Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([C:15]3[C:16](=[O:22])[NH:17][C:18](=[O:21])[NH:19][CH:20]=3)[C:7]3[C:8]([CH:13]=[CH:14][C:4]=2[CH:3]=1)=[N:9][CH:10]=[CH:11][CH:12]=3.[H-].[Na+].I[CH3:28]>CN(C)C=O.O>[CH3:28][N:19]1[CH:20]=[C:15]([CH:6]2[C:7]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[CH:13]=[CH:14][C:4]3[CH:3]=[C:2]([CH3:1])[CH:24]=[CH:23][C:5]2=3)[C:16](=[O:22])[NH:17][C:18]1=[O:21]
Reactant: Cc1ccc2c(c1)C=Cc1ncccc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)C=Cc1ncccc1C2c1cn(C)c(=O)[nH]c1=O
Reaction time: 16 h

Procedure:
A solution of the product of example 22 step (iv) (0.68 g) in dry N,N-dimethylformamide (10 ml) was treated in one portion with sodium hydride (60% dispersion by wt, 0.086 g). After 1 hr iodomethane (0.13 ml) was added and the solution was stirred for 16 hr. The reaction mixture was diluted with water (50 ml) and the mixture was extracted with ethyl acetate (3×20 ml). The combined extracts were dried (Na2SO4) and the solvent was evaporated under reduced pressure. Purification was by chromatography eluting with 50-60% acetone in isohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Nc1ccc(Cl)cc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(Cl)cc1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
4-Chloroaniline (6.697 g, 52 mmol) was dissolved in pyridine (250 mL). The resulting mixture was cooled down to 0° C. 4-fluoro-benzenesulfonyl chloride (7.775 g, 40 mmol) was added in portions. The mixture was stirred between 0° C. and room temperature overnight. Solvents were evaporated to dryness. The crude oil was dissolved in ethyl acetate (150 mL) and washed with 10% HCl (2×75 mL) and brine (1×75 mL). Organic phase was dried over magnesium sulfate before filtering and removal of solvent. The resulting solid was recrystallized in cyclohexane/ethyl acetate 9:1. The desired product, e.g. 4-fluoro-N-(4-chlorophenyl)benzenesulfonamide (6.630 g, 58%), was obtained as a colorless solid, in 97.3% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[N:5]2.CN(C)C=O.S(Cl)([Cl:22])=O>ClCCl>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([Cl:22])=[O:14])[CH:6]=[N:5]2
Reactant: O=C(O)c1cnc2cc(I)ccc2n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cnc2cc(I)ccc2n1
Temperature: 25 °C

Procedure:
To a solution of compound 23 (200 mg, 0.67 mmol) in dry dichloromethane (10 mL), under argon and at 0° C., was added dropwise dry N,N-dimethylformamide (100 μL) and thionyl chloride (200 μL, 2.74 mmol). The reaction mixture was stirred at reflux for 3 h. After cooling to room temperature, the solvent was removed under reduced pressure to afford crude 6-iodoquinoxaline-2-carbonyl chloride. This was suspended in dry tetrahydrofuran (10 mL) and were successively added, under argon, p-nitrophenol (93 mg, 0.67 mmol) and dropwise a solution of triethylamine (95 μL, 0.68 mmol) in dry tetrahydrofuran (5 mL). The solution was stirred at 50° C. for 18 h. After cooling to room temperature, dichloromethane (30 mL) was added and the resulting solution was washed with a 5% aqueous sodium carbonate solution (20 mL). The aqueous layer was extracted with dichloromethane (5×15 mL) and the organic layers were combined, dried on magnesium sulfate and evaporated under reduced pressure. The resulting precipitate was triturated with ether (5 mL) and collected by filtration to afford ester 24 (225 mg, 0.53 mmol) as a beige solid. Yield 80%; mp 228-230° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.71 (d, 2H, J=7 Hz), 8.09 (d, 1H, J=9 Hz), 8.30 (dd, 1H, J=2, 9 Hz), 8.41 (d, 2H, J=7 Hz), 8.72 (d, 1H, J=2 Hz), 9.60 (s, 1H).
