Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:6]=2[CH:7]=1)=[O:2].C([O-])(=O)C.[Na+].[Br:19]Br>ClCCl>[CH:1]([C:3]1[O:4][C:5]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]([Br:19])[C:6]=2[CH:7]=1)=[O:2]
Reactant: COc1cccc2cc(C=O)oc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(Br)c2cc(C=O)oc12

Procedure:
2-Formyl-7-methoxybenzofuran (1.0 g) was stirred in dichloromethane (10 ml) under nitrogen at 0° C. Sodium acetate (1.4 g) was added followed by the dropwise addition of bromine (0.29 ml). Further dichloromethane (20 ml) was added to the mixture to facilitate stirring and the mixture was stirred overnight. The reaction mixture was diluted with dichloromethane (40 ml) and washed with water (30 ml). Drying over magnesium sulfate followed by removal of the solvent in vacuo gave a pale orange solid. Purification by flash chromatography on silica eluting with 10% ethyl acetate in hexane gave the title compound (0.50 g) as a beige solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10]([O:12][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl(cis-3-hydroxycyclobutyl)carbamate (2.0 g, 10.7 mmol) was dissolved in dry THF (50 mL) under nitrogen atmosphere, and the solution cooled to 0° C. To this clear solution, sodium hydride (60% dispersion in oil, 0.428 g, 10.7 mmol) was added portion wise (evolution of H2 observed). The mixture was stirred at rt for 30 min then benzyl bromide (1.91 mL, 16.04 mmol) added dropwise and the resulting yellow suspension stirred at rt for 16 h. The reaction was quenched with sat aq. NH4Cl solution (20 mL) and partitioned between sat aq. NaHCO3 (40 mL) and DCM (60 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (gradient 0-50% EtOAc in cyclohexane) to afford the title compound as a white solid (2.40 g, 81%). 1H NMR (CDCl3, 400 MHz): δ 7.41-7.22 (5H, m), 4.66 (1H, br, NH), 4.42 (2H, s), 3.83-3.65 (2H, m), 2.79-2.61 (2H, m), 1.86-1.72 (2H, m), 1.46 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:13]=[CH:14][C:15](F)=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O.CCOCC>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([O:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)c1cc(Cl)ccc1F
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1Oc1ccc(F)cc1
Temperature: 120 °C
Yield: 64.8 %

Procedure:
To a stirred solution of 4-fluorophenol (1.60 g, 14.3 mmol) and sodium hydride (0.34 g, 14.3 mmol) in N,N-dimethylforamide (30 mL) was added a solution of methyl 5-chloro-2-fluorobenzoate (2.70 g, 14.3 mmol) in N,N-dimethylforamide (30 mL) at 0° C. The resulting mixture was heated at 120° C. for 16 h. After cooling to room temperature, the mixture was diluted with ether (300 mL) and washed with water (150 mL×3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (20:1) to afford 2.60 g (65%) of the title compounds as slight yellow oil: 1H-NMR (CDCl3) δ 7.88 (1H, d, J=2.8 Hz), 7.40 (1H, dd, J=8.8, 2.8 Hz), 7.06–6.85 (5H, m), 3.84 (3H, s).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][C:12]2=[O:23])[CH3:10])[CH2:4][CH2:3]1.[O:24]=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2[NH:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl>[CH3:22][O:21][C:18]1[CH:19]=[C:20]2[C:15]([N:14]=[CH:13][C:12](=[O:23])[N:11]2[CH:9]([CH3:10])[CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:35][C:33]3[CH:32]=[CH:31][C:28]4[O:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=4[N:34]=3)[CH2:3][CH2:4]2)=[CH:16][CH:17]=1
Reactant: COc1ccc2ncc(=O)n(C(C)CN3CCC(N)CC3)c2c1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(C(C)CN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2c1
Yield: 43 %

