Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][NH:22][C:21](=[O:25])[N:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Cl.Cl[CH2:32][C:33]1[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][N:22]([CH2:32][C:33]4[CH:34]=[N:35][N:36]([CH3:38])[CH:37]=4)[C:21](=[O:25])[N:20]=3)=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:26]([F:27])([F:29])[F:28]
Reactant: N#Cc1cc(COc2cc[nH]c(=O)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Cn1cc(CCl)cn1
Agent: Cl
Product: Cn1cc(Cn2ccc(OCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)c(C#N)c3)nc2=O)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-{[(2-oxo-1,2-dihydro-4-pyrimidinyl)oxy]methyl}benzonitrile and 4-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride. LC-MS (ESI): m/z 514 [M+H]+; 3.97 min (ret time).
Reaction SMILES: C(N)C1C=CC=CC=1.[NH2:9][C:10]1[S:11][CH:12]=[C:13]([CH3:15])[N:14]=1.[CH3:16][C:17]1[N:18]=[C:19]([N:22]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=3)[C:23]2=[O:37])[S:20][CH:21]=1>>[CH3:15][C:13]1[N:14]=[C:10]([NH:9][C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([CH2:27][N:24]3[CH2:25][CH2:26][N:22]([C:19]4[S:20][CH:21]=[C:17]([CH3:16])[N:18]=4)[C:23]3=[O:37])=[CH:29][CH:30]=2)[S:11][CH:12]=1
Reactant: Cc1csc(N)n1
Reactant: Cc1csc(N2CCN(Cc3ccc(C(=O)O)cc3)C2=O)n1
Solvent: NCc1ccccc1
Product: Cc1csc(NC(=O)c2ccc(CN3CCN(c4nc(C)cs4)C3=O)cc2)n1
Yield: 41 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with 2-amino-4-methylthiazole to react with 4-((3-(4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)methyl)benzoic acid, the title compound was obtained as a white powder in 41% yield: mp 197-198° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 11.54 (br s, 1H), 7.87 (d, J=6.0 Hz, 2H), 7.37 (d, J=6.0 Hz, 2H), 6.52 (s, 1H), 6.43 (s, 1H), 4.53 (s, 2H), 4.11-4.06 (m, 2H), 3.46-3.41 (m, 2H), 2.30 (s, 3H), 1.97 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 164.8, 158.9, 158.7, 156.0, 147.3, 146.9, 141.2, 132.1, 128.5, 128.3, 108.6, 106.9, 47.7, 42.3, 42.0, 17.3, 16.6; MS (ES+) m/z 414.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][N:5]2[C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1.[I:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[NH:22][C:21](=[O:28])[C:20]2=[CH:29]OC>CN(C)C=O>[I:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[NH:22][C:21](=[O:28])[C:20]2=[CH:29][NH:15][C:12]1[CH:13]=[CH:14][C:9]([N:5]2[CH2:4][CH:3]3[CH2:8][CH:6]2[CH2:7][N:2]3[CH3:1])=[CH:10][CH:11]=1
Reactant: COC=C1C(=O)NC(=O)c2ccc(I)cc21
Reactant: CN1CC2CC1CN2c1ccc(N)cc1
Solvent: CN(C)C=O
Product: CN1CC2CC1CN2c1ccc(NC=C2C(=O)NC(=O)c3ccc(I)cc32)cc1
Yield: 39.6 %

Procedure:
A solution of 4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-phenylamine (0.1 g, 0.49 mmol), 6-Iodo-4-methoxymethylene-4H-isoquinoline-1,3-dione (0.2 g, 0.6 mmol), and N,N-dimethylformamide (0.2 mL) is heated at 90° C. overnight. After the solvent is removed, the residue is treated with ethyl ether and filtered to give crude product as light brown solid. It is purified by HPLC to yield 97 mg (39% yield) of 6-iodo-4-{[4-(5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-phenylamino]-methylene}-4H-isoquinoline-1,3-dione as bright orange solid. mp 210-211° C.
Reaction SMILES: [C:1]([N:9]1[CH2:17][C@@H:16]([O:18][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:15][C@H:10]1[C:11]([O:13]C)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[OH-].[Li+]>C1COCC1>[C:1]([N:9]1[CH2:17][C@@H:16]([O:18][S:19]([C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=2)(=[O:20])=[O:21])[CH2:15][C@H:10]1[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](C(=O)O)N(C(=O)c3ccccc3)C2)cc1
Reaction time: 3 h

