Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19][C:20]([NH:22][C:23]3[N:27]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)[N:26]=[C:25]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH:24]=3)=[O:21])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:39]([N:41]=[C:42]=[O:43])[CH3:40].CN(C=O)C>C(Cl)Cl>[C:35]([C:25]1[CH:24]=[C:23]([NH:22][C:20]([NH:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:9]([CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:42]([NH:41][CH2:39][CH3:40])=[O:43])[CH:7]=3)=[CH:10][CH:11]=2)=[O:21])[N:27]([C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=2)[N:26]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Cc3ccnc(N)c3)c3ccccc23)cc1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)Nc1cc(Cc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)ccn1
Temperature: 0 °C
Reaction time: 21 h

Procedure:
To a solution of 1-(4-((2-aminopyridin-4-yl)methyl)naphthalen-1-yl)-3-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)urea (55 mg, 0.11 mmol) in dry DCM (4.0 mL) under N2 at 0° C. was added ethyl isocyanate (22 μL, 0.27 mmol). The reaction mixture was maintained at 0° C. for 20 min, was then warmed to RT for 2 hr and dry DMF (200 μL) was added. Additional aliquots of ethyl isocyanate were added after 3.5 hr (22 μL, 0.27 mmol), after 21 hr (43 μL, 0.54 mmol) and after 28 hr (65 μL, 0.81 mmol). After 43 hr the reaction was quenched by the addition of a solution of NH3 (1% in MeOH, 3.0 mL) and after 45 min the resulting mixture was evaporated in vacuo. The residue was subjected to SCX capture and release and the crude product so obtained was purified by flash column chromatography (SiO2, 12 g, [5% MeOH in EtOAc] in isohexane, 0-80%, gradient elution) to afford the title compound, Example 23, as a white solid (26 mg, 40%); Rt 2.22 min (Method 2); m/z 576 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.04 (3H, t), 1.28 (9H, s), 2.39 (3H, s), 3.14 (2H, m), 4.33 (2H, s), 6.40 (1H, s), 6.76 (1H, dd), 7.16 (1H, s), 7.36 (2H, d), 7.39 (1H, d), 7.45 (2H, d), 7.53 (2H, m), 7.87 (1H, d), 7.92 (1H, d), 8.01-8.04 (2H, overlapping m), 8.15 (1H, br t), 8.78 (1H, s), 9.04 (1H, s), 9.07 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29].[I-].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:23][CH2:24][NH:25][C:26](=[O:30])[O:27][CH2:28][CH3:29])=[CH:8][CH:7]=1
Reactant: Oc1ccc(Oc2cccc(Cl)c2)cc1
Reactant: CCOC(=O)NCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)NCCOc1ccc(Oc2cccc(Cl)c2)cc1

Procedure:
To a solution of 13.2 g of 4-(3-chlorophenoxy)phenol (m.p. 53°-54° C.) are added 16.6 g of finely powdered potassium carbonate, 13.6 g of ethyl 2-chloroethylcarbamate and 1 g of powdered potassium iodide. With stirring, the reaction mixture is heated to +95° C. over 15 hours and then filtered. The filtrate is taken up in ice-water and extracted three times with ether. The organic extracts are washed with water, dried over sodium sulfate and concentrated by evaporation. The crude product is purified by chromatography over silica gel with a 1:3 mixture of ether/hexane to give the pure ethyl 2-[4-(3-chlorophenoxy)phenoxy]ethylcarbamate of m.p. 45°-46° C. The 1H-NMR spectrum is in conformity with the indicated structure.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:15])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH2:13])=[CH:8][C:7]=1[OH:14].Br[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.O>CN(C)C=O>[NH2:13][C:9]1[C:10]([Cl:12])=[CH:11][C:6]([C:5]([OH:4])=[O:15])=[C:7]([O:14][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[CH:8]=1
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Reactant: BrCC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(OCC2CCCCO2)c(C(=O)O)cc1Cl
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
