Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2](C)=[CH2:3].[C:8]([NH2:12])(=[O:11])[CH:9]=[CH2:10].C(OC)(=O)C(C)=C.C(N)(=O)C=C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>O>[C:1]([O:6][CH3:7])(=[O:5])[CH:2]=[CH2:3].[C:8]([NH2:12])(=[O:11])[CH:9]=[CH2:10]
Reactant: C=C(C)C(=O)OC
Agent: C=CC(N)=O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: C=CC(=O)OC

Procedure:
A solution prepared by dissolving 0.05 parts of methyl methacrylate/acrylamide copolymer suspension (this was prepared as follows: 20 parts by weight of methyl methacrylate, 80 parts by weight of acrylamide, 0.3 parts by weight of potassium persulfate, and 1500 parts by weight of ion-exchanged water were put into a reactor, and kept at 70° C. while purged with nitrogen gas; the reaction was continued until the monomers were completely converted into a polymer, and an aqueous solution of methyl acrylate-acrylamide copolymer was obtained; thus obtained, the aqueous solution was used as a suspension) in 165 parts of ion-exchanged water was fed into a stainless autoclave having a capacity of 5 liters and equipped with a baffle and a Pfaudler stirrer, and stirred at 400 rpm, and then purged with nitrogen gas. Next, a mixture of the following substances was added to it with stirring, and heated up to 70° C. At the time when the inner temperature reached 70° C., the polymerization began. After kept as such for 180 minutes, the polymerization finished. After this, the reaction system was cooled and the polymer was separated, washed and dried in an ordinary manner to a copolymer (A-1) in the form of beads. The yield of polymerization of the copolymer (A-1) was 98%.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=1)([O-])=O>CO.[Pd]>[NH:8]1[C:7]2[CH:11]=[CH:12][C:4]([NH2:1])=[CH:5][C:6]=2[N:10]=[CH:9]1
Reactant: O=[N+]([O-])c1ccc2nc[nH]c2c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2[nH]cnc2c1
Yield: 9.9 %

Procedure:
A solution of 5-nitrobenzimidazole (10.0 g, 613 mmol) in methanol (250 mL) was hydrogenated in the presence of 10% Pd/C (0.40 g) at atmospheric pressure for 20 h. The mixture was filtered through Celite® and the solvent removed under reduced pressure to afford the pure product (8.1 g, 100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.C(=O)([O-])[O-].[NH4+:34].[NH4+]>C(Cl)Cl.C(O)C>[ClH:28].[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)(=[NH:34])[NH2:2]
Reactant: Cc1cc(OCc2cccc(C#N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(OCc2cccc(C(=N)N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.9 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(3-cyanophenyl) methoxy]-5-methylphenyl ester (207 mg, 0.5 mmol), as prepared in the preceding step, in methylene chloride (10 mL) was added 37% HCl in ethanol (10 mL) at 0° C. The mixture was allowed to stand at 0° C. for 3 days. The solvent was evaporated in vacuo and the residue was co-evaporated with methylene chloride several times. The residue was dissolved in ethanol (10 mL) and ammonium carbonate (192 mg, 2.0 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. Methylene chloride (150 mL) was added to the mixture. The methylene chloride solution was washed with 10% K2CO3 (2×50 mL) and dried over K2CO3. The solvent was removed in vacuo, HCl in methanol (30 mL) was added, and the solvent again removed in vacuo. The residue was purified by flash chromatography (10% methanol in methylene chloride) to give the title compound as a white solid (112 mg, 48%). 1H-NMR (300 MHz, DMSO-d6) δ 2.23 (s, 3 H), 5.11 (s, 2 H), 6.54 (s, 1 H), 6.56 (s, 1 H), 6.88 (s, 1 H), 7.58 (t, 1 H, J=6.5 Hz), 7.61 (t, 1 H, J=12.2 Hz), 7.66 (d, 1 H, J=3.9 Hz), 7.73-7.95 (m, 5 H), and 9.40 (br s, 4 H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C21H19N2O4SCl: 431.1 (M+H), 453.1 (M+Na). Found: 431.0, 452.9.
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[N:15][CH:16]=2)[CH2:7][CH2:6]1)=[NH:4].[C:29](O)(=O)[CH:30]([CH3:32])[CH3:31].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:30]([C:32]1[O:1][N:2]=[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([CH2:17][O:18][C:19]4[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=4)=[N:15][CH:16]=3)[CH2:7][CH2:6]2)[N:4]=1)([CH3:31])[CH3:29]
Reactant: CC(C)C(=O)O
Reactant: CS(=O)(=O)c1ccc(OCc2ccc(C3CCN(C(=N)NO)CC3)cn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nc(N2CCC(c3ccc(COc4ccc(S(C)(=O)=O)cc4)nc3)CC2)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.4 %

