Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][C:10]1[C:14](B2OC(C)(C)C(C)(C)O2)=[C:13]([CH3:24])[O:12][N:11]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[Br:8][C:6]1[CH:7]=[C:2]([C:14]2[C:10]([CH3:9])=[N:11][O:12][C:13]=2[CH3:24])[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: Cc1noc(C)c1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1noc(C)c1-c1cncc(Br)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of 3,5-dibromopyridine (0.20 g, 0.85 mmol) in 1,4-dioxane (8 mL) and H2O (0.55 mL) under nitrogen was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.13 g, 0.93 mmol), and potassium carbonate (0.35 g, 2.5 mmol). The reaction mixture was degassed with nitrogen for 15 min. (1,1′-Bis(diphenylphosphino)ferrocene)palladium (II) chloride dichloromethane complex (62 mg, 0.08 mmol) was added and the reaction mixture was again degassed for 10 min with nitrogen. The reaction mixture was stirred at 95° C. for 16 h, then allowed to cool to room temperature and quenched by the addition of water. The reaction mixture was transferred to a separation funnel and the aqueous layer extracted with ethyl acetate. The combined organic portions were washed with water and saturated NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide 4-(5-bromopyridin-3-yl)-3,5-dimethylisoxazole (0.15 g, 71%) as a white solid. LCMS Method T: retention time 1.52 min, [M+1]=253.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:38])[CH:7]([NH:22][CH:23]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:20])[CH:16]=2)[C:11]1=[O:21])([CH3:4])[CH3:3].ClCCl.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>N1C=CC=CC=1>[CH3:1][C:2]([O:5][C:6](=[O:38])[C@H:7]([NH:22][C@H:23]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:8][CH2:9][N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:20][S:43]([CH3:42])(=[O:45])=[O:44])[CH:16]=2)[C:11]1=[O:21])([CH3:4])[CH3:3]
Reactant: CC(C)CC(NC(CCN1C(=O)c2ccc(N)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
100 mg of 2-[1-(benzylamino)carbonyl-3-methyl-butylamino]-4-(5-amino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butanoic acid-1,1-dimethylethyl ester, prepared as in Example 73 where the protecting group Rp, 1,1-dimethylethyl, was not removed following the condensation reaction seen in Scheme 2, was added to 5 mL dichloromethane under nitrogen. The mixture was cooled to 0° C. and 0.1 mL of pyridine was added, followed by 0.014 mL methanesulfonyl chloride. The mixture was allowed to warm to room temperature and was stirred overnight. The solvent was removed by Evaporation and the residue was purified by reverse phase H.P.L.C. The solvent was removed by evaporation to give the title compound; 45 mg
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:19]([OH:21])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18].C([Sn](CCCC)(CCCC)[C:27]([O:29]CC)=[CH2:28])CCC>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:27]([C:2]1[CH:3]=[C:4]([C:19]([OH:21])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18])(=[O:29])[CH3:28]
Reactant: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
Bis(triphenylphosphine) palladium (II) chloride (12.78 mg, 0.02 mmol) was added to a stirred mixture of 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (215 mg, 0.61 mmol) and tributyl(1-ethoxyvinyl)stannane (0.226 mL, 0.67 mmol) in 1,4-dioxane (5 mL) and the mixture was purged with nitrogen. The resulting mixture was stirred at 100° C. for 3 hrs. HCl2N (0.5 mL) was added and the reaction mixture was stirred at 50° C. for 25 minutes then allowed to cool to room temperature and concentrated under vacuum. The product was diluted with diethyl ether and pentane to afford a solid, which was collected by filtration and washed with ether/pentane to give 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (200 mg, 104%) as a beige solid. Mass Spectrum: M+H+ 318.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:11]=O)[C:5]([CH:9]=O)=[CH:6][C:7]=1[Cl:8].[C:13]1(=[O:20])[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[C:4](=[CH:11][C:18]3[C:13](=[O:20])[C:14]4[C:15]([C:16](=[O:19])[C:17]=3[CH:9]=2)=[CH:11][C:4]2[C:5](=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:9]=4)[CH:3]=1
Reactant: O=Cc1cc(Cl)c(Cl)cc1C=O
Reactant: O=C1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1c2cc3cc(Cl)c(Cl)cc3cc2C(=O)c2cc3cc(Cl)c(Cl)cc3cc21
Temperature: 25 °C

