Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([NH:15][C:16]([C@H:18]1[N:22]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:21][CH2:20][S:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)=O.[O:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[CH2:43][NH:44][CH3:45]>>[C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:31][C:26]([S:23]([N:22]2[CH2:21][CH2:20][S:19][C@H:18]2[C:16]([NH:15][C@H:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][N:44]([CH2:43][C:39]2[O:38][CH:42]=[CH:41][CH:40]=2)[CH3:45])=[O:17])(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)OCC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1
Reactant: CNCc1ccco1
Product: CN(CC[C@H](NC(=O)[C@@H]1SCCN1S(=O)(=O)c1ccc(-c2ccccc2)cc1)c1ccccc1)Cc1ccco1

Procedure:
Following the general method A as outlined in Example 16, starting from (3S)-3-({[(2S)-3-([1,1′-biphenyl]-4-ylsulfonyl)-1,3-thiazolidin-2-yl]carbonyl}amino)-3-phenylpropyl methanesulfonate (Intermediate 9) and 2-furyl-N-methylmethanamine, the title compound was obtained in 98.2% purity by HPLC.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[CH:8]=[N+:7]([O-])[CH:6]=[CH:5]2.BrC1C=C2C(=CC=1)C([Cl:25])=NC=C2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8]([Cl:25])=[N:7][CH:6]=[CH:5]2
Reactant: [O-][n+]1ccc2cc(Br)c(Cl)cc2c1
Reactant: Clc1nccc2cc(Br)ccc12
Product: Clc1cc2c(Cl)nccc2cc1Br

