Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]([C:8]([O:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])=[O:9])=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][CH:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])=[O:9])=[CH:31][CH:32]=1
Reactant: O=C(NCCOC(=O)c1ccc([N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C(=O)OCCNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A solution of 2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethyl 4-nitrobenzoate (7.47 g, 17 mmoles) in 1 liter of ethyl acetate, containing 1.5 g of 10% Pd on carbon (wet) is evacuated and filled with H2 twice. The mixture is subjected to hydrogen at 1 atmosphere of pressure for two hours. The catalyst is filtered off on a Celite pad and the solution is concentrated in vacuo, yielding a yellow oil. Purification on silica gel using a gradient of 30-45% ethyl acetate in hexanes provided 5.436 g (80%) of the title compound as a white solid. 400 MHz 1H NMR (CDCl3) δ: 7.86 (d, J=8.4 Hz, 2H), 7.75 (d, J=7.3 Hz, 2H), 7.58 (d, J=7.3 Hz, 2H), 7.39 (t, J=7.3 Hz, 2H), 7.30 (t, J=7.5 Hz, 1H), 6.64 (d, J=8.4 Hz, 2H), 5.13 (br. t, 1H), 4.40 (d, J=7.0 Hz, 2H), 4.36 (t, J=5.1 Hz, 2H), 4.22 (t, J=7.0 Hz, 1H), 4.1-4.0 (br. s, 2H), 3.65-3.55 (m, 2H). LCMS: 403 [M+H].
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C([N-]C(C)C)(C)C.[Li+].[CH2:21]([C@H:28]1[CH2:32][O:31][C:30](=[O:33])[N:29]1[C:34](=[O:37])[CH2:35][CH3:36])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O:38]=[C:39]1[CH2:42][N:41]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[CH2:40]1>C1COCC1>[OH:38][C:39]1([C@@H:35]([CH3:36])[C:34](=[O:37])[N:29]2[C@@H:28]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:32][O:31][C:30]2=[O:33])[CH2:42][N:41]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])[CH2:40]1
Reactant: CCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[C@@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C1(O)CN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
To a solution of diisopropylamine (6.5 mL, 46.3 mmol) in THF (200 mL) at −78° C. was added butyllithium (17 mL of a 2.5 M solution in hexanes, 42.5 mmol) over 5 min. The solution of lithium diisopropylamide was stirred for 15 min at −78° C. A solution of (S)-4-benzyl-3-propionyl-2-oxazolidinone (9.0 g, 38.6 mmol) in THF (100 mL) was added to the lithium diisopropylamide by addition funnel over 26 min. The reaction temperature was kept below −70° C. during the course of the addition. After the addition, the mixture was stirred for a further 30 min at −78° C. Then phenylmethyl 3-oxoazetidine-1-carboxylate (9.5 g, 46.3 mmol) was added by addition funnel over 25 minutes as a solution in THF (100 mL). Again, the reaction mixture was kept below −70° C. during the reagent addition. After stirring for an additional 1 hour at −78° C., the reaction mixture was quenched with saturated ammonium chloride solution and was then allowed to warm to rt. Water was added to dissolve any precipitated ammonium chloride, and ethyl acetate was added. The layers were partitioned, and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with 5% aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (50% ethyl acetate:50% hexanes) to provide phenylmethyl 3-hydroxy-3-{(1R)-1-methyl-2-oxo-2-[(4S)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]ethyl}azetidine-1-carboxylate as a white crystalline solid (6.03 g, 13.8 mmol, 36% yield). 1H NMR (400 MHz, CDCl3) δ 7.37 (m, 8H), 7.20 (d, 2H), 5.12 (s, 2H), 4.66 (m, 1H), 4.27-4.20 (m, 2H), 4.10 (q, 1H), 4.03-3.93 (m, 3H), 3.28 (dd, 1H), 2.77 (dd, 1H), 1.29 (d, 3H).
