Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:20][CH2:19][C:18](OS(C)(=O)=O)([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]3)[O:11][C:10]2=[O:32])=[CH:5][CH:4]=1)#[N:2].CS(Cl)(=O)=O.[N:38]1C=CC=CC=1>N.C(O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH:12]([CH2:14][N:15]3[CH2:20][CH2:19][C:18]([NH2:38])([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][CH2:16]3)[O:11][C:10]2=[O:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)CC1(OS(C)(=O)=O)CCN(CC2CN(c3ccc(C#N)cc3)C(=O)O2)CC1
Reactant: c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)CC1(N)CCN(CC2CN(c3ccc(C#N)cc3)C(=O)O2)CC1
Reaction time: 2 h

Procedure:
1 g of ethyl 1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)-4-methanesulfonyloxypiperidine-4-acetate (obtainable from the 4-hydroxy compound (see Example 13) with methanesulfonyl chloride/pyridine) is dissolved in a 2% NH3 solution in 10 ml of a 1:1 mixture of ethanol and THF, and the solution is left to stand at 20° for 2 hours. The solution is concentrated by evaporation and subjected to conventional work-up to give ethyl 1-(3-(4-cyanophenyl)-2-oxo-5-oxazolidinylmethyl)-4-aminopiperidine-4-acetate, FAB 387.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[OH:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:18][CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1
Reactant: OCc1cccnc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2cccnc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, 3-(hydroxymethyl)pyridine and DBU in DME. EI-MS m/e (%): 293 (M+, 54), 276 ([M—NH3]+, 36), 92 (100), 65 (44), 39 (23).
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[O:21]([C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])[CH2:26]2)[CH3:22]>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:26]3[C:25]4[C:29](=[CH:30][CH:31]=[C:23]([O:21][CH3:22])[CH:24]=4)[NH:28][C:27]3=[O:32])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Reactant: COc1ccc2c(c1)CC(=O)N2
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(OC)cc43)c(C)c2C1=O
Yield: 65 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-methoxyl-1,3-dihydro-indol-2-one (prepared according to U.S. Pat. No. 6,114,371) as starting materials to give 5-(2-diethylamino-ethyl)-2-(5-methoxy-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetra hydro-pyrrolo[3,2-c]pyridin-4-one (80 mg, 65.0%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[C:10]=1[NH2:16].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([F:27])[C:25]=1F)[C:21]#[N:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[C:10]=1[NH:16][C:25]1[C:18]([F:17])=[CH:19][C:20]([C:21]#[N:22])=[CH:23][C:24]=1[F:27]
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: Cc1nn(C)c(-c2ccc(F)cc2Cl)c1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1nn(C)c(-c2ccc(F)cc2Cl)c1Nc1c(F)cc(C#N)cc1F
Temperature: 210 °C

Procedure:
A mixture of 5-(2-chloro-4-fluorophenyl)-1,3-dimethyl-1H-pyrazol-4-amin (i.e. the product of Step B) (0.25 g, 1.0 mmol), 3,4,5-trifluorobenzonitrile (0.188 g, 1.2 mmol) and cesium carbonate (0.390 g, 1.2 mmol) in acetonitrile (3 mL) was heated at 210° C. in a Biotage Initiator™ microwave apparatus for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through a pad of silica gel on a sintered glass frit funnel. The filtrate was concentrated under reduced pressure and the resulting material was purified by silica gel chromatography (30% ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (0.065 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:4]([CH2:17][OH:18])[CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])=[C:4]([CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1COS(C)(=O)=O
Reaction time: 3 h

Procedure:
A solution of the product of part (d) (1 g) and triethylamine (0.51 ml) in dichloromethane (10 ml) was cooled to 0° C. Methanesulfonyl chloride (0.29 ml) was then added dropwise and the reaction was allowed to reach room temperature. After stirring for 3 hours the reaction was diluted with dichloromethane, washed with water, NaHCO3 (aq), brine, dried (MgSO4) and concentrated in vacuo to give the subtitle compound as an oil (1.13 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[C:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:9]=2[C:10](=[O:12])[CH:11]=1.[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:13])[C:4]2[CH:5]=[CH:6][CH:7]=[N:8][C:9]=2[C:10](=[O:12])[C:11]=1[C:16]1[N:15]([CH3:14])[CH:19]=[CH:18][CH:17]=1
Reactant: O=C1C(Cl)=CC(=O)c2ncccc21
Reactant: Cn1cccc1
Solvent: CC(=O)O
Product: Cn1cccc1C1=C(Cl)C(=O)c2cccnc2C1=O
Yield: 40 %

