Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([N:15]1[C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][O:17][C:16]1=[O:26])(=[O:14])/[CH:10]=[CH:11]/[CH2:12][CH3:13]>O1CCCC1>[C:20]1([C@H:19]2[CH2:18][O:17][C:16](=[O:26])[N:15]2[C:9](=[O:14])[CH2:10][C@H:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH3:13])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC[C@H](CC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccccc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a suspension of copper (I) bromide dimethyl sulfide complex (12.4 g, 60.6 mmol) in dry tetrahydrofuran (150 mL) at −10° C. was added phenyl magnesium chloride solution (30.3 mL, 60.6 mmol, 2 M in tetrahydrofuran). The reaction mixture was stirred at −10° C. for 1 hour, then a solution of (S)-3-((E)-pent-2-enoyl)-4-phenyl-oxazolidin-2-one (9.9 g, 40.4 mmol) in tetrahydrofuran (100 mL) was added dropwise via cannula. The reaction mixture was stirred at −10° C. for 0.5 hours, then at room temperature for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution (150 mL), concentrated under reduced pressure to half of its volume. The mixture was extracted with ethyl acetate (2×250 mL). The organic layer was separated, combined and dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography over silica gel eluted with 2:1 ethyl acetate/hexanes to give (S)-4-phenyl-3-((R)-3-phenyl-pentanoyl)-oxazolidin-2-one as a colorless oil which solidified on standing at room temperature (9.56 g, 73%).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH3:12])[C:5]([O:6][CH2:7][CH2:8][OH:9])=[C:4]([CH3:13])[CH:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)([OH:16])=[O:15].[F-].[Cs+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OC(=O)C)C.O.C(O)C>[OH:9][CH2:8][CH2:7][O:6][C:5]1[C:10]([CH3:12])=[CH:11][C:2]([C:20]2[CH:21]=[CH:22][C:17]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=2)=[CH:3][C:4]=1[CH3:13]
Reactant: Cc1cc(Br)cc(C)c1OCCO
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccc(C(=O)O)cc2)cc(C)c1OCCO
Temperature: 90 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
A mixture of 2-(4-bromo-2,6-dimethylphenoxy)ethanol (0.65 g), 4-carboxyphenylboronic acid (0.87 g), tetrakis(triphenylphosphine)palladium(0) (0.15 g), cesium fluoride (2.40 g), 1,4-dioxane (7.5 mL), ethanol (2.5 mL) and water (1.5 mL) was stirred at 90° C. overnight under an atmosphere of argon. Water and ethylacetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1-2/1) to afford the title compound (0.29 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([O:8][CH3:9])=[C:6](C(O)=O)[S:5][C:4]=1C(O)=O>[Cu].CS(C)=O>[CH2:1]1[CH2:9][O:8][C:7]2[C:3](=[CH:4][S:5][CH:6]=2)[O:2]1
Reactant: COc1c(C(=O)O)sc(C(=O)O)c1OC
Agent: [Cu]
Solvent: CS(C)=O
Product: c1scc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
3,4-Dimethoxy-2,5-thiophenedicarboxylic acid (232 g) and copper powder (23 g) were added to DMSO (650 g) at room temperature. The reaction mixture was stirred under oxygen atmosphere for 30 minutes at room temperature and then heated at 120° C. for 7 hours. The reaction mixture was then poured into ice water (500 mL), and the crude product was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was removed by evaporation. The residue was vacuum-distilled at 50 mmHg to give 127 g of 3,4-ethylenedioxythiophene in high purity (96% or higher). The purity was confirmed by gas chromatographic analysis. The chemical structure was confirmed by mass analysis and 1H-NMR.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:17][N:18]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:25]N1C(=O)CCC1=O>C1COCC1>[Br:25][C:12]1[NH:11][C:10]2[C:9](=[O:15])[N:8]3[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:17][N:18]=[C:7]3[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(-c3ccccc3)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(-c3ccccc3)nnc12
Temperature: 70 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
To a mixture of 9-pentyl-3-phenyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (30 mg, 0.093 mmol) in THF (30 mL) was added N-bromosuccinimide (19.9 mg, 0.112 mmol). The mixture was stirred at 70° C. for 3 hours. The reaction mixture was concentrated in vacuo and the crude residue was purified using preparative LCMS to yield the desired product (8.7 mg, 23.3% yield). LCMS calculated for C17H18BrN6O (M+H) 401.1. Found 401.1, 403.1
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[CH2:7][C@H:8]([NH:23][C:24](=[O:39])[CH:25]([N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[C:29]1=[O:38])[CH2:26][CH3:27])[C@H:9]([OH:22])[CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:40])[CH2:7][C@H:8]([NH:23][C:24](=[O:39])[C@@H:25]([N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35](=[O:37])[CH3:36])[C:29]1=[O:38])[CH2:26][CH3:27])[C:9](=[O:22])[CH2:10][O:11][C:12]1[C:13]([F:21])=[C:14]([F:20])[CH:15]=[C:16]([F:19])[C:17]=1[F:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(C(=O)N[C@@H](CC(=O)OC(C)(C)C)[C@H](O)COc1c(F)c(F)cc(F)c1F)n1cccc(NC(C)=O)c1=O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC[C@@H](C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)COc1c(F)c(F)cc(F)c1F)n1cccc(NC(C)=O)c1=O
Reaction time: 2 h
Yield: 85 %

