Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18](C2CCCCO2)[N:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[NH:18][N:17]=[CH:16][CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CO[C@H]2CCC[C@@H]2c2ccnn2C2CCCCO2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CO[C@H]2CCC[C@@H]2c2ccn[nH]2)cc1
Reaction time: 12 h
Yield: 98.5 %

Procedure:
To a solution of the 5-[(1R*,2S*)-2-(benzyloxy)cyclopentyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (1.15 g, 3.52 mmol) prepared in Example 148a in dichloromethane (10 mL), trifluoroacetic acid (5.0 mL) was added at room temperature, and the reaction solution was stirred for 12 hours. The reaction solution was concentrated, and a saturated aqueous solution of sodium hydrogencarbonate (50 mL) was added to the residue, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was washed with saturated saline (50 mL) and dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=1:1) to yield the title compound (840 mg, 98%) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[C:23]1[C:32]2[N:31]=[CH:30][CH:29]=[N:28][C:27]=2[C:26]([C:33](O)=[O:34])=[CH:25][CH:24]=1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:33]([C:26]3[C:27]4[N:28]=[CH:29][CH:30]=[N:31][C:32]=4[C:23]([C:17]4[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:16]=4[CH3:15])=[CH:24][CH:25]=3)=[O:34])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc(N)cn2)CC1
Reactant: Cc1cccc(C)c1-c1ccc(C(=O)O)c2nccnc12
Product: Cc1cccc(C)c1-c1ccc(C(=O)Nc2ccc(N3CCN(C)CC3)nc2)c2nccnc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but stirring the reaction mixture for 20 h at rt, using 6-(4-methylpiperazin-1-yl)-pyridin-3-ylamine (prepared as described in Example 33 but using N-methyl-piperazine in Step 33.2) and 8-(2,6-dimethyl-phenyl)-quinoxaline-5-carboxylic acid (Example 71). Title compound: ESI-MS: 453.1 [M+H]+; tR=3.55 min (System 1).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:11][N:10]=2)[N:6]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[O:22])[CH2:5]1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]1[CH2:8][C@@H:7]([C:9]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:16][CH2:17][N:18]([C:42](=[O:44])[CH3:43])[CH2:19][CH2:20]3)[O:11][N:10]=2)[N:6]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)=[O:22])[CH2:5]1
Reactant: CC(=O)Cl
Reactant: CON=C1C[C@@H](c2noc(CN3CCNCC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON=C1C[C@@H](c2noc(CN3CCN(C(C)=O)CC3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution containing 1 equivalent of (3EZ,5S)-1-([1,1′-biphenyl]-4-ylcarbonyl)-5-[5-(1-piperazinylmethyl)-1,2,4-oxadiazol-3-yl]-3-pyrrolidinone O-methyloxime (Example 48) in dry DCM at 0° C. were added 1.5 equivalent of triethyl amine and 1 equivalent of acetyl chloride. The reaction mixture was stirred at this temperature for 30 minutes and then hydrolyzed with ice. The reaction was then made basic with a sodium carbonate solution (10%) and extracted with DCM. The organic phase was dried with magnesium sulfate and solvent removal afforded a residue which was purified by flash-chromatography to give the expected product, (3EZ,5S)-5-{5-[(4-acetyl-1-piperazinyl)methyl]-1,2,4-oxadiazol-3-yl}-1-([1,1′-biphenyl]-4-ylcarbonyl)-3-pyrrolidinone O-methyloxime as a mixture of E-/Z-isomers, in 70% yield (94.4% purity by HPLC). The pure Z-isomer could be separated by flash-chromatography using cyclohexane/ethylacetate (1/1) as eluent, and was obtained in 40% yield (98.0% purity by HPLC).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([OH:14])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].[OH-].[Na+].[C:20](OC(=O)C)(=[O:22])[CH3:21]>O>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:14][C:20](=[O:22])[CH3:21])[C:11]([CH3:15])([CH3:16])[C:10]=2[CH:17]=1)(=[O:3])=[O:4]
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1O
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)OC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C

