Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH3:5][N:6]([CH3:8])[NH2:7].C[O:10][C:11]([C:13]1[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])[CH:14]=1)=O.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCOCC1>[CH3:5][N:6]([CH3:8])[NH:7][C:11]([C:13]1[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]2[C:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:22][O:23][C:24]=2[CH3:25])[CH:14]=1)=[O:10]
Reactant: CN(C)N
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)no1
Agent: C[Al](C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NN(C)C)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.9 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 0.6 mL, 1.3 mmol) was added dropwise (exothermic) to a solution of N,N-dimethylhydrazine (76 mg, 1.3 mmol) in dioxane (5 mL) and the resulting mixture was stirred at room temperature for 1 h. Then 3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.32 mmol) was added. The resulting mixture was then heated at 85-90° C. for 4 h and then cooled to room temperature and then poured into Seignette's salt and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, dichloromethane:methanol=9:1 to 4:1) afforded the title compound (24 mg, 22%) which was obtained as a colourless oil. MS: m/e=343.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][CH:5]=[C:6](Cl)[N:7]=1.[CH3:11][O-:12].[Na+]>CO>[Cl:1][C:2]1[C:3]([CH:9]=[O:10])=[N:4][CH:5]=[C:6]([O:12][CH3:11])[N:7]=1
Reactant: C[O-]
Reactant: O=Cc1ncc(Cl)nc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1cnc(C=O)c(Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
To a solution of 3,5-dichloro-pyrazine-2-carbaldehyde (150 mg, 0.85 mmol) in methanol (5 mL) is added sodium methoxide (25% w/w in MeOH, 183 mg, 0.85 mmol) at 0° C. After the mixture is stirred at 0° C. for 2 hours and then at room temperature overnight, the reaction is quenched with saturated NH4Cl (1 mL) and solvent removed in vacuo until dryness. DCM (20 mL) is added, and the solution is dried and solvent removed to give 140 mg of 3-chloro-5-methoxy-pyrazine-2-carbaldehyde as an oil.
Reaction SMILES: [C:1](/[N:9]=[C:10](\SC)/[NH:11][C@:12]([C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[C:29]([F:37])[CH:28]=1)([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][NH2:41]>CC#N.[N+]([O-])([O-])=O.[Ag+]>[F:37][C:29]1[CH:28]=[C:27]([C@@:12]([NH:11][C:10]2[NH:9][C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:41][N:40]=2)([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=1
Reactant: CS/C(=N\C(=O)c1ccccc1)N[C@@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Reactant: NN
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Product: Fc1ccc([C@](Cc2ccccc2)(Nc2nnc(-c3ccccc3)[nH]2)c2cc(F)cc(C(F)(F)F)c2)cc1
Temperature: 60 °C
Yield: 69.2 %

Procedure:
To a solution of (S,Z)-methyl N′-benzoyl-N-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)carbamimidothioate (58 mg, 0.1 mmol) and TEA (28 μL, 0.2 mmol) in CH3CN (1 mL) was added drop wise a solution of AgNO3 (26 mg, 0.15 mmol) in CH3CN (1 mL), followed by the addition of NH2NH2 (10 μL, 0.1 mmol). The reaction mixture was heated at 60° C. for 1 h and allowed to cool to room temperature. The solid was removed by filtration and the filtrate was concentrated. The residue was purified by ISCO chromatography (4 g column) using hexanes/EtOAc (0-30%) over 10 min to give (S)-N-(1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-5-phenyl-4H-1,2,4-triazol-3-amine as a white solid (36 mg, 69% yield). LCMS: RT=4.25 min [M+H] 520.97 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 7.77 ppm, 2H, dd, J=7.83, 1.52 Hz; 7.37 ppm, 4H, m; 7.26 ppm, 4H, m; 7.10 ppm, 3H, m; 6.98 ppm, 2H, m; 6.63 ppm, 2H, d, J=7.33 Hz; 3.97 ppm, 1H, m; 3.85 ppm, 1H, m.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[OH:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][CH:21]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+].Cl>N1C=CC=CC=1.[Cu]I>[CH2:17]([O:16][C:14](=[O:15])[C:13]1[CH:19]=[CH:20][CH:21]=[C:11]([O:10][C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH:12]=1)[CH3:18]
Reactant: COc1ccc(Br)cn1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(Oc2ccc(OC)nc2)c1
Temperature: 0 °C
Yield: 23.6 %