Procedure:
4,5-Dichlorobenzene-1,2-dicarbaldehyde (2.0 g, 9.90 mmol) and 1,4-cyclohexanedione (0.62 g, 5.53 mmol) were stirred in 60 mL ethanol. To this was added dropwise with stirring, 10 mL of 5% aq potassium hydroxide. Upon addition of first drop, solution became black, brown, and then solids precipitate. Reaction mixture was stirred at RT for 1 h and refluxed for 2 h. Reaction mixture was cooled to RT, solids filtered, washed with water, dried to give 2,3,9,10-tetrachloro-6,13-pentacenequinone as brown solids in good yields (1.73 g, 70%). LDI-MS m/z: 446 [M+].
Reaction SMILES: [CH2:1]([S:3]([N:6]([CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[O:18][C:17]([CH3:27])([CH3:26])[CH2:16]1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11](OC)=[O:12])(=[O:5])=[O:4])[CH3:2].[NH3:28]>CO>[CH2:1]([S:3]([N:6]([CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=2)[O:18][C:17]([CH3:27])([CH3:26])[CH2:16]1)[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH2:28])=[O:12])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N(CCCCC(=O)OC)C1CC(C)(C)Oc2ccc(C)cc21
Reactant: N
Solvent: CO
Product: CCS(=O)(=O)N(CCCCC(N)=O)C1CC(C)(C)Oc2ccc(C)cc21
Reaction time: 216 h

Procedure:
A solution of 0.4 g (1 mmol) of methyl 5-[ethylsulfonyl-(2,2,6-trimethyl-chroman-4-yl)amino]pentanoate and 1.5 ml of liquid ammonia in 10 ml of methanol is allowed to stand at RT for 9 days. After concentrating in vacuo, the residue is treated with water and extracted with EA. 0.37 g of 5-[ethylsulfonyl-(2,2,6-trimethylchroman-4-yl)amino]pentanamide is obtained; m.p. 127-129° C.
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:32]CS(C)(=O)=O)C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=[C:4]([O:38][CH3:39])[CH:3]=1.[CH3:40][O:41]C1C(OC)=CC=CC=1B(O)O>CCCCCCC.CCOC(C)=O>[CH3:39][O:38][C:4]1[C:3]([O:41][CH3:40])=[CH:2][CH:7]=[CH:6][C:5]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH3:32]
Reactant: COc1cccc(B(O)O)c1OC
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CNc1cnccc1-c1cccc(OC)c1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate b) and 2,3-dimethoxyphenylboronic acid (CAS RN 28611-39-4) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow solid (79%). MS (ESI): m/z=245.128 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[BH4-].[Na+].Cl>C(O)C.O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[OH:11]
Reactant: O=C1CCc2c(Br)cccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OC1CCc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 4-bromo-1-indanone (1.0 g) in a mixture of ethanol (6 ml) and tetrahydrofuran (3 ml) was added sodium borohydride (0.09 g) at an ice temperature. The reaction mixture was stirred at the same temperature overnight and poured into dilute hydrochloric acid, and the aqueous layer was saturated with saline and extracted with ether. The organic layer was washed with a saturated aqueous saline, dried over sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residual concentrate (1.02 g) thus obtained was used for the next reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][S:14][CH:15]=[C:11]2[N:10]=[C:9]1[S:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O:26]C1C=CC(COC(N2C3=CSC=C3N=C2S(CC2C=CC(C)=CN=2)=O)=O)=CC=1.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2=[CH:13][S:14][CH:15]=[C:11]2[N:10]=[C:9]1[S:16]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=1)=[O:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(CSc2nc3cscc3n2C(=O)OC(C)(C)C)nc1
Reactant: COc1ccc(COC(=O)n2c(S(=O)Cc3ccc(C)cn3)nc3cscc32)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(CS(=O)c2nc3cscc3n2C(=O)OC(C)(C)C)nc1

Procedure:
1.1 g (3 mmol) of the title compound from Example 23 were dissolved in 50 ml of CH2Cl2, and 50 ml of the KH2PO4 /Na2HPO4 buffer solution from Example 22 were added. At 10° C. a total of 900 mg (4.5 mmol) of m-chloroperbenzoic acid in CH2Cl2 was added dropwise in portions until the precursor has been completely used up.
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)[CH2:7][CH2:6][CH2:5]1.Cl>C1COCC1.O>[CH:4]1([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)[CH2:5][CH2:6][CH2:7]1
Reactant: CCOC(=O)c1csc(C2CCC2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1csc(C2CCC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (0.38 g) was added to a solution of ethyl 2-cyclobutylthiazole-4-carboxylate (example 58, step b) (0.48 g) in a mixture of THF (8 mL) and water (2 mL). The resulting suspension was stirred overnight at RT. The reaction was acidified with aqueous HCl solution (2M, 5 mL) and evaporated to dryness. The residue was partitioned between brine (5 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2×20 mL). The combined organic solutions were dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a white solid. Yield 0.38 g.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[S:2]1.[S:14]([NH2:18])([NH2:17])(=[O:16])=[O:15].[H-].[Na+]>C1(C)C=CC=CC=1.CN(C)C=O>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:17][S:14]([NH2:18])(=[O:16])=[O:15])=[O:13])[S:2]1
Reactant: NS(N)(=O)=O
Reactant: O=C(O)CCCCCC1CCSS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: NS(=O)(=O)NC(=O)CCCCCC1CCSS1
Yield: 19.3 %

