Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[C:11]([SH:20])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[C:21](#[N:24])[CH:22]=[CH2:23]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[C:11](=[S:20])[N:10]([CH2:23][CH2:22][C:21]#[N:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-n2c(-c3ccc(F)cc3)cnc2S)cc1
Reactant: C=CC#N
Solvent: C1COCCO1
Product: Cc1ccc(-n2c(-c3ccc(F)cc3)cn(CCC#N)c2=S)cc1
Temperature: 70 °C

Procedure:
A mixture 5-(4-fluorophenyl)-1-p-tolyl-1H-imidazole-2-thiol (1 eq) in dioxane is stirred and Triton B is added. The mixture is heated to 70° C. and acrylonitrile (1 eq) is added and heated for 3 hours. The cooled mixture is partitioned between aqueous 0.1N HCl and ethyl acetate. The organic layer is washed with water and brine, dried over sodium sulfate, filtered and the solvent removed under reduce pressure. Flash chromatography (SiO2) gives 3-(5-(4-fluorophenyl)-1,2-dihydro-2-thioxo-1-p-tolylimidazol-3-yl)propanenitrile.
Reaction SMILES: Cl.NO.[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:18])[CH:13]=[CH:14][N:15](C)C)=[CH:8][CH:7]=1)#[N:5]>CO.O>[O:18]1[C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]#[N:5])=[CH:7][CH:8]=2)=[CH:13][CH:14]=[N:15]1
Reactant: CN(C)C=CC(=O)c1ccc(C#N)cc1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CO
Product: N#Cc1ccc(-c2ccno2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.3 %

Procedure:
Hydroxylamine hydrochloride (21.40 g, 308 mmol) was added to a suspension of 1-(4-cyanophenyl)-3-dimethylaminopropen-1-one (55.96 g, 280 mmol) in MeOH (450 ml) and the reaction stirred at room temperature for 24 h. The reaction was diluted with water (400 ml) and the resultant precipitate collected by filtration, washed with water (5×150 ml) and dried in vacuo to give 4-(5-isoxazolyl)-benzonitrile as a pale yellow solid (42.53 g) m.p. 148-149°. δH (CDCl3) 8.35 (1H, d, J 1.8 Hz), 7.91 (2H, d, J 8.3 Hz), 7.77, (2H, d, J 8.3 Hz), 6.66 (1H, d, J 1.8 Hz).
Reaction SMILES: C1(C)C=CC=CC=1.[O:8]=[C:9]1[CH2:16][C:13]([CH3:15])([CH3:14])[CH2:12][C:11]([CH3:17])=[CH:10]1.[OH2:18]>[O-]S([O-])(=O)=O.[Cu+2].CCCCCC>[CH3:17][C:11]1[C:12](=[O:18])[C:13]([CH3:15])([CH3:14])[CH2:16][C:9](=[O:8])[CH:10]=1
Reactant: O
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC1=CC(=O)CC(C)(C)C1=O
Reaction time: 90 h

Procedure:
A 1-1 three-neck flask equipped with a gas inlet frit, a stirrer and an intensive condenser was charged with 350 ml of toluene, 350 g of isophorone, 11.4 g of H3 [P(Mo3O10)4 ]×H2O, 1.4 g of CuSO4 ·5H2O and 1.4 g of MoO3. After compressed air had been passed through at 110° C. for 90 hours, the reaction mixture was added a little at a time at 80° C. into 4 1 of boiling n-hexane. The mixture was then filtered, and the filtrate was concentrated in a rotary evaporator. The yellowish oil obtained by distillation at 97° C./13 mbar was converted into almost colorless crystals at -18° C. by addition of 10% by volume of n-hexane.
Reaction SMILES: C([NH:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH2:18][Cl:19])=[CH:12][C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1)(OCC)=O.S(=O)(=O)(O)O.[OH-].[Na+]>C(O)(=O)C>[NH2:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([CH2:18][Cl:19])=[CH:12][C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)Nc1ccc2c(CCl)cc(=O)oc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1ccc2c(CCl)cc(=O)oc2c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A mixture of 7-carbethoxyamino-4-chloromethylcoumarin (2.81 g, 0.01 mole), concentrated sulfuric acid (10 mL) and glacial acetic acid (10 mL) is heated at 130° C. in an oil bath for 1 hour. On cooling, a yellow precipitate is deposited. The mixture is poured into 200 mL of ice-water and left overnight. The resulting solution is made slightly basic (pH 8) with dilute NaOH solution and is then cooled by the addition of ice chips. The yellow precipitate is filtered, washed with water and dried. The product is recrystallized from chloroform to give yellow needles. Yield: 79%.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1)([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:8]1[C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[CH:16][CH:15]=2)([C:10]([F:12])([F:11])[F:13])[C:28]2([CH2:30][CH2:29]2)[C:31]1=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1(C(NCc2ccccc2)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1N(Cc2ccccc2)C(c2ccc(OCCCC(F)(F)F)cc2)(C(F)(F)F)C12CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.3 %

