Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH:15]([CH3:17])[CH3:16])([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[O:5][C:4](=[O:18])[CH:3]=1.[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:19]([C:23]1[CH:28]=[C:27]([CH2:29][OH:30])[C:26]([CH3:31])=[CH:25][C:24]=1[S:32][C:3]1[C:4](=[O:18])[O:5][C:6]([CH:15]([CH3:16])[CH3:17])([CH2:8][CH2:9][C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[CH2:7][C:2]=1[OH:1])([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: CC(C)C1(CCc2nccs2)CC(O)=CC(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3nccs3)(C(C)C)OC2=O)c(C(C)(C)C)cc1CO

Procedure:
The title compound was prepared according to General Method 16a using 4-hydroxy-6-isopropyl-6-(2-thiazol-2-yl-ethyl)-5,6-dihydro-pyran-2-one (Example E-2; 0.25 g, 0.95 mmol), toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl)ester (Example BB-2; 0.42 g, 1.15 mmol), potassium carbonate (0.52 g, 3.76 mmol), and DMF (5 mL). The product was chromatographed on silica gel, eluting with 5% MeOH in CH2Cl2, to give the title compound, mp 108-110° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([OH:6])=[O:5])[CH3:2].S(=O)(=O)(O)O.[CH3:16]O>>[CH3:16][O:5][C:4](=[O:6])[CH:3]([CH2:1][CH3:2])[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC(CC)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCCCC(CC)C(=O)OC
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
173.0 g of a feed mixture consisting of 598.4 g of 2-ethyl-hexanoic acid, 397.8 g of methanol, and 3.8 g of concentrated sulfuric acid is placed in a 1-liter flask equipped with a bottom valve, a stirrer, an internal thermometer, and a Claisen bridge including a receiver. The flask contents are stirred for 30 minutes at 120° C. and the distilled amounts are collected in the receiver. While a temperature of 120° C. is maintained, the feed mixture is added continuously to the flask in an amount sufficient to maintain a constant reactor volume of 300 to 320 ml, allowing for the distilled amounts and amounts drawn off through the bottom valve. After the system has been adjusted to equilibrium, the following balance is obtained with a test period of 6 hours:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7](Br)[CH:8]=[CH2:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:9]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:8]=[CH2:7]
Reactant: C=CCBr
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The piperidine from Example 114 (56 mg, 0.15 mmol) was dissolved in dimethylformamide (2 mL) and was treated with allyl bromide (17 μL, 0.18 mmol), and potassium carbonate (63 mg, 0.45 mmol) and the mixture was stirred at r.t. for 4 hrs. The mixture was diluted with water (2 mL) and the solution was washed with ethyl acetate (3×10 mL). The organic phase was dried (MgSO4) and evaporated to give a pale oil which was purified by column chromatography on silica gel eluting with 80% ethyl acetate in hexanes to give the N-allylpiperidin. 1H NMR (CDCl3) 7.42-7.37 (4H, m), 7.13-7.02 (2H, m), 6.90-6.83 (1H, m), 5.83-5.71 (1H, m), 5.12-5.08 (2H, m), 2.99-2.95 (2H, m), 2.86 (2H, d, J=6.5 Hz), 2.84-2.38 (4H, m), and 1.91-1.85 (2H, m); MS MH+=412(414).
Reaction SMILES: B(F)(F)F.CCOCC.C(C1OC1)Cl.[CH:15]([NH:18][C:19](=O)[C:20]([C:22]1[S:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)=[O:21])([CH3:17])[CH3:16]>CCOCC>[CH:15]([NH:18][CH2:19][CH:20]([C:22]1[S:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[OH:21])([CH3:17])[CH3:16]
Reactant: COc1ccc(C(=O)C(=O)NC(C)C)s1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCC1CO1
Product: COc1ccc(C(O)CNC(C)C)s1
Temperature: 25 °C
Reaction time: 56 h