Procedure:
1-[2-(4-aminopiperidin-1-yl)-1-methylethyl]-7-methoxyquinoxalin-2(1H)-one (Intermediate 221) (160 mg crude, 0.51 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (91 mg, 0.51 mmol), and sodium triacetoxy borohydride (320 mg, 1.5 mmol) were reacted as described according to Example 69. Chromatography on silica gel eluting with 5% methanol/dichloromethane containing 0.25% ammonium hydroxide gave 105 mg (63%) of the title compound as an off-white solid.
Reaction SMILES: CS(C)=O.[CH:5]([C:7]1[O:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6].C([O-])(=O)C.[K+].I[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][NH:25][C:24]2=[O:31]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[O:31]=[C:24]1[C:23]2[C:28](=[CH:29][CH:30]=[C:21]([C:10]3[O:11][C:7]([CH:5]=[O:6])=[CH:8][CH:9]=3)[CH:22]=2)[N:27]=[CH:26][NH:25]1
Reactant: O=c1[nH]cnc2ccc(I)cc12
Reactant: O=Cc1ccc(B(O)O)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(-c2ccc3nc[nH]c(=O)c3c2)o1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98 %

Procedure:
A 5:2 v/v solvate mixture of Dimethyl sulfoxide (DMSO) and H2O (1400 mL) was degassed for 30 min at ambient temperature using nitrogen. Under an atmosphere of nitrogen, 5-formylfuran-2-ylboronic acid ((VIa); 26.8 g, 193 mmol) was added into this mixture and dissolved. [HP(t-Bu)3]BF4 (840 mg, 2.94 mmol) and palladium acetate (Pd(OAc)2, 680 mg, 2.94 mmol) was added and the mixture was stirred at ambient temperature for 20 min. Then, potassium acetate (AcOK, 18.8 g, 192 mmol) was added into the reactor and was stirred for 20 min. 6-Iodoquinazolin-4(3H)-one ((Va); 40 g, 147 mmol) was added. Then the reaction mixture was heated to 80±5° C. (internal temperature). Upon completion of the reaction (HPLC), the reaction mixture was hot-filtered, then hot water (400 mL, 80±5° C.) was added into the filtrate. This was slowly cooled to 0-15° C. (solid started to precipitate at 70° C. (internal temperature)) and was then filtered. The filter cake was washed with H2O (80 mL), then with MeCN (60 mL), and dried in vacuo at 60±5° C. for 6 h to provide 5-(4-oxo-3,4-dihydroquinazolin-6-yl)-furan-2-carbaldehyde ((IX); 34.6 g, 144 mmol) with 99.7% HPLC purity in 97.6% HPLC yield. 1H NMR (300 MHz, d6-DMSO): δ 7.47 (d, J=3.8 Hz, 1H), 7.69 (d, J=3.8 Hz, 1H), 7.77 (d, J =8.6 Hz, 1H), 8.17 (s, 1H), 8.27 (dd, J=8.6, 2.1 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 9.66 (s, 1H); 13C NMR (75 MHz, CDCl3): δ 110.5, 122.6, 123.9, 126.0, 127.5, 129.0, 131.4, 147.1, 150.1, 152.7, 157.6, 161.2, 178.8; ESI-MS, Pos: [M+H]+m/z 241; IR (cm−1): 1713, 1671, 1604, 1462; m.p.: 267° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:22][CH2:23][NH2:24])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:22][CH2:23][NH:24][C:25](=[O:27])[CH3:26])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCc1ccc(OCc2ccccc2)cc1-c1cccc(F)c1
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1ccc(OCc2ccccc2)cc1-c1cccc(F)c1

Procedure:
80 mg, 0.25 mmol of 29 was added to a 25 mL oven-dried flask containing 5 mL freshly distilled DCM, under argon atmosphere. Acetic anhydride (21 μL, 0.22 mmol) and triethyl amine (35 μL) were then added to the solution and the resultant mixture stirred at room temperature for 3 h. The reaction mixture was then quenched by addition of saturated ammonium chloride, and extracted into DCM. The combined organic layers were dried (Na2SO4) and concentrated to a crude mixture, which was purified by column chromatography (Silica gel, 3:1 hexane:EtOAc) to give the desired product.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:22])[CH2:11][NH:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:29][CH2:30][C:31](Cl)=[O:32]>C(OCC)(=O)C>[CH2:2]([O:9][C:10](=[O:22])[CH2:11][N:12]([C:31](=[O:32])[CH2:30][Cl:29])[CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)CCl
Reactant: O=C(CNC1Cc2ccccc2C1)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C(CN(C(=O)CCl)C1Cc2ccccc2C1)OCc1ccccc1

