Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[N:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)Cc1cncc(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cncc(Br)c1

Procedure:
A mixture of (5-bromo-pyridin-3-yl)-acetic acid (ABCR, Karlsruhe, Germany, 4.54 mmol) and concentrated sulfuric acid (0.02 ml) in MeOH was refluxed for 13.5 h. The RM was concentrated, taken in EtOAc and sonicated. The organic layer was washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a brown oil. (HPLC: tR 2.21 min (Method A); M+H=230, 232 MS-ES)
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[CH:9]=[CH:8][C:7]=1[CH2:22][CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25])([O-:5])=[O:4].CI.[CH2:31](O)C>CN(C)C=O.O>[N+:3]([C:6]1[CH:11]=[C:10]([C:12]([O:21][CH3:31])([C:13]([F:14])([F:15])[F:16])[C:17]([F:18])([F:19])[F:20])[CH:9]=[CH:8][C:7]=1[CH2:22][CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25])([O-:5])=[O:4]
Reactant: CCO
Reactant: CN(C)C(=O)CCc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(c1ccc(CCC(=O)N(C)C)c([N+](=O)[O-])c1)(C(F)(F)F)C(F)(F)F

Procedure:
To a suspension of 2.15 (0.085 mole) of sodium hydride in 200 ml dimethylformamide is added 29.1 g (0.075 mole) of 3-{2-nitro-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl}-N,N-dimethylpropanamide in in 50 ml dimethylformamide at such a rate that excessive foaming is avoided. To the resulting suspension, stirred in a nitrogen atmosphere, is added 14.2 g (0.10 mole) of methyl iodide to give a reaction mixture, which is stirred at room temperature overnight. The reaction mixture is then treated with 5 ml of ethanol, poured into 1-liter of water and extracted with ether. The resulting ether solution is washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated at reduced pressure to obtain a residual oil which is chromatographed on Silicar® CC-7. Elution with chloroform gives a major fraction consisting of 16 g which is recrystallized from hexane to give 3-{2-nitro-4-[2,2,2-trifluoro-1-methoxy-1-(trifluoromethyl)ethyl]phenyl}-N,N-dimethylpropanamide having a melting point of 51° -54°.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[C:19]1([NH2:26])[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O.C(O)(=O)C>[NH:25]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:26]=[C:15]1[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: Nc1ccccc1N
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3ccccc3[nH]2)[nH]1
Yield: 21 %

Procedure:
The product is prepared according to the procedure described in Example 3, using 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 248 mg of benzene-1,2-diamine and 330 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2.5 ml of pyridine and 2.5 ml of dimethylformamide and then in 5 ml of acetic acid. After refluxing for one hour and purification by silica column chromatography, eluent: CH2Cl2/MeOH: gradient from 100/0 to 90/10, 75 mg of 2-(1H-benzimidazol-2-ylmethyl)-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a beige powder, the characteristics of which are the following:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl.[CH3:10][N:11]([CH3:15])[CH2:12][CH2:13]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C=O)C.O>[CH3:10][N:11]([CH2:12][CH2:13][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:15]
Reactant: CN(C)CCCl
Reactant: Oc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1ccc(Br)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
4-Bromophenol (10.0 g, 57.8 mmol) and 2-dimethylaminoethyl chloride hydrochloride (8.33 g, 57.8 mmol) were dissolved in DMF (200 ml), and potassium carbonate (24.0 g, 173 mmol) and sodium iodide (0.87 g, 5.78 mmol) were added under ice-cooling. The mixture was stirred for 13 hr at room temperature and at 70° C. for 3 hr. Water (400 ml) was added to the reaction mixture and the mixture was extracted with chloroform (2×200 ml). The organic layer was washed successively with water (2×200 ml) and saturated brine (200 ml), dried over anhydrous magnesium sulfate and concentrated. The obtained residue was dissolved in 1N hydrochloric acid (100 ml) and washed with ethyl acetate (2×200 ml). Sodium hydroxide (4 g) was added to the aqueous layer to make the layer alkaline, and the mixture was extracted with chloroform (2×200 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. Hexane was added to the obtained residue and insoluble matter was filtered off. The mother liquor was concentrated to give the title compound (5.25 g, 37%) as a transparent oil.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH3:11])[N+:7]([O-:10])=[CH:8][CH:9]=1)([O-])=O.[CH3:12][O-:13].[Na+].[Na]>CO>[CH3:12][O:13][C:4]1[CH:5]=[C:6]([CH3:11])[N+:7]([O-:10])=[CH:8][CH:9]=1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc[n+]([O-])c(C)c1

