Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:53])([CH2:51][CH3:52])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)[CH2:19][CH2:18]1>O.C(OCC)(=O)C>[OH:13][C:14]([CH3:53])([CH2:51][CH3:52])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][N:50]=[C:24]23)[CH2:19][CH2:18]1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)CC)CC2)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)CC)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (0.11 g), sodium hydrogen carbonate (0.18 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-({4-[trans-4-(2-hydroxy-2-methylbutoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.060 g) was added, and the mixture was stirred at 90° C. for 24 hr and then at room temperature for 35 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (1 mL). N,N′-Carbonyldiimidazole (0.021 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.019 mL) were added, and the mixture was stirred at room temperature for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.049 g, 73%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[Cl:18][C:19]1[CH:20]=[C:21]([SH:26])[CH:22]=[CH:23][C:24]=1[Cl:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: O=C1CCc2cc(OCCCCSc3ccc(Cl)c(Cl)c3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 6-(4-chloro-butoxy)-3,4-dihydro-carbostyril (m.p. 147°-148° C.) and 3,4-dichloro-thiophenol.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH2:14][CH3:15])([F:13])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:49][C:44]2[CH:45]=C[CH:47]=[N:48][C:43]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN1CC(N)C1>>[CH:1]1([N:6]2[CH2:12][C:11]([CH2:14][CH3:15])([F:13])[C:10](=[O:16])[N:9]([CH3:17])[C:8]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:49][CH:44]5[CH2:43][N:48]([CH3:47])[CH2:45]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: CN1CC(N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CCC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CN(C)C4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7-ethyl-7-fluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylazetidin-3-amine hydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (t, J=7.3 Hz, 3 H) 1.6-1.87 (m, 7 H) 1.89-1.99 (m, 3 H) 2.29 (s, 3 H) 3.04 (t, J=7.1 Hz, 2 H) 3.27 (s, 3 H) 3.59 (t, J=7.2 Hz, 2 H) 3.64-3.87 (m, 2 H) 3.95 (s, 3 H) 4.29-4.53 (m, 1 H) 4.79 (t, J=8.1 Hz, 1 H) 7.42-7.59 (m, 2 H) 7.82 (s, 1 H) 8.17 (s, 1 H) 8.34 (d, J=8.3 Hz, 1 H) 8.61 (d, J=6.8 Hz, 1 H). [M+H] calc'd for C27H36FN7O3, 526; found 526.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C:10](=[C:27]([CH3:29])[CH3:28])[N:11]1[C:14](=[O:15])[C:13]([Br:17])([Br:16])[CH:12]1S(C1C=C(C)ON=1)(N)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:31]Br.[Br-]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:30])[C:10](=[C:27]([CH3:29])[CH3:28])[N:11]1[C:14](=[O:15])[C:13]([Br:17])([Br:16])[CH:12]1[Br:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrBr
Reactant: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C(Br)(Br)C1[SH](N)(=O)c1cc(C)on1
Agent: [Br-]
Solvent: ClC(Cl)Cl
Product: CC(C)=C(C(=O)OCc1ccccc1)N1C(=O)C(Br)(Br)C1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.6 %

Procedure:
3,3-dibromo-alpha-(1-methylethylidene)-2-[(5-methyl-isoxazole-3-yl)-aminosulfinyl]-4-oxo-1-azetidine acetic acid benzyl ester (5.61 g; 0.01 mole) was dissolved in chloroform (120 mL), bromine on a polymer carrier (12.5 g; the content of bromide bound to the polymer matrix with polyvinylpyrrolidone was 26%, 0.02 mole) (prepared according to J. Johar, M. Zupan and B. Sket, J. Chem. Soc. Perkin Trans. I, 2059, (1982)) was added and it was stirred for 12 hours at room temperature. The polymer was sucked off and the filtrate was evaporated to dryness. The obtained product was passed through a Merck 60 silica gel column with methylene chloride and thereafter 2,3,3-tribromo-alpha-(1-methylethylidene)-4-oxo-1-azetidine acetic acid benzyl ester (2.36 g, 47.6%) was isolated, m.p. 68°-70° C.
Reaction SMILES: C([Li])CCC.C[Si]([C:10]#[CH:11])(C)C.[C:12]([N:31]1[CH:35]=[N:34][C:33]([CH:36]=[O:37])=[N:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[F-].[K+]>O1CCCC1.ClCCl.CO>[C:12]([N:31]1[CH:35]=[N:34][C:33]([CH:36]([OH:37])[C:10]#[CH:11])=[N:32]1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C#C[Si](C)(C)C
Agent: [F-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: C#CC(O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -20 °C