Procedure:
A stirred solution of (S,S)-3-[2-(3-Acetylamino-2-oxo-2H-pyridin-1-yl)-butyrylamino]-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (221 mg, 0.385 mmol) in anhydrous DCM (10 mL) was treated with 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (212 mg, 0.5 mmol) at 0° C. The resulting mixture was kept at 0° C. for 2 hr, diluted with ethyl acetate, then poured into a 1:1 mixture of saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium thiosulfate. The organic layer was removed and the aqueous layer re-extracted with ethyl acetate. The combined organic extracts were dried (Magnesium sulfate) and concentrated. The residue was purified by flash chromatography (50-50% ethyl acetate/hexane) to afford the title compound as a white solid (187 mg, 85%); 1H NMR (400 MHz, CDCl3) δ 0.93 (3H, t), 1.36 (3H, s), 1.95 (1H, m), 2.21 (3H, s), 2.25 (1H, m), 2.73 (2H, dd), 2.89 (1H, dd), 4.91 (1H, m), 5.04-5.17 (2H, m), 5.47 (1H, m), 6.34 (1H, t), 6.80 (1H, m), 7.19 (1H, m), 7.68 (1H, d), 8.36-8.41 (2H, m).
Reaction SMILES: [CH2:1]([N:8]1[C:15]2[CH:16]=[C:17]([CH:20]([C:22]3[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:23]=3[Cl:29])O)[CH:18]=[CH:19][C:14]=2[O:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.OS(C(F)(F)F)(=O)=O>FC(F)(F)C(O)=O>[CH2:1]([N:8]1[C:15]2[CH:16]=[C:17]([CH2:20][C:22]3[CH:27]=[C:26]([Br:28])[CH:25]=[CH:24][C:23]=3[Cl:29])[CH:18]=[CH:19][C:14]=2[O:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(c1ccc2c(c1)N(Cc1ccccc1)CC1(CC1)O2)c1cc(Br)ccc1Cl
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(Br)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CC1(CC1)O2
Temperature: 50 °C
Yield: 92.5 %

Procedure:
To an ice cold solution of (4-benzylspiro[3H-1,4-benzoxazine-2,1′-cyclopropane]-6-yl)-(5-bromo-2-chloro-phenyl)methanol (780 mg, 1.7 mmol) in trifluoroacetic acid (4 mL) was added triethylsilane (1.32 mL, 8.3 mmol) followed by triflic acid (0.15 mL, 1.7 mmol). After heating the mixture for 15 min at 50° C., the reaction was cooled to room temperature. Trifluoroacetic acid was evaporated under reduced pressure, and the resulting residue was taken in saturated aq. sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography to furnish 4-benzyl-6-[(5-bromo-2-chloro-phenyl)methyl]spiro[3H-1,4-benzoxazine-2,1-cyclopropane] (715 mg).
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:18](=O)[O:17][CH:16]3O)=[CH:7][CH:6]=1>C(O)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:18](=[O:17])[NH:2][N:1]=[CH:16]3)=[CH:7][CH:6]=1
Reactant: COc1ccc(C=Cc2ccc3c(c2)C(O)OC3=O)cc1
Reactant: NN
Solvent: CCO
Product: COc1ccc(/C=C/c2ccc3c(=O)[nH]ncc3c2)cc1
Reaction time: 5 h

