Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])C.[OH-:27].[Na+].OO.Cl>O.C1COCC1>[OH:27][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:3])=[O:26]
Reactant: [OH-]
Reactant: C=CCCCCCCCCCCCCCCCCCCCC(=O)OCC
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCCCCCCCCCCCCCCCCCO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
22-Hydroxy-docosanoic acid was synthesized according to Mori et al., Liebigs Ann. Chem., (1991), 253-257. Briefly, under N2 atmosphere 6.6 g Docos-21-enoic acid ethyl ester and 30 ml THF were combined and cooled down to 0° C. Then 0.5 eq. (9 ml) borane/THF complex was added dropwise and the mixture was allowed to stir for 2 hours at room temperature. After the addition of 1.2 ml H2O the suspension was again cooled down to 0° C. and 15 ml 3M NaOH and 2 ml 35% H2O2 were added. The mixture was stirred for one hour at 50° C. Then the temperature was brought to room temperature and the pH was adjusted to pH 2-3 with 2N HCl. The solid was fritted, washed with H2O, codistilled three times with CHCl3 and recrystallized from CHCl3. After a further treatment with NaOH (3M in H2O) in THF at 50° C. over 1.5 days the pH was again adjusted to pH 2-3 and the crude product was fritted, washed with H2O and codistilled two times with CHCl3. The product was characterized by thin layer chromatography and 1H-NMR.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:31][CH3:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18](=O)[C:17]3[C:16]([C:27]([O:29]C)=O)=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11]2)=[CH:6][CH:5]=1.O.[NH2:34][NH2:35]>>[CH3:1][O:2][CH:3]([O:31][CH3:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[NH:11][C:12]3[C:17]4[C:18](=[N:34][NH:35][C:27](=[O:29])[C:16]=4[CH:15]=[CH:14][CH:13]=3)[CH:19]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][CH:5]=1
Reactant: NN
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccccc1)C(c1ccc(C(OC)OC)cc1)N2
Solvent: O
Product: COC(OC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
Methyl 2-(4-(dimethoxymethyl)phenyl)-4-oxo-3-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (120 mg, 0.28 mmol) and 85% hydrazine monohydrate (20 mL) were added and the mixture was stirred under 40° C. for 3 h. The resulting mixture was evaporated under reduced pressure to 10 mL and then filtered to give 8-(4-(dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (89 mg, yield 78%). LC-MS (ESI) m/z: 414 (M+1)+.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[N:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[C:14]=[O:15].[NH4+].[Cl-]>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:14]([NH:13][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)=[O:15])[CH:3]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Ic1c[nH]c2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)n1cc(I)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-iodoindole (583 mg, 2.4 mmol) (Witulski, B.; Buschmann, N.; Bergstrasser, U. Tetrahedron 2000, 56, 8473-8480.) in DMF (10 mL) at 0° C. was added NaH (125 mg, 3.1 mmol, 60% dispersion in mineral oil). The reaction mixture was allowed to warm to room temperature and stir for 0.5 h. Then 1-isocyanato-3-(trifluoromethyl)benzene (0.38 mL, 2.64 mmol) was added and allowed to stir for an additional 0.5 h. Sat. aq. NH4Cl (20 mL) was added and the mixture was poured onto water (50 mL). The aqueous layer was extracted with Et2O (3×25 mL). The combined organics were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude concentrate was purified via automated flash chromatography (silica gel, 0 to 50% EtOAc in hexanes, gradient elution) to afford 3-iodo-N-(3-(trifluoromethyl)phenyl)-1H-indole-1-carboxamide.
Reaction SMILES: C(O[CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C.[O:28]1[CH:32]=[CH:31][CH:30]=[CH:29]1>FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>[CH2:5]([C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:27])[CH:16]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:9]2[S:8][CH:7]=1)[C:32]1[O:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(=O)OCC1=CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Reactant: c1ccoc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(Cc3ccco3)=CS[C@H]12
Reaction time: 0.25 h

