Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][CH2:9][C:10]1([CH2:23][C:24]([CH3:26])=[CH2:25])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1>ClCCl>[CH3:25][C:24]1([CH3:26])[CH2:23][C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9][O:8]1
Reactant: C=C(C)CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC2(CCNCC2)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
Trifluoroacetic acid (20 mL) was added to a solution of 1-(1,1-dimethylethyl) 4-(hydroxymethyl)-4-(2-methyl-2-propenyl)-1-piperidinecarboxylate (Description 90, 1.14 g, 4.2 mmol) in dichloromethane (4 mL) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and water (40 mL) was added. The pH was adjusted to 12 with aqueous sodium hydroxide (4M) and the mixture was extracted with ethyl acetate (4×40 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (10 mL) and ethereal hydrogen chloride (1M, 10 mL) was added. The solvent was evaporated under reduced pressure and the residue was triturated with ethyl acetate (15 mL). The solid was collected and dried in vacuo to give the title compound as a colorless solid (483 mg, 56%). m/z (ES+) 170 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH:5]([N:15]1[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]1=[O:17])[C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1.N1C=CC=CC=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>>[C:30]([O:1][CH2:2][CH2:3][O:4][CH:5]([N:15]1[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]1=[O:17])[C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)(=[O:32])[CH3:31]
Reactant: O=c1[nH]c(=O)n(C(OCCO)c2ccc3c(c2)OCO3)cc1F
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCOC(c1ccc2c(c1)OCO2)n1cc(F)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-[α-(2-Hydroxyethoxy)-3,4-methylendioxybenzyl]-5-fluorouracil obtained in Example 10 was dissolved in acetic anhydride (20 ml) and pyridine (20 ml) followed by stirring at room temperature for 3 hours. The reaction mixture was poured into ice-water and the resulting oil was extracted with chloroform (100 ml). The extract was washed with hydrochloric acid and then water, dried over magnesium sulfate and evaporated under reduced pressure to remove chloroform. The residue was treated with ligroinacetone to give 4.3 g of crystalline 1-[α-(2-acetoxyethoxy)-3,4-methylenedioxybenzyl]-5-fluorouracil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]2[N:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=[C:14]2[N:13]=[C:12]([CH3:23])[CH:11]=1>C(O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[N:15]3[N:16]=[C:17]([C:19]([F:20])([F:22])[F:21])[N:18]=[C:14]3[N:13]=[C:12]([CH3:23])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)n2nc(C(F)(F)F)nc2n1
Reactant: Nc1ccc(Cl)cc1
Solvent: CCO
Product: Cc1cc(Nc2ccc(Cl)cc2)n2nc(C(F)(F)F)nc2n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 66 %

Procedure:
4-chloroaniline (0.355 g, 2.78 mmol) was added to a well-stirred absolute ethanol solution of 7-chloro-5-methyl-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine (0.547 g, 2.32 mmol, 15-20 mL). After stirring for 6-8 hours at room temperature, the desired product crystallized and was then filtered. Subsequent purification using column chromatography gave the final product in 66% yield.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](Cl)=[N:9]2)=[CH:4][N:3]=1.[CH3:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:17]3[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=3)=[N:9]2)=[CH:4][N:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1ccc2cnc(Br)cc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccc3cnc(Br)cc3n2)cn1
Temperature: 60 °C
Yield: 54.8 %