Reaction SMILES: C=O.[CH2:3]([N:10]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]1=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.[CH2:18]([NH:25][CH2:26][C:27](O)=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1(C)C=CC=CC=1>[CH2:3]([N:10]1[C:14](=[O:15])[CH:27]2[CH:12]([CH2:13][N:25]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:26]2)[C:11]1=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)CNCc1ccccc1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Agent: C=O
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C2CN(Cc3ccccc3)CC2C(=O)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of paraformaldehyde (3.37 g), N-benzylmaleimide (2.80 g) and N-benzylglycine hydrochloride (3.02 g) in toluene (100 mL) was heated to reflux with azeotropic removal of water for 16 hours. The mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/hexane) to afford the title compound 1 as a low melting white solid (3.60 g, 75%). LCMS: Rf: 2.616 min, M+H+: 321.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](=[O:29])SC2C=CC=CN=2)=[CH:3]1.[CH:30]([NH2:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:37]1([CH:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:43][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4](=[CH:3][C:2](=[O:1])[CH2:19][CH2:18]2)[CH2:5][CH2:6]4)=[O:29])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
Following a procedure similar to that described in Example 2(b), but using S-2-pyridyl 3-oxo-4-androstene-17β-thiocarboxylate [prepared as described in Example 2(a)] and benzhydrylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 85%.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][C@@H:3]1[C:17]([O:19]CC)=[O:18].O.[OH-].[Na+]>C(O)C>[CH2:10]([O:9][C:7]([N:5]1[CH2:6][C@H:2]([OH:1])[C@@H:3]([C:17]([OH:19])=[O:18])[CH2:4]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 0 °C
Yield: 226.9 %

Procedure:
639 g of 1-benzyl 3-ethyl (3S,4R)-4-hydroxypyrrolidine-1,3-dicarboxylate (equivalent to 1.03 mol) was dissolved in 3.02 L of ethanol and 3.02 L of water was added to the solution. While the mixture was stirred and cooled in an ice bath, a sodium hydroxide solution (formed by dissolving 124 g of sodium hydroxide (3.09 mol) in 3.02 L of water) was added dropwise at an internal temperature of 6.0 to 9.8° C. and the mixture was subsequently stirred at an internal temperature of 6 to 10° C. for 1 hour. This was followed by addition of 60.4 g of active carbon. The mixture was then taken out of the ice bath and stirred at room temperature for 30 minutes. The insoluble material was separated by filtration and washed with 1.21 L of water. The filtrate and the wash were combined and concentrated under reduced pressure. To the resulting residue, 3.02 L of diisopropyl ether was added and the mixture was stirred for 5 minutes. Subsequently, the mixture was allowed to standard the aqueous layer (bottom layer) was collected. To the aqueous layer, 3.02 L of diisopropyl ether was added and the mixture was stirred for 5 minutes. The mixture was allowed to stand again and the aqueous layer (bottom layer) was collected. While the aqueous layer was stirred, 0.54 L of 6 mol/L hydrochloric acid was added dropwise (pH changed from 12.8 to 1.5). To the resulting mixture, 4.83 L of ethyl acetate and 1.21 kg of sodium chloride were added and the mixture was stirred for 5 minutes. The mixture was then allowed to stand and the organic layer (top layer) was collected. To the organic layer, 3.02 L of 28% brine was added and the mixture was stirred for 5 minutes. The mixture was then allowed to stand again and the organic layer (top layer) was collected. To the organic layer, 302 g of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. The resulting solid was separated by filtration and washed with 0.90 L of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure to give 620 g of a crude product of the title compound as a pale brown solid. This product was used in the subsequent step without further purification.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([OH:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][C:16](=[O:18])[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Reaction time: 3 h
Yield: 61.5 %

Procedure:
To a stirred solution of 1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-ol (27 mg, 0.11 mmol) in dichloromethane (2 ml) was added Dess Martin periodinane (80 mg, 0.19 mmol) at room temperature. The mixture was stirred for 3 hours and then concentrated and purified by FCC (eluting with DCM/MeOH/NH3 gradient 95:5:1 to 90:10:1) to provide the title compound as colourless oil (17 mg, 63%).
