Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].CC.C#C.[O:9]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>C1COCC1>[C:1]([CH:19]([OH:20])[C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=1)#[CH:2]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC[Mg]Br
Agent: C#C
Agent: CC
Agent: [Cl-]
Solvent: C1CCOC1
Product: C#CC(O)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
Acetylene is dried through three traps, dry-ice-acetone, concentrated sulfuric acid and calcium chloride, and bubbled at about 5 psi pressure into dry THF (100 ml) for 10 minutes. Ethyl magnesium bromide (commercial, 0.14 mol) is added drop after drop over 2 hours at such a rate that the evolution of ethane is slowly and steady. After the addition, acetylene is bubbled through for 15 minutes. m-Phenoxybenzaldehyde (27.7 g, 0.14 mol) in THF (25 ml) is added to the reaction of 15° to 20° C. The reaction is allowed to raise to room temperature and stirred overnight. The complex is decomposed with saturated ammonium chloride solution. The product is extracted with ether, washed with water and dried (Na2SO4). Evaporation of the solvents, followed by vacuum distillation using Kugelrohn gives the alcohol (21.5 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]([CH2:23][P:24]([O:30]C(C)C)([O:26]C(C)C)=[O:25])=[CH:8][CH:9]([NH:20]C=O)[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])(=[O:3])[CH3:2].C[Si](C)(C)Br.C(O)C1C=CC=CC=1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][C:7]([CH2:23][P:24]([OH:26])([OH:30])=[O:25])=[CH:8][CH:9]([NH2:20])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(=CC(NC=O)C(=O)OCc1ccccc1)CP(=O)(OC(C)C)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: OCc1ccccc1
Product: CC(=O)OCCC(=CC(N)C(=O)OCc1ccccc1)CP(=O)(O)O
Reaction time: 24 h

Procedure:
1.75 g (3.6 mmol) of benzyl 6-acetoxy-2-formylamino-4-diisopropylphosphonomethyl-hex-3-enoate are dissolved in 15 ml of CH2Cl2. Then 1.88 ml (14.5 mmol) of trimethylbromosilane are added to this solution at room temperature. The reaction mixture is allowed to stand for 24 hours at room temperature. After addition of 15 ml of benzyl alcohol the reaction mixture is allowed to stand for 48 hours at room temperature and then concentrated by evaporation at 70° C. under a high vacuum. The residue is dissolved in 15 ml of ethanol and then a mixture of 15 ml of propylene oxide and 15 ml of ethanol is added dropwise to this solution. The suspension so obtained is stirred for 30 minutes in an ice bath and then filtered with suction. The crystals so obtained are recrystallised hot from ethanol/water and dried, giving white crystals of benzyl 6-acetoxy-2-amino-4-phosphonomethyl-hex-3-enoate. Melting point: 204°-205° C. (decomp.).
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[C:16]([CH2:17][CH2:18][C:5]=2[CH:4]=[C:3]([CH:19]=[O:20])[CH:2]=1)=[CH:15][C:14]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=1[CH:8]=3.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH:1]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[CH:4]=[C:3]([CH:19]=[O:20])[CH:2]=1)[CH:15]=[C:14]1[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]1)=[CH:8]3
Reactant: O=Cc1ccc2c(c1)CCc1cc3c(cc1-2)CCCC3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: O=Cc1ccc2c(ccc3cc4ccccc4cc32)c1
Yield: 28.9 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser and N2 inlet line with bubbler added 5,6,8,9,10,11-hexahydrobenz[a]anthracene-3-carbaldehyde (7A, 10.41 g, 39.7 mmol), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (Aldrich, 27.02 g, 0.119 mol) and dry PhCH3 (500 mL). The mixture was refluxed for 2 h until no more starting material remained by TLC, cooled and filtered to give a deep red solution. The solution was applied to a 40×10 cm column of SiO2 and eluted with additional PhCH3 as the solvent. The appropriate fractions were combined and the solvent removed to give 6.01 g of crude material. This was crystallized twice from PhCH3 /hexane (1:4) and dried to give 2.94 g (28.9% yield) of benz[a]anthracene-3-carbaldehyde, mp 144°-145°, (C,H).
