Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]([C:28]1[CH:49]=[CH:48][C:31]([C:32]([NH:34][C@H:35]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:33])=[CH:30][CH:29]=1)=[CH:10][N:11]1[C:16]([OH:17])=[C:15]2[CH:18]=[C:19]([NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[N:20]=[C:14]2[N:13]=[CH:12]1>C(O)(=O)C.CO.[Pt](=O)=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]([C:28]1[CH:49]=[CH:48][C:31]([C:32]([NH:34][C@H:35]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[O:33])=[CH:30][CH:29]=1)[CH2:10][N:11]1[C:16]([OH:17])=[C:15]2[CH:18]=[C:19]([NH:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:26])[CH3:25])[N:20]=[C:14]2[N:13]=[CH:12]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(=Cn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)COC2CCCCO2)cc1)C(=O)OCC
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(COC2CCCCO2)Cn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)cc1)C(=O)OCC

Procedure:
A solution of 1.16 g of diethyl N-[4-(1-(tetrahydropyr-2-yloxy)-3-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidin-3-yl)prop-2-en-2-yl)benzoyl]glutamate and 174 mg (20%) of amorphous platinum (IV) oxide in 150 ml of glacial acetic acid is hydrogenated for 10 hours at 50 psi. The reaction mixture is diluted with 50 ml of methanol and filtered through Celite. The filtrate is concentrated and diluted with ethyl acetate. The solid which forms after cooling for 15 hour is collected by filtration, washed with cold ethyl acetate and dried to give diethyl N-[4-(1-(tetrahydropyr-2-yloxy)-3-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidin-3-yl)prop-2-yl)benzoyl]glutamate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[S:15]([NH:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:22]([CH3:42])=[CH:21][C:20]=1[OH:43])(=[O:17])=[O:16].[Cl-].[NH4+].O>[Fe].C(O)(C)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[S:15]([NH:18][C:19]1[CH:24]=[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:22]([CH3:42])=[CH:21][C:20]=1[OH:43])(=[O:16])=[O:17]
Reactant: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc([N+](=O)[O-])ccc2OCCOC)c(O)cc1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCCCCOc1cc(NS(=O)(=O)c2cc(N)ccc2OCCOC)c(O)cc1C
Reaction time: 1 h

Procedure:
32 g of 2-[2'(2-methoxyethoxy)-5'-nitrobenzenesulfonamido]-4-hexadecyloxy-5-methylphenol prepared as described in Step (b) above, 24 g of iron powder, 12 g of Fe2O4, 0.6 g of ammonium chloride and 25 ml of water were added to 300 ml of isopropyl alcohol and the mixture was refluxed on a stream bath with stirring for 1 hour. After completion of the reaction, the mixture was filtered while hot and the filtrate was cooled with ice. The crystals thus precipitated were recovered by filtration, washed with 50 ml of isopropyl alcohol and air-dried. Yield: 23 g; Melting Point: 142°to 144° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[CH:7][CH:6]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14](OC)=[CH:13][CH:12]=2)[C:5](=[O:19])[CH:4]=1.[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]N.C(Cl)(Cl)Cl.CO>CO>[C:11]1([CH:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:9][C:6]2[C:5](=[O:19])[CH:4]=[C:3]([CH2:2][OH:1])[N:8]([CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])[CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(COC2C=NC(CO)=CC2=O)cc1
Reactant: CN(C)CCN
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN(C)CCn1cc(OC(c2ccccc2)c2ccccc2)c(=O)cc1CO
Reaction time: 14 h

Procedure:
To a suspension of 1.542 g of 6-hydroxymethyl-3-(p-methoxybenzyl)oxy-4-pyridone in 10 ml of methanol is added 4.408 g of N,N-dimethylethylenediamine, and the mixture is stirred for 14 hours. The reaction mixture is condensed under reduced pressure, and subjected to flash column chromatography on 50 g of Wako-Gel C-300 (manufactured by Wako Pure Chemical Industries, Ltd.) with an eluent of chloroform-methanol (10:1) to perform separation and purification. The title compound is obtained as colorless crystal in a yield of 1.174 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[OH-].[Na+].Br[CH2:13][CH2:14][O:15][CH3:16]>C(O)C.O>[CH3:16][O:15][CH2:14][CH2:13][O:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=1
Reactant: COCCBr
Reactant: OCc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COCCOc1cccc(CO)c1
Temperature: 25 °C

