Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2[CH:3]=[CH:2]1)[CH2:7]3.[C:11]1(O)C=CC=CC=1.C([O-])(=O)C.C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C(O)(=O)C(C)=C.C1(C=CC(O)=CC=1)O>C=CC1C=CC=CC=1>[CH:7]([C:8]1[CH:9]=[CH:10][CH:6]=[CH:5][C:4]=1[CH:3]=[CH2:2])=[CH2:11]
Reactant: Oc1ccccc1
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: C=C(C)C(=O)O
Agent: CC(=O)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C=Cc1ccccc1
Product: C=Cc1ccccc1C=C

Procedure:
A reactor is charged with 600 g of an epoxy resin prepared from dicyclopentadiene and phenol having an average functionality of about 3.2 and an epoxide equivalent weight (EEW) of 265. The resin is heated at 120° C. for 1 hour with 0.43 g of a 70 weight percent methanolic solution of ethyltriphenylphosphonium acetate.acetic acid complex catalyst with a nitrogen sparge. To the resulting mixture is added 200 g of the diglycidyl ether of bisphenol A having an EEW of 179 thereby forming a homogeneous solution having an EEW of 208. The mixture of epoxy resins is reacted catalytically with a stoichiometric equivalent amount (322 g) of glacial methacrylic acid in the presence of air and 400 ppm hydroquinone at 100° C. to 115° C. until a 1.1% acid concentration is reached. The vinyl ester resin is dissolved in 508 g of styrene and 127 g of divinyl benzene to yield a blend containing about 36 percent monomeric diluent by weight. The diluent contained 80% by weight styrene and 20% by weight divinylbenzene.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[CH2:19]([O:26][C:27]1[CH:31]=[C:30]([C:32](O)=[O:33])[O:29][N:28]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[CH2:19]([O:26][C:27]1[CH:31]=[C:30]([C:32]([N:16]2[CH2:17][CH2:18][N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:14][CH2:15]2)=[O:33])[O:29][N:28]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Reactant: O=C(O)c1cc(OCc2ccccc2)no1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2cc(OCc3ccccc3)no2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (2.1 g, 7.2 mmol), 3-(benzyloxy)isoxazole-5-carboxylic acid (1.58 g, 7.2 mmol), triethylamine (2.79 mL, 20.0 mmol), EDCI (1.92 g, 10.0 mmol) and HOBt (1.53 g, 10.0 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by NH-silica gel column chromatography (hexane/ethyl acetate 90:10 to 50:50). Solvent was removed to obtain a solid (2.2 g, 73%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH2:12][N:13]([CH2:23][C:24]1[C:29]([CH3:30])=[CH:28][C:27]([Cl:31])=[CH:26][N:25]=1)[C:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH3:15].[Li+].[BH4-].[OH-].[Na+].C(Cl)Cl>CO.C1COCC1>[Cl:31][C:27]1[CH:28]=[C:29]([CH3:30])[C:24]([CH2:23][N:13]([CH2:12][C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH2:3][OH:2])[C:14]([CH3:15])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH3:22])=[N:25][CH:26]=1
Reactant: COC(=O)c1cc(C#N)ccc1CN(Cc1ncc(Cl)cc1C)C(C)(C)c1ccccn1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CN(Cc1ccc(C#N)cc1CO)C(C)(C)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
To a solution of 2-{[(5-chloro-3-methyl-pyridin-2-ylmethyl)-(1-methyl-1-pyridin-2-yl-ethyl)-amino]-methyl}-5-cyano-benzoic acid methyl ester (0.4561 g, 1.0 mmol) in MeOH (5 mL) and THF (5 mL) at 0° C. was added LiBH4. The reaction was stirred at room temperature for 3 hours, then 1N NaOH (25 mL) was added and stirred for 10 minutes. CH2Cl2 (35 mL) was added, the phases were separated, and the aqueous layer was extracted with CH2Cl2 (4×15 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (100:1:1 CH2Cl2-MeOH—NH4OH) provided 0.3847 g (91%) of COMPOUND 404 as a white solid. 1H NMR (CDCl3) δ 1.61 (s, 6H), 2.09 (s, 3H), 3.71 (s, 2H), 3.98 (s, 2H), 4.50-4.51 (m, 2H), 6.39 (s, 1H), 7.09 (1H, J=6.0 Hz), 7.15 (s, 1H), 7.23-7.31 (m, 2H), 7.54-7.58 (m, 2H), 7.65-7.68 (m, 1H), 8.04 (s, 1H), 8.50 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.64, 24.64, 52.42, 53.30, 62.46, 64.46, 111.26, 119.08, 122.35, 122.53, 130.18, 130.98, 131.00, 133.10, 134.03, 136.42, 137.59, 141.71, 144.61, 144.95, 148.30, 155.91, 165.29. ES-MS m/z 422.2 (M+H). Anal. Calcd. for C24H25N4ClO.0.1H2O: C, 68.19; H, 6.01; N, 13.25; Cl, 8.39. Found: C, 68.01; H, 6.04; N, 13.20; Cl, 8.84.
Reaction SMILES: [C:1]([NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)(=[O:4])[CH2:2][CH3:3].FC(F)(F)C(O)=O.[N+:25]([O-])([OH:27])=[O:26]>O.C(OCC)C>[C:1]([NH:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[C:12]=2[N+:25]([O-:27])=[O:26])[CH2:7]1)(=[O:4])[CH2:2][CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)NC1CCc2cc(OC)ccc2C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCC(=O)NC1CCc2c(ccc(OC)c2[N+](=O)[O-])C1
Reaction time: 8 h

