Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[O:15])[S:13][C:6]=12>C(O)(=O)C.[Fe]>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([CH2:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]([C:16]4[O:17][CH:18]=[CH:19][CH:20]=4)=[O:15])[S:13][C:6]=23)=[C:2]([F:1])[CH:24]=1
Reactant: O=C(c1ccco1)c1cc2nccc(Cc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(Cc2ccnc3cc(C(=O)c4ccco4)sc23)c(F)c1
Reaction time: 0.05 h
Yield: 18 %

Procedure:
To as solution of 240 (20 mg, 0.052 mmol) in acetic acid (2 mL) at 100° C., was added iron powder (15 mg, 0.260 mmol). The reaction mixture was stirred for 3 minutes, filtered through a celite pad and concentrated under reduced pressure. The residue was purified by flash chromatography, eluent EtOAc/hexane (3:7) to afford title compound 241 (3.3 mg, 18% yield) as a yellow solid. MS (m/z): 355.1 (M+1).
Reaction SMILES: CC([O:4][CH2:5][CH:6]1[O:11][CH:10](Br)[CH:9]([O:13]C(C)=O)[CH:8]([O:17]C(C)=O)[CH:7]1[O:21]C(C)=O)=O.[CH3:25][O:26][C:27]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34])=[O:28].S([O-])([O-])(=O)=O.[Ca+2]>ClCCl.C(=O)([O-])[O-].[Ag+2]>[O:34]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][C:27]([O:26][CH3:25])=[O:28])[C@@H:10]1[O:11][C@H:6]([CH2:5][OH:4])[C@H:7]([OH:21])[C@H:8]([OH:17])[C@H:9]1[OH:13]
Reactant: COC(=O)CCCCCO
Reactant: CC(=O)OCC1OC(Br)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COC(=O)CCCCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.6 %

Procedure:
A solution of acetobromogalactose (38.4 g) in 200 mL dry dichloromethane was added over a period of 60 min to a vigorously stirred suspension containing 5-methoxycarbonylpentanol (30.0 g), anhydrous silver carbonate (31.7 g, Aldrich), 3 Å molecular sieves (30.0 g) and anhydrous calcium sulphate (20.0 g) in dry dichloromethane (350 mL). After 20 h, the solution was filtered over celite and the solution was evaporated to dryness. The syrup was dissolved in pyridine (75 mL) containing acetic anhydride (50 mL) and 4-N,N-dimethylaminopyridine (10 mg) and stirred at room temperature for 3 h. The reaction mixture was then poured over crushed ice (200 g) and the product was extracted with dichloromethane (2×200 mL). The combined dichloromethane layer was washed with ice cold 1M hydrochloric acid and this procedure was repeated till the aqueous layer was acidic. Finally, the dichloromethane layer was washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulphate and evaporated. To the crude syrup, n-hexane was added (200 mL), shaken well and the hexane layer was decanted. This procedure was repeated thrice. Finally, the syrup was dissolved in anhydrous methanol (300 mL). 15 mL of 0.5M sodium methoxide solution was added and this mixture was stirred at room temperature for 3 h. The reaction mixture was neutralized with IR-120 H+ resin, filtered and evaporated to a dry residue to yield the titled compound (26.1 g). [α]D25 -3.8±2° (c 1.03, MeOH). 1H n.m.r.(CD3OD) ∂: 4.19 (d, J=7.3 Hz, H-1), 3.89 and 3.54 (m, 2 H, OCH2 -of aglycon), 3.82 (dd, J=1.0, 3.2 Hz, H-4), 3.76-3.68 (m, H-6a,b), 3.64 (s, COOCH3), 3.50-3.47 (m, H-2, H-5), 3.44 (dd, J=3.2, 9.5 Hz, H-3), 2.32 (t, J=7.3 Hz, CH2COO), 1.65 and 1.40 (6 H, hydrogens of pentyl group). 13C n.m.r. (CD3OD) ∂: 105.1, 76.8, 75.3, 72.8, 70.6, 70.6, 62.7, 52.0, 34.9, 30.5, 26.8, 25.9. Anal. Calcd for C13H24O8 :C, 50.6; H, 7.8. Found: C, 49.47; H, 7.78.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@H:18]([NH:22][C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH:20]=[CH2:21])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C12BC(CCC1)CCC2.[OH-:42].[Na+].OO>C1COCC1>[CH2:26]([O:25][C:23]([NH:22][C@@H:18]([C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)[CH2:19][CH2:20][CH2:21][OH:42])=[O:24])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C=CC[C@@H](NC(=O)OCc1ccccc1)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(N[C@H](CCCO)c1nc(-c2ccccc2)c(-c2ccccc2)o1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (4R)-4-(4,5-diphenyloxazol-2-yl)-4-benzyloxycarbonylamino-1-butene (5.2 g) in THF (50 ml) was added 9-borabicyclo[3.3.1]nonane (9-BBN) (98 ml, 0.5M solution of THF) at 0° C. After stirred for 4 hours at room temperature, 2N NaOH solution (20 ml) and 35% H2O2 solution (20 ml) were added to the mixture at the 0° C. The mixture was stirred for 1 hour at the same temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (1R)-N-benzyloxycarbonyl-4-hydroxy-1-(4,5-diphenyloxazol-2-yl)butylamine (13 g). MS (m/z): 443 (M+ +1) IR (Neat): 3300, 1700 cm-1NMR (CDCl3, δ): 1.6-2.2 (4H, m), 3.68 (2H, m), 5.10-5.2 (1H, m), 5.14 (2H, s), 5.73 (1H, d, J=10.0 Hz), 7.2-7.7 (15H, m)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1I>>[NH2:9][C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[F:12]
Reactant: Fc1ccccc1I
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Product: Nc1cc(Br)ccc1-c1ccccc1F

