Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[CH2:20][CH2:19]2)[C:13]1=[O:34].C(N(CC)CC)C>ClCCl>[Si:1]([O:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])[CH2:20][CH2:19]2)[C:13]1=[O:34])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCCN(CCO)C2=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
tert-Butyl(dimethyl)silyl chloride (0.30 g) was added to a solution of benzyl 4-[3-(2-hydroxyethyl)-2-oxotetrahydropyrimidin-1(2H)-yl]piperidin-1-carboxylate (0.60 g) obtained in Example 39a) and triethylamine (0.28 mL) in dichloromethane (20 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (from hexane/ethyl acetate=1/1 to hexane/ethyl acetate=1/4) to obtain the title compound (0.78 g, 99%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1C=CC(SCCl)=CC=1.[CH:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12].CC(C)([O-])C.[K+].C1CCCCC=1>CN(C=O)C.C(Cl)Cl>[Cl:1][CH2:2][N:13]([CH:11]=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCSc1ccc(Cl)cc1
Reactant: O=CNc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: O=CN(CCl)c1ccccc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
4-Chloro-1-(chloromethylthio)benzene (21 mmol) was added to a mixture of formanilide (21 mmol) and potassium tert-butoxide (21 mmol) in DMF (200 ml). The mixture was stirred at 80° C. for 4 hours before the solvent was distilled off and the residue dissolved in ether and washed five times with water, and the dried (MgSO4) solution evaporated. Yield: 5.37 g (92%), m.p. 67° C. (Pet. ether/ether). The product (17.8 mmol) was dissolved in CH2Cl2 (100 ml) and SO2Cl2 (17.8 mmol) in CH2Cl2 (25 ml) was added with stirring at 5° C. for 30 minutes. The mixture was stirred for 15 minutes before cyclohexene (19.3 mmol) in CH2Cl2 (25 ml) was added. The mixture was evaporated and the residue washed with hexane and dried. The product was used in the Example 28 without further purification. 1H NMR (CDCl3,δ): 5.50 (s, --CH2 --), 7.34 (Ph), 8.33 (CHO).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.Br[CH2:10][CH2:11][CH2:12][CH2:13]Br>>[N:1]1([CH:2]2[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NC1CCC(O)CC1
Reactant: BrCCCCBr
Product: OC1CCC(N2CCCC2)CC1

Procedure:
Prepared from 4-amino-cyclohexanol and 1,4-dibromo-butane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[C:5]2=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:47][CH2:48][OH:49]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([I:30])[CH:27]=[CH:26][C:25]=3[O:31][CH:32]3[CH2:33][CH2:34][N:35]([CH2:47][CH2:48][OH:49])[CH2:36][CH2:37]3)[C:5]2=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OC2CCNCC2)N1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OC2CCN(CCO)CC2)N1
Temperature: 80 °C
Yield: 34 %

Procedure:
To a solution of racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(4-piperidinyloxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.15 mmol) prepared in example 5a in ethanol (2 mL) was added triethylamine (45.7 mg, 0.46 mmol) and 2-bromoethanol (42.4 mg, 0.345 mmol) (Aldrich). The reaction mixture was heated at 80° C. for 18 h, then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (MeOH:EtOAc:NEt3=12:88:5) to give racemic(2′R, 3R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-{2-[1-(2-hydroxy-ethyl)-4-piperidinyloxy]-5-iodo-phenyl}spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 36 mg, 34%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[O:6][CH2:5]2.[Br:13]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:13][CH:5]1[C:4]2[C:8](=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[C:7](=[O:12])[O:6]1
Reactant: NC(=O)CCC(=O)NBr
Reactant: O=C1OCc2cc(Cl)c(Cl)cc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1OC(Br)c2cc(Cl)c(Cl)cc21
Yield: 99.1 %