Procedure:
0.04 g of 3-acetoxymethyl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid and 0.027 g of furane are simultaneously dissolved in 2 ml of trifluoroacetic acid; the solution is left to stand for 15 minutes at room temperature and is then diluted with an equal volume of toluene. The mixture is evaporated to dryness under reduced pressure and the residue is worked up in accordance with the process described in example 6. 3-Furfuryl-7-(N-phenylacetyl-amino)-ceph-2-em-4ξ-carboxylic acid is thus obtained, showing the following Rf values in a thin layer chromatogram (silica gel): 0.75 (system n-butanol/acetic acid/water, 67:10:23) and 0.52 (system n-butanol/ethanol/water, 40:10:50).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18](OS(C(F)(F)F)(=O)=O)[CH:19]=3)[CH2:14][CH2:13][N:12]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:10][CH2:9][CH2:8]1.[CH3:36][N:37](C)C=O>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N>[C:36]([C:18]1[CH:19]=[C:20]2[C:15]([CH2:14][CH2:13][N:12]([C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[CH:11]2[C:7]2([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:10][CH2:9][CH2:8]2)=[CH:16][CH:17]=1)#[N:37]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1C1(c2ccccn2)CCC1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCc2ccc(C#N)cc2C1C1(c2ccccn2)CCC1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
Dipalladium trisdibenzylidene acetone (0.14 g, 0.153 mmol) and diphenylphosphinoferrocene (0.338 g, 0.61 mmol) were suspended in dimethylformamide (15 ml) under an argon atmosphere. tert-Butyl 1-[1-(pyridin-2-yl)cyclobutyl]-7-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.782 g, 1.562 mmol) was added and the reaction mixture was heated to 90° C. Zinc cyanide (0.215 g, 1.831 mmol) was added over 30 min in small portions. Stirring at 90° C. was continued for 15 min. After cooling to room temperature the catalyst was removed by filtration and washed with dimethylformamide. The dimethylformamide filtrate was poured in water (200 ml). The water was extracted with dichloromethane (3×). The combined organic extracts were washed with water, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, dichloromethane, methanol). Yield: 197 mg (0.506 mmol, 33%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17]([OH:19])=O)=[CH:5][CH:4]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][N:27]=[C:26]2[CH2:32][CH3:33].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[CH2:32]([C:26]1[C:25]2[C:29](=[CH:30][CH:31]=[C:23]([NH:22][C:17]([C:10]3[CH:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:21])[F:1])=[CH:4][CH:5]=4)[CH2:14][C:13](=[O:15])[NH:12][C:11]=3[CH3:16])=[O:19])[CH:24]=2)[NH:28][N:27]=1)[CH3:33]
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Reactant: CCc1n[nH]c2ccc(N)cc12
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCc1n[nH]c2ccc(NC(=O)C3=C(C)NC(=O)CC3c3ccc(C(F)(F)F)cc3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.3 %

Procedure:
The product of Example 5, Step 2 (125 mg, 0.418 mmol, 1.00 equiv), 5-amino-3-ethylindazole (67 mg, 0.418 mmol, 1.0 equiv), and EDC (96 mg, 0.501 mmol, 1.20 equiv) were suspended in 1.25 mL DMF. Et3N (0.070 mL, 0.501 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was triturated with EtOAc and CH2Cl2, filtered, and washed with CH2Cl2 to provide 32 mg (17%) of the title compound as an off white solid. MS (ES+) m/e 443 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:12]C1C=C(C=CC=1)C(OO)=O.[OH-].[Na+].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl.ClCCl.O>[Cl:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc2cccnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Clc1ccc2ccc(Cl)nc2c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 36.8 %

