Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12](=[O:23])[N:11](CC3C=CC=C(C#N)C=3)[C:10](=[O:33])[CH:9]=2)[CH2:3]1.[CH3:34][O:35][C:36](=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43]Br)[CH:38]=1>>[CH3:34][O:35][C:36](=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:11]2[C:10](=[O:33])[CH:9]=[C:8]([N:4]3[CH2:5][CH2:6][CH2:7][C@@H:2]([NH2:1])[CH2:3]3)[N:13]([CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#[N:18])[C:12]2=[O:23])[CH:38]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: N#Cc1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1
Product: COC(=O)c1cccc(Cn2c(=O)cc(N3CCC[C@@H](N)C3)n(Cc3ccccc3C#N)c2=O)c1

Procedure:
Title compound 24 was prepared by the methods used in the preparation of compound 17, except that 3-bromomethyl-benzoic acid methyl ester was used in the place of m-cyano-benzyl bromide. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1) δ 7.99 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 5.44 (s, 1H), 5.12-5.31 (ABq, J=43.7, 15.9 Hz, 2H), 5.08 (s, 2H), 3.90 (s, 3H), 3.31-3.39 (m, 2H), 2.98 (d, J=11.9 Hz, 1H), 2.87 (m, 1H), 2.71 (m, 1H), 2.11 (m, 1H), 1.89 (m, 1H), 1.73-1.59 (m, 2H). MS (ES) [m+H] calc'd for C26H28N5O4, 474.2. found 474.2.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH2:17][Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1.CCOCC>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Br[Mg]CCc1ccccc1
Reactant: O=Cc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: Oc1ccc(C(O)CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of p-hydroxybenzaldehyde (1.50 g) in THF (30 mL) was added dropwise a solution of 2-phenylethyl magnesium bromide in ether (15.2 mL, 1.7M) at 0°. After being stirred overnight at room temperature (RT) using a mechanical stirrer, it was poured onto a buffer (pH 7), extracted with ethyl acetate and the organic phase was dried and evaporated. The title compound was obtained after crystallization from ethyl acetate/hexane and was used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:14][CH:13]2[CH:9]([CH2:10][C:11]3[S:17][C:16](Br)=[CH:15][C:12]=32)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:19][Zn]C.C1(C)C=CC=CC=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4]([N:6]1[CH2:14][CH:13]2[CH:9]([CH2:10][C:11]3[S:17][C:16]([CH3:19])=[CH:15][C:12]=32)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: C[Zn]C
Reactant: CCOC(=O)N1CCC2Cc3sc(Br)cc3C2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC2Cc3sc(C)cc3C2C1
Yield: 59 %

Procedure:
A solution of the product from step b) (863 mg, 2.62 mmol) in dioxane (13.1 ml) was treated with Pd(dppf)2Cl2 (128 mg, 0.157 mmol) and a 2M solution of dimethylzinc in toluene (2.62 ml, 5.24 mmol) at 102° C. for 1 h. The reaction was cooled to 220C and carefully quenched with sat. NH4Cl (3 ml). After the effervescence subsided, the reaction was extracted with EtOAc (3×50 ml). The combined organic extracts were dried (MgSO4), concentrated and eluted through a plug of silica-gel using 50:50 hexanes:EtOAc to give 411 mg (59%) of the subtitle compound. MS calculated for C14H19NO2S+H 266, observed 266.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:18]([O-])=O)[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:21])[CH3:6])[CH3:2].[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([NH2:18])[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:21])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)N1C(=S)COc2cc(F)c([N+](=O)[O-])cc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)C(C)N1C(=S)COc2cc(F)c(N)cc21
Temperature: 25 °C
Yield: 16.5 %

