Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][S:7][C:8]1[C:13]([NH:14][C:15](=[O:18])[CH2:16]O)=[C:12]([S:19][CH3:20])[CH:11]=[C:10]([CH3:21])[N:9]=1.C(N(CC)CC)C.[Br-:29].[Na+]>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[CH3:6][S:7][C:8]1[C:13]([NH:14][C:15](=[O:18])[CH2:16][Br:29])=[C:12]([S:19][CH3:20])[CH:11]=[C:10]([CH3:21])[N:9]=1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CO
Reactant: [Br-]
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(C)nc(SC)c1NC(=O)CBr
Temperature: 11 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
Under cooling with ice, methanesulfonyl chloride (31.7 g, 276.7 mmol) was added dropwise to a solution of N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-hydroxyacetamide (65.0 g, 251.6 mmol), triethylamine (30.5 g, 301.4 mmol), and 4-dimethylaminopyridine (3.07 g, 25.13 mmol) in DMF (455 mL) while the reaction mixture was maintained at 11° C. or lower, followed by stirring for 0.5 hours under cooling with ice. After HPLC was performed to confirm that starting materials had been completely consumed, the crystals (triethylamine hydrochloride) that precipitated were collected through filtration, followed by washing with DMF (195 mL). The filtrate and the wash liquid were combined, and sodium bromide (51.8 g, 503.5 mmol) was added to the resultant mixture. The reaction mixture was stirred under heat at an internal temperature of 55 to 60° C. for 3 hours. Subsequently, water (650 mL) was added to the reaction mixture, and the resultant mixture was stirred at an internal temperature of 21 to 25° C. for 2 hours. The crystals that precipitated were collected through filtration, followed by washing with water and drying through air blow. The crude target product was dissolved in methanol (500 mL) through heating, and the reaction mixture was cooled. The crystals that precipitated were collected through filtration, followed by drying through air blow at 60° C., to thereby yield N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]-2-bromoacetamide (54.38 g, yield: 67.3%, HPLC: 99.32%).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[C:14]1([CH3:22])[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[CH:21])[CH:15]=1.CCCCCC>COCCOC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH3:22][C:14]1[CH:15]=[C:16]([C:20]#[C:21][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C#Cc1cccc(C)c1
Reactant: Brc1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1cccc(C#Cc2nccs2)c1
Yield: 16.3 %

Procedure:
2-Bromo-1,3-thiazole (2.0 g, 13 mmol) and CuI (330 mg, 1.7 mmol) were combined in DME (25 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (5.7 mL, 43 mmol) and PdCl2(PPh3)2 (604 mg, 0.86 mmol) were added and m-tolylacetylene (1.0 g, 8.6 mmol) was added dropwise. The reaction mixture was heated under reflux for 4 h at which time GC/MS showed the reaction was complete. The mixture was filtered through Celite™, and the filter pad was washed thoroughly with ethyl acetate. The combined filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with water (200 mL), brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane then 98:2 hexane:ethyl acetate to afford 2-[2-(3-methylphenyl)ethynyl]-thiazole (280 mg, 16% yield) as a yellow oil which was still impure by 1H NMR analysis. The compound (280 mg) was dissolved in DMSO and purified by preparative HPLC with a 30 min gradient from 70:30 water:acetonitrile to 100% acetonitrile to afford pure 2-[(3-methylphenyl)ethynyl]-1,3-thiazole (122 mg, 6% yield) as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 7.84 (d, J=3.0 Hz, 1H), 7.40–7.34 (m, 3H), 7.28–7.18 (m, 2H), 2.34 (s, 3H). MS (ESI) 200.1 (M++H).
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH2:44]([O:46][C:47](=[O:56])[CH2:48][C:49]1[CH:50]=[N:51][C:52](Br)=[N:53][CH:54]=1)[CH3:45].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH2:44]([O:46][C:47](=[O:56])[CH2:48][C:49]1[CH:50]=[N:51][C:52]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:11])([CH3:13])[CH3:12])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])=[N:53][CH:54]=1)[CH3:45]
Reactant: CCOC(=O)Cc1cnc(Br)nc1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)Cc1cnc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)nc1
Temperature: 95.5 °C
Reaction time: 9 h
Yield: 86.1 %

