Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2[C:7]([NH:26][C:27]3[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=3)=[N:8][C:9]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]3[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:10][C:5]=2[CH2:4][NH:3]1.[Cl:34]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:34][C:10]1[C:5]2[CH2:4][NH:3][C:2](=[O:1])[C:6]=2[C:7]([NH:26][C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[N:8][C:9]=1[NH:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(Cl)c3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A vial was charged with tert-butyl (1S,2R)-2-(3-oxo-4-(m-tolylamino)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (63 mg, 0.140 mmol) and N-chlorosuccinimide (18.63 mg, 0.140 mmol) in DCM (1.4 mL) to give a yellow solution. The solution was stirred for 1 h at RT. The crude reaction mixture was diluted with DCM (20 mL) and washed with saturated aq NaHCO3 (2×10 mL) followed by water (10 mL) and brine (10 mL). The organic layers were combined, dried over sodium sulfate, and concentrated to a residue which was purified by flash column chromatography. The collected fractions were concentrated to a brown residue to give the title compound as a cream colored solid upon drying (38.1 mg, 56%). [M+H] calc'd for C25H32ClN5O3, 486; found, 486.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH:2]([NH:1][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:24]([F:23])=[CH:25][CH:26]=2)=[O:35])[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[OH:4])=[CH:18][CH:17]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: CC(C)(C)c1ccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-tert-butylphenyl)-1-(3-chlorophenyl)propan-1-ol (355 mg, 1.17 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (223 mg, 1.17 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (336 mg, 1.76 mmol) and 1-hydroxybenzotriazole hydrate (179 mg, 1.17 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=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (333 mg, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][CH3:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[C:13](O)(=[O:15])[CH3:14]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6]([OH:8])=[CH:14][C:13](=[O:15])[N:11]2[CH3:12])=[CH:9][CH:10]=1
Reactant: CC(=O)O
Reactant: CNc1cc(Cl)ccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cn1c(=O)cc(O)c2ccc(Cl)cc21

Procedure:
Refluxing a solution of 4-chloro-N-methyl anthranilic acid (13.6g; 0.073 mole) in acetic acid (37 ml) and acetic anhydride (37 ml) for 6 hours and work up as described in Example 35(a) gave the title compound; m.p. (AcOH, EtOH) 308°-9°. (Found; C, 56.97; H, 4.03; N, 6.89 Cl, 16.82; C10H8NClO 2 requires; C, 57.29; H, 3.85; N, 6.68; Cl, 16.91%).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:37]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:37][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:7][CH:8]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:30][CH2:31][CH3:32])[O:33][CH2:34][CH3:35])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[N:26]=[CH:25][CH:24]=[CH:23]2)=[O:15]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Yield: 76.8 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl(S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-7) (2.41 g, 3.31 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=chloroform:methanol=100:0 and 8:2) to obtain the title compound (1.29 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: CC(=O)OCCBr
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1ccc(Cl)cc1C=O

Procedure:
5-Chloro-2-hydroxy-benzaldehyde (2 g, 12.8 mmol), acetic acid 2-bromo-ethyl ester (2.57 g, 15.4 mmol), K2CO3 (5.3 g, 38.5 mmol) and KI (0.26 g, 1.54 mmol) were mixed in DMF (20 mL). Then the reaction tube was placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated at 130° C. for 30 min. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in CH2Cl2 and the organic layer was washed with water for several times. Then the organic layer was dried over anhydrous Na2SO4 and concentrated to obtain a yellow solid. (2.7 g)
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=1.Cl[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=1.Cl>CN(C=O)C>[Cl:17][C:16]1[C:11]([O:3][C:4]2[CH:8]=[C:7]([CH3:9])[NH:6][N:5]=2)=[N:12][CH:13]=[C:14]([Cl:18])[CH:15]=1
Reactant: Cc1cc(O)n[nH]1
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ncc(Cl)cc2Cl)n[nH]1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
Sodium hydride (60% in oil, 0.2 g, 5.5 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (0.49 g, 5.0 mmol) in DMF (10 ml) at 0° C., and the mixture was stirred for 30 minutes while it was allowed to have room temperature gradually. Then, 2,3,5-trichloropyridine (0.9 g, 5.0 mmol) was added, and the mixture was stirred under heating at 70° C. for 2 days. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (20 ml) and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/7→1/2), to give a white solid of 3-(3,5-dichloropyridin-2-yloxy)-5-methylpyrazole (0.7 g, yield: 57.4%). mp: 109-111° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.32 (s, 3H), 5.86 (s, 1H), 7.77 (d, J=2.3 Hz, 1H), 8.03 (d, J=2.3 Hz, 1H), 9.40-11.50 (br s, 1H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][NH:4][C:5](=[O:22])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][O:16]C(=O)C)[C:7]=1[OH:21]>[OH-].[Na+]>[F:24][C:2]([F:1])([F:23])[CH2:3][NH:4][C:5](=[O:22])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][OH:16])[C:7]=1[OH:21]
Reactant: CC(=O)OCC(=O)Nc1cc(F)cc(C(=O)NCC(F)(F)F)c1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(CO)Nc1cc(F)cc(C(=O)NCC(F)(F)F)c1O
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
5.9 g (17 mmol) of 3-acetoxyacetamido-5-fluoro-2-hydroxy-benzoic acid-(2,2,2,-trifluoro-ethyl)amide is dissolved in 34 ml of 1N NaOH and stirred for 30 minutes at 40° C. The reaction solution is then cooled to room temperature and filtered over 200 ml of cation exchanger. The eluate is evaporated to dryness in a vacuum and the residue is chromatographed on silica gel 60 with ethyl acetate/acetone. 3.3 g=62.7% of the theoretical yield is obtained as an amorphous material.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[F:27][C:28]1[N:33]=[CH:32][C:31]([C:34]2([CH2:40]O)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>ClCCl>[F:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2([CH2:40][I:20])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:32][N:33]=1
Reactant: II
Reactant: OCC1(c2ccc(F)nc2)CCOCC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(C2(CI)CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.6 %

