Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].C([N+:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:10][CH:9]=1)CCCCC.N1C=CC(O)=CC=1.COCCOCCOCCOCCOS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][N:8]=[CH:9][CH:10]=1
Reactant: CCCCCC[n+]1ccc(OCCOCCOCCOCCOC)cc1
Agent: COCCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: Oc1ccncc1
Agent: [Br-]
Product: COCCOCCOCCOCCOc1ccncc1
Temperature: 100 °C

Procedure:
Preparation of 1-hexyl-4-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]ethoxy}-ethoxy)-pyridinium bromide—Pyridin-4-ol (1.50 g, 15.77 mmol) and toluene-4-sulfonic acid 2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethyl ester (5.62 g, 19.71 mmol) were combined in a 50 mL round bottomed flask equipped with condenser, magnetic stir bar, and a positive flow of nitrogen. The solution was heated in a 100° C. oil bath for 24 hrs. The solution was then cooled and placed on a vacuum line at 1 mmHg and heated at 80° C. for 6 hrs to removed residual starting materials. The by-product was removed via washing with deionized water (3×15 mL) to afford 4-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-pyridine. The product may be subsequently purified employing column chromatography techniques at this point or may proceed directly to the addition of 1-bromohexane (3.90 g, 23.66 mmol) in 25 mL tetrahydrofuran. Stirring the resulting reaction mixture at 50° C. for 24 hrs resulted in the desired product, 1-hexyl-4-(2-{2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxy}-ethoxy)-pyridinium bromide in a 38% yield (2.70 g, 5.99 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH2:23]([N:25]1[CH:30]=[C:29]([C:31](O)=[O:32])[C:28](=[O:34])[N:27]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[C:26]1=[O:42])[CH3:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13][CH3:14])[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:31]([C:29]2[C:28](=[O:34])[N:27]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:26](=[O:42])[N:25]([CH2:23][CH3:24])[CH:30]=2)=[O:32])=[CH:20][CH:21]=1
Reactant: CCn1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc(OC)c2nccc(Oc3ccc(N)cc3)c2c1
Product: CCn1cc(C(=O)Nc2ccc(Oc3ccnc4c(OC)cc(OC)cc34)cc2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 4-(6,8-dimethoxy-quinolin-4-yloxy)-phenylamine and 1-ethyl-3-(4-fluorophenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=127-9° C.; LCMS m/z=557 (M+1); 1H NMR (DMSO) δ: 10.93 (s, 1H), 8.87 (s, 1H), 8.45 (d, 1H, J=5 Hz), 7.79 (d, 2H, J=8.8 Hz), 7.41-7.45 (m, 2H), 7.33-7.37 (m, 2H), 7.24- (d, 2H, J=8.8 Hz), 7.10 (d, 1H, J=2.3 Hz), 6.86 (d, 1H, J=2.3 Hz), 6.61 (d, 1H, J=5 Hz), 4.01 (q, 2H, J=7 Hz), 3.94 (s, 3H), 3.89 (s, 3H), 1.29 (t, 3H, J=7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([O:13]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH:5]=1.[C:24]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([NH:32][C:31]2[CH:33]=[CH:34][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][CH:30]=2)=[O:13])[CH:5]=1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COC(=O)c1cccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Solvent: c1ccncc1
Product: COC(=O)c1cccc(NC(=O)Nc2ccc(C(C)(C)C)cc2)c1

Procedure:
A solution of methyl-3-[N-(4-nitrophenoxycarbonyl)amino]benzoate (0.19 g, 0.60 mmol) and 4-tert-butylaniline (0.10 mL, 0.60 mmol) in pyridine (5 mL) was heated to reflux for 16 h. The solution was cooled and evaporated, and the residual material was taken up in ethyl acetate (100 mL). This was washed with 1 N aq. sodium hydroxide and brine, dried over magnesium sulfate, filtered and evaporated. The residual solid was triturated with ether, collected by filtration and dried under vacuum to afford the product, methyl-3-[3-(4-tert-butylphenyl)-ureido]-benzoate, as a solid (0.19 g, 0.58 mmol, 97%).
Reaction SMILES: NO.[C:3]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][S:14][CH:13]2[C:17]([NH:19][CH:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:21][CH2:22]O)=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:36]([NH2:47])(=[O:46])[C:37]1[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:39](N)=[O:40].CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:3]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:16][CH2:15][S:14][CH:13]2[C:17]([NH:19][CH:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:21][CH2:22][N:47]2[C:36](=[O:46])[C:37]3[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:39]2=[O:40])=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: NC(=O)c1ccccc1C(N)=O
Reactant: O=C(NC(CCO)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: NO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NC(CCN1C(=O)c2ccccc2C1=O)c1ccccc1)C1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57 %

