Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[C:32]([OH:34])=[O:33].C([O-])(O)=O.[Na+]>C1COCC1.O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[C:32]([OH:34])=[O:33])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCCN1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)C1CCCCN1C(=O)c1cccc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 27 %

Procedure:
Triethylamine (3.36 ml) was added to a stirred solution of 3-benzyloxybenzoic acid (5.0 g) and isobutyl chloroformate (3.13 ml) in THF (67 ml) under ice-cooling and the resulting mixture was stirred at the same temperature for 1 hour. A solution of 2-piperidinecarboxylic acid (4.14 g) and NaHCO3 (3.32 g) in water (40 ml) was added dropwise to the stirred mixture at the same temperature and the mixture was stirred at the same temperature for 2 hours and at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and 1N HCl. The organic layer was separated, washed with 1N HCl (twice) and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford 1-(3-benzyloxybenzoyl)-2-piperidinecarboxylic acid (2.01 g) as a amorphous powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[N:13][C:12]([N:15]([CH2:23][C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)([CH3:26])[CH3:25])C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)=[N:7][CH:8]=1)#[N:2].OO.C(=O)([O-])[O-:37].[K+].[K+].Cl.O1CCOCC1>O.C(OCC)(=O)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([C:24]([CH3:25])([CH3:26])[CH2:23][NH:15][C:12]2[N:13]=[N:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:37])=[CH:8][N:7]=3)=[CH:10][CH:11]=2)=[CH:32][CH:31]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N(CC(C)(C)c1ccc(F)cc1)c1ccc(-c2ccc(C#N)cn2)nn1
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(CNc1ccc(-c2ccc(C(N)=O)cn2)nn1)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a 20 dram vial was added crude tert-butyl 6-(5-cyanopyridin-2-yl)pyridazin-3-yl(2-(4-fluorophenyl)-2-methylpropyl)carbamate, hydrogen peroxide (2 mL), and potassium carbonate (150 mg). The reaction was stirred for 30 min and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with brine (20 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was subsequently treated with 4N HCl/dioxane (1 mL). The reaction was stirred for 1 h at room temperature, concentrated, quenched with aqueous sodium bicarbonate, and extracted with ethyl acetate (20 mL). The organic layer was then dried (Na2SO4), filtered, and concentrated to give a crude solid that was purified by reverse phase column chromatography to afford 10 mg of 6-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)nicotinamide, m/z=366.1 [M+H].
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C:9](=[O:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23].[CH3:24][Li].[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[N:3]=[C:4]2[C:13]3[NH:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C@@H:10]([OH:20])[C@:9]([CH3:24])([OH:21])[C:8]=3[CH:7]=[CH:6][N:5]2[C:22]=1[CH3:23]
Reactant: Cc1nc2c3c(ccn2c1C)C(=O)[C@H](O)[C@@H](c1ccccc1)N3
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nc2c3c(ccn2c1C)[C@@](C)(O)[C@H](O)[C@@H](c1ccccc1)N3

Procedure:
3.5 g of (8R,9R)-2,3-dimethyl-8-hydroxy-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one are suspended in 70 ml of tetrahydrofuran under argon and treated dropwise at −50° C. with a solution of methyllithium (1.6M solution in diethyl ether). The temperature is then allowed to rise to room temperature, and the mixture is poured into a saturated aqueous ammonium chloride solution and extracted three times with 100 ml of dichloromethane each time. The combined organic phases are washed with a little water, dried over sodium sulfate and concentrated to dryness in vacuo. The oily residue obtained is chromatographed on silica gel (eluent: dichloromethane/methanol 13/1). 1.66 g of the title compound are obtained as colorless crystals of melting point 137-8° C. (diethyl ether).
