Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:22])[C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:23][CH:24]([CH3:30])[CH2:25][CH2:26][C:27](Cl)=[O:28].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[CH3:23][CH:24]([CH3:30])[CH2:25][CH2:26][C:27]([NH:1][CH2:2][C@H:3]([OH:22])[C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)CN
Reactant: CC(C)CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)CCC(=O)NC[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
To the resultant compound from Example 9 (94.6 mg, 0.299 mmol) in methylene chloride ,(5 mL) at 0° C. was added 4-methylpentanoyl chloride (52 ul, 0.37 mmol) and triethylamine (71 ul, 0.51 mmol). The mixture was stirred at 0° C. for 90 min, diluted with ethyl acetate, washed sequentially with 0.5M H3PO4 solution, 2M NaOH solution and brine, and then dried over Na2SO4 and evaporated to afford 0.118 g (95%) of the desired compound, m.p. 179°-183° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:22]([F:40])([F:39])[C:23]([F:38])([F:37])[C:24]([F:36])([F:35])[C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([N:15]([CH3:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=O)=[CH:8][CH:7]=[CH:6]2.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:42].N1C=CC=CC=1>O>[CH3:1][O:2][C:3]1[C:4]([C:22]([F:40])([F:39])[C:23]([F:38])([F:37])[C:24]([F:36])([F:35])[C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[S:42])[N:15]([CH3:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:8][CH:7]=[CH:6]2
Reactant: COC(=O)CN(C)C(=O)c1cccc2c(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(OC)ccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CN(C)C(=S)c1cccc2c(C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(OC)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
N-[[6-methoxy-5-(tridecafluorohexyl)-1-naphthalenyl]carbonyl-N-methylglycine, methyl ester (100 mg, 0.165 mmol), prepared as in Example 5, phosphorus pentasulfide (67 mg) and dry pyridine (2 ml) were refluxed for 2 hours. After stirring overnight at room temperature, the mixture was refluxed for 2 additional hours, poured into water and extracted with ether. The ether extract was washed with 1N aqueous hydrochloric acid, water, saturated sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated giving 92.8 mg of the crude N-[[6-methoxy-5-(tridecafluorohexyl)-1-naphthalenyl]thioxomethyl]-N-methylglycine, methyl ester, which was used in the next preparation without further purification. ms: m/e 622 (M+H)+, 562, 519, 503, 352. nmr (CDCl3): δ2.84 & 3.04 (2s, 3H, N--CH3, rotamers); δ3.82 & 3.95 (2s, 3H, O--CH3, rotamers) δ3.4 & 5.5 (2d, 2 H, CH2, J=17); δ7.3 (m, 3H, Har); δ8.2 (m, 2H, Har).
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].[I-:19].[Na+]>CC(C)=O>[I:19][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18]
Reactant: [I-]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CI
Yield: 47.4 %

Procedure:
A suspension of 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [4 g, 13.7 mmol; PCT Int. Appl. (2002), WO 0262774 A1] and sodium iodide (10.3 g, 68.6 mmol) in acetone (70 ml) was stirred at reflux temperature for 2 h under an argon atmosphere. The yellow precipitate was filtered off, the filtrate evaporated to dryness under reduced pressure and dissolved in tert-butyl methyl ether and brine/ice water 1/1. The aqueous layer was extracted one more time with tert-butyl methyl ether, the combined extracts washed with ice water/aqueous sodium thiosulfate, ice water/brine 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue recrystallized from tert-butyl methyl ether/heptane to give 2.5 g (6.5 mmol, 48%) of the title compound as yellow crystals.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.Cl>CCOCC>[OH:11][C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1
Reactant: Br[Mg]c1ccccc1
Reactant: O=C1CCc2ccccc2C1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: OC1(c2ccccc2)CCc2ccccc2C1