Procedure:
Intermediates of general structure (XXVI), e.g., 3-([1,1′-biphenyl]-4-ylsulfonyl)-N-(3-hydroxy-1-phenylpropyl)-1,3-thiazolidine-2-carboxamide (1.0 g, 1.0 eq, 2.07 mmol) were dissolved in 20 ml dry THF under nitrogen. Phthalamide (395 mg, 1.5 eq, 2.69 mmol), diethylazodicarboxylate (470 mg, 1.5 eq, 2.69 mmol) and polymer bound triphenyl phosphine (1.0 g, 1.5 eq, 2.70 mmol) were then added and the reaction mixture was shaken for 12 hours at RT. The triphenyl phosphine resin was filtered off and the THF solution evaporated in vacuo. The residue was taken up in DCM and washed twice with a saturated sodium carbonate solution and then water. The organic layer was dried with magnesium sulfate and concentrated in vacuo to give a crude product which was purified on silica gel using cyclohexane/ethyl acetate(7/3) as eluent, to obtain the desired products, e.g., 3-([1,1′-biphenyl]-4-ylsulfonyl)-N-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-phenylpropyl]-1,3-thiazolidine-2-carboxamide in 57% yield as a white oil in 96% purity by HPLC.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[CH3:33][S:34]([O:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH2:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:6]=[CH:5][CH:4]=1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1COc1cccc(CO)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1COc1cccc(COS(C)(=O)=O)n1
Reaction time: 2 h
Yield: 104.2 %

Procedure:
tert-Butyl (2S)-2-({[6-(hydroxymethyl)pyridin-2-yl]oxy}methyl)piperidine-1-carboxylate (520 mg, 1.61 mmol) and DIPEA (0.842 ml, 4.84 mmol) dissolved in DCM (10 ml) was cooled using an ice bath. Methanesulfonyl chloride (0.191 ml, 2.419 mmol) was added and the reaction stirred for 2 h. DCM (150 ml) and water (150 ml) were added and the phases separated. The organic phase washed with water (150 ml), dried through a phase separator and evaporated in vacuo, yielding the title compound as a light yellow oil (672 mg (104%)) which was used directly in the next step without further purification. MS (ESI+) 401.20 (M+1H+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:31][NH2:32].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](=[O:18])[NH:32][CH2:31][C:30]3[CH:33]=[CH:34][C:35]([Cl:36])=[C:28]([Cl:27])[CH:29]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCc4ccc(Cl)c(Cl)c4)cc3)c(Cl)cc21
Reaction time: 16 h
Yield: 94.2 %

Procedure:
4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (51.5 mg, 0.137 mmol), in 1:1 DMF:DCM (0.1 M) was sequentially treated with 3,4-dichlorobenzylamine (26.5 mg, 0.150 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.4 mg, 0.164 mmol), and 1-Hydroxy-7-azabenzotriazole (5.58 mg, 0.0410 mmol) at ambient temperature. After 16 hours the reaction was applied directly to a silica gel column and eluted with a gradient (15% to 60%) of ethyl acetate-hexanes to provide the title compound (69.0 mg, 0.129 mmol, 94.4% yield) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].[C:23]([O:26][CH2:27][CH3:28])(=[O:25])C.[Cl-].[Na+]>CC(C)=O.O.C(OC(Cl)=O)C1C=CC=CC=1>[CH2:27]([O:26][C:23]([NH:1][CH2:2][C:3]1([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1)=[O:25])[C:28]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC1(CN)CCOCC1
Reactant: CCOC(C)=O
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC1(CNC(=O)OCc2ccccc2)CCOCC1
Reaction time: 2 h