Procedure:
Starting with 6-Bromo-7-chloro-isoquinoline 2-oxide (10), the desired 6-Bromo-1,7-dichloro-isoquinoline was prepared by the method, described for 6-Bromo-1-chloro-isoquinoline (5). Rt=1.85 min (Method C). Detected mass: 276.1/278.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]([CH3:15])=[CH:5]2.[C:16]1([S:22]([C:25]2[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=2[CH:27]=O)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:33]([SiH](CC)CC)[CH3:34].FC(F)(F)C(O)=O.N#N.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH2:33][CH3:34])=[O:13])[C:6]([CH3:15])=[C:5]2[CH2:27][C:26]1[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=1[S:22]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:24])=[O:23]
Reactant: CC[SiH](CC)CC
Reactant: Cc1cc2cc(F)ccc2n1CC(=O)O
Reactant: O=Cc1ccccc1S(=O)(=O)c1ccccc1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2(5-fluoro-2-methyl-1H-indol-1-yl)acetic acid (1.29 g, 1.49 mmol), 2-(phenylsulfonyl)benzaldehyde (1.50 g, 6.10 mmol) and triethylsilane (4.30 ml, 27.0 mmol) in dichloromethane (40 ml) was added trifluoroacetic acid (1.25 ml, 16.5 mmol) dropwise under N2 at 0° C. over 30 minutes. The reaction was warmed to room temperature and stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate solution was added and the product extracted with dichloromethane. The combined organic extracts were washed with saturated brine, dried over MgSO4 and concentrated in vacuo giving a brown oil which was triturated with petroleum ether (40-60° C.) to give a white solid (1.34 g, 2.88 mmol 52%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8](=[O:10])[CH3:9])=[CH:3][CH:2]=1.[C:11](#[N:15])/[CH:12]=[CH:13]/[CH3:14].C[O-].[Na+].[Na]>CO.C(Cl)Cl.C(O)(=O)C>[C:8]([CH:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH:13]([CH3:14])[CH2:12][C:11]#[N:15])(=[O:10])[CH3:9]
Reactant: CC(=O)Cc1ccncc1
Reactant: C/C=C/C#N
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)C(c1ccncc1)C(C)CC#N
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a stirred mixture mixture containing 59.6 g of 1-(4-pyridinyl)propanone and 100 ml of crotononitrile was added a solution of sodium methoxide in methanol obtained by adding 1 pellet of sodium shot to 20 ml of methanol. The reaction mixture was heated on a steam bath with stirring. After about 5 minutes, there was an exothermic reaction which raised the reaction temperature to 100° C. The resulting mixture was allowed to cool to room temperature and stand overnight (about 16 hours). To the reaction was added 100 ml of 10% acetic acid and 300 ml of methylene dichloride; and, the mixture was shaken well. The layers were separated and the methylene dichloride layer was dried over anhydrous magnesium sulfate and filtered. The methylene dichloride was distilled off in vacuo and the residual oil was distilled under vacuum using a small column to produce 85.0 g of 4-acetyl-3-methyl-4-(4-pyridinyl)butanenitrile, b.p. 130°-135° C. at 0.05 mm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:17])([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([OH:12])([CH3:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH2:18]([O:20][C:21](OCC)(OCC)OCC)[CH3:19]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([F:17])[C:9]([CH3:11])([CH3:10])[O:12][C:21]([O:20][CH2:18][CH3:19])=[N:16][S:13]2(=[O:14])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(OCC)(OCC)OCC
Reactant: CC(C)(O)C(F)(c1cccc(Br)c1)S(N)(=O)=O
Solvent: CC(=O)O
Product: CCOC1=NS(=O)(=O)C(F)(c2cccc(Br)c2)C(C)(C)O1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 75 mg of 1-(3-bromophenyl)-1-fluoro-2-hydroxy-2-methylpropane-1-sulfonamide in 5 ml of tetraethoxymethane and 1 ml of acetic acid was stirred at 100° C. for 1.5 hours. The conversion was checked by LCMS. Since it was incomplete, the reaction mixture was stirred at 100° C. for a further 3.5 hours. After the removal of the solvents under reduced pressure, the residue was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (45.6 mg) with a molecular weight of 380.2 g/mol (C13H15BrFNO4S).
Reaction SMILES: [F:1][C:2]1[C:3]([C:14](Cl)=[N:15][OH:16])=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1.[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([Cl:31])[C:20]=1[Cl:32]>CN(C=O)C>[F:1][C:2]1[C:3]([C:14]2[CH2:26][C:25]([C:23]3[CH:22]=[C:21]([Cl:31])[C:20]([Cl:32])=[C:19]([Cl:18])[CH:24]=3)([C:27]([F:30])([F:29])[F:28])[O:16][N:15]=2)=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2cc(F)c(C(Cl)=NO)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2cc(F)c(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of the crude compound 6-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (310 mg, 0.95 mmol) and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (262 mg, 0.95 mmol) in DMF (5 mL) at rt was added TEA (158 μL, 1.2 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with DCM (60 mL×3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 6-fluoro-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (86 mg; yield 16% over 3 steps from the aldehyde) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.352 (s, 1H), 7.875 (s, 2H), 7.826 (d, J=6.0 Hz, 1H), 7.513 (d, J=10.0 Hz, 1H), 4.399 (d, J=18.5 Hz, 1H), 4.274 (d, J=18.5 Hz, 1H), 1.482 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS: m/z=495.9 (M+1, ESI+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH2:18][C:19]([OH:21])=O.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=2[C:37]([F:40])([F:39])[F:38])[CH2:25][CH2:24]1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH2:18][C:19]([NH:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][N:26]2[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]2)=[C:31]([C:37]([F:40])([F:39])[F:38])[CH:32]=1)=[O:21]
Reactant: CN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1c(Cl)cc(-n2cnc3cccnc32)cc1Cl
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(NC(=O)Cc3c(Cl)cc(-n4cnc5cccnc54)cc3Cl)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 7 but using (2,6-dichloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 56.1) and 4-(4-methyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (WO 03/099771). Title compound: ES-MS: 576.8/578.9 [M+H]+; tR=3.72 min (System 1); Rf=0.17 (CH2Cl2/(2N NH3 in MeOH), 95:5).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6]CC#N)=[N+:2]=[N-:3].[OH-:10].[K+].[CH2:12]([OH:14])[CH3:13]>O>[N:1]([CH2:4][CH2:5][CH2:6][CH2:13][C:12]([OH:10])=[O:14])=[N+:2]=[N-:3]
Reactant: [OH-]
Reactant: N#CCCCCN=[N+]=[N-]
Reactant: CCO
Agent: [K+]
Solvent: O
Product: [N-]=[N+]=NCCCCC(=O)O
Temperature: 23 °C