Procedure:
A solution of 2.58 mmol of 6-chloroquinoline-5,8-dione with 20.7 mmol of 1-methylpyrrole in 50 ml of acetic acid is stirred at room temperature for 24 hours. The medium is subsequently concentrated under reduced pressure, the residue is extracted with chloroform and the combined organic phases are washed in succession with aqueous sodium carbonate solution and then water before being dried over magnesium sulphate, filtered and concentrated under vacuum. The crude product obtained is purified by chromatography on a silica gel column to give 6-chloro-7-(1-methyl-1H-pyrrol-2-yl)quinoline-5,8-dione with a yield of 40%.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.C(N(CC)CC)C.[P:41]([O-:58])([O:50]CC1C=CC=CC=1)[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CS(C)=O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([O:20][C:19]1[C:18](=[O:28])[N:17]2[C:12]([C:13]([CH3:30])([CH3:29])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:8]([NH:7][CH2:6][C:5]1[CH:31]=[CH:32][C:2]([F:1])=[CH:3][C:4]=1[P:41](=[O:50])([OH:58])[O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:9])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1P(=O)(O)OCc1ccccc1)c(OCc1ccccc1)c2=O
Temperature: 80 °C
Yield: 70.5 %

Procedure:
A solution of N-(4-fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.200 g, 0.35 mmol) in dimethyl sulfoxide (5 ml) was flushed with argon and then treated triethylamine (0.25 ml, 1.8 mmol), tetrakis(triphenylphosphine)palladium(0) (0.10 g) and dibenzyl phosphite (0.25 ml, 1.06 mmol). The reaction mixture was then sealed and heated at 80° C. for 16 h. The reaction mixture was then diluted with ethyl acetate, washed with 0.1 N hydrochloric acid, brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the residue by preparative HPLC (column YMC Pack C-18, 5μ, 20×250 mm, elution gradient acetonitrile-water 0.1% trifluoroacetic acid) gave 0.150 g (60% yield) of the title material as a white solid; mp 142° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.58 (6H, s, 2×CH3), 4.0 (4H, m, 2×CH2), 4.73 (2H, broad s, OCH2), 5.05 (2H, d, J=8.6 Hz, NCH2), 5.28 (2H, s, OCH2), 7.20 (1H, m, aromatic), 7.29-7.34 (6H, m, aromatics), 7.45-7.64 (6H, m, aromatics), 8.24 (1H, broad, NH). MS (ESI+) m/z 608 [M+H+].
Reaction SMILES: [C:1](#[N:6])[CH2:2][CH2:3][CH2:4][CH3:5].C([Sn](=O)CCCC)CCC.C[Si]([N:21]=[N+:22]=[N-:23])(C)C>C1(C)C=CC=CC=1>[CH2:2]([C:1]1[NH:23][N:22]=[N:21][N:6]=1)[CH2:3][CH2:4][CH3:5]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCCC#N
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCCc1nnn[nH]1
Yield: 84.9 %

Procedure:
Following the procedure described in Example 21, valeronitrile (845 mg, 10.16 mmol) was reacted with dibutyltin oxide (254 mg, 1.02 mmol) and trimethylsilyl azide (2.70 ml, 19.8 mmol) in toluene (20 mL) to give 1.088 g (85%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ0.95 (t, J=7 Hz, 3H), 1.43 (sextet, J=7 Hz, 2H), 1.87 (pentet, J=7 Hz, 2H), 3.12 (t, J=7 Hz, 2H). 13C NMR (CDCl3, 75 MHz) 13.42, 22.04, 23.08, 29.62, 156.94. IR (CDCl3) 2900, 1555 cm-1. MS (DCl/NH3) m/e 127 (M+H)+, 144 (M+H+NH3)+. Anal calcd for C5H10N4 : C, 47.60; H, 7.99; N, 44.41. Found: C, 47.14; H, 7.99; N, 43.75.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[N:10][C:11]([CH3:17])=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:20])=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2nc(C)ccc2c1=O
Product: CCOC(=O)c1cnc2nc(C)ccc2c1Cl
Yield: 57 %

