Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:15]=[C:14]([N:16]2[C:24]3[CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][C:20](=[O:27])[C:19]=3[C:18]([CH3:28])=[N:17]2)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:35]=[C:36]([O:40][CH3:41])[C:37]=1[O:38][CH3:39])[NH2:34]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:25][C:22]1([CH3:26])[CH2:23][C:24]2[N:16]([C:14]3[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([NH:34][C:33]4[CH:35]=[C:36]([O:40][CH3:41])[C:37]([O:38][CH3:39])=[C:31]([O:30][CH3:29])[CH:32]=4)[CH:15]=3)[N:17]=[C:18]([CH3:28])[C:19]=2[C:20](=[O:27])[CH2:21]1
Reactant: Cc1nn(-c2ccc(C#N)c(Br)c2)c2c1C(=O)CC(C)(C)C2
Reactant: COc1cc(N)cc(OC)c1OC
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(Nc2cc(-n3nc(C)c4c3CC(C)(C)CC4=O)ccc2C#N)cc(OC)c1OC
Temperature: 120 °C
Yield: 246.6 %

Procedure:
Sodium tert-butoxide (269 mg, 2.80 mmol, 2.0 equiv) was added to a stirred solution/suspension of 2-bromo-4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (500 mg, 1.40 mmol, 1.0 eq.), 3,4,5-trimethoxyaniline (513 mg, 2.80 mmol, 2.0 eq.), palladium (II) acetate (16 mg, 0.07 mmol, 0.05 eq.), and 1,1′-bis(diphenylphosphino)ferrocene (78 mg, 0.14 mmol, 0.10 eq.) in 3.75 mL of toluene. The reaction vial was capped, and the reaction mixture was heated 20 minutes at 120° C. under microwave irradiation. The individual reaction mixtures were diluted with ethyl acetate, combined, and partitioned with water. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified on a Biotage System (SiO2, hexanes-ethyl acetate) to afford 4-(6,6-dimethyl-4-oxo-3-methyl-4,5,6,7-tetrahydro-indazol-1-yl)-2-(3,4,5-trimethoxyanilino)-benzonitrile (1.59 g, 82%) as a tan solid: LC/MS (m/z): [M+H]+ 461.9.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-])=O)=[CH:9][CH:10]=2)[C:5](=[O:15])[CH2:4][CH2:3]1>CCOC(C)=O.[Pd]>[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[C:5](=[O:15])[CH2:4][CH2:3]1
Reactant: CC1(C)CCC(=O)c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CCC(=O)c2cc(N)ccc21

Procedure:
A solution of 230.0 mg (1.05 mmol) 3,4-dihydro-4,4-dimethyl-7-nitro-1(2H)-naphthalenone (Compound Y) in 5.0 ml of EtOAc was stirred at room temperature with a catalytic amount of 10% Pd-C under 1 atm of H2 for 24 hours. The catalyst was removed by filtration through a pad of Celite, and the filtrate concentrated under reduced pressure to give the title compound as a dark green oil. 1H NMR (CDCl3): δ 7.30 (1H, d, J=2.7 Hz), 7.22 (1H, d, J=8.4 Hz), 6.88 (1H, dd, J=2.7, 8.5 Hz), 2.70 (2H, t, J=6.6 Hz), 1.97 (2H, t, J=6.6 HZ), 1.34 (6H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C@H:9]1[C@H:13]([C:14]([F:17])([F:16])[F:15])[CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[N+](C1C=CC([O:28][C:29](=O)[NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]3=[O:43])=[CH:33][C:32]=2[F:44])=CC=1)([O-])=O>>[C:1]([O:5][C:6](=[O:18])[NH:7][CH2:8][C@H:9]1[C@H:13]([C:14]([F:15])([F:16])[F:17])[CH2:12][N:11]([C:29](=[O:28])[NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]3=[O:43])=[CH:33][C:32]=2[F:44])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CNC[C@H]1C(F)(F)F
Product: CC(C)(C)OC(=O)NC[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1C(F)(F)F