Procedure:
n-Butyllithium (18.5 ml, 1.6M in hexane) was added dropwise with stirring under nitrogen, to a solution of trimethylsilylacetylene (4.2 ml) in dry tetrahydrofuran (60 ml) whilst maintaining the temperature below -60° C. After a further thirty minutes, the mixture was treated, dropwise with stirring at<-60° C. with a solution of 1-trityl-1,2,4-triazole 3-carboxaldehyde (10.0 g, prepared as described in Example 3) in dry dichloromethane (30 ml). After a further fifteen minutes at -60° C., the mixture was allowed to warm to -20° C. over thirty minutes, then quenched into a mixture of saturated ammonium chloride solution (100 ml) and ethyl acetate (200 ml). The organic layer was washed with water (50 ml) and brine (100 ml), dried over magnesium sulphate, and evaporated under reduced pressure to give crude 1-trimethylsilyl-3(1-trityl-1,2,4-triazol-3-yl)-prop-1-yn-3-ol as a brown oil. A solution of this material and potassium fluoride (3.5 g) in methanol (200 ml) was allowed to stand at room temperature for eighteen hours, evaporated under reduced pressure and the residue partitioned between dichloromethane (200 ml) and brine (100 ml). The organic layer was dried over magnesium sulphate, evaporated under reduced pressure and the residue chromatographed on silica, using dichloromethane-ether (3:1) as eluant, to give 3(1-trityl-1,2,4-triazol-3-yl)prop-1-yn-3-ol (5.9 g, m.p. 138°-139° C.). NMR (CDCl3): δ2.59(1H,d), 4.35(1H,d), 5.68(1H,dd), 7.1-7.4(15H,m), 7.95(1H,s).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[CH:15](=[O:17])[CH3:16].Cl>O1CCCC1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:8]=1[CH:15]([CH3:16])[OH:17]
Reactant: CC=O
Reactant: COc1cccc(F)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(F)c1C(C)O
Reaction time: 1 h

Procedure:
n-Butyl lithium (3.9 mls of 1.14M in hexane) was added dropwise to a solution of 3-fluoroanisole (0.45 mls) in dry tetrahydrofuran (10 mls) at -75° under nitrogen. The solution was kept at -75° for 1 hour, and then acetaldehyde (0.68 mls) was added dropwise and the mixture allowed to warm up. 2M Hydrochloric acid (20 mls) was added, the mixture was extracted with ether, the organic solution was dried (MgSO4) and the solvent was evaporated. The product was distilled to give the title compound as an oil (0.4 g). NMR (CDCl3) δ 7.17 (1H, d of t, 4-H), 6.75-6.6(2H, m, 3-H, 5-H), 5.24(1H, m, CHO--), 3.89(3H, s, OCH3), 3.27 (1H, d OH), 1.56(3H, d, CH3).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:10][CH:9]=2)[C:5]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:4][N:3]=1.[CH2:26]([Br:35])[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]>>[Br-:35].[NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]#[N:21])=[CH:12][CH:13]=2)[C:5]([CH2:22][CH2:23][CH2:24][CH3:25])=[N:4][N+:3]=1[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCCc1nnc(N)n1Cc1ccc(-c2ccccc2C#N)cc1
Product: CCCCc1n[n+](CC(=O)c2ccccc2)c(N)n1Cc1ccc(-c2ccccc2C#N)cc1
Product: [Br-]
Yield: 86 %

Procedure:
Reaction of 3-amino-5-butyl-4-[(2'-cyanobiphenyl-4-yl)methyl]-4H-1,2,4-triazole (from Example 1, Step D) with phenacyl bromide (2-bromoacetophenone) according to the procedure of Example 1, Step E, gave an 86% yield of the title compound as a stiff, yellow foam, suitable for use without further purification.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C:10]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>O1CCOCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:10]2[NH:9][C:2](=[O:3])[O:13][C:12](=[O:14])[C:11]=2[CH:15]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Yield: 92.4 %

