Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(O[N:5]=[CH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:17]=[C:18]([NH:22][C:23](=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH:19]=[CH:20][CH:21]=1)C.[NH2:29][NH:30][C:31](=O)[CH2:32][N:33]([CH3:35])[CH3:34].C[O-].[Na+]>CO>[CH3:34][N:33]([CH2:32][C:31]1[NH:30][N:29]=[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:28])[CH2:24][CH:25]([CH3:26])[CH3:27])[CH:19]=[CH:20][CH:21]=2)[N:5]=1)[CH3:35]
Reactant: CN(C)CC(=O)NN
Reactant: CCON=Cc1ccc2[nH]nc(-c3cccc(NC(=O)CC(C)C)c3)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(=O)Nc1cccc(-c2n[nH]c3ccc(-c4n[nH]c(CN(C)C)n4)cc23)c1

Procedure:
The title compound was prepared according to example Example 329 C using N-{3-[5-(ethoxyiminomethyl)(1H-indazol-3-yl)]phenyl}-3-methylbutanamide hydrochloride (0.400 g, 0.997 mmol), N-amino-2-(dimethylamino)acetamide (0.350 g, 2.99 mmol) and sodium methoxide in methanol (0.348 mL, 4.37 M). The title compound was isolated after purification by preparative HPLC (0.074 g, 18% yield): 1H NMR (CD3OD) δ 8.73 (s, 1H), 8.19 (s, 1H), 8.08 (d, 1H), 7.75 (t, 2H), 7.69 (d, 1H), 7.51 (t, 1H), 3.81 (s, 2H), 2.45 (s, 6H), 2.3 (d, 2H), 2.21 (m, 1H), 1.04 (d, 6H); ES-MS (m/z) 418 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:27])=[CH:6][C:7]([CH3:26])([CH3:25])[NH:8]2.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:36])=[C:33](O)[CH:34]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1.CCCCCC>[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:36])=[C:31]([CH:30]=1)[O:1][CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([CH3:27])=[CH:6][C:7]([CH3:26])([CH3:25])[NH:8]2
Reactant: Cc1ccc(F)cc1O
Reactant: COCOc1ccc(-c2ccc3c(c2CO)C(C)=CC(C)(C)N3)c(OC)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: c1ccccc1
Product: COCOc1ccc(-c2ccc3c(c2COc2cc(F)ccc2C)C(C)=CC(C)(C)N3)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
5-Hydroxymethyl-6-(2-methoxy-4-methoxymethoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 1-1, 511.7 mg, 1.39 mmol), 5-fluoro-2-methylphenol (182 μL, 1.67 mmol), tri-n-butylphosphine (521 μL, 2.09 mmol), and 1,1′-(azodicarbonyl)dipiperidine (526 mg, 2.08 mmol) were dissolved in anhydrous benzene (8 mL), and then the mixture was stirred under argon atmosphere at room temperature for 1 hour. Hexane (15 mL) was added to the reaction mixture, and the unsoluble materials were filtered out. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (411.4 mg) as a colorless amorphous product. (Yield 62%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[C@@H:12]([F:13])[C@H:11]([O:14]CC3C=CC(C)=CC=3)[C@@H:10]([CH2:23][O:24]CC3C=CC(C)=CC=3)[S:9]2)[C:4](=[O:33])[N:3]=1.CO>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]([CH:8]2[S:9][C@H:10]([CH2:23][OH:24])[C@@H:11]([OH:14])[C@@H:12]2[F:13])[C:4](=[O:33])[N:3]=1
Reactant: Cc1ccc(COC[C@H]2SC(n3ccc(N)nc3=O)[C@@H](F)[C@@H]2OCc2ccc(C)cc2)cc1
Solvent: ClCCl
Solvent: CO
Product: Nc1ccn(C2S[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)n1
Temperature: 0 °C
Yield: 161.8 %

