixture was stirred at 80° C. for 16 hr under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate/petroleum ether) to give the title compound (0.08 g).
Reaction SMILES: [CH3:1][C:2]1[C:3](O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:13]1([C:16]2[O:20][N:19]=[C:18]([CH2:21][N+:22]#[C-:23])[N:17]=2)[CH2:15][CH2:14]1>>[CH:13]1([C:16]2[O:20][N:19]=[C:18]([C:21]3[N:22]=[CH:23][N:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[N:11]=[C:2]([CH3:1])[C:3]=34)[N:17]=2)[CH2:15][CH2:14]1
Reactant: [C-]#[N+]Cc1noc(C2CC2)n1
Reactant: Cc1nc2ccccc2nc1O
Product: Cc1nc2ccccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
M.p. 165°-167° C., from 3-methyl-2-quinoxalinol and 5-cyclopropyl-3-isocyanomethyl-1,2,4-oxadiazole. (Compound 7)
Reaction SMILES: Cl.[F:2][C:3]([F:19])([F:18])[C:4]1[CH:5]=[C:6]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:7]=[CH:8][CH:9]=1.[Cl:20]C1C=C(C=CC=1)C(OO)=[O:25]>C(Cl)Cl>[F:19][C:3]([F:2])([F:18])[C:4]1[CH:5]=[C:6]([S:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:25])[CH:7]=[CH:8][CH:9]=1.[ClH:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1cccc(SCc2ccccn2)c1
Agent: Cl
Solvent: ClCCl
Product: O=S(Cc1ccccn1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred suspension of 2-(((3-trifluoromethylphenyl)thio)methylpyridine, hydrochloride (2.0 g) in methylene chloride (50 ml) at 0° C. was treated portionwise with m-chloroperoxybenzoic acid (1.5 g) over 1/2 hour. The mixture was allowed to warm to ambient temperature and the mixture was stirred a further 1/2 hour. The solution was washed with saturated Na2CO3 solution and water, dried (MgSO4) and evaporated. The residue was converted into the hydrochloride, in acetone with ethereal HCl solution, which was recrystallised from acetone-ether to give the title compound, hydrochloride (1.0 g) mp 135°-6° C. (Found: C,48.3; H,3.7; N,4.0 C13H10F3NOS.HCl requires C,48.4; H,3.45; N,4.35%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:11][CH2:10][CH:9]([NH:12][C:13](=O)[CH2:14][CH3:15])[CH2:8]1.O.[OH-].[Na+]>C1COCC1>[CH2:13]([NH:12][CH:9]1[CH2:10][CH2:11][O:7][CH2:8]1)[CH2:14][CH3:15]
Reactant: CCC(=O)NC1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCNC1CCOC1

Procedure:
A suspension of 21.7 g (0.57 mol) of lithium aluminum hydride in 500 ml of THF was admixed dropwise with a solution of 81 g (0.57 mol) of N-(tetrahydrofuran-3-yl)propionamide, and the solution was heated at reflux for 2 h. Excess lithium aluminum hydride was hydrolyzed by dropwise addition of 16 ml of water, 50 ml of 10% strength aqueous sodium hydroxide solution and another 45 ml of water. The white suspension was heated at reflux for one hour, causing the insoluble components to aggregate to a coarse white precipitate. The mixture was filtered off from the precipitate, the precipitate was thoroughly rinsed with ether and the combined filtrates were distilled. B.p. 64° C. (12 mm), yield 41 g. 1H NMR (270 MHz, in CDCl3): δ=0.92 (t, 3H), 1.15 (s, 1H), 1.50 (sext., 2H), 1.70 (m, 1H), 2.10 (m, 1H), 2.55 (m, 2H), 3.38 (m, 1H), 3.56 (dd, 1H), 3.70-3.96 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:25][O:26][CH2:27]Cl>>[CH3:25][O:26][CH2:27][O:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1cc2c(cc1-c1ccc(O)c(C=O)c1)C(C)(C)CCC2(C)C
Reactant: COCCl
Product: COCOc1ccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)cc1C=O
Yield: 102.7 %

Procedure:
In a similar manner to Example 10(b), by reaction of 3 g (9.3 mmol) of 2-hydroxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl) benzaldehyde [prepared in Example 16(a)] with 777 μl (10.2 mmol) of methoxymethyl chloride, 3.5 g (100%) of the expected product are obtained in the form of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:18](=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:18])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C([O-])O
Reactant: O=C(O)C=Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C=Cc1ccc(Cl)cc1

