Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClCCCl.CC#N.C(OC1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH:20][C:21]2[CH:26]=[C:25]([NH:27][CH3:28])[CH:24]=[CH:23][C:22]=2[N+:29]([O-:31])=[O:30])=[O:19])=[CH:13]C=1)C.[C:32](Cl)(=[O:37])[CH2:33][CH:34]([CH3:36])[CH3:35].[CH3:39][CH2:40][O:41][CH2:42][CH3:43]>CN(C1C=CN=CC=1)C>[CH2:40]([O:41][C:42]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([NH:20][C:21]2[CH:26]=[C:25]([N:27]([CH3:28])[C:32](=[O:37])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH:24]=[CH:23][C:22]=2[N+:29]([O-:31])=[O:30])=[O:19])=[CH:13][CH:43]=1)[CH3:39]
Reactant: CCOCC
Reactant: CC(C)CC(=O)Cl
Reactant: CCOc1ccc(CC(=O)Nc2cc(NC)ccc2[N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CC#N
Product: CCOc1ccc(CC(=O)Nc2cc(N(C)C(=O)CC(C)C)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
To a 1:1/DCE:CH3CN solution (50 mL) of 4-ethoxy-N-[5-(methylamino)-2-nitrophenyl]-benzeneacetamide (845 mg, 2.56 mmol) and DMAP (470 mg, 1.5 eq) was added isovaleryl chloride (0.47 mL, 1.5 eq). The solution was stirred at rt for 48 h. The solution was then washed with 5% KHSO4, saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 7:1/CH2Cl2:ether to give the desired product 4-ethoxy-N-[5-[methyl(3-methyl-1-oxobutyl)amino]-2-nitrophenyl]-benzeneacetamide (1.06 g, 99% yield); 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.21 (d, J=8.8 Hz, 1H), 7.26 (m, 3H), 6.96 (m, 2H), 4.06 (m, 2H), 3.76 (s, 2H), 3.31 (s, 3H), 2.15 (m, 3H), 1.42 (t, J=7.2 Hz, 3H), 0.88 (d, J=6.8 Hz, 6H).
Reaction SMILES: C([NH:8][C:9]1[N:14]=[CH:13][C:12]([N:15]([CH3:35])[C:16](=[O:34])[C:17]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)([CH3:19])[CH3:18])=[C:11]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH3:42])[CH:10]=1)C1C=CC=CC=1.Cl>C(O)C.CO.[Pd]>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([N:15]([CH3:35])[C:16](=[O:34])[C:17]([C:20]2[CH:21]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:25]=2)([CH3:19])[CH3:18])=[C:11]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH3:42])[CH:10]=1
Reactant: Cc1ccccc1-c1cc(NCc2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1ccccc1-c1cc(N)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 81 %

Procedure:
A solution of 750 mg (1.28 mmol) N-(6-benzylamino-4-o-tolyl-pyridin-3-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 25 ml of a 5 N solution of hydrochloric acid in ethanol was evaporated to dryness and the residue was dissolved in 30 ml methanol and hydrogenated in the presence of 60 mg 10% palladium on activated charcoal (room temperature, 10 bar) for 20 h. After filtration of the catalyst and evaporation of the solvent the residue was dissolved in 30 ml ethyl acetate, washed twice with saturated aqueous sodium hydrogencarbonate solution and dried (magnesium sulfate). Evaporation of the solution afforded 514 mg (81%) of the title compound as light brown crystals. MS m/e (%): 496 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[C:10]([CH2:15][CH3:16])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].II>C(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([NH:8][NH:9][CH:10]([CH2:15][CH3:16])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=NNC(=O)OC(C)(C)C)C(C)(C)C
Agent: [Pd]
Agent: II
Solvent: ClCCl
Product: CCC(NNC(=O)OC(C)(C)C)C(C)(C)C

Procedure:
Approximately 10.3 g N′-(1-ethyl-2,2-dimethyl-propylidene)-hydrazinecarboxylic acid tert-butyl ester was mixed with 4.14 g (3.9 mmol) 10% Pd/C in CH2Cl2 under an atmosphere of hydrogen in a Parr shaker for four hours. The reaction was monitored by TLC (I2 indicator), and the crude product was twice chromatographed using 10% ether in hexane to yield N′-(1-ethyl-2,2-dimethylpropyl)-hydrazinecarboxylic acid tert-butyl ester. 1H NMR (CDCl3, 500 MHz) δ (ppm): 6.05 (br, 1H), 3.9 (br, 1H)), 2.45 (m, 1H), 1.6 (m, 1H), 1.5 (s, 9H), 1.25 (m, 1H), 1.1 (t, 3H), 0.92 (s, 9H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:36][O:37][C:38](=[O:45])[C@@H:39]([C:41]([SH:44])([CH3:43])[CH3:42])[NH2:40]>C(Cl)Cl.C(OCC)(=O)C>[CH3:7][C:4]([CH3:5])([O:3][C:1]([NH:8][C@H:9]([C:17]([NH:40][C@@H:39]([C:38]([O:37][CH3:36])=[O:45])[C:41]([SH:44])([CH3:43])[CH3:42])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:2])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](N)C(C)(C)S
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(C)(C)S
Temperature: 0 °C
Reaction time: 18 h
Yield: 91 %

