Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:10]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([CH:34]=1)[O:30][CH2:31][CH:32]=O.[BH4-].[Na+]>CO>[F:24][C:25]1[CH:26]=[CH:27][C:28]([O:35][CH3:36])=[C:29]([CH:34]=1)[O:30][CH2:31][CH2:32][NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:10]=1
Reactant: COc1ccc(F)cc1OCC=O
Reactant: COc1ccc(CCN)cc1S(N)(=O)=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(F)cc1OCCNCCc1ccc(OC)c(S(N)(=O)=O)c1
Temperature: 75 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
A suspension of 1.50 g of 5-(2-aminoethyl)-2-methoxybenzenesulfonamide hydrochloride and 0.8 ml of triethylamine in 50 ml of methanol was heated for 30 minutes at 75° C. To the reaction mixture was added 1.00 g of 2-(5-fluoro-2-methoxyphenoxy)acetaldehyde and the reaction mixture was heated for 10 minutes at 75° C. To the solution was added 0.45 g of sodium borohydride under ice cooling and the solution was stirred for 1 hr at room temperature. The reaction mixture was evaporated, acidified with 10% hydrochloric acid and washed with ether. The aqueous layer was made alkaline with potassium carbonate and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was solidified with a mixture of methanol and ether and the precipitate was filtered to give 0.46 g of the desired compound as pale brown crystals which were recrystallized from N,N-dimethylformamide as pale yellow crystals, m.p. 201°-205° C.
Reaction SMILES: [C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](C)[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23]C1C=C2C(=CC=1)N(CC)C(=O)C2=O>>[C:1]([O:9][CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:23])[CH:17]=2)[N:12]([CH2:20][CH3:21])[C:11]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN1C(=O)C(=O)c2cc(Cl)ccc21
Reactant: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(C)ccc21
Product: CCN1C(=O)C(OC(=O)c2ccccc2)c2cc(Cl)ccc21

Procedure:
Was made in an analogous fashion to 1-ethyl-5-methyl-2-oxoindolin-3-yl benzoate using 5-chloro-1-ethylindoline-2,3-dione. 1H-NMR δ 8.11 (dd, 2H), 7.60 (dt, 1H), 7.47 (m, 2H) 7.45 (m, 1H), 7.33 (dd, 1H), 6.80 (d, 1H), 6.10 (d, 1H), 3.85 (m, 2H), 1.33 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]([CH2:11][N+:12]([O-])=O)[O:8][B:7]([OH:15])[C:6]=2[C:5]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:4][CH:3]=1.N>CCO.[Ni]>[NH2:12][CH2:11][CH:9]1[O:8][B:7]([OH:15])[C:6]2[C:5]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]1=2
Reactant: CC(C)(C)OC(=O)NCCCOc1ccc(Cl)c2c1B(O)OC2C[N+](=O)[O-]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCOc1ccc(Cl)c2c1B(O)OC2CN
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl 3-(4-chloro-1-hydroxy-3-(nitromethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-7-yloxy)propylcarbamate (480 mg, 1.2 mmol), Raney-Ni (500 mg) and 2 M NH3 in EtOH (3 mL) in EtOH (15 mL) was shaken under an atmosphere of H2 for 2 h at room temperature. The mixture was filtered through a bed of Celite and the filtrate was concentrated in vacuo. The resulting solid was used directly for the next step.
Reaction SMILES: [Li][CH2:2]CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:25]=[CH:24][C:20]2[N:21]=[CH:22][S:23][C:19]=2[CH:18]=1.CN(C)P(N(C)C)(N(C)C)=O.CI>O1CCCC1.[NH4+].[Cl-]>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:25]=[CH:24][C:20]2[N:21]=[CH:22][S:23][C:19]=2[CH:18]=1)[CH3:2]
Reactant: [Li]CCCC
Reactant: COC(=O)Cc1ccc2ncsc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(C)c1ccc2ncsc2c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A solution of n-BuLi (2.5M in hexane, 27.0 ml) was added to a stirred solution of diisopropylamine (7.08 g, 70.0 mmol) in anhydrous tetrahydrofuran (150 ml) cooled to −30° C. under a nitrogen atmosphere. The mixture was stirred for 30 minutes the reaction mixture was cooled to −78° C. To this solution was added a solution of benzothiazol-6-yl-acetic acid methyl ester (10.4 g, 50.0 mmol) in 10 ml of tetrahydrofuran and hexamethylphosphoramide (13.5 g, 75.0 mmol). The mixture was stirred at −78° C. for 2 hours before the addition of a solution of methyl iodide (10.2 g, 72.0 mmol) in anhydrous tetrahydrofuran at −78° C. The mixture was stirred for a further 2 hours at −78° C. The reaction mixture was warmed slowly to room temperature and diluted with aqueous saturated solution of NH4Cl (200 ml). The mixture was extracted with ethyl acetate (×2) and the combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give brown oil. This oil was purified via flash column chromatography eluting with petroleum and ethyl acetate (10:1) to return the title compound as a pale yellow oil (4.5 g, 40.5%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][C@H:4]([CH3:18])[N:3]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].[Cl-].[NH4+]>CO.O.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH2:5][C@H:4]([CH3:18])[N:3]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C@H:2]([CH3:1])[CH2:7]2)=[CH:10][CH:11]=1
Reactant: C[C@@H]1CN(Cc2ccc([N+](=O)[O-])cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: C[C@@H]1CN(Cc2ccc(N)cc2)C[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 70.4 %

