Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])[CH:17]=1)[C:10]([CH3:31])([CH3:30])[CH2:9]2)=[O:5])C.Cl>CO.O1CCCC1.[OH-].[Na+].O>[CH2:28]([N:25]([CH2:26][CH3:27])[C:23](=[O:24])[NH:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:30])([CH3:31])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1)[CH3:29]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N(CC)CC)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)C(=O)Nc1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 10.1 %

Procedure:
A mixture of 2-[3-(3,3-diethyl-ureido)-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (846 mg, 2 mmol) in methanol (10 mL) and tetrahydrofuran (15 mL), 30% sodium hydroxide in water (10 mL) was stirred at 60° C. for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(3,3-diethyl-ureido)-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (80 mg, 10%) as a white solid: LC/MS m/e calcd for C23H29N3O3 (M+H)+: 396.51, observed: 396.2.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4](N)=[O:5].C(OC(=O)C)(=[O:15])C.C(O)(=O)C.N([O-])=O.[Na+]>C(OCC)C>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:15])=[O:5]
Reactant: Cc1cc(Cl)nc(Cl)c1C(N)=O
Reactant: CC(=O)OC(C)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cc(Cl)nc(Cl)c1C(=O)O
Reaction time: 18 h

Procedure:
A solution of 2,6-dichloro-4-methyl-nicotinamide (6.40 g) in 2:1 acetic anhydride/acetic acid (156 mL) was treated with sodium nitrite (21.5 g), stirred for 18 hours, poured into diethyl ether (600 mL) and filtered. The filtrate was concentrated with a toluene azeotrope, and the concentrate was treated with brine and extracted with ethyl acetate. The extract was dried (MgSO4), filtered, and concentrated; and this concentrate was suspended in hexane, sonicated and filtered.
Reaction SMILES: O[CH:2]=[C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6]CC)=O.[NH:15]([C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[NH2:16].[OH-].[Na+].Cl>C(O)C.O>[N:18]1[CH:19]=[CH:20][CH:21]=[N:22][C:17]=1[N:15]1[C:4](=[O:6])[C:3]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:2][NH:16]1
Reactant: CCOC(=O)C(=CO)c1ccccc1
Reactant: NNc1ncccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1c(-c2ccccc2)c[nH]n1-c1ncccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
19.2 g (0.1 mol) of ethyl α-hydroxymethylene-phenylacetate and 11 g (0.1 mol) of 2-hydrazino-pyrimidine in 150 ml of ethanol are boiled under reflux for 3 hours. The mixture is cooled to room temperature, and 9 g (0.1 mol) of concentrated sodium hydroxide solution are then added dropwise, while stirring. Stirring is then continued for 2 hours at room temperature, and the mixture is then boiled under reflux for 2 hours. The mixture is neutralized with concentrated hydrochloric acid, and diluted with 1 l of water. The precipitated crystals are filtered off under suction and dried in the air. 15 g (63% of theory) of 1-pyrimid-2-yl-4-phenyl-pyrazolin-5-one of melting point 159° to 160° C. (from ethanol) are obtained.
Reaction SMILES: [N:1]1([C:6]2N=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.Cl.[CH3:17]N(C)CCCN=C=NCC.O.N1(O)C2C=CC=CC=2N=N1.[Cl-].[O:40]=[C:41]1[C:50]2[C:45](=[CH:46][C:47]([C@H:51]3[O:56][CH2:55][C@@H:54]4[CH2:57][NH2+:58][CH2:59][CH2:60][N:53]4[CH2:52]3)=[CH:48][CH:49]=2)[CH2:44][CH2:43][O:42]1.CN1CCOCC1>ClCCl>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:12][C:13]([N:58]3[CH2:59][CH2:60][N:53]4[C@H:54]([CH2:55][O:56][C@H:51]([C:47]5[CH:46]=[C:45]6[C:50](=[CH:49][CH:48]=5)[C:41](=[O:40])[O:42][CH2:43][CH2:44]6)[CH2:52]4)[CH2:57]3)=[O:15])=[CH:10][CH:17]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)nc1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C1OCCc2cc([C@@H]3CN4CC[NH2+]C[C@H]4CO3)ccc21
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: O=C1OCCc2cc([C@@H]3CN4CCN(C(=O)Cc5ccc(-n6cnnn6)cc5)C[C@H]4CO3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[6-(1H-Tetrazol-1-yl)pyridine-3-yl]acetic acid (82 mg, 0.40 mmol, 1.3 eq), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (83 mg, 0.43 mmol, 1.4 eq) and 1H-1,2,3-benzotriazol-1-ol hydrate (66 mg, 0.43 mmol, 1.4 eq) were dissolved in dichloromethane (3 mL) in a 16 mL reaction vial. The mixture was stirred at r.t. for 30 min under N2. To the above mixture was added the dichloromethane solution (2 mL) of (3R,9aS)-3-(1-oxo-3,4-dihydro-1H-isochromen-6-yl)octahydropyrazino[2,1-c][1,4]oxazin-8-ium chloride (100 mg, 0.31 mmol, 1.0 eq) that was neutralized with N-methylmorpholine (34 μL, 0.31 mmol, 1.0 eq). The reaction was stirred at r.t. for 18 h, diluted with dichloromethane (10 mL), washed with saturated sodium bicarbonate solution (2×10 mL), brine (5 mL) and water (5 mL). The organic phase was dried over MgSO4, filtered and concentrated to give the crude product. The desired product was obtained after purification by flash column chromatography (0-10% MeOH/CH2Cl2) followed by preparative TLC (NH4OH/MeOH/CHCl3: 0.5:4.5:95): LC-MS (IE, m/z): [(M+1)-28]+=448.5, [(M+Na]+=498.4: 1H NMR (500 MHz, CDCl3, δ in ppm): 9.41 (1H, m), 7.99 (2H, m), 7.81 (1H, m), 7.28 (2H, m), 4.55-4.75 (1H, m), 4.45-4.55 (2H, m), 3.93 (1H, dd, J=3.2 Hz, J=11.2 Hz), 3.70-3.92 (3H, m), 3.40-3.55 (2H, m), 3.01 (2H, t, J=6.0 Hz), 2.80-3.00 (3H, m), 2.33 (1H, t, J=2.6 Hz,), 2.15-2.30 (3H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[OH:20])[N:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(N(CC)CC)C>C(Cl)Cl>[F:19][C:18]1[C:13]([C:4]2[N:3]=[C:2]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=2)=[C:14]([OH:20])[CH:15]=[CH:16][CH:17]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCNCC3)nc(-c3c(O)cccc3F)nc2c1
Yield: 84.3 %