Procedure:
12.2 g of 2-propanoylamino-6-methoxy-1,2,3,4-tetrahydronaphthalene are introduced into 100 ml of trifluoroacetic acid, and 3 ml of nitric acid (d=1.49) are added dropwise thereto. Stirring is continued for 8 hours and the mixture is then taken up in water and diethyl ether. To separate the nitro isomers, the mixture is subjected to chromatography under pressure, on a silica column, elution being carried out with an 8/2 methylene chloride/ethyl acetate mixture. 5 g of the isomer nitrated in the 7-position and 3.8 g of the isomer nitrated in the 5-position are finally collected.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:8][CH:9]2OCC[O:10]2)[CH:5]=[CH:4][N:3]=[CH:2]1>Cl>[Cl:21][C:16]1[CH:15]=[C:14]([CH:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:8][CH:9]=[O:10])[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: Clc1ccc(C(CC2OCCO2)Cn2ccnc2)cc1Cl
Agent: Cl
Product: O=CCC(Cn1ccnc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.2 %

Procedure:
5N Aqueous hydrochloric acid solution (100 ml) was added to an ice-cooled solution of 1-(imidazol-1-yl)-2-(3,4-dichlorophenyl)-3-(1,3-dioxolan-2-yl)propane (11 g) (see Preparation 17) in tetrahydrofliran (100 ml). The mixture was allowed to warm slowly to room temperature and then left to stand for 24 hours. The tetrahydrofuran was removed under reduced pressure and the acidic phase extracted with dichloromethane (2×100 ml). The organic phases were combined, washed with brine and dried over anhydrous sodium sulphate. The solvent was removed under reduced pressure to give the crude product which was chromatographed on silica gel eluting with a solvent gradient of 97.5:2.5 changing to 95:5, by volume, dichloromedane:methanol, to give 3-(3,4-dichlorophenyl)-4-(imidazol-1-yl)butan-1-al (4.4 g) as a viscous oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20]O)=[CH:16][CH:15]=1.[C:24]1(=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[NH:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][N:25]2[C:26](=[O:33])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:24]2=[O:34])=[CH:22][CH:23]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCOc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCOc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 51.1 %