Procedure:
A solution of (cis)-1-benzoyl-4-tosyloxy-L-proline, methyl ester (from the previous step) in THF.H2O (25 ml-5 ml) was stirred under argon and treated with lithium hydroxide mono hydrate (672 mg, 16 mmole). The reaction was stirred for 3 hours, concentrated in vacuo, acidified to pH 1.5 with HCl, and extracted with ethyl acetate. The organic extracts were dried, filtered and concentrated in vacuo to a white solid which was recrystallized twice from ethyl acetate to afford the title compound.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3](OC)=[O:4].[H][H]>O1CCCC1>[CH3:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4]
Reactant: COC(=O)[C@@H](C)Cc1ccccc1
Reactant: [H][H]
Solvent: C1CCOC1
Product: C[C@H](CO)Cc1ccccc1

Procedure:
Methyl (S)-2-methyl-3-phenylpropionate (5 mmol, 78.4% ee), a ruthenium complex 1 (0.01 mmol), and tetrahydrofuran (2 mL) were charged into a 100-mL autoclave equipped with a stirrer. Then, the mixture was subjected to hydrogenation at a hydrogen pressure of 5 MPa at 80° C. for 16 hours. The reaction liquid was analyzed by gas chromatography. As a result, (S)-2-methyl-3-phenylpropanol was obtained at a conversion rate of 99.0% and a selectivity of 98.6%. The obtained alcohol had an optical purity of 77.9% ee.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[CH:18]=1)[CH2:5][NH:6]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:6][CH2:5][C:4]1[CH:14]=[CH:15][C:16]([C:17]2[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[CH:18]=2)=[C:2]([F:1])[CH:3]=1
Reactant: Cn1cc(-c2ccc(CNC(=O)OC(C)(C)C)cc2F)ccc1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2ccc(CN)cc2F)ccc1=O

Procedure:
The crude tert-butyl 3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzylcarbamate 21-6 (10 mg, obtained in Step 3) was stirred with trifluoroacetic acid (TFA, 0.3 mL) in dichloromethane (1 mL) overnight. Evaporation under reduced pressure (with the addition of some toluene to aid evaporation of the residual TFA) followed by lyophilization gave the crude 5-(4-(aminomethyl)-2-fluorophenyl)-1-methylpyridin-2(1H)-one 21-7.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][CH:25]=[N:26]4)=[CH:21][CH:20]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Brc1ccc2cccnc2c1
Reactant: Fc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Fc1ccc2c(c1)c1c(n2-c2ccc3cccnc3c2)C2CCN(CC2)C1

Procedure:
The reaction of 9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (230 mg, 1.0 mmol; Example 161) and 7-bromoquinoline (312 mg, 1.5 mmol; Ark Pharm) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.95-2.22 (m, 4H) 2.96-3.03 (m, 1H) 3.09-3.29 (m, 4H) 4.32 (s, 2H) 6.86 (td, J=9, 2 Hz, 1H) 7.07-7.17 (m, 2H) 7.58-7.67 (m, 2H) 7.97 (d, J=2 Hz, 1H) 8.18 (d, J=9 Hz, 1H) 8.50 (d, J=8 Hz, 1H) 8.95 (dd, J=4, 2 Hz, 1H); MS (DCI/NH3) m/z 358 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1.Br[CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([O:22][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:24])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(Cl)c1
Reaction time: 0.05 h
Yield: 95.7 %

Procedure:
40% Methanolic Triton B (0.053 mL, 0.12 mM) was added to a solution of the 9-[(3-chlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (33.2 mg, 0.12 mM) in 2 mL DMF at room temperature. After 3 minutes, t-butyl bromoacetate (53.8 mg, 0.27 mM) was added and the resultant mixture stirred at room temperature for 20 h. The mixture was diluted with ethyl acetate, washed four times with H2O, once with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 42.1 mg (95%) of the {9-[(3-chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, tert-butyl ester as a white solid. 1H NMR (DMSO-d6) δ7.6 (d, 1H, J=8 Hz), 7.5-6.8 (m, 10H), 6.55 (d, 1H, J=8 Hz), 5.7 (s, 2H), 4.8 (s, 2H), and 1.45 (s, 9H). IR (CDCl3, cm−1) 3450, 3400, 1744, 1676, 1591, 1457, 1369, and 1150. MS (FD) m/e 464, 466.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([N+:12]([O-])=O)[C:4]=1[CH3:15].[N-:16]=[N+:17]=[N-].[Na+]>CS(C)=O>[N:12]([C:5]1[C:4]([CH3:15])=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10])=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1C
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc([N+](=O)[O-])c(N=[N+]=[N-])c1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1-methoxy-2-methyl-3,4-dinitrobenzene (3.4 g, 16 mmol) in 60 mL of DMSO was added NaN3 (2.1 g, 32 mmol) at one portion and the reaction was stirred for 72 hours at room temperature. Then the reaction was poured into 500 mL of ice water, and then was extracted with DCM (100 mL×3). The combined organic layers were washed with water, dried and concentrated to about 100 mL of solvent. Then 100 mL of toluene was added and the residual DCM was removed under reduced pressure, the toluene solution of 2-azido-4-methoxy-3-methyl-1-nitrobenzene was used directly the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[F:12][C:13]1[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[CH:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: OCc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCc2cccc(F)c2)c(Br)c1
Yield: 92 %

