Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=1)([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=1)([CH2:11][OH:12])[CH2:6][OH:7]
Reactant: CCCCCCc1ccc(CCCCC(COC(C)=O)(COC(C)=O)NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCc1ccc(CCCCC(N)(CO)CO)cc1
Yield: 56.1 %

Procedure:
2-Acetamido-1,3-diacetoxy-2-[4-(4-hexylphenyl)butyl]propane (200.2 mg) was dissolved in 7 ml of methanol and 1N sodium hydroxide was added thereto. The mixture was refluxed under heating for 5 hours. The solvent was distilled away and the residue obtained was purified by silica gel thin layer chromatography (methanol:chloroform=1:3) to give 79.7 mg of 2-amino-2-[4-(4-hexylphenyl)butyl]-1,3-propanediol as white crystals.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].C1C(=O)N([Br:16])C(=O)C1.O>CN(C=O)C>[Br:16][C:5]1[S:1][C:2]([CH2:6][C:7]#[N:8])=[CH:3][CH:4]=1
Reactant: N#CCc1cccs1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
To a solution of 2-(thiophen-2-yl)acetonitrile (1.23 g, 10 mmol, 1.0 eq) in DMF (10 mL), NBS (1.96 g, 11 mmol, 1.1 eq) was added. The mixture was stirred at room temperature for 2 h. Water was added to the reaction mixture. After extraction with EtOAc (3×), the organic layers were washed with water, brine, dried (Na2SO4) and filtered. The filtrate was concentrated and the resulting residue was purified by silica gel chromatography (petroleum/EtOAc from 100:1 to 10:1) to affords 2-(5-bromothiophen-2-yl)acetonitrile (738 mg, 60%). LC-MS (m/z)=202 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[N:34][O:35][CH3:36])[C:9]([NH:11][CH:12]2[C:32](=[O:33])[N:14]3[C:15]([C:19]([O:21]CC4C=CC([N+]([O-])=O)=CC=4)=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[N:3]=1>[Pd].O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[N:34][O:35][CH3:36])[C:9]([NH:11][CH:12]2[C:32](=[O:33])[N:14]3[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[N:3]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1nccc(N)n1
Agent: [Pd]
Solvent: C1CCOC1
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1nccc(N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
A mixture of 4-nitrobenzyl 7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer) (3.0 g) and 10% palladium on carbon (1.5 g) in 50% aqueous tetrahydrofuran (90 ml) was stirred under hydrogen atmosphere for 3 hours at ambient temperature. The catalyst was removed by filtration and the filtrate was concentrated to half of the original volume. The remaining aqueous solution was diluted with water (100 ml), washed with ethyl acetate, adjusted to pH 3 with 10% hydrochloric acid and subjected to column chromatography over nonionic adsorption resin, "Diaion HP20". The column was washed with water and eluted with 10% methanol. The eluent containing a desired compound was evaporated to remove the methanol in vacuo and then lyophilized to give 7-[2-(4-aminopyrimidin-2-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer) (750 mg), mp 191°-197° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7]([Cl:13])=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14](=[O:28])[CH:15]=[CH:16][C:17]1[N:18]=[C:19]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[S:20][CH:21]=1.CC(O)=O.OP(O)(O)=O>CC#N.[Cl-].[Cl-].[Zn+2]>[Cl:13][C:7]1[C:6]2[C:2]3[NH:1][CH:16]([C:17]4[N:18]=[C:19]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[S:20][CH:21]=4)[CH2:15][C:14](=[O:28])[C:3]=3[O:4][C:5]=2[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc2oc(C(=O)C=Cc3csc(NC(=O)C(C)C)n3)c(N)c2c1Cl
Agent: O=P(O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: CC#N
Product: COc1ccc2oc3c(c2c1Cl)NC(c1csc(NC(=O)C(C)C)n1)CC3=O
Temperature: 80 °C
Reaction time: 8 h
Yield: 19.2 %