Procedure:
To an ice cooled solution of triphenylphosphine (983 mg, 3.75 mmol), iodine (952 mg, 3.75 mmol) in dichloromethane (20 mL) was added imidazole (278 mg, 4.09 mmol). The solution was stirred at ambient temperature for 1 h, followed by the addition of (4-(6-fluoropyridin-3-yl)tetrahydro-2H-pyran-4-yl)methanol (360 mg, 1.70 mmol) in 10 mL dichloromethane. The reaction mixture was heated to 60° C. in an oil bath for 48 h. Solid was filtered off, the filtrate was purified by flash column chromatography on silicagel (ISCO) eluting with 0-80% ethyl acetate in heptane to give to give 2-fluoro-5-(4-(iodomethyl)tetrahydro-2H-pyran-4-yl)pyridine (330 mg, 1.03 mmol, 60.3% yield) as light yellow color oil. LCMS (m/z): 322 (MH+), 0.77 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([O:16]CC)=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].C(O)C.[OH-].[K+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([OH:16])=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25]
Reactant: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(Cl)ccc2n(C)c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(=O)c(C(=O)O)c(-c2ccccc2Cl)c2cc(Cl)ccc21
Yield: 99.7 %

Procedure:
A mixture of ethyl 6-chloro-4-(2-chlorophenyl)-1,2-dihydro -1-methyl-2-oxoquinoline-3-carboxylate (1.3 g), ethanol (6.0 ml) and potassium hydroxide (0.6 g) was refluxed for 15 minutes. The mixture was diluted with water and acidified by addition of 2N-hydrochloric acid. The precipitated crystals were collected and recrystallized from ethanol to obtain colorless plates of 6-chloro-4-(2-chlorophenyl) -1,2-dihydro-1-methyl-2-oxo-3-quinolinecarboxylic acid (1.20 g, 85.0%). mp 197°-198° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[I:11].Cl[CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[O:16]([CH2:15][CH2:14][CH2:13][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[C:5]([I:11])=[N:6]1)[Si:17]([C:20]([CH3:22])([CH3:21])[CH3:23])([CH3:18])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCCCl
Reactant: Fc1ccc2[nH]nc(I)c2c1
Product: CC(C)(C)[Si](C)(C)OCCCn1nc(I)c2cc(F)ccc21
Yield: 79 %

Procedure:
The title compound was prepared from 5-fluoro-3-iodo-indazole and (3-chloropropoxy)tert-butyldimethylsilane (Org. Lett., 2000, 3473) in 79% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 0.06 (6H, s), 0.89 (9H, s), 2.07-2.13 (2H, m), 3.55 (2H, t, J=6.0 Hz), 4.49 (2H, t, J=6.0 Hz), 7.10 (1H, dd, J=2.4, 8.4 Hz), 7.18 (1H, td, J=2.4, 8.8 Hz), 7.40 (1H, dd, J=4.0, 8.8 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12]([NH2:15])(=[O:14])=[O:13].[H-].[Na+].[OH2:18]>C(OCC)(=O)C>[Cl:11][C:4]1[C:3]([S:12]([NH2:15])(=[O:14])=[O:13])=[C:2]([OH:18])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Temperature: 45 °C
Reaction time: 72 h
Yield: 76.8 %

