Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20]>CO>[OH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][CH3:12])[N:3]=1
Reactant: Nc1ccccc1O
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CO
Product: COc1ccc([N+](=O)[O-])c(Nc2ccccc2O)n1
Yield: 94.6 %

Procedure:
A mixture of 188.6 (1 mole) of 2-chloro-6-methoxy-3-nitropyridine and 262 g (2.4 mole) of o-aminophenol is heated in 500 ml of methanol gradually up to reflux. After heating for a period of 2 hours, the mixture is filtered off hot by suction; the suction cake is washed with enough methanol until the filtrate runs off practically colorless and is dried. Bright red crystals with a melting point of 206°-7° C. are obtained in a yield of 94.6% of theory.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:23]=[CH:22][C:21]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=4)[C:27]([O:29]C)=O)=[CH:20][C:14]=3[C:15]=2[C:16](=[O:19])[NH:17][CH3:18])=[CH:7][CH:6]=1.O/[N:35]=[C:36](\[NH2:40])/[CH:37]([CH3:39])[CH3:38]>CCO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:23]=[CH:22][C:21]([C:24]4[CH:33]=[CH:32][CH:31]=[C:26]([C:27]5[O:29][N:40]=[C:36]([CH:37]([CH3:39])[CH3:38])[N:35]=5)[CH:25]=4)=[CH:20][C:14]=3[C:15]=2[C:16]([NH:17][CH3:18])=[O:19])=[CH:7][CH:6]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)OC)c3)cc12
Reactant: CC(C)/C(N)=N/O
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nc(C(C)C)no4)c3)cc12
Yield: 19.5 %

Procedure:
Sodium methoxide (33 mg, 0.620 mmol) was added to a stirring slurry of methyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate (50 mg, 0.124 mmol) and (Z)—N′-hydroxyisobutyrimidamide (38 mg, 0.372 mmol) in EtOH (2.5 mL) at rt. The mixture was subjected to microwave irradiation for 5 min at 160° C. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (11 mg, 20%). 1H NMR (400 MHz, DMSO-d6) d ppm 8.46-8.54 (1 H, m), 8.35 (1 H, s), 8.11 (1 H, d, J=7.78 Hz), 7.97-8.08 (3 H, m), 7.92-7.97 (1 H, m), 7.73-7.84 (3 H, m), 7.40 (2 H, t, J=8.91 Hz), 3.12-3.23 (1 H, m), 2.87 (3 H, d, J=4.52 Hz), 1.36 (6 H, d, J=7.03 Hz). LC-MS retention time: 1.80 min; m/z (MH+): 456. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=16.33 min, purity=99%; Column: Waters Xbridge Phenyl column 4 6×150 mm, 3.5 mm, Rt=13.72 min, purity=99%.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C([N:14](CC)CC)C.O>C(Cl)(Cl)Cl>[Br:1][CH2:2][C:3]([NH2:6])=[O:4].[Br:1][CH2:2][C:3]([NH2:14])=[O:4].[NH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: O=C(Br)CBr
Reactant: CCN(CC)CC
Agent: C1CNCCN1
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC(=O)CBr
Temperature: -15 °C
Reaction time: 1 h
Yield: 49.2 %

