Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][PH:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:5])[CH3:2].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>O1CCCC1>[CH2:1]([O:3][P:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(OCC)[PH](=O)OCC
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(OCC)P(=O)(Cc1ccccc1)OCC
Reaction time: 1.5 h

Procedure:
A solution of diethoxymethylphosphinic acid ethyl ester is added within a period of 90 minutes, under argon, to a suspension of 13.2 g of 99% sodium hydride in 500 ml of tetrahydrofuran, the temperature being maintained at 20°. The reaction is exothermic and is accomplished by the evolution of gas. The mixture is then stirred for 90 minutes, and 85.5 g of benzyl bromide are then added within a period of 20 minutes. The mixture is then stirred at room temperature for 24 hours and cooled to 0°, and 100 ml of water are added carefully. The organic solvents are removed under reduced pressure and the residue is partitioned between water and dichloromethane. The organic phase is separated off, washed with water, dried over sodium sulfate and concentrated by evaporation. Distillation of the residue under reduced pressure yields diethoxymethyl(benzyl)phosphinic acid ethyl ester having a boiling point of 103°-110° (3×10-4 bar).
Reaction SMILES: [OH:1][CH2:2][C@:3]12[CH2:29][CH2:28][C@@H:27]([C:30]([CH3:32])=[CH2:31])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:26])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C@@H:12]([OH:25])[CH2:11][CH2:10]3)[CH2:7][CH2:6]1.C[N+]1([O-])CCOCC1>C(#N)C.C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH3:21][C@:18]12[C@@:17]3([CH3:22])[C@@H:8]([C@:9]4([CH3:26])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:23])([CH3:24])[C:12](=[O:25])[CH2:11][CH2:10]4)[CH2:7][CH2:6][C@@H:5]1[C@H:4]1[C@H:27]([C:30]([CH3:32])=[CH2:31])[CH2:28][CH2:29][C@:3]1([CH:2]=[O:1])[CH2:20][CH2:19]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To suspension of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-3a-(hydroxymethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysen-9-ol (20 g, 45.2 mmol) in acetonitrile (200 mL) and DCM (300 mL) was added 4 angstrom molecular sieves (5 g) and the mixture was stirred for 10 minutes at rt. To the mixture was then added NMO (15.88 g, 136 mmol) and TPAP (0.794 g, 2.259 mmol). The dark green mixture was stirred under nitrogen overnight. Additional NMO (2.0 g) and TPAP (0.08 g) were added and the mixture was stirred at rt for 7 h. The mixture was filtered through a pad of silica gel and celite which was washed with dichloromethane then 25% EtOAc in hexanes. The filtrate was concentrated under reduced pressure and purified using a Thomson 240 g silica gel column and a 15-20% ethyl acetate in hexanes gradient. The title product was isolated as a white foam (17.6 g, 40.1 mmol, 89%). 1H NMR (400 MHz, chloroform-d) δ=9.68 (d, J=1.5 Hz, 1H), 4.77 (d, J=2.0 Hz, 1H), 4.66-4.63 (m, 1H), 2.89 (td, J=11.2, 5.8 Hz, 1H), 2.56-2.36 (m, 2H), 2.16-2.03 (m, 2H), 1.97-1.84 (m, 2H), 1.71 (s, 3H), 1.08 (s, 3H), 1.03 (s, 3H), 1.00 (s, 3H), 0.97 (s, 3H), 0.94 (s, 3H), 1.83-0.87 (m, 18H).
