Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21])([O-:13])=[O:12]>C([O-])(O)=O.[Na+].C(OCC)C.O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][S:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N+:11]([O-:13])=[O:12])(=[O:21])=[O:22])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Cc1cc(O)cc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
Orcinol monohydrate (4.27 g, 30.0 mmol) and 2-nitrobenzenesulfonyl chloride (6.65 g, 30.0 mmol) were mixed in saturated aqueous NaHCO3 (100 mL) and diethyl ether (100 mL). The biphasic mixture was stirred vigorously at ambient temperature overnight. The reaction mixture was diluted with water (150 mL) and extracted into ethyl acetate (3×100 mL). The organic phase was washed with brine (2×100 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane to 5% ethyl acetate in dichloromethane) to give the title compound as a pale yellow solid (6.10 g, 73%). 1H-NMR (300 MHz, CDCl3) δ 8.09 (d, J=7.8 Hz, 1H), 7.85 (m, 2H), 7.71 (m, 1H), 6.62 (s, 1H), 6.59 (s, 1H), 6.51 (s, 1H), 5.06 (s, 1H), 2.26 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]N)=[CH:5][CH:4]=1)#[N:2].C[O:12]COC.C(=O)([O-])[O-].[NH4+].[NH4+].S(=O)(=O)(O)O>O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: COCOC
Reactant: N#Cc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: N#Cc1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 38.9 %

Procedure:
13.2 g of p-cyanobenzylamine, 30.0 g of formaldehyde dimethyl acetal, 38.4 g of ammonium carbonate and 80 ml of water were reacted after adjusting the pH of the solvent to 2.5 by sulfuric acid, at 90° C. for 4 hours while stirring. The reaction solution was cooled to room temperature and then cooled on ice. The crystals precipitated were collected by filtration, washed with water and dried to obtain 5.1 g (yield: 39%) of p-cyanobenzaldehyde. The purity was 99.5% or more.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:12](Cl)=[O:13]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:6]=[C:12]=[O:13])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: NC(=O)c1ccccc1Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1ccccc1Cl

Procedure:
2-Chlorobenzamide was dissolved in dichloromethane, mixed with 1.5 eq. of oxalyl chloride and heated to reflux for 16 hours. The reaction mixture was concentrated under high vacuum and reacted in stage b without further purification.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[CH3:16].C(OC([N:24]1[CH2:28][C@H:27]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][C@H:25]1[C:37](O)=[O:38])=O)(C)(C)C>>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:37]([C@@H:25]3[CH2:26][C@@H:27]([CH2:29][C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[CH2:28][NH:24]3)=[O:38])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[CH3:16]
Reactant: CC(C)(C)OC(=O)N1C[C@H](Cc2ccc(F)cc2)C[C@H]1C(=O)O
Reactant: Cc1cc(Oc2ccc(N)cc2)ccc1F
Product: Cc1cc(Oc2ccc(NC(=O)[C@@H]3C[C@@H](Cc4ccc(F)cc4)CN3)cc2)ccc1F
Yield: 73 %

Procedure:
Proceeding as in Reference 6, but substituting 4-(4-fluoro-3-methylphenoxy)aniline and (2S,4R)-1-(tert-butoxycarbonyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxylic acid, gave (2S,4R)—N-(4-(4-fluoro-3-methylphenoxy)phenyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide (282 mg, 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](O)=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]1[CH:22]=[CH:21][C:15]([CH:16](O)[C:17]([OH:19])=[O:18])=[CH:14][CH:13]=1)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:22]=[CH:21][C:15]([CH:16]2[C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[O:19][C:17]2=[O:18])=[CH:14][CH:13]=1)[CH3:10]
Reactant: CCOc1ccc(C(O)C(=O)O)cc1
Reactant: Cc1ccc(O)cc1
Product: CCOc1ccc(C2C(=O)Oc3ccc(C)cc32)cc1
Reaction time: 2 h
Yield: 76 %