Procedure:
To a solution of 2-hydroxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (10 parts) in water (100 parts) containing sodium hydroxide (15 parts) was slowly added acetic anhydride (10 parts) with cooling to keep the temperature below 10° C. An oil separated which solidified on scratching. This was filtered off, washed with water, dried and recrystallised from 90% aqueous ethanol to give 2-acetoxy-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate, melting point 84°-85° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[N:32]=[C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:30]=[CH:29][CH:28]=1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:37][CH2:38][N:33]([C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[N:32]=3)[CH2:34][CH2:35]2)=[O:48])[C:44]=1[CH3:45]
Reactant: COc1cccc(N2CCNCC2)n1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)n1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(6-Methoxy-pyridin-2-yl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.45 (t, 1H), 6.34 (d,1H), 6.05 (d, 1H), 5.37 (s, 2H), 3.77 (s, 3H), 3.50 (m, 6H), 3.34 (m, 2H), 2.18 (s, 3H) ppm; MS (ES) M+H expected=418.1, found=418.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[C:10](=[O:27])[N:11]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:12]=[CH:13][C:14]=2[N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:4][CH:3]=1.C[Sn](C)(C)[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:11]2[C:10](=[O:27])[C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)=[CH:3][CH:4]=3)=[C:14]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[CH:13]=[N:12]2)=[CH:21][CH:22]=1
Reactant: O=c1c(Oc2ccc(Br)cc2)c(-n2ccnc2)cnn1-c1ccc(Cl)cc1
Reactant: C[Sn](C)(C)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1c(Oc2ccc(-c3ccncc3)cc2)c(-n2ccnc2)cnn1-c1ccc(Cl)cc1

Procedure:
1.5 mmol of 4-(4-bromophenyl)oxy-2-(4-chlorophenyl)-5-(1H-imidazol-1-yl)-3(2H)-pyridazinone, 2.1 mmol of 4-trimethylstannylpyridine, 0.1 mmol of bis(triphenyl-phosphine)palladium dichloride and 1.3 mmol of ethyldiisopropylamine in 5 ml of dimethylformamide are heated at 100° C. for 5 hours. The solvent is removed in a rotary evaporator, and the residue is purified by chromatography on silica gel (elution with ethyl, acetate/methanol mixtures). 0.3 g (45% of theory) is obtained of m.p. 188° C.
Reaction SMILES: ClC1SC(C[N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH2:15])[CH2:9]2)=CC=1.[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:8]2[CH2:13][CH2:12][O:11][CH:10]([CH2:14][NH2:15])[CH2:9]2)=[CH:19][CH:18]=1
Reactant: NCC1CN(Cc2ccc(Cl)s2)CCO1
Reactant: Fc1ccc(CCl)cc1
Product: NCC1CN(Cc2ccc(F)cc2)CCO1

Procedure:
Intermediate 21 was prepared in an analogous manner to Intermediate 1 (Alternative Procedure) from Intermediate 19 and 4-fluorobenzyl chloride, followed by deprotection to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2[Cl:17].C([O:20][CH:21]=[C:22]([C:28]([CH3:30])=[O:29])[C:23](OCC)=O)C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:28]([CH:22]1[C:21](=[O:20])[C:3]2[C:2](=[C:11]3[C:6](=[CH:5][CH:4]=2)[C:7]([Cl:17])=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:9]=[N:10]3)[N:1]=[CH:23]1)(=[O:29])[CH3:30]
Reactant: CCOC(=O)c1cnc2c(N)cccc2c1Cl
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c3c(ccc2c1Cl)C(=O)C(C(C)=O)C=N3
Temperature: 90 °C
Yield: 29 %

Procedure:
A mixture of 8-amino-4-chloro-3-ethoxycarbonylquinoline (0.3 g) and ethyl 2-ethoxymethyleneacetoacetate (Annalen, 1897, 297, 16, 0.25 g) was heated at 90° C. for 2.5 hours. The mixture was cooled to ambient temperature and the resulting solid added to diphenyl ether at reflux. The mixture was refluxed for 45 minutes, and cooled to 60° C. The mixture was diluted with carbon tetrachloride (50 ml) and cooled to ambient temperature with stirring. The mixture was filtered and the solid so obtained purified by flash chromatography on silica using increasingly polar mixtures of methanol and chloroform. The product so obtained was recrystallised from methanol to give 3-acetyl-7-chloro-8-ethoxycarbonyl-4-oxo-3,4-dihydro-1,10-phenanthroline in 29% yield, mp 288-290° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12](C(OC(C)(C)C)=O)[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:27].Cl.CO>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:27]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2ccccc21
Agent: Cl
Solvent: CO
Product: O=C1NCc2c(Cl)ccc(-c3cc4ccccc4[nH]3)c21
Yield: 82.4 %

