Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]([F:21])([F:20])[C:3]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1)([F:5])[F:4].I[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CS(C)=O.Cl>O.[Cu]>[O:13]([C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[O:6][C:3]([F:5])([F:4])[C:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([F:21])[F:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Ic1ccccc1
Reactant: FC(F)(I)C(F)(F)Oc1cccc(Oc2ccccc2)c1
Agent: [Cu]
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(Oc1cccc(Oc2ccccc2)c1)C(F)(F)c1ccccc1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
The 1-iodo-2-(m-phenoxyphenoxy)-1,1,2,2-tetrafluoroethane (2.06 g, 5 mmoles) is then mixed with iodobenzene (1.12 g, 5.5 mmoles), activated copper (0.7 g, 11 mmoles) and 20 ml dimethyl sulfoxide (DMSO) and heated to 120° C. The mixture is heated and stirred at 120° C. for 16 hours and then cooled, diluted with 100 ml water, acidified with HCl and the product is extracted with ethyl acetate (2×40 ml). A colorless oil, 1-(m-phenoxyphenoxy)-2-phenyl-1,1,2,2-tetrafluoroethane, is recovered in a yield of 69 percent based on 1-iodo-2-(m-phenoxyphenoxy)-1,1,2,2-tetrafluoroethane (1.3 g). The identity of the product is confirmed by mass spectrometry. The 1-(m-phenoxyphenoxy)-2-phenyl-1,1,2,2-tetrafluoroethane has a pour point of -23° C.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[CH:10][N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:27])[CH:20]=[C:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:16]2=[N:15][C:14]=1[CH3:28].C1COCC1.[Li]C(C)(C)C.[F:39]NS(C1C=CC=CC=1)(=O)=O>CCOC(C)=O>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[C:10]([F:39])[N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:27])[CH:20]=[C:21]([CH:22]([CH2:23][CH3:24])[CH2:25][CH3:26])[C:16]2=[N:15][C:14]=1[CH3:28]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3Cl)c(C)nc12
Reactant: O=S(=O)(NF)c1ccccc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4nc(F)nn4C)cc3Cl)c(C)nc12
Temperature: 25 °C
Yield: 22.2 %

Procedure:
To a −78° C. solution of 3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.40 g, 0.72 mmol) and THF (8 mL) is added 1.7 M tert-BuLi (0.47 mL, 0.80 mmol). After 30 minutes the solution is transferred via a cannula into a solution of N-fluorobenzenesulfonamide (0.40 g, 1.25 mmol) and THF. After 30 minutes the solution warmed to ambient temperature. The solution is diluted with EtOAc (40 mL), washed with water (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated. The solution is purified by ISCO (20%-30% EtOAc gradient) furnish the title compound (0.068 g, 0.16 mmol, 16%). 1H NMR (CDCl3) δ 0.87 (t, J=7.5 Hz, 6H), 1.71-1.93 (m, 4H), 2.53 (s, 3H), 2.54 (s, 3H), 3.26-3.36 (m, 1H), 4.08 (d J=2.7 Hz, 3H), 6.75 (s, 1H), 7.97 (s, 1H). LC/MS (m/z): calcd. for C20H22ClFN6S (M+H)+: 433.2; found: 433.2.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[NH2:19][C:20](N)=S>CS(C)=O>[C:6]1([C:4]2[C:3]3[C:2](=[CH:15][CH:14]=[C:13]([N+:16]([O-:18])=[O:17])[CH:12]=3)[N:1]=[CH:20][N:19]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1
Reactant: NC(N)=S
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc2ncnc(-c3ccccc3)c2c1
Temperature: 140 °C
Yield: 39.6 %

Procedure:
To a 20 mL microwave reaction vial with a micro magnetic stir bar, were added 0.297 g of 2-amino-5-nitrobenzophenone, 0.186 g of thiourea and 3.0 mL of DMSO. Then the vial was sealed and heated with microwave at 140° C. for 20 hours. Two layers of liquid formed with brown liquid on the top and a dark brown gel like layer at the bottom. The reaction mixture was extracted with EtOAc and purified on column chromatography using hexane/EtOAc (5:1 to 4:1) as eluent, and 0.122 g of 4-phenyl-6-nitro-quinazoline was obtained, in a yield of 39.7%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:15])[N:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:10][CH2:9]2)[CH:7]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1ccc(=O)n(C2CCC(=O)CC2)c1
Product: Cc1ccc(=O)n(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 5-methyl-1-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [Li+].[BH4-].[OH:3][C@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:6]([C:16](OC)=[O:17])[CH2:5]1>C1COCC1>[OH:3][C@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C@@H:6]([CH2:16][OH:17])[CH2:5]1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1CO
Temperature: 70 °C
Yield: 57.9 %

