Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=[O:11].Cl[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([NH2:23])=O>>[C:20]1([C@H:9]2[C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:10](=[O:11])[NH:12][C:10]2=[O:11])[C:15]2=[C:16]3[C:17](=[CH:18][CH:19]=[CH:14]2)[CH2:7][CH2:2][CH2:3][N:23]3[CH:21]=1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Reactant: NC(=O)Cc1ccccc1Cl
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccccc1Cl

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(2-chlorophenyl)-pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with 2-chlorophenylacetamide. 1H NMR (DMSO-d6) 400 MHz δ: 11.655 (s, 1H), 7.41-7.48 (m, 2H), 7.27-7.35 (m, 3H, J=7.2), 7.87 (d, 1H, J=7.6), 6.81-6.88 (m, 2H), 4.632 (d, 1H, J=7.6 Hz), 4.494 (d, 1H, J=7.2), 4.07-4.10 (m, 2H), 2.884 (m, 2H), 2.09 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=1.CCN(CC)CC.[Cl:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Cl)[N:24]=1>CCCCO>[Cl:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25]([NH:12][CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:14][CH:13]=2)[N:24]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: NCc1ccc(-c2ccccn2)cc1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: Clc1nc(NCc2ccc(-c3ccccn3)cc2)c2[nH]cnc2n1
Temperature: 110 °C

Procedure:
4-(2-Pyridyl)benzylamine (2.0 g, 1.05 mmol) and 3 ml of NEt3 are added to a solution of 2,6-dichloropurine (2.3 g, 10 mmol) in 20 ml of n-BuOH. After heating at 110° C. for 3 h, the mixture is cooled to 20° C. and the solid is filtered off, washed with 5 ml of cold butanol and then dried under vacuum. Yd=85. M.p. >250° C. 1H NMR (d6-DMSO) δ 4.80 (s, 2H, CH2); 7.20 (m, 1H, Hpyridyl); 7.45 (d, 2H, Hphenyl); 7.72 (m, 2H, Hpyridyl); 7.95 (m, 3H, Hphenyl and H-8), 8.54 (d, 1H, J=4.8 Hz, Hpyridyl).
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].Cl[S:19]([OH:22])(=[O:21])=[O:20].Cl.C[O-].[Na+:26]>C(Cl)(Cl)Cl>[S:19]([O-:22])([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:21])=[O:20].[Na+:26]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCC(C)CCCCCCO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCC(C)CCCCCCOS(=O)(=O)[O-]
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
Into a dried 1 L 3 neck round bottom flask fitted with a nitrogen inlet, dropping funnel, thermometer, mechanical stirring and nitrogen outlet is added chloroform (300 ml) and 7-methylpentadecanol (119 g, 0.496 mol), prepared as an intermediate in Example II. Chlorosulfonic acid (61.3 g, 0.52 mol) is slowly added to the stirred mixture while maintaining 25-30° C. temperature with an ice bath. Once HCl evolution has stopped (1 hr.) slowly add sodium methoxide (25% in methanol) while keeping temperature at 25-30° C. until a aliquot at 5% concentration in water maintains a pH of 10.5. To the mixture is added methanol (1 L) and 300 ml of 1-butanol. Vacuum filter off the inorganic salt precipitate and remove methanol from the filtrate on a rotary evaporator. Cool to room temperature, add 1 L of ethyl ether and let stand for 1 hour. The precipitate is collected by vacuum filtration. The product is dried in a vacuum oven at 50C for 3 hrs. to obtain a white solid (82 g, 90% active by cat SO3 titration).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:22])[CH2:3]1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].[OH-].[Na+]>O>[CH3:1][C:2]1([CH3:23])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:17][CH:16]=4)=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:22])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(O)cc4)[nH]c3cc21
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CC(=O)Nc2cc3nc(-c4ccc(OS(C)(=O)=O)cc4)[nH]c3cc21