Procedure:
To a solution of 2-(7-fluoro-6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (3.05 g, 9.29 mmol) in MeOH (45 ml) and THF (45 mL) was added zinc powder (6.07 g, 92.9 mmol) and ammonium chloride (4.97 g, 92.9 mmol). The reaction mixture was heated to reflux for 3 h then cooled to ambient temperature. The reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The residue was purified by column on silica gel (eluting with 0-30% EtOAc in petroleum ether to give 2-(6-amino-7-fluoro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.458 g, 16%). 1H NMR (DMSO-d6, 400 MHz): δ 6.89 (d, J=11.2 Hz, 1H), 6.61 (d, J=8.4 Hz, 1H), 6.21 (brs, 1H), 5.04 (brs, 2H), 4.78 (s, 2H), 3.99-4.03 (m, 2H), 1.62 (d, J=7.2 Hz, 3H), 1.07 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]([CH3:5])[CH3:4].[C:7]([SH:11])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([S:11][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)S
Reactant: CC(C)CCBr
Product: CC(C)CCSC(C)(C)C
Yield: 86 %

Procedure:
The title compound was prepared from isoamyl bromide and tert-butyl mercaptan according to the method of Example 1, 86% yield, bp 55°-56° C./7 mm Hg, n20D=1.4460; 1H NMR (CDCl3) δ 0.92 (d, J=6 Hz, 6H, CH3), 1.32 (s, 9H, CH3), 1.45 (q, 2H, CH2), 1.68 (septet, 1H, CH), 2.52 (t, J =6 Hz, 2H, CH2).
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][C:8](=[O:10])[CH3:9])([O:3][CH3:4])=[O:2].OO.C(=O)(O)[O-:14].[Na+]>>[CH3:4][O:3][C:1](=[O:2])[CH2:5][CH2:6][CH:7]1[O:10][CH:8]1[CH:9]=[O:14]
Reactant: O=C([O-])O
Reactant: COC(=O)CCCC(C)=O
Agent: OO
Agent: [Na+]
Product: COC(=O)CCC1OC1C=O

Procedure:
Mono-methyl succinate (1), wherein alk is methyl, was chlorinated with oxalyl chloride in dimethyl formamide and methylene chloride to afford 3-carbomethoxypropionyl chloride (2). Compound (2) was catalytically hydrogenated over palladium-charcoal catalyst in the presence of 2,6-lutidine to yield 3-carbomethoxypropionaldehyde (3) which was reacted with formylmethylene triphenylphosphorane under Wittig reaction conditions to obtain 5-carbomethoxy-2-pentanal (4). Compound 4 was epoxidized with aqueous hydrogen peroxide in the presence of 1N sodium bicarbonate to afford methyl-4,5-epoxy-6-oxohexanoate (5). Compound (5) was reacted with tridecyltriphenylphosphonium ylid to give methyl-4,5-epoxy-6(Z)-nonadecenoate (6).
Reaction SMILES: [C:1]([C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[C:19]4[CH:26]=[CH:25][NH:24][C:20]=4[N:21]=[CH:22][N:23]=3)[C:13]=2[CH3:27])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[C:32]1([S:38]([N:24]2[C:20]3[N:21]=[CH:22][N:23]=[C:18]([C:14]4[C:13]([CH3:27])=[C:12]([NH:11][C:9](=[O:10])[C:8]5[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:29][CH:28]=5)[CH:17]=[CH:16][CH:15]=4)[C:19]=3[CH:26]=[CH:25]2)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2[nH]ccc12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of Intermediate 51 (7.51 g, 19.54 mmol) in THF (500 ml) at 0° C. was added NaH (1.172 g, 29.3 mmol) portionwise. The mixture was stirred at 0° C. for 3 hrs, then benzenesulfonyl chloride (3.70 ml, 25.4 mmol) was added and stirring was continued at r.t. overnight. The reaction mixture was quenched with sat. aqueous NH4Cl solution, and extracted with EtOAc. The organic layer was dried, filtered, and evaporated to dryness. Purification by flash chromatography (silica gel, cyclohexane/EtOAc gradient) yielded Intermediate 52.