Procedure:
To freshly distilled boron trifluoride etherate (61.0 mmoles) dissolved in 30 ml anhydrous ether, distilled epichlorohydrin (4.19 g, 46.0 mmoles) is added at such a rate to cause the solution to reflux. After addition, the solution is heated at reflux for 1.5 hr with vigorous stirring. The reaction mixture is cooled and most of the ether is removed with a pipette and the solid residue is dried with a stream of dry nitrogen. Anhydrous methylene chloride (50 ml) and the N-isopropyl-5-methoxy-2-thiopheneglyoxylamide (8.0 g, 39.0 mmole), described above, is added and the solution is stirred at room temperature for 56 hr. The methylene chloride is evaporated and replaced with 50 ml anhydrous methanol. The solution is cooled to 0° C. and sodium borohydride (4.0 g) is added portionwise over a period of 4 hr. The mixture is brought to room temperature, stirred for 24 hr then quenched with ice-water. The aqueous solution is extracted several times with ether. The combined ether extract are washed with water and brine, dried (MgSO4) and concentrated. The product is purified by chromatography on silica gel (400 g, chloroformmethanol, 8:2). Evaporation of the eluate and recrystallization of the residue from hexane gives the title compound; mp 81° C, γmaxCHCl 33300, 3100, 1650, 1505, 1220 cm-1.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:19]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH2:7][N:8]([CH3:19])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCc1cccc(Br)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 113.6 %

Procedure:
19 g (475 mmol) of sodium hydride (60% in oil) are added portionwise to a solution of 128 g (447 mmol) of tert-butyl (3-bromobenzyl)carbamate in 800 ml of DMF, and the reaction medium is stirred until the evolution of gas has ceased. 29.3 ml (470 mmol) of methyl iodide are added dropwise and stirring is continued for 18 hours. The reaction medium is poured into ice-cold water and extracted with ethyl acetate. The organic phase is separated out by settling of the phases, dried over magnesium sulfate and evaporated. 152.5 g of tert-butyl (3-bromobenzyl)-N-methylcarbamate are obtained in a yield of 92%.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[CH2:12]([N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Solvent: CCO
Product: CC1(C)CC(O)CC(C)(C)N1Cc1ccccc1

Procedure:
A mixture of 31.4 parts of 2,2,6,6-tetramethylpiperidin-4-ol and 17.1 parts of benzyl bromide in 125 parts of ethyl alcohol was heated under reflux conditions for 96 hours. The cooled reaction mixture was filtered to remove 2,2,6,6-tetramethylpiperidin-4-ol hydrobromide formed during the reaction and the ethyl alcohol solvent was removed by distillation under reduced pressure. Purification of the residue by chromatography on a aluminia column using chloroform as the solvent gave 1-benzyl-2,2,6,6-tetramethylpiperidin-4-ol having a melting point of 151°-2°C and the following elemental analysis by weight
Reaction SMILES: [O-]CC.[Na+].[C:5]1([SH:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[F:12][C:13]([F:31])([F:30])[C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18](Cl)[CH:17]=[C:16]([C:26]([F:29])([F:28])[F:27])[N:15]=1>C(O)C>[F:30][C:13]([F:12])([F:31])[C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([S:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:17]=[C:16]([C:26]([F:29])([F:28])[F:27])[N:15]=1
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: Sc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(Sc2ccccc2)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 65.5 %