Procedure:
A mixture of 162 g (1.50 mol) of 4-methylphenol and 196.2 g (1.0 mol) of 4-ethoxymandelic acid are stirred under nitrogen for 2 hours at 140°-150° C. Stirring is then continued for 1.5 hours at 150° C. under a slight vacuum (50 mbar). Excess 4-methoxyphenol is removed by distillation under a high vacuum. Crystallisation of the residue from xylene/ethanol yields 204 g (76%) of 3-(4-ethoxyphenyl)-5-methylbenzofuran-2-one of m.p. 82°-86° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.Br.C(O)(=O)C>CCOCC>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCCCc2ccc(OC)cc2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: Oc1ccc(CCCCCCc2ccc(O)cc2)cc1
Yield: 77.3 %

Procedure:
A mixture of 40.0 g of 1,6-bis(4-methoxyphenyl)hexane of Example 2, 150 ml of HBr (48%) and 150 ml of glacial acetic acid was refluxed for 5 hours. It was concentrated by evaporation to give a dark brown semi-solid. This was dissolved in ether, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 28.0 g of dark brown semi-solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][CH2:9][N:10]=[N+]=[N-])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:27]=[CH:26][C:20]([CH2:21][O:22][C:23](Cl)=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15].C(N(CC)CC)C>CO.[OH-].[OH-].[Pd+2]>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22][C:23](=[O:24])[NH:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])=[CH:26][CH:27]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCN=[N+]=[N-]
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
A solution of (2-azidoethyl)carbamic acid t-butyl ester (1.22 g, 6.55 mmol) in methanol (60 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide on charcoal (1.22 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered, and the filtrate concentrated under reduced pressure. To a solution of the obtained crude product in methylene chloride (60 ml) were added chloroformic acid p-nitrobenzyl ester (2.12 g, 9.8 mmol) and triethylamine (1.37 ml, 9.8 mmol) in an ice bath, and the reaction mixture was stirred at room temperature overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (3:1) as the eluant to afford (2-t-butoxycarbonylaminoethyl)carbamic acid p-nitrobenzyl ester (1.46 g, yield 66%) as a white solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH:9]([C:22]([OH:24])=O)[CH:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[OH-].[K+].Cl[C:28](OC1C=CC=CC=1)=[O:29].Cl>O1CCCC1.O>[O:29]=[C:28]1[N:8]([CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[C@@H:9]2[C:22]([O:13][C:11](=[O:12])[C@@H:10]2[N:14]1[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:24]
Reactant: O=C(O)C(NCc1ccccc1)C(NCc1ccccc1)C(=O)O
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1OC(=O)[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
220 g (0.67 mol) of meso-2,3-bis(benzylamino)succinic acid were placed under a nitrogen atmosphere in a 2 l flask fitted with two dropping funnels, a pH electrode, and a stirrer. The meso-2,3-bis(benzylamino)succinic acid was then suspended, while stirring, in 800 ml of tetrahydrofuran and 400 ml of deionized water, and brought into solution by the addition of 108 ml of a 50% potassium hydroxide solution. 