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.[C@@H:23]1([NH2:28])[CH2:26][CH2:25][C@@H:24]1[NH2:27]>CS(C)=O>[NH2:27][C@H:24]1[CH2:25][CH2:26][C@H:23]1[NH:28][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
Reactant: N[C@@H]1CC[C@@H]1N
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N[C@@H]1CC[C@@H]1N
Temperature: 95 °C
Reaction time: 2 h
Yield: 9.4 %

Procedure:
Prepared according to Example 127, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 130 mg, 0.439 mmol), cis-cyclobutane-1,2-diamine (Frontier Scientific Services, Newark, Del.; 113 mg, 1.316 mmol), and DMSO (4.4 mL) and stirring at 95° C. for 2 h. Purification by reverse phase HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 70%) provided rac-2-(3-((cis-2-aminocyclobutyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (15 mg, 9.4%). 1H NMR (400 MHz, MeOH-d4) δ ppm 7.83-7.88 (1H, m) 7.55-7.61 (1H, m) 7.34 (1H, t, J=1.00 Hz) 7.09 (1H, s) 4.21-4.30 (1H, m) 3.59-3.67 (1H, m) 3.45-3.53 (1H, m) 3.16-3.23 (1H, m) 3.11-3.15 (1H, m) 2.93-3.08 (1H, m) 2.58 (3H, s) 2.34-2.42 (1H, m) 2.19-2.27 (1H, m) 1.56-1.69 (2H, m). m/z (ESI, +ve) 363.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:19])=[C:13]2[C:5]=1[CH:6]1[CH:11]([C:12]2=[O:20])[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:21]I.O>CN(C)C=O>[CH3:3][C:4]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:19])=[C:13]2[C:5]=1[CH:6]1[C:11]([CH3:21])([C:12]2=[O:20])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CI
Reactant: COc1c(C)cc(C)c2c1C(=O)C1CCCCC21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C)cc(C)c2c1C(=O)C1(C)CCCCC21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.42 Grams of 60% sodium hydride was gradually added to a solution prepared by dissolving 17.7 g of 5,7-dimethyl-8-methoxy-1,2,3,4,4a,9a-hexahydro-9-fluorenone in 100 ml of dimethylformamide under ice-cooling, followed by stirring at room temperature for 30 minutes. Then, 5.4 ml of methyl iodide was added thereto under ice-cooling, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into 3 liters of water and extracted with chloroform. The organic layer was dried with magnesium sulfate and then the solvent was distilled off. The residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:20) to obtain 9.6 g of 5,7,9a-trimethyl-8-methoxy-1,2,3,4,4a,9a-hexahydro-9fluorenone. fluorenone.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([C:24](=[O:28])[C:25]([NH2:27])=[O:26])=[C:9]([CH2:22][CH3:23])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].CO.Cl>CCOC(C)=O>[NH2:27][C:25](=[O:26])[C:24]([C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[NH:5][CH2:4][C:3]([OH:29])=[O:2])[N:10]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:9]=1[CH2:22][CH3:23])=[O:28]
Reactant: CCc1c(C(=O)C(N)=O)c2c(NCC(=O)OC)cccc2n1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1c(C(=O)C(N)=O)c2c(NCC(=O)O)cccc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 190 mg (0.48 mmol) of [[3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]amino]acetic acid methyl ester, 5 ml of 1N NaOH, and 15 ml of MeOH was refluxed 0.33 hour, cooled, and stirred at room temperature for 1 hour. EtOAc and acqueous HCl were added and the EtOAc layer was washed with brine, dried over MgSO4, and evaporated in vacuo. The residue was crystallized from MeOH to give 96 mg (53%) of ([3-(Aminooxoacetyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]amino]ac(e,tic acid melting at 151-157° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][N:6]=1.C([Li])CCC.[C:12](Cl)(=[O:14])[CH3:13]>O1CCCC1>[CH2:1]([C:2]1[O:3][CH2:4][CH2:5][N:6]=1)[C:12]([CH3:13])=[O:14]
Reactant: CC(=O)Cl
Reactant: CC1=NCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)CC1=NCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8.5 g. (0.1 mole) of 2-methyl-1,3-oxazoline in 85 ml. of dry tetrahydrofuran, and cooled in an acetone-dry ice bath to -60° C., is added 6.4 g. (0.1 mole) of n-butyl lithium and the reaction mixture allowed to stir for 1 hour. To the cloudy solution is then added 7.8 g. (0.1 mole) of acetyl chloride at such a rate that the temperature is maintained below -50° C. The reaction mixture is allowed to warm to room temperature and is then filtered and the solvent removed in vacuo. The desired product is purified by distillation under reduced pressure.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:21][CH:20]=[CH:19][C:16]=3[NH:17][N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22]C(C)([O-])C.[K+].C([O-])(O)=O.[Na+]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[S:21][CH:20]=[CH:19][C:16]=3[N:17]([CH3:22])[N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: c1ccc(CN2CCN(c3n[nH]c4ccsc34)CC2)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(N2CCN(Cc3ccccc3)CC2)c2sccc21