Procedure:
2-Tetralone (8.76 g) in dry ether (100 ml) was added dropwise to phenyl magnesium bromide (generated from bromobenzene 19.16 g) in dry ether (300 ml). The mixture was refluxed for 1 hr. The reaction mixture was decomposed by careful addition of water. The resulting emulsion was clarified by addition 2M-hydrochloric acid (250 ml) and ether (500 ml). The ether layer was separated and washed with water (100 ml), dilute sodium hydrogen carbonate solution solution (200 ml) and water (100 ml) and dried (magnesium sulphate and evaporated in vacuo to afford 2-hydroxy-2-phenyl-1,2,3,4-tetrahydronaphthalene as an oil. (8.8 g), characterised by its nmr spectrum
Reaction SMILES: CO.C[O-].[Na+].Cl.[NH2:7][C:8]([NH2:10])=[NH:9].Cl.Cl[C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)[CH:16]=1)=[O:14]>O1CCCC1.ClCCl>[N:27]1[CH:28]=[CH:29][C:24]([N:17]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:23]3[C:15]([C:13]([NH:9][C:8]([NH2:10])=[NH:7])=[O:14])=[CH:16]2)=[CH:25][CH:26]=1
Reactant: N=C(N)N
Reactant: O=C(Cl)c1cn(-c2ccncc2)c2ncccc12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: N=C(N)NC(=O)c1cn(-c2ccncc2)c2ncccc12
Temperature: 20 °C
Reaction time: 1 h
Yield: 2.3 %

Procedure:
20 cm3 of methanol and then a solution of 70 cm3 of 0.5M sodium methoxide were added, at a temperature in the region of 20° C. under an argon atmosphere, to 3.34 g (35 mmol) of guanidine hydrochloride and the reaction mixture was stirred at a temperature in the region of 20° C. for 1 h. The reaction mixture was subsequently concentrated to dryness under reduced pressure (2.7 kPa) and the residue was 3 times in succession taken up in 20 cm3 of dichloromethane (stabilized over amylene) and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained was taken up in 50 cm3 of tetrahydrofuran under an argon atmosphere at a temperature in the region of 20° C. and 1.8 g (7 mmol) of 3-chlorocarbonyl-1-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine hydrochloride, in suspension in 50 cm3 of dichloromethane, were added with stirring, followed by 50 cm3 of tetrahydrofuran and 50 cm3 of dichloromethane. After stirring at a temperature in the region of 20° C. for 15 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa). The residue was taken up in 50 cm3 of ethanol and the mixture was heated at reflux for 5 minutes and then reconcentrated to dryness under reduced pressure (2.7 kPa). The residue was purified by flash chromatography on a column of silica gel (0.04–0.06 mm), elution being carried out with an ethyl acetate/methanol/aqueous ammonia (80/20/5 by volume) mixture. The fractions comprising the expected product were combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue was taken up in 30 cm3 of water and the solution was basified with 1N sodium hydroxide and then 50 cm3 of ethyl acetate were added. After filtration, the organic phase was separated by settling, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2.7 kPa). The residue was triturated in 20 cm3 of diisopropyl ether, filtered and dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 45 mg of N-[1-(pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]guanidine were thus obtained in the form of a white powder melting at 210° C. Mass spectrum: EI: m/z=280 M+ base peak.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]([NH2:13])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[N:23]([O-])=O.[Na+]>O>[N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]3[N:13]=[N:23][N:14]([CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:9]=3[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=N[O-]
Reactant: Nc1ccc(Cn2ccnc2)cc1NCc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: c1ccc(Cn2nnc3ccc(Cn4ccnc4)cc32)cc1
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 40.9 %

Procedure:
To a stirred and cooled (0° C.) mixture of 3.9 parts of 4-(1H-imidazol-1-ylmethyl)-N2 -(phenylmethyl)-1,2-benzenediamine and 9.6 parts of concentrated hydrochloric acid was added dropwise a solution of 1.86 parts of sodium nitrite in 8 parts of water. Upon complete addition, stirring was continued for 10-15 minutes at this low temperature. The reaction mixture was allowed to reach room temperature and poured into ice water. The whole was extracted with dichloromethane. The acid aqueous layer was treated with a concentrated ammonium hydroxide solution while cooling and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by filtration over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography over silica gel using a mixture of ethyl acetate, methanol and methanol, saturated with ammonia (95:2.5:2.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The product was filtered off, washed with 2,2'-oxybispropane and dried in vacuo at 50° C., yielding 1.6 parts (40.9%) of 6-(1H-imidazol-1-ylmethyl)-1-(phenylmethyl)-1H-benzotriazole; mp. 85.4° C. (compound 80).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:13]([CH3:24])=[N:14][C:15]([CH3:23])=[C:16]([C:18](OCC)=[O:19])[CH:17]=1)=O)C.O>C(OCC)C>[OH:9][CH2:10][C:12]1[CH:17]=[C:16]([CH2:18][OH:19])[C:15]([CH3:23])=[N:14][C:13]=1[CH3:24]
Reactant: CCOC(=O)c1cc(C(=O)OCC)c(C)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1nc(C)c(CO)cc1CO
Temperature: 40 °C