200 ml of 2.4 mole eq. phenyl chloroformate were added dropwise to the solution within 3.5 hours. The pH was maintained between 9 and 11 during the addition of phenyl chloroformate by the successive addition of 50% potassium hydroxide solution and the internal temperature was maintained between 30° C. and 35° C. After the addition was completed, the mixture was stirred at about 30° C. for 2 hours and then the pH was adjusted to about 7-8 with concentrated hydrochloric acid. The aqueous solution was extracted twice with toluene and 500 ml of tetrahydrofuran were added to the combined aqueous phases. The mixture was adjusted to a pH of 1.0 with 37% hydrochloric acid, and the aqueous phase was separated off. 400 ml of toluene were added to the tetrahydrofuran phase and the tetrahydrofuran was distilled off under reduced pressure. The remaining water was removed azeotropically with toluene. After the addition of 700 ml of toluene and 130 ml of acetic anhydride, the mixture was heated to 80° C. After the 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid anhydride had crystallized out, the obtained suspension was cooled to 10° C. within 2 hours in order to complete the crystallization. The crystalline 2-oxo-1,3-dibenzyl-cis4,5-imidazolidinedicarboxylic acid anhydride was filtered off and washed twice with toluene. After drying to constant weight under reduced pressure, there were obtained 173.6 g (78% yield) of 2-oxo-1,3-dibenzyl-cis4,5-imidazolidinedicarboxylic acid anhydride in the form of an analytically pure, colourless solid, with a melting point of 240.2° C. 3.0 g of 2-oxo-1,3-dibenzylamino-cis4,5-imidazolidinedicarboxylic acid anhydride were further obtained on evaporation of the main solution.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]([O:15][CH2:16][CH3:17])[CH2:13][CH:12]([OH:18])[C:11]2=[O:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](O)(=[O:22])[CH3:21]>>[C:1]1([S:7]([N:10]2[CH:14]([O:15][CH2:16][CH3:17])[CH2:13][CH:12]([O:18][C:20](=[O:22])[CH3:21])[C:11]2=[O:19])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)O
Reactant: CCOC1CC(O)C(=O)N1S(=O)(=O)c1ccccc1
Product: CCOC1CC(OC(C)=O)C(=O)N1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 0.50 g of 1-benzenesulfonyl-2-oxo-3-hydroxy-5-ethoxypyrrolidine (trans isomer) in 10 cm3 anhydrous acetic acid is heated to boiling for 1 hour. It is allowed to cool to room temperature and the acetic anhydride is evaporated. It is dissolved in toluene and the azeotrope is evaporated under reduced pressure. The residue is chromatographed on silica by elution with a mixture of ethylacetate-hexane (1-1); 0.48 g of the expected product is obtained.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.N1CCCCC1.[S:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>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.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:32]#[C:31][C:29]([C:25]4[S:24][CH:28]=[CH:27][N:26]=4)([OH:33])[CH3:30])[CH:10]=3)[CH:6]=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: C#CC(C)(O)c1nccs1
Reactant: Nc1nccc(-n2ncc3ccc(I)cc32)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(O)(C#Cc1ccc2cnn(-c3ccnc(N)n3)c2c1)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-(6-iodo-1H-indazol-1-yl)pyrimidin-2-amine (1-a1) (150 mg, 0.285 mmol) and piperidine (1 mL) was added tetrakis(triphenylphosphine)palladium (49.3 mg, 0.043 mmol), copper(I) iodide (8.1 mg, 0.043 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (I-1) (131 mg, 0.854 mmol). The reaction was purged with N2 and stirred at RT for 30 min. The reaction mixture was concentrated in vacuo and the residue purified by reverse phase preparative HPLC to afford the title compound: 1H NMR (500 MHz, DMSO) δ 1.95 (3H, s), 7.04 (2H, br. s.), 7.08-7.13 (2H, m), 7.35 (1H, dd, J=8.20, 1.26 Hz), 7.70 (1H, d, J=3.15 Hz), 7.79 (1H, d, J=3.15 Hz), 7.89 (1H, d, J=8.51 Hz), 8.30 (1H, d, J=5.67 Hz), 8.50 (1H, s), 8.91 (1H, s). LC-MS: m/z=+363.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.[C-:13]#[N:14].[K+].C(O)C>O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][C:13]#[N:14]
Reactant: [C-]#N
Reactant: FC(F)(F)c1ccccc1CBr
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccccc1C(F)(F)F