Procedure:
A mixture of 2,6-dichloro-3-nitrobenzenesulfonamide (2.61 g, 9.64 mmol), 60% sodium hydride (1.15 g, 28.9 mmol) and water (174 μL, 9.64 mmol) was heated to 45° C. while kept at argon atmosphere for 3 days. The reaction was monitored by 1H NMR. 0.1 equivalent water was added to the mixture when the reaction was not completed. The solvent was evaporated when the reaction almost completed indicated by 1H NMR. The residue was diluted with ethyl acetate and washed with 1N aq. HCl. The solvent was concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate/hexane/acetic acid (50/48/2, v/v/v), gave the desired product (1.87 g, 77%). EI-MS (m/z)250.84, 252.89 (M−).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: O=C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)c2cccs2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a mixture of 2-piperazinone (0.98 g, 9.79 mmol, Sigma-Aldrich, St. Louis, Mo.) and triethylamine (Aldrich, 2.0 mL, 14.35 mmol) in CH2Cl2 (20 mL) at 0° C. was added a solution of 2-thiophenesulfonyl chloride (1.79 g, 9.79 mmol, Sigma-Aldrich, St. Louis, Mo.) in CH2Cl2 (10 mL). After 30 min, the mixture was diluted with saturated aqueous NaHCO3 (10 mL) and stirred at room temperature for 3 d. The slurry was filtered and washed with water (3×5 mL) to give 4-(2-thiophenylsulfonyl)-2-piperazinone as a white powder (2.1 g).
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][O:33][C:34](=[O:44])[C:35]([CH3:43])=[CH:36][CH:37]([NH:41][CH3:42])[CH:38]([CH3:40])[CH3:39]>C(Cl)Cl>[CH3:32][O:33][C:34](=[O:44])[C:35]([CH3:43])=[CH:36][CH:37]([N:41]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH3:42])[CH:38]([CH3:40])[CH3:39]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CNC(C=C(C)C(=O)OC)C(C)C
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(C)C(C=C(C)C(=O)OC)C(C)C)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 2,5-dimethyl-4-methylamino-hex-2-enoic acid methyl ester (86 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 630 (M+).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[NH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]3[CH:3]=[C:2]([NH:30][C:31]4[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=4)[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:28])([CH3:27])[CH3:29]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: N#Cc1ccc(N)cc1
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(C#N)cc4)cc3n2C(=O)OC(C)(C)C)cn1

Procedure:
The title compound was prepared from tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (10) (50 mg, 0.108 mmol) and 4-aminobenzonitrile (15.3 mg, 0.13 mmol, 1.2 eq) using the method described for Preparation 35 and using silica gel column chromatography eluting with EtOAc:hexane:triethylamine 10:10:1 (9 mg, 17%). 1H-NMR (500 MHz, CDCl3) 1.53 (s, 9H), 1.69 (s, 9H), 6.62 (s, 1H), 6.93 (s, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.74 (s, 1H), 7.83 (s, 1H), 8.23 (s, 1H), 8.54 (s, 1H).
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[SH:43][C@@H:44]1[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])[C@H:46]([CH:62]2[CH2:66][CH2:65][N:64]([C:67]([O:69][CH2:70][C:71]3[CH:76]=[CH:75][C:74]([N+:77]([O-:79])=[O:78])=[CH:73][CH:72]=3)=[O:68])[CH2:63]2)[CH2:45]1>>[OH:40][C@@H:38]([C@H:37]1[C:36](=[O:41])[N:21]2[C:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])=[C:18]([S:43][C@@H:44]3[CH2:48][N:47]([C:49]([O:51][CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N+:59]([O-:61])=[O:60])=[CH:57][CH:58]=4)=[O:50])[C@H:46]([CH:62]4[CH2:66][CH2:65][N:64]([C:67]([O:69][CH2:70][C:71]5[CH:72]=[CH:73][C:74]([N+:77]([O-:79])=[O:78])=[CH:75][CH:76]=5)=[O:68])[CH2:63]4)[CH2:45]3)[C@H:19]([CH3:42])[C@H:20]12)[CH3:39]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 77.7 %

