Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[C:19]2[CH2:18][CH2:17][N:16]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[OH:30])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH2:15][C:14]=2[CH:13]=[CH:12]1.C(N(CC)CC)C>ClCCl>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([S:20]([N:16]2[CH2:17][CH2:18][C:19]3[O:11][CH:12]=[CH:13][C:14]=3[CH2:15]2)(=[O:22])=[O:21])=[CH:28][CH:27]=1)(=[O:30])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=S(=O)(c1ccc(C(O)c2ccccc2)cc1)N1CCc2occc2C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1ccc(S(=O)(=O)N2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.16 ml (1.2 mmol) of oxalyl chloride in 30 ml of dichloromethane, 0.17 ml (2.5 mmol) of dimethyl sulfoxide was added dropwise at -78° C., followed by stirring for 5 minutes. To the solution, a solution of 0.303 g (0.820 mmol) of 4-(6,7-dihydro-4H-furo[3,2-c]pyridin-5-ylsulfonyl)phenylphenylmethanol in 10 ml of dichloromethane was added at -78° C., followed by stirring for 15 minutes. To this mixture, 0.69 ml (4.9 mmol) of triethylamine was added; the mixture was allowed to warm to room temperature. After the reaction mixture was washed with water, the water layer was re-extracted with diethyl ether. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) and washed with diethyl ether-hexane to yield the desired product.
Reaction SMILES: Cl.CN.[CH3:4][C:5]1[CH:29]=[C:28]([C:30]([N:32]2[CH2:38][CH2:37][CH2:36][CH2:35][C:34]3[CH:39]=[CH:40][CH:41]=[CH:42][C:33]2=3)=[O:31])[CH:27]=[CH:26][C:6]=1[CH2:7][NH:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[F:21])[N:14]([CH2:22][CH:23]=O)[C:13](=[O:25])[CH2:12]1)=[O:10].[CH:43]([N:46](C(C)C)CC)(C)C.C([BH3-])#N.[Na+]>CO.C1(C)C=CC=CC=1.C(O)(=O)C>[CH3:4][C:5]1[CH:29]=[C:28]([C:30]([N:32]2[CH2:38][CH2:37][CH2:36][CH2:35][C:34]3[CH:39]=[CH:40][CH:41]=[CH:42][C:33]2=3)=[O:31])[CH:27]=[CH:26][C:6]=1[CH2:7][NH:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[F:21])[N:14]([CH2:22][CH2:23][NH:46][CH3:43])[C:13](=[O:25])[CH2:12]1)=[O:10]
Reactant: Cc1cc(C(=O)N2CCCCc3ccccc32)ccc1CNC(=O)N1CC(=O)N(CC=O)c2cccc(F)c21
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CNCCN1C(=O)CN(C(=O)NCc2ccc(C(=O)N3CCCCc4ccccc43)cc2C)c2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Methylamine hydrochloride (68 mg, 1.0 mmol) was added to a solution of 8-fluoro-3-oxo-4-(2-oxoethyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid 2-methyl-4-(2,3,4,5-tetrahydrobenzo[b]azepine-1-carbonyl)benzylamide from Example 10 (53 mg, 0.1 mmol) in methanol (4.0 ml) then the mixture was cooled in an ice/water bath. Diisopropylethylamine (185 μl, 1.0 mmol) was added and the mixture was stirred for 20 mins. Acetic acid (0.40 ml) and sodium cyanoborohydride (6.3 mg, 0.1 mmol) were added and the mixture was allowed to warm to room temperature. The mixture was stirred for 3 h, diluted with toluene and evaporated in vacuo. The residue was partitioned between EtOAc and saturated sodium hydrogen carbonate solution and separated. The organic phase was washed with brine, dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant dichloromethane:methanol:triethylamine 95:4:1) to give a white solid; yield 22 mg, 41%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5](O)=[O:6].C[CH2:15][N:16](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([NH:16][CH3:15])=[O:6]
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1cc(F)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a roundbottom flask charged with 3-fluoro-5-nitrobenzoic acid (1.00 g, 5.40 mmol) was added DMF (6.75 mL), followed by Hunig's base (1.13 mL, 6.48 mmol), and HATU (2.157 g, 5.67 mmol). The flask was sealed with a septum and methanamine (2.0 M in THF) (13.5 mL, 27.0 mmol) was added via syringe. The resulting orange reaction mixture was stirred overnight at RT. After 16 h, the reaction mixture was diluted with CH2Cl2 (70 mL) and the resulting mixture was transferred to a separatory funnel and extracted with sat. aq. NaHCO3 (3×30 mL). The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. Purification with medium pressure silica gel chromatography using 70:30 Hex:EtOAc as the eluent afforded 3-fluoro-N-methyl-5-nitrobenzamide (961 mg, 4.85 mmol, 90%) as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[C@H:15]([CH3:14])[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1Cc2ccccc2CN1
Product: C[C@@H]1Cc2ccccc2CN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[CH:27]=[C:26]([Cl:28])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[N:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[CH:27]=[C:26]([Cl:28])[S:25][C:15]=3[N:16]=2)=[CH:24][CH:23]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Clc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: O=[N+]([O-])c1cccc(CNc2nc(-c3ccncc3)nc3sc(Cl)cc23)c1