Procedure:
To a suspension of tert-butyl (4-(aminomethyl)tetrahydro-2H-pyran-4-yl)carbamate (G15, 195 mg) and sodium carbonate (449 mg) in acetone (5 mL) and water (2 mL), benzyloxycarbonyl chloride (241 μL) was added at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, ethyl acetate and saturated aqueous sodium chloride were added. The organic layer was separated, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 0% hexane in ethyl acetate) to obtain tert-butyl (4-(((benzyloxycarbonyl)amino)methyl)tetrahydro-2H-pyran-4-yl)carbamate (G16, 141 mg).
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][N:16]2[C:20]([CH3:22])([CH3:21])[C:19](=[O:23])[NH:18][C:17]2=[O:24])[N:8]=1.[F-].[K+].C([Si](CC)(CC)[C:30]([F:33])([F:32])[F:31])C.CN(C=O)C>ClCCl.[Cu]I.CN1C(=O)CCC1>[CH3:21][C:20]1([CH3:22])[N:16]([CH2:15][CH2:14][NH:13][C:9]2[N:8]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[C:30]([F:33])([F:32])[F:31])[CH:12]=[CH:11][N:10]=2)[C:17](=[O:24])[NH:18][C:19]1=[O:23]
Reactant: CC[Si](CC)(CC)C(F)(F)F
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2sccc2I)n1
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2sccc2C(F)(F)F)n1
Temperature: 80 °C
Reaction time: 72 h

Procedure:
A sealed tube charged with 1-(2-(4-(3-iodothiophen-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethylimidazolidine-2,4-dione (0.300 g, 0.656 mmol), copper (I) iodide (0.275 g, 1.44 mmol), spray-dried potassium fluoride (0.075 g, 1.3 mmol), triethyl(trifluoromethyl)silane (0.25 mL, 1.3 mmol), DMF (1.0 mL), and NMP (1.0 mL) was heated to 80° C. and allowed to stir for 72 h. At that time, the mixture was diluted with 20 mL dichloromethane and filtered. The pale green filtrate was then purified through Celite and the plug was washed with 10% MeOH/dichloromethane and H2O. The organic solvents were removed from the biphasic mixture in vacuo and the aqueous residue was then partitioned between dichloromethane and H2O. The organic phase was separated, concentrated and the residue purified by flash chromatography, eluting with 1-6% MeOH/dichloromethane to afford the product as a white solid. MS (M+H)+ 400.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.Cl.[NH:27]1[C@H:31]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:30][C@@H:29]2[CH2:42][CH2:43][CH2:44][C@H:28]12>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]([N:27]2[C@H:31]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:30][C@@H:29]3[CH2:42][CH2:43][CH2:44][C@H:28]23)=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCC[C@@H]2N1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCC[C@@H]2N1C(=O)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
4.92 g (30 mmol) of 4-phenylbutyric acid are dissolved together with 8.4 ml of triethylamine in 200 ml of dry tetrahydrofuran. While cooling in ice, 2.9 ml of ethyl chloroformate are added dropwise. After stirring at 0° C. for 1 hour, 7.4 g of benzyl (2S,3aS,6aS)-octahydrocyclopenta[b]pyrrole-2-carboxylate hydrochloride are added, and the mixture is stirred at room temperature for a further 12 hours. Filtration is followed by concentration, and the residue is taken up in 3% NaHCO3 /ethyl acetate. The organic phase is separated off and washed with 10% strength citric acid, 3% strength NaHCO3 solution and saturated brine, once each, dried with MgSO4 and concentrated. Chromatography on silica gel with ethyl acetate/cyclohexane (1:2) as mobile phase results in 9.05 g of the title compound as a colorless oil.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH4+].[Cl-].[CH3:15][C:16]1(C)[S:20][C@@H]2[C@H](NC(C(C(O)=O)C3C=CC=CC=3)=O)C(=O)N2[C@H:17]1C(O)=O.C1C([C@@H](O)[C@H](NC(C(Cl)Cl)=O)CO)=CC=C([N+]([O-])=O)C=1.C1[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H]1N>C1N(CCCS(O)(=O)=O)CCOC1>[CH3:15][CH:16]([S:20][C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4])[CH3:17]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)C(C(=O)O)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C(N[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1)C(Cl)Cl
Agent: O=S(=O)(O)CCCN1CCOCC1
Product: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
All liquid cultivations were conducted in MOPS minimal medium (Teknova) [14] cultures supplemented with 5 g/l glucose and an additional 4 g/l NH4Cl. When appropriate, antibiotics were added in the following concentrations: 100 μg/ml carbenicillin for the maintenance of pTrc- or pET-derived plasmids, 34 μg/ml chloramphenicol for pHACM-derived plasmids, 68 μg/ml chloramphenicol for pACYC-derived plasmids and pRARE2 (Novagen), and 20 μg/ml kanamycin for pACKm-derived plasmids. Isopropyl-β-D-thiogalactopyranoside (IPTG, EMD Chemicals) was provided at a concentration of 1 mM for the induction of expression from both trc and T7 promoters. Cultures for L-phenylalanine auxotrophic (ΔpheA) strains were additionally supplemented with L-phenylalanine (Sigma) at a concentration of 0.35 mM. For malonyl CoA availability experiments, cerulenin (Cayman Chemicals) and sodium malonate dibasic (Sigma) were added at a concentration 20 μg/ml and 2 g/l (1 g/l added twice), respectively.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][CH3:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:13][CH2:14][OH:15].B(F)(F)F.CCOCC.[C:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(=O)[CH2:26][CH3:27]>ClCCl>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][C:25]1([CH2:26][CH3:27])[C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH2:13][CH2:14][O:15]1)=[CH:3][C:2]([Br:1])=[CH:10][C:9]=3[CH2:11][CH3:12])[CH3:34]
Reactant: CCOC(=O)CC(=O)CC
Reactant: CCc1cc(Br)cc2c(CCO)c[nH]c12
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CC1(CC)OCCc2c1[nH]c1c(CC)cc(Br)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 53 %