Procedure:
To a 1 L three-necked flask equipped with a magnetic stir bar, reflux condenser and addition funnel, was added bromo acetyl bromide (82.8 g, 0.41 mole) in CHCl3 (170 mL). The addition funnel was charged with a solution of piperazine (0.2 mole, 17.2 g) and triethylamine (70 mL) in CHCl3 (180 mL). The flask was chilled to -15° C. by means of a CH3CN/liquid N2 bath, and the amine was slowly added to the acid bromide. After the addition was complete the mixture was allowed to warm to ambient temperature and was stirred for 1 hour. The flask was then cooled to 0° C. and H2O (100 mL) was slowly added. The mixture was diluted with CHCl3 (500 mL) and the layers were separated. The organic layer was extracted with H2O (5×50 mL), 0.05 N NaOH (5×50 mL) and H2O (200 mL), and dried (Na2SO4). The dark orange solution was filtered and concentrated to a beige solid. The material was purified by filtration through a bed of silica gel. The product eluted with 2-5% methanol/CH2Cl2. After combining and concentrating the desired fractions, 15.0 g (49.2%) of a white solid was obtained. The title product was recrystallized from warm 2-propanol (400 mL) affording 9.95 g. 1H NMR (CDCl3): δ3.61 (dt, 6 H), 3.85 (s, 4 H).
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[CH:16]([CH3:18])[CH3:17]>C1COCC1.ClCCl>[C:15]([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)(=[O:19])[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)C(=O)Cl
Reactant: OCc1ccco1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)C(=O)OCc1ccco1
Temperature: 5 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
Furfuryl alcohol (5 mL, 1 eq.) was dissolved in THF (20 mL) in a dry, round bottomed flask and stirred with triethylamine (10 mL, 1.25 eq.). The solution was cooled to 5° C. and isobutyryl chloride (60.1 mL, 1.0 eq.) was added dropwise. The mixture was stirred for 2 h at 20° C. The reaction was worked up by diluting with dichloromethane (30 mL) and filtered through a celite plug to remove the triethylammonium chloride, and the solvent was removed under vacuum. The residue was purified by silica column chromatography using tert-butylmethyl ether-hexane (1:5) (Rf 0.54) to give an oil (8.5 g 87.5% yield). IR (cm−1): 1737 (C═O st), 3145, 3124 (═C—H st), 816, 745 (C—H δ, furan ring). 1H NMR (CDCl3, 300 MHz): δ 2.57 (sept, 1H, C—H(CH3)2, J=6.9 Hz), 1.17 (d, 6H, CH(CH3)2, J=6.9 Hz), 5.06 (s, 2H, CH2O) ppm. Furan ring: 6.39 (bd, 1H, H-3′, J3′,4′=3.3 Hz), 6.35 (dd, 1H, H-4′, J4′,5′=1.8 Hz), 7.41 (m, 1H, H-5′) ppm. 13C NMR (CDCl3, 75 MHz): δ 176.7 (C═O), 33.9 [CH(CH3)2], 18.9 [CH(CH3)2] ppm. Furan ring: 149.8 (C-2′), 110.5, 110.3 (C-3′, C-4′), 143.1 (C-5′) ppm. CI-Mass Spectrometry. m/z: 168 (M+), 97 [(OCH2-fur)+], 81 (main peak) [(CH2-fur)+], 71 [(CH3)2CHCO)+]. HRMS: Theoretical molecular weight for C9H12O3 (M+) 168.078644, experimental molecular weight: 168.078182.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]([NH:9][CH:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])=[O:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].[Cl-].[Na+]>CS(C)=O>[CH2:33]([O:32][C:30]([CH2:29][C:10]1([NH:9][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:21][CH:20]=2)=[O:8])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][C:11]1=[O:19])=[O:31])[CH3:34]
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(CC(=O)NC2C(=O)Nc3ccccc32)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CC1(NC(=O)Cc2ccc(C)cc2)C(=O)Nc2ccccc21
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of 0.72 g of (RS)-3-((4-methylbenzyl)carbonylamino)indolin-2-one in 20 ml of dry dimethyl sulfoxide was added 3 ml of a 1M solution of potassium t-butoxide in dry dimethyl sulfoxide at room temperature under a nitrogen atmosphere, followed by stirring for 30 minutes. To the mixture was added dropwise 0.37 ml of ethyl bromoacetate, followed by stirring at the same temperature for 30 minutes. The reaction mixture was treated with an aqueous solution of sodium chloride and extracted with ethyl ether. The ethyl ether layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=40/1) to give 0.30 g (32%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[CH:12]=[CH:11][C:10]([Cl:15])=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:16]#[N:17])=[CH:4][N:3]=1.[CH:18]1([CH:21]([CH:23]2[CH2:25][CH2:24]2)[NH2:22])[CH2:20][CH2:19]1>O1CCOCC1>[Cl:15][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[C:2]([NH:22][CH:21]([CH:23]4[CH2:25][CH2:24]4)[CH:18]4[CH2:20][CH2:19]4)=[N:3][CH:4]=[C:5]([C:16]#[N:17])[C:6]=3[NH:7][C:8]=2[CH:9]=1
Reactant: NC(C1CC1)C1CC1
Reactant: N#Cc1cnc(Cl)c2c1[nH]c1cc(Cl)ccc12
Solvent: C1COCCO1
Product: N#Cc1cnc(NC(C2CC2)C2CC2)c2c1[nH]c1cc(Cl)ccc12
Temperature: 135 °C

