Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH2:14][OH:15]>CCO>[NH2:13][C:12](=[N:14][OH:15])[C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: NO
Reactant: COC(=O)c1cc(C#N)ccc1Cl
Solvent: CCO
Product: COC(=O)c1cc(C(N)=NO)ccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.1 %

Procedure:
Methyl 2-chloro-5-cyanobenzoate (1.55 g; 7.92 mmol; 1 eq.) was suspended in EtOH (31 mL). Hydroxylamine (1.17 mL; 39.62 mmol; 5 eq.) was added in one portion. The reaction mixture was stirred at RT for 6 hours. The mixture was concentrated affording the title compound as a beige solid (1.65 g, 91%). 1H NMR (DMSO-d6, 300 MHz) δ 9.92 (br s, 1H), 8.19-8.18 (m, 1H), 7.92-7.90 (m, 1H), 7.68-7.65 (m, 1H), 6.04 (br s, 2H), 3.95 (s, 3H). LC/MS (Method B): 229.0 (M+H)+; 227.0 (M−H)−.
Reaction SMILES: [NH2:1][C@H:2]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[OH:47])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[C:7]([CH3:27])[N:6]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:5]1=[O:40].[CH3:48][O:49][C:50](=[O:55])[CH2:51][CH2:52][CH:53]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>>[CH3:48][O:49][C:50](=[O:55])[CH2:51][CH2:52][CH2:53][NH:1][C@H:2]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[OH:47])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]3[O:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[C:7]([CH3:27])[N:6]([CH2:28][C:29]2[C:34]([C:35]([F:38])([F:36])[F:37])=[CH:33][CH:32]=[CH:31][C:30]=2[F:39])[C:5]1=[O:40]
Reactant: Cc1c(N2CCN(Cc3ccc(C(F)(F)F)o3)CC2)c(=O)n(C[C@H](N)c2ccccc2O)c(=O)n1Cc1c(F)cccc1C(F)(F)F
Reactant: COC(=O)CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CCCN[C@@H](Cn1c(=O)c(N2CCN(Cc3ccc(C(F)(F)F)o3)CC2)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
To a solution of 3-[(R)-2-amino-2-(2-hydroxy-phenyl)-ethyl]-1-(2-fluoro-6-trifluoromethyl-benzyl)-6-methyl-5-[4-(5-trifluoromethyl-furan-2-ylmethyl)-piperazin-1-yl]-1H-pyrimidine-2,4-dione (15-1) (67 mg, 0.100 mmol) in 1,2-dicholoroethane (2 mL) were 4-oxo-butyric acid methyl ester (17 mg, 0.150 mmol) and sodium triacetoxyborohydride (42 mg, 0.200 mmol) in the order, followed by stirring at room temperature for 1.5 hrs. The solution was neutralized with an aqueous saturated sodium bicarbonate solution to separate an organic layer. After concentration of the organic layer, the residue was purified using silica gel chromatography(eluent: dichloromethane/methanol, 30/1) and dried in a vacuum to afford 40 mg of the compound as a colorless oil (yield 53%). 1H NMR (300 MHz, CDCl3) δ 1.79 (2H, m), 2.20-2.33 (4H, m), 2.32 (3H, s), 2.48 (2H, m), 2.60 (2H, t), 2.80 (2H, m), 3.58 (2H, m), 3.61 (2H, s), 3.63 (3H, s), 4.06-4.15 (2H, m), 4.42 (1H, dd), 5.42 (2H, dd), 6.30 (1H, d), 6.72-6.78 (3H, m), 7.06-7.15 (2H, m), 7.26 (1H, m), 7.41 (1H, m), 7.55 (1H, d)
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[C:6]([CH3:14])=[CH:5][C:4]1=[O:15])[CH3:2].[C:16]([NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33]Cl)[CH2:27][CH2:26]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:16]([NH:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][O:13][C:10]2[CH:11]=[C:12]3[C:7]([C:6]([CH3:14])=[CH:5][C:4](=[O:15])[N:3]3[CH2:1][CH3:2])=[CH:8][CH:9]=2)[CH2:27][CH2:26]1)(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCn1c(=O)cc(C)c2ccc(O)cc21
Reactant: O=C(NC1CCN(CCCCl)CC1)c1ccccc1
Product: CCn1c(=O)cc(C)c2ccc(OCCCN3CCC(NC(=O)c4ccccc4)CC3)cc21
Yield: 59 %