Procedure:
2 g. (6.5 mmole) 8,8-dimethyl-2-(4-hydroxyphenyl)-5,6,7,8-tetrahydro-1H-imidazo[4,5-g]quinolin-6-one (see Example 30 d)) were suspended in 10 ml. water and, while cooling with ice, 5 ml. (65 mmole) methanesulphonic acid chloride and 50 ml. 2N aqueous sodium hydroxide solution were alternatingly added dropwise thereto in such a manner that a pH value of about 10 to 13 was always present. When the reaction was completed, the reaction mixture was filtered off with suction, the product was washed with water and purified by column chromatography (elution agent: methylene chloride/ methanol/acetic acid; 10:1:0.2 v/v/v). The evaporation fractions were suspended in water, rendered ammoniacal and washed with water to give 1.5 g. (68% of theory) of the title compound; m.p. 209°-215° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Al+3].[Li+].[CH3:7][C:8]1[CH:9]=[C:10]([S:15]C#N)[CH:11]=[CH:12][C:13]=1[OH:14].O>O1CCCC1>[CH3:7][C:8]1[CH:9]=[C:10]([SH:15])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: Cc1cc(SC#N)ccc1O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(S)ccc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 250 ml three-necked flask, to a stirred mixture of lithium aluminum tetrahydride (LiAlH4, 0.8 g, 21 mmol) and tetrahydrofuran (30 ml) was added dropwise a solution of 3-methyl-4-hydroxy-phenyl thiocyanic acid (1.1 g, 6.6 mmol) in tetrahydrofuran (THF 30 ml) at 0° C. (cooled with chilled water). After 30 min of stirring at 0° C. and another 2 hours of stirring at room temperature, the reaction was quenched by addition of broken ice in an ice water bath. The value of pH of the mixture was adjusted to 3-4 by adding 6 N hydrochloric acid, and then the aqueous phase was extracted with ethyl acetate (3×100 ml). The combined organic layer was washed with a saturated solution of sodium chloride (2×100 ml), dried over anhydrous magnesium sulfate, filtrated, and evaporated in vacuo to yield a crude product of 3-methyl-4-hydroxy-mercaptobenzene (yellow liquid).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]([CH3:32])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@@H:20]([CH3:31])[CH2:19]3)=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Cl)nc3)cc2)CCN1C(=O)OC(C)(C)C
Reactant: Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2ccc(N(C)C(=O)c3ccc(Oc4ccccc4F)nc3)cc2)CCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 7 h
Yield: 32.6 %

Procedure:
1,1-Dimethylethyl (2S)-4-({4-[[(6-chloro-3-pyridinyl)carbonyl](methyl)amino]phenyl}methyl)-2-methyl-1-piperazinecarboxylate (D54) (0.1 g, 0.218 mmol) and 2-fluorophenol (0.025 g, 0.436 mmol) were dissolved in DMF (5 mL). Potassium carbonate (0.06 g, 0.436 mmol) was added and the mixture was heated to 80° C. overnight then at 130° C. for 7 h. The mixture was left to stand at room temperature overnight and the solvent removed under vacuum. The residue was partitioned between EtOAc and water. The organic layer was dried and concentrated to produce a brown oil. The crude product was purified by MDAP to yield the formic acid salt. The salt was taken up in DCM and washed with sat. NaHCO3. The DCM layer was dried and concentrated to yield the title compound as a colourless oil (0.038 g). δH (CDCl3, 400 MHz) 8.02 (1H, d), 7.68 (1H, dd), 7.23 (2H, d), 7.15 (4H, m), 6.98 (2H, d), 6.78 (1H, d), 4.18 (1H, br.s), 3.80 (1H, d), 3.48 (3H, s), 3.46 (1H, d), 3.33 (1H, d), 3.08 (1H, td), 2.69 (1H, d), 2.51 (1H, d), 2.10 (1H, dd), 1.98 (1H, m), 1.46 (9H, s), 1.20 (3H, d). MS (ES): MH+ 535.3.
Reaction SMILES: O[CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])O)[OH:4].S(=O)(=O)(O)O.[OH-].[Na+].S(OC)(OC)(=O)=O>C1(C)C(C)=CC=CC=1>[CH2:11]1[O:12][C@@H:5]2[C@@H:3]([OH:4])[CH2:2][O:8][C@@H:7]2[C@@H:9]1[OH:10]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Solvent: COS(=O)(=O)OC
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Yield: 83.5 %