Reaction SMILES: [OH:1][CH:2]([CH2:15][OH:16])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1.[C:17](Cl)(=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>ClCCl.N1C=CC=CC=1>[CH2:17]([O:1][CH:2]([CH2:15][O:16][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:7][CH:6]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: OCC(O)C#Cc1ccc(-c2cccs2)s1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(C#Cc1ccc(-c2cccs2)s1)OCCCCCCCCCCCCCCCCCC
Reaction time: 48 h

Procedure:
170 mg (0.68 mmole) of 5-(3,4-dihydroxy-1-butynyl)2,2-bithiophene was dissolved in a mixture of 10 ml of dichloromethane and 0.2 ml of pyridine. 0.7 g of stearoyl chloride dissolved in 10 ml of dichloromethane was then dropped into the reaction mixture in ice bath. This reaction solution was stirred for 2 days. It was monitored by thin layer chromatography to determine if there were 3 products obtained, i.e. a mixture of 1 diester and 2 monoesters.
Reaction SMILES: C(O[C:4](=[O:13])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[Cl:14][C:15]1[C:16]([CH3:24])=[C:17]([N:21]=[C:22]=[S:23])[CH:18]=[CH:19][CH:20]=1>C(Cl)(Cl)Cl>[Cl:14][C:15]1[C:16]([CH3:24])=[C:17]([N:21]2[C:4](=[O:13])[CH2:5][N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:22]2=[S:23])[CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CNc1ccccc1
Reactant: Cc1c(Cl)cccc1N=C=S
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)cccc1N1C(=O)CN(c2ccccc2)C1=S
Yield: 33.5 %

Procedure:
A mixture of N-phenyl glycine ethyl ester (8.95 g), 3-chloro-2-methylphenylisothiocyanate (9.18 g), and chloroform (200 mL) was heated at reflux for 18 hours. The solvent was evaporated to dryness. The residue was mixed with ethanol (150 mL), and triethyl amine (3 mL). The mixture was heated at reflux for 3 hours. The solvent was evaporated. The residue was dissolved in ethyl acetate (300 mL) and washed with 1N HCl (2×200 mL), then with water (200 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was treated with diethyl ether. The solid was collected by filtration and air dried to give the title compound (5.3 g) as an off-white solid, m.p. 154°-156° C. Anal. Calcd. for. C16H13Cl N2O S: C, 60.66; H, 4.14; N, 8.84. Found: C, 60.48; H, 4.05; N, 8.76. Mass spectrum (+FAB, [M+H]+) m/z 317/319.
Reaction SMILES: [C-]#N.[Na+].[N:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28](=[O:43])/[CH:29]=[CH:30]/[C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[C:36](=[N:40][O:41][CH3:42])[CH2:35][CH2:34]3)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[CH2:12]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([C:28](=[O:43])[CH2:29][CH:30]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[C:36](=[N:40][O:41][CH3:42])[CH2:35][CH2:34]3)[C:10](=[O:11])[C:7]2[CH:8]=[CH:9][N:4]=[CH:5][CH:6]=2)[CH2:26][CH2:27]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccncc1
Reactant: CON=C1CCc2cc(/C=C/C(=O)C3CCN(C(=O)OCc4ccccc4)CC3)ccc21
Agent: O=C([O-])O
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C1CCc2cc(C(CC(=O)C3CCN(C(=O)OCc4ccccc4)CC3)C(=O)c3ccncc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