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>ClCCl.C(N(CC)CC)C>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[S:1][CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13]
Reactant: C=CC(=O)OC
Reactant: OCc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCSc1ccccc1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a stirring solution of 2-mercaptobenzyl alcohol (1.00 g, 7.10 mmol) in dichloromethane (20 mL) at 0° C. was added methyl acrylate (0.70 mL, 7.70 mmol) followed by triethylamine (50 μL, 0.35 mmol). The mixture was allowed to warm to room temperature and stir for 4 h, at which point the solvent was removed with a rotary evaporator. The residue was subjected to column chromatography on silica gel (0-10% ethyl acetate in dichloromethane), affording 1.40 g (86%) of methyl 3-(2-hydroxymethylphenylthio)propionate. 1H NMR (CDCl3) δ2.63 (t, 2, J=7), 3.18 (t, 2, J=7), 3.68 (s, 3), 4.79 (s, 2), 7.27 (m, 2), 7.43 (m, 2).
Reaction SMILES: C(OC([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11]([O:23][CH3:24])([C:16]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:12]2)=O)(C)(C)C.C(Cl)[Cl:26]>Cl.O1CCOCC1>[ClH:26].[CH3:24][O:23][C:11]1([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12][CH:13]2[NH:8][CH:9]([CH2:15][CH2:14]2)[CH2:10]1
Reactant: ClCCl
Reactant: COC1(c2ncccc2C)CC2CCC(C1)N2C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC1(c2ncccc2C)CC2CCC(C1)N2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-Methoxy-3-(3-methyl-pyridin-2-yl)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.09 g) was dissolved in a solution of hydrogen chloride in dioxane (4 N, 1.5 mL). The mixture was stirred for 1 hour at 50° C., DCM (3 mL) added and stirred for 5 minutes. The solvent was removed by evaporation under vacuum afford the title compound as a white solid. LCMS m/z 233.1 [M+H]+. R.T.=1.72 min (Analytical Method 3).
Reaction SMILES: [Br:1]Br.C([O-])(=O)C.[K+].[C:8]([C:10]1[CH:11]=[C:12]([C:17]2[N:18]=[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[S:20][CH:21]=2)[CH:13]=[CH:14][C:15]=1[F:16])#[N:9].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[Br:1][C:21]1[S:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:18][C:17]=1[C:12]1[CH:13]=[CH:14][C:15]([F:16])=[C:10]([C:8]#[N:9])[CH:11]=1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(C#N)c2)cs1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [K+]
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(-c2ccc(F)c(C#N)c2)c(Br)s1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
At room temperature, 8.10 g (50.6 mmol) of bromine and 4.97 g (50.6 mmol) of potassium acetate are added to 1.40 g (5.07 mmol) of the compound from Example 28A in 80 ml of conc. acetic acid. The mixture is stirred at 100° C. for 48 h, whereby after 24 and 36 h, bromine (in each case 4.05 g, 25.3 mmol) and potassium acetate (in each case 2.49 g, 25.3 mmol) are again added. A 1M aqueous sodium thiosulfate solution is subsequently added, and the reaction solution is extracted with dichloromethane. The combined organic phases are dried over MgSO4, filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 20:1→10:1). 1.55 g (84% of theory) of the title compound are obtained.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:30])/[C:18](=[CH:20]/[C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)/[CH3:19])=[CH:12][CH:11]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.O.[OH-].[Na+]>C1COCC1>[NH2:27][C:24]1[CH:25]=[CH:26][C:21](/[CH:20]=[C:18](\[CH3:19])/[C:17]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([CH:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:7]([CH3:8])[CH3:9])=[CH:11][CH:12]=2)=[O:30])=[CH:22][CH:23]=1
Reactant: C/C(=C\c1ccc([N+](=O)[O-])cc1)C(=O)Nc1ccc(C(C(C)C)n2ccnc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C/C(=C\c1ccc(N)cc1)C(=O)Nc1ccc(C(C(C)C)n2ccnc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54 %

Procedure:
A mixture of (±)-(E)-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]-2-[(4-nitrophenyl)-methylene]propanamide (0.00742 mol) in THF (80 ml) and TiCl3 (30 ml) was stirred at 0° C. for 15 minutes. The mixture was poured into water, ice and NaOH 3N and extracted with CH2Cl2 (2×100 ml). The combined organic layers were dried, filtered and the solvent evaporated. The residue was taken up in CH2Cl2 and (C2H5)2O. The precipitate was filtered off and stirred K2CO3 10% and CH2Cl2, dried, filtered off and evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off, taken up in Na2CO3 10% and CH2Cl2. The organic layer was dried, filtered off and evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.1). The pure fractions were collected and evaporated. The residue was crystallized from (C2H5)2O, yielding 1.5 g (±)-(E)-2-[(4-aminophenyl)methylene]-N-[4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenyl]propanamide (compound 611).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][CH3:23])[CH2:18][CH2:17]2)[N:15]=1)[C:11]#[N:12]>CN(C=O)C>[Cl:7][C:8]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([NH:22][CH3:23])[CH2:18][CH2:17]2)[CH:13]=[C:10]([C:11]2[NH:12][N:3]=[N:2][N:1]=2)[CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CNC1CCN(c2cc(C#N)cc(Cl)n2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC1CCN(c2cc(-c3nnn[nH]3)cc(Cl)n2)CC1
Temperature: 120 °C
Yield: 37.1 %

Procedure:
Sodium azide (131 mg, 2.02 mmol) and NH4Cl (108 mg, 2.02 mmol) were added to a solution of 2-chloro-6-[4-(methylamino)piperidin-1-yl]isonicotinonitrile (Intermediate 63, 507 mg, 2.02 mmol) in anhydrous DMF (3 ml). The mixture was heated at 120° C. under nitrogen gas for 1 h where LCMS showed the expected mass. The mixture was filtered and was purified by semi-preparative HPLC eluting with acetonitrile/water (0.1% TFA) and the title compound was concentrated in vacuo to give a hygroscopic brown solid (220 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([NH:8][C:9](=O)[CH3:10])[CH:7]=1.[N-:16]=[N+:17]=[N-:18].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([N:8]2[C:9]([CH3:10])=[N:18][N:17]=[N:16]2)[CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Nc1cc(Br)ccc1S(C)(=O)=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: Cc1nnnn1-c1cc(Br)ccc1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A solution of N-(5bromo-2-methanesulfonyl-phenyl)-acetamide (350 mg, 1.2 mmol) in acetonitrile (6 mL) at 25° C. was treated with sodium azide (78 mg, 1.2 mmol). The reaction mixture was cooled to 0° C. and then treated with trifluoromethanesulfonic anhydride (0.24 mL, 1.2 mmol). The resulting reaction mixture was allowed to warn to 25° C. where it was stirred overnight, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The resulting residue was diluted with ethyl acetate (50 mL) and water (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 8/1 hexanes/ethyl acetate) afforded 1-(5-bromo-2-methanesulfonyl-phenyl)-5-methyl-1H-tetrazole (254 mg, 67%) as a white solid: mp 174-184° C.; EI-HRMS m/e calcd for C9H9BrN4O2S (M+) 315.9630, found 315.9634.
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]12([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH2:28][CH:23]3[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]3)[CH2:20]1)[CH2:26]2>>[C:19]12([CH2:29][CH2:30][C:31]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[N:4]=[C:3]3[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:32])[CH2:26][CH:25]3[CH2:24][CH:23]([CH2:22][CH:21]([CH2:27]3)[CH2:20]1)[CH2:28]2
Reactant: Nn1c(-c2ccccc2)nc2ccccc2c1=O
Reactant: O=C(Cl)CCC12CC3CC(CC(C3)C1)C2
Product: O=C(CCC12CC3CC(CC(C3)C1)C2)Nn1c(-c2ccccc2)nc2ccccc2c1=O

Procedure:
3-Amino-2-phenyl-4(3H)-quinazolinone and the product of Example 13A were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.93-1.13 (m, 2H), 1.23-1.33 (m, 6H), 1.51-1.65 (m, 6H), 1.85-1.89 (m, 3H), 1.96-2.08 (m, 2H), 7.44-7.55 (m, 3H), 7.58-7.64 (m, 3H), 7.75 (d, J=7.8 Hz, 1H), 7.89-7.94 (m, 1H), 8.18 (dd, J=8.0, 1.2 Hz, 1H), 11.06 (s, 1H) ppm; MS (DCI/NH3) m/z 428 (M+H)+; Elemental Analysis: Calculated for C27H29N3O2: C, 75.85; H, 6.84; N, 9.83. Found: C, 75.75; H, 6.97; N, 9.84.
