Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:15]([Cl:16])=[N:14][C:13](Cl)=[CH:12][N:11]=1)=[O:9].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[OH:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:16][C:15]1[C:10]([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[O:9])=[N:11][CH:12]=[C:13]([O:26][C:20]2[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=2[F:18])[N:14]=1
Reactant: O=C(c1ccccc1Cl)c1ncc(Cl)nc1Cl
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1Cl)c1ncc(Oc2ccc(F)cc2F)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a dimethylformamide, i.e., DMF, (25 mL) solution of (2-chlorophenyl)-(3,5-dichloropyrazin-2-yl)methanone (2.1 g, 7.3 mmol, 1.0 eq) under nitrogen was added 2,4-difluorophenol (0.7 mL, 7.3 mmol, 1.0 eq) and potassium carbonate (1.21 g, 8.76 mmol, 1.2 eq). The resulting mixture was stirred overnight at room temperature and then concentrated. The residue was dissolved in dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated to give a crude oil which was purified via a chromatography using dichloromethane/hexanes (1:1) as the eluent to give [3-chloro-5-(2,4-difluorophenoxyl)pyrazin-2-yl]-(2-chlorophenyl)methanone (2.46 g, 6.45 mmol, 88% yield). Mass spec., M+1=382.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]([CH2:15][C:16]([F:19])([F:18])[F:17])([C:11]([F:14])([F:13])[F:12])[O:10][C:6]=2[CH:5]=1)([O-])=O.[H][H]>O1CCCC1>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]([CH2:15][C:16]([F:19])([F:18])[F:17])([C:11]([F:12])([F:13])[F:14])[O:10][C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)OC(CC(F)(F)F)(C(F)(F)F)O2
Yield: 71.2 %

Procedure:
57.4 g of the product from Example 15a were dissolved in 400 ml of tetrahydrofuran and hydrogenated in the presence of 4 g of catalyst (palladium on carbon, 10% by weight) for 5 hours at 30° C. at 50 bar with hydrogen. The mixture was then filtered, the solvent removed, and the remaining filtrate distilled under a high vacuum. 37 g of product (=63% of theory) were obtained with a boiling point of 83° C. at 0.07 mbar. 19F-NMR: -59.0 and -84.6 ppm; 1H-NMR: 2.98 ppm.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14](O)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:14]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Prepared in the same manner as intermediate 18. To a solution of tert-butyl 1-piperazinecarboxylate (15.0 g. 80.5 mmol) and benzoic acid (8.94 g, 73.2 mmol) in CH2Cl2 (500 mL), was added DMAP (9.84 g, 80.5 mmol) and EDC (15.39 g, 80.5 mmol). The reaction mixture was stirred at rt for 17 h, and then washed with excess hydrochloric acid (5×250 mL, 1 N aq.) and water (350 mL). The organic layer was dried (MgSO4) and evaporated in vacuo to give N-Benzoyl-N′-Boc piperazine as an off white solid (21 g, 99%). 1H NMR (300 MHz, CD3OD) δ 7.46 (m, 5H), 3.80-3.30 (b m, 8H), 1.47 (s, 9H); LC/MS (ES+) m/z (M+H)+=291, (2M+H)+=581, HPLC Rt=1.430.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][NH:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([N:7]1[CH2:6][CH2:5][C:4]2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10][C:9]=2[CH2:8]1)(=[O:21])[CH3:20]
Reactant: Cc1ccc2c(n1)CCNC2
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCc2nc(C)ccc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.4 %