Procedure:
A solution of 5-azidovaleronitrile (12.4 g, 0.1 mol) in ethanol (50 ml) was diluted with water (12 ml) and treated with potassium hydroxide (8.4 g, 0.15 mol). The reaction mixture was refluxed for 18 h, cooled to 23° C. and washed with ether. The aqueous solution was acidified with concentrated hydrochloric acid, saturated with sodium chloride and extracted with ethyl acetate. The organic extracts were combined and dried over anhydrous sodium sulfate. The ethyl acetate was evaporated under reduced pressure and the resulting yellow liquid was distilled under high vacuum; bp 104°-6° C./(0.3 mm); 10.8 g; 87%; ir (neat) νmax : 2095 (N3) and 1708 cm-1 (C=O of carboxylic acid; 1Hmr (CDCl3) δ: 11.63 (1H, s, H of carboxylic acid), 3.3 (2H, m, δ-H), 2.4 (2H, m, α-H) and 2.0-1.2 ppm (4H, β -H and γ-H).
Reaction SMILES: [CH3:1][C@@H:2]1[O:9]C(=O)[C@H](C)[O:5][C:3]1=[O:4].[C:11]1(=[O:18])[O:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[C:3]([OH:5])(=[O:4])[CH:2]([CH3:1])[OH:9].[OH:4][CH:12]([CH2:13][CH2:14][CH2:15][CH3:16])[C:11]([OH:17])=[O:18]
Reactant: C[C@@H]1OC(=O)[C@H](C)OC1=O
Reactant: O=C1CCCCCO1
Product: CC(O)C(=O)O
Product: CCCCC(O)C(=O)O

Procedure:
The same procedure as in Preparation Example 4 was effected except that 6 mols of L-lactide and 14 mols of ε-caprolactone were used, thereby obtaining a lactic acid-hydroxycaproic acid copolymer (hereinafter referred to as "PCLA2"). This PCLA2 had a weight average molecular weight of 72000, and a molar ratio of a lactic acid unit to a hydroxycaproic acid unit in the copolymer was 33 to 67.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:18]I>C1COCC1>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([CH3:18])[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cnc(CCNC(=O)OC(C)(C)C)c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
To a solution of [2-(1H-imidazol-4-yl)-ethyl]-carbamic acid tert-butyl ester (512 mg, 2.42 mmol) in THF (20 mL) at −10° C. was added NaH (60%, 97 mg, 2.42 mmol). After stirring at −10° C. for 30 min, MeI (0.14 mL, 2.17 mmol) was added. After stirring at −10° C. for 2.5 h, the reaction mixture was concentrated to afford a yellow oil. Purification by flash column chromatography on silica gel using 2% MeOH/CH2Cl2 afforded [2-(1-methyl-1H-imidazol-4-yl)-ethyl]-carbamic acid tert-butyl ester as a yellow oil (144 mg, 34%). Deprotection with TFA using General Procedure F gave [2-(lmethyl-1H-imidazol-4-yl)-ethyl]-amine as a yellow oil (51 mg, 25%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH:9]1(Br)[CH2:12][CH2:11][CH2:10]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(OC2CCC2)cc1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
2.50 g (14.5 mmol) 4-bromophenol, 2.05 mL (21.7 mmol) cyclobutylbromide and 7.99 g (57.8 mmol) K2CO3 are dissolved in 25 mL DMF and stirred at 120° C. for 12 h. Afterwards the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is dried over MgSO4 and the solvent is removed in vacuo. The crude product is used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:22])[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[O:10][C@@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]1[CH:18]([CH3:20])[CH3:19].Cl[C:24]1[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O.O>[CH3:22][C@:3]1([NH:2][C:24]2[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:21])[O:10][C@@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]1[CH:18]([CH3:19])[CH3:20]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)N
Reactant: FC(F)(F)c1cnc(Cl)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)N[C@H]1CCC[C@]1(C)Nc1cnc(C(F)(F)F)cn1

Procedure:
A solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-amino-2-methylcyclopentyl)carbamate hydrochloride (5.14 g, 15.44 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 2.097 ml, 16.98 mmol) and DIPEA (8.10 ml, 46.32 mmol) in DMSO (51.5 ml) was heated to 140° C. for 17 hours. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined organics were washed with brine (3×200 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-15% ethyl acetate/petrol) to afford the title compound as a single diastereomer.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27][C:28]#N)[CH:24]=[N:25][CH:26]=2)=[CH:17][CH:16]=1.O1CCCC1.[OH-:37].[Na+].Cl.[OH2:40]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:31]=[CH:30][C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH2:27][C:28]([OH:40])=[O:37])[CH:24]=[N:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: O
Reactant: [OH-]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cncc(CC#N)c2)cc1
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2cncc(CC(=O)O)c2)cc1
Yield: 97 %