Procedure:
To a solution of Intermediate 14E (506 mg, 1.1 mmol) in CH2Cl2 (11 mL) was added oxalyl chloride (0.12 mL, 2.2 mmol) followed by several drops of DMF. The reaction was stirred at rt for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography (24 g silica gel, eluted with EtOAc in hexanes) to provide Intermediate 14F (389 mg, 72%) as a yellow oil. LCMS Anal. Calc'd for C23H21F6NO2 457.41, found [M+H] 458.2.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[Na].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1>CN(C)C=O.C(Cl)Cl>[F:10][C:7]1[CH:8]=[CH:9][C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: c1nc[nH]n1
Reactant: N#Cc1cc(F)ccc1F
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc(F)ccc1-n1cncn1
Temperature: 80 °C
Yield: 49 %

Procedure:
A suspension of 2,5-diflurobenzonitrile (4.5 g, 32.35 mmol) and 1,2,4-triazole sodium salt (3.6 g, 40 mmol) in dimethylformamide (40 mL) was heated at 80° C. for 15 h. The reaction mixture was then cooled, diluted with CH2Cl2 (200 mL), washed with water (3×30 mL) and brine (30 mL), then dried (Na2SO4), filtered and concentrated to give a white solid which was purified by flash column chromatography (SiO2) using 1:1 to 3:1 ethyl acetate/Hexanes to afford the title compound (2.98 g, 49% yield) as a white powder. 1H NMR (500 MHz, CDCl3) δ: 8.70 (1H, s), 8.18 (1H, s), 7.76 (1H, dd, J=9.0, 4.8 Hz), 7.55 (1H, dd, J=7.3, 2.8 Hz), 7.51–7.47 (1H, m). LCMS (M+H) calcd for C9H6FN4: 189.17. found: 189.10.
Reaction SMILES: [CH2:1]([O:12][C:13]1[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:14]=1[CH:15]=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].N[C@H](C(O)=O)CCSC>CS(O)(=O)=O.C(OCC)(=O)C>[CH2:1]([O:12][C:13]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:14]=1[CH:15]=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCCOc1ccc(OC)cc1C=O
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCOc1ccc(O)cc1C=O
Yield: 49.8 %

Procedure:
The 2-undecyloxy-5-methoxybenzaldehyde (16.2 g, 52.9 mmoles) in 100 ml of methanesulfonic acid was treated with L-methionine (16 g, 0.1057 mole) at room temperature for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with ice-cold water and saturated sodium chloride solution. The organic extract was dried with anhydrous magnesium sulfate, treated with charcoal and the solvent was removed in vacuo. The resulting solid was recrystallized twice from hexane to give 7.7 g (50%) of the product as a white solid, mp 66-67° C.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12]CC)=[O:11])=[CH:6][C:5]=1[NH2:17])(=[O:3])[CH3:2].[Li+:18].[OH-]>C1COCC1>[C:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH2:17])(=[O:3])[CH3:2].[Li+:18]
Reactant: CCOC(=O)COc1ccc(C(C)=O)c(N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCC(=O)[O-])cc1N