A solution of sodium cyanide (240 mg, 4.8 mmol) in DMF (15 ml) was treated with a solution of pyridine-4-carbaldehyde (1.71 g, 16 mmol) in DMF (25 ml). After 15 minutes a solution of the product of Step 2 (6.92 g, 16 mmol) in DMF (20 ml) was added dropwise. After stirring at room temperature for 18 hours the mixture was diluted with saturated sodium bicarbonate solution and ethyl acetate. The organic phase was washed with water and brine, dried and concentrated in vacuo and the residue purified by silica gel chromatography to give the title compound (5.6 g, 65%); MS(ES+) m/e 540 [M+H]+.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[C@@:13]3([CH3:19])[N:14]=[C:15]([NH2:18])[S:16][CH2:17][C@H:12]3[CH2:11][O:10][C:8]=2[CH:9]=1.[OH-].[Na+].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:5]1[C:4]([F:3])=[CH:9][C:8]2[O:10][CH2:11][C@@H:12]3[CH2:17][S:16][C:15]([NH2:18])=[N:14][C@:13]3([CH3:19])[C:7]=2[CH:6]=1
Reactant: BrBr
Reactant: C[C@]12N=C(N)SC[C@H]1COc1cc(F)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: C[C@]12N=C(N)SC[C@H]1COc1cc(F)c(Br)cc12
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
Bromine (0.20 mL, 3.80 mmol) was added dropwise to a solution of rel-(4aR,10bS)-8-fluoro-10b-methyl-4,4a,5,10b-tetrahydrochromeno[4,3-d][1,3]thiazin-2-amine from step F6 (644 mg, 2.55 mmol), in acetic acid (20 mL) at rt. The mixture was stirred for 30 min. The reaction was poured onto ice. The slurry was made pH 3 upon slow addition of 50% NaOH/water. The aqueous mixture was made basic pH 7-8 by the addition of solid sodium bicarbonate. The aqueous layers were extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (0.25%-10% MeOH/CHCl3) to afford rel-(4aR,10bS)-9-bromo-8-fluoro-10b-methyl-4,4a,5,10b-tetrahydrochromeno[4,3-d][1,3]thiazin-2-amine (667 mg, 1.62 mmol, 64% yield) as a viscous oil. LCMS (M+H)+=333.02. 1H NMR (500 MHz, methanol-d4) δ 7.73 (d, J=7.5 Hz, 1H), 6.79 (d, J=9.8 Hz, 1H), 4.53 (dd, J=11.9, 2.9 Hz, 1H), 4.30 (dd, J=12.0, 6.0 Hz, 1H), 3.50 (dd, J=13.7, 3.9 Hz, 1H), 3.23 (dd, J=13.6, 8.1 Hz, 1H), 2.64 (dtd, J=10.0, 3.9, 3.0 Hz, 1H), 1.80 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25].CN(C)C=O>C(N(CC)CC)C>[O:11]1[C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[CH2:14][CH2:15][CH:10]1[CH2:9][N:8]([CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:21][CH2:22][CH2:23][C:24]#[N:25]
Reactant: c1ccc(CNCC2CCc3ccccc3O2)cc1
Reactant: N#CCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCCCN(Cc1ccccc1)CC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 72 h
Yield: 69.6 %

Procedure:
A mixture of 12.5 g of 3,4-dihydro-N-(phenylmethyl)-2H-1-benzopyran-2-methanamine, 9 g of 4-bromobutanenitrile, 200 ml of N,N-dimethylformamide and 10 ml of N,N-diethylethanamine was stirred for 72 hour at room temperature. The reaction mixture was evaporated and the residue was partitioned between 1,1'-oxybisethane and water. The organic layer was separated, dried, filtered and evaporated, yielding 11 g (68.7%) of (±)-4-[[(3,4-dihydro-2H-1-benzopyran-2-yl)methyl](phenylmethyl) amino]-butanenitrile (interm. 53).