Procedure:
A mixture of 75 g. (0.31 mole) of o-trifluoromethylbenzyl bromide, 120 g. (0.55 mole) of potassium cyanide, 150 ml. of water and 600 ml. of absolute ethanol is stirred and heated under reflux for 20 hours. The reaction mixture is diluted with 4 liters of water and is extracted with 500 ml. of ether. The extract is dried over anhydrous potassium carbonate and evaporated. Distillation gives 45 g. of the desired product b.p. 103°-105° C./10 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH:12]([C:14]1[NH:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])[C:15]=1[CH3:23])=O>N1CCCCC1.C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:14]1[NH:18][C:17]([CH3:19])=[C:16]([C:20]([OH:22])=[O:21])[C:15]=1[CH3:23]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
The reaction mixture of 5-fluorooxindole (100 mg, 0.66 mmol), 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (133 mg, 0.79 mmol), and 10 drops of piperidine in ethanol (3 mL) was stirred at 60° C. overnight and filtered. The solid was washed with 1 M of aqueous hydrochloride solution, water, and dried to afford 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (201 mg, quantitative) as a yellow solid. MS m/z (relative intensity, %) 299 ([M−1]+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][S-:12].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:12][CH3:11])[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(C=O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.1 %

Procedure:
A solution of 3-chloro-4-fluorobenzaldehyde (50.0 g) in N,N-dimethylformamide (350 mL) was cooled to −10° C., and sodium methanethiolate (25 g) was added. The reaction solution was warmed to room temperature, and stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give the title compound (33.6 g, yield 59%) as colorless crystals. The mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-30:70, volume ratio) and recrystallized from hexane-ethyl acetate to give the title compound (12.3 g, yield 21%) as colorless crystals. melting point 58-59° C.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[S:27])=[CH:21][CH:20]=1)([CH3:18])[CH3:17].CO>C1COCC1>[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([N:12]2[CH2:13][CH2:14][CH2:15][N:9]([C:7](=[O:8])[CH2:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:10][CH2:11]2)=[S:27])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1ccc(N=C=S)cc1
Reactant: O=C(CC1CCCC1)N1CCCNCC1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1ccc(NC(=S)N2CCCN(C(=O)CC3CCCC3)CC2)cc1
Reaction time: 8 h
Yield: 71 %

Procedure:
The 1-(2-cyclopentyl-acetyl)-1,4-diazepane (100 mg; 0.475 mmol) and 4-isopropylphenyl isothiocyanate (80 mg; 0.45 mmol) were mixed together at room temperature in 5 mL anhydrous THF. The reaction mixture was left stirring overnight, then 1 mL methanol was added and the solvents were evaporated in vacuo. The crude mixture was purified by flash column chromatography on SiO2 using 0-50% EtOAc in hexanes mixtures as eluent, followed by 1-4% methanol in DCM mixtures. The desired product was isolated as a colorless foam, 180 mg (71% yield). ES+MS: 388 amu (MH+).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH2:13][CH2:12]3)[CH:6]=[N:7][CH:8]=1.[C:21]([O:24][CH2:25][C:26](Cl)=[O:27])(=[O:23])[CH3:22].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:19][N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:5]3[CH:4]=[C:3]([NH:2][C:26]([CH2:25][O:24][C:21](=[O:23])[CH3:22])=[O:27])[CH:8]=[N:7][CH:6]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:13][C:14]1=[O:20]
Reactant: CC(=O)OCC(=O)Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc(N)c3)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
To a solution of 6-(5-amino-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (intermediate A-2, 0.045 g, 0.155 mmol) in DCM (1.5 mL) was added TEA (0.039 g, 0.388 mmol) followed by 2-chloro-2-oxoethyl acetate (0.017 g, 0.124 mmol) in DCM (1 mL) and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with DCM, poured into aq. NaHCO3 (10 mL) and the aqueous layer was extracted with DCM (2×25 mL). Combined organics were washed with brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.025 g, 46%) as a light brown solid. MS: 354.2 (M+H+).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH:9]2[C:14](=O)[CH:13]3[CH2:16][CH2:17][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].NN.C(O)COCCO>O>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:16][CH2:17][N:10]2[CH2:11][CH2:12]3)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C2CCN(CC2)C1CC(c1ccccc1)c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: c1ccc(C(CC2CC3CCN2CC3)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.75 h