Procedure:
Ethyl 2-(4-acetyl-3-aminophenoxy)acetate (TU3205-036) (1.02 g) was dissolved in THF (17 mL) and treated with aqueous LiOH (1 M, 4.3 mL) at ambient temperature for 1 hour. LC-MS analysis showed a clean complete reaction. The reaction mixture was concentrated under reduced pressure, affording lithium 2-(4-acetyl-3-aminophenoxy)acetate (TU3205-042) as a yellowish solid. MS (ESI+): calcd. for free acid 210.10. found 210.10 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11])([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:23])[CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18])[CH3:13].N1C=CC=CC=1>C(O)C.CCCCCC.C(Cl)(Cl)Cl>[CH2:12]([O:14][C:15]([C:16]1[C:17]([CH3:18])=[N:11][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[C:20]=1[CH3:21])=[O:23])[CH3:13]
Reactant: NNc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2ccccc2[N+](=O)[O-])c1C

Procedure:
Similar to Example 1, o-nitrophenylhydrazine (20 mmol, 3.4 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (20 mmol, 3.4 g) were mixed in a solution of 50% pyridine in ethanol and heated under reflux. The solvents then were removed under vacuum, and the residue was resuspended in chloroform. The resulting mixture was washed with water and dried over NaSO4. The solids then were filtered, and the solvents removed under vacuum. A precipitate formed when the oily solid was dissolved in a solution of 20% hexane in chloroform. The solid was collected and discarded, and the filtrate was purified over silica gel. The named product was contaminated, then was further purified by recrystallization from ethanol to yield a solid having a melting point of 128° C.-130° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([S:14](Cl)(=[O:16])=[O:15])=[CH:5][N:4]=1.CC[N:20](C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([S:14]([NH2:20])(=[O:16])=[O:15])=[CH:5][N:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ncc(S(=O)(=O)Cl)c2c(C)cccc12
Solvent: ClCCl
Product: COc1ncc(S(N)(=O)=O)c2c(C)cccc12
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 1-methoxy-5-methylisoquinolin-4-sulfonylchloride (Intermediate-38) (1 equiv) in CH2Cl2 was added, DIPEA (2 equiv) and the corresponding amine (1.3 equiv) under N2 and the mixture was stirred for 10 min at 0° C. and then at RT for 1 h. It was quenched with ice water, extracted with CH2Cl2 (2×100 mL), washed with water (1×100 mL), dried, filtered and concentrated under reduced pressure to furnish the product in 69-75% yield.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@:4]([CH3:24])([C:14]([O:16]CC2C=CC=CC=2)=[O:15])[CH2:3]1>CO.[Pd]>[C:10]([O:9][C:7]([N:5]1[CH2:6][C@@H:2]([OH:1])[CH2:3][C@@:4]1([CH3:24])[C:14]([OH:16])=[O:15])=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@@]1(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@@]1(C)C(=O)O

Procedure:
To nitrogen flushed pressure bottle, were added Pd/C (200 mg) and (2S,4S)-2-benzyl 1-tert-butyl 4-hydroxy-2-methylpyrrolidine-1,2-dicarboxylate (1.4 g, 4.17 mmol) in MeOH (300 mL). The reaction mixture was hydrogenated at 50 psi overnight. The reaction mixture was passed through a pad of celite, washed with MeOH, and concentrated. The residue (0.86 g, 84%) was used for the next step without purification. 1H NMR (CD3OD, 400 MHz) δ 4.32-4.39 (m, 1H), 3.62-3.68 (m, 1H), 3.34-3.37 (m, 1H), 2.12-2.22 (m, 2H), 1.51 and 1.49 (s, 3H), 1.43 and 1.40 (s, 9H).
Reaction SMILES: [Br:1][C:2]#[C:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1.[OH-].[Na+]>CO.C1COCC1.O>[Br:1][C:2]#[C:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C#CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(C#CBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a solution of methyl 4-(bromoethynyl)benzoate (67 g, 280 mmol) in CH3OH/THF/H2O=5/5/1 (1100 mL) was added NaOH (44.84 g) and the reaction mixture was stirred at 25° C. for 3 hr. The volatiles were removed under reduced pressure and the resulting solution was neutralized with 1 N HCl to pH 3-5. Solids were collected by filtration, washed with water and dried at 50° C. for 5 hr to yield 4-(bromoethynyl)benzoic acid (INT-1) (61 g, 96%).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=1)[C:3]#[CH:4].C([Mg]Cl)#C.O=CC1C=CC(O)=C(OC)C=1.Br[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1/[C:32](=[CH:40]/[C:41]1[NH:42][CH:43]=[CH:44][C:45]=1[O:46][CH3:47])/[C:33](=[O:39])[NH:34]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=1)[C:3]#[C:4][C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1/[C:32](=[CH:40]/[C:41]1[NH:42][CH:43]=[CH:44][C:45]=1[O:46][CH3:47])/[C:33](=[O:39])[NH:34]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CC(O)c1ccc(O)c(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Mg]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(O)C#Cc2cccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)ccc1O

