Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:14]COCCOC)=[C:9](B(O)O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:22]1[CH:23]=[C:24]([Cl:29])[C:25]([Cl:28])=[N:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CCOCC>COCCOC.O.Cl.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:14])=[C:9]([C:22]2[CH:27]=[N:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCOCOc1ccc(C(C)(C)C)cc1B(O)O
Reactant: Clc1cc(Br)cnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CC(C)(C)c1ccc(O)c(-c2cnc(Cl)c(Cl)c2)c1
Temperature: 80 °C

Procedure:
A mixture of 5-(tert-butyl)-2-((2-methoxyethoxy)methoxy)benzeneboronic acid (Intermediate 7) (1.0 g, 3.54 mmol), 5-bromo-2,3-dichloropyridine (0.80 g, 3.53 mmol) and potassium carbonate (1.5 g, 10.85 mmol) in DME (20 mL) and water (5 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)palladium (0) (200.0 mg, 0.17 mmol) was added and the mixture heated at 80° C. overnight. The cooled reaction mixture was extracted with ethyl acetate (50 mL), the organic phase separated, dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified using flash chromatography on silica eluting with 30% ethyl acetate in hexanes to give the MEM ether intermediate. The MEM ether was stirred in 10% hydrochloric acid in ethanol at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure to give 4-(tert-butyl)-2-(5,6-dichloropyridin-3-yl)phenol.
Reaction SMILES: [OH-].[K+].[C:3]1([S:9]([NH:12][C:13]2[S:14][CH:15]=[C:16]([CH2:18][C:19]([O:21]CC)=[O:20])[N:17]=2)(=[O:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C>O>[C:3]1([S:9]([NH:12][C:13]2[S:14][CH:15]=[C:16]([CH2:18][C:19]([OH:21])=[O:20])[N:17]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=C(O)Cc1csc(NS(=O)(=O)c2ccccc2)n1
Yield: 92.6 %

Procedure:
To an aqueous solution of potassium hydroxide (5.0 g.) in water (150 ml.) was added ethyl 2-benzenesulfonamidothiazol-4-ylacetate (9.1 g.) at 10° C. with stirring, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was adjusted to pH 4 to 4.5 with acetic anhydride, and the mixture was stirred under ice-cooling till the crystals precipitated. The crystals were collected by filtration and dried to give 2-benzenesulfonamidothiazol-4-ylacetic acid (7.7 g.), mp 94° to 96° C. (dec.).
Reaction SMILES: C([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:17]([O-])=O)[CH:14]=2)[CH2:9]1)C1C=CC=CC=1>[Pd].CO>[NH2:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:16]2
Reactant: O=[N+]([O-])c1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)CNC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.1 %

Procedure:
7.23 g of 2-benzyl-5-nitroisoindoline was dissolved into 100 ml of methanol and to the solution was added 1.5 g of 10% palladium on carbon. The mixture was stirred under a hydrogen gas stream under atmospheric pressure for 2 days at room temperature and another 5 days at 40° C. The catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by vacuum distillation (bath temperature: 150°-180° C., pressure: 0.1 mmHg) to obtain 2.94 g of 5-aminoisoindoline.
Reaction SMILES: C1(C(O)=O)CCCC(C(O)=O)C1.[C:13]([C:15]12[CH2:22][C:19]([NH:23][C:24]([C:26]3[CH:31]=[N:30][CH:29]=[CH:28][N:27]=3)=[O:25])([CH2:20][CH2:21]1)[CH2:18][CH2:17][CH2:16]2)#[CH:14].Br[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[N:34]=1>C(#N)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:39][C:35]1[N:34]=[C:33]([C:14]#[C:13][C:15]23[CH2:22][C:19]([NH:23][C:24]([C:26]4[CH:31]=[N:30][CH:29]=[CH:28][N:27]=4)=[O:25])([CH2:20][CH2:21]2)[CH2:18][CH2:17][CH2:16]3)[CH:38]=[CH:37][CH:36]=1
Reactant: C#CC12CCCC(NC(=O)c3cnccn3)(CC1)C2
Reactant: Cc1cccc(Br)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)C1CCCC(C(=O)O)C1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1cccc(C#CC23CCCC(NC(=O)c4cnccn4)(CC2)C3)n1
Temperature: 70 °C
Yield: 36.1 %