Procedure:
A suspension of 5,6-Dichloro-3H-isobenzofuran-1-one (1.45 g), N-bromosuccinamide (1.27 g) and catalytic benzoyl peroxide in chloroform (30 mL) was heated to reflux for 1 hour. After cooling, the reaction mixture was washed with water, brine, dried (magnesium sulfate), filtered and concentrated to give the sub-title compound as a white solid (1.82 g, 91%). 1H NMR (400 MHz, CDCl3) δ 7.36 (1H, s), 7.77 (1H, s), 8.03 (1H, s) ppm.
Reaction SMILES: [CH:1]([CH:4]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[C:12]([CH:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)#[N:13].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH:1]([CH:4]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:5]([O:7][CH:14]([C:12]#[N:13])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: C=C(C)CC(C(=O)O)C(C)C
Reactant: N#CC(Br)c1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)CC(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-isopropyl-4-methylpent-4-enoic acid (1.0g), alpha-cyano-3-phenoxybenzyl bromide (1.9g) and potassium carbonate (1.0g) in anhydrous acetone (40ml) was stirred at room temperature for 4 hours. Water was added to the reaction mixture and the product extracted with ether, the ethereal extracts washed with water (X2) and dried over magnesium sulphate. Evaporation of the solvent gave a crude product which was purified by chromatography on silica gel using 3% acetone in 60°-80° C. petroleum ether as eluent to give the desired ester. R.I. nD20 1.5343.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[C:7]([CH2:21][C:22]([O:24]CC)=[O:23])=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[N:10]=[CH:9]2)([O-:5])=[O:4]>O1CCOCC1>[N+:3]([C:6]1[C:7]([CH2:21][C:22]([OH:24])=[O:23])=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][O:16]1)[N:10]=[CH:9]2)([O-:5])=[O:4]
Reactant: CCOC(=O)Cc1c([N+](=O)[O-])ccc2c1cnn2C1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)Cc1c([N+](=O)[O-])ccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 1N-aqueous sodium hydroxide solution (8.64 ml, 8.64 mmol) was added to a solution of ethyl (5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazol-4-yl)acetate (1.92 g, 5.76 mmol) in dioxane (20 ml), and the resulting mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and water, ethyl acetate and 1N-hydrochloric acid were added to the residue. The resulting mixture was extracted with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby (5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazol-4-yl)acetic acid was obtained. N,N-dimethyl-formamide (20 ml) and then potassium carbonate (800 mg, 5.79 mmol) were added thereto, and the resulting mixture was stirred at 50° C. for 30 minutes. Water, ethyl acetate, toluene and 1N-hydrochloric acid were added thereto, followed by extraction with ethyl acetate/toluene=1/1, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby 4-methyl-5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazole (1.39 g, 93%) was obtained.
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][CH:28]4[CH2:30]O4)[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:32])[CH2:4][CH2:5][C:6](=[O:31])[CH:7]=1.I(O)(=O)(=O)=O>O1CCCC1.O.ClCCl>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@@H:14]([O:26][CH2:27][CH:28]=[CH2:30])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][OH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:32])[CH2:4][CH2:5][C:6](=[O:31])[CH:7]=1
Reactant: C[C@]12CCC(=O)C=C1CC[C@H]1[C@@H]3C[C@@H](OCC4CO4)[C@](O)(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: [O-][I+3]([O-])([O-])O
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: C=CCO[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Yield: 22.7 %

Procedure:
A solution of 20.1 g of crude 9-fluoro-11β,17,21-trihydroxy-16α-(oxiranyl-methoxy)pregn-4-ene-3,20-dione, 21-acetate in 300 ml of tetrahydrofuran is stirred with a solution of 30 g of periodic acid in 75 ml of water for 63/4 hours. The solution is diluted with water and extracted with chloroform. The chloroform extract was washed with 5% sodium bicarbonate solution, dried, and evaporated in vacuo to give 18.2 g of crude product. This material is dissolved in 60 ml of dichloromethane and chromatographed on a 450 g -silica gel column. Fractions of 250 ml are collected as the column is eluted with 3 liters of dichloromethane, 3 liters of chloroform, and then 3 liters of 19:1 chloroform-ethyl acetate. Fractions 17-21 are combined and evaporated in vacuo to give 4.4 g of 9-fluoro-16α -allyloxy-11β,17,21-trihydroxypregn-4-ene-3,20-dione, 21-acetate.
Reaction SMILES: [CH:1]12[NH:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:7]2[CH:4]3[CH2:5][CH2:6][CH:1]2[CH:2]([NH:8][C:9]2[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]4)[CH2:3]3)=[CH:22][CH:21]=1
Reactant: c1cc2[nH]ncc2cc1NC1CC2CCC1N2
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(CN2C3CCC2C(Nc2ccc4[nH]ncc4c2)C3)cc1