Temperature: -30 °C

Procedure:
To a stirred solution of 3-(4-benzyl-piperazin-1-yl)-1H-thieno[3,2-c]pyrazole (318.0 g, 1.07 mol) in THF (2.5 L) was added a mixture of potassium t-butoxide (134.4 g, 1.2 mol) in THF (1.5 L) dropwise over a period of 1 hour while keeping the reaction temperature below 25° C. After complete addition, the mixture was cooled to −30° C. and Mel (65.4 mL, 1.05 mol) was added dropwise over a period of 30 minutes. The mixture is then slowly warmed to room temperature overnight. To the reaction mixture is slowly added saturated NaHCO3 (1 L). The solution is then evaporated to remove the THF and the resulting aqueous mixture is taken up in EtOAc and washed with water and brine. The EtOAc extract is dried (Na2SO4), filtered and evaporated. The viscous concentrate is filtered through a silica gel plug with 1:1 EtOAc/heptane and evaporated yielding a viscous oil that is then dried under vacuum where it solidifies and yields 326.03 g (98%) as a 12:1 ratio of regioisomers in favor of the desired product.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][CH2:5][CH2:6][CH2:7][OH:8].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[N:17]1[C:22]2[N:23]=[C:24](S(C)(=O)=O)[N:25]=[C:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[CH3:34])[C:21]=2[CH:20]=[CH:19][C:18]1=[O:39]>>[F:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[C:11]=1[N:17]1[C:22]2[N:23]=[C:24]([O:8][CH2:7][CH2:6][CH2:5][S:4][CH3:3])[N:25]=[C:26]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[CH3:34])[C:21]=2[CH:20]=[CH:19][C:18]1=[O:39]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CSCCCO
Agent: [H-]
Agent: [Na+]
Product: CSCCCOc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reaction time: 0.08 h

Procedure:
NaH (12 mg, 0.5 mmol) was added to 3-(methylthio)-1-propanol (0.5 mL) and the mixture was stirred under Ar at 230. After 5 min, gas evolution ceased, and the product of Example 48 (223 mg, 0.5 mmol) was added in a single portion. The mixture was stirred for 30 minutes. Most of the excess 3-(methylthio)-1-propanol was removed in vacuo, and the residue partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 10-30% EtOAc/hexane, followed by recrystallization from CH2Cl2/hexane gave the title compound as a white crystalline solid. mp 127-128°, LC MS m/z=472 (MH+) Retention time=2.47 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]2[O:12][C:11](=[O:13])[N:10]([C@@H:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[C:26](Br)([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>BrC(Br)(C(OCC)=O)C(OCC)=O.CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[O:12][C:11](=[O:13])[N:10]([C@H:14]([CH3:24])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]4[O:22][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])([C:32]([O:34][CH2:35][CH3:36])=[O:33])[O:23][C:18]=4[CH:17]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Reactant: C[C@@H](Cc1ccc(O)c(O)c1)N1C[C@@H](c2cccc(Cl)c2)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)N3C[C@H](c4cccc(Cl)c4)OC3=O)cc2O1
Yield: 66.1 %

Procedure:
A mixture of 0.8 g of the above oxazolidinone, 0.74 g of diethyl dibromomalonate, 1.2 g of anhydrous potassium carbonate and 20 ml of acetone are stirred overnight with the addition of a few drops of diethyl dibromomalonate. The mixture is filtered, washed with acetone and the combined filtrate and wash are evaporated to a yellow oil. The oil is purified by flash chromatography, eluting with 5 percent acetone in toluene. The pure fractions are combined and evaporated, giving 766 mg of (R*,S*)-(±)-5-(2-(5-(3-chlorophenyl)-2-oxo-3-oxazolidinyl)propyl)-1,3-benzodioxole-2,2-dicarboxylic acid, diethyl ester as a colorless oil.