Procedure:
A suspension of 5-bromo-2-methoxy-pyridine (5.4 g, 29 mmol), ethyl 3-hydroxybenzoate (4.0 g, 24 mmol), K2CO3 (4.3 g, 30 mmol), Cu powder (0.30 g, 4.8 mmol) and CuI (0.30 g, 1.56 mmol) in pyridine (25 ml) was refluxed for 18 h. The resulting mixture was mixed with 100 g of crushed ice, neutralized with 1N hydrochloric acid to pH 7.5 and extracted with ether. The extract was evaporated in vacuo, the obtained crude product was purified by column chromatography on silica (eluent hexanes-ethyl acetate 8:1) to afford 1.55 g (20%) of 3-(6-methoxy-pyridin-3-yloxy)-benzoic acid ethyl ester as colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(CC)CC)C>C1C=CC=CC=1.CN(C)C=O>[CH3:18][O:17][N:16]([CH3:15])[C:5]([CH:3]1[CH2:4][CH:2]1[CH3:1])=[O:7]
Reactant: CNOC
Reactant: CC1CC1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CC1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methylcyclopropanecarboxylic acid (10 g in a mixture of 200 mL benzene and 2 mL N,N-dimethylformamide) at 0° C. was added 10.5 mL of oxalyl chloride and the mixture stirred at 0° C. for 30 minutes then warmed to room temperature for 30 minutes. At this time, 14.6 g of N,O-dimethylhydroxylamine hydrochloride was added followed by 41 mL of triethylamine. The mixture was stirred at room temperature for one hour then quenched by the addition of saturated sodium bicarbonate. The aqueous portion was extracted with ethyl acetate and the combined organics washed with brine, dried over sodium sulfate and concentrated in vacuo. The product was purified by distillation under reduced pressure to give 8.9 g as an oil.
Reaction SMILES: [C:1](OC)(OC)(OC)[CH2:2][CH2:3][CH3:4].Cl.N1C=CC=CC=1.[NH2:18][C:19]1[CH:20]=[N:21][C:22]2[C:27]([C:28]=1[NH:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])=[CH:26][CH:25]=[C:24]([Br:35])[CH:23]=2>C1(C)C=CC=CC=1>[Br:35][C:24]1[CH:25]=[CH:26][C:27]2[C:28]3[N:29]([CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])[C:1]([CH2:2][CH2:3][CH3:4])=[N:18][C:19]=3[CH:20]=[N:21][C:22]=2[CH:23]=1
Reactant: CCCC(OC)(OC)OC
Reactant: CC(C)(O)CNc1c(N)cnc2cc(Br)ccc12
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CC(C)(C)O
Yield: 76.7 %

Procedure:
Trimethyl orthobutyrate (11.61 mL, 72.6 mmol) and catalytic pyridine hydrochloride were added to a solution of 1-(3-amino-7-bromoquinolin-4-ylamino)-2-methylpropan-2-ol (22.51 g, 72.6 mmol) in anhydrous toluene (120 mL), and the reaction was heated at reflux for two hours. The solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was removed under reduced pressure until a precipitate began to form. Hexanes were added, and the precipitate was isolated by filtration to provide 20.17 g of 1-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol.
Reaction SMILES: [CH3:1][C@@:2]1([O:30]C(=O)C)[C@H:6]([O:7]C(=O)C)[C@@H:5]([CH2:11][O:12]C(=O)C)[O:4][C@H:3]1[N:16]1[CH:29]=[C:20]2[CH:21]=[CH:22][C:23]3[C:24](=[S:28])[NH:25][N:26]=[CH:27][C:18]([C:19]=32)=[N:17]1.[OH-].[Na+].C(O)(=O)C>C(O)C.O>[CH3:1][C@@:2]1([OH:30])[C@H:6]([OH:7])[C@@H:5]([CH2:11][OH:12])[O:4][C@H:3]1[N:16]1[CH:29]=[C:20]2[CH:21]=[CH:22][C:23]3[C:24](=[S:28])[NH:25][N:26]=[CH:27][C:18]([C:19]=32)=[N:17]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc3ccc4c(=S)[nH]ncc(n2)c34)[C@](C)(OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2ccc3c(=S)[nH]ncc(n1)c23
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.7 %