Procedure:
In a nitrogen atmosphere, 3.0 mL of a methylene chloride solution 1 mol/L boron trichloride was added to a solution of 70 mg of (3S,4S,5R)-2-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-3-fluoro-4-((4-methylbenzyl)oxy)-5-(((4-methylbenzyl)oxy)methyl)thiolane in 4.6 mL of methylene chloride under cooling on dry ice/acetone, and the obtained mixture was then stirred at the same temperature as described above for 3.5 hours. Thereafter, the temperature of the reaction mixture was increased to 0° C., and the mixture was then stirred for 30 minutes. Thereafter, 3.0 mL of methanol was added to the reaction mixture, and the thus obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, a solid was then collected by filtration, and it was then purified by silica gel column chromatography (chloroform/methanol=100/0 to 60/40), so as to obtain 63 mg of (2R,3S,4S)-5-(4-amino-2-oxo-1,2-dihydropyrimidin-1-yl)-4-fluoro-2-(hydroxymethyl)thiolan-3-ol in the form of a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]1.[Cl:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]2[CH:24]=[C:23]([CH2:25]Cl)[CH:22]=[CH:21][N:20]=2)=[CH:13][C:12]=1[O:27][CH3:28]>>[Cl:10][C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]2[CH:24]=[C:23]([CH2:25][N:1]3[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3][CH2:2]3)[CH:22]=[CH:21][N:20]=2)=[CH:13][C:12]=1[O:27][CH3:28]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1Cl
Reactant: NC(=O)C1CCNCC1
Product: COc1cc(-c2cc(CN3CCC(C(N)=O)CC3)ccn2)cc(OC)c1Cl

Procedure:
Piperidine-4-carboxamide (301 mg) and 2-(4-chloro-3,5-dimethoxyphenyl) 4-chloromethyl pyridine (600 mg) were coupled in the same manner as described in Example 2 to give the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([OH:18])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:1]([O:18][C:12]1[CH:11]=[C:10]([Br:9])[CH:17]=[CH:16][C:13]=1[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Benzyl bromide (1.35 ml) was added to a mixture of 4-bromo-2-hydroxybenzaldehyde (2.07 g) and potassium carbonate (1.38 g) in DMF (20 ml) and the mixture was stirred at ambient temperature for 10 hours. The reaction mixture was poured into water (50 ml) to give 2-benzyloxy-4-bromobenzaldehyde as a solid which was filtered and dried, yield 2.88 g. The material was used in subsequent reactions without purification.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)=[C:5]([CH3:7])[N:6]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[CH:13][C:8]([C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])=[N:9][C:10]1=[O:14]
Reactant: ClCCCCBr
Reactant: Cc1nc(C)c(-c2cc[nH]c(=O)n2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C)c(-c2ccn(CCCCCl)c(=O)n2)s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
To a solution of 4-(2,4-Dimethyl-thiazol-5-yl)-1H-pyrimidin-2-one (120 mg, 0.58 mmol) in dry DMF (21 ml), 60% NaH (24 mg, 0.75 mmol) was added portionwise under inert atmosphere. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (86 μl, 0.75 mmol) was added at room temperature and the mixture was stirred overnight then was heated at 69° C. for 2 hours. Water was added and the mixture extracted with diethyl ether to remove the dialkylated product and finally with ethyl acetate. Ethyl acetate was washed with brine, dried (Na2SO4) and evaporated to give 80 mg of the title compound as a solid (48% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[N:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:17].[Na+]>CO>[CH3:10][C:6]1[N:5]=[C:4]([CH:1]([NH2:17])[CH3:2])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(C)n1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(C(C)N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
To a solution of 2-acetyl-6-methylpyridine (4.7 g, 34.8 mmol) in anhydrous methanol (100 ml) was added ammonium acetate (26.8 g, 348 mmol) and sodium cyanoborohydride (1.75 g, 27.8 mmol) and the resulting mixture stirred at RT overnight. The mixture was evaporated and the residue dissolved in water and basified by the addition of KOH and extracted with DCM (×3). The DCM layers were combined and washed with sat. NaCl, dried over MgSO4, filtered and evaporated. The residue was purified by column chromatography on silica to afford the title compound (i-14) (eluent: 5% MeOH in DCM) to give 2.8 g (59%) as a clear oil. 1H NMR (CDCl3): 1.41 (d, J 6.7 Hz, 3H), 1.78 (brs, 2H), 2.54 (s, 3H), 4.21 (q, J 6.7 Hz, 1H), 6.99 (d, J 7.6 Hz, 1H), 7.09 (d, J 7.7 Hz, 1H), 7.52 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH2:12][CH2:13][C:14](Cl)=[O:15].COC1C=CC([N+]([O-])=O)=CC=1CCC(O)=O.S(Cl)(Cl)=O.[CH:37]([NH:40][CH:41]([CH3:43])[CH3:42])([CH3:39])[CH3:38]>ClCCl>[CH:37]([N:40]([CH:41]([CH3:43])[CH3:42])[C:14](=[O:15])[CH2:13][CH2:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:39])[CH3:38]
Reactant: COc1ccc([N+](=O)[O-])cc1CCC(=O)Cl
Reactant: CC(C)NC(C)C
Agent: COc1ccc([N+](=O)[O-])cc1CCC(=O)O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1CCC(=O)N(C(C)C)C(C)C
Reaction time: 16 h