A suspension of 50% sodium hydride/oil dispersion (1.00 g, 0.025 mole) in anhydrous dimethylformamide (40 ml) under nitrogen was treated with 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester (4.03 g, 0.020 mole), stirred for 30 minutes, then treated with 2-(bromomethy)tetrahydro-2H-pyran (4.66 g, 0.026 mole). The mixture was heated to 95°±5° C. for 1.5 hours, then cooled and added to water (250 ml). The aqueous mixture was extracted with ether (2×200 ml), and the combined ethereal solution was dried (magnesium sulfate), concentrated in vacuo, an taken up in 95% ethanol (40 ml), water (20 ml) and 50% sodium hydroxide (20 ml) were added, and the mixture was refluxed for one hour, cooled on an ice bath, and concentrated in vacuo in order to remove most of the ethanol. Water was added to a total volume of 200 ml, and the aqueous solution was extracted with ether (2×100 ml), cooled on an ice bath, and adjusted to pH~4 with concentrated hydrochloric acid (32 ml). A solid soon precipitated, and this was filtered, washed with water, air dried, and recrystallized from ethyl acetate to afford 3.45 g (60%) of the title compound as colorless crystals; mp 146.5°-147.5° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]([NH2:5])=[O:4].[S:12](Cl)(Cl)=O.O>ClCCl.C(N(CC)CC)C>[C:8]([O:7][CH2:6][C:2]1[C:3]([OH:4])=[N:5][S:12][N:1]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OCC(N)C(N)=O
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OCc1nsnc1O
Temperature: -78 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
After dissolving 8.17 g of 2-amino-3-(tert-butoxy)propionamide in 150 ml of dichloromethane, 16.37 ml of triethylamine was added and the solution was cooled to −78° C., and then 4.10 ml of thionyl chloride was added dropwise while stirring at below −50° C. After stirring for 30 minutes, the temperature was raised to room temperature and stirring was continued overnight. Water was added to the reaction solution, and extraction was performed with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered with silica gel. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (1.98 g, 21% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[F-].[Li+].[NH3:16]>CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[NH2:16]
Reactant: FC(F)(F)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: N
Agent: [F-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: -95 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
3,4,5-Trichloro-trifluoromethylbenzene (0.681 g, 2.73 mmol), lithium fluoride (7.1 mg, 0.273 mmol) and N-methylpyrrolidone (1.8 ml) are mixed in an autoclave. The autoclave is cooled to −95° C. and then ammonia (1.3 g, 76.4 mmol) is added. The autoclave is then heated at 250° C. and with stirring for 4 h and is subsequently allowed to return to room temperature. The reaction product is extracted by washing with water and with dichloromethane and then the organic phase is evaporated, after having been dried. 0.453 g (1.97 mmol) of 2,6-dichloro-4-trifluoromethylaniline is obtained with a degree of conversion of the 3,4,5-trichloro-trifluoromethylbenzene of 97%, a ratio equal to 83/17 for the selectivity for 2,6-dlchloro-para-trifluoromethylaniline with respect to 2,6-dichloro-meta-trifluoromethylaniline and an 87% yield of 2,6-dichloro-para-trifluoromethylaniline.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].O>O1CCOCC1>[CH3:1][NH:2][C:3]([C:5]1[CH:11]=[CH:10][C:8]([NH:9][C:15](=[O:16])[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CNC(=O)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
To a suspension of 4-(methylcarbamoyl)aniline (1.0 g) in 1,4-dioxane (10 ml) were added 1N sodium hydroxide solution (13.4 ml) and phenyl chloroformate (1.26 g) under ice-cooling, and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was poured into water and extracted with a mixture of chloroform and methanol. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate to give phenyl 4-(methylcarbamoyl)phenylcarbamate (1.70 g) as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.Cl[CH:15]([C:22]1[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=1)[CH2:16][N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[CH3:33][O:32][C:24]1[CH:23]=[C:22]([CH:15]([S:3][C:4]2[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:27]=[C:26]([O:28][CH3:29])[C:25]=1[O:30][CH3:31]
Reactant: COC(=O)c1ccc(S)cc1
Reactant: COc1cc(C(Cl)Cn2ccnc2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2cc(OC)c(OC)c(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