Procedure:
To a suspension of compound 23.1 (180 mg, 0.38 mmol) in 4 mL ethanol was added 0.22 mL of 1N sodium hydroxide solution in water. The mixture was stirred at room temperature for 1.5 hr. after which time the pH was brought to 6 with acetic acid and the solvent evaporated. The residue was purified on silica gel column (10:1 CH2Cl2:MeOH) to afford 30 mg of product 23.2. 1H NMR (DMSO-d6) δ 10.49 (s, 1H), 8.52 (s, 1H), 7.50 (s, 1H), 7.00 (d, J 12 Hz, 1H), 6.08 (s, 1H), 5.65 (d, J 12 Hz, 1H), 5.18 (m, 3H), 3.82 (m, 3H), 3.68 (m, 1H), 0.73 (s, 3H).
Reaction SMILES: C[O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:24](=[CH:25][CH:26]=1)[O:23][C:11]1([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:27].[OH-].[Na+]>>[C:17]1([N:14]2[CH2:15][CH2:16][C:11]3([CH2:10][C:9](=[O:27])[C:8]4[C:24](=[CH:25][CH:26]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:28])=[O:2])[CH:7]=4)[O:23]3)[CH2:12][CH2:13]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(c3ccccc3)CC1)O2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(c3ccccc3)CC1)O2
Yield: 87.6 %

Procedure:
(E)-3-{1′-Phenyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (541 mg, 1.43 mmol) was hydrolyzed with NaOH following the procedure described in Example 1, Step A, giving (E)-3-{1′-phenyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid as a white solid (455 mg, 87%). The resulting product was treated with NH2OTHP according to the procedure described in Example 1, Step B, giving (E)-3-{1′-phenyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as a yellow solid (393 mg, 69%). Finally, the removal of the THP protecting group following the procedure described in Example 2, Step D gave the crude product, which was purified by preparative HPLC giving 50 mg of (E)-3-{1′-phenyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide as its trifluoro acetic salt.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][C:13]1[N:14]2[CH:20]=[N:19][CH:18]=[C:15]2[S:16][CH:17]=1.[CH2:21]([O:24][C:25]([N:27]1[C@H:31]([CH:32]=[O:33])[CH2:30][C@@H:29]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:28]1)=[O:26])[CH:22]=[CH2:23].O>C1COCC1>[CH2:21]([O:24][C:25]([N:27]1[C@H:31]([CH:32]([OH:33])[C:17]2[S:16][C:15]3=[CH:18][N:19]=[CH:20][N:14]3[C:13]=2[CH3:12])[CH2:30][C@@H:29]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])[CH3:37])[CH2:28]1)=[O:26])[CH:22]=[CH2:23]
Reactant: Cc1csc2cncn12
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1sc2cncn2c1C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
A 1.69 M n-butyllithium/n-hexane solution (7.4 ml) is added dropwise to a solution of 1.56 g of 3-methylimidazo[5,1-b]thiazole in 25 ml of dry THF over a period of 10 min while maintaining the temperature at −70° C. or below, and the mixture is stirred at that temperature for 2 hr. A solution of 3.54 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-formylpyrrolidine in 15 ml of THF is gradually added dropwise to the mixed solution, the temperature is raised from −70° C. to 0° C. over a period of 3 hr, the mixture is stirred at 0° C. for 2 hr and at room temperature for 2 hr. Water is added to the reaction solution, and the mixture is extracted three times with ethyl acetate. The organic layer is washed twice with saturated saline, dried over anhydrous magnesium sulfate, and filtered, and the solvent is removed by evaporation under reduced pressure to give a crude product which is then successively purified by column chromatography on silica gel (ethyl acetate) and on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 2.74 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-[1-hydroxy-1-(3-methylimidazo[5,1-b]thiazol-2-yl)methyl]pyrrolidine (a diastereomer mixture) as a colorless amorphous material.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([O:21][CH3:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:29])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([O:21][CH3:22])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COC1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: COC1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-methoxypiperidin-1-yl)quinolin-7-yl]ethanone (0.0206 g, 0.0646 mmol) and ammonium acetate (0.0498 g, 0.646 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.16 mL, 0.16 mmol). The reaction was heated at 65° C. overnight. The resulting mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined extracts were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C17H23ClN3O (M+H)+: m/z=320.2; Found: 320.1.
Reaction SMILES: [OH:1][C:2]1([C:29]2[S:33][C:32](S(C)(=O)=O)=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1.[CH:38]([O:41][Na])([CH3:40])[CH3:39]>>[OH:1][C:2]1([C:29]2[S:33][C:32]([O:41][CH:38]([CH3:40])[CH3:39])=[N:31][CH:30]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:11][CH:10]([NH:12][C:13]([CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=3)=[O:14])[CH2:9]2)[CH2:4][CH2:3]1
Reactant: CC(C)O[Na]
Reactant: CS(=O)(=O)c1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1
Product: CC(C)Oc1ncc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)s1

