Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[C:2]=[O:3].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([NH2:27])=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=23)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([NH:27][C:2]([NH:1][CH2:4][CH:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)=[O:3])=[N:20][N:21]3[CH:26]=[CH:25][CH:24]=[N:23][C:22]=23)=[CH:14][CH:13]=1
Reactant: O=C=NCC1CCOCC1
Reactant: Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Product: O=C(NCC1CCOCC1)Nc1nn2cccnc2c1-c1ccc(Cl)cc1

Procedure:
4-(Isocyanatomethyl)tetrahydropyran (Maybridge) and the product from Example 99A were processed using method analogous to that described in Example 99B to afford the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.51 (dd, J=6.9, 1.8 Hz, 1H), 8.47 (dd, J=4.1, 1.8 Hz, 1H), 8.21-8.31 (m, 1H), 7.54-7.56 (m, 2H), 7.46-7.49 (m, 2H), 6.89-6.90 (bs, 1H), 6.81 (dd, J=6.9, 4.1 Hz, 1H), 4.01 (dd, J=11.1, 3.6 Hz, 2H), 3.41 (td, J=11.7, 1.8 Hz, 2H), 3.33 (t, J=6.3 Hz, 2H), 1.84-1.95 (m, 1H), 1.69-1.75 (m, 2H), 1.42 (qd, J=12.3, 4.5 Hz, 2H); MS (ESI) m/z 386 (M+H)+; Anal. calculated for C19H20ClN5O2: C, 59.14; H, 5.22; N, 18.15; Cl, 9.19. Found C, 58.96; H, 5.13; N, 17.99; Cl, 9.39.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[S:3]([O:6][C:7]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][C:8]2=C)(=[O:5])=[O:4].[O:17]=[O+][O-].CSC.O>CO>[F:1][C:2]([F:16])([F:15])[S:3]([O:6][C:7]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH2:9][C:8]2=[O:17])(=[O:5])=[O:4]
Reactant: O=[O+][O-]
Reactant: C=C1CC2CCC1(OS(=O)(=O)C(F)(F)F)C2
Solvent: CO
Solvent: CSC
Solvent: O
Product: O=C1CC2CCC1(OS(=O)(=O)C(F)(F)F)C2
Temperature: 25 °C
Yield: 60 %

Procedure:
A solution of methylenebicyclo[2.2.1]heptan-1-yl trifluoromethanesulfonate (7.6 g, 0.03 mol) in methanol (100 mL) was cooled to −40° C. and an ozone stream was passed through the reaction mixture. When the color of the mixture turned to blue, the ozone was eliminated by passing a stream of argon through the solution for 10 min. Dimethyl sulfide (5 mL) was added to the mixture and the reaction mixture was allowed to warm to room temperature. The resulting mixture was poured into water and extracted with DCM (2×40 mL). The combined extracts were washed with brine (100 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to give the desired product (4.6 g, 18.1 mmol, yield: 60%) as a yellowish oil. 1H NMR (400 MHz, CDCl3) δ ppm 2.73 (brs, 1H), 2.44-2.34 (m, 2H), 2.26-2.13 (m, 4H), 2.06-2.02 (m, 1H), 1.70-1.66 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Br:12]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Br:12][C:8]1[N:6]2[N:7]=[C:2]([CH3:1])[CH:3]=[C:4]([CH3:11])[C:5]2=[N:10][CH:9]=1
Reactant: Cc1cc(C)c2nccn2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c2ncc(Br)n2n1
Reaction time: 2 h
Yield: 83.5 %