Procedure:
Nine and one-half ml of hydrazine was added to a solution of 8.0 gm 5-(p-methoxyphenyl)ethenyl-3-hydroxyphthalide in 100 ml ethanol and the mixture was refluxed with stirring for 5 hours. The reaction mixture was cooled and the product filtered off and washed with isopropanol and dried. Wt=4.0 gm, m.p.=280°-289°.
Reaction SMILES: [F-].[K+].I[C:4]1[N:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7].CN(C)C=O.[F:17][C:18]([Si](C)(C)C)([F:20])[F:19]>O1CCCC1.[Cu]I.O.CN1CCCC1=O>[F:17][C:18]([F:20])([F:19])[C:4]1[N:11]=[CH:10][CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: N#Cc1cccnc1I
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: N#Cc1cccnc1C(F)(F)F
Temperature: 120 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To an oven-dried, N2-purged, 100-mL, round-bottomed flask containing a magnetic stir bar were added copper(I) iodide (1.26 g, 6.6 mmol) and potassium fluoride (383 mg, 6.6 mmol). The flask was heated to 120° C. for 1 hour under vacuum. After cooling to room temperature, 2-iodonicotinonitrile (1.38 g, 6.00 mmol) was added followed by the addition via syringe of anhydrous dimethylformamide (6 mL) and anhydrous N-methylpyrrolidinone (6 mL). A solution of (trifluoromethyl)trimethylsilane (12 mL of 0.5 M, 6.00 mmol) in tetrahydrofuran was added via syringe and the reaction mixture was stirred at room temperature overnight. Water (20 mL) was added. The mixture was transferred to a separatory funnel and extracted with ether (3×30 mL). The combined organic extracts were washed with ammonium hydroxide (30 mL), 1N hydrochloric acid (30 mL), and saturated sodium bicarbonate (30 mL). The ether solution was dried over magnesium sulfate and concentrated by rotary evaporator. The product was purified by flash chromatography (silica gel: 35% ethyl acetate, 65% hexanes, product Rf˜0.3) to give 800 mg (77%) of the title compound as a white powder. 1H NMR (CDCl3) δ 7.69 (dd, J=8.0, 4.9 Hz, 1H), 8.21 (dd, J=8.0, 1.5 HZ, 1H), 8.92 (dd, J=4.7, 9.4 Hz, 1H).
Reaction SMILES: [CH:1]([NH:5][CH:6]([CH2:8][CH3:9])[CH3:7])([CH2:3][CH3:4])[CH3:2].[C:10](Cl)([Cl:12])=[O:11]>ClC1C=CC=CC=1>[CH:1]([N:5]([CH:6]([CH2:8][CH3:9])[CH3:7])[C:10]([Cl:12])=[O:11])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)NC(C)CC
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: CCC(C)N(C(=O)Cl)C(C)CC
Yield: 100 %

Procedure:
A mixture of 129.0 g of di-sec.-butylamine and 129.0 g of chlorobenzene was reacted with phosgene in accordance with Example 1. When the phosgenation was complete, the mixture was heated under reflux for a further hour, the residual phosgene was then removed by blowing out with nitrogen, and, after the solvent had been removed under a moderate vacuum, the main product was collected by distillation. N,N-di-sec.-butylcarbamoyl chloride was obtained in this manner in a yield of 186.0 g and in a purity of 99.8%. The yield of 100% strength carbamoyl chloride was 185.6 g, corresponding to 96.9% of theory. A residue of 2.5 g (corresponding to 1.2% of the theoretical yield) remained in the distillation flask.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[C:11]([N:17]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]3)[C:12]([CH2:15][OH:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[CH2:24](N(CC)CC)C.CS(Cl)(=O)=O.C[O-].[Na+]>O1CCCC1.[Cl-].[Na+].O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([CH2:15][O:16][CH3:24])=[C:11]([N:17]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[N:18]3)[N:10]=2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)cnc2CO)n1
Agent: CS(=O)(=O)Cl
Agent: C[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: COCc1ncc(Nc2ccc(Cl)cc2)nc1-n1nc(C)cc1C
Reaction time: 0.25 h
Yield: 9.7 %