Procedure:
2-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol (4.37 g, 15.14 mmol) was suspended in CH2Cl2 (65 mL) under an N2 atmosphere and placed into an ice water bath. To this solution was added a solution of piperazine (4.00 g, 45.42 mmol) and triethylamine (4.2 mL, 30.28 mmol) in CH2Cl2 (15 mL) in one portion. After stirring the reaction for 30 minutes, it was partitioned between CH2Cl2 and H2O and separated, and the aqueous layer was extracted twice more with CH2Cl2. The organic phase was dried over Na2SO4, filtered, and concentrated to a bright yellow solid which was purified via silica gel chromatography using a 95%/5% mixture of CH2Cl2/MeOH to afford 3-fluoro-2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (4.32 g, 85%) as a bright yellow solid. LC/MS: m/z 339.3 (M+H)+ at 1.80 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:15])[N+:8]([O-])=[C:7]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:6]=12>CO>[CH3:3][O:4][C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH3:15])[N:8]=[C:7]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:6]=12
Reactant: [H][H]
Reactant: COC(=O)c1c(OC)c2c([n+]([O-])c1C)CCCCC2
Solvent: CO
Product: COC(=O)c1c(C)nc2c(c1OC)CCCCC2
Yield: 99.5 %

Procedure:
Methanol (5.0 ml) was added to Raney nickel water suspension (0.2 ml) and stirred at room temperature for 30 minutes in an atmosphere of hydrogen. The reaction solution was mixed with methanol solution (6.0 ml) of methyl 4-methoxy-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-carboxylate N-oxide (607.9 mg, 2.29 mmol) and stirred at room temperature for 30 hours in an atmosphere of hydrogen. After removal of the catalyst by filtration, the resulting residue was washed with methanol, the solvent was evaporated under reduced pressure, and the thus obtained residue was dissolved in ethyl acetate and dried over anhydrous sodium sulfate. After evaporation of the solvent under reduced pressure, the resulting residue was purified by a silica gel column chromatography (ether:hexane=2:1) to obtain the title compound (567.8 mg, 99.6%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])#[N:25].Cl.CCOCC>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([C:29]([C:28]4[CH:27]=[C:26]([CH:34]=[CH:33][CH:32]=4)[C:24]#[N:25])=[O:30])[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: N#Cc1cccc(C(=O)Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(C(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 mL, 0.29 mmol) were dissolved in THF (2 mL). 3-Cyanobenzoyl chloride (48 mg, 0.29 mmol) was added dropwise, and the reaction solution was allowed to stir at room temperature for 1 h. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. The resulting precipitate was filtered and dried under vacuum to provide 23 (25 mg, 28% yield) as a pale yellow solid. LC-MS (M+H=337, obsd.=337).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:12]([OH:22])[CH:11]=1)([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:23]=O.Cl.[H][H]>[Pd]>[CH3:9][C:2]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH3:23])[CH2:17]2)=[C:12]([OH:22])[CH:11]=1)([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C=O
Reactant: [H][H]
Reactant: CCCCCCC(C)(C)c1ccc(C2CCCNC2)c(O)c1
Agent: [Pd]
Agent: Cl
Product: CCCCCCC(C)(C)c1ccc(C2CCCN(C)C2)c(O)c1
Yield: 90 %