Procedure:
To a solution of 3.63 g (24.7 mmol) of 6,8-dimethylimidazo[1,2-b]pyridazine in 25 mL of chloroform was added 4.84 g (27.2 mmol) of N-bromosuccinimide. After 2 h. 1 mL of a saturated aqueous solution of sodium bicarbonate was added. The layers were separated. The organic layer was dried (Na2SO4) and the solvent was removed with a rotary evaporator. The residue was purified by flash chromatography to give 4.66 g of the title compound as a while solid, m.p. 137°-139° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([Si:15]([CH3:36])([CH3:35])[O:16][CH:17]1[CH2:22][CH:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:20][C:19]([OH:34])([C:31]([O-])=[O:32])[CH2:18]1)([CH3:14])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1>[C:27]([Si:24]([CH3:26])([CH3:25])[O:23][CH:21]1[CH2:22][CH:17]([O:16][Si:15]([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:35])[CH3:36])[CH2:18][C:19]([OH:34])([CH2:31][OH:32])[CH2:20]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(O[Si](C)(C)C(C)(C)C)CC(O)(C(=O)[O-])C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC1CC(O[Si](C)(C)C(C)(C)C)CC(O)(CO)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
Diisobutyl aluminum hydride (6 mL, 9 mmol, 1.5M in toluene) was added to a solution of the ester 14 (0.56 g, 1.3 mmol) in anhydrous toluene (20 mL) at -78° C. After 20 min the solution was warmed to 0° C. and stirred for 1 h. The solution was slowly quenched by adding to a stirred 0° C. solution of 2N potassium sodium tartrate. Ethyl acetate was added and the organic layer separated and the water phase extracted with ethyl acetate. The combined organic phase was washed with brine, dried over anhydrous MgSO4, filtered and evaporated. The material was further purified by column chromatography on silica gel with ethyl acetate hexane mixtures to give the diol 15 (0.3 g, 59%) 1H NMR (CDCl3, 500 MHz) δ0.11 (s, 3H), 0.12 (s, 3H), 0.14 (s, 3H), 0.16 (s, 3H), 0.90 (s, 9H), 0.91 (s, 9H), 1.28 (dd, 1H), 1.43 (dd, 1H), 2.00 (ddd 3H), 2.16 (dd, 1H), 3.33 (dd, 1H), 3.40 (dd, 1H), 4.34 (m, 2×1H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>CCO.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH2:11]([O:13][P:14]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])(=[O:18])[O:15][CH2:16][CH3:17])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1I
Reactant: CCOP(OCC)OCC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCO
Product: CCOP(=O)(OCC)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
3.9 g of Cu(II) acetate are added to a solution of 5 g 1-iodo-2-nitrobenzene and 5 g of triethylphosphite in 20 ml of EtOH, the mixture obtained is refluxed for 24 hours, cooled to rt and partitioned between EtOAc and half-saturated aqueous NaCl-solution. The organic layer obtained is dried, solvent is evaporeated and the evaporation residue is subjected to column chromatography (silicagel, toluene:acetonitrile=3:1). (2-Nitro-phenyl)-phosphonic acid diethyl ester is obtained in the form of an orange oil. MS: MNa+ 282
Reaction SMILES: [CH2:1]([N:3]([CH2:34][CH3:35])[CH2:4][CH:5]([OH:33])[CH2:6][N:7]1[C:19]2[C:18]3[NH:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]=3[C:16]3[C:27](=[O:32])N(C)[C:29](=[O:30])[C:15]=3[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:2].Cl.[OH-:37].[K+]>>[CH2:34]([N:3]([CH2:1][CH3:2])[CH2:4][CH:5]([OH:33])[CH2:6][N:7]1[C:19]2[C:18]3[NH:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]=3[C:16]3[C:27](=[O:37])[O:32][C:29](=[O:30])[C:15]=3[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:35]
Reactant: [OH-]
Reactant: CCN(CC)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5[nH]c4c21)C(=O)N(C)C3=O
Agent: Cl
Agent: [K+]
Product: CCN(CC)CC(O)Cn1c2ccccc2c2c3c(c4c5ccccc5[nH]c4c21)C(=O)OC3=O

Procedure:
The starting material is prepared in the following manner: 440 mg (0.94 mmol) (±)-12-(3-diethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-6-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole are heated under reflux for 1.5 hours in 100 ml 10% methanolic potassium hydroxide solution. After cooling the reaction mixture is acidified with semi-concentrated hydrochloric acid, filtered and the filtrate evaporated. The residue is taken up in 10% potassium carbonate solution and ethyl acetate and the organic phase is washed with water and dried over anhydrous sodium sulphate. It is filtered, evaporated and the residue is stirred with 25 ml diisopropyl ether and the crystals formed are filtered off. (±)-12-(3-Diethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-5,7-dioxoindolo-[2,3-a]furano[3,4-c]carbazole is obtained in the form of yellow crystals which decompose from about 200° C.
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[C:9](=[O:21])[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]>CO.[Ni]>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:10]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=[CH:8][C:9]2=[O:21])=[CH:17][CH:16]=1
Reactant: CCCCc1cccc(=O)n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Solvent: CO
Product: CCCCc1cccc(=O)n1Cc1ccc(N)cc1