Reaction SMILES: [CH2:1]([CH:8]([S:13]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[CH2:30])=[CH:27][CH:26]=1.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(Cl)Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([CH:8]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH:30]=[CH:29][C:28]2[CH:31]=[CH:32][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:9][C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC(Cc1ccccc1)S(=O)(=O)c1ccc(Br)cc1
Reactant: C=Cc1ccc(OC)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Product: O=C(O)CC(Cc1ccccc1)S(=O)(=O)c1ccc(C=Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 3-benzyl-3-(4-bromophenylsulfonyl)-propionic acid (250 mg), p-methoxystyrene (0.1 ml), diisopropylethylemine (0.25 ml), palladium acetate (5 mg) and tri(o-methylphenyl)phosphine (16 mg) was stirred overnight at 80° C. The reaction mixture was dissolved in methylene chloride and washed with aqueous citric acid. Solvent was removed from the methylene chloride solution, and the residue chromatographed on silica gel (preparative TLC, eluting with 10% methanol/methylene chloride), to afford 3-benzyl-3-(4-styrylphenylsulfonyl)-propionic acid (21 mg).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)([OH:3])=O.[N:18]#[C:19][NH2:20]>>[C:19]([N:20]=[C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:6][CH:5]=1)[OH:3])#[N:18]
Reactant: O=C(O)c1ccc(OCCn2ccnc2)cc1
Reactant: N#CN
Product: N#CN=C(O)c1ccc(OCCn2ccnc2)cc1

Procedure:
Treatment of 1-[2-(4-carboxyphenoxy)ethyl]imidazole with N,N'-carbonyldiimidazole followed by cyanamide as described in Example 36 above gave N-cyano-4-[2-(1-imidazolyl)ethoxy]benzenecarboximidic acid, m.p. 199°-200° C. (d) (from water). Found: C, 60.59; H, 4.64; N, 22.20. C13H12N4O2 requires: C, 60.93; H, 4.72; N, 21.87%.
Reaction SMILES: I.[CH:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[NH:18])SC)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH2:19][CH2:20][CH2:21][CH2:22]N>C(O)CCCC>[CH:2]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]=[C:15]3[NH:18][CH2:22][CH2:21][CH2:20][NH:19]3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NCCCN
Reactant: CSC(=N)Nc1ccc(C2CCCCC2)cc1
Agent: I
Solvent: CCCCCO
Product: c1cc(C2CCCCC2)ccc1N=C1NCCCN1

Procedure:
A solution of 3.6 g of N-(4-cyclohexylphenyl)-S-methyl-isothiourea hydroiodide and 1 ml of 1,3-diaminopropane in 15 ml of amyl alcohol is refluxed for 21/2 hours. After distilling off the solvent the residue is taken up in methylene chloride and washed with dilute alkaline solution and water. The methylene chloride is distilled off and the crude final product is recrystallised from acetonitrile. The resulting 2-(4-cyclohexylphenyl)imino-hexahydropyrimidine has a melting point of 179°-181° C.
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCCCCC>C(OCC)(=O)C>[C:2]12([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: Nc1ccccc1
Reactant: BrC12CC3CC(CC(C3)C1)C2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1ccc(NC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 200 °C
Reaction time: 20 h

Procedure:
Under a nitrogen (N2) atmosphere was combined 10.0 g (46.5 mmol) of 1-bromoadamantane and 20 ml of aniline. The reaction was stirred for 20 hours at 200° C., and then cooled and fractionated on silica gel using 6:1 hexane:ethyl acetate (EtOAc) to afford, after concentration in vacuo and refractionation using toluene, 5.65 g (54%) of N-1-adamantylaniline.