Procedure:
The reaction was carried out as described in Example 107, but using 5 ml of a solution of 1.6 mmol of 6(1,2-dithiolan-3-yl)hexanoic acid (prepared as described in Example 104) in toluene, 7 ml of anhydrous dimethylformamide, 308 mg of N,N'-carbonyldiimidazole, 365 mg of sulfamide and 83 mg of sodium hydride (as a 55% w/w dispersion in mineral oil). The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 3:2 and 2:1 by volume mixtures of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was recrystallized from a 1:2 by volume mixture of ethyl acetate and hexane, to obtain 92 mg of the title compound as pale yellow crystals, melting at 130 to 132° C.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.Cl[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1>CN(C=O)C>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1
Reactant: Clc1ncccn1
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ncccn2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 86.1 %

Procedure:
Sodium hydride (60% in oil, 1.44 g, 36.00 mmol) was added to a 0° C. solution of 4-hydroxybenzaldehyde (4.40 g, 36.03 mmol) in DMF (16 mL). After stirring for 20 min at 0° C., the mixture was allowed to warm to RT and a solution of 2-chloropyrimidine (4.12 g, 35.97 mmol) in DMF (8 mL) was added. The resulting mixture was heated to 100° C. for 18 h. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water and brine, dried (MgSO4), and concentrated to provide 6.20 g (86%) of the title compound. MS 201 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-y)-4-benzylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17][NH:18][CH:19]1[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH2:22][CH2:21][CH2:20]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Br[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[C:52]#[N:53])=[CH:42][CH:41]=1>CC#N>[NH2:53][CH2:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:18]([CH2:17][C:9]2[NH:8][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH:19]2[C:28]3[N:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:22][CH2:21][CH2:20]2)=[CH:41][CH:42]=1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: NCc1ccccc1-c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 32.7 %

Procedure:
Using the general alkylation procedure: To a solution of (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.194 g, 0.51 mmol) in CH3CN (5 mL) was added N,N-diisopropylethylamine (0.30 mL, 1.72 mmol) followed by 4′-bromomethyl-2-cyanobiphenyl (0.303 g, 1.11 mmol) and the resultant mixture heated to 60° C. for 25 h. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2—CH3OH—NH4OH) followed by radial chromatography on silica gel (2 mm plate, 100:1:1 CH2Cl2—CH3OH—NH4OH) provided a tan foam (79 mg).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@@H:19]6[CH2:25][C:23](=[O:24])[CH2:22][CH2:21][C@:20]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:4][CH2:3]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.O>[CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@@H:19]6[CH2:25][C@@H:23]([OH:24])[CH2:22][CH2:21][C@:20]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:4][CH2:3]1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5CC(=O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Smilagenone (657 g) was dissolved in tetrahydrofuran (4000 ml) and the solution purged with nitrogen and cooled to provide an internal temperature of ca. −10° C. L-Selectride® (2400 ml 1M in THF) was added over ca. 50 minutes and stirred for 90 minutes. A solution of citric acid (600 g) in water (2000 ml) was added slowly, maintaining the temperature below 0° C. The mixture was allowed to warm to ambient temperature and stirred for 30 minutes. The aqueous layer was separated and extracted with dichloromethane (2000 ml) and the layers separated. The aqueous layer was extracted with dichloromethane (1500 ml). The combined organic extracts were washed with water (4000 ml) and dried over MgSO4. The organic extracts were evaporated to dryness to yield smilagenin.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[S:26]1[CH2:30][C:29](=[O:31])[NH:28][C:27]1=[O:32].C([O-])(=O)C.[Na+]>O.CC(C)=O>[F:24][C:2]([F:1])([F:25])[S:3]([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]=[C:30]3[S:26][C:27](=[O:32])[NH:28][C:29]3=[O:31])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: O=Cc1ccc(OCCc2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccc(OCCc3ccc(OS(=O)(=O)C(F)(F)F)cc3)cc2)S1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 23.6 %

