Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:11]=[C:10](F)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:5]=1[C:6]#[N:7]>C1COCC1>[Cl:3][C:4]1[CH:11]=[C:10]([NH:2][CH3:1])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1cc([N+](=O)[O-])c(F)cc1Cl
Reactant: CN
Solvent: C1CCOC1
Product: CNc1cc(Cl)c(C#N)cc1[N+](=O)[O-]
Temperature: -20 °C
Reaction time: 1 h

Procedure:
A solution of MeNH2 in THF (14.9 mL, 2 M, 29.8 mmol) was added dropwise to a solution of 2-chloro-4-fluoro-5-nitrobenzonitrile (3.0 g, 15 mmol) in THF (100 mL) at −20° C. The mixture was stirred at −20° C. for 1 h and thereafter concentrated, washed with brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The resulting residue was washed with PE to give the sub-title compound.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=3)=[CH:23][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Cl.Cl[CH2:39][C:40]1[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=1.O>CN(C)C=O>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:39][C:40]4[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=4)[CH:29]=3)=[CH:25][CH:26]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCc1ccncc1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(O)c3)cc1)n2C1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(Oc3cccc(OCc4ccncc4)c3)cc1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Ethyl 1-cyclohexyl-2-[4-(3-hydroxyphenyloxy)phenyl]-benzimidazole-5-carboxylate (78 g) obtained in Example 28 was suspended in dimethylformamide (800 ml), and sodium hydride (60% oil, 14 g) was added under ice-cooling. The mixture was stirred for 1 hr at room temperature. After the reaction mixture was ice-cooled, 4-chloromethylpyridine hydrochloride (29 g) was added and the mixture was stirred for 30 min. The mixture was then stirred overnight at room temperature. Water was added to the reaction mixture and the precipitated crystals were collected by filtration. The resulting crystals were recrystallized from ethyl alcohol to give the title compound (77 g, yield 82%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[NH:23]1[CH2:26][CH2:25][CH2:24]1>CO>[N:23]1([C:4]2[C:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=4)[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: C1CNC1
Reactant: FC(F)(F)Oc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: FC(F)(F)Oc1ccc(C2CCc3c2nc(Cl)nc3N2CCC2)cc1
Yield: 89.9 %

Procedure:
A solution of 2,4-dichloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (250 mg, 0.716 mmol) and azetidine (82 mg, 1.432 mmol) in MeOH (3 mL) was stirred at rt for 1 h. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to afford 4-(azetidin-1-yl)-2-chloro-7-(4-(trifluoromethoxy)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (238 mg, 0.644 mmol, 90% yield). LC-MS (M+H)+=371.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([NH2:48])=[S:47])=[CH:44][CH:43]=1.CCN(C(C)C)C(C)C>ClCCl>[F:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([NH:48][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])=[S:47])=[CH:44][CH:43]=1
Reactant: NC(=S)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC(=S)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
1-tert-Butoxycarbonylpiperidine-4-carboxylic acid (0.70 g, 3.05 mmol, Aldrich) and HATU (1.74 g, 4.58 mmol) were suspended in dichloromethane (10.0 ml) at room temperature for 20 minutes, followed by addition of 4-fluorothiobenzamide (0.47 g, 3.05 mmol) in one portion. The mixture was stirred at room temperature for 40 minutes, and DIEA (1.18 g, 9.16 mmol) was added. After stirring at room temperature overnight, the solvent was removed under reduced pressure. The residue was passed through a silica gel cartridge using a gradient of 0˜50% ethyl acetate in hexanes to give the title compound as a bright yellow solid.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])(=O)=O)=CC=1.[OH:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.[H-].[Na+]>CN(C)C=O>[CH2:21]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C=CCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCCCCCCCCOc1ccc(C(=O)OCC)cc1
Yield: 95.5 %