Reaction SMILES: C([O-])=O.[NH4+].[O:5]=[C:6]([N:31]1[CH2:36][CH2:35][N:34]([C:37](=[O:48])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]([F:47])([F:46])[F:45])[CH2:33][CH2:32]1)[CH2:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23]CC2C=CC=CC=2)=[CH:13][CH:12]=1)=[O:10]>CO.O.[Pd]>[O:5]=[C:6]([N:31]1[CH2:36][CH2:35][N:34]([C:37](=[O:48])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]([F:46])([F:47])[F:45])[CH2:33][CH2:32]1)[CH2:7][NH:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[OH:23])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2OCc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2ccccc2O)cc1
Temperature: 25 °C
Yield: 47 %

Procedure:
Ammonium formate (350 mg, 5.5 mmol) was added to a stirred solution of 2′-Benzyloxy-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (prepared by the method as described above) (156 mg, 0.26 mmol) in a mixture of MeOH (10 mL) and water (2 ml). 10% Pd/c (40 mg) was then added and the resulting mixture stirred at room temperature under an inert atmosphere. The reaction mixture was then stirred at reflux temperature for 3 hrs. The mixture was filtered over a bed of celite. The celite was washed with MeOH and the filtrate was concentrated. The residue was dissolved in EtOAc, washed with 5% aqueous NaOH solution, followed by saturated brine solution. The organic layer was dried over Na2SO4 and concentrated to get the residue. The residue was purified by preparative HPLC to afford 62 mg (47% yield) of 2′-Hydroxy-biphenyl-4-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 98.83%. 1H NMR (DMSO-d6): δ 9.6 (s, 1H), 8.64-8.5 (bs, 1H), 7.92-7.72 (m, 4H), 7.72-7.5 (m, 4H), 7.26-7.12 (d, 1H), 7.24-7.16 (t, 1H), 7.0-6.84 (m, 2H), 4.24-4.06 (bd, 2H), 3.82-3.52 (m, 4H), 3.52-3.42 (bs, 2H), 3.24-3.02 (bd, 2H).
Reaction SMILES: [F:1][CH:2]([F:22])[C@:3]1([C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=2[F:21])[NH:8][C:7](=[S:9])[CH2:6][CH2:5][C:4]1([F:11])[F:10].[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:18][C:16]1[CH:15]=[CH:14][C:13]([F:21])=[C:12]([C@@:3]2([CH:2]([F:22])[F:1])[NH:8][C:7](=[S:9])[CH2:6][CH2:5][C:4]2([F:10])[F:11])[CH:17]=1
Reactant: O=[N+]([O-])c1ccc(F)c([C@@]2(C(F)F)NC(=S)CCC2(F)F)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(F)c([C@@]2(C(F)F)NC(=S)CCC2(F)F)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
To a suspension of (S)-6-(difluoromethyl)-5,5-difluoro-6-(2-fluoro-5-nitrophenyl)piperidine-2-thione (1.00 g, 2.94 mmol) in ethanol (15 mL) and water (4 mL) was added iron powder (821 mg, 145 mmol) and NH4Cl (786 mg, 14.7 mmol, 5.0 Eq). The black mixture was stirred at 60° C. for 18 hours. After the reaction mixture was cooled to 25° C., the crude product was filtered and the residue was washed with ethanol (100 mL). The combined filtrates were concentrated and the resulting solid was dispersed in ethyl acetate (100 mL). The mixture was filtered and the filtrate was washed with water (30 mL), brine (20 mL) and concentrated. The crude product was purified by flash chromatography on silica (petroleum ether:ethyl acetate=3:1˜2:1) to give (S)-6-(5-amino-2-fluorophenyl)-6-(difluoromethyl)-5,5-difluoropiperidine-2-thione (819 mg, 2.51 mmol, 85.3% yield). 1H NMR (DMSO-d6, 400 MHz): δ 10.97 (s, 1H), 7.03-6.90 (m, 2H), 6.64-6.55 (m, 2H), 5.19 (s, 2H), 3.19-3.15 (m, 1H), 3.03-2.94 (m, 1H), 2.35-2.24 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.C[Mg]Cl.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[CH3:27]O>O1CCCC1>[CH2:20]([O:19][C:17]([N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:2])[CH2:4][CH:5]1[CH3:27])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1ccnc2ccccc12