Procedure:
Degassed N,N-dimethylformamide (0.30 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 30.0 mg, 0.0494 mmol), 2-bromopyrimidine-5-acetic acid ethyl ester (Example 43-(3); 22.9 mg, 0.027 mmol), tetrakis(triphenylphosphine)palladium (0) (24.7 mg, 0.021 mmol) and potassium phosphate (29.3 mg, 0.138 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 91 to 100° C. for nine hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=10/1) to give the title compound (15 mg, 45%).
Reaction SMILES: [Cl:1][CH:2]=[C:3]([Cl:5])Cl.[Na].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].C(OCCO)C>C(Cl)Cl>[Cl:5][C:3]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[CH:2][Cl:1]
Reactant: ClC=C(Cl)Cl
Reactant: COC(=O)c1cccc(O)c1
Agent: [Na]
Solvent: ClCCl
Solvent: CCOCCO
Product: COC(=O)c1cccc(OC(Cl)=CCl)c1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
185 parts of trichloroethylene are introduced into a suspension of 180 parts of the sodium salt of methyl 3-hydroxybenzoate in 200 parts of ethylene glycol monoethyl ether in an autoclave, and the mixture is stirred for 2 hours at 150° C. The solvent is then stripped off under reduced pressure, the viscous residue is taken up in 300 parts of methylene chloride and the solution is filtered in the presence of active charcoal and is chromatographed over neutral alumina. After removing the methylene chloride under reduced pressure from the whole eluate, the residue is distilled through a Vigreux column at 125°-131° C./0.6 mbar, giving methyl 3-(1',2'-dichlorovinyloxy)-benzoate, of nD25 =1.5419.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Br:31])[C:27]([Br:30])=[C:28]([Br:29])[C:4]=2[N:3]=1.[C-]#N.[K+].CCO>CCOC(C)=O>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([Br:31])[C:27]([Br:30])=[C:28]([Br:29])[C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3c(Br)c(Br)c(Br)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3c(Br)c(Br)c(Br)cc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 0.430 g (0.664 mmol) of the blocked nucleoside (102) and 0.216 g (3.317 mmol) of KCN in 13 of mL of 70% EtOH was stirred at room temperature for 6 hr. The reaction mixture was diluted with 75 mL of EtOAc. The EtOAc solution was washed with H2O (50 mL), sat. NaCl solution (50 mL), dried (Na2SO4), and evaporated. The residue was chromatographed on a silica column (1.9×15 cm, eluted successively with CHCl3, 1%, 2%, 3% MeOH/CHCl3). Evaporation of fractions 43-60 (10 mL per fraction) and recrystallization from MeOH/MeCN gave 0.157 g (2 crops, 44%) of 103 as white crystals. MP: 168°-170° C. MS: (FAB) m/e 518.7947 (28%, MH+ =518.7957). 1H NMR (DMSO-d6): d 8.76 (s, 1, 7-H), 5.87 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.51 d, 1, 2'-OH, J2'-2'OH =6.0 Hz), 5.42 (t, 1, 5'-OH, J5'-5'OH =4.5 Hz), 5.30 (d, 1, 3'-OH, J3'-3'OH =4.5 Hz), 4.37 (m, 1, 2'-H, J2'-3' =5.5 Hz), 4.14 (m, 1, 3'-H, J3'-4' =2.0 Hz), 4.02 (m, 1, 4'-H, J4'-5' =J4'-5" =2.5 Hz), 3.71 (m, 2, 5'-H and 5"-H, J5'-5" =12.0 Ha). 13C NMR (DMSO-d6): d 142.32 (C2), 140.92 (C3a), 132.50 (C7a), 120.62 (C5), 118.44 (C6), 117.10 (C7), 115.34 (C4), 89.58 (C1'), 86.50 (C4'), 71.93 (C2'), 69.63 (C3'), 60.89 (C5'). Anal. Calcd. for C12H10Br3ClN2O4 0.3 MeCN: C, 28.36; H, 2.06; N, 6.04. Found: C, 28.25; H, 1.84; N, 5.90. (the Content of 0.3 MeCN was also indicated by 1H NMR.)
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:19]=1[C:42]([O:44]CC)=[O:43].[OH-].[Na+]>O1CCCC1.CO>[NH2:3][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:19]=1[C:42]([OH:44])=[O:43]
Reactant: CCOC(=O)c1c(/C=C/CCCCN2C(=O)c3ccccc3C2=O)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: NCCCC/C=C/c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(F)cc12
Temperature: 50 °C