Procedure:
A solution of Nα -Boc-phenylalanine (10.0 in 50 mL of methylene chloride (CH2Cl2) was cooled to -78° C. under an argon atmosphere. To this magnetically-stirred solution was added N-methylmorpholine (NMM) (3.8 g, 37.7 mmol) and isobutylchloroformate (IBCF) (5.15 g, 37.7 mmol). The reaction was allowed to slowly warm to 0° C., and then was maintained at this temperature for 45 minutes. The mixture was then recooled to -78° C., and treated with 3.8 g (37.7 mmol) of NMM and 7.5 g (37.7 mmol) of D-penicillamine methylester hydrochloride. After the reaction had warmed to room temperature and was stirred for 18 hours, it was diluted with 600 mL of ethyl acetate (EtOAc) and washed with 3×175 mL of 0.5 N potassium bisulfate (KHSO4) and 150 mL of a saturated aqueous sodium chloride solution (brine). The organic solution was then dried over anhydrous sodium sulfate (Na2SO 4), filtered, and stripped of all solvent under reduced pressure. The white solid residue title product was obtained in 91% yield (14.07 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH:20](I)([CH3:22])[CH3:21].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl.CO>CC(O)C.Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH:20]([CH3:22])[CH3:21])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(C)I
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)N1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Temperature: 0 °C
Yield: 30 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (1 g) is alkylated using isopropyl iodide (1.6 ml; 15.5 mmol) and K2CO3 (2.1 g; 15.2 mmol) at RT for 7 days. After aqueous work-up and flash chromatography on silica gel eluting with CH2Cl2/MeOH (30:1) the pure alkylated acetamide (0.45 g; 1.46 mmol) is de-acetylated under reflux in 2-propanol (1.5 ml) and hydrochloric acid (6 N; 5.5 ml). After completion of the reaction the mixture is poured into ice-water and the precipitate is collected to give pure 5-amino-1-isopropyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (0.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[C:11](OC)(=[O:16])[C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH2:9][C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: CC(=O)c1ccccc1Cl
Reactant: COC(=O)C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)CC(=O)c1ccccc1Cl
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
In dimethylformamide (22 ml), 1-(2-chlorophenyl)ethanone (3.56 g) and dimethyl oxalate (3.26 g) were dissolved, and 60% sodium hydride suspension in oil (1.1 g) was added thereto while stirring at 5° C. The mixture was heated at a room temperature for one hour and then at 50° C. for 30 minutes. After being allowed to cool, the mixture was acidified with 2-N hydrochloric acid, and the precipitated crystal was separated by filtration, washed with water, and dried to give the title compound (3.83 g, 69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)=[O:12])[C:4]=1[CH3:22].[CH2:23]=[O:24]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11]([C:13]2[N:14]([CH2:23][OH:24])[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)=[O:12])[C:4]=1[CH3:22]
Reactant: COc1c(C)cnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Reactant: C=O
Solvent: ClCCl
Product: COc1c(C)cnc(CS(=O)c2nc3ccccc3n2CO)c1C
Reaction time: 0.03 h

Procedure:
2-[[(4-Methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole (3.15 g, 10 mmoles) and N,N-dimethylaminopyridine (120 mg, 1 mmol) was dissolved in methylene chloride (50 ml). A solution of formaldehyde (5M, 10 ml, 50 mmol) was added and the mixture was stirred violently for 2 minutes. The phases were separated and the methylene chloride solution was dried (sodium sulphate), filtered and evaporated to dryness. The slightly red residue was the title compound as an essentially pure oil.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([Sn](CCCC)(CCCC)CCCC)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH2:2][CH3:3].Br[C:27]1[N:28]=[C:29]([N:37]2[CH2:42][CH2:41][N:40]([CH:43]=[O:44])[CH2:39][CH2:38]2)[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C.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>[CH:43]([N:40]1[CH2:39][CH2:38][N:37]([C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:36]=[C:27]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH2:1][CH2:2][CH3:3])(=[O:5])=[O:6])=[CH:12][CH:11]=3)[N:28]=2)[CH2:42][CH2:41]1)=[O:44]
Reactant: O=CN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(S(=O)(=O)CCC)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)c1ccc(-c2cc3ccccc3c(N3CCN(C=O)CC3)n2)cc1
Yield: 61.8 %