Procedure:
In a manner analogous to that described in Example 11, by the reaction of 1-ethyl-7-hydroxy-4-methyl-2-oxo-1,2-dihydroquinoline with 3-(4-benzamido-piperidino)-propyl chloride, there is obtained, in a yield of 59% of theory, 7-[3-(4-benzamido-piperidino)-propoxy]-1-ethyl-4-methyl-2-oxo-1,2-dihydroquinoline; m.p. 164°-165° C. (after recrystallization from dichloromethane/diethyl ether).
Reaction SMILES: [C:1]([C@:9]1([N+:22]([O-:24])=[O:23])[C@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:13]2[CH2:21][C@H:10]1[CH:11]=[CH:12]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCCC1CCC2.[OH-:34].[Na+].OO>C1COCC1.CCO>[C:1]([C@@:9]1([N+:22]([O-:24])=[O:23])[C@H:10]2[CH2:21][C@H:13]([CH2:12][C@@H:11]2[OH:34])[C@H:14]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: O=C(c1ccccc1)[C@@]1([N+](=O)[O-])[C@@H]2C=C[C@@H](C2)[C@H]1c1ccccc1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(c1ccccc1)[C@]1([N+](=O)[O-])[C@H](c2ccccc2)[C@H]2C[C@H](O)[C@@H]1C2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of Compound 9 (2.20 g, 6.90 mmol) in THF (18 mL, 0.38M) was treated with 9-BBN (8.62 mmol, 1.25 equiv) in THF (17.25 mL, 0.5M) and the mixture was allowed to stir at 25° C. under N2 for 10 hours. The resulting mixture was treated successively with 4.15 mL of EtOH, 1.5 mL of 20 percent aqueous NaOH, and 1.65 mL of 50 percent aqueous H2O2. The reaction solution was warmed at 50° C. for one hour, recooled to 25° C., and partitioned between EtOAc (200 mL) and H2O (200 mL). The EtOAc layer was dried (Na2SO4) and concentrated under reduced pressure. Chromatography (SiO2, 5×15 cm, 10-25 percent EtOAc-hexane gradient elution) afforded the major isomer Compound 10 (1.29 g, 55.5 percent; Rf =0.32, 20 percent EtOAc-hexane) and Compound 11 (1S*,2R*,4S*,5R*,6S*-5-benzoyl-2-hydroxy-5-nitro-6-phenyl-bicyclo[[2.2.1]heptane, 400 mg, 17.2 percent; Rf =0.26, 20 percent EtOAc-hexane) as white solids cleanly separated from one another in a 3.2:1 ratio (1.69 g total, 2.32 g theoretical, 73 percent). For Compound 10: mp 168°-169° C. (EtOAc-hexane, colorless needles); 1H NMR (CDCl3, 250 MHz) δ7.38 (d, 2H, J=8.2 Hz), 7.31-6.94 (m, 8H), 4.33 (d, 1H, J=2.4 Hz, C5-H), 3.85 (d, 1H, J=6.8, C2-H), 3.29 (s, 1H, C1-H), 2.63 (d, J=11.3 Hz, C7-H syn to ketone), 2.46 (d, 1H, J=4.3 Hz, C4-H), 2.26-2.16 (m, 2H), 1.67-1.60 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ189.9, 138.8, 133.7, 133.0, 128.9, 128.5, 128.3, 127.8, 127.4, 105.0, 69.3, 55.5, 55.4, 44.6, 42.1, 35.7; IR (neat) vmax 3331, 2968, 2900, 1689, 1538, 1444, 1353, 1234, 1096, 1063 cm-1 ; FABHRMS (NBA-NaI) m/e 360.1230 (C20H19NO4+Na+ requires 360.1212). Anal. Calcd for C20H19NO4 : C, 71.20; H, 5.68; N, 4.15. Found: C, 71.13; H, 5.89; N, 4.10. For Compound 11: 1H NMR (CDCl3, 250 MHz) δ7.34 (d, 2H, J=8.0 Hz), 7.25-6.90 (m, 8H), 4.18 (m, 2H), 3.25 (m, 1H), 2.62 (d, 1H, J=11.2 Hz), 2.26 (s, 1H), 2.12 (d, 1H, J=11.4 Hz), 1.80-1.62 (m, 2H), 1.45 (m, 1H); FABHRMS (NBA-CsI) m/e 470.0368 (C2H19NO4 +Cs+ requires 470.0368).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]([N+:16]([O-])=O)=[C:8]2[C:3]=1[NH:4][C:5](=[O:20])[C:6](=[O:19])[NH:7]2.Cl[Sn]Cl.O>CCO>[NH2:16][C:9]1[C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[NH:7][C:6](=[O:19])[C:5](=[O:20])[NH:4]2
Reactant: O=c1[nH]c2c(Cl)cc(C(F)(F)F)c([N+](=O)[O-])c2[nH]c1=O
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1c(C(F)(F)F)cc(Cl)c2[nH]c(=O)c(=O)[nH]c12
Reaction time: 12 h
Yield: 93.9 %

