Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]Br.C([O:6][CH2:7][CH3:8])C.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:22]=[CH:21][C:18](C#N)=[CH:17][CH:16]=1.[Cl-].[NH4+].C(OCC)(=O)C>ClCCl>[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:16]=[CH:17][C:18]([C:7](=[O:6])[CH3:8])=[CH:21][CH:22]=1
Reactant: CCOCC
Reactant: N#Cc1ccc(-c2ccccn2)cc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
After 21 ml of a 3M methyl magnesium bromide-diethyl ether solution was added dropwise to a solution of 3.10 g of 4-(2-pyridyl)benzonitrile in 120 ml of dichloromethane under ice-cooling in a nitrogen atmosphere, the mixture was stirred at room temperature for 20 hours. After the reaction, an aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture, followed by stirring of the resulting mixture. The ethyl acetate layer was separated from the reaction mixture, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:2) to obtain the crude desired compound as crystals. Further, the crude compound was washed with diisopropyl ether-hexane to obtain 1.56 g of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH:7]([NH2:28])[C@H:8]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH:9]([C:11]1[O:12][C:13]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16](F)[C:14]=2[N:15]=1)[OH:10])([CH3:4])([CH3:3])[CH3:2].[Cl:30]C1C=C(F)C=C([N+]([O-])=O)C=1O.ClC1C=C(Cl)C=C([N+]([O-])=O)C=1O>>[C:1]([O:5][C:6](=[O:29])[CH:7]([NH2:28])[C@H:8]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[CH:9]([C:11]1[O:12][C:13]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:30])[C:14]=2[N:15]=1)[OH:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cc(F)cc(Cl)c1O
Reactant: C=CCOC(=O)[C@@H](C(N)C(=O)OC(C)(C)C)C(O)c1nc2c(F)cc(Cl)cc2o1
Agent: O=[N+]([O-])c1cc(Cl)cc(Cl)c1O
Product: C=CCOC(=O)[C@@H](C(N)C(=O)OC(C)(C)C)C(O)c1nc2c(Cl)cc(Cl)cc2o1

Procedure:
Compound 718 was prepared by a similar method as that used for compound 714, except compound 711 was replaced with 2,4-dichloro-6-nitrophenol. ##STR97##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:24]2[N:28]=[CH:27][CH:26]=[N:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C@H:10]1[CH2:14][CH2:13][CH2:12][C@@H:11]1[NH:15]C(=O)OC(C)(C)C)=[O:8].Cl>C(Cl)Cl.O1CCOCC1>[ClH:1].[NH2:15][C@H:11]1[CH2:12][CH2:13][CH2:14][C@@H:10]1[NH:9][C:7](=[O:8])[C:6]1[CH:23]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:24]1[N:25]=[CH:26][CH:27]=[N:28]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1NC(=O)c1cc(Cl)ccc1-n1nccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@H]1CCC[C@@H]1NC(=O)c1cc(Cl)ccc1-n1nccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-[5-chloro-2-(2H-1,2,3-triazol-2-yl)benzamido]cyclopentyl]carbamate (170 mg, 0.418 mmol) in DCM (5 ml) was added HCl in 1,4-dioxane (4 M, 3 ml). The reaction was stirred at room temperature overnight and then concentrated in vacuo. The solid was triturated with diethyl ether (3×1 ml) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]#[N:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1>COCCO.[Pd]>[S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=1)([OH:24])(=[O:23])=[O:22].[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)[CH2:12][CH2:13][NH2:14]
Reactant: N#CCc1cc(F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COCCO
Product: NCCc1cc(F)cc(C(F)(F)F)c1