Procedure:
To a mixture of 11E (2.6 g, 6.19 mmol) in MeCN (30 mL) was added ZnCl2 (1.27 g, 1.5 eq, 9.3 mmol) at room temperature, followed by AcOH (30 mL) and H3PO4 (30 mL) The reaction mixture was stirred 80° C. overnight. After reaction completed, the mixture was cooled and poured into crushed ice under stirring, neutralized to pH=7˜8, extracted with ethyl acetate, dried and concentrated to give 1.6 g of crude product, which was purified by column chromatography on silica gel to give 500 mg of pure product (11F).
Reaction SMILES: C([O:5][C:6](=O)[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:8]=1[S:17][CH2:18][C:19]([O:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:20])CCC.[H-].[Na+].CCCCCC.C(OCC)(=O)C>CN(C=O)C.C(O)(=O)C>[CH2:22]([O:21][C:19]([C:18]1[S:17][C:8]2[CH:9]=[C:10]([O:15][CH3:16])[C:11]([O:13][CH3:14])=[CH:12][C:7]=2[C:6]=1[OH:5])=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOC(=O)CSc1cc(OC)c(OC)cc1C(=O)OCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCCOC(=O)c1sc2cc(OC)c(OC)cc2c1O
Yield: 94 %

Procedure:
19.22 g (50 mmol) XII were stirred for 3.5 h at room temperature with 2.75 g (63 mmol), 60%) NaH in 250 ml DMF. The mixture was then hydrolyzed with 50 ml saturated NH4Cl solution and the solvent was removed. The residue was taken up in 500 ml CHCl3, filtered, washed with water and dried over Na2SO4. Flash chromatography (250 g SiO2, n-hexane:ethyl acetate=5:1+1% acetic acid) gave 14.70 g (47 mmol, 95%) XIII.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:13])=[CH2:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[N:22]#CBr>O.C(N(CC)CC)C.C(Cl)(Cl)Cl>[O-:4][C:5]#[N:22].[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH3:13])=[CH2:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#CBr
Agent: C=C(C)c1ccc(OC(C)=O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C=Cc1ccccc1
Product: N#C[O-]
Reaction time: 0.25 h

Procedure:
An 88.0 gram portion of the hydrolyzed p-isopropenylphenyl acetate and styrene copolymer and 600 grams of chloroform were added to a reactor and maintained under a nitrogen atmosphere with stirring. The transparent viscous solution was coold to 0° C., then 34.96 grams of cyanogen bromide (0.30 mole) was added. Thirteen minutes (780 s) later, 34.96 grams of triethylamine (0.33 mole) was added to the reactor over a 31 minute (1860 s) period and so as to maintain the reaction temperature at -1° to 2° C. After completion of triethylamine addition, the reactor was maintained at 2° to 5° C. for an additional 30 minutes (1800 s), followed by addition of 1000 milliliters of chilled water to the reactor. After 15 minutes (900 s), the water and chloroform plus product layers were separated. The chloroform plus product layer was washed with 500 milliliters 5 percent aqueous hydrochloric acid and then dried over anhydrous sodium sulfate. Filtration provided a dry chloroform solution of cyanate of hydrolyzed p-isopropenylphenyl acetate and styrene copolymer. Infrared spectrophotometric analysis confirmed the product structure as indicated by the disappearance of phenolic hydroxyl group absorbance of the appearance of cyanate group absorbance.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=O)=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].O.O[N:33]1[C:37]2C=CC=[CH:41][C:36]=2N=N1.Cl.C(/N=N/CCCN(C)C)C.N1CCC1>C(Cl)Cl.CO>[N:33]1([C:28](=[O:30])[CH2:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH2:19][CH2:18][C@@H:16]3[CH2:17][C@@H:15]3[CH:12]3[CH2:13][CH2:14][N:9]([C:7]4[O:6][N:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[N:8]=4)[CH2:10][CH2:11]3)=[CH:22][CH:23]=2)[CH2:41][CH2:36][CH2:37]1
Reactant: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)cc3)CC2)n1
Reactant: On1nnc2ccccc21
Agent: C1CNC1
Agent: CC/N=N/CCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)c1noc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N4CCC4)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-(4-(2-((1S,2R)-2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yl)cyclopropyl)ethoxy)phenyl)acetic acid (100 mg, 0.242 mmol), 1-hydroxybenzotriazole hydrate (55 mg, 0.363 mmol), and (E)-3-(ethyldiazenyl)-N,N-dimethylpropan-1-amine hydrochloride (70.0 mg, 0.363 mmol) were dissolved in CH2Cl2 (4 ml). The mixture was stirred at RT for 5 min. and azetidine (21 mg, 0.363 mmol) was added. The mixture was stirred at RT overnight and loaded directly on Preparative TLC that was developed with 5% MeOH in DCM. The desired product (Rf=0.35 @ 5% MeOH in DCM) was collected to give the title compound. 1H NMR (500 MHz, CDCl3) δ 7.20 (d, 2H), 6.90 (d, 2H), 4.05-4.15 (m, 8H), 3.41 (s, 2H), 3.05 (m, 2H), 2.96 (m, 1H), 2.26 (m, 2H), 2.18 (m, 1H), 1.95 (m, 2H), 1.50 (m, 3H), 1.35 (d, 6H), 0.95-1.05 (m, 2H), 0.68 (m, 2H), −0.40 (m, 1H). LC/MS (m/z): 453 (M+H)+, GPR119 Human EC50: 1.8 nM.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[O:14][CH3:15])[CH:6]=1.[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:13]=[CH:12][C:10]([N:11]=[C:16]=[S:17])=[CH:9][C:8]=2[O:14][CH3:15])[CH:6]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.3 %

