Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:48][CH:49]1[NH:53][CH2:52][C:51]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)([OH:54])[CH2:50]1>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([C:14]([N:53]3[CH:49]([CH3:48])[CH2:50][C:51]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)([OH:54])[CH2:52]3)=[O:16])=[CH:12][O:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1
Reactant: CC1CC(O)(c2ccccc2)CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(-c2nocc2C(=O)N2CC(O)(c3ccccc3)CC2C)cc1
Yield: 52.9 %

Procedure:
A solution of 3-(4-methoxyphenyl)isoxazole-4-carboxylic acid (7 mg, 0.03 mmol), N-ethyl-N-isopropylpropan-2-amine (16 μL, 0.09 mmol, 3 equ.) and TBTU (12 mg, 0.036 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 5-methyl-3-phenylpyrrolidin-3-ol (5 mg, 0.03 mmol). After 1 h at rt the crude product was purified by RP-HPLC. The pure fractions were basified (NaHCO3) and extracted with ethyl acetate, dried (Na2SO4), evaporated and dried in vacuum to yield the title compound (6 mg). MS (ESI, pos. ion) m/z: calcd for C22H22N2O4: 378.1580, found 378.1580.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH:11]([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH:11]([CH3:19])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: Oc1ccc(Cl)cc1Br
Product: CC(Oc1ccc(Cl)cc1Br)C(=O)OC(C)(C)C

Procedure:
The subtitle compound was prepared by the method of example 1 step (i) using 2-bromo-4-chlorophenol and 2-bromopropionic acid, tert-butyl ester, yield 1.1 g
Reaction SMILES: [C:1]([C:3]([NH:8][C:9](=[O:15])/[CH:10]=[CH:11]\[C:12]([OH:14])=O)([CH3:7])[CH:4]([CH3:6])[CH3:5])#[N:2].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH:4]([C:3]([CH3:7])([N:8]1[C:9](=[O:15])[CH:10]=[CH:11][C:12]1=[O:14])[C:1]#[N:2])([CH3:6])[CH3:5]
Reactant: CC(C)C(C)(C#N)NC(=O)/C=C\C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(C)C(C)(C#N)N1C(=O)C=CC1=O
Yield: 62 %

Procedure:
A solution of N-(1-cyano-1,2-dimethylpropyl)maleamic acid (595 g, 2.83 mol) in acetic anhydride (3.96 liters) containing sodium acetate (13.72 g, 0.167 mol) is heated under reflux for one hour, cooled and the solvent removed in vacuo. The product is distilled* at 120°-130° C./0.1 mm to give 337 g (63%) of product.
Reaction SMILES: [ClH:1].C[CH2:3][CH2:4][CH2:5][C@H:6]([NH:15]C(=O)OC(C)(C)C)[C:7](=[O:14])[CH2:8][NH:9][CH2:10][CH:11]([CH3:13])[CH3:12].[C:23](O)(=O)C>Cl>[ClH:1].[ClH:1].[NH2:15][C@@H:6]([CH2:5][CH:4]([CH3:3])[CH3:23])[C:7](=[O:14])[CH2:8][NH:9][CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(=O)O
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)CNCC(C)C
Agent: Cl
Product: CC(C)CNCC(=O)[C@@H](N)CC(C)C
Reaction time: 0.33 h

Procedure:
(S)-[4-Methyl-1-[[(2-methylpropyl)amino]acetyl]butyl]carbamic acid, 1,1-dimethylethyl ester, hydrochloride (0.66 g, 1.95 mmol) was dissolved in a solution of hydrogen chloride in acetic acid (1.5N, 7 ml) and allowed to stand at room temperature for 20 minutes. It was evaporated in vacuo and then re-evaporated from benzene. The residue was crystallized from isopropanol yielding 240 mg of the title compound, melting point 148°-150° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH2:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1>C(#N)C.CN(C)C=O.O>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: O=C(O)[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 85 °C

