Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(OC(C)(C)C)=O.N[C:10]1[O:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=1.[ClH:20]>[Cu](Cl)Cl.C(#N)C>[Cl:20][C:10]1[O:11][CH:12]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:14]=1
Reactant: Cl
Reactant: CCOC(=O)c1coc(N)n1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)O[N+](=O)[O-]
Solvent: CC#N
Product: CCOC(=O)c1coc(Cl)n1
Temperature: 80 °C

Procedure:
To a mixture of tert-butyl nitrate (2.86 mL), copper(II) chloride (3.23 g) and acetonitrile (64 mL) was added ethyl 2-amino-1,3-oxazole-4-carboxylate obtained in Step A (2.50 g) at 60° C. The reaction mixture was heated at 80° C. for 3 hr, and cooled to room temperature. The reaction mixture was poured into 1 M hydrochloric acid, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.90 g).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][C:39]=1[F:40])[NH:17][C:18]1[CH:34]=[C:33]([F:35])[C:32]([F:36])=[CH:31][C:19]=1[C:20]([NH:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21]>>[Cl:13][C:14]1[CH:15]=[C:16]([N:17]2[C:18]3[C:19](=[CH:31][C:32]([F:36])=[C:33]([F:35])[CH:34]=3)[C:20](=[O:21])[N:22]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:1]2=[O:2])[CH:37]=[CH:38][C:39]=1[F:40]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(F)cc1Nc1ccc(F)c(Cl)c1
Product: O=c1c2cc(F)c(F)cc2n(-c2ccc(F)c(Cl)c2)c(=O)n1OCc1ccccc1
Yield: 19.6 %

Procedure:
Using General Method 3, the reaction of carbonyldiimidazole (4.9 g, 30 mmol) and crude 2-(3-chloro-4-fluoro-anilino)-N-benzyloxy-4,5-difluoro-benzamide (Example W, 6.1 g, 15 mmol) provided 1.27 g of the title compound as a solid, mp 184-186° C.
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]1([NH2:9])[CH2:8][CH2:7]1.C[O:11][C:12](=O)[C:13]1[CH:18]=[C:17]([N:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]3([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[OH:35])[CH2:28][CH2:27]3)[C:20]2=[O:36])[C:16]([CH3:37])=[C:15]([F:38])[CH:14]=1.Cl>C1COCC1.O>[CH:6]1([NH:9][C:12](=[O:11])[C:13]2[CH:18]=[C:17]([N:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[OH:35])[CH2:28][CH2:27]4)[C:20]3=[O:36])[C:16]([CH3:37])=[C:15]([F:38])[CH:14]=2)[CH2:8][CH2:7]1
Reactant: NC1CC1
Reactant: COC(=O)c1cc(F)c(C)c(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (30.1 ml of a 2M solution in THF) was added over 20 min to a solution of cyclopropylamine (10.61 mL) and 3-fluoro-5-[3-[[1-(2-hydroxyphenyl)cyclopropyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid methyl ester (Preparation 1j, 6.16 g) in tetrahydrofuran (200 mL) and the reaction stirred at room temperature under nitrogen for 1 h. Water (100 mL) and 2M HCl (200 mL) were cautiously added and the aqueous layer extracted with dichloromethane (3×200 mL) and the combined organic extracts dried (MgSO4) and the solvent removed to give the subtitle compound (5.00 g).
Reaction SMILES: [N:1]1([S:7]([CH2:10][C@H:11]([NH:15][C@@H:16]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:17]([F:20])([F:19])[F:18])[C:12]([OH:14])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[NH2:29][C:30]1([C:33]#[N:34])[CH2:32][CH2:31]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[C:33]([C:30]1([NH:29][C:12](=[O:14])[C@@H:11]([NH:15][C@@H:16]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:17]([F:18])([F:20])[F:19])[CH2:10][S:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)(=[O:9])=[O:8])[CH2:32][CH2:31]1)#[N:34]
Reactant: N#CC1(N)CC1
Reactant: O=C(O)[C@H](CS(=O)(=O)N1CCOCC1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)N2CCOCC2)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 3-(morpholin-4-sulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)-ethylamino]-propionic acid (0.034 g, 0.082 mmol) and the HCl salt of 1-aminocyclopropane-carbonitrile (OmegaChem, 0.013 g, 0.107 mmol) in DMF (1 mL) at rt was added solid HATU (PacificChem, 0.041 g, 0.107 mmol) in one portion followed by DIPEA (Aldrich, 0.043 mL, 0.246 mmol) to produce a bright yellow, clear solution. After stirring at rt for 1 h, the reaction was diluted in EtOAc and quenched with 10% aqueous NaHCO3. Water was added to dissolve precipitated solids. The aqueous layer was separated and extracted with EtOAc. The combined organics were washed with brine and dried over anhydrous Na2SO4. Following concentration in vacuo, the crude product was purified by column chromatography on SiO2 (2/1 EtOAc/Hex). Following concentration in vacuo, 0.020 g (51%) of N-(1-cyanocyclopropyl)-3-(morpholin-4-sulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]propionamide was obtained as a white foamy solid with repeated concentration from CH2Cl2. LC/MS: 501.4 (M+Na)+; 479.3 (M+H)+; 477.2 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]([CH3:23])=[CH2:22])[C:9]([CH:11]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>BrC1C=CC=CC=1>[CH2:1]([N:8]1[C:9](=[O:10])[C@@H:11]2[C@:21]([CH3:22])([CH2:23][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=32)[CH2:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)CN(Cc1ccccc1)C(=O)C1Cc2c(Cl)cccc21
Solvent: Brc1ccccc1
Product: C[C@]12CCc3c(Cl)cccc3[C@@H]1C(=O)N(Cc1ccccc1)C2
Yield: 12.3 %