Procedure:
7 g (18.7 mmole) of 4-[2-(4-formylphenoxy)ethyl]phenyl trifluoromethanesulfonate, 2.74 g (23.4 mmole) 2,4-thiazolidinedione and 3.8 g (46.8 mmole) sodium acetate were mixed and heated under vacuum to 140° C. when it melted. It was kept at 140° C. for 20 minutes and thereafter taken off the heat, water:acetone (2:1) was added, the formed crystals were filtered off and recrystallization in dichloromethane gave 2.09 g (yield 24%) 5-(4-[2-(4-trifluoromethanesulfonyloxyphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=O)[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl.[NH2:33][OH:34].C([O-])(=O)C.[NH4+].C(O)C.O>O>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[N:33][OH:34])[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(C(C)=NO)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidinyl]propoxy]-3-methoxyphenyl]ethanone (4.3 g, 10 mmol), prepared as in Example 3 above, hydroxylamine hydrochloride (1.3 g, 18 mmol), ammonium acetate (1.7 g, 22 mmol) and ethanol-H2O was stirred and refluxed for 16 hours. The reaction was poured into water, and the mixture was cooled in an ice bath for 2 hours. The resultant, white solid was collected washed with water, and dried to yield 4,6 g or hydrochloride salt of the oxime, m.p.=216°-218° C. The compound was dispersed in water, and ammonium hydroxide was added until the suspension was decidedly basic. The basic suspension was then extracted with dichloromethane, and after washing with water, drying (MgSO4) and concentrating the extract, 3.0 g of white solid melting at 168°-170° C. were harvested. The compound, was recrystallized from dimethylformamide to yield 2.3 g (52%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxime as a white solid, m.p.=168°-170° C. ANALYSIS: Calculated for C24H28FN3O4: 65.29%C 6.39%H 9.52%N Found: 65.27%C 6.44%H 9.46%N
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[OH:18].C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>[Cu]=O.C1(C)C=CC=C(C)C=1>[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[O:18][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1
Reactant: Cc1cccc(C)c1O
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1cccc(C)c1
Solvent: c1ccncc1
Product: Cc1cccc(C)c1Oc1cccc(C=O)c1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A mixture of 3-bromobenzaldehyde (6.1 g, 32.7 mmol), 2,6-dimethylphenol (4.0 g, 32.7 mmol), copper oxide (II) (4.4 g, 55.6 mmol), potassium carbonate (9.0 g, 65.4 mmol), pyridine (40 mL) and m-xylene (20 mL) was stirred under a nitrogen atmosphere at 140° C. for 16 hrs. The reaction mixture was cooled, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure to give crude 3-(2,6-dimethylphenoxy)benzaldehyde (including side product).
Reaction SMILES: CC(CCCC(C)CCCC(C)CCCC(C)C)=CCC1C(C)=C([N:16]=[N:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)C2C(=CC=CC=2)C=1O.C1(C)C=CC=CC=1.CO>[N+](C1C=CC=CC=1CCCCCCCCOCCCCCCCCC1C=CC=CC=1[N+]([O-])=O)([O-])=O>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][NH2:16])=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: CC(=CCc1c(C)c(N=Nc2ccc([N+](=O)[O-])cc2)c2ccccc2c1O)CCCC(C)CCCC(C)CCCC(C)C
Agent: O=[N+]([O-])c1ccccc1CCCCCCCCOCCCCCCCCc1ccccc1[N+](=O)[O-]
Solvent: CO
Solvent: Cc1ccccc1
Product: NNc1ccc([N+](=O)[O-])cc1

Procedure:
2-(3,7,11,15-tetramethyl-2-hexadecenyl)-3-methyl-4-[(4-nitrophenyl)azo]-1-naphthol, TLC, silica gel 60 (Merck), mobile solvent: toluol/methanol=50:1; Rf =0.22, from 4-nitrophenylhydrazine, Transmission spectra at an acid or alkaline pH in o-nitrophenyloctyl ether yield λmax values of 455 or 637 nm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[O:18]([C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.N1C=CC=CC=1.C(OCCO)C>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:28][C:27]1[CH:29]=[CH:30][CH:31]=[C:25]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:26]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3cccc(Oc4ccccc4)c3)c2cc1OC
Temperature: 139 °C
Yield: 77.8 %

Procedure:
A mixture of 0.248 g (1 mmol)of 4-chloro-6,7-dimethoxy-quinoline-3-carbonitrile, 0.204 g (1.1 mmol) of 3-phenoxyaniline, 0.116 g (1 mmol) pyridine hydrochloride and 12 ml of 2-ethoxyethanol was heated in a 138-140° C. oil bath for 3 hours; progress of the reaction was monitored by TLC. When TLC indicated the disappearance of starting material, the reaction was cooled and concentrated in vacuo to a thick oil. To this oil was added 50 ml of water followed by 5 ml of 1M NaHCO3, approximately pH 8. The resulting precipitate was collected, washed with water and diethyl ether, and dried in vacuo at 65° C. to give 0.309 g (78%) of the desired product as cream crystals. MP 253-254° C.; : mass spectrum (electrospray, m/e,): 397.0(M+H)+.