Procedure:
2,5-Dibromo-1-nitrobenzene and o-fluoroiodobenzene were reacted under Ullmann conditions to give 4-bromo2'-fluoro-2-nitrobiphenyl, b.p. 125°-140°C./0.2mm (m.p. 71°-73°C. after recrystallisation from industrial methylated spirits). This was reduced to give 2-amino-4-bromo-2'-fluorobiphenyl, m.p. 52°-54°C., which was deaminated to give the product, b.p. 105°-115°C./0.5mm (m.p. 40°-42°C. after recrystallisation from petroleum, b.p. 40°-60°C.).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([NH2:11])=[N:9][CH:10]=1)(=[O:4])=[O:3].Br[C:13]1[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:19][C:17]1[CH:18]=[C:13]([NH:11][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][N:9]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CS(=O)(=O)c1ccc(N)nc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(S(C)(=O)=O)cn2)c1=O
Temperature: 100 °C
Yield: 27.9 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1,4-dioxane (15 mL), 117c (1.7 g, 10 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (5.2 g, 20 mmol) and cesium carbonate (6.4 g, 20 mmol). Xantphos (300 mg, 0.8 mmol) and Pd2(dba)3 (500 mg, 0.8 mmol) were added, and the reaction mixture was heated at 100° C. for 5 h (hours). After this time the reaction was cooled to room temperature. The mixture was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified on flash column eluting with DCM:MeOH (20:1) to afford 117d (1 g, 30%). MS: [M+H]+ 358.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:25])=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C@@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13])[N:8]=[CH:7]2.[C:26](OC)(OC)(OC)[O:27][CH3:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:26][O:27][C:28]1[O:25][C:3]2[CH:4]=[CH:5][C:6]3[CH:7]=[N:8][N:9]([CH2:11][C@@H:12]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH3:13])[C:10]=3[C:2]=2[N:1]=1
Reactant: COC(OC)(OC)OC
Reactant: C[C@@H](Cn1ncc2ccc(O)c(N)c21)NC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: COc1nc2c(ccc3cnn(C[C@H](C)NC(=O)OCc4ccccc4)c32)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product from Step D (0.47 g) was combined with tetramethyl orthocarbonate (15 mL), p-toluenesulfonic acid hydrate (10 mg) and the mixture was stirred at room temperature for 1 h. The reaction was quenched with triethylamine (1 ml) and the reaction mixture was evaporated to a residue which was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give a colorless oil (60 mg): LC/MS m/z 381.
Reaction SMILES: Cl[C:2]1S[C:5]([C:7]2[C:16]([O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[CH:4][C:3]=1[CH3:32]>C(N(CC)CC)C.CN(C)C=O.[OH-].[Pd+2].[OH-]>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:17][C:16]1[C:7]([CH2:5][CH2:4][CH:3]([CH3:32])[CH3:2])=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3-c3cc(C)c(Cl)s3)c2cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3CCC(C)C)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
4-[2-(5-Chloro-4-methyl-thiophen-2-yl)-quinolin-3-yloxy]-6,7-dimethoxy-quinoline (compound 290) (7 mg) was dissolved in triethylamine/N,N-dimethylformamide (0.5 ml/1.5 ml) to prepare a solution, 20% palladium hydroxide (68 mg) was added to the solution, and the mixture was stirred under a hydrogen gas atmosphere at room temperature overnight. The reaction solution was filtered, and the solvent was then removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (3.6 mg, yield 56%).
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10](=[O:33])[CH:11]([N:13]2[C@H:16]([S:17][C:18](=[O:20])[CH3:19])[C@@H:15]([O:21][C:22](=O)COC3C=CC=CC=3)[C:14]2=[O:32])O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:38])=O>O1CCOCC1>[N+:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10](=[O:33])[CH:11]([N:13]2[C@H:16]([S:17][C:18](=[O:20])[CH3:19])[C@@H:15]([O:21][CH3:22])[C:14]2=[O:32])[Cl:38])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)S[C@@H]1[C@@H](OC(=O)COc2ccccc2)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CO[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2 g of poly-Hunig base in 8 ml of dioxan is stirred at room temperature for 30 minutes, a solution of 962 mg of 2-[(3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl]-2-hydroxyacetic acid p-nitrobenzyl ester in 10 ml of dioxan is added, then a solution of 0.38 ml of thionyl chloride in 8 ml of dioxan is added slowly. The mixture is stirred for 2 hours at room temperature, the poly-H/e,uml/u/ nig base is filtered off and the filtrate is concentrated by evaporation in vacuo. The residue is purified by chromatography over silica gel with toluene/ethyl acetate (1:1) and yields the 2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester in crude form.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([NH:30][C:31]([NH:33][C:34]4[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:41])=[O:32])=[N:25][CH:26]=[N:27]3)=[CH:22][C:21]=2[O:42][CH3:43])[CH2:12][CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([NH:30][C:31]([NH:33][C:34]4[C:35]([Cl:41])=[CH:36][CH:37]=[CH:38][C:39]=4[Cl:40])=[O:32])=[N:25][CH:26]=[N:27]3)=[CH:22][C:21]=2[O:42][CH3:43])[CH2:12][CH2:11]1
Reactant: COc1cc2c(NC(=O)Nc3c(Cl)cccc3Cl)ncnc2cc1OCCCN1CCC(CNC(=O)OC(C)(C)C)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(NC(=O)Nc3c(Cl)cccc3Cl)ncnc2cc1OCCCN1CCC(CN)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 58.6 %