Reaction SMILES: [Cl-].[Cl-].[CH3:3][SiH:4]([Zr+2:6]([CH:16]1[C:24]2[CH:19]([CH2:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)[CH:7]1[C:15]2[CH:10]([CH2:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)[CH3:5].C([Sn]([F:38])(CCCC)CCCC)CCC>ClCCl>[F-:38].[F-:38].[CH3:5][SiH:4]([Zr+2:6]([CH:7]1[C:15]2[CH:10]([CH2:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)[CH:16]1[C:24]2[CH:19]([CH2:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)[CH3:3]
Reactant: CCCC[Sn](F)(CCCC)CCCC
Agent: C[SiH](C)[Zr+2](C1CCC2CC=CC=C21)C1CCC2CC=CC=C21
Agent: [Cl-]
Solvent: ClCCl
Product: [F-]
Reaction time: 1 h

Procedure:
To a murky green-yellow solution of rac-dimethylsilyl-bis(tetrahydro-indenyl)zirconium dichloride [DMS bis(THI) ZrCl2] (1.00 g, 2.19 mmol, 1.00 eq.) in dichloromethane (15 mL) was added tributyltin fluoride (1.42 g, 4.59 mmol, 2.10 eq.). The reaction lightened immediately. The reaction was stirred for one hour and was then filtered to give a straw-yellow solution and a small amount of brownish solid. The solution was then evaporated in vacuo, leaving a manila-colored, thick suspension. The suspension was washed with pentane (20 mL, then 3×5 mL) to give a white, micro crystalline solid. The solid was dried in vacuo to yield 0.76 g (82%). 1H NMR (CD2Cl2): δ 0.80 (s, 6H, SiMe2, 1.45-1.9 and 2.4-2.7 (br, m, 16H, aliphatic-ring-H), 5.61 (d, 2H, cyclopentadienyl-ring-H), 6.27 (br, s, 2H, cyclopentadienyl-ring-H). 19F NMR (CD2Cl2): δ 19.9 (s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1I.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.CCOCC>[C:16]([O:15][C:13]([N:20]1[CH2:25][CH2:24][N:23]([C:7]2[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=2[Cl:1])[CH2:22][CH2:21]1)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: FC(F)(F)c1ccc(I)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)(C)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2Cl)CC1
Temperature: 100 °C
Yield: 10 %

Procedure:
A mixture of 0.5 g (1.6 mmol) of 3-chloro-4-iodobenzotrifluoride 0.7 g (3.8 mmol), N-Boc-piperazine, 41 mg (0.04 mmol) Tris(dibenzylideneacetone)dipalladium chloroform complex, 0.44 g (4.43 mmol) sodium-t-butoxide and 48 mg (0.16 mmol) tri-o-tolylphosphine in 6 ml dioxane was heated overnight at 100° C. The solution was allowed to cool to room temperature, taken up in ether (30 ml) and washed with brine (25 ml). The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was chromatographed over on silica gel: Eluent: Heptane-AcOEt 0-10% over 15 min to provide the title compound (0.06 g, 10%) as a brown oil, MS (m/e): 365.1 (MH+, 100%).
