Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14](I)=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(N(CC)CC)C.[C:28]1(=[O:34])[CH2:33][CH2:32][CH2:31][CH:30]=[CH:29]1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH3:19])=[CH:15][C:14]([C:30]1[CH2:31][CH2:32][CH2:33][C:28](=[O:34])[CH:29]=1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: O=C1C=CCCC1
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(I)cc3c2c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc2[nH]c3ccc(C4=CC(=O)CCC4)cc3c2c1C
Yield: 7.2 %

Procedure:
In a pressure vessel, 1.08 g (3 mmol) of 6-iodo-4-methyl-β-carboline-3-carboxylic acid ethyl ester is heated to 140° C. for 3 hours with 72 mg (0.06 mmol) of palladium(II) acetate, 0.48 ml (3.6 mmol) of triethylamine, and 432 mg (4.5 mmol) of 2-cyclohexen-1-one in 10 ml of absolute dimethylformamide. After concentration, the mixture is chromatographed over silica gel with methylene chloride:ethanol=10:2. After recrystallization of the combined polar fractions from methylene chloride/cyclohexane, 75 mg (6.7% of theory) of 6-(1-oxo-2-cyclohexen-3-yl)-4-methyl-β-carboline-3-carboxylic acid ethyl ester is obtained, mp 245°-248° C. After recrystallization from ethyl acetate, the combined nonpolar fractions, which are chromatographed twice over silica gel with toluene:glacial acetic acid:water=10:10:1, yield 60 mg (5.8% of theory) of 6-(1-oxocyclohex-3-yl)-4-methyl-β-carboline-3-carboxylic acid ethyl ester, mp 182°-189° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([B:10]([OH:12])[OH:11])[CH:9]=1)([OH:3])=O.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[N:15]1([C:1]([C:4]2[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([B:10]([OH:12])[OH:11])[CH:9]=2)=[O:3])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: COc1ccc(C(=O)O)cc1B(O)O
Reactant: C1COCCN1
Product: COc1ccc(C(=O)N2CCOCC2)cc1B(O)O

Procedure:
The title compound was prepared in analogy to the procedure described for intermediate K using 5-carboxy-2-methoxyphenyl boronic acid and morpholine; ESI-MS: 266.5 [M+H]+ (LC-MS 2); 1H-NMR (DMSO-d6, 400 MHz) δ 7.84 (s, 1H), 7.57 (d, 1H), 7.46 (d, 1H), 7.03 (d, 1H), 3.83 (s, 3H), 3.62-3.60 (m, 4H), 3.49-3.42 (m, 4H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[OH-:22].[Na+]>>[O:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:10]2[CH:9]=[C:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:22])[CH:7]=3)[CH:13]=[CH:12][N:11]=2)[CH2:16][CH2:17]1
Reactant: Fc1cc(-c2ccnc(NC3CCOCC3)c2)ccn1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: O=c1cc(-c2ccnc(NC3CCOCC3)c2)cc[nH]1
Temperature: 95 °C
Yield: 98 %

Procedure:
2′-Fluoro-N-(tetrahydro-2H-pyran-4-yl)-4,4′-bipyridin-2-amine (0.64 g, 2.3 mmol) was combined with 1M HCl (25 mL, 25 mmol) and heated to 95° C. for 3 hours. Upon cooling, the mixture was neutralized (pH 7-8) with of 1M NaOH (25 mL). The resulting slurry was cooled to 0° C. and filtered. The solids were washed with water and dried to give 4-(2-(tetrahydro-2H-pyran-4-ylamino)pyridin-4-yl)pyridin-2(1H)-one (0.62 g, 2.3 mmol, 98% yield) as a solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:20]1([S:26]([CH:29]2[CH:39]([C:40]3[CH:45]=[C:44](Br)[CH:43]=[C:42]([CH3:47])[N:41]=3)[NH:38][C:31]3([CH2:35][CH2:34][N:33]([CH3:36])[C:32]3=[O:37])[CH2:30]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>COCCOC.O.O.CCOC(C)=O>[C:20]1([S:26]([CH:29]2[CH2:30][C:31]3([CH2:35][CH2:34][N:33]([CH3:36])[C:32]3=[O:37])[NH:38][CH:39]2[C:40]2[CH:45]=[C:44]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[CH:43]=[C:42]([CH3:47])[N:41]=2)(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Br)cc(C2NC3(CCN(C)C3=O)CC2S(=O)(=O)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(C2NC3(CCN(C)C3=O)CC2S(=O)(=O)c2ccccc2)n1
Temperature: 120 °C
Yield: 103.2 %