Procedure:
To a mixture of 2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile (0.66 g), tetrahydrofuran (1 mL) and ethanol (5 mL) was added a 2N aqueous sodium hydroxide solution (5 mL) and the mixture was stirred with heating under reflux for 8 hrs. 1N Hydrochloric acid (10 mL) and water were added to the reaction mixture, and the precipitated solid was collected by filtration and dried with air to give crystals (0.67 g, 97%) of 2-[5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetic acid. Recrystallization from tetrahydrofuran-hexane gave pale-brown prism crystals. melting point: 139-140° C.
Reaction SMILES: [C:1]([Si:5]([CH3:51])([CH3:50])[O:6][CH:7]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:8][CH2:9][CH:10]([CH:25]([C:36]1[CH:41]=[CH:40][C:39](OC)=[CH:38][CH:37]=1)[NH:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)[C:11](N1C(C2C=CC=CC=2)COC1=O)=[O:12])([CH3:4])([CH3:3])[CH3:2].C[Si](C([Si](C)(C)C)[C:57](N)=[O:58])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OC)(C)(C)C>C(O)(=O)C>[C:1]([Si:5]([CH3:51])([CH3:50])[O:6][CH:7]([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:8][CH2:9][CH:10]1[CH:25]([C:36]2[CH:37]=[CH:38][CH:39]=[C:40]([O:58][CH3:57])[CH:41]=2)[N:26]([C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)[C:11]1=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(C(Nc2ccc([N+](=O)[O-])cc2)C(CCC(O[Si](C)(C)C(C)(C)C)c2ccccc2)C(=O)N2C(=O)OCC2c2ccccc2)cc1
Reactant: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: COc1cccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccccc3)C(=O)N2c2ccc([N+](=O)[O-])cc2)c1
Yield: 70 %

Procedure:
A mixture comprising 6.1 g (8.6 mmol) of product 3, 7.3 ml of bistrimethylsilylacetamid, 0.5 g of Tetrabutylammoniumfluorid and 100 ml of tert-butylmethylether is stirred under a argon atmosphere for 10 h at room temperature. After finishing of the reaction 5 ml of acetic acid are added slowly by cooling with ice and evaporated. The residue is separated by chromatography on silica gel (ethylacetate/heptane=1/2). 3.3 g (70%) of product 4 is obtained in form of a light yellow compound in solid form: C31H38N2O5Si (546.74) MS (ESI+) 547.3 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH2:12][C@@:11]3([CH:17]4[CH2:18][CH2:19][N:14]([CH2:15][CH2:16]4)[CH2:13]3)[O:10][C:7]2=[N:8][CH:9]=1)([O-])=O>CO>[NH2:1][C:4]1[CH:5]=[C:6]2[CH2:12][C@@:11]3([CH:17]4[CH2:16][CH2:15][N:14]([CH2:19][CH2:18]4)[CH2:13]3)[O:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc2c(c1)C[C@]1(CN3CCC1CC3)O2
Solvent: CO
Product: Nc1cnc2c(c1)C[C@]1(CN3CCC1CC3)O2
Yield: 91.6 %

Procedure:
The enantiomer (S)-(+)-5′nitrospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](6.85 g, 26.2 mmol) treated in the same way as described in example 8A in ammoniated methanol provided the title compound (5.55 g, 24 mmol, 92%): electrospray MS (m/z, relative intensity) 232 ([MH]+, 100).
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH:5]=[CH:6][C:7](=[O:10])[C:8]=1[OH:9])[CH3:2].[OH-].[Na+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO.O.C(OCC)C>[CH2:13]([O:9][C:8]1[C:7](=[O:10])[CH:6]=[CH:5][O:4][C:3]=1[CH2:1][CH3:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCc1occc(=O)c1O
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CCc1occc(=O)c1OCc1ccccc1
Yield: 65.1 %