Procedure:
The product from Example 7b (1.0 g, 4.30 mmol) was reacted with 12 mL of POCl3 for 4 h following the procedure from Example 7d giving the title compound as a brownish-pink solid (619 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:12]([O-])([O-:14])=[O:13].[K+].OS(O)(=O)=O>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Clc1cccc2ncccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc(Cl)c2cccnc12
Yield: 72.4 %

Procedure:
In a similar fashion using route 7 general procedure 15, 5-chloroquinoline (1 g, 6.13 mmol), potassium nitrate (800 mg, 7.98 mmol) and H2SO4 (3 ml) and gave the title compound (926 mg, 73%). The structure was confirmed by 1H NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[NH:20][CH2:19][CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]2=3)=[CH:5][CH:4]=1.Br[CH:22]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:23]([NH:25][CH3:26])=[O:24].C(N(C(C)C)C(C)C)C.[I-].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]2[N:20]([CH:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:23]([NH:25][CH3:26])=[O:24])[CH2:19][CH2:18][C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]2=3)=[CH:5][CH:4]=1
Reactant: CNC(=O)C(Br)c1ccccc1
Reactant: COc1ccc(CCC2NCCc3ncccc32)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(c1ccccc1)N1CCc2ncccc2C1CCc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 6 h
Yield: 34.7 %

Procedure:
To a solution of 615 mg (2.29 mmol) 5-[2-(4-methoxy-phenyl)-ethyl]-5,6,7,8-tetrahydro-[1,6]naphthyridine in 25 mL acetonitrile, were added 682 mg (2.98 mmol) 2-bromo-N-methyl -2-phenyl-acetamide, 1.2 mL (6.87 mmol) N-ethyldiisopropylamine and 343 mg (2.29 mmol) sodium iodide. The solution was stirred at 60° C. for 6 h. The solvent was removed in vacuo and the residue was taken in ethyl acetate. The mixture was washed once with water and once with a 2M Na2CO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 330 mg (35%) of 2-{5-[2-(4-methoxy-phenyl)-ethyl]-7,8-dihydro-5H-[1,6]naphthyridin-6-yl}-N-methyl-2-phenyl-acetamide (diastereoisomer 1, first eluting diastereoisomer) as yellow foam
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][N:16]=1.CN(C=O)C>C1COCC1>[ClH:14].[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:27][CH2:28][CH2:29][CH2:30][N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)=[C:22]([O:25][CH3:26])[CH:23]=4)[N:18]=[CH:17][N:16]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: O=C1Cc2ccc(F)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc2c(C3C(=O)Nc4cc(F)ccc43)ncnc2cc1OCCCN1CCOCC1
Product: Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
A solution of 6-fluorooxindole (227 mg, 1.5 mmol), (prepared according to Synthesis 1993, 51), in THF (3 ml) was added dropwise under nitrogen to sodium hydride (42 mg, 1.75 mmol, pre-washed with hexane). After stirring the resulting mixture for 20 minutes at ambient temperature, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (169 mg, 0.5 mmol), (prepared as described for the starting material in Example 5), was added as a solid, followed by DMF (3 ml). The mixture was then heated at 75° C. for 1 hour, allowed to cool and the solvent removed by evaporation The mixture was partitioned between water and ether. The aqueous layer was separated and adjusted to pH8 with 2M hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with brine, dried and volatiles removed by evaporation. The residue was triturated with ether and collected by filtration. This solid was dissolved in methylene chloride/methanol, a 5M solution of hydrogen chloride in isopropanol (0.5 ml) was added and the volatiles removed by evaporation. The resulting solid was collected by filtration, washed with ether and dried under vacuum to give 4-(6-fluorooxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline hydrochloride (198 mg, 81%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@@H:13]([C:17]([OH:19])=[O:18])[CH:14]([CH3:16])[CH3:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH3:24]CCCCCC>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@H:13]([CH:14]([CH3:16])[CH3:15])[C:17]([O:19][CH3:24])=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)cc1
Reactant: CCCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](NS(=O)(=O)c1ccc(OC)cc1)C(C)C
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To a solution of N-[4-methoxybenzenesulfonyl]-(D)-valine (8369 g, 29.13 mol) in methanol (30 L) at 5° C. is added thionyl chloride (2176 mL, 29.7 mol) over 2.5 hours. After stirring for 3 hours at 5° C., the reaction is stirred for 36 hours at room temperature. Most of the solvent is evaporated, and the crude product is dissolved in toluene (80 L). The toluene layer is then washed with water (20 L), saturated sodium bicarbonate (20 L), water again (20 L), 2N hydrochloric acid (20 L), brine (20 L), dried (Na2SO4), and the solvent is evaporated. The solid obtained is dissolved in ethyl acetate (8 L) and heptane (16 L) is added to induce crystallization. The precipitated product is collected by filtration to provide methyl 2(R)-[[4-methoxybenzenesulfonyl]amino]-3-methylbutanoate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[OH:12])[CH3:2].[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[O:12][CH3:14])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(F)cc1O
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: CCOC(=O)c1ccc(F)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To a solution of compound 4 (19.9 g, 0.109 mol) in acetonitrile (200 mL) was added cesium carbonate (42.0 g, 0.129 mol). The resulting mixture was stirred at rt for 30 min. followed by addition of methyl iodide (13.5 mL, 0.218 mol). The resulting mixture was stirred at rt O/N and filtered through Celite. The solvent was removed under reduced pressure to give crude product 5 (20.0 g, 93%) and used in the next step without further purification. 1H NMR 400 MHz (CDCl3) δ: 7.81-7.78 (m, 1H), 6.60-6.58 (m, 2H), 4.38 (q, J=7.0 Hz, 2H), 3.82 (s, 3H), 1.39 (t, J=7.0 Hz, 3H); MS (ES) m/z: 199 (M+1)+.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:24])[N:9]2[CH2:15][CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:2]=[CH2:3].[CH2:25]([C:28]1[CH:37]=[C:36]2[C:31](CCC(=O)N2CC=CC2C=CC=CC=2)=[CH:30][C:29]=1O)[CH:26]=[CH2:27].[Br-]>CO.[OH-].[K+]>[CH2:1]([C:4]1[C:13]([O:14][CH2:27][CH:26]=[CH:25][C:28]2[CH:37]=[CH:36][CH:31]=[CH:30][CH:29]=2)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:24])[N:9]2[CH2:15][CH:16]=[CH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1cc2c(cc1O)CCC(=O)N2CC=Cc1ccccc1
Reactant: C=CCc1c(O)ccc2c1CCC(=O)N2CC=Cc1ccccc1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=CCc1c(OCC=Cc2ccccc2)ccc2c1CCC(=O)N2CC=Cc1ccccc1
Yield: 41.4 %

