Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[NH:8][N:7]=1)=[O:5])[CH3:2].[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH3:12])[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(O)[nH]n1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc(OC)[nH]n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38 %

Procedure:
5-Hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (300 mg, 1.92 mmol) was dissolved in anhydrous N,N-dimethylformamide (DMF) (35 ml) and cesium carbonate (626 mg, 1.92 mmol) was added. The resulting suspension was treated with iodomethane (120 μl, 273 mg, 1.92 mmol) and stirred for 12 h at room temperature. The reaction mixture was quenched with saturated potassium hydrogen sulfate solution and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml). The extract was dried over sodium sulfate, evaporated and the crude product was purified by column chromatography on silica gel. Elution with ethyl acetate/n-heptane (1:3) yielded 124 mg (38%) of a white solid.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(NC(=NC(C)C)O[C:21]([CH3:24])([CH3:23])[CH3:22])(C)C>C(Cl)Cl>[C:21]([O:11][CH2:10][C@H:9]([C:12]([OH:14])=[O:13])[NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of N-BOC-D-serine (10 g, 48.7 mmol) in methylene chloride (50 ml) was added N,N′-diisopropyl-O-tert-butylisourea (35 ml, 3.5 M) via addition funnel, over 30 min. The reaction mixture was maintained at 0° C. for 2 hrs and then warmed to room temperature over night. The material was again cooled to 0° C. and a second portion of N,N′-diisopropyl-O-tert-butylisourea (28 ml, 3.5 M) was added. The material was stirred for 2 hrs at 0° C. and then warmed again to room temperature over night. Purification by flash silica gel chromatography using (20%) ethyl acetate/hexanes as eluant gave O-tert-butyl-N-BOC-D-serine (7.97 g) as a viscous oil which solidified on standing.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: FC(F)(F)c1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2cccc(C(F)(F)F)n2)cc1
Temperature: 130 °C
Yield: 95.1 %

Procedure:
To a solution of 2-chloro-6-(trifluoromethyl)pyridine (1.5 g, 8.26 mmol) and 4-hydroxybenzaldehyde (1.009 g, 8.26 mmol) in DMF (18 mL), was added K2CO3 (1.713 g, 12.39 mmol). The mixture was heated at 130° C. for 5 h, and then transferred to a sealed tube and heated with a microwave condition at 135° C. for 3 h. After cooling, the reaction mixture was diluted in water, extracted with EA. The organic phase was washed with water and brine, dried over Na2SO4, concentrated to afford the title compound (2.10 g) as a brown oil. LCMS: rt=3.25 min, [M+H+]=268
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([C:17](O)=[O:18])[CH2:15][N:16]=1)=[CH:8]2.[N:28]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>CN(C)C=O.O>[CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([C:17]([NH2:28])=[O:18])[CH2:15][N:16]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(C3=NCC(C(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cccc2cc(C3=NCC(C(N)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 11.1 %

Procedure:
To a solution of 2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-5-carboxylic acid (0.090 g) in N,N-dimethylformamide (6 ml) were added 1H-1,2,3-benzotriazol-1-ol (0.034 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.049 g), and the mixture was stirred at 50° C. for 45 min. 28% Aqueous ammonia (2 ml) was added to the reaction, and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography. (ethyl acetate:methanol=100:0-90:10), and recrystallized from hexane-ethyl acetate to give the title compound (0.010 g, yield 11%) as colorless crystals.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][S:8]([O:11]S(C)(=O)=O)(=[O:10])=[O:9].[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[C:27]1[C:28](=[O:46])[NH:29][C:30](=[O:45])[C:31]=1[C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]([CH2:41][CH2:42][CH2:43]O)[N:33]=1.Cl>C1COCC1>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[CH:21]=[C:20]2[C:27]1[C:28](=[O:46])[NH:29][C:30](=[O:45])[C:31]=1[C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]([CH2:41][CH2:42][CH2:43][O:11][S:8]([CH3:7])(=[O:10])=[O:9])[N:33]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: Cn1cc(C2=C(c3nn(CCCO)c4ccccc34)C(=O)NC2=O)c2cc(Cl)ccc21
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cn1cc(C2=C(c3nn(CCCOS(C)(=O)=O)c4ccccc34)C(=O)NC2=O)c2cc(Cl)ccc21
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
Pyridine (0.37 g, 4.62 mmol) and methanesulfonic anhydride (0.54 g, 3.08 mmol) were added to Compound 74 (0.67 g, 1.54 mmol) in THF (10 mL). The mixture was heated at 50° C. for 2 h, then cooled to rt. Another portion of THF (5 mL) was added, followed by 1N HCl (5 mL). The mixture was stirred for another 15 min, then extracted with EtOAc several times. The combined EtOAc layers were washed once with 1 N HCl (10 mL), water (2×20 mL) and saturated NaCl (20 mL), then dried (Na2SO4) and evaporated in vacuo to obtain 3-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-[3-[(methylsulfonyl )oxy]propyl]-1H-indazol-3-yl]-1H-pyrrole-2,5-dione as Compound 26a (0.73 g, 92%) as a reddish solid. ES-MS m/z 513 (MH+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12](O)=[O:13])[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([N:32]3[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]3)=[O:13])[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Br)CC1
Reactant: CS(=O)(=O)N1CCNCC1
Agent: Cl
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(C)(=O)=O)CC4)[nH]c3cc2Br)CC1
Yield: 45 %