Procedure:
6 ml of dimethylformamide was added to 6.20 g (19.1 mM) of 10-undecenyl p-toluenesulfonate and 3.17 g (19.1 mM) of ethyl p-hydroxybenzoate, followed by sufficient stirring. Into the resultant solution was added 0.77 g (19.3 mM) of sodium hydride (60%), followed by heat-refluxing for 7 hours. After the reaction, dimethylformamide was distilled off, followed by addition of water and extraction with ether. To the ether extract liquid was added anhydrous sodium sulfate for drying, followed by distilling-off of the ether and separation-purification by column chromatography (developer solvent: methylene chloride) to obtain 5.80 g (18.2 mM) of ethyl p-(10-undecenyl)oxybenzoate. Yield: 91.2%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[C:15](\[CH3:24])/[CH2:16][O:17][CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:10][CH:9]=2)[CH:2]=1.[CH2:25]=[C:26]1[O:30][C:28](=[O:29])[CH2:27]1>C(OCC)(=O)C.C(N(CC)CC)C>[C:28]([O:21][CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][O:17][CH2:16]/[C:15](/[CH3:24])=[CH:14]/[C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:9][CH:10]=1)(=[O:29])[CH2:27][C:26]([CH3:25])=[O:30]
Reactant: C=C1CC(=O)O1
Reactant: C/C(=C\c1ccc(Cc2cccnc2)cc1)COCC(C)(C)CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)OCC(C)(C)COC/C(C)=C/c1ccc(Cc2cccnc2)cc1
Yield: 60.9 %

Procedure:
In 50 ml of ethyl acetate was dissolved 9.2 g of 3-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]-2,2-dimethylpropanol, and one drop of triethylamine was added to the resulting solution. To the solution was added dropwise a mixture of 3.1 g of diketene and 9.2 ml of ethyl acetate under reflux over one hour, and the resulting mixture was then subjected to reaction at the same temperature for 30 minutes. Subsequently, the solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Merck Silica Gel, 70-230 mesh, eluant: toluene:ethyl acetate (4:1 by volume)] to obtain 7.05 g (yield 60.8%) of oily 3-[(E)-3-[4-(pyridin-3-ylmethyl)phenyl]-2-methylallyloxy]-2,2-dimethylpropyl acetoacetate.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23]([OH:25])=O)[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH2:26][CH:27]1[CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28]1.C(=O)([O-])[O-]>C(Cl)Cl>[NH:29]1[CH2:30][CH:27]([NH:26][C:23]([C:20]2[CH:21]=[CH:22][C:15]3[O:14][CH2:13][CH2:12][C:11]4[N:17]([N:18]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[CH:10]=4)[C:16]=3[CH:19]=2)=[O:25])[CH2:28]1
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)O)ccc1OCC2
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)NC3CNC3)ccc1OCC2
Reaction time: 1.5 h

Procedure:
Following the procedure for 126, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid was reacted with 1,1-dimethylethyl 3-aminoazetidine-1-carboxylate then the crude product was suspended in DCM and treated with MP carbonate resin and stirred for 1.5 h. The mixture was filtered, the filtrate concentrated in vacuo and the resultant residue triturated in diethyl ether to give 156 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.11 (d, J=6.84 Hz, 1H); 8.46 (d, J=2.18 Hz, 1H); 8.05 (t, J=0.64 Hz, 1H); 7.90-7.85 (m, 1H); 7.37-7.30 (m, 1H); 6.92 (s, 1H); 5.62-5.53 (m, 1H); 4.82-4.73 (m, 1H); 4.57 (t, J=5.76 Hz, 2H); 3.95-3.81 (m, 4H); 3.25 (t, J=5.78 Hz, 2H); 1.50 (d, J=6.58 Hz, 6H). LCMS RT=6.45 min, M+H+=394
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[C:7](=[O:19])[C@H:6]1[CH2:20][CH2:21][CH2:22][NH:23][C:24]([NH:36]C(OCC1C=CC=CC=1)=O)=[N:25]C(OCC1C=CC=CC=1)=O)=[O:4].[ClH:47].[H][H]>[Pd].C(OCC)(=O)C.CO>[ClH:47].[CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=2)(=[O:11])=[O:10])[C:7](=[O:19])[C@H:6]1[CH2:20][CH2:21][CH2:22][NH:23][C:24]([NH2:36])=[NH:25])=[O:4]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1S(=O)(=O)c1ccc(C)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H]1[C@H](CCCNC(=N)N)C(=O)N1S(=O)(=O)c1ccc(C)cc1
Yield: 24 %