Procedure:
3.19 Grams of the mixture of 5-allyl-1-cinnamyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone and 7-allyl-1-cinnamyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone obtained in Example 13 was dissolved in 100 ml of methanol containing 1 g of potassium hydroxide. Under stirring, 2 g of cinnamy bromide was added thereto at room temperature, then stirred at room temperature for 1 hour, further stirred at 60° C. for 4 hours. After the reaction was finished, the reaction mixture was concentrated to a half volume under reduced pressure, 100 ml of water was added and stirred vigorously, then extracted with 200 ml of ethyl acetate. The extract was washed with water and an aqueous solution saturated with sodium chloride and dried with anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration, the filtrate was concentrated to dryness. The residue was subjected to treatment by means of a silica gel flush column chromatography by using a mixed solvent of ethyl acetate: n-hexane as the eluent. The second eluted portion was collected and concentrated and crystallized from diethyl ether-n-hexane, there was obtained 1.8 g (41.4%) of 5-allyl-1-cinnamyl-6-cinnamyloxy-3,4-dihydro-2(1H)-quinolinone. Colorless granular crystals (recrystallized from diethyl ether-n-hexane). Melting point: 66°-68° C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:20]I.N1C=CN=C1.O[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[C:36]([O:40][CH2:41][C@@H:42]2[CH2:46][CH2:45][CH2:44][N:43]2[CH3:47])[CH:37]=[N:38][CH:39]=1>C(Cl)Cl>[I:20][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]1[CH:35]=[C:36]([O:40][CH2:41][C@@H:42]2[CH2:46][CH2:45][CH2:44][N:43]2[CH3:47])[CH:37]=[N:38][CH:39]=1
Reactant: CN1CCC[C@H]1COc1cncc(CCCCCCO)c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN1CCC[C@H]1COc1cncc(CCCCCCI)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
To a stirred solution of PPh3 (300 mg, 1.14 mmol) in dry CH2Cl2 (7 mL) was added I2 (295 mg, 1.16 mmol) in one time. After 15 min, imidazole (90 mg, 1.32 mmol) was added. The mixture was stirred at room temperature for 20 min, and then 5-(6-hydroxy-1-hexanyl)-3-(1-methyl-2(S)-pyrrolidinylmethoxy)pyridine (150 mg, 0.52 mmol) in CH2Cl2 (1 mL) was added in dropwise. After stirred at room temperature for additional 3 h, the reaction mixture was quenched by addition of brine and diluted with CH2Cl2 (50 mL). The organic phase was separated, washed with aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography with EtOAc-Et3N (1:0 to 25:1) to give an oil (190 mg, 92%). 1H NMR (CDCl3) δ 8.23 (s, 2H), 7.19 (s, 1H), 3.99 (dd, 1H, J=9.3, 5.4 Hz), 3.92 (dd, 1H, J=9.3, 5.4 Hz), 3.25 (t, 2H, J=6.8 Hz), 3.14-3.08 (m, 1H), 2.69-2.61 (m, 1H), 2.48 (s, 3H), 2.46 (t, 2H, J=6.6 Hz), 2.35-2.26 (m, 1H), 2.10-1.95 (m, 1H), 1.90-1.65 (m, 5H); 13C NMR (CDCl3) δ 154.41, 144.55, 137.10, 123.04, 120.82, 92.51, 77.83, 71.15, 63.97, 57.65, 41.65, 32.33, 29.09, 28.48, 22.99, 18.35, 5.97.
Reaction SMILES: Cl[CH:2]([C:7]1[O:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]=1[CH2:12][CH3:13])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=1>>[CH2:12]([C:11]1[C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=2[O:8][C:7]=1[CH:2]([NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=1)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH3:13]
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: CCc1c(C(Cl)CC(C)C)oc2ccccc12
Product: CCc1c(C(CC(C)C)Nc2ccc(C(=O)NCCC(=O)O)cc2)oc2ccccc12
Yield: 32 %

