Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].CS([C:11]1[N:12]([C@H:24]([CH3:38])[CH2:25][CH2:26][NH:27]C(=O)OCC2C=CC=CC=2)[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=1)(=O)=O.C(Cl)Cl.O>C1COCC1>[CH3:38][C@@H:24]1[N:12]2[C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=[CH:15][C:14]=3[N:23]=[C:11]2[NH:27][CH2:26][CH2:25]1
Reactant: C[C@H](CCNC(=O)OCc1ccccc1)n1c(S(C)(=O)=O)nc2cnc3ccccc3c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1CCNc2nc3cnc4ccccc4c3n21
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
Potassium tert-butoxide (86 mg) was added to a solution of benzyl (3R)-3-[2-(methylsulfonyl)-1H-imidazo[4,5-c]quinolin-1-yl]butylcarbamate (380 mg, 0.84 mmol) in 10 mL of THF. The reaction was stirred for about two hours at room temperature, and an analysis by thin layer chromatography (TLC) indicated the presence of starting material. Additional potassium tert-butoxide (120 mg) was added, and the reaction was stirred over three days at room temperature. CH2Cl2 (20 mL) and H2O (20 mL) were added. The layers were separated, and the organic fraction was washed sequentially with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Chromatography (SiO2, 10-30% CMA/CHCl3) afforded (11S)-11-methyl-8,9,10,11-tetrahydropyrimido[1′,2′:1,2]imidazo[4,5-c]quinoline (170 mg) as an off white solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.C(O)(=O)[CH2:30][C:31]([OH:33])=[O:32].N1CCCCC1>N1C=CC=CC=1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:26]=[CH:27][CH:28]=1)[CH2:16][O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[CH:30][C:31]([OH:33])=[O:32]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccccc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1ccccc1OCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
2-[3-(Quinolin-2-ylmethoxy)-benzyloxy]-benzaldehyde (110 mg, 0.3 mmol, example 56) is dissolved in pyridine (1 mL). Malonic acid (63 mg, 0.6 mmol) and piperidine (10 μL, 0.1 mmol) are added and the contents are heated to 85° C. for 2 hrs, then at 110° C. for another 2 hrs. The reaction is cooled and placed under a nitrogen stream at 40° C. to remove the pyridine. A small amount of toluene is added and the contents are again placed under a nitrogen stream at 40° C. (repeat). The crude material is purified on silica gel by flash chromatography (silica, 2.5% methanol in dichloromethane) to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.33 (d, 1H), 8.21–8.16 (m, 2H), 7.81–7.70 (m, 3H), 7.56–7.50 (m, 2H), 7.37–7.25 (m, 3H), 7.03–6.93 (m, 4H), 6.50 (d, 1H), 5.48 (s, 2H), 5.14 (s, 2H); MS (ion spray) 412 (M+H)+.
Reaction SMILES: C(P(C#N)(CC)=O)C.[NH2:9][CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23](=[O:26])[NH:24][N:25]=3)[CH:17]=2)[CH2:12]1.Br.[CH3:28][C:29]([CH3:34])=[CH:30][C:31](O)=[O:32].C(N(CC)CC)C>CN(C)C=O>[CH3:28][C:29]([CH3:34])=[CH:30][C:31]([NH:9][CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:20]3[CH:21]=[CH:22][C:23](=[O:26])[NH:24][N:25]=3)[CH:17]=2)[CH2:12]1)=[O:32]
Reactant: NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Reactant: CC(C)=CC(=O)O
Agent: Br
Agent: CCP(=O)(C#N)CC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)=CC(=O)NCC1Cc2ccc(-c3ccc(=O)[nH]n3)cc2C1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 79.8 %