Procedure:
1.548 g (8.5 mol) of sorbitol, 3,000 ml of xylene and 20 ml of concentrated sulfuric acid were heated to reflux with stirring and about 306 ml of water were removed. The xylene was then removed by distillation (the last amount under vacuum) and the residue was taken up in 3,000 ml of tert.-butanol, heated to 55° to 65° C., 2,432 ml (30.4 mol) of an aqueous solution of sodium hydroxide and 2,682 g (21.25 mol) of dimethyl sulfate were added dropwise simultaneously at this temperature while keeping the mixture always alkaline. When the addition is completed, the mixture was stirred for three hours at 60° C. and the alcohol was then removed up to a distillation temperature of 97° to 98° C. The residue was taken up in 8,500 ml of water and the aqueous solution was extracted three times with 1,000 ml portions of ethylene chloride. The solvent was evaporated from the combined organic phases and was fractioned in a column to recover the fraction in the boiling range of 118° to 120° C. mbar which was 1,037 g (70% yield) of dimthyl isosorbide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([O:10][C:11]1[C:12](=O)[C:13](=[O:18])[C:14]=1[O:15]CC)[CH3:9]>C(O)C>[NH:1]([C:12]1[C:13](=[O:18])[C:14](=[O:15])[C:11]=1[O:10][CH2:8][CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CCO
Product: CCOc1c(Nc2ccccc2)c(=O)c1=O

Procedure:
0.01 mol of aniline is added to a solution of 0.01 mol of 3,4-diethoxy-3-cyclobutene-1,2-dione in 30 ml of anhydrous ethanol. The mixture is refluxed for 12 hours and the precipitate that forms is filtered off while hot. The resulting residue is solidified in the presence of ether enabling the expected product to be isolated.
Reaction SMILES: Cl.[CH2:2]([O:5][NH2:6])[CH2:3][CH3:4].C(Cl)CCl.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19]>O>[CH2:2]([O:5][NH:6][C:18](=[O:19])[O:20][CH2:21][CH3:22])[CH2:3][CH3:4]
Reactant: CCCON
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCCl
Product: CCCONC(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.6 %

Procedure:
22 g (197 mmol) of n-propoxyamine hydrochloride was dissolved in 100 ml of water, and 200 ml of ethylene dichloride was added thereto. Then, 27.2 g (197 mmol) of potassium carbonate was added in several times under cooling, and then 21.3 g (196 mmol) of ethyl chloroformate was dropwise added thereto at a temperature of not higher than 10° C. After raising the temperature to room temperature, the mixture was further stirred at the same temperature for 4 hours. The ethylene dichloride layer was separated, and then the aqueous layer was extracted twice with 100 ml of chloroform. The ethylene dichloride layer and the chloroform layer were put together, and washed with a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure. 27 g of ethyl N-n-propoxycarbamate was obtained by distillation under reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:21]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cccc(NC(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(N(Cc2ccccc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 3-(tert-butoxycarbonylamino)benzoate (1.08 g) described in a document (Bioorg. Med. Chem. 2010, 18, 3175.) in DMF (40 mL) was added sodium hydride (258 mg). The reaction mixture was stirred at room temperature for 15 min, and benzyl bromide (613 μL) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (125 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][C:16]([CH3:21])=[C:17]([CH2:19][OH:20])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:15][C:16]([CH3:21])=[C:17]([CH2:19][O:20][C:29]3[CH:30]=[CH:31][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:27][CH:28]=3)[N:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1CO
Reactant: CS(=O)(=O)c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1sc(C2CCN(C(=O)OC(C)(C)C)CC2)nc1COc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-hydroxymethyl-5-methyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.18 g, 0.6 mmol), 4-methanesulfonyl-phenol (0.1 g, 0.6 mmol) and PPh3 (0.19 g, 0.72 mmol) in THF (5 mL) was added diethylazodicarboxylate (DEAD) (0.22 g, 0.72 mmol) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed and the residue was purified by flash chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 7.9 (2H, d, J=9 Hz), 7.09 (2H, d, J=9 Hz), 5.2 (2H, s), 4.28-4.10 (2H, m), 3.14-3.04 (1H, m), 3.04 (3H, s), 2.9-2.8 (2H, m), 2.44 (3H, s), 2.1˜2 (2H, m), 1.76-1.64 (2H, m), 1.47 (9H, s).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[N:8]=1)=O.[NH:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=1)N>CN(C)C=O>[CH3:23][S:20]([C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:25]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH3:33])[CH:28]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1)(=[O:22])=[O:21]
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(S(C)(=O)=O)c2)ccc1=O
Reactant: Cc1cc(NN)ccn1
Solvent: CN(C)C=O
Product: Cc1cc(-n2nccc2-c2nn(-c3cccc(S(C)(=O)=O)c3)ccc2=O)ccn1
Yield: 34.1 %

