Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[O:7])=[C:4]([OH:21])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl>CC(C)=O.C(OCC)(=O)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][O:21][C:4]1[CH:3]=[C:2]([F:1])[CH:20]=[CH:19][C:5]=1[C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH3:34]
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)c1ccc(F)cc1O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(F)ccc1C(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Yield: 165 %

Procedure:
A solution of 4-fluoro-2-hydroxy-N-(3-nitro-benzyl)-benzamide (5.00 g, 17.2 mmol) in acetone (86.0 mL) was treated with aq 2 N K2CO3 (13.0 mL, 25.8 mmol) and ethyl bromoacetate (1.50 mL, 9.66 mmol) and heated to 50° C. for 2 h. The solution was cooled to 0° C. and acidified to pH of 1 with 2 N HCl. The solution was diluted with ethyl acetate and washed with saturated aq NaCl. The organic layer was dried over MgSO4, filtered and concentrated. Purification by MPLC(10–100% ethyl acetate in heptane, 23 mL/min, 75 min) to give [5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester as a pale yellow solid (6 g, 93%): mp 78–80° C.; Rf 0.26 (40% ethyl acetate in heptane); 1H NMR (DMSO-d6 300 MHz) δ 9.01 (t, J=6 Hz, 1 H), 8.19 (t, J=1.8 Hz, 1 H), 8.10 (dd, J1=8.1 Hz, J2=1.5 Hz, 1 H), 7.89 (dd, J1=8.7 Hz, J2=6.9 Hz, 1 H), 7.79 (d, J=7.5 Hz, 1 H), 7.61 (t, J=8.1 Hz, 1 H), 7.11 (dd, J, =11.1 Hz, J2=2.4 Hz, 1 H), 6.92 (dt, J1=8.4 Hz, J2=2.4 Hz, 1 H), 5.0 (9, 2 H), 4.63 (d, J=6.3 Hz, 2 H), 4.15 (q, J=7.2 Hz, 2 H) 1.17 (t, J=6.5 Hz, 3 H). ESI-LC/MS m/z calcd for C18H17FN2O6: 376.4. Found 377.0 (M+1)+. Anal. calcd for C18H17FN2O6: C, 57.45; H, 4.55; N, 7.44. Found: C, 57.47; H, 4.64; N, 7.28.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[O-:16][C:17]#[N:18].[K+].[OH-].[Na+]>O>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:17]([OH:16])[N:18]=[C:4]2[OH:5]
Reactant: N#C[O-]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Oc1nc(O)c2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.9 %

Procedure:
To a mixture of 2-amino-5-chlorobenzoic acid (25.3 g), acetic acid (9.0 mL), and water (650 mL) was added an aqueous solution (130 mL) of potassium cyanate (15.5 g), and the mixture was stirred at room temperature for 2 days. Sodium hydroxide (59 g) was added over 30 min. Water (100 mL) was added, and then the precipitated solids were collected by filtration. The resulting solids were suspended in water (700 mL), followed by addition of 4 M hydrochloric acid (55 mL), and then the precipitated solids were collected by filtration to obtain 6-chloroquinazoline-2,4-diol (19.1 g).
Reaction SMILES: C[N:2]([CH3:20])[CH:3]=[C:4]([C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1F)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:21][CH:22]([F:25])CN.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[F:21][CH:22]([F:25])[CH2:20][N:2]1[C:12]2[C:11](=[CH:16][C:15]([I:17])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(I)ccc1F
Reactant: NCC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn(CC(F)F)c2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (335 mg, 0.86 mmol) and 2,2-difluoroethylamine (76 mg, 0.94 mmol) in ethanol (3 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and dissolved in DMF (3 mL). Potassium carbonate (178 mg, 1.28 mmol) was added to the reaction mixture and the reaction was heated to 70° C. for 3 h, then cooled to room temperature and poured into water. The title compound formed a precipitate which was collected by filtration and placed upon lyophilizer overnight to remove residual water. MS (ESP): 408 (M+H+) for C14H12F2INO3; NMR: 1.29 (t, J=7 Hz, 3H), 4.25 (q, J=7 Hz, 2H), 4.96 (m, 2H), 6.50 (t, J=20 Hz, 1H), 7.73 (m, 1H), 8.08 (m, 1H), 8.50 (m, 1H), 8.70 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10](I)=[C:9]([O:14][CH3:15])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)CCC>C1(C)C=CC=CC=1.[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)=[C:9]([O:14][CH3:15])[C:8](=[O:16])[NH:7][C:6]=2[CH:17]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc([N+](=O)[O-])cc1
Reactant: COc1c(I)c(=O)c2ccc(Cl)cc2[nH]c1=O
Agent: Cl[Pd+]
Agent: [CH2-]c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1c(-c2ccc([N+](=O)[O-])cc2)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Yield: 60.8 %