Procedure:
To a solution of 2-methyl-5,6,7,8-tetrahydro-1,6-naphthyridine [Shiozawa et al., Chem. Pharm. Bull., 32 2522, (1984)] (2.73 g, 0.0184 mol) in CH2Cl2 (30 ml) and triethylamine (5.1 ml, 0.0368 mol) was added acetyl chloride (1.57 ml, 0.0221 mol) at 0° C. The reaction mixture was stirred for 24 h at room temperature, after which time the reaction mixture was washed sequentially with saturated aqueous sodium bicarbonate, H2O, saturated brine, dried over MgSO4 and evaporated under reduced pressure to afford the subtitle compound (3.27 g, 93%). Rf 0.5 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/z 191 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:23])/[CH:14]([O:21][CH3:22])[CH2:15][C:16]([O:18]CC)=[O:17])=[C:9]([O:24][CH3:25])[C:8]([CH3:26])=[C:7]2[C:3]=1[C:4](=[O:27])[O:5][CH2:6]2>CCCCCC.C(Cl)Cl>[OH:1][C:2]1[C:10]([CH2:11]/[CH:12]=[C:13](\[CH3:23])/[CH:14]([O:21][CH3:22])[CH2:15][C:16]([OH:18])=[O:17])=[C:9]([O:24][CH3:25])[C:8]([CH3:26])=[C:7]2[C:3]=1[C:4](=[O:27])[O:5][CH2:6]2
Reactant: CCOC(=O)CC(OC)/C(C)=C/Cc1c(O)c2c(c(C)c1OC)COC2=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1c(C)c2c(c(O)c1C/C=C(\C)C(CC(=O)O)OC)C(=O)OC2

Procedure:
By following the procedure of Example ZA-6A and substituting methyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) 2,4-dimethyl-4-hexenoate with ethyl (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3-methoxy-4-methyl-4-hexenoate and the corresponding compounds of Formula I-ZA-M1 prepared as described in Part A above, there are obtained (E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3-methoxy-4-methyl-4-hexenoic acid, m.p. 133°-135° C. (hexane/methylene chloride) and the corresponding compounds of Formula I-ZA-M2 as identified in the following table.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][C@H:49]([CH3:52])[C@H:48]([C:53](O)=[O:54])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>ClCCl>[CH3:52][C@H:49]1[CH2:50][CH2:51][N:46]([C:44]([O:43][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:45])[CH2:47][C@H:48]1[C:53]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:54]
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (4.12 g, 10.85 mmol), diisopropylethylamine (2.33 g, 18.08 mmol) and pyrrolidine (782 mg, 10.85 mmol) were added to a solution of cis-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (2.2 g, 9.04 mmol) in anhydrous dichloromethane (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 h. The mixture was quenched with water and was extracted with dichloromethane. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford cis-tert-butyl 4-methyl-3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate (2.6 g).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[O:14]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:22][C:21](=O)[CH2:20]2)=[N:15]1>O1CCCC1>[O:14]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:22][C:21](=[CH:5][C:3]#[N:4])[CH2:20]2)=[N:15]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CC(c2ccon2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC=C1CC(c2ccon2)C1
Reaction time: 0.08 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 75 mg, 1.88 mmol) was added at once to a solution of diethyl cyanomethylphosphonate (0.33 mL, 2.1 mmol) in tetrahydrofuran (8 mL). After stirring for 5 minutes, a solution of 3-isoxazol-3-ylcyclobutanone (258 mg, 1.88 mmol) in tetrahydrofuran (20 mL) was added. After 2 hours reaction time, the reaction mixture was partitioned between ethyl acetate and brine and the layers separated. The aqueous layer was extracted with two further portions of ethyl acetate and the combined extracts were dried over sodium sulfate, decanted and concentrated. The residue was then azeotroped with toluene and the product was used without further purification in Step 9.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[CH2:14][CH:13]=[C:12]([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH:27]=[CH:26]1.C(OC(=O)C)(=O)C.C1(C=CC(O)=CC=1)O>C(O)(=O)C>[ClH:1].[CH2:2]([N:9]1[CH2:10][CH2:11][C:12]2[CH:13]([CH:26]3[C:25](=[O:31])[O:30][C:28](=[O:29])[CH:27]3[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:15]=2)[CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1C=CC(=O)O1
Reactant: COc1ccc(C=CC2=CCN(Cc3ccccc3)CC2)cc1
Agent: Cl
Agent: Oc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C2C=C3CCN(Cc4ccccc4)CC3C3C(=O)OC(=O)C23)cc1