Procedure:
9.3 Parts 3-(2,2-diphenylethyl-1-azabicyclo[2.2.2]-octan-3-one, 1.30 parts potassium hydroxide, 3.6 parts by volume of an 85% solution of hydrazine in water, and 59 parts diethylene glycol are combined and refluxed, with stirring, under nitrogen for 2.75 hours. Stirring and heating are then discontinued and the reaction mixture is allowed to stand for 16 hours at which time the mixture is heated to distill until a head temperature of 235° C. is reached. After cooling to room temperature, the mixture is partitioned between 900 parts by volume of a 5% sodium chloride solution and two 430 parts portions of ether. The ethereal extracts are combined, washed with water, dried over anhydrous sodium sulfate and stripped in vacuo to give an oil which solidifies upon standing. This solid is crystallized from n-pentane to afford, as a white solid, 2-(2,2-diphenylethyl)-1-azabicyclo[2.2.2]-octane, melting at about 87.5°-89.0° C. This compound is represented by the following structural formula. ##STR10##
Reaction SMILES: [CH3:1][S:2][C:3]([S:8][CH3:9])=[CH:4][N+:5]([O-:7])=[O:6].[OH:10]O>C(O)(=O)C.CC(CC)=O>[CH3:1][S:2]([C:3]([S:8][CH3:9])=[CH:4][N+:5]([O-:7])=[O:6])=[O:10]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: OO
Solvent: CCC(C)=O
Solvent: CC(=O)O
Product: CSC(=C[N+](=O)[O-])S(C)=O
Reaction time: 17 h

Procedure:
To a stirred solution in acetic acid (4,500 ml) of 1,1-bismethylthio-2-nitroethylene (165 g) at 60° was added over 15 minutes 30% (100 volume) hydrogen peroxide (113 ml) and the reaction mixture maintained, with stirring, at 60° for 17 hours. Evaporation of the solvent under reduced pressure gave a residue which was taken up in methylethylketone, reevaporated and finally crystallised from methylethylketone to yield the title product as a yellow solid m.p. 137°-143°. Further purification yielded the pure "Z" and "E" isomers. One of these had m.p. 145°-148° and from the mother liquors the other isomer was obtained after further working up and recrystallisation from methylal, m.p. 90°-93°.
Reaction SMILES: NCCCCCC(O)=[O:8].[CH:10]1([N:16]=[C:17]=[N:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C)C=O>[CH:19]1([NH:18][C:17](=[O:8])[NH:16][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NCCCCCC(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 18 atom homobifunctional linker was then synthesized from 5.0 g disuccinimidyl ester intermediate dissolved in 150 ml dry dimethylformamide, 4.20 g 6-aminocaproic acid and 6.93 g dicyclohexylcarbodiimide. The 6-aminocaproic acid was added to the dimethylformamide solution, and the resulting reaction mixture was stirred under a nitrogen blanket for three hours at room temperature of about 22°. The dicyclohexylcarbodiimide was then added, and the reaction mixture was stirred under a nitrogen blanket for about 16 hours at room temperature. Dicyclohexyl urea precipitate which had formed was then separated from the reaction mixture by filtration, and dimethylformamide was evaporated from the filtrate under reduced pressure. Trituration with ether followed by drying under high vacuum yielded 7.94 g 18 atom homobifunctional linker.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:5](=[CH:10][C:11]([N:22]([CH3:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:12]([N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH:13]=1)[C:6]([O:8]C)=O.[NH3:31]>C(O)CO>[CH3:15][N:14]([C:12]1[CH:13]=[C:4]2[C:3](=[O:2])[NH:31][C:6](=[O:8])[C:5]2=[CH:10][C:11]=1[N:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:29])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(N(C)c2ccccc2)c(N(C)c2ccccc2)cc1C(=O)OC
Reactant: N
Solvent: OCCO
Product: CN(c1ccccc1)c1cc2c(cc1N(C)c1ccccc1)C(=O)NC2=O

Procedure:
Analogously to Example 1, 66 mg (0.16 mmol) of 4,5-bis(N-methyl-N-phenylamino)phthalic acid dimethyl ester (Example 14 A) in 5 ml of ethylene glycol are heated at 120° and, with stirring, ammonia gas is passed through the mixture for 18 hours. The reaction mixture is cooled, and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with hexane/ethyl acetate 1:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of slightly yellow crystals, FAB-MS: 358 [M+ +H], 1H-NMR (CDCl3): 3.05 (s, 6H).