Procedure:
To a solution of 1,1-dimethylethyl (2R,6S)-2,6-dimethyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D27) (2.62 g, 7.53 mmol) in MeOH (25 ml) and water (25 ml) heated to 80° C. was added iron powder (1.26 g, 22.54 mmol) and ammonium chloride (2.01 g, 37.58 mmol). The reaction was stirred vigorously at 80° C. for 1.5 h and then the iron residues removed by filtration through Celite®. The filtrate was concentrated and the residue partitioned between DCM and water. The aqueous layer was further extracted with DCM (×2) and the combined organics were dried and concentrated to give the crude product as a yellow foam (2.01 g). Column chromatography eluting with 0-100% Et2O/petroleum ether gave the title compound (1.694 g). δH (CDCl3, 400 MHz) 7.12 (2H, d), 6.64 (2H, d), 4.05 (2H, m), 3.64 (2H, br. s), 3.36 (2H, s), 2.59 (2 h, d), 2.06 (2H, dd), 1.46 (9H, s), 1.27 (6H, d). MS (ES): MH+ 320.3, MNa+ 342.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([C@@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][OH:19])[C:13]=3[CH:26]=2)[CH:5]=[C:4]([F:27])[C:3]=1[C:28]([F:31])([F:30])[F:29]>C(Cl)(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[N:15][N:14]([C@@H:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[O:19])[C:13]=3[CH:26]=2)[CH:5]=[C:4]([F:27])[C:3]=1[C:28]([F:31])([F:30])[F:29]
Reactant: OC[C@H](c1ccccc1)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=C[C@H](c1ccccc1)n1nnc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc21
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A mixture of (S)-6-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]-β-phenyl-1H-benzotriazole-1-ethanol (1.0 g, 0.0022 mole) in chloroform is treated with MnO2, (1.0 g, 0.0115 mole) stirred at 40° C. for 18 hours and filtered through a bed of diatomaceous earth. The filtrate is concentrated in vacuo to give a residue which is chromatographed using silica gel and 10% tetrahydrofuran in carbon tetrachloride to yield the title product as a white solid, 0.42 g, mp 84°-85° C., characterized by elemental and NMR analyses.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@H:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][O:10][C:9]2=[O:19])[CH:5]=[CH:4][N:3]=1.[CH:20]1([C@@H:23]([NH2:25])[CH3:24])[CH2:22][CH2:21]1>CN1C(=O)CCC1>[CH:20]1([C@@H:23]([NH:25][C:2]2[N:7]=[C:6]([N:8]3[C@H:12]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH2:11][O:10][C:9]3=[O:19])[CH:5]=[CH:4][N:3]=2)[CH3:24])[CH2:22][CH2:21]1
Reactant: C[C@H](N)C1CC1
Reactant: O=C1OC[C@@H](c2ccccc2)N1c1ccnc(Cl)n1
Solvent: CN1CCCC1=O
Product: C[C@H](Nc1nccc(N2C(=O)OC[C@H]2c2ccccc2)n1)C1CC1
Temperature: 180 °C
Yield: 13.6 %