Procedure:
In a similar manner to Step 3 of Example 1, 4-chloro-7-(1-(tert-butoxycarbonyl)indol-2-yl)isoindolinone (39.3 mg, 0.103 mmol) was dissolved in methanol (3.9 mL), and the solution was treated with 10% hydrogen chloride-methanol solution (3.9 mL), followed by purification by preparative thin-layer chromatography (chloroform/acetone=12/1) to obtain Compound 16 (24 mg, yield 83%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>C(Cl)(Cl)Cl.CO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:10]=1
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Reactant: NCc1ccccn1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Fc1nc(NCc2ccccn2)c2nc[nH]c2n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a stirred solution of 6-chloro-2-fluoro-9H-purine (prepared according to Gray, N. S.; Kwon, S.; Schultz, P. G. Tetrahedron Lett 1997, 38, 1161-1164; 0.4 g, 2.31 mmol) in BunOH (25 mL) under Ar, cooled to 0° C., was added Pri2NEt (1.13 mL, 6.49 mmol) followed by 2-(aminomethyl)pyridine (0.48 mL, 4.66 mmol). The reaction mixture was stirred at 0° C. for 3 h, and then allowed to return to RT over 30 min. and stirred at this temperature for 1 h, when TLC (9:1 CHCl3/MeOH) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between citric acid solution (200 mL, 10% aq) and EtOAc (200 mL), the aqueous phase was separated and extracted with more EtOAc (2×100 mL). The pH of the aqueous phase was adjusted to 7.0 with NaOH solution (50% w/v, aq), extracted with EtOAc (4×100 mL), and the bulked organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient column chromatography on silica gel, eluted with CHCl3/MeOH (95:5→85:15), to afford the title compound as a light yellow solid (0.40 g, 71%). Mp 217-220° C. 1H-NMR (d6-DMSO, 250 MHz): δ 4.58 (d, 2H, J=5.68 Hz, —HNCH2-Pyr), 7.29, 7.71, 8.49 (3×m, 4H, Pyr), 8.10 (s, 1H, —N═CH—NH—), 8.69 (bs, 1H, —HNCH2-Pyr), 13.07 (bs, 1H, —N═CH—NH—). FAB-MS m/z (relative intensity): 245 ([M+H]+, 55), 176 (30), 154 (100), 136 (85). Accurate Mass (M+H): Actual: 245.0951, Measured: 245.0942. Microanalysis (Expected:Measured) C11H9N6F.0.4H2O: C, 52.55:52.91; H, 3.93:3.49; N, 33.42:33.26.
Reaction SMILES: C([Li])CCC.[C:6]([C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)([CH3:9])([CH3:8])[CH3:7].[C:15](=[O:17])=[O:16]>C1COCC1>[C:6]([C:10]1[O:11][C:12]([C:15]([OH:17])=[O:16])=[CH:13][CH:14]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1ccco1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)O)o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
n-Butyllithium (25 mL, 40 mmol, 1.6 M in hexane solution, 1.1 equiv) is added dropwise to a solution of 4.5 g of 2-t-butylfuran (36 mmol) in 60 mL of dry THF at −78° C. under N2. After 30 min, the cooling bath is replaced with an ice bath and the mixture stirred at 0° C. for 1 h. Dry CO2, generated from dry ice and dried over an anhydrous Na2SO4 tower, is bubbled into the reaction mixture over 20 min at −78° C. and then at 0° C. The reaction mixture is acidified with 1 M HCl to pH 1, then extracted with ethyl acetate. The organic layer is washed with brine, dried (NaSO4) and concentrated to give 4.2 g of 2-tertbutyl 5-furanoic acid as a pale yellow solid (69%). 1H NMR (CDCl3) d 11.0 (br s, 1H), 7.19 (d, 1H, J=3.3 Hz), 6.11 (d 1H, J=3.3 Hz), 1.29 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl.[Cl:10][CH2:11][C:12](=N)OCC>C(O)C>[Cl:10][CH2:11][C:12]1[O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=N)CCl
Reactant: Nc1ccccc1O
Agent: Cl
Solvent: CCO
Product: ClCc1nc2ccccc2o1
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of o-aminophenol (4.00 g, 36.6 mmol) and ethyl chloroacetimidate hydrochloride (8.68 g, 54.98 mmol) in ethanol (55 mL) was heated at reflux for 18 hours. The reaction mixture was cooled to room temperature and vacuum filtered. The filtrate was concentrated in vacuo, diluted with dichloromethane and filtered again. The methylene chloride filtrate was dried (MgSO4) and concentrated to afford 3.99 g (65%) of product as a brown oil which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.P(Br)(Br)[Br:12].[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:12][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1cc(C)c(N)c(Cl)n1
Reactant: BrP(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)c(N)c(Br)n1
Reaction time: 48 h
Yield: 38 %