Procedure:
The same procedure as in Example 1--1 was carried out by using p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (1.39 g, 2.34 mmol) and (2S,4S)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidine (1.24 g, 2.34 mmol, compound of Reference Example 5-6) to obtain p-nitrobenzyl (IR,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-N-(p-nitrobenzyloxycarbonyl)-2-[N-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]pyrrolidin-4ylthio]-1-carbapen-2-em-3-carboxylate (1.59 g, yield: 77.7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C@@H:10]([OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]([F:43])([F:42])[C:23]1[CH:24]=[C:25]([C@@H:33](OC(=N)C(Cl)(Cl)Cl)[CH3:34])[CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1>>[F:21][C:22]([F:42])([F:43])[C:23]1[CH:24]=[C:25]([C@H:33]([O:20][C@@H:10]2[C@@H:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)[CH3:34])[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1
Reactant: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@H](c2ccc(F)cc2)[C@@H](O)C1
Product: C[C@@H](O[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared from (3R,4S) tert-butyl-3-hydroxy-4-(4-fluorophenyl)pyrrolidine-1-carboxylate (Step B, Rt 13.686 min) and (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroethanimidoate (Example 1, step C) according to the procedure for Example 1, Step D. The product mixture was further purified by preparative HPLC on ChiralPak OD column eluting with heptanes/ethanol (98/2) to obtain the faster moving minor isomer (epimeric at the benzylic methyl position) and slower moving title compound. 1H-NMR (CDCl3): (rotamers): δ: 1.43-47 (2d, 3H, 6.5 Hz), 1.49-1.52 (2s, 9H), 3.3-3.5 (m, 3H), 3.75-3.95 (m, 3H), 4.53 (q, 1H, 6.5 Hz), 6.95 (t, 2H), 7.05 (m, 2H), 7.53 (s, 2H), 7.76 (s, 1H)ppm. MS: 466 (M-t-Bu)+ observed.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[C:17]4[CH:25]=[CH:24][CH:23]=[CH:22][C:18]4=[CH:19][CH:20]=3)[O:15][C:14]([NH2:26])=[C:13]2[C:27]2[N:31]=[C:30]([CH2:32]Cl)[O:29][N:28]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[CH2:34]([N:36](CC)CC)C.CN>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[C:17]4[CH:25]=[CH:24][CH:23]=[CH:22][C:18]4=[CH:19][CH:20]=3)[O:15][C:14]([NH2:26])=[C:13]2[C:27]2[N:31]=[C:30]([CH2:32][NH:36][CH3:34])[O:29][N:28]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: COc1cc(C2C(c3noc(CCl)n3)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC
Reactant: CCN(CC)CC
Agent: CN
Solvent: CC#N
Solvent: O
Product: CNCc1nc(C2=C(N)Oc3c(ccc4ccccc34)C2c2cc(Br)c(OC)c(OC)c2)no1
Temperature: 25 °C

Procedure:
4-(3-Bromo-4,5-dimethoxy-phenyl)-3-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-4H-benzo[h]chromen-2-ylamine (24) (528 mg, 1 mmol) and triethylamine (140 μl, 1 mmol) and 2M methanolic solution of methylamine (600 μl, 1.2 mmol) is taken in acetonitril (10 ml) and stirred at room temperature under LC-MS control till the reaction is complete. The reaction mixture is diluted with water to about 50 ml and stirred for 2 h at room temperature. Thus resulting precipitates are separated by filtration, washed well with water and is dried under high vacuum to get solids of the title compound.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[N:7]2[C:8]3[CH:27]=[CH:26][CH:25]=[N:24][C:9]=3[O:10][C:11]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:2]([F:1])([F:29])[C:3]1[N:7]2[C:8]3[CH:27]=[CH:26][CH:25]=[N:24][C:9]=3[O:10][C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:6]2=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1c(C(F)(F)F)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc2n1-c1cccnc1OC21CCNCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
To a solution of tert-butyl 9′-(trifluoromethyl)spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine]-1-carboxylate (83 mg, 0.20 mmol) in CH2Cl2 (3 mL) was added TFA (1.0 mL, 13 mmol) and the mixture was stirred at room temperature for 15 min before being evaporated to dryness. The residue was taken up in EtOAc and sat. aq. Na2CO3, the layers were separated, and aqueous layer was extracted with EtOAc (2×). The organics were combined, washed with sat. aq. Na2CO3, brine, dried (Na2SO4) and evaporated to dryness to give 9′-(trifluoromethyl)-spiro[piperidine-4,6′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazine] as a pale yellow solid (59 mg). ESI-MS m/z calc. 309.1, found 310.3 (M+1)+; Retention time: 1.32 minutes (3 min run).