Procedure:
5-Fluoro-2-nitrobenzotrifluoride (1.46 g, 7.0 mmol) and trans-4-aminocyclohexane carboxylic acid (1.0 g, 7.0 mmol) were dissolved in a mixture of acetonitrile (42 mL), dimethylformamide (21 mL), and water (7 mL). The resulting solution was heated to 85° C. and then maintained at this temperature overnight. After cooling to room temperature, the mixture was partly concentrated under vacuum, diluted with ethyl acetate (50 mL), and washed with water (30 mL). The aqueous phase was acidified to pH 4 by the addition of 1 M HCl. This formed a precipitate, which was isolated by filtration. The filtrate was extracted with ethyl acetate (2×10 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under vacuum to afford a solid. Both solids were combined and dried under vacuum. The desired product was isolated as a yellow solid (2.4 g, quantitative yield).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[C:12]4[O:17][CH2:16][O:15][C:13]4=[CH:14][C:8]=3[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][N:5]2[C:24]=1[CH3:25].C([Li])CCC.CN(C)[CH:33]=[O:34].O>O1CCCC1>[CH:33]([C:2]1[N:3]=[C:4]2[CH2:10][C:9]3[CH:11]=[C:12]4[O:17][CH2:16][O:15][C:13]4=[CH:14][C:8]=3[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:6][N:5]2[C:24]=1[CH3:25])=[O:34]
Reactant: Cc1c(Br)nc2n1N=C(c1ccccc1)c1cc3c(cc1C2)OCO3
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C=O)nc2n1N=C(c1ccccc1)c1cc3c(cc1C2)OCO3
Reaction time: 0.25 h

Procedure:
120 mg of 9-bromo-8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is mixed in 15 ml of tetrahydrofuran at −78° C. with 0.36 ml of butyllithium (hexane, 1 mol) and stirred for 15 minutes. It is then mixed at this temperature with 0.6 ml of dimethylformamide and stirred for 15 minutes. After stirring to room temperature, it is mixed with water, the tetrahydrofuran is distilled off and extracted with ethyl acetate. After the solvent is distilled off, it is chromatographed on silica gel with dichloromethane:ethanol=95:5 as an eluant. 46 mg of 9-formyl-8-methyl-5-phenyl-11H-1,3-dioxolo[4,5-h]imidazo[1,2-c][2,3]benzodiazepine is obtained.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[CH:14][C:9]=2[S:8](=[O:26])(=[O:25])[CH:7]=1)C.C1COCC1.CO.O.[OH-].[Li+]>O>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:13]1[CH:12]=[CH:11][C:10]2[C:6]([CH2:5][C:4]([OH:27])=[O:3])=[CH:7][S:8](=[O:26])(=[O:25])[C:9]=2[CH:14]=1
Reactant: CCOC(=O)CC1=CS(=O)(=O)c2cc(OCc3ccc(Cl)cc3Cl)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1=CS(=O)(=O)c2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.5 %

Procedure:
To a mixture of ethyl(6-((2,4-dichlorobenzyl)oxy)-1,1-dioxido-1-benzothiophen-3-yl)acetate (8.00 g), THF (64 mL), MeOH (64 mL) and H2O (32 mL) was added lithium hydroxide hydrate (1.58 g) and the resulting mixture was stirred at 25° C. for 16 h. The solvent was removed under reduced pressure. The residue was suspended in water, and the mixture was acidified by 6N HCl. The resulting solid was collected by filtration, and dried under reduced pressure to give the title compound (4.00 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.CN([P+]([O:49][N:50]1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.Cl.NO>CN(C)C=O.C(Cl)(Cl)Cl.CO>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:27](=[O:31])[N:28]([CH3:29])[CH3:30])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:22])[NH:50][OH:49])=[CH:18][CH:17]=2)=[CH:25][CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1)NC(=O)OC(C)(C)C
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN(C)C=O
Solvent: CO
Solvent: CN1CCOCC1
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(C(=O)NO)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 45.8 %

