Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C1C=CC=CC=1[CH:5]=[CH:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][C:8]=1[N+:23]([O-:25])=[O:24].C(O[C:34](OCC)([N:41](C)[CH3:42])C1C=CC=CC=1)C.CC1N=C(C(OCC)=O)C(C(OCC)=O)=CC=1[N+]([O-])=O>>[CH3:34][N:41]([CH3:42])[CH:5]=[CH:6][C:7]1[N:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:9][C:8]=1[N+:23]([O-:25])=[O:24]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(C=Cc2ccccc2N(C)C)nc1C(=O)OCC
Reactant: CCOC(OCC)(c1ccccc1)N(C)C
Agent: CCOC(=O)c1cc([N+](=O)[O-])c(C)nc1C(=O)OCC
Product: CCOC(=O)c1cc([N+](=O)[O-])c(C=CN(C)C)nc1C(=O)OCC

Procedure:
Diethyl 6-[2-(dimethylamino)styryl]-5-nitro-2,3-pyridinedicarboxylate is also prepared, using the above method, from N,N-dimethylbenzamide diethyl acetal and diethyl 6-methyl-5-nitro-2,3-pyridinedicarboxylate. A modification in the procedure of the latter is that upon cooling the dark red solution is partitioned between ether and water. The ethereal layer is separated and concentrated in vacuo to a dark red oil, which was carried on without purification.
Reaction SMILES: [NH4+].C(OC([N:9]1[CH:13]=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH:19]=2)[N:11]=[CH:10]1)=O)(C)(C)C>>[NH:9]1[CH:13]=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH:19]=2)[N:11]=[CH:10]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cn(C(=O)OC(C)(C)C)cn2)CC1
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]cn2)CC1
Reaction time: 5 h

Procedure:
A methanolic solution of ammonium (2.0 ml) was added to 50 mg of the compound prepared in the above 2), i.e. tert-butyl 4-(1-tert-butoxycarbonyl-1H-imidazol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate and the mixture was stirred for 5 hours. The solvent was evaporated in vacuo and the precipitate was filtered to give 32 mg of the title product as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[C:11](=O)[CH2:12][N:13]([CH3:17])[S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=[CH:7]1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[C:11](=[N:20][OH:21])[CH2:12][N:13]([CH3:17])[S:14](=[O:16])(=[O:15])[C:9]=2[CH:8]=[CH:7]1
Reactant: NO
Reactant: CN1CC(=O)c2c(ccn2CCCCCl)S1(=O)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1CC(=NO)c2c(ccn2CCCCCl)S1(=O)=O
Yield: 45.1 %

Procedure:
A suspension of 145 mg (0.5 mmol) of Compound 17, 104 mg (1.5 mmol) of hydroxylamine hydrochloride and 123 mg (1.5 mmol) of sodium acetate in 15 ml of methanol was refluxed for 166 hours. The reaction mixture was concentrated under reduced pressure, followed by the addition of a half-saturated aqueous solution of potassium carbonate to the residue. The resulting mixture was extracted with chloroform (twice). The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluent:chloroform), whereby 69 mg of the title compound were obtained (yield: 45%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1.Cl>C(O)C.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:3]=1)[NH2:10]
Reactant: COc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: COc1ccc(Br)cc1N
Temperature: 25 °C
Yield: 72.2 %