Procedure:
Diethyl azodicarboxylate (1.25 g, 7.20 mmol) was added to a solution of 2-(4-fluorophenoxy)ethanol (1.12 g, 7.20 mmol), isoindoline-1,3-dione (1.06 g, 7.20 mmol) and triphenylphosphine (1.89 g, 7.20 mmol) in tetrahydrofuran (20 ml) at 0° C. The reaction mixture was stirred at room temperature for 17 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 10/90 to 12.5/87.5) to give 2-(2-(4-fluorophenoxy)ethyl)isoindoline-1,3-dione (1.05 g, 51%) as a white solid: LCMS: 286 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]([C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21])([CH3:18])([CH3:17])[CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(C)(C)C)CC1
Reaction time: 16 h
Yield: 83.9 %

Procedure:
A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1 g, 0.00502 mole) in dry 1,2-dichloroethane (10 mL) was stirred under an atmosphere of nitrogen for 10 minutes. 2-Tert-butylaniline (0.974 g, 0.00652 mole), acetic acid (0.301 g, 0.005 mole) and sodium triacetoxyborohydride (1.596 g, 0.00753 mole) were then added portionwise and stirring was continued at ambient temperature for 16 hours. The reaction mixture was basified with sodium bicarbonate solution and the product was extracted with dichloromethane. The dichloromethane layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting transparent viscous liquid was purified by column chromatography using neutral aluminium oxide (1-2% ethyl acetate in hexane) to afford 1.4 g (83%) of 4-(2-tert-butyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 7.25 (m, 1H), 7.15 (t, 1H), 6.8-6.6 (m, 2H), 4.0 (dd, 2H), 3.9-3.8 (dd, 2H), 3.6 (bs, 1H), 3.1 (t, 2H), 2.2-2.2 (dd, 2H), 1.5-1.4 (d, 18H). A solution of 4-(2-tert-butyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.35 g, 0.00406 mole) in ethyl acetate.HCl (10 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with ether and dried to afford 0.9 g (72%) of (2-tert-butyl-phenyl)-piperidin-4-yl-amine dihydrochloride. LCMS: 233.19 (M+1)+, 86.32%, 1H NMR (DMSO-d6): δ 9.1 (d, 2H), 7.2 (d, 1H), 7.1 (s, 3H), 6.8 (d, 1H), 6.6 (t, 1H), 3.7 (m, 1H), 3.4 (m, 3H), 3.0 (q, 3H), 2.6 (t, 1H), 2.2 (d, 2H), 1.7 (m, 2H), 1.4 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[CH3:19].Cl.F[B-](F)(F)F.[NH4+].[N:27]([O-])=O.[Na+].[Cl-].[Na+].C([O-])(=O)C.[K+]>O.C1OCCOCCOCCOCCOCCOC1>[NH:1]1[C:2]2[C:3](=[CH:4][C:5]([O:6][C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[C:9]([O:11][CH3:12])=[O:10])=[CH:17][CH:18]=2)[CH:19]=[N:27]1
Reactant: COC(=O)c1ccccc1Oc1ccc(N)c(C)c1
Reactant: O=N[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Product: COC(=O)c1ccccc1Oc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.2 %