Procedure:
N-(Indan-2-yl)glycine benzyl ester hydrochloride (6 g) is added to a mixture of 300 ml of ethyl acetate and 200 ml of 5% aqueous potassium carbonate, followed by vigorous stirring. To the resulting solution is added dropwise 6 ml of chloroacetyl chloride over 30 minutes with ice cooling. Thereafter, stirring is continued for an hour. The ethyl acetate layer is then separated, washed with water and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Addition of ether to the residue gives 6 g of N-chloroacetyl-N-(indan-2-yl)glycine benzyl ester as colorless scales melting at 99.5°-100.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][C:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)([C:12]([O:14]CC2C=CC=CC=2)=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:23][CH2:22][C:11]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)([C:12]([OH:14])=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(CC2(C(=O)OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc(CC2(C(=O)O)CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
A mixture of benzyl N-t-butoxycarbonyl-4-(3-methylbenzyl)-isonipecotate (2.36 g, 5.57 mmol), 5% palladium on charcoal (250 mg), and glacial acetic acid (3 mL) in methanol (75 mL), was hydrogenated at 50 psi. in a Parr shaker at room temp. overnight. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to provide the title product as white solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH2:11])[CH3:10])[CH:6]=[N:7][CH:8]=1.C(N(CC)CC)C.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH:11][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])[CH3:10])[CH:6]=[N:7][CH:8]=1
Reactant: C[C@@H](N)c1cncc(Br)c1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N[C@H](C)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
To a 100-mL flask are added (1R)-1-(5-bromo(3-pyridyl))ethylamine HCl salt (0.5 g, 2.105 mmol), DCM (5 mL), and triethylamine (1.2 mL, 8.52 mmol). The mixture is cooled to 0° C. Ethanesulfonyl chloride (0.24 mL, 2.526 mmol, dissolved in 3 mL of DCM) is added dropwise. The mixture is stirred at 0° C. for 15 min. The ice/water bath is removed and the mixture is stirred at room temperature for 25 min. The mixture is diluted with EtOAc (50 mL), washed with water (3×5 mL), and brine, dried over sodium sulfate, filtered, and concentrated. The resulting crude product is purified by normal phase chromatography using 0-5% MeOH in DCM as the gradient to afford ethanesulfonic acid [(R)-1-(5-bromo-pyridin-3-yl)-ethyl]-amide (482.5 mg, 78% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[C:16]([OH:18])=O>C1C=CC=CC=1>[OH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][C:7]=1[C:16]([Cl:3])=[O:18]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cnc2ccccc2c1O
Solvent: c1ccccc1
Product: O=C(Cl)c1cnc2ccccc2c1O

Procedure:
3.8 ml of thionyl chloride were added to a suspension of 8.2 g of 4-hydroxy-quinoline-3-carboxylic acid in 160 ml of benzene and the mixture was refluxed for an hour and then cooled. The mixture was vacuum filtered and the precipiate was empasted with a little anhydrous benzene and was dried to obtain 9 g of 4-hydroxy-quinoline-3-carboxylic acid chloride melting at 260° C. The said product was then reacted with 4.35 g of 2-aminothiazole as in Example 1 to obtain 4.3 g of N-(2-thiazolyl)-4-hydroxy-quinoline-3-carboxamide melting at 349°-350° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:16](OCC)[O:17]CC)=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4].C(O)=O>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH:16]=[O:17])=[CH:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:4]
Reactant: CCOC(OCC)c1cc(-c2ccccc2)c(C(=O)OC)s1
Solvent: O=CO
Solvent: C1COCCO1
Product: COC(=O)c1sc(C=O)cc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A solution of 5-Diethoxymethyl-3-phenyl-thiophene-2-carboxylic acid methyl ester (5.07 g, 15.82 mmol) in dioxane (25 ml) was cooled to 0° C. (ice bath). 95% formic acid (50 ml) was added dropwise and the mixture was stirred at 0° C. for 30 min and then at rt for 60 min. The reaction mixture was quenched by pouring into EtOAc. The organic layer was washed with water, dried over Na2SO4 and concentrated under reduced pressure to afford the desired product (3.50 g, 90% yield).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH2:20]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23].CCOC(C)=O>CS(C)=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:19])[N:24]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCCCNCCCC
Reactant: CC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCN(CCCC)C(=O)Nc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.1 %