Procedure:
(E)-ethyl 3-(6-(1,3-dioxoisoindolin-2-yl)hex-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate (The synthesis of this compound was described in EXAMPLE 160B as an intermediate.) was dissolved in a mixture of tetrahydrofuran and methanol and 5 equivalents of aqueous NaOH (10%) was added. The mixture was heated at 50° C. for 2 days. The reaction mixture was concentrated and the residue was purified by reverse phase HPLC (mobile phase: 0-100% acetonitrile in 0.1% TFA aqueous solution during 60 min) on a C18 column to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 8.18 (d, J=9.21 Hz, 1H), 7.82-7.89 (m, 1H), 7.57-7.70 (m, 4H), 7.42-7.55 (m, 4H), 7.37 (t, J=7.67 Hz, 1H), 7.01-7.14 (m, 2H), 6.84 (d, J=7.67 Hz, 1H), 6.14-6.29 (m, 1H), 4.80 (t, J=7.83 Hz, 2H), 4.13 (t, J=5.68 Hz, 2H), 2.70-2.97 (m, 2H), 2.11-2.37 (m, 4H), 1.41-1.76 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]3[C:11]([CH2:23][CH2:24][CH2:25][OH:26])([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:12]([C:14](=[O:16])[CH3:15])=[N:13][N:7]3[C:6]=2[CH:27]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:14]([C:12]1[C:11]([CH2:23][CH2:24][CH:25]=[O:26])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:8]2[CH2:9][O:10][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:27][C:6]=3[N:7]2[N:13]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)C1=NN2c3cc(F)ccc3OCC2C1(CCCO)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(=O)C1=NN2c3cc(F)ccc3OCC2C1(CCC=O)c1ccccc1
Reaction time: 1.5 h

Procedure:
1-[8-Fluoro-3-(3-hydroxypropyl)-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazin-2-yl]ethanone (5-8; a racemic mixture, 1.23 g, 3.34 mmol) was dissolved in anhydrous CH2Cl2 (20 mL) and was treated with Dess-Martin periodinane (2.26 g, 5.3 mmol) and the resulting cloudy yellow solution was stirred 1.5 h. Upon completion, the cloudy solution was treated with 10 mL sat. sodium thiosulfate/NaHCO3 solution (1:1) and stirred 30 min. The mixture was extracted with EtOAc (3×20 mL), and the combined organics were dried (MgSO4), filtered and concentrated. The crude residue 3-(2-acetyl-8-fluoro-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazin-3-yl)propanal (5-9; a racemic mixture) was carried directly into the next transformation: MS (M+H+, C21H19FN2O3) 367.3 found 367.4 required.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][N:16]([CH:21]2[CH2:24][CH2:23][CH2:22]2)[CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:9][CH:8]=1.B(OC(C)C)(OC(C)C)OC(C)C.[ClH:38].C(=O)([O-])[O-].[Na+].[Na+].[NH2:45][C:46]1[C:47]([C:53]([NH:55][C:56]2[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=2)=[O:54])=[N:48][C:49](Br)=[CH:50][N:51]=1>O1CCCC1.C(Cl)Cl.C(OCC)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:38].[NH2:45][C:46]1[C:47]([C:53]([NH:55][C:56]2[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=2)=[O:54])=[N:48][C:49]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][N:16]([CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH:17]3[CH2:20][CH2:19][CH2:18]3)=[CH:9][CH:8]=2)=[CH:50][N:51]=1
Reactant: Brc1ccc(CCCN(C2CCC2)C2CCC2)cc1
Reactant: Nc1ncc(Br)nc1C(=O)Nc1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)OB(OC(C)C)OC(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: Nc1ncc(-c2ccc(CCCN(C3CCC3)C3CCC3)cc2)nc1C(=O)Nc1cccnc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
n-Butyllithium (0.97 mL, 1.55 mmol) was added dropwise over 20 min to a cooled (−78° C.) solution of N-[3-(4-bromophenyl)propyl]-N,N-dicyclobutylamine (0.10 g, 0.31 mmol) and triisopropyl borate (0.21 mL, 0.93 mmol) in anhydrous tetrahydrofuran (2 mL) under a nitrogen atmosphere. The reaction mixture was stirred for 2 h at −78° C. HCl (aq 3 M, 0.6 mL) was added to the reaction mixture and the mixture was allowed to warm to room temperature. Tetrahydrofuran (2 mL) was added, followed by sodium carbonate (1.1 g, 10.8 mmol), Pd(dppf)Cl2 (0.010 g, 12.2 μmol) and 3-amino-6-bromo-N-pyridin-3-ylpyrazine-2-carboxamide (0.10 g, 0.34 mmol). The mixture was heated to 65° C. for 15 h. The solvent was removed and purification by column chromatography on silica using a gradient methylene chloride to methylene chloride/methanol, (2:1), as the eluent gave a yellow solid. The solid was dissolved in methylene chloride (10 mL) and 1 M HCl in diethyl ether was added while stirring. The formed yellow precipitate was filtered and dried to give 75 mg (53% yield) of the title compound as yellow solid: 1H NMR (D2O, 400 MHz) δ 9.47 (s, 1H), 8.73 (s, 1H), 8.69 (d, J=8.6 Hz, 1H), 8.61 (d, J=5.6 Hz, 1H), 8.10 (dd, J=15, 6 Hz, 1H), 7.98 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 3.80 (m, 2H), 3.01 (m, 2H), 2.75 (m, 2H), 2.28 (m, 4H), 2.17 (m, 4H), 2.03 (m, 2H), 1.79 (m, 4H); MS (ESI) 457 m/z (M++1).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]1CCN2C(=NCCC2)CC1>CCOC(C)=O.O>[CH3:12][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Oc1cccc2ccccc12
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc2ccccc12
Temperature: 90 °C