Procedure:
Methyl 2-(4-amino-3-methylphenoxy)benzoate (500 mg, 1.94 mmol) was suspended in water (5.7 ml), followed by adding thereto concentrated hydrochloric acid (1.0 ml) and ammonium tetrafluoroborate (693 mg) at 0° C. An aqueous sodium nitrite solution (134 mg/1 ml) was added dropwise to the suspension. A saturated aqueous sodium chloride solution was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting dark-blue oil was dissolved in chloroform (15 ml), and potassium acetate (381 mg, 3.88 mmol) and 18-crown-6 (15 mg) were added thereto at room temperature and then stirred for 2 hours. To the resulting suspension was added a saturated aqueous sodium chloride solution, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The organic layer dried was concentrated and then purified by a silica gel column chromatography (chloroform/methanol=70/1) to obtain methyl 2-(1H-indazol-5-yloxy)benzoate (157 mg, two steps 30%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([F:8])[CH2:4][PH:5](=[O:7])[OH:6].[CH3:9][Si](N[Si](C)(C)C)(C)C.CCN(C(C)C)C(C)C.CI>C(Cl)Cl.COCCOCCOC>[NH2:1][CH2:2][C@H:3]([F:8])[CH2:4][P:5]([CH3:9])(=[O:6])[OH:7]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: NC[C@H](F)C[PH](=O)O
Solvent: CI
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CP(=O)(O)C[C@@H](F)CN
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
A suspension of compound (2S)-(3-amino-2-fluoropropyl)phosphinic acid (1.2 g, 8.5 mmol) in HMDS (8.96 mL, 42.4 mmol) was heated to reflux for 15 h. The reaction was cooled to room temperature, treated with diglyme (9.6 mL) and heated to reflux for 7 h. After the mixture was cooled to room temperature, Hünig's base (1.47 mL, 8.4 mmol) was added followed by dropwise addition of methyl iodide (1.58 mL, 25.4 mmol). The reaction was stirred overnight then it was diluted with methylene chloride and extracted with 2 N HCl solution. The aqueous layer was washed with methylene chloride and diethyl ether and then evaporated under reduced pressure. The crude product was passed through a Dowex 50WX8-200 mesh H+ form column eluting with 1:1 methanol/water until no further material was detected by TLC analysis. The product was then eluted with 1:3 concentrated ammonium hydroxide solution/methanol. Further purification by column chromatography on silica gel eluting with methylene chloride, methanol, concentrated ammonium hydroxide solution (6:3:1) afforded (2S)-(3-amino-2-fluoropropyl)(methyl)phosphinic acid as a white solid (504 mg, 38%). 1H NMR (300 MHz, D2O) δ5.20 (m, 0.5H), 5.03 (m, 0.5H), 3.20-3.42 (m, 2H), 1.80-2.22 (m, 2H), 1.30 (d, J=14.0 Hz, 3H).
Reaction SMILES: [N+]([C:4]1[C:21]2[C:20](=[O:22])[C:19]3[C:10](=[CH:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:9](=[O:23])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].[C:30]1([OH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CS(C)=O>[O:36]([C:4]1[C:21]2[C:20](=[O:22])[C:19]3[C:10](=[CH:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:9](=[O:23])[C:8]=2[CH:7]=[CH:6][CH:5]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1c2cc3ccccc3cc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1c2cc3ccccc3cc2C(=O)c2c(Oc3ccccc3)cccc21

Procedure:
3 g (9.9 mmol) of 1-nitronaphthacene-5,12-dione (Example 42), 2.73 g (19.8 mmol) of potassium carbonate, 1.39 g (14.8 mmol) of phenol and 30 ml of DMSO are stirred at a bath temperature of 100° C. for 6 hours. After cooling, the mixture is partitioned between methylene chloride/dilute hydrochloric acid. The organic phase is separated off, washed with water, dried over sodium sulfate and evaporated. The product is obtained in a pure form by chromatography on silica gel (mobile phase: methylene chloride); yield 2.52 g (73%); melting point 195°-200° C.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>C(Cl)Cl>[CH2:1]([O:19][C:29](=[O:30])[CH2:28][Cl:27])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCCO
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCCOC(=O)CCl
Temperature: 0 °C