Procedure:
Under ice cooling, 1.71 g of diethylphosphoryl cyanide was added to 80 ml of a suspension containing 3.06 g of 2-aminomethyl-5-[pyridazin-3(2H)-on-6-yl]indane·hydrobromide and 1.15 g of 3-methylcrotonic acid suspended in dimethylformamide, and then 20 ml of a solution containing 2.89 g of triethylamine dissolved in dimethylformamide was added dropwise to the mixture. The resulting mixture was stirred at the same temperature for 2.5 hours. The reaction mixture was poured into ice water, and crystals precipitated were collected by filtration. The crystals obtained were washed with water, dried and then recrystallized from ethyl acetate-methanol to obtain 2.45 g of 2-[(3-methylcrotonoyl)amino]methyl-5-[pyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:3]=1[CH2:4][O:5]C1CCCCO1.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCOC(C)=O>[F:1][C:2]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=[CH:12][C:3]=1[CH2:4][OH:5]
Reactant: Fc1cc(Oc2ccccc2)ccc1COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: OCc1ccc(Oc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
Mix under nitrogen atmosphere 2-(2-fluoro-4-phenoxy-benzyloxy)-tetrahydro-pyran (2.05 g, 6.8 mmol), methanol (60 mL) and p-toluenesulfonic acid monohydrate (260 mg, 1.35 mmol). Stir at ambient temperature for 16h. Dilute with EtOAc. Wash with saturated aqueous NaHCO3. Separate the organic layer, dry over Na2SO4 and concentrate in vacuo to give the desired intermediate (1.41 g, 95%). MS (ES+) m/z: 201 (M−OH)+.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][C:24]([NH2:28])([CH2:26][CH3:27])[CH3:25].CO.C(Cl)Cl>CS(C)=O>[CH3:22][C:3]1[C:2]([NH:28][C:24]([CH2:26][CH3:27])([CH3:25])[CH3:23])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CCC(C)(C)N
Solvent: CO
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C
Temperature: 70 °C
Yield: 51.9 %

Procedure:
Prepared similar to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48.0 mg, 0.162 mmol) and 2-methylbutan-2-amine (Aldrich; 0.047 mL, 0.405 mmol) in DMSO (1.0 mL), heating 70° C. for 9 h. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished 2-(2-methyl-3-(tert-pentylamino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (30.5 mg, 0.084 mmol, 52% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.51 (1H, br. s.), 7.94 (1H, dd, J=7.5, 0.8 Hz), 7.65 (1H, dd, J=8.1, 0.7 Hz), 7.38 (1H, t, J=7.8 Hz), 7.11 (1H, d, J=2.0 Hz), 5.38 (1H, br. s.), 4.77 (1H, s), 3.66 (2H, td, J=6.8, 1.9 Hz), 2.99 (2H, t, J=6.8 Hz), 2.57 (3H, s), 2.03 (2H, q, J=7.4 Hz), 1.61 (6H, s), 0.97 (3H, t, J=7.4 Hz). m/z (ESI, +ve) 364.2 (M+H)+.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9](C)C)[CH2:3][CH2:2]1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:20]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:13])[CH:21]=3)[C@H:5]2[CH3:9])[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(F)cc1F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1N(c2ccc(C#N)c(F)c2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-methylpyrrolidin-3-ol 0.5 oxalate (200 mg), 2,4-difluorobenzonitrile (255 mg) and lithium carbonate (180 mg), the title compound was obtained as a colorless solid (yield: 188 mg, yield: 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([C:7]1[C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6].[N+](=[CH2:21])=[N-]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[C:5]([C:7]1[C:12]([C:13]([O:15][CH3:21])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cccnc1C(=O)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cccnc1C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-Chlorobenzoyl)-3-carboxypyridine was dissolved in a solution of 10% methanol and methylene chloride. Diazomethane was added and the solution was stirred for 1 hour at room temperature. The solution was extracted with methylene chloride followed by methylene chloride +1% methanol The desired product was combined from recrystallization (ethyl ether/hexane) and from the filtrate to yield 1.23 g of 2-(3-chlorobenzoyl)-3-methoxycarbonyl-pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:23]=[CH:22][N+:21]([O-])=[CH:20][CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:26][N:27](C)C(Cl)=O.C[Si](C#N)(C)C.CCOCC>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:26]#[N:27])[CH:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(c1cc[n+]([O-])cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CN(C)C(=O)Cl
Agent: C[Si](C)(C)C#N
Solvent: CCOCC
Solvent: ClCCl
Product: CC(c1ccnc(C#N)c1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 60 h
Yield: 93.6 %

