Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH3:11].[Br:12]([O-])(=O)=O.[Na+].CCOC(C)=O.S(=O)(O)[O-].[Na+]>O>[Br:12][CH2:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1]
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Reactant: [O-][Br+2]([O-])[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CBr)c(F)c1
Reaction time: 144 h

Procedure:
To a solution of 2-Fluoro-1-methyl-4-nitro-benzene (1 g, 6.45 mmol) and sodium bromate (2.92 g, 19.33 mmol) in an EtOAc:water (12 mL:9 mL) mixture, is added dropwise via addition funnel a 3.85M solution of sodium bisulfite 5.20 mL, 19.33 mmol). The mixture is vigorously stirred for six days and then sodium bisulfite (10 mL) is added and organic layer separated and washed with aqueous saturated solution of sodium bicarbonate. The organic phase is dried with magnesium sulfate, filtered and evaporated at reduced pressure to afford a mixture of title compound and starting 2-fluoro-1-methyl-4-nitro-benzene in a 5:1 ratio (1H-NMR) which is used in the next step without further purification. ES+(m/z) 235 [M+H]).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([Sn](CCCC)(CCCC)CCCC)[N:6]=[CH:5][N:4]=1.[Cl:22][C:23]1[C:28](Cl)=[N:27][CH:26]=[CH:25][N:24]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:22][C:23]1[C:28]([C:7]2[CH:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][N:6]=2)=[N:27][CH:26]=[CH:25][N:24]=1
Reactant: Clc1nccnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(SC)ncn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CSc1cc(-c2nccnc2Cl)ncn1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
A mixture of 4-methylsulfanyl-6-tributylstannanyl-pyrimidine (4) (1.80 g, 4.33 mmol), 2,3-dichloro-pyrazine (1.94 g, 13 mmol), PPh3 (0.907 g, 3.46 mmol) and palladium (II) acetate (194 mg, 0.866 mmol) in dioxane (15 mL) is degassed and sealed in a pressure tube. After stirring at 120° C. for 16 h, the reaction mixture is evaporated and purified by silica gel flash chromatography eluting with ethyl acetate in hexanes from 10% to 30% to afford the desired product 4-(3-chloro-pyrazin-2-yl)-6-methylsulfanyl-pyrimidine (37).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:32])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[C:16]([F:25])[CH:15]=2)=[CH:8][C:7]=1[CH2:26][N:27]([CH:29]1[CH2:31][CH2:30]1)[CH3:28])([CH3:3])[CH3:2].O1CCCC1.O.O.[OH-].[Li+]>CO>[CH:1]([O:4][C:5](=[O:32])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[CH:8][C:7]=1[CH2:26][N:27]([CH:29]1[CH2:31][CH2:30]1)[CH3:28])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C(=O)OC(C)C)c(CN(C)C3CC3)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)OC(=O)c1ccc(C#Cc2ccc(CC(=O)O)c(F)c2)cc1CN(C)C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
A solution of 2-[(cyclopropyl-methyl-amino)-methyl]-4-(3-fluoro-4-methoxycarbonylmethyl-phenylethynyl)-benzoic acid isopropyl ester (Intermediate 124, 0.04 g, 0.09 mmol) in a mixture of methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was treated with lithium hydroxide monohydrate (0.042 g, 1 mmol) and the resulting reaction mixture was stirred at ambient temperature for 2 h. The volatiles were evaporated in vacuo, the residue was neutralized with saturated, aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a solid. Preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase afforded the title product as a white solid (0.026 g, 54%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[OH:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14]>>[OH:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:11]([OH:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1ccc(N)cc1O
Product: COc1ccc(Nc2ncc(F)c(Nc3ccc(OC)c(O)c3)n2)cc1O