Procedure:
To an ice-cooled solution of z,z,z-octadeca-6,9,12-trienol (2 g, 7.56 mmol) and triethylamine (2.02 g, 20 mmol) in methylene chloride (20 ml) was added dropwise with stirring chloroacetyl chloride (1.13 g, 10 mmol) in methylene chloride (20 ml) under an atmosphere of nitrogen. On completion of the reaction as shown by tlc, the mixture was washed with water (2×100 ml) and saturated sodium chloride solution (100 ml). The organic phase was dried with magnesium sulfate, filtered and concentrated under reduced pressure. Toluene (100 ml) was added to azeotropically remove final traces of water. z,z,z-octadeca-6,9,12-trienyl-(2-chloro)acetate was obtained as a dark brown oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH2:11])=[C:3]([NH2:12])[CH:2]=1.N1C2C(=NC=CC=2)C(N)=[C:15](N)[CH:14]=1.C(Cl)(=O)C>C(O)(=O)C>[CH3:14][C:15]1[NH:11][C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[N:1]=[CH:2][C:3]=2[N:12]=1
Reactant: Nc1cnc2ccccc2c1N
Reactant: Nc1cnc2cccnc2c1N
Solvent: CC(=O)Cl
Solvent: CC(=O)O
Product: Cc1nc2cnc3ccccc3c2[nH]1

Procedure:
Compounds of the invention can also be prepared according to Reaction Scheme V, wherein Bn, E, R, R3-1, and n are as defined above; P is an amino protecting group; and Da is —(CH2)1-4—. In step (1) of Reaction Scheme V, a benzyloxy-4-chloro-3-nitroquinoline or benzyloxy-4-chloro-3-nitro[1,5]naphthyridine of Formula XLI is reacted with tert-butylamine in the presence of base, and the tert-butyl group is subsequently removed under acidic conditions to provide a 3-nitroquinolin-4-amine or 3-nitro[1,5]naphthyridin-4-amine of Formula XLII, which is reduced in step (2) to provide a quinoline-3,4-diamine or [1,5]naphthyridine-3,4-diamine of Formula XLIII. In step (3) of Reaction Scheme V, a. quinoline-3,4-diamine or [1,5]naphthyridine-3,4-diamine of Formula XLIII is reacted with acetic acid or acetyl chloride to provide a 2-methyl-1H-imidazo[4,5-c]quinoline or a 2-methyl-1H-imidazo[4,5-c][1,5]naphthyridine of Formula XLIV, which undergoes protection at the 1-position in step (4) with a suitable protecting group. In step (5) of Reaction Scheme V, the 2-methyl group of a 1H-imidazo[4,5-c]quinoline or 1H-imidazo[4,5-c][1,5]naphthyridine of Formula XLV is deprotonated with n-butyllithium and subsequently reacted with an alkylating agent of formula Br—CH2-Da-CH2—Cl, and the product of Formula XLVI is then deprotected using conventional methods to provide a 1H-imidazo[4,5-c]quinoline or 1H-imidazo[4,5-c][1,5]naphthyridine of Formula XLVII. The compound of Formula XLVII is then cyclized to provide a compound of Formula XLVIII. Steps (1) through (7) of Reaction Scheme V can be carried out using the conditions described in U.S. Pat. No. 5,482,936 (Lindstrom).
Reaction SMILES: C(OC([C:6]1[CH:10]=[CH:9][N:8]([CH2:11][C@@H:12]([C@H:22]([O:34][Si](C(C)(C)C)(C)C)[C:23]2[CH:28]=[C:27]([O:29][CH3:30])[C:26]([CH3:31])=[C:25]([O:32][CH3:33])[CH:24]=2)[CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:7]=1)=O)C.C([O:44][C:45]([C:47]1C=CN[CH:48]=1)=[O:46])C.C(OC(C1C=NN(C[C@@H]([C@H](O[Si](C(C)(C)C)(C)C)C2C=C(OC)C(C)=C(OC)C=2)CCCC2C=CC=CC=2)C=1)=O)C>>[CH3:30][O:29][C:27]1[CH:28]=[C:23]([C@@H:22]([OH:34])[C@@H:12]([CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:11][N:8]2[CH:9]=[CH:10][C:6]([CH2:48][CH2:47][C:45]([OH:46])=[O:44])=[CH:7]2)[CH:24]=[C:25]([O:32][CH3:33])[C:26]=1[CH3:31]
Reactant: CCOC(=O)c1cc[nH]c1
Reactant: CCOC(=O)c1ccn(C[C@H](CCCc2ccccc2)[C@H](O[Si](C)(C)C(C)(C)C)c2cc(OC)c(C)c(OC)c2)c1
Agent: CCOC(=O)c1cnn(C[C@H](CCCc2ccccc2)[C@H](O[Si](C)(C)C(C)(C)C)c2cc(OC)c(C)c(OC)c2)c1
Product: COc1cc([C@@H](O)[C@@H](CCCc2ccccc2)Cn2ccc(CCC(=O)O)c2)cc(OC)c1C