Procedure:
Acid compound 11 (1.9 g, 4.43 mmol) was dissolved in N,N-dimethylformamide (20 mL) and stirred under an atmosphere of argon. N-Methylmorpholine (1.95 mL, 18.0 mmol) was added, the reaction mixture was cooled to 0° C. and BOP reagent (2.16 g, 4.88 mmol) was added. After 20 min, hydroxylamine hydrochloride (0.62 g, 8.87 mmol) was added and the reaction mixture was warmed up to room temperature and stirred overnight. The solvent was removed under reduced pressure and residual material was partitioned between EtOAc (50 mL) and saturated NH4Cl solution (1×30 mL). The organic layer was dried and concentrated to yield the crude material. Flash chromatography over silica gel using chloroform-methanol (19:1) yielded the desired hydroxamic acid compound 12 (0.9 g, 46%). 1H NMR (DMSO-d6): 8.95 (br, 1H), 7.73 (d, J=9.2 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.55 (m, 1H), 2.91 (s, 3H), 2.70-2.90 (m, 5H), 1.30 (s, 9H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C@H:8]1[CH2:13][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:11]([CH2:21][C:22](OCC)=[O:23])[CH2:10][CH2:9]1>O1CCCC1>[NH2:7][C@H:8]1[CH2:13][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:11]([CH2:21][CH2:22][OH:23])[CH2:10][CH2:9]1
Reactant: CCOC(=O)C[C@H]1CC[C@@H](N)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N[C@@H]1CC[C@H](CCO)N(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of lithium aluminum hydride (97 mg, 2.55 mmol) in tetrahydrofuran (5 mL) was added a solution of ethyl [cis-5-amino-1-benzylpiperidin-2-yl]acetate (352 mg, 1.27 mmol, step 7 of Example 1) in tetrahydrofuran (4 mL) at 0° C., and the mixture was stirred at 0° C. for 1 h, then stirred at room temperature for 1 h. The mixture was quenched with water (0.1 mL) at 0° C., and stirred for 30 min at 0° C. 15% aqueous sodium hydroxide solution (0.1 mL) was added at 0° C., and the mixture was stirred at room temperature for 30 min. Water (0.3 mL) was added, and the mixture was stirred at room temperature for 30 min. The mixture was filtered through Celte pad washing with tetrahydrofuran (100 mL). The filtrate was concentrated under reduced pressure to give 322 mg (quant.) of the title compound as a slightly yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14](NC(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:25]>O1CCOCC1>[ClH:25].[CH2:1]([O:8][C:9]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NN1CCC(C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
1-[(1,1-Dimethylethoxycarbonyl)amino]-piperidine-4-carboxylic acid benzyl ester (7 g, 21.0 mmol), from step 2, was dissolved in 1,4-dioxane (20 ml). To this solution, HCl 4N in 1,4-dioxane (7.8 ml, 300 ml, 12 eq.) was added and the resulting solution was stirred overnight at room temperature. The solid was filtered, suspended in n-hexane (50 ml), and filtered to give a white solid. Yield 54%, 2.5 g.
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]1[O:19][C@@H:18]1[CH2:20]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O>>[O:19]1[CH2:17][C@H:18]1[CH2:20][O:10][C:7]1[CH:8]=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1cc2c(cc1OC[C@@H]1CO1)OCO2
Yield: 57.4 %

Procedure:
The title compound (2.01 g, 10.35 mmol) was prepared according to Procedure A using the following amounts: sesamol (2.49 g, 18.02 mmol), potassium carbonate (2.74 g, 19.83 mmol) and (2S)-(+)-glycidyl-3-nitrobenzenesulfonate (4.67 g, 18.02 mmol).
Reaction SMILES: [CH2:1]1[CH:11]2[CH:12]3[CH:7]([CH2:8][CH2:9][CH2:10]2)[CH2:6][CH2:5][C:4](=[O:13])[N:3]3[C:2]1=[O:14].[OH-:15].[Na+]>O>[O:14]=[C:2]1[CH2:1][CH:11]2[CH:12]([CH:7]([CH2:6][CH2:5][C:4]([OH:15])=[O:13])[CH2:8][CH2:9][CH2:10]2)[NH:3]1
Reactant: O=C1CCC2CCCC3CC(=O)N1C23
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCC1CCCC2CC(=O)NC12
Reaction time: 1 h

Procedure:
A solution of 0.15 g (0.0007 mol)octahydro-4Hpyrrolo [3,2,1-ij]quinoline-2,4(1H)-dione (6aα, 9aα, 9bα) in 1 ml of water is treated with 0.7 ml of 1N sodium hydroxide solution. The solution is stirred one hour and is passed over a 2 g Dowex-H+ column. The eluate is concentrated at reduced pressure and the solid is recrystallized from ethanol to yield crystalline octahydro-2-oxo-1H-indole-7-propanoic acid (3aα, 7β, 7aα) with a melting point of 180°-181° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[C:23][C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14].I[C:28]1[CH:29]=[C:30]([O:34][CH3:35])[CH:31]=[CH:32][CH:33]=1.C(NCC)C.C(O)=O>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:9])[F:10])=[CH:4][C:3]=1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19](/[C:22](/[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[CH:29]=2)=[CH:23]\[C:24]([NH2:26])=[O:25])=[CH:18][CH:17]=1)=[O:14]
Reactant: NC(=O)C#Cc1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reactant: COc1cccc(I)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: CCNCC
Product: COc1cccc(/C(=C/C(N)=O)c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c1
Temperature: 75 °C
Yield: 29.8 %