Procedure:
7-Chloroquinoline (2.2 g, 13.45 mmol) was dissolved in chloroform (100 mL) and treated with 3-chloroperoxybenzoic acid (3.32 g, 13.45 mmol). The reaction was stirred at 45° C. for 30 minutes after which the oxidation was deemed complete. Water (100 mL), 1 N sodium hydroxide (50 mL) and dichloromethane (200 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude N-oxide was treated with phosphorus oxychloride (20 ml, 218 mmol) and heated at 110° C. After 5 minutes the chlorination was deemed complete and the solution evaporated to dryness under reduced pressure. The crude product was partitioned between water (50 mL), 1 N sodium hydroxide (50 mL) and ethyl acetate (200 mL). The organic phase was dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to ethyl acetate gradient) gave the desired 2,7-dichloroquinoline (0.98 g, 4.95 mmol, 36.8% yield).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([O:33]CC)=[O:32])[CH2:28]5)[S:24][CH:25]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)(=O)C.CO>O1CCOCC1.O>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([OH:33])=[O:32])[CH2:28]5)[S:24][CH:25]=4)[N:17]=3)[S:10][C:11]=2[C:12]([F:14])([F:13])[F:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CN(Cc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cs2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C1CN(Cc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cs2)C1
Yield: 53.2 %

Procedure:
To a solution of ethyl 1-[(4-{5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methyl]azetidine-3-carboxylate (70 mg, 0.13 mmol) that was obtained in Example 3 (3d) in dioxane (2 ml) was added a 1N aqueous solution of sodium hydroxide (0.39 ml, 0.39 mmol) with stirring, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, acetic acid (22 μl, 0.39 mmol) was added to the reaction mixture to quench the reaction, and the resulting mixture was evaporated in vacuo. To the residue thus obtained were added successively methanol (1 ml) and water (1 ml) with stirring, and the white solid precipitated was collected by filtration using a Kiriyama funnel, washed with a mixed solvent of water and methanol (3:7) and dried in vacuo to afford the title compound (34 mg) in a yield of 53% as a crystalline white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:15])[C@@H:10]([CH2:12][O:13][CH3:14])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>ClCCl>[CH3:26][C:25]([NH:11][C@@H:10]([C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15])[CH2:12][O:13][CH3:14])=[O:27]
Reactant: COC[C@@H](N)C(=O)NCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COC[C@@H](NC(C)=O)C(=O)NCc1ccccc1
Reaction time: 0.17 h

Procedure:
N-benzyl-O-methyl-D-serinamide (92 g), was mixed with dichloromethane (368 ml) at ambient temperature and stirred for 10 minutes to get a clear solution. To this solution, dimethylaminopyridine (0.47 g) was added at ambient temperature. Acetic anhydride (45.09 g) was slowly added over 15-20 minutes at ambient temperature. The solution was stirred for 2 hours at room temperature. The reaction mixture was washed with sodium hydroxide (19.16 gm dissolved in 291 ml water), and deionized water (276 ml). The layers were separated and solvent was completely recovered under vacuum at 35-40° C. to get crude product. Yield=82.6 gm; Chiral purity=100%.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=[O:20].[C:21]1([CH:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28][C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:29](=[O:30])[CH2:28][CH:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:3]1=[O:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Reactant: NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CC(c1ccccc1)c1ccccc1)NC1CCN(C(c2ccccc2)c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 3-amino-1-benzhydryl-pyrrolidin-2-one (42) (0.2 g, 0.75 mmol) in dry CH2Cl2 (20 ml)was added 3,3-diphenylpropionic acid (0.19 g, 0.82 mmol) under nitrogen. To the reaction was added EDC (0.18 g, 0.9 mmol) and DMAP (cat), and the reaction mixture was stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue was dissolved in ethyl acetate: water (10:1) (100 ml). The organic was washed with water (25 ml, 2×) and 10% NaOH (25 ml), dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using hexane:ethyl acetate (2:1) to give the desired product in 70% yield
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][N:32]=4)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:36])([F:35])[F:34])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:37](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(OCC)(=O)C>CO.CO.C(Cl)Cl>[CH3:37][N:3]1[CH2:4][CH2:5][CH:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([CH2:22][CH2:23][C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][N:32]=4)[C:27]([NH2:29])=[O:28])[C:19]([C:33]([F:36])([F:34])[F:35])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: NC(=O)c1ccnc(CCc2nc(Nc3ccc(C4CCNCC4)cc3)ncc2C(F)(F)F)c1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4cc(C(N)=O)ccn4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.2 %