48.5 mg of a 55% w/w suspension of sodium hydride in mineral oil were added, whilst ice-cooling, to a solution of 187 mg of methyl 4-mercaptobenzoate in 1.3 ml of dry dimethylformamide, and the reaction mixture was then stirred at room temperature for 30 minutes. To this solution was added 1.3 ml of dry dimethylformamide containing 330 mg of 1-[2-chloro-2-(3,4,5-trimethoxyphenyl)ethyl]imidazole, and the reaction mixture was heated at 60°-70° C. for 7.5 hours. At the end of this time, the resulting mixture was treated and purified by the same method as described in Example 1, to give 187.7 mg of the title compound as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH:17]=[O:18])[N:14](C(O)C(OC)=O)[C:13]1=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])O.[K+].[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH2:17][OH:18])[NH:14][C:13]1=[O:25])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(O)N1C(=O)[C@H](NC(=O)OCc2ccccc2)[C@H]1CC=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: O=C(N[C@H]1C(=O)N[C@@H]1CCO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
The aldehyde (318 mg) obtained above was dissolved in methanol (5 ml) and the solution was cooled to 0° C. 1N Aqueous potassium hydrogen carbonate (0.5 ml) was added and the mixture was stirred at 0° C. for 5 minutes and at ambient temperature for 30 minutes. Sodium borohydride (38 mg) was then added to the mixture at 0° C. and the mixture was stirred at the same temperature for 15 minutes and quenched by addition of acetic acid (0.15 ml). After concentration in vacuo, the residue was dissolved in chloroform and washed with brine containing sodium hydrogen carbonate. The aqueous layer was extracted three times with chloroform. The combined extracts were dried over magnesium sulfate and evaporated in vacuo to give a crystalline solid, which was chromatographed on silica gel (6 g, eluting with 3-10% methanol in dichloromethane) to give 113 mg of (3R,4R)-3-benzyloxycarbonylamino-4-(2-hydroxyethyl)azetidin-2-one.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@@H:10]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][N:8]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:7]1)=[O:5])C.O.[OH-].[Li+].O>C1COCC1>[CH2:20]([N:8]1[CH2:9][C@H:10]([CH2:11][NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CNC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1CN(Cc2ccccc2)C[C@H]1C(=O)O
Temperature: 40 °C

Procedure:
To a solution of 2.9 (3R,4R) and (3S,4S)-1-benzyl-4-(tert-butoxycarbonylamino-methyl)-pyrrolidine-3-carboxylic acid ethyl ester (8.0 mmol) in 50 ml THF were added 671 mg lithium hydroxide mono hydrate (16 mmol) and 0.5 ml water. The solution was stirred at 40° C. and the reaction monitored by TLC. After 72 h the solvent was evaporated, the residue dissolved in dichloromethane, washed with water and brine, dried over Mg sulfate, filtered and evaporated. The residue was crystallized from a dichloromethane/hexane mixture.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH2:25][CH2:24][CH2:23]1>>[N:22]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]3=[O:21])[CH2:25][CH2:24][CH2:23]1
Reactant: C1CNC1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(N3CCC3)cc2c1=O
Yield: 45 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with azetidine according to the GPA affording 15 mg (45%) of a red powder. Rt=3.92 min.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=3[F:21])=[N:7][C:6]=2[CH:5]=[C:4]([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)[CH:3]=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CO.[H][H].[Pd]>[F:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=3[F:21])=[N:7][C:6]=2[CH:5]=[C:4]([CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]2)[CH:3]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(F)c3oc(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)CC1
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(F)c3oc(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)CC1
Yield: 67.7 %

Procedure:
Following the general procedure-1 Tert-butyl 4-{7-fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate (180 mg) obtained from intermediate 31 (600 mg, 1.38 mmol) and tert-butyl 4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (456 mg, 1.38 mmol). Tert-butyl 4-{7-fluoro-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridine-1(2H)-carboxylate (150 mg, 0.30 mmol) dissolved in MeOH and added Pd/C (71 mg). This mixture was stirred in an auto clave in hydrogen atmosphere at 55 Psi for 12 h. Reaction mixture filtered through celite and washed the cetile with MeOH. Methanol was removed on rotavapour to obtain the titled compound (100 mg) as a brown solid. M.P.: 188-192.4° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.47 (t, J 7.12, 1H), 7.89 (t, J 7.6, 2H), 7.49 (s, 1H), 7.07 (d, J 11.2, 1H), 4.28 (bs, 2H), 3.13 (s, 3H), 2.90-2.72 (m, 3H), 1.95-1.85 (m, 2H), 1.72-1.56 (m, 2H). 1.49 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[C:9]([OH:10])=[C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([CH3:19])=[N:6][CH:5]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[C:9]([O:10][C:21](=[O:23])[CH3:22])=[C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]([CH3:19])=[N:6][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cnc(C)c(OCc2ccccc2)c1O
Product: COC(=O)c1cnc(C)c(OCc2ccccc2)c1OC(C)=O
Yield: 90 %

Procedure:
After a solution of the compound 5 (19.1 g, 70 mmol) in acetic anhydride (134 ml) was stirred at 130° C. for 40 minutes, the solvent was distilled off under reduced pressure to obtain 4-acetoxy-5-benzyloxy-6-methyl-nicotinic acid methyl ester 6 (19.9 g, 90%) as a flesh colored crystal.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].C(N(CC)CC)C.[CH2:28]([N:31]=[C:32]=[O:33])[CH2:29][CH3:30]>C1COCC1>[C:7]([C:6]1[C:5]([N+:2]([O-:4])=[O:3])=[CH:12][CH:11]=[CH:10][C:9]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:32]([NH:31][CH2:28][CH2:29][CH3:30])=[O:33])[CH2:16]1)#[N:8]
Reactant: CCCN=C=O
Reactant: N#Cc1c(OCC2CCCNC2)cccc1[N+](=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCNC(=O)N1CCCC(COc2cccc([N+](=O)[O-])c2C#N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.4 %

Procedure:
To a solution of 2-nitro-6-(piperidin-3-ylmethoxy)benzonitrile hydrochloride (Example 220d) (0.10 g, 0.34 mmol) in THF (6 mL) were added triethylamine (0.10 mL, 0.76 mmol) and propylisocyanate (0.05 mL, 0.52 mmol) and the reaction mixture was stirred at r.t. under nitrogen for 3 hour then filtered and evaporated, to give 3-((2-cyano-3-nitrophenoxy)methyl)-N-propylpiperidine-1-carboxamide (0.13 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 0.81 (t, J=7.2 Hz, 3H), 1.34-1.41 (m, 4H), 1.62-1.64 (bm, 1H), 1.87-1.95 (bm, 2H), 2.64-2.77 (m, 2H), 2.93-2.98 (m, 2H), 3.77 (bd, J=12.8 Hz, 1H), 3.98 (bd, J=12.8 Hz, 1H), 4.09-4.13 (m, 1H), 4.17-4.20 (m, 1H), 6.38 (d, J=5.6 Hz, NH), 7.74 (bdd, J=1.6 Hz, J=8.0 Hz, 1H), 7.88-7.94 (m, 2H). MS 347 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[C:6]([Cl:18])[C:7]=1[C:8]1[S:9][C:10]2[C:11](Cl)=[N:12][CH:13]=[CH:14][C:15]=2[N:16]=1.[NH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=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>O1CCOCC1.CO.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].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>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[C:6]([Cl:18])[C:7]=1[C:8]1[S:9][C:10]2[C:11]([NH:21][C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=3)=[N:12][CH:13]=[CH:14][C:15]=2[N:16]=1
Reactant: Cc1cc(N)ncn1
Reactant: OCc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc3nc(-c4c(Cl)cc(CO)cc4Cl)sc23)ncn1
Yield: 39.8 %

Procedure:
A mixture of [3,5-dichloro-4-(4-chloro-thiazolo[5,4-c]pyridin-2-yl)-phenyl]-methanol (0.063 g, 0.18 mmol), 4-amino-6-methylpyrimidine (0.022 g, 0.20 mmol), Pd2(dba)3 (0.003 g, 3.6 mmol), XantPhos (0.003 g, 5.0 pmol) and cesium carbonate (0.117 g, 0.36 mmol) in dioxane (1.1 mL) was degassed with nitrogen and subjected to microwave irradiation at 150° C. for 30 minutes. Further 4-amino-6-methylpyrimidine (0.011 g, 0.10 mmol), Pd2(dba)3 (0.006 g, 7.2 pmol), and XantPhos (0.006 g, 10.0 pmol) were added and the mixture subjected to further microwave irradiation at 150° C. for 60 minutes. The reaction mixture was diluted with MeOH and passed through a nylon filter. The filtrate was concentrated under reduced pressure then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M ammonia in MeOH. The eluent was concentrated under reduced pressure and the resultant residue was purified by silica gel flash chromatography eluting with 0-100% EtOAc in DCM to give the desired compound as a yellow solid (0.030 g, 40% yield). 1H NMR (300 MHz, CDCl3): δ 8.68 (s, 1H), 8.42 (br s, 1H), 8.18-8.04 (m, 1H), 7.77 (d, J=5.7 Hz, 1H), 7.50 (s, 2H), 4.72 (s, 2H), 2.55 (s, 3H). LCMS (Method C): RT=2.90 min, m/z: 418 [M+H+].