Procedure:
To a stirred mixture of 2-ethyl-3-hydroxy-4-pyrone (49 g, 0.35 mol) in methanol (600 ml) and sodium hydroxide (16 g, 0.4 mol) dissolved in water (50 ml) was added benzyl chloride (47.2 ml, 0.41 mol) dropwise at room temperature. After heating under reflux for 48 hours the reaction mixture was cooled, filtered and the filtrate rotary evaporated to provide an oil. The oil was extracted with dichloromethane (300 ml), the solution washed with 5% w/v sodium hydroxide solution (3×250 ml) and water (3×250 ml), then dried over anhydrous sodium sulphate, filtered and rotary evaporated to provide an oil which was dissolved in diethyl ether and crystallized by coating with liquid nitrogen. Recrystallization from diethyl ether gave the title compound as colourless crystals (52.5 g, 65%), m.p. 33°-34° C.
Reaction SMILES: Br[CH:2]([CH2:11][CH2:12][CH2:13][CH3:14])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH:15]([O-:17])=O.[NH4+:18].[OH-].[Na+]>C(O)=O>[C:5]1([C:3]2[N:18]=[CH:15][O:17][C:2]=2[CH2:11][CH2:12][CH2:13][CH3:14])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCCCC(Br)C(=O)c1ccccc1
Reactant: O=C[O-]
Reactant: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CCCCc1ocnc1-c1ccccc1
Reaction time: 3 h
Yield: 41.2 %

Procedure:
A mixture of α-bromohexanophenone (25.5 g, 0.1 mole), ammonium formate (22 g, 0.35 mole) and formic acid (110 mL) was refluxed with stirring for 3 h. The reaction mixture was poured onto ice and made basic with 10 N NaOH and extracted with ether. The organic layer was washed with water, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane. To provide the desired compound as an oil (8.3 g, 41%); 1H NMR (δ, CDCl3, 400 MHz) 7.55 (m, 2H), 7.40 (s, 1H), 7.34 (dd, J=7,7 Hz, 2H), 7.22 (dd, J=7, 7 Hz, 1H), 2.74 (m, 2H), 1.6 (m, 2H), 1.30 (m, 2H), 0.84 (t, J=7 Hz, 3H) ppm.
Reaction SMILES: I[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][N:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[CH3:12][Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:17]#[C:16][Si:13]([CH3:15])([CH3:14])[CH3:12])[C:7]([CH:8]=[O:9])=[CH:6][N:5]=1
Reactant: COc1cc(I)c(C=O)cn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C#C[Si](C)(C)C)c(C=O)cn1
Yield: 67 %

Procedure:
4-Iodo-6-methoxynicotinaldehyde (0.41 g, 1.6 mmoles), trimethylsilylacetylene (0.35 mL, 2.8 mmol), PdCl2(PPh3)2 (catalytic amount), CuI (catalytic amount), triethylamine (2 mL) and THF (10 mL) were stirred at 60° C. for 2 h. The volatiles were evaporated and the residue was taken up in water and extracted with ether. The organic phase was dried, filtered and concentrated. Purification by column chromatography with EtOAc-heptanes (1:3) as eluent gave 0.25 g (68% yield) of 6-methoxy-4-[(trimethylsilyl)ethynyl]nicotinaldehyde.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][C:28]=2[C:30](Cl)=[O:31])[CH:23]=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:28]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:29]=3[N:20]=[CH:21][CH:22]=[CH:23]4)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1cccc2cccnc12
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cccc2cccnc12

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and quinoline-8-carbonyl chloride were combined to provide N8-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-8-quinolinecarboxamide as a tan powder, m.p. 91.0-93.0° C. 1H NMR (300 MHz, DMSO-d6) δ 10.80 (t, J=5.5 Hz, 1H), 8.79 (dd, J=4.3, 1.8 Hz, 1H), 8.55-8.49 (m, 2H), 8.24 (s, 1H), 8.17 (dd, J=8.1, 1.5 Hz, 1H), 8.06 (d, J=7.2 Hz, 1H), 7.73 (t, J=7.8 Hz, 1H), 7.63-7.59 (m, 2H), 7.40 (dt J=7.1, 1.2 Hz, 1H), 7.14 (dt, J=7.1, 1.2 Hz, 1H), 6.57 (broad s, 2H), 4.68 (t, J=7.0 Hz, 2H), 3.51 (m, 2H), 2.02 (m, 2H), 1.69 (m, 2H); MS (EI) m/e 410.1858 (410.1855 calcd for C24H22N6O).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>O1CCCC1>[CH2:16]([NH:20][C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: C1CCOC1
Product: CCCCNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
5.0 g of succinimide ester of N-(tert-butoxycarbonyl)-L-proline (0.016 mmol), marketed by Novabiochem, are dissolved in tetrahydrofuran (50 ml). 1.533 ml of n-butylamine (0.015 mmol) are then added thereto, at 0° C. over 10 minutes, and the mixture is stirred for one hour. The solvent is removed and the resulting crude material is purified by chromatography on silica, using ethyl acetate as eluent. An oil is obtained.