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3-nitrobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:15]1[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[C:4]([CH:14]=1)[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:10])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccc1CNC(=O)OC(C)(C)C
Solvent: CC#N
Product: COc1ccc(Br)cc1CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
6.04 g of t-butyl N-(2-methoxybenzyl)carbamate was dissolved in 50 ml of acetonitrile, and 4.6 g of N-bromosuccinimide was added. After stirring for 3 hours at room temperature, the solvent was evaporated. The residue was dissolved in ethyl acetate, and successively washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was washed with mixture solution of methyl t-butylmethyl ether and hexane, to give 6.97 g of t-butyl N-(5-bromo-2-methoxybenzyl)carbamate.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[C:21](/[CH3:27])=[CH:22]/[C:23](OC)=[O:24])=[CH:17][CH:16]=1.[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18](/[C:21](/[CH3:27])=[CH:22]/[CH2:23][OH:24])=[CH:19][CH:20]=1
Reactant: COC(=O)/C=C(\C)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: C/C(=C\CO)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1

Procedure:
According to the method described for Reference Example 23, methyl (E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-butenoate was subjected to reduction with diisobutylaluminum hydride to give (E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-buten-1-ol. Recrystallization from ethyl acetate--hexane gave colorless prisms, m.p.126°-127° C.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1)([CH3:6])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[CH3:6][C:2]([N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1)([CH3:1])[C:3]([O:5][CH2:17][CH3:18])=[O:4]
Reactant: CC(C)(C(=O)O)n1cccn1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)(C)n1cccn1

Procedure:
2-Methyl-2-(1H-pyrazol-1-yl)propanoic acid 16 was treated with sulfuric acid in ethanol to give 17.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH:17]([CH3:19])[NH:16][C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]1[S:34][C:33]2[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:32]=2[CH:31]=1>CN(C=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH:17]([CH3:19])[N:16]([CH2:29][C:30]4[S:34][C:33]5[CH:35]=[C:36]([Cl:39])[CH:37]=[CH:38][C:32]=5[CH:31]=4)[C@@H:15]([CH3:20])[C:14]3=[O:21])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: CC1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1
Reactant: Clc1ccc2cc(CBr)sc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccc3c(N)ncnc3c2)C(=O)[C@H](C)N1Cc1cc2ccc(Cl)cc2s1
Reaction time: 8 h
Yield: 10.3 %