Procedure:
In like manner to N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-hydroxy-4-methoxylaniline were reacted to yield N2,N4-bis(3-hydroxy-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.82 (d, 1H J=4 Hz), 7.18 (m, 2H), 6.95 (m, 2H), 6.83 (m, 2H) 3.93 (s, 6H); LCMS: ret. time: 16.63 min.; purity: 97%; MS (m/e): 373 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:19][C:20]([OH:25])([CH2:23][CH3:24])[C:21]#[CH:22]>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C.[I-]>[CH3:1][O:2][C:3](=[O:18])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:22]#[C:21][C:20]([OH:25])([CH3:19])[CH2:23][CH3:24])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Reactant: C#CC(C)(O)CC
Agent: Cl[Pd]Cl
Agent: [I-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(C)(O)C#Cc1ccc(C(CC2CCCC2)C(=O)OC)cc1
Temperature: 70 °C
Yield: 102.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (716 mg, 2.0 mmol) and triethylamine (2 mL, 0.01 mmol) in N,N-dimethylformamide (2 mL) was treated with 3-methyl-1-pentyn-3-ol (0.56 mL, 5.0 mmol). The resulting reaction mixture was degassed with argon and then treated with cooper iodide (10 mg, 0.05 mmol) and bis(triphenylphosphine)palladium (II) chloride (15 mg, 0.02 mmol). The reaction was then heated at 70° C. for 24 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL) and a half-saturated aqueous sodium chloride solution (1×20 mL). The aqueous layer was back extracted with ethyl acetate (1×40 mL). The combined organic extracts were washed with a half-saturated aqueous sodium chloride solution (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 60/40 ethyl acetate/hexanes) afforded 3-cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-propionic acid methyl ester (673 mg, 98%) as an orange oil: EI-HRMS m/e calcd for C21H28O3 (M+) 328.2038, found 328.2040.
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[CH:12]=[C:11]([CH3:13])[N:10]([C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[C:21]([N:23]2[C@H:32]([CH2:33][OH:34])[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl[CH2:46][C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48].Cl>O1CCCC1.C(OCC)(=O)C>[CH2:50]([O:49][C:47](=[O:48])[CH2:46][O:20][C:18]1[CH:17]=[CH:16][C:15]([C:21]([N:23]2[C@H:32]([CH2:33][OH:34])[CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:22])=[C:14]([N:10]2[C:11]([CH3:13])=[CH:12][C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:35][CH2:36][CH2:37][CH3:38])=[N:9]2)[CH:19]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(CCl)OCc1ccccc1
Reactant: CCCCN(CCCC)C(=O)c1cc(C)n(-c2cc(O)ccc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)C(=O)c1cc(C)n(-c2cc(OCC(=O)OCc3ccccc3)ccc2C(=O)N2Cc3ccccc3C[C@H]2CO)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.5 %

Procedure:
A solution of 1-[5-hydroxy-2-((S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-phenyl]-5-methyl-1H-pyrazole-3-carboxylic acid dibutylamide (intermediate E, 29 mg, 0.056 mmol) and potassium tert-butoxide (0.062 mL, 1M, 0.062 mmol) in tetrahydrofuran (0.5 mL) was stirred at ambient temperature for 10 minutes. Benzyl 2-chloroacetate (0.010 mL, 0.067 mmol) was added and the mixture was stirred at ambient temperature for 2 hours. Ethyl acetate and aqueous HCl solution was added until the pH was about 7. The organic layer was eluted through a short pad of silica gel column and the crude material was purified by HPLC and prep TLC to afford the title compound (1.3 mg, 3.5% yield). MS (ESI) [m/e, (M+H)+]=667.3. 1H NMR (400 MHz, chloroform-d) δ ppm 6.74-7.70 (m, 12H), 6.15-6.31 (m, 1H), 3.94-5.36 (m, 8H), 2.56-3.71 (m, 6H), 2.09-2.35 (m, 3H), 0.65-1.70 (m, 14H).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1>C(O)CC(C)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([C:3]3[NH:12][C:11](=[O:13])[C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[N:4]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CC(C)CCO
Product: O=c1[nH]c(N2CCN(c3ccc(F)cc3)CC2)nc2c1CCCC2

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and 1-(4-fluorophenyl)piperazine (91.8 μl; 0.51 mmol) are suspended in isoamyl alcohol (1 ml), and the mixture is irradiated in the microwave (CEM Discover) at 150° C. for 2 h with stirring. The precipitated crystals are filtered off with suction, rinsed thoroughly with ethanol and diethyl ether and filtered off with suction. The crude product obtained in this way is rinsed again with hot ethanol and diethyl ether, filtered off with suction and dried in vacuo at 50° C.; yield: 86 mg (50%), crystals;
Reaction SMILES: I[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH2:11][C:10]3([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[O:9][C:8]2=[O:17])=[CH:4][CH:3]=1.[CH2:20]([N:27]1[CH2:32][CH2:31][O:30][CH:29](B(O)O)[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.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>[N:27]1([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[C:2]2[CH:19]=[CH:18][C:5]([CH2:6][N:7]3[CH2:11][C:10]4([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[O:9][C:8]3=[O:17])=[CH:4][CH:3]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: OB(O)C1CN(Cc2ccccc2)CCO1
Reactant: O=C1OC2(CCCCC2)CN1Cc1ccc(I)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: COCCOC
Solvent: ClCCl
Product: O=C1OC2(CCCCC2)CN1Cc1ccc(-c2ccccc2CN2CCOCC2)cc1
Yield: 83.5 %