Reaction SMILES: [C:1]1([NH:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([CH:18]([C:24](OCC)=[O:25])[C:19](OCC)=[O:20])[CH:16]=[CH2:17].[Na]>>[CH2:15]([CH:18]1[C:19](=[O:20])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:24]1=[O:25])[CH:16]=[CH2:17]
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Reactant: c1ccc(NNc2ccccc2)cc1
Agent: [Na]
Product: C=CCC1C(=O)N(c2ccccc2)N(c2ccccc2)C1=O
Yield: 30.2 %

Procedure:
Prepared from 1,2-diphenylhydrazine (5.2 g; 28.0 mmol), diethyl allylmalonate (5.0 g; 25.0 mmol), and sodium (0.58 g; 25.0 mmol) using the procedure of Example 3. The crude product was recrystallized from absolute ethanol to give 2.21 g (30%) tan crystals, mp 135-137° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][O:19][CH3:20].[OH-].[K+].[CH:23]1[CH:28]=[CH:27][C:26]([S:29]([O:32][CH2:33][CH2:34][C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[O:41][CH2:40][CH2:39][C:38]3=[O:45])(=[O:31])=[O:30])=[CH:25][CH:24]=1.P([O-])([O-])(O)=O.[K+].[K+].CN1CCCCC1=O.C1(S(O)(=O)=O)C=CC=CC=1>CC(C)=O.C(OCCCC)(=O)C.C1(C)C=CC=CC=1.O1CCCC1.O>[C:26]1([S:29]([OH:32])(=[O:31])=[O:30])[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1.[Br:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][CH:8]2[CH2:9][CH2:10][N:11]([CH2:33][CH2:34][C:35]3[CH:36]=[C:37]4[C:42](=[CH:43][CH:44]=3)[O:41][CH2:40][CH2:39][C:38]4=[O:45])[CH2:12][CH2:13]2)=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][O:19][CH3:20]
Reactant: COCCOc1cc(CC2CCNCC2)ccc1Br
Reactant: O=C1CCOc2ccc(CCOS(=O)(=O)c3ccccc3)cc21
Agent: CN1CCCCC1=O
Agent: Cl
Agent: O=P([O-])([O-])O
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CCCCOC(C)=O
Product: COCCOc1cc(CC2CCN(CCc3ccc4c(c3)C(=O)CCO4)CC2)ccc1Br
Temperature: 115 °C
Reaction time: 6 h
Yield: 88.7 %

Procedure:
4-[4-Bromo-3-(2-methoxyethoxy)benzyl]piperidine hydrochloride (2.0 g, 5.48 mmol) was added to an aqueous potassium hydroxide solution (prepared from potassium hydroxide [0.43 g, 6.58 mmol] and water [10 ml]), followed by extraction with toluene (10 ml×2). All the organic layers were combined, and the solvent was distilled off under reduced pressure. 6-(2-p-Benzenesulfonyloxyethyl)-2,3-dihydro-4H-chromen-4-one (1.91 g, 5.76 mmol), dipotassium hydrogen phosphate (2.87 g, 16.5 mmol), N-methyl-2-piperidone (0.6 ml), and toluene (20 ml) were added to the concentrated residue, and the mixture was stirred at 110 to 120° C. for 6 hours. After cooling to 40 to 50° C., water (20 ml), tetrahydrofuran (10 ml), and toluene (10 ml) were added thereto. The organic layer was washed with water (10 ml). The solvent was distilled off under reduced pressure to obtain a concentrated residue. The obtained concentrated residue was dissolved in acetone (6.0 ml) without further purification, and a solution of benzenesulfonic acid (0.93 g, 5.76 mmol) in acetone (4.0 ml) was added dropwise thereto at 50 to 60° C. The mixture was stirred at 50 to 60° C. for 30 minutes. Then, n-butyl acetate (20.0 ml) was added dropwise thereto, and the mixture was further stirred for 1 hour. After cooling to room temperature, n-butyl acetate (10 ml) was added dropwise thereto, and the mixture was stirred for 3.5 hours in an ice bath. The precipitate was collected by filtration, washed with cold acetone (4.0 ml×2), and dried under reduced pressure to obtain the title compound (3.21 g, 89%).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[O:12][C@@:11]([CH3:19])([CH:14]([O:17][CH3:18])[O:15][CH3:16])[C@H:10]3[O:20][C@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[CH:24][CH:23]=1>>[N+:1]([C:4]1[C:13]2[O:12][C@@:11]([CH3:19])([CH:14]([O:17][CH3:18])[O:15][CH3:16])[C@@H:10]([OH:20])[C@H:9]([N:28]([C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[CH2:29][C:30]3[N:31]=[N:32][N:33]([CH3:35])[N:34]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@]1(C)Oc2c(cccc2[N+](=O)[O-])[C@@H]2O[C@@H]21