Procedure:
7-Bromo-2-chloro-1,6-naphthyridine (Preparation 61, 44.5 mg 0.183 mmole) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (53.4 mg 0.256 mmole) were stirred in THF (1 mL) and 2M aqueous sodium carbonate solution (0.35 mL) was added. Palladium(dppf)dichloride.dichloromethane complex (4.0 mg, 0.0049 mmole) was added and the reaction heated at 60° C. for 4.5 hours under nitrogen. The reaction was diluted with ethyl acetate (15 mL) and the solution was washed with brine (7 mL). The brine was backwashed with ethyl acetate (7 mL) and the combined organic layers were dried and concentrated in vacuo. The residue was purified using preparative TLC eluting with EtOAc to afford the title compound (29 mg, 54%).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.I[CH2:13][CH3:14]>O1CCCC1>[CH2:13]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:14]
Reactant: c1ccc2c(c1)CCN2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
NaH (10 g) was added to a chilled (0° C.) solution of indoline (30 g, 252.10 mmol) in tetrahydrofuran (300 mL). The resulting solution was then stirred at room temperature for 30 minutes. Iodoethane (50 g, 322.58 mmol) was then added dropwise and the resulting solution was maintained at room temperature for an additional 3 hours. The reaction mixture was then quenched by adding ethanol (100 mL). The resulting solution was extracted with dichloromethane (3×500 mL), and the organic layers were combined and concentrated. The residue was purified by column chromatography using a 100:1 ethyl acetate/petroleum ether solvent system to give 29 g (78%) of 1-ethylindoline as yellow oil.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:14])[CH2:7][N:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)[CH3:4].[Cl:15][C:16]1[S:20][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:18][CH:17]=1>C1COCC1.CCOC(C)=O>[CH2:3]([O:5][C:6](=[O:14])[CH2:7][N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][S:21]([C:19]2[S:20][C:16]([Cl:15])=[CH:17][CH:18]=2)(=[O:23])=[O:22])[CH2:9]1)[CH3:4]
Reactant: CCOC(=O)CN1CC[C@@H](N)C1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CC[C@@H](NS(=O)(=O)c2ccc(Cl)s2)C1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
8.1 A suspension of 540 mg ((R)-3-amino-pyrrolidin-1-yl)-acetic acid ethyl ester dihydrochloride (example 1.2) in 5 ml THF was treated with 1.2 ml TEA and 530 mg 5-chlorothiophene-2-sulfonylchloride. The reaction mixture was stirred over night at r.t., then taken up in EtOAc and washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated to give 690 mg [(R)-3-(5-chloro-thiophene-2-sulfonylamino)-pyrrolidin-1-yl]-acetic acid ethyl ester. Oil. 353.1 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1ccccc1N1CCN(C(=O)Nc2cc3ccccc3nc2OC)CC1
Yield: 88 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)N.C(ON=O)CC(C)C.[Si:17]([O:24][CH2:25][C:26]1[O:27][CH:28]=[CH:29][CH:30]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([C:28]2[O:27][C:26]([CH2:25][O:24][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])=[CH:30][CH:29]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccco1
Reactant: Nc1cccc(Br)c1
Agent: CC(C)CCON=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(-c2cccc(Br)c2)o1
Temperature: 50 °C
Yield: 26 %

Procedure:
To a stirred solution of m-bromoaniline (6.88 g; 0.04M) in 42.2 g (0.2M) of 2-(t-butyldimethylsilyloxymethyl)furan at 0° was added isoamylnitrite (10.75 mL: 0.08M) dropwise over a period of 0.5 hr. The resulting mixture was then heated 16 hours at 50° C. The reaction mixture was cooled and diluted with 150 mL of ether and washed with 2×100 mL of ice cold water. The organic phase was dried over anhydrous magnesium sulfate, and the residue was distilled after filtering through 50 G of silica gel bed, to give 26% of the desired 2-(3'-bromophenyl)-5-(t-butyldimethylsilyloxymethyl)furan as a colorless liquid boiling at 163°-7°/~0.5 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14]OS(C)(=O)=O)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:8].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@@H:12]([CH2:14][N:25]3[C:21](=[O:31])[C:22]4[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:24]3=[O:26])[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
A solution of mesylate 105 (26.38 g, 63.57 mmol) in anhydrous N,N-dimethylformamide (DMF, 120 mL) was treated with solid potassium phthalimide (12.95 g, 70.0 mmol, 1.1 equiv) at 25° C., and the resulting reaction mixture was warmed to 70° C. for 2 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to room temperature before being quenched with H2O (400 mL). The resulting mixture was stirred at room temperature for 10 min before being cooled to 0-5° C. for 1 h. The white precipitate was collected by filtration, washed with water (3×100 mL), and dried in vacuo to afford the desired (5R)-2-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione 106 (27.85 g, 94%) as an off-white powder. This product was directly used in subsequent reactions without further purification. C18H12FIN2O4, LCMS (EI) m/e 467 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](=[O:18])[CH2:11][CH2:12][C:13]([O:15]CC)=O.[Na].C(O)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10](=[O:18])[CH2:11][CH2:12][C:13]1=[O:15]
Reactant: CCOC(=O)CCC(=O)Cc1ccc(C)cc1C
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(C2C(=O)CCC2=O)c(C)c1
Yield: 49.2 %

