Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.C(OCCO)C.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1.Cl.N1C=CC=CC=1>>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[S:12][C:3]=23)=[C:26]([F:31])[CH:25]=1
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: N#Cc1cnc2c(sc3ccccc32)c1Nc1ccc(Cl)cc1F
Temperature: 25 °C
Yield: 66 %

Procedure:
A solution of 237 mg (0.97 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 6 mL of 2-ethoxyethanol containing 0.15 mL (1.36 mmol) of 4-chloro-2-fluoroaniline and 112 mg of pyridine hydrochloride is heated at reflux temperature for 30 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the resultant solid is collected by filtration, washing with hexane to give 225 mg (66%) of an off-white solid, mp 250-251° C.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].[O:25]1[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][N:18]([C:30]([C:27]5[CH:28]=[CH:29][O:25][N:26]=5)=[O:31])[CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Reactant: O=C(O)c1ccon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CN(C(=O)c5ccon5)CC4C3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (8-4, 100 mg, 0.30 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 52 mg, 0.46 mmol, 1.5 equiv), DIPEA (0.16 mL, 0.91 mmol, 3.0 equiv) and HATU (175 mg, 0.46 mmol, 1.5 equiv) were added to anhydrous acetonitrile (3 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 8-5 as a white solid. MS m/z (M+H): calculated=422.2188; observed=422.2201. 1H NMR δ (ppm)(CHCl3-d): 8.42 (1H, dd, J=7.77, 1.64 Hz), 7.12 (1H, dd, J=8.03, 1.54 Hz), 7.01 (1H, dd, J=8.02, 4.63 Hz), 6.76 (1H, d, J=1.64 Hz), 6.43 (1H, d, J=13.40 Hz), 4.32 (1H, dd, J=12.00, 8.94 Hz), 4.19 (1H, dd, J=12.14, 2.21 Hz), 4.15-4.08 (1H, m), 4.08 (1H, t, J=8.61 Hz), 4.01-3.85 (1H, m), 3.64 (2H, s), 3.49 (3H, d, J=2.90 Hz), 3.22-3.05 (1H, m), 3.06-2.98 (1H, m), 2.85-2.70 (1H, m), 1.02 (9H, s).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([NH:10][C:11]1[N:12]=[C:13](C2N=CNN=2)[C:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[CH:18]=[CH:17][C:15]=2[N:16]=1)(=[O:9])[CH3:8]>O1CCOCC1>[C:7]([NH:10][C:11]1[N:12]=[C:13]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:14]2[N:20]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[CH:18]=[CH:17][C:15]=2[N:16]=1)(=[O:9])[CH3:8]
Reactant: C1CNCCN1
Reactant: COc1ccc(-c2ccc3nc(NC(C)=O)nc(-c4nc[nH]n4)c3n2)cc1OC
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc3nc(NC(C)=O)nc(N4CCNCC4)c3n2)cc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Piperazine (258 mg; 3 mmole) was added to a stirred suspension of 2-acetamido-6-(3,4-dimethoxyphenyl)-4-(1,2,4-triazolyl)pyrido[3,2-d]pyrimidine (586 mg; 1.5 mmole) in dioxane (50 ml). The mixture was stirred at room temperature for 24 hours and the volatiles were removed under reduced pressure, yielding 2-acetamido-4-(N-piperazinyl)-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidine as a crude residue. The latter was dissolved in DMF and m-tolyl isocyanate (0.66 ml, 5 mmole) was added. After 18 hours at room temperature, the solvent was removed and the residue was suspended in a mixture of CH2Cl2 (20 ml) and sodium ethoxide 0.2 N (20 ml). The suspension was stirred during 16 hours and neutralized with 5-6 N HCl in isopropyl alcohol. The crude residue was purified by silica gel column chromatography, the mobile phase consisting of a CH3OH/CH2Cl2 mixture in a ratio gradually ranging from 2:98 to 5:95, thus resulting in the pure title compound (350 mg, yield 43%) which was characterized by its mass spectrum as follows: MS (m/z): 542 ([M+H]+, 100).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(OCC)(=O)C>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:23])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14](=[O:22])[C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)=[CH:19][CH:20]=3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(O)cc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.8 %

