Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C[O:3][C:4](=O)[CH2:5][C:6]1=[N:7][N:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[C:9](=[O:21])/[C:10]/1=[C:11](/[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)\[CH3:12].Cl>CC(O)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[N:8]1[C:9](=[O:21])[C:10]2=[C:11]([CH3:12])[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:4](=[O:3])[CH:5]=[C:6]2[NH:7]1
Reactant: COC(=O)CC1=NN(c2ccccc2Cl)C(=O)/C1=C(\C)NCc1ccccn1
Agent: Cl
Agent: [Na]
Solvent: CC(C)O
Product: Cc1c2c(=O)n(-c3ccccc3Cl)[nH]c2cc(=O)n1Cc1ccccn1
Yield: 82 %

Procedure:
An isopropanolic solution of i-PrONa, obtained by dissolving of sodium (0.082 g, 3.57 mmol, 1 equiv) in i-PrOH (75 ml), was treated with methyl[(4E)-1-(2-chlorophenyl)-5-oxo-4-{1-[(pyridin-2-ylmethyl)amino]ethylidene}-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (VIII) (1.42 g, 3.57 mmol, 1 equiv.). The reaction mixture was refluxed for 1 h, then cooled and neutralized to pH 7 by addition of 0.59 ml of a 20% aqueous HCl solution. 50 ml of i-PrOH were removed in vacuo and 25 ml of H2O were added before placing the flask in the fridge overnight. The white precipitate formed was filtered off, washed with water (2×5 ml), then with cyclohexane and dried in vacuo. 1.07 g of pure product 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione was obtained. Yield 82%. 1H-NMR: (500 MHz, DMSO-d6, ppm): 2.78 (s, 3H), 5.41 (s, 2H), 5.66 (s, 1H), 7.31-7.28 (m, 1H), 7.32 (d, J 7.9 Hz, 1H), 7.50-7.47 (m, 2H), 7.60-7.56 (m, 1H), 7.66-7.64 (m, 1H), 7.79 (td, J 7.6, 1.9 Hz, 1H), 8.48 (m, 1H), 10.73 (s, br, 1H). MS (ESI+): 367.9; MS (ESI−): 365.7.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:35])[CH2:19][O:20][CH2:21][C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:26]=2[C:27]([OH:29])=[O:28])=[O:23])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO>[Cl:34][C:31]1[CH:32]=[CH:33][C:25]([NH:24][C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18](=[O:35])[NH:17][C:13]2[CH:12]=[CH:11][CH:16]=[C:15]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:14]=2)=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28]
Reactant: OB(O)c1cccnc1
Reactant: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(-c2cccnc2)c1

Procedure:
0.48 g (3.88 mmol) of 3-pyridineboronic acid, 1.3 g (2.85 mmol) of 2-[((2-[(3-bromophenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester, 95.9 mg (0.08 mmol) of tetrakis(triphenyl phosphine)palladium (0), and 0.41 g (3.88 mmol) of 2N sodium carbonate were heated under reflux for 8 hours in 9.2 mL of toluene and 2.6 mL of methanol. After completion of the reaction, the solvent was distilled off under reduced pressure, and ethyl acetate was added to separate the solid by filtration. Thereafter, the organic layer was washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The resulting crude product was separated and purified using silica gel column chromatography to give 5-chloro-2-([(2-oxo-2-([3-(pyridin-3-yl)phenyl]amino)ethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 62%).
Reaction SMILES: [C:1]([C:3]1[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][C:4]=1[O:17][CH2:18][CH3:19])#N.[OH-:20].[K+].Cl.[OH2:23]>>[CH2:18]([O:17][C:4]1[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:12]=[C:13]([O:14][CH2:15][CH3:16])[C:3]=1[C:1]([OH:23])=[O:20])[CH3:19]
Reactant: [OH-]
Reactant: O
Reactant: CCOC(=O)c1cc(OCC)c(C#N)c(OCC)c1
Agent: Cl
Agent: [K+]
Product: CCOc1cc(C(=O)O)cc(OCC)c1C(=O)O
Temperature: 130 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 4-cyano-3,5-diethoxybenzoate (1.0 g, 3.8 mmol) and KOH (5.0 g, 89.3 mmol) in water (30 mL) was stirred at 130° C. overnight. The mixture was acidified with aqueous HCl (2M) until pH=5. Solvent removed in vacuo and used for next step directly without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:4].[H][H]>O1CCOCC1.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)=[O:4]
Reactant: COC(=O)C=Cc1ccc(C(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: COC(=O)CCc1ccc(C(=O)O)cc1

