Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:29])[CH2:21][C:22]4[CH:27]=[CH:26][C:25](Br)=[CH:24][N:23]=4)[CH:16]=[N:17][CH:18]=3)=[O:12])=[CH:9][N:8]([C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])[C:6]=2[N:7]=1.[CH3:35][N:36](C=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:29])[CH2:21][C:22]4[CH:27]=[CH:26][C:25]([C:35]#[N:36])=[CH:24][N:23]=4)[CH:16]=[N:17][CH:18]=3)=[O:12])=[CH:9][N:8]([C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])[C:6]=2[N:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Br)cn3)c2)c2cnc(N)nc21
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C#N)cn3)c2)c2cnc(N)nc21
Temperature: 100 °C
Yield: 31 %

Procedure:
To a solution of N-{5-[2-Amino-7-(2-hydroxy-1,1-dimethyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl]-pyridin-3-yl}-2-(5-bromo-pyridin-2-yl)-acetamide (Example 316, 75 mg, 0.143 mmol) in DMF (2 mL) was added Zn(CN)2 (25 mg, 0.215 mmol) and the reaction mixture was degassed with argon for 10 minutes. Pd2 (dba)3 (3 mg, 0.002 mmol) and 1,1′-bis(diphenylphosphino)ferrocene 6 mg, 0.011 mmol) were then added and the resultant reaction mixture was heated at 100° C. for 40 minutes under microwave irradiation. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (2×10 mL) and brine (10 mL). The organic layer was dried (Na2SO4) and evaporated in vacuo. The crude material was purified by preparative TLC (7% MeOH in DCM) to afford the title compound as yellow solid in 31% yield, 21 mg.
Reaction SMILES: [Mg].II.Br[CH2:5][CH:6]=[CH2:7].[F:8][C:9]1[CH:14]=[CH:13][C:12]([Si:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)(Cl)[CH2:16][Cl:17])=[CH:11][CH:10]=1.[Cl-].[NH4+]>CCOCC>[CH2:5]([Si:15]([CH2:16][Cl:17])([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=1)[CH:6]=[CH2:7]
Reactant: Fc1ccc([Si](Cl)(CCl)c2ccc(F)cc2)cc1
Reactant: C=CCBr
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: C=CC[Si](CCl)(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.04 g (0.0428 mol) of magnesium turnings and about 0.05 g of iodine in 50 ml of ether was stirred under nitrogen while a solution of 4.7 ml (0.0544 mol) of 3-bromopropene in ether was added dropwise. The iodine color quickly disappeared, and the reaction temperature was kept around 30° C. by cooling with ice-water. The resulting solution was stirred 2 hours at room temperature. A solution of 10.0 gm (0.033 mol) of bis(4-fluorophenyl)chlorochloromethylsilane in 20 ml of ether was then added over 5 minutes, and the resulting mixture was allowed to stir overnight. The solution was treated with 20 ml of saturated aqueous ammonium chloride and extracted with ether. The ether was washed with water and with brine. Drying over magnesium sulfate and removal of solvent afforded a clear colorless oil which was distilled at 0.4 torr (bp 120°-130° C.) to give the title compound: nmr (CDCl3) 2.3 (2H, d, J=8 Hz), 3.3 (1H, s), 5.0 (2H, m), 5.8 (1H, m), 7.1 (4H, t, J=9 Hz), 7.6 (4H, d of d, J=9,6 Hz).
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][CH:23]1[CH2:27][CH2:26][CH2:25][NH:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][C@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC[C@@H]3C)nc2c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
Into a 20-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (500 mg, 1.67 mmol, 1.00 equiv), 2-methylpyrrolidine (285 mg, 2.92 mmol, 2.00 equiv), potassium carbonate (693.8 mg, 4.01 mmol, 3.00 equiv), N,N-dimethylformamide (6 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 12×20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100). This resulted in 590.7 mg (92%) of methyl 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate as yellow oil. Then the isomer was sent for chiral-prep-HPLC to get the product of (S)-methyl 3-(2-methylpyrrolidin-1-yl)-2-phenylquinoxaline-6-carboxylate (193.6 mg).
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]1([CH2:13][OH:14])[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH2:13]([O:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]=[CH:17]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: OCC1CC=CCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C1=CC(COCc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 208.3 %