Procedure:
To a solution of 1-naphthol (1.0 g, 6.94 mmol) in DMC (10 mL), DBU (1.06 g, 6.94 mmol) was added and the resulting mixture was heated to reflux (90° C.) for 16 hours. The reaction was cooled to ambient temperature and diluted with EtOAc (50 mL) and H2O (40 mL). The organic layer was separated and washed in sequence with 2M HCl (2×40 mL), 2M NaOH (2×40 mL) and H2O. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give 1-methoxynaphthalene as an oil. The yield of 1-methoxynaphthalene as determined by HPLC was 99% conversion.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:7]1[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][C:4]([CH2:9][OH:10])=[CH:5][CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(CO)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCCO
Product: Cc1ccc(CO)cc1-c1ccccc1
Temperature: 100 °C
Yield: 88.2 %

Procedure:
To a mixture of compound PPP, (3-iodo-4-methyl-phenyl)-methanol, (4 g, 16.12 mmol) and phenylboronic acid (2.06 g, 16.89 mmol) in 1-propanol (30 mL) was successively added palladium(II) acetate (0.01276 g, 0.05 mmol), triphenyl phosphine (0.042 g, 0.161 mmol), aq. sodium carbonate solution (2 M, 11.44 mL, 22.88 mmol), and water (6 mL). The mixture was heated to 100° C. until reaction is complete (tlc), cooled, quenched with water (20 mL) and extracted into ethyl acetate (3×50 mL). Combined organic layer was washed with 2% aq. sodium bicarbonate (2×25 mL), brine (1×50 mL), dried (MgSO4) and concentrated to yield 2.82 g of (6-methyl-biphenyl-3-yl)-methanol, compound QQQ, that was directly taken into next step without any further purification; Rt: 10.95 min.
Reaction SMILES: C[N:2]([CH:4]=[N:5][C:6]([CH:8]([CH2:36][CH2:37][C:38]([F:41])([CH3:40])[CH3:39])[CH2:9][CH:10]([O:32][C:33](=[O:35])[CH3:34])[CH:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)C.[NH2:42]N.C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[F:41][C:38]([CH3:39])([CH3:40])[CH2:37][CH2:36][CH:8]([C:6]1[NH:5][CH:4]=[N:2][N:42]=1)[CH2:9][CH:10]([O:32][C:33](=[O:35])[CH3:34])[CH:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN
Reactant: CC(=O)OC(CC(CCC(C)(C)F)C(=O)N=CN(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)OC(CC(CCC(C)(C)F)c1nnc[nH]1)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1
Temperature: 50 °C
Yield: 100 %