Procedure:
8-Chloro-4-iodo-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.50 g) was dissolved in toluene (12 mL). To this stirred suspension was added trans-benzyl(chloro)bis(triphenylphosphine)palladium(II) (0.050 g) and tributyl(4-nitrophenyl)tin (0.70 g). The resulting suspension was stirred at reflux for 48 hours, then cooled to room temperature, applied directly to a silica column (1.5 cm by 15 cm), and eluted with dichloromethane (250 mL), (ether:dichloromethane (20:80)(250 mL), and methanol:dichloromethane (5:95)(250 mL) to afford the title product (0.30 g, 61%) as a light green solid; mp 250°-251° C. (dec); NMR: 8.24 (d,2, J=9.0), 7.68 (d,1, J=8.6), 7.54 (d,2, J=8.9), 7.42 (d,1, J=2.0), 7.32 (dd,1, J=9.0, 2.1), 3.72 (s,3); MS: m/z=359(M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45].C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12][O:13][N:35]1[C:39](=[O:40])[C:38]2[C:37](=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:36]1=[O:45])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCO)OCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(NCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
Benzyl(2-hydroxyethyl)carbamate (5.857 g, 30.0 mmol) was stirred under an argon atmosphere at room temperature with dehydrated tetrahydrofuran (150 mL). Then, triphenylphosphine (7.90 g) and N-hydroxyphthalimide (Pht-OH, 4.89 g) were added. After the reaction mixture was under ice cooling, 2.2M diethyl azodicarboxylate toluene solution (13.7 mL) was added dropwise gradually, followed by stirring overnight at room temperature. After completion of the reaction, the residue resulting from distilling off the solvent under reduced pressure was subjected to silica gel column chromatography (hexane/ethyl acetate=1/1) to afford 9.36 g of the title compound (yield 92%).
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:39][CH3:40])[C:23]([F:41])=[CH:22][N:21]=1>>[F:41][C:23]1[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[O:39][CH3:40])=[N:25][C:20]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: COc1cc2c(cc1N)CCN(CC(N)=O)CC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1F
Product: COc1cc2c(cc1Nc1ncc(F)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(CC(N)=O)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-acetamide and (2-Chloro-5-fluoro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 61e. Product isolated as a pale yellow solid (0.013 g, 14%). MP: 98-140° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 8.27 (d, 1H, J=8.6 Hz), 8.16 (s, 1H), 7.92 (d, 1H, J=2.8 Hz), 7.40 (s, 1H), 7.25-7.17 (m, 2H), 6.64 (s, 1H), 6.56-6.54 (m, 1H), 6.53-6.49 (m, 1H), 5.52-5.41 (m, 1H), 3.93-3.84 (m, 10H, 3.16-3.10 (m, 6H), 2.90-2.82 (m, 4H), 2.76-2.68 (m, 4H). MS: 552.28 (MH)+.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Br[C:13]1[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][C:13]3[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=3)=[N:3][C:4]=2[CH:10]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: Cc1ccc2nc(S)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2[nH]c(Sc3ccc(C=O)s3)nc2c1
Temperature: 110 °C
Yield: 47.4 %