Procedure:
A solution of 3-(2-methoxy-5-nitrophenyl)propionyl chloride(0.46 g, 1.9 mmol), prepared from 3-(2-methoxy-5-nitrophenyl)propionic acid (Asano et al., J. Pharm. Soc. Japan, 1950, 70, 480) and thionyl chloride, in dichloromethane (5 mL) was added in one portion to a solution of diisopropylamine (0.67 g, 6.6 mmol) in dichloromethane (20 mL), stirred for 16 h, washed with water (2×20 mL), dried (Na2SO4), and concentrated in vacuo to give the title compound: MS(ES) m/3 309.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][NH2:8].[C:9](N1C=CN=C1)(N1C=CN=C1)=[S:10].O>CN(C=O)C>[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:9]=[S:10]
Reactant: COCCOCCN
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCN=C=S
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
To a solution of 2-(2-methoxyethoxyl)ethanamine (0.820 g, 6.88 mmol) in DMF (69 mL) at 0° C. was added dropwise a solution of 1,1′-thiocarbonyldiimidazole (1.349 g, 7.57 mmol) in 21 mL of DMF. The mixture was warmed to RT and stirred for 90 min. The mixture was poured into water (130 mL) and extracted with Et2O (70 mL). The Et2O layer was washed with water, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo (325 torr, bath temp: 24° C.) to afford 1-isothiocyanato-2-(2-methoxyethoxyl)ethane (0.678 g, 4.21 mmol, 61% yield) as a yellow oil. The crude material was used in next step.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:54](O)=[O:55])[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][C@H:48]([CH3:52])[CH2:47]2)=[CH:42][C:41]3=[O:53])[CH:27]=[C:28]([F:30])[CH:29]=1.CCN(C(C)C)C(C)C.[NH:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1>CC(N(C)C)=O>[F:30][C:28]1[CH:27]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:54]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][CH2:67]3)=[O:55])[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][C@H:48]([CH3:52])[CH2:47]2)=[CH:42][C:41]3=[O:53])[CH:25]=[C:24]([F:23])[CH:29]=1
Reactant: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)O)cc(C4CCCN4c4cc(F)cc(F)c4)c3o2)CCO1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)N4CCOCC4)cc(C4CCCN4c4cc(F)cc(F)c4)c3o2)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
TBTU (154 mg, 0.48 mmol) was added to a stirred solution of 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (90 mg, 0.19 mmol), DIPEA (0.083 mL, 0.48 mmol) dissolved in DMA (2 mL) under nitrogen. The resulting solution was stirred at room temperature for 30 min. Morpholine (0.050 mL, 0.57 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was purified by preparative HPLC. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-6-(morpholine-4-carbonyl)-4H-chromen-4-one (68 mg, 66%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([S:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]O.C(OCC)(=O)C>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][O:20][C:19](=[O:21])[CH2:18][S:17][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1
Reactant: OCc1cccc(F)c1
Reactant: O=C(O)CSc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(CSc1ccc(C(=O)Nc2ccc(F)cc2)cn1)OCc1cccc(F)c1
Yield: 26.5 %

Procedure:
A solution of [5-(4-fluorophenylcarbamoyl)pyridin-2-ylsulfanyl]acetic acid (0.030 g, 0.10 mmole), 3-fluorobenzyl alcohol (0.10 mL, 1.0 mmol), and sulfuric acid (1 drop) in toluene (5 mL) was heated at reflux. After 2 h the reaction mixture was poured into ethyl acetate and washed with saturated sodium bicarbonate and dried over sodium sulfate. Removal of the solvents provided a solid. Purification by trituration using ethyl acetate/hexanes gave 0.011 g (27%) of the titled product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s 1H); 8.86 (m, 1H); 8.12 (m, 1H); 7.74 (m, 2H); 7.51 (m, 1H); 7.35 (m, 1H); 7.15 (m, 5H); 5.16 (m, 2H), 4.18 (m, 2H); MS (EI) m/z 413.05 (M−H)−.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11]Br)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[NH2:14][C:15]([NH2:17])=[S:16].C([O-])(O)=O.[Na+]>CCO.O>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:15]([NH2:17])[S:16][CH:11]=2)=[CH:6][CH:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)CBr)cc1
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=Nc1ccc(-c2csc(N)n2)cc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(4-azidophenyl)-2-bromoethanone (1.37 g, 5.71 mmol) in EtOH (15 mL) at room temperature was added thiourea (0.476 g, 6.25 mmol). The reaction mixture was heated to 70° C. for 3 d, poured into a solution of NaHCO3 (602 mg) in water (50 mL) and stirred for 30 min. The precipitate that formed was collected by filtration, washed with water, and dried under high vacuum to give 4-(4-azidophenyl)thiazol-2-amine.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH:9]([C:8]1[CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([O:14][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:6]([O:12][CH3:13])[CH:7]=1)=[O:10]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 0.05 h
Yield: 73.6 %

