Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=2[Cl:22])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[CH:25]1C=CC=CC=1.CO>CN(C)C=O.O>[C:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:14][C:13]=3[Cl:22])[CH2:25]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNc2ccccc2)c(Cl)c1
Reactant: c1ccccc1
Agent: C=O
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: NS(=O)(=O)c1ccc(N2CN(c3ccccc3)CC2=O)c(Cl)c1
Reaction time: 24 h

Procedure:
2-Phenylamino-N-(2-chloro-4-sulphamoylphenyl)-acetamide (0.8g) was dissolved in dimethylformamide (20ml) and paraformaldehyde (100 g) in water (5 ml) added thereto. The mixture was kept at 80° for 24 hours and then the DMF was evaporated. The residue was recrystallised from ethanol to yield the product (500 mg.), m.p. 204°; mixed melting point with the product of Example 3(c) 206°. The product was found identical with the product of Example 3(c) on thin layer chromatography (Kieselgel F254, Merck; benzene; methanol 16:1) and on IR spectroscopy.
Reaction SMILES: CCO[C:4]([C:6]([O:8]CC)=O)=[O:5].[CH2:11]([NH:13][CH2:14][CH2:15][NH2:16])[CH3:12]>C(O)C>[CH2:11]([N:13]1[CH2:14][CH2:15][NH:16][C:6](=[O:8])[C:4]1=[O:5])[CH3:12]
Reactant: CCNCCN
Reactant: CCOC(=O)C(=O)OCC
Solvent: CCO
Product: CCN1CCNC(=O)C1=O
Yield: 76.1 %

Procedure:
Into a mixture comprising 8 g of a diethyl ester of oxalic acid and 8 ml of ethanol was dropped at room temperature 4.4 g of N-ethyl ethylenediamine. The resulting mixture was allowed to react for 3 hours, an then heated to remove the ethanol. Subsequently, the residue was recrystallized from 10 ml of dioxane to obtain 5.4 g of 1-ethyl-2,3-dioxopiperazine, m.p. 124° C., yield 76.0%.
Reaction SMILES: C(Cl)(=O)CCCCC(Cl)=O.OCC[C:14]1(C)[CH2:19][CH2:18][C:17]2[C:20](C)=[C:21](O)[C:22](C)=[C:23](C)[C:16]=2[O:15]1.C(Cl)(=O)CCC(Cl)=O>>[O:15]1[C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[CH2:18][CH2:19][CH2:14]1
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCO)O2
Agent: O=C(Cl)CCC(=O)Cl
Agent: O=C(Cl)CCCCC(=O)Cl
Product: c1ccc2c(c1)CCCO2

Procedure:
The same reaction and isolation procedures as Synthesis Example 1 were followed except that 10 millimoles each of the 2-substituted ethyl alcohols of Table 2 and 5 millimoles of adipoyl chloride were used in lieu of 2.5 g of 3,4-dihydro-2-(2-hydroxyethyl)-2,5,7,8-tetramethyl-2H-benzopyran-6-ol and 5 millimoles of succinyl chloride to give the corresponding 3,4-dihydro-2H-benzopyran derivative. The results are given in Table 2.
Reaction SMILES: [Br-].[F:2][C:3]([F:8])([F:7])[C:4]([Zn+])=[CH2:5].Br[C:10]1[CH:11]=[C:12]([Cl:18])[C:13]([Cl:17])=[C:14]([CH3:16])[CH:15]=1>O1CCCC1.CN(C)C=O>[Cl:18][C:12]1[CH:11]=[C:10]([C:4]([C:3]([F:8])([F:7])[F:2])=[CH2:5])[CH:15]=[C:14]([CH3:16])[C:13]=1[Cl:17]
Reactant: Cc1cc(Br)cc(Cl)c1Cl
Reactant: C=C([Zn+])C(F)(F)F
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=C(c1cc(C)c(Cl)c(Cl)c1)C(F)(F)F
Temperature: 100 °C
Reaction time: 3.5 h