Procedure:
25.9 g of p-chlorocinnamic acid was dissolved in 250 ml of methanol, to the solution was added 1.5 ml of concentrated sulfuric acid, and the mixture was refluxed for 2 hours. The reaction mixture was poured on ice, and the mixture was alkalized with sodium bicarbonate and extracted twice with 1000 ml of chloroform. The extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate and evaporated to remove the solvent under a reduced pressure, and resulting residue was applied to a silica gel column and eluted with hexane/ethyl acetate (10:1), to obtain 26.5 g of the methyl p-chlorocinnamate.
Reaction SMILES: [N:1](OC)=[O:2].[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[S:13][C:14]1[CH:24]=[C:23]([C:25](=[O:28])[CH2:26][CH3:27])[CH:22]=[CH:21][C:15]=1[NH:16][S:17]([CH3:20])(=[O:19])=[O:18]>O1CCCC1.Cl.CCOCC>[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[S:13][C:14]1[CH:24]=[C:23]([C:25](=[O:28])[C:26](=[N:1][OH:2])[CH3:27])[CH:22]=[CH:21][C:15]=1[NH:16][S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CON=O
Reactant: CCC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=NO)C(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Temperature: 3 °C
Reaction time: 5 h
Yield: 91.3 %

Procedure:
Methyl nitrite [prepared from sodium nitrite (1.4 g), methanol (0.9 ml) and sulfuric acid (0.7 ml) in water (2.3 ml)] was introduced into an ice-cooled mixture of 2'-(2,4-difluorophenylthio)-4'-propionylmethanesulfonanilide (2.54 g) in tetrahydrofuran (10 ml) and 12% hydrogen chloride in ether (10 ml). The mixture was stirred for 5 hours at 3° C. and evaporated. The residual solid was recrystallized from ethanol to give colorless crystals of 2'-(2,4-difluorophenylthio)-4'[2-(hydroxyimino)-1-oxopropyl]methanesulfonanilide (2.5 g).
Reaction SMILES: ClS(O)(=O)=O.[F:6][C:7]1[CH:8]=[C:9]([CH2:17][CH2:18][C:19]([OH:21])=O)[CH:10]=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14].C(OCC)(=O)C>CCCCCC>[F:6][C:7]1[C:12]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:10]=[C:9]2[C:8]=1[C:19](=[O:21])[CH2:18][CH2:17]2
Reactant: O=C(O)CCc1ccc(C(F)(F)F)c(F)c1
Agent: O=S(=O)(O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C1CCc2ccc(C(F)(F)F)c(F)c21
Temperature: 0 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
Chlorosulfonic acid (12.6 mL) was added to a stirred solution of 3-(3-fluoro-4-(trifluoromethyl)phenyl)propanoic acid (I-77b: 1.0 g, 4.2707 mmol). The resulting mixture was stirred for 5 hours at 0° C. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was quenched with ice water and extracted with chloroform (2×150 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (5% ethyl acetate in hexane), afforded 550 mg of the product (58.9% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]([CH3:30])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:1]([O:5][C:6](=[O:26])[N:7]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:28]([CH3:30])[CH3:27])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:23]([O-:25])=[O:24])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)Nc1cccc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 14.4 g of N-(5-(3-aminophenoxy)-2-nitrophenyl)-N-methylcarbamic acid t-butyl ester, 2.90 g of acetone, 3.00 g of acetic acid, 10.6 g of sodium triacetoxyborohydride and 200 ml of anhydrous tetrahydrofuran was stirred at room temperature for 4 days. The reaction mixture was concentrated, followed by addition of water and extraction with ethyl acetate. After the extraction solution was dried over anhydrous sodium sulfate, the solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate/n-hexane=2/3) to give N-(5-(3-isopropylamino-phenoxy)-2-nitrophenyl)-N-methylcarbamic acid t-butyl ester, as an intermediate. This intermediate was dissolved in 200 ml of methanol, followed by addition of 2.02 g of 10% palladium-carbon, and the mixture was vigorously stirred under a hydrogen atmosphere at room temperature for 2.5 hours. After completion of the reaction, the catalyst was filtered, and the solvent was distilled off to give the title compound (12.0 g, 81% yield).
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])=[CH:14][CH:15]=2)[C:10]([CH2:35][CH3:36])=[CH:9]1)C.C(OCC)C>C1COCC1>[CH2:35]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])[CH:12]=2)[N:8]([CH2:7][C:6]([OH:37])=[O:5])[CH:9]=1)[CH3:36]
Reactant: CCOC(=O)Cn1cc(CC)c2cc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCc1cn(CC(=O)O)c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A 1 M aqueous solution of LiOH (2.3 ml, 2.3 mmol) was added to a solution of {3-ethyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester (577 mg, 1.15 mmol) in THF (6 ml). After stirring for 1 h at ambient temperature, additional 0.58 ml of the 1N LiOH solution were added and the reaction mixture was stirred for further 2.5 h. Diethyl ether (10 ml) was added, the resulting precipitate was filtered off and redissolved in ethyl acetate and 25% aqueous HCl solution (2 ml). The organic layer was washed with water and dried over sodium sulfate. Removal of the solvent under reduced pressure gave 365 mg (0.77 mmol, 67%) {3-ethyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:9]1.[SH:31][CH2:32][C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CCCCCC.C(OCC)(=O)C.C(#N)C>[C:25]1([C:10]2[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:31][CH2:32][C:33]([O:35][CH3:36])=[O:34])[N:9]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)CS
Reactant: BrCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CSCCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Yield: 95.4 %