Procedure:
To a solution of 5-nitrovanilline (591 mg, 3.0 mmol) in DMF (9.0 mL) was added cesium carbonate (2.00 g, 6.16 mmol), followed by ethyl bromoacetate (3.33 mL, 30 mmol). The red mixture was left under stirring at 110° C. until it became yellow, and then for further 3 minutes. After evaporation of DMF under reduced pressure, 22 mL of water were added and the mixture was extracted with dichloromethane (60 mL). The organic phase was washed with brine (15 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel (eluent: dichloromethane) to give 625 mg of a solid (74% yield). 1H NMR (250 MHz, CDCl3): δ 1.30 (t, J=7.2 Hz, 3H), 4.01 (s, 3H), 4.27 (q, J=7.2 Hz, 2H), 4.91 (s, 2H), 7.65 (s, 1H), 7.90 (s, 1H), 9.95 (s, 1H). 13C NMR (63 MHz, CDCl3): δ 14.6, 57.2, 62.0, 70.0, 113.9, 120.4, 132.0, 145.2, 145.9, 154.2, 168.5, 189.3.
Reaction SMILES: [OH:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C1(=O)O[CH2:15][CH2:14][O:13]1>>[OH:13][CH2:14][CH2:15][O:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2c(O)cccc2o1
Reactant: O=C1OCCO1
Product: Nc1nc2c(OCCO)cccc2o1
Yield: 46 %

Procedure:
The title compound was prepared according to the procedure of Example 91, Step 1, starting from 4-hydroxy-2-amino-1,3-benzoxazol* (0,97 g, 6.5 mmol) and ethylene carbonate (0.63 g, 7.1 mmol). Solid; yield 46%; mp 124-126° C. Anal. (C9H10N2O3) C, H, N.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:21])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)(Cl)Cl>[F:1][C:2]1[C:3]([O:21][S:29]([CH3:28])(=[O:31])=[O:30])=[C:4]2[C:9]3=[C:10]([C:12](=[O:19])[CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:14][N:8]3[N:7]([CH3:20])[CH2:6][CH2:5]2)[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cn2c3c(c(O)c(F)cc3c1=O)CCN2C
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C1CN2c3c(cc(F)c(OS(C)(=O)=O)c3CCN2C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
304 mg of the compound (167) obtained in Example 44 was added to 2 ml of pyridine, and 120 mg of methane-sulfonyl chloride was added to the solution. The solution was stirred for 3 hours at room temperature. 50 ml of chloroform was added to the solution, and the solution was washed with aqueous 5% citric acid solution. The organic layer was separated, and after drying over magnesium sulfate, the solvent was removed by distillation. To the residue, ethanol was added, and the solid matter was filtered off and washed with isopropyl ether to obtain 260 mg of the subject compound (168).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=1.[Br:18]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:18][CH2:17][C:14]1[CH:15]=[CH:16][C:7]2[CH:6]=[CH:5][C:4]3[N:3]=[C:2]([CH3:1])[NH:11][C:10](=[O:12])[C:9]=3[C:8]=2[CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccc3nc(C)[nH]c(=O)c3c2c1
Solvent: c1ccccc1
Product: Cc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1