Procedure:
a mixture of 0.82 g of 2-mercapto-5-methyl-benzimidazole (5 mmoles), 0.6 ml of 5-bromo-2-thiophenecarboxaldehyde (5 mmoles) and 1.4 g of potassium carbonate in 10 ml of DMF is heated at 110° C. for 2 hours. The mixture is cooled down to room temperature, then poured into 200 ml of water and extracted twice with 50 ml of ethyl acetate. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated. The crude product is purified on silica gel using DCM/MeOH as eluent to give 0.65 g of 5-(5-methyl-1H-benzimidazol-2-ylsulfanyl)-thiophene-2-carbaldehyde. (Yield=47%). Analytical LC/MS method A: ([M+H]+): 275). RT: 3.42 min (gradient 5 to 85% acetonitrile in 7 min).
Reaction SMILES: C(O)C.C(O)(=O)C.[Cl:8][C:9]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[CH2:29][CH2:28]2)[C:24]([N+:41]([O-])=O)=[CH:23][C:10]=1[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22])=[O:12]>[Fe]>[NH2:41][C:24]1[C:25]([N:27]2[CH2:28][CH2:29][N:30]([C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[CH2:31][CH2:32]2)=[CH:26][C:9]([Cl:8])=[C:10]([CH:23]=1)[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=[O:22])=[O:12]
Reactant: Cc1ccc(F)cc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCCC3=O)cc2[N+](=O)[O-])CC1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(F)cc1N1CCN(c2cc(Cl)c(C(=O)NCCCN3CCCC3=O)cc2N)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
In a 50 ml round bottom flask equipped with a magnetic stir bar and fitted with a septum and a nitrogen inlet, the iron powder (377 mg, 6.75 mmol) was suspended in clean, dry, reagent-grade ethanol (12 ml, 205.52 mmol) and allowed to stir at room temperature under nitrogen. To this was added the acetic acid (1.20 ml, 20.96 mmol) and the reaction was allowed to stir to ensure homogeneity. The 2-chloro-4-[4-(5-fluoro-2-methyl-phenyl)-piperazin-1-yl]-5-nitro-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide 16f (140.10 mg, 0.27 mmol) was added in one portion and the reaction was warmed to 75° C. and allowed to stir for 3 h. After 3 h, the reaction was cooled to room temperature and filtered through Celite, washing heavily with methanol. The collected organic solution was then concentrated under reduced pressure and the resultant red oil was taken up in 50 ml of ethyl acetate and was washed with 50 ml of saturated NaHCO3 (aq) solution. The product was then extracted from the aqueous using ethyl acetate (3×20 ml) and the organic phases were combined, washed with brine (1×50 ml) and dried over Na2SO4. The solution was then decanted, and the solvent was removed under reduced pressure. The product, 5-amino-2-chloro-4-[4-(5-fluoro-2-methyl-phenyl)-piperazin-1-yl]-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-benzamide 16g (130 mg, 0.27 mmol), was isolated as a brown solid and carried forward without further purification. LCMS (m/e)=488 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:5]=[N:6][C:7]=1[CH3:8].[CH:22]([Sn](CCCC)(CCCC)CCCC)=[CH2:23]>C1(C)C=CC=CC=1.C1(P([Pd-4](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)C=CC=CC=1>[CH3:8][C:7]1[N:6]=[CH:5][C:4]([O:9][CH2:10][C@@H:11]2[CH2:14][CH2:13][N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:3][C:2]=1[CH:22]=[CH2:23]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1ncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cc1Br
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)cnc1C
Temperature: 25 °C
Yield: 59.6 %