Procedure:
Using Method D above, 3-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-1-propyne (197 mg, 1.1 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to vanillin (Aldrich) according to Method B above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 1) (116 mg, 0.36 mmol) using (Ph3P)2PdCl2 (33 mg) (Aldrich) and CuI (18 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 16 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(4-hydroxy-3-methoxyphenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 31 mg, 21%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[CH:15]=[CH:14][C:13]=2[C:12]2[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1.O.[OH-].[Na+]>Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([C:19]#[N:20])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:21][N:22]=[C:23]([NH:24][CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH3:34])(=[O:32])=[O:33])[CH2:27][CH2:26]3)[C:11]=2[N:10]=1
Reactant: C[Si](C)(C)CCOCn1nc(NC2CCN(S(C)(=O)=O)CC2)c2nc(-c3c(F)cccc3F)c3cc(C#N)ccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)N1CCC(Nc2n[nH]c3c2nc(-c2c(F)cccc2F)c2cc(C#N)ccc23)CC1
Temperature: 100 °C
Yield: 55 %

Procedure:
A microwave tube of maximum capacity 20 ml, equipped with a magnetic stirrer, is charged with 300 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1-([2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile in 12 ml of 5N hydrochloric acid. The reaction mixture is microwave-heated at 100° C. for 5 min and then poured into 20 ml of water, brought to a pH of 7 by addition of 9.3N sodium hydroxide solution, and extracted with three times 20 ml of AcOEt. The combined organic phases are dried over MgSO4, filtered and concentrated under RP. The product is purified by flash chromatography on silica gel (15-40 μm), eluting with a mixture of DCM and AcOEt (50/50 by vol.), to give 130 mg of 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile (yellow solid). 1H NMR (400 MHz, DMSO-d6) 1.67 (m, 2 H) 2.11 (m, 2 H) 2.87 (s, 3 H) 2.90 (m, 2 H) 3.56 (m, 2 H) 3.80 (m, 1 H) 6.20 (broad d, J=7.7 Hz, 1 H) 7.34 (m, 2 H) 7.70 (m, 1 H) 8.18 (broad s, 1 H) 8.28 (broad d, J=8.6 Hz, 1 H) 8.56 (d, J=8.6 Hz, 1 H) 13.07 (s, 1H) LC-MS-DAD-ELSD: 483 (+)=(M+H)(+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.C([S:31][CH2:32][CH:33]([CH3:37])[C:34](O)=[O:35])(=O)C>ClCCl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:34](=[O:35])[CH:33]([CH3:37])[CH2:32][SH:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SCC(C)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
L-Proline tert-butyl ester (5.1 g) is dissolved in dichloromethane (40 ml) and the solution stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (6.2 g) dissolved in dichloromethane (15 ml) is added followed immediately by a solution of 3-acetylthio-2-methylpropanoic acid (4.9 g) in dichloromethane (5 ml). After 15 minutes stirring in the ice bath and 16 hours at room temperature, the precipitate is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo. The residue, N-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester, is purified by column chromatography (silica gel, chloroform), yield 7.9 g. The named product is obtained by following the procedure of Example 29, step (b).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:14][O:13]1.[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH:26]([CH3:34])[CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[OH:13][CH:12]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:11])[O:8][CH2:9][C:10]=2[C:2]=1[CH3:1])[CH2:14][N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH:26]([C:17]2[CH:18]=[CH:19][C:20]3[C:21](=[O:25])[O:22][CH2:23][C:24]=3[C:16]=2[CH3:15])[CH3:34])[CH2:29][CH2:30]1
Reactant: Cc1c(C(C)CN2CCNCC2)ccc2c1COC2=O
Reactant: Cc1c(C2CO2)ccc2c1COC2=O
Product: Cc1c(C(C)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)ccc2c1COC2=O