Procedure:
A solution of 2.5 g of 3-fluoro-5-trifluoromethylphenylacetonitrile and 2.34 g (12.3 mmol) of p-toluenesulfonic acid in 75 ml of ethylene glycol monomethyl ether is hydrogenated for 3 hours at room temperature at 40 psi, using 200 mg 10% palladium on carbon catalyst. The catalyst is filtered off and the solvent evaporated to half the volume. Upon standing, the p-toluenesulfonic acid salt of the desired 3-fluoro-5-trifluoromethylphenethylamine crystallizes. The white crystals. 4.26 g (91%) are collected by filtration.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16]([Br:30])=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([O:26]C(=O)C)[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CN>C(O)C>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16]([Br:30])=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[NH:21][C:20](=[O:26])[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: CC(=O)Oc1ccc2c(Br)c([C@@H](COC(=O)C(C)(C)C)OC(C)(C)C)c(C)cc2n1
Agent: CN
Solvent: CCO
Product: Cc1cc2[nH]c(=O)ccc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 78 °C
Yield: 57.3 %

Procedure:
To the solution of (S)-2-(2-acetoxy-5-bromo-7-methylquinolin-6-yl)-2-tert-butoxyethyl pivalate (130 mg) in ethanol (7.5 mL) was added aqueous methylamine solution (0.5 mL, 50%). The mixture was heated at 78° C. for 80 min. Concentration and purification gave (S)-2-(5-bromo-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyethyl pivalate (68 mg). LCMS-ESI+ (m/z): 438.2, 440.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].Cl.Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][N:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)[CH2:17][CH2:16]1)(=[O:11])=[O:10]
Reactant: c1ccc2c(c1)CCN(CC1CCNCC1)C2
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=S(=O)(c1cc(Cl)ccc1Cl)N1CCC(CN2CCc3ccccc3C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 131.8 %

Procedure:
2,5-dichlorobenzene-1-sulfonyl chloride (108.1 mg, 0.44 mmol) was added to a solution of 2-(piperidin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride (92.1 mg, 0.40 mmol) and N,N-diisopropylethylamine (206.9.2 mg, 1.60 mmol) in CH2Cl2 (10 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×10 mL), dried over Na2SO4, and evaporated to dryness. The free base was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.10 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (138 mg, 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]([F:16])([F:15])[F:14])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[F:14][C:13]([F:16])([F:15])[O:12][C:5]1[CH:4]=[CH:3][C:2]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[CH:7][C:6]=1[NH:8][C:9](=[O:11])[CH3:10]
Reactant: CN1CCNCC1
Reactant: CC(=O)Nc1cc(Br)ccc1OC(F)(F)F
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Product: CC(=O)Nc1cc(N2CCN(C)CC2)ccc1OC(F)(F)F
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Pd2(dba)3 (157 mg, 0.17 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)-biphenyl (134.7 mg, 0.34 mmol), N-(5-bromo-2-trifluoromethoxy-phenyl)-acetamide (5.05 g, 17 mmol)) were charged in a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. Lithium bis(trimethylsilyl)amide solution (1M in THF, 37.6 mL) and N-methylpiperazine (2.3 mL, 20.5 mmol) were added and the reaction mixture refluxed for 3 h. The reaction mixture was then allowed to cool to room temperature and concentrated. The crude solid was purified by flash chromatography on silica gel (eluant: DCM/EtOH 90/10) to afford 4.78 g (88% yield) of the N-[2-trifluoromethoxy-5-(4-methyl-piperazin-1-yl)-phenyl]-acetamide.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26](O)=[O:27])=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.[CH3:35][NH:36][C:37]([CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38]>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26]([N:42]3[CH2:43][CH2:44][CH:39]([C:37]([NH:36][CH3:35])=[O:38])[CH2:40][CH2:41]3)=[O:27])=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)=[CH:13][N:14]=1
Reactant: CNC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CCC(=O)O)c3n2)cn1
Product: CNC(=O)C1CCN(C(=O)CCn2cnc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)CC1