Procedure:
To a suspension of 4-nitro-2-picoline-1-oxide (0.952 g) in dry methanol (20 ml) was added dropwise a solution of sodium methox-ide prepared from sodium (0.60 g) and methanol (10 ml) under stirring at cooling in an ice-bath. The mixture was stirred for 3 hours under the same condition. The resultant mixture was concentrated in vacuo. The residue was treated with chloroform and water. The organic layer was washed with water and a brine, and dried over sodium sulfate. Removal of the solvent gave 4-methoxy-2-picoline-1-oxide (0.958 g).
Reaction SMILES: [CH3:1]C1C=CC(S(O)(=O)=O)=CC=1.[OH:12][C:13]1[CH:14]=[C:15]([C:20]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21]2)[CH:16]=[CH:17][C:18]=1[OH:19]>>[CH3:1][O:24][C:23]([C:20]1([C:15]2[CH:16]=[CH:17][C:18]([OH:19])=[C:13]([OH:12])[CH:14]=2)[CH2:22][CH2:21]1)=[O:25]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2ccc(O)c(O)c2)CC1
Product: COC(=O)C1(c2ccc(O)c(O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 775.8 %

Procedure:
To a solution of 1-(3,4-dihydroxyphenyl)cyclopropanecarboxylic acid (4.5 g) MeOH (30 mL) was added TsOH (0.25 g, 1.3 mmol). The stirring was continued at 50° C. overnight before the mixture was cooled to room temperature. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 3:1) to give 1-(3,4-dihydroxy-phenyl)-cyclopropanecarboxylic methyl ester (2.1 g). 1H NMR (DMSO 300 MHz) δ 8.81 (brs, 2 H), 6.66 (d, J=2.1 Hz, 1 H), 6.61 (d, J=8.1 Hz, 1 H), 6.53 (dd, J=2.1, 8.1 Hz, 1 H), 3.51 (s, 3 H), 1.38-1.35 (m, 2 H), 1.07-1.03 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[Se:10](=O)=O>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][Se:10][N:9]=[C:4]2[CH:3]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=[Se]=O
Solvent: CCO
Product: Clc1ccc2n[se]nc2c1
Temperature: 25 °C

Procedure:
A solution of 4-chlorobenzene-1,2-diamine (1.50 g, 10.5 mmol) in EtOH (15 mL) was heated to reflux and selenium dioxide (1.28 g, 11.5 mmol) was added. The reaction was refluxed for 30 min and cooled to ambient temperature. The precipitated solid was filtered, washed thoroughly with H2O and dried under high vacuum to give the title compound. MS: m/z=219 (M+1).
Reaction SMILES: Cl.C([O:4][C:5]([C@@H:7]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[S:19][CH2:18]1)[CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:6])C.[OH-].[Na+]>CO>[C:5]([C@@H:7]([NH:16][C@@H:17]1[C:23](=[O:24])[N:22]([CH2:25][C:26]([OH:28])=[O:27])[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[S:19][CH2:18]1)[CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([OH:6])=[O:4]
Reactant: CCOC(=O)[C@H](CCC1CCCCC1)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCC2CCCCC2)C(=O)O)CSc2ccccc21
Reaction time: 2 h
Yield: 77.3 %

Procedure:
In 2 ml of methanol are dissolved 0.1 g of 3(R)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride and 1.5 ml of 1N aqueous sodium hydroxide. The solution is allowed to stand at room temperature for 2 hours, concentrated to about 1 ml at a temperature of not higher than 40° C. under reduced pressure, and acidified slightly with 1N hydrochloric acid to give 0.067 g of 3(R)-[1(S)-carboxy-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as colorless prisms, m.p. 207°-210° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]1[C:12]2[CH2:13][NH:14][CH2:15][C:11]=2[CH2:10][N:9]1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])=[O:17].Cl[C:29]1[N:30]=[N:31][C:32]([O:35][CH2:36][C:37]2[N:38]=[CH:39][S:40][CH:41]=2)=[CH:33][CH:34]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[S:40]1[CH:41]=[C:37]([CH2:36][O:35][C:32]2[N:31]=[N:30][C:29]([N:14]3[CH2:13][C:12]4[CH2:8][N:9]([C:16]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[C:24]([F:27])([F:25])[F:26])=[O:17])[CH2:10][C:11]=4[CH2:15]3)=[CH:34][CH:33]=2)[N:38]=[CH:39]1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CC2=C(CNC2)C1
Reactant: Clc1ccc(OCc2cscn2)nn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc(OCc3cscn3)nn1)C2