Procedure:
A solution of N-hydroxy-4-[2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]piperidin-1-carboxamidine (98 mg, 0.242 mmol), isobutyric acid (22 μL, 0.242 mmol) and 1-hydroxybenzotriazole monohydrate (41 mg, 0.267 mmol) in N,N-dimethylformamide (2 mL) was cooled in an ice bath followed by the addition of N,N-diisopropylethylamine (0.14 mL, 0.800 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg, 0.291 mmol). The mixture was stirred at room temperature overnight, poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. A suspension of the residue in toluene (4 mL) was refluxed for 2 hours, allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2→1/5) to give a crystal. The crystal was recrystallized from ethyl acetate/hexane to give the title compound as a white crystal (59 mg, yield 53%).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C[Si](N([Li])[Si](C)(C)C)(C)C.[P:25](Cl)(=[O:40])([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[O:33]([P:25]([O:1][C:2]1[N:3]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:5][O:6][CH:7]=1)([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCOCC1=O
Reactant: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: [Cl-]
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
Tert-butyl 3-oxomorpholine-4-carboxylate (5.2 g, 25.8 mmol) was dissolved in dry THF (52 ml). The mixture was cooled to −30° C. and (bis(trimethylsilyl)amino) lithium (1M THF solution, 28.4 ml, 28.4 mmol) was added dropwise. The resulting mixture was stirred for 1 hr, then diphenyl phosphorochloridate (7.3 g, 27.1 mmol) was added dropwise. The resulting mixture was allowed to warm slowly to ambient temperature over 6 hrs, after which time no starting material was present by HPLC. The reaction mixture was poured into saturated ammonium chloride solution (100 ml) and diluted with ethyl acetate (100 ml). The organic phase was separated and washed with sat NaHCO3 (50 ml), then brine (50 ml), dried (MgSO4), filtered and concentrated. The residue was purified on silica gel, eluting with 25-30% ethyl acetate/petrol. This gave the title compound as an oil which solidified on standing (7.59 g, 68%); 1H-NMR (CDCl3) 1.35 (9H, s), 3.54 (2H, dt), 3.87 (2H, m), 6.26 (1H, s), 7.11-7.17 (6H, m), 7.24-7.28 (4H, m); 31P-NMR (CDCl3)-16.07; 13C-NMR (CDCl3) 28.1, 42.0, 65.8, 120.0, 120.03, 120.09, 120.13, 125.19, 125.61, 125.62, 129.6, 129.86, 129.9; MS ES(+) 378.0 (M+-tBu).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[NH:30]1[CH2:33][CH:32]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31]1>C(Cl)Cl.C(Cl)(Cl)Cl>[C:19]([C:7]1[C:5]2[N:6]=[C:2]([N:30]3[CH2:33][CH:32]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31]3)[O:3][C:4]=2[C:10]([F:11])=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]=1[CH3:18])#[N:20]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CCOC(=O)CC1CNC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CC1CN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)C1
Yield: 76.3 %

Procedure:
Under nitrogen atmosphere, 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (400 mg, 1.40 mmol) was dissolved in methylene chloride (15 ml), then diisopropylethylamine (537 μl, 3.08 mmol) and ethyl azetidine-3-acetate (503 mg, 2.80 mmol) dissolved in methylene chloride (5 ml) were added, followed by heating under reflux for 19 hours. After cooling, diluting with chloroform and washing with water, the organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. From the eluate with ethyl acetate/hexane (1:1, v/v), the entitled compound (420 mg, 76%) was obtained as a colorless oil.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([N:20]4[CH2:25][CH2:24][C:23]([NH:27]C(=O)OCC5C=CC=CC=5)([CH3:26])[CH2:22][CH2:21]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl>O.C(Cl)Cl>[N:1]1[N:2]=[C:3]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[C:13]([N:20]4[CH2:21][CH2:22][C:23]([CH3:26])([NH2:27])[CH2:24][CH2:25]4)[CH:14]=[CH:15][CH:16]=3)[N:11]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC1(NC(=O)OCc2ccccc2)CCN(c2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC1(N)CCN(c2cccc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 69.4 %