Procedure:
Propyl-(4-tributylstannylphenyl)sulfone (1.59 g) and 3-bromo-1-(4-formylpiperazin-1-yl)isoquinoline (0.93 g) were heated under reflux in the presence of tetrakistriphenylphosphinepalladium(0) (0.13 g) in xylene in nitrogen atmosphere overnight. After cooling, the reaction solution was diluted with ethyl acetate and filtered. The filtrate was extracted with 5N hydrochloric acid, and the resulting aqueous layer was washed with ethyl acetate. Then, it was adjusted to pH 10 by a 8N aqueous solution of sodium hydroxide, extracted with ethyl acetate, washed with a 10% aqueous solution of sodium carbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (toluene/acetone system), to give 1-(4-formylpiperazin-1-yl)-3-[4-(propylsulfonyl)phenyl]isoquinoline (0.76 g).
Reaction SMILES: [F:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:4][C:5]2[N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=2[CH:21]=1.[H][H]>FC(F)(F)C(O)=O.[Pd]>[F:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)=[CH:4][C:5]2[N:14]3[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1c(=O)c2cc(F)c(N3CCN(C)CC3)cc2n2ccccc12
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c2n(c3cc(N4CCN(C)CC4)c(F)cc3c1=O)CCCC2
Yield: 90.5 %

Procedure:
A mixture of 0.35 g of ethyl 8-fluoro-9-(4-methyl-1-piperazinyl)-6-oxo-6H-benzo[c]quinolizine-5-carboxylate and 0.47 g of 10% palladium-on-carbon in 50 ml of trifluoroacetic acid was shaken under 40 lb. of hydrogen in a Parr apparatus for 18 hours. The mixture was filtered and the solvent evaporated. The concentrate was partitioned between aqueous potassium carbonate and dichloromethane. The organic layer was dried and the solvent removed giving 0.32 g of the desired compound, mp 163°-165° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[O:7][CH2:8][CH2:9][S:10][C:11]=1[C:12]([OH:14])=O.[NH2:15][C:16]1[CH:17]=[CH:18][C:19]([Cl:26])=[C:20]([CH:25]=1)[C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[Cl:26][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:12]([C:11]2[S:10][CH2:9][CH2:8][O:7][C:6]=2[CH3:5])=[O:14])=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: CC1=C(C(=O)O)SCCO1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(NC(=O)C2=C(C)OCCS2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
Thionyl chloride (4.1 g, 0.034 mole) was added to a stirred mixture of 5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxylic acid (4.3 g, 0.027 mole) and methylene chloride (35 ml). The mixture was warmed to a gentle reflux for about 3.5 hours, left stirring overnight at room temperature, and then evaporated under reduced pressure. The solid residue, crude 5,6-dihydro-2-methyl-1,4-oxathiin-3-carbonyl chloride, was dissolved in methylene chloride (50 ml) and the solution treated dropwise at 5°-10° C. over 2 hours with a solution of methyl 5-amino-2-chlorobenzoate (5.1 g, 0.027 mole) and triethylamine (3.1 g, 0.031 mole) in methylene chloride (35 ml). The reaction mixture was stirred at room temperature for a further 3 hours and worked up by washing in sequence with water (50 ml), dilute hydrochloric acid (3.5%, 50 ml), water (50 ml), dilute sodium hydroxide (2%, 25 ml) and water (50 ml). The methylene chloride was then evaporated to leave an oil (8.2 g), which slowly solidified. Recrystallization from methanol (75 ml) gave a beige solid, m.p. 115°-117° C. (5.5 g, 62.5% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=2)[CH3:9])[CH2:4][CH2:3]1.N1C=CC=CC=1.[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([Cl:28])=[O:27]>ClCCl>[ClH:28].[ClH:28].[F:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:25]=1[C:26]([NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([N:8]([CH3:9])[CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)[CH:11]=1)=[O:27]
Reactant: CN1CCC(N(C)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCC(N(C)c2cccc(NC(=O)c3c(F)cccc3F)c2)CC1
Product: Cl
Yield: 106 %