Procedure:
PdCl2(Ph3P)2 (128.4 mg, 0.1800 mmol) was added to a degassed mixture of 4-trifluoromethylphenyl-boronic acid (365.03 mg, 1.92 mmol), sodium carbonate (582.01 mg, 5.49 mmol) and 7-(benzene-sulfonyl)-8-(4-bromo-6-methyl-2-pyridyl)-3-methyl-3,9-diazaspiro[4.4]nonan-4-one (which may be prepared as described in Description 12) (850 mg, 1.83 mmol) in DME (12 mL) and water (4 mL) under N2 in a microwave vial and the reaction was heated in the microwave at 120° C. for 1 hour. The mixture was diluted with water/EtOAc, filtered, and the phases separated. The organic layer was dried (Na2SO4) and the solvent evaporated to afford a light brown solid. This was purified using a Biotage SP4, 25 g SNAP cartridge, eluting with 0 to 10% MeOH/EtOAc to afford the 3-(benzenesulfonyl)-7-methyl-2-[6-methyl-4-[4-(trifluoromethyl)-phenyl]-2-pyridyl]-1,7-diazaspiro[4.4]nonan-6-one (D16) (1 g, 1.8883 mmol) as an off-white solid (with traces of impurities);
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10](=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[C:21](O)(=O)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reactant: C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(C2CCCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Oxo-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 1.0E1 mmol) and piperazine, 1-methyl- (1.10 g, 11.0 mmol) were dissolved in a solution of Acetic acid (0.500 mL, 8.79 mmol) and Methylene chloride (50.0 mL, 7.80E2 mmol). After stirring at room temperature for 15 minutes, Sodium triacetoxyborohydride (4.2 g, 2.0E1 mmol) was added and the reaction was allowed to stir overnight at room temperature. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane/ethyl acetate. Combined extracts were then dried over sodium sulfate, filtered and reduced. TLC showed evidence of a new product (iodine visualization). 2.25 g of crude 3-(4-Methyl-piperazin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester was used without further purification.
Reaction SMILES: [CH2:1]([C:9]1[CH:25]=[CH:24][C:12]([C:13](=[O:23])[CH2:14][C:15]2[CH:16]=C([CH:20]=[CH:21][CH:22]=2)C#N)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[C:27]([OH:30])(=[O:29])[CH3:28]>O>[CH2:1]([C:9]1[CH:25]=[CH:24][C:12]([C:13](=[O:23])[CH2:14][C:15]2[CH:16]=[C:28]([CH:20]=[CH:21][CH:22]=2)[C:27]([OH:30])=[O:29])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(C(=O)Cc2cccc(C#N)c2)cc1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CCCCCCCCc1ccc(C(=O)Cc2cccc(C(=O)O)c2)cc1

Procedure:
The acid chloride prepared from 3-cyanophenylacetic acid (5 g) as described in Example 18 is added at once to 1-phenyloctane (5.9 g, 0.03 moles) in methylene chloride (20 ml). Anhydrous aluminium chloride (4.96 g, 0.037 moles) is added in 1 portion and the resulting mixture heated under reflux for 2 hours. The reaction mixture is cooled and poured into a mixture of ice water (200 ml) and concentrated hydrochloric acid (20 ml). The mixture is extracted with ether (3×50 ml) and the combined extracts dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is chromatographed on silica gel (hexane: ether; 70:30) to yield 3-(4-n-octylphenacyl)benzonitrile (3.12 g, m.p. 59°-64° C). This nitrile is heated under reflux in a mixture of concentrated hydrochloric acid (30 g) and acetic acid (30 g) for 48 hours. The reaction mixture is diluted with water (60 ml) and extracted with ether (3×50 ml). The combined ether extracts are washed with water (50 ml) then dried over magnesium sulfate, filtered, and evaporated to dryness. The residue is recrystallized from heptane and again from aqueous ethanol to provide 3-(4-octyl-phenacyl)benzoic acid (1.5 g), m.p. 103°-110° C.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:30]1(C)C=CC=CC=1.[Si](C=[N+]=[N-])(C)(C)C.C(O)(=O)C>CO>[O:8]([CH:9]([C:22]1[O:23][C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(C(=O)O)o1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazole-5-carboxylic acid (281 mg, 6.673 mmol) was dissolved in a mixture of MeOH:toluene (4 mL: 10 mL), cooled to 0° C. and TMSCHN2 (2 M in hexanes, 3 equiv) was added dropwise under Ar. The reaction mixture was stirred at room temperature for 0.5 h before it was cooled to 0° C. and acetic acid was added dropwise until the solution turned from yellow to clear. The mixture was evaporated in vacuo and the resulting solid was dissolved in EtOAc. The solution was washed with saturated aqueous NaHCO3, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude ester which was purified by flash chromatography (10-30% EtOAc/hexanes) to afford the pure ester as a clear oil (225 mg, 78%): 1H NMR (CDCl3, 500 MHz) δ 7.78 (s, 1H), 7.36-7.33 (m, 2H), 725-7.23 (m, 3H), 4.92 (t, 1H, J=7.0 Hz), 3.98 (s, 3H), 2.67 (t, 2H, J=7.5 Hz), 2.12-1.94 (m, 2H), 1.72-1.67 (m, 2H), 1.53-1.43 (m, 6H), 0.98 (s, 9H), 0.17 (s, 3H), 0.08 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 169.0, 158.5, 143.1, 142.6, 134.5, 128.8, 128.6, 126.0, 69.1, 52.5, 36.7, 36.3, 31.8, 29.5, 26.1, 26.1, 25.4, 18.6, −4.6, −4.8.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([O:36]CC)=[O:35])[CH:28]=[C:27]4[CH3:39])=[CH:20][CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1.Cl.O>O1CCCC1.CO>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[C:5]=1[C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([C:34]([OH:36])=[O:35])[CH:28]=[C:27]4[CH3:39])=[CH:20][CH:19]=2)=[C:14]([CH:40]([CH3:42])[CH3:41])[O:13][N:12]=1
Reactant: CCOC(=O)c1cc(C)c2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)nc2ccc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3)cc12
Temperature: 90 °C
Yield: 90.6 %