Procedure:
A solution of N-benzyl-3-chloro-N-(2-methylallyl)-1,2-dihydrocyclobutabenzene-1-carboxamide (5.52 mmol, 1.8 g) in bromobenzene (21 ml) was irradiated in a microwave for 30 min at 210 degrees. The bromobenzene was removed under reduced pressure and then purified by flash chromatographed using ethyl acetate in heptane (10 to 20%) to afford trans-2-benzyl-6-chloro-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-1-one (221 mg, 12% yield), followed by cis-2-benzyl-6-chloro-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-1-one (649 mg, 36% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][C:11](=O)[CH2:10][CH2:9][CH2:8][C:7]=2[CH:14]=1.FC(F)(F)S(OC1CCCC2C=C(OC)C=CC=2C=1)(=O)=O.C([Sn](CCCC)(CCCC)[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=1[N+:49]([O-:51])=[O:50])CCC>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[C:11]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][C:42]=3[N+:49]([O-:51])=[O:50])[CH2:10][CH2:9][CH2:8][C:7]=2[CH:14]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(OC)cc1[N+](=O)[O-]
Reactant: COc1ccc2c(c1)CCCC(=O)C2
Agent: COc1ccc2c(c1)CCCC(OS(=O)(=O)C(F)(F)F)=C2
Product: COc1ccc2c(c1)CCCC(c1ccc(OC)cc1[N+](=O)[O-])=C2

Procedure:
Synthesized from 2-methoxy-5,7,8,9-tetrahydrobenzocyclohepten-6-one according to an analogous synthetic method to Preparation Example 82, 2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl trifluoromethanesulfonate (3.0 g) and tributyl(4-methoxy-2-nitrophenyl)tin (10.8 g) were used according to an analogous synthetic method to Preparation Example 77 to provide the title compound (2.8 g).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[C:9]3[N:10]([N:14]=[C:15]([NH2:17])[N:16]=3)[CH:11]=[CH:12][N:13]=2)[C:4]([CH3:18])=[N:3]1.ClC1C2N(N=C(N)N=2)C=CN=1.CN1C(C)=C(B(O)O)C(C)=N1.Cl[C:42]1[CH:50]=[C:49]2[C:45]([C:46]([CH3:53])([CH3:52])[C:47](=[O:51])[NH:48]2)=[CH:44][CH:43]=1>>[CH3:52][C:46]1([CH3:53])[C:45]2[C:49](=[CH:50][C:42]([NH:17][C:15]3[N:16]=[C:9]4[C:8]([C:5]5[C:4]([CH3:18])=[N:3][N:2]([CH3:1])[C:6]=5[CH3:7])=[N:13][CH:12]=[CH:11][N:10]4[N:14]=3)=[CH:43][CH:44]=2)[NH:48][C:47]1=[O:51]
Reactant: Cc1nn(C)c(C)c1-c1nccn2nc(N)nc12
Reactant: CC1(C)C(=O)Nc2cc(Cl)ccc21
Agent: Cc1nn(C)c(C)c1B(O)O
Agent: Nc1nc2c(Cl)nccn2n1
Product: Cc1nn(C)c(C)c1-c1nccn2nc(Nc3ccc4c(c3)NC(=O)C4(C)C)nc12