Procedure:
To the product from Step A (0.115 g, 0.233 mmol) was added HCl (1.17 mL, 7.00 mmol, 6.0N aqueous). The mixture was stirred at 90° C. for 45 minutes. The mixture was then cooled to ambient temperature and diluted with water (10 mL) and with CH2Cl2 (10 mL). The layers were mixed and separated and the aqueous phase was washed once more with CH2Cl2 (10 mL) and was then treated with saturated aqueous Na2CO3 until pH=10. The aqueous phase was then extracted with CH2Cl2 (3×10 mL). The combined organic phases were washed with water followed by brine and then dried over Na2SO4, filtered and concentrated to provide 0.058 g (66%) of the product >96% pure by HPLC. MS ESI (+) m/z 359.1 (M+1) detected.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[NH:12][C:13]([C:15]1[C:16]2[N:17]=[CH:18][CH:19]=[N:20][C:21]=2[C:22]([C:25]2[C:30]([Cl:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=2[Cl:36])=[CH:23][CH:24]=1)=[O:14].Cl.C([O-])([O-])=O.[Na+].[Na+]>CCO>[NH:9]1[CH:10]=[CH:11][N:7]=[C:8]1[NH:12][C:13]([C:15]1[C:16]2[N:17]=[CH:18][CH:19]=[N:20][C:21]=2[C:22]([C:25]2[C:26]([Cl:36])=[C:27]([O:34][CH3:35])[CH:28]=[C:29]([O:32][CH3:33])[C:30]=2[Cl:31])=[CH:23][CH:24]=1)=[O:14]
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nccn3COCC[Si](C)(C)C)c3nccnc23)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3ncc[nH]3)c3nccnc23)c1Cl
Temperature: 65 °C
Reaction time: 10 h
Yield: 79.1 %

Procedure:
A mixture of 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid [1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-amide (Step 14.1) (0.527 g, 0.82 mmol), 5 N HCl (7 mL), and EtOH (4 mL) was stirred at 65° C. for 10 h. The reaction mixture was allowed to cool to rt, basified by addition of a saturated aqueous solution of Na2CO3, and extracted with DCM. The combined organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) to afford 0.288 g of the title compound as a yellow solid: ESI-MS: 443.9/445.9 [M+H]+; tR=3.74 min (System 1); TLC: Rf=0.30 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([C:14](=[O:16])[CH3:15])=[CH:12][CH:11]=[C:10]([C:17]([F:20])([F:19])[F:18])[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=O.C[O-].[Na+].Cl>CO.O>[CH3:30][O:29][C:27](=[O:28])[C:26]1[CH:31]=[CH:32][C:23](/[CH:21]=[CH:15]/[C:14](=[O:16])[C:13]2[C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:9][C:10]([C:17]([F:20])([F:18])[F:19])=[CH:11][CH:12]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccc(C(F)(F)F)nc1Nc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(/C=C/C(=O)c2ccc(C(F)(F)F)nc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.9 %

Procedure:
A mixture of 1-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-ethanone (4.28 g, 15.3 mmol) in methanol (60.4 mL) at 25° C. was treated with methyl 4-formylbenzoate (3.01 g, 18.3 mmol) and sodium methoxide in methanol (25% wt, 6.99 mL, 30.5 mmol). The reaction was stirred at 25° C. for 2 d. At this time, the reaction was diluted with water (50 mL), neutralized with a 2N aqueous hydrochloric acid solution, and extracted with methylene chloride (3×75 mL). The combined organics were dried over sodium sulfate and filtered. Silica gel was added to the filtrate, concentrated in vacuo and dried under high vacuum. Flash chromatography (40 g silica column, 10-100% ethyl acetate/hexanes) afforded 4-[(E)-3-oxo-3-(2-phenylamino-6-trifluoromethyl-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (4.04 g, 62%) as an orange solid.
Reaction SMILES: [C:1]1([N:7]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=2)[C:8]2[CH:20]=[CH:19][C:11]3[O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:37]1[CH:38]=[CH:39][C:40]2[NH:41][C:42]3[C:47]([C:48]=2[CH:49]=1)=[CH:46][CH:45]=[CH:44][CH:43]=3.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:39]1[C:40]2[NH:41][C:42]3[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:48]=2[CH:49]=[C:37]([C:25]2[CH:26]=[C:21]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]3[CH:20]=[CH:19][C:11]4[O:12][C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[C:10]=4[CH:9]=3)[CH:22]=[CH:23][CH:24]=2)[CH:38]=1
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: CC1(C)OB(c2cccc(N(c3ccccc3)c3ccc4oc5ccccc5c4c3)c2)OC1(C)C
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(N(c2cccc(-c3ccc4[nH]c5ccccc5c4c3)c2)c2ccc3oc4ccccc4c3c2)cc1