Procedure:
The title compound was prepared as a white solid from N-({1-[4-hydroxy-4-(2-methanesulfonyl-thiazol-5-yl)-cyclohexyl]-azetidin-3-ylcarbamoyl}-methyl)-3-trifluoromethyl-benzamide (less polar isomer, 47a),and i-PrONa (prepared in situ from IPA and 95% NaH) using the procedure described in Example 52.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[N:5][C:6]2[C:11]([C:12]=1[C:13]([O:15][CH3:16])=[O:14])=[CH:10][C:9]([S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[C:8]([O:23][CH2:24][CH3:25])[CH:7]=2.[NH:36]1[CH2:41][CH2:40][CH:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)[CH2:38][CH2:37]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:24]([O:23][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:3]([CH2:2][N:36]3[CH2:41][CH2:40][CH:39]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[CH2:38][CH2:37]3)[C:4]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)=[N:5]2)=[CH:10][C:9]=1[S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])[CH3:25]
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CBr)c(C(=O)OC)c2cc1S(=O)(=O)C(C)C
Reactant: C1CC(N2CCOCC2)CCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCOCC4)CC3)c(C(=O)OC)c2cc1S(=O)(=O)C(C)C
Yield: 32.2 %

Procedure:
A solution of methyl 3-(bromomethyl)-7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (3.5 g, 6.09 mmol), 4-(4-piperidinyl)morpholine (1.778 g, 7.31 mmol), and N,N-diisopropylethylamine (2.13 mL, 12.19 mmol) in acetonitrile (50 mL) was stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure, and the residue was partitioned between a 10% sodium carbonate solution and methylene chloride. The organic phase was separated and washed with Na2CO3. The organic phase was extracted with 2N HCl (three times). The aqueous extracts were cooled in an ice bath and adjusted to pH 12 with 6N NaOH. The precipitated solid was extracted with methylene chloride (three times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to afford methyl 7-(ethyloxy)-6-[(1-methylethyl)sulfonyl]-3-{[4-(4-morpholinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.3 g, 31% yield) as a yellow solid. This material was used without further purification. MS (m/z) 664.2 (M+H+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([CH3:19])[C:12]2([C:16](O)=[O:17])[C:13]([CH2:15][CH:9]1[CH2:10][CH2:11]2)=[O:14].O>CCOCC>[CH3:7][C:8]1([CH3:19])[CH:9]2[CH2:10][CH2:11][C:12]1([CH2:16][OH:17])[CH:13]([OH:14])[CH2:15]2
Reactant: CC1(C)C2CCC1(C(=O)O)C(=O)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC1(C)C2CCC1(CO)C(O)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled mixture of lithium aluminum hydride (4 g, 105.4 mmol) in ether was added dropwise a solution of camphorsulfonyl chloride (10 g, 39.88 mmol) and ketopinic acid, prepared as described in Step 1, above. After the addition was complete, the ice bath was removed and the mixture was stirred at ambient temperature for 2 hrs. The mixture was cooled again and wet ether was added cautiously. When the violent reaction subsided, water was added. The mixture was then extracted three times with ethyl acetate. The combined extracts were washed with water and brine and dried over anhydrous magnesium sulfate. Evaporation of the solution gave 4.8 g of a white powder. NMR(δ): 0.90 (s, 3H), 1.20 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[C:5]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:17]=2)[C:12](O)=[O:13])=[N:6][S:7][N:8]=1)([CH3:3])[CH3:2].[CH3:25][C:26]1[N:27]=[CH:28][C:29]([CH2:32][NH2:33])=[N:30][CH:31]=1>>[CH:1]([C:4]1[C:5]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=3)[CH:17]=2)[C:12]([NH:33][CH2:32][C:29]2[CH:28]=[N:27][C:26]([CH3:25])=[CH:31][N:30]=2)=[O:13])=[N:6][S:7][N:8]=1)([CH3:3])[CH3:2]
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3nsnc3C(C)C)c2)nc1
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)cn3)cc(-c3nsnc3C(C)C)c2)nc1