Procedure:
To a stirred slurry of 1,7-dichloro-5H-pyrido[4,3-b]indole-4-carbonitrile (16 g, 61 mmol) in dioxane (122 mL) was added dicyclopropylmethanamine (17 g, 153 mmol). The reaction mixture was heated to 135° C. for 1 d, cooled to room temperature, and concentrated. The residue was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc (×3). The combined organics were washed with brine, dried (sodium sulfate), concentrated, and purified by flash chromatography to give the title compound. LRMS (APCI) calc'd for (C19H17ClN4) [M+H]+, 337.1. found 337.1.
Reaction SMILES: [C:1]1([C:7]([SH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21](OC(C)(C)C)=[O:22]>C(Cl)Cl>[N:21]([S:20][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:22]
Reactant: CC(C)(C)ON=O
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=NSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
Triphenylmethyl mercaptan (0.050 g, 0.18 mmol) was dissolved in anhydrous methylene chloride and cooled to 0° C. Tert-butyl nitrite (0.186 g, 1.80 mmol) was added and the resulting mixture was stirred at 0° C. for 30 min. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. The solvent and excess of tert-butyl nitrite were evaporated to give the title compound as a green solid (0.054 g, 98%). 1H NMR (CDCl3) δ: 7.13-7.18 (m, 4 H), 7.25-7.39 (m, 11⌴H).
Reaction SMILES: N[C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:3]([OH:5])=[O:4].[Br-:21].[K+].NC(CCCCNC(OCC1C=CC=CC=1)=O)C(O)=O>Br>[CH2:14]([O:13][C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][C@H:2]([Br:21])[C:3]([OH:5])=[O:4])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [Br-]
Reactant: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Br
Agent: NC(CCCCNC(=O)OCc1ccccc1)C(=O)O
Agent: [K+]
Product: O=C(NCCCC[C@H](Br)C(=O)O)OCc1ccccc1
Temperature: 0 °C

Procedure:
(S)-2-Amino-6-{[(benzyloxy)carbonyl]amino}hexanoic acid, 20.0 g (0.14 mole), and potassium bromide, 28.9 g (0.24 mole), were dissolved in 80 mL of ˜6N aqueous HBr, previously chilled to 0° C. A stream of nitrogen was bubbled through the solution and the mixture was chilled to −10° C. by means of a cold bath. Sodium nitrite, 5.9 g (0.86 mole) was added in portions over 30 min with stirring, while maintaining the temperature of the reaction from −13° C. to −10° C. After 6 hours stirring at −10° C., the mixture was extracted with ethyl ether, 4×50 mL and the resulting solution dried with magnesium sulfate. The mixture was filtered to remove the drying agent and evaporated to give an orange oil. The oil was purified by flash chromatography, chloroform-hexanes to give a clear and colorless oil. The yield was 20.0 g, i.e., 81%, based on starting 2-amino-6-{[(benzyl-oxy)carbonyl]-amino}hexanoic acid. NMR is consistent with structure. (Nicolaides et al.)
Reaction SMILES: N.[Na].[CH3:3][N:4]([CH2:6][C:7]#[CH:8])[CH3:5].Cl.Br[CH2:11][CH2:12][CH2:13][NH2:14]>C(OCC)C>[CH3:3][N:4]([CH3:5])[CH2:6][C:7]#[C:8][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: C#CCN(C)C
Reactant: NCCCBr
Agent: Cl
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: CN(C)CC#CCCCN
Reaction time: 1 h
Yield: 16 %

Procedure:
A flask fitted with a dry ice condenser was charged with liquid ammonia (250 ml). To this was added sodium (0.24 mol) in portions together with a few grains of ferric nitrate; subsequently dimethylaminoprop-2-yne (0.24 mol) was added. The reaction mixture was stirred for one hour, 3-bromopropylamine hydrochloride (0.24 mol) was added in portions and the mixture stirred for a further two hours. Anhydrous diethyl ether (150 ml) was added and excess ammonia was allowed to evaporate overnight. The reaction mixture was dissolved in methanol and evaporated under reduced pressure to afford a residue, which was partitioned between chloroform and water. The aqueous layer was washed with chloroform (5×150 ml). The chloroform extracts were combined, dried over MgSO4, filtered and evaporated under reduced pressure to give 6-dimethylaminohex-4-ynylamine as an oil (5.4 g).
Reaction SMILES: C1C([N+]([O-])=[O:8])=CC=C(O)C=1.CC(CC(CCC(O)=O)=O)=O.N1CCC[C@H]1C(O)=O.[CH:30]1([N:36]=[C:37]=[N:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)(Cl)Cl>[C:37]([NH:36][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)([NH:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:8]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CC(=O)CC(=O)CCC(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.17 h