Procedure:
Reaction of Intermediate 24 with 4-methoxybenzaldehyde affords the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].[F:8][C:9]1[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=1[C:19]1[CH:20]=[C:21]2[CH:27]=[C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[O:25][C:22]2=[CH:23][N:24]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH:5]([O:4][C:2]([N:31]1[CH2:32][CH2:33][CH:28]([C:26]2[O:25][C:22]3=[CH:23][N:24]=[C:19]([C:10]4[CH:11]=[CH:12][C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:9]=4[F:8])[CH:20]=[C:21]3[CH:27]=2)[CH2:29][CH2:30]1)=[O:3])([CH3:7])[CH3:6]
Reactant: CS(=O)(=O)c1ccc(-c2cc3cc(C4CCNCC4)oc3cn2)c(F)c1
Reactant: CC(C)OC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Isopropyl chloroformate (1 mol/L in toluene; 0.30 mL) is added to a solution of 5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine (75 mg) and N,N-diisopropyl-ethylamine (0.10 mL) in tetrahydrofuran (1 mL) chilled in an ice bath. The solution is stirred at room temperature for 3 h. The solution is concentrated and the residue is taken up in water and dichloromethane. The resulting mixture is extracted with dichloromethane and the combined extracts are dried (Na2SO4). The solvent is evaporated and the residue is purified by HPLC on reversed phase (methanol/water) to give the title compound. Mass spectrum (ESI+): m/z=461 [M+H]+.
Reaction SMILES: C(CC[N:5]1[C:9]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([O:15]C)=[O:14])=[N:8][N:7]=[N:6]1)#N.O.[OH-].[Li+]>C1COCC1.O.Cl>[NH:8]1[C:9]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=2)[C:13]([OH:15])=[O:14])=[N:5][N:6]=[N:7]1
Reactant: COC(=O)c1cccc(-c2nnnn2CCC#N)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
To a solution of methyl 3-(1-(2-cyanoethyl)-1H-tetrazol-5-yl)benzoate (180 mg, 0.7 mmol) in 20 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (50 mg, 2.1 mmol) in 5.0 mL of water. The reaction mixture was stirred at RT for 16 h. THF was removed under reduced pressure to give a yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with EtOAc (2×25 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford 100 mg (58% yield) of 3-(1H-tetrazol-5-yl)benzoic acid. MS found: (M+H)+=191.
Reaction SMILES: CC(C[Al](C[CH:11]([CH3:13])[CH3:12])CC(C)C)C.[CH2:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:20]=C>CCCCCC>[CH3:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:13][CH2:11][CH3:12]
Reactant: C=CCCCC
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Reactant: C=C
Solvent: CCCCCC
Product: CCCCCCCCCC
Temperature: 10 °C

Procedure:
In a 200 ml glass flask replaced with nitrogen, 52.7 ml of hexane was placed, and the hexane slurry of the solid catalyst component (X-4) (4.0 g in terms of solid part) prepared above was introduced. Next, the system was cooled down to 10° C., then 5.32 mmol of TIBAL and 0.535 ml of 1-hexene were added, and feed of ethylene was started at 30 l/hr at atmospheric pressure. Polymerization was carried out at 25° C. until the integrated absorption quantity of ethylene by the solid catalyst component became 10.3 liters, and after the polymerization was completed, the system was replaced with nitrogen. Thus, prepolymerizaion was completed. Thereafter, the supernatant liquid was removed by decantation, and the remainder was washed with decane three times to give a decane slurry. Thus, a prepolymerized catalyst (XP-4) was prepared. A part of the resulting decane slurry of the prepolymerized catalyst (XP-4) was withdrawn, and the concentration was examined. As a result, the Zr concentration was 0.067 mg/ml, and the Al concentration was 4.77 mg/ml.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]4([OH:36])[CH2:35][CH2:34][S:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])[CH:12]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:41])=[O:4])[CH:8]=[N:9][CH:10]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]2([OH:36])[CH2:35][CH2:34][S:33][CH2:32][CH2:31]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C2(O)CCSCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C2(O)CCSCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)O)c2)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.1 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.28 mL, 0.28 mmol) was added to a solution of {5-[4-(1-ethyl-1-{4-[(E)-2-(4-hydroxy-tetrahydro-thiopyran-4-yl)-vinyl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-pyridin-3-yl}-acetic acid methyl ester (Example 139-(1); 50 mg, 0.09 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature for five hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate:methanol=5:2) to give the target compound as a colorless oil (22 mg, 45%).
Reaction SMILES: C([O:4][C:5]([CH3:36])([CH3:35])[C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:17][CH2:16]2)[N:13]=1)=[O:7])(=O)C.[OH-].[Na+]>C(O)C>[OH:4][C:5]([CH3:36])([CH3:35])[C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:19][CH2:20]2)[N:13]=1)=[O:7]
Reactant: CC(=O)OC(C)(C)C(=O)Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(O)C(=O)Nc1nc(CN2CCC(OC(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 40 °C
Reaction time: 6 h
Yield: 64.4 %