Procedure:
To a solution of 1.80 g (11.0 mmol) of 2-chloro-4,6-dimethyl-pyridin-3-ylamine (prepared as described in J. M. Klunder et al. J. Med. Chem., 35, 1992, 1887-1897) in toluene (10 ml) was added PBr3 (18 ml). The reaction mixture was stirred for 48 h under reflux. After cooling the reaction mixture, it was poured onto ice, basified with NaOH 2 M solution (400 ml) and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated. The crude residue was purified by flash chromatography (cyclohexane/ethyl acetate 7:3) to yield 2.31 g (38%) of 2-bromo-4,6-dimethyl-pyridin-3-ylamine containing small amount of 2-chloro-4,6-dimethyl-pyridin-3-ylamine as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:17](I)[CH2:18][CH3:19]>CC(C)=O.[Ag]=O>[CH2:17]([N:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=2)[CH2:10]1)[CH2:18][CH3:19]
Reactant: CCCI
Reactant: FC(F)(F)c1cccc(C2CCCNC2)c1
Agent: O=[Ag]
Solvent: CC(C)=O
Product: CCCN1CCCC(c2cccc(C(F)(F)F)c2)C1

Procedure:
A mixture of 4.6 g of the product of Step A in 25 ml of acetone was stirred until dissolution occured and then 2.5 g of silver oxide were added thereto. The mixture was cooled on an ice bath and 2.5 ml of propyl iodide were added dropwise over 5 minutes. The temperature went back to room temperature and the mixture was stirred for 16 hours and was filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 85-10-5 cyclohexane-chloroform-triethylamine mixture and evaporation to dryness under reduced pressure yielded 4.3 g of N-propyl-3-(m-trifluoromethylphenyl)-piperidine.
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][CH2:4][NH:5][CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.[C:59]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])(=[O:64])[CH2:60][C:61]([O-])=[O:62].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCCl.CN(C1C=CN=CC=1)C>[C:66]([O:65][C:59](=[O:64])[CH2:60][C:61]([N:5]([CH2:6][C@:7]12[CH2:45][CH2:44][C@@H:43]([C:46]([CH3:48])=[CH2:47])[C@@H:8]1[C@@H:9]1[C@@:22]([CH3:25])([CH2:23][CH2:24]2)[C@@:21]2([CH3:26])[C@@H:12]([C@:13]3([CH3:42])[C@@H:18]([CH2:19][CH2:20]2)[C:17]([CH3:28])([CH3:27])[C:16]([C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:31][CH:30]=2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH2:4][CH2:3][N:2]([CH3:1])[CH3:49])=[O:62])([CH3:69])([CH3:68])[CH3:67]
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[B-](F)(F)F
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(CN(CCN(C)C)C(=O)CC(=O)OC(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Yield: 97.5 %

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((2-(dimethylamino)ethylamino)methyl)-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 (27 mg, 0.040 mmol) in DCE (2 ml) was added Hunig's base (0.021 ml, 0.121 mmol), DMAP (1 mg, 8.19 μmol), Mono-tert-butyl malonate (0.012 ml, 0.080 mmol), and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (19.38 mg, 0.060 mmol). The mixture was stirred at rt. After 5 h of stirring, the mixture was loaded directly onto a silica gel column and was purified using a 0-5% MeOH in dichloromethane gradient to afford tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-((3-tert-butoxy-N-(2-(dimethylamino)ethyl)-3-oxopropanamido)methyl)-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 as a white foam (31.8 mg, 0.039 mmol, 97% yield). LCMS: m/e 813.4 (M−H)−, 3.46 min (method 6).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH-].[K+]>CO>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=1)#[CH:11]
Reactant: C[Si](C)(C)C#Cc1ccc(C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C#Cc1ccc(C(=O)O)cc1
Yield: 96 %