Procedure:
To a solution of [5-(4-chloro-phenylamino)-3-(3,5-dimethyl -pyrazol-1-yl)-pyrazin-2-yl]-methanol (50 mg, 0.15 mmol) and triethyl amine (0.06 mL, 0.45 mmol) in tetrahydrofuran (5 mL) was added methanesulfonyl chloride (0.23 mL, 0.30 mmol) and the solution was stirred for 15 min. Sodium methoxide (30 5 in methanol, 0.85 mL, 4.5 mmol) was added and the mixture was stirred for 1.5 hour. Water (20 mL) and brine (30 mL) was added and the qquosus phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulphate, filtrated and concentrated in vacuo. The crude product was purified by flash chromatography to give (4-chloro-phenyl)-[6-(3,5-dimethyl-pyrazol-1-yl)-5-methoxymethyl-pyrazin-2-yl]-amine (5 mg, 8%) as an orange solid. Mp. 147-151° C. LC-ESI-HRMS of [M+Na]+ shows 366.1087 Da. Calc. 366.109788 Da, dev. −3 ppm
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.Cl>B(Br)(Br)Br>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[S:10][C:6]=2[CH:5]=[C:4]([OH:19])[CH:3]=1
Reactant: COc1ccc(-c2nc3c(Br)cc(OC)cc3s2)cc1
Agent: BrB(Br)Br
Agent: Cl
Product: Oc1ccc(-c2nc3c(Br)cc(O)cc3s2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Bromo-6-methoxy-2-(4-Methoxy-phenyl)-benzothiazole (200 mg, 0.57 mmol) was suspended in boron tribromide (1M in methylene chloride, 7.5 mL) and stirred at room temp under nitrogen for 3.0 hr. Reaction was poured into aqueous hydrochloric acid (1M) and extracted with ethyl acetate. Ethyl acetate extracts were washed with: 1) hydrochloric acid (1.0M), 2) saturated brine and concentrated in vacuo. Washed solid was further purified by flash chromatography on silica affording the title compound (184 mg, 100%) as a yellow solid. MH+=322
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[C:30](=[NH:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:43]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N=C(c3ccccc3)c3ccccc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 90, Step 1, using the following starting materials: {3-[4-bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and benzophenone imine.
Reaction SMILES: CI.[CH3:3][C:4]1[N:8]=[C:7]([CH2:9][C:10](=[O:12])[CH3:11])[O:6][N:5]=1.[C:13](=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CCCCCCC>[CH3:3][C:4]1[N:8]=[C:7]([CH:9]([CH3:13])[C:10](=[O:12])[CH3:11])[O:6][N:5]=1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)Cc1nc(C)no1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CI
Product: CC(=O)C(C)c1nc(C)no1
Temperature: 20 °C
Reaction time: 12 h
Yield: 32 %

Procedure:
Methyl iodide (0.375 ml, 6 mmol) was added to a mixture of 1-(3-methyl-[1,2,4]oxadiazol-5-yl)-propan-2-one (0.84 g, 6 mmol) and potassium carbonate (4.15 g, 30 mmol) in acetoniotrile (8 mL), and the mixture was stirred at 20° C. for 12 h. Insoluble material was filtered off and the filtrate was diluted with dichloromethane. The solution was washed with 1 N hydrochloric acid and with brine, dried over sodium sulfate, and evaporated under reduced pressure. The residual oil was subjected to column chromatography on silica gel. Heptane/0-20% ethyl acetate eluted successively the title compound 3-methyl-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-butan-2-one (181 mg, 18%), obtained as colorless oil, Rf 0.4 (SiO2, ethyl acetate/heptane 1:1), MS ISP (m/e): 169.1 [(M+H)+]; 3-(3-Methyl-[1,2,4]oxadiazol-5-yl)-butan-2-one (296 mg, 3 2%), obtained as colorless oil, Rf 0.2 (SiO2, ethyl acetate/heptane 1:1), MS ISP (m/e): 155.1 [(M+H)+]; and 3-hydroxy-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-butan-2-one (204 mg, 20%), obtained as colorless oil, Rf 0.1 (SiO2, ethyl acetate/heptane 1:1),
Reaction SMILES: [Br:1]Br.[F:3][CH:4]([F:16])[O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=1.O.O.O.C([O-])(=O)C.[Na+].ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:1][C:11]1[C:9]([NH2:10])=[C:8]([N+:13]([O-:15])=[O:14])[CH:7]=[C:6]([O:5][CH:4]([F:16])[F:3])[CH:12]=1
Reactant: Nc1ccc(OC(F)F)cc1[N+](=O)[O-]
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Nc1c(Br)cc(OC(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (10 cm3) was added to a stirred suspension of 4-difluoromethoxy-2-nitroaniline (available as described for example in Example B5(b) of U.S. Pat. No. 4,686,230.) (26.6 g) and sodium acetate trihydrate (19.5 g) in carbon tetrachloride (250 mls). After stirring at ambient temperature for a period of 30 minutes, the reaction mixture was added to dichloromethane (350 mls) and washed with aqueous sodium metabisulphite solution, followed by aqueous sodium bicarbonate solution, and finally brine. The organic layer was the dried over anhydrous magnesium sulphate, and removal of the solvent by evaporation under reduced pressure, gave 6-bromo-4-difluoromethoxy-2-nitroaniline as an orange-brown solid. Melting Point: 60.5°-61.5° C. (cyclohexane).
Reaction SMILES: [OH:1][C:2]([CH3:40])([CH3:39])[C:3]#[C:4][C:5]1[N:6]=[C:7]([N:10]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:11][C@@H:12]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[S:8][CH:9]=1.C1C(=O)N([Br:48])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:48][C:9]1[S:8][C:7]([N:10]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:11][C@@H:12]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[N:6][C:5]=1[C:4]#[C:3][C:2]([OH:1])([CH3:40])[CH3:39]
Reactant: CC(C)(O)C#Cc1csc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(O)C#Cc1nc(N(C[C@H](Cc2ccc(C(F)(F)F)cc2)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)sc1Br
Reaction time: 3 h
Yield: 24.3 %