Procedure:
A mixture of 3-{4-[({[2-fluoro-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}prop-2-ynamide (31.0 mg, 0.085 mmol), 3-iodoanisole (0.010 mL, 0.089 mmol), diethylamine (0.029 mL, 0.281 mmol), formic acid (0.0083 mL, 0.221 mmol), and bis(dibenzylideneacetone)palladium(0) (3.4 mg, 0.006 mmol) in 1.4 mL EtOAc (degassed) was heated at 75° C. for 17 hours. The reaction was partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed with dilute aqueous HCl, then aqueous NaHCO3, brine, and dried with anhydrous Na2SO4 to give 20 mL of EtOAc solution of crude material. The EtOAc solution was filtered past a plug of silica gel eluting with EtOAc, evaporated, and the resulting solid chromatographed eluting with CHCl3/MeOH to give the title compound as a light tan solid (12.0 mg, 30%). 1H NMR (Acetone-d6) δ: 8.80 (d, J=5.9 Hz, 1H), 8.46 (s, 1H), 8.42 (d, J=2.6 Hz, 1H), 7.33-7.47 (m, 4H), 7.23-7.29 (m, 1H), 7.15 (d, J=8.5 Hz, 2H), 6.91-7.00 (m, 2H), 6.82-6.87 (m, 2H), 6.65 (br. s., 1H), 6.47 (s, 1H), 3.77 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][NH:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:23][CH2:24][CH2:25][CH2:26]I>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12]([CH2:26][CH2:25][CH2:24][Cl:23])[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: ClCCCI
Reactant: CC(C)(C)[Si](C)(C)OCC1CNCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC1CN(CCCCl)CCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.1 %

Procedure:
A solution of 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine (2.1 g, 9.07 mmol) in DCM (20 mL) was treated with triethylamine (3.8 mL, 27.2 mmol) and 1-chloro-3-iodopropane (1.95 mL, 18.1 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was concentrated under reduced pressure then purified by MPLC (ISCO, 0% MeOH/100% DCM to 25% MeOH/75% DCM). The product was isolated as an oil (560 mg, 20%): HPLC MS RT=2.66 min, MH+=308.4, 310.4; 1H NMR (DMSO-d6) δ: 3.79-3.69 (1H, m), 3.63 (2H, t) 3.59-3.52 (1H, m), 3.50-3.36 (3H, m), 2.73 (1H, d), 2.61 (1H, d), 2.35 (2H, t), 1.94 (1H, td), 1.83 (2H, qt), 1.73 (1H, t), 0.83 (9H, s), 0.00 (6H, s).
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C=C)[CH2:2]CC.Cl[C:17]1[O:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([C:17]1[O:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1)=[CH2:2]
Reactant: CCOC(=O)c1cnc(Cl)o1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C=Cc1ncc(C(=O)OCC)o1
Temperature: 100 °C
Reaction time: 4 h
Yield: 90.4 %

Procedure:
To a solution of tributyl(vinyl)stannane (1.1 mL, 3.83 mmol) and ethyl 2-chlorooxazole-5-carboxylate (546 mg, 3.11 mmol) in dioxane (37 mL) is added Pd(PPh3)2Cl2 (222 mg, 0.32 mmol) at room temperature. After stirring at 100° C. under nitrogen for 4 hours, the solution is cooled to ambient temperature and then quenched with H2O. The crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography (eluent: heptane/EtOAc=90:10 to 80:20) to give ethyl 2-vinyloxazole-5-carboxylate (470 mg). HPLC retention time=0.39 minutes (condition B); MS (m+1)=168.2; 1H NMR (400 MHz, CD3OD) δ ppm 1.38 (t, J=7.1 Hz, 3H) 4.38 (q, J=7.2 Hz, 2H) 5.88 (d, J=11.4 Hz, 1H) 6.39 (d, J=17.7 Hz, 1H) 6.69 (dd, J=17.6, 11.2 Hz, 1H) 7.83 (s, 1H)
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15].C(N(CC)CC)C>C(O)(C)C>[OH:16][CH:13]([CH2:14][OH:15])[CH2:12][NH:11][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCC(O)CO
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1NCC(O)CO
Yield: 61 %