Procedure:
LiBH4 (6.46 mmol as a solution in THF) was added to an ice cooled solution of (1,1-dimethylethyl) 2-methyl(2R,4R)-4-hydroxy-1,2-pyrrolidinedicarboxylate (0.36 g, 1.47 mmol) in THF. The reaction was heated at 70° C. for 48 hours. The reaction was quenched with isopropanol and then saturated NaHCO3. The mixture was diluted with water and extracted twice with ethyl acetate. The organic layers were washed with 1N NaOH, dried over MgSO4 and concentrated to give 0.185 g of the title compound. 1H NMR 400 MHz, DMSO-D6) δ ppm 1.4 (m, 9 H), 1.8 (m, 1 H), 2.0 (m, 1 H), 3.0 (m, 1 H), 3.4 (m, 1 H), 3.5 (m, 2 H), 3.7 (m, 1 H), 4.1 (m, 1 H), 4.9 (dd, J=5.3, 5.3 Hz, 1 H), 5.1 (m, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:11][N:10]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C2C=CC=CC=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+].ClC1C2C(=CC=CC=2)[N:34]=[CH:33][N:32]=1.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]1[CH2:9][N:10]([C:12]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:34]=[CH:33][N:32]=2)[CH2:11]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Clc1ncnc2ccccc12
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=C[O-]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1CN(c2ncnc3ccccc23)C1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
The (1-benzhydrylazetidin-3-yl)-carbamic acid tert-butyl ester (500 mg, 1.48 mmol), Pd/C (10% w/w, 157 mg, 0.07 mmol), and ammonium formate (932 mg, 14.8 mmol) were weighed into a 25 RBF equipped with a condenser, degassed 3 times, and suspended/dissolved in 6 mL of methanol. The mixture was heated to 60 C for 4 hours to completion and was allowed to cool to room temperature. The mixture was filtered through a plug of celite washed with ethanol, and the filtrate was concentrated in vacuo. The residue was re-dissolved in 30 mL of DCM, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude intermediate. The intermediate and 4-chloroquinazoline (268 mg, 1.63 mmol) were dissolved in 6 mL of NMP, then treated with diisopropylethyl amine (515 μL, 2.96 mmol). The solution was heated to 80° C. overnight to completion affording an orange mixture. After cooling to room temperature, the solution was diluted with ethyl acetate and poured into diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 9:1 MeOH:EtAc) to afford the pure (1-quinazolin-4-yl-azetidin-3-yl)-carbamic acid tert-butyl ester as a tan solid (390 mg, 88%). 1H NMR (DMSO-d6, 400 MHz) δ 8.47 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.78 (t, J=7.6 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.67 (m, 1H), 7.48 (t, J=7.6 Hz, 1H), 4.73 (m, 2H), 4.50 (m, 1H), 4.30 (m, 2H), 1.41 (s, 9H). LCMS (APCI+) m/z 301 [M+H]+; Rt=2.26 min.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[CH:31]2>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[NH:33][CH:32]=[CH:31]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCCOc1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Fc1ccc2c(C3CCN(CCCOc4ccc5[nH]ccc5c4)CC3)noc2c1