Procedure:
5-(2-{4-[2-Hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}-1-methylethyl)-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 12 starting from 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (58 mg, 0.31 mmol, 1.2 mmol) and 4-methyl-5-(1-methyl-2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[C:16]2[N:15]=[C:14]([CH3:17])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6].OO.C([O-])(O)=[O:38].[Na+]>CC(O)=O>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:28](=[O:38])[CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[C:16]2[N:15]=[C:14]([CH3:17])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C([O-])O
Reactant: COc1cc(C(=O)N2CCCSc3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(C)nc12
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(C(=O)N2CCCS(=O)c3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(C)nc12
Reaction time: 4 h

Procedure:
To a solution of 2-methoxy-N-(2-methyl-1H-benzimidazol-4-yl)-4-(2,3,4,5-tetrahydro-1,5-benzothiazepin-5-yl)carbonylbenzamide (20 mg) in AcOH (1 ml), was added 30% aqueous H2O2 (1 ml), and the mixture was stirred for 4 hours. Saturated aqueous NaHCO3 was added to the reaction mixture, and the mixture was extracted with AcOEt, washed with brine and dried over Na2CO3. The solvent was removed under reduced pressure to give 2-methoxy-N-(2-methyl-1H-benzimidazol-4-yl)-4-(1-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-5-yl)carbonylbenzamide (20 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C@@H:16]1[CH2:18][O:17]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C@@H:16]([OH:17])[CH2:18][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H]1CO1
Reactant: C1CCNC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN1CCCC1

Procedure:
Using general procedure 1 with [(1R)-1-{(2R)-oxiran-2-yl}-2-phenyl-ethyl]carbamic acid tert-butylester (0.133 g, 0.50 mmol) and pyrrolidine (0.210 mL, 2.50 mmol) gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]([CH3:22])[C:20](=[O:23])[N:19]([CH3:24])[C:18](=[O:25])[CH:17]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C[Si](Cl)(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].[OH-].[Na+]>O.N1C=CC=CC=1.O1CCOCC1>[CH3:22][N:21]1[C:16]([N:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])=[CH:3][CH:4]=3)[CH2:15][CH2:14]2)=[CH:17][C:18](=[O:25])[N:19]([CH3:24])[C:20]1=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(N2CCN(CCCOc3ccc(N)cc3)CC2)cc(=O)n(C)c1=O
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Cn1c(N2CCN(CCCOc3ccc(NS(C)(=O)=O)cc3)CC2)cc(=O)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
20 ml of a dioxane solution containing 1.1 g of 6-[4-(3-[4-aminophenoxy]propyl)piperazin-1-yl]-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione obtained in Example 6 and 1.8 ml of pyridine was cooled to 0° C., and 0.95 ml of trimethylsilyl chloride was further added, followed by stirring at the same temperature for 5 minutes and then at room temperature for 30 minutes. The reaction solution was cooled to 0° C. again, and 0.6 ml of methanesulfonyl chloride was added dropwise thereto. The solution was stirred at the same temperature for 5 minutes and further at room temperature for 1 hour, and then cooled on an ice water bath. Afterward, 10 ml of ice water was added dropwise, and 50 ml of water and 70 ml of a 1N aqueous sodium hydroxide solution were further added. The resultant aqueous solution was washed with chloroform (500 ml×2), made weakly acidic with concentrated hydrochloric acid and then washed with chloroform (50 ml). In succession, potassium carbonate was added to this solution to adjust its pH to 7, and the solution was extracted with chloroform (50 ml×3), dried over sodium sulfate and then concentrated to obtain 0.9 g of crystalline 1,3-dimethyl-6-[4-(3-[4-methanesulfonylaminophenoxy]propyl)piperazin-1-yl]-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:28]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29](B(O)O)=[CH:30][CH:31]=[CH:32][CH:33]=1>>[C:28]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:29]=[CH:30][CH:31]=[CH:32][C:33]=1[N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[C:20](=[O:27])[O:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(-c4ccccc4-c4ccccc4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VI as described above, the arylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 2-biphenylboronic acid gave the title compound.