Procedure:
The title compound was synthesized in analogy to example 1, from 6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate a) and 1-methylsulfonyl-piperazine to afford the title compound as a light-yellow solid (45%).
Reaction SMILES: [C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[I:16])([CH3:4])([CH3:3])[CH3:2].[CH3:19]C(C)([O-])C.[K+].CI>C1COCC1>[C:1]([Si:5]([CH3:18])([CH3:17])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:19])[N:11]=[C:10]2[I:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]nc(I)c2c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1nc(I)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
In a round-bottomed flask, 5-(tert-butyl-dimethyl-silanyloxy)-3-iodo-1H-indazole (1.65 g, 4.41 mmol) was dissolved in THF (16 ml). The solution was cooled to 0° C. and potassium tert-butoxide (697 mg, 6.22 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min then methyl iodide (0.38 ml, 6.08 mmol) was added dropwise. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 4.5 h. The reaction was quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-10% EtOAc) to give 770 mg (45%) of 5-(tert-butyl-dimethyl-silanyloxy)-3-iodo-1-methyl-1H-indazole as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.CN(C)CCN(C)C.C([Li])CCC.[Cl:22][C:23]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])=[O:26]>O1CCCC1>[Cl:22][C:23]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=1[Cl:34])([C:5]1[N:4]([CH2:3][O:2][CH3:1])[CH:8]=[CH:7][N:6]=1)[OH:26]
Reactant: COCn1ccnc1
Reactant: O=C(c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCn1ccnc1C(O)(c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1Cl
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a solution of 7.6 g (0.0676 mol) of 1-(methoxymethyl)imidazole and 8.1 g (0.0676 mol) of N,N,N',N'-tetramethylethylenediamine in 150 ml of anhydrous tetrahydrofuran were added dropwise under a nitrogen atmosphere at -60° C., 43 ml. (0.070 mol) of n-butyl lithium solution (15% in n-hexane). The solution was stirred at -60° C. for one hour. Then 23 g (0.0676 mol) of 2,2',4,4'-tetrachlorobenzophenone (prepared as described by S. D. Wilson and Yuan Ying Cheng, J. Org. Chem. 5, 223-6 (1940)) in 150 ml. of anhydrous tetrahydrofuran were added dropwise. The solution was stirred another hour at -60° C. and one night at room temperature. The reaction mixture was decomposed with 100 ml. of water and extracted with diethyl ether. The organic phase was dried over sodium sulphate and concentrated and the residue was extracted with a mixture of 2N hydrochloric acid and diethyl ether on which a solid substance was formed, which was crystallised from a mixture of isopropyl alcohol and diethyl ether. The product appeared to be the hydrochloride of the desired compound, contaminated with the compound without methoxymethyl group. Ammonia and diethyl ether were added to liberate the free base. The ethereal phase was concentrated and the residue was four times crystallised from a mixture of isopropyl alcohol and petroleum ether (boiling range 60°-80° C.). α,α-Bis-(2,4-dichlorophenyl)-1-(methoxymethyl)imidazole-2-methanol was obtained. Melting point 145.5°-146° C.
Reaction SMILES: O=[O+][O-].[O:4]=O.[C:6]1([CH:12]([O:19][C:20](=[O:59])[CH:21]([N:25]2[CH:28]([S:29][S:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[CH:27]([NH:40][C:41](=[O:57])[CH:42]([NH:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:26]2=[O:58])[C:22](=[CH2:24])C)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CSC>C(Cl)Cl>[C:6]1([CH:12]([O:19][C:20](=[O:59])/[C:21](/[N:25]2[CH:28]([S:29][S:30]([C:33]3[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=3)(=[O:31])=[O:32])[CH:27]([NH:40][C:41](=[O:57])[CH:42]([NH:49][C:50]([O:52][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:51])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:26]2=[O:58])=[C:22](\[OH:4])/[CH3:24])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Reactant: O=O
Agent: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: C/C(O)=C(/C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Reaction time: 0.12 h