Procedure:
Step A (3): Dichloromethane (125 mL) was added to a flask charged with 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (4.55 g, 20.3 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (4.72 g, 20.3 mmol). The resulting mixture was stirred for 24 h at rt. The crude reaction mixture was concentrated and the crude products were purified using silica gel chromatography to afford 4-chloro-1-(4-isothiocyanato-2-methoxy-phenyl)-1H-imidazole (4.28 g, 79% yield) as a white solid. LC-MS (M+H)+ 266.0. 1H NMR (500 MHz, chloroform-d) δ ppm 7.60 (d, J=1.53 Hz, 1 H) 7.24 (d, J=8.24 Hz, 1 H) 7.09 (d, J=1.83 Hz, 1 H) 6.93 (dd, J=8.24, 2.14 Hz, 1 H) 6.89 (d, J=2.14 Hz, 1 H) 3.88 (s, 3 H).
Reaction SMILES: [F:1][C:2]([F:34])([CH2:30][CH2:31][CH2:32][CH3:33])[C:3](=[O:29])/[CH:4]=[CH:5]/[C@H:6]1[C@H:10]([O:11]CC2C=CC=CC=2)[CH2:9][C:8](=[O:19])[C@@H:7]1[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]>C(OCC)(=O)C.[Pd]>[CH3:33][CH2:32][CH2:31][CH2:30][C:2]([F:34])([F:1])[C@:3]1([OH:29])[O:11][C@@H:10]2[CH2:9][C:8]([C@H:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C@H:6]2[CH2:5][CH2:4]1)=[O:19]
Reactant: CCCCC(F)(F)C(=O)/C=C/[C@H]1[C@H](OCc2ccccc2)CC(=O)[C@@H]1C/C=C\CCCC(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC(F)(F)[C@@]1(O)CC[C@H]2[C@@H](CC(=O)[C@@H]2CCCCCCC(=O)O)O1
Reaction time: 10 h
Yield: 70 %