Procedure:
A mixture of 600 mg. (1.98 mmoles) of 3-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]-piperidine, 0.78 ml. of 37% formaldehyde, 1.98 ml. of 1 N hydrochloric acid and 150 mg. of 5% palladium-on-carbon is hydrogenated under 55 p.s.i. of hydrogen for 1.5 hours. The reaction mixture is filtered through diatomaceous earth and concentrated under reduced pressure. The residue is diluted with 75 ml. of saturated sodium bicarbonate and extracted with two 75 ml. portions of dichloromethane. The combined extract is washed with 75 ml. of saturated sodium chloride, dried over magnesium sulfate and evaporated to yield 567 mg. (90%) of the title compound as an oil.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4]1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].CCN(C(C)C)C(C)C.C(Cl)Cl>[Pd].CCO>[CH3:9][S:10]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([NH:2][CH3:1])[CH2:4]1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: CNC1CCCNC1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCO
Product: CNC1CCCN(S(C)(=O)=O)C1

Procedure:
1-(Methanesulfonyl)-3-(methylamino)piperidine was prepared from N3-Cbz protected 3-methylamino-piperidine: i) CH3SO2Cl, i-Pr2NEt, CH2Cl2; ii) H2 (1 atm), 10% Pd/C, EtOH. (m/z): [M+H]+ calcd for C7H16N2O2S 193.10; found, 193.0. 1H-NMR (DMSO-d6; TFA salt): δ (ppm) 3.4 (dd, 1H), 3.2 (m, 2H), 3.10 (s, 3H), 3.0-2.9 (m, 2H), 2.8 (s, 3H), 1.85-1.75 (m, 2H), 1.6-1.4 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[CH3:17][S:18]([O:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(Br)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(Br)cn1
Reaction time: 2.5 h

Procedure:
A solution of (5-bromo-pyridin-2-yl)-methanol (20.0 g, 106 mmol) in 150 mL of dichloromethane was cooled to 0° C. under nitrogen. Triethylamine (19.3 mL, 138 mmol) was added, followed by methanesulfonyl chloride (9.95 ml, 128 mmol). After 2.5 hours, the mixture was quenched with 50 mL of water and diluted with 100 mL of dichloromethane. The organic layer was washed with an additional 50 mL of water and then the aqueous layer was extracted with 100 mL of methylene chloride. The organic extracts were dried over sodium sulfate, filtered and concentrated to provide (5-bromopyridin-2-yl)methyl methanesulfonate as a red solid that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 268.1 for M+H+(81Br).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([O:20][S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2].[O:30]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O1CCOCC1.O.[NH4+].[Cl-]>[OH:30][C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([O:20][S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2]
Reactant: CC(C)c1cc(-c2cccc(OS(=O)(=O)c3ccccc3)c2)c2ncccc2c1
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(O)c1cc(-c2cccc(OS(=O)(=O)c3ccccc3)c2)c2ncccc2c1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To solution of KBrO3 (1.1 eq) in 5 mL of dioxane/water (3/2; 0.14M) was added the quinoline of EXAMPLE 25 (1.0 eq) and CAN (0.1 eq). The mixture was stirred at 75° C. for 16 h, poured in saturated aqueous NH4Cl and extracted with CH2Cl2 (2×). The combined organic extracts were dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 1:1) afforded the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[C:4](Cl)[C:3]=1[Cl:15].[OH-:16].[Na+].[OH2:18]>>[Cl:15][C:3]1[C:4]([OH:18])=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:16]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(Cl)c1Cl
Reactant: O
Reactant: [OH-]
Agent: [Na+]
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(O)c(Cl)c1O
Reaction time: 6 h
Yield: 75 %