Procedure:
An ozone/oxygen stream (0.5 mmol per minute) is passed for 7 minutes into a solution, cooled to -70° C., of 2.30 g (3.0 mmols) of 2-[4-(p-toluenesulphonylthio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-methylene-butyric acid diphenylmethyl ester in 230 ml of methylene chloride. After adding 1 ml of dimethyl sulphide, the solution is stirred for a further hour without cooling and is then concentrated by evaporation in vacuo. The residue is recrystallised from methylene chloride/ether/hexane and gives 2-[4-(p-toluenesulphonylthio)-3-(α-tert.butoxycarbonylamino-α-phenylacetylamino)-2-oxoazetidin-1-yl]-3-hydroxy-crotonic acid diphenylmethyl ester of melting point 182°-184° C; UV spectrum (ethanol): λmax =259 mμ (ε=13,400); IR spectrum (methylene chloride): characteristic bands at 2.92, 5.59, 5.83, 5.92, 6.03 (shoulder), 6.18 and 6.68μ; thin layer chromatogram: Rf value~0.55 (silica gel; toluene/ethyl acetate, 1:1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][CH2:6]2.C(O[C:14]1[O:15][CH2:16][CH2:17][N:18]=1)C.C1C2C(=CC=CC=2)C=CC=1S(O)(=O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:14]1[O:15][CH2:16][CH2:17][N:18]=1)[CH2:6]2
Reactant: Fc1cccc2c1CNC2
Reactant: CCOC1=NCCO1
Agent: O=S(=O)(O)c1ccc2ccccc2c1
Solvent: Cc1ccccc1
Product: Fc1cccc2c1CN(C1=NCCO1)C2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 4-fluoroisoindoline (400 mg), 2-ethoxy-2-oxazoline (400 mg), and β-naphthylsulfonic acid (30 mg) in 50 ml of toluene was stirred at 100° C. for 1 hour. The solvent as removed under reduced pressure, and the residue chromatographed on silica gel, eluting with 1-4% methanol in ethyl acetate, to give 4-fluoro-2-(oxazolin-2-yl)isoindoline, a compound of Formula (IB), m.p. 125°-129° C.
Reaction SMILES: [Mg].[CH2:2](Cl)[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH3:4].II.BrCCBr.[C:19](=[O:21])=[O:20]>O1CCCC1>[CH3:4][C:3]([CH3:5])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][C:19]([OH:21])=[O:20]
Reactant: O=C=O
Reactant: CC(C)(CCl)c1ccccc1
Agent: II
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC(C)(CC(=O)O)c1ccccc1
Reaction time: 5 h
Yield: 81 %

Procedure:
Following a literature procedure, (Leffler, J. E.; Barbas, J. T. JACS. 1981, 103(26), 7768-7773), to a mixture of magnesium turnings (9.5 g) and neophyl chloride (7.5 mL) in tetrahydrofuran (100 mL) is added a spatula tip of iodine and 1,2-dibromoethane (1 mL). The mixture is heated gently with under a heat gun to initiate a vigorous reaction. A solution of neophyl chloride (57 mL) in tetrahydrofuran (360 mL) is added dropwise over the course of 90 minutes. Following completion of the addition, the reaction mixture is stirred for an additional five hours, then solid carbon dioxide (25 g) is added to the flask. After 10 minutes, the flask is transferred to a 40° C. water bath until all carbon dioxide had sublimed. The solvent is then removed under reduced pressure to afford the title compound (58 g, 81%) as a white paste. MS (ES+): (M+H)=178.8
Reaction SMILES: [N:1]1([C:7](=[O:12])[CH2:8][C:9](=O)[CH3:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26]C=1)=O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(O)C>[Cl:20][C:17]1[CH:16]=[C:15]2[C:14](=[CH:19][CH:18]=1)[N:13]=[C:9]([CH3:10])[C:8]([C:7]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:12])=[C:21]2[C:22]1[CH:24]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)CC(=O)N1CCCCC1
Reactant: Nc1ccc(Cl)cc1CC(=O)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCO
Product: Cc1nc2ccc(Cl)cc2c(-c2ccccc2)c1C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.9 %