Procedure:
Combine 1-methyl-4-(N-(3-aminophenyl)-N-methylamino)piperidine (Preparation 11, 101 mg, 0.307 mmol), dichloromethane (6 mL) and pyridine (0.125 mL, 1.535 mmol) at 0° C. Add 2,6-difluorobenzoyl chloride (0.048 mL, 0.384 mmol) neat and continue stirring for 1 hr. Dilute with dichloromethane (5 mL) and wash with sodium hydroxide (1N aq., 2×8 mL). Combine the organic layers, dry over magnesium sulphate, filter under reduced pressure and concentrate to dryness. Purify by flash chromatography, eluting with a 20/1 mixture of dichloromethane/(2N ammonia in methanol) to give the free base of the title compound (88 mg, 80%). Following a salt formation method similar to that described in Example 1 gives the title compound as a yellow solid (89 mg): mass spectrum (free base, ion spray): m/z=360.1 (M+1), 1H NMR (free base, CDCl3): 7.56 (bs, 1H), 7.44–7.34 (m, 2H), 7.20 (t, J=8.2 Hz, 1H), 7.00 (t, J=8.2 Hz, 2H), 6.78 (d, J=8.0 Hz, 1H), 6.59 (dd, J=2.2 Hz, 8.2 Hz, 1H), 3.71–3.63 (bm, 1H), 3.14–3.04 (bm, 2H), 2.82 (s, 3H), 2.41 (bs, 3H), 2.11–1.97 (bm, 2H), 1.79 (bd, J=13 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.[CH2:42]([N:44]([C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[CH:49]=1)[CH2:45][CH2:46][NH2:47])[CH3:43]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:47][CH2:46][CH2:45][N:44]([CH2:42][CH3:43])[C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([CH3:54])[CH:49]=2)=[O:40])=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCN(CCN)c1cccc(C)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1)c1cccc(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (151 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1-ethyl-N1-(3-methylphenyl)-1,2-ethanediamine (91 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (139 mg, yield 82%).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].FC(F)(F)C(O)=O.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[Cl:53])[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[O:40])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:20]1=[O:46].N1C=CC=CC=1>C(Cl)Cl>[C:1]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[Cl:53])[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:41]([CH2:44][CH3:45])[CH2:42][CH3:43])=[O:40])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:20]1=[O:46])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(NCCCCCN)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(NCCCCCNC(C)=O)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Reaction time: 1 h
Yield: 56.1 %

Procedure:
A solution of 0.034 g of acetyl chloride in 0.5 ml of DCM is added at RT to a solution of 0.276 g of the compound obtained in EXAMPLE 199, in the form of the free base, and 2 ml of pyridine in 2 ml of DCM and the mixture is stirred for 1 hour. A further 0.034 g of acetyl chloride is added and the reaction mixture is stirred for 30 minutes at RT and concentrated under vacuum. The residue is taken up with AcOEt, the organic phase is washed with water and with a saturated solution of NaCl and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (50/50; v/v) as the eluent to give 0.14 g of the expected product after crystallization from a DCM/iso ether mixture. M.p.=195°-198° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:51]([O:53][C:54]1[CH:62]=[CH:61][CH:60]=[CH:59][C:55]=1[CH:56]([OH:58])[CH3:57])[CH3:52]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:58][CH:56]([C:55]2[CH:59]=[CH:60][CH:61]=[CH:62][C:54]=2[O:53][CH2:51][CH3:52])[CH3:57])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOc1ccccc1C(C)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccccc1C(C)OC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C
Temperature: 25 °C
Yield: 59 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (83 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (115 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-ethoxy-α-methylbenzyl alcohol (70 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (78 mg, yield 55%).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.C([Li])CCC.CCCCCC.[CH3:24][C:25](=[C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28]1)[CH3:26].[Cl-].[NH4+]>O1CCCC1>[CH2:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([C:25]([CH3:26])([CH3:24])[CH2:1][C:2]2[N:3]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:4]=[CH:5][N:6]=2)=[CH:28]1
Reactant: Cc1nccn1-c1ccccc1
Reactant: CC(C)=C1C=Cc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(Cc1nccn1-c1ccccc1)C1=CCc2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 1.58 g 2-methyl-1-phenyl-1H-imidazole (10 mmol) in 15 ml of tetrahydrofuran was cooled to −78° C. and 6.25 ml of 15% n-butyl-lithium in hexane (10 mmol) were added. The resulting mixture was stirred for an additional 20 min and then treated with a solution of 1.56 g 1-(1-methylethylidene)-1H-indene (10 mmol) in 5 ml tetrahydrofuran with vigorous stirring while the temperature was maintained at −78° C. The reaction mixture was allowed to reach room temperature, stirred for 14 h and hydrolyzed with saturated ammonium chloride solution. The organic layer was isolated and the aqueous layer was extracted three times with dichloromethane. The organic layers were dried over MgSO4, filtered and the solvent removed. The crude product was purified by column chromatography with silica as stationary phase. At the beginning a 5/1 hexane/ethyl acetate elution mixture was used (for the separation from 1-(1-methylethylidene)-1H-indene). Then, the elution mixture was changed to 1/1 hexane/ethyl acetate. After removal of the solvent 2.13 g (69%) of 2-[2-(1H-inden-3-yl)-2-methylpropyl]-1-phenyl-1H-imidazole was obtained as an oil.