Procedure:
To a solution of 3-hydroxybenzyl alcohol (27A) (12.41 g, 100 mmol) in ethanol (150 mL) was added aqueous NaOH (10 N, 10 mL), followed by 1-bromo-2-methoxyethane (27B) (13.9 g). The reaction mixture was heated to reflux overnight. Then the reaction mixture was allowed to cool to RT, and diluted with water. The mixture was subsequently extracted with CH2Cl2, and the combined organic phase was dried with anhydrous MgSO4 filtered, and concentrated in vacuum to give the product (27C) a yellow oil, which was used for the next reaction without further purification. 1H NMR (300 MHz, CDCl3): δ 1.82 (br, 1H), 3.44 (s, 3H), 3.74 (t, 2H, J=4.8 Hz), 4.12 (t, 2H, J=4.8 Hz), 4.65 (s, 2H), 6.84-6.95 (m, 3H), 7.22-7.26 (m, 1H). LCMS: purity >94%. ESI-MS: M/Z 183(M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18](I)[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.[Si:21]([C:25]#[CH:26])([CH3:24])([CH3:23])[CH3:22]>C1COCC1.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:19]=[C:18]([C:26]#[C:25][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([NH2:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: C#C[Si](C)(C)C
Reactant: Cn1cc(C(N)=O)c(Nc2ccc(I)cc2F)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(C(N)=O)c(Nc2ccc(C#C[Si](C)(C)C)cc2F)cc1=O
Yield: 100 %

Procedure:
4-(2-Fluoro-4-iodoanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was reacted with TMS-acetylene in the presence of CuI, (Ph3P)2PdCl2 and TEA in THF/DMF (1:1) as for example 2. The residue resulting from removal of the reaction solvents under reduced pressure was purified by column chromatography on silica gel (10% MeOH/CH2Cl2 as eluant) to give 4-{2-fluoro-4-[(trimethylsilyl)ethynyl]anilino}-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a pale yellow solid (100%), used directly in the next step. 1H NMR [(CD3)2SO, 400 MHz] δ 10.66 (s, 1H), 8.38 (s, 1H), 7.92 (br s, 1H), 7.50 (t, J=8.5 Hz, 1H), 7.48 (br s, 1H), 7.42 (dd, J=11.5, 1.8 Hz, 1H), 7.30 (dd, J=8.3, 1.4 Hz, 1H), 5.73 (s, 1H), 3.38 (s, 3H), 0.23 (s, 9H). HRMS (EI+) calcd C18H20FN3O2Si (M+) 357.1309, found 357.1308.
Reaction SMILES: [CH:1]1([O:6][C:7](=[O:23])[CH:8]([O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:24][N:25]1[CH:29]([CH2:30][CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:28][N:27]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=2)[C:26]1=[O:54].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([O:6][C:7](=[O:23])[CH:8]([O:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:31][CH2:30][CH:29]3[CH2:28][N:27]([CH2:43][C:44]4[CH:49]=[CH:48][C:47]([C:50]([F:52])([F:53])[F:51])=[CH:46][CH:45]=4)[C:26](=[O:54])[N:25]3[CH3:24])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Reactant: O=C(OC1CCCC1)C(Cc1ccc(O)cc1)OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CC(OC2CCCC2)C(=O)OC2CCCC2)cc1
Temperature: 65 °C
Yield: 63.3 %