Procedure:
3-(2-(2-(Tert-butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)propanoic acid (50 mg) was reacted with N-methylpiperidine-4-carboxamide via General Procedure F followed by Boc deprotection via General Procedure E to give 10.9 mg 111 as white solid following reverse phase purification. MS (Q1) 495.3 (M)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([Cl:21])=[CH:11][C:12]([N+:18]([O-])=O)=[C:13]([CH2:15][C:16]#N)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.O>C(O)C.[Pt](=O)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][C:10]=1[Cl:21])[NH:18][CH:16]=[CH:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCc1cc(OCc2ccccc2)c(Cl)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Clc1cc2[nH]ccc2cc1OCc1ccccc1
Reaction time: 12 h
Yield: 17.7 %

Procedure:
To a solution of (5-benzyloxy-4-chloro-2-nitrophenyl)acetonitrile (4.170 g) in ethanol (70 mL) was added platinum (IV) oxide (0.344 g) at room temperature and this mixture was stirred under a hydrogen atmosphere (30-35 psi) for 12 hours. To this reaction mixture were added acetic acid (7 mL) and water (7 mL), and this mixture was stirred under same condition for 24 hours. After this reaction mixture was replaced under argon atmosphere, the insoluble material was removed by filtration. To this filtrate was added water and this resulting mixture was extracted with diethyl ether. This organic layer was washed with brine, and dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=75/25) to give the title compound (0.629 g).
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[N+:19]([C:22]1[N:26]=[CH:25][NH:24][N:23]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:16][C:15]([CH3:18])([CH3:17])[CH2:14][N:13]1[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:2][N:24]1[CH:25]=[N:26][C:22]([N+:19]([O-:21])=[O:20])=[N:23]1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: O=[N+]([O-])c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)Cn1c(Cn2cnc([N+](=O)[O-])n2)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (3 mmol) and 3-nitro-[1,2,4]triazole (3 mmol) are dissolved in DMSO (20 ml). Potassium carbonate (6 mmol) is added to the solution. The mixture is allowed to stir at room temperature overnight. The reaction mixture is diluted with H2O and extracted with AcOEt. The organic layer is dried over MgSO4 and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:5) to give 7-(2,2-dimethyl-propyl)-6-(3-nitro-[1,2,4]triazol-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 41% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:14](C)(OC3C=CC(C4NN=NN=4)=CC=3)C)[C:11]3[CH:35]=[C:36](F)[C:37](F)=[CH:38][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[F:41][C:42]1[CH:43]=[C:44]([CH:47]=[C:48]([F:51])[C:49]=1[OH:50])[C:45]#[N:46].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:14][O:50][C:49]3[C:42]([F:41])=[CH:43][C:44]([C:45]#[N:46])=[CH:47][C:48]=3[F:51])[C:11]3[CH:35]=[CH:36][CH:37]=[CH:38][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(Oc1ccc(-c2nnn[nH]2)cc1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: N#Cc1cc(F)c(O)c(F)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: N#Cc1cc(F)c(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3ccccc32)c(F)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 32, intermediate b), 3,5-difluoro-4-hydroxybenzonitrile (commercially available), triphenylphosphine and di-tert-butyl azodicarboxylate. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Colorless foam. MS (Turbo Spray): m/z=492.4 [M+H].
Reaction SMILES: ClC(OCC(C)C)=O.[Cl:9][C:10]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:11]=1[C:12]([OH:14])=O.C(N(CC)CC)C.[CH:29]1([NH2:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:29]1([NH:35][C:12](=[O:14])[C:11]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:10]=2[Cl:9])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCCCC1)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 0.75 h