Procedure:
To a solution of (Z)-7-[(1R,2R,3R)-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(phenylmethoxy)-5-oxocyclopentyl]-5-heptenoic acid (10, R1 is phenyl, R2 and R3 are H, R6 is H, and the S/D bond between the carbon at position 9b1 and the carbon at position 9b2 is a double bond, 50 mg) in ethyl acetate (5 mL), was added 10% palladium on carbon (5 mg) and the suspension was hydrogenated at atmospheric pressure for 10 hours. After the completion of the reaction, the mixture was filtered through Celite® and the crude material was re-crystallized using ethyl acetate/heptanes to yield Lubiprostone as a crystalline material in 70% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:23]=[C:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:40])[F:39])[CH:25]=[CH:26][C:27]=3[C:28]([O:30]C)=[O:29])[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]([OH:19])[C:15]([F:16])([F:17])[F:18])[C:11](=[O:20])[N:10]([CH2:21][C:22]3[CH:23]=[C:24]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]([F:41])([F:39])[F:40])[CH:25]=[CH:26][C:27]=3[C:28]([OH:30])=[O:29])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
195 mg (0.36 mmol) of the compound from Example 130 were dissolved in 3 ml of THF, and 0.4 ml a 1 N aqueous lithium hydroxide solution were added. The mixture was stirred at RT for 20 h. For work-up, the solvent was removed under reduced pressure, the residue was taken up in about 5 ml of water and 0.07 ml of 6 N hydrochloric acid was added. The mixture was stirred for 15 min, and the precipitated solid was then filtered off with suction and dried under high vacuum. This gave 146 mg (73% of theory) of the target compound.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][NH:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.C(OC(=O)C)(=O)C>>[C:6]1([C:4]2[O:13][C:1](=[O:12])[CH2:2][N:3]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1CN=C(c2ccccc2)O1
Temperature: 80 °C

Procedure:
101.6 g (0.567 mol) of hippuric acid was dispersed in 330 ml (3.49 mol) of acetic anhydride and heated to 80° C. in a water bath for about 20 minutes, thereby obtaining a solution of 2-phenyl-2-oxazolin-5-one. The thus obtained solution was cooled to -20° C. in a dry ice acetone bath. Thereto 93 g of anhydrous sodium acetate was added and the diaszonium salt solution prepared in advance was added to the mixture with vigorous stirring at a rate so as to maintain the reaction temperature at not higher than -10° C. After the completion of the dropping, the reaction mixture was held at -10° C. for 2 hours, and thereafter was stirred for 5 hours in an ice bath. Further, the mixture was stirred for one night in a water bath, and thereafter 1.5 l of water was added to filter out a yellow precipitate, which was washed with water to obtain the objective product.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:8])=[C:5]([Br:7])[N:6]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]1[CH2:22][CH:23]([CH3:25])[CH3:24])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:7][C:5]1[N:6]=[C:2]([N:19]2[CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C@@H:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:18]2)[S:3][C:4]=1[CH3:8]
Reactant: CC(C)C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Cc1sc(Br)nc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1sc(N2CCN(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C2)nc1Br
Temperature: 25 °C

Procedure:
2,4-dibromo-5-methyl-thiazole (1.189 g, 3.563 mmol), (S)—N-Boc-2-isobutylpiperazine (863.5 mg, 3.563 mmol) and potassium carbonate (1.477 g, 10.69 mmol) in DMF (15 mL) were heated at 95° C. for 18 h. Cooled to rt, diluted with EtOAc, washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (40 g SiO2, 0 to 5% EtOAc/petrol) to leave impure product as a very pale orange sticky oil (930 mg, 49% based on 78.9% purity); 1H NMR DMSO-d6 δ 0.90 (t, 6H), 1.36-1.31 (br m, 2H), 1.42 (s, 9H), 1.46-1.42 (masked signal, 1H), 2.18 (s, 3H), 3.02-2.91 (m, 2H), 3.14 (dd, 1H), 3.60 (d, 1H), 3.78-3.68 (m, 1H), 3.86 (d, 1H), 4.19 (br s, 1H); ES+ 420.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[Cl:36][C:37]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:38]=1[CH2:39]Br>>[Cl:36][C:37]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:38]=1[CH2:39][N:23]1[C:24]2[C:29](=[CH:28][C:27]([N+:32]([O-:34])=[O:33])=[CH:26][CH:25]=2)[C:30](=[O:31])[N:21]([CH:18]2[CH2:19][CH2:20][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)[C:22]1=[O:35]
Reactant: Clc1cccc(Cl)c1CBr
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(Cc5c(Cl)cccc5Cl)c4=O)CC3)c2cc1OC
Yield: 29 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and 2,6-dichlorobenzyl bromide was used in place of methyl iodide. As a result, 117.1 mg (yield: 29%) of Compound 10 was obtained as pale yellow crystals.
Reaction SMILES: [CH2:1]([OH:10])[C:2]([CH2:4][O:5]P(O)(O)=O)=[O:3].[N:11]([CH:14]([CH2:17][OH:18])[CH:15]=[O:16])=[N+:12]=[N-:13].[OH-].[Na+].CO>C(O)C(N)(CO)CO>[N:11]([C@H:14]([CH2:17][OH:18])[C@H:15]([OH:16])[C@@H:1]([OH:10])[C:2](=[O:3])[CH2:4][OH:5])=[N+:12]=[N-:13]
Reactant: O=C(CO)COP(=O)(O)O
Reactant: [N-]=[N+]=NC(C=O)CO
Agent: NC(CO)(CO)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [N-]=[N+]=N[C@H](CO)[C@H](O)[C@@H](O)C(=O)CO
Reaction time: 48 h
Yield: 30 %