Procedure:
A 1 N solution of sodium hydroxide (93.1 μL, 93.1 μmol) was added to ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-methyl-2-quinolinecarboxylate (26.8 mg, 46.6 μmol) in tetrahydrofuran and methanol (1:1, 931.4 μL) and the mixture was heated in the microwave at 90° C. for 10 minutes. After cooling, the mixture was neutralized with 1 N hydrochloric acid (93.1 μL), water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate, filtered and concentrated to give 23.1 mg (91%) of 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-4-methyl-2-quinolinecarboxylic acid as a solid. 1H NMR (400 MHz, d6-DMSO): δ 13.29 (br s, 1H), 8.24 (d, J=2 Hz, 1H), 8.16 (d, J=9 Hz, 1H), 8.10 (dd, J=9, 2 Hz, 1H), 7.98 (s, 1H), 7.77 (d, J=9 Hz, 2H), 7.65-7.62 (m, 2H), 7.55 (dd, J=9, 7 Hz, 1H), 6.94 (d, J=9 Hz, 2H), 4.89 (s, 2H), 3.48 (septet, J=7 Hz, 1H), 2.81 (s, 3H), 1.35 (d, J=7 Hz, 6H). HRMS C30H24Cl2N2O4 m/z 547.1191 (M+H)+Cal; 547.1199 (M+H)+Obs.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([O:33][CH2:34][C:35]([O:37]C)=[O:36])[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C1COCC1.CO>O>[C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([O:33][CH2:34][C:35]([OH:37])=[O:36])[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Yield: 81.3 %

Procedure:
In a similar manner as described in step 2 of Example 6, the title compound was prepared from methyl [(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]acetate (0.20 g, 0.38 mmol), prepared in the previous step, and 1N NaOH (0.58 mL, 0.58 mmol) in 1.67:1.67:1 THF:MeOH:water (39 mL). Purification on a Biotage Horizon™ system with a KP-Sil Flash 25+M column (40 g Silica Gel, 60 Å) using 25% EtOAc in hexane with 1% formic acid as the eluent gave [(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]acetic acid as an off-white solid (0.155 g, 79%), mp 154–156° C. Elemental Analysis for C30H22F3NO3.0.02 H2O Calc'd: C, 71.80; H, 4.43; N, 2.79. Found: C, 71.96; H, 4.55; N, 2.61.
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[O:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1B(O)O>C1(C)C=CC=CC=1.CCO.C([O-])([O-])=O.[Na+].[Na+]>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[O:4][CH:3]=1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: COc1ccc2c(=O)c(Br)coc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2coc3cc(OC)ccc3c2=O)c(OC)c1
Reaction time: 5 h