Procedure:
The mixture of 2-bromo-1-fluoro-4-nitrobenzene (5 g), (3-fluorophenyl)methanol (2.86 g) and K2CO3 (9.4 g) in Acetone (50 mL) was refluxed for 4 h. The solid was filtered and the solvent was removed. The obtained yellow solid was recrystallized from EtOAc/Hexane to provide brown solid (6.8 g). Yield: 92%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1>CC#N>[CH2:24]([O:11][C:3]1[CH:4]=[C:5]([CH2:8][C:9]#[N:10])[CH:6]=[CH:7][C:2]=1[Cl:1])[C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: N#CCc1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCc1ccc(Cl)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
To a solution of (4-chloro-3-hydroxy-phenyl)acetonitrile (6.2 g, 37 mmol) in CH3CN (80 mL) was added K2CO3 (10 g, 74 mmol) and BnBr (7.6 g, 44 mmol). The mixture was stirred at room temperature overnight. The solids were filtered off and the filtrate was evaporated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 50:1) to give 2-(3-(benzyloxy)-4-chlorophenyl)-acetonitrile (5.6 g, 60%). 1H NMR (400 MHz, CDCl3) δ 7.48-7.32 (m, 6H), 6.94 (d, J=2 Hz, 2H), 6.86 (dd, J=2.0, 8.4 Hz, 1H), 5.18 (s, 2H), 3.71 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[CH:14]=1>>[Cl:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: Clc1cccc(CBr)c1
Product: O=[N+]([O-])c1cc(OCc2cccc(Cl)c2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 1-chloro-3-bromomethyl benzene using the conditions described in Example 237C to provide 4-(3-chloro-benzyloxy)-1-chloro-2-nitro-benzene which was treated sequentially using the procedures from Examples 237D and 237E to provide the title compound.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[OH-].[K+].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=1>CO.O>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=[C:3]2[C:4](=[O:10])[CH:5]3[CH2:8][CH2:9][N:2]2[CH2:7][CH2:6]3)[CH:14]=1
Reactant: O=C1CN2CCC1CC2
Reactant: O=Cc1cccnc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1C(=Cc2cccnc2)N2CCC1CC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Quinuclidin-3-one hydrochloride (4.6 g, 28.3 mmol) and powdered anhydrous potassium hydroxide (2.1 g, 37.2 mmol) were dissolved in methanol (25 ml) and stirred for 15 mins. Pyridine-3-carboxaldehyde (3.2 g, 29.5 mmol) was then added in one portion and the mixture was stirred for an additional 20 hrs. The reaction mixture was then diluted with 40 ml water and cooled to 0° C. yielding 2-((3-pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one as a yellow precipitate, which was collected, washed with distilled water and dried under vacuum (5.16 g, 81.4%). 2-((3-Pyridyl)methylene)-1-azabicyclo[2.2.2]octan-3-one (1.0 g, 4.7 mmol) was combined with 50 ml methanol and 0.2 g palladium on charcoal (5% w/w) in a hydrogenation vessel. Hydrogenation (50 psig) was carried out for 4 hrs., after which time the slurry was carefully filtered through a pad of Celite filter aid. Evaporation of solvent gave 2-((3-pyridyl)methyl)-1-azabicyclo[2.2.2]octan-3-one as white semisolid, which dissolved in ethanol give a white crystalline solid upon cooling (0.82 g 88%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][N:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[OH:20][C@H:21]1[CH2:25][CH2:24][N:23](O)[CH2:22]1>CCO>[N+:1]([C:4]1[N:5]=[CH:6][C:7]([N:23]2[CH2:24][CH2:25][CH:21]([OH:20])[CH2:22]2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O[C@H]1CCN(O)C1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(N2CCC(O)C2)cn1
Temperature: 85 °C
Yield: 47.3 %