Procedure:
To a stirred mixture of intermediate 1, N-(5-ethynylbicyclo[3.2.1]octan-1-yl)pyrazine-2-carboxamide (40 mg, 0.16 mmol) and 2-bromo-6-methylpyridine (30 mg, 0.18 mmol) in TEA (0.5 mL) and acetonitrile (2 mL) was added Pd(PPh3)4 (2 mg, 0.02 mmol), followed by an addition of CuI (4 mg, 0.02 mmol). After heated at 70° C. for three hours, the reaction was cooled to room temperature, diluted with ethyl acetate (30 mL), washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by Prep HPLC to afford 20 mg (36%) of the title compound, pyrazine-2-carboxylic acid [5-(6-methyl-pyridin-2-ylethynyl)-bicyclo[3.2.1]oct-1-yl]-amide, as a white solid. 1HNMR (500 MHz, CDCl3): δ 9.40 (s, 1H), 8.75 (s, 1H), 8.51 (s, 1H), 7.91 (s, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.06 (d, J=7.5 Hz, 1H), 2.55-2.52 (m, 4H), 2.29-1.76 (m, 11H); ESI-MS m/z: 347 (M+H)+.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([O:15]C)[C:8]=2[CH:7]=1)(=[O:5])=[O:4])[CH3:2].B(Br)(Br)Br>>[CH2:1]([S:3]([C:6]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([OH:15])[C:8]=2[CH:7]=1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1cc2c(OC)cccc2o1
Agent: BrB(Br)Br
Product: CCS(=O)(=O)c1cc2c(O)cccc2o1
Yield: 86.5 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 2-(ethylsulfonyl)-4-methoxybenzo(b)furan (3.50 g) and boron tribromide (7.0 ml), the title compound (2.85 g) was obtained as colorless crystals, melting point 145-147° C.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[NH2:11][C:12]1[CH:31]=[CH:30][C:15]2[C:16]([N:19]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:29])=[N:17][O:18][C:14]=2[CH:13]=1>C(Cl)Cl>[O:29]=[C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27](=[O:28])[N:19]1[C:16]1[C:15]2[CH:30]=[CH:31][C:12]([NH:11][CH:8]=[O:10])=[CH:13][C:14]=2[O:18][N:17]=1
Reactant: Nc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1
Reactant: O=CO
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CNc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Acetic anhydride (2.63 mL, 27.9 mmol) was added to formic acid (1.04 mL, 27.9 mmol) at 0° C. The mixture was heated to 60° C. for 30 minutes. After that 2-(6-aminobenzo[d]isoxazol-3-yl)isoindoline-1,3-dione 1-4 (390 mg, 1.39 mmol) dissolved in CH2Cl2 (10 mL) was added at 0° C. The mixture was stirred for 1 h at room temperature. The mixture was concentrated and the residue was triturated with CH2Cl2/hexane (1:1) to give 300 mg (70%) of 1-5 as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) (rotamer ratio: s-cis/s-trans=3:1) δ 10.75 (0.75H, br s), 10.58 (0.25H, br d, J=11.3 Hz), 9.04 (0.25H, br d, J=11.3 Hz), 8.43 (0.75H, br s), 8.29 (0.75H, br s), 8.07 (2H, m), 7.99 (2H, m), 7.81 (1H, d, J=8.4 Hz), 7.80 (0.25H, br s), 7.43 (0.75H, d, J=8.4 Hz), 7.28 (0.25H, br d, J=8.4 Hz); ESI-MS m/z 308 [C16H9N3O4+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[C:19]([O:21]C)[CH:18]=[CH:17][C:4]=1[C:5]([N:7]([CH:14]([CH3:16])[CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:4]=1[C:5]([N:7]([CH:14]([CH3:16])[CH3:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:6]
Reactant: COc1ccc(C(=O)N(c2ccccc2)C(C)C)c(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)N(C(=O)c1ccc(O)cc1O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 2,4-dimethoxy-N-(1-methylethyl)-N-phenylbenzamide (2.4 g, 8.03 mmol) in 10 ml of dichloromethane at 0° C. was treated with 1N boron tribromide (33.2 mL, 33.2 mmol) and stirred at room temperature for 1 hour. The reaction is poured in to the ice water. After stirring for 15 minutes, the reaction was partitioned between ethyl acetate and brine, dried over magnesium sulfate and concentrated in vacuo to afford yellow foam. This material is purified by chromatography on silica gel (70 g) with 3-5% methanol/dichloromethane as the eluent to afford 2,4-dihydroxy-N-(1-methylethyl)-N-phenylbenzamide as colorless foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]([C@@H:21]3[CH2:27][CH2:26][C@@H:25]4[CH2:28][N:22]3[C:23](=[O:37])[N:24]4[O:29]CC3C=CC=CC=3)=[O:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:18][C:19]([C@@H:21]3[CH2:27][CH2:26][C@@H:25]4[CH2:28][N:22]3[C:23](=[O:37])[N:24]4[OH:29])=[O:20])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)[C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)ccc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)[C@@H]3CC[C@@H]4CN3C(=O)N4O)ccc2C1
Reaction time: 8 h