Procedure:
To 1M solution of 1-(trifluoromethyl)ethenyl zinc bromide in tetrahydrofuran (see J. Org. Chem. 1991, 56, 7336 for preparation) (19 mL) was added a solution of 5-bromo-2,3-dichlorotoluene (2.2 g) in N,N-dimethylformamide (10 mL), then tetrahydrofuran was distilled off under reduced pressure. Dichlorobis(triphenylphosphine)palladium(II) (0.26 g) was added to the residual N,N-dimethylformamide solution, which was stirred at 100° C. for 3.5 hours under nitrogen atmosphere and then cooled to room temperature. To the resulting mixture was added tetrahydrofuran-hexane 2:5 mixture (200 mL) and filtered, and the filtrate was washed with water (100 mL) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with hexane to afford the title compound as a brown oil (2.3 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)=[O:4].[CH3:18][O:19][C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:25]2[CH:26]=[CH:27][C:22]([C:20]([O:19][CH3:18])=[O:21])=[CH:23][CH:24]=2)=[CH:11][CH:10]=1)=[O:4]
Reactant: O=C(NCCCc1ccc(I)cc1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(CCCNC(=O)C(F)(F)F)cc2)cc1
Temperature: 75 °C
Reaction time: 10 h
Yield: 36 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[3-(4-iodophenyl)propyl]acetamide (2.5 g) in 1,2-dimethoxyethane (15 ml) was added [4-(methoxycarbonyl)phenyl]boronic acid (1.51 g), tetrakis(triphenylphosphine)palladium (809 mg) and aqueous solution of sodium carbonate (2M, 7 ml), and the mixture was stirred at 75° C. for 10 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=2/1) to give methyl 4′-[3-[(trifluoroacetyl)amino]propyl]-1,1′-biphenyl-4-carboxylate (920 mg).
Reaction SMILES: [N+](C1C=CC(COC([NH:12][CH:13]2[CH2:16][N:15]([C:17]([C@@H:19]3[CH2:23][C@H:22]([S:24][C:25]4[C@H:26]([CH3:49])[C@@H:27]5[C@@H:44]([C@H:45]([OH:47])[CH3:46])[C:43](=[O:48])[N:28]5[C:29]=4[C:30]([O:32]CC4C=CC([N+]([O-])=O)=CC=4)=[O:31])[CH2:21][N:20]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:18])[CH2:14]2)=O)=CC=1)([O-])=O.[H][H]>O1CCCC1.O.[Pd]>[NH2:12][CH:13]1[CH2:14][N:15]([C:17]([C@@H:19]2[CH2:23][C@H:22]([S:24][C:25]3[C@H:26]([CH3:49])[C@@H:27]4[C@@H:44]([C@H:45]([OH:47])[CH3:46])[C:43](=[O:48])[N:28]4[C:29]=3[C:30]([OH:32])=[O:31])[CH2:21][NH:20]2)=[O:18])[CH2:16]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC(NC(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CC(N)C4)C3)[C@H](C)[C@H]12
Yield: 54.7 %