Procedure:
8 g (38.8 mmol) of 4-(2-methoxycarbonylvinyl)benzoic acid (step a) were suspended in 250 ml of dioxane and hydrogenated under 1 bar of hydrogen over palladium/charcoal (10%) at room temperature for 7 h. The mixture was filtered and the solvent was evaporated in vacuo. Yield: 8.05 g (100%).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.O[CH2:9][NH:10][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1>FC(F)(F)C(O)=O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([NH:10][CH2:9][S:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:18])[CH:13]=1
Reactant: O=C(NCO)c1cccnc1
Reactant: Sc1ccncc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCSc1ccncc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
To a mixture of 1.11 g (10 mmol) of 4-mercaptopyridine and 1.52 g (10 mmol) of N-(hydroxymethyl)nicotinamide, 30 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off and 30 ml of ethanol was added to the residue. The solvent was distilled off and water was added to the residue. The mixture was neutralized with saturated aqueous sodium bicarbonate, followed by extraction with chloroform. After washing with saturated saline, the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol =5:1) to give 390 mg of the desired compound (15.9% yield, yellow solid).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=[O:12])[CH:7]=[CH:6][C:5]=1[OH:14].[N+](C(OCC)=O)(C(OCC)=O)=[N-].[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([O:14][CH:32]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27]2)=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=1[OH:10])(=[O:12])[CH3:13]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: OC1=CCCCC1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1c(OC2C=CCCC2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2,4-dihydroxy-3-propylacetophenone, 40 g, diethyl diazodicarboxylate, 51 g, and cyclohexen-2-ol, 20 g, in tetrahydrofuran, 1.5 L, cooled at 0° C., was added slowly a solution of triphenylphosphine, 80 g, in THF, 0.5 L. The mixture was stirred at room temperature for 18 hours. The volatiles were removed in vacuo. The residue was dissolved in a minimum amount of CH2Cl2 and placed on a silica gel column. Elution with 1% EtOAc/hexane yielded 20 g of the title compound as an oil. NMR (ppm) (CDCl3): 12.75 (1H, s, phenolic OH), 7.60 (1H, d, J-9 Hz, H ortho to acetyl), 6.53 (1H, d, J-9 Hz, H meta to acetyl), 5.90 (2H, m, olefinic proton), 4.87 (1H, m, CHOAc), 2.60 (3H, s, CH3).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:28]([OH:30])=[O:29].[CH3:1][C@@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:28]([C:25]1[CH:26]=[N:27][C:22]([CH3:21])=[CH:23][CH:24]=1)=[O:29]
Reactant: C[C@@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@H]2C)cn1
Product: O=CO
Yield: 151.7 %

Procedure:
To a solution of (3R)-3-methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 12) (80 mg, 0.259 mmol) in DMF (4 ml) was added 6-methyl-3-pyridinecarboxylic acid (35.6 mg, 0.259 mmol), HOBT.H2O (39.7 mg, 0.259 mmol), HBTU (98 mg, 0.259 mmol) and DIPEA (0.136 ml, 0.778 mmol) and the reaction mixture was stirred at room temperature for 1 h. The DMF was evaporated in vacuo then 5 ml of DCM were added and washed with saturated NaHCO3 solution (5 ml), dried on a phase separation cartridge and evaporated in vacuo. The crude material was dissolved in MeCN/DMSO 1:1 and purified by MDAP to give the title compound (93 mg).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[O:11])[CH2:4]1)#[N:2].C(Cl)(Cl)[Cl:20].C(O)(=[O:25])C>Cl.O>[CH3:1][N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[O:11])[CH2:4]1.[ClH:20].[C:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[O:11])[CH2:4]1)(=[O:25])[NH2:2]
Reactant: ClC(Cl)Cl
Reactant: CC(=O)O
Reactant: N#CN1CCCC(CC(=O)c2ccccc2F)C1
Agent: Cl
Solvent: O
Product: CN1CCCC(CC(=O)c2ccccc2F)C1
Product: NC(=O)N1CCCC(CC(=O)c2ccccc2F)C1
Reaction time: 15.75 h