Procedure:
To a solution of the product of Step 1 (79.6 mg, 0.157 mmol) in methanol (4 mL) and ethyl acetate (2 mL), was added 10% palladium on carbon (18 mg) and the reaction mixture was stirred under an atmosphere of hydrogen (balloon) overnight. LC/MS analysis showed the reaction was not quite complete so an additional 10% palladium on carbon (10 mg) was added and the reaction mixture was stirred under an atmosphere of hydrogen (balloon) for an additional 6 hours. The reaction mixture was filtered through a microfilter and the collected solid was washed well with methanol. The filtrate was concentrated under vacuum and azeotroped with toluene to afford the title compound as a light brown oil which was used directly in the next step without purification
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]2[CH2:13][CH2:14][CH2:15][CH:16]([C:19]([O:21][CH3:22])=[O:20])[C:17](=O)[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(N(CC)CC)C.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>ClCCl.CO.O>[CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]2[CH2:13][CH2:14][CH2:15][C:16]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CCCc2ccc(OCc3ccccc3)cc2C1=O
Agent: CS(=O)(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)C1=Cc2cc(OCc3ccccc3)ccc2CCC1
Temperature: -40 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To methyl 3-benzyloxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylate (2.81 g, 8.66 mmol) dissolved in a mixed solvent of dichloromethane (40 ml) and methanol (10 ml) was added at −40° C. (inner temperature) sodium borohydride (500 mg, 13.2 mmol), and the resulting mixture was stirred at −15° C. to −10° C. for 2 hours. The reaction mixture was cooled to −40° C., was mixed with water (20 ml) and extracted with dichloromethane (40 ml, 10 ml×2). The combined organic layers were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure. To the residue dissolved in THF (30 ml) were added at 0° C. triethylamine (6.04 ml, 43.3 mmol) and methanesulfonyl chloride (1.10 ml, 13.0 mmol), and the resulting mixture was stirred at room temperature for 20 hours. In order to complete the reaction, DBU (3.89 ml, 26.0 mmol) was added, and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, was mixed with water and was extracted with ethyl acetate (30 ml×3). The combined organic layers were washed with 1 N hydrochloric acid (5 ml×3), were dried with anhydrous magnesium sulfate and were then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 60 g, ethyl acetate/hexane=1/30 →1/9). The objective fractions were concentrated under reduced pressure to obtain methyl 2-benzyloxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (2.32 g, 7.52 mmol, 87%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:9](Br)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH2:10][CH2:9][CH2:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[CH3:1])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1ccncc1C
Product: Cc1cnccc1CCCc1ccccc1
Yield: 92.1 %

Procedure:
1.0 g (9.35 mmol) of 3,4-dimethylpyridine and 1.73 g (9.35 mmol) of phenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 1.82 g of the desired compound (yield: 92.4%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:31])[CH2:22][C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:32]1[CH2:34][C@@H:33]1[CH2:35][O:36][C:37]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:38]=1[CH:39]=[CH:40][CH:41]=[N:42]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:31])[CH2:22][C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH2:34][C@@H:33]([OH:32])[CH2:35][O:36][C:37]3[CH:46]=[CH:45][CH:44]=[C:43]4[C:38]=3[CH:39]=[CH:40][CH:41]=[N:42]4)[CH2:27][CH2:26]2)=[O:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: O=C(CC(=O)N1CCNCC1)NC(CCCc1ccccc1)CCCc1ccccc1
Solvent: CCO
Product: O=C(CC(=O)N1CCN(C[C@@H](O)COc2cccc3ncccc23)CC1)NC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C

