Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH3:29])[C:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:39]2)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:5]1[N:6]([CH3:29])[C:7]([C:10](=[S:39])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=2[O:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCCCc1ncc(C(=O)c2ccc(OC)cc2OCC(=O)OC(C)(C)C)n1C
Solvent: Cc1ccccc1
Product: CCCCc1ncc(C(=S)c2ccc(OC)cc2OCC(=O)OC(C)(C)C)n1C

Procedure:
2-n-Butyl-1-methyl-5-(2-t-butoxycarbonylmethoxy-4-methoxybenzoyl)-1H-imidazole (465 mg, 1.16 mmol) dissolved in toluene (5 ml) was mixed with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (258 mg, 0.638 mmol) and the solution heated to 95° for 1 h under argon. The reaction was cooled and the toluene solution applied directly to a silica gel column. Elution with 50% EtOAc/hexanes afforded the title compound as a deep purple-green solid. (206 mg, 53%).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[F:6][C:7]1[C:12]([CH:13]=[O:14])=[C:11]([F:15])[C:10]([F:16])=[C:9](F)[C:8]=1[F:18].C(Cl)(=O)C.O>CC(N(C)C)=O>[F:6][C:7]1[C:8]([F:18])=[C:9]([S:3][C:1](=[O:4])[CH3:2])[C:10]([F:16])=[C:11]([F:15])[C:12]=1[CH:13]=[O:14]
Reactant: CC([O-])=S
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Agent: [K+]
Solvent: O
Solvent: CC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(=O)Sc1c(F)c(F)c(C=O)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
Potassium thioacetate (1.28 g, 11.2 mmol) was added to a solution of pentafluorobenzaldehyde (1.24 mL, 10.2 mmol) in anhydrous DMA (20 mL). After a strong exotherm subsided, the mixture was stirred at rt for 30 min. Acetyl chloride (1.60 mL, 22.4 mmol) was added and the mixture was stirred for another 30 min, then poured into water and extracted twice with ethyl ether. The combined organic extracts were dried (Na2SO4) and evaporated to obtain an orange oil which was chromatographed (silica, CH2Cl2/hexanes, 2:3) affording a pale-yellow solid. Recrystallization from heptane gave white crystals (1.77 g, 69%). mp 86-87° C.; 1H NMR δ 2.53 (s, 3H), 10.30 (s, 1H); 13C NMR δ 30.9, 115.5, 117.2, 145.3, 148.7, 182.9, 187.9; FAB-MS obsd 252.9936, calcd exact mass 252.9946; Anal. Calcd. for C9H4F4O2S: C, 42.86; H, 1.60; S, 12.72. Found: C, 43.00; H, 1.71; S, 12.67.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH:11]C(C2C=CC=CC=2)C)[CH:9]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:6]1[CH2:7][CH2:8]2)=[O:4]>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([NH2:11])[CH:9]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:6]1[CH2:7][CH2:8]2)=[O:4]
Reactant: COC(=O)C1C(NC(C)c2ccccc2)C2CCC1N2C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1C(N)C2CCC1N2C(=O)OC(C)(C)C
Reaction time: 19 h
Yield: 92.5 %

Procedure:
A mixture of 3-(1-phenyl-ethylamino)-7-aza-bicyclo[2.2.1]heptane-2,7-dicarboxylic acid 7-tert-butyl ester 2-methyl ester (0.28 g, 0.8 mmol) and 20% palladium hydroxide on carbon (0.2 g) in methanol (5 mL) was stirred under a hydrogen atmosphere (1 atm) for 19 h. The mixture was then filtered through a thin pad of celite and concentrated to provide 3-amino-7-aza-bicyclo[2.2.1]heptane-2,7-dicarboxylic acid 7-tert-butyl ester 2-methyl ester as a colorless oil (0.2 g, 71.4%). MS: 269 (M+H)+.
Reaction SMILES: NC(=O)[C@@H:3]([NH:8][C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH:5](C)C.NCCC[OH:43]>>[OH:43][CH2:5][CH2:4][CH2:3][NH:8][C:9](=[O:37])[C@@H:10]([NH:15][C:16]([N:18]1[C:26]2[CH2:25][CH2:24][N:23]([CH3:27])[CH2:22][C:21]=2[C:20]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[F:36])=[N:19]1)=[O:17])[C:11]([CH3:13])([CH3:12])[CH3:14]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C)C(N)=O
Reactant: NCCCO
Product: CN1CCc2c(c(-c3cc(F)c(F)cc3F)nn2C(=O)N[C@H](C(=O)NCCCO)C(C)(C)C)C1