Procedure:
Isobutyl chloroformate (1.43 ml) was added under ice cooling to a solution of 2-chloro-5-nitrobenzoic acid (2.01 g) and triethylamine (1.53 ml) in methylene chloride (40 ml). The mixture was stirred under ice cooling for 45 min. Thereafter, cyclohexylamine (1.25 ml) was added thereto. The reaction solution was stirred at room temperature for 1.5 hr. The precipitated crystals were dissolved in chloroform. The organic layer was washed with water, dilute hydrochloric acid, and water in that order, dried over magnesium sulfate, and then concentrated under the reduced pressure. Ethyl ether was added to the residue. The precipitated crystals were collected by filtration, and then dried to give 2.63 g of N-cyclohexyl-2-chloro-5-nitrobenzamide.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1)C=C.[C:18]1(OC2C=CC=CC=2)[CH:23]=CC=C[CH:19]=1.CCCCCC>C1(C2C=CC=CC=2)C=CC=CC=1>[CH2:23]([C:6]1[C:5](=[O:4])[C:14]2[C:9](=[C:10]([N+:15]([O-:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH:18]=[CH2:19]
Reactant: C=CCOc1ccnc2c([N+](=O)[O-])cccc12
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCCCCC
Product: C=CCc1c[nH]c2c([N+](=O)[O-])cccc2c1=O
Temperature: 90 °C
Yield: 84.1 %

Procedure:
A solution of 4-allyloxy-8-nitroquinoline (3.72 g) in biphenyl (2.59 g) and diphenyl ether (7.4 g) was heated at 200° C. for 10 minutes. After cooling, n-hexane (40 ml) was added thereto, and the mixture was warmed at 90° C. After cooling, the resulting precipitate was collected by filtration to give 3-allyl-1,4-dihydro-8-nitro-4-oxoquinoline (3.13 g).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)[C:10](=[O:35])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(=O)([O-])[O-].[K+].[K+].[C:42]([O:46][CH3:47])(=[O:45])[CH:43]=[CH2:44].O>CN(C)C=O>[O:1]=[C:2]1[N:11]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([O:21][CH:22]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:20]2)[C:10](=[O:35])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:44][CH2:43][C:42]([O:46][CH3:47])=[O:45]
Reactant: C=CC(=O)OC
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCn1c(=O)n(CCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c(=O)c2ccccc21
Temperature: 120 °C
Reaction time: 20 h
Yield: 42 %

Procedure:
2,4-Dioxo-3-[3-(4-diphenylmethoxypiperidino)propyl]-1,2,3,4-tetrahydroquinazoline (3.50 g) obtained in Example 79 and potassium carbonate (1.24 g) were suspended in N,N-dimethylformamide (50.0 ml), and then methyl acrylate (1.01 ml) was added. The reaction mixture was stirred at 120° C. for 20 hours, poured onto an iced water, and then extracted with ethyl acetate. After the extract was washed with water and dried (Na2SO4), the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluting with n-hexane-ethyl acetate (3:1, v/v) to give the title compound (1.73 g, 42%) as a crystal. This product was used in the next reaction without further purification.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)=O)C.[H-].[Na+].[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>O1CCCC1>[CH:4]([CH2:6][CH2:7][CH2:8][C:9]1[N:10]=[CH:11][N:12]([Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:13]=1)=[O:3]
Reactant: C[Si](C)(C)Cl
Reactant: CCOC(=O)CCCc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)n1cnc(CCCC=O)c1
Reaction time: 0.08 h

Procedure:
A solution of 1.82 g of 4-(3-ethoxycarbonylpropyl)-1H-imidazole in 30 ml of tetrahydrofuran under nitrogen is treated with 0.5 g of sodium hydride (50% oil dispersion) at 0° for 30 min and 1.45 ml of trimethylsilyl chloride at 0° for 3 h. The reaction mixture is washed with cold 0.5N sodium bicarbonate solution, dried over sodium sulfate and evaporated to dryness. The oil is redissolved in 100 ml of methylene chloride at -78° under nitrogen and 12.82 ml of diisobutylaluminium hydride (1.56M) is added dropwise. The reaction mixture is stirred for 5 min at -78°, quenched with 1 ml of methanol followed by 10 ml of water and filtered through Celite®. The organic phase is separated, dried over sodium sulfate and evaporated to yield the title compound (a).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=1)[CH2:7][N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[NH:10][C:9]1=[O:19])(O)=[O:2].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>O.CN(C=O)C>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:30][CH2:31][N:32]([C:1]([C:4]2[CH:5]=[C:6]([CH:20]=[CH:21][CH:22]=2)[CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][C:9]2=[O:19])=[O:2])[CH2:33][CH2:34]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cccc(Cn2c(=O)[nH]c(=O)c3ccccc32)c1)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.7 %