Procedure:
A solution of potassium t-butoxide (1.0M in THF, 8.27 mL, 8.27 mmol) was added dropwise to a solution of (±)-3 cyclohexene-1-methanol (853 mg, 7.60 mmol) in THF (35 mL) at 2520 C. under N2. The resultant mixture was stirred at 25° C. for 30 minutes. Benzyl bromide (1.0 mL, 3.37 mmol) was added dropwise. The reaction mixture was allowed to stir at room temperature for 16 hours and then treated with saturated aqueous NH4 Cl (5 mL) and concentrated. The residue was dissolved in ether (50 inL), washed with water (20 mL) and brine (20 mL), and dried over MgSO4. The solvent was evaporated under reduced pressure. The residue was subjected to radial chromatography on silica gel eluting with 5 percent EtOAc in hexane to give (±)-3-(benzyloxy)methyl-1-cyclohexene (1.42 g, 92 percent) as a colorless oil. NMR
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:16]([C:19]3[S:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[C:20]=3[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)=[CH:31][CH:30]=3)=[CH:15][C:10]=2[C:11]([O:13]C)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.[OH-].[Na+:49]>CO>[Na+:49].[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:18]=[CH:17][C:16]([C:19]3[S:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[C:20]=3[CH2:28][C:29]3[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][N:38]4[CH2:39][CH2:40][CH2:41][CH2:42]4)=[CH:33][CH:34]=3)=[CH:15][C:10]=2[C:11]([O-:13])=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)ccc1OCCN1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C([O-])c1cc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)ccc1OCCN1CCCC1
Yield: 81 %

Procedure:
The title compound was prepared in 81% yield from methyl 2-[2-(1-pyrrolidinyl)ethoxy]-5-[3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophen-2-yl]benzoate (Part C) by saponification of a stirred solution (about 10% w/v) in 1:1 THF:MeOH with 1 N NaOH (1 equivalent) at room temperature (about 22 h). The reaction mixture was evaporated under reduced pressure and dried in a vacuum oven over P2O5 to provide the acid salt.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:19]=[C:18]3[C:12]([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)=[N:11]2)=[CH:6][CH:5]=1.[CH3:21][CH:22]([CH3:25])[CH:23]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH3:1][NH:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:19]=[C:18]3[C:12]([CH2:13][CH2:14][N:15]([CH2:21][CH:22]([CH3:25])[CH3:23])[CH2:16][CH2:17]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)C=O
Reactant: CNC(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)c1ccc(-n2cc3c(n2)CCN(CC(C)C)CC3)cc1
Temperature: 25 °C

Procedure:
A solution of N-methyl-4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzamide (may be prepared as described in Description 25) (30.0 mg, 0.11 mmol) in dichloromethane (3 ml) was treated with 2-methylpropanal (20.0 μl, 0.22 mmol) and acetic acid (1 drop) and stirred at room temperature. Sodium triacetoxyborohydride (47.0 mg, 0.22 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with methanol and passed down a SCX cartridge eluting with methanol and then a 2M solution of ammonia in methanol. The basic fractions were combined and evaporated to afford the title compound (E5); MS (ES+) m/e 327 [M+NH3]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:13](I)=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.[CH:15]1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN1C(=O)CCC1.[Sn](C)(C)(C)C>[NH4+].[Cl-].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[OH:1][CH2:2][CH2:3][C:4]1[C:13]([CH3:15])=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1
Reactant: O=C1OCc2cc(CCO)c(I)cc21
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: C[Sn](C)(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc2c(cc1CCO)COC2=O
Temperature: 50 °C

Procedure:
To a flask charged with 5-(2-hydroxyethyl)-6-iodo-2-benzofuran-1(3H)-one (6.00 g, 19.7 mmol) and a stir bar was added Pd2(dba)3 (452 mg, 0.493 mmol), PPh3 (1 g, 4 mmol) and NMP (50 mL). The mixture was purged with N2 and heated to 50° C. for 10 min, followed by addition of CuI (375 mg, 1.97 mmol). After the mixture was heated for another 10 min, Sn(CH3)4 (5.30 g, 29.6 mmol) was added into the reaction, and it was heated to 120° C. for 2 h. After cooled to room temperature, the mixture was diluted with saturated NH4Cl (200 mL) and extracted with EtOAc (3*200 mL). The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to give 5-(2-hydroxyethyl)-6-methyl-2-benzofuran-1(3H)-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].C(N(CC)CC)C.[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=O)=[CH:19][CH:18]=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(Cl)Cl.CO>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[O:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]=2)=[CH:19][CH:18]=1
Reactant: Nc1cnccc1O
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Brc1ccc(-c2nc3cnccc3o2)cc1
Reaction time: 16 h