Procedure:
8-(1,3,5-Trimethylpyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-amine, synthesized by reaction of 8-chloro-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine with (1,3,5-trimethylpyrazol-4-yl)boronic acid following procedure 1, is coupled with 6-chloro-3,3-dimethyl-1,3-dihydro-indol-2-one under Buchwald Hartwig conditions using general procedure 2.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CC[O:9]CC.[F:12][C:13]1[CH:14]=[C:15]([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].OO.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.O.C(O)C>[F:12][C:13]1[CH:14]=[C:15]([C@@H:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C@H:22]2[OH:9])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1F
Reactant: CCOCC
Agent: FB(F)F
Agent: OO
Agent: [BH4-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2O)cc1F
Temperature: 25 °C
Yield: 186.3 %

Procedure:
To a suspension of NaBH4 (0.37 g, 9.8 mmol) in tetrahydrofuran (50 mL) was added BF3.OEt2 (1.3 mL, 10 mmol) at 0° C. The reaction mixture was warmed to rt for 1 h and then re-cooled to 0° C. Tert-butyl 4-(3-fluoro-4-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (1 g, 3.3 mmol) in tetrahydrofuran (10 mL) was then added. The resulting mixture was allowed to warm to rt over 2 h. It was then re-cooled to 0° C. and water (4 mL), ethanol (4 mL), 30% H2O2 (3 mL, 29.4 mmol) and a NaOH solution (4 mL, 3.25 mmol) were added sequentially and the final mixture was heated to 65° C. for 12 h. It was cooled to room temperature, and 50 mL water and 200 mL ethyl acetate were added. The layers were separated and the aqueous layer was twice extracted with 150 mL of ethyl acetate. The combined organic layers were washed with 1N HCl followed by brine. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to obtain 2 g of crude (±)-rel-(3S,4S)-tert-butyl 4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate as a brown gum. The crude compound was purified on a 40 g silica gel column eluting with 30% ethyl acetate in petroleum ether to obtain 450 mg of the pure product as a liquid. LCMS (Method P) RT 0.98 min, m/z 252 (M+H+−t-butyl), 270 (M+H+−t-butyl, —H2O); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 9H) 1.46-1.58 (m, 1H) 1.61-1.71 (m, 1H) 2.32-2.48 (m, 2H) 2.62-2.77 (m, 1H) 3.34-3.47 (m, 1H) 3.80 (s, 3H) 3.91-4.01 (m, 1H) 4.05-4.14 (m, 1H) 4.82 (s, 1H) 6.96-7.02 (m, 1H) 7.03-7.13 (m, 2H).
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][OH:15])[C:9]=1[CH3:16].Cl[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([N+:27]([O-:29])=[O:28])=[CH:25][N:26]=2)[N:23]=1.O>O1CCCC1>[CH3:16][C:9]1[C:10]([CH2:14][OH:15])=[N:11][CH:12]=[CH:13][C:8]=1[S:7][CH2:6][CH2:5][CH2:4][S:3][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([N+:27]([O-:29])=[O:28])=[CH:25][N:26]=2)[N:23]=1
Reactant: Cc1c(SCCCS)ccnc1CO
Reactant: O=[N+]([O-])c1cnc2ccc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.9 g of sodium hydride (80% strength suspension) are suspended in 350 ml of tetrahydrofuran under a nitrogen atmosphere. A solution of 73 g (0.31 mol) of [4-(3-mercaptopropylsulfanyl)-3-methylpyridin-2-yl]methanol in tetrahydrofuran (350 ml) is then added dropwise with vigorous stirring at room temperature during the course of 2 h. The suspension is then stirred at room temperature for a further 2.5 h. A solution of 51.6 g (0.26 mol) of 6-chloro-3-nitroimidazo[1,2-b]pyridazine in tetrahydrofuran (1000 ml) is then added dropwise during the course of 3.5 h and the mixture is stirred at room temperature for a further 18 h. The mixture is then cooled to 0° C. and cautiously treated with water (500 ml) with vigorous stirring. The organic solvent is then distilled off. The aqueous residue is diluted with a further 500 ml of water and cooled to 0° C. The beige precipitate is filtered off, washed with water and dried in a high vacuum at 40° C. The crude product is then dissolved in hot toluene (1.2 l) and clarified with activated carbon (25 g) and kieselguhr (15 g). After filtration at boiling heat, the solution is concentrated to 750 ml and treated with diisopropyl ether (1.2 l). For complete precipitation, the suspension is cooled to 0° C. with stirring. The precipitate is filtered off and then dried in vacuo at 40° C. For further purification, the product is suspended in hot methanol (1.2 l) and treated again with diisopropyl ether (500 ml) after cooling to room temperature. After filtration and drying in vacuo, 82 g (80%) of the title compound of m.p. 127-129° C. are isolated.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH2:15])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])O.[Na+].[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH:15][C:29]([O:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:30])[CH2:10][CH2:11][S:12]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)c1ccc2c(c1)SCCC2N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)SCCC2NC(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To an ethyl acetate (200 ml) solution of 4-aminothiochromane-7-carboxylic acid methyl ester (8.00 g) was added saturated aqueous sodium hydrogencarbonate solution (200 ml), and benzyloxycarbonyl chloride (6.75 g) was added at room temperature. The mixture was stirred at the same temperature for 2 hrs. The reaction mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography to give the objective 4-(benzyloxycarbonylamino)thiochromane-7-carboxylic acid methyl ester (12.8 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[S:13][CH:14]=[CH:15][C:3]=12.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]2[S:13][CH:14]=[CH:15][C:3]=12
Reactant: CCOC(=O)c1cnc2sccc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2sccc2c1Cl
Temperature: 0 °C
Yield: 35.4 %