Procedure:
A mixture of the product of part (i) (20.0 g) and N,N-dimethylcarbamoyl chloride (6.80 g) in dichloromethane (250 ml) was stirred at room temperature for 2.5 days, giving a clear solution. Trimethylsilyl cyanide (6.35 g) was added and stirring was continued for a further 48 hours. Additional quantities of N,N-dimethylcarbamoyl chloride (1.30 g) and trimethylsilyl cyanide (1.30 g) were then added and the solution was stirred for a further 36 hours. The reaction was then washed successively with 10% potassium carbonate solution, brine and then dried (MgSO4). Evaporation of the solvent gave a solid which was stirred with ether and filtered to give the title compound, (19.2 g), m.p. 188°-189°.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[CH2:7][CH2:6]2)[O:4]CC1.Cl.O>O1CCOCC1>[O:4]=[C:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[CH2:9][CH2:10]1
Reactant: N#Cc1ccccc1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccccc1C1CCC(=O)CC1
Temperature: 80 °C

Procedure:
To a stirring solution of 2-(1,4-Dioxaspiro[4.5]dec -8-yl)benzonitrile (8.7 g, 35.7 mmol) in dioxane (200 mL) was added 1N HCl (200 mL) and the reaction heated to 80° C. for 2 hours. The reaction was cooled to room temperature and poured into water (1 L) the mixture was extracted with ethyl acetate (3×250 mL). The combined organics were washed with brine (200 mL) and then dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure to give the product.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8](OCC)=[O:9])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][OH:9])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cccc(OC(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 3-isopropyloxybenzoate (12.0. g, 61.8 mmol) in tetrahydrofuran (100 ml) was added lithium aluminum hydride (3.52 g, 92.7 mmol) by small portions under ice-cooling. The mixture was stirred at room temperature for 1 hr. and water (10 ml) was added under ice-cooling to allow decomposition. Insoluble material was filtered off and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the objective substance (10.0 g, 97%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][N:5]([CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:25][C:26]1([CH3:35])[CH2:31]C(O)[CH2:29][C:28]([CH3:34])([CH3:33])[NH:27]1.CC(C)([O-])C.[K+].CO>CCCCCCC>[CH3:25][C:26]1([CH3:35])[CH2:31][CH:1]([O:2][C:3](=[O:24])[CH2:4][N:5]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:29][C:28]([CH3:34])([CH3:33])[NH:27]1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CCCCCCCCN(CC(=O)OC)C1CC(C)(C)NC(C)(C)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCCC
Product: CCCCCCCCN(CC(=O)OC1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Yield: 73.6 %

Procedure:
To the same flask as used in Example 1 were added 34 g (0.1 mole) of N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-octylglycine methyl ester, 17.3 g (0.11 mole) of 2,2,6,6-tetramethyl-4-piperidinol, 1.2 g of potassium tert-butoxide and 100 g of heptane. The temperature was raised with stirring, and reaction was carried out at 98° to 105° C. for 6 hours, during which methanol was removed from the reaction system by means of the Deanstark trap. After completion of the reaction, water was added to the reaction solution to dissolve the product in the heptane layer. The heptane layer was separated, and heptane in the layer was removed by distillation to obtain 34.3 g of N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-octylglycine(2,2,6,6-tetramethyl-4-piperidinyl)ester as a pale brown oily product. Yield, 74% based on N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-octylglycine methyl ester.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[NH2:16][C@@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[CH:21]=[CH:22][C:23]=2[CH3:27])[CH2:18]1>CN(C)C=O>[NH3:4].[CH3:27][C:23]1[CH:22]=[CH:21][C:20]([N:28]2[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]2)=[C:19]2[C:24]=1[CH2:25][CH2:26][C@@H:17]([NH:16][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:15][CH:14]=1)[CH2:18]2
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: Cc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](N)C2
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCN(C)CC2)c2c1CC[C@@H](NC(=O)c1ccc(N3CCOCC3)cc1)C2
Product: N
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 146.9 %