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[NH3:27]>CO.O1CCCC1>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[O:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4](=[O:25])[C:3]([NH2:27])=[O:2])=[CH:6][CH:7]=1
Reactant: N
Reactant: COC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)C(=O)c1ccc(OCCOc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in methanol (40 mL) and tetrahydrofuran (40 mL) was chilled in an ice bath and saturated with ammonia gas. The cooling bath was removed and the mixture was stirred at room temperature for 4 hours and the solution was evaporated to dryness. Crystallization from tetrahydrofuran-ethyl alcohol provided 0.4 g of 4-[[2-(2-naphthalenyloxy)ethyl]oxy]-alpha-oxobenzeneacetamide as a colorless solid, mp 194°-196° C.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:10]([NH:12][NH2:13])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C1COCC1>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:10]([NH:12][NH:13][C:24]([CH3:25])=[O:26])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: NNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 50 ml of THF is dissolved 2.03 g (6.5 m mols) of Z-Phe-NH-NH2, and under cooling, 1.4 ml of acetic anhydride and 0.9 ml of TEA are added dropwise. The mixture is stirred at room temperature for 2 hours. The crystals are collected by filtration, washed with diethyl ether and recrystallized from AcOEt. 1.9 g (83%); m.p. 205°-206° C.; [α]D23 -16.4° (c=0.5, DMF); Rf1 =0.60.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:24])[C@H:15]([NH2:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25](N(C1C=CC=CC=1C(F)(F)F)C(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C@@H:14]([OH:24])[C@H:15]([NH:23][C:25](=[O:27])[CH3:26])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)N(C(C)=O)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1[C@@H](O)[C@H](N)Cc1ccccc1
Solvent: ClCCl
Product: CC(=O)N[C@H](Cc1ccccc1)[C@H](O)[C@H]1CNCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
Dissolve 2-(R)-(2-(R)-amino-1-(S)-hydroxy-3-phenyl-propyl)-piperazine-1-carboxylic acid tert-butyl ester (232 mg, 0.69 mmol) in 7 ml of dry CH2Cl2 and add N-acetyl-N-(2-trifluoromethyl-phenyl)-acetamide (Tetrahedron Letters, 38(21), 3751 (1997)) (162 mg, 0.66 mmol). Stir at room temperature overnight. Subject reaction mixture to silica gel chromatography, eluting ethyl acetate/triethylamine 98:2 to obtain 122 mg of the title compound (60% yield based on 79% conversion) and 50 mg of starting amine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[C@H:5]([CH2:7][SH:8])[NH2:6])[CH3:2].[CH:10](=O)[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13]>>[C:4]([C@@H:5]1[CH2:7][S:8][CH:10]([C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[OH:13])[NH:6]1)([O:3][CH2:1][CH3:2])=[O:9]
Reactant: CCOC(=O)[C@@H](N)CS
Reactant: O=Cc1ccccc1O
Product: CCOC(=O)[C@@H]1CSC(c2ccccc2O)N1

Procedure:
The procedure of M. Schubert (J. Biol. Chem., 114, 341 (1936)) was used to prepare 57 starting from L-cysteine ethyl ester and salicylaldehyde. Purification by silica gel chromatography afforded 57 as a thick oil. TLC (silica gel; 3:1 cyclohexane-EtOAc) showed a mixture of 2 isomers, Rf=0.4, 0.5. IR (film): 3300 (sharp), 3000, 1740, 1430 cm-1. NMR (CCl4): 1.28 (3H, t, J=7); 2.9-3.5 (2H, m); 3.8-4.4 (3H, m); 5.50, 5.80 (1H, 2x broad s); 6.5-7.3 (4H, m).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH2:22][C@H:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=1)[CH2:24][OH:25]>>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([C@@H:23]([NH:22][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:24][OH:25])[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: COc1ccc([C@@H](N)CO)cc1OC
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: COc1ccc([C@H](CO)Nc2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2[N+](=O)[O-])cc1OC
Yield: 53 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with (R)-2-amino-2-(3,4-dimethoxy-phenyl)-ethanol according to the GPA affording 24.8 mg (53%) of a red powder. Rt=3.80 min.