Procedure:
Compound 80 was prepared according to the procedure described for the synthesis of compound 72 by replacing leucine amide with 3-amino-propan-1-ol. LCMS (+ESI) m/z=482.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.II.[B:21](OC)([O:24]C)[O:22]C.Cl>C1COCC1>[CH2:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:21]([OH:24])[OH:22])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCc1ccc(-c2ccc(Br)cc2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: II
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(B(O)O)cc2)cc1
Temperature: -78 °C
Yield: 78 %

Procedure:
4-Bromo-4′-pentylbiphenyl (3 g, 9.9 mmol) was added in one portion to Mg (0.27 g, 11.1 mmol), treated with I2, in THF (40 mL). The mixture was heated at reflux for 3 h, cooled to −78° C. and trimethyl borate (2.06 g, 19.8 mmol) was added dropwise. The mixture was warmed to room temperature over 1 h, acidified with HCl (2 M, 50 mL), extracted with Et2O (3×50 mL). The combined ethereal washes were extracted with NaOH (100 mL, 1 M). The aqueous phase was acidified with concentrated HCl, extracted with Et2O (3×50 mL), dried (MgSO4) and the solvent removed under reduced to give the title compound (2.07 g, 78%) as an off white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reaction time: 2 h
Yield: 88.6 %

Procedure:
At 0° C., to a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (4 g, 20.20 mmol) and DMAP (3 g, 24 mmol) in DCM (50 mL) was added methanesulfonyl chloride (2.7 g, 24 mmol). After stirred for 2 h, the mixture was filtrated. The filtrate was washed by 0.5N HCl (50 mL), Na2CO3 aqueous solution (1 M, 50 mL) and brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give the title compound as a yellow solid (5 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:4][CH:5]=[CH:6][N:7]=1.N1C=CC=CC=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:15]1([C:14]([NH:2][C:3]2[NH:4][CH:5]=[CH:6][N:7]=2)=[O:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ncc[nH]1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ncc[nH]1)c1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of 6.8 g. of 2-aminoimidazole hydrochloride in 100 ml. of pyridine at -20°C. there is added 6.8 ml. of benzoyl chloride. The thus-obtained reaction mixture is allowed to warm slowly to between 20°-30°C. (room temperature), and maintained at this temperature for 12 hours, diluted with water and filtered to give a residue which is recrystallized from methanol to yield 2-phenylcarbonylaminoimidazole [(III), R = phenyl].
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:24])=[N:19][CH:20]=[CH:21][C:22]=3[F:23])[CH:12]=2)[CH:10]=1)=[O:5].Br[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1>>[F:24][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:27]4[N:32]=[CH:31][CH:30]=[CH:29][N:28]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[C:22]([F:23])[CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1
Reactant: Brc1ncccn1
Product: O=C(c1cn(-c2cccc(-c3c(F)ccnc3F)c2)cn1)c1ncccn1

Procedure:
This compound is prepared by method C using compound 12j and 2-bromopyrimidine
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][Si](C=[N+]=[N-])(C)C>CO>[NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc(C(=O)O)c(N)cc1Cl
Solvent: CO
Product: COC(=O)c1cc(OC)c(Cl)cc1N
Yield: 46 %

Procedure:
A solution of 2-amino-4chloro-5-methoxybenzoic acid (3.0 g, 15.0 mmol; prepared according to the procedure of Denny, et al., J. Med. Chem. 34:217-222 (1991)) in 70 ml MeOH was treated with excess trimethylsilyl diazomethane. The solution was concentrated and the residue flash chromatographed on silica (9:1 hexane/EtOAc to give the title compound (46%): mp 63°-64° C.; 1H NMR (300 MHz, CDCl3) δ 6 3.83 (s, 3H), 3.90 (s, 3H), 5.48 (bs, 2H), 6.75 (s, 1H), 7.39 (s, 1H); MS (DCI/NH3) m/z 216 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18]OCC)[C:6]=2[CH:22]=1.C(OC(=O)C)(=O)C.[IH:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([CH2:16][CH2:17][CH2:18][I:30])[C:6]=2[CH:22]=1
Reactant: CCOCCCC1c2ccccc2C=Cc2ccc(Cl)cc21
Reactant: I
Solvent: CC(=O)OC(C)=O
Product: Clc1ccc2c(c1)C(CCCI)c1ccccc1C=C2
Temperature: 65 °C