Procedure:
A mixture of 1-{7-[3-(4-tert-butoxycarbonylaminomethylpiperidin-1-yl)propoxy]-6-methoxyquinazolin-4-yl}-3-(2,6-dichlorophenyl)urea (0.075 g), trifluoroacetic acid (0.35 ml) and chloroform (1.5 ml) was stirred at ambient temperature for 40 minutes. The mixture was evaporated and the residue was stirred under a 1N aqueous sodium hydroxide solution (3 ml) for 1 hour. The resultant solid was isolated and dried. There was thus obtained the title compound (0.037 g); NMR Spectrum: (DMSOd6) 1:12 (m, 3H), 1.62-1.7 (m, 2H), 1.9 (t, 2H), 2.0 (m, 4H), 2.38-2.54 (m, 4H), 2.92 (m, 2H), 3.3 (m, partially obscured by a water signal), 3.95 (s, 3H), 4.26 (t, 2H), 7.28 (s, 1H), 7.41 (t, 1H), 7.62 (d, 2H), 8.06 (s, 1H), 8.66 (s, 1H); Mass Spectrum: M+H+ 533 and 535.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][O:26]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1.Cl>CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][OH:26])=[CH:23][CH:24]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: Cl
Solvent: CO
Product: OCc1ccc(C2CCNCC2OCc2ccc3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
A solution of 1.10 g (1.59 mmol) of tert-butyl (3RS,4RS)-3-naphthalen-2-ylmethoxy-4-(4-trityloxymethyl-phenyl)-piperidine-1-carboxylate in 50 ml of methanol was treated at room temperature with 30 ml of a 2M solution of hydrogen chloride in methanol and the mixture was stirred at room temperature for 4 hours. Subsequently, the solution was evaporated under reduced pressure and the residue was partitioned between 30 ml of saturated sodium carbonate solution and 50 ml of ethyl acetate. The aqueous phase was again extracted with 50 ml of ethyl acetate, thereafter the organic phases were combined, dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 90:10 mixture of methylene chloride and methanol as the eluent. There were obtained 462 mg (83% of theory) of (3RS,4RS)-[4-[3-(naphthalen-2-ylmethoxy)-piperidin-4-yl]-phenyl}-methanol as a colourless solid; MS: 348 (M+H)+.
Reaction SMILES: CCCCCC.[H-].[Na+].COP([CH2:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])(OC)=O.[CH:26]([C:28]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[C:29]=1[C:30]([O:32][CH3:33])=[O:31])=O>C1COCC1>[CH2:19]([O:18][C:16](=[O:17])/[CH:15]=[CH:26]/[C:28]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[C:29]=1[C:30]([O:32][CH3:33])=[O:31])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COP(=O)(CC(=O)OCc1ccccc1)OC
Reactant: COC(=O)c1c(C=O)cccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)c1c(/C=C/C(=O)OCc2ccccc2)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.6 %