Procedure:
Using 2-(1-chloro-3-methylbutyl)-3-ethyl-1-benzofuran (300 mg) synthesized in Example A31(4) and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (283 mg) synthesized in Example 1(2) and in the same manner as in Example A22(4), the title object compound (162 mg, 32%) was obtained as a pale-brown solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([N+:24]([O-])=O)=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[CH2:11][N:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=3[O-:22])[C:9]=2[CH:23]=1)(=O)[CH3:2]>C(O)(=O)C.[C].[Pd]>[CH3:2][C:1]1[NH:24][C:6]2[CH:7]=[C:8]3[O:13][C:12]([CH3:15])([CH3:14])[CH2:11][N:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N+:17]=4[O-:22])[C:9]3=[CH:23][C:5]=2[N:4]=1
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)(C)CN2c1cccc[n+]1[O-]
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1nc2cc3c(cc2[nH]1)OC(C)(C)CN3c1cccc[n+]1[O-]
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 41.6 %

Procedure:
To a solution of 500 mg 2-(6-acetamido-3,4dihydro-2,2-dimethyl-7-nitro-2H-1,4-benzoxazin-4-yl)pyridine 1-oxide in 10 ml acetic acid, was added 40 mg 10% palladium-carbon to perform catalytic hydrogenation, the reaction mixture was filtered by the use of Celite, and the filtrate was stirred at 100° C. for 30 minutes. After cooling, the solvent was distilled off under reduced pressure, the rest was neutralized by addition of a saturated aqueous solution of sodium bicarbonate and extracted with chloroform, the extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off from the dried solution under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (elutant: 1:1 mixture of chloroform and methanol), and further recrystallized from ethanol-isopropyl ether, thus giving 180 mg of 2-(7,8-dihydro-2,6,6-trimethyl-6H-[1,4]oxazino[2,3-f]benzimidazol-8-yl)pyridine 1-oxide.