Procedure:
3630 mg of 4-nitrobenzyl (1R,5S,6S)-2-{(2S,4S)-2-[3-(4-nitrobenzyloxycarbonylamino)azetidin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in Example 121(1)] were dissolved in 190 ml of a 3:2 by volume mixture of tetrahydrofuran and water, and 5500 mg of a 10% w/w palladium-on-carbon catalyst were added to the resulting solution. The mixture was then hydrogenated at 30° C. for 1.5 hours in an atmosphere of hydrogen. At the end of this time, the catalyst was removed by filtration, the filtrate was washed with diethyl ether and the resulting aqueous solution was concentrated to 10 ml by evaporation under reduced pressure. The resulting solution was subjected to reverse phase silica gel column chromatography (Cosmosil 75C18 -prep, 250 ml, manufactured by Nacalai Tesque), eluted with mixtures of acetonitrile and water in proportions of 0:100, 2:98, 4:96, 6:94 by volume, in that order. The fractions containing the title compound were collected, concentrated by evaporation under reduced pressure and freeze-dried, to obtain 901 mg of the title compound as a powder.
Reaction SMILES: [ClH:1].O1CCOCC1.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][N:17]2[C:29]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:39])[CH2:34][CH2:33]2)=[O:30])[CH:9]=1>CO>[ClH:1].[ClH:1].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][NH:20][CH2:19][CH2:18][N:17]2[C:29]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:39])[CH2:34][CH2:33]2)=[O:30])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC2CCN(C(=O)OCc3ccccc3)CC2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCC(OC(=O)N2CCNCC2COc2cccnc2)CC1
Reaction time: 1 h
Yield: 100 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of 1-(1-(benzyloxycarbonyl)piperidin-4-yl) 4-tert-butyl 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (88.8 mg, 0.160 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 84.4 mg (100%) of the desired product as a white solid. LC-MS: RT=4.94 min, [M+H]+=455.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:10][Mg+].[Br-].[BH4-].[Na+].[OH-].[Na+]>C1COCC1.O.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH2:9])[CH3:10])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(Br)cn1
Reactant: C[Mg+]
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(N)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a stirred solution of 5-bromo-pyridine-2-carbonitrile (1 g, 5.46 mmol) in dry THF (10 mL) was added dropwise MeMgBr (2.03 mL, 6.09 mmol, 3M in THF) at −20° C. under N2 atmosphere. After the addition, the reaction mixture was stirred at room temperature for 30 mins. The suspension was then treated with methanol (20 mL) and NaBH4 (0.4 g, 13.3 mmol). The reaction was stirred at room temperature for 10 hrs and then poured into H2O (10 mL) and aqueous NaOH (2M, 10 mL), extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL×3), dried over Na2SO4 and concentrated in vacuum. The residue was purified by a silica gel column chromatography (petroleum:EtOAc 3:1) to give 1-(5-bromo-pyridin-2-yl)-ethylamine (0.65 g, 59%) as a yellow liquid.
Reaction SMILES: [F:1][C:2]1[C:7]([B-:8]([C:31]2[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=2[F:41])([C:20]2[C:25]([F:26])=[C:24]([F:27])[C:23]([F:28])=[C:22]([F:29])[C:21]=2[F:30])[C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])=[C:6]([F:42])[C:5]([F:43])=[C:4]([F:44])[C:3]=1[F:45].[Li+].Cl.[CH3:48][N:49]([CH3:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O>[F:37][C:36]1[C:31]([B-:8]([C:9]2[C:14]([F:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([F:18])[C:10]=2[F:19])([C:7]2[C:6]([F:42])=[C:5]([F:43])[C:4]([F:44])=[C:3]([F:45])[C:2]=2[F:1])[C:20]2[C:21]([F:30])=[C:22]([F:29])[C:23]([F:28])=[C:24]([F:27])[C:25]=2[F:26])=[C:32]([F:41])[C:33]([F:40])=[C:34]([F:39])[C:35]=1[F:38].[CH3:48][NH+:49]([CH3:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: CN(C)c1ccccc1
Agent: Cl
Agent: Fc1c(F)c(F)c([B-](c2c(F)c(F)c(F)c(F)c2F)(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Agent: [Li+]
Solvent: O
Product: C[NH+](C)c1ccccc1

Procedure:
Thereafter, lithium tetrakis(pentafluorophenyl)borate (16 mmol) was reacted with dimethylaniline hydrochloride (16 mmol) in water, to obtain 11.4 mmol of dimethylanilinium tetrakis(pentafluorophenyl)borate as a white solid product.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)CCC>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[N:3][CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: C1CNCCN1
Solvent: CCCCO
Product: O=[N+]([O-])c1cnc(N2CCNCC2)c([N+](=O)[O-])c1
Yield: 32.2 %

Procedure:
In n-butanol (20 ml), 1 g of 2-chloro-3,5-dinitropyridine and 2.1 g of anhydrous piperazine were refluxed for 2 hours. Thereafter, n-butanol was distilled off under reduced pressure, followed by extraction with 2N-NaOH and chloroform. The chloroform layer was washed with saturated saline and then dried with anhydrous magnesium sulfate. Under reduced pressure, chloroform was distilled off to obtain 0.4 g of the intended product (yield: 32%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][S:11]([OH:14])(=O)=[O:12])=[N:2]1.P(Cl)(Cl)([Cl:17])=O>>[CH:8]1[CH:9]=[C:4]2[C:3]([CH2:10][S:11]([Cl:17])(=[O:14])=[O:12])=[N:2][O:1][C:5]2=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=S(=O)(O)Cc1noc2ccccc12
Product: O=S(=O)(Cl)Cc1noc2ccccc12

Procedure:
1,2-Benzisoxazole-3-methanesulfonic acid (1) (1.00 g, 4.7 mmol) was mixed with xylenes (10 mL) and phosphorous oxychloride (1.0 mL, 11 mmol) and heated to reflux until the reaction was complete. The mixture was filtered through CELITE™ and evaporated to dryness to yield 1,2-benzisoxazole-3-methanesulfonyl chloride (2) as a light brown solid. It was dissolved in ethyl acetate (10 mL), cooled in an ice-bath and treated with ammonia. Work-up analogous to example 2 gave pure zonisamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[K+].[K+].[C:16]1([CH:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:23]2[CH2:26][CH:25](S(C)(=O)=O)[CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH:22]([N:23]1[CH2:26][CH:25]([NH:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:24]1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CS(=O)(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1NC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 80 °C
Yield: 14.5 %