Procedure:
Trichloromethyl chloroformate (4.8 mL, 300 mmol) was added to a stirred solution of Compound 57 (6.84 g, 40 mmol) in dry dioxane at room temperature and the solution was refluxed for 4 h. The solution was cooled in an ice bath and the solids formed were filtered. The solids were washed by ether and dried under vacuum at room temperature to yield 7.3 g (92%) of white solids. 1H NMR (DMSO-d6): δ 7.47 (d, J=8.6 Hz, 1H), 7.70 (dd, J=8.6, 1.8 Hz, 1H), 7.82 (d, J=1.1, 1H), 11.63 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[K+].OO.O.CC[O:29]C(C)=O>CCO.O>[F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[NH:14][CH:15]=[C:16]([C:18]([NH2:19])=[O:29])[N:17]=3)=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1c[nH]c(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(=O)c1c[nH]c(-c2ccc(Oc3ccc(F)cc3)cc2)n1

Procedure:
To a solution of 0.56 g (6.83 mmol) of sodium acetate in 10 mL of water was added 1.29 g (4.78 mmol) of 1,1-dibromo-3,3,3-trifluoroacetone. The resulting solution was warmed for 30 minutes and then cooled in an ice/water bath. A solution of 4-(fluorophenoxy)benzaldehyde (789 mg, 3.65 mmol) in MeOH was added, followed by 10 mL of a concentrated aqueous NH4OH solution. Additional MeOH was added until a homogenous solution formed. After stirring at room temperature overnight, the reaction was diluted with water. The precipitate that formed was collected, washed with water and dried. Column chromatography (gradient from 8/2 to 2/3 hexane/EtOAc) afforded 0.6 g of a solid. A mixture of 0.5 g of the solid and 80 mL of a concentrated aqueous NH4OH solution was diluted with MeOH until a solution formed. The reaction was heated in a sealed tube for 1.5 days. After cooling to room temperature, the mixture was added to a water/EtOAc mixture. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, dried (Na2SO4), filtered and concentrated to dryness. Column chromatography (1:1 hexane/EtOAc) gave 2-[4-(4-fluorophenoxy)phenyl]-1H-imidazole-4-carbonitrile as a solid. 1H NMR (DMSO-d6): δ 13.37 (br s, 1H), 8.23 (s, 1H), 7.95 (d, 2H, J=8.7 Hz), 7.27 (t, 2H, J=8.9 Hz), 7.15 (dd, 2H, J=9.3, 4.5 Hz), 7.08 (d, 2H, J=8.7 Hz). To a solution of the nitrile in EtOH was added 1 g of KOH dissolved in 5 ml of water and 1.5 mL of a 30% aq. H2O2 solution. After heating at reflux for 3 hours, the reaction was added to water/EtOAc. The organic layer was dried (Na2SO4), filtered and evaporated in vacuo. The residue was subjected to flash chromatography (100% EtOAc) affording the title compound as a white solid, TLC Rf0.34 (5% MeOH/EtOAc). 1H NMR (CDCl3): δ 12.90 (br s, 1H), 8.08 (br s, 1H), 7.97 (d, 2H, J=9.0 Hz), 7.70 (s, 1H), 7.63 (br s, 1H), 7.26 (t, 2H, J=8.7 Hz), 7.15-7.10 (m, 2H), 7.07 (d, 2H, J=8.7 Hz).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([I:9])=[CH:4][N:3]=1.N1C=CC=CC=1.[NH2:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19]>CN1C(=O)CCC1>[F:8][C:7]1[C:2]([NH:16][CH2:17][C:18]([CH3:21])([OH:20])[CH3:19])=[N:3][CH:4]=[C:5]([I:9])[CH:6]=1
Reactant: CC(C)(O)CN
Reactant: Fc1cc(I)cnc1F
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CC(C)(O)CNc1ncc(I)cc1F
Temperature: 100 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
2,3-Difluoro-5-iodopyridine (500 mg, 2.07 mmol) was dissolved in NMP (500 μl) and pyridine (201 μl, 2.49 mmol, 1.2 equiv.) and 1-amino-2-methylpropan-2-ol (555 mg, 6.22 mmol, 3 equiv.) were added at room temperature. The mixture was stirred for 16 hours at 100° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 1-(3-fluoro-5-iodopyridin-2-ylamino)-2-methylpropan-2-ol (590 mg, 1.9 mmol, 91.7% yield) was obtained as a colorless oil, MS: m/e=311.0 (M+H+).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.CC([O:19][B:20](OC(C)C)[O:21]C(C)C)C.[F:29][C:30]([F:40])([F:39])[C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[C:33]#[N:34]>C1COCC1>[C:33]([C:32]1[C:31]([C:30]([F:39])([F:40])[F:29])=[CH:38][CH:37]=[CH:36][C:35]=1[B:20]([OH:21])[OH:19])#[N:34]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1ccccc1C(F)(F)F
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1c(B(O)O)cccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 249.7 %