Procedure:
To a cooled (0° C.) suspension of commercially available 4-hydroxy-3-amino-pyridine 14 (4 g, 36 mmol) in DCM (200 ml) were added triethyl amine (6.3 ml, 1.25 eq) and a solution of 4-bromo-benzoyl chloride (15, Rb=H, 8 g, 36 mmol, 1 eq, 0.3M in DCM). The reaction mixture was allowed to reach room temperature and the mixture was stirred for 16 hrs. The mixture was filtered, washed with DCM and ether to furnish crude 16 (Rb=H) as a solid material which was used in the next step without further purification. Hexachloroethane (10.2 g, 43 mmol, 2.5 eq) was dissolved in DCM (150 ml) and triphenyl phosphine (13.56 g, 51.69 mmol, 3 eq) and triethyl amine (19.2 ml, 137.8 mmol, 8 eq) was added. The mixture was stirred for minutes at room temperature and crude compound 16 (Rb=H) was added slowly in 5 equal portions. The mixture was stirred at room temperature for 64 hrs after which time TLC analysis (DCM/MeOH, 97/3, v/v, Rf 0.3) revealed complete reaction. The solution was concentrated and the residue was suspended in DCM. The mixture was filtered and the residue washed with DCM and diethyl ether to give crude 17 (Rb=H) which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:2]1.Br[CH2:33][C:34]1[O:38][N:37]=[CH:36][CH:35]=1>>[O:38]1[C:34]([CH2:33][N:1]2[CH2:2][CH:3]([CH2:5][C:6]3[N:7]([CH3:31])[C:8]4[C:13]([N:14]=3)=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=[C:10]([N:21]3[C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[N:23]=[C:22]3[CH3:30])[N:9]=4)[CH2:4]2)=[CH:35][CH:36]=[N:37]1
Reactant: BrCc1ccno1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(Cc4ccno4)C3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(8-(azetidin-3-ylmethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 5-(bromomethyl)isoxazole were reacted to give 571. LCMS m/z: 250.7 (2M+H+)
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28]([O:30]CC)=O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:20][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:30])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]=2)[CH2:22]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CC(C)(C)[Si](OC1CN(c2nc(C(=O)Nc3ccccc3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (2.00 g, 4.29 mmol) (obtained as described in Reference Example 2(1)) in toluene (100 ml) was added a solution of 0.67M aniline-trimethylaluminium in benzene (14.6 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux for 3 hours. After checking the completion of the reaction, 10% aqueous acetic acid solution (100 ml) and ethyl acetate (200 ml) were added to the reaction mixture in an ice bath and the resulting mixture was stirred at room temperature for 3 hours. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (2:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-phenylcarbamoyl-1,3-thiazol-2-yl)azetidine (2.20 g, yield 100%) as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[CH2:11](O)[CH3:12].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: O=C(O)c1cccc(Cl)n1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(Cl)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
A flask equipped with a condenser was charged with 6-chloropicolinic acid (23.5 g, 149 mmol), 100 mL of ethanol and 400 mL of toluene. To this was added 4 mL of sulfuric acid and the mixture was warmed to reflux for three hours, and then allowed to cool to ambient temperature. The reaction mixture was concentrated under reduced pressure and the resulting oil was taken up in 200 mL of ethyl acetate, washed with 10% aqueous potassium carbonate, dried over sodium sulfate and concentrated under reduced pressure to give 26 g of ethyl 6-chloropicolinate (94%).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:13])=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=1>CO>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:13])=[C:8]([CH:10]([OH:12])[CH3:11])[CH:9]=1
Reactant: CC(=O)c1cc(Br)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
Sodium borohydride (1.182 g, 51.4 mmol) was added to a stirred solution of 1-(5-bromo-2-chlorophenyl)ethanone (10 g, 42.8 mmol) in methanol at 0° C. The resulting bubbling white mixture was allowed to warm to ambient temperature and stirred for 2 h. The reaction mixture was quenched with acetone (50 mL) and concentrated by rotary evaporation. The residue was partitioned between ethyl acetate and water. The organic phase was dried and concentrated to yield the title compound (10 g, 99% yield) as a white solid: 1H NMR (CDCl3) δ 7.75 (d, 1H), 7.32 (m, 1H), 7.19 (m, 1H), 5.23 (q, 1H), 1.95 (d, 1H), 1.48 (d, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([C:18](=O)[CH:19]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)[CH3:20])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[OH-].[Na+]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH:19]([C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[CH3:20])[CH2:16][CH2:17]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C(=O)N1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(CN1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 65 °C