Procedure:
An ethyl acetate/methanol (2.5 mL/2.5 mL) solution of compound 8 (197 mg, 0.3 mmol) and 1N HCl (0.6 mL), containing 10% palladium on carbon catalyst, was stirred under one atmosphere of hydrogen until TLC indicated the disappearance of the starting 8. The suspension was filtered through a pad of Celite, and the filtrate was concentrated to afford 30 mg (24%) of the title product as a foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([O:11][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=[C:8]([O:10][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCCc2ccccc2)cc(OCCCc2ccccc2)c1
Yield: 74.2 %

Procedure:
A mixture of 1.68 g (0.01 mol) of 3,5-dihydroxybenzoic acid methyl ester, 3.4 mL (0.022 mol) of 3-bromopropylbenzene and 2.8 g (0.02 mol) of potassium carbonate in 50 mL of anhydrous DMF was stirred and heated at 100° for 18 hours. The solvent was removed at reduced pressure, the residue was acidified and the product was extracted with ethyl acetate. The dried extract was concentrated to dryness and the residue was purified by chromatography on 150 g of silica gel using 10 % ethyl acetate-hexane to give 3.0 g of 3,5-bis(3-phenylpropoxy)benzoic acid methyl ester as an oil. The nmr and mass spectra were consistent with the structure.
Reaction SMILES: [OH:1][C@@H:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:3]=[CH2:4].CCCCCC.[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:1][C@@H:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH:3]=[CH2:4])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=C[C@@H](O)CCCCC
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C=C[C@H](CCCCC)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3(S)-hydroxy-1-octene (6.41 g., 0.05 mole) in dry dimethylformamide is added dropwise to a stirred suspension of hexane (2 × 10 ml.) -- prewashed sodium hydride (50% dispersion in mineral oil, 2.64 g., 0.055 mole) in dry dimethylformamide (45 ml.) at 25° C. Upon cessation of gas evolution, the reaction mixture is cooled to 0° to 5° C. and treated with a solution of benzyl bromide (10.3 g., 0.06 mole) in dry dimethylformamide (10 ml.). The resulting mixture is stirred at 25° C. for 16 hours, then is heated at 100° C. for 1 hour. After cooling to 25° C., the reaction mixture is diluted with ice water (50 ml.) and extracted with ether four times. The combined organic extract is washed with 2N hydrochloric acid and saturated aqueous brine, dried over magnesium sulfate and filtered. In vacuo evaporation of the filtrate leaves an oily residue which affords the title compound upon distillation as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:3]1>CCO.[Pd]>[CH3:1][NH:2][CH2:6][CH2:5][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:3]
Reactant: CN1CCC(c2ccccc2)O1
Agent: [Pd]
Solvent: CCO
Product: CNCCC(O)c1ccccc1
Reaction time: 5 h

Procedure:
2-Methyl-5-phenylisoxazolidine (54.3 g, 333 mmol) and Pd/C (2.7 g) in EtOH (55.0 g) are heated to 60°-80° C. in a 300-mL, stirred (700 rpm), Hastalloy autoclave which is kept pressurized to 55 psig with H2 for 5 hours. After cooling, the mixture is filtered and the EtOH removed in vacuo to give N-methyl-3-phenyl-3-hydroxypropylamine.
Reaction SMILES: Cl.[NH:2]=[C:3]1[NH:7][C:6](=[NH:8])[CH2:5][S:4]1.[NH:9]=[C:10]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12](=N)[NH:11]1>CO>[NH:9]=[C:10]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12](=[C:5]2[S:4][C:3](=[NH:2])[NH:7][C:6]2=[NH:8])[NH:11]1
Reactant: N=C1CSC(=N)N1
Reactant: N=C1NC(=N)C2=C1CCCC2
Agent: Cl
Solvent: CO
Product: N=C1NC(=N)C(=C2NC(=N)C3=C2CCCC3)S1