Procedure:
A stirred mixture of 4-bromo-2-nitroanisole (98.56 g) and iron powder (113.7 g) in ethanol (1.51) was heated to reflux and treated dropwise with hydrochloric acid (350 ml, 0.5N) over 1 hour. After refluxing for a further 3 hours the reaction mixture was cooled to room temperature then filtered through hyflosupercel. The filtrate was evaporated and the residue was treated with saturated sodium bicarbonate solution (21) then filtered. The solid was washed with water then recrystallised from cyclohexane to give the title compound (61.98 g) as a pale brown solid, m.p. 93-93° C.
Reaction SMILES: [OH-].[Na+].BrBr.[CH3:5][C:6]12[C:18]3[C:10](=[CH:11][C:12]([C:19](=[O:21])C)=[CH:13][C:14]=3[CH2:15][CH2:16][CH2:17]1)[CH2:9][CH2:8][CH2:7]2.S([O-])([O-])=[O:23].[Na+].[Na+].Cl>O1CCOCC1.O>[CH3:5][C:6]12[C:18]3[C:14](=[CH:13][C:12]([C:19]([OH:23])=[O:21])=[CH:11][C:10]=3[CH2:9][CH2:8][CH2:7]1)[CH2:15][CH2:16][CH2:17]2
Reactant: O=S([O-])[O-]
Reactant: CC(=O)c1cc2c3c(c1)CCCC3(C)CCC2
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC12CCCc3cc(C(=O)O)cc(c31)CCC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2.5 N Aqueous sodium hydroxide (9.3 ml) was cooled to 0° C., slowly added with bromine (0.30 ml), and then diluted with 1,4-dioxane (10 ml) to obtain a yellow solution. A solution of 1-(6a-methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenyl)ethanone (0.409 g) in water (5 ml) and 1,4-dioxane (10 ml) was cooled to 0° C., and slowly added with the yellow solution prepared above, and the mixture was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. The reaction mixture was cooled to 0° C., and added with 10% aqueous sodium sulfite, the mixture was made acidic with 2 N aqueous hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethyl acetate-n-hexane to obtain the title compound (0.333 g, yield: 81%) as colorless needles (melting point: 213-215° C.).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([O:8][CH2:9][C@H:10]([OH:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)COCc1ccccc1
Solvent: CCO
Product: CCOC(=O)C[C@@H](O)COCc1ccccc1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
300.0 g (1.27 moles) ethyl 4-benzyloxy-3-oxobutyrate, 300 ml ethanol, and 104.5 mg (0.127 mmol) [RuCl{(S)-segphos}]2(μ-Cl)3[Me2NH2] were introduced in a nitrogen stream into a 1-L autoclave and flushed with hydrogen, and after introduction of hydrogen at a pressure of 1 MPa, the mixture was heated with stirring. The mixture was reacted at 90 to 95° C. for 7 hours. After the reaction solution was cooled to room temperature, the hydrogen was purged and replaced by nitrogen. The reaction solution was concentrated in a rotary evaporator and the residue was distilled under reduced pressure to give 265.1 g of the title compound (chemical purity, 95.5%; optical purity, 99.1% ee; and yield, 87.6%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH3:10])=[CH:8][C:7](Br)=[CH:6][C:5]=1[Cl:12].[Cl:14]CCl>CN(C=O)C.Cl[Cu]>[CH3:1][O:2][C:3](=[O:13])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([Cl:14])=[CH:6][C:5]=1[Cl:12]
Reactant: COC(=O)c1c(C)cc(Br)cc1Cl
Reactant: ClCCl
Agent: Cl[Cu]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cc(Cl)cc1Cl
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 65 %

Procedure:
A solution of the 4-bromo-2-chloro-6-methyl-benzoic acid methyl ester (1.31 g, 5 mmol) in DMF was treated with CuCl (1.96 g, 20 mmol) and stirred at 140° C. for 1-2 h. After this time, the reaction mixture was diluted with dichloromethane (15 mL) and the solids removed by filtration. The filtrate was concentrated. Silica gel column chromatography using, typically 30% ethyl acetate in hexane, afforded 2,4-dichloro-6-methyl-benzoic acid methyl ester (0.72 g, 65%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=[CH:7]2.[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH:21]2[CH2:22][CH2:23][N:24]([C:12]([C:9]3[CH:8]=[CH:7][C:6]4[C:11](=[C:2]([OH:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=3)=[O:14])[CH2:25][CH2:26]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc(OC2CCNCC2)cc1
Reactant: O=C(O)c1ccc2cccc(O)c2n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc2cccc(O)c2n1)N1CCC(Oc2ccc(Cl)cc2)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a solution of 8-hydroxyquinoline-2-carboxylic acid (15 mg, 0.079 mmol), 4-(4-chlorophenoxy)piperidine (20 mg, 0.096 mmol), and triethylamine (0.044 mL, 0.32 mmol) in DMF was added HBTU (46 mg, 0.12 mol) at room temperature. The reaction mixture was stirred at 60° C. for 2 hours. The mixture was diluted with ethyl acetate (3 mL) and washed with water (1.5 mL). The organic layer was dried over sodium sulfate, and concentrated by N2-flow. The residue was diluted with methanol and applied onto a strong cation exchange cartridge (BondElute(registered trademark) SCX, 1 g/6 mL, Varian Inc.), and the solid phase matrix was rinsed with methanol (6 mL). The crude mixture was eluted in a collection tube with 1 mol/L ammonia in methanol (6 mL) and concentrated by N2-flow. The residue was purified by preparative LC-MS to give 6.6 mg (22% yield) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12](Cl)[C:11]=2[N:10]=[C:9]1[OH:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:23]>CO>[NH2:23][C:12]1[C:11]2[N:10]=[C:9]([OH:22])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:20]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: N
Reactant: Oc1nc2c(Cl)nc3ccccc3c2n1Cc1ccccc1
Solvent: CO
Product: Nc1nc2ccccc2c2c1nc(O)n2Cc1ccccc1
Temperature: 170 °C