Procedure:
A mixture of 2-cyclopentyloxy-3-(4-hydroxy-phenyl)-propionic acid cyclopentyl ester(0.090 g, 0.283 mmol), toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (0.140 g, 0.307 mmol) and Cs2CO3 (0.138 g, 0.423 mmol) in DMF (10 mL) was heated to 65° C. under N2 for 16 h. The reaction was cooled and quenched with 1 N HCl (10 mL) and worked up extractively with Et2O and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 3:1 hexanes:acetone to afford 0.108 g (64%) 2-cyclopentyloxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid cyclopentyl ester. 1H NMR. MS (ES+) Calc'd for C33H42N2O5F3 (M+1) 603. Found m/z 603 (100%).
Reaction SMILES: C1C2C(COC([N:18]3[C@H:27]([C:28](O)=[O:29])[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:31]([C:35]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH2:40][NH:41][CH2:42][CH2:43][C:38]=2[C:37](=[O:44])[O:36]1)[CH:32]([CH3:34])[CH3:33].CCN(C(C)C)C(C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH2:31]([C:35]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH2:40][N:41]([C:28]([C@@H:27]3[CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][NH:18]3)=[O:29])[CH2:42][CH2:43][C:38]=2[C:37](=[O:44])[O:36]1)[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CNCC2
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)[C@@H]1Cc3ccccc3CN1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
To a solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (147 mg, 0.369 mmol), 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (50 mg, 0.184 mmol), and N,N′-diisopropylethylamine (112 mg, 0.870 mmol) in THF (5 mL) was added BOP reagent (144 mg, 0.326 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness, re-dissolved in 20% piperidine in DMF (5 mL), and stirred at room temperature for 1 hour. The crude reaction mixture was concentrated and purified by column chromatography (12 g, SiO2, 0 to 100% ethyl acetate in hexanes) to provide 3-isobutyl-3-phenyl-5-((S)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (54 mg, 68%) as a mixture of diastereoisomers in form of white solid: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.81-1.01 (m, 6H), 1.59-1.74 (m, 1H), 1.75-1.88 (m, 1H), 2.26-2.52 (m, 3H), 2.71-2.85 (m, 1H), 2.87-3.10 (m, 1H), 3.37-3.72 (m, 2H), 3.76-3.99 (m, 2H), 4.00-4.15 (m, 3H), 4.62-4.86 (m, 1H), 7.01-7.22 (m, 4H), 7.28-7.45 (m, 5H); MS m/z 431 (M+H)+, 429 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH2:11]([O:13][CH:14]([O:17][CH2:18][CH3:19])[CH2:15]Br)[CH3:12].CCO.[OH-].[Na+]>O>[Cl:1][C:2]1[N:6]([CH2:15][CH:14]([O:17][CH2:18][CH3:19])[O:13][CH2:11][CH3:12])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CCOC(CBr)OCC
Reactant: Clc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(Cn1c(Cl)nc2ccccc21)OCC

Procedure:
A mixture of 2-chloro-1H-benzimidazole (6.10 g), bromoacetaldehyde diethyl acetal (7.22 mL), EtOH (70 mL), and 8 M NaOH aqueous solution (10 mL) was refluxed for 3 d. The reaction mixture was poured into water and the mixture was extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (10/1) to give 2-chloro-1-(2,2-diethoxyethyl)-1H-benzimidazole (5.50 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1.[F:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][C:41]=1F)[C:35]([O:37][CH3:38])=[O:36].[H-].[Na+].O>CS(C)=O>[F:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][C:41]=1[O:1][C:2]1[CH:3]=[C:4]([C:14]2[NH:15][C:16]([C:19]3[S:20][CH:21]=[CH:22][N:23]=3)=[CH:17][CH:18]=2)[CH:5]=[C:6]([O:8][C@@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:7]=1)[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)c1ccc(F)c(F)c1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(-c3nccs3)n2C(=O)OC(C)(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)OC)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 17.8 %

Procedure:
t-Butyl 2-{3-hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-1-carboxylate (485 mg, 1.127 mmol) synthesized in Example (38d) and commercially available methyl 3,4-difluorobenzoate (540 mg, 3.137 mmol) were dissolved in dimethyl sulfoxide (10 mL), and sodium hydride (60%, 180 mg, 4.50 mmol) was added, followed by stirring at 100° C. for 2.5 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (50 mL) was added, and extraction was carried out with diethyl ether (50 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=10%-30%) to afford the desired compound (97 mg, yield 18%) as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2([O:16][CH2:17][CH3:18])[CH2:15][CH2:14]2)=[C:9]([CH:19]([CH3:21])[CH3:20])[CH:8]=1)(=O)=O.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>C(N(CC)CC)C.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:17]([O:16][C:13]1([C:10]2[CH:11]=[CH:12][C:7]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:8][C:9]=2[CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]1)[CH3:18]
Reactant: CCOC1(c2ccc(OS(=O)(=O)C(F)(F)F)cc2C(C)C)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC1(c2ccc(C#C[Si](C)(C)C)cc2C(C)C)CC1