Reaction SMILES: S(Cl)(Cl)=O.CC1C=C(C)C=CC=1C(O)=O.CC1C=C(C)C=CC=1C(Cl)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=1.[CH3:49][C:50]1[CH:55]=[C:54]([CH3:56])[CH:53]=[CH:52][C:51]=1[C:57]([N:59]=[C:60]=[S:61])=[O:58]>C1(C)C=CC=CC=1.C(O)C>[CH3:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][C:38]=1[O:39][CH3:40])[N:35]=[CH:34][CH:33]=[C:32]2[O:41][C:42]1[CH:48]=[CH:47][C:45]([NH:46][C:60]([NH:59][C:57](=[O:58])[C:51]2[CH:52]=[CH:53][C:54]([CH3:56])=[CH:55][C:50]=2[CH3:49])=[S:61])=[CH:44][CH:43]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccc(C(=O)N=C=S)c(C)c1
Agent: Cc1ccc(C(=O)Cl)c(C)c1
Agent: Cc1ccc(C(=O)O)c(C)c1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4C)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,4-dimethylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,4-dimethyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 2,4-dimethyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dimethyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 93%).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46](OB(O)O)=[CH:45][CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(N(CC)CC)C.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.O1CCCC1>[CH2:35]([O:42][C:43]1[CH:48]=[CH:47][C:46]([N:32]2[CH2:31][CH2:30][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)=[CH:45][CH:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCNCC2)c2ncnn12
Reactant: OB(O)Oc1ccc(OCc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCN(c3ccc(OCc4ccccc4)cc3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4′-[(5-oxo-4-piperidin-4-yl-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (452 mg), 4-benzyloxyphenylboric acid (456 mg), copper(II) acetate (276 mg), molecular sieves 4A (1.50 g), triethylamine (506 mg), pyridine (396 mg) and tetrahydrofuran (10 mL) was stirred at room temperature for 2 days. Ethyl acetate was added to the reaction mixture, and the mixture was filtered through Celite-basic silica gel. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=75/25→60/40 (volume ratio)] to give the title compound as a colorless amorphous compound (364 mg, 57%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC([Si](C)(C)[O:24][CH2:25][CH2:26][CH:27]([CH:35]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)[CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Br:44])=[CH:40][CH:39]=1)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(C)C>O1CCCC1>[OH:24][CH2:25][CH2:26][CH:27]([CH:35]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=1)[CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][C:41]([Br:44])=[CH:42][CH:43]=1)[C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29]
Reactant: COc1ccc(COC(CCc2ccc(Br)cc2)C(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(COC(CCc2ccc(Br)cc2)C(CCO)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
A solution of tetra-n-butylammonium fluoride (0.45 ml) was added dropwise over 15 minutes to a stirred solution of the compound (200 mg) obtained from step 4 above in tetrahydrofuran (5 ml) at 0° C. under nitrogen atmosphere. The reaction mixture was allowed to warm to room temperature at which stirring was continued for 2 hour. The volatiles were evaporated under reduced pressure and the residue thus obtained was partitioned between ethyl acetate and water. The phases were separated and the aqueous layer was washed with ethyl acetate. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound (120 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:18][C:9]2=[N:10][CH:11]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:13]=[C:8]2[CH:7]=1.[H-].[Na+].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28]Cl.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:18]([CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)[C:9]2=[N:10][CH:11]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:13]=[C:8]2[CH:7]=1
Reactant: ClCc1ccccn1
Reactant: CS(=O)(=O)c1cnc2[nH]c(-c3ccco3)cc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ccco1)n2Cc1ccccn1
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