Procedure:
A mixture of (R)-3-(2-chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one (55.3 mg, 0.20 mmol), (S)-1-cyclopropylethylamine (40 μL, 0.26 mmol, 1.3 equiv) and iPr2Net (0.20 mL, 1.15 mmol, 5.7 equiv) in NMP (1 mL) was heated in the microwave at 180° C. for 20 min. The reaction mixture was filtered and purified by reverse phase HPLC to give (R)-3-(2-(((S)-1-cyclopropylethyl)amino)pyrimidin-4-yl)-4-phenyloxazolidin-2-one as a white solid (8.8 mg) in 10% yield. 1H NMR (400 MHz, CD3OD) δ 7.72 (d, J=6.26 Hz, 1H), 7.29-7.43 (m, 6H), 5.76 (dd, J=4.11, 8.80 Hz, 1H), 4.28 (dd, J=4.30, 8.61 Hz, 1H), 3.06-3.19 (m, 1H), 1.39 (dd, J=3.52, 6.65 Hz, 1H), 0.88-0.97 (m, 1H), 0.83 (br. s., 3H), 0.53-0.62 (m, 1H), 0.50 (dt, J=4.11, 8.51 Hz, 1H), 0.33 (qd, J=4.78, 9.54 Hz, 1H), 0.26 (td, J=4.60, 9.59 Hz, 1H); HRMS(A) m/z 325.1667 (M+H)+, Rt 1.54 min; UPLC 2.807 min.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[N:16]=[CH:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:19]N1C(=O)CCC1=O>O1CCCC1>[Br:19][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[N:16]=[CH:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2ncnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2ncnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
To the mixture of 4-pentyl-1,4-dihydro-9H-[1,2,4]triazolo[1,5-a]purin-9-one (19 mg, 0.077 mmol) in tetrahydrofuran (10 mL) was added N-bromosuccinimide (20 mg, 0.12 mol) at rt. The mixture was stirred at 70° C. for 1 hour. The mixture was concentrated and purified by preparative LCMS to yield the desired product (3.10 mg, 12.4%). LCMS calculated for C11H14BrN6O (M+H): 325.0. Found: 325.0, 327.0.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:16]C.Cl.N1C=CC=CC=1>Cl>[OH:16][C:3]1[CH:4]=[C:5]([C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[OH:1]
Reactant: COc1cc(C(=O)C(C)C)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)C(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
8.0 g of 4'-hydroxy-3'-methoxy-2-methyl-5'-nitropropiophenone are treated with 64 g of pyridine hydrochloride and stirred at 180° for 45 minutes. After cooling the reaction mixture is poured into 500 ml of ice-water, whereupon it is made acid with 20 ml of 3N hydrochloric acid and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate and evaporated in a water-jet vacuum. After crystallization from methylene chloride/n-hexane there is obtained 3',4'-dihydroxy-2-methyl-5'-nitropropiophenone in the form of yellow crystals of m.p. 98°-99°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C@H:4]([CH2:37][CH:38]([CH3:40])[CH3:39])[NH:5][C:6](=[O:36])[C@@H:7]([CH3:35])[NH:8][C:9](=[O:34])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)[NH:11]C(OC(C)(C)C)=O.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[CH3:1][O:2][C:3](=[O:41])[C@H:4]([CH2:37][CH:38]([CH3:40])[CH3:39])[NH:5][C:6](=[O:36])[C@@H:7]([CH3:35])[NH:8][C:9](=[O:34])[C@H:10]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)[NH2:11]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1

Procedure:
Nα-t-butoxycarbonyl-O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester, 5.7 g., 10 mmol, in 20 ml. of dichloromethane and 50 ml. of trifluoroacetic acid are reacted together for 10 minutes at 25° C. The solution is evaporated and the residual oil used directly.
Reaction SMILES: C([C:5]1[CH:6]=[C:7](C(C)(C)C)[C:8]2[O:12][C:11](=[O:13])[CH:10](O)[C:9]=2[CH:15]=1)(C)(C)C.CC1C=CC=CC=1C>O>[O:12]1[C:8]2[CH:7]=[CH:6][CH:5]=[CH:15][C:9]=2[CH2:10][C:11]1=[O:13]
Reactant: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OC(=O)C2O
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1Cc2ccccc2O1