Procedure:
Succinylacetonyl-proline was converted to succinylacetonyl-proline-NH-PEG by adding succinylacetonyl-proline to a condensing agent in the presence of p-nitrophenol in chloroform. The reaction was carried out in 10 ml of chloroform by adding 0.55 g (4.0 mmole) of p-nitrophenol to 0.64 g (3.9 mmole) of succinylacetone-proline. Next, 0.80 g (3.3 mmole) of the condensing agent, dicyclohexylcarbodiimide was added. The latter was dissolved in 2 ml chloroform, and added slowly to the mixture with stirring. Within 10 minutes, a white precipitate of dicyclohexylurea formed, and a spectrophotometric determination [L. Aldwin and D. E. Nitecki, 1987, Anal. Biochem., 164:494-501] of the amount of ester present at that time indicated that there was approximately 61.5% ester present. A similar determination two hours later revealed no change in the amount of ester formed. Dicyclohexylurea was removed by filtering the solution, followed by the addition of 0.45 g (1.1 mmole) PEG-4000-NH2 to the filtrate. The reaction mixture was allowed to stir at room temperature overnight. The product, succinylacetonyl-proline-NH-PEG was purified as follows.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]12[C:15]([O:18][CH3:19])([O:16][CH3:17])[C:10]([Cl:20])([C:11]([Cl:14])=[C:12]1[Cl:13])[CH:9]1[CH:5]2[O:6]C(=O)[O:8]1>O.C1COCC1.Cl>[Cl:3][C:4]12[C:15]([O:16][CH3:17])([O:18][CH3:19])[C:10]([Cl:20])([C:11]([Cl:14])=[C:12]1[Cl:13])[CH:9]([OH:8])[CH:5]2[OH:6]
Reactant: COC1(OC)C2(Cl)C(Cl)=C(Cl)C1(Cl)C1OC(=O)OC12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC1(OC)C2(Cl)C(Cl)=C(Cl)C1(Cl)C(O)C2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
Potassium hydroxide (112 g, 1.20 mol) in water (1 L) was treated with 1,7,8,9-tetrachloro-10,10-dimethoxy-3,5-dioxa-tricyclo[5.2.1.02,6]dec-8-en-4-one (358.3 g, 1.23 mol) in THF (500 mL) via addition funnel, producing a slight exotherm. The reddish solution was stirred overnight at room temperature. By morning, the solution became a murky dispersion, which was diluted with water (500 mL), and 12N HCl (20 mL) to pH 10. The product was extracted with EtOAc (1×1000 mL) and ether (1×500 mL). The combined organic layers were washed with 1N HCl (1×300 mL), water (1×300 mL), saturated aqueous NaHCO3 solution (1×300 mL) and saturated aqueous NaCl solution (1×300 mL), dried over Na2SO4, filtered and concentrated to give a light brown solid (310 g, 78%). (TLC 40% EtOAc/hexanes Rf 0.55); 1H NMR (400 MHz, CDCl3) δ 4.46 (s, 2H), 3.54 (s, 3H), 3.51 (s, 3H); GCMS m/z 322 (M)+, 287, 289 (M-Cl)+; mp 160–162° C.; Anal. Calcd for C9H10Cl4O4: C, 33.37; H, 3.11. Found C, 33.34; H, 3.16.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12].[OH-].[Na+].CO>O1CCCC1>[CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]([OH:22])=[O:21])(=[O:12])=[O:13]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc2c(c1)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc2c(c1)CCCC2
Temperature: 50 °C
Yield: 75.6 %