Procedure:
A mixture of 5-chloro-8-nitro-7-trifluoromethyl-1,4-dihydroquinoxaline-2,3-dione (25 mg, 0.08 mmol), SnCl2.2 H2O (97 mg, 0.34 mmol) and EtOH (3 mL) was heated at 75° C. with stirring for 12 h. Work-up as above gave 21 mg (93%) of the title compound as a yellow powder. Mp >360° C. 1H NMR (DMSO-d6) 11.441 (s, 1H), 11.324 (s, 1H), 7.241 (s, 1H), 5.916 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:24]4=[N:25][C:26]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:27][C:28](=[O:29])[N:23]4[CH2:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:6]=[CH:7][CH:8]=1.[CH3:36][C:37]([CH3:39])=O.[BH4-].[Na+]>>[CH:37]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:24]4=[N:25][C:26]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:27][C:28](=[O:29])[N:23]4[CH2:22][CH2:21][CH2:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:6]=[CH:7][CH:8]=1)([CH3:39])[CH3:36]
Reactant: CC(C)=O
Reactant: CC(Cc1cccc(CN)c1)Nc1nccc(N2CCCn3c2nc(-c2ccccc2)cc3=O)n1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)NCc1cccc(CC(C)Nc2nccc(N3CCCn4c3nc(-c3ccccc3)cc4=O)n2)c1
Reaction time: 0.17 h

Procedure:
A solution of 9-{2-[2-(3-Aminomethyl-phenyl) -1-methyl-ethylamino]-pyrimidin-4-yl}-2-phenyl-6,7,8,9-tetrahydro -pyrimido[1,2-a]pyrimidin-4-one (79 mg, 0.17 mmol) and acetone (0.015 mL, 0.21 mmol) was stirred for 10 min prior to adding sodium borohydride (108 mg, 3.4 mmol). After 10 min, solvent removed under vacuum and residue partitioned between dichloromethane (10 mL) and saturated sodium chloride. Product isolated as a white solid after purification on silica. M+1=509.
Reaction SMILES: Br[C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[OH:13])=[O:4].N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[F:14][C:2]1([F:15])[O:13][C:7]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[NH:5][C:3]1=[O:4]
Reactant: O=C(Nc1ccc(F)cc1O)C(F)(F)Br
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1Nc2ccc(F)cc2OC1(F)F
Temperature: 80 °C
Reaction time: 8 h
Yield: 105.8 %

Procedure:
To 2-bromo-2,2-difluoro-N-(4-fluoro-2-hydroxyphenyl)acetamide (33 g, 116 mmol) in dry Toluene was added 1,8-Diazabicyclo[5.4.0]undec-7-en (DBU, 17.51 ml, 116 mmol). The resulting mixture was stirred overnight at 80° C. The reaction was quenched in saturated aqueous NH4Cl solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried with Na2SO4 and concentrated to afford 24.94 g of the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:14][O-:15].[Na+]>>[CH3:14][O:15][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: C[O-]
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Agent: [Na+]
Product: COc1cc(C(F)(F)F)ccc1C=O
Temperature: 50 °C
Reaction time: 6 h
Yield: 84.6 %