Reaction SMILES: [CH:1]1([CH2:4]Br)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[I:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:16](=[O:19])[NH:17][CH:18]=1>CN(C)C=O.O>[CH:1]1([CH2:4][N:17]2[CH:18]=[C:13]([I:12])[CH:14]=[C:15]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:16]2=[O:19])[CH2:3][CH2:2]1
Reactant: O=C(Nc1cc(I)c[nH]c1=O)OCc1ccccc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(I)cn(CC2CC2)c1=O)OCc1ccccc1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
Cyclopropylmethyl bromide (0.100 mL, 0.99 mmol) and cesium carbonate (0.323 mg, 0.99 mmol) were added to a solution of benzyl 5-iodo-2-oxo-1,2-dihydropyridin-3-ylcarbamate (0.245 g, 0.66 mmol) in dimethylformamide (3 mL) and stirred overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. Purification by chromatography (silica gel, 10% to 50% ethyl acetate in hexanes gradient elution) gave the title compound (0.190 g). MS 425 (M+1)
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:16]([O:17]CC2C=CC=CC=2)[C@H:15]([O:25]CC2C=CC=CC=2)[C@@H:14]([CH2:33][O:34][C:35]2[CH:36]=[C:37]([C:41]3[CH:46]=[CH:45][C:44]([C@@H:47]4[C@@H:50]([CH2:51][CH2:52][C@@H:53]([C:55]5[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=5)[OH:54])[C:49](=[O:62])[N:48]4[C:63]4[CH:68]=[CH:67][C:66]([F:69])=[CH:65][CH:64]=4)=[CH:43][CH:42]=3)[CH:38]=[CH:39][CH:40]=2)[O:13][C@@H:10]1[O:11][CH3:12])C1C=CC=CC=1>C(O)C.[Pd]>[F:69][C:66]1[CH:67]=[CH:68][C:63]([N:48]2[C:49](=[O:62])[C@H:50]([CH2:51][CH2:52][C@@H:53]([C:55]3[CH:56]=[CH:57][C:58]([F:61])=[CH:59][CH:60]=3)[OH:54])[C@H:47]2[C:44]2[CH:43]=[CH:42][C:41]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH2:33][C@H:14]4[O:13][C@H:10]([O:11][CH3:12])[C@H:9]([OH:8])[C@@H:16]([OH:17])[C@@H:15]4[OH:25])[CH:36]=3)=[CH:46][CH:45]=2)=[CH:64][CH:65]=1
Reactant: CO[C@H]1O[C@H](COc2cccc(-c3ccc([C@@H]4[C@@H](CC[C@H](O)c5ccc(F)cc5)C(=O)N4c4ccc(F)cc4)cc3)c2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CO[C@H]1O[C@H](COc2cccc(-c3ccc([C@@H]4[C@@H](CC[C@H](O)c5ccc(F)cc5)C(=O)N4c4ccc(F)cc4)cc3)c2)[C@@H](O)[C@H](O)[C@H]1O
Yield: 34.2 %

Procedure:
Methyl 2,3,4-tri-O-benzyl-6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-α-D-glucopyranoside (70 mg, 0.08 mmol) was dissolved in absolute ethanol (3 mL). 10% Pd/C (wet, 14% w/w) was added and the vessel sealed. The solution was degassed by evacuation and flushing with hydrogen gas at balloon pressure. The reaction was monitored by TLC (1:1 hexane-ethyl acetate). Upon completion, the catalyst was filtered by passing through a plug of Celite® and washing with additional ethanol. The filtrate was concentrated in vacuo and purified by preparative HPLC (Polaris C18-A 10 μ 250×21.2 mm column, 30% to 95% acetonitrile-0.1% trifluoroacetic acid in water) affording methyl 6-O-(4′-{(2S,3R)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}biphenyl-3-yl)-α-D-glucopyranoside (18.1 mg, 36% yield); 1H NMR (300 MHz, CDCl3/1% CD3OD) δ 7.58 (d, J=8.4 Hz, 2H), 7.38-7.23 (m, 7H), 7.17-7.14 (m, 2H), 7.04-6.92 (m, 5H), 4.80 (d, J=3.9 Hz, 1H), 4.70 (d, J=2.4 Hz, 1H), 4.67 (t, J=5.7 Hz, 1H), 4.37-4.33 (m, 1H), 4.26-4.21 (m, 1H), 3.92-3.87 (m, 1H), 3.74-3.45 (m, 3H), 3.42 (s, 3H), 3.18-3.10 (m, 1H), 2.01-1.88 (m, 4H) ppm; MS [M−OH]+ 644.0.