Procedure:
Borane tetrahydrofuran complex 1M (0.714 ml, 0.714 mmol) was added to a stirred solution of 1-[2-(4-nitrophenyl)ethyl]-4-[2-(4-nitrophenyl)propanoyl]piperazine (92 mg, 0.22 mmol) in THF then refluxed for 1 hr. LC-MS and TLC showed starting material left. More borane-THF complex 1M (0.71 ml, 0.71 mmol) was added to the reaction and refluxed for 5 hrs. The reaction was cooled and added 6N HCl and then warmed to 65° C. for 0.5 hour. The reaction was poured into 1N NaOH and extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine then dried and concentrated. The residue was purified by mass directed HPLC. LC-MS (IE, m/z): 399 [M+1]+. (0.34 μM)
Reaction SMILES: [C:1]([S:9][CH2:10][CH:11]([CH3:26])[C:12]([N:14]1[CH2:18][CH2:17][CH:16]=[C:15]1[C:19]([O:21]C(C)(C)C)=[O:20])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[C:1]([S:9][CH2:10][CH:11]([CH3:26])[C:12]([N:14]1[CH2:18][CH2:17][CH:16]=[C:15]1[C:19]([OH:21])=[O:20])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)N1CCC=C1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(CSC(=O)c1ccccc1)C(=O)N1CCC=C1C(=O)O

Procedure:
The t-butyl ester product from part (a) is treated with anisole and trifluoroacetic acid according to the procedure of Example 1(c) to yield (±)-1-[3-(benzoylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:5][CH:4]([CH2:6][C@H:7]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8](=[O:12])[C:9]([CH3:11])=[CH2:10])[CH2:3]1.[O-]Cl.[Na+].C(=O)(O)[O-:26].[Na+]>CN(C=O)C>[F:1][C:2]1([F:21])[CH2:3][CH:4]([CH2:6][C@H:7]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C:8]([C@@:9]2([CH3:11])[CH2:10][O:26]2)=[O:12])[CH2:5]1
Reactant: C=C(C)C(=O)[C@H](CC1CC(F)(F)C1)NC(=O)OC(C)(C)C
Reactant: O=C([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CC(F)(F)C1)C(=O)[C@@]1(C)CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of (S)-tert-butyl 1-(3,3-difluorocyclobutyl)-4-methyl-3-oxopent-4-en-2-ylcarbamate (0.80 g, 2.6 mmol) in DMF (20 mL) was cooled to 0° C. and 10% aqueous NaClO solution (7.90 mL, 10.6 mmol) was added while keeping the internal temperature below 5° C. The reaction mixture was stirred for 1 h at 0° C. and poured into saturated aqueous sodium bicarbonate (50 mL). The resulting mixture was extracted with EtOAc (50 mL×3). The organic extracts were combined, washed with brine (100 mL×2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=200:1 to 50:1) to afford tert-butyl ((S)-3-(3,3-difluorocyclobutyl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)carbamate (510 mg, 62% yield). 1H NMR (300 MHz, CDCl3): δ 5.02 (d, J=8.7 Hz, 1H), 4.25 (m, 1H), 3.23 (d, J=4.5 Hz, 1H), 2.93 (d, J=4.8 Hz, 1H), 2.73 (m, 2H), 2.25 (m, 3H), 1.92 (m, 1H), 1.55 (m, 1H), 1.54 (s, 3H), 1.43 (s, 9H). MS (EI) for C15H23F2NO4, found 358.14 [M+K]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[CH:7]=1.[F:17][C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20](F)[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=1)[O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Reactant: O=C(Nc1nc2ccc(O)cn2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc2ccc(Oc3cc(F)cc([N+](=O)[O-])c3)cn2n1)C1CC1
Temperature: 140 °C
Reaction time: 6 h
Yield: 485.3 %

Procedure:
A mixture of N-(6-hydroxy[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (200 mg, 0.917 mmol), 1,3-difluoro-5-nitrobenzene (437 mg, 2.75 mmol), potassium carbonate (380 mg, 2.75 mmol) and N,N-dimethylformamide (6 mL) was stirred at 140° C. for 6 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (1.59 g, 89%) as a yellow solid.
Reaction SMILES: C1([O:7][C:8](=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[CH:28][C:27]=3[F:48])[CH:22]=[CH:21][N:20]=2)C(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>CN(C)C=O>[F:48][C:27]1[CH:28]=[C:29]([NH:32][C:33]([C:35]2([C:38]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)=[O:47])[CH2:37][CH2:36]2)=[O:34])[CH:30]=[CH:31][C:26]=1[O:25][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:8]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:7])[CH:24]=1
Reactant: C1COCCN1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CCOCC1
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of [4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (80 mg) in N,N-dimethylformamide (1.0 ml) was added morpholine (0.055 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent; ethyl acetate). Fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added diethyl ether:heptane=1:2 to precipitate a solid. The solvent was concentrated under reduced pressure to provide the titled compound as white powder (52.3 mg, 81%).