Procedure:
77.1 Using general procedure H, (3S,4S)-(4-trifluoromethyl-pyrrolidin-3-ylmethyl)-carbamic acid tert-butyl ester (H. Fukui et al., Bioorganic & Medicinal Chemistry Letters, 1998, 8, 2833) was coupled with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give {(3R,4S)-1-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-4-trifluoromethyl-pyrrolidin-3-ylmethyl}-carbamic acid tert-butyl ester. Orange oil. MS 499.3 ([M+H]+)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[N:23]=[C:22](Cl)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[CH:36]=[C:37]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])[CH:38]=[CH:39][CH:40]=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:34][C:35]4[CH:36]=[C:37]([NH:41][C:42](=[O:45])[CH:43]=[CH2:44])[CH:38]=[CH:39][CH:40]=4)[N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc(Nc2ccc3c(cnn3Cc3ccccc3)c2)n1
Reactant: C=CC(=O)Nc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Nc2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)n2)c1
Temperature: 100 °C

Procedure:
To a slurry of (1-benzyl-1H-indazol-5-yl)-(4-chloro-[1,3,5]triazin-2-yl)-amine (Step 3) (50.0 mg, 0.148 mmol) in IpOH (2.5 ml) was added DIEA (0.039 mL, 0.222 mmol) and N-(3-aminophenyl)acrylamide (26.5 mg, 0.163 mmol). The mix was heated at 100° C. for 18 h. The solution was then cooled to RT. A precipitate fell out of solution and was filtered off and dried under reduced pressure to give N-{3-[4-(1-benzyl-1H-indazol-5-ylamino)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide: MS m/z=463[M+H]+. Calc'd for C26H22N8O: 462.19.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:11][C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1>>[Br:1][C:2]1[N:3]=[C:4]([O:9][CH3:10])[C:5]([NH:8][S:18]([C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([Cl:11])[CH:13]=2)(=[O:20])=[O:19])=[N:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: COc1nc(Br)cnc1N
Product: COc1nc(Br)cnc1NS(=O)(=O)c1cccc(Cl)c1

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 5-bromo-3-methoxy-2-pyrazinamine (0.1 g) and 3-chlorobenzenesulphonyl chloride (0.13 g).
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[O:5][C:6]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:7][C:8]=1[C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=1)=[O:10]>O.C1COCC1>[CH3:3][C:4]1[O:5][C:6]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:7][C:8]=1[C:9]([NH:11][CH2:12][CH2:13][C:14]1[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=1)=[O:10]
Reactant: COC(=O)c1ccccc1COc1ccc(CCNC(=O)c2cc(-c3ccccc3)oc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)cc1C(=O)NCCc1ccc(OCc2ccccc2C(=O)O)cc1
Yield: 71 %