Procedure:
To a stirred solution of N-cyclopropyl-3-[(4-hydroxybenzoyl)amino]-4-methylbenzamide (500 mg, 1.61 mmol) in DMF (2.5 mL) was added potassium carbonate (446 mg, 3.22 mmol). The resulting mixture was stirred at room temperature for 15 minutes. 2-Chloromethyl-pyridine hydrochloride (291 mg, 1.78 mmol) was added and the resulting mixture stirred and heated to 50° C. for 18 h. The mixture was cooled to room temperature and saturated aqueous potassium carbonate solution (15 mL) and ethyl acetate (5 mL) were added. The resulting mixture was stirred for 20 minutes. The solid was collected by filtration, washed with saturated aqueous potassium carbonate solution, ethyl acetate and isohexane and dried giving the title compound as a solid (425 mg, 60%); NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.68 (m, 2H), 2.29 (s, 3H), 2.86 (m, 1H), 5.33 (s, 2H), 7.16 (m, 2H), 7.34 (m, 2H), 7.55 (m, 1H), 7.62 (m, 1H), 7.81 (s, 1H), 7.86 (m, 1H), 7.98 (m, 2H), 8.36 (s, 1H), 8.60 (m, 1H), 10.00 (s, 1H); Mass Spectrum: M+H+ 401.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[CH:29]1([NH:32][C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)[CH:4]=3)[N:9]=[C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)[N:7]=2)[CH2:31][CH2:30]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(N4CCCCC4)cc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc(NC3CC3)c3cc(N4CCCCC4)c(Cl)cc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-chloro-4-oxo-6-(piperidin-1-yl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and cyclopropylamine in step E. MS (ESI): predicted mass calcd. for C20H21ClN6O2, 412.9
Reaction SMILES: [CH2:1](I)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:13][CH2:12][CH2:9][CH2:10][CH2:11][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCI
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C

Procedure:
All the five compounds were prepared by the same method. The compounds I-8, I-9, I-10, I-11 and I-12 were synthesized by separately reacting allyl iodide, compounds I-4, I-5, I-6 and I-7 with 4-hydroxybiphenyl-4'-carboxylic acid. The synthesis of compound I-12 was described below as an example. 3.62 g (0.0157 mole) 4-hydroxylbiphenyl-4'-carboxylic acid, 500 ml ethanol, 50 ml water, 0.5 g KI and 2.02 g (0.036 mole) NaOH were heated to reflux for one hour. 7 g compound I-7 was then added dropwise. The mixture was refluxed for 12 hours and then 100 ml of 10% NaOH aqueous solution was added. The mixture was again heated to reflux for 2 hours, and cooled to room temperature. Water and diluted HCl were poured into the cooled mixture to precipitate, and the precipitated white solid was filtered and recrystallized from acetic acid to obtain 4.43 g of white crystals. mp: I-8: 231.8° C.; I-9: 223.7° C.; I-10: 213.9° C.; I-11: 202.8° C.; I-12: 161.4° C. Yield: I-8: 66.9%;I-9: 84.03%; I-10: 81.4%; I-11: 89.96%; I-12: 80.6%. 1H-NMR:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16](=O)[NH:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]2[S:37][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[N:18][N:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)NNC(=O)c2ccncc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(OCc2nnc(-c3ccncc3)s2)CC1

Procedure:
4-{2-Oxo-2-[N′-(pyridine-4-carbonyl)hydrazino]ethoxy}piperidine-1-carboxylic acid tert-butyl ester (Preparation 16) was treated with Lawesson's reagent in a similar manner to that described in Example 138, affording the title compound: RT=3.47 min, m/z (ES+)=377.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[OH:11])([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C(#N)C>[CH2:18]([O:11][C:5]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Yield: 103.2 %