Procedure:
Formaldehyde solution (37% aq; 24 μL, 0.30 mmol) was added to a solution of 2-(2-(2-((4-(Piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)isonicotinamide (I131) (28 mg, 60 μmol) in dry MeOH (2 mL). Sodium triacetoxyborohydride (63 mg, 0.30 mmol) was added and the resulting mixture stirred at room temperature for 2 hours under nitrogen. Ethyl acetate was added and the resulting solution adsorbed onto silica gel. Chromatography (SiO2, 0-50% MeOH/DCM) gave the title compound (34) (14 mg, 49%) as a colouless solid; 1H NMR (400 MHz, d4-MeOD) δ 8.58 (d, J=4.9 Hz, 1H), 8.51 (s, 1H), 7.73 (s, 1H), 7.61 (dd, J=5.2, 1.6 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.6 Hz, 2H), 3.51-3.31 (m, 4H), 2.99 (d, J=11.7 Hz, 2H), 2.56-2.44 (m, 1H), 2.32 (s, 3H), 2.15 (d, J=2.8 Hz, 2H), 1.87-1.70 (m, 4H). LCMS Method C: it 4.50 min; m/z 485.1 [M+1]+, 483.1 [M−1]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=[O:17])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(O[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=O.C1(O)CCCCC1>C1(C)C=CC=CC=1.CCCCCC.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([O:18][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)OC1CCCCC1
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Solvent: OC1CCCCC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(=O)c(C(=O)OC2CCCCC2)nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
To an ice cooled suspension of 5.29 g (0.02 mol) 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methyl pyridazine-3-carboxylic Acid (see Example 12) and 2.02 g (0.02 mol) of triethylamine in 75 ml of toluene there is added 3.25 g (0.02 mol) of cyclohexyl chloroformate. The suspension formed is stirred at room temperature for 15 minutes and to it there is added 3.2 g (0.022 mol) of cyclohexanol in 50 ml of toluene. The mixture is stirred at room temperature for 38 hrs. and to it there is added 100 ml of water. The mixture is stirred at room temperature for 1 hr. and the toluene layer is isolated and poured into 600 ml of hexane. The suspension formed is stirred at room temperature for 1/2 hr. and is vacuum filtered. The filter cake is air dried to afford 4.5 g (65% yield) of product, mp 160°-162° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1.C(N(CC)CC)C.C1(S([C:25]2[N:34]=[C:33]3[C:28]([C:29](=[O:48])[C:30]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:31][N:32]3[C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])=[CH:27][C:26]=2[F:49])(=O)=O)C=CC=CC=1.C(OCC)C>C(O)C>[NH2:3][CH:4]1[CH2:8][CH2:7][N:6]([C:25]2[N:34]=[C:33]3[C:28]([C:29](=[O:48])[C:30]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:31][N:32]3[C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[F:42])=[CH:27][C:26]=2[F:49])[CH2:5]1
Reactant: NC1CCNC1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(S(=O)(=O)c3ccccc3)c(F)cc2c1=O
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(N)C3)c(F)cc2c1=O
Yield: 86.6 %