Procedure:
DHAP (0.5 mmole) was added to an aqueous solution of 2-azido-3-hydroxypropanal (1 mmole in 40 ml) and the pH value adjusted to 7.0 with 10N NaOH. To this solution was added rhamnulose-1-phosphate aldolase from E. coli (4 g), which had been treated with egg white lysozyme (40 mg) in Tris buffer (pH 7.5, 25 ml) for one hour at 35° C., to form a mixture and the mixture stirred slowly for two days. The stirred mixture was adjusted to a pH value of 4.7, and acid phosphatase (400 units) added. The resulting mixture was incubated at 37° C. for 48 hours, neutralized to a pH value of 7.0 and lyophilized. The residue was treated with MeOH and filtered to remove the insoluble material. The MeOH was removed under reduced pressure and the crude product purified with silica gel column chromatography (CHCl3 :MeOH=6:1) to give 5-azido-5-deoxy-D-xylohexulose in 30 percent yield.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1.Br[C:15]1[CH:16]=[C:17]([C:20](=[O:23])[CH2:21][CH3:22])[S:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CO.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>[OH:4][C:5]1[CH:6]=[C:7]([C:15]2[CH:16]=[C:17]([C:20](=[O:23])[CH2:21][CH3:22])[S:18][CH:19]=2)[CH:8]=[CH:9][CH:10]=1
Reactant: COCOc1cccc(B(O)O)c1
Reactant: CCC(=O)c1cc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCC(=O)c1cc(-c2cccc(O)c2)cs1

Procedure:
In a manner similar to that of Example 1(h), by reaction of 4.6 g (25 mmol) 3-methoxymethoxyphenylboronic acid (described in Example 1(g)) and 5 g (22.8 mmol) of 1-(4-bromo-2-thiophenyl)-1-propanone with 22.8 mL of 2.0M potassium carbonate and 1.32 g of tetrakis(triphenylphosphine)palladium, followed by deprotection in methanol, the desired product is obtained in the form of a white solid (m.p.=112° C.; m=3.87 g: Y=73%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([CH3:11])=[CH:6][C:5]=1[Cl:12].[BH4-].[Li+].Cl.[OH-].[Na+]>C1COCC1>[NH2:10][C:8]1[C:7]([CH3:11])=[CH:6][C:5]([Cl:12])=[C:4]([CH2:3][OH:2])[CH:9]=1
Reactant: COC(=O)c1cc(N)c(C)cc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(CO)cc1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
To a solution of 5-amino-2-chloro-4-methyl-benzoic acid methyl ester (0.44 g, 2.204 mmol) in THF (5 ml) was added lithium borohydride (012 g, 5.509 mmol). The mixture was heated at reflux for three hours. The mixture was cooled to 0° C., acidified with 2N aqueous HCl, and the mixture was stirred for 10 minutes. The mixture was taken to pH7 with 2N aqueous NaOH and the product was extracted with EtOAc. The combined extracts were washed with water, brine dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the crude product by flash chromatography (hexanes:EtOAc 6:4) gave 0.278 g (73%) of (5-amino-2-chloro-4-methyl-phenyl)-methanol as a white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[CH3:17][S:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:22]2[CH:23]=[CH:24][C:19]([S:18][CH3:17])=[CH:20][CH:21]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(NCCCCO)c1ccc(Br)cc1
Reactant: CSc1ccc(B(O)O)cc1
Product: CSc1ccc(-c2ccc(S(=O)(=O)NCCCCO)cc2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(4-hydroxybutyl)-amide and 4-methylthiophenyl boronic acid were reacted to give the title compound as a white solid. δC (DMSO, 62.9 MHz): 14.5, 25.9, 29.6, 42.6, 60.2, 125.9 126.2, 127.1, 127.3, 127.5, 134.8, 139.1 and 143.1.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[CH:6]=[CH:7][C:8]2[O:14][C:12](=[O:13])[NH:11][C:9]=2[CH:10]=1.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>CN(C)C=O>[Cl:15][CH2:16][CH2:17][C:18]([C:6]1[CH:5]=[CH:10][C:9]2[NH:11][C:12](=[O:13])[O:14][C:8]=2[CH:7]=1)=[O:19]
Reactant: O=C(Cl)CCCl
Reactant: O=c1[nH]c2ccccc2o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: O=C(CCCl)c1ccc2[nH]c(=O)oc2c1