Procedure:
(3,4,5,6-Tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)(2-trifluoromethylphenyl)methanone trifluoroacetate (example 1b) (500 mg, 1.26 mmol) was reacted analogously to example 4b with 3-chloro-6-(thiazol-4-ylmethoxy)pyridazine (287.3 mg, 1.26 mmol). Yield: 36 mg (5%), M+H+: 474.26.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:17]2([CH3:20])[CH2:19][CH2:18]2)=[C:12]([C:14](O)=[O:15])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+].CO>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][C:11]([C:17]2([CH3:20])[CH2:19][CH2:18]2)=[C:12]([CH2:14][OH:15])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)O)c(C2(C)CC2)s1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1nc(CO)c(C2(C)CC2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
Dissolve 2-tert-butoxycarbonylamino-5-(1-methyl-cyclopropyl)-thiazole-4-carboxylic acid (2 g, 6.7 mmol) in THF (100 mL) and cool to 0° C. under nitrogen. Add triethylamine (0.93 mL, 1 equiv.) followed by the dropwise addition of isobutyl chloroformate (0.87 mL, 1 equiv.). Stir 30 minutes at 0° C. then filter, washing with THF. Cool filtrate back to 0° C. then add sodium borohydride (0.76 g, 3 equiv.) in one sum followed by the dropwise addition of methanol (4.1 mL, 15 equiv.). After 45 minutes at 0° C. remove cooling bath and let warm to room temperature for 15 minutes. Quench reaction (cautiously) with 1 N HCl (aq), approximately 50 mL. Extract with DCM. Wash organics with aqueous saturated sodium chloride. Dry organics over MgSO4 then filter and concentrate. Purify on silica gel (2:1 Hexanes:Ethyl Acetate→1:1 Hexanes:Ethyl Acetate) to give a white solid (1.11 g, 58%). LCMS (ES), m/z 229 (M+1, product→t Butyl).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:21]=[C:11]3[CH:12]=[C:13]([C:16]([O:18]CC)=[O:17])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.O.O[Li].O.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:21]=[C:11]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccn2nc(-c3ccc(Br)cc3)cc2c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccn2nc(-c3ccc(Br)cc3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(4-bromophenyl)pyrazolo[1,5-a]pyridine-5-carboxylate (2.40 g, 7.0 mmol) was dissolved in THF (50 mL) and water was added (12 mL) followed by LiOH—H2O (877 mg, 20.9 mmol). The mixture was stirred overnight at room temperature and 1M HCl (ca 28 mL) was added. The mixture was extracted with EtOAc (2×25 mL) and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford a crude white solid that was directly used into the next step. LCMS m/z 317.0, 319.0 (M+H)+, ret. time 2.62 min.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.[CH2:18]([N:21]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=2)[C:19]#[CH:20].O>O1CCCC1.C(N(CC)CC)C.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:11]=[C:5]1[NH:6][C:7]2[C:3](/[C:4]/1=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)=[C:2]([C:20]#[C:19][CH2:18][N:21]1[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=3)[CH:10]=[CH:9][CH:8]=2
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Reactant: C#CCn1c(=O)c2ccccc2c2ccccc21
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1Nc2cccc(C#CCn3c(=O)c4ccccc4c4ccccc43)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (from Example 71, infra) (50 mg, 0.15 mmol), and 5-(2-propynyl)-6(5H)-phenanthridinone (45 mg, 0.19 mmol) (prepared according to Walser et al., J. Med. Chem. 34(3), 1209-1221 (1991)) in 1 mL tetrahydrofuran and 1 mL triethylamine was degassed by bubbling argon through the solution for 10 minutes. At this time, copper (I) iodide (11 mg, 0.06 mmol) and tetrakis(triphenylphosphine) palladium(0) (3 mg, 0.03 mmol) were added, and the reaction was stirred at room temperature for 72 hours. Water (10 mL) was then added and the precipitate was filtered off and dried. The product was purified via flash column chromatography (SiO2, 230-400 mesh) with ethyl acetate/hexane, to yield a yellow powder which was recrystallized from ethyl acetate/hexane, to give (Z)-5-[3-[2,3-dihydro-2-oxo-3-(1H-pyrrol-2-ylmethylene)-1H-indol-4-yl]-2-propynyl]-6(5H)-phenanthridinone. (Yield 25 mg, 38%).
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.Cl.[C:6]([O:10][NH2:11])([CH3:9])([CH3:8])[CH3:7]>>[C:6]([O:10][N:11]=[CH:3][CH2:2][Cl:1])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)ON
Reactant: O=CCCl
Agent: Cl
Product: CC(C)(C)ON=CCCl
Temperature: 25 °C
Yield: 93.7 %