Procedure:
A mixture of 2-(2-acetoxy-2-methylpropionylamino)-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (1.1 g), 1N sodium hydroxide (2.2 ml) and ethanol (23 ml) was heated at 40° C. with stirring for 6 hours. The reaction mixture was concentrated under reduced pressure and the residue was extracted with a mixture of chloroform and methanol (10:1 V/V). The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was distilled off and the residue was pulverized with 70% ethanol and collected by filtration. Recrystallization from 70% ethanol gave 2-(2-hydroxy-2-methylpropionylamino)-4-[4-(diphenylmethoxy)piperidinomethyl]thiazole (0.65 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:5]=[CH:6][C:7]=1[NH:8][NH2:9].[CH:21]1[C:26]([CH:27]([CH:30]=O)[CH:28]=O)=[CH:25][CH:24]=[N:23][CH:22]=1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:19])[CH3:18])[O:12][C:11]2=[O:20])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:30]=[C:27]([C:26]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:28]=[N:9]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(NN)c(F)c2)C(=O)O1
Reactant: O=CC(C=O)c1ccncc1
Solvent: CCO
Product: CC(=O)NC[C@H]1CN(c2ccc(-n3cc(-c4ccncc4)cn3)c(F)c2)C(=O)O1
Yield: 66.3 %

Procedure:
100 mg (0.354 mmol) of (S)—N-{[3-(3-fluoro-4-hydrazinophenyl)-2-oxooxazolidin-5-yl]methyl}-acetamide and 52.8 mg (0.354 mmol) of 2-(4-pyridyl)malondialdehyde were combined with 5 mL ethanol as a solvent. Then, the resultant mixture was slowly heated to reflux, thereby the solid was substantially dissolved. TLC monitoring was performed to determine completion of the reaction. Then, the resultant mixture was cooled to room temperature and vacuum filtered to afford the product (13a) as a light yellow solid, with a yield of 66.3%, melting point: 203.8-205.0° C., HPLC: 99.97%.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.[NH:53]1[CH:57]=[N:56][C:55]([C:58](O)=[O:59])=[N:54]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:58]([C:55]2[N:56]=[CH:57][NH:53][N:54]=2)=[O:59])[CH2:25]1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(O)c1nc[nH]n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CN(C(=O)c2nc[nH]n2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 57 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 1H-1,2,4-triazole-3-carboxylic acid as the starting materials in 57% yield. LCMS for C25H24ClN10O2 (M+H)+: m/z=531.0.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH3:13][O:14][C:15](=[O:53])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[N:27]([CH:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:26]=2[CH2:48][CH2:49][OH:50])=[CH:18][C:17]=1[O:51][CH3:52]>ClCCl>[CH3:13][O:14][C:15](=[O:53])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[N:27]([CH:35]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:26]=2[CH2:48][CH2:49][O:50][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:18][C:17]=1[O:51][CH3:52]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(OCCc2c(CCO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCCc2c(CCOS(C)(=O)=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
MeSO2Cl (0.03 mL, 0.39 mmol) and Et3N (0.07 mL, 0.48 mmol) were added to a solution of the alcohol from step 5 (0.11 g, 0.19 mmol) in dichloromethane (8 mL) at 0° C. Reaction was stirred at 0° C. for one hour and then warmed to room temperature and stirred an additional hour. Reaction solution was concentrated by rotary evaporation. Obtained 0.123 g of 4-{2-[1-Benzhydryl-5-chloro-2-(2-methanesulfonyloxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-methoxy-benzoic acid methyl ester in quantitative yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:10]([C:12]1[O:13][CH:14]=[CH:15][CH:16]=1)=O)=[CH:6]N(C)C)[CH3:2].[N+]([O-])(O)=O.[NH2:22][C:23]([NH2:25])=[NH:24].C([O-])(=O)C.[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:24][C:23]([NH2:25])=[N:22][CH:6]=1)=[O:17])[CH3:2]
Reactant: N=C(N)N
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccco1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=[N+]([O-])O
Product: CCOC(=O)c1cnc(N)nc1-c1ccco1
Temperature: 90 °C
Yield: 27.8 %

Procedure:
Following the method of Sansebastiano et al. (Il Farmaco 1993, 48, 335), to a stirred solution of 2.44 g (10.3 mmol) 3-dimethylamino-2-(furan-2-carbonyl)-acrylic acid ethyl ester and 2.26 g (18.5 mmol) guanidine nitrate in 20 ml DMF was added 1.51 g (18.5 mmol) sodium acetate and the mixture heated at 90° C. for 36 h. The reaction mixture was then partitioned between ether and water. The phases were separated and the aqueous phase extracted twice more with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was recrystallised from ether/ethyl acetate/hexane to afford 669 mg (28%) 2-amino-4-furan-2-yl-pyrimidine-5-carboxylic acid ethyl ester as a white crystalline solid. Chromatography (ethyl acetate/hexane 2/1) of the mother liquor afforded a further 150 mg (6%) product. ES-MS m/e (%): 234 (M+H+, 100), 206 ([M—C2H4]+, 35), 188 ([M+H-EtOH]+, 42).