Procedure:
To a mixture of 1.70 g (0.025 mol) of sodium ethoxide in 100 ml ethanol was added 2.74 g (0.025 mol) of thiophenol followed by 5.3 g (0.016 mol) of product of Example 19. The reaction mixture was held at reflux for 2 days and filtered. The filtrate was poured into water and extracted into ether. The ether extract was washed with 10% NaOH, dried (MgSO4) had concentrated to give 4.14 g (63.6%) of product as a solid; mp 58°-61° C.
Reaction SMILES: [CH3:1][C:2]([CH3:26])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[C@H:9]([C:23]([NH2:25])=[O:24])[CH2:8]1)=[O:6])[CH3:3].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:41](N)([CH3:44])([CH3:43])[CH3:42].C(N(CC)CC)C>CN(C=O)C>[C:41]([NH:25][C:23]([C@@H:9]1[CH2:8][N:7]([C:5]([O:4][C:2]([CH3:26])([CH3:1])[CH3:3])=[O:6])[CH2:12][CH2:11][N:10]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=[O:24])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)[C@H](C(N)=O)C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)NC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To 9.90 g (27.16 mmol) of 4-(1,1-dimethylethoxy-carbonyl)-1-(phenylmethoxycarbonyl)-piperazine-2(S)-carboxamide dissolved in 75 mL of DMF and cooled to 0° C. were added 5.73 g (29.88 mmol) of EDC, 4.03 g (29.88 mmol) of HOBt, 3.14 mL (29.88 mmol) of t-butylamine, and finally 4.16 mL (29.88 mmol) of triethylamine. The reaction mixture was stirred for 18 hours and the reaction volume was concentrated under reduced pressure. The residue was then diluted with 600 mL of EtOAc and washed with 10% HCl (2×75 mL), saturated NaHCO3 (1×75 mL), water (3×75 mL) and brine (1×50 mL), dried over MgSO4 and concentrated to a solid. This solid was triturated with EtOAc: hexane (1:2) and filtered to provide the title compound as a white solid; mp 134°-135° C.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16].C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[O:10]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1ccccc1CBr
Reactant: O=C1NCc2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CCCCCC
Product: N#Cc1ccccc1CN1Cc2ccccc2C1=O
Temperature: 70 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.066 g, 0.5 mmol,), 2-bromomethyl-benzonitrile (0.117 g, 0.6 mmol), Cs2CO3 (0.408 g, 1.25 mmol), and 18-crown-6 (0.013 g, 0.05 mmol) in acetone (3 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-benzonitrile (0.055 g, 44%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.22 (s, 2H), 5.08 (s, 2H), 7.28-7.70 (m, 7H), 7.92 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>CN(C=O)C>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COc1cccc(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a solution of 2-methyl-3-(methyloxy)phenol (Intermediate 59, 1.3 g) in DMF (50 mL) was added sodium hydride (60% in mineral oil, 480 mg, 0.012 molat 0° C. and the mixture was stirred for 30 minutes. 2-Chloro-5-nitropyridine (1.9 g, 0.012 mol, Aldrich) was added and the mixture was heated at 60° C. for 3 hours. The mixture was poured into H2O (100 mL) and extracted with ethyl acetate (4 times 100 mL). The combined ethyl acetate phases were dried over sodium sulphate and concentrated under vacuum to give a residue which was purified by column chromatography on silica gel (PE:EtOAc=10:1) to afford the title compound (2.3 g) as a liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.CO.Cl.CC#N>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][OH:25])=[O:23])=[CH:16][CH:15]=3)[CH2:9]2)=[O:7])=[CH:32][CH:33]=1
Reactant: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1)NOC1CCCCO1
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: O=C(/C=C/c1ccc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 187.7 %

Procedure:
To a solution of (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (76 mg) in MeOH (1.3 mL) was added hydrogen chloride methanol reagent 10 (0.32 mL, Tokyo Kasei), and the mixture was stirred at ambient temperature for 1 hour. To the reaction mixture was added CH3CN and the solvent was removed in vacuo. Obtained colorless solid was triturated with CH3CN to give (2E)-3-(4-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}phenyl)-N-hydroxyacrylamide hydrochloride (64.1 mg) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:22])=O>ClCCCl.CN(C=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][N:14]2[CH:18]=[N:17][N:16]=[N:15]2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:22])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)c(OCCn2cnnn2)c1Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cl)c(OCCn2cnnn2)c1Cl
Yield: 100.4 %

Procedure:
2,4-dichloro-3-[2-(1H-tetrazol-1-yl)ethoxy]benzoic acid (0.46 g) and thionyl chloride (0.36 g) were added in 1,2-dichloroethane (10 ml), two drops of DMF were added and the mixture was refluxed by heating for 3 hours. After cooling, the solvent was distilled off to obtain the desired 2,4-dichloro-3-[2-(1H-tetrazol-1-yl)ethoxy]benzoyl chloride (0.49 g).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13].N1C=CC=CC=1.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:16][CH2:15]1)=[O:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCNCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Yield: 76 %