Procedure:
Lithium hydroxide (3.3 mg, 0.136 mmol) in water (1 ml) was added into methyl 2-[(4-{2-[(2-methyl-5-phenyl-3-furoyl)amino]ethyl}phenoxy)methyl]benzoate (32 mg, 0.068 mmol) dissolved in THF(2 ml). The mixture was then irradiated in a microwave oven (Smith Synthesizer) at 150° C. for 7 minutes and then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜4, and extracted with ethyl acetate (×2). The organic extracts were combined and washed with brine and dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, then MeOH/DCM (1:99 and 2:98) as eluant gave 22 mg the desired product, yield 71%.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[C:18]([S:23][CH3:24])[C:19]2=4)[NH:14][CH:13]=3)[N:9]([CH3:25])[CH2:8]1)=O)[CH3:2].P(Cl)(Cl)(Cl)=O.C(OC([S-])=[S:37])C.[K+]>C(Cl)Cl>[CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[C:18]([S:23][CH3:24])[C:19]2=4)[NH:14][CH:13]=3)[N:9]([CH3:25])[CH2:8]1)=[S:37])[CH3:2]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(SC)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)C(=S)N[C@H]1C[C@@H]2c3c(SC)ccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At -20° C., 5.79 g of 1,1-diethyl-3-(6-methyl-12-methylthio-8α-ergolinyl)urea (15 mmol) is dissolved in a mixture of 4.13 g of freshly distilled phosphorus oxychloride (45 mmol) and 50 ml of anhydrous methylene chloride and the temperature is allowed to rise within 4 hours to +10° C. The mixture is stirred overnight at room temperature and then another 2 hours at 40° C.,and the solvent is subsequently distilled off under vacuum. The residue is dissolved in 50 ml of anhydrous acetonitrile, cooled to -10° C., combined with 7.2 g of potassium ethylxanthate (45 mmol), and stirred at room temperature for 20 hours. The solvent is exhaustively removed by distillation; then the mixture is distributed between ethyl acetate and saturated sodium carbonate solution; the organic phase is dried with sodium sulfate and evaporated. The residue is crystallized from ethyl acetate, yielding 82%.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([O:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=1.C[Si](C)(C)[C:27]([F:30])([F:29])[F:28].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C1COCC1>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@:7]([OH:15])([C:27]([F:30])([F:29])[F:28])[C:6]=2[CH:5]=[C:4]([O:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)CCCOc1cc(Cl)c2c(c1)C(=O)c1ccccc1-2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CCCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere, ethyl 4-(4-chloro-9-oxo-9H-fluorene-2-yloxy)butyrate (69.4 g) was dissolved in THF (700 ml), and N-(4-tert-butylbenzyl)cinchonidium 4-methoxyphenoxide (6.4 g) was added. To the reaction mixture was added dropwise a solution of trimethyl(trifluoromethyl)silane (52.0 ml) in THF (140 ml) at −16° C., and the mixture was stirred at the same temperature for 15 min. To the reaction mixture were successively added acetic acid (23.0 ml) and 1M tetrabutylammonium fluoride/THF solution (222 ml), and the mixture was stirred at room temperature for 1 hr. The solvent in the reaction mixture was evaporated, and to the obtained residue were added toluene (500 ml) and saturated aqueous sodium hydrogen carbonate (200 ml) to allow for layer separation. The obtained organic layer was washed successively with saturated aqueous sodium hydrogen carbonate (150 ml, twice), 1N aqueous sodium hydroxide (100 ml), water (100 ml), 1N hydrochloric acid (100 ml), water (100 ml) and saturated brine (100 ml). To the obtained organic layer were added anhydrous magnesium sulfate and silica gel (150 g), and the mixture was stirred for 10 min. The insoluble material was filtered off, and the insoluble material was washed successively with toluene (300 ml) and ethyl acetate (800 ml). The obtained filtrate and the toluene washing were combined and the solvent was evaporated to give the title compound (72.1 g). Also, the solvent in the ethyl acetate washing was evaporated, to the obtained residue were added silica gel (40 g) and a mixed solvent of hexane and ethyl acetate (ethyl acetate:hexane 2:1, 300 ml), and the mixture was stirred at room temperature. The insoluble material was filtered off, and the insoluble material was washed with a mixed solvent of hexane and ethyl acetate (ethyl acetate:hexane=2:1, 300 ml). The solvent in the obtained filtrate was evaporated to further give the title compound (20.3 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:12][CH3:13])[C:4]1[N:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][CH:5]=1)[CH3:2].Cl.[CH2:15]([OH:18])[CH2:16][CH3:17]>>[CH2:12]([N:3]([CH2:1][CH3:2])[C:4]1[N:9]=[CH:8][C:7]([C:10](=[NH:11])[O:18][CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1)[CH3:13]
Reactant: CCCO
Reactant: CCN(CC)c1ccc(C#N)cn1
Agent: Cl
Product: CCCOC(=N)c1ccc(N(CC)CC)nc1
Temperature: 0 °C