Procedure:
3-(4-Iodo-benzyl)-1-oxa-3-aza-spiro[4.5]decan-2-one (55 mg, 0.148 mmol) and benzylmopholine-2-boronic acid (49 mg, 0.222 mmol) were mixed in ethylene glycol dimethyl ether (1 mL) and sodium carbonate (2M) aqueous solution (1 mL). Tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (17 mg, 0.0148 mmol) was added and the reaction mixture was heated at 100˜110° C. for 1˜1.5 hours. The reaction was diluted with dichloromethane (DCM), washed with water (4 mL) and brine (4 mL). The organic phase was separated, dried over anhydrous sodium sulfate and concentrated. The crude residue was purified on silica gel eluting with 5-30% ethyl acetate in hexane to give the product as off-white solid (52 mg, 83%). 1H NMR (300 MHz, CDCl3): δ 7.49 (m, 1H), 7.42 (d, 2H), 7.32 (m, 5H), 4.5 (s, 2H), 3.65 (t, 4H), 3.39 (s, 2H), 3.18 (s, 2H), 2.36 (t, 4H), 1.82 (m, 4H), 1.54 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH3:15])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CON(C)[C:25](=[O:27])[CH3:26]>O1CCCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH2:15][C:25](=[O:27])[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)cccc1NC(=O)OC(C)(C)C
Reactant: CON(C)C(C)=O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(=O)Cc1c(Cl)cccc1NC(=O)OC(C)(C)C
Temperature: -10 °C
Yield: 88.7 %

Procedure:
To a cold solution of (3-Chloro-2-methyl-phenyl)-carbamic acid tert-butyl ester (5.0 g, 20.7 mmol) in anhydrous tetrahydrofuran (100 ml) at −40° C. under N2, was added a solution of s-butyl lithium (40 ml, 52 mmol, 1.3 M in cyclohexane) dropwise and maintained the reaction temperature below −30° C. To the bright yellow solution at −50° C. was added a solution of N-methoxy N-methylacetamide (2.33 g, 22.6 mmol) in anhydrous tetrahydrofuran (40 ml) dropwise and maintained the reaction temperature between −50° C. to −40° C. The mixture was allowed to warm to −10° C. over a period of 35 minutes and was then partitioned between diethyl ether and 0.3 N hydrochloric acid solution. The organic extract was washed with water and brine, dried (anhydrous sodium sulfate), and concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 20% ethyl acetate in hexane to give crude [3-Chloro-2-(2-oxo-propyl)-phenyl]-carbamic acid tert-butyl ester (5.21 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][N:9]([C:12]3[CH:13]=[C:14]([CH:19]=[CH:20][N:21]=3)[C:15](OC)=[O:16])[C:8]2=[O:22])=[CH:4][CH:3]=1.[C-:25]#[N:26].[Na+]>C(N)C1C=CC=CC=1>[CH2:25]([NH:26][C:15](=[O:16])[C:14]1[CH:19]=[CH:20][N:21]=[C:12]([N:9]2[CH2:10][CH2:11][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:24][CH:23]=3)[C:8]2=[O:22])[CH:13]=1)[C:2]1[CH:24]=[CH:23][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 120.5 %