Procedure:
1-Methyl-3-(2-fluorophenacyl)piperidine was prepared essentially as described in Example 5. The 1-cyano analog was prepared from the 1-methyl compound by the procedure of Example 20. The crude 1-cyano-3-(2-fluorophenacyl)piperidine, 66.4 g, was dissolved in a mixture of 470 ml of glacial acetic acid, 150 ml of concentrated hydrochloric acid, and 150 ml of water. The resulting solution, under nitrogen, was heated on a steam-bath for 17.5 hours. The reaction solution was worked up essentially as described in Example 21, except that an oil separated during the diethyl ether extraction. The oil and diethyl ether extracts were combined and diethyl ether was distilled. The residue was subjected to the hydrolysis procedure, except that the volume of glacial acetic acid was reduced to 400 ml and hydrolysis time was reduced to 15.75 hours. Work-up procedure was the same. During diethyl ether extraction, an oil again separated. The addition of chloroform to the multilayer mixture caused a precipitate to form in both the aqueous and chloroform layers. Solid also formed in the oil layer which remained insoluble. The solid in the chloroform layer was isolated by filtration and recrystallized three times from acetone/diethyl ether to give 1-carbamoyl-3-(2-fluorophenacyl)piperidine hydrochloride, mp 125°-128°. The following elemental analysis was obtained:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:12])[CH:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1.N1C=CC=CC=1.O>ClCCl>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1cc(Cl)c(Cl)cc1F
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Cl)cc2F)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 4,5-dichloro-2-fluoro-benzoyl chloride (794.5 mg, 3.49 mmol) in dichloromethane (7.3 mL) was added drop-wise to a mixture of methyl 4-aminobenzoate (528.0 mg, 3.49 mmol), pyridine (847.6 μL, 10.48 mmol) and dichloromethane (11.0 mL) at 0° C. The reaction was stirred and allowed to warm up to room temperature over 1.5 hours. To the reaction, water (10 mL) was added. The solid was isolated by filtration, washed with water (2×10 mL) and hexane (2×10 mL) to yield methyl 4-[(4,5-dichloro-2-fluoro-benzoyl)amino]benzoate (955 mg, 80%) as a light pink solid. ESI-MS m/z calc. 341.00, found 342.2 (M+1)+; Retention time: 1.75 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.03 (d, J=6.7 Hz, 1H), 8.02-7.95 (m, 2H), 7.93 (d, J=9.4 Hz, 1H), 7.88-7.76 (m, 2H), 3.84 (s, 3H) ppm.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[NH3:19]>C1COCC1>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14]([NH2:19])=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1csnc1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2.92 g (0.010 mol) of 3-(α,α,α-trifluoro-m-tolyl)-4-isothiazolecarbonyl chloride in 10 ml of THF was added to a solution of excess ammonia gas in THF stirred in a dry ice acetone bath. The mixture was slowly warmed to 23° with stirring. The solid NH4Cl was removed by filtration, and the filtrate was concentrated to about 20 ml. Then 100 ml of ether was added, and the solution was extracted with two portions of 10% Na2CO3 solution and once with saturated NaCl solution. The ether layer was dried (CaSO4 ) and concentrated to 2.25 g (83%) of white solid, m.p. 141°-141.5°; infrared (mineral oil mull) 2.92, 3.11, 6.09, 6.11 μ.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.COC1C(OC)=C(OC)C=C(/[CH:46]=[CH:47]/[C:48]([N:50]2[C:55](=[O:56])[CH:54]=[CH:53][CH2:52]C2)=[O:49])C=1.N(CCO)(CCO)CCO>C1(C)C=CC=CC=1.C1COCC1>[C:48]([NH:50][C:55](=[O:56])/[CH:54]=[CH:53]/[CH3:52])(=[O:49])[C:47]([CH3:46])=[CH2:1]
Reactant: COc1cc(/C=C/C(=O)N2CCC=CC2=O)cc(OC)c1OC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: OCCN(CCO)CCO
Product: C=C(C)C(=O)NC(=O)/C=C/C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 47 %