Procedure:
Using General Procedure D; 4-(1-ethoxycyclopropyl)-3-isopropylphenyl 1,1,1-trifluoromethansulfonate (Intermediate 101, 240.0 mg, 0.68 mmol) in triethylamine (2 mL) and DMF (6 mL) was sparged with argon for 5 minutes. Trimethylsilylacetylene (0.70 g, 7.1 mmols) was then added followed by dichlorobis-(triphenylphosphine)palladium(II) (38.0 mg, 0.05 mmol). The resulting reaction mixture was heated to 95° C. for 5d. The title compound, 200.0 mg (99%), was isolated by chromatography (0-2% EtOAc-hexanes) as an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>ClCCl.CN(C1C=CN=CC=1)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:26])[CH3:25])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(Cc1ccc(O)cc1Br)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)OCc2ccccc2)c(Br)c1
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of benzyl (2-bromo-4-hydroxyphenyl)acetate (2.00 g) in dichloromethane (30.0 mL) were added tert-butyl (chloro)dimethylsilane (1.13 g) and N,N-dimethyl-4-aminopyridine (913 mg) under ice-cooling, followed by stirring for 2 hours under ice-cooling. The reaction mixture was diluted with water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain benzyl (2-bromo-4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)acetate (2.63 g).
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>ClCCCl>[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
Solvent: ClCCCl
Product: O=S(=O)(Cl)Cc1noc2ccccc12

Procedure:
1,2-Benzisoxazole-3-methanesulfonic acid (1) (1.00 g, 4.7 mmol) was mixed with 1,2-dichloroethane (10 mL) and phosphorous oxychloride (2.0 mL, 21 mmol). The mixture was heated to reflux until the reaction was complete, filtered through CELITE™ and evaporated to give 1,2-benzisoxazole-3-methanesulfonyl chloride (2). It was converted into zonisamide in analogy to the previous examples.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH:16]3[CH2:18][CH2:19][CH:13]2[CH2:14][CH2:15]3)=[CH:6][CH:5]=1)#[CH:3].[Li]CCCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[CH:13]12[CH2:14][CH2:15][CH:16]([CH2:18][CH2:19]1)[CH2:17][N:12]2[CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:2]#[C:3][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:21][CH:20]=1
Reactant: CCOC(=O)Cl
Reactant: C#Cc1ccc(OCCCN2CC3CCC2CC3)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc(OCCCN2CC3CCC2CC3)cc1

Procedure:
In the b) route of scheme 2,2-azabicyclo[2.2.2]octane hydrochloride (isoquinuclidine hydrochloride) (8) is reacted with TMS-ethynyl-phenyl ether derivative (3) in the presence of K2CO3 and potassium iodide (KI). The resulting 2-[3-(4-ethynylphenoxy)propane-1-yl]-2-azabicyclo[2.2.2]octane (9) is treated with ethyl ether solution in saturated hydrochloride gas (HCl gas in ether) to obtain 2-[3-(4-ethynylphenoxy)propane-1-yl]-2-azabicyclo[2.2.2]octane hydrochloride (compound 10). Further, this compound 10 is treated with n-BuLi, then it is reacted with ethyl chloroformate in tetrahydrofuran (THF) to give an ethyl 4-[3-(2-azabicyclo[2.2.2]octan-2-yl)propoxy]phenylpropiolate (11), then it is treated by the same method as mentioned above to provide an ethyl 4-[3-(2-azabicyclo[2.2.2]octan-2-yl)propoxy]phenylpropiolate hydrochloride (compound 12). In case of both R1 and R2 are hydrogen and m is 0 or 2 in the compounds of general formula (1), compound 13 (m=0) and compound 14 (m=2), it is prepared by the same method of scheme 1 and a) route of scheme 2 using either a 1,2-dibromoethane or a 1,4-dibromobutane in the place of a 1-bromo-3-chloropropane. ##STR4##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:32])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([O:23]CC2C=CC=CC=2)=[C:19]2[C:14]=1[CH2:15][CH2:16][C:17](=[O:31])[NH:18]2.C(O)C.[ClH:41].[H][H]>CO.[C].[Pd]>[ClH:41].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:32])[CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]2[C:14]=1[CH2:15][CH2:16][C:17](=[O:31])[NH:18]2
Reactant: COc1ccc(CCNCC(O)COc2ccc(OCc3ccccc3)c3c2CCC(=O)N3)cc1OC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: COc1ccc(CCNCC(O)COc2ccc(O)c3c2CCC(=O)N3)cc1OC
Temperature: 25 °C