Procedure:
2-Fluoro-4-(trifluoromethyl)benzaldehyde (5.0 g, 26 mmol) was diluted with sodium methoxide (57 ml of 0.5 M in methanol; 29 mmol), heated to 50° C. and stirred for 6 hours. The reaction was then partially concentrated, diluted with ethyl acetate and water. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-methoxy-4-(trifluoromethyl)benzaldehyde (4.5 g, 22 mmol, 85% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([Cl:10])[CH:4]=1.C[Si]([C:15]#[N:16])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CC#N>[Cl:10][C:5]1[CH:4]=[C:3]([CH2:2][C:15]#[N:16])[CH:8]=[CH:7][C:6]=1[F:9]
Reactant: C[Si](C)(C)C#N
Reactant: Fc1ccc(CBr)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: N#CCc1ccc(F)c(Cl)c1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a solution of 4-bromomethyl-2-chloro-1-fluoro-benzene (3.7 g, 16.5 mmol) in CH3CN (30 mL) was added trimethylsilyl cyanide (2.1 mL) and TBAF (4.8 g, 18.4 mmol). The resulting mixture was heated at reflux for 30 min. After cooling of the mixture to room temperature, it was extracted with EtOAc. The organic layer was washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was then purified by silica gel flash column chromatography to give the title compound (1.7 g, 60.7%) as an oil.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[C:8]([O:21][CH3:22])[CH:7]=1)(=[O:5])=[O:4])[CH3:2].Br[C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[C:26]#[N:27].C(=O)([O-])[O-].[Na+].[Na+]>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>[Cl:32][C:30]1[CH:31]=[C:24]([C:9]2[CH:10]=[CH:11][C:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])=[CH:7][C:8]=2[O:21][CH3:22])[C:25]([C:26]#[N:27])=[CH:28][CH:29]=1
Reactant: CCS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Reactant: N#Cc1ccc(Cl)cc1Br
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1ccc(-c2cc(Cl)ccc2C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of 2-(4-(ethylsulfonyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 21, 542 mg, 1.66 mmol) in dioxane (10 mL) and water (2 mL) was added 2-bromo-4-chlorobenzonitrile (300 mg, 1.38 mmol), and sodium carbonate (441 mg, 4.16 mmol). The reaction was degassed and then tetrakis(triphenylphosphine)palladium(0) (160 mg, 0.14 mmol) was added and the reaction mixture further degassed. The reaction was on a preheated hot plate (110° C.) for 16 hours. The reaction mixture was cooled to room temperature and filtered through celite and the solvent removed in vacuo. The crude material was purified by silica gel column chromatography eluting with EtOAc:cyclohexane 1:1 to give the title compound as a dark solid in 62% yield, 0.345 g.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[C:8]2[NH:10][CH:11]=[C:12]([C:15]#[N:16])[C:13](=O)[C:7]2=[CH:6][C:5]=1[NH:17][C:18]([CH3:20])=[O:19].[Cl:21]Cl>>[CH3:1][CH2:2][O:3][C:4]1[CH:9]=[C:8]2[N:10]=[CH:11][C:12]([C:15]#[N:16])=[C:13]([Cl:21])[C:7]2=[CH:6][C:5]=1[NH:17][C:18]([CH3:20])=[O:19]
Reactant: CCOc1cc2[nH]cc(C#N)c(=O)c2cc1NC(C)=O
Reactant: ClCl
Product: CCOc1cc2ncc(C#N)c(Cl)c2cc1NC(C)=O

Procedure:
3-Cyano-7-ethoxy-4-hydroxy-6-N-acetylquinoline 6 was reacted with a chlorine-substituting reagent to yield 4-Chloro-3-cyano-7-ethoxy-6-N-acetylquinoline 7 followed by condensation with 3-chloro-4-fluoroaniline optionally in the presence of acid to yield N-[4-(3-Chloro-4-fluoro-phenylamino)-3-cyano-7-ethoxy-quinolin-6-yl]-acetamide 8.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:12]2=[O:28])=[CH:7][CH:6]=1.[CH:29]1([CH2:32][NH:33][CH3:34])[CH2:31][CH2:30]1>>[CH:23]1([O:22][C:19]2[CH:18]=[CH:17][C:16]([N:13]3[CH:14]=[CH:15][N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:33]([CH2:32][CH:29]5[CH2:31][CH2:30]5)[CH3:34])=[CH:6][CH:7]=4)[C:12]3=[O:28])=[CH:21][CH:20]=2)[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: CNCC1CC1
Reactant: O=c1n(-c2ccc(OCCBr)cc2)ccn1-c1ccc(OC2CCCC2)cc1
Product: CN(CCOc1ccc(-n2ccn(-c3ccc(OC4CCCC4)cc3)c2=O)cc1)CC1CC1