Procedure:
To an ice cooled solution of piperidine-4-carboxylic acid [2-(2,4-dichlorophenoxy)phenyl]-amide (AMR01038, 100 mg, 0.274 mmol) in dry DCM (10 mL) were added pyridine (0.044 mL, 0.548 mmol) and benzoyl chloride (0.047 mL, 0.411 mmol). The reaction mixture was stirred at room temperature until TLC showed consumption of starting material (1 h), and quenched with saturated NaHCO3. The resulting solution was extracted with DCM (3×20 mL), and the combined organic layers were washed with water, 1M HCl (3×20 mL) and brine, dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel of the crude product using hexane to EtOAc gradient as eluent gave 1-benzoylpiperidine-4-carboxylic acid [2-(2,4-dichloro-phenoxy)phenyl]amide (98 mg, 76%) as a white solid, mp 176-177° C. Rf: 0.17 (hexane/EtOAc 1:1) LC/MS (APCI) tr=1.10 min, m/z 471.26 (58), 469.31 (M++H, 100) HPLC tr=2.88 min (99.48%) 1H NMR (270 MHz, CDCl3) δ 1.85 (4H, m, 2CH2), 2.55 (1H, tt, CH), 3.01 (2H, m, CH2), 3.89 (1H, m, ½CH2), 4.74 (1H, m, ½CH2), 6.72 (1H, dd, J=8.2, 1.5 Hz, ArH), 6.95 (1H, d, J=8.6 Hz, ArH), 7.01 (1H, td, ArH), 7.14 (1H, td, ArH), 7.22 (1H, dd, J=8.6, 2.5 Hz, ArH), 7.39 (5H, s, ArH), 7.49 (1H, d, J=2.5 Hz, ArH), 7.78 (1H, br s, NH) and 8.38 (1H, br d, J=8.2, ArH). Anal. Calcd. for C25H22Cl2N2O3: C, 63.97; H, 4.72; N, 5.97. Found: C, 64.10; H, 4.83; N, 5.88%.
Reaction SMILES: C([O:3][C:4]1[C:8]([O:9]CC)=CSC=1)C.[SH:12]CC(O)C.O.[C:18]1(C)[CH:23]=[CH:22][C:21]([S:24](O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:18][C:23]1[S:12][S:24][CH:21]2[O:3][CH2:4][CH2:8][O:9][C:22]=12
Reactant: CC(O)CS
Reactant: CCOc1cscc1OCC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=C2OCCOC2SS1

Procedure:
11.68 g (67.8 mmol) of 3,4-diethoxythiophene, 12.5 g (135.6 mmol) of 1-mercapto-2-propanol and 1.29 g (6.8 mmol) of p-toluenesulphonic acid monohydrate were heated to reflux under an N2 atmosphere in 200 ml of toluene for 10 h. The further workup was as described in Example 1.
Reaction SMILES: [CH3:1]N(C)C=O.P(Cl)(Cl)(Cl)=O.[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[NH:19][C:20]1[N:33]=C(OC)[C:31]([F:36])=[CH:30][C:21]=1[C:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:23].O.[CH:38]([Cl:41])(Cl)Cl>C(OCC)C>[Cl:41][C:38]1[N:33]=[C:20]2[C:21]([C:22](=[O:23])[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:1][N:19]2[C:13]2[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=2[F:11])=[CH:30][C:31]=1[F:36]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)CC(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Reactant: CN(C)C=O
Solvent: O
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
Into 4 ml of N,N-dimethylformamide was dropped 250 mg of phosphorus oxychloride with ice-cooling, and 200 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate was added thereto after stirring at the same temperature for 10 minutes. The resulting mixture was subjected to reaction at 50° to 60° C. for 3.5 hours. The reaction mixture was poured into 50 ml of iced water, and 20 ml of chloroform was added thereto, after which the organic layer was separated, washed with 20 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained was added 5 ml of diethyl ether, after which crystals were collected by filtration to obtain 150 mg (yield 72.2%) of ethyl 7-chloro-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 217°-220° C. This was recrystallized from an acetone-methanol mixture (1:1 by volume) to obtain crystals having a melting point of 219°-221° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:25]3=[CH:26][C:27]4[O:31][CH2:30][O:29][C:28]=4[CH:32]=[C:24]3[O:23][CH2:22]1)[C:5](=[O:21])[N:6]2[CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1.BrC1C=CC=[C:39]2[C:35]=1[C:36]1([C:52]3=CC4OCOC=4C=[C:51]3[O:50][CH2:49]1)C(=O)[N:38]2CCCCC.COC1N=CC(B(O)O)=CC=1.CN(C)C1N=CC(B(O)O)=CC=1>>[CH3:49][O:50][C:51]1[N:38]=[CH:39][C:35]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:25]4=[CH:26][C:27]5[O:31][CH2:30][O:29][C:28]=5[CH:32]=[C:24]4[O:23][CH2:22]2)[C:5](=[O:21])[N:6]3[CH2:11][C:12]2[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[CH:36][CH:52]=1
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Reactant: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Agent: CN(C)c1ccc(B(O)O)cn1
Agent: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2cccc3c2C2(COc4cc5c(cc42)OCO5)C(=O)N3Cc2ccc(C(F)(F)F)o2)cn1