Procedure:
To a suspension of hexane-washed sodium hydride (0.42 g of 60% suspension in mineral oil, 10.52 mmol) in 120 mL of THF at 0° C. was added benzyl 2-(dimethoxyphosphoryl)acetate (2.72 g, 10.52 mmol) dropwise in 10 mL of THF. The resulting mixture was stirred 5 min at 0° C. and then was allowed to warm to ambient temperature and stirred for 20 min. To this solution was added methyl 2-formyl-6-(trifluoromethyl)benzoate (2.22 g, 9.56 mmol) dropwise in 10 mL of THF. The resulting solution was stirred at ambient temperature for 1 h. The reaction mixture was quenched with 1N HCl (100 mL) and extracted with ethyl acetate. The organics were washed with sat'd aq NaHCO3 and brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo to afford 3.4 g (97%) of the title compound which was sufficiently pure to be used without purification. 1H NMR (CDCl3): δ 7.79 (d, 1H, J=7.9 Hz), 7.72-7.67 (m, 2H), 7.55 (t, 1H, J=7.9 Hz), 7.38-7.30 (m, 5H), 6.47 (d, 1H, J=15.8 Hz), 5.23 (s, 2H), 3.94 (s, 3H). LRMS (ESI): 387.17 (M+H+Na)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22].[Cl:23][CH2:24][C:25](OC(=O)CCl)=O.C>CN(C)C=O.C(#N)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:25]([CH2:24][Cl:23])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22]
Reactant: O=C(CCl)OC(=O)CCl
Reactant: CN1Cc2c(C(N)=NO)ncn2-c2ccc(F)c(Cl)c2C1=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)c(Cl)c2C1=O
Reaction time: 2 h
Yield: 68.4 %

Procedure:
A suspension of 7.0 g (0.0216 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime in 70 ml of N,N-dimethylformamide was treated with 4.38 g (0.0256 mol) of chloroacetic anhydride. The yellow solution obtained was stirred at 100° for 2 hrs. and then completely freed from the solvents. The oily product was taken up in 300 ml of acetonitrile, whereupon the solution was treated with active charcoal, boiled at reflux and filtered while hot over 100 g of silica gel; the silica gel was rinsed with 200 ml of acetone and the filtrate was evaporated. The crystalline foam was suspended in 100 ml of ether and suction filtered. Additional material could be obtained from the mother liquor. There was obtained a total of 5.65 g (68%) of 7-chloro-3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a ][1,4]benzodiazepin-6-one as white-yellowish crystals; m.p. 215°-218°.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:46][CH2:45][N:44]3[C:37](=[CH:38][C:39]4[CH2:40][C:41]([CH3:48])([CH3:47])[CH2:42][C:43]=43)[C:36]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:32]=[C:22]3[CH2:23][N:24]([CH:27]([CH3:31])[CH2:28][O:29][CH3:30])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[CH:13]=1)(=O)C.[OH-].[Li+]>C1COCC1.C(O)(C)C.O>[OH:4][CH2:5][C:6]1[C:7]([N:35]2[CH2:46][CH2:45][N:44]3[C:43]4[CH2:42][C:41]([CH3:48])([CH3:47])[CH2:40][C:39]=4[CH:38]=[C:37]3[C:36]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:32]=[C:22]3[CH2:23][N:24]([C@H:27]([CH3:31])[CH2:28][O:29][CH3:30])[CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:33])[N:14]([CH3:34])[CH:13]=1
Reactant: COCC(C)N1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4COC(C)=O)cn(C)c3=O)cc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC[C@@H](C)N1CCn2nc(Nc3cc(-c4ccnc(N5CCn6c(cc7c6CC(C)(C)C7)C5=O)c4CO)cn(C)c3=O)cc2C1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a solution of 300d (200 mg, 0.30 mmol) in THF/i-propanol/water (6/3/3 mL) was added lithium hydroxide (36 mg, 1.5 mmol). The mixture was stirred at 30° C. for 1 h and concentrated under reduced pressure. The residue was partition between ethyl acetate (15 mL) and (10 mL). The water phase was extracted with ethyl acetate (3×10 mL). The combined organic layer was dried, filtered, and concentrated under reduced pressure. Prep-HPLC and chiral resolution afforded the two enantiomers: 300 (35 mg, 18.6%) as white solid; and 303 (28 mg, 15%) as white solid. MS-ESI: [M+H]+ 627.4. 1H NMR (500 MHz, CDCl3) δ 8.49 (d, J=5.0 Hz, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.41 (s, 1H), 7.35 (d, J=5.0 Hz, 1H), 6.85 (s, 1H), 5.72 (s, 1H), 5.05-5.03 (m, 1H), 4.67-4.45 (m, 1H), 4.52-4.50 (m, 1H), 4.35-4.31 (m, 1H), 4.18-4.16 (m, 2H), 4.09-4.07 (m, 2H), 3.87-3.85 (m, 3H), 3.71 (s, 3H), 3.56-3.52 (m, 1H), 3.45-3.43 (m, 1H), 3.38 (s, 3H), 3.11-3.08 (m, 3H), 2.60-2.58 (m, 2H), 2.53 (s, 2H), 1.29 (s, 6H), 1.17 (d, J=6.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([SH:13])=[CH:11][CH:10]=[C:9]2[CH:14]=[O:15])=[N:4][CH:5]=[CH:6][CH:7]=1.CI.[C:18](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([S:13][CH3:18])=[CH:11][CH:10]=[C:9]2[CH:14]=[O:15])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(S)n1-c1ncccc1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(C=O)n1-c1ncccc1Cl
Yield: 64.2 %