Procedure:
To a solution of 4.1 g (0.033 mol) of o-anisidine in 20 mL DMF, 4.6 g (0.033 mol) of K2CO3 was added, followed by 9.5 g (0.030 mol) of 1-(diphenylmethyl)-3-methane sulfonyl azetidine. The reaction was heated at 80° C. for 5 h. Water was added and the product was extracted with ether. The organic phase was dried and the solvent was removed under vacuo. The residue was filtered through silica gel, starting with 100% methylene chloride, then 25% ethyl acetate/hexane to give 1.5 g of the desired product: mp 75-77° C. 1H NMR (300 MHz, CDCl3) δ 2.89 (dd, 2H), 3.70 (dd, 2H), 3.84 (s, 3H), 4.13 (m, 1H), 4.40 (m, 1H), 4.38 (s,1H), 6.42 (dd,1H), 6.69 (dd, 1H), 6.79 (m, 2H), 7.20 (m, 2H), 7.26 (m, 4H), 7.42 (m, 4H); MS (ES) m/z (relative intensity): 345 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[C:34]([O:40][CH3:41])[C:4]=1/[CH:5]=[CH:6]/[S:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([NH:19][C:20](=[O:33])[C:21]2[CH:26]=[C:25]([N+:27]([O-])=O)[CH:24]=[C:23]([N+:30]([O-])=O)[CH:22]=2)[CH:12]=1)(=[O:9])=[O:8].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[CH3:1][O:2][C:3]1[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[C:34]([O:40][CH3:41])[C:4]=1/[CH:5]=[CH:6]/[S:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([NH:19][C:20](=[O:33])[C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[C:23]([NH2:30])[CH:22]=2)[CH:12]=1)(=[O:8])=[O:9]
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Nc2ccc(OC)c(NC(=O)c3cc([N+](=O)[O-])cc([N+](=O)[O-])c3)c2)c(OC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Nc2ccc(OC)c(NC(=O)c3cc(N)cc(N)c3)c2)c(OC)c1

Procedure:
A solution of (E)-2,4,6-trimethoxystyryl-N-[3-(3,5-dinitrobenzamido)-4-methoxyphenyl]sulfonamide (Example 5) is reduced by following the sodium hydrosulfite reduction procedure as described in General Method B to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][NH:8][C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[O:18])[N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:21][CH:20]=4)[C:15](=[S:31])[NH:14][C:13]=3[N:32]=2)=[CH:5][CH:4]=1.I[CH2:36][CH3:37].[OH-].[Na+].Cl>O.CN(C)C=O>[CH2:36]([S:31][C:15]1[N:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]([F:29])([F:28])[F:30])=[CH:21][CH:20]=2)[C:17](=[O:18])[C:12]2[CH:11]=[CH:10][C:9]([NH:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:34][CH:33]=3)=[N:32][C:13]=2[N:14]=1)[CH3:37]
Reactant: CCI
Reactant: COc1ccc(CNc2ccc3c(=O)n(-c4ccc(OCC(F)(F)F)cc4)c(=S)[nH]c3n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc2nc(NCc3ccc(OC)cc3)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
7-[(4-Methoxybenzyl)amino]-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (108 mg), iodoethane (53 μl) and 1M aqueous sodium hydroxide solution (220 μl) were added to N,N-dimethylformamide (2 ml), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1M hydrochloric acid and water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the white title compound (63 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:28])[C:8](=[O:9])[N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)[C:6](=[O:22])[N:5]1[CH2:23][CH2:24][CH2:25][CH2:26][OH:27].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.P(O)(O)([O-])=O.[K+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:22]=[C:6]1[N:5]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:4]([CH3:28])([CH3:3])[C:8](=[O:9])[N:7]1[C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([C:18]([F:19])([F:20])[F:21])[CH:11]=1
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCO
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])(O)O
Agent: [H-]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
48 mg of sodium hydride were added in several lots to 370 mg of the product of Example 58 in solution in 4 ml of dimethylformamide and the mixture was stirred for 30 minutes. Then, 0.12 ml of benzyl bromide and 40 mg of tetrabutylammonium iodide were added and after 90 minutes of reaction, the same amount of each reagent was added. The mixture was stirred for one hour and the reaction medium was poured into an ice-cooled aqueous solution of monopotassium phosphate. Extraction was carried out with ether and the extracts were washed with water and dried. The solvent was eliminated under reduced pressure and the residue was chromatographed on silica (eluant: methylene chloride--acetone 99-1) to obtain 140 mg of the expected product melting at 75°-76° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[Na+].Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:13][C:14]=1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1cccnc1
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: c1ccc(N2CCCC2)nc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 221.1 %