Procedure:
A solution of 1.7 g of 6-butyl-1-p-nitrobenzyl-1,2-dihydro-2-oxopyridine in 50 ml of methanol is hydrogenated on 1.7 g of Raney Ni at 20° until the uptake of H2 has ceased. The mixture is filtered and evaporated to give 1-p-aminobenzyl-6-butyl-1,2-dihydro-2-oxopyridine.
Reaction SMILES: [I:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]([CH2:20][C:21]2[N:22]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[CH:23]=[CH:24][N:25]=2)[CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:20][C:21]2[N:22]([CH2:26][C:27]([OH:29])=[O:28])[CH:23]=[CH:24][N:25]=2)[CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][CH:15]=2)=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)Cc1ccc(I)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(CCN(Cc2ccc(I)cc2)Cc2nccn2CC(=O)O)cc1

Procedure:
A solution of tert-butyl 2-(2-(((4-iodobenzyl)(4-sulfamoylphenethyl)amino)methyl)-1H-imidazol-1-yl)acetate (24 mg, 0.0393 mmol) in DCM (1.0 mL) and TFA (1.0 mL) was stirred at room temperature for 5 hrs. Solvent was removed under a stream of nitrogen to give a residue, which was purified by HPLC to give compound (20) containing 2 TFA as a white solid (30 mg, 100%). 1H NMR (400 MHz, DMSO-d6) 7.68-7.57 (m, 6H), 7.26 (d, J=8.0 Hz, 2H), 7.25 (s, 2H), 7.13 (d, J=8.4 Hz, 2H), 4.90 (s, 2H), 3.94 (s, 2H), 3.67 (s, 2H), 2.80 (t, J=7.8 Hz, 2H), 2.55 (t, J=7.8 Hz, 2H); MS (ESI), 555.0 (M+H)−.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[C:11]([NH2:13])=[O:12])([CH3:3])[CH3:2].[C:14]([CH2:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=1)#[N:15].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O.CNCCNC>[Cu]I.C1(C)C=CC=CC=1>[C:14]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:13][C:11]([C@@H:5]2[CH2:6][C@H:7]([CH3:10])[CH2:8][CH2:9][C@H:4]2[CH:1]([CH3:2])[CH3:3])=[O:12])=[CH:19][CH:18]=1)#[N:15]
Reactant: N#CCc1ccc(I)cc1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C(N)=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C(=O)Nc1ccc(CC#N)cc1
Temperature: 100 °C
Reaction time: 21 h

Procedure:
A 250 mL 3-neck flask was fitted with a condenser and a nitrogen inlet was charged with 10.00 g (0.0546 mol) of (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide, 0.522 g (0.0027 mol) copper (I) iodide, 13.26 g (0.0546 mol) of 4-(cyanomethyl)phenyl iodide, 23.18 g (0.109 mol) of potassium phosphate. The system was purged with nitrogen and a magnetic stir bar was added. After the addition of 170 mL of toluene, 3.42 g (0.190 mol) of water and 0.964 g (0.0109 mol) of N,N′-dimethylethylene diamine, the mixture was heated to 100° C. and stirred for 21 h under nitrogen. The crude reaction mixture was filtered through 50 g of silica gel (wet with 1:1 ethyl acetate/methylene chloride), and the bed was rinsed three times with 1:1 ethyl acetate/methylene chloride (150+75+75 mL). Concentration of the mixture in vacuo provided N-[4-(cyanomethyl)phenyl]-(1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarboxamide as a thick oil oil which was further purified by flash chromatography on silica gel eluting with mixtures of ethyl acetate and hexanes. The product has the following properties with the structure confirmed by obtaining an X-ray crystal structure of a sample crystallized from hexane/ethyl acetate.
Reaction SMILES: [C:1]1([CH2:6][CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH:2]=1.[Br-].Cl.[CH2:14](OCC)C>>[C:1]1([CH2:6][CH2:7][CH2:8][C:9]([CH3:14])([OH:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(=O)CCCC1=CCCC1
Reactant: CCOCC
Agent: Cl
Agent: [Br-]
Product: CC(C)(O)CCCC1=CCCC1
Temperature: 25 °C
Yield: 11 %