Procedure:
A solution of 21 g (0.06 moles) 1-benzyl-1,2,3,6-tetrahydro-4-(p-methoxystyryl)-pyridine, hydrochloride, from example 6, 37.8 g ground maleic anhydride, 135 ml. glacial acetic acid, 135 ml. acetic anhydride and 20 mg hydroquinone is refluxed under nitrogen for 1/2 hour. The solution is allowed to cool and evaporate to an oil. The crude Diels-Alder adduct (quantitative yield of 2-benzyl-1,2,3,4,6,7,8,8a-octahydro-6-(p-methoxyphenyl)-7,8-isoquinoline-dicarboxylic acid anhydride hydrochloride) is dissolved in 500 ml. methanol and 20 ml. hydrochloric acid in isopropanol and refluxed for 18 hours. The solution is allowed to cool and evaporated. The residue is triturated in ether and solid filtered to afford a quantitative yield of 2-benzyl-1,2,3,4,6,7,8,8a-octahydro-6-(p-methoxyphenyl)-7,8-isoquinoline-dicarboxylic acid, dimethyl ester, hydrochloride. After recrystallization from acetone-ether the mp is 200° to 209°C with decomposition.
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].[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23](Cl)[C:24]3[CH:29]=[C:28]([CH3:30])[S:27][C:25]=3[N:26]=2)=[CH:17][CH:16]=1>>[CH3:12][O:13][C:14](=[O:32])[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[N:22]=[C:23]([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:24]3[CH:29]=[C:28]([CH3:30])[S:27][C:25]=3[N:26]=2)=[CH:19][CH:20]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3cccc([N+](=O)[O-])c3)c3cc(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3-nitrobenzylamine is reacted with 4-(4-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3-nitrobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[N:31][CH:32]=1>>[CH3:34][O:33][C:30]1[N:31]=[CH:32][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:28][CH:29]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: COc1ccc(Br)cn1
Product: COc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 5-bromo-2-methoxypyridine (169 mg, 1.0 mmol) according to general procedure II. Obtained as a red solid (85 mg, 18%). MS (ISP) 463.2[(M+H)+]; mp 166-168° C.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:14]([O:18][C:19](=[O:27])[C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)C>[OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][N:5]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([O:18][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:27])=[CH:21][CH:22]=2)[CH2:4][CH2:3]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(O)(c3ccccc3)CC2)cc1
Temperature: 125 °C
Reaction time: 16 h

Procedure:
A solution of 4-hydroxy-4-phenyl piperidine (221 mg, 1.25 mmol) in DMSO (1 mL) was treated with tert-butyl-4-fluorobenzoate (196 mg, 1.00 mmol) and powdered potassium carbonate (173 mg, 1.25 mmol), stirred vigorously at 125° C. for 16 hours, cooled to room temperature, diluted with diethyl ether, washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI(+)) m/e 354 (M+H)+.
Reaction SMILES: C(O[C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.Cl.[C:12]([NH:16][NH2:17])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(O)C>[C:12]([N:16]1[C:9]([NH2:10])=[C:6]([C:7]#[N:8])[C:4]([CH3:5])=[N:17]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)NN
Reactant: CCOC(C)=C(C#N)C#N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nn(C(C)(C)C)c(N)c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 148.1 %

Procedure:
To a slurry of 1-ethoxyethylidene malononitrile (68.0 g, 0.5 mol), tert-butylhydrazine hydrochloride (62.3 g, 0.5 mol) in ethanol (500 ml) was added triethylamine (70 ml, 0.5 mol). The reaction mixture was stirred at room temperature for 2 hours, cooled in an ice-bath and a solid was collected by filtration and was washed with ether. The mother liquor was concentrated and the solid residue was recrystallized from ethanol. The two solid fractions were combined and dried at 65° C. in high vacuum for 24 hours to afford 132 g of 1-tert-butyl-3-methyl-5-amino-1H-pyrazole-4-carbonitrile as a white solid which is contaminated with triethylamine hydrochloride (approximately 2/3mol).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])=[N:6][CH:7]=1.CO.[C:19]1([CH3:28])[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[Si:10]([C:9]#[C:8][C:5]1[CH:4]=[CH:3][C:2]([C:22]2[CH:23]=[CH:24][C:19]([CH3:28])=[CH:20][CH:21]=2)=[CH:7][N:6]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)C#Cc1ccc(Br)cn1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccc(C#C[Si](C)(C)C(C)(C)C)nc2)cc1