Procedure:
The procedure of Example 1 is repeated several times using the amounts of 1,2,3-trichloro-4,6-dinitrobenzene (TCDNB), water and caustic soda shown in Table 1. (Caustic soda is added in a 50 weight percent aqueous solution, but the quantity shown is the quantity of caustic soda alone.) The TCDNB is mixed with water in a 1000 ml resin kettle equipped with a double-paddle stirrer, a thermometer and a reflux condenser. The stirrer is set for 1000 rpm. The reaction mixture is heated. The caustic soda solution is added in each case when the temperature reaches about 70° C. The temperature of the reaction is raised to and maintained at about the temperature shown in Table 1. Samples are analyzed by GC at regular intervals throughout the reaction. Each reaction is continued for 6 hours and then terminated, except that the reaction of sample 15 is terminated after 3 hours when GC shows that the reaction is completed. The GC analysis shows that those samples having an asterisk (*) were not complete when the reaction was terminated after 6 hours. Samples without an asterisk yield 2-chloro-4,6-dinitroresorcinol with at least 90 percent purity and a 75 percent yield. The major impurity in samples with an asterisk is unconverted 2,3-dichloro-4,6-dinitrophenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH2:11][C:12](=[O:18])[NH:13]2.[OH:19][CH:20]([CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1[CH:31]=O)=[O:24].N1CCCCC1>C(O)C>[OH:19][CH:20]([CH2:33][N:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[CH2:21][NH:22][C:23]([C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][C:26]=1/[CH:31]=[C:11]1\[C:12](=[O:18])[NH:13][C:14]2[C:10]\1=[C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH:17]=[CH:16][CH:15]=2)=[O:24]
Reactant: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2F)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCC(O)CN2CCCC2)c(/C=C2\C(=O)Nc3cccc(-c4ccc(F)cc4F)c32)[nH]1
Yield: 60 %

Procedure:
4-(2,4-Difluoro-phenyl)-1,3-dihydro-indol-2-one (73.5 mg, 0.3 mmol) was condensed with 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-pyrrolidin-1-yl-propyl)-amide (excess) and piperidine in ethanol to give 75 mg (60%) of the titled compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1.CCCCC.[H-].[Na+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[N:13]([CH2:28][C:27]1[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=1)[C:12]1[CH2:11][CH2:10][CH2:9][C:8](=[O:15])[C:7]2=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C1CCCc2[nH]c3c(Cl)cccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C1CCCc2c1c1cccc(Cl)c1n2Cc1ccc(F)cc1
Reaction time: 0.37 h
Yield: 70.8 %