Procedure:
5-Bromo-6-methyl-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (0.95 g, 2.7 mmol, Step 34a above) was treated with vinyl tributyltin (1.62 mL, 5.56 mmol) and tetrakis(triphenylphosphino)palladium(0) (0.29 g, 0.25 mmol) in toluene (30 mL) at 90° C. overnight. The reaction was cooled to ambient temperature and chromatographed on silica gel with 2:1 hexane-EtOAc eluent to provide 6-methyl-5-vinyl-3-(1-t-butyloxycarbonyl-(2S)-azetidinylmethoxy)pyridine (0.49 g, 60%): MS (CI/NH3) m/z: 305 (M+H)+ ; 1H NMR (300 MHz, CDCl3) δ 1.42 (s, 9H), 2.22-2.38 (m, 2H), 2.52 (s, 3H), 3.91 (dt, J=2, 6 Hz, 2H), 4.13 (dd, J=3, 10 Hz, 1H), 4.30-4.36 (m, 1H), 4.49-4.55 (m, 1H), 5.40 (dd, J=1, 11 Hz, 1H), 5.64 (dd, J=1, 17 Hz, 1H), 6.84 (dd, J=11, 17 Hz, 1H), 7.32 (d, J=3 Hz, 1H), 8.13 (d, J=3 Hz, 1H). The product from above (0.47 g,1.53 mmol) was treated with 8 mL of 1:1 TFA-methylene chloride at 0° C. for 2 hours. The volatile components were evaporated in vacuo, and the residue was diluted with saturated aqueous sodium bicarbonate and extracted with CH2Cl2. The combined organic layers were washed with water and dried over MgSO4 to provide the product (277 mg, 89% yield). Half of the sample was dissolved in ether and treated with 1 M HCl in ether to provide 85 mg of the title compound as an off-white solid: mp 154-155° C.; [α]D -8.9 (c 0.45, MeOH); 1H NMR (CD3OD) δ 2.63-2.77 (m, 2H), 2.74 (s, 3H), 4.08-4.16 (m, 2H), 4.52-4.64 (m, 2H), 4.85-4.95 (m, 1H), 5.80 (d, J=11 Hz, 1H), 6.15 (d, J=17 Hz, 1H), 7.02 (dd, J=11, 17 Hz, 1H), 8.36 (d, J=2 Hz), 1H, 8.48 (d, J=2 Hz, 1H); MS (CI/NH3) m/z; 205 (M+H)+ ; Anal. Calcd for C12H16N2O.2.1 HCl: C, 51.32; H, 6.50; N, 9.97. Found: C, 51.60; H, 6.21; N, 9.82.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:10]([CH3:13])[CH2:11]O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P([N:75]=[N+:76]=[N-:77])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[N:75]([CH2:11][C@H:10]([CH3:13])[C@H:9]([C@H:14]1[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[N:15]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[N+:76]=[N-:77]
Reactant: C[C@@H](CO)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CN=[N+]=[N-])[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a solution of (R)-tert-butyl 4-((1R,2S)-1-(tert-butyldimethylsilyloxy)-3-hydroxy-2-methylpropyl)-2,2-dimethyloxazolidine-3-carboxylate (1.0 equiv.), DIAD (2.0 equiv.), and PPh3 (2.0 equiv.) in THF (0.18 M) was added DPPA (2.0 equiv., 1M solution in THF). The reaction mixture was stirred at room temperature overnight. Upon removal of the volatiles under vacuo, the residue was purified by silica gel column chromatography eluting with ethyl acetate and hexanes (1:6) to give (R)-tert-butyl 4-((1R,2S)-3-azido-1-(tert-butyldimethylsilyloxy)-2-methylpropyl)-2,2-dimethyloxazolidine-3-carboxylate as the major product (5:2) in 86% yield. LC/MS=329.3 (M+H-Boc), Rt=1.40 min (Frac 65%-95% method).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[O:18])[S:10]2)=[C:4]([F:19])[C:3]=1[OH:20].[CH2:21](Br)[C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:17]3[N:12]([CH2:13][CH2:14][CH2:15][CH2:16]3)[C:11](=[O:18])[S:10]2)=[C:4]([F:19])[C:3]=1[O:20][CH2:23][C:22]#[CH:21]
Reactant: O=c1sc(=Nc2ccc(Cl)c(O)c2F)n2n1CCCC2
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1c(Cl)ccc(N=c2sc(=O)n3n2CCCC3)c1F

Procedure:
Into a reaction flask equipped with a Dimroth condenser, 2.2 g (7 mmol) of 9-(4-chloro-2-fluoro-3-hydroxyphenylimino)-8-thia-1,6-diazabicyclo[4.3.0]nonane-7-one, 1.1 g (9 mmol) of propargyl bromide, 1.3 g (9 mmol) of potassium carbonate and 20 ml of acetonitrile, were charged, and refluxed under heating for 3 hours to complete the reaction.
Reaction SMILES: O.[CH:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10](O)[CH2:11][OH:12]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[C:3]1([CH:2]2[O:12][CH2:11][CH2:10][O:9]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: c1ccc(C2OCCO2)cc1
Yield: 89 %

Procedure:
A 500-mL three-necked flask equipped with a reflux condenser having a Dean-Stark water trap was charged with 5.0 g of benzaldehyde, 29.3 g of ethylene glycol, 0.09 g of p-toluenesulfonic acid monohydrate and 250 mL of benzene, and the contents were refluxed for 21 h. The resultant reaction solution was allowed to stand for cooling and then washed with 50 mL of a saturated aqueous solution of sodium hydrogen carbonate and 50 mL of water. After vacuum-concentrating the organic phase, 6.3 g of the aimed 2-phenyl-1,3-dioxolane was obtained by vacuum distillation (89% yield).
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1C=CN=C1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:31]([C:33]1[N:34]=[C:35]([C@@H:38]([NH2:49])[CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)[S:36][CH:37]=1)[CH3:32]>C(Cl)Cl>[CH2:31]([C:33]1[N:34]=[C:35]([C@@H:38]([NH:49][C:11](=[O:13])[CH2:10][CH2:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=2)[S:36][CH:37]=1)[CH3:32]
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: CCc1csc([C@@H](N)Cc2ccc([N+](=O)[O-])cc2)n1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CCc1csc([C@H](Cc2ccc([N+](=O)[O-])cc2)NC(=O)CCC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Benzoylpropionic acid (0.250 g) is dissolved in CH2Cl2 (5 mL), N-methyl imidazole (0.333 mL) is added and the resulting solution is cooled to 0° C. after which a solution of p-toluenesulfonyl chloride (0.320 g) in CH2Cl2 (2 mL) is added dropwise. After 0.5 hours (S)-1-(4-ethylthiazol-2-yl)-2-(4-nitrophenyl)ethanamine, 3, (0.388 g) is added. The reaction is stirred for 18 hours at room temperature and then concentrated in vacuo. The resulting residue is dissolved in EtOAc and washed with 1N HCl and brine. The solution is dried over Na2SO4, filtered, and concentrated and the crude material purified over silica to afford 0.415 g of the desired product.
Reaction SMILES: [CH3:1][CH:2]([O:4][P:5]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)(=[O:10])[O:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[H][H]>[Pd].CC(O)C>[CH3:9][CH:7]([O:6][P:5]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)(=[O:10])[O:4][CH:2]([CH3:1])[CH3:3])[CH3:8]
Reactant: CC(C)OP(=O)(OC(C)C)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)OP(=O)(OC(C)C)c1ccc(N)cc1
Yield: 92.5 %