Procedure:
1-Benzyl-4-chloro-1H-imidazo[4,5-c]quinolin-2-ol (approximately 1.1 g) and ammonia (approximately 100 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 170° C. for five days. The resulting solution was concentrated under reduced pressure, and the residue was purified by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0:0:100 to 0.2:4.8:95). A solid was present on top of the column; the solid was collected, washed with acetonitrile (6×100 mL), and purified again by automated flash chromatography (silica cartridge, eluting with aqueous ammonium hydroxide:methanol:dichloromethane in a gradient from 0.2:4.8:95 to 1:19:80) to provide 70 mg of 4-amino-1-benzyl-1H-imidazo[4,5-c]quinolin-2-ol as a white solid, mp greater than 250° C.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[N+:9]([O-:12])([OH:11])=[O:10].[CH3:13][C:14]1[CH:18]=[C:17]([CH3:19])[N:16]([C:20]([NH2:22])=[NH:21])[N:15]=1>C(#N)C>[N+:9]([O-:12])([OH:11])=[O:10].[CH3:13][C:14]1[C:18]([N+:7]([O-:8])=[O:6])=[C:17]([CH3:19])[N:16]([C:20]([NH2:22])=[NH:21])[N:15]=1
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O=[N+]([O-])O
Solvent: CC#N
Product: Cc1nn(C(=N)N)c(C)c1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
2 g of nitronium tetrafluoroborate were added little by little to a suspension of 2.01 g of 3,5-dimethyl-1H-pyrazole-1-carboxamidine nitrate in 150 ml of absolute acetonitrile, with cooling with ice in argon atmosphere, and the reaction mixture was stirred for 30 minutes with cooling with ice. The solvent was removed by distillation under reduced pressure, and the residue was washed with chloroform to obtain 2.43 g of 3,5-dimethyl-4-nitro-1H-pyrazole-1-carboxamidine nitrate.
Reaction SMILES: N1C(=O)CC[C@@H]1C(O)=O.[NH2:10][C@@H:11]1[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[NH:13][C:12]1=[O:22].CN(C)C=O.C(N(CC)CC)C.[C:35](Cl)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCC)C>[C:35]([NH:10][C@@H:11]1[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[NH:13][C:12]1=[O:22])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C1CC[C@H](C(=O)O)N1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccccc2CC[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
A round-bottom flask was fitted with a condenser, stirbar and septa. 3(R)-Amino-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one D-pyroglutamic acid salt (10.0 g, 32.8 mmol), N,N-dimethylformamide (200 mL) and triethylamine (12 mL, 86.1 mmol) were added, giving a mixture which was heated to 120° C. To the resulting solution was added trityl chloride (9.04 g, 32.4 mmol). The reaction was then cooled to 60° C., maintained at 60° C. for 4 hours, and then allowed to slowly cool to room temperature. After 18 hours, the reaction mixture was diluted with diethyl ether (300 mL) and washed first with 400 mL 1:1 H2O:saturated aqueous NaCl solution, then with 2×100 mL H2O. The aqueous washes were combined and extracted with diethyl ether (100 mL). The organic extracts were combined, dried over MgSO4, filtered and concentrated in vacuo to give an oil which that purified via flash chromatography on silica gel (25% ethyl acetate/hexanes) to give the desired product.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH:14]=[CH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:12][C:11]([C:22]([F:25])([F:24])[F:23])=[N:10]2)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl>[CH:14]([C:13]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[N:10]=[C:11]([C:22]([F:25])([F:24])[F:23])[CH:12]=1)=[CH:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(-n2nc(C(F)(F)F)cc2C=Cc2ccccc2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc(-n2nc(C(F)(F)F)cc2C=Cc2ccccc2)cc1
Temperature: -40 °C
Reaction time: 8 h

Procedure:
1-(4-Methoxyphenyl)-5-styryl-3-trifluoromethyl-1H-pyrazole (0.14 g, 0.4 mmol) was dissolved in dichloromethane (1.2 mL) and cooled to −40° C. Boron tribromide (1.2 mL, 1 M in dichloromethane, 1.2 mmol) was added, and the reaction was stirred overnight, warming up to room temperature. Saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The extracts were dried over MgSO4 and concentrated. The reaction was assumed to be quantitative. LC-MS (C18H13F3N2O calculated 330) m/z 331 (M+H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:10][C:11](=[CH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=O)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28]([O-:32])(=[O:31])(=[O:30])=[O:29].[CH3:33][C:34]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[O+:37]=[C:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:35]=1.C(OC(=O)C)(=O)C>>[Cl:28]([O-:32])(=[O:31])(=[O:30])=[O:29].[C:22]1([C:9]2[O:8][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:12][C:11](=[CH:13][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:33][C:34]3[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[O+:37]=[C:36]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH:35]=3)[CH:10]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cc(-c2ccccc2)[o+]c2ccccc12
Reactant: O=C(C=C1C=C(c2ccccc2)OC(c2ccccc2)=C1)c1ccccc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: C(=C1C=C(c2ccccc2)OC(c2ccccc2)=C1)C(=Cc1cc(-c2ccccc2)[o+]c2ccccc12)c1ccccc1