Procedure:
To a solution of 2,2,6,6-tetramethylpiperidine (0.99 g, 7.02 mmol) in THF (25 ml) was added n-BuLi (2.80 ml, 2.5 M hexane solution, 7.02 mmol) at −10° C. After stirring for 10 min, this solution was cooled to −78° C., tris(1-methylethyl)borate (1.58 g, 8.4 mmol) was added, and the mixture was stirred for 5 min. To this solution was added a solution of 2-(trifluoromethyl)benzonitrile (1.00 g, 5.85 mmol) in THF (10 ml), and the mixture was stirred at −78° C. for 2 hr. The reaction solution was allowed to warm to room temperature, the reaction was quenched with acetic acid, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, the precipitated solid was filtered off, and the filtrate was concentrated to give the title compound (3.14 g) as a mixture. This was used for the next reaction without performing further purification and identification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.C(O)(=O)[CH2:15][C:16]([OH:18])=[O:17].N1CCCCC1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6](/[CH:7]=[CH:15]/[C:16]([OH:18])=[O:17])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)c([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1ccc(/C=C/C(=O)O)c([N+](=O)[O-])c1
Temperature: 125 °C
Yield: 65.2 %

Procedure:
To a mixture of 4-methoxy-2-nitrobenzaldehyde (20 g, 0.11 mol) and malonic acid (28.8 g, 0.28 mol) in pyridine (200 mL) is added piperidine (1 mL, catalytic amount) and the mixture is refluxed at 125° C. under nitrogen for 12 h. After cooling to room temperature, the solvent is removed under reduced pressure and the residue is acidified with 1.5 N HCl. The product is extracted with EtOAc and the organic layer is washed with water and brine then dried over Na2SO4. The solvent is removed under reduced pressure to afford 16 g (65%) of the title compound as a pale brown solid. 1H NMR (DMSO-d6, 400 MHz) δ 12.59 (bs, 1H), 7.91-7.93 (m, 1H), 7.68-7.72 (m, 1H), 7.56 (s, 1H), 7.31-7.33 (m, 1H), 7.46-7.50 (m, 1H), 3.87 (s, 3H).
Reaction SMILES: C(O[C:4](=[O:14])[C:5]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[CH:6]O)C.[NH:15]([C:17]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1)[NH2:16]>>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:5]2[C:4](=[O:14])[N:15]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:20]=[CH:19][N:18]=3)[NH:16][CH:6]=2)[CH:9]=1
Reactant: NNc1cc(C(F)(F)F)ccn1
Reactant: CCOC(=O)C(=CO)c1cccnc1
Product: O=c1c(-c2cccnc2)c[nH]n1-c1cc(C(F)(F)F)ccn1

Procedure:
The compound is prepared analogously to Example 2 from 18 mg (0.09 mmol) of the compound from Example 2A and 18 mg (0.10 mmol) 2-hydrazino-4-(trifluoromethyl)pyridine [R. A. Evans, C. Wentrup, J. Chem. Soc. Chem. Commun. 15, 1062-1064 (1992)]. 11.7 mg (41% of th.) of the title compound are obtained as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13]C)[NH:9][C:8](=[O:15])[N:7]=[C:6]2[CH3:16].C([O:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24])C.Br>>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[NH:9][C:8](=[O:15])[N:7]=[C:6]2[CH3:16].[C:20]([OH:25])(=[O:19])[CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: COc1cc2[nH]c(=O)nc(C)c2cc1OC
Reactant: CCCCC(=O)OCC
Agent: Br
Product: CCCCC(=O)O
Product: Cc1nc(=O)[nH]c2cc(O)c(O)cc12