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Cl[CH2:13][CH2:14][C:15](OCC)=O.C(=O)([O-])O.[Na+]>>[N+:8]([C:6]1[CH:5]=[CH:4][C:3]2[O:11][C:15]([CH:14]=[CH2:13])=[N:1][C:2]=2[CH:7]=1)([O-:10])=[O:9]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(=O)CCCl
Agent: O=C([O-])O
Agent: [Na+]
Product: C=Cc1nc2cc([N+](=O)[O-])ccc2o1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
A reaction mixture of 1.54 g (10 mmol) of 2-amino-4-nitrophenol, 1.36 g (10 mmol) of ethyl 3-chloropropionate and 20 g polyphosphoric acid is stirred for 2 hours at 170° C. Then the mixture is neutralized by the addition of saturated sodium hydrogen carbonate solution at ambient temperature. The aqueous phase is extracted with dichloromethane. The organic phase is dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: dichloromethane/ethanol (20:1)). Yield: 0.3 g (15.8% of theory); C9H6N2O3 (M=190.16); calc.: molecular ion peak (M+H)+: 191; found: molecular ion peak (M+H)+: 191; Rf value: 0.8 (silica gel, dichloromethane/ethanol (20:1)).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[H-].[Na+].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Cl>CN(C)C=O>[CH3:8][C:7]1[CH:9]=[C:2]([O:10][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[C:14]([F:13])([F:23])[F:24])[CH:3]=[C:4]([OH:5])[CH:6]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: FC(F)(F)c1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O)cc(OCc2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
Orcinol monohydrate (4.30 g, 30 mmol) in N,N-dimethylformarnide (20 mL) was added to a suspension of sodium hydride (1.5 g, 60 mmol) in N,N-dimethylformamide (30 mL), and the mixture was stirred at ambient temperature for 30 minutes. To the above solution was slowly added 2-trifluoromethylbenzyl chloride (5.0 g,25 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at ambient temperature for 3 hours. After carefully quenching with water (100 mL), the mixture was extracted with ethyl acetate (3×100 mL). The ethyl acetate solution was washed with brine (2×100 mL) and dried over Na2SO4. After evaporating the solvent in vacuo, the residue was purified by flash column chromatography (3:1 hexane/ethyl acetate) to give the title compound as a white solid (2.9 g, 41%). 1H-NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.8 Hz, 1 H), 7.68 (d, J=7.9Hz, 1 H), 7.56 (t, J=7.7 Hz, 1 H), 7.41 (t, J=7.7 Hz, 1 H), 6.39 (s, 1 H), 6.28 (s, 2 H), 5.22 (s, 2 H), 4.79 (s, 1 H), 2.27 (s, 3 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH:26]([CH2:31][CH3:32])[CH2:27][CH2:28][CH2:29][CH3:30])=[O:23])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1Cl
Reactant: CCCCC(CC)COC(=O)CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCC(CC)COC(=O)CCSc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 67 %