Procedure:
(3 S,5RS)-1-(4-Amino-quinazolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one (260 mg, 0.56 mmol), EXAMPLE 88, is dissolved in 5 mL of DMF. Potassium carbonate (193.4 mg, 1.4 mmol) is added followed by the addition of 2-bromomethyl-6-chloro-benzo[b]thiophene (218 mg, 0.84 mmol), EXAMPLE 5. Reaction is left to stir overnight. The crude mixture is purified by reverse phase HPLC (10-70% ACN/H2O) to afford the product (27 mg, 6%) as a clear wax with a melting point of 130-131° C. C24H24ClN5OS MS m/z: 466, 468.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21]OS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCOCC1>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(CCN3CCCCC3)cc2c1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of 5-(2-methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (450 mg, 1.16 mmol, Example 56, Step D) in dioxane (10 mL) was added piperidine (1.1 mL, 11.6 mmol). The mixture was stirred at 80° C. for 2 hours and then partitioned between methylene chloride and water. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a solid residue, which was recrystallized from ethyl acetate and diethyl ether to give 275 mg (63%) of the desired product as a white solid: mp 159-161° C.; MS(APCI+): m/z 377.1 (MH+); Anal. Calcd for C24H28N2O2.1.04H2O: C, 72.93; H, 7.67; N, 7.09. Found: C, 72.54; H, 7.31; N, 7.04.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:27][CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH2:24][OH:25])=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:38].C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:14]3[NH:38][C:17]([C:19]4[S:20][C:21]([CH2:24][OH:25])=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:27][CH:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: [NH4+]
Reactant: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ncc(CO)s1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(CO)s3)[nH]2)cc1)C1CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
A mixture of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(hydroxymethyl)-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (0.50 g), ammonium acetate (0.39 g) and acetic acid (4 mL) was stirred at 100° C. for 1 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (0.45 g, yield 95%) was obtained as a colorless amorphous solid from a fraction eluted with tetrahydrofuran-hexane (5:1, volume ratio). MS: 473 (MH+).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5].Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[OH:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][S:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5]
Reactant: CC(C)(CCS)NC(=O)OCc1ccccc1
Reactant: OCCOCCOCCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(CCSCCOCCOCCO)NC(=O)OCc1ccccc1
Temperature: 70 °C
Yield: 32.6 %

Procedure:
To a solution of benzyl 4-mercapto-2-methylbutan-2-ylcarbamate (6.70 g, 26.4 mmol) in N,N-dimethylformamide (100 ml) was added 2-(2-(2-chloroethoxy)ethoxy)ethanol (4.0 ml, 28 mmol) and cesium carbonate (8.06 g, 24.7 mmol). The suspension was heated to 70° C. for 17 hours, cooled to room temperature, and concentrated in vacuo. The residue was purified by flash chromatography (20% to 100% ethyl acetate in hexanes) to afford the title compound as a clear oil (3.32 g, 8.61 mmol, 33%). 1H NMR (CDCl3, 400 MHz) δ 1.31 (s, 6H), 1.95-1.99 (m, 2H), 2.51-2.56 (m, 3H), 2.71 (t, J=5.6 Hz, 2H), 3.55-3.79 (m, 10H), 4.85 (s, 1H), 5.05 (s, 2H), 7.2-7.4 (m, 5H); LRMS (ESI/APCI) m/z 386 [M+H]+, 408 [M+Na]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[C:16](Cl)([N:18]=[C:19]=[O:20])=[O:17]>>[O:17]=[C:16]1[NH:18][C:19](=[O:20])[C:7]2[CH2:6][O:5][CH2:4][CH:3]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[C:2]=2[O:1]1
Reactant: O=C=NC(=O)Cl
Reactant: N#Cc1ccc(C2COCCC2=O)cc1
Product: N#Cc1ccc(C2COCc3c2oc(=O)[nH]c3=O)cc1