Procedure:
5-(Cyclopent-1-enyl)-2-pentanone (5.95 g; 39 mmol) in ethyl ether (6 ml) was added dropwise to a 3M solution of methylnagnesium bromide in the same solvent (17 ml; 51 mmol) during 15 minutes. After 2 hours at reflux, the mixture was cooled down to room temperature, poured into ice (20 g), acidified with 5N HCl (20 ml) and extracted with MTBE (60 ml). The aqueous phase was separated and extracted again with MTBE (2×100 ml). The combined organic phases were washed with saturated NaHCO3 (80 ml), H2O (80 ml), brine (80 ml), dried over MgSO4 and concentrated in vacuo. Bulb-to-bulb distillation (80° C./0.06 torr) yielded quantitatively 5.84 g of 5-(cyclopent-1-enyl)-2-methylpentan-2-ol containing 11% of 5-cyclopentylidene-2-methylpentan-2-ol.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([OH:12])(=[O:11])[C:8]([OH:10])=[O:9].[OH:13][C:14]1[CH:15]=[CH:16][C:17]2[C:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:25]([CH3:35])[CH:24]=3)=[C:20]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][N:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)=[C:38]([O:50]C)[CH:37]=3)[S:19][C:18]=2[CH:52]=1.CCS.[Al+3].[Cl-].[Cl-].[Cl-].C([O-])(O)=O.[Na+]>ClCCCl>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7]([OH:12])(=[O:11])[C:8]([OH:10])=[O:9].[OH:50][C:38]1[CH:37]=[C:36]([C:20]2[S:19][C:18]3[CH:52]=[C:14]([OH:13])[CH:15]=[CH:16][C:17]=3[C:21]=2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[C:25]([CH3:35])[CH:24]=2)[CH:41]=[CH:40][C:39]=1[O:42][CH2:43][CH2:44][N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: COc1cc(-c2sc3cc(O)ccc3c2Cc2ccc(CN3CCCC3)c(C)c2)ccc1OCCN1CCCC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Al+3]
Solvent: ClCCCl
Solvent: CCS
Product: Cc1cc(Cc2c(-c3ccc(OCCN4CCCC4)c(O)c3)sc3cc(O)ccc23)ccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-[[4-[6-hydroxy-2-[3-methoxy-4-[2-(1-pyrrolidinyl)ethoxy)phenyl]benzo[b]thiophen-3-yl]methyl-2-methylphenyl]methyl]pyrrolidine (Example 127, Part D; 182 mg, 0.327 mmol) in 5 mL of 1,2-dichloroethane was cooled to 0° C. and treated with EtSH (195 μL, 2.62 mmol) followed by AlCl3 (262 mg, 1.96 mmol). The resulting mixture was allowed to warm to ambient temperature. After 16 h, the reaction mixture was poured into 10 mL of saturated aqueous NaHCO3 solution. The aqueous layer was extracted with 5% MeOH/CHCl3 (3×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by radial chromatography (SiO2; gradient of 1% to 4% MeOH in CHCl3, saturated with NH4OH) gave 96 mg (0.177 mmol; 54%) of a white foam. Subsequent dioxalate salt formation as described in Example 1, Part C afforded the title compound as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:13]=[C:12]([C:14]([OH:16])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O1CCCC1>[C:17]([NH:1][CH2:2][CH2:3][C:4]1[N:13]=[C:12]([C:14]([OH:16])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)(=[O:19])[CH3:18]
Reactant: NCCc1nc(C(=O)O)c2ccccc2n1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(=O)NCCc1nc(C(=O)O)c2ccccc2n1
Temperature: 25 °C