Procedure:
1-[4-(2-Bromoethoxy)phenyl]-3-(4-cyclopentyloxyphenyl)-1,3-dihydroimidazol-2-one was reacted with cyclopropylmethyl(methyl)amine as described in example 5. The product with the molecular weight of 447.58 (C27H33N3O3); MS (ESI): 448 ([M+H]+) was obtained in this way.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]([C:12]([OH:14])=O)[C:10]=1[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][CH:23]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:24]1=[O:25]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:11]2[C:10]=1[C:18](=[O:20])[N:22]([CH:23]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:24]1=[O:25])[C:12]2=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1C(=O)O
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccccc4)c3C2=O)C(=O)N1
Yield: 113.9 %

Procedure:
A mixture of 3-benzyloxy-phthalic acid (1.08 g, 4.00 mmol) and rac-α-aminoglutarimide hydrochloride (0.65 g, 4.0 mmol) in pyridine (10 mL) was heated to reflux for 4 h. The reaction mixture was cooled and the solvent was evaporated under vacuum. The residue was suspended in ethyl acetate (200 mL) and washed with dilute aqueous HCl (100 mL). The organic phase was combined with the insoluble precipitate and evaporated to dryness. The resulting solid was triturated with ethyl acetate (100 mL), filtered, washed with additional ethyl acetate (50 mL), and dried to give the title compound (1.66 g, 86% yield); mp 238-240° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 7.23 (96.71%); 1H NMR (DMSO-d6) δ 1.99-2.08 (m, 1H), 2.45-2.62 (m, 2H), 2.81-2.94 (m, 1H), 5.10 (dd, J=12.6 Hz, J=5.3 Hz, 1H), 5.38 (s, 2H), 7.32-7.53 (m, 6H), 7.60 (d, J=8.5 Hz, 1H), 7.83 (t, J=8.2 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 48.8, 70.0, 115.6, 116.6, 120.2, 127.3, 128.0, 128.5, 133.3, 136.2, 137.0, 155.5, 165.3, 166.8, 169.9, 172.8; Anal. Calcd for C20H16N2O5: C, 65.93; H, 4.43; N, 7.69. Found: C, 65.54; H, 4.35; N, 7.63.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:8]=1[C:9]([OH:11])=[O:10]>>[Cl:6][C:7]1[C:15]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:14][CH:13]=[C:12]([Cl:16])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Temperature: 150 °C
Yield: 85 %