Procedure:
4.6 g (15.00 mmol) 5-bromo-2-((tert-butyldimethylsilyl)ethynyl)pyridine are added to 12 mL methanol and 50 mL 1,4-dioxane. Then the mixture is charged with 2.40 g (17.3 mmol) p-tolyl-boronic acid, 0.1 g (0.15 mmol) bis(triphenyphosphine)-dichloropalladium and 16.5 mL (33.0 mmol) of a 2N aq. Na2CO3 solution. The reaction mixture is stirred at reflux for 2 h. Then the solvent is removed in vacuo to some extent and the residue is diluted with EtOAc and water. The organic layer is sequently washed with 50 mL half sat. Na2CO3 solution (1×) and 50 mL water (1×). The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The residue is treated with DIPE and PE to receive a precipitate which is filtered and dried to yield the desired product.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[CH:16]=[CH:17][C:11]=2[N:10]([CH3:26])[C:9]1=[O:27])(=[O:3])[CH3:2].C1C(=O)N([Br:35])C(=O)C1>C(Cl)Cl.O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[C:12]2[N:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[CH:16]=[C:17]([Br:35])[C:11]=2[N:10]([CH3:26])[C:9]1=[O:27])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCn1c(=O)c2c(ccn2Cc2ccc(Cl)cc2)n(C)c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCCn1c(=O)c2c(c(Br)cn2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
To a solution of 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H, 4H,5H)-yl)propyl acetate (1.50 g, 3.85 mmol) in DCM (1 mL) was added NBS (0.68 g, 3.85 mmol). The reaction was stirred at RT for 1 h then diluted with DCM (10 mL) and water (5 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 3-(7-bromo-5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-1H-pyrrolo[3,2-d]pyrimidin-3(2H,4H,5H)-yl)propyl acetate (1.2 g, 66.5% yield) as a solid. LCMS: MH+ 468 and TR=1.777 min. Used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C1C(=O)N([Br:16])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][Br:16])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cncc(Br)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cncc(Br)n1
Temperature: 55 °C
Reaction time: 48 h

Procedure:
To a solution of 2-bromo-6-methyl-pyrazine (3.0 g, 17.31 mmol) in CCl4 (25 mL) was added NBS (4.60 g, 26.01 mmol) and AIBN (0.248 g, 1.734 mmol) at RT. The mixture was stirred at 55° C. for 48 h. H2O was added followed by extraction with EtOAc (3×100 mL). The combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified over silica eluting with 5% EtOAc:Hexane to obtain i (1.40 g, 32%). 1H NMR (CDCl3, 400 MHz): δ 8.64 (s, 1H), 8.62 (s, 1H) and 4.50 (s, 2H).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][CH:16]=1.O>CN(C)C=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])=[CH:19][CH:20]=1
Reactant: OCCCCc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
tert-Butyldimethylchlorosilane (1.13 g) and imidazole (513 mg) were added to a solution of 4-(4-bromophenyl)butan-1-ol (1.15 g) in N,N-dimethylformamide (35 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. Water was added to the reaction solution, followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1→50:1→20:1) to give the title compound (1.78 g, quant.).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.[CH3:19][Mg]Cl.S(=O)(=O)(O)O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2([CH3:19])[C:8]3[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=[O:12])[O:7]2)=[CH:17][CH:18]=1
Reactant: C[Mg]Cl
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(c2ccc(Cl)cc2)OC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
Over a period of 30 minutes a solution of 130 g of 2-(4-chlorobenzoyl)benzoic acid in 300 ml of anhydrous tetrahydrofuran was added drop-wise under nitrogen to 900 ml of a stirred 3M solution of methylmagnesium chloride in anhydrous tetrahydrofuran. After the addition the reaction mixture was kept at reflux temperature for 1 hour. Afterwards it was cooled in an ice bath to room temperature and 1 L of an aqueous 2N sulfuric acid solution was added slowly, followed by 600 ml of toluene. The organic layer was separated and washed with brine, dried and evaporated in vacuo. Bulb to bulb destination (0.1 mm Hg/160° C.) afforded 60 g of 3-(4-chlorophenyl)-3-methyl-1(3H)-isobenzofuranone as a yellow oil. M.S. (C.I.) (M/Z): 260 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5](=[O:9])[NH:6][C:7]=1[CH3:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(=O)[nH]c1C
Agent: O=S(=O)(O)O
Product: Cc1cc([N+](=O)[O-])c(=O)[nH]c1C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
5,6-Dimethyl-2-pyridone (1-013-03) (3.695 g) was dissolved in conc. sulfuric acid (38 mL) under ice-cooling, and the reaction mixture was stirred under ice-cooling, and then to the reaction mixture was added dropwise 70% nitric acid (3.53 mL) at 3 to 5° C. as internal temperature for 50 min, and then the reaction mixture was stirred. After 2 h, the reaction mixture was poured gradually into ice and the resulting crystal was filtered. The crystal was washed with water to give 5,6-dimethyl-3-nitro-2-pyridone (1-013-04) (3.102 g, 61.5%, m.p.: 251-257 (dec)). Furthermore the aqueous layer was extracted five times with chloroform, the organic layer was dried over magnesium sulfate, and evaporated under reduced pressure. The resulting crystal was filtered to give an additional 5,6-dimethyl-3-nitro-2-pyridone (1-013-04)(271 mg, 5.4%).
Reaction SMILES: ClC(OCC)=O.Br.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[C:18]([C:20]2[C:21]3[C:26]([N:27]=[C:28]4[C:33]=2[CH:32]=[CH:31][CH:30]=[CH:29]4)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])=[CH:13][CH:12]=1)([OH:10])=[O:9].C(N(CC)CC)C.Br.COC1C=CC(N(S(C2C=CC(CCCCC(O)=O)=CC=2)(=O)=O)C(C2C3C(N=C4C=2C=CC=C4)=CC=CC=3)=O)=CC=1.O[N:94]1[C:98](=[O:99])[CH2:97][CH2:96][C:95]1=[O:100]>O1CCCC1>[C:95]1(=[O:100])[N:94]([O:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:43])=[CH:41][CH:42]=3)(=[O:35])=[O:36])[C:18]([C:20]3[C:33]4[C:28]([N:27]=[C:26]5[C:21]=3[CH:22]=[CH:23][CH:24]=[CH:25]5)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:19])=[CH:15][CH:16]=2)=[O:10])[C:98](=[O:99])[CH2:97][CH2:96]1
Reactant: Cc1ccc(S(=O)(=O)N(C(=O)c2c3ccccc3nc3ccccc23)c2ccc(C(=O)O)cc2)cc1
Reactant: O=C1CCC(=O)N1O
Agent: Br
Agent: CCOC(=O)Cl
Agent: COc1ccc(N(C(=O)c2c3ccccc3nc3ccccc23)S(=O)(=O)c2ccc(CCCCC(=O)O)cc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)N(C(=O)c2c3ccccc3nc3ccccc23)c2ccc(C(=O)ON3C(=O)CCC3=O)cc2)cc1
Reaction time: 1 h