Procedure:
A mixture of 1-(6-bromohexyl)-3,4,5-triphenyl-lH-pyrazole (6.53 g, 14 mmol), methyl mercaptoacetate (1.66 g, 15 mmol), potassium carbonate (2.26 g, 16.5 mmol), potassium iodide (catalytic amount) and acetonitrile (150 mL) was heated at reflux for 4 hours. The mixture was cooled, filtered and concentrated in vacuo to give an oil. Chromatography on a column of silica gel using a mixture of hexane and ethyl acetate (4:1) as eluent furnished methyl [[6-(3,4,5-triphenyl-lH-pyrazol-1-yl)hexyl]thio]acetate (6.47 g, 91%) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].CS[C:17](SC)=[CH:18][N+:19]([O-:21])=[O:20].C(N(CC)CC)C>C(#N)C>[C:11]([O:10][C:8]([NH:7][CH2:6][CH2:5][N:4]1[CH2:3][CH2:2][NH:1][C:17]1=[CH:18][N+:19]([O-:21])=[O:20])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: CC(C)(C)OC(=O)NCCNCCN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCN1CCNC1=C[N+](=O)[O-]
Yield: 64.6 %

Procedure:
A stirred mixture of 2.03 gram (0.010 mole) of N-{2-[(2-aminoethyl)amino]ethyl}(tert-butoxy)carboxamide (commercially available), 1.18 gram (0.010 mole) of 1,1-di(methylthio)-2-nitroethene and 2 mL (excess) of triethylamine in 40 mL of acetonitrile was warmed to reflux where it was maintained for four hours. After this time the reaction mixture was concentrated under reduced pressure to a solid residue. The residue was washed with diethyl ether and dried, yielding 1.76 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH:13]=[CH2:14])[CH2:3]1.[O:26]1[CH2:31][CH2:30][N:29]([CH2:32][C:33]([OH:35])=[S:34])[CH2:28][CH2:27]1.O>CC(C)=O>[OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[C:18](=[O:24])[CH2:17][C@@:16]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13][CH2:14][S:34][C:33](=[O:35])[CH2:32][N:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)[CH2:3]1
Reactant: C=CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: OC(=S)CN1CCOCC1
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CCSC(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Yield: 66.8 %