Reaction SMILES: S(Cl)(Cl)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([N:14]2[C:18](=O)[C:17]([CH3:20])=[CH:16][S:15]2)[CH:10]=[CH:11][C:12]=1[Cl:13]>C(Cl)CCl>[CH3:20][C:17]1[CH2:16][S:15][N:14]([C:9]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=2)[CH:18]=1
Reactant: Cc1csn(-c2ccc(Cl)c(Cl)c2)c1=O
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCCl
Product: CC1=CN(c2ccc(Cl)c(Cl)c2)SC1
Reaction time: 8 h

Procedure:
Dithio-(3',4'-dichloro)-diisobutyranilide, 12.8 g. (0.0234 mole), was slurried in 250 ml. of ethylene dichloride, and a solution of 9.5 g. (0.0702 mole) of sulfuryl chloride in 25 ml. of ethylene dichloride was added dropwise at 25°-30° C. over one hour. The slurry was stirred overnight to insure completion of the reaction and then filtered to give 8.6 g. of gray 2-(3,4-dichlorophenyl)-4-methyl-3-isothiazolone, m.p. 160°-161° C. The product was crystallized from ethyl acetate to give a m.p. of 161°-163° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1([CH3:36])[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:35])[CH:30]=2)[NH:25]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:35][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:36])([CH3:23])[CH:33]=[C:32]2[CH3:34]
Reactant: CC1=CC(C)(C)Nc2ccc(O)cc21
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Product: COc1cc2c(Oc3ccc4c(c3)C(C)=CC(C)(C)N4)ncnc2cc1OCCCN1CCCC1
Yield: 37.9 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (0.13 g, 0.4 mol), (prepared as described for the starting material in Example 9), was reacted with 2,2,4-trimethyl-1,2-dihydroquinolin-6-ol (95 mg, 0.5 mmol), (IZV. ACAD. NAVK. SSSR. Ser. Khim. 1981, 9, 2008), to give 6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)-4-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yloxy)quinazoline (90 mg, 47%).
Reaction SMILES: [O-][N+:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[N:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=[N:14][C:4]=2[CH:3]=1.[NH4+:28].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)Cl>ClCCCl>[NH2:28][C:3]1[C:4]2[N:14]=[CH:13][N:12]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:5]=2[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[N:2]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NCCOCCn1cnc2c[n+]([O-])c3ccccc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCOCCn1cnc2c(N)nc3ccccc3c21
Reaction time: 3 h

Procedure:
A solution of tert-butyl 2-[2-(5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.60 g, 12.4 mmol) in 150 mL of 1,2-dichloroethane was heated to 80° C. and treated with 10 mL of concentrated NH4OH solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (2.71 g, 14.2 mmol) over a 10 min period. The reaction mixture was treated with an additional 2 mL of concentrated NH4OH solution and then sealed in a pressure vessel and heating was continued for 3 h. The reaction mixture was then cooled and treated with 100 mL of CH2Cl2. The reaction mixture was then washed with H2O, 1% Na2CO3 solution (3×) and brine. The organic portion was dried over Na2SO4 and concentrated to give 4.56 g of tert-butyl 2-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.