Procedure:
Into a 500-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-(2-aminoethyl)quinazoline-4-carboxylic acid (3.2 g, 14.73 mmol, 1.00 equiv) in tetrahydrofuran (32 mL). This was followed by the addition of acetyl acetate (32 mL) dropwise with stirring at room temperature. The resulting solution was stirred for 18 h at room temperature. The reaction was then quenched by the addition of 50 mL of water. The mixture was concentrated under vacuum. The crude product was purified by Flash. This resulted in 900 mg (24%) of 2-(2-acetamidoethyl)quinazoline-4-carboxylic acid as a white solid. MS (ESI) m/z 260 ([M+H]+).
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][O:7][N:8]=[C:9]([C:26](OCC)([O:29]CC)[CH2:27][Br:28])[C:10]([NH:12][CH:13]1[C:24](=[O:25])[N:15]2[CH:16]([C:21]([OH:23])=[O:22])[CH:17]([OH:20])[CH2:18][S:19][C@H:14]12)=[O:11]>CC(C)=O>[CH3:6][O:7][N:8]=[C:9]([C:26](=[O:29])[CH2:27][Br:28])[C:10]([NH:12][CH:13]1[C:24](=[O:25])[N:15]2[CH:16]([C:21]([OH:23])=[O:22])[CH:17]([OH:20])[CH2:18][S:19][C@H:14]12)=[O:11]
Reactant: CCOC(CBr)(OCC)C(=NOC)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(C)=O
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Yield: 43.5 %

Procedure:
70% Perchloric acid (3.4 ml) was added to a solution of 7-(2-methoxyimino-3,3-diethoxy-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 5.0 g) in acetone (40 ml) under ice-cooling and stirred at the same temperature for an hour. The precipitates were collected by filtration, washed with acetone (5 ml) twice and dried to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 1.85 g).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>CN(C)C=O.C(Cl)(Cl)(Cl)Cl>[CH2:5]([C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([Cl:3])=[O:24])=[CH:21][CH:20]=2)=[N:17][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCc1cnc(-c2ccc(C(=O)O)cc2)nc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCc1cnc(-c2ccc(C(=O)Cl)cc2)nc1

Procedure:
10 ml of CCl4, 5 ml of thionyl chloride and one drop of dimethylformamide were added to 2.0 g of 4-(5-octyl-2-pyrimidinyl)benzoic acid. The mixture was refluxed for 3 hours under stirring. The solvent was distilled off initially under normal pressure and then under reduced pressure. As a result, 2.2 g of 4-(5-octyl-2-pyrimidinyl)benzoic acid chloride was obtained in the form of a colorless plate-form crystal. 1.2 g of the thus obtained 4-(5-octyl-2-pyrimidinyl)benzoic acid chloride was dissolved in a mixed solvent composed of 20 ml of CCl4 and 5 ml of anhydrous pyridine under stirring. The thus obtained solution was added with a solution prepared by dissolving 0.7 g of (S)-4-(1-oxo-2-methylbutyl)phenol in 10 ml of CCl4, and the admixture was stirred at the room temperature for one night. The admixture was heated to reflux for 3 hours. 200 ml of water and 100 ml of ethyl ether were added to the reaction admixture, followed by stirring. The organic phase was separated, and rinsed initially with a dilute hydrochloric acid solution, then with an aqueous solution of NaHCO3 and finally with a saturated aqueous solution of NaCl. The rinsed organic phase was added with anhydrous Na2SO4 and allowed to stand for one night to dry the same. After removing the drying agent by filtration, the solvent was distilled off to obtain 1.86 g of a crude product. The crude product was refined through silica gel column chromatography while using a mixed solvent of hexane/ethyl acetate (ratio by volume: 8/2). The refined product was recrystallized from ethanol to obtain 200 mg of (S)-4-(1-oxo-2-methylbutyl)phenyl 4-(5-octyl-2-pyrimidinyl)benzoate in the form of a colorless crystal.
Reaction SMILES: [CH3:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:9]([C:15]4[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1.[NH2:29]C(C)(CC(C)C)C(O)=O>CN(C=O)C>[CH3:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[C:8]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:9]([C:15]4[CH:22]=[CH:21][C:18]([CH2:19][NH2:29])=[CH:17][CH:16]=4)=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][N:3]=1
Reactant: CC(C)CC(C)(N)C(=O)O
Reactant: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3ccn12
Solvent: CN(C)C=O
Product: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(CN)cc4)nc3ccn12
Temperature: 150 °C