Procedure:
To a ice-cooled mixture of lithium aluminum hydride (95%) (6.7 g, 168 mmol) in anhydrous diethyl ether (750 mL) is added a solution of 2,6-dimethyl-pyridine-3,5-dicarboxylic acid diethyl ester (31.5 g, 125 mmol) in diethyl ether (250 mL) via cannula under a stream of nitrogen. After the addition is complete, the reaction mixture is warmed to 40° C. for 0.5 h. After cooling to 0° C., water (50 mL) is added slowly under a stream of nitrogen. The resulting solids are filtered, washed with diethyl ether (250 mL), suspended in methanol (700 mL) and warmed to a gentle reflux (1 h). The remaining aluminum salts are filtered hot and washed with hot methanol (200 mL). The filtrate is concentrated and dried in vacuo to afford 5-hydroxymethyl-2,6-dimethyl-pyridin-3-yl-methanol as a white solid and is used in the subsequent step without further purification: Rf 0.16 (10% methanol in chloroform); 1H NMR (DMSO-d6, 300 MHz) δ 7.62 (s, 1 H), 4.45 (s, 4 H), 2.34 (s, 6 H); ESI-LCMS m/z calcd for C9H13NO2: 167.1; found 168.0 (M+1)+.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[N:4]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:3]=1.[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC>[O:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[N:4]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:3]=1
Reactant: CCOC(=O)c1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: OB(O)c1cc2ccccc2o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: CCOC(=O)c1ccc2c(c1)c(-c1cc3ccccc3o1)nn2C1CCCCO1
Temperature: 90 °C
Reaction time: 8 h
Yield: 363.3 %

Procedure:
A solution of ethyl 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carboxylate (500 mg, 1.41 mmol), 2-benzofuran boronic acid (454 mg, 2.82 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complex with dichloromethane(163 mg, 0.141 mmol), and potassium phosphate (1.5 g, 7.05 mmol) in ethylene glycol dimethyl ether (12 mL) was allowed to stir under a nitrogen atmosphere at 90° C. overnight. The reaction was extracted with ethyl acetate and purified by silica gel chromatography to yield the title compound (2.0 g, 90% yield). ES-MS (m/z) 391 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](Cl)=[N:8][C:6]=2[N:7]=1.[CH3:21][NH2:22]>CO>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]([NH:22][CH3:21])=[N:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[CH:4][C:5]=3[CH:11]=2)=[CH:13][CH:14]=1
Reactant: CN
Reactant: COc1ccc(-c2cc3cnc(N)nc3nc2Cl)cc1
Solvent: CO
Product: CNc1nc2nc(N)ncc2cc1-c1ccc(OC)cc1

Procedure:
A mixture of 3.4 g of 2-amino-7-chloro-6-(4-methoxyphenyl)-pyrido[2,3-d]pyrimidine from Example 12, 40 mL of anhydrous methylamine, and 10 mL of methanol were heated in a bomb on a steam bath for 4 hours. After cooling, the suspension was washed out of the bomb with 50 mL of methanol/water (50:50) and the solvents were evaporated in vacuo. The solid residue was slurried with 50 mL of water, filtered, and crystallized from ethanol to afford 2.2 g of the title compound 6-(4-methoxyphenyl)-N7 -methyl-pyrido[2,3-d]pyrimidine-2,7-diamine, mp 270°-275° C. dec.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:22]=2[CH3:31])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].C(Br)(Br)(Br)[Br:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:33][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][C:22]=2[CH3:31])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CO)c2)c(C)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CBr)c2)c(C)c1
Temperature: 25 °C