Reactant: CO
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: CC1CC(=O)c2ccccc2N1C(=O)OCc1ccccc1
Yield: 98 %

Procedure:
To a solution of 4-methoxy quinoline (3g) in tetrahydrofuran (80 ml), under nitrogen, and under cooling at −78° C. in an acetone-dry ice bath and under stirring, a solution of methyl magnesium chloride at 3 M/l in tetrahydrofuran was added dropwise (77 ml) for 30 minutes. The mixture was stirred for 30 minutes and then benzyl chloroformate (32.15 g) was added dropwise for 45 minutes at −78° C. The mixture was stirred at room temperature over night. The reaction mixture was hydrolyzed with methanol (200 ml) and then with HCl 1 mol/l (200 ml) and finally concentrated. Dichloromethane (200 ml) and aqueous solution of sodium bicarbonate were added to the mixture under stirring. The separate organic layer was washed with an aqueous solution of sodium chloride (200 ml). The solvent was removed under reduce pressure to give an oil, which was chromatographed in silica gel with an eluent of cyclohexane/ethyl acetate (95/5). The fractions containing the desired compound were combined and evaporated to give an oil (5.44 g, 98% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N+:18]([O-])([O:20]C(C)C)=[O:19].S(=O)(=O)(O)O>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[OH:1][C:2]1[C:3]([N+:18]([O-:20])=[O:19])=[C:4]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(C)O[N+](=O)[O-]
Reactant: COc1ccc(C(=O)c2ccccc2)cc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccccc2)c([N+](=O)[O-])c1O

Procedure:
To a stirred solution of 3-hydroxy-4-methoxybenzophenone (10.0 g, 43.8 mmol) in dichloromethane (100 mL) at room temperature was added tetrabutylammoniumhydrogen sulphate (0.74 g, 5 mol %) followed by isopropyl nitrate (11.5 g, 87.6 mmol). Sulphuric acid (96%, 10 mL) was then added dropwise causing a gently exothermic reaction, and, after stirring for forty minutes, the reaction mixture was poured onto water (300 mL). The phases were separated and the aqueous phase was extracted by dichloromethane (30 mL). The combined organic phases were washed with brine and dried over anhydrous sodium sulphate. Filtration and evaporation of the solvent (40° C., water aspirator pressure) afforded a solid residue which was recrystallised from a small volume of ethanol (96%, 10 mL) to afford yellow crystals, (7.97 g, 67%) of m.p. 137–139° C., identified by NMR as the ortho-nitrated title product. Concentration of the mother liquors and subsequent chromatography on silica gel using a petroleum ether:ethyl acetate solvent mixture (2:1) allowed the isolation of a small amount of a minor product, corresponding (TLC) to a standard of the para-nitrated product, 3-hydroxy4-methoxy-6-nitrobenzophenone (1.43 g, 12%), m.p. 154–156° C. (79% combined yield, Ortho:Para selectivity, 5.6:1)
Reaction SMILES: NC1(C(NC2C=CC(C=CC([O-])=O)=CC=2)=O)CCCC1.CCOC1N(C(OCC)=O)C2C(=CC=CC=2)C=C1.[NH2:39][C:40]1[CH:45]=[CH:44][C:43](/[CH:46]=[CH:47]/[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:42][CH:41]=1.[C:53]([O:57][C:58]([NH:60][C:61]1([C:66](O)=[O:67])[CH2:65][CH2:64][CH2:63][CH2:62]1)=[O:59])([CH3:56])([CH3:55])[CH3:54]>C1COCC1>[C:53]([O:57][C:58]([NH:60][C:61]1([C:66]([NH:39][C:40]2[CH:41]=[CH:42][C:43](/[CH:46]=[CH:47]/[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:44][CH:45]=2)=[O:67])[CH2:65][CH2:64][CH2:63][CH2:62]1)=[O:59])([CH3:56])([CH3:55])[CH3:54]
Reactant: CCOC(=O)/C=C/c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Agent: CCOC(=O)N1c2ccccc2C=CC1OCC
Agent: NC1(C(=O)Nc2ccc(C=CC(=O)[O-])cc2)CCCC1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCCC2)cc1