Procedure:
To a solution of 2-(5-bromo-7-ethyl-1H-indol-3-yl)-ethanol in dichloromethane at room temperature under nitrogen was added boron trifluoride diethyl etherate (0.809 g, 5.7 mmol), followed by ethyl propionylacetate (1.038 g, 7.2 mmol). The reaction mixture was stirred at room temperature for 5 hours. It was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 15-20% ethyl acetate/hexane) to give the title compound (0.994 g, 53% yield). ES-MS (m/z) 394 [M+1]+, 392 [M−1]−.
Reaction SMILES: CCCCCC.[H-].[K+].[OH:9][C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1.S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:28][C@H:29]1[O:31][CH2:30]1)(=O)=O>C1COCC1>[O:31]1[CH2:30][C@H:29]1[CH2:28][O:9][C:10]1[C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:23])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: O=C1c2ccccc2-c2c(O)cccc21
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1c2ccccc2-c2c(OC[C@@H]3CO3)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.6 %

Procedure:
A stirred suspension of hexane washed potassium hydride (0.204 g, 5 mmol) in THF was treated in one portion with 4-hydroxy-9-fluorenone (1.0 g, 5.1 mmol). To the purple suspension was added (S)-glycidyl nosylate (1.0 g, 5 mmol) and the mixture was stirred at ambient temperature overnight. The reaction was partitioned with EtOAc. The organic phase was washed with H2O, brine and dried (Na2SO4). The solvent was removed in vacuo to provide crude product. Purification by flash chromatography (CH2Cl2-hexane 3:1) provided 0.210 g of product as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[N:22]2)=[CH:17][CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[N:22]3)=[CH:17][CH:16]=2)[C:9]1=[O:13]
Reactant: Brc1ccc2cccnc2c1
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3cccnc3c2)C1=O
Yield: 65.2 %

Procedure:
Using the same reaction conditions as described in example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 116 mg, 0.6554 mmol) was reacted with 7-bromo-quinoline (150 mg, 0.72098 mmol), 1,4-dioxane (50 mL), copper iodide (12.4 mg, 0.06554 mmol), trans-1,2-diamino cyclohexane (22.5 mg, 0.19638 mmol) and potassium phosphate (347.3 g, 1.6365 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 130 mg of the product (65.3% yield).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.OC1C2N=NNC=2C=CC=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C.[C:49]([C:51]1[N:56]=[CH:55][C:54]([C:57]2[C:69]3[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[N:62]([C:70]4[CH:78]=[CH:77][C:73]([C:74](O)=[O:75])=[C:72]([NH:79][CH:80]5[CH2:85][CH2:84][O:83][CH2:82][CH2:81]5)[CH:71]=4)[C:61]=3[CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:52]=1)#[N:50]>CN(C)C=O.O>[C:49]([C:51]1[N:56]=[CH:55][C:54]([C:57]2[C:69]3[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[N:62]([C:70]4[CH:78]=[CH:77][C:73]([C:74]([NH2:8])=[O:75])=[C:72]([NH:79][CH:80]5[CH2:81][CH2:82][O:83][CH2:84][CH2:85]5)[CH:71]=4)[C:61]=3[CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:52]=1)#[N:50]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: N#Cc1ccc(-c2cccc3c2c2ccccc2n3-c2ccc(C(=O)O)c(NC3CCOCC3)c2)cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: Oc1cccc2[nH]nnc12
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#Cc1ccc(-c2cccc3c2c2ccccc2n3-c2ccc(C(N)=O)c(NC3CCOCC3)c2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.8 %