Procedure:
To a 0° C. solution of methyl 2″-(hydroxymethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate (1.500 g, 3.49 mmol) in CH2Cl2 (14 mL) was added CBr4 (2.429 g, 7.33 mmol), and then a solution of triphenyl phosphine (1.830 g, 6.98 mmol) in CH2Cl2 (15 mL). The solution was warmed to room temperature and stirred for twelve hours. The reaction was concentrated, and the residue was purified by flash chromatography on silica gel (0 to 25% EtOAc/hexanes) to afford methyl 2″-(bromomethyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate. Rf=0.59 (50% EtOAc/hexanes). LCMS=494.8 (M+1)+. 1H NMR (CDCl3, 500 MHz), δ 7.95 (s, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.40-7.33 (m, 3H), 7.21 (d, J=2.3 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 4.44-4.39 (m, 2H), 3.93 (s, 3H), 3.82 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[O:9]([CH3:11])[Na].O>CS(C)=O>[CH3:11][O:9][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1
Reactant: CO[Na]
Reactant: Cc1ccnc(Cl)c1
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(C)ccn1
Temperature: 100 °C
Reaction time: 4 h
Yield: 46.8 %

Procedure:
A mixture of 2-chloro-4-methylpyridine (20 g, 0.156 mol) and NaOCH3 (9.3 g, 0.172 mol) in DMSO (200 mL) was stirred at 100° C. for 4 hours. The solution was added to H2O and then extracted with ethyl acetate (50 mL×2). The organic layer was washed with H2O (300 mL) brine (300 mL) and dried concentrated to give 2-methoxy-4-methylpyridine (9 g, 46%). LC-MS: 124 [M+H]+, tR=1.21 min.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:10]([O-:12])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[NH2:17].C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:10](=[O:12])[CH:4]([O:3][CH2:1][CH3:2])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: CCOC(=O)C(OCC)C(=O)[O-]
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C(OCC)C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 30 %

Procedure:
Mono-ethyl ethoxymalonate (2.75 grams, 0.02 mole), prepared in Part A, 3,5-dichloroaniline (2.53 grams, 0.02 mole) and 1,3-dicyclohexylcarbodiimide (3.22 grams, 0.02 mole) were reacted in a manner similar to that described in Example LVII to give 1.92 grams (0.006 mole) of ethyl 3-[(3,5-dichlorophenyl)amino]-2-ethoxy-3-oxopropanoate having a melting point of 89.0° C.-92.5° C. An analytical sample recrystallized from ethyl acetate-hexane had a melting point of 84° C.-86° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[N:14]([CH2:15][CH2:16][CH:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[OH:18])[C:13](=[O:25])[NH:12][C:11]1=[O:26])([OH:3])=[O:2].[CH2:27](O)[CH3:28]>S(=O)(=O)(O)O>[CH2:27]([O:2][C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[N:14]([CH2:15][CH2:16][CH:17]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[OH:18])[C:13](=[O:25])[NH:12][C:11]1=[O:26])=[O:3])[CH3:28]
Reactant: CCO
Reactant: O=C(O)CCCCCCC1C(=O)NC(=O)N1CCC(O)C1CCCCC1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCCCCC1C(=O)NC(=O)N1CCC(O)C1CCCCC1
Reaction time: 18 h

Procedure:
A solution of 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin (diastereomer of m.p. 96°-98°) (Example 14c) (4 g) in ethanol (60 ml) and concentrated sulphuric acid (1.6 ml) was allowed to stand at room temperature for 18 hours. The alcohol was evaporated, water was added, and the precipitated oil was extracted with ether. The ether solution was washed with sodium bicarbonate solution and with water, dried (MgSO4) and evaporated to give a single diastereomer of 5-(6-ethoxycarbonylhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin as a colourless oil, soon solidifying, and crystallising from cyclohexane in small colourless plates, m.p. 62°-63°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].Br[C:18]1[S:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[C:20]([C:27]2[C:36]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=3[C:30]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:29][CH:28]=2)[C:19]=1[CH3:41]>C1(C)C=CC=CC=1.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[S:22][C:21]([C:23]([O:25][CH2:26][CH3:11])=[O:24])=[C:20]([C:27]3[C:36]4[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=4[C:30]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:29][CH:28]=3)[C:19]=2[CH3:41])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1sc(Br)c(C)c1-c1ccc(S(N)(=O)=O)c2c1CCCC2
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)c2c1CCCC2
Temperature: 25 °C
Yield: 34.4 %