Procedure:
3α-Hydroxy-21-methylene-5α-pregnane-11,20-dione (500 mg) was dissolved in acetone (20 ml) and the solution treated with morpholinothioacetic acid (300mg), at reflux for 3 hours. The mixture was poured into water and the emulsion extracted with either. The extracts were washed with water, dried over anhydrous sodium sulphate and evaporated to a foam (540 mg) which was purified by preparative t.l.c. in ethyl acetate/petrol (1:1). The main band gave title compound (490mg.) as a white foam. [α]D + 48° (c = 1.03).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:33]=[C:32]5[C:28]([C:29]([F:34])=[N:30][NH:31]5)=[CH:27][CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:45](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[CH:33]=[C:32]5[C:28]([C:29]([F:34])=[N:30][N:31]5[CH3:45])=[CH:27][CH:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(F)n[nH]c5c4)c3)sc2c1-c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(F)nn(C)c5c4)c3)sc2c1-c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a mixture of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-(3-fluoro-1H-indazol-6-yl)pyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (39.7 mg, 0.0631 mmol) and cesium carbonate (62 mg, 0.189 mmol) in anhydrous DMF (1.0 mL) at 0° C. was added iodomethane (5.9 μL, 0.0947 mmol) and reaction stirred for 1 h. More iodomethane (3.0 μL) was added and reaction was stirred for 30 minutes, and stored in freezer overnight. Reaction mixture was diluted with ethyl acetate, washed with 5% lithium chloride solution (3×), brine, dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 40% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C35H33ClFN4O3S: 643.2 (M+H+); Found: 643.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19]CC)=O.[Cl:22]N1C(=O)CCC1=O>O1CCOCC1>[O:19]=[C:17]1[CH2:16][C:3]2[C:2](=[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[CH:6]=[C:5]([Cl:22])[CH:4]=2)[NH:1]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2Cl)c1N
Solvent: C1COCCO1
Product: O=C1Cc2cc(Cl)cc(Oc3ccccc3Cl)c2N1

Procedure:
Ethyl 2-[2-amino-3-(2-chlorophenoxy)phenyl]acetate (1.50 g.), N-chlorosuccinimide (700 mg.) and dioxane (30 ml.) were treated in a similar manner to that of the Preparation 31 to give crystals of the captioned compound (0.50 g.), mp 196° to 198° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrCCCC1C=CC=CC=1.[Mg].II.[O:25]1[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[CH:26]1.S(=O)(=O)(O)O>C(OCC)C>[OH:31][CH:30]([C:27]1[CH:28]=[CH:29][O:25][CH:26]=1)[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]CCCc1ccccc1
Reactant: O=Cc1ccoc1
Agent: BrCCCc1ccccc1
Agent: II
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: OC(CCCc1ccccc1)c1ccoc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 3-phenylpropyl magnesium bromide (4.5 ml of a 2.73M solution in ethyl ether, 12.3 mmol, generated from 1-bromo-3-phenylpropane and magnesium and initiated with iodine) at 0° under argon, was added dropwise 3-furaldehyde (1.08 g., 11.2 mmol) in 5 ml ethyl ether. This solution was allowed to warm to room temperature, stirred for 20 minutes, and then poured over crushed ice containing several drops of concentrated sulfuric acid. The resulting mixture was partitioned between ethyl ether and 5% sodium bisulfite. The organic portion was washed with 5% sodium bicarbonate solution, water, saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give an oil. This material was further purified by flash chromatography (silica, 20% ethyl acetate/hexane) to give the desired alcohol.
Reaction SMILES: COC[N:4]1[C:8]2=[N:9][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:11][CH:12]=[C:7]2[N:6]=[C:5]1[C:19]1[S:20][C:21]2[C:27]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:26][CH:25]=[C:24]([O:34][CH3:35])[C:22]=2[N:23]=1.Cl>>[CH3:35][O:34][C:24]1[C:22]2[N:23]=[C:19]([C:5]3[NH:4][C:8]4=[N:9][C:10]([N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)=[CH:11][CH:12]=[C:7]4[N:6]=3)[S:20][C:21]=2[C:27]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:26][CH:25]=1
Reactant: COCn1c(-c2nc3c(OC)ccc(N4CCOCC4)c3s2)nc2ccc(N3CCOCC3)nc21
Agent: Cl
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccc(N5CCOCC5)nc4[nH]3)nc12

Procedure:
0.065 g 3-Methoxymethyl-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-5-morpholin-4-yl-3H-imidazo[4,5-b]pyridine (0.13 mmol) was treated with 5N HCl (2 ml) at 90° C. for 1.5 h. The reaction mixture was concentrated, taken up in water (3 ml) and adjusted to pH 10 with ammonium hydroxide (25%), whereupon a precipitation formed. The precipitation was filtered and the crystals were triturated in hot ethanol. After drying in vacuo 0.036 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-5-morpholin-4-yl-3H-imidazo[4,5-b]pyridine (61%) was obtained as a yellow solid; M.p.: 260–262° C.