Procedure:
4-Morpholinobenzoic acid (92 mg, 0.44 mmol) was dissolved in dry N,N-dimethylformamide (2 mL) and flushed with nitrogen. To the solution was added 1,1-carbonyldiimidazole (76 mg, 0.47 mmol) and the reaction mixture was stirred at 75° C. for 1.5 h. The solution was cooled to room temperature and (R)-2-amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (110 mg, 0.42 mmol), dissolved in dry N,N-dimethylformamide (2 mL) was added. The solution was stirred at room temperature for 30 h. The solvent was evaporated in vacuo giving 290 mg of a crude product. Purification by preparative TLC on silica gel using chloroform/methanol/conc. NH3 (95:5:0.5) as the eluent afforded 145 mg (73% yield) of the title compound as a white solid: mp >231° C. (dec); EIMS (70 eV) m/z (relative intensity) 448 (3, M+); [α]21D -60° (c 0.15, chloroform).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH2:25])[CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH:25][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)=[O:12])[CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: CCCC(N)c1ccc(OC)cc1
Product: CCCC(NC(=O)c1ccc2c(c1)OCO2)c1ccc(OC)cc1

Procedure:
Prepared in a similar manner to example 4 using benzo[1,3]dioxole-5-carboxylic acid and 1-(4-methoxy-phenyl)-butylamine 1H NMR (500 MHz, CDCl3): δ 0.93-0.95 (t, 3H), 1.30-1.39 (m, 2H), 1.80-1.90 (m, 2H), 3.79 (s, 3H), 5.08-5.09 (dd, 1H), 6.00 (s, 2H), 6.10-6.12 (d, 1H), 6.79-6.80 (d, 1H), 6.87(s, 1H), 6.88 (s, 1H), 7.25-7.28 (m, 4H). MS (M+H, 328.1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1.CO>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)Cc1ccc(O)c(Cl)c1

Procedure:
A mixture of 67 g (0.38 moles) of 3-chloro-4-hydroxyphenylacetic acid, 1.5 g of p-toluenesulfonic acid, and 250 ml of methanol was refluxed overnight, i.e., about 18 hours. The excess methanol was removed by vacuum to give a thick tawny oil. This oil was dissolved in ether, twice washed with water, and dried over anhydrous sodium sulphate. The ethereal solution was filtered, the ether removed and a tawny oil remained. Using as solvent 2.5% v/v methanol in chloroform and a silica gel matrix, thin-layer chromotography showed that the oil was essentially homogeneous, there being only a trace impurity present at the origin, which is believed to be unreacted acid. This oil was satisfactory for use as the starting material for forming the ether of Example 1B.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:23]=2[NH:22][CH:21]=[C:20]3[Cl:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1.[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1.CN(C)C=O>O>[Cl:24][C:20]1[C:19]2[C:23](=[C:15]([NH:14][S:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)=[CH:6][CH:7]=3)(=[O:13])=[O:12])[CH:16]=[CH:17][CH:18]=2)[NH:22][CH:21]=1
Reactant: O=S(=O)(Nc1cccc2c(Cl)c[nH]c12)c1ccc(CCCBr)cc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(Nc1cccc2c(Cl)c[nH]c12)c1ccc(CCCn2ccnc2)cc1
Temperature: 80 °C
Yield: 77.1 %

Procedure:
To 4-(3-bromopropyl)-N-(3-chloro-1H-indole-7-yl)benzenesulfonamide (213 mg, 0.5 mmol) were added 170 mg (2.5 mmol) of imidazole and 6 ml of dimethylformamide, followed by heating at 80° C. for 3 hours in a nitrogen atmosphere. Then, the reaction mixture was poured into water and extracted with chloroform. The extract was dried over magnesium sulfate and concentrated. Then, the residue was purified by silica gel column chromatography, to give 160 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:4]=2[C:5](=[O:8])[NH:6][N:7]=1.[H-].[Na+].[CH3:23]I>CN(C=O)C.O>[NH2:1][C:2]1[C:3]2[CH:11]=[CH:10][N:9]([C:12]3[C:13]([CH3:20])=[CH:14][C:15]([CH3:19])=[CH:16][C:17]=3[CH3:18])[C:4]=2[C:5](=[O:8])[N:6]([CH3:23])[N:7]=1
Reactant: Cc1cc(C)c(-n2ccc3c(N)n[nH]c(=O)c32)c(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(-n2ccc3c(N)nn(C)c(=O)c32)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.6 %