Procedure:
0.2 g of (1H-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (BOP), 62 mg of hydroxybenzotriazole (HOBT), 33 mg of ammonium chloride and 0.25 ml of diisopropylethylamine are successively added to a solution of 0.15 g of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzoic acid in 20 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 12 hours and then diluted with distilled water and extracted with ethyl acetate. The organic phase is subsequently washed with distilled water and a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (70/30 by volume), so as to give 100 mg of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=1)[CH3:11].C(=O)([O-])O.[Na+].[CH2:25]([NH2:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O>[CH2:25]([N:31]1[CH2:2][CH:3]2[CH:5]([C:4]2([C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[C:18]#[N:19])[CH3:11])[C:6]1=[O:8])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCN
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc(C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(C#N)c1
Temperature: 25 °C
Yield: 35.2 %

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-(3-cyanophenyl)-2-methylcyclopropanecarboxylate (Preparation 35, 5.82 g, 21.1 mmol) in N,N-dimethylformamide (20 ml) at room temperature was added sodium hydrogen carbonate (1.77 g, 21.1 mmol) followed by hexylamine (16.7 ml, 0.13 mol). The mixture was then heated under reflux for 16 h, cooled to room temperature and poured onto ice. After warming to room temperature, the mixture was partitioned against diethyl ether (50 ml). The two layers were separated and the aqueous layer was extracted with diethyl ether (2×30 ml). The ethereal extracts were washed with water (50 ml), dried (MgSO4), filtered and concentrated in vacuo. The crude oil was purified by silica column chromatography eluting with a gradient of hexane:ethyl acetate (5:1 to 0:100) to afford the title compound (2.2 g, 35%) as a colourless oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([N+:14]([O-:16])=[O:15])[N:7]=1.Cl[CH2:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20].[K]>C1COCC1.CN(C=O)C>[C:22]1([S:19]([CH2:18][C:9]2[C:8]([N+:14]([O-:16])=[O:15])=[N:7][C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)=[C:11]([O:12][CH3:13])[CH:10]=2)(=[O:21])=[O:20])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc([N+](=O)[O-])nc1C1OCCO1
Reactant: O=S(=O)(CCl)c1ccccc1
Agent: [K]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(CS(=O)(=O)c2ccccc2)c([N+](=O)[O-])nc1C1OCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.3 %

Procedure:
A mixture of 0.6 g (2.6 mmol) 2-[1,3]dioxolan-2-yl-3-methoxy-6-nitro-pyridine, 0.55 g (2.9 mmol) of chloromethylphenylsulfone and 2.9 ml (2.9 mmol) of potassium t-butoxode (1M solution in THF) in 5 ml of DMF were combined at 5° C. and stirred at ambient temperature for 18 hours. The reaction mixture was quenched with 25 ml of water and extracted with ethyl acetate. The ethyl acetate extracts were combined, dried (Na2SO4), and evaporated. The residue was chromatographed on silica using 5:1 chloroform/ethyl acetate as the elutant. Appropriate fractions were combined and evaporated to yield 0.28 g of 3-benzenesulfonylmethyl-6-[1,3]dioxolan-2-yl-5-methoxy-2-nitro-pyridine as an oil. TLC: Rf=0.4 (1:1 chloroform/ethyl acetate). 1H NMR (CDCl3) δ 7.7 (m, 3H), 7.55 (m, 2H), 7.42 (s, 1H), 6.30 (s, 1H), 4.90 (s, 2H), 4.30 (m, 2H), 4.10 (m, 2H), 4.02 (s, 3H).). Mass Spectrum: m/e=381.0 (p+1).