Procedure:
To a solution of 262.3 g (1.00 mol) of 5,7-di-tert-butyl-3-hydroxy-3H-benzofuran-2-one (compound (201), Table 2, Example 1a) in 500 ml (4.05 mol) of o-xylene are added 40 g of Fulcat 22B and the mixture is refluxed for 1.5 hours on a water separator. The Fulcat 22B catalyst is then removed by filtration and excess p-xylene is removed by distillation on a vacuum rotary evaporator. Crystallisation of the residue from 500 ml of methanol yields 244 g (69%) of 3-(3,4-dimethylphenyl)-5,7-di-tert-butyl)-3H-benzofuran-2-one, m.p. 130°-132° C. (compound (103), Table 1), which additionally contains c. 1.3% of the structural isomer [3-(2,3-dimethylphenyl)-5,7-di-tert-butyl-3H-benzofuran-2-one, compound (103A)]. The mother liquor yields a further 42.4 g of product which, according to GC-MS analysis, consists of 12.3% of the compound (103) and 87.7% of the isomeric compound (103A).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:12][C:13](=O)[CH3:14])[CH:6]=1)[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([NH:25]N)[CH:21]=[CH:22][C:23]=1[F:24]>>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:21]3[C:20](=[CH:19][C:18]([Cl:17])=[C:23]([F:24])[CH:22]=3)[NH:25][C:13]=2[CH3:14])[CH:6]=1)[CH3:2]
Reactant: NNc1ccc(F)c(Cl)c1
Reactant: CCOC(=O)c1cccc(SCC(C)=O)c1
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)c(F)cc23)c1

Procedure:
Prepared according to the procedure described in Example 2, step 1, using the following starting materials: 3-(2-Oxo-propylsulfanyl)-benzoic acid ethyl ester and (3-Chloro-4-fluoro-phenyl)-hydrazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][C:16]=1[F:17])[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:18])[C:6]([C:19](OCC)=[O:20])=[C:5]2[OH:24].C(N(C(C)C)C(C)C)C.Cl.[NH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][C:16]=1[F:17])[C:8]1([CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[C:7](=[O:18])[C:6]([C:19]([NH:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:20])=[C:5]2[OH:24]
Reactant: CCOC(=O)C1=C(O)c2cc(F)c(F)cc2C2(CCOCC2)C1=O
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(F)c(F)cc2C2(CCOCC2)C1=O
Reaction time: 0.17 h

Procedure:
Ethyl 6,7-difluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (1.06 g, 3133 μmol) was dissolved in 1,4-dioxane (3133 μL) and N-ethyl-N-isopropylpropan-2-amine (1637 μL, 9400 μmol). tert-Butyl 2-aminoacetate hydrochloride (788 mg, 4700 μmol) was added, and the reaction was placed in a microwave at 140° C. for 10 minutes. The reaction mixture was then diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound as a white solid after purification via preparatory LC. MS (m/z)=424 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([F:11])[CH:6]=1)[OH:4].[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37](O)=[O:38])=[CH:29][CH:28]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][N:8]=[C:7]([F:11])[CH:6]=2)[OH:4])=[O:38])=[CH:29][CH:28]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccnc(F)c1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2-fluoropyridin-4-yl)-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propan-1-ol (194 mg, 0.54 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (101 mg, 0.54 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 mg, 0.80 mmol) and 1-hydroxybenzotriazole hydrate (82 mg, 0.54 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (189 mg, 66%).
Reaction SMILES: [Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](Cl)=[O:6].[C:10]([C:14]1[CH:15]=[C:16]([NH2:35])[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:20]=2)[N:18]=1)([CH3:13])([CH3:12])[CH3:11]>>[Cl:1][C:2]([Cl:9])([Cl:8])[CH2:3][O:4][C:5](=[O:6])[NH:35][C:16]1[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)[CH:20]=2)[N:18]=[C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:15]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1

Procedure:
The title compound was prepared starting from 2,2,2-trichloroethylchloroformate and Intermediate 4a by using an analogous procedure to that described for Example 3 step c. LCMS (Method 4): Rt 3.85, m/z 536 [MH+].
Reaction SMILES: Cl[C:2]1[C:3]([C:20]([NH2:22])=[O:21])=[N:4][C:5]([CH2:18][CH3:19])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:7]=1.[CH3:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH2:26].C(N(C(C)C)CC)(C)C.CN1CCCC1=O>O>[CH2:18]([C:5]1[N:4]=[C:3]([C:20]([NH2:22])=[O:21])[C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:30][C:24]=2[CH3:23])=[N:7][C:6]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH3:19]
Reactant: Cc1cc(N2CCOCC2)ccc1N
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Oc1cccc([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCOCC3)cc2C)nc1Oc1cccc([N+](=O)[O-])c1
Yield: 36 %