Procedure:
In 3 ml of ethanol was suspended 120 mg of 3-aminopyrrolidine dihydrochloride, and 250 mg of triethylamine was added thereto to form a solution. Subsequently, 300 mg of ethyl 7-benzenesulfonyl-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-caboxylate was added to the solution, and the resulting mixture was subjected to reaction at 45° to 50° C. for 4 hours. To the reaction mixture was added 10 ml of diethyl ether, and crystals were collected by filtration and washed with 12 ml of water to obtain 230 mg (yield 86.6%) of ethyl 7-(3-amino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate. The physical properties of this compound were identical with those of the compound obtained in Example 64.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C@H:6]1[C@@H:9]([N:10]=[N+:11]=[N-:12])[C:8](=[O:13])[NH:7]1)(=O)=O.[Li+].[Br-:22].C(OCC)(=O)C>CN(C)C=O>[N:10]([C@H:9]1[C:8](=[O:13])[NH:7][C@H:6]1[CH2:5][Br:22])=[N+:11]=[N-:12]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2N=[N+]=[N-])cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@H]1C(=O)N[C@H]1CBr

Procedure:
A degassed solution of cis-3-azido-4-oxo-2-azetidinylmethyl tosylate (0.41 g, 1.4 mmol) in dimethylformamide (5 ml) was heated to 90° with LiBr (0.43 g, 5 mmol) for 4 hours. The reaction was poured into ethyl acetate and washed copiously with water. The dried solution was evaporated to give the title compound.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[O:12]1[C:16]2[CH:17]=[CH:18][C:19](B(O)O)=[CH:20][C:15]=2[CH2:14][CH2:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(O)C.O>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[N:8][C:9]=4[NH2:11])[NH:4][N:3]=3)=[CH:20][C:15]=2[CH2:14][CH2:13]1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: Nc1ncnc2[nH]nc(-c3ccc4c(c3)CCO4)c12
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.70 g, 2.68 mmoles) in DMF (10 ml), ethanol (6 ml) and water (6 ml), 2,3-dihydrobenzofuran-5-boronic acid (0.527 g, 3.21 mmoles) and sodium carbonate (0.852 g, 8.04 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.610 g, 0.528 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as brown solid (0.198 g, 29% yield1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.42(s,1H), 8.18(s,1H), 7.48(s,1H), 7.36(d, J=8.1 Hz, 1H), 6.90(d, J=8.2 Hz, 1H), 4.61(d, J=8.7 Hz, 2H),3.27(d, J=8.7 Hz, 2H).
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:24]=[C:23]2[C:18]([CH:19]=[C:20]([CH2:25][CH:26]3[S:30][C:29](=N)[NH:28][C:27]3=[O:32])[CH:21]=[N:22]2)=[CH:17][CH:16]=1.C([OH:35])C>Cl>[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:24]=[C:23]2[C:18]([CH:19]=[C:20]([CH2:25][CH:26]3[S:30][C:29](=[O:35])[NH:28][C:27]3=[O:32])[CH:21]=[N:22]2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CC3SC(=N)NC3=O)cnc2c1
Reactant: CCO
Agent: Cl
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2cc(CC3SC(=O)NC3=O)cnc2c1
Yield: 11 %

Procedure:
In a mixture of 3N hydrochloric acid (4 mL) and ethanol (2 mL) was dissolved 5-[[7-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-quinolyl]methyl]-2-iminothiazolidin-4-one (100 mg, 0.22 mmol.). The resulting solution was heated under reflux for 12 hours. After the completion of reaction was confirmed, ethanol was distilled off. To the residue were added ethyl acetate and aqueous sodium hydrogen carbonate. The organic portion was recovered, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/3), to give 11 mg of the desired compound as pale brown crystalline powder (yield 11%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12](OC)=[O:13])=[CH:7][CH:6]=2.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][OH:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2ncc(Br)cc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2ncc(Br)cc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
To a stirred solution of methyl 3-bromo-quinoline-6-carboxylate (1.09 g, 4 mmol) in THF (50 mL) at 0° C. was added LiAlH4 (0.155 g, 4 mmol) in small portions. The resulting mixture was stirred at 0° C. for 0.5 h. Water (0.2 mL) was added dropwise, followed by 0.2 mL of 10% aq. NaOH and 0.2 mL of water. The solid was removed and the solvent was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/hexane gradient to afford the title compound (413 mg, 42%). LCMS (method A): [MH]+=238/240, tR=4.453 min.