Procedure:
A solution of 2-chloro-3-nitropyridine (3.22 g, 20.3 mmol), 3-amino-1,2-propanediol (1.85 g, 20.3 mmol) and triethylamine (2.05 g, 20.3 mmol) in isopropanol (80 mL) was stirred at 20°-25° C. for 18 hours and then at reflux for 6 hours. After concentrating under reduced pressure, the residue was flash chromatographed over silica gel. Elution with 5% MeOH-95% CHCl3 and recrystallization from EtOAc-hexane afforded analytically pure product (2.64 g, 61%), m.p. 95.5°-98.0° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[N:35]1[CH2:38][CH2:37][C:36]1=[O:39].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CC#N.CN(C)C=O>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][NH:26][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:23])=[C:29]([N:35]2[CH2:38][CH2:37][C:36]2=[O:39])[CH:30]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: NCc1ccc(F)cc1N1CCC1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1CCC1=O)c(OCc1ccccc1)c2=O
Temperature: 23 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
To a solution of intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylic acid, (0.142 g, 0.430 mmol) in CH3CN: dimethylformamide (30 mL: 5 mL) was added intermediate 120, 1-(2-(aminomethyl)-5-fluorophenyl)azetidin-2-one hydrochloride, (0.100 g, 0.43 mmol), (benzotriazole-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.207 g, 0.470 mmol) and diisopropylethylamine (280 μL, 1.72 mmol). The reaction mixture was stirred at 23° C. for 18 h. The solvents were removed in vacuo and 1N HCl (50 mL) added. This was extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified on a Biotage system using a silica gel column with ethyl acetate as eluent to afford the title compound (0.157 g, 72% yield). 1H NMR (400 MHz, MeOD) δ ppm: 7.88 (1H, d, J=8.3 Hz), 7.76 (1H, d, J=8.0 Hz), 7.58–7.30 (4H, m), 7.10 (1H, dd, J=10.2, 2.5 Hz), 6.90 (1H, m), 5.20 (2H, s), 4.55 (2H, s), 4.04 (2H, m), 3.96 (2H, m), 3.78 (2H, t, J=4.2 Hz), 3.10 (2H, t, J=4.2 Hz), 1.58 (6H, s); LCMS (M+H)+ m/z 506.
Reaction SMILES: [C:1]1([C:7]2(N(C)CCCCCCC)[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>C(OCC)(=O)C>[CH3:23][CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:33]([CH2:25][CH2:24][CH2:29][CH2:28][CH2:27][CH2:26][CH3:30])[CH2:34][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:22]
Reactant: CCCCCCCN(C)C1(c2ccccc2)CCCC1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: CCOC(C)=O
Product: CCCCCCCN(CC1(c2ccccc2)CCCC1)C(=O)Nc1c(C(C)C)cccc1C(C)C
Yield: 109.2 %

Procedure:
1-Phenylcyclopentyl-N-heptylmethylamine (5.46 g; 0.02M) was dissolved in 75 mL of ethyl acetate. To this solution was added, with stirring, a solution of 2,6-diisopropyl phenyl isocyanate (4.06 g; 0.02M) in 25 mL of ethyl acetate. The reaction mixture was stirred at room temperature overnight, concentrated to dryness, and the resulting white solid was chromatographed on silica using hexane:ethyl acetate (8:2) as the eluant to yield 5.2 g of the title compound, mp 95-97° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:17]([OH:19])=[O:18])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16])(=[O:3])[CH3:2].[OH-].[NH4+]>O>[C:1]([NH:4][C@@H:5]([C:17]([OH:19])=[O:18])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)NC(Cc1c(C)[nH]c2ccccc12)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N[C@H](Cc1c(C)[nH]c2ccccc12)C(=O)O
Reaction time: 24 h

Procedure:
Nα -Acetyl-2-methyl-D,L-tryptophan [Y. Yabe et al. Chem. Pharm. Bull. 27(8) 1907-1911 (1979)] 1.3 g (5 mmol), was suspended in 50 ml of water and dissolved by adding concentrated ammonium hydroxide to a pH of 7.5. 5 mg of acylase (from porcine kidney, Sigma Grade III lyophilized) was added and the mixture kept at 40° C. for 24 hours. The insoluble material was separated by filtration and the filtrate was lyophilized to dryness. The residue was dissolved in the upper phase (10 ml) of n-BuOH-AcOH-H2O (16:1:20) and chromatographed on a 3.5 × 50 cm column of Sephadex G-25 (Pharmacia, Fluka) collecting 10 ml fractions. The less polar fractions (N° 16-25) were pooled to give mainly undigested Nα -acetyl-2-methyl-D-tryptophan which, without purification, was hydrolized under N2 with a solution of 1 g KOH in 25 ml of water at 100° F. for 24 hours. Acetic acid (2 ml) and water (10 ml) were added to the hot solution and placed in the refrigerator for 12 hours. The crude resulting 2-methyl-D-tryptophan was filtered, washed and dried and recrystallized from hot water (charcoal) to yield the title compound, m.p. 244°-246°, [α]D20 +18.6, [c0.26(H2O)].