Reactant: Cn1nnc(CNc2ccc(Cl)cc2)n1
Product: COC(OC)[C@]1(C)Oc2c(cccc2[N+](=O)[O-])[C@@H](N(Cc2nnn(C)n2)c2ccc(Cl)cc2)[C@@H]1O
Yield: 14.8 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using (2R,3S,4S)-8-nitro-2-methyl-2-dimethoxymethyl-3,4-epoxy-3,4-dihydro-2H-1-benzopyran (751 mg, 2.67 mmol) and N-(4-chlorophenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine (597 mg, 2.67 mmol). The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (200 mg, yield: 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:36])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH2:27][O:28]C5CCCCO5)=[CH:24][C:19]=4[O:18][C:17]3=[O:35])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:37][CH3:38].C(O)(C(F)(F)F)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:36])[CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH2:27][OH:28])=[CH:24][C:19]=4[O:18][C:17]3=[O:35])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(OCCOC5CCCCO5)ccc43)CC2)ccc1Cl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCN(C(=O)Cn3c(=O)oc4cc(OCCO)ccc43)CC2)ccc1Cl

Procedure:
To a solution of 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-3H-benzooxazol-2-one (55) (50 mg) in THF was added 1 mL of TFA and the resultant solution was stirred for 1 hour. The reaction mixture was purified by HPLC to provide 3-{2-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-2-oxo-ethyl}-6-(2-hydroxy-ethoxy)-3H-benzooxazol-2-one (56): LCMS observed for (M+H)+: 462.5.
Reaction SMILES: C(O[C:6]([N:8]1[C:16]2[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]3[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=3[C:11]=2[CH:10]([CH2:24][Cl:25])[CH2:9]1)=[O:7])(C)(C)C.[C:26]([NH:31][C:32]1[CH:33]=[C:34](/[CH:38]=[CH:39]/C(O)=O)[N:35]([CH3:37])[CH:36]=1)(=[O:30])[CH2:27][CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl>CC(N(C)C)=O>[C:26]([NH:31][C:32]1[CH:33]=[C:34](/[CH:38]=[CH:39]/[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([N+:17]([O-:19])=[O:18])[C:13]4[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=4[C:11]=3[CH:10]([CH2:24][Cl:25])[CH2:9]2)=[O:7])[N:35]([CH3:37])[CH:36]=1)(=[O:30])[CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC(CCl)c2c1cc([N+](=O)[O-])c1ccccc21
Reactant: CCCC(=O)Nc1cc(/C=C/C(=O)O)n(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: CCCC(=O)Nc1cc(/C=C/C(=O)N2CC(CCl)c3c2cc([N+](=O)[O-])c2ccccc32)n(C)c1
Yield: 61.6 %

Procedure:
Deprotection of 13 (300 mg, 0.83 mmol) as in Example C above and reaction with (E)-4-butyrylamino-1-methyl-2-pyrroleacrylic acid (197 mg, 0.83 mmol), EDCI.HCl (397 mg, 2.07 mmol) and DMA gave a product that was chromatographed on silica gel. Elution with CH2Cl2 /EtOAc (1:1), followed by crystallisation from CH2Cl2 /iPr2O gave 14i (246 mg, 62%), mp 216° C. 1H NMR [(CD3)2SO] δ 9.79 (S, 1 H, NH), 9.22 (s, 1 H, H-4), 8.32 (d, J=8.7 Hz, 1 H, H-6), 8.17 (d, J=8.1 Hz, 1 H, H-9), 7.76-7.65 (m, 2 H, H-7,8), 7.64 (d, J=14.9 Hz, 1 H, COCH=CH), 7.25 (d, J=1.6 Hz, 1 H, H-5'), 6.81 (d, J=1.6 Hz, 1 H, H-3'), 6.71 (d, J=15.0 Hz, 1 H, COCH=CH), 4.65-4.50 (m, 3 H, H-1,2), 4.08 (d, J=3.6 Hz, 2 H, CH2Cl), 3.71 (s, 3 H, NCH3), 2.22 (t, J=7.3 Hz, 2 H, COCH2), 1.60 (sextet, J=7.4 Hz, 2 H, CH2CH3), 0.90 (t, J=7.4 Hz, 3 H, CH2CH3). Anal. Calculated for C25H25ClN4O4 : C, 62.4;H, 5.2; N, 11.7. Found: C, 62.6; H, 5.2; N, 11.5%.