Procedure:
To 2-nitro-5-fluorophenol (6.28 g) in acetonitrile (50 ml) was added potassium carbonate (5.6 g) and benzyl bromide (7.2 g). The mixture was stirred at reflux for 2 hrs, added to water and extracted with diethyl ether. The organic layer was washed with brine, dried and evaporated to dryness to give 2-(benzyloxy)-4-fluoro-nitrobenzene (10.2 g) as a solid. nmr (deuterochloroform): 5.2d (s), 2H; 6.7d, (m), 1H; 6.8d (q), 1H; 7.4d (m), 5H; 8.0d, (q), 1H;
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH:5]1[CH2:9][O:8][C:7]2([CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)[O:6]1.[Cl:23][C:24]1[S:25][C:26]([CH2:29]Cl)=[CH:27][N:28]=1>C1(C)C=CC=CC=1>[Cl:23][C:24]1[S:25][C:26]([CH2:29][O:3][CH2:4][CH:5]2[CH2:9][O:8][C:7]3([CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:13][CH2:14]3)[O:6]2)=[CH:27][N:28]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: OCC1COC2(CCN(CCc3ccccc3)CC2)O1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Clc1ncc(COCC2COC3(CCN(CCc4ccccc4)CC3)O2)s1
Temperature: 28 °C

Procedure:
To 8.64 g (0.36 mole) of sodium hydride in toluene (250 ml) was added 2-hydroxymethyl-8-phenethyl-1,4-dioxa-8-azaspiro[4,5]decane (compound 1.50 gm, 0.18 mole) in toluene (350 ml) with stirring at 28° C. The phase transfer catalyst tetrabutylammonium bromide TBAB 2 gm was added and 31 gm of 2-chloro-5-chloromethylthiazole in toluene (225 ml) was then added drop wise at 10° C. and the reaction mixture was refluxed for 15 hrs. The reaction mixture was washed with water and the product was extracted with methylene chloride 100 ml. The solvent was distilled off to get thick dark colored liquid. The yield of the product was 85%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.IC.[CH3:30]N(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:26][CH3:30])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: CN(C)C=O
Reactant: COC(=O)COc1ccc(Cl)c2[nH]c(C)c(Cc3ccc(Cl)cc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Cc3ccc(Cl)cc3)c(OC)c12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A mixture of [8-chloro-3-(4-chlorobenzyl)-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.13 g), iodomethane (0.20 mL), N,N-dimethylformamide (1.0 mL) and potassium carbonate (0.14 g) were stirred at room temperature for 22 hours. The mixture was diluted with water and extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (1:19 to 19:1 by volume) gave title compound as a gum, 0.059 g.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:5][CH:4]=1.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K]>CN(C)C=O>[C:22]1(=[O:32])[N:26]([CH2:2][C:3]2[CH:21]=[CH:20][C:6]([CH2:7][O:8][N:9]3[C:13](=[O:14])[C:12]4=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]4[C:10]3=[O:19])=[CH:5][CH:4]=2)[C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C1c2ccccc2C(=O)N1OCc1ccc(CCl)cc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
A mixture of N-(4-chloromethylbenzyloxy)phthalimide (18.5 g.) and potassium phthalimide (15.4 g.) in N,N-dimethylformamide (180 ml.) was stirred at 60° C. for 5 hours. The mixture was poured into ice-water and the precipitates were collected by filtration. The precipitates were washed with water and acetone in turn to give N-(4-phthalimidomethylbenzyloxy)-phthalimide (21.0 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].[Br:34][CH2:35][CH2:36][CH2:37][CH2:38]Br.O>CN(C)C=O>[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][O:21][C:15]1[CH:14]=[C:13]2[C:18]([C:9]([O:8][C:6]3[CH:5]=[CH:4][C:3]([NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25])=[C:2]([Cl:1])[CH:7]=3)=[N:10][CH:11]=[N:12]2)=[CH:17][C:16]=1[O:19][CH3:20]
Reactant: BrCCCCBr
Reactant: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1OCCCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A starting compound (N′-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl) oxy]phenyl}-N,N-dimethylurea, 80 mg), potassium carbonate (138 mg), and 1,4-dibromobutane (0.12 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give an intermediate (N′-(4-{[7-(4-bromobutoxy)-6-methoxy-4-quinazolinyl]oxy}-2-chloro-phenyl)-N,N-dimethylurea). The intermediate, potassium carbonate (138 mg), and morpholine (0.043 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 47 mg (yield 44%) of the title compound.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11]Cl)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[C-:13]#[N:14].[Na+].O>CS(C)=O>[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][C:13]#[N:14])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC[C@H](CCl)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCC[C@H]1CC[C@H](CC#N)CC1
Temperature: 140 °C