Procedure:
A suspension of 4-(benzyloxy)-1-chloro-2-nitrobenzene (5.00 g, 19.0 mmol), 2-ethylhexyl 3-sulfanylpropanoate (4.55 g, 20.9 mmol) and potassium carbonate (3.93 g, 28.4 mmol) in DMF (20 mL) was stirred under heating at 60° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by 15 silica gel column chromatography (hexane:ethyl acetate=19:1 to 3:1) to give the title compound (5.67 g, yield 67%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH:34]=O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]([CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=1)[CH2:34][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Cl)cnc1CNCCCCN(C)C(=O)OC(C)(C)C
Reactant: O=Cc1nccc2ccccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CN(CCCCN(C)C(=O)OC(C)(C)C)Cc1nccc2ccccc12

Procedure:
Using General Procedure B: Reaction of {4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-amino]-butyl}-methyl-carbamic acid tert-butyl ester, isoquinoline-1-carbaldehyde and NaBH(OAc)3 in CH2Cl2 gave {4-[(5-chloro-3-methyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-amino]-butyl}-methyl-carbamic acid tert-butyl ester as a light brown solid. 1H NMR (CDCl3): δ 1.29 (br, 2H), 1.41 (s, 9H), 1.50 (br, 2H), 2.01 (s, 3H), 2.59 (t, 2H, J=7.0 Hz), 2.68 (s, 3H), 3.02 (br, 2H), 3.78 (s, 2H), 4.19 (s, 2H), 7.35 (s, 1H), 7.45 (t, 1H, J=7.0 Hz), 7.55 (d, 1H, J=7.0 Hz), 7.62 (t, 1H, J=7.0 Hz), 7.78 (d, 1H, J=7.0 Hz), 8.05 (d, 1H, J=7.0 Hz), 8.29 (s, 1H), 8.42 (d, 1H, J=5.8 Hz). Deprotection with TFA using General Procedure F gave N-(5-chloro-3-methyl-pyridin-2-ylmethyl)-N-isoquinolin-1-ylmethyl-N1-methyl-butane-1,4-diamine.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]([O:16][C:17](=[O:31])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[NH2:30])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(Cl)Cl>[C:12]([O:16][C:17](=[O:31])[CH2:18][N:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[NH2:30])[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)CNCc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(Cc1ccc([N+](=O)[O-])cc1N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
Benzyl chloroformate (6.8 mL, 48 mmol) was added slowly to a solution of (2-amino-4-nitro-benzylamino)-acetic acid tert-butyl ester (9.08 g, 32 mmol) and triethylamine (13.5 mL, 97 mmol) in dry methylene chloride (300 mL) at 0° C. The mixture was stirred for 2 h and warmed to room temperature for another 1 h. The mixture was concentrated and chromatograph with hexanes and ethyl acetate to give [(2-amino-4-nitro-benzyl)-benzyloxycarbonyl-amino]-acetic acid tert-butyl ester (8.39 g) as a yellow solid (62%): 1H NMR (300 MHz, CDCl3) δ 7.58 (br, 1H), 7.5 (d, 1H), 7.3 (br, 5H), 7.12 (d, 1H), 5.15 (s, 2H), 4.55 (s, 2H), 3.78 (s, 2H), 1.33 (s, 9H); MS (m/e): 416.3 (M+1).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Cl[CH2:9][C:10]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([OH:16])[CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13]>CN(C)C=O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:10]([OH:16])([CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:9][N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)=[CH:22][CH:21]=1
Reactant: c1nc[nH]n1
Reactant: C[Si](C)(C)CC(O)(CCl)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CC(O)(Cn1cncn1)c1ccc(F)cc1
Temperature: 90 °C
Yield: 47 %

Procedure:
1.62 g (0.04 mole) of a 60% w/v dispersion of sodium hydride in mineral oil were added to 60 ml of dimethylformamide. Whilst the mixture was being stirred in an ice bath, 2.91 g (0.04 mole) of 1,2,4-triazole were added, and the mixture was stirred for a further 30 minutes at room temperature. At the end of this time, 5.5 g (0.021 mole) of 1 chloro-2-(4-fluorophenyl)-3-trimethylsilyl-2-propanol (prepared as described in Example 40) were added to the reaction mixture, which was then heated for 30 minutes at 90° C. whilst stirring. The reaction mixture was cooled and then poured into 200 ml of ice-water, and the resulting mixture was extracted with 300 ml of ethyl acetate. The organic extract was washed three times, each time with 100 ml of a saturated aqueous solution of sodium chloride. It was then dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure, to afford a crude oily product. 2.9 g (yield 47%) of the title compound, melting at 118 119° C., were obtained by purification of this crude oily product by silica gel column chromatography, using mixtures of ethyl acetate and hexane in proportions of 1:5, 1:1 and 2:1 as the eluent.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][CH:12]=[CH:11][N+:10]=2[O-])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].P(Cl)(Cl)([Cl:32])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][C:12]([Cl:32])=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2ncc[n+]([O-])c2-c2ccc(OC)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2ncc(Cl)nc2-c2ccc(OC)cc2)cc1
Temperature: 0 °C

Procedure:
To 20 ml of phosphorus oxychloride was added with stirring 3.918 g of 2,3-bis(p-methoxyphenyl)pyrazine oxide. The mixture was heated under reflux for 30 minutes. After allowed to cool, the reaction mixture was poured into ice water and then made basic with potassium carbonate to precipitate the product, which was collected by filtration. There was obtained 2.823 g of 2,3-bis(p-methoxyphenyl)-5-chloropyrazine. A mixture of 653 mg of said compound, 414 mg of anhydrous potassium carbonate and 116 mg of tetrakis(triphenylphosphine)palladium was suspended in an atmosphere of argon in 10 ml of dry N,N-dimethylformamide. To the suspension was added 2 ml of a hexane solution of triethylborane (15%). The resulting mixture was heated under reflux for 2 hours, followed by removal of the solvent by distillation under reduced pressure. Water was added to the residue, and the resulting mixture was extracted three times with methylene chloride. The organic layer from the extraction was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent by distillation under reduced pressure afforded 850 mg of an extraction residue. The residue was subjected to column chromatography on silica gel. There was obtained 555 mg of 2,3-bis(p-methoxyphenyl)-5-ethylpyrazine from the eluates with a 1:1 hexane:methylene chloride mixture. M.P. 76.5°-78° C. (colorless needles, recrystallized from ethanol). Physical properties of the product support a chemical structure of the below formula (XII).
Reaction SMILES: [C:1]([CH2:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([OH:3])=[O:2].[CH2:18](O)[CH3:19]>>[C:1]([CH2:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([O:3][CH2:18][CH3:19])=[O:2]
Reactant: CC(C)(CCCCC1CCCC1=O)CC(=O)O
Reactant: CCO
Product: CCOC(=O)CC(C)(C)CCCCC1CCCC1=O