Procedure:
A solution of methyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinate (0.26 g, 0.78 mmol) and sodium cyanide (78 mg, 1.56 mmol) in benzylamine (5.0 mL) was stirred at 95° C. for 16 hours and concentrated in vacuo. The residue was purified by column chromatography eluting with 0 to 90% of ethyl acetate in hexanes to give N-benzyl-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide as a colorless solid (0.19 g, yield 59%): mp 167-169° C.; 1H NMR (300 MHz, CDCl3) δ 8.57 (d, J=0.6 Hz, 1H), 8.37 (d, J=5.1 Hz, 1H), 7.42-7.18 (m, 8H), 7.08-6.98 (m, 2H), 6.79 (br s, 1H), 4.62 (d, J=6.0 Hz, 2H), 4.41 (s, 2H), 4.03 (t, J=7.5 Hz, 2H), 3.36 (t, J=7.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 165.7, 164.0, 160.7, 157.0, 153.0, 148.4, 143.0, 137.7, 132.1, 132.0, 129.9, 129.8, 128.8, 128.0, 127.7, 116.1, 115.8, 115.6, 109.0, 47.2, 44.2, 41.3, 41.0; MS (ES+) m/z 405.2 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][S:14](O)(=[O:16])=[O:15])=[C:8]([O:18][CH3:19])[CH:7]=1.C(OCC)(=O)C>CN(C=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][S:14]([Cl:3])(=[O:16])=[O:15])=[C:8]([O:18][CH3:19])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Cl)ccc1C=CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Cl)ccc1C=CS(=O)(=O)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
Thionyl chloride (8.1 mL, 111.19 mmol) was added dropwise at 0° C. to a solution of 2-(4-chloro-2-methoxy-phenyl)-ethenesulfonic acid (5.53 g, 22.24 mmol) in DMF (10 mL). The reaction mixture was stirred at RT for 3 h and then was poured onto crushed ice. Ethyl acetate (50 mL) was added to the mixture. The organic phase was separated, washed with brine (3×20 mL), dried over MgSO4 and concentrated under reduced pressure. The oily residue was purified on silica gel using hexane/ethyl acetate, 4:1 to give the target compound which was then recrystallized from pentane/diethyl ether to afford the title compound (2.30 g, 61% over 3 steps) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][O:8][C:9]1[C:17]([CH2:18]Cl)=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:20][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[C:1]([O:5][C:6]([CH:7]1[O:8][C:9]2=[CH:10][CH:11]=[C:12]3[C:16]([N:15]([CH2:20][C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])[N:14]=[CH:13]3)=[C:17]2[CH2:18]1)=[O:31])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](Cn1ncc2ccc(OCC(=O)OC(C)(C)C)c(CCl)c21)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C[C@H](Cn1ncc2ccc3c(c21)CC(C(=O)OC(C)(C)C)O3)O[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Yield: 18 %

Procedure:
To a solution of the product from Step B (2.90 g, 6.18 mmol) in anhydrous 1-methyl-2-pyrrolidone (30 mL) was added sodium hydride (60%, 0.371 g, 9.27 mmol). The mixture was heated at 50° C. overnight and at ambient temperature for 2 days, cooled and poured into a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate. Chromatography on silica (gradient, 2% to 25% ethyl acetate in hexane) gave an oil (0.48 g, 18%): LC/MS (+APCI) m/z 433(M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: Clc1ccc(I)cn1
Reactant: C1COCCN1
Product: Ic1ccc(N2CCOCC2)nc1

Procedure:
A solution of 2-chloro-5-iodo pyridine (0.200 g, 0.836 mmol) in morpholine (3.0 mL) was refluxed for 12-15 h. The reaction mass was quenched in ice and the solid obtained was filtered off to afford 0.170 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 3.40 (t, J=4.8 Hz, 4H), 3.67 (t, J=4.5 Hz, 4H), 6.74 (d, J=8.7 Hz, 1H), 7.77-7.81 (m, 1H), 8.28 (s, 1H).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7](Cl)(=O)=O)=[CH:3][CH:2]=1.[C:12]1([S:18](Cl)(=O)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18][S:7][C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: c1ccc(SSc2ccccc2)cc1
Yield: 93 %

Procedure:
One proceeds according to Example 1 except that p-toluene sulfonyl chloride is replaced by benzene sulfonyl chloride as starting material. Thus 10 g of phenyl-disulfide are obtained, yield 93%. Mp.: 58°-60° C.
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.C(#[N:17])C.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C>[CH:8]1[CH:7]=[CH:6][C:5]2[O:1][N:2]=[C:3]([CH2:10][S:11]([OH:14])(=[O:12])=[NH:17])[C:4]=2[CH:9]=1
Reactant: CC#N
Reactant: O=S(=O)(O)Cc1noc2ccccc12
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: N=S(=O)(O)Cc1noc2ccccc12
Temperature: 65 °C