Procedure:
To an ice-cooled solution of 4-amino-1-mesityl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (268 mg, 1.0 mmol) in DMF (3 ml) was added sodium hydride (60% in oil, 44 mg, 1.1 mmol) and the mixture was stirred for 10 minutes. Methyl iodide (0.081 ml, 1.3 mmol) added and the mixture was stirred at room temperature for 1 hour. Additional sodium hydride (60% in oil, 44 mg, 1.1 mmol) and methyl iodide (0.081 ml, 1.3 mmol) were added and the mixture was stirred for 1 hour. The resulting mixture was diluted with water (30 ml) and extracted with ethyl acetate (30 ml×2). The extracts were combined, washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to silica gel column chromatography eluting with hexane/ethyl acetate (1:1-2:3) to give 140 mg (50%) of the title compound as crystals.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH3:12])=[O:10].[CH3:13][N:14]=[C:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl:23]([OH:27])(=[O:26])(=[O:25])=[O:24]>Cl.C(Cl)(Cl)Cl>[Cl:23]([OH:27])(=[O:26])(=[O:25])=[O:24].[CH3:1][N:2]1[C:6]([C:15](=[N:14][CH3:13])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:5]([CH3:7])[CH:4]=[C:3]1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: CN=C(Cl)c1ccccc1
Reactant: COC(=O)Cc1cc(C)cn1C
Agent: Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClC(Cl)Cl
Product: CN=C(c1ccccc1)c1c(C)cc(CC(=O)OC)n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.1 %

Procedure:
Methyl 1,4-dimethyl-1H-pyrrole-2-acetate (1.66 g, 10 mmole) was placed in a 25 ml round bottom flask and treated with alcohol free chloroform (2 ml) and N-methyl benzimidoyl chloride (1.78 g, 12 mmole). The solution was treated with several drops of ethereal hydrogen chloride--mild exotherm. The reaction was protected with a calcium chloride drying tube and stirred at room temperature for about four hours. The reaction was diluted with chloroform, quenched into saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated. The viscous residue was dissolved in absolute ethanol (6 ml) and treated with 70% perchloric acid (1.42 g, 10 mmole). The resulting crystalline solid was isolated by filtration and washed with ethanol/ether (1 to 3 by volume) and air dried to yield 2.39 g (62%) of the title compound as a bright yellow solid, m.p. 149°-150° C.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)([CH:13]=[O:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].O.O.P([O-])(O)(O)=[O:24].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>O1CCCC1.O>[CH:15]1([C:11]2([C:13]([OH:24])=[O:14])[CH2:12][CH:7]3[CH2:6][N:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[CH2:9][CH:8]3[CH2:10]2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=P([O-])(O)O
Reactant: CN(C)C(=O)N1CC2CC(C=O)(C3CCCC3)CC2C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)N1CC2CC(C(=O)O)(C3CCCC3)CC2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
5-Cyclopentyl-5-formyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 16b (0.266 g, 0.955 mmol) was dissolved in a solvent mixture of 20 mL of tetrahydrofuran and 10 mL of water. Then sodium dihydrogenphosphate dihydrate (0.448 g, 2.87 mmol), sodium chlorite (0.26 g, 2.87 mmol) and 2-methyl-2-butene (0.24 mL, 2.88 mmol) were added at 0° C. The reaction mixture was stirred at 0° C. for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated to remove tetrahydrofuran and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-cyclopentyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 16c (0.28 g, yield 99.6%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[O:11][N:10]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[O:11][N:10]=1
Reactant: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C(C)C)ccc1N

Procedure:
A solution of 3-(2,6-dichlorophenyl)-5-isopropyl-4-[(3-methyl-4-nitrophenoxy)methyl]isoxazole (0.36 g, 0.86 mmol) in ethanol (3 mL) was treated with tni(II)chloride (0.71 g, 3.2 mmol) and refluxed overnight. Water (15 mL) was added and the pH adjusted to 10-11 with solid sodium carbonate. The product was then extracted with chloroform; the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and condensed to a residue which was chromatographed on silica gel using 50% ethyl acetateihexane. Yield=0.24 g. (72%) of 4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}-2-methylphenylamine.