Procedure:
Into a solution of 6-diethylamino-3-cyanopyridine (460 mg, 2.63 mmol) in 1-propanol (15 ml) was passed hydrogen chloride gas at a temperature of 0°-5° C. for 30 minutes. The reactor was tight sealed, and the mixture was stirred at 0° C. over night. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was added to a concentrated sodium carbonate solution. After it was confirmed that the solution showed an alkaline pH (9 or more), it was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product of propyl 6-diethylamino-3-pyridinecarboximidate as an oil. The oil was dissolved in acetonitrile (2 ml), and an aqueous solution (5 ml) of NaH2PO4 ·2H2O (1.62 g, 10.4 mmol), Na2HPO4 (370 mg, 2.61 mmol) and cyanamide (220 mg, 5.24 mmol) was added to the solution. The mixture was stirred at room temperature over night. After the reaction was completed, the reaction mixture was extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography with a mixed solvent of methanol and chloroform to give propyl N-cyano-6-diethylamino-3-pyridinecarboximidate (630 mg, yield 92%) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:7][CH:6]=1.[C:18]([CH2:21][N:22]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29][N:28]([CH2:34][C:35]([OH:37])=[O:36])[CH2:27][CH2:26][N:25]([CH2:38][C:39]([OH:41])=[O:40])[CH2:24][CH2:23]1)([OH:20])=[O:19].[OH-].[K+]>O1CCOCC1.O>[OH:1][CH:2]([CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:7][CH:6]=1)[CH2:17][N:31]1[CH2:32][CH2:33][N:22]([CH2:21][C:18]([OH:20])=[O:19])[CH2:23][CH2:24][N:25]([CH2:38][C:39]([OH:41])=[O:40])[CH2:26][CH2:27][N:28]([CH2:34][C:35]([OH:37])=[O:36])[CH2:29][CH2:30]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: OCCCCCc1ccc(OCC2CO2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)COc2ccc(CCCCCO)cc2)CCN(CC(=O)O)CC1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
12.3 g (51.97 mmol) of 2,3-epoxy-1-[4-(5-hydroxypentyl)-phenoxy]-propane and 10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) are dissolved in a mixture of 50 ml of dioxane and 80 ml of water, and the pH is brought to pH 10 with 6N potassium hydroxide solution. It is stirred for 24 hours at 40° C. It is evaporated to dryness, the residue is taken up with 200 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 3 with 5N hydrochloric acid and evaporated to dryness. The residue is concentrated by evaporation in a vacuum and boiled out (extracted) with 200 ml of methanol/50 ml of methylene chloride. It is cooled in an ice bath and filtered off from precipitated potassium chloride. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 50 ml of water/20 ml of ethanol and then added to a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water. After concentration by evaporation in a vacuum, 8.92 g (53% of theory) of the title compound is obtained as strongly hygroscopic, vitreous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:10][CH:9]1[C:11]1[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=1.[C:26]1([SH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][NH:8][CH2:10][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=1)[S:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1OCCN1CC1c1ccc(C)c(S(N)(=O)=O)c1
Reactant: Sc1ccccc1
Solvent: CO
Product: COc1ccccc1OCCNCC(Sc1ccccc1)c1ccc(C)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
In 50 ml of methanol was dissolved 2.5 g of 5-{1-[2-(2-methoxyphenoxy)ethyl]aziridin-2-yl}-2-methylbenzenesulfonamide and after adding 1 g of thiophenol to the solution and stirring the mixture overnight at room temperature, methanol was distilled off. The residue was subjected to silica gel column chromatography and the product was eluted by a mixed solvent of chloroform and methanol (9:1 by volume ratio) to provide 2.4 g of 5-{2-[2-(2-methoxyphenoxy)ethylamino]-1-phenylthioethyl}-2-methylbenzenesulfonamide as a viscous oily material.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.[NH2:11][CH2:12][CH2:13][N:14]1[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]1[CH3:20]>O1CCCC1>[CH3:20][C:15]1[N:14]([CH2:13][CH2:12][NH:11][C:8](=[O:10])[CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[C:18]([CH3:19])=[CH:17][CH:16]=1
Reactant: O=C(O)CN1CCCC1=O
Reactant: Cc1ccc(C)n1CCN
Solvent: C1CCOC1
Product: Cc1ccc(C)n1CCNC(=O)CN1CCCC1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
14.3 g (0.1 mol) of (2-oxo-1-pyrrolidinyl)acetic acid and 16.2 g (0.1 mol) of N,N'-carbonyldiimidazole are heated under reflux in 70 ml of tetrahydrofuran for 15 min. After cooling, 13.8 g (0.1 mol) of 1-(2-aminoethyl)-2,5-dimethylpyrrole in 70 ml of tetrahydrofuran are added dropwise. After the reactionmixture has been stirred at room temperature for 6 h, it is concentrated, acifified with dilute acetic acid and extracted with methylene chloride. The methylene chloride extract is concentrated, and the residue is triturated with ether, filtered off with suction and recrystallized from dibuyl ether. Yield: 9.0 g (34% of theory), Melting point: 109°-111° C. Elemental analysis: C14H21N3O2 (263.34) calculated: C 63.9 H 8.0 N 16.0 O 12.2 found: C 63.8 H 8.0 N 15.9 O 12.2
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:23][CH3:24])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4].[C:25](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:23]([CH3:25])[CH3:24])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: CNn1c(C(=O)OC)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Cl)ccc2c(=O)n1N(C)C
Temperature: 80 °C
Reaction time: 72 h
Yield: 56.3 %