Procedure:
3-Chloro-5-(3-ethoxypropyl)-5H-dibenzo[a,d]cycloheptene (0.03 mole) is dissolved in 45 ml. of acetic anhydride. The solution is heated to 65°C. and nitrogen is passed through while 30 ml. of hydriodic acid (sp. gr., 1.5) is added gradually, keeping the temperature below 90°C. The solution is heated to approximately 80°C. for 30 minutes, then cooled and poured into ice-water. The product is extracted into ether, the extract washed with dilute sodium thiosulfate solution, followed by dilute sodium bicarbonate solution and finally with water. The product is isolated by evaporation of the ether.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][C:18]2=[O:23])=[CH:13][N:12]([CH2:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])[C:11]1=[O:33])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:47](Br)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C.ClCCl>[C:1]([O:5][C:6](=[O:40])[NH:7][C@H:8]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:9][N:10]1[C:15](=[O:16])[C:14]([N:17]2[CH2:22][CH2:21][N:20]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:19][C:18]2=[O:23])=[CH:13][N:12]([CH2:24][C:25]2[C:26]([F:32])=[CH:27][CH:28]=[CH:29][C:30]=2[F:31])[C:11]1=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N2CCNCC2=O)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cn1c(=O)c(N2CCN(Cc3ccccc3)CC2=O)cn(Cc2c(F)cccc2F)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of {(R)-2-[3-(2,6-difluoro-benzyl)-2,6-dioxo-5-(2-oxo-piperazin-1-yl)-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenyl-ethyl}-carbamic acid tert-butyl ester (7) (20 mg, 0.036 mmol) in DMF (1 mL) were added potassium carbonate (12 mg, 0.09 mmol) and benzyl bromide (7 mg, 0.040 mmol) in that order, followed by stirring at room temperature for 1 hr. The solution was diluted with dichloromethane and washed with distilled water. The organic layer thus formed was separated and concentrated, and the residue was purified using silica gel chromatography (eluent: dichloromethane/methanol, 30/1) and dried in a vacuum to afford 22 mg of the compound as a white solid (yield 96%). 1H NMR (300 MHz, CDCl3) δ 1.32 (9H, s), 2.86 (2H, t), 3.32 (2H, s), 3.58 (2H, m), 3.73 (2H, s), 4.04 (1H, m), 4.46 (1H, t), 5.05 (3H, m), 5.53 (1H, m), 6.98 (2H, t), 7.24-7.38 (6H, m), 7.56 (2H, m), 7.71 (1H, d), 8.20 (1H, dd), 8.26 (1H, s)
Reaction SMILES: IC.[Cl:3][C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[C:22]([CH:24]5[CH2:26][CH:25]5[C:27]([OH:29])=[O:28])[N:21]([CH3:30])[C:20]=4[CH:31]=3)[C:12](=[O:32])[CH:11]=2)=[CH:6][CH:5]=1.[C:35](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:3][C:4]1[CH:34]=[CH:33][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[N:23]=[C:22]([CH:24]5[CH2:26][CH:25]5[C:27]([O:29][CH3:35])=[O:28])[N:21]([CH3:30])[C:20]=4[CH:31]=3)[C:12](=[O:32])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1c(C2CC2C(=O)O)nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C1CC1c1nc2ccc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
Iodomethane (0.111 ml) was added to a solution of (1RS,2SR)-2-(6-(4-((4-chlorobenzyl)oxy)-2-oxopyridin-1(2H)-yl)-1-methyl-1H-benzimidazol-2-yl)cyclopropanecarboxylic acid (400 mg) and potassium carbonate (246 mg) in DMF (5 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (MeOH/EtOAc) to give the title compound (205 mg) as a pink solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16]([O:18][CH2:19][CH2:20]Br)[CH3:17].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][CH2:16][O:18][CH2:19][CH3:20])=[C:4]([CH3:9])[CH:3]=1
Reactant: CCOCCBr
Reactant: Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCOc1ccc(Br)cc1C
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 82.3 %

Procedure:
To a solution of 4-bromo-2-methylphenol (9.3 g) in DMF (50 ml) was added potassium carbonate (9.62 g) and then was added dropwise 2.-bromoethyl ethyl ether (7.99 g), and the mixture was stirred at 70° C. for 3 days. To the mixture was added dropwise 2-bromoethyl ethyl ether (1.52 g), and the mixture was stirred at 70° C. for 4.5 hours and cooled. To the mixture was added water, and the mixture was extracted with ether. The organic layer was washed with 1N sodium hydroxide solution and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was distilled under reduced pressure (3 mmHg, 170° C.) to give colorless oil of 4-bromo-2-methyl-(2-ethoxyethoxy)benzene (10.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH3:17])[N:12]=[N:11]1.CN(C)C(=O)C.[H-].[Na+].[CH3:26][O:27][CH2:28]Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:26][O:27][CH3:28])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][CH3:17])[N:12]=[N:11]1
Reactant: CCn1nnn(-c2cc(O)c(Cl)cc2Cl)c1=O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CCn1nnn(-c2cc(OCOC)c(Cl)cc2Cl)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.5 %