Procedure:
Esterification of 2-(6-carboxy-5,5-dimethylhexyl)cyclopentan-1-one with ethanol by the procedure of Example 456 is productive of the subject compound.
Reaction SMILES: ClN1[C:7](=[O:8])[N:6](Cl)C(=O)N(Cl)C1=O.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[CH:19][C:18](C(N)=O)=[C:17]2[NH:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1CCN2C(=NCCC2)CC1>CO>[Br:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]=[CH:19][C:18]3[NH:6][C:7](=[O:8])[N:27]([CH:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[C:17]=3[C:16]=2[CH:15]=1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: NC(=O)c1cnc2ccc(Br)cc2c1NC1CCOCC1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1[nH]c2cnc3ccc(Br)cc3c2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 161.3 %

Procedure:
1,3,5-Trichloro-1,3,5-triazinane-2,4,6-trione (18.9 g, 81.9 mmol) was added portionwise to a mixture of 6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxamide (57.3 g, 163.7 mmol) and DBU (54.7 g, 360.1 mmol) in MeOH (500 mL) at 0° C. The resulting mixture was allowed to warm and stirred at r.t. for 30 minutes. The resulting mixture was evaporated to dryness and the residue triturated with a mixture of petroleum ether/EtOAc (5:1, 1000 mL) to afford the desired material (46.0 g, 81%) as a yellow solid. NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 1.55-1.64 (2H, m), 1.87-1.98 (2H, m), 3.28-3.42 (2H, m), 3.79-3.89 (2H, m), 3.95-3.98 (1H, m), 7.62 (1H, bs), 7.70-7.85 (2H, m), 7.89 (1H, d), 8.12 (1H, bs), 8.60 (1H, s), 8.71 (1H, s).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[NH:12][C:13]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1nc(-c2ccc(C(C)(C)C)cc2)[nH]c1-c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2nc(C(=O)O)c(-c3ccc([N+](=O)[O-])cc3)[nH]2)cc1
Yield: 88.1 %

Procedure:
Ethyl 2-(4-tert-butylphenyl)-5-(4-nitrophenyl)imidazole-4-carboxylate (22.5 g), ethyl alcohol (1.2 L) and 1 M aqueous sodium hydroxide solution (225 ml) were reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(4-tert-butylphenyl)-5-(4-nitrophenyl)imidazole-4-carboxylic acid (18.4 g), melting point 223° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[NH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27]>CN(C)C=O>[Cl:1][C:2]1[N:10]([CH2:11][CH:12]=[CH2:13])[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[C:4]=2[N:3]=1
Reactant: FC(F)(F)CCCBr
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC(F)(F)F
Yield: 55 %

Procedure:
8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (1.5 g, 6.64 mmol), sodium carbonate (844 mg, 7.9 mmol) and 4-bromo-1,1,1-trifluorobutane (1.39 g, 7.3 mmol) were stirred in dimethylformamide (25 ml, dry) for seven days. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed with hydrochloric acid (2N), brine, dried (MgSO4) and then evaporated to dryness. The crude product was triturated with ether and the solid collected by filtration to afford 8-chloro-7-(2-propen-1-yl)-3-(4,4,4-trifluorobutyl)-3,7-dihydro-1H-purine-2,6-dione as a white solid (1.23 g, 57%). m/z 337 [MH+].