Procedure:
Initially, 4-bromoacetophenone (3) can be treated with powdered phosphorous pentachloride to produce 1-(4-bromophenyl)-1-chloroethylene (4). Compound 4 was then treated with potassium hydroxide to produce 4-bromophenylacetylene (5) at a 60% yield. Treatment of compound 5 with ethyl magnesium bromide was followed by reaction with chlorotrimethylsilane. The resulting product (4-bromophenylethynyl) trimethylsilane (6) was recovered with a 90% yield. Compound 6 was then treated with ethyl magnesium bromide, followed by reaction with carbon dioxide to produce (4-carboxyphenylethynyl) trimethylsilane (7) in 89% yield. Compound 7 was then deprotected using KOH in methanol to form 4-ethynylbenzoic acid (8) in 96% yield. Compound 8 is a useful building block for forming a variety of molecular switches in accordance with the present invention, and was used in forming molecular switches of the following examples.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[C:9]([OH:11])[C:8]([Br:12])=[C:7]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[CH:6]=1)C.[OH-].[Na+]>C(O)C.O>[Br:12][C:8]1[C:9]([OH:11])=[CH:10][C:5]([C:4]([OH:24])=[O:3])=[CH:6][C:7]=1[O:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=1[Cl:23]
Reactant: CCOC(=O)c1cc(O)c(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(O)c(Br)c(OCCc2ccc(Cl)cc2Cl)c1
Yield: 18.2 %

Procedure:
A solution of 25.6 g (59 mmol) of 4-bromo-3-[2-(2,4-dichlorophenyl)ethoxy]-5-hydroxybenzoic acid ethyl ester in 300 ml of ethanol and 2.36 g (65 mmol) of sodium hydroxide in 15 ml of water was stirred at room temperature for 12 h. The solvent was removed and the residue was distributed between water and ethyl acetate. The aqueous solution was acidified with 1 N HCl and the precipitate was filtered to give 4.35 g (31%) of the title compound.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[CH3:25][C@H:26]1[CH2:30][CH2:29][C:28](=O)[CH2:27]1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[C:28]3[CH2:29][CH2:30][C@H:26]([CH3:25])[CH2:27]3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: C[C@H]1CCC(=O)C1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Solvent: CC(=O)N(C)C
Product: C[C@H]1CCC(=Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)C1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.065 g, 0.18 mmol) was reacted with (3S)-3-methylcyclopentanone (0.54 g, 5.6 mmol) in N,N-dimethylacetamide (2 mL) in a sealed tube at 135° C. for 90 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with ethyl acetate/hexane (2:1) and filtered to give the title compound.
Reaction SMILES: [Na+].[OH:2][C:3]1[CH:4]=[C:5]([S:27]([O-:30])(=[O:29])=[O:28])[C:6]2[CH:7]=[CH:8][C:9]3[C:18]4[C:17]=2[C:16]=1[CH:15]=[CH:14][C:13]=4[C:12]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:11][C:10]=3[S:23]([O-:26])(=[O:25])=[O:24].[Na+].[Na+].C(N(C(C)C)CC)(C)C.Br[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50]CC)=[O:49]>CO>[C:48]([CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][O:2][C:3]1[CH:4]=[C:5]([S:27]([OH:30])(=[O:29])=[O:28])[C:6]2[CH:7]=[CH:8][C:9]3[C:18]4[C:17]=2[C:16]=1[CH:15]=[CH:14][C:13]=4[C:12]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:11][C:10]=3[S:23]([OH:26])(=[O:24])=[O:25])([OH:50])=[O:49]
Reactant: CCOC(=O)CCCCCBr
Reactant: O=S(=O)([O-])c1cc(O)c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c4ccc1c2c34
Agent: [Na+]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CCCCCOc1cc(S(=O)(=O)O)c2ccc3c(S(=O)(=O)O)cc(S(=O)(=O)O)c4ccc1c2c43
Reaction time: 8 h

Procedure:
A mixture of 8-hydroxypyrene-1,3,6-trisulfonate sodium salt (2.6 g), diisopropylethylamine (2 g) and ethyl 6-bromohexanoate (7 g) in methanol (150 mL) was refluxed for 24 hours. The solvent was removed by rotary evaporation. The product was purified by HPLC. The isolated ethyl ester was redissolved in methanol (100 mL). About 0.5 g NaOH dissolved in 25 mL water was added. The resulting solution was stirred overnight. The methanol was removed by rotary evaporation. To the remaining aqueous solution was added acid until the solution became acidic. The precipitate was collected by filtration and dried under vacuum to give 8-(5-carboxypentoxy)pyrene-1,3,6-trisulfonic acid.