Procedure:
A mixture of 6 parts of 2,4-diiminothiazolidine hydrochloride, 6 parts of 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 100 parts of anhydrous methyl alcohol was stirred and heated at reflux under an atmosphere of nitrogen for approximately 16 hours. The reaction was then cooled and filtered. The solid product collected by filtration was converted to the free base by treatment with a slight excess of a methyl alcohol solution of triethylamine and the product thus obtained was recrystallized from acetic acid. The resultant acetate salt was treated with dilute ammonium hydroxide and the product isolated to obtain in the free-base form 1-imino-4,5,6,7-tetrahydro-3-(2,4-diimino-5-thiazolidinylidene)isoindoline as a greenish-brown powder melting at 215°-223° C (dec).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]2[C:6]=1[C:7]([CH3:17])([CH3:16])[C:8](=[O:15])[NH:9]2)C=C.CN(C)[C:20]1[CH:25]=CC=C[CH:21]=1>>[CH2:25]([C:13]1[C:5]([OH:4])=[C:6]2[C:10](=[C:11]([CH3:14])[CH:12]=1)[NH:9][C:8](=[O:15])[C:7]2([CH3:16])[CH3:17])[CH:20]=[CH2:21]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc(C)c2c1C(C)(C)C(=O)N2
Product: C=CCc1cc(C)c2c(c1O)C(C)(C)C(=O)N2
Temperature: 205 °C
Reaction time: 17 h

Procedure:
5.67 g (24.5 mmol) of 4-allyloxy-2,3-dihydro-3,3,7-trimethyl-1H-indol-2-one was added to 13 ml of N,N-dimethylaniline and the mixture was heated with stirring for 17 hours at 205° C. under a nitrogen atmosphere. After the reaction, N,N-dimethylaniline was removed by evaporation under reduced pressure. The residue was dissolved in chloroform and washed with water, 2N hydrochloric acid, and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was purified by column chromatography (silica gel, 10:1 mixture of chloroform and ethyl acetate) and precipitated in n-hexane. Filtration of the precipitate afforded 4.77 g (yield, 84.1%) of light yellow crystals of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[C:14]([F:20])=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.CS(O)(=O)=O.CS(O)(=O)=O.[NH2:37][CH:38]1[CH2:41][NH:40][CH2:39]1>>[NH2:37][CH:38]1[CH2:41][N:40]([C:15]2[C:16]([F:18])=[CH:17][C:10]3[C:11]([C:14]=2[F:20])=[N:12][C:13]2[N:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7](=[O:21])[C:8]=2[CH:9]=3)[CH2:39]1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: NC1CNC1
Agent: CS(=O)(=O)O
Product: CCOC(=O)c1cn(C2CC2)c2nc3c(F)c(N4CC(N)C4)c(F)cc3cc2c1=O
Yield: 53.8 %

Procedure:
8-(3-Amino-1-azetidinyl)-1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 2, but starting with 1.3 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8,9-trifluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine and 1.32 g of 3-aminoazetidine dimethanesulphonate. After recrystallization in 50 cm3 of ethanol, 0.8 g of 8-(3-amino-1-azetidinyl)-1-cyclopropyl-3-ethoxycarbonyl-7,9-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine is obtained in the form of a yellow solid, melting point 236°-238° C.
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1.[CH2:15]1[CH2:20][O:19][CH:18]=[CH:17][CH2:16]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>>[I:1][C:2]1[N:6]([CH:18]2[CH2:17][CH2:16][CH2:15][CH2:20][O:19]2)[N:5]=[CH:4][C:3]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1
Reactant: C1=COCCC1
Reactant: CSc1nccc(-c2cn[nH]c2I)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CSc1nccc(-c2cnn(C3CCCCO3)c2I)n1
Temperature: 60 °C
Reaction time: 6 h
Yield: 60933.3 %

Procedure:
A mixture of compound A (75.0 g, 0.235 mmol), DHP (39.6 g, 0.471 mmol) and TsOH.H2O (7.5 g) was stirred at 60° C. for 6 h. The mixture was cooled to room temperature and concentrated. The residue was purified by chromatography (EtOAc:petroleum ether=1:15) to give 4-(5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine (B) (57.6 g, 60.8%). 1H NMR (400 MHz, CDCl3): δ 8.495 (d, 1H), 8.400 (s, 1H), 7.638 (d, 1H), 5.398 (m, 1H), 4.070 (m, 1H), 3.732 (m, 1H), 2.796 (s, 3H), 2.110 (m, 3H), 1.900 (m, 3H).
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH2:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH2:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23]
Reactant: OC[C@@H](O)CCc1ccc2ccccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: OC[C@@H](O)CCc1ccc2ccccc2c1O
Reaction time: 6 h
Yield: 93.7 %