Procedure:
A mixture of 3-chloro-6-ethyl-5-(3-nitrophenoxy)pyrazine-2-carboxamide (300 mg), 2-methyl-4-(morpholin-4-yl)aniline (200 mg), diisopropylethylamine (330 μL), and N-methylpyrrolidone (2 mL) was reacted in a microwave reaction device at 180° C. for 2 hours. The reaction mixture was left to be cooled, and then 5 mL of water was added thereto. The precipitated solid was collected by filtration and purified by silica gel column chromatography (eluent; ethyl acetate:hexane=1:9-7:3) to obtain 6-ethyl-3-{[2-methyl-4-(morpholin-4-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (160 mg) as a brown solid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[F:26][C:27]1[CH:32]=[C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])[CH:30]=[C:29]([F:38])[C:28]=1[C:39]1[N:44]=[C:43]([C:45](O)=[O:46])[CH:42]=[CH:41][C:40]=1[F:48]>>[NH2:9][C@H:8]1[C@H:2]([OH:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:45](=[O:46])[C:43]2[CH:42]=[CH:41][C:40]([F:48])=[C:39]([C:28]3[C:29]([F:38])=[CH:30][C:31]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:32][C:27]=3[F:26])[N:44]=2)[CH2:6][CH2:7]1
Reactant: COCCOc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](O)CO1
Product: COCCOc1cc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](O)CO3)ccc2F)c(F)c1
Yield: 71 %

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3S,4R,7S)-3-hydroxy-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 94), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-5-fluoropicolinic acid (see US2012/225062) gave 191 as a white solid (73 mg, 71%). 1H NMR (400 MHz, d6-DMSO) δ 10.22 (s, 1H), 8.25 (dd, J=8.6, 4.0 Hz, 1H), 8.12 (t, J=8.9 Hz, 1H), 7.82 (s, 1H), 6.97 (d, J=10.2 Hz, 2H), 4.79 (dd, J=10.8, 3.4 Hz, 2H), 4.26-4.20 (m, 2H), 3.90-3.67 (m, 4H), 3.73-3.67 (m, 2H), 3.63 (dd, J=12.8, 5.8 Hz, 1H), 3.62-3.02 (m, 3H), 2.73-2.64 (m, 1H), 2.00-1.92 (m, 1H), 1.92-1.79 (m, 1H), 1.79-1.72 (m, 1H), 1.55-1.42 (m, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 536 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.ON1C2C=CC=CC=2N=N1.[F:44][C:45]([F:61])([F:60])[C:46]1[CH:47]=[C:48]([CH2:56][C:57](O)=[O:58])[CH:49]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:51]=1.Cl.CN(C)CCCN=C=NCC>C(#N)C>[F:44][C:45]([F:60])([F:61])[C:46]1[CH:47]=[C:48]([CH2:56][C:57]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:58])[CH:49]=[C:50]([C:52]([F:53])([F:54])[F:55])[CH:51]=1
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and 3,5-di-(trifluoromethyl)-phenylacetic acid (0.7 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The reaction mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (40 mL), 1NHCl (2×30 mL), water (40 mL), and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (eluent:EtOAc: CH2Cl2 3:7) to afford 2-(3,5-bis-trifluoromethyl-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.6 g, 54%) as a white solid: mp 202-204° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=13.69 min. (97%); 1H NMR (DMSO-d6) δ 2.03-2.08 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.92 (m, 1H), 3.82 (s, 2H), 4.75 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.67-7.83 (m, 3H), 8.00 (s, 3H), 8.82 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) δ 21.93, 30.89, 37.91, 40.88, 48.83, 117.94, 120.21 (120.26, 120.31), 121.98, 117.94 (121.55, 125.17, 128.75), 127.19, 130.14, 129.28 (129.71, 130.57), 131.54, 133.27, 134.60, 138.86, 139.45, 166.87, 167.39, 169.43, 169.76, 172.71; Anal. Calcd. for C24H17N3O5F6: C, 53.24; H, 3.16; N, 7.76; F, 21.05. Found: C, 53.16; H, 2.99; N, 7.73; F, 21.14.