Procedure:
N-phenyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)dibenzo[b,d]furan-2-amine (3.25 g, 7.0 mol), and 3-bromo-9H-carbazole (1.73 g, 7.0 mmol) were mixed in 45 mL of toluene and 15 mL of ethanol. To the solution was bubbled with nitrogen for 15 min. Pd2(dba)3 (0.16 g, 0.18 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.29 g, 7.0 mmol) and K3PO4 (4.49 g, 21.1 mmol) were then added. The mixture was refluxed overnight under nitrogen.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:39])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:42]1[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=1>>[C:1]([O:5][C:6](=[O:40])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:39])[C:16]2[CH:21]=[C:20]([O:22][C:42]3[CH:49]=[CH:48][C:45]([C:46]#[N:47])=[CH:44][CH:43]=3)[CH:19]=[C:18]([O:23][C:24]3[CH:25]=[CH:26][C:27]([CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:28][CH:29]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(O)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Product: CC(C)(C)OC(=O)NCc1ccc(Oc2cc(Oc3ccc(C#N)cc3)cc(C(=O)NC3CCC(NC(=O)OC(C)(C)C)CC3)c2)cc1
Yield: 92.8 %

Procedure:
Using 1.4 g (2.51 mmol) of {4-[3-[4-tert-Butoxycarbonylaminomethylphenoxy]-5-hydroxybenzoylamino]-cyclohexyl}carbamic acid tert-butyl ester and 4-fluoro-benzonitrile (0.76 g, 6.27 mmol) and following the procedure of Example 42(b) afforded 1.53 g of the required product. 1H NMR (DMSO-d6): δ 1.3 (4H, m), 1.4 (18H, s), 1.8 (4H, m), 3.2 (1H, m), 3.7 (1H, m), 4.15 (2H, d), 6.72 (1H, d), 7.20 (1H, s), 7.06 (2H, d), 7.18 (2H, d), 7.28 (2H, d), 7.38 (3H, d), 7.86 (2H, s), 8.3 (1H, d).
Reaction SMILES: [CH2:1]([C:8]1([OH:32])[CH2:13][CH2:12][N:11]([CH2:14][C:15](=[O:31])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][Si](C(C)(C)C)(C)C)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[ClH:51]>C1COCC1.CO>[ClH:51].[CH2:1]([C:8]1([OH:32])[CH2:9][CH2:10][N:11]([CH2:14][C:15](=[O:31])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)CN2CCC(O)(Cc3ccccc3)CC2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cc1ccc(O)cc1)CN1CCC(O)(Cc2ccccc2)CC1
Yield: 36 %

Procedure:
1-(4-Benzyl-4-hydroxy-piperidin-1-yl)-3-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propan-2-one (0.400 g, 0.88 mmol) was dissolved in THF (4 ml) and stirred for 16 hours at room temperature in the presence of 1N tetra-n-butylammonium fluoride (1 ml, 1 mmol). The reaction mixture was quenched with 20% NH4Cl (15 ml) and the aqueous phase was extracted with ethyl acetate (3×20 ml). Combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (ethyl acetate) to give a yellow oil which was dissolved in MeOH (2 ml) and treated with 1N HCl (0.5 ml). The solution was concentrated, the residue was dissolved in isopropanol (i-PrOH) and ether was added to provide 1-(4-Benzyl-4-hydroxy-piperidin-1-yl)-3-(4-hydroxy-phenyl)-propan-2-one hydrochloride (0.120 g, 36%) as white solid, m.p. 180°-181° C. and MS: m/e=340.3 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH:14]1([C:18](O)=[O:19])[CH2:17][CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:14]1([C:18]([NH:1][C@H:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][C:4]([O:6][CH3:7])=[O:5])=[O:19])[CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)C[C@H](N)c1ccccc1
Reactant: O=C(O)C1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C[C@H](NC(=O)C1CCC1)c1ccccc1