Procedure:
Experimental Procedure: Triphenylphosphine (79.0 mg, 0.30 mmol) and DIAD (61.0 mg, 0.30 mmol) were dissolved to a 1:1 mixture of THF and toluene (2 mL); then mono-demethylated piperlongumine (46.0 mg, 0.15 mmol) was added. After 10 min, triethanolamine (6.80 mg, 0.05 mmol) was added to the mixture. The reaction was stirred at room temperature for 3 h. At the end, the solvent was evaporated under vacuum. The crude product was purified by preparative TLC(CH2Cl2/MeOH=9/1) to afford the desired product in 47% yield.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[CH2:15]([O:22][C@H:23]1[C@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:26]([CH2:36][O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:25][CH:24]1Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC#N>[Cl:1][C:2]1[N:3]([C@@H:24]2[O:25][C@H:26]([CH2:36][O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:27]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:23]2[O:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: ClC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: Clc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1cc2nc(Cl)n([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
Compound 5 (598 mg 2.7 mmole) was dissolved in dry CH3CN(60 ml) and 97% NaH (80 mg, 3 mmole) was added. The mixture was stirred under N2 for 1 hour at room temperature. Then 2,3,5-tri-O-benzyl-D-arabinofuranosyl chloride (prepared from 2,3,5-tri-O-benzyl-1-O-p-nitrobenzoyl-D-arabinofuranose) (1.83 g, 3 mmole)) dissolved in dry CH3CN (20 ml) was added dropwise. The mixture was stirred under N2 for overnight at room temperature. The reaction solution was filtered through Celite. The filtrate was evaporated to give a syrup and this syrup was subjected to flash column chromatography on silica gel (Kieselgel 60, 230-400 mesh) and eluted with CH2Cl2. The fractions containing 133 were combined and evaporated to give 1.6 g (95.0%) of 133. (IR KBr cm-1 : 1140-1060 (C--O--C)).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].CO[C:13](=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16](I)[CH:15]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]2[C@:31]3([C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:40])[CH2:30]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]2[C@@:31]3([C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([N:8]5[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]5)=[O:21])[CH:15]=4)[C:32]3=[O:40])[CH2:30]2)=[CH:27][CH:28]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@H]2c1ccc(Cl)cc1
Reactant: COC(=O)c1cccc(I)c1
Reactant: CS(=O)(=O)N1CCNCC1
Product: CS(=O)(=O)N1CCN(C(=O)c2cccc(N3C(=O)[C@@]4(C[C@@H]4c4ccc(Cl)cc4)c4ccccc43)c2)CC1