Procedure:
3-((E)-3-Dimethylamino-acryloyl)-1-(3-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-7) (0.05 g; 0.144 mmol) and 4-hydrazino-2-methylpyridine (0.03 g; 0.187 mmol) are dissolved in a sealed tube in dimethylformamide (0.6 ml) and irradiated at 180° C. for 10 min. The solvent of the reaction mixture is removed and the crude product is purified by preparative HPLC yielding 0.02 g (34.1%) of the final product. MS: M=408.4 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: C1=COCCC1
Reactant: Oc1ccc(F)c(Br)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(OC2CCCCO2)cc1Br
Reaction time: 2 h

Procedure:
Under a nitrogen atmosphere, to a solution of 3-bromo-4-fluorophenol (1.2 g) in toluene (62.8 mL) were added 3,4-dihydro-2H-pyran (1.15 mL) and pyridinium p-toluenesulfonate (0.237 g) at room temperature, and the mixture was stirred for 2 hr. The reaction mixture was poured into water at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.63 g) as a colorless oil.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:23][CH:24]4[CH2:29][CH2:28][C:27]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])([CH2:30][CH3:31])[CH2:26][CH2:25]4)[C:13]=3[C:12]1=2)(C(C)(C)C)(C)C>C1COCC1>[CH2:30]([C:27]1([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:28][CH2:29][CH:24]([O:23][C:14]2[C:13]3[C:12]4[C@@H:11]([CH2:10][CH2:9][OH:8])[CH2:22][CH2:21][C:20]=4[S:19][C:18]=3[N:17]=[CH:16][N:15]=2)[CH2:25][CH2:26]1)[CH3:31]
Reactant: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Solvent: C1CCOC1
Product: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CCO)CC4)CC1
Reaction time: 3 h
Yield: 92.8 %

Procedure:
To a 25-mL round-bottom flask containing a solution of tert-butyl N-(4-[[(3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]-1-ethylcyclohexyl)carbamate (240 mg, 0.42 mmol, 1.00 equiv) in 10 mL of THF was added TBAF-3H2O (264 mg, 0.84 mmol, 2.01 equiv) at room temperature. The resulting solution was stirred for 3 h at this temperature and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to give 180 mg (94%) of the desired tert-butyl N-(1-ethyl-4-[[(3R)-3-(2-hydroxyethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2 (6),9,11-tetraen-12-yl]oxy]cyclohexyl)carbamate as a colorless oil. MS: m/z 462 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH2:17][O:18][CH2:19][C:20]#[CH:21])[C:4]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1.I[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][C:2]1[N:3]([CH2:16][CH2:17][O:18][CH2:19][C:20]#[C:21][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]2[C:13]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1
Reactant: C#CCOCCn1c(C)nc2c(N)nc3c(c21)CCCC3
Reactant: Ic1ccccc1
Product: Cc1nc2c(N)nc3c(c2n1CCOCC#Cc1ccccc1)CCCC3
Temperature: 50 °C
Reaction time: 18 h
Yield: 21.7 %