Yield: 41 %

Procedure:
(E)-ethyl (3-(4-(1-aminocyclopentanecarboxamido)phenyl)acrylate. EEDQ (593 mg, 2.4 mmol) was added to a solution of (E)-ethyl 3-(4-aminophenyl)acrylate (417 mg, 2.18 mmol) and 1-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (500 mg, 2.18 mmol) in THF (6 mL). The solution was stirred at reflux for 3–4 hours. The mixture was concentrated and the residue partitioned between dichloromethane and water. The organic layer was washed sequentially with dilute HCl, water, and brine. The solution was dried over Na2SO4 and filtered. Dilution of the filtrate with hexanes resulted in the crystallization of (E)-ethyl 3-(4-(1-(tert-butoxycarbonylamino)cyclopentanecarboxamido)phenyl)acrylate as a pale yellow solid (360 mg, 37% yield). ESI-MS m/z 403 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([S:19][NH2:20])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[CH2:12]3)[C:6]=2[N:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:26]>CCO>[NH2:1][C:2]1[N:3]=[C:4]([S:19]([NH2:20])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[CH2:12]3)[C:6]=2[N:7]=1
Reactant: NSc1nc(N)nc2c1ccn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Product: Nc1nc(S(N)=O)c2ccn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
2-Amino-7-(2-deoxy-β-D-erythro-pentofuranosyl)pyrrolo[2,3-d1pyrimidine-4-sulfenamide 38 (300 mg, 1 mmol) was suspended in EtOH (120 mL) and cooled to 0° C. m-Chloroperoxybenzoic acid (85%, 100 mg, 1 mmol) in EtOH (30 mL) was added dropwise during 1.5 h. After stirring for an additional 30 min at 0° C., the mixture was concentrated to 10 mL in vacuo below 25° C. Ethyl ether (100 mL) was added to the concentrate solution and allowed to stand in the refrigerator overnight. The precipitate was collected by filtration, washed with ethyl ether and dried at 25° C. under reduced pressure to yield 110 mg (35%) of desired compound 39: m.p. 122 C (dec): UV: λmax (pH 1) 352 nm (ε3,100): 272 (3,100), 240 (21,100): λmax (pH 7 ) 336 nm (ε4,800), 239 (21,500): λmax (pH 11) 337 nm (ε4,600), 239 (20,500): IR (KBr) 1060 (S=O) cm-1 :1H NMR (DMSO-d6): δ6.45 (s, 2, exchangeable in D2O, SONH2), 6.49, (dd, 1, J =8.3 and 5.9 Hz, C1'H), 6.62 (s, 2, exchangeable in D2O, NH2), 6.73 (d, 1, J 3.8 Hz, C5H), 7.38 (d, 1, J =3.8 Hz, C6H). Anal. Calcd for C11H15N5O4S: C, 42.16: H, 4.82: N, 22.35: S, 10.23. Found: C, 41.91: H, 4.86: N, 22.07: S, 9.91.
Reaction SMILES: F[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O1CCCC1.[CH2:15]([N:17](CC)[CH2:18][CH3:19])[CH3:16].N1CCCC1>O>[N:17]1([C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:18][CH2:19][CH2:16][CH2:15]1
Reactant: CCN(CC)CC
Reactant: N#Cc1cccnc1F
Solvent: C1CCOC1
Solvent: C1CCNC1
Solvent: O
Product: N#Cc1cccnc1N1CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To an oven-dried, N2-purged, 50-mL flask containing a magnetic stir bar were added 2-fluoronicotinonitrile (1.22 g, 10.0 mmol), anhydrous tetrahydrofuran (5 mL), and triethylamine (3.04 g, 4.19 mL, 30.0 mmol). The flask was sealed with a septum and cooled to 0° C. in an ice bath. Neat pyrrolidine (1.04 g, 1.24 mmol, 15.0 mmol) was added via syringe. The mixture was stirred at 0° C. for 30 minutes and then allowed to warm to room temperature overnight. Water (10 mL) was added and the mixture was transferred to a separatory funnel. The mixture was extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to a brown oil. The product was recrystallized from ethyl acetate/hexanes to give 1.29 g (75%) of the title compound as a tan powder. MS (ESI+) m/z 174.0 (M+H)+; 1H NMR (DMSO-d6) δ 1.91-1.95 (m, 4H), 3.63-3.68 (m, 4H), 6.68 (dd, J=7.6, 4.6 Hz, 1H), 7.91 (dd, J=7.6, 1.9 Hz, 1H), 8.31 (dd, J=4.7, 2.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][CH2:7][C:8]([OH:10])=O)=[O:5].[C:11]([CH:13]1[CH2:15][NH:14]1)#[N:12].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:1][O:2][CH2:3][C:4]([NH:6][CH2:7][C:8]([N:14]1[CH2:15][CH:13]1[C:11]#[N:12])=[O:10])=[O:5]