Reaction SMILES: C[O-].[Na+].CO.[C:6]([CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:10])[CH:7]([CH3:9])[CH3:8].O[N:17]=[C:18](Cl)[C:19]1[C:20]([CH3:26])=[N:21][CH:22]=[CH:23][C:24]=1[CH3:25]>C1COCC1>[CH3:26][C:20]1[C:19]([C:18]2[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:6]([CH:7]([CH3:9])[CH3:8])[O:10][N:17]=2)=[C:24]([CH3:25])[CH:23]=[CH:22][N:21]=1
Reactant: COC(=O)CC(=O)C(C)C
Reactant: Cc1ccnc(C)c1C(Cl)=NO
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2c(C)ccnc2C)noc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
A 0.5 N solution of sodium methoxide in methanol (2.8 mL, 1.4 mmol) was added to a solution of methyl isobutyrylacetate (0.19 mL, 1.34 mmol) in THF (0.24 mL) at 0° C. A solution of the crude N-hydroxy-2,4-dimethyl-3-pyridinecarboximidoyl chloride (0.22 g, 1.2 mmol) in THF (2.2 mL) was added and the resulting mixture was allowed to warm to room temperature and stir overnight. The solution was concentrated and the residue was partitioned between ethyl acetate and brine. The organic layer was dried with MgSO4, filtered and concentrated. The residue was chromatographed (silica gel, hexane to 3:2 ethyl acetate:hexane) to provide methyl 3-(2,4-dimethyl-3-pyridinyl)-5-(1-methylethyl)-4-isoxazolecarboxylate (0.17 g, 52%). ESI-LCMS m/z 275 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[C:39]([O:43][C:44](=[O:49])[NH:45][CH2:46][CH2:47]O)([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:39]([O:43][C:44]([NH:45][CH2:46][CH2:47][O:23][C:22](=[O:24])[CH2:21][O:20][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:26][CH:25]=1)=[O:49])([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C(O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOC(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reaction time: 16 h
Yield: 48.3 %

Procedure:
[4-(4-Benzyloxycarbonylaminobutyl)phenoxy]acetic acid 48 (240 mg, 0.67 mmol) was dissolved in anhydrous CH2Cl2 (6 mL). To the solution was added DMAP (98 mg, 0.80 mmol), followed by EDC-HCl (154 mg, 0.81 mmol). The reaction mixture was stirred at room temperature for 15 min. (2-Hydroxyethyl)carbamic acid tert-butyl ester (0.21 mL, 1.34 mmol) was then added and the stirring was continued for 16 h. Solvent was removed by rotary evaporation. The residue was subjected to flash silica gel column chromatography eluting with ethyl acetate/dichloromethane (1:20, 1:15, and 1:10, v/v) to give the desired ester 44a as a colorless oil (162 mg, 48% yield). 1H NMR (300 MHz, CDCl3) δ 1.35-1.65 (m, 4H), 1.44 (s, 9H), 2.45-2.58 (m, 2H), 3.10-3.22 (m, 2H), 3.25-3.42 (m, 2H), 4.18-4.28 (m, 2H), 4.62 (s, 2H), 4.70 (br s, 1H), 4.84 (br s, 1H), 5.08 (s, 2H), 6.81 (d, 2H), 7.07 (d, 2H), 7.25-7.38 (m, 5H). m/z (ESI) 501 [C27H36N2O7+H]+.
Reaction SMILES: C(OC([NH:8][C:9](=[O:20])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=1)[NH2:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[I:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C@@H:10]([C:9]([NH2:8])=[O:20])[NH2:11])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NC(=O)[C@@H](N)Cc1ccc(I)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)[C@@H](N)Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
N-(tert-Butoxycarbonyl)-4-iodo-(L)-phenylalaninamide (4.24 g) was dissolved in DCM (20 mL) and to the solution was added TFA (20 mL). The reaction mixture was stirred, at room temperature, for 0.5 h then concentrated to dryness under reduced pressure. The crude material obtained was loaded onto an SCX cartridge. Non-basic impurities were washed off with a 1:1 mixture of DCM and methanol, then the cartridge was eluted with 10% ammonia in methanol. Eluent from the latter was concentrated to dryness to give the free base of the sub-title compound (3 g) as a white solid.