Procedure:
Using the general method of Example 12 Part A, 2-methyl-1-[2-(prop-2-ynyloxy)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (0.396 g, 1.392 mmol) was reacted with iodobenzene (0.17 mL, 1.532 mmol) at ambient temperature. After 18 hours the reaction was incomplete. The solution was heated to 50° C. for 3 hours to complete the reaction. The volatiles were removed under reduced pressure. The resulting oil was partitioned between dichloromethane and 4% aqueous sodium carbonate and the organic layer removed. The aqueous layer was extracted with dichloromethane (3×). The organic fractions were combined, dried with anhydrous sodium sulfate and the volatiles were removed under reduced pressure. The resulting oil was purified by chromatography over silica gel (95/5 dichloromethane/methanol). The resulting white solid was dissolved in dichloromethane (2 mL) and reacted with 1M HCl in ether (2 mL). The volatiles were removed under reduced pressure and the resulting solids recrystallized from methanol to provide 0.1089 g of 2-methyl-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (hydrochloride),.g as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)=[O:11].C(N(CC)C(C)C)(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br>ClCCl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)=[O:11]
Reactant: COc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: Clc1cccc(CBr)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NCc2cccc(Cl)c2)c(C(=O)c2ccc(C(C)C)cc2)c1

Procedure:
To a solution of 100 mg (0.327 mmol) (2-amino-5-methoxy-phenyl)-(4-isopropyl-phenyl)-methanone in 1 ml dichloromethane is added 140 μl (0.818 mmol) N,N-diisopropyl-ethylamine and 48.7 μl (0.360 mmol)3-chloro-benzyl bromide. The reaction mixture is heated under reflux for 4 days and extracted with water/dichloromethane. The organic residue is chromatographed. For further purification the corresponding hydrochloride is precipitated form an etheric solution by addition of gaseous hydrochloric acid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.Cl[CH2:17][C:18](=O)[CH3:19]>>[CH3:19][C:18]1[CH:1]=[C:2]2[N:7]([CH:17]=1)[CH:6]=[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:4]=[CH:3]2
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)cn1
Reactant: CC(=O)CCl
Product: Cc1cc2ccc(NC(=O)OC(C)(C)C)cn2c1
Yield: 31 %

Procedure:
This compound is obtained according to the same procedure as the compound of Preparation III using the Tschitschibabin reaction, starting with 5.79 g of tert-butyl (6-methylpyridin-3-yl)carbamate [described in J. Med. Chem.; (2000), 43, 5017-5029] and chloroacetone. 1.96 g of a pasty residue are obtained.
Reaction SMILES: [CH:1]([CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([Cl:16])[C:8]([Cl:15])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:17])([CH3:3])[CH3:2].[H-].[Na+].[CH3:20]I>COCCOC>[CH3:20][C:4]1([CH:1]([CH3:3])[CH3:2])[CH2:12][C:11]2[C:6](=[C:7]([Cl:16])[C:8]([Cl:15])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:17]
Reactant: CI
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C(C)C)C2
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C(C)C)C2
Temperature: 30 °C

Procedure:
A stirred suspension of 2-isopropyl-5-methoxy-6,7-dichloro-1-indanone (7.3 g., 0.025 mole) and sodium hydride (810 mg., 0.028 mole) in anhydrous 1,2-dimethoxyethane (250 ml.) is heated in an inert atmosphere at 80°-85° C. for 1 hour, cooled to 30° C. and treated with methyl iodide (6 ml.). The reaction mixture is heated to 80° C., then the solvent is distilled at reduced pressure and the residue poured into ice water. The 2-methyl-2-isopropyl-5-methoxy-6,7-dichloro-1-indanone which separates (7.0 g.) melts at 143° C. after recrystallization from ethanol-water.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2([Cl:16])[Cl:15])(=[O:4])=[O:3].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(Cl)Cl>[CH2:17]([NH:24][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[C:8]2([Cl:16])[Cl:15])(=[O:4])=[O:3])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: O=C1Nc2ccc(S(=O)(=O)NCc3ccccc3)cc2C1(Cl)Cl
Reaction time: 4 h

Procedure:
To a solution of 5-chlorosulfonyl-3,3-dichloro-2-oxindole (100 mg, 400 umol) in methylene chloride (3 mL) was added benzylamine (135 uL, 1.2 mmol) dropwise. After stirring for 4 h. 3 N hydrochloric acid was added along with an additional volume of methylene chloride (20 mL). The organic layer was dried over magnesium sulfate, filtered, and silica gel flash chromatography (25 to 35% ethyl acetate/hexanes) yielded the title compound. ES (−) MS m/e=369 (M−H).