Reactant: COCC(=O)NCC(=O)O
Reactant: N#CC1CN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COCC(=O)NCC(=O)N1CC1C#N

Procedure:
2.94 g. N-Methoxyacetylglycine are dissolved in 29 ml. tetrahydrofuran and mixed, with stirring and ice cooling, with 1.36 g. 2-cyanoaziridine and 4.3 g. dicyclohexylcarbodiimide, whereafter the reaction mixture is stirred for 2 hours. After filtering off the dicyclohexylurea, from the filtrate there are obtained 2.8 g. of crystals which, for purification, are dissolved in ethyl acetate and reprecipitated with ligroin. There is thus obtained 1-(N-methoxyacetylglycyl)-2-cyanoaziridine; M.p. 70°-72° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:15]3[O:16][CH2:17][CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:13]4[C:14]=3[C:10]([C:11](=[O:25])[NH:12]4)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1.[H-].[Na+].[CH3:29]I>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]2[C:15]3[O:16][CH2:17][CH:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:13]4[C:14]=3[C:10]([C:11]([O:25][CH3:29])=[N:12]4)=[CH:9][CH:8]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2c(=O)[nH]n3c2c1OCC3c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nn2c3c(c(-c4c(C)noc4C)ccc13)OCC2c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 9-(3,5-dimethylisoxazol-4-yl)-3-phenyl-2,3-dihydro[1,4]oxazino[2,3,4-hi]indazol-6(5H)-one (0.030 g, 0.086 mmol) in N,N-dimethylformamide (0.41 mL) was treated with sodium hydride (6.91 mg, 0.173 mmol) and stirred for 2 h. The reaction mixture was treated with methyl iodide (7.0 μL, 0.112 mmol) and stirred for 1 h. The reaction mixture was cooled to 0° C. and quenched with saturated ammonium chloride solution. The aqueous solution was extracted with ethyl acetate to give a crude tan solid. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 30 mL/min) gave Example 2 (1.3 mg, 4%, first peak to elute) and Example 3 (2 mg, 6%, second peak to elute) (two separate passes through the preparative LCMS system was needed to isolate both peaks). Example 2: 1H NMR (500 MHz, CDCl3) δ 7.48-7.39 (m, 4H), 7.37-7.30 (m, 2H), 6.97 (d, J=8.0 Hz, 1H), 4.74 (dd, J=11.9, 8.2 Hz, 1H), 4.55 (dd, J=12.0, 3.0 Hz, 1H), 4.34 (dd, J=8.1, 2.8 Hz, 1H), 2.95 (s, 3H), 2.35 (s, 3H), 2.23 (s, 3H); LCMS calculated for C21H20N3O3 (M+H)+: m/z=362.1. found: 362.1. Example 3: 1H NMR (500 MHz, CDCl3) δ 7.39-7.30 (m, 3H), 7.27 (d, J=8.3 Hz, 1H), 7.18-7.10 (m, 2H), 6.81 (d, J=8.3 Hz, 1H), 5.37 (dd, J=5.4, 3.4 Hz, 1H), 4.67 (dd, J=11.4, 3.4 Hz, 1H), 4.51 (dd, J=11.5, 5.5 Hz, 1H), 4.04 (s, 3H), 2.34 (s, 3H), 2.23 (s, 3H); LCMS calculated for C21H20N3O3 (M+H)+: m/z=362.1. found: 362.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([CH3:16])[C@H:14](COCC2C=CC=CC=2)[C@H:13]([NH:26]C(OC(C)(C)C)=O)[C@@H:12]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:40](=[O:42])=[O:41].[CH3:43]O>Cl>[NH2:26][C@H:13]1[CH2:14][C@H:16]([C:40]([O:42][CH3:43])=[O:41])[CH2:15][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[C@H:12]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CO
Reactant: C[C@@H]1[C@H](COCc2ccccc2)[C@H](NC(=O)OC(C)(C)C)[C@H](c2ccccc2)N1C(=O)OCc1ccccc1
Reactant: O=C=O
Agent: Cl
Product: COC(=O)[C@H]1C[C@H](N)[C@H](c2ccccc2)N(C(=O)OCc2ccccc2)C1

Procedure:
A suspension of (2S*,3S*,5S*)-1-benzyloxycarbonyl-3-(N-tert-butoxycarbonyl)amino-5-methoxycarbonyl-2-phenylpiperidine (1.01 g, 2.16 mmol) in Hydrogen Chloride, Methanol Reagent 10 (20.0 ml) was stirred and heated at reflux for 10 minutes; the reaction mixture became homogeneous with evolution of CO2 gas. This mixture was concentrated in vacuo, and the syrupy residue was basified with sat. Na2CO3 aq. solution. The mixture was extracted with CH2Cl2 (×4). The combined CH2Cl2 extracts were dried (Na2SO4), and concentrated in vacuo to give crude title compound (0.789 g, quantitative) as a pale yellow syrup. IRmax (film): 3375(m), 3310(w), 1730(br., s), 1700(br., s), 1603(m), 1585(m), 1497(s), 1122(s), 740(s), 700(s) cm-1 ; 1H-NMR δ: 7.45-7.15(m, 10H), 5.26(d, J=5.9 Hz, 1H), 5.15(d, J=12.5 Hz, 1H), 5.01(d, J=12.5 Hz, 1H), 4.51(dd, J=13.9, 2.1 Hz, 1H), 3.65(s, 3H), 3.56-3.43(m, 1H), 3.54(dd, J=13.9, 4.2 Hz, 1H), 2.95-2.85(m, 1H), 2.22(ddd, J=14.9, 4.0, 4.0 Hz, 1H), 1.95(ddd, J=14.9, 10.9, 6.6 Hz, 1H) ppm.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[N:5]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:4]1)(=[O:27])=[O:26]
Reactant: CC(C)(C)OC(=O)NN1C[C@H](CO)OC1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NN1C[C@@H](COS(C)(=O)=O)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a turbid solution of (R)-tert-butyl 5-(hydroxymethyl)-2-oxooxazolidin-3-ylcarbamate (840 mg, 3.62 mmol) in DCM (10 mL), triethylamine (458 mg, 4.52 mmol) and methanesulfonyl chloride (518 mg, 4.52 mmol) were added and the reaction was stirred, at r.t., under nitrogen, for 2 h 30 min. The solution was washed with: cold water (resulting pH=7-8), cold citric acid (resulting pH=4-5) and cold brine. The organic layer was dried over Na2SO4 and evaporated and the residue (beige foam) was triturated with diisopropyl ether, affording (S)-(3-(tert-butoxycarbonylamino)-2-oxooxazolidin-5-yl)methyl methanesulfonate (1.055 g, 3.40 mmol) as a white solid, that was dissolved in 7 mL of DMF. Sodium methanethiolate (317 mg, 4.52 mmol) was added to the solution and the mixture was stirred at 60° C. for 3 h. AcOEt was added and the solution was washed with cold water, cold citric acid (until pH=6) and cold brine. The organic layer was dried over Na2SO4 and evaporated to leave a yellow oil. The title compound was precipitated by crystallization from diisopropyl ether as a white solid, recovered by filtration on Buchner (429 mg, 1.635 mmol). Yield=45%.
Reaction SMILES: O[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9].C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>C(Cl)Cl>[Br:13][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)CCC/C=C\CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCC/C=C\CBr
Reaction time: 0.67 h
Yield: 95.7 %

Procedure:
To a solution of alcohol 39 (1.48 g, 9.36 mmol) and carbon tetrabromide (3.40 g, 10.25 mmol) in dry CH2Cl2 (50 mL) was added triphenylphosphine (2.70 g, 10.30 mmol) in portions. The reaction mixture was stirred for 40 min and MeOH (1 mL) was added. Concentration on a rotary evaporator, followed by flash chromatography using 50:1 hexane/EtOAc as eluent, gave 40 as a colorless oil (1.98 g, 96%): IR (neat) 3020 (w), 2945, 2860 (w), 1740 (s), 1435, 1370, 1200, 1165 cm-1 ; 1H NMR (CDCl3) δ 5.77 (m, J1 =10.5 Hz, J2 =8.3 Hz, J3 =1.4 Hz, 1H), 5.56 (m, J1 =10.6 Hz, J2 =7.5 Hz, 1H), 3.98 (d, J=8.1 Hz, 2H), 3.67 (s, 3H), 2.34 (t, J=7.4 Hz, 2H), 2.19 (dq, J1 =7.5 Hz, J2 =1.4 Hz, 2H), 1.74 (p. J=7.3 Hz, 2H); 13C NMR (CDCl3) δ 173.55, 134.48, 126.26, 51.37, 33.06, 26.60, 26.01, 24.28. A minor amount (ca. 5%) of methyl trans-7-bromo-5-heptenoate could be seen in the 1H NMR spectrum at δ 3.93.