Procedure:
A solution of 2-nitro-5-bromopyridine (320 mg, 2.02 mmol) in EtOH (6 mL) was treated with diisopropylethylamine (710 μL, 520 mg, 4.04 mmol) and (S)-3-hydroxypyrrolidinol (350 mg, 4.04 mmol). The mixture was heated in a sealed tube at 85° C. for 21.5 h then cooled and partitioned between CH2Cl2 and water. The organic layer was dried over Na2SO4, filtered and concentrated and the residue was chromatographed on a silica gel column with a 40-100% EtOAc in hexanes to 0-30% THF in EtOAc gradient to afford the product, as a yellow solid (200 mg, 47% yield). HRMS m/z calcd for C9H11N3O3 [M+H]+: 210.0873; Found: 210.0873.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]=[C:9]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[S:8][N:7]=2)=[CH:2]1.Cl.CCCCCC>C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]=[C:9]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[S:8][N:7]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccoc3)ns2)CC1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1cc(-c2nsc(N3CCNCC3)n2)co1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 4-[3-(3-furyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxylate (3.30 g, 9.81 mmol) was dissolved in ethyl acetate (50 ml), and a solution of 4 N hydrogen chloride in ethyl acetate (25 ml) was added thereto, followed by stirring at room temperature for 18 hours. Hexane (120 ml) was poured to the reaction mixture, and a solid was separated by filtration. The obtained solid was dissolved in an aqueous saturated sodium hydrogen carbonate solution, followed by stirring at room temperature for 2 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with a mixed solution of ethyl acetate/tetrahydrofuran (1:1). The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue, and 1.30 g (56.0%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:13]2[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:25]=1[NH2:26])=[CH:17][CH:16]=[CH:15][CH:14]=2>C(O)C>[C:1]1([C:7]2[CH:9]=[N:26][C:25]3[C:12](=[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:18]4=[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]4=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1c(N)c2ccccc2c2ccccc12
Reactant: O=CC(=O)c1ccccc1
Solvent: CCO
Product: c1ccc(-c2cnc3c4ccccc4c4ccccc4c3n2)cc1
Yield: 92 %

Procedure:
First, 2.16 g of phenylglyoxal and 3.36 g of 9,10-diaminophenanthrene were dissolved in a solvent of 100 mL of dehydrated ethanol under a nitrogen atmosphere. The solution was refluxed for 7 hours to be reacted. The white power precipitated through the reaction was filtered. The residue was washed with ethanol and then ether to give a dibenzo[f,h]quinoxaline derivative, Hdbq-P, which was the target substance (yield: 92%). Synthesis scheme of Step 1 is shown in (a-1) below.
Reaction SMILES: [CH3:1][P:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:20]=[CH:19][N:18]=[C:17]3[C:13]=2[N:14]=[CH:15][N:16]3[CH:21]=[CH2:22])=[CH:7][CH:6]=1)([CH3:4])=[O:3].[Cl:23][C:24]1[C:29](I)=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:23][C:24]1[C:29](/[CH:22]=[CH:21]/[N:16]2[CH:15]=[N:14][C:13]3[C:17]2=[N:18][CH:19]=[N:20][C:12]=3[NH:11][C:8]2[CH:9]=[CH:10][C:5]([P:2]([CH3:1])([CH3:4])=[O:3])=[CH:6][CH:7]=2)=[C:28]([CH3:31])[CH:27]=[CH:26][N:25]=1
Reactant: Cc1ccnc(Cl)c1I
Reactant: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)ncnc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: Cc1ccnc(Cl)c1/C=C/n1cnc2c(Nc3ccc(P(C)(C)=O)cc3)ncnc21
Temperature: 120 °C

Procedure:
N-(4-(Dimethylphosphoryl)phenyl)-9-vinyl-9H-purin-6-amine (Example 3, 1 mmol), 2-chloro-3-iodo-4-methylpyridine compound (1.3 mmol), disopropylethyl amine (3 mmol), palladium acetate (0.05 mmol), tri-o-tolylphosphine (0.1 mmol) in DMF (5 mL) was thoroughly purged with argon for 10-15 min. and sealed and heated for 120° C. for 18 h. until the starting materials disappeared. The reaction mix. was passed through celite, and washed with dichloromethane containing 30% methanol. The filtrate was concentrated in vacuo. The residue was purified by Biotage-S column chromatography using 1/1 hexane ethyl acetate, ethyl acetate and 1-10% methanol containing ethyl acetate: MS [M+H]+ 439.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH:7]=[CH2:8])(=O)[CH:2]=[CH2:3].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14]CCC>>[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:9])[CH:7]=[CH2:8]
Reactant: C=CC(=O)OC(=O)C=C
Reactant: CCCCCCCCO
Product: C=CC(=O)OCCCCCCCC
Reaction time: 4 h
Yield: 81.3 %