Procedure:
2.0 g of 5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-8-benzyloxy-3,4-dihydrocarbostyril was suspended in 50 ml of methanol, and an ethanol solution containing hydrogen chloride was added to the suspension until the mixture showed acidity. After the mixture became homogenous, 0.7 g of 10% palladium carbon was added thereto followed by stirring at room temperature and at atmospheric pressure thereby absorbing hydrogen. The reaction completed when the absorption of hydrogen ceased. The catalyst was removed by filtration, and the methanol evaporated. A small amount of ethanol was added to the residue to crystallize the product. Recrystallization from ethanol gave 1.5 g of 5-[3-(3,4-dimethoxyphenethylamino)-2-hydroxypropoxy]-8-hydroxy-3,4-dihydrocarbostyril hydrochloride as colorless powdery crystals having a melting point of 171°-173° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:32]=[CH:31][C:10]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[CH:25]=3)=[O:23])[CH:17]=[CH:18][C:19]=2[CH3:20])=[O:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O>[CH2:1]([N:3]([CH2:6][C:7]1[CH:32]=[CH:31][C:10]([C:11]([NH:13][C:14]2[CH:15]=[C:16]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH:25]=3)=[O:23])[CH:17]=[CH:18][C:19]=2[CH3:20])=[O:12])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3ccnc(Cl)c3)ccc2C)cc1
Solvent: O
Product: CCN(CC)Cc1ccc(C(=O)Nc2cc(NC(=O)c3ccnc(N4CCOCC4)c3)ccc2C)cc1
Temperature: 110 °C

Procedure:
Using an analogous procedure to that described in Example 3, a mixture of N-[3-(4diethylaminomethylbenzamido)-4-methylphenyl]-2-chloropyridine-4-carboxamide (0.5 g) and morpholine (5 ml) was stirred and heated to 110° C. for 16 hours. The resultant solution was cooled to ambient temperature and poured into water. The resultant solid was isolated, washed with diethyl ether and dried under vacuum at 40° C. There was thus obtained the title compound (0.021 g); NMR Spectrum: (DMSOd6) 1.0 (t, 6H), 2.2 (s, 3H), 2.44-2.49 (m, 4H), 3.42-3.57 (m. 4H), 3.6 (s, 2H), 3.65-3.63 (m, 4H), 7.08 (d, 1H), 7.2-7.25 (m, 2H), 7.45 (d, 2H), 7.58 (d, 1H), 7.79 (s, 1H), 7.92 (d, 2H), 8.26 (d, 1H), 9.83 (s, 1H), 10.28 (s, 1H); Mass Spectrum: M+H− 502.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[C:11]([O:24]C)[CH:10]=3)[CH3:2].[H-].[Na+].C(S)CCC.Cl>CN(C=O)C>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][CH:12]=[C:11]([OH:24])[CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(NCc3ccccc3)c3ccc(OC)cc3nc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCS
Product: CCn1ncc2c(NCc3ccccc3)c3ccc(O)cc3nc21
Temperature: 0 °C
Yield: 37.7 %

Procedure:
1-Ethyl-7-methoxy-N-(phenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (4 g, 0.012 mol) in DMF (70 ml) is treated with 60% NaH (2.4 g, 0.06 mol), followed by butane thiol (5.4 g, 0.06 mol). The reaction mixture is refluxed overnight and then is poured into ice water. The mixture is acidified with 2N HCl and then is extracted with ethyl acetate (2×500 ml). The aqueous layer is treated with solid NaHCO3 to adjust the pH to about 8, then the mixture is extracted with ethyl acetate (2×500 ml). The ethyl acetate layers are combined, washed with water, filtered and evaporated. The solid residue is recrystallized from ethyl acetate (2×) to afford 1.44 g of 1-ethyl-7-hydroxy-N-(phenylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 252°-254° C.
Reaction SMILES: Cl.[Cl-].[N:3]1[CH:8]=[CH:7][C:6]([N+:9]2[CH:14]=[CH:13]C=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N1CCOCC1)=[O:16]>>[O:16]1[CH2:13][CH2:14][N:9]([C:6]2[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=2)[CH2:10][CH2:11]1
Reactant: O=CN1CCOCC1
Reactant: c1cc[n+](-c2ccncc2)cc1
Agent: Cl
Agent: [Cl-]
Product: c1cc(N2CCOCC2)ccn1
Yield: 59 %

Procedure:
With complete analogy to Examples 5 and 6, the reaction of 4-pyridylpyridinium chloride hydrochloride with N-formylmorpholine produced, in a 59% yield, 4-morpholinopyridine, m.p. 93-95° C. (from ligroin).