Procedure:
To a stirred mixture of 0.8 g (0.0029 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-1,4-dihydro-4-ethyl-5H-tetrazol-5-one, 2.8 g (0.032 mole) of N,N-dimethylacetamide, and 0.14 g (0.0029 mole) of sodium hydride (50% in oil) in 25 mL of toluene was added 0.47 g (0.0058 mole) of chloromethyl methyl ether. The reaction mixture was stirred at room temperature for approximately 18 hours then poured into ice water and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate evaporated to leave a solid. The solid was purified by recrystallization from heptane to yield 0.19 g of 1-(2,4-dichloro-5-methoxymethoxyphenyl)-1,4-dihydro-4-ethyl-5H-tetrazol-5-one, mp 112°-113° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:23]([CH2:24][C:25](O)=[O:26])[CH2:22][C:21]([CH3:29])([CH3:28])[O:20][CH2:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C([O-])(=O)C.[NH4+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:19][O:20][C:21]([CH3:28])([CH3:29])[CH2:22][N:23]3[CH2:24][C:25](=[O:26])[N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Reactant: C1CCNCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC1(C)CN(CC(=O)N2CCCCC2)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Yield: 90 %

Procedure:
The desired compound was prepared according to Method F from [(S)-5-(6-Chloro-9H-beta-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholin-4-yl]-acetic acid and piperidine in 90% yield. 1H-NMR (300 MHz, DMSO-d6): δ 1.17 (s,3H), 1.29 (s,3H), 1.35-1.60 (m,6H), 2.25 (d,1H), 2.71 (d,1H), 3.15 (d,1H), 3.26 (dd,1H), 3.37 (dd,1H), 3.45-3.65 (m, 2H), 3.65 (d, 1H), 3.70 (m, 1H), 3.89 (m, 2H) 7.95 (d,1H), 8.15 (d,1H), 8.20 (d,1H), 8.37 (d,1H), 9.01 (s,1H), 10.43 (s,1H), 11.32 (s,1H). Retention Time (LC, method: ammonium acetate standard): 1.86 min. MS (M+H+): 484.3.
Reaction SMILES: [CH2:1]([C:4]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.C1C[O:29]CC1.O>CCOC(C)=O.O=[Os](=O)(=O)=O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:4]2([CH2:1][CH2:2][OH:29])[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH3:12])[CH2:6][CH2:5]2)=[CH:20][CH:21]=1
Reactant: C=CCC1(c2ccc(F)cc2)CCN([C@@H](C)c2ccccc2)C(=O)O1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccccc1)N1CCC(CCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-allyl-6-(4-fluorophenyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one (0.1016 g, 0.30 mmol, 1.0 equiv) in THF-H2O (1:1, 6 mL) were added NaIO4 (0.3240 g, 1.5 mmol, 5 equiv) and OsO4 (2.5 wt. % solution in t-BuOH, 0.0507 g, 0.0049 mmol, 0.016 equiv), and the mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in MeOH (3 mL) and NaBH4 (0.100 g) was added. After the mixture was stirred for 1.5 h at rt, acetone was added. The solvents were removed in vacuo, the residue was treated with saturated brine, extracted with CH2Cl2, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford the two diastereomers of 6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1-phenylethyl)-1,3-oxazinan-2-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]3([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)OCC(C)(C)C[O:16]3)[C@H:9]2[C:31]2[CH:45]=[CH:44][C:34]([O:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])=[CH:33][CH:32]=2)=[CH:4][CH:3]=1>C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[O:16])[C@H:9]2[C:31]2[CH:45]=[CH:44][C:34]([O:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:33][CH:32]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C2(CS[C@H]3C(=O)N(c4ccc(F)cc4)[C@@H]3c3ccc(OCC(=O)OC(C)(C)C)cc3)OCC(C)(C)CO2)cc1
Solvent: O=CO
Product: COc1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)O)cc2)cc1
Reaction time: 1.5 h
Yield: 89 %