Procedure:
0.11 g (1 mmol) of ethyl chloroformate is added, while stirring at -15° C., to a solution of 0.57 g (1 mmol) of N-(4-carboxyphenyl)-N-(4-toluenesulfonyl)acridine-9-carboxamide hydrobromide and 0.21 g (2 mmol) of triethylamine in 25 ml of anhydrous tetrahydrofuran. The mixture is stirred at the same temperature for 1 hour and then 0.12 9 (1 mmol) of N-hydroxysuccinimide is added. After a further hour, the mixture is left to stand at room temperature for 15 hours. It is evaporated in vacuo, the residue is taken up in ethyl acetate, and the solution is washed with water, sodium bicarbonate solution and water and dried over sodium sulfate. Evaporation yields 0.42 g (70.8% of theory) of the desired product.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([CH2:13][OH:14])=[C:10]([Cl:12])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]1([C:7]2[N:8]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([CH3:20])=[CH:18][CH:17]=3)[C:9]([CH2:13][OH:14])=[C:10]([Cl:12])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1[nH]c(-c2ccccc2)nc1Cl
Reactant: Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CO)cc1

Procedure:
1 g of 2-phenyl-4-chloro-5-hydroxymethylimidazole, together with 0.7 ml of p-methylbenzyl bromide and 3 g of potassium carbonate, was stirred in 10 ml of dimethylformamide at 30° C. for 2 days. The reaction solution was poured into 100 ml of water, and the precipitate deposited was chromatographed on a column of 30 g of silica gel, followed by eluting with chloroform. The initially eluted fraction was collected, and recrystallization from aqueous methanol yielded 0.5 g of 2-phenyl-4-chloro-5-hydroxymethyl-1-(4-methylbenzyl)imidazole as colorless, needle-formed crystals, m.p. 173°-175° C.