Procedure:
To a hot solution of 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (2.0 g, 8.9 mmol) in benzene (1000 ml) under nitrogen was added N-bromosuccinimide (NBS) (2.0 g, 11 mmol). The solution was stirred at reflux for 1 hour and then concentrated in vacuo to give crude 9-bromomethyl-3-methylbenzo[f]quinazolin-1(2H)-one. The solid was suspended with diethyl N-(4-amino-2-fluorobenzoyl)-L-glutamate (T. R. Jones et al., UK Patent GB 2175 903A, 1986) (6.0 g, 18 mmol) in DMF (20 ml) and stirred under nitrogen at 100° C. for 30 minutes. The reaction mixture was allowed to cool, N-methylmorpholine (1.0 ml, 9.1 mmol) (Aldrich) was added, and the solution concentrated under high vacuum. The residue was purified with silica gel chromatography eluting with methylene chloride:THF (5:1). Fractions containing product were concentrated in vacuo to a thick paste, the solid suspended in a small volume of diethyl ether, filtered under nitrogen, and dried under high vacuum to give diethyl N-(4-(((1,2-dihydro-3-methyl-1oxobenzo[f]quinazolin-9-yl)methyl)amino)-2-fluorobenzoyl)-L-glutamate as a white solid (2.3 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.15 (t, J=7 Hz, 3H, ester CH3), 1.18 (t, J=7 Hz, 3H, ester CH3), 1.87-2.13 (m, 2H, glu CH2), 2.38 (t, J=7 Hz, 2H, ester CH2), 2.43 (s, 3H, C3 --CH3), 4.02 (q, J=7 Hz, 2H, ester CH2), 4.09 (q, J=7 Hz, 2H, ester CH2), 4.34-4.44 (m, 1H, glu CH), 4.57 (d, J=6 Hz, 2H, C9 --CH2), 6.39 (dd, J=15,2 Hz, 1H, Ar), 6.53 (dd, J=9,2 Hz, 1H, Ar), 7.30 (t, J= 6 Hz, 1H, ArNH), 7.44 (dd, J=9,9 Hz, 1H, Ar), 7.60 (d, J=9 Hz, 1H, Ar), 7.61 (dd, J=8,2 Hz, 1H, Ar), 7.88 (dd, J=7,5 Hz, 1H, glu NH), 8.01 (d, J=8 Hz, 1H, Ar), 8.22 (d, J=9 Hz, 1H, Ar), 9.85 (s, 1H, Ar), 12.53 (s, 1H, N2H). Mass spectrum (CI-CH4): 563 (M+1, 100%). Anal. Calculated for C30H31FN4O6 : C, 64.05; H, 5.55; N, 9.96. Found: C, 64.14; H, 5.59; N, 9.94.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH:6]([NH:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Cl)[CH:33]=1>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][CH2:5][CH:6]([NH:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:38][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[CH:10][CH:9]=1
Reactant: COC(=O)CCC(Cc1ccc(O)cc1)NC(=O)CCCCCCc1ccccc1
Reactant: ClCc1cccnc1
Agent: Cl
Product: COC(=O)CCC(Cc1ccc(OCc2cccnc2)cc1)NC(=O)CCCCCCc1ccccc1
Yield: 68.8 %

Procedure:
Prepared from (RS)-5-(4-Hydroxy-phenyl)-4-(7-phenyl-heptanoylamino)-pentanoic acid methyl ester 92 (502 mg, 1.22 mmol) and 3-picolylchloride hydrochloride (300 mg, 1.83 mmol) to afford 94 (422 mg, 69%). 13C NMR (CDCl3) δ 174.4, 173.0, 157.3, 149.5, 149.1, 142.8, 135.5, 132.8, 130.6, 128.5, 128.4, 125.8, 123.7, 114.9, 67.7, 51.9, 50.3, 40.6, 37.0, 36.0, 31.4, 31.1, 29.2, 29.1, 29.0, 25.8. ESMS 503 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:34]=2)[N:31]=1.O>N1C=CC=CC=1>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([N:32]=[C:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)c1nc2ccc(Cl)nn2n1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)c1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2n1
Temperature: 80 °C
Reaction time: 13.5 h
Yield: 38.8 %

Procedure:
563 mg of 4-(diphenylmethoxy)-1-piperidinepropanamine and 442 mg of tert-butyl (6-chloro[1,2,4]triazolo[1,5-b]pyridazin-2-yl)carboxylate were dissolved in 5 ml of pyridine, followed by stirring at 80° C. for 13.5 hours. After cooling, water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected and concentrated under reduced pressure; the residue was crystallized by the addition of ethyl acetate, collected by filtration, washed with ethyl ether and dried to yield 365 mg of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([N:26]2[CH2:30][CH2:29][CH:28]([C:31](O)=[O:32])[C:27]2=[O:34])[CH:19]=[CH:20][C:21]=1[C:22]([F:25])([F:24])[F:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:31]([CH:28]1[CH2:29][CH2:30][N:26]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([F:25])([F:23])[F:24])=[C:16]([F:15])[CH:17]=2)[C:27]1=[O:34])=[O:32]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C(O)C1CCN(c2ccc(C(F)(F)F)c(F)c2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)C1CCN(c2ccc(C(F)(F)F)c(F)c2)C1=O
Yield: 19.6 %

Procedure:
This compound was prepared according to method A with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 1-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxopyrrolidine-3-carboxylic acid (0.130 g; 0.445 mmol), HATU (0.166 g; 0.437 mmol) and N,N-diisopropylethylamine (0.186 mL; 1.06 mmol) in DMF (5 mL). The crude material was purified by flash chromatography on silica gel (eluent: 2 to 20% of ethyl acetate in dichloromethane) to give 0.0389 g (20%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(3-fluoro-4-(trifluoromethyl)phenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.