Yield: 123.4 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.6 g, 11.8 mmol), K2CO3 (1.6 g, 11.6 mmol), KI (200 mg), 5-(3-chloropropoxy)indole (2.2 g, 10.5 mmol) and Ch3CN (100 ml) was stirred at reflux under N2 for 18 hours. The cooled reaction was poured into H2O and the aqueous mixture was extracted with EtOAc. The EtOAc extract was washed 2 times with H2O, 2 times with brine and after drying with MgSO4 the solvent was removed in vacuo to yield 5.1 g of a dark oil. The oil was purified by preparative HPLC (Water's Associates Prep LC/System 500, using 2 silica gel columns and 4% MeOH-CH2Cl2 as eluent) to afford 2.65 g (65%) of a beige solid. Recrystallization from ethanol gave 2.2 g (54%) of a beige powder, m.p.=118°-121° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:11]=1[NH2:12])=[O:6].N#N.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29]Cl>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10][C:11]=1[NH:12][CH2:29][C:23]1[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=1[Cl:21])=[O:6]
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-c2ccccc2)cc1NCc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in oil, 180 mg, 4,72 mmol) was added to an ice-cold solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (1000 mg, 4,29 mmol) in 25 ml of dimethylformamide in an atmosphere of N2. After 5 min, 2,4-dichloro-1-chloromethyl-benzene (755 mg, 3,86 mmol) was added to the solution and then the reaction mixture was stirred for 30 min at 0° C. and 30 min at room temperature. The mixture was partitioned between ether (20 mL) and water (20 mL) and the organic layer was separated. The aqueous phase was washed twice with ether (2×20 mL) and the combined ether layer was dried (MgSO4) and concentrated. The residue obtained was then purified by precipitation. The crude product was taken in 25 ml of ethyl acetate, a yellow precipitate came out which was filtered to obtain 3-(2,4-Dichloro-benzylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester, 835 mg (55%). 1H-NMR (DMSO, 400 MHz): 7.67 ppm (m, 2H, Haro); 7.44-7.35 ppm (m, 6H, Haro); 7.26 ppm (s, 1H, Haro); 4.63 ppm (d, 2H, N—CH2); 3.75 ppm (s, 3H, O—CH3)
Reaction SMILES: C(=O)(O)[O-].[Na+].[OH:6][CH2:7][C:8]1[S:12][C:11]([SH:13])=[N:10][N:9]=1.CC(O[CH2:18][C:19]1[CH2:28][S:27][C@@H:22]2[C@H:23]([NH2:26])[C:24](=[O:25])[N:21]2[C:20]=1[C:29]([OH:31])=[O:30])=O.Cl>O>[NH2:26][CH:23]1[C:24](=[O:25])[N:21]2[C:20]([C:29]([OH:31])=[O:30])=[C:19]([CH2:18][S:13][C:11]3[S:12][C:8]([CH2:7][OH:6])=[N:9][N:10]=3)[CH2:28][S:27][C@H:22]12
Reactant: OCc1nnc(S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc(CO)s3)CS[C@H]12
Yield: 66.7 %