Procedure:
A mixture of dipropan-2-yl(4-nitrophenyl)phosphonate (287 mg, 1.0 mmol), i-PrOH (30 ml) and 10% Pd/C (30 mg) was hydrogenated under 50 psi of hydrogen pressure at 40° C. for 6 h. The reaction mixture was then filtered and the filtrate concentrated in vacuo to afford 238 mg of desired dipropan-2-yl(4-aminophenyl)phosphonate (yield: 92%), which used directly in further chemistries without purification. 1H-NMR (DMSO-d6, 400 MHz): δ=1.11 (d, J=6.0 Hz, 6H), 1.21 (d, J=6.4 Hz, 6H), 4.38-4.43 (m, 2H), 5.74 (s, br, 2H), 6.56-6.59 (m, 2H), 7.27-7.32 (m, 2H). MS: m/z 257.90 [MH+].
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[N:7]=1)=[O:5].[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23](Cl)=[O:24])[CH2:19][CH2:18]1)=[O:16].C(N(CC)CC)C>C(#N)C>[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23](=[O:24])[NH:2][CH2:3][C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[N:7]=2)=[O:5])[CH2:19][CH2:18]1)=[O:16]
Reactant: NCC(=O)c1cccc(Br)n1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)Cl)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](C(=O)NCC(=O)c2cccc(Br)n2)CC1

Procedure:
To a suspension of 2-amino-1-(6-bromopyridin-2-yl)ethanone hydrochloride (10.00 g, 39.8 mmol) obtained in Step 1, trans-4-chlorocarbonylcyclohexanecarboxylic acid methyl ester (9.00 g, 44.0 mmol) in acetonitrile (200 ml), a solution of triethylamine (13.9 ml, 100 mmol) in acetonitrile (60 ml) was added dropwise while ice-cooled for 2 hours. After the reaction solution was concentrated, water was added and extracted with ethyl acetate. The organic layer was sequentially washed with 10% aqueous citric acid, a saturated aqueous sodium bicarbonate, a saturated brine and dried over magnesium sulfate. After concentrated, the residue was purified by flash chromatography on silica gel (n-hexane:ethyl acetate=1:2) and the title compound (7.38 g, 48%) was obtained.
Reaction SMILES: CO[C:3](=O)[CH:4]([N+:15]([O-:17])=[O:16])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:6].[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=C.Cl>C(O)(C)(C)C.C(OCC)C>[CH3:24][O:23][C:19](=[O:22])[CH2:6][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)[CH:4]([N+:15]([O-:17])=[O:16])[CH2:3][CH2:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C(C(C)c1ccc(Cl)c(Cl)c1)[N+](=O)[O-]
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(Cl)c(Cl)c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 350 g of nitro-3-(3,4-dichlorophenyl)butanoic acid methyl ester, 118 g of methyl acrylate and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate and evaporated to give 4-nitro-3-(3,4-dichlorophenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH2:31][CH:30]([C:34](O)=O)[CH2:29]1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][CH:10]([C:17]2[N:18]=[C:34]([CH:30]3[CH2:31][CH2:32][CH2:33][N:28]([CH3:27])[CH2:29]3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CN1CCCC(C(=O)O)C1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1CC(c2noc(C3CCCN(C)C3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 72 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and 1-methyl-3-piperidinecarboxylic acid, the title compound was obtained in 72% yield (99.2% purity by HPLC).