Procedure:
In a dry 100 mL flask equipped with an N2 inlet adapter, a rubber septum and a magnetic stirring bar, was placed phenyl N-(4-acetylphenyl)carbamate (6.38 g, 25 mmol) in DMSO (50 mL). Dibutylamine (4.42 mL, 26.25 mmol) was slowly added to the mixture. The resulting solution was stirred at room temperature for 15 min, after which time EtOAc (250 mL) was added to the reaction mixture. The latter was washed successively with H2O (2×50 mL), aqueous 1N HCl (100 mL), H2O (100 mL), aqueous 1N NaOH (100 mL) and brine (100 mL), dried (MgSO4) and concentrated under reduced pressure to give a crude solid. The solid was triturated with Et2O/hexane to yield 6.98 g (96% yield) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:21]([NH:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2)c(Cl)c1
Reaction time: 15 h
Yield: 85.6 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.31 g, 6.56 mmol) and phenyl isocyanate (0.71 ml, 6.56 mmol) in THF (20 ml) was added Et3 N (0.19 ml, 1.33 mmol) at room temperature. After 15 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-chloro-4-(N′-phenylureido)phenylacetate (1.79 g, 86%) as a pale brown solid. 1H-NMR (CDCl3) δ 3.56 (s, 2H), 3.70 (s, 3H), 6.70 (m, 1H), 7.06 (s, 1H), 7.14–7.18 (m, 2H), 7.26 (dd, J=7.8, 1.9 Hz, 1H), 7.33–7.38 (m, 4H), 8.14 (dd, J=8.3, 3.0 Hz, 1H); MS (ESI) m/z 319 (M++1), 321 (M++3).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[C@@H:6]([CH3:53])[C:7]([S:25][C@@H:26]1[CH2:30][CH2:29][O:28][C@@H:27]1[CH2:31][NH:32][C:33](=[O:52])[C@@H:34]([NH:38]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH:35]([CH3:37])[CH3:36])=[C:8]2[C:12]([O:14]CC1C=CC([N+]([O-])=O)=CC=1)=[O:13])[CH3:3].O>C(O)CCCC.[Pd]>[NH2:38][C@@H:34]([CH:35]([CH3:37])[CH3:36])[C:33]([NH:32][CH2:31][C@@H:27]1[C@H:26]([S:25][C:7]2[C@H:6]([CH3:53])[C@H:5]3[N:9]([C:10](=[O:11])[C@@H:4]3[C@H:2]([OH:1])[CH3:3])[C:8]=2[C:12]([OH:14])=[O:13])[CH2:30][CH2:29][O:28]1)=[O:52]
Reactant: CC(C)[C@H](NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)NC[C@H]1OCC[C@H]1SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Agent: [Pd]
Solvent: O
Solvent: CCCCCO
Product: CC(C)[C@H](N)C(=O)NC[C@H]1OCC[C@H]1SC1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2[C@H]1C
Reaction time: 20 h
Yield: 80.5 %