Procedure:
Sodium bicarbonate (0.84 g.) and 5-hydroxymethyl-1,3,4-thiadiazole-2-thiol (0.74 g.) were dissolved in water (40 ml.), and the solution was warmed on a water bath. To the solution was added all at once 7-aminocephalosporanic acid (1.36 g.) at 45° C. The mixture was stirred at 70°-73° C for an hour. After the reaction, the reaction mixture was cooled to 0°-5° C and adjusted to pH 5.0 with 10% hydrochloric acid. The precipitating crystals were collected by filtration to give 7-amino-3-(5-hydroxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (1.20 g.). m.p. 194°-199° C (dec.)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.[Cl:14][CH:15](Cl)[C:16](=O)[CH3:17]>C1(C)C=CC=CC=1>[Cl:14][CH2:15][C:16]1[N:13]=[C:11]([CH:10]=[CH:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:12][CH:17]=1
Reactant: COc1ccc(C=CC(N)=O)cc1
Reactant: CC(=O)C(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(C=Cc2nc(CCl)co2)cc1
Yield: 84.1 %

Procedure:
MS: M=178.2 (API+). 1H-NMR(400 MHz, D6-DMSO): δ=3.79(s, 1H, OCH3), 6.46(d, 1H, 2-H), 6.97(d, 2H, 3′-/5′-H), 6.99(br, 1H, NH), 7.36(d, 1H, 3-H), 7.44(br, 1H, NH), 7.50(d, 2H, 2′-/6′-H). 48.0 g (271 mmol) 3-(4-Methoxyphenyl)-acrylamide, 44.4 g (350 mmol) dichloro acetone and 400 ml toluene were kept at reflux temperature for 24 h with continuous removal of water by applying a Dean-Stark trap. After removal of solvents in vacuo, the residue was intensively shaken with 600 ml water, the precipitate isolated by filtration, washed with water and heptane. Drying at 40° C. in vacuo gave 56.9 g (84%) 4-Chloromethyl-2-[2-(4-methoxyphenyl)-vinyl]-oxazole.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[Si:28]([O:35][CH:36]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42](B(O)O)[CH:43]=2)[CH2:38][CH2:37]1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:42]2[CH:43]=[C:44]3[C:39](=[CH:40][CH:41]=2)[CH2:38][CH2:37][CH:36]3[O:35][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:29])[CH3:30])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2ccc(B(O)O)cc21
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nc(C)n(-c2ccc3c(c2)C(O[Si](C)(C)C(C)(C)C)CC3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (3.0 g), (3-{[tert-butyl(dimethyl)silyl]oxy}-2,3-dihydro-1H-inden-5-yl)boronic acid (3.07 g), triethylamine (6.0 mL), pyridine (3.0 mL) and molecular sieves 4 A (6.0 g) in methylene chloride (50 mL) was added copper(II) acetate (3.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (3.7 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([NH2:23])=[O:22])[CH2:17][CH2:16]1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([NH:23][C:12]2[CH:11]=[CH:10][C:5]([CH2:6][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:4][CH:3]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCN(C(N)=O)CC3)c2cc1OC
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(CN5CCCCC5)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 92 %

Procedure:
In 10 ml of toluene was suspended 593.5 mg (2.16 mmol) of 6,7-dimethoxy-4-piperazinylquinazoline obtained by the method described in South African Patent No. 67 06512 (1968), and 362.6 ml (2.16 mmol) of 4-(chloromethyl)phenyl isocyanate was added thereto, followed by stirring at room temperature for 3 hours. After the reaction mixture was filtered, the obtained crystals were washed with diisopropyl ether and dried under reduced pressure to give 916.8 mg (2.08 mmol, 96%) of N-[4-(chloromethyl)phenyl]-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide. In 10 ml of dimethylformamide was dissolved 422.9 mg (0.96 mmol) of the obtained N-l4-(chloromethyl)phenyl]-4-(6,7-dimethoxy-4-quinazolinyl)-1-piperazinecarboxamide, and 0.28 ml (2.83 mmol) of piperidine was added thereto, followed by stirring at room temperature for 7 hours. Then, the reaction mixture was poured into water and the precipitated crystals were collected by filtration, followed by purification by silica gel column chromatography to give 430.9 mg (0.88 mmol) of the desired compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=O)[NH:9][C:8]=1[C:19]([O:21][CH3:22])=[O:20].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[C:8]([C:19]([O:21][CH3:22])=[O:20])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCCCc1c(C(=O)OC)[nH]c(=O)n1-c1ccccc1
Product: COCCCCc1c(C(=O)OC)nc(Cl)n1-c1ccccc1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
Methyl 5-(4-methoxybutyl)-2-oxo-1-phenyl-2,3-dihydro-1H-imidazole-4-carboxylate (1.50 g) was dissolved in phosphorus oxychloride (18 ml) and the mixture was stirred at 100° C. for 10 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (454 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1([C@@H](N)C)C=CC=CC=1.[CH:19]([C:21]([F:24])([F:23])[F:22])=[O:20].Cl>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[F:22][C:21]([F:24])([F:23])[C@H:19]([OH:20])[CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O=CC(F)(F)F
Reactant: CC(=O)c1ccccc1
Agent: C[C@H](N)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(C[C@@H](O)C(F)(F)F)c1ccccc1
Temperature: 20 °C
Reaction time: 1.33 h
Yield: 91.3 %