Procedure:
3-(Piperazin-1-yl)-3-oxopropionic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (38) (209.5 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 15 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (neat ethyl acetate, then 50%→100% acetone in hexanes, then 5% ethanol in acetone) affording the desired product as a solid. ESMS: MH− 623.4
Reaction SMILES: Br[CH:2]=[C:3]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.[Cl:32][C:33]1[CH:41]=[CH:40][C:39]2[NH:38][C:37]3[CH2:42][CH2:43][N:44]([CH3:46])[CH2:45][C:36]=3[C:35]=2[CH:34]=1>CN(C=O)C.[Cu]I>[Cl:32][C:33]1[CH:41]=[CH:40][C:39]2[N:38](/[CH:2]=[C:3](/[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)\[C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[C:37]3[CH2:42][CH2:43][N:44]([CH3:46])[CH2:45][C:36]=3[C:35]=2[CH:34]=1
Reactant: BrC=C(c1ccccc1)c1ccncc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2/C=C(/c2ccccc2)c2ccncc2)C1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
4-(2-Bromo-1-phenylvinyl)pyridine (310 mg, 1.1 mmol) was dissolved in DMF (5 mL) and potassium phosphate (424 mg, 2 mmol) was added followed by copper (I) iodide (19 mg, 0.1 mmol) and L-proline (23 mg, 0.2 mmol). 8-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was added and the mixture purged with nitrogen for 2 min. The reaction mixture was stirred at 85° C. overnight. Water was added and the solid mass was filtered under vacuum. The crude compound was purified on silica gel (100-200 mesh) using 0-10% MeOH:DCM as eluent. The compound was further purified through reverse phase HPLC. Yield: 21 mg (TFA salt). 1H NMR (CDCl3, TFA salt) δ (ppm): 8.58 (d, 2H), 7.50 (m, 2H), 7.36-7.18 (m, 7H), 7.08 (d, 1H), 6.90 (d, 1H), 4.65 (m, 1H), 4.05 (m, 1H), 3.80 (m, 1H), 3.30 (m, 2H), 3.0 (s, 3H), 2.80 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@H:27]2[C:31](=[O:36])[NH:32][CH2:33][CH2:34][F:35])=[O:25])[N:19]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[Li+].[OH-]>C1COCC1>[C:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][C@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@H:27]2[C:31](=[O:36])[NH:32][CH2:33][CH2:34][F:35])=[O:25])[N:19]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[N:18]=1)=[O:16])[C:3]([OH:43])=[O:2])([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCCF)n(-c2ccccc2)n1)C(=O)O
Reaction time: 2 h

Procedure:
To a solution of 1.30 g (S)-2-({5-[2-((S)-2-(2-Fluoro-ethylcarbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester 1-methyl ester in 9 ml THF were added 52 mg LiOH (as solution in 3 ml water). After 2 h the reaction mixture was neutralized with Amberlite IR-120, filtrated and washed with methanol.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][O:4][CH2:3]1.[S:6]([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)([O-])(=[O:8])=[O:7].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH-].[Na+]>O>[S:6]([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)([O:1][C:2]1[CH2:3][O:4][CH:5]=1)(=[O:8])=[O:7]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: OC1COC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC2=COC2)cc1
Reaction time: 1 h
Yield: 94 %

Procedure:
The unpurified 3-hydroxyoxetane produced in Example 11 was used directly in the synthesis of its tosylate. To a stirred suspension of 315 g of the material (containing 3.4 moles of 3hydroxyoxetane) and 743 g (3.9 moles) of technical grade p-toluenesulfonyl chloride in 600 mL of water, was added dropwise, over a period of 25 minutes, a solution of 218 g (5.45 moles) of sodium hydroxide in 225 mL of water. The reaction was exothermic and ice bath cooling was used to keep the reaction temperature below 70° C. When the exothermic reaction subsided (10 minutes), the cooling bath was removed and the reaction temperature was allowed to decrease to 40° C. over a 1 hour period. The product was isolated by filtration, washed with four 200 ml portions of warm (45°-55° C.) water, and air dried to give 730 g (94% yield) of 3-oxetyl tosylate, mp 86°-88° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.CC([N:24]([CH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:39][CH2:38][NH:37][CH2:36]2)=[CH:31][CH:30]=1)C(=O)[O-])(C)C>>[NH2:24][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]2[CH2:39][CH2:38][N:37]([C:11]3[CH:12]=[C:13]4[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]4[CH:1]4[CH2:3][CH2:2]4)=[CH:9][C:10]=3[F:15])[CH2:36]2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)N(Cc1ccc(C2CCNC2)cc1)C(=O)[O-]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: NCc1ccc(C2CCN(c3cc4c(cc3F)c(=O)c(C(=O)O)cn4C3CC3)C2)cc1