Procedure:
4-(4-oxotetrahydro-2H-pyran-3-yl)benzonitrile (Intermediate AA(2)) was reacted as described in Intermediate X(3) with carbonisocyanatidic chloride to give 4-(2,4-dioxo-2,3,4,5,7,8-hexahydropyrano[3,4-e][1,3]oxazin-8-yl)benzonitrile (Intermediate AA(3)). LC-MS (M+H)+=271.1. 1H NMR (400 MHz, CDCl3) δ ppm 7.57-7.78 (m, 2H) 7.41-7.51 (m, 2H) 4.61-4.75 (m, 1H) 4.50 (dd, J=15.49, 2.14 Hz, 1H) 4.04-4.20 (m, 2H) 3.78 (br. s., 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1Cl>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[CH:5]1[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]1=[O:9]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)C(c2ccc([N+](=O)[O-])cc2Cl)C(=O)C1
Temperature: 75 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
A solution containing 42.05 g (0.300 mol) of 5,5-dimethyl-1,3-cyclohexanedione and 100 g (0.718 g-atom) of anhydrous potassium carbonate in 300 ml of dry dimethylformamide was heated to 75° C. under nitrogen and stirred for one hour. The 3, 4-dichloronitrobenzene, 57.60 g (0.300 mol) was dissolved in 100 ml dimethylformamide and added dropwise to the reaction mixture while stirring and maintaining the temperature of the reaction mixture at 75° C. A deep red-colored solution formed, and when the addition was complete the reaction temperature was raised to 100° C. and held at this temperature for 3 hours. Most of the dimethylformamide was removed by vacuum distillation. The residue was poured into 21 of ice water and extracted three times with 500 ml of benzene. Nitrogen was then passed through the aqueous solution while warming to remove dissolved benzene. The aqueous solution was cooled in an ice bath and acidified to give a tacky precipitate, which, upon warming solidified and was collected by suction filtration. The product was recrystallized from acetone to give 31.7 g (36%) of 2-(2'-Chloro-4'-nitrophenyl)-5,5-dimethyl-1, 3-cyclohexanedione as a white powder, m.p. 250°-253° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([O:16][CH3:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>>[CH2:1]([O:8][C:9]1[CH:15]=[C:14]2[C:12](=[C:11]([O:16][CH3:17])[CH:10]=1)[NH:13][CH:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21]2=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1cc(OCc2ccccc2)ccc1N
Product: CCOC(=O)c1c[nH]c2c(OC)cc(OCc3ccccc3)cc2c1=O
Yield: 79.3 %

Procedure:
4-Benzyloxy-2-methoxyaniline (2.9 g) and diethyl ethoxymethylenemalonate (2.7 g) were reacted in the same manner as in Experimental Example 1 to obtain 6-benzyloxy-3-ethoxycarbonyl-8-methoxy-4(1H)-quinolone (3.5 g). The compound (2.0 g) was subjected to hydrolysis and decarboxylation in the same manner as in Experimental Example 8 to obtain 6-benzyloxy-8-methoxy-4(1H)-quinolone (compound 26, 1.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]#[N:10])=[C:7]([CH3:11])[C:6]([C:12](=[O:21])[CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]2=[O:20])=[CH:5][CH:4]=1.[CH3:22][C:23]1[C:31]2[CH2:30][O:29][C:28](=[O:32])[C:27]=2[CH:26]=[CH:25][C:24]=1[C@@H:33]1[CH2:35][O:34]1>CCO>[OH:34][C@H:33]([C:24]1[CH:25]=[CH:26][C:27]2[C:28](=[O:32])[O:29][CH2:30][C:31]=2[C:23]=1[CH3:22])[CH2:35][N:17]1[CH2:18][CH2:19][N:14]([CH2:13][C:12]([C:6]2[C:7]([CH3:11])=[C:8]([C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]#[N:10])=[O:21])[C:15](=[O:20])[CH2:16]1
Reactant: COc1ccc(C(=O)CN2CCNCC2=O)c(C)c1C#N
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Solvent: CCO
Product: COc1ccc(C(=O)CN2CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC2=O)c(C)c1C#N
Temperature: 140 °C