Procedure:
A mixture of 1 g. 2,6-diphenyl-4-phenacylidene-4H-pyran, 1.3 g. of 4-methylflavylium perchlorate and 20 ml. of acetic anhydride was refluxed for 15 minutes, chilled and the solid was collected and purified by extraction. The resultant product had a melting point of 299°-300° C. and was identified as the above-noted pyrylium salt having an empirical formula of C41H29ClO6.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:11][C:12](=O)[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)(O)[O-].[Na+]>>[C:2]1([C:1]2[O:8][CH:11]=[C:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Cc1coc(-c2ccccc2)n1
Temperature: 120 °C
Yield: 38 %

Procedure:
A mixture of benzamide (60.0 g) and ethyl 4-chloroacetoacetate (49.4 g) was heated at 120° C. for 2 hours. After cooling, aqueous sodium bicarbonate solution was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated. The residue was purified by chromatography on silica gel with ethyl ether-hexane (1:9) to yield ethyl 2-phenyl-4-oxazoleacetate as an oil (26.4 g, 28.0%). NMR (CDCl3)δ: 1.27 (3H, t, J=7 Hz), 3.68 (3H, s), 4.15 (2H, q, J=7 Hz), 7.4 (3H, m), 7.67 (1H, s), 8.0 (2H, m).
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[C:2]1=[S:13].[OH-].[Na+].Cl.Cl[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>C(O)C>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[CH2:18][S:13][C:2]1[N:3]2[C:12]3[C:7]([CH2:6][CH2:5][CH2:4]2)=[CH:8][CH:9]=[CH:10][C:11]=3[N:1]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: S=c1[nH]c2cccc3c2n1CCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2nc(CSc3nc4cccc5c4n3CCC5)ccc2c1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
A solution of 5,6-dihydro-4H-imidazo[4,5,1-ij]-quinoline-2(1H)-thione (2.02 g, 11.6 mmol) in ethanol (25 ml) and 1N-sodium hydroxide was treated with 2-(chloromethyl)quinoline hydrochloride (2.48 g, 11.6 mmol) heated to reflux, cooled to room temperature, and the ethanol removed by evaporation in vacuo. The aqueous mixture was filtered and the precipitate washed with water (5×50 ml), dried in vacuo, and recrystallised from cyclohexane - EtOAc to give 5,6-dihydro-2-(quinolin-2-ylmethylthio)-4H-imidazo[4,5,1-ij]quinoline (2.13 g, 55%) as yellow crystals mp 125°-126° C. (Found: C, 72.8; H, 5.3; N,12.4 C20H17N3S requires C, 72.5; H, 5.2; N, 12.7%).
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[OH-].[Na+].O.[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[C:12]1([NH:18][C:19]([N:1]=[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][N:3]2[CH3:8])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN1CCCCC1=N
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CN1CCCCC1=NC(=O)Nc1ccccc1
Temperature: 25 °C

Procedure:
The hydrochloride salt of 2-imino-1-methylpiperidine (7.43 g.; 0.05 mole) is converted to free base by adding 5 mls. of 50% NaOH to an aqueous slurry (using a minimal amount of water) of the salt and then extracting with benzene. After drying over K2CO3, the benzene solution is stirred at room temperature and 5.96 g. (0.05 mole) of phenylisocyanate, dissolved in anhydrous benzene, is added dropwise. Cloudiness occurs and eventually solid precipitates from the solution. The reaction mixture is stirred at room temperature overnight (about 17 hours). The solid is collected, m.p. = 145°-158° C. The filtrate is taken to dryness in vacuo to give further solid material. Repeated recrystallizations of the combined solids from methanol yields the pure product, 1-phenyl-3-(1-methyl-2-piperidylidene)urea, m.p. = 160°-161° C.
Reaction SMILES: [Na].C(OC(=O)CC(CCl)=O)(C)C.[CH:13]([O:16][C:17](=[O:30])[CH2:18][C:19]([CH2:21][O:22]CC1C=CC=CC=1)=[O:20])([CH3:15])[CH3:14]>O1CCCC1>[CH:13]([O:16][C:17](=[O:30])[CH2:18][C:19]([CH2:21][OH:22])=[O:20])([CH3:15])[CH3:14]
Reactant: CC(C)OC(=O)CC(=O)COCc1ccccc1
Agent: CC(C)OC(=O)CC(=O)CCl
Agent: [Na]
Solvent: C1CCOC1
Product: CC(C)OC(=O)CC(=O)CO