Procedure:
To a stirred solution of free pyrrolidine (79.3 mg; 0.22 mmol) and sodium t-butoxide (29 mg; 0.31 mmol) in dry toluene (3 mL) was added, sequentially, 3-bromopyridine (22.9 μL; 0.24 mmol), tris-(dibenzylideneacetone)dipalladium (0)(3.9 mg; cat.), and (R)-(+)-1,1′-bi-2-naphthol (5.4 mg; cat.) at room temperature under a nitrogen atmosphere. The resulting mixture was heated to 80° C., held 3 hours, then allowed to cool back to room temperature. The reaction then was diluted with ethyl acetate (40 mL), washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography on silica gel (40% ethyl acetate in hexanes) to provide the N-pyridyl pyrrolidine (72.1 mg; 75%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([CH:26]1[NH:30][C:29](=[O:31])[N:28]([CH3:32])[C:27]1=[O:33])[CH3:25]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:30]4[CH:26]([CH2:24][CH3:25])[C:27](=[O:33])[N:28]([CH3:32])[C:29]4=[O:31])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CCC1NC(=O)N(C)C1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Product: CCC1C(=O)N(C)C(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Yield: 64.7 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165 and 5-ethyl-3-methylimidazolidine-2,4-dione (63 mg) described in Preparation Example 215 and by the reaction and treatment in the same manner as in Example 536, the title compound (113 mg) was obtained.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][CH2:9][C:10]([NH2:12])=[O:11].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:8][CH2:9][C:10]([NH2:12])=[O:11])=[S:4]
Reactant: NNC(N)=S
Reactant: NC(=O)CCC(=O)c1ccccc1
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=O)CCC(=NNC(N)=S)c1ccccc1
Yield: 75 %

Procedure:
Thiosemicarbazide (1.38 g, 15.1 mmol) was added to a solution of 4-oxo-4-phenyl-butyramide (1.63 g, 9.22 mmol), prepared in the previous step, in 50 ml of methanol plus 2.5 ml of 1 N HCl plus 2.5 ml of water and the reaction stirred at room temperature for 28 hours. The solid formed was collected by filtration and dried to give 1.73 g of a purple solid. Recrystallization of the solid from methanol gave the title compound (1.34 g, 58%) as a purple solid, mp 186-188° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][C:13]12[CH2:20][CH2:19][C:16]([C:21](O)=[O:22])([CH2:17][CH2:18]1)[CH2:15][CH2:14]2.O1CCCC1>O.C(OCC)(=O)C>[OH:22][CH2:21][C:16]12[CH2:17][CH2:18][C:13]([CH3:12])([CH2:20][CH2:19]1)[CH2:14][CH2:15]2
Reactant: CC12CCC(C(=O)O)(CC1)CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC12CCC(CO)(CC1)CC2
Reaction time: 0.5 h

Procedure:
0.0952 Mole of lithium aluminum hydride is dissolved in 200 ml. of anhydrous diethyl ether, under nitrogen, and cooled to 0° C. 0.0952 Mole of 4-methylbicyclo[2.2.2]oct-1-yl carboxylic acid in 100 ml. of tetrahydrofuran is added dropwise, then the mixture stirred for 30 minutes. Excess lithium aluminum hydride is decomposed by the cautious addition of ethyl acetate, followed by the careful addition of 10 ml. of water. The mixture is then filtered and the filtrate washed with ethyl ether, then dried over anhydrous magnesium sulfate and filtered. The solvent is then evaporated from the filtrate, under vacuum, affording 1-(hydroxymethyl)-4-methylbicyclo[2.2.2]octane.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([OH:7])=O.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([C:8]([I:17])=[C:9]([N:12]([CH3:16])[C:13](=[O:15])[CH3:14])[C:10]=1[I:11])[C:5]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:7]
Reactant: C1COCCN1
Reactant: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)O)c1I
Product: CC(=O)N(C)c1c(I)c(N)c(I)c(C(=O)N2CCOCC2)c1I

Procedure:
4-[3-Amino-2,4,6-triiodo-5-(N-methylacetamido)benzoyl]morpholine [C; R° is CH3CON(CH3), Q is H, Z is morpholino] was prepared from the acid chloride of 3-amino-5-(N-methylacetamido)-2,4,6-triiodobenzoic acid and morpholine according to the procedure described in Example 45, part (a). The product obtained was used directly in the procedure described in part (b) below.