Procedure:
A solution of 13 (4.0 g, 15.8 mmol) and 2,4-dimethoxy benzeneboronic acid (3.4 g, 19.0 mmol) and Pd(Ph3)4 (0.79 g) in toluene/EtOH (50 mL/5 mL) and 2M Na2CO3 aq. (30 mL) was heated to reflux. After 5 h, the reaction was cooled and the organic layer dried over MgSO4, concentrated and chromatographed on silica gel (EtOAc/hexanes 3:7 to EtOAc/hexanes 1:1) to yield 14 as a solid which was triturated with MeOH to give a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[CH:24]=[C:25]([C:28](O)=[O:29])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]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.[CH3:64][N:65]([CH3:71])[C@H:66]1[CH2:70][CH2:69][NH:68][CH2:67]1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[CH:24]=[C:25]([C:28]([N:68]5[CH2:69][CH2:70][C@H:66]([N:65]([CH3:71])[CH3:64])[CH2:67]5)=[O:29])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: O=C(O)c1ccc2c(c1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Reactant: CN(C)[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)[C@H]1CCN(C(=O)c2ccc3c(c2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
To a stirred solution of 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid (70 mg; 0.16 mmol) in DMF (5 ml) was added HATU (103 mg; 0.27 mmol), DIPEA (50 μl; 0.27 mmol) and (S)-(−)-3-(dimethylamino)pyrrolidine (50 μl; 0.38 mmol). The reaction mixture was stirred at r.t. for 4 h upon which time it was diluted with EtOAc (20 ml) and washed successively with satd. NaHCO3 (20 ml) and brine (2 20 ml). The organic layer was dried (Na2SO4), concentrated and purified by prep. LCMS to give 420 as an off-white solid (50 mg; 58%). δH (400 MHz, CDCl3) 1.77-1.92 (br m, 1H), 2.06-2.17 (m, 1H), 2.24 (br s, 3H), 2.35 (br s, 3H), 2.60-2.83 (m, 1H), 3.16 (br s, 2H), 3.29-3.98 (m, 4H), 4.33 (br s, 2H), 6.94-7.20 (m, 4H), 7.32-7.39 (m, 1H), 7.50-7.60 (m, 1H), 7.77 (s, 1H), 8.11 (s, 1H). [M+H]+: 522
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:27][C:28](=[O:30])[CH3:29])[CH2:7][S:8]([CH2:11][CH2:12][C:13]([NH:16]C(OCC1C=CC=CC=1)=O)([CH3:15])[CH3:14])(=[O:10])=[O:9])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][CH2:5][CH:6]([O:27][C:28](=[O:30])[CH3:29])[CH2:7][S:8]([CH2:11][CH2:12][C:13]([NH2:16])([CH3:15])[CH3:14])(=[O:9])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CS(=O)(=O)CCC(C)(C)NC(=O)OCc1ccccc1)OC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OCC(CS(=O)(=O)CCC(C)(C)N)OC(C)=O
Reaction time: 1.5 h

Procedure:
To a solution of 3-(3-(benzyloxycarbonylamino)-3-methylbutylsulfonyl)propane-1,2-diyl diacetate (401.9 mg, 0.9062 mmol) in methanol (10 ml) was added palladium on carbon (10%, 45 mg). The solution was purged with nitrogen gas, and then the suspension was put under a blanket of hydrogen gas (1.3 atm). The suspension was stirred for 1.5 hours, filtered through a 0.45 um PTFE filter, and concentrated in vacuo. The residue was used without any further purification. LRMS (ESI/APCI) m/z 310 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH2:10][C:9]([CH3:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(N(CC)CC)C>[C:1]1([N:7]2[C:11](=[O:12])[CH:10]([C:29](=[O:30])[NH:28][C:25]3[CH:26]=[CH:27][C:22]([S:21][CH3:20])=[CH:23][CH:24]=3)[C:9]([CH3:13])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(N=C=O)cc1
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CSc1ccc(NC(=O)C2C(=O)N(c3ccccc3)N=C2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The mixture of 2.6 g of 1-phenyl-3-methyl-2-pyrazolin-5-one, 75 ml of benzene, 1.8 g of triethylamine and 2.5 g of p-methylthiophenylisocyanate is stirred at ambient temperature and allowed to stand overnight. It is evaporated; the residue taken up in methanol, the solution is filtered and combined with the mixture of 10 ml of 5 N hydrochloric acid and 250 ml of water. The precipitate formed is collected, washed with water, dried, triturated with diethyl ether and dissolved in 2 N aqueous sodium hydroxide. The solution is filtered, acidified with 5 N hydrochloric acid, the precipitate washed with water, dried, triturated with methanol and recrystallized from ethyl acetate, to yield the 1-phenyl-3-methyl-4-(p-methylthiophenylcarbamoyl)-2-pyrazolin-5-one melting at 196°-199°.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)=[C:20](/[CH:37]=[CH:38]\[CH3:39])[CH:19]=1)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][C:9]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[C:20](/[CH:37]=[CH:38]\[CH3:39])[CH:19]=1)([C:10]([F:11])([F:12])[F:13])[C:14]([F:16])([F:17])[F:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C/C=C\c1cc(C(OCc2ccccc2)(C(F)(F)F)C(F)(F)F)ccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 141.1 %