Procedure:
A mixture of 6-Methoxy-2-methyl-3-[(2-oxopiperazin-1-yl)acetyl]benzonitrile (40 mg, 0.14 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (40 mg, 0.21 mmol) in EtOH (2 mL) was heated to 140° C. for 1 hour. The reaction mixture was concentrated to dryness, and dissolved in MeOH, filtered and shot into Mass-directed HPLC for separation to give the title product. LC-MS (IE, m/z): 478 [M+1]+.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CS(C)=O.CO.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:8]([O:9][CH3:4])=[O:10])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(C(=O)OC)cc2)C(=O)O1
Reaction time: 12 h
Yield: 164.7 %

Procedure:
To a 16 mm culture tube with a Teflon-coated stirring bar, a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (87 mg, 0.209 mmol) in dry DMSO (4 mL) and dry methanol (1.5 mL), triethylamine (60 μL, 2 equiv), Pd(OAc)2 (10 mg, 0.2 equiv) and 1,3-bis(diphenylphosphino)propane (35 mg, 0.4 equiv) were added. The tube was sealed with a septum and Parafilm tape. The reaction mixture was purged with CO gas through a long needle for 1 min. A balloon filled with CO gas was attached to maintain a CO atmosphere. The reaction mixture was submerged in an oil bath preheated to 85° C. and stirred vigorously. After 12 h, LC-MS showed the reaction was complete. The mixture was filtered through a thin pad of Celite. The Celite was washed with EtOAc (35 mL). The filtrate was washed with 3% aq HCl (10 mL), water (2×8 mL) and brine (2×7 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 12-g silica gel cartridge eluted with a 10-60% EtOAc in hexanes gradient to afford methyl 4-((S)-1-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)benzoate (68.4 mg, 83%). LC-MS Method 1, tR=1.79 min, m/z=398. 1H NMR (CDCl3) 7.79 (d, 2H), 7.26 (m, 2H), 7.04 (t, 2H), 6.94 (d, 2H), 5.69 (m, m, 2H), 5.07 (dd, 2H), 3.89 (s, 3H), 2.94 (m, 1H), 2.58 (m, 2H), 1.54 (d, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[O:12][CH:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[O:12][CH:13]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCC(Oc1cccc(OCc2ccccc2)c1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC(Oc1cccc(OCc2ccccc2)c1)c1ccccc1
Yield: 59.3 %

Procedure:
A mixture of ethyl (RS)-4-(3-benzyloxy-phenoxy)-4-phenylbutanoate (1 g), aqueous potassium hydroxide solution (5 mL;10% w/v) and methanol (50 mL) is stirred at reflux for 30 minutes. The reaction mixture is then evaporated to dryness and the residue is partitioned between ethyl acetate (100 mL) and dilute hydrochloric acid (50 mL; 1 N). The organic layer is washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a brown oil, which slowly crystallises. Recrystallisation from cyclohexane gives (RS)-4-(3-benzyloxyphenoxy)-4-phenylbutanoic acid (0.55 g), in the form of a beige solid, m.p. 100-104° C. [Elemental analysis:- C,76.3;H,6.21%; Calculated:- C,76.2;H,6.12%].
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6](O)=[O:7].C1(P([N:27]=[N+:28]=[N-:29])(C2C=CC=CC=2)=O)C=CC=CC=1.N#N>C1COCC1>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([N:27]=[N+:28]=[N-:29])=[O:7]
Reactant: Cc1ccccc1C=CC(=O)O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: N#N
Solvent: C1CCOC1
Product: Cc1ccccc1C=CC(=O)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 66.4 %

Procedure:
To a stirred solution of o-methylcinnamic acid (Intermediate-1) (30 g, 185 mmol) in dry THF (100 mL) was added TEA (51.5 mL, 37 mmol) and diphenylphosphoryl azide (DPPA) (56 g, 204 mmol) slowly under N2 atmosphere and the mixture was stirred at room temperature for 2-3 h. It was quenched with cold water, extracted with EtOAc (3×200 mL), washed with water (2×200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product. It was recrystallized from MeOH to obtain the desired compound (23 g, 66%).