Procedure:
Using ethyl1-{(2S)-2-[(S)-{[tert-butyl(dimethyl)silyl]oxy}(3,5-dimethoxy-4-methylphenyl)methyl]-5-phenylpentyl}-1H-pyrrole-3-carboxylate (produced by carrying out procedures similar to Example 24 using the compound produced in Example 16 and ethyl1H-pyrrole-3-carboxylate) instead of ethyl1-{(2S)-2-[(S)-{[tert-butyl(dimethyl)silyl]oxy}(3,5-dimethoxy-4-methylphenyl)methyl]-5-phenylpentyl}-1H-pyrazole-4-carboxylate, procedures similar to Example 29→Example 33→Example 34→Example 36→Example 37 were carried out to give the title compound having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:24])[N:15]([CH3:23])[CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[CH:8]=2)=[C:4]([F:27])[CH:3]=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]2([C:41](O)=[O:42])[CH2:40][CH2:39]2)=[O:37])=[CH:31][CH:30]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:41]([C:38]2([C:36]([NH:35][C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)=[O:37])[CH2:40][CH2:39]2)=[O:42])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:15]([CH3:23])[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[O:24])[CH:8]=1
Reactant: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)CC1
Reaction time: 3.5 h
Yield: 41.6 %

Procedure:
3-[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea (40.8 mg) was dissolved in N,N-dimethylformamide (1.0 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (73 mg), triethylamine (0.0456 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (145 mg) were added under a nitrogen atmosphere at room temperature and stirred for 3.5 hr. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3) to provide the titled compound as white powder (26.3 mg, 42%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:7][CH:8]=1)([O-:3])=[O:2].[K].C(=O)([O-])[O-].I[CH2:19][CH:20]([CH3:23])[CH2:21][CH3:22]>CC(C)=O>[CH3:19][CH:20]([CH2:21][CH3:22])[CH2:23][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc([N+](=O)[O-])c[nH]1
Reactant: CCC(C)CI
Agent: O=C([O-])[O-]
Agent: [K]
Solvent: CC(C)=O
Product: CCC(C)Cn1cc([N+](=O)[O-])cc1C(=O)OC
Temperature: 25 °C
Yield: 70 %

Procedure:
Methyl 3-nitropyrrole-2-carboxylate (22) (2.7 g, 15.9 mmol), potassium, carbonate (6.5 g), and iodo-2-methylbutane (5.2 ml) were dissolved in 100 ml of acetone and refluxed for 10 hours. The reaction mixture was then cooled to room temperature, concentrated in vacuo, partitioned between 200 ml of dichloromethane and 200 ml of water and extracted with dichloromethane (2×200 ml). The combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The resulting yellow oil was purified by flash chromatography to provide the substituted nitro pyrrole 23 (2.5 g, 70% yield). 1H NMR (DMSO-d6) δ 8.30 (d, 1H, J=2.0 Hz), 7.33 (d, 1H, J=1.9 Hz), 4.15 (d, 2H, J=7.4 Hz), 3.77 (s, 3H), 2.03 (m, 1H, J=3.1 Hz), 0.80 (d, 6H, J=6.7 Hz); 13C NMR (DMSO-d6) δ 160.30, 134.79, 129.80, 122.40, 112.76, 105.00, 56.63, 52.41, 29.72, 19.73; FABMS, 226.096 calcd, 226.095 found.