Procedure:
To a solution of acetic acid 3-(dimethylaminomethylene-carbamoyl)-6-fluoro-6-methyl-1-{2-phenyl-1-[(quinoxaline-2-carbonyl)-amino]-ethyl}-heptyl ester (580 mg, 1.03 mmol) in acetic acid (2.5 mL) was added hydrazine (35 wt. % in water, 0.040 mL). The resulting solution was heated to 50° C. for 4 hours, cooled to ambient temperature, diluted with ethyl acetate, and neutralized with saturated aqueous sodium bicarbonate. The organic later was dried over sodium sulfate, filtered, and concentrated to give the title compound as a white foam (580 mg, >100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24](O)=[O:25])=[C:12]2[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].Cl>O1CCCC1.CN(C)C=O.COCCOC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:13]([CH2:24][OH:25])=[C:12]2[C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2c(C(=O)O)n(CC(C)C)c(=O)c3ccc(OCc4ccccc4)cc23)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Solvent: CN(C)C=O
Solvent: COCCOC
Solvent: C1CCOC1
Product: Cc1ccc(-c2c(CO)n(CC(C)C)c(=O)c3ccc(OCc4ccccc4)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a mixed solution of 6-benzyloxy-2-isobutyl-4-(4-methylphenyl)-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (5.74 g, 13 mmol) in tetrahydrofuran (50 ml) were added oxalyl chloride (1.4 ml, 15.6 mmol) and N,N-dimethylformamide (3 drops), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 ml) The obtained solution was added dropwise to a suspension of sodium tetrahydroborate (1.72 g, 45.5 mmol) in 1,2-dimethoxyethane (50 ml) at 0° C. The obtained mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 6-benzyloxy-3-hydroxymethyl-2-isobutyl-4-(4-methylphenyl)-1-(2H)-isoquinolinone (4.41 g, 79.5%) as crystals.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:22])[CH:4]=[C:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH3:21])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCO.CCOC(C)=O.C(Cl)Cl.[Pd]>[CH3:1][NH:2][C:3](=[O:22])[CH2:4][CH:5]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH3:21])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]cc(C)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)CC(c1ccccc1)c1ccc2[nH]cc(C)c2c1
Reaction time: 20 h

Procedure:
To a solution of N-methyl-3-(3-methyl-1H-indol-5-yl)-3-phenyl-acrylamide LXXII (386 mg, 1.33 mmol) in EtOH/EtOAc/DCM (2/1.5/1, 55 ml) was added Degoussa-type catalyst (Pd/C 10%, 40 mg), and the mixture was hydrogenated in a Parr apparatus at 50 psi of H2 for 20 hours. The reaction mixture was filtered through celite, and the filter cake was washed with MeOH, EtOAc and DCM. The filtrate was concentrated to afford N-Methyl-3-(3-methyl-1H-indol-5-yl)-3-phenyl-propionamide LXXIII as a white foamy solid (341 mg, 89% yield).
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:30])=[C:27]([OH:29])[CH:28]=1.N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:24]1/[C:23]([NH2:22])=[CH:28][C:27](=[O:29])[C:26]([CH3:30])=[CH:25]/1
Reactant: Cc1ccc(N)cc1O
Reactant: Nc1c(N)n2n(c1=O)CCC2
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: O
Solvent: CCO
Product: CC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)C(N)=CC1=O

Procedure:
0.58 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulphonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.58 mmol of 5-amino-2-methyl phenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [CH3:1][C:2]([CH:4]=[O:5])=[O:3].N[C@@H:7]([CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:19]([NH:21][CH2:22][C:23](O)=O)=O)CS)=O)C(O)=O.Cl([O-])(=O)(=O)=O.[C:31]1([NH2:38])[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37]>C(C=O)=O>[N:15]1[C:13]2[C:22](=[CH:23][CH:7]=[CH:11][CH:12]=2)[N:21]=[CH:19][CH:16]=1.[CH3:1][C:2]([CH:4]=[O:5])=[O:3].[C:31]1([NH2:38])[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Agent: CC(=O)C=O
Agent: Nc1ccccc1N
Agent: O=CC=O
Product: c1ccc2nccnc2c1
Reaction time: 1 h

Procedure:
Methylglyoxal-containing PBS(-) solution and glutathione-containing PBS(-) solution (pH7.4) were combined to prepare solutions containing 400 μM methylglyoxal and 0, 1, 2, 4, or 8 mM glutathione. The solutions were incubated at 37° C. Samples were taken after 0, 2, 4, 8, and 24 hours; and 40 μl of 2 M perchlorate, 40 μl of 1% o-phenylenediamine, and 100 μl of 200 μM glyoxal were added to 100 μl of each sample. The mixtures were stirred, and then incubated at 25° C. for one hour. Quinoxaline derivative, which was produced by the reaction of methylglyoxal and o-phenylenediamine, was separated and quantified by HPLC using reverse-phase column according to the method of Ohmori et al. (Ohmori, S. et al., J. Chromatogr. 414: 149–155, 1987).