Procedure:
To 9.81 g of 40% aqueous chloroacetaldehyde solution was added 3.77 g of O-tert-butylhydroxylamine hydrochloride with stirring at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated, which afforded 4.21 g (yield, 94%) of chloroacetaldehyde O-tert-butyloxime, nD23.2 1.4418.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH:23]1[S:27][C:26](=[O:28])[N:25]([CH2:29][C:30]([OH:32])=[O:31])[C:24]1=[O:33])(O)[C:7]1[N:8]=[C:9]([NH:12][C:13](NC2C=CC=CC=2)=[O:14])[S:10][CH:11]=1)=[O:5])[CH3:2].[C:34]1(NC(=O)NC2SC=C(C(=O)C(OCC)=O)N=2)C=CC=CC=1.O=C1N(CC(O)=O)C(=O)CS1.N1CCCCC1.C(OC(=O)C)(=O)C>O.N1C=CC=CC=1.C(O)C>[C:13]([NH:12][C:9]1[S:10][CH:11]=[C:7]([C:6](=[C:23]2[S:27][C:26](=[O:28])[N:25]([CH2:29][C:30]([OH:32])=[O:31])[C:24]2=[O:33])[C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:8]=1)(=[O:14])[CH3:34]
Reactant: CCOC(=O)C(O)(c1csc(NC(=O)Nc2ccccc2)n1)C1SC(=O)N(CC(=O)O)C1=O
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2)n1
Agent: O=C(O)CN1C(=O)CSC1=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=O)N(CC(=O)O)C1=O)c1csc(NC(C)=O)n1
Temperature: 60 °C

Procedure:
A mixture comprising 0.6 g of crude 5-{1-ethoxycarbonyl-1-hydroxy-1-[2-(3-phenylureido)thiazol-4-yl]methyl}-2,4-dioxothiazolidine-3-acetic acid [prepared from 2.6 g of ethyl 2-(3-phenylureido)thiazol-4-ylglyoxylate, 1.2 g of 2,4-dioxothiazolidine-3-acetic acid, 1.2 g of piperidine and 30 ml of ethanol by a procedure similar to that of Example 24], 0.5 g of acetic anhydride and 4 ml of pyridine was heated at 60° C. for 17 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated off under reduced pressure. The resulting oil was purified by silica gel column chromatography, using as eluent a 8:2:0.5 to 7:3:0.5 by volume mixture of benzene ethyl acetate and acetic acid, giving the desired compound as a yellow powder having the following physical properties.
Reaction SMILES: Cl[Si](C)(C)C.BrCCBr.I[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.[NH2:24][C:25]1[C:30]2=[C:31]([C:35]([C:37]3[CH:38]=[C:39]([NH:43][C:44]([NH:46][C:47]4[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][C:48]=4[Cl:54])=[O:45])[CH:40]=[CH:41][CH:42]=3)=[O:36])[CH:32]=[C:33](Br)[N:29]2[N:28]=[CH:27][N:26]=1>CC(N(C)C)=O.O.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[NH2:24][C:25]1[C:30]2=[C:31]([C:35]([C:37]3[CH:38]=[C:39]([NH:43][C:44]([NH:46][C:47]4[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][C:48]=4[Cl:54])=[O:45])[CH:40]=[CH:41][CH:42]=3)=[O:36])[CH:32]=[C:33]([CH:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[N:29]2[N:28]=[CH:27][N:26]=1
Reactant: Nc1ncnn2c(Br)cc(C(=O)c3cccc(NC(=O)Nc4ccc(Cl)cc4Cl)c3)c12
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: Nc1ncnn2c(C3CCNCC3)cc(C(=O)c3cccc(NC(=O)Nc4ccc(Cl)cc4Cl)c3)c12
Temperature: 50 °C
Reaction time: 1 h
Yield: 8.1 %