Procedure:
The title compound was prepared in analogy to Example 85 starting from 1-methanesulfonyl-piperazine, methyl-3-iodobenzoate (commercially available), (1R,2R) and (1S,2S)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C28H26ClN3O4S: 535, observed (M+H)+: 536.2 1H NMR (400 MHz, MeOD-d4) δppm 2.22-2.36 (m, 2 H) 2.90 (s, 3 H) 3.35-3.39 (m, 1 H) 3.58-4.01 (m, 8 H) 6.16 (d, J=7.58 Hz, 1 H) 6.82 (t, J=7.58 Hz, 1 H) 6.95 (d, J=7.58 Hz, 1 H) 7.16 (t, J=7.83 Hz, 1H) 7.27-7.40 (m, 4 H) 7.58 (d, J=7.33 Hz, 1 H) 7.62-7.79 (m, 3 H).
Reaction SMILES: [C:1]([C:3]1[CH:48]=[CH:47][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C@@H:15]([NH:21][C:22]([C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:46])[CH2:31][CH2:32][CH:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)[CH2:25]3)=[O:23])[CH2:16][C:17]([O:19]C)=[O:18])[CH:12]=[N:13][CH:14]=2)=[CH:5][C:4]=1[F:49])#[N:2].CO.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C(O)(C)(C)C>[C:1]([C:3]1[CH:48]=[CH:47][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C@H:15]([NH:21][C:22]([C@H:24]3[CH2:29][CH2:28][CH2:27][N:26]([C:30](=[O:46])[CH2:31][CH2:32][CH:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[CH2:25]3)=[O:23])[CH2:16][C:17]([OH:19])=[O:18])[CH:12]=[N:13][CH:14]=2)=[CH:5][C:4]=1[F:49])#[N:2]
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccc(C#N)c(F)c2)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(C)(C)O
Product: N#Cc1ccc(COc2cncc([C@@H](CC(=O)O)NC(=O)[C@H]3CCCN(C(=O)CCC4CCNCC4)C3)c2)cc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 47.1 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-1-(5-(4-cyano-3-fluorobenzyloxy)pyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (10 mg, 15 μmol) as solved in tert.-butanol (0.6 mL) and methanol (0.6 mL) and barium hydroxide octahydrate (23 mg, 74 μmol) was added. After stirring for 45 minutes room temperature the solvent was distilled off at 0° C. by high vacuum. The residue was acidified with formic acid (1 mL). After 18 hours at 5° C. the solvent was distilled off at 0° C. by high vacuum and the residue was purified by preparative HPLC to yield 4 mg of (3R)-3-{5-[(4-cyano-3-fluorobenzyl)oxy]pyridin-3-yl}-3-[({(3S)-1-[3-(piperidin-4-yl)propanoyl]piperidin-3-yl}carbonyl)amino]propanoic acid.
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([CH2:7][N:8]([CH2:20][C@@H:21]2[C@@H:28]3[C@@H:24]([O:25][C:26]([CH3:30])([CH3:29])[O:27]3)[C@H:23]([N:31]3[C:35]4[N:36]=[CH:37][N:38]=[C:39]([NH:40][CH2:41][C:42]5[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=5[O:50][CH3:51])[C:34]=4[CH:33]=[CH:32]3)[CH2:22]2)[CH:9]2[CH2:12][CH:11]([CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])[CH2:10]2)[CH2:6][CH2:5]1.Cl>O1CCCC1.CO>[CH:4]1([CH2:7][N:8]([CH2:20][C@@H:21]2[C@@H:28]3[C@@H:24]([O:25][C:26]([CH3:30])([CH3:29])[O:27]3)[C@H:23]([N:31]3[C:35]4[N:36]=[CH:37][N:38]=[C:39]([NH:40][CH2:41][C:42]5[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][C:43]=5[O:50][CH3:51])[C:34]=4[CH:33]=[CH:32]3)[CH2:22]2)[CH:9]2[CH2:12][CH:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:10]2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)CCC1CC(N(CC2CC2)C[C@H]2C[C@@H](n3ccc4c(NCc5ccc(OC)cc5OC)ncnc43)[C@@H]3OC(C)(C)O[C@H]23)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(CC3CC3)C3CC(CCC(=O)O)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Lithium hydroxide, monohydrate (0.62 g, 15 mmol) added to a solution of ethyl 3-(3-((cyclopropylmethyl)(((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)cyclobutyl)propanoate (0.98 g, 1.5 mmol) in Tetrahydrofuran (13 ml) and Methanol (3 ml). The reaction was stirred for 24 hours at RT, acidified with 1 N HCl to pH=6. The volatiles removed in vacuo and remaining water removed by azeotropic distillation with ethanol followed by 18 hours on lyophilizer. The resulting off white solid was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](/[CH:21]=[C:22]2\[O:23][C:24]3[C:31]([CH2:32][N:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)=[C:30]([OH:46])[CH:29]=[CH:28][C:25]=3[C:26]\2=[O:27])=[CH:13]1)(=[O:11])=[O:10].FC(F)(F)C(O)=O>C(Cl)Cl>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](/[CH:21]=[C:22]2\[O:23][C:24]3[C:31]([CH2:32][N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[C:30]([OH:46])[CH:29]=[CH:28][C:25]=3[C:26]\2=[O:27])=[CH:13]1)(=[O:10])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4c(Cl)cccc4Cl)c4ccccc24)C3=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C1/C(=C/c2cn(S(=O)(=O)c3c(Cl)cccc3Cl)c3ccccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 218.8 %

Procedure:
A solution of tert-butyl (Z)-4-[(2-{[1-(2,6-dichlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.133 g, 0.194 mmol) in methylene chloride (5 mL) was added with trifluoroacetic acid (5 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, then a solution of the resulting residue in methanol (8 mL) was added with a 5% solution of hydrogen chloride in methanol (2 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the resulting solid was suspended in acetonitrile and thereby washed to obtain (Z)-2-{[1-(2,6-dichlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.0930 g, 72%).
Reaction SMILES: C(O)C.[C:4]([C:8]1[C:9](=[O:28])[C:10]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:11][C:12](=[N:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=2)[CH:13]=1)([CH3:7])([CH3:6])[CH3:5].C(=O)([O-])[O-].[K+].[K+]>[Pd].O>[C:4]([C:8]1[CH:13]=[C:12]([CH:11]=[C:10]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]=1[OH:28])[NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][CH:20]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)C1=CC(=Nc2ccc(C(=O)O)cc2)C=C(C(C)(C)C)C1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(Nc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1O

Procedure:
To a mixture of 200 ml of ethanol and 25.0 g (0.0736 mole) of 2,6-di(tertiary-butyl)-4-(4'-carboxyphenylimino)-2,5-cyclohexadien-l-one and 12 g (0.087 mole) of potassium carbonate warmed on a steam bath was added 1.0 g of palladium on charcoal. The mixture was reduced using a Paar apparatus for 2 hours. The mixture was diluted with 300 ml of water, filtered through celite, and the filtrate acidified with 6N hydrochloric acid. The yellow solid precipitate was collected by filtration to provide 4-[3,5-di(tertiary-butyl)-4-hydroxyanilino]benzoic acid, m.p. 241°-242° C.