Procedure:
When 6,7-dimethoxy-4-methyl-2(1H)quinazolinone-1-pentanoic acid ethyl ester is hydrolyzed with 40% aqueous HBr for 24 hours as in Example 27 the title compound is obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[CH3:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:17])[CH:23]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1
Reactant: Cc1cccc(B(O)O)c1
Product: Cc1cccc(-c2ccc(S(=O)(=O)NCCCCO)cc2)c1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(4-hydroxybutyl)-amide and 3-methylphenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 21.1, 25.8, 29.5, 42.6, 60.2, 124.1, 127.1, 127.3, 129.0, 138.4, 138.6, 139.2 and 143.9.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[NH:4][CH2:5][C@@:6]1(CC2C=CC=CC=2)[CH2:10][CH2:9][C@@H:8]([CH3:11])[CH2:7]1.I([O-])(=O)(=O)=O.[Na+].C(#N)C.[OH2:29].C([O:32][CH2:33][CH3:34])C>C(Cl)(Cl)(Cl)Cl.[Ru](Cl)(Cl)Cl>[CH3:1][O:2][C:3]([NH:4][CH2:5][C@@:6]1([CH2:34][C:33]([OH:32])=[O:29])[CH2:10][CH2:9][C@@H:8]([CH3:11])[CH2:7]1)=[O:19]
Reactant: O
Reactant: CCOCC
Reactant: COC(=O)NC[C@@]1(Cc2ccccc2)CC[C@@H](C)C1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)NC[C@@]1(CC(=O)O)CC[C@@H](C)C1
Temperature: 0 °C
Reaction time: 20 h
Yield: 14 %

Procedure:
((1S,3R)-1-Benzyl-3-methyl-cyclopentylmethyl)-carbamic acid methyl ester (2.6 g, 9.9 mmol) and sodium periodate (29.8 g, 140 mmol) were stirred together in carbon tetrachloride (30 mL), acetonitrile (30 mL), and water for 6 hours. The mixture was cooled to 0° C., and ruthenium(III) chloride (0.04 g, 0.2 mmol) was added to the reaction mixture. The reaction was allowed to warm to room temperature and stirred for 20 hours. Diethyl ether (50 mL) was added, and the mixture was then extracted with saturated aqueous sodium hydrogen carbonate (200 mL). The aqueous layer was acidified to pH 1 with 4N hydrochloric acid and re-extracted with ethyl acetate (200 mL), dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by chromatography (silica gel, eluting with a gradient of heptane to 1:1 heptane:ethyl acetate) to give 0.32 g (14%) of [(1S,3R)-1-(methoxycarbonylamino-methyl)-3-methyl-cyclopentyl]-acetic acid;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[NH:8][C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:18])=O.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[Cl:18][C:9]1[N:8]=[C:7]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: NCc1ccccc1
Reactant: O=c1[nH]c(=O)c2cc([N+](=O)[O-])ccc2[nH]1
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(Cl)nc(NCc3ccccc3)c2c1
Reaction time: 2 h

Procedure:
To 367 mg (1.77 mmol) of 6-nitroquinazoline-2,4 (1H,3H)-dione was added 15.13 g (98.70 mmol) of phosphorus oxychloride to effect reaction in the same manner as in Example 10. Next, to the reaction mixture was added dropwise 379 mg (3.54 mmol) of benzylamine under ice cooling, and the resulting mixture was stirred under ice cooling for 2 hours. Water was added to the reaction mixture, and crystals thus precipitated were filtered out to obtain 2-chloro-4-benzylamino-6-nitroquinazoline. To this was added 761 mg (13.33 mmol) of allylamine, and the resulting mixture was stirred at room temperature for 2.5 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 224 mg (yield: 56.8%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.B.[Na].Cl.[CH2:12](O)[CH3:13]>>[CH:12]1([CH2:13][NH:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:6][CH2:7][CH2:8][CH2:3][CH2:2]1
Reactant: NCc1cccnc1
Reactant: CCO
Agent: B
Agent: Cl
Agent: [Na]
Product: c1cncc(CNCC2CCCCC2)c1

Procedure:
To 100 ml of ethanol were added 7.0 g of cyclooctylaldehyde and 5.4 g of 3-aminomethylpyridine, and the mixture was subjected to a reaction for 4 hours at about 50° C. After cooling, 2.0 g of sodium boron hydride was added while 20° C. or below was kept by ice cooling, and the mixture was subjected to a reaction for 1 hour at room temperature. The reaction mixture was acidified with 2N hydrochloric acid and concentrated to dryness. To the residue was added an aqueous potassium carbonate solution to make the residue alkaline. The mixture was extracted with chloroform. The extract was washed with water and then dried with anhydrous sodium sulfate. The solvent was removed by evaporation. The residue was subjected to distillation under reduced pressure to obtain 6.4 g of N-(cyclohexylmethyl)-N-(3-pyridylmethyl)amine.