Procedure:
tert-Butyl {4-[(2R,3R)-1-(4-fluorophenyl)-3-({[2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)-4-oxoazetidin-2-yl]phenoxy}acetate (0.65 g, 1.02 mmol) was dissolved in formic acid (10 ml) and stirred for 90 minutes. The mixture was concentrated under reduced pressure (temperature <30° C.) and the crude oil was purified by flash-chromatography (hexane:acetone:formic acid 60:40:0.1) to afford 0.45 g (88%) of the title compound as a pale yellow solid. 1H-NMR (CDCl3, 200 MHz): δ 3.9 (s, 3H), 4.1 (d, 1H), 4.1 (s, 2H), 4.7 (s, 2H), 4.9 (d, 1H), 6.9-7.1 (m, 6H), 7.2-7.4 (m, 4H), 7.9-8.0 (d, 2H). MS (CI) M/z: 494.1 (M+−1), 495.1 (M+)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH:11]1[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15]I.[H-].[Na+]>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9](=[O:14])[N:10]([CH:11]1[CH2:12][CH2:13]1)[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C(NC1CC1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of cyclopropyl-carbamic acid benzyl ester (11.8 g) and methyl iodide (excess) in THF (80 mL) and DMF (20 mL) at 0° C. was added NaH (2.20 g, 91.6 mmol) and the resulting mixture was warmed to room temperature and stirred overnight. The reaction was then quenched at 0° C. by sat. NaHCO3. The separated aqueous phase was extracted several times with EtOAc. The combined extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (5% to 20% EtOAc/hexanes) to give cyclopropyl-methyl-carbamic acid benzyl ester (11.32 g, 91%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[N+:18]([O-])=O)[C:10]1=[O:21].[H][H]>CO.[Pd]>[NH2:18][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH2:17][N:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=1[CH3:1])[C:10]2=[O:21]
Reactant: Cc1cccc(N2Cc3c(cccc3[N+](=O)[O-])C2=O)c1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(N2Cc3c(N)cccc3C2=O)c1C

Procedure:
To a solution of 7 (0.110 g ) in 15 mL methanol was added 10% Pd/C (0.020 g) under nitrogen atmosphere. Hydrogen was applied to the mixture at 1 atmosphere for 2 h. The mixture was filtered and concentrated in vacuo to obtain the product. NMR (300 MHz, CDCl3) δ 7.41 (1H, d, J=6 Hz), 7.33 (1H, t, J=6 Hz), 7.18 (1H, s), 7.16 (1H, d, J=2 Hz), 7.10 (1H, t, J=4 Hz), 6.69 (1H, d, J=6 Hz), 4.54 (2H, s), 3.75 (2H, b), 2.33 (3H, s), 2.12 (3H, s).
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([O:13][CH3:14])(=[O:12])[C:8]([O:10]C)=O.[C:15]([C:18]1[C:19](=[O:41])[N:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[F:40])[CH:21]=[C:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH:23]=1)(=[O:17])[CH3:16].Cl>C1COCC1>[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[CH2:24][C:22]1[CH:23]=[C:18]([C:15](=[O:17])[CH:16]=[C:8]([OH:10])[C:7]([O:13][CH3:14])=[O:12])[C:19](=[O:41])[N:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[F:40])[CH:21]=1
Reactant: COC(=O)C(=O)OC
Reactant: CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(O)=CC(=O)c1cc(Cc2ccc(F)cc2F)cn(Cc2ccccc2F)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of sodium t-butoxide (4.49 g, 45.3 mmol) in anhydrous THF (230 ml) was added dimethyl oxalate (5.41 g, 45.3 mmol) in anhydrous THF (60 ml) under argon condition. The mixture was stirred at room temperature for 30 min and a solution of 3-acetyl-5-(2,4-difluorobenzyl)-1-(2-fluorobenzyl)pyridin-2(1H)-one 6 (4.21 g, 11.3 mmol) in THF (60 ml) was added. The reaction mixture was stirred at room temperature for 3 h and then cooled in ice bath, and then 1N HCl (230 ml) was added in one portion. The crude product was extracted with ethyl acetate (2×230 ml). The combined organic layers were washed with saturated brine (2×230 ml) and ethyl acetate was distilled off to give a brown residue, which was triturated with methanol. The product was obtained by vacuum filtration. Yield 2.59 g (50%). 1H NMR (CDCl3, 500 MHz): δ 8.18 (d, 1H, J=3.1 Hz), 7.89 (s, 1H), 7.53 (s, 1H), 7.49-7.46 (s, 1H), 7.35-7.31 (s, 1H), 7.16-7.07 (m, 3H), 6.87-6.80 (m, 2H), 5.20 (s, 2H), 3.90 (s, 3H), 3.75 (s, 2H). 13C NMR (CDCl3, 125 MHz): δ 185.0, 171.9, 162.8, 162.6, 162.2, 160.6, 160.2, 159.6, 144.8, 142.0, 131.7, 131.2, 130.6, 124.8, 123.6, 122.4, 121.9, 117.7, 115.7, 111.7, 104.3, 101.8, 53.2, 47.6, 30.6.