To a solution of 2-(2-furanyl)-5-methanesulfonyl-1H-pyrrolo [2,3-b]pyridine (140 mg) in N,N-dimethylformamide (5 ml), 60% sodium hydride (53.6 mg) was added at 0° C. under nitrogen atmosphere and the mixture was stirred for 30 minutes. Subsequently, 2-picolyl chloride hydrochloride (105 mg) was added thereto, followed by stirring at 15 to 30° C. for 15 hours. The reaction solution was then poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with toluene, washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (ethyl acetate:n-hexane 1:1). The resulting crystal was further recrystallized from methanol to obtain 69.3 mg (37%) of the desired product as a pale yellow needle-like crystal.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.C(N=C=NC(C)C)(C)C.O.N1(O)C2C=CC=CC=2N=N1.[C:41]12([C:51](O)=[O:52])[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2>CN(C=O)C.CO>[C:41]12([C:51]([N:10]3[CH2:11][CH2:12][C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[C@H:9]3[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=3)=[O:52])[CH2:48][CH:47]3[CH2:46][CH:45]([CH2:44][CH:43]([CH2:49]3)[CH2:42]1)[CH2:50]2
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: O=C(N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1)C12CC3CC(CC(C3)C1)C2
Temperature: 65 °C

Procedure:
A solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.05 g, 0.2 mmol) in DMF (1 mL) was treated with N-((isopropylimino)methyl-ene)propan-2-amine (0.07 mL, 0.5 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.04 g, 0.2 mmol), and 1-adamantanecarboxylic acid (TCI, 0.04 g, 0.2 mmol). The resulting mixture was heated at 65° C. for 12 h. The reaction was cooled to RT and the filtrate was purified by preparative HPLC [gradient 10-90% MeCN (0.1% TFA)/H2O (0.1% TFA)] to give the pure product. It was dissolved in methanol (10 mL) and neutralized by passing the solution through a Polymer Lab-HCO3 Macroporous resin cartridge, and the filtrate was concentrated to give (1R)-2-(tricyclo[3.3.1.1˜3,7˜]dec-1-ylcarbonyl)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline as a colorless solid. MS (ESI, positive ion) m/z: 440 (M+H).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:32])[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:5]=2[O:4]1.C([Li])CCC.[CH2:38]1[O:48][C:41]2([CH2:46][CH2:45][C:44](=O)[CH2:43][CH2:42]2)[O:40][CH2:39]1>O1CCCC1>[CH3:32][C:3]1([CH3:2])[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]=[C:44]3[CH2:45][CH2:46][C:41]4([O:48][CH2:38][CH2:39][O:40]4)[CH2:42][CH2:43]3)[C:5]=2[O:4]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC1(C)Cc2cccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2O1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)Cc2cccc(C=C3CCC4(CC3)OCCO4)c2O1

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 2, using 18.4 grams (0.039 mole) of (2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethyl)triphenylphosphonium bromide, 15.4 mL (0.039 mole) of n-butyllithium (2.5M in hexanes), and 5.0 grams (0.032 mole) of 1,4-cyclohexanedione mono-ethylene ketal in about 55 mL of dry tetrahydrofuran, yielding 8-(2,3-dihydro-2,2-dimethylbenzofuran-7-ylmethylene)-1,4-dioxaspiro[4.5]decane
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[C:7]([C:11]1[CH:16]=[C:15]([NH2:17])[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]=1[OH:22])([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[C:7]([C:11]1[CH:16]=[C:15]([NH:17][C:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4])[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:12]=1[OH:22])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: C/C=C/C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C/C=C/C(=O)Nc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