Procedure:
8-Chloro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.1973 g, 0.90 mmol) is added to a slurry of pentane-washed NaH (0.0286 g, 0.72 mmol) in DMF (1 mL) and, after stirring for 22 min, p-fluorobenzyl bromide (0.14 mL, 0.0011 mol) is added. Starting material remained after 30 min, so additional NaH (0.0166 g, 0.42 mmol) and DMF (1.8 mL) are added. The mixture is stirred for 1 h, at which time the mixture is partitioned between aq. sodium bicarbonate and ethyl acetate. The organic layer is dried over sodium sulfate and concentrated to dryness. The resulting solids are recrystallized from 30% ethyl acetate/hexane and dichloromethane to give 0.2088 g (71%) of the title compound; mp 166-166.5° C.; MS (ESI+) for C19H15ClFNO m/z 328.1 (M+H)+; IR (drift) 1639, 1607, 1510, 1485, 1449, 1426, 1413, 1226, 1189, 1157, 1108, 1095, 830, 790, 734 cm−1; 1H NMR (CDCl3) δ2.22, 2.59, 2.84, 5.78, 6.97, 7.19, 8.27. Anal. Calcd for C19H15ClFNO: C, 69.62; H, 4.61; N, 4.27. Found: C, 69.44; H, 4.55; N, 4.34.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:42])C=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[N:4]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]([CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N+:8]([O-:42])=[CH:7][C:6]=2[N:15]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1nc2cnc3ccccc3c2n1CCCCN(C(=O)OC(C)(C)C)C1CCOCC1
Solvent: ClC(Cl)Cl
Product: CCc1nc2c[n+]([O-])c3ccccc3c2n1CCCCN(C(=O)OC(C)(C)C)C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [4-(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-ylcarbamate in chloroform was added m-chloroperbenzoic acid (4 eq.) and stirred at ambient temperature for 2 hrs. Reaction mixture was then diluted with chloroform and washed with saturated sodium bicarbonate solution. Organic layer was dried over sodium sulphate and concentrated under reduced pressure to yield sticky mass. Product was then purified using silica gel column chromatography to afford tert-butyl [4-(2-ethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)butyl]tetrahydro-2H-pyran-4-ylcarbamate.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.[NH2:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12].[H][H].N1C2C(=CC=CC=2)C=C1.[NH2:27][C@H:28]([C:39](O)=[O:40])[CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1>>[CH3:12][C@H:11]([NH:10][C:39]([C@@H:28]([NH2:27])[CH2:29][C:30]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[NH:32][CH:31]=1)=[O:40])[C:13]([OH:15])=[O:14]
Reactant: C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: [H][H]
Agent: c1ccc2[nH]ccc2c1
Product: C[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
NMR (1H) in DMSO-d6 10.92 (1H, s) NH indole, 8.45 (1H, broad s) NH Ala, 7.63 (1H, d) H4 indole, 7.32 (1H, d) H7 indole, 7.20 (1H, s) H2 indole, 7.05 (1H, t) H6 indole, 6.97 (1H, t) H5 indole, 4.16 (1H, broad q) HαAla, 3.76 (1H, dd) Hα Trp, 3.19 (1H, dd) HβA Trp, 2.90 (1H, dd) HβB Trp, 1.25 (1H, t) CH3 Ala
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]([OH:5])[OH:4].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH3:16][C:17]1[CH:22]=[CH:21][C:20](S(O)(=O)=O)=[CH:19][CH:18]=1>C1C=CC=CC=1>[CH2:8]([O:4][CH:3]([O:5][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:2]([Cl:7])([Cl:6])[Cl:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: CCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCCCOC(OCCCCCCC)C(Cl)(Cl)Cl

Procedure:
A mixture of 5 g of chloral hydrate, 12 g of heptanol, 0.1 g of 4-methyl-benzene-sulphonic acid and 50 ml of benzene is kept at reflux temperature and the formed water is separated by means of a Dean-Stark apparatus. Afater a reaction time of 9 hours the benzene is washed with a sodium hydrogen carbonate solution and water, dried on magnesium sulfate, then vacuum distilled.
Reaction SMILES: [Br:1]C[C:3]1[C:8]2=[CH:9][O:10][N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18]COCC>>[Br-:1].[N:11]1[O:10][C:9]([CH2:18][C:15]2[CH:16]=[CH:17][NH+:12]=[CH:13][CH:14]=2)=[C:8]2[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=12
Reactant: BrCc1cccc2nocc12
Reactant: c1ccncc1
Reactant: CCOCC
Product: [Br-]
Product: c1ccc2c(Cc3cc[nH+]cc3)onc2c1
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 3.99 g (18.8 mmoles) (2) in 30 ml ether under nitrogen was added 1.49 g (18.8 mmoles) pyridine. A white precipitate formed and the mixture was stirred overnight. The precipitate was then filtered off, washed with ether, and dried to give 3.64 g (66%) 4-(2,1-benzisoxazolyl)methylpyridinium bromide, m.p. 172°-174°; nmr (DMSO-d6): 6.3 (s, 2H), 7.5 (m, 3H), 8.2 (m, 2H), 8.9 (m, 1H), 9.6 (dd, 2H), 10.3 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]12[CH2:11][CH2:10][N:7]([CH2:8][CH2:9]1)[CH2:6][C:5]2=[O:12])[CH:2]=[CH2:3].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH-].[Na+]>C(O)C>[CH2:1]([C:4]12[CH2:9][CH2:8][N:7]([CH2:10][CH2:11]1)[C:6](=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]2=[O:12])[CH:2]=[CH2:3]
Reactant: C=CCC12CCN(CC1)CC2=O
Reactant: O=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCC12CCN(CC1)C(=Cc1ccccc1)C2=O
Yield: 98 %

Procedure:
4-Allyl-1-azabicyclo[2.2.2]octan-3-one, 57 (17.66 g, 107 mmol), benzaldehyde (12.49 g, 117 mmol) and sodium hydroxide (0.46 g, 11.5 mmol) were dissolved in 80 ml of ethanol, and the resultant mixture was heated at reflux for 1 hour. After the mixture was cooled down, yellow solids were collected to provide 4-allyl-2-benzylidene-1-azabicyclo[2.2.2]octane-3-one (26.66 g, 98%).