Procedure:
In 40 cm3 of DMSO, 38 g (0.20 mol) of trans-4-butyl cyclohexylchloromethane and 12 g (0.24 mol) of NaCN were stirred and heated with a mantle heater to 140° C. The reaction product was cooled to room temperature, combined with 100 cm3 of water, extracted with chloroform, and washed with water. The chloroform was distilled off. The oily residue was subjected to vacuum distillation (b.p. 90° C./3 mmHg) to yield 34 g (0.19 mol) of trans-4-butylcyclohexyl acetonitrile.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2=[O:14].[B:15]1(B2OC(C)(C)C(C)(C)O2)[O:19]C(C)(C)C(C)(C)[O:16]1.C([O-])(=O)C.[K+].O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][C:7]1([CH3:13])[CH2:6][C:5](=[O:14])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([B:15]([OH:19])[OH:16])[CH:3]=2)[O:8]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CC1(C)CC(=O)c2cc(Br)ccc2O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(=O)c2cc(B(O)O)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
A solution of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (21 g), pinacol diborane (25 g), palladium acetate (0.92 g) and potassium acetate (2.4 g) in N,N-dimethylformamide (250 mL) was stirred at 90° C. for 2 hr under an argon atmosphere. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (80 mL), and 0.5 M hydrochloric acid (40 mL) and sodium periodate (7.0 g) were added at 0° C. The reaction mixture was stirred at room temperature for 2 hr and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate and hexane to give the title compound (15 g, 84%) as a colorless solid.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH3:30][O:31][C:32](=[O:41])[C@H:33]([CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)[NH2:34].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[CH3:30][O:31][C:32](=[O:41])[C@H:33]([CH2:35][C:36]1[N:40]=[CH:39][NH:38][CH:37]=1)[NH:34][C:13](=[O:14])[CH:12]([CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Reactant: O=C(CC(Cc1cccc2ccccc12)C(=O)O)NCCc1ccccc1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Reaction time: 16 h
Yield: 95.9 %

Procedure:
To a suspension of 3.00 g of (±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionic acid and 2.01 g of L-histidine methyl ester dihydrochloride in 24 ml of N,N-dimethylformamide were added successively 2.16 ml of diphenylphosphoryl azide and 3.81 ml of triethylamine under ice-cooling, and the mixture was stirred for 16 hours under ice-cooling. The reaction mixture was evaporated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Diethyl ether was added to the residue, the precipitated crystals were collected by filtration to obtain 4.08 g of N-[(±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine methyl ester as a white powder. To a solution of 4.00 g of the ester compound obtained in 25 ml of methanol was added 2.75 g of hydrazine monohydrate, and the mixture was stirred for 4 hours at room temperature. The reaction mixture was evaporated under reduced pressure. The residue was washed with diethyl ether, and dried under reduced pressure below 40° C. to obtain 3.90 g of N-[(±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine hydrazide as a white powder. In 5 ml of methanol was dissolved 2.20 g of the hydrazide compound obtained with heating at 40° C., and insoluble materials were filtered off. The filtrate was allowed to stand overnight at room temperature, and then precipitated crystals were collected by filtration to obtain 0.70 g of N-[(±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine hydrazide as a white powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][O:26][CH3:27].C(N(CC)CC)C.[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][O:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:43])=[O:42])[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
Under a nitrogen atmosphere a solution of 1-(8-aminooctyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 2.7 mmol) in dichloromethane (50 mL) was cooled to 0° C. Triethylamine (415 μL, 2.98 mmol) was added followed by benzenesulfonyl chloride (345 μL, 2.71 mmol). The reaction mixture was allowed to warm slowly to ambient temperature and then it was maintained overnight. The reaction mixture was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography (50 g of silica gel eluting with 7.5% methanol in dichloromethane). The purified material was recrystallized from propyl acetate, triturated with hexanes, and then dried in a vacuum oven to provide 590 mg of N-{8-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]octyl}benzenesulfonamide as a yellow powder, m.p. 146–149° C. Analysis: Calculated for C27H35N5O3S: % C, 63.63; % H, 6.92; % N, 13.74. Found: % C, 62.96; % H, 7.03; % N, 13.09. Karl Fisher showed 0.16% or 0.045 mole water.