N-(3,5-di tert.butyl-4-hydroxyphenyl)crotonamide was prepared by adding a solution of 11.5 grams to crotonyl chloride in 50 milliliters of benzene to a solution of 2,6-di tert.butyl-4-aminophenol prepared as described in Example 2 to which had been added 6 grams of sodium carbonate. The addition was accomplished in 30 minutes at 25° C. to 38° C. The mixture was stirred for 11/4 hours and the solid product was filtered, washed thoroughly with 2% hydrochloric acid, and dried. The yield was 12.8 grams of product which melted at 211° C. to 214° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[N:4][C:5]([F:21])=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1.Cl.[CH3:24][O:25][C:26](=[O:29])[CH2:27][NH2:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[Cl:20][C:6]1[C:5]([F:21])=[N:4][C:3]([NH:28][CH2:27][C:26]([O:25][CH3:24])=[O:29])=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:17]([CH3:19])[CH3:18])[CH:10]=1
Reactant: COc1ccc(Oc2c(Cl)c(F)nc(F)c2Cl)cc1C(C)C
Reactant: COC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNc1nc(F)c(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
To a solution of 3,5-dichloro-2,6-difluoro-4-(3-isopropyl-4-methoxyphenoxy)pyridine. (584 mg) and glycine methyl ester hydrochloric acid (220 mg) in DMF (5.0 mL) was added potassium carbonate powder (500 mg) in one portion. The resulting mixture was stirred at ambient temperature for 20 hours. The reaction mixture was diluted with brine, extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (50 mL×3), dried (Na2SO4), and concentrated. Chromatography with ethyl acetate-hexanes (0-50% gradient elution) afforded the title compound as a colorless oil (434 mg, 62%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:19])[CH:15]([CH3:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]>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>[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:33]=[CH:32][C:31]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:19])[CH:15]([CH3:18])[CH:16]=[CH2:17])=[CH:4][CH:3]=3)=[CH:30][CH:29]=2)[CH2:26][CH2:27]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C=CC(C)C(O)c1c(C)noc1-c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C=CC(C)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-methyl-but-3-en-1-ol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:27])[NH:10][C@@H:11]([CH2:21][C:22]2[NH:26][CH:25]=[N:24][CH:23]=2)[C:12](=[O:20])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:7]1)=[O:5])C.[Li+].[OH-]>CO.O>[NH:24]1[CH:23]=[C:22]([CH2:21][C@H:11]([NH:10][C:9]([C@H:8]2[O:7][C@@H:6]2[C:4]([OH:5])=[O:3])=[O:27])[C:12](=[O:20])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:26]=[CH:25]1
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)Nc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccccc1)[C@H](Cc1c[nH]cn1)NC(=O)[C@H]1O[C@@H]1C(=O)O
Yield: 38.7 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 18a (155 mg, 0.3 mmol); LiOH (14 mg, 0.58 mmol); MeOH/H2O (1.5 mL: 0.5 mL: 0.5 mL); yielded 28 as a white solid (40 mg, 27.1%). 1H NMR (MeOD-d4, 400 MHz): δ 8.66 (s, 1H); 7.57-7.55 (d, 2H, J=7.86 Hz); 7.29-7.27 (t, 3H); 7.10-7.07 (t, 1H); 4.97-4.94 (q, 1H); 3.64-3.63 (d, 1H, J=1.66 Hz); 3.529-3.525 (d, 1H, J=1.66 Hz); 3.36-3.15 (m, 2H). 13C NMR (MeOD-d4, 100 MHz): 169.79, 167.26, 166.95, 137.90, 134.99, 128.37, 124.10, 120.11, 54.13, 52.94, 51.67. ESI-HRMS (m/z): [M+H+] calcd. for C16H16N4O5: 345.1194, observed: 345.1185. HPLC Method 1: Rt=18.2 min, purity=95.2%.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][N:13]([CH3:24])[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[NH:17][C:18](=[O:20])[CH3:19]>>[C:18]([NH:17][C:16]1[CH:15]=[C:14]([N:13]([CH3:12])[CH3:24])[CH:23]=[CH:22][C:21]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5])(=[O:20])[CH3:19]
Reactant: CC(=O)Nc1cccc(N(C)C)c1
Reactant: O=C1OC(=O)c2ccccc21
Product: CC(=O)Nc1cc(N(C)C)ccc1C(=O)c1ccccc1C(=O)O

Procedure:
Condensation of phthalic anhydride and m-(dimethylamino)acetanilide by the method of part A of Example 1 affords 2-(2-acetamido-4-(dimethylamino)benzoyl)benzoic acid (II: Y'2 = CH3CONH, Y'4 = (CH3)2N, Z4 = Z'5 = Z'6 = Z7 = H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]3[N:20]([C:32]4[CH:37]=[CH:36][C:35]([N:38]5[S:42](=[O:44])(=[O:43])[NH:41][C:40](=[O:45])[CH2:39]5)=[CH:34][CH:33]=4)[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[Cl:31])[N:23]=3)=[CH:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:11])[CH3:10].[CH:46](=O)[CH2:47][CH2:48][CH3:49]>>[CH2:46]([NH:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][C:19]3[N:20]([C:32]4[CH:37]=[CH:36][C:35]([N:38]5[S:42](=[O:44])(=[O:43])[NH:41][C:40](=[O:45])[CH2:39]5)=[CH:34][CH:33]=4)[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=4[Cl:31])[N:23]=3)=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]([CH3:10])[CH3:11])[CH2:47][CH2:48][CH3:49]