Procedure:
Utilizing 21.46 g. (0.0864 mol) of ethyl 5-(2',4'-dimethylphenyl)-4-ketopentanoate, 4.00 g. (0.173 mol) of sodium, 125 ml of dry ethanol, 200 ml of toluene, and the procedure described in Example I, Part D, 8.60 g (49% yield) of 2-(2',4'-dimethylphenyl)-1,3-cyclopentanedione was obtained as a white, crystalline solid, m.p. 198.0°-200.5° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].CCN(C(C)C)C(C)C.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC#N>[O:12]=[C:3]1[CH:2]([NH:1][S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1
Reactant: NC1Cc2ccccc2NC1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2ccccc2CC1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.5 %

Procedure:
To a suspension of 3-amino-3,4-dihydro-1H-quinolin-2-one (177.6 mg, 0.59 mmol) (prepared according to the procedures by Davis, A. L.; et al, Arch. Biochem. Biophys., 102, 48 (1963)) in CH3CN (5 mL) was added DIPEA (0.24 mL, 1.44 mmol), followed by addition of benzene sulfonylchloride (0.09 mL, 0.71 mmol). The mixture was stirred at RT for 1.5 h, then concentrated in vacuo. The residue was taken into EtOAc (30 mL), washed with water, brine, dried (MgSO4) and concentrated. The residue was chromatographed (silica gel) eluting with EtOAc (50-90%) in hexane to give the title compound (140 mg, 78%).
Reaction SMILES: [NH2:1][C:2]([CH3:10])([CH3:9])[CH2:3][NH:4][S:5]([CH3:8])(=[O:7])=[O:6].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1.CCN(CC)CC>C1COCC1>[Cl:11][C:12]1[N:17]=[C:16]([NH:1][C:2]([CH3:10])([CH3:9])[CH2:3][NH:4][S:5]([CH3:8])(=[O:7])=[O:6])[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(N)CNS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CNS(C)(=O)=O)Nc1nc(Cl)ncc1Cl
Temperature: 60 °C
Reaction time: 0.08 h
Yield: 48.2 %

Procedure:
N-(2-Amino-2-methyl-propyl)-methanesulfonamide (1.15 g, 6.90 mmol, 1.2 eq.) in THF (20 mL) was cooled to 0° C. and 2,4,5-trichloropyrimidine (1.05 g, 5.75 mmol, 656 μL, 1.0 eq.) was added. The reaction was stirred for 5 minutes and then NEt3 (2.07 mL) was added. After 5 minutes, external cooling was removed and the reaction was heated at 60° C. overnight under a nitrogen atmosphere. The reaction was then partitioned between CH2Cl2 (150 mL) and sat. NaHCO3 (150 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (75 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated under reduced pressure onto basic alumina. Purification by basic alumina chromatography (dry loaded) using a gradient of 0-60% EtOAc/hex as the eluting solvent to obtain N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-2-methyl-propyl]-methanesulfonamide as a white solid (868 mg, 48%). m.p.=156-158° C.; LCMS (m/e) 313 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.04 (s, 1H), 5.57 (bs, 1H), 5.25-5.16 (m, 1H), 3.54 (d, 2H, J=6.8 Hz), 3.00 (s, 3H), 1.53 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([CH2:11]O)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].P(Br)(Br)[Br:14]>C(Cl)Cl>[Br:14][CH2:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10]
Reactant: Cc1c(CO)ccc(C#N)c1Cl
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Cc1c(CBr)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 3 h
Yield: 28.3 %