Procedure:
A mixture of 6-chloro-2-methylamino-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (800 mg), potassium carbonate (400 mg), methyl iodide (20 ml) and DMF (20 ml) was stirred at 80° C. for 3 days. The reaction mixture was concentrated, and ethyl acetate was added to the obtained residue. The mixture was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) and crystallized from isopropyl ether to give the title compound (469 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[CH2:9])=[CH:4][CH:3]=1.[OH-].[K+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1
Reactant: C=C(Cl)c1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Product: C#Cc1ccc(Br)cc1
Yield: 60 %

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:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH:12][S:13]([CH2:16][CH2:17][C:18]([OH:20])=O)(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:22][CH2:23][CH2:24][C:25]1[C:33]2[S:32][C:31](=[O:34])[NH:30][C:29]=2[C:28]([OH:35])=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C.Cl>CN(C)C=O>[OH:35][C:28]1[C:29]2[NH:30][C:31](=[O:34])[S:32][C:33]=2[C:25]([CH2:24][CH2:23][NH:22][C:18](=[O:20])[CH2:17][CH2:16][S:13]([NH:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:14])=[O:15])=[CH:26][CH:27]=1
Reactant: O=C(O)CCS(=O)(=O)NCCOCCc1ccccc1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCS(=O)(=O)NCCOCCc1ccccc1)NCCc1ccc(O)c2[nH]c(=O)sc12
Temperature: -15 °C
Reaction time: 0.08 h

Procedure:
A solution of the product from step b) (3.89 g), 7-(2-aminoethyl)4-hydroxy-1,3-benzothiazol-2(3H)-one hydrochloride (3.22 g), bromotripyrrolidinophosphonium hexafluorophosphate, PyBroP, (6.32 g) in dimethylformamide (50 ml) was cooled to -15° C. and diisopropylethylamine (9.0 ml) was added dropwise over 5 minutes. The solution was stirred at -15° C. for 5 min then allowed to warm to 13° C. over 4 hours. This mixture was then added dropwise over 40 min to dilute hydrochloric acid (2N, 500 ml) and after stirring over the weekend the solid was collected by filtration. This solid was dried in vacuo to give the subtitle compound (4.5 g).
Reaction SMILES: [CH2:1]([S:8]([C:11]1[N:16]=[C:15]2[NH:17][C:18](=[O:28])[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Br:27])[CH2:20][C:14]2=[CH:13][N:12]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31][O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]Cl)[CH:35]=1>CN(C)C=O>[CH2:1]([S:8]([C:11]1[N:16]=[C:15]2[N:17]([CH2:40][C:36]3[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=3)[C:33]([O:32][CH3:31])=[O:42])[C:18](=[O:28])[N:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Br:27])[CH2:20][C:14]2=[CH:13][N:12]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2nc(S(=O)(=O)Cc3ccccc3)ncc2CN1c1ccccc1Br
Reactant: COC(=O)c1cccc(CCl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2C(=O)N(c3ccccc3Br)Cc3cnc(S(=O)(=O)Cc4ccccc4)nc32)c1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
A solution of 1 g (2.2 mmol) of 7-benzylsulfonyl-3-(2-bromophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one in 20 ml of dimethylformamide was cooled to 0° C. under a nitrogen atmosphere, treated with 112 mg (4.2 mmol) of 60% sodium hydride in mineral oil then stirred for 30 minutes. 440 mg (2.4 mmol) of methyl-3-(chloromethyl)benzoate was added, then the reaction was heated at 90° C. for 3 hours. The solvent was evaporated and the residue partitioned between ethyl acetate (40 ml) and water (40 ml), the ethyl acetate layer was separated, washed with saturated aqueous sodium bicarbonate (40 ml), dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate/hexane. Product containing fractions were combined and evaporated to give 750 mg (56%) of methyl 3-[[7-benzylsulfonyl 3-(2-bromophenyl)-1,2,3,4-tetrahydro-2-oxopyrimido[4,5-d]pyrimid-1-yl]methyl]benzoate as a white solid. [Mass spectrum (ESI) MH+ =607].