Procedure:
A mixture of ethyl 4-chlorothieno[2,3-b]pyridine-5-carboxylate (800 mg, 3.31 mmol) [Khan, M. A.; Guarconi, A. E., J. Heterocyclic Chem., 14, 807 (1977)] in 15 mL of ethanol and 5 mL of 2.5 N sodium hydroxide is heated at reflux for 90 minutes. The mixture is cooled to 0° C. and the pH is adjusted to 4 by the addition of 2 N hydrochloric acid. The mixture is stirred at room temperature and the resulting precipitate is collected by filtration and washed with water to provide 250 mg of 4-chlorothieno[2,3-b]pyridine-5-carboxylic acid as a white solid, mp 172–174° C.; 1H NMR (DMSO-d6) δ 7.62 (d, J=6 Hz, 1H), 8.14 (d, J=6 Hz, 1H), 8.94 (s, 1H); MS 212.0 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][S:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[S:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:6]=[CH:7][C:2]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Brc1ccc(N2CCSCC2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(N2CCSCC2)nc1
Temperature: 98 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(5-bromopyridin-2-yl)thiomorpholine 219-2 (2.37 g, 9.15 mmol), diethyl malonate (2.04 g, 12.8 mmol), Pd(OAc)2 (102 mg, 0.46 mmol), biphenyl-2-yl-di-tert-butylphosphine (270 mg, 0.9 mmol) and t-BuONa (1.76 g, 18.3 mmol) in toluene (45 ml) was stirred under argon at 98° C. for 1 hour. After cooled to room temperature, the mixture was filtered through celite and washed with ethyl acetate. The filtrate was evaporated and the residue was subjected to silica gel column chromatography to give diethyl 2-(6-thiomorpholinopyridin-3-yl)malonate 219-3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: OCCCCCCCl
Reactant: Oc1cccc(-c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCCCCOc1cccc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of 15.0 g (0.088 mole) of 3-hydroxybiphenyl, 13.3 g (0.097 mole) of 6-chlorohexan-1-ol, and 13.8 g (0.01 mole) of potassium carbonate in 250 ml of dry dimethylformamide is stirred and heated to reflux for 3 hours. The mixture is cooled to room temperature, diluted with water, and extracted with ether, the ether extracts dried and evaported under reduced pressure to give a light yellow oil. The crude product is vacuum distilled to give a fraction boiling between 150° and 190° C. (0.05 mmHg), and solidifying to a soft solid, corresponding to the pure desired product.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1.[NH2:20][C:21]1[C:25]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:24][NH:23][N:22]=1>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:22]3[N:23]=[CH:24][C:25]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)=[C:21]3[N:20]=2)=[CH:5][CH:4]=1
Reactant: Nc1n[nH]cc1-c1cccnc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(-c4cccnc4)c3n2)cc1
Yield: 69.6 %