Procedure:
(4-chlorophenyl)boronic acid [0.027 g, 0.17 mmol] and potassium carbonate (0.043 g, 0.31 mmol) were added to a solution of methyl 5-bromo-4-methyl-3-(4-sulfamoyl-5,6,7,8-tetrahydronaphthalen-1-yl)thiophene-2-carboxylate (59d, 0.07 g, 0.16 mmol) in a mixture of 1 ml toluene and 4 ml ethanol at 25° C. A nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis (triphenylphosphine)palladium(0) (0.009 g, 0.008 mmol) under nitrogen atmosphere and the reaction mixture was heated at a temperature of about 95° C. to about 100° C. for 3 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite, the celite cake washed with 10 ml ethyl acetate. The combined filtrate so obtained was then concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 30% ethyl acetate in hexanes as an eluent to obtain the title compound (0.027 g, 35.0%).
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3C=C[C:23]([C:26]([OH:28])=O)=[CH:22][C:20]=3[N:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].[CH2:33](Cl)[CH2:34]Cl.Cl.[CH3:38][NH:39][CH3:40]>CN(C1C=CN=CC=1)C>[CH3:38][N:39]([CH3:40])[C:26]([C:23]1[CH:22]=[CH:20][C:19]2[O:18][C:17]([C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:30])[C:2]([CH3:32])([CH3:1])[CH3:31])=[C:7]([CH3:29])[CH:8]=3)([CH2:15][CH3:16])[CH2:13][CH3:14])=[N:21][C:33]=2[CH:34]=1)=[O:28]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2cc(C(=O)O)ccc2o1
Reactant: ClCCCl
Reactant: CNC
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2cc(C(=O)N(C)C)ccc2o1
Yield: 50.2 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzooxazole-5-carboxylic acid (150 mg, 0.343 mmol), DMAP (125 mg, 1.03 mmol), EDC (99 mg, 0.514 mmol), and dimethylamine hydrochloride (42 mg, 0.514 mmol) are reacted analogous to Example 3 to give the title product (80 mg, 50%). MS (ES) m/e: 465.3 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([CH:5]([F:10])[C:6]([F:9])([F:8])[F:7])[CH2:3][OH:4].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24].CS(O)(=O)=O.C1C=CC=CC=1>O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:4][CH2:3][C:2]([F:11])([F:1])[CH:5]([F:10])[C:6]([F:9])([F:7])[F:8])=[O:24]
Reactant: OCC(F)(F)C(F)C(F)(F)F
Reactant: O=C(O)CCCCCCCCCCBr
Agent: CS(=O)(=O)O
Solvent: c1ccccc1
Solvent: O
Product: O=C(CCCCCCCCCCBr)OCC(F)(F)C(F)C(F)(F)F

Procedure:
A 500 ml one-necked flask fitted with a Dean Stark trap was charged with 36.4 g (0.2 m) of 2,2,3,4,4,4-hexafluorobutanol, 53.0 g (0.2 m) of 11-bromoundecanoic acid, 0.5 g methane sulfonic acid and 100 ml of dry benzene. The reaction mixture was refluxed until the theoretical amount of water, 3.6 ml, was removed. The reaction mixture was washed with a 10% sodium carbonate solution. The benzene was removed under vacuum giving 2,2,3,4,4,4-hexafluorobutyl 11-bromoundecylate. IR analysis showed the following major absorption bands: 2930, 2860, 1760, 1190, 1110 cm-1.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:10][NH:9][N:8]=2)=[CH:4][CH:3]=1.Br[CH2:19][CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>CN(C)C=O.O>[CH2:19]([N:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[N:8]1)[CH:20]([CH3:22])[CH3:21]
Reactant: Brc1ccc(-c2n[nH]cc2-c2ccncc2)s1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)Cn1cc(-c2ccncc2)c(-c2ccc(Br)s2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
To a solution of 4-[3-(5-bromo-2-thienyl)-1H-pyrazol-4-yl]pyridine (1 eq, 8.8 mmol) in 50 mL N,N-dimethylformamide were added 1-bromo-2-methylpropane (1.5 eq, 13.2 mmol) and cesium carbonate (1.1 eq, 9.7 mmol). The reaction mixture was stirred overnight at room temperature and poured in 500 mL of water. The resulting precipitate was filtered and dried. The solid was then recristallised in a mixture diisopropylether:dichloromethane to afford 1.81 g of 4-[1-isobutyl-3-(5-bromo-2-thienyl)-1H-pyrazol-4-yl]pyridine (53% yield).