Procedure:
56.1 g (0.42 mole) of aluminum chloride are weighed into a ground-necked flask, 10 cm3 of dimethylformamide are then added using a dropping funnel and the mixture is left stirring until it becomes homogeneous. 8.1 g (0.06 mole) of benzoxazolinone are then added and the mixture is left stirring for 10 minutes before adding (0.072 mole) of 3-chloropropionic acid chloride. This mixture is maintained in an oil bath at 80°-85° C. for approximately 2 hours 30 minutes. After cooling, the reaction mixture is poured into ice-cold water. The precipitate is drained and washed with water to neutrality. The product is recrystallized in ethanol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]([NH:26][C:27]([N:29]2[CH2:34][CH2:33][CH:32]([N:35]3[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[NH:37][C:36]3=[O:45])[CH2:31][CH2:30]2)=[O:28])[CH2:15][C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([CH3:25])[CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH:5]=[C:4]([CH3:46])[N:3]=1>CO.[Pd]>[CH3:25][C:23]1[CH:24]=[C:16]([CH2:15][CH:14]([NH:26][C:27]([N:29]2[CH2:30][CH2:31][CH:32]([N:35]3[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[NH:37][C:36]3=[O:45])[CH2:33][CH2:34]2)=[O:28])[C:10]2[N:9]([CH2:8][C:6]3[CH:7]=[CH:2][N:3]=[C:4]([CH3:46])[CH:5]=3)[CH:13]=[CH:12][N:11]=2)[CH:17]=[C:18]2[C:22]=1[NH:21][N:20]=[CH:19]2
Reactant: Cc1cc(Cn2ccnc2C(Cc2cc(C)c3[nH]ncc3c2)NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc(Cl)n1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(Cn2ccnc2C(Cc2cc(C)c3[nH]ncc3c2)NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)ccn1
Reaction time: 8 h

Procedure:
N-(1-(1-((2-Chloro-6-methylpyridin-4-yl)methyl)-1H-imidazol-2-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl)-4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamide (15.0 mg, 0.024 mmol) in methanol (1.0 mL) was flushed with nitrogen, and treated with palladium (10% on charcoal, 1.5 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. After 24 h, the reaction was charged with additional palladium (10% on charcoal, 1.5 mg). The flask was flushed with hydrogen and allowed to stir under an atmosphere of hydrogen overnight. The reaction was flushed with nitrogen, filtered through celite, and concentrated in vacuo. Column chromatography gave 2.4 mg (17%). 1H-NMR (CD3OD, 500 MHz) δ 1.49-1.63 (m, 4H), 2.32 (s, 3H), 2.43 (s, 3H), 2.69-2.78 (m, 2H), 3.98-4.12 (m, 2H), 5.11-5.24 (m, 3H), 5.39 (d, J=17.1, 1H), 6.55 (d, J=0.9, 1H), 6.72 (s, 1H), 6.80 (d, J=7.9, 1H), 6.85 (s, 1H), 6.97 (dd, J=7.6, 7.3, 1H), 7.06 (s, 1H), 7.10-7.76 (m, 6H), 8.03 (d, J=5.2, 1H). Mass spec.: 604.96 (MH)+.