Procedure:
A mixture of 0.50 g of 1-(3-chloro-2-pyridinyl)-5-mercapto-1H-pyrrole-2-carbaldehyde, 0.36 g of methyl iodide, 0.43 g of potassium carbonate and 50 ml of N,N-dimethylformamide was stirred at room temperature for 1 day Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed successively with water and an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.34 g of 1-(3-chloro-2-pyridinyl)-5-methylthio-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [C:1]([N:4]1[C:9]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:8]=2[O:7][C:6]([CH3:18])([CH3:17])[CH2:5]1)(=[O:3])[CH3:2]>C(O)C.[Ni]>[C:1]([N:4]1[C:9]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:8]=2[O:7][C:6]([CH3:18])([CH3:17])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Agent: [Ni]
Solvent: CCO
Product: CC(=O)N1CC(C)(C)Oc2ccc(N)cc21
Yield: 98.9 %

Procedure:
To a suspension of 20.9 g 4-acetyl-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine in 200 ml ethanol, was added a catalytic amount of Raney nickel, and the catalytic hydrogenation was carried out at ordinary temperature and pressure. The catalyst was filtered off from the reaction mixture, and the solvent was distilled off from the filtrate, giving 18.2 g of crude 4-acetyl-6-amino-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazine.
Reaction SMILES: [OH-:1].[K+:2].O=C[C@@H:5]([C@H:7]([C@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6]>CO.O>[O:1]=[C:5]([O-:6])[C@H:7]([C@H:9]([C@@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8].[K+:2]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C([O-])[C@@H](O)[C@@H](O)[C@H](O)CO
Yield: 573.9 %

Procedure:
Air was sparged at 100 mL/min through a rapidly stirred solution of potassium hydroxide (41.9 g, 65.5 mmol) and D-galactose (45.0 g, 25.0 mmol) in a mixture of methanol/water (375 mL/180 mL) at 60 psi in a Parr bomb (1 L). The temperature was maintained at 35°-36° C. throughout the reaction. After sparging for 24 hours (h), methanol (50 mL) was added and sparging continued for a total of 45 h. The reaction mixture was cooled and vented. The bomb was opened and the light yellow mixture was filtered to remove a small amount of solids. The bomb and filter were rinsed with water (5 mL) in which most of the solids dissolved. The filtrate was stirred and diluted with methanol (850 mL). Crystallization occurred after approximately 500 mL of methanol had been added. After stirring for 4 h, the crystals were collected by filtration and vacuum dried to provide 29.3 g (57% yield) of potassium D-lyxonate 1 as a white solid: DISC mp 171.25° C.; Analysis calculated for C5H9O6K: C, 29.41; H, 4.44. Found: C, 28.86; H, 4.16. This white solid material was used in Example 2 without further purification.