Procedure:
Following the procedure of step 4 of Example 1, 3-(4-isopropyl-[1,2,5]thiadiazol-3-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid was reacted with C-(5-methyl-pyrazin-2-yl)-methylamine to afford 3-(4-isopropyl-[1,2,5]thiadiazol-3-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-5-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=445.
Reaction SMILES: [OH-].[Na+].Br[C:4]1[CH:5]=[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1B(O)O>COCCOC.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>[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[C:4]1[CH:5]=[C:6]([C:10]2[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:13]=[C:12]([C:21]3[CH:22]=[CH:23][C:24]([C:30]4[CH:29]=[CH:28][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH:31]=4)=[CH:25][CH:26]=3)[N:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Brc1ccc(-c2nc(-c3cccc(Br)c3)n(-c3ccccc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: c1ccc(-n2nc(-c3ccc(-c4ccc5ccccc5c4)cc3)nc2-c2cccc(-c3ccc4ccccc4c3)c2)cc1
Temperature: 85 °C
Yield: 36.9 %

Procedure:
Sodium hydroxide solution (0.2 g NaOH dissolved in 5 ml of water) and 0.12 g (0.1 mmol) of Pd(PPh3)4 are added to 0.9 g (1.97 mmol) of the triazole obtained in step A) and 0.82 g (4.7 mmol) of naphthalene-2-boronic acid in 15 ml of 1,2-dimethoxy ethane under a nitrogen atmosphere. The reaction mixture is heated at 85° C. for 24 h, cooled and extracted with ethyl acetate. The organic solvent is removed and the residue is chromatographed. 0.4 g of desired compound A-21 is obtained as greenish solid (yield (40%); mp: 156-158° C.).
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[F:30])([C:21]#[N:22])[CH:10]([CH2:31][C:32]([C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:36])([CH3:34])[CH3:33])[NH:9]1)=[O:7])(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[CH2:38]([O:37][C:35]([C:32]([CH3:34])([CH3:33])[CH2:31][CH:10]1[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]1([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[F:30])[C:21]#[N:22])=[O:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)C1NC(CC(C)(C)C(=O)OCc2ccccc2)C(C#N)(c2ccc(Cl)cc2F)C1c1cccc(Cl)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F)C(=O)OCc1ccccc1
Yield: 86 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methyl-propyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 103b (0.98 g, 1.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-(2-benzyloxycarbonyl-2-methyl-propyl)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white gum (0.94 g, 86%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]([O:15][CH2:16][CH:17]=[CH2:18])([C:11]([O:13][CH3:14])=[O:12])[CH2:6][C:7]([O:9][CH3:10])=[O:8].[CH2:20]([O:22][SiH:23]([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[CH3:21]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]([C:11]([O:13][CH3:14])=[O:12])([O:15][CH2:16][CH2:17][CH2:18][Si:23]([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])[O:22][CH2:20][CH3:21])[CH2:6][C:7]([O:9][CH3:10])=[O:8]
Reactant: C=CCOC(CC(=O)OC)(CC(=O)OC)C(=O)OC
Reactant: CCO[SiH](OCC)OCC
Solvent: Cc1ccccc1
Product: CCO[Si](CCCOC(CC(=O)OC)(CC(=O)OC)C(=O)OC)(OCC)OCC
Temperature: 80 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
In a round-bottom flask, 3-allyloxy-3-methoxycarbonyl-pentanedioic acid dimethyl ester (2.74 g, 10 mmol) was introduced in 25 mL of dry toluene, followed by triethoxysilane (2.63 g, 16 mmol). Hydrosilylation catalyst, platinum-divinyltetramethyldisiloxane complex in xylenes solution (0.02 mL), was added and the mixture was stirred at 80° C. in a dry atmosphere for 16 hours. The volatiles were then removed in vacuo. The residue was dissolved in dry dichloromethane, a spatula of activated carbon was added, and the mixture was stirred for 3 hours under nitrogen. The mixture was then filtered over a 0.45 μm Teflon filter and the solution was evaporated to dryness to yield the title compound (3.75 g, 86%) as an oil that was used without further purification.