Procedure:
A suspension of 4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)benzaldehyde (13, 0.25 g, 0.69 mmol) and 2-amino-2,4-dimethylpentanoic acid (3-7, 0.101 g, 0.69 mmol) in DMF (3 mL) was heated at 150° C. for 30 min. The reaction mixture cooled and the solvent was removed in vacuo. The crude residue was dissolved in 3N HCl (2.5 mL) and was heated at 100° C. for 30 min. The mixture was cooled and purified via reverse phase HPLC (5-65% acetonitrile/water over 15 min) to give, upon evaporation of the solvents, the title compound as a yellow solid. HRMS m/z (M+1) Calcd: 366.1713. Found 366.1715.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[N+:6]([O-])[CH:7]=1.C[Si]([C:14]#[N:15])(C)C.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:7]([C:14]#[N:15])=[N:6][C:5]([CH3:9])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccc(Br)c[n+]1[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(Br)c(C#N)n1
Temperature: 100 °C

Procedure:
To the solution of 5-bromo-2-methylpyridine 1-oxide (8.935 g, 47.52 mmol) in acetonitrile (240 mL) was added trimethylsilyl cyanide (TMSCN) (25 mL, 190 mmol) and triethylamine (20 mL, 142.56 mmol). The reaction was heated at 100° C. for 16 h. The mixture was cooled to rt and concentrated in vacuo. The crude was purified by silica gel chromatography using 0-50% EtOAc in hexane to obtain the title compound.
Reaction SMILES: [OH:1][C:2]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)([CH:13]([CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:14]([O:16]CC1C=CC=CC=1)=[O:15])[C:3]([O:5]CC1C=CC=CC=1)=[O:4].[H][H]>C(O)C.[Pd].[C]>[OH:1][C:2]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)([CH:13]([CH:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)[C:14]([OH:16])=[O:15])[C:3]([OH:5])=[O:4]
Reactant: O=C(OCc1ccccc1)C(C1CCOCC1)C(O)(C(=O)OCc1ccccc1)C1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C(C1CCOCC1)C(O)(C(=O)O)C1CCOCC1
Reaction time: 24 h
Yield: 95.6 %

Procedure:
To a solution of dibenzyl 2-hydroxy-2,3-bis(tetrahydro-2H-pyran-4-yl)succinate (2.0 g, 4.15 mmol) in ethanol (50 ml) was added 10% Pd-carbon (300 mg) under a nitrogen atmosphere. The atmosphere in the system was replaced five times with nitrogen gas and was filled with hydrogen gas, and the system was stirred under a hydrogen atmosphere for 24 hr. The catalyst was collected by filtration through Celite pad and was washed with ethanol. The filtrate was concentrated under reduced pressure to give the title compound as a colorless solid (1.2 g, yield 96%).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[O:3].[CH:7]1[CH:8]=[CH:9][C:10]2[N:15](O)N=[N:13][C:11]=2[CH:12]=1.C(Cl)CCl.C(N(CC)CC)C>C(O)(C(F)(F)F)=O.ClCCl>[C:1]([N:13]1[CH2:11][CH2:12][CH2:7][C@@H:8]1[CH2:9][C:10]#[N:15])(=[O:6])[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)C(=O)O
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(=O)C(=O)N1CCC[C@@H]1CC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[(2R)-1-(carbo-tert-butyloxy)pyrrolidin-2-yl]acetonitrile (1.0 g, 4.75 mmol) was stirred in TFA and dichloromethane (1:1 mixture, 12 mL) at room temperature for 3 hr. The solvent was removed under reduced pressure and the residue was taken up in acetonitrile (25 mL). To this solution was added pyruvic acid (450 mg, 5.0 mmol), followed by HOBT (0.8 g, 6 mmol), EDC (1.0 g, 5.5 mmol), and triethylamine (1.0 mL, 7.0 mmol). The reaction was stirred at room temperature overnight. After removal of solvent, the crude product was purified by flash chromatography on a Biotage® system (silica, 30-90% ethyl acetate in hexanes) to yield [(2R)-1-pyruvoylpyrrolidin-2-yl]acetonitrile as yellow oil. MS (M+Na): 203.2