Procedure:
To a solution of (2S)-4-[1-(benzyloxy)-2-naphthyl]-1,2-butanediol (5.63 g, 17.5 mmol) in ethanol (150 mL), palladium on carbon (10 wt. %, 0.56 g) was added, and the reaction mixture was shaken under an H2 atmosphere (50 psi) for 6 h. The reaction mixture was filtered (celite) and the solvent removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 4:1) gave 3.81 g (94%, 50% ee) of (2S)-4-(1-hydroxy-2-naphthyl)-1,2-butanediol as a colorless oil which crystallizes upon standing. [α]D25=+11.93 (c 10.06 in chloroform, 50% ee); Rf=0.50 (silica, ethyl acetate:hexanes 4:1); mp 105-108° C.; Anal. Calcd. for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.20; H, 7.18.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH:19]=[CH2:20]>>[CH2:20]([NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCBr
Reactant: NCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=CCCNCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of 2-phenylethylamine (72 mL, 570 mmol) is added K2CO3 (82 g, 570 mmol) and 4-bromo-1-butene (25 g, 185 mmol). The solution is stirred overnight at room temperature. The solution is evaporated to dryness and H2O/EtOAc (1:1) (600 mL) is added. The mixture is extracted with EtOAc (4×150 mL). The organic extracts are combined, dried and concentrated under vacuum. The residue is purified by flash chromatography (silica gel; Hexane/EtOAc 1:8) to provide 20 g (62%) of the title compound. M+H+=176.10.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].Br[CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=1>C(O)C>[CH3:1][S:2]([CH2:7][C:8]1[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=1)(=[O:4])=[O:3]
Reactant: CS(=O)[O-]
Reactant: COC(=O)c1ccc(CBr)s1
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(CS(C)(=O)=O)s1
Yield: 29.4 %

Procedure:
Methyl 5-(methylsulfonylmethyl)thien-2-ylcarboxylate may be obtained in the following manner: 31.7 g of sodium methyl sulfinate are added to a solution of 73 g of methyl 5-(bromomethyl)thien-2-ylcarboxylate in 150 cm3 of ethanol and the suspension obtained is heated under reflux for 7 hours. The reaction medium is then concentrated to dryness under reduced pressure (2.7 kPa). The residue is extracted with four times 500 cm3 of ethyl acetate, the combined organic phases are washed successively with 250 cm3 of distilled water and 250 cm3 of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and incompletely concentrated under reduced pressure. The solid which appears is isolated by filtration, rinsed with three times 25 cm3 of ice-cold ethyl acetate and provides 21.4 g of methyl 5-(methylsulfonylmethyl)thien-2-ylcarboxylate in the form of a cream-colored powder.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1B(O)O.[CH2:15]([O:19][C:20]1[C:25]([C:26]2[NH:27][C:28](=[O:41])[C:29]3[C:30](=[C:32]([CH2:39][CH3:40])[N:33]([CH2:35][CH2:36][O:37][CH3:38])[N:34]=3)[N:31]=2)=[CH:24][C:23](I)=[CH:22][N:21]=1)[CH2:16][CH2:17][CH3:18]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:15]([O:19][C:20]1[C:25]([C:26]2[NH:27][C:28](=[O:41])[C:29]3[C:30](=[C:32]([CH2:39][CH3:40])[N:33]([CH2:35][CH2:36][O:37][CH3:38])[N:34]=3)[N:31]=2)=[CH:24][C:23]([C:8]2[O:7][CH:11]=[CH:10][CH:9]=2)=[CH:22][N:21]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCOc1ncc(I)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Reactant: OB(O)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCOc1ncc(-c2ccco2)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Yield: 69.1 %

Procedure:
Pd(PPh3)4 (46.5 mg, 0.04 mmol) was added to a stirred mixture of potassium carbonate (55 mg, 0.40 mmol), 2-furylboronic acid (54 mg, 0.48 mmol) and the title compound of Example 1 (200 mg, 0.40 mmol) in degassed dioxan/water (10 mL of 4:1 mixture). The mixture was heated at reflux for 2 h and cooled. The solvent was removed in vacuo and the residue triturated with ethyl acetate to give an orange solid. Purification by flash column chromatography (elution with 50:1 dichloromethane/methanol) gave the title compound as a cream solid (121 mg, 58%).