Procedure:
A mixture of Zn dust (42 mg) in dimethylacetamide (0.5 mL) was treated with a mixture of chlorotrimethylsilane/1,2-dibromoethane (7/5 v/v, 0.020 mL). The reaction was heated to 50° C. for 30 minutes and then slowly cooled to room temperature. A solution of tert-butyl 4-iodopiperidine-1-carboxylate (165 mg, 0.53 mmol) in dimethylacetamide (1 mL) was added. The reaction was stirred at room temperature for one hour. This solution was added to a mixture of 95G (22 mg), PdCl2(dppf)2 (3 mg), CuI (6 mg) in dimethylactamide (1.2 mL). The reaction was heated under a nitrogen atmosphere at 80° C. for 18 hours. The reaction was diluted with water and extracted with EtOAc. The resulting solid was collected by filtration and the layers were separated. The organic layer was combined with the solid material and concentrated to dryness. The resulting residue was dissolved in CH2Cl2 (1 mL) and treated with trifluoroacetic acid (2 mL). The reaction mixture was concentrated and the residue was purified by preparative reversed phase HPLC (YMC S5 ODS 20×100 mm, 10-90% aqueous methanol over 10 minutes containing 0.1% TFA, 20 ml/min, monitoring at 220 nm). The desired fractions were passed through an SCX cartridge and concentrated to afford the desired compound (1.8 mg). Compound 102 had an analytical HPLC retention time=2.900 min. (Chromolith SpeedROD column 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm) and a LC/MS M++1=524+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:16]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=3)=[C:15]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)=[CH:29][CH:28]=3)[S:14][C:13]=2[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:44][CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>>[CH3:26][O:25][C:20]1[CH:19]=[C:18]([CH2:17][C:16]2[C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:41][C:13]=3[S:14][C:15]=2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH2:44][CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: COc1cc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1O
Reactant: ClCCN1CCCC1
Agent: Cl
Product: COc1cc(Cc2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(OCc4ccccc4)ccc23)ccc1OCCN1CCCC1
Yield: 30 %

Procedure:
The title compound was prepared in 30% yield from 6-benzyloxy-3-[(3-methoxy-4-hydroxyphenyl)methyl]-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene (Part E) and 1-(2-chloroethyl)pyrrolidine hydrochloride by a method similar to that outlined in Example 188, Part A.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[C:7](=[O:21])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:9][CH:10]=1.C(O)(=O)C>CO.[Zn]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[C:7](=[O:21])[N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:9][CH:10]=1
Reactant: COC(=O)CCC1=CCN(Cc2ccc([N+](=O)[O-])cc2)C1=O
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CCC1=CCN(Cc2ccc(N)cc2)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.3 %

Procedure:
90 mg of 3-[1-(4-nitro-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (0.3 mmol) was dissolved in methanol solution at room temperature. And then 290 mg of Zn (4.44 mmol) and 0.02 ml of acetic acid (0.3 mmol) were added thereto and the mixture was stirred for 48 hrs at room temperature. The resulting compound was purified by Silica gel column chromatography with ethylacetate as an eluant to give 20 mg of 3-[1-(4-amino-benzyl)-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-propionic acid methyl ester (h) (yield: 25%).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O[C:15]1[CH:16]=[C:17]([C:21]2([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:18]=[CH:19][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][O:11][C:19]3[CH:18]=[C:17]([C:21]4([O:27][CH3:28])[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:16]=[CH:15][CH:20]=3)=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC1(c2cccc(O)c2)CCOCC1
Reactant: OCc1ccc(-n2ccnc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1(c2cccc(OCc3ccc(-n4ccnc4)cc3)c2)CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
To a stirred solution of 4-(1-imidazolyl)benzyl alcohol (Eur. J. Med. Chem., 1992, 27, 219) (0.87 g, 5.0 mmol), 4-(3-hydroxyphenyl)-4-methoxy-3,4,5,6-tetrahydro-2H-pyran (J. Med. Chem., 1992, 35, 2600) (1.03 g, 4.9 mmol) and triphenylphosphine (1.55 g, 5.9 mmol) in THF (30 ml) cooled to 0° C. was added dropwise a solution of diethyl azodicarboxylate (DEAD) (1.03 g, 12.0 mmol) in THF (10 ml) over 20 min under a nitrogen atmosphere. After completion of addition, the mixture was stirred at 0° C. for 30 min and allowed to warm to room temperature, and then volatiles were removed under reduced pressure. Chromatographic purification of the residue (SiO2, 230 g; gradient elution, 15% to 30% acetone in dichloromethane) provided 0.27 g of the title compound as a gum, which solidified on standing at room temperature. Fractions contaminated with triphenylphosphine oxide were combined, concentrated to dryness, solidified by triturating with diisopropyl ether and recrystallized from diisopropyl ether / ethyl acetate to provide 0.16 g of the title compound. Combined solids were further purified by recrystallization from diisopropyl ether / ethyl acetate afforded the title compound as tiny colorless needles (0.30 g, 17%).