Procedure:
Chlorosulfonic acid was slowly added to 2,6-dichlorobenzoic acid at RT under N2. The reaction was heated to 150° C. for 3 h, then slowly poured over ice and the product extracted into Et2O. The organic layer was dried over MgSO4, filtered and concentrated to give 2,6-dichloro-3-(chlorosulfonyl)benzoic acid 880-1a as a brown solid (12.9 g, 85% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[N:18]1([CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)CCC>[N:27]1([CH2:26][CH2:25][CH2:24][N:18]2[CH2:19][CH2:20][N:21]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=3)[CH2:22][CH2:23]2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: C(CN1CCNCC1)CN1CCOCC1
Reactant: Nc1cc(Cl)ncn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(CCCN3CCOCC3)CC2)ncn1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.368 g, 2.84 mmol) and diisopropylethylamine (0.367 g, 2.84 mmol) were suspended in n-butanol. 4-(3-piperazin-1-ylpropyl)morpholine 10-1 (0.61 g, 2.84 mmol) was then added. The reaction was stirred at 125° C. for 18 hours. Upon cooling the resulting solid was filtered off, washed with ethyl ether and dried to afford 10-2. 1NMR (DMSO): 7.94 ppm (s, 1H); 6.18 ppm (s, 2H); 5.58 ppm (s, 1H); 3.56 ppm (t, 4H); 3.39 ppm (t, 4H); 2.38 ppm (t, 4H); 2.31 ppm (m, 8H); 1.60 ppm (p, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].OS(O)(=O)=O.[CH3:29]O>>[CH3:29][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
34 g (~0.1 mol) of 3-nitro-4-phenoxy-5-sulphamylbenzoic acid are dissolved in 150 ml of methanol and are heated to the boil. 5.4 ml of concentrated H2SO4 are then added slowly dropwise and the mixture is heated at reflux temperature for 10 hours. On cooling, 3-nitro-4-phenoxy-5-sulphamylbenzoic acid methyl ester crystallises.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][C:22](=[O:25])[N:21]4[CH2:26][CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:29]=[C:20]34)[CH:16]=[CH:15][N:14]=2)[CH3:11])=[CH:5][CH:4]=1.N12CCCN=C1CCCCC2.C1(P([N:61]=[N+:62]=[N-:63])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:61]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[CH2:24][CH2:23][C:22](=[O:25])[N:21]4[CH2:26][CH:27]=[C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:29]=[C:20]34)[CH:16]=[CH:15][N:14]=2)[CH3:11])=[CH:5][CH:4]=1)=[N+:62]=[N-:63]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(Cc1ccc(CO)cc1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CC(Cc1ccc(CN=[N+]=[N-])cc1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The mixture of 1-{2-[2-(4-hydroxymethyl-phenyl)-1-methyl-ethylamino]-pyrimidin-4-yl}-8-phenyl-1,2,3,6-tetrahydro -pyrimido[1,2-a]pyrimidin-4-one (0.11 g, 0.24 mmol) and 1,8-diaza-bicyclo[5.4.0]undec-7-ene (47 μL, 0.312 mmol) in tetrahydrofuran (5 mL) was brought to 0° C. followed by the addition of diphenylphosphoryl azide (68 μL, 0.312 mmol). The mixture was removed from the ice-bath and stirred at room temperature for 17 h. The mixture was concentrated and chromatographed on silica gel using 0-8% 2M NH3 MeOH/CH2Cl2to afford a white solid. M+1=494.
Reaction SMILES: [OH-].[Na+].C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]3[CH:24]=[CH2:25])=[CH:16][C:15]=2[F:30])[CH2:10][CH2:9]1)=O)C>C(O)(=O)C>[F:30][C:15]1[CH:16]=[C:17]2[C:22](=[N:23][C:14]=1[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[N:21]([CH:24]=[CH2:25])[CH:20]=[C:19]([C:26]([OH:28])=[O:27])[C:18]2=[O:29]
Reactant: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C(=O)OCC)CC3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C=Cn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)nc21
Yield: 80.1 %

Procedure:
Ethyl 1-(2-chloroethyl)-7-(4-ethoxycarboxyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (2.27 g) was dissolved in ethanol (15 ml) by heating, and to the solution was added a solution of potassium hydroxide (0.84 g) in ethanol (15 ml). The resulting solution was heated to reflux for 2 hours with stirring. The resulting crystals were colleced by filtration and washed with ethanol. The crystals were then dissolved in 20 ml of water by heating, and the solution was adjusted to pH 4-5 with 10% acetic acid. The resulting crystals were collected by filtration, washed with ethanol and recrystallized from a mixture of ethanol and chloroform to give 1.74 g of 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylic acid (mp 246°-248° C.). Five percent sodium hydroxide solution (30 ml) was added to 1.5 g of 7-(4-ethoxycarbonyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-1-vinyl-1,8-naphthyridine-3-carboxylic acid. The mixture was heated to reflux for 5 hours with stirring. After cooling, the solution was adjusted to pH 7 with acetic acid. The resulting precipitate was collected by filtration. The precipitate was dissolved in aqueous 10% acetic acid under heating, and the solution was adjusted to pH 9 with ammonia solution. The resulting precipitate was collected by filtration to give 0.98 g of 6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1-vinyl-1,8-naphthyridine-3-carboxylic acid, m.p. 256°-260° C.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(O)=[O:2].C(Cl)(=O)C([Cl:19])=O>O1CCCC1>[C:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:1]([Cl:19])=[O:2])=[CH:6][CH:7]=1)([O:14][CH3:15])=[O:13]
Reactant: COC(=O)Cc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(CC(=O)Cl)cc1
Temperature: 45 °C

Procedure:
A 3.04 g portion of methyl 4-carboxymethylphenylacetate, prepared above, was dissolved in 50 mL of anhydrous tetrahydrofuran. After the addition of2.5 mL oxalyl chloride, the mixture was stirred for 4 hours. The solvents were evaporated under a stream of dry nitrogen as the flask was warmed to 45° C. Any remaining solvent or oxalyl chloride was then removed under high vacuum; the product was used without further purification.