Procedure:
To a mixture of 1.0 g of 4-nitrobenzyl (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-{[(2R,3R)-2-({[(2S)-3-methyl-2-({[(4-nitrobenzyl)oxy]carbonyl}-amino)butanoyl]amino}methyl)tetrahydrofuran-3-yl]thio}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in 50 ml of 1-pentanol is added 50 ml of water followed by 0.5 g of 10% palladium-on-carbon. The reaction mixture is then hydrogenated in a Parr apparatus at 54 psi for 20 hours. The mixture is filtered through a pad of diatomaceous earth and the pad washed with an additional 40 ml of water. The filtrate is transferred to a separatory funnel, and the aqueous layer separated. The 1-pentanol layer is washed with an additional 10 ml of water. The combined aqueous layers are washed with 100 ml of ethyl acetate and lyophilized to afford 0.47 g(81%) of the desired product. MS (ES), m/z:442.3 (M+H)+, 98% area percent pure by analytical HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1>C(O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)cc3)oc2C)cc1
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
Ethyl 3-[{[4-({1-[5-(4-methoxyphenyl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (660 mg) which is a synthetic intermediate in Example 151 was dissolved in ethanol-hexane (1:1, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with ethanol-hexane (1:1, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 21.4 min were collected, and concentrated. The obtained amorphous compound (319 mg) was dissolved in ethanol (5 mL) and tetrahydrofuran (5 mL), 1N lithium hydroxide (1.3 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (20 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (284 mg, 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH2:13][NH:14][C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16].[C:22]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]([CH3:46])=[C:31]([CH2:33][CH2:34]OS(C3C=CC(C)=CC=3)(=O)=O)[N:32]=2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:34][CH2:33][C:31]2[N:32]=[C:28]([C:25]3[CH:26]=[CH:27][C:22]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)=[CH:23][CH:24]=3)[O:29][C:30]=2[CH3:46])=[CH:8][C:7]=1[CH2:13][NH:14][C:15]([O:17][CH:18]([CH3:19])[CH3:20])=[O:16]
Reactant: COC(=O)CCc1ccc(O)cc1CNC(=O)OC(C)C
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Product: COC(=O)CCc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1CNC(=O)OC(C)C

Procedure:
3-[4-Hydroxy-2-(isopropoxycarbonylamino-methyl)-phenyl]-propionic acid methyl ester (Preparation 17) and toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyl-oxazol-4-yl)ethyl ester (Preparation 1) were combined according to Standard procedure A to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].[CH2:14]([NH2:19])[CH2:15][CH2:16][CH2:17][NH2:18]>C1(C)C=CC=CC=1.O>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:19][C:9](=[O:10])[C:8]2[CH:7]=[CH:6][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:13][CH:12]=2)=[O:10])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: NCCCCN
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)NCCCCNC(=O)c2ccc(C(=O)OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Carbomethoxybenzoyl chloride (19.07 g, 0.096 mol) was dissolved in toluene (380 mL) in a 3-necked, 1000 mL round-bottomed flask equipped with mechanical stirrer, thermometer, and addition funnel. A solution of 1,4-butanediamine in water (80 mL) was added dropwise over a period of 40 minutes while the temperature of the reaction mixture was maintained at 25° C. by a water bath. A white solid formed immediately and the reaction mixture stirred for an additional 2 hours. The solid was collected on a frit and washed with toluene, water, 5% HCl, and water. Recrystallization from DMF gave white crystals which were dried in a vacuum oven at 60° C.; yield 17.91 g (90%); m.p. 260°-261° C. 1H NMR (200 MHz, DMSO-d6) δ8.70 (2H, m), 8.05-7.93 (8H, m) 3.88 (6H, s) 3.34 (4H, s), 1.58 (4H, s); IR (nujol) 3300, 1720, 1625, 1530, 1275, 1105, 860, 730 cm-1 ; low res. MS (Cl, isobutane) 413 (MH+); 13C NMR (75 MHz, DMSO-d6) δ166.9, 165.7, 165.4, 165.2, 138.7, 131.6, 129.0, 127.5, 127.2, 52.3, 26.5.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(=O)(O)[O-].[Na+]>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[S:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: Sc1ccccc1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Sc1ccccc1

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g), thiophenol (10.25 ml), and 1N sodium bicarbonate (300 ml) was refluxed for 3 hours. After cooling, the precipitated sodium salt of 3-nitro-4-phenylthio-5-sulphamyl-benzoic acid was filtered off. The sodium salt was dissolved in hot water (200 ml), and 3-nitro-4-phenylthio-5-sulphamyl-benzoic acid was precipitated by the addition of 4N hydrochloric acid until the pH was 1. After isolation and recrystallization from aqueous ethanol, the acid was obtained with a melting point of 245°-247° C.