Procedure:
To a solution of the amino ester from Example 6, Step A (4.2 mmol, 896 mg) and cyclobutanecarboxylic acid (5.0 mmol, 476 μL) in 10 mL of DCM containing N,N-diisopropylethylamine (12.5 mmol, 2.17 mL) was added 1-(3-dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (5.0 mmol, 958 mg). After 16 h the reaction mixture was washed with H2O (10 mL), 1 M citric acid (10 mL) and saturated NaHCO3 (10 mL). The organic phase was dried with MgSO4 and the solvent removed under reduced pressure to afford the product as a white solid. MS (ESI): m/z 485 (M+H). HPLC B: 1.58 min.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].C(O)(=O)C.[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[I:22])(=[O:12])[CH3:11]>O.C(O)C>[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[N:1][NH:2][C:3]([NH2:5])=[S:4])=[CH:16][C:15]=1[I:22])(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1ccc(C=O)cc1I
Reactant: NNC(N)=S
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C=NNC(N)=S)cc1I
Reaction time: 0.75 h

Procedure:
A solution of 0.728 g (0.008 mole) of thiosemicarbazide (Aldrich T3,340-5) in 25 mL of water containing 1.6 mL of glacial acetic acid was added to a solution of 2.319 (0.008 mole) of 4-acetamido-3-iodobenzaldehyde (33) in 40 mL of absolute ethanol (heating was required to make this dissolve) at 80°. The mixture was stirred at this temperature for 45 minutes. A white precipitate developed in the solution which was filtered after cooling the reaction mixture to give 2.55 (88%) of 34 as white crystals, mp 241-43° (dec.). Infrared (IR) and NMR analysis gave the following results:
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([C:11]2[N:12]([CH3:16])[CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([C:14]2[CH:15]=[C:11]([C:9]([C:6]3[CH:7]=[N:8][C:3]([Cl:2])=[CH:4][CH:5]=3)=[O:10])[N:12]([CH3:16])[CH:13]=2)=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Cn1cccc1C(=O)c1ccc(Cl)nc1
Agent: Cl
Product: Cn1cc(C(=O)c2ccc(Cl)cc2)cc1C(=O)c1ccc(Cl)nc1

Procedure:
Following the protocol of Example 8 and employing (6-chloropyridin-3-yl)-(1-methyl-1H-pyrrol-2-yl)methanone hydrochloride in place of (1-methyl-1H-pyrrol-2-yl)-pyridin-3-ylmethanone hydrochloride and 4-chlorobenzoyl chloride in place of 4-fluorobenzoyl chloride, the title compound was obtained and recrystallized from MTBE: mp 150-152° C. ES-MS m/z=360 (M++H). 1H NMR (300 MHz, CDCl3) δ 4.1 (s, 3H); 7.2 (s, 1H); 7.5 (m, 3H); 7.56 (s, 1H); 7.8 (dd, 2H); 8.05 (d, 1H); 8.8 (s, 1H). Anal calc'd for C18H12C2N2O2: 60.19; H, 3.37; N, 7.8. Found: C, 59.9; H, 3.34; N, 7.71.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][CH:19]=2)[CH:4]=1.Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:41]([O:40][C:38]([CH2:37][NH:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:5]([NH:16][C:17](=[O:35])[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:20][CH:19]=2)[CH:4]=1)=[O:39])[CH3:42]
Reactant: CCOC(=O)COc1ccc(N)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(OCC(=O)OCC)c(NC(=O)c2ccc(OCCCCc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
A mixture of 200 mg of ethyl 4-amino-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate hydrochloride, 70.4 mg of ethyl bromoacetate, 114 mg of anhydrous potassium carbonate and 5 ml of N,N-dimethylformamide was stirred at room temperature overnight. To the reaction mixture was added 30 ml of ethyl acetate. After washing with water, the system was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with a toluene-ethyl acetate (4:1) mixture to obtain 140 mg of ethyl 4-(ethoxycarbonylmethylamino)-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.