Procedure:
tert-Butyl (Z)-4-{4-[2-(benzyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl]-2-(prop-1-en-1-yl)phenyl}piperazine-1-carboxylate (67 mg, 0.119 mmol) was dissolved in dichloromethane (2.0 mL). Under ice-cold conditions, trifluoroacetic acid (200 μL) was added and stirred at room temperature for 0.5 hours. The reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate under ice-cold conditions, and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (chloroform). The title compound (77 mg (yield >99%)) was obtained as a white pink oil.
Reaction SMILES: [I-].[CH2:2]([O:9][C:10]1[C:11]([C:19]2[CH:24]=[CH:23]C=CC=2[P+](C)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[CH3:44][N:45]1[CH:49]=[CH:48][N:47]=C1C=O>C1COCC1.C(OCC)C.O>[CH2:2]([O:9][C:10]1[C:11]([CH:19]=[CH:24][C:23]2[N:45]([CH3:44])[CH:49]=[CH:48][N:47]=2)=[CH:12][C:13]2[O:17][CH2:16][CH2:15][C:14]=2[CH:18]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cn1ccnc1C=O
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1-c1cc2c(cc1OCc1ccccc1)CCO2
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cn1ccnc1C=Cc1cc2c(cc1OCc1ccccc1)CCO2
Temperature: -20 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A flame dried, N2 purged, 100 ml round bottom flask equipped with a dropping funnel, thermometer and magnetic stirrer was charged with 5-(benzyloxy)-2,3-dihydrobenzofuran-6-yl methyltriphenylphosphonium iodide (3.0 g, 4.8 mmoles) and anhydrous THF (15 ml). The suspension was cooled to -20° C. and a 1.55M solution of n-butyllithium (3.1 ml, 4.8 mmoles) was added dropwise, while maintaining an internal reaction temperature of -20° C. The suspension became a red solution and stirring was continued 1 hour more at 0° C. The reaction mixture was chilled to -25° C. and a solution of 1-methylimidazole-2-carboxaldehyde (525 mg, 4.8 mmoles) in THF. (10 ml) was added dropwise over 5 minutes. The reaction mixture was allowed to warm to room temperature and stir for 12 hours. It was then cooled to 0° C. and water (1.0 ml) added. It was further stirred for 1/2 hour whereupon the solvent was removed in vacuo to afford the crude product. The crude product was dissolved in ethyl ether (20 ml) and water (20 ml). The layers were partitioned and separated. The organic phase was washed with water (2×20 ml), dried over MgSO4, suction filtered, and the filtrate concentrated in vacuo to yield a crude yellow oil. Further purification was achieved by high performance liquid chromatography to produce approximately a 1:1 ratio of cis and trans isomers of 1-(5-benzyloxy-2,3-dihydrobenzofuran-6-yl)-2-(1-methyl-imidazol-2-yl)ethene (600 mg, 38%).
Reaction SMILES: [O:1]1[C:5]2=[N:6][C:7]3[C:13](=O)[O:12][C:10](=[O:11])[C:8]=3[CH:9]=[C:4]2[CH:3]=[CH:2]1.[NH2:15][C:16]([CH3:23])([CH:20]([CH3:22])[CH3:21])[C:17]([NH2:19])=[O:18].CCOCC>C1COCC1>[CH:20]([C:16]1([CH3:23])[C:17](=[O:18])[NH:19][C:13]([C:7]2[N:6]=[C:5]3[O:1][CH:2]=[CH:3][C:4]3=[CH:9][C:8]=2[C:10]([OH:12])=[O:11])=[N:15]1)([CH3:22])[CH3:21]
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: O=C1OC(=O)c2nc3occc3cc21
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C1(C)N=C(c2nc3occc3cc2C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
Furo[2,3-b]pyridine-5,6-Dicarboxylic anhydride (2.50 g, 0.013 mol) is suspended in 40 mLs anhydrous THF and (+)-2-amino-2,3-dimethylbutyramide (1.72 g, 0.013 mol) is added. The mixture is stirred under N2 at room temperature for 16 hours. The solution is poured into 150 mLs anhydrous ether, and the resulting solid is collected in 88.6% crude yield. The unpurified adduct is converted to the indicated product in the manner described in Example 38 for the racemic mixture. The (+)-isomer is recrystallized from absolute ethanol, and is isolated in 27.0% yield from the adduct., mp 244°-245° C. [α]D25 =44.5°.