Procedure:
(S)-tert-butyl 1-(N-(4-(3-hydroxy-3-methylbut-1-ynyl)thiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.18 g, 0.31 mmol) was taken up in 5 mL of CCl4 and NBS (0.11 g, 0.62 mmol) was added. After 3 hours, the solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (5% to 40% EtOAc/hexanes) to afford (S)-tert-butyl 1-(N-(5-bromo-4-(3-hydroxy-3-methylbut-1-ynyl)thiazol-2-yl)-tert-butoxylcarbonylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.05 g, 24% yield) as a white solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[CH3:18][N:19]([CH3:29])[C:20]1[N:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:18][N:19]([CH3:29])[C:20]1[N:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([F:17])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: CN(C)c1ccc(B(O)O)cn1
Product: Cc1c2n(c3c(-c4ccc(N(C)C)nc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, grey solid (76 mg, 90%), MS (ISP) m/z=339.5 [(M+H)+], mp 259° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 6-dimethylamino-pyridin-3-ylboronic acid (53.9 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[C:3]=1[C:10]([O:12]CC1C=CC=CC=1)=[O:11].C(=O)(O)[O-].[Na+:24].C>CO.O.[Pd]>[Cl:1][C:2]1[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[C:3]=1[C:10]([O-:12])=[O:11].[Na+:24]
Reactant: O=C(OCc1ccccc1)C1=C(Cl)CC2CC(=O)N12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C([O-])C1=C(Cl)CC2CC(=O)N12

Procedure:
Benzyl 3-chloro-1azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (28 mg) in methanol (2.5 ml) and water (0.5 ml) containing sodium bicarbonate (8.5 ml) is hydrogenated with 10% palladium on powdered charcoal (30 mg) at 40 psi for 30 minutes. The mixture is filtered and the catalyst is washed with water (5 ml). The combined filtrate is concentrated in vacuo to 1/2 its volume, washed with ethylacetate, and lyophilized to provide sodium 3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: N[C@@H:2]([CH2:9][C:10]([OH:12])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:13][C@H](CC(O)=O)C1C=CC=CC=1>>[NH2:13][C@H:9]([C:10]([OH:12])=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N[C@@H](CC(=O)O)c1ccccc1
Reactant: N[C@H](CC(=O)O)c1ccccc1
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
The optical purity of (S)-β-phenylalanine was calculated from the peak area of the chromatogram obtained under analysis conditions illustrated in (1) above. Furthermore, the reaction yield of (S)-β-phenylalaninewas calculated from the peak area of the chromatogram obtained under analysis conditions illustrated in (2) above. Concretely, when the reaction solution contained a solid of β-phenylalanine or a solid of L-phenylalanine, a solution obtained by collecting a part of the reaction solution containing these solids, mixing with a 0.2 mol/l hydrochloric acid solution and dissolving these solids was analyzed. The amount (g) of (S)-β-phenylalanine synthesized was calculated from the peak area of the chromatogram using a calibration curve of (S)-β-phenylalanine standards to determine the yield from (Formula 1). Yield (%)=Amount of (S)-β-phenylalanine synthesized (g)/Amount of L-phenylalanine added (g)×100  (Formula 1)
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11](B(O)O)=[CH:12][C:3]1=2.Br[C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([Cl:26])[CH:25]=1)[C:21]#[N:22]>[Pd]>[Cl:26][C:24]1[CH:23]=[C:20]([CH:19]=[C:18]([C:11]2[CH:10]=[CH:9][C:4]3[NH:5][C:6](=[O:8])[O:7][C:2]([CH3:16])([CH3:1])[C:3]=3[CH:12]=2)[CH:25]=1)[C:21]#[N:22]
Reactant: N#Cc1cc(Cl)cc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Agent: [Pd]
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(Cl)cc(C#N)c3)cc21

Procedure:
4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-boronic acid (0.45 g, 2.04 mmol) was heated with 3-bromo-5-chlorobenzonitrile (0.42 g, 1.94 mmol) in the presence of soda ash (0.23 g, 2.17 mmol) and the 5% Pd/C catalyst in a solvent to produce 3-chloro-5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)benzonitrile in good yields and purity. See, Table 2.