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.88 g, 3.3 mmol) and 1,1-dimethylethyl[[4-(3-pyrrolidinyl)phenyl]methyl]carbamate, a procedure analogous to that given in Example 6 provided the title compound (1.02 g) as a bright yellow solid, mp 268°-272° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:9][OH:10])=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:10][CH2:9][C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([Cl:8])[CH:4]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cc(Cl)ncc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 0° C. solution of (5-bromo-2-chloropyridin-4-yl)methanol (1.96 g, 8.81 mmol) in CH2Cl2 (25 mL) was treated with triethylamine (2.456 ml, 17.62 mmol) and methanesulfonyl chloride (0.824 ml, 10.57 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was diluted with additional CH2Cl2, then washed with aqueous NaHCO3, followed by brine. The organic was dried over sodium sulfate, filtered and the filtrate evaporated. The crude was purified by silica gel chromatography to give the titled compound. 1H NMR (CDCl3, 500 MHz): δ 8.50 (s, 1H), 7.47 (s, 1H), 5.24 (s, 2H), 3.16 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1.[C:18](OC=O)(=[O:20])C>O1CCCC1>[CH:18]([N:12]1[CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[S:8][C:7]2[CH:17]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]1=2)=[O:20]
Reactant: CC(=O)OC=O
Reactant: COc1ccc2c(c1)Sc1ccccc1CN2
Solvent: C1CCOC1
Product: COc1ccc2c(c1)Sc1ccccc1CN2C=O
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
To a solution of 10,11-dihydro-7-methoxydibenzo[b,f][1,4]thiazepin (6.5 g,26.6 mmoles) in tetrahydrofuran (100 ml) was added 5 ml of formic acetic anhydride. The mixture was stirred at from 0 to 5° C. for 15 minutes. The mixture was then concentrated in vacuo. The residue was taken up in ether and a solid crystallized out. The solid was filtered, washed with ether and air-dried to give the title compound, m.p. 98°-100°.
Reaction SMILES: [C:1]([C@@H:9]1[CH2:13][CH:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[N:11](/[CH:27]=[CH:28]/[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:35])(=O)C1C=CC=CC=1.[H-].[Na+].C=O>C1(C)C=CC=CC=1>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:12]2[N:11](/[CH:27]=[CH:28]/[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:10](=[O:35])[C:9](=[CH2:1])[CH2:13]2)=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)[C@@H]1CC(Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Agent: C=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(/C=C/c2ccccc2)C1=O
Temperature: 25 °C

Procedure:
(S)-3-Benzoyl-5-biphenyl-4-ylmethyl-1-((E)-styryl)-pyrrolidin-2-one (4a, R1=styryl, R4=phenyl) (0.50 g, 1.1 mmol) is dissolved in 2 mL of anhydrous toluene, add sodium hydride (65 mg, 1.5 mmol) in portions then paraformaldehyde (66 mg, 2.2 mmol) in one portion, the result mixture is heat to reflux for 4 h under nitrogen atmosphere. The reaction mixture is cooled to room temperature, then quench with saturated NH4Cl aqueous solution, extract with toluene, the organic extracts are washed with saturated Na2CO3 aqueous solution and brine, dry over anhydrous Na2SO4, evaporate the solvent under vacuum to obtain (R)-5-biphenyl-4-ylmethyl-3-methylene-1-((E)-styryl)-pyrrolidin-2-one (1a, R1=styryl) which could be used in next step directly. 1HNMR (400 MHz, CDCl3): 2.68 (m, 2H, 3-CHH+5-CH2H), 2.81 (m, 1H, 3-CHH), 3.28 (m, 1H, 5-CH2H), 4.32 (m, 1H, 4-CH), 5.35 (s, 1H, C═CHH), 6.04 (s, 1H, C═CHH), 6.23 (d, 1H, C═CHH), 7.21˜7.72 (m, 15H, aromatic+C═CHH).