Procedure:
Following the procedure as described in EXAMPLE 4, and making non-critical variations using 4′-bromo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (6-methoxypyridin-3-yl)boronic acid to replace [6-(dimethylamino)pyridin-3-yl]boronic acid, the title compound was obtained (51%) as a colorless solid: mp 174-176° C.; 1H NMR (300 MHz, CDCl3) δ 7.73 (d, 1H), 7.69 (d, 1H), 7.34 (t, 1H), 7.03 (d, 1H), 6.89-6.86 (m, 2H), 6.65 (d, 1H), 6.61 (d, 1H), 6.56 (d, 1H), 6.17 (d, 2H), 5.87 (d, 2H), 4.99 (ABq, 2H), 4.56 (ABq, 2H), 3.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.7, 163.5, 158.4, 156.1, 151.8, 151.8, 149.2, 147.8, 146.1, 142.3, 141.6, 138.8, 136.9, 132.6, 130.0, 129.1, 127.8, 127.2, 126.2, 119.9, 112.7, 112.7, 110.9, 109.6, 109.5, 108.5, 102.3, 101.6, 93.6, 78.2, 58.5, 53.6, 37.0; MS (ES+) m/z 537.4 (M+1).
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]2[N:17]=[C:16]([NH2:21])[C:15]3[N:22]=[C:23]([CH2:28][O:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][CH3:27])[C:14]=3[C:13]=2[CH:12]=1>ClCCl>[ClH:6].[NH2:21][C:16]1[C:15]2[N:22]=[C:23]([CH2:28][O:29][CH2:30][CH3:31])[N:24]([CH2:25][CH2:26][CH3:27])[C:14]=2[C:13]2[CH:12]=[C:11]([O:10][CH2:9][CH2:8][NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCCn1c(COCC)nc2c(N)nc3ccc(OCCN)cc3c21
Solvent: ClCCl
Product: CCCn1c(COCC)nc2c(N)nc3ccc(OCCNC(=O)C(C)C)cc3c21
Product: Cl
Reaction time: 16 h
Yield: 77.8 %

Procedure:
Isobutyryl chloride (0.160 mL, 1.53 mmol) was added dropwise to a solution of 8-(2-aminoethoxy)-2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.500 g, 1.46 mmol) in dichloromethane (10 mL), and the reaction was stirred for 16 hours. A precipitate formed, and dichloromethane (10 mL) was added. The precipitate was isolated by filtration, washed with dichloromethane (20 mL) and diethyl ether (75 mL), and dried for one hour under reduced pressure to provide 0.511 g of N-(2-{[4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-yl]oxy}ethyl)-2-methylpropanamide hydrochloride as an off-white solid, mp 240-242° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24].CN(C)P(N(C)C)(N(C)C)=O>O>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][CH2:14][NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1ccccc1CCCBr
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCc2ccccc2OC)cc1

Procedure:
A mixture of 14.5 g. of ethyl p-aminobenzoate, 10 g. of 1-bromo-3-(o-methoxyphenyl)propane and 50 ml. of hexamethylphosphoramide is heated at 130° C. for 15 hours, cooled and diluted with 20 ml. of water. The mixture is chilled, diluted with 50 ml. of cold ethanol:H2O (1:1) and filtered. The solid is washed with three 50 ml. portions of cold ethanol-water (1:1) and with water to give crystals, m.p. 106°-109° C. Recrystallization from ethanol (100 ml.) gives yellow crystals, m.p. 111°-113° C.