Procedure:
To a solution of 78 (71 mg, 0.20 mmol) in tetrahydrofuran (1 mL) were added aqueous sodium hydroxide (2 mL; 2N) and methanol (2 mL). The reaction mixture was heated at 50° C. for 27 hours, allowed to cool to room temperature, and then extracted with aqueous sodium hydroxide (20 mL; 2N). The aqueous layer was washed with diethyl ether (30 mL×2), acidified with aqueous hydrochloric acid (20 mL; 6N), and extracted with dichloromethane (40 mL). The organic layer was separated, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to yield the title compound as a white solid (51 mg).
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:23]([N:25]([C@@H:27]([C@@H:55]([CH3:58])[CH2:56][CH3:57])[C@H:28]([O:53][CH3:54])[CH2:29][C:30]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[C@H:37]([O:51][CH3:52])[C@@H:38]([CH3:50])[C:39](=[O:49])[NH:40][CH2:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:31])[CH3:26])=[O:24])[CH:20]([CH3:22])[CH3:21])=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>O1CCCC1>[CH3:54][O:53][C@@H:28]([C@@H:27]([N:25]([CH3:26])[C:23](=[O:24])[C@H:19]([CH:20]([CH3:22])[CH3:21])[NH2:18])[C@@H:55]([CH3:58])[CH2:56][CH3:57])[CH2:29][C:30]([N:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C@H:37]([O:51][CH3:52])[C@@H:38]([CH3:50])[C:39](=[O:49])[NH:40][CH2:41][CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)=[O:31]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: CCNCC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](N)C(C)C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To #72 (5.16 g, 6.47 mmol, 1 eq.) in tetrahydrofuran (10 mL, 0.65 M) was added diethylamine (10 mL). After 2 hours, the reaction was concentrated in vacuo and the residue was purified by silica gel chromatography (Gradient: 0% to 10% methanol in dichloromethane) to give #73 (2414 mg, 65%). LC-MS: m/z 576.5 [M+H+], retention time=0.64 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ 7.80-7.88 and 7.99-8.10 (2 m, total 1H), 7.14-7.31 (m, 5H), 3.17 and 3.18 (2 s, total 3H), 2.87 and 3.03 (2 br s, total 3H), 1.02-1.08 (m, 3H).
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH2:10][OH:11])[CH:6]=1)([CH3:4])[CH3:3]>O1CCOCC1.[O-2].[O-2].[Mn+4]>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[O:11])[CH:6]=1)([CH3:3])[CH3:4]
Reactant: CC(C)(O)c1cc(CO)no1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CC(C)(O)c1cc(C=O)no1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
5.38 g of [5-(1-hydroxy-1-methylethyl)isoxazol-3-yl]methanol was dissolved in 100 ml of 1,4-dioxane, and 29.74 g of manganese dioxide was then added. The mixture was stirred and heated under reflux for 10 hours. The reaction mixture was cooled to room temperature and then filtered through Celite®. The filtrate was concentrated under reduced pressure to obtain 4.63 g of 5-(1-hydroxy-1-methylethyl)-isoxazole-3-carbaldehyde.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([I:14])=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]([C:16]([O:18]CC)=O)=[CH:5]2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.ClCCl.Cl>CO>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:16]([C:6]2[C:7](=[O:15])[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=3)[N:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=2)=[O:18])=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cn(C2CC2)c2ccc(I)cc2c1=O
Reactant: NCc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1cn(C2CC2)c2ccc(I)cc2c1=O
Temperature: 180 °C

Procedure:
To a flask containing ethyl 1-cyclopropyl-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate from Preparation No. 19 (0.19 g) is added p-chlorobenzylamine (1.0 mL). The reaction is tightly capped and heated to 180° C. for 1 hour. The reaction is cooled to room temperature and partioned between dichloromethane containing methanol and dilute hydrochloric acid. The aqueous layer is extracted with dichloromethane and the combined organic layers are washed with brine, dried and concentarted under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% to 6% methanol in dichloromethane. The product containing fractions are evaporated to give 0.10 g of the title compound as a tan solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](O)[CH2:9][C@H:8]1[CH2:13][C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)=[O:6])[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:51]([OH:59])(=[S:58])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:58][C:51](=[O:59])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[CH2:9][C@H:8]1[CH2:13][C:14]1[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: OC(=S)c1ccccc1
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1cnn(C)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1Cc1cnn(C)c1
Reaction time: 0.25 h

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-hydroxy-2-{(1-methylpyrazol-4-yl)methyl)pyrrolidine (15.3 g) and triphenylphosphine (19.67 g) in tetrahydrofuran (180 ml) was added diethyl azodicarboxylate (13.06 g) at -30° C. After 15 minutes, thiobenzoic acid (9.5 ml) was added thereto. The mixture was warmed up to 0°~5° C. over 25 minutes and stirred for 2 hours. After evaporation of tetrahydrofuran, the resulting residue was dissolved in ethyl acetate (500 ml). The organic layer was washed with saturated sodium bicarbonate solution (×3), water and brine, dried over magnesium sulfate and evaporated under reduced pressure. After storing the residue overnight in an ice box, a precipitate had appeared. To the precipitate was added a solution of diisopropyl ether (IPE)--diethyl ether (1:1, 100 ml) and the solid was removed by filtration. The filtrate was evaporated and the residue was column chromatographed on silica gel (1.1 kg, eluting with AcOEt-IPE=2:3 to 1:1) to give (2R,4S)-1-allyloxycarbonyl-4-benzoylthio-2-{(1-methylpyrazol-4-yl)methyl}pyrrolidine (21.8 g).