Procedure:
To a solution of compound 7B (700 mg, 3.9 mmol) in CH2Cl2 (15 mL) was added PBr3 (5.8 mL, 5.8 mmol, 1N in CH2Cl2) at −15° C., and stirred at −15° C. for 3 hr. The reaction was slowly quenched with saturated NaHCO3 solution at −15° C. The organic layer was separated, dried over MgSO4, and concentrated. Purification by silica gel chromatography (0-10% EtOAc in hexanes) provide the title compound (270 mg) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH2:17])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28]>C(Cl)Cl.ClC(OC(C)C)=O>[C:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][NH:17][C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)NCc1cc(O)ccc1CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.3 %

Procedure:
A slurry of 3-(2-aminomethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (75.4 g, 0.3 mol) in CH2Cl2 (900 mL) at 1° C. was treated with triethylamine (60.7 g, 0.6 mol). Isopropyl chloroformate (300 mL, 0.3 mol, 1M in toluene) was added while maintaining the temperature less than 12° C. The resulting solution was stirred 16 h at ambient temperature. After 16 h, additional isopropyl chloroformate (15 mL, 0.015 mol, 1.0M in toluene) was added, and the reaction was stirred for 1 h. The reaction mixture was washed with 1N HCl (2×200 mL) and saturated NaHCO3 solution (2×200 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by filtration through Merck silica gel 62 (750 grams, CH2Cl2/MeOH 100/0 to 96/4) to give the title compound (95.48 g, 94.3%). 1H NMR (300 MHz, CDCl3): δ 1.20-1.24 (d, 6H), 1.40 (s, 9H), 2.46-2.52 (t, 2H), 2.81-2.86 (t, 2H), 4.294.32 (d, 2H), 4.86-4.97 (m, 1H), 5.19-5.28 (m, 1H), 6.67-6.72 (dd, 2H), 6.76 (s, 1H), 6.97-7.00 (d, 1H). MS (ES−) m/z 336.1 [M−H]−.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.O>O1CCCC1>[N:13]1([C:2]2[N:11]=[C:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: C1CCNC1
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(N3CCCC3)nc(N3CCCC3)nc2c1

Procedure:
Ten grams of 2,4-dichloroquinazoline was added carefully to a solution of 25 ml of pyrrolidine in 200 ml of tetrahydrofuran. The resulting mixture was heated at reflux overnight and then was poured into a mixture of ice and water. The resulting mixture was extracted several times with ether. The ether extracts were combined and washed with water. The ether phase then was dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was recrystallized from a 1:1 benzene:hexane mixture to give 10.1 g of 2,4-bispyrrolidinylquinazoline; m.p. 127°-129°. The following analytical data were obtained:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]3[CH2:18][CH2:19][N:20](C([O-])=O)[CH:16]3[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:17]3[CH2:18][CH2:19][NH:20][C@H:16]3[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])N1CCC2C(c3ccc(F)cc3)Nc3ccccc3C21
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc([C@@H]2Nc3ccccc3[C@@H]3NCC[C@H]23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.2 %