Reactant: CC(C)Cc1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)cc1N
Reactant: CCCC=O
Product: CCCCNc1cc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3ccc(N4CC(=O)NS4(=O)=O)cc3)cc2)ccc1CC(C)C

Procedure:
5-{4-[2-(3′-Amino-4′-isobutyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-[1,2,5]thiadiazolidin-3-one-1,1-dioxide (22 mg, 0.03 mmol) was reacted with butyraldehyde (2.2 mg, 0.03 mmol) according to general procedure X to give 5-{4-[2-(3′-butylamino-4′-isobutyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
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]([NH2:20])=[CH:13][CH:12]=3)=[O:5])[CH3:2].Cl/[CH:22]=[CH:23]\[CH2:24][CH2:25]Cl.C(N(C(C)C)C(C)C)C>C(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]([N:20]1[CH:25]=[CH:24][CH:23]=[CH:22]1)=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: Cl/C=C\CCCl
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(N)cc3c2c1C
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ncc2[nH]c3ccc(-n4cccc4)cc3c2c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.25 g of 6-amino-4-methyl-beta-carboline-3-carboxylic-acid-ethylester in 70 ml of ethanol, together with 1.7 ml of 1,4-dichloro-2-cis-butene and 4.5 g of ethyldiisopropylamine is heated for 10 h at 50° C. After stirring in 250 ml of ice water, the precipitate is filtered, washed and dried in vacuum. The raw product (3.4 g of a mixture of dihydropyrrole derivative and pyrrole derivative) is dissolved in 600 ml of methylene chloride and, after addition of 17 g of pyrolusite, is stirred for 2 h at room temperature. After filtering, and distilling off the solvent, 2.75 g of raw product is obtained crystallizing out of acetone. In this manner, 2.13 g of 4-methyl-6-(1-pyrrolyl)-beta-carboline-3-carboxylic-acid-ethylester with a m.p. of 214°-217° C. is obtained.
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7].C(=O)([O-])[O-].[K+].[K+].[OH:14][C:15]1[CH:16]=[C:17]([Br:23])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>CN(C=O)C>[CH3:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([Br:23])=[CH:16][C:15]=1[O:14][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[O:7]
Reactant: COc1ccc(Br)cc1O
Reactant: O=C1CCCC1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Br)cc1OC1CCCC1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
17.7 g (0.15 mol) of 2-chlorocyclopentanone and 41.4 g (0.3 mol) of potassium carbonate are added to a solution of 20 g (0.1 mol) of 3-hydroxy-4-methoxy-bromobenzene in 300 ml of absolute DMF and the mixture is stirred at RT for 12 h. After filtering off the solids, the filtrate is concentrated, the residue is taken up in 500 ml of ethyl ether and the solution is extracted by shaking with 3×200 ml of distilled water. Column chromatography affords 21.1 g of the title compound as a brown oil [TLC (petroleum ether/ethyl acetate 6:4) Rf =0.47].
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:10]O)=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8].C(Br)(Br)(Br)[Br:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:10][Br:13])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[CH3:8]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(Cl)nc(CO)c1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(Cl)nc(CBr)c1Br
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of (3-bromo-6-chloro-4-methylpyridin-2-yl)methanol (22.9 g, 97 mmol) in CH2Cl2 (1.5 L) was cooled to 0° C. CBr4 (48.2 g, 145 mmol) was added, followed by Ph3P (38.1 g, 145 mmol). The reaction was stirred at 0° C. for 20 minutes and then warmed to r.t. for 16 hours. The reaction was then concentrated and the residue was purified by flash chromatography on silica gel with 0 to 10% EtOAc/heptanes to afford of 3-bromo-2-(bromomethyl)-6-chloro-4-methylpyridine. 1H NMR (CDCl3, 500 MHz) δ 7.16 (s, 1H), 4.67 (s, 2H), 2.43 (s, 3H).