Procedure:
Reaction of 1-(4-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (142 mg, 0.5 mmol), prepared from commercially available 4-trifluoromethyl-acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (142 mg, 70%). MS (ISP) 409.2 [(M+H)+]; mp 163° C.
Reaction SMILES: C(O)C.[OH-].[K+].[CH2:6]([N:12]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])CCC#N)[CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].O>C(Cl)(Cl)Cl>[CH2:6]([NH:12][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[CH2:22])[CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCN(CCC#N)CCCCC=C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: C=CCCCCNCCCCC=C
Yield: 20.5 %

Procedure:
Next, ethanol (8.6 ml) and potassium hydroxide (0.85 g, 13 mmol) were added to 3-(di-5-hexenyl)aminopropionitrile (2.0 g, 8.6 mmol), and the obtained mixture was refluxed for 7.5 hours. The reaction mixture was allowed to stand, then water (150 ml) and chloroform (150 ml) were added to the reaction mixture. After separation, the organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by basic silica gel column chromatography to give the target compound (0.32 g, 21%) as a pale yellow oily matter.
Reaction SMILES: O.Cl.[N+:3]([C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[NH:9][C:10](=[O:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])([O-])=O.[OH-].[Na+]>C(O)C.[Fe]>[NH2:3][C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[NH:9][C:10](=[O:18])[C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15]
Reactant: O=C(Nc1cccc([N+](=O)[O-])c1)C(F)(F)C(F)(F)F
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cccc(NC(=O)C(F)(F)C(F)(F)F)c1

Procedure:
Iron powder, 80 g., is suspended in 125 ml of ethyl alcohol and 100 ml of water and 6 ml of concentrated HCl is added. The mixture is heated to reflux and 140 g. of m-nitro pentafluoropropionanilide is added portionwise to keep the mixture at reflux. When reaction is complete, 6 g. of 50% NaOH is added and the mixture filtered to remove iron oxides and the filtrate stripped under vacuum. The product crystallizes from the aqueous solution giving 107 g., m.p. 86°-88° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)C(O)C1
Reactant: BrCc1ccc2ccccc2c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Br)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
By alkylating tert-butyl (3RS,4RS)-4-(4-bromophenyl)-3-hydroxy-piperidine-1-carboxylate with 2-bromomethyl-naphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-bromophenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 495, 497 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([S:17](=[O:20])(=[O:19])[NH2:18])[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5]O.C(O)(=O)C.[BrH:25]>C(OCC)C>[BrH:25].[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([S:17](=[O:20])(=[O:19])[NH2:18])[C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Br:25]
Reactant: Nc1cc(CO)cc(S(N)(=O)=O)c1Cc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: Nc1cc(CBr)cc(S(N)(=O)=O)c1Cc1ccccc1

Procedure:
3-Amino-4-benzyl-5-sulfamylbenzyl alcohol (12.5 g; prepared as described in Example 4) is while stirring added in portions to acetic acid saturated with dry hydrogen bromide (60 ml), and the mixture is stirred for 24 hours. The resulting solution is diluted with diethyl ether (150 ml) and cooled to precipitate 3-amino-4-benzyl-5-sulfamylbenzyl bromide hydrobromide as a hygroscopic material with a melting point of 195°-198° C.