Procedure:
According to another embodiment of the invention, the olefin acid anhydrides are reacted with alcohols to give high yields of the acrylate esters at room temperature. In particular, acrylic anhydride has been reacted with a series of alcohols ranging from C-1 to C-18 to give high yields of the acrylate esters at room temperature. The synthesis of acrylate esters by the reaction of alcohols with acrylic anhydride were found to proceed essentially to completion at room temperature to yield only the desired acrylate esters. The following mechanism is proposed for this reaction: ##STR3## No significant competing reactions were observed, such as the Michael addition reactions that often accompany the production of acrylate esters under reflux conditions. The following are representative of this embodiment: (1) the reaction of n-butyl alcohol with acrylic anhydride was completed in 3.5 hours and yielded 91.2% of n-butyl acrylate; (2) the reaction of n-octyl alcohol with acrylic anhydride was completed in 4 hours to obtain an 81.3% yield of n-octyl acrylate; and (3) the reaction of cis-12,13-epoxy-cis-9-octadecenol with acrylic anhydride was completed in 55 hours to give an 88.4% yield of cis-12, 13-epoxy-cis-9-octadecenyl acrylate.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:9][C:10]([CH3:15])=[CH:11][C:12](O)=[O:13].O>C(Cl)Cl>[CH3:9][C:10]1([CH3:15])[CH2:11][C:12](=[O:13])[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2]1
Reactant: CC(C)=CC(=O)O
Reactant: Oc1cccc(O)c1
Solvent: O
Solvent: ClCCl
Product: CC1(C)CC(=O)c2ccc(O)cc2O1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
In a flask were placed 55.1 grams (0.5 mole) of resorcinol and 55.1 grams (0.5 mole) 3,3-dimethylacrylic acid. Then, 150 grams of polyphosphoric acid was added, and a steam bath applied to the flask. A red liquid began to form; the temperature of the reaction mixture quickly rose to 120° C. The flask was stirred for 45 minutes at 110° C., then allowed to cool. The contents were poured into a mixture of 500 milliliters water and 400 milliliters methylene chloride then stirred and filtered. The precipitate was washed several times with portions of methylene chloride, water and toluene. There was obtained 65.8 grams, (68% of theoretical yield) 2,2-dimethyl-7-hydroxy-4-chromanone, m.p. 170°-174° C.
Reaction SMILES: C([O:5]C(N[C@@H](CCOC1C=CC=C(C#N)C=1)C(OCC1C=CC=CC=1)=O)=O)(C)(C)C.[CH3:31][N:32]([CH3:66])[C:33]([C:35]1[CH:65]=[CH:64][C:38]([C:39](N[C@@H](CCOC2C=CC=C(C#N)C=2)C(OCC2C=CC=CC=2)=O)=[O:40])=[CH:37][CH:36]=1)=[O:34]>>[CH3:66][N:32]([CH3:31])[C:33]([C:35]1[CH:36]=[CH:37][C:38]([C:39]([OH:40])=[O:5])=[CH:64][CH:65]=1)=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOc1cccc(C#N)c1)C(=O)OCc1ccccc1
Reactant: CN(C)C(=O)c1ccc(C(=O)N[C@@H](CCOc2cccc(C#N)c2)C(=O)OCc2ccccc2)cc1
Product: CN(C)C(=O)c1ccc(C(=O)O)cc1

Procedure:
The title compound was obtained in the same manner as in step 6 in Example 1 by treating benzyl (2S)-2-t-butoxycarbonylamino-4-(3-cyanophenoxy)butyrate (the compound in step 1 in Example 91) and benzyl (2S)-2-(4-dimethylcarbamoylbenzoylamino)-4-(3-cyanophenoxy)butyrate obtained in the same manner as in step 2 in Example 91 from 4-dimethylcarbamoylbenzoic acid as the starting material.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:15]=[C:14]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=2)=[CH:8][CH:7]=1.[CH:35]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)([CH2:37][CH3:38])[CH3:36]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:15]=[C:14]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:42]3[CH:43]=[CH:44][C:39]([CH:35]([CH2:37][CH3:38])[CH3:36])=[CH:40][CH:41]=3)=[CH:29][CH:28]=2)=[CH:8][CH:7]=1
Reactant: CCC(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CNc1ccc(Cn2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Product: CCC(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3Cc3ccc(NCC(=O)OC)cc3)cc2)cc1

Procedure:
{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-phenylamino}-acetic acid methyl ester (1.4 g, 2.5 mmol) was coupled with 4-sec-butyl phenyl-boronic acid (600 mg, 3.3 mmol) following general procedure G to give {4-[2-(4′-sec-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-phenylamino}-acetic acid methyl ester.