Procedure:
Sodium benzylate in tetrahydrofuran was reacted using the procedure of Example 1 with 4-chloroacetoacetic isopropyl ester. The resultant 4-benzyloxyacetoacetic acid isopropyl ester was subsequently hydrogenolyzed. The 4-hydroxyacetoacetic isopropyl ester thus formed was converted at ambient temperature into tetronic acid by treatment with 18 percent HCl. The total yield, related to the 4-chloroacetoacetic isopropyl ester, was 78 percent.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[C:14]([O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][CH:21]=1)([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>ClCCl>[C:14]([O:18][C:19](=[O:28])[C:20]1[CH:21]=[CH:22][C:23]([CH2:26][NH:27][S:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])=[CH:24][CH:25]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)c1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CNS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
2-Nitro-benzenesulfonyl chloride (8.55 g, 38.6 mmol) and 4-aminomethyl-benzoic acid tert-butyl ester (8.0 g, 38.6 mmol) were mixed in 400 mL of dichloromethane. Triethylamine (10.8 mL, 77.2 mmol) was added, and the resulting mixture was stirred at room temperature for 16 hours. The reaction was partitioned between 1M HCl and dichloromethane. The organic layer was dried (magnesium sulfate), filtered, and rotary evaporated to give 14.46 g (95%) of 4-[(2-nitro-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester as an off-white solid. 1H-NMR (CDCl3); δ 8.00 (dd, 1H), 7.84 (m, 3H), 7.67 (m, 2H), 7.27 (dd, 2H), 5.76 (bt, 1H), 4.36 (d, 2H), and 1.57 (s, 9H). MS: M+=392.1 Da Step (2): Synthesis of 4-[(2-Amino-benzenesulfonylamino)-methyl]-benzoic acid tert-butyl ester
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:15].[C:16]([O:21][CH2:22][CH3:23])(=[O:20])[CH:17]([CH3:19])[CH3:18]>C1COCC1>[CH2:22]([O:21][C:16](=[O:20])[C:17]([CH3:19])([CH3:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:15])[CH3:23]
Reactant: BrCCCCCBr
Reactant: CCOC(=O)C(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCCCCBr
Temperature: 25 °C
Reaction time: 20 h
Yield: 60 %

Procedure:
Under argon atmosphere and cooling with an ice-bath, a solution of lithium diisopropylamide in THF (1.7 L, 2.0 M, 3.4 mol) was slowly dropped into a solution of 1,5-dibromopentane (950 g, 4.0 mol) and ethyl isobutyrate (396 g, 3.4 mol) in THF (5 L) while keeping the temperature below +5° C. The reaction mixture was stirred at room temperature for 20 h and quenched by slow addition of saturated ammonium chloride solution (3 L). The resulting solution was divided into three 4-L portions. Each portion was diluted with saturated ammonium chloride solution (5 L) and extracted with ethyl acetate (2×2 L). Each 4-L portion of ethyl acetate was washed with saturated sodium chloride solution (2 L), 1 N hydrochloric acid (2 L), saturated sodium chloride solution (2 L), saturated sodium bicarbonate solution (2 L), and saturated sodium chloride solution (2 L). The three separate ethyl acetate layers were combined into a single 12-L portion, dried over magnesium sulfate, and concentrated in vacuo to give the crude material (1.7 L) which was purified by vacuum distillation. Two fractions were obtained: the first boiling at 88-104° C./0.6 torr (184.2 g), the second at 105-120° C./1.4 torr (409.6 g) for a total yield of 60%. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.11 (q, 2 H, J=7.2 Hz), 3.39 (t, 2 H, J=6.8 Hz), 1.85 (m, 2 H), 1.56-1.35 (m, 4 H), 1.24 (t, 3 H, J=7.2 Hz), 1.31-1.19 (m, 2 H), 1.16 (s, 6 H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 177.9, 60.2, 42.1, 40.5, 33.8, 32.6, 28.6, 25.2, 24.2, 14.3. HRMS (EI, pos): Calcd. for C11H22BrO2 (MH+): 265.0803, found: 265.0810.