Procedure:
A mixture of benzyl(3aR*,4R*,9bR*)-4-(4-fluorophenyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (500 mg, 1.24 mmol) and 10% palladium on carbon (50% aqueous, 0.3 g) in ethanol (20 ml) was stirred at room temperature under hydrogen atmosphere for 2 hrs. The catalyst was filtered off, and the mixture was washed with ethanol. The solvent was evaporated under reduced pressure to give the title compound (350 mg, ca. 100%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[Br:32][CH2:11][CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: OCCCc1ccc(F)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(CCCBr)c(F)c1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
Compound 65-2 (940 mg) was dissolved in methylene chloride (10 ml), triphenylphosphine (1.58 g) and N-bromosuccinimide (1.07 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (1.03 g) as a colorless oil.
Reaction SMILES: [CH:1]1[C:14]2[C:5]([S:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[CH:4][C:3](=[O:15])[CH:2]=1.C(N(CC)CC)C.[CH2:23]([SH:27])[CH2:24][CH2:25][CH3:26].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>CO>[CH2:23]([S:27][C:2]1[C:3](=[O:15])[CH:4]=[C:5]2[C:14](=[N:13][C:12]3[C:7]([S:6]2)=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:1]=1)[CH2:24][CH2:25][CH3:26]
Reactant: O=c1ccc2nc3ccccc3sc-2c1
Reactant: CCCCS
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCSc1cc2nc3ccccc3sc-2cc1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3H-phenothiazin-3-one (0.64 g) in 75 ml methanol was added triethylamine (1.0 ml) and n-butanethiol (0.58 ml). The mixture was stirred at room temperature for 48 hours. Then 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.67 g) was added. The mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was chromatographed on neutral alumina (Act III) and eluted with 15% EtOAc/hexane to afford the title compound (0.4 g), m.p. 133° C.
Reaction SMILES: [CH2:1]([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[H-].[Na+].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>CN(C=O)C>[CH3:23][CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34]([NH:18][S:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:16])=[O:17])=[O:35])[CH3:22]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCCCCCCCS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCS(=O)(=O)NC(=O)Nc1c(C(C)C)cccc1C(C)C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
A solution of 1-tetradecylsulfonamide (9.0 g, 32.4 mmoles) in DMF (90 mL) was added dropwise to a stirred suspension of NaH (1.63 g, 68 mmoles) in 30 mL of DMF. The solution was stirred 60 minutes, then 2,6-diisopropylphenyl isocyanate (7.0 mL, 33 mmoles) was added dropwise. The mixture was stirred overnight at room temperature, then quenched by dropwise addition of 1M HCl. The mixture was then partitioned between H2O and ethyl acetate (500 mL each). The aqueous layer was further extracted with ethyl acetate. The combined ethyl acetate extracts were diluted with hexane (100 mL) and then washed exhaustively with H2O. The organic extracts were dried, filtered, and concentrated to a solid residue, which was triturated with ether and the solid isolated by suction filtration and dried. Isolated 9.70 g of solid, m.p. 135-137° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH3:13])[CH:5]=1.C[O:16]C(OC)N(C)C.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([CH:13]=[O:16])[CH:5]=1
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C)c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-methyl4-nitro-benzoic acid methyl ester (24.99 g, 128.1 mmol) and N,N-dimethylformamide dimethyl acetal (40.0 mL, 300 mmol) was heated at 140° C. for 22.5 h. After cooling to rt, the reaction mixture was concentrated and the residue was crystallized from MeOH to give a purple solid. This solid was dissolved in THF (500 mL) and water (500 mL), and sodium periodate (62.62 g, 292.8 mmol) was added followed by additional sodium periodate (15.6 g, 72.9 mmol) two hours later. After stirring at rt for an additional 1 h, the reaction mixture was filtered through Celite washing with EtOAc (2 L). The filtrate was washed with saturated NaHCO3 (600 mL) and the organic layer was dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was passed through a pad of silica gel, washing with CH2Cl2/hexanes (75%-100%). The filtrate was concentrated and dried to give 3-formyl-4-nitro-benzoic acid methyl ester as yellowish solid. MS (EI): cal'd 210.0 (MH+), exp 210.2 (MH+).