Procedure:
At first, 5.5 g (40 mmol) of zinc chloride were added to a toluene solution (4 liters) containing 504 g (4.2 mol) of acetophenone (1a) as a ketone and 485 g (4.0 mol) of (S)-1-phenylethylamine ((S)-2a) as an optically active primary amine, followed by heating under reflux for 20 hr and by removing water (formed as a by-product) with a Dean-Stark tube during the reaction, in order to conduct the reaction. Then, 564 g (4.0 mol) of fluoral.ethylhemiacetal (4a) were dropped to the reaction liquid by spending 80 minutes at a temperature of not higher than 5° C., followed by stirring at 20° C. for 24 hr, thereby conducting the reaction. Then, 4-liter of 1N HCl were added to the reaction liquid, followed by stirring at room temperature for 1 hr, then washing with 2-liter of water, then concentration, and then vacuum drying, thereby obtaining 797 g of (R)-4,4,4-trifluoro-3-hydroxy-1-phenyl-1-butanone ((R)-5aa, purity: 71%). Its optical purity was found to be 59% ee by a chiral HPLC (DAICEL AS, n-hexane:i-propanol=95:5, 254 nm).
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1.C1C[O:16]CC1>>[Br:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([OH:16])[CH:3]=2)[CH:8]=1
Reactant: Nc1ccc2cc(Br)ccc2c1
Reactant: C1CCOC1
Product: Oc1ccc2cc(Br)ccc2c1

Procedure:
According to a known method described in a reference [L. C. Anderson et al., Journal of the American Chemical Society (J. Am. Chem. Soc.), vol. 65, p.241, 1943], a solution of 2-amino-6-bromonaphthalene (223 mg) obtained from commercially available 2-bromo-6-hydroxynaphthalene (TCI) in anhydrous THF (10 ml) was added with 30% potassium hydride (191 mg, Ald) under ice cooling and stirred for 1 hour. The reaction mixture was cooled to −78° C. under argon atmosphere, added dropwise with-1.7 M solution of t-butyllithium in pentane (1.88 ml) over 10 minutes and stirred for 30 minutes. The reaction mixture was added dropwise with (iPrO)3B (0.92 ml) over 10 minutes, stirred for 30 minutes, then warmed to room temperature and further stirred for 3 hours. The reaction mixture was added with water (3 ml) and 0.5 M aqueous sulfuric acid (4 ml) and extracted with diethyl ether (100 ml×3). The organic layer was washed with saturated brine and dried, and then the solvent was evaporated under reduced pressure to obtain crude 6-amino-2-naphthaleneboronic acid (402 mg). According to the procedure described in the synthesis method of Compound of Example 001 (Preparation Method 4, Step d-1) with the modifications that the reaction was carried out for 13 hours, and the purification was performed by flash column chromatography (hexane:ethyl acetate=4:1), a solution of the above compound in ethanol (0.5 ml), Intermediate 3 (119 mg), 2 M aqueous sodium carbonate (1.5 ml) and (Ph3P)4Pd (61 mg) were reacted and treated to obtain the title compound (Compound No. 011, 129 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH2:13])=[O:12])[CH:2]=1.C([N:21](C(OC(C)(C)C)=O)[C@H:22]([C:27]([NH:29][C@@H:30]([C:41]([OH:43])=[O:42])[CH2:31][C:32]1[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=1)=[O:28])[CH2:23][CH2:24][CH2:25][NH2:26])(OC(C)(C)C)=O.[CH3:51][S:52]([OH:55])(=[O:54])=[O:53].C1(CC[C@@H](NC(=O)[C@@H](N)CCCN)C(=O)NC2C=NC3C(C=2)=CC=CC=3)C=CC=CC=1>>[S:52]([OH:55])(=[O:54])(=[O:53])[CH3:51].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([NH2:13])=[O:12])[CH:2]=1.[NH2:21][C@H:22]([C:27]([NH:29][C@@H:30]([C:41]([OH:43])=[O:42])[CH2:31][C:32]1[CH:33]=[C:34]([F:40])[C:35]([F:39])=[C:36]([F:38])[CH:37]=1)=[O:28])[CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H](CCCN)C(=O)N[C@H](Cc1cc(F)c(F)c(F)c1)C(=O)O
Agent: CS(=O)(=O)O
Agent: NC(=O)c1cnc2ccccc2c1
Agent: NCCC[C@H](N)C(=O)N[C@H](CCc1ccccc1)C(=O)Nc1cnc2ccccc2c1
Product: NCCC[C@H](N)C(=O)N[C@H](Cc1cc(F)c(F)c(F)c1)C(=O)O

Procedure:
NaNd-bis-Boc-L-ornithyl-(3,4,5-trifluoro)-D-Phenylalanine Quinoline-3-amide was converted into mono-mesylate salt of the tile product according to the procedure described for compound 3 to give the title product (0.15 g) as off white solid.