Procedure:
1-(3-carboxybenzyl)quinazoline-2,4(1H,3H)-dione (0.2 mmol), 1-(pyridin-2-yl)piperazine (0.2 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU, 0.26 mmol), N,N-diisopropylethylamine (DIPEA, 0.4 mmol) and DMF (5 mL) were added into a 50 mL two-mouth flask. The obtained mixture was stirred at room temperature for 3 hours. To the mixture was added 50 mL of water and it was extracted by dichloromethane (DCM, 50 mL×2). The organic layer was washed by 1N HCl (50 mL×2) and saturated NaCl aquenous solution (50 mL×2), dried with anhydrous sodium sulphate, and evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography (ethyl acetate) to give the title compound as white solid (7.7 mg, 8.6% yield). 1H NMR (DMSO-d6): 11.69 (s, 1H), 8.09 (dd, J=5.0 and 1.7 Hz, 1H), 7.99 (dd, J=8.0 and 1.7 Hz, 1H), 7.64 (t, J=7.1 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.40-7.21 (m, 6H), 6.77 (d, J=8.7 Hz, 1H), 6.64 (dd, J=7.1 and 5.0 Hz, 1H), 5.34 (s, 2H), 3.40-3.20 (m, 8H). MS: m/z 442.3 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:9]([C:21](O)=[O:22])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH2:36].O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([N:8]([C@@H:9]([CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[C:21]([NH:36][CH2:35][C:34]([O:33][CH3:32])=[O:37])=[O:22])[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CN
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC(=O)CNC(=O)[C@H](Cc1ccc2ccccc2c1)N(Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred mixture of N-benzyl-N-(tert-butoxycarbonyl)-3-(2-naphthyl)-L-alanine (2.9 g), glycine methyl ester hydrochloride (0.9 g) and 1-hydroxybenzotriazole hydrate (1.06 g) in dichloromethane (50 ml) was added dropwise 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.43 ml) at ice-bath temperature. The resulting mixture was stirred at room temperature for 2 days and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was separated, washed with dilute hydrochloric acid and brine, and dried over magnesium sulfate. Evaporation of the solvent gave (2S)-2-[N-benzyl-N-(tert-butoxycarbonyl)amino]-N-methoxycarbonylmethyl-3-(2-naphthyl)propanamide.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:16][O:17][C:18](=[O:21])[CH2:19][NH2:20].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[CH3:16][O:17][C:18](=[O:21])[CH2:19][N:20]=[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CN
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 205.1 %

Procedure:
A 500 mL, 1-necked rbf equipped with a magnetic stirrer, and a Dean-Stark apparatus with a nitrogen inlet was charged with benzophenone (58.0 g, 0.318 mol), glycine methyl ester hydrochloride (20 g, 0.159 mol) and toluene (100 mL). The resulting white suspension was heated to reflux and DIEA (56 mL, 0.318 mol) was added over three hours using a syringe pump. The resulting pale yellow solution was stirred at reflux for an additional 1 h. Upon reaction completion, the reaction mixture was cooled to rt. The reaction mixture was then washed with water (50 mL). The layers were separated and the organic solution was washed with water (50 mL) and concentrated in vacuo at 35-40° C. to give (Benzhydrylideneamino)-acetic acid methyl ester (82.59 g). In a similar fashion, (benzhydrylideneamino)-acetic acid ethyl ester was prepared.