Procedure:
To a solution of 1-(piperidin-1-yl)butane-1,3-dione (1.08 g, 6.5 mmol) in ethanol (20 ml) at room temperature was added 2-amino-5-chlorophenylacetophenone (1.16 g 5.0 mmol) followed by ytterbium triflate (294 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 12 hours. The white powdery precipitate that was formed in the reaction mixture was filtered off, washed with ethanol, and dried under reduced pressure to provide (6-chloro-2-methyl-4-phenylquinolin-3-yl)(piperidin-1-yl)methanone (874 mg, 48%) as a white powder. 1H NMR (CDCl3, 400 MHz) δ 8.1 (d, 1H, J=8.6 Hz); 7.67 (dd, 1H, J=8.6, 2.3 Hz); 7.63 (d, 1H, J=2.3 Hz); 7.6-7.5 (m, 4H); 7.33-7.28 (m, 1H); 3.55 (ddd, 1H, J=13.3, 7.4, 3.1 Hz); 3.37 (ddd, 1H, J=13.3, 7.4, 3.1 Hz); 3.05 (ddd, 1H, J=13.3, 7.4, 3.1 Hz); 2.80 (ddd, 1H, J=13.3, 7.4, 3.1 Hz); 2.77 (s, 3H); 1.60-1.2 (m, 5H); 1.0 (m, 1H). LC MS (CI) shows M+H 365.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.1 %

Procedure:
To a solution of 4-(4-Chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (80 mg, 67%).
Reaction SMILES: [NH:1]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20]C(C)(C)C)=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>O>[NH:1]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[C@H:2]([C:10]([NH:12][C@H:13]([C:18]([OH:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg Z-Phe-Leu-OtBu was added to 5 mL CF3COOH to which a drop of water had been added. The mixture was stirred for 2 h at ambient temperature, concentrated in vacuo and co-evaporated with 10 mL toluene (2×) to obtain Z-Phe-Leu-OH in quantitative yield. 1H-NMR (CDCl3, 300 MHz): δ 7.31-7.04 (m, 10H), 6.82 (d, 1H, J=6.6 Hz), 5.79 (d, 1H, J=7.3 Hz), 4.93 (s, 2H), 4.44 (m, 2H), 2.94 (m, 2H), 1.51 (m, 3H), 0.77 (m, 6H).
Reaction SMILES: CC1C=C(N2CC[N:9]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=CC=[CH:17][CH:16]=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.CC1OC(CN)=CC=1>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:9][CH2:12][C:13]4[O:14][C:15]([CH3:20])=[CH:16][CH:17]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1ccc(CN)o1
Product: Cc1ccc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)cc2C)o1
Yield: 78 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (5-methylfuran-2-yl)methanamine, the title compound was obtained as a yellowish solid in 78% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.08-6.98 (m, 2H), 6.12 (d, J=2.4 Hz, 1H), 6.07 (s, 1H), 5.93 (t, J=4.8 Hz, 1H), 5.89 (d, J=2.4 Hz, 1H), 4.49 (d, J=4.8 Hz, 2H), 4.42 (s, 2H), 3.83-3.74 (m, 2H), 3.49-3.39 (m, 2H), 2.48 (s, 3H), 2.27 (s, 3H); MS (ES+) m/z 450.1 (M+23).
Reaction SMILES: C1C=CC=CC=1.[C:7]1([CH:17]2[NH:21][CH2:20][CH2:19][O:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(N(CC)CC)C>[C:7]1([CH:17]2[N:21]([C:24](=[O:25])[CH2:23][Cl:22])[CH2:20][CH2:19][O:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)CCl
Reactant: c1ccc2c(C3NCCO3)cccc2c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(CCl)N1CCOC1c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Nineteen and nine tenths (19.9) ml of a benzene solution containing 5 g. of 2-α-naphthyl oxazolidine was combined with 50 ml. of benzene and 2.8 g. of chloroacetyl chloride. To this was added 2.6 g. of triethylamine, dropwise with stirring in an ice bath. The mixture was stirred at room temperature for 30 minutes after addition was complete, washed with water, separated and dried over magnesium sulfate. The solvent was stripped under vacuum. There was obtained a yield of 6.7 g. of an oil, the title compound, ND30 =1.6030.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].CN(C)[CH:26]=[O:27]>C1COCC1>[CH:26]([C:13]1[CH:14]=[CH:15][S:11][C:12]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:27]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1cccs1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1sccc1C=O
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of tert-butyllithium in pentane (1.7 M, 35.4 mL, 60.2 mmol, 2.40 equiv) was added to a solution of tert-butyl 2-thienylcarbamate (10-2, 5.00 g, 25.1 mmol, 1 equiv) in THF (75 mL) at −78° C., and the resulting mixture was stirred at −78° C. for 1.5 h. N,N-Dimethylformamide (5.83 mL, 75.3 mmol, 3.00 equiv) was added, and the mixture was then warmed to 0° C. The reaction mixture was partitioned between water (300 mL) and EtOAc (2×200 mL). The combined organic layers were then dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography (hexane, initially, grading to 30% hexane in EtOAc) to give tert-butyl 3-formyl-2-thienylcarbamate (10-3) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 10.51 (s, 1H), 9.80 (s, 1H), 7.11 (d, 1H, J=5.7 Hz), 6.68 (d, 1H, J=5.9 Hz), 1.55 (s, 9H).