Procedure:
1,2-Benzisoxazole-3-methanesulfonic acid (1) (20.0 g, 93.8 mmol) was mixed with acetonitrile (60 mL) and heated to reflux. The clear solution was cooled to 65° C. and phosphorous oxychloride (5.7 mL; 62.3 mmol) was added. The mixture was heated to reflux for 10 hours and then cooled to room temperature. Ethyl acetate (100 mL) was added and the mixture was filtered through CELITE™, which was subsequently washed with ethyl acetate (40 mL). The filtrate was cooled in an ice bath and ammonia gas was bubbled through the solution for 1 hour. The mixture was concentrated and water (100 mL) was added. The mixture was heated to reflux and cooled. It was concentrated, cooled in an ice-bath and filtered to yield crude zonisamide. Purification was achieved by recrystallization from iso-propanol/water. The yield of purified product was 78.8%.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[C:10]([C:12]([O:14]C)=[O:13])[N:11]=1)=[O:5].[OH-].[Na+].Cl>CO>[F:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[S:8][C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1)=[O:5]
Reactant: COC(=O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1nc(NC(=O)c2c(F)cccc2F)sc1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
Into a solution of Compound 35 (884 mg, 2 mmol) in 20 mL of MeOH was added NaOH (400 mg, 10 mmol). The solution was heated to reflux for 1 hour and cooled down to room temperature. The reaction was neutralized with 2N HCl and extracted with Et2O. The combined extracts were washed with water, dried (Na2SO4), filtered and concentrated. Recrystallization from Et2O gave Compound 66 (810 mg, 95%) as a white solid.
Reaction SMILES: O[C:2]([C:5]1[C:6]([OH:17])=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)([CH3:4])[CH3:3].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH:2]([C:5]1[C:6]([OH:17])=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)([CH3:4])[CH3:3]
Reactant: COc1ccc2cc(O)c(C(C)(C)O)cc2c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2cc(O)c(C(C)C)cc2c1
Reaction time: 0.67 h
Yield: 53.7 %

Procedure:
To a stirring solution of 3-(1-hydroxy-1-methyl-ethyl)-6-methoxy-naphthalen-2-ol (2.4 g, 10.33 mmol) in 50 mL dichloromethane at room temperature under nitrogen atmosphere, was added triethyl silane (16.5 mL, 103.3 mmol) followed by trifluoroacetic acid (7.96 mL, 103.3 mmol). The reaction mixture was stirred for 40 minutes, after which solvent was removed under reduced pressure. The residue was partitioned between dichloromethane and saturated aqueous potassium carbonate solution. The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give 1.2 g of 3-isopropyl-6-methoxy-naphthalen-2-ol as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[C:10]=2[CH:30]=1)=[O:5])[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[C:10]=2[CH:30]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(C=Cc4ccccc4)cc3)c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc2nc(C)n(Cc3ccc(CCc4ccccc4)cc3)c2c1

Procedure:
Five-percent palladium on carbon was added to a solution of 0.320 g of 6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethenyl)benzyl]benzimidazole in 10 ml of ethanol in a nitrogen atmosphere, and the mixture was stirred in a hydrogen atmosphere for 23 hours. The solid material was separated through filtration, and the filtrate was concentrated to give 6-ethoxycarbonyl-2-methyl-1-[4-(2-phenylethyl)benzyl]-benzimidazole (368). This compound was used in the subsequent reaction at once.
Reaction SMILES: [C:1]([CH2:9]C(O)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1>>[CH3:9][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(O)CC(=O)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)c1ccccc1
Yield: 100 %

Procedure:
When reacting 10 mmol of benzoylacetic acid with 20 mmol DBU at 25° C. for 3 hrs., phenyl methyl ketone was obtained in a yield of 100% of theory.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH3:21]>[Ni]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH3:21]
Reactant: COC(=O)Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1C
Agent: [Ni]
Product: COC(=O)Cc1ccc(Nc2ncccc2N)cc1C
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
A suspension of 2.2 g of [2-methyl-4-(3-nitro-pyridin-2-ylamino)-phenyl]-acetic acid methyl ester and 220 mg of Raney Ni is stirred for 6.5 hours at rt under a hydrogen atmosphere. The mixture obtained is filtered through a pad of celite and concentrated. [4-(3-Amino-pyridin-2-ylamino)-2-methyl-phenyl]-acetic acid methyl ester is obtained. ES-MS: 272.1 [M+H]+; tR=2.53 min (System 1).