Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:25]([C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)=[CH:24][N:23]=[C:22]([NH:31][CH2:32][CH2:33][NH:34]C2C=CC([N+]([O-])=O)=CN=2)[N:21]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]1[C:25]([C:26]2[NH:30][CH:29]=[CH:28][N:27]=2)=[CH:24][N:23]=[C:22]([NH:31][CH2:32][CH2:33][NH:34][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=2)[N:21]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: FC(F)(F)c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl](2-{[5-(trifluoromethyl)(2-pyridyl)]amino}ethyl)amine (71480) was prepared from 2-chloro-5-(trifluoro-methyl)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [C:1]([Si:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([OH:16])=[C:11]([Cl:17])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].N12CCN(CC1)CC2.[CH3:38][N:39]([CH3:43])[C:40](Cl)=[S:41]>CN(C)C=O.C(OCC)(=O)C>[C:1]([Si:5]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][C:40](=[S:41])[N:39]([CH3:43])[CH3:38])=[C:11]([Cl:17])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(=S)Cl
Reactant: CC(C)(C)[Si](OCCc1cc(Cl)c(O)c(Cl)c1)(c1ccccc1)c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=S)Oc1c(Cl)cc(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.5 %

Procedure:
A solution of 4-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-2,6-dichloro-phenol (70) (289 mg, 0.78 mmol) in N,N-dimethylformamide (4 mL) at 25° C. was treated with 1,4-diazabicyclo[2.2.2]octane (172 μL, 1.56 mol) and dimethylthiocarbamoyl chloride (154 mg, 1.25 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was diluted with ethyl acetate and was then washed with a 1N aqueous hydrochloric acid solution, water, and a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95:5 petroleum ether/ethyl acetate) afforded dimethyl-thiocarbamic acid O-{4-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-2,6-dichloro-phenyl}ester (71) (376 mg, 90%) as a white solid; EI(+)-HRMS m/e calcd for C27H31Cl2N2O2SSi (M+H)+ 532.1295, found 532.1292. Exact Mass=531.1222; Molecular weight=532.61
Reaction SMILES: [OH-].[K+].FC(F)(F)C([N:7]1[CH2:12][CH2:11][CH2:10][CH:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[CH2:8]1)=O.O>CO>[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][O:13][CH:9]3[CH2:10][CH2:11][CH2:12][NH:7][CH2:8]3)=[CH:20][CH:19]=2)=[CH:23][CH:24]=1
Reactant: O=C(N1CCCC(OCc2ccc(Oc3ccc(F)cc3)cc2)C1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Fc1ccc(Oc2ccc(COC3CCCNC3)cc2)cc1
Yield: 95.6 %

Procedure:
A 1 mol/L aqueous potassium hydroxide solution (2 mL) was added to 1-trifluoroacetyl-3-[4-(4-fluorophenoxy)benzyloxy]piperidine (434 mg, 1.09 mmol) in methanol (4 mL). The mixture was refluxed for 2 hours and was allowed to cool. Water was then added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and the washed product was dried over magnesium sulfate. The solvent was evaporated to give 314 mg (95%) of the desired compound as a colorless oil.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=1)[NH2:31].[C:37]1(=O)[CH2:42][CH2:41][CH2:40][C:39](=[O:43])[CH2:38]1.CO>O>[F:26][C:27]([F:35])([F:36])[C:28]1[CH:29]=[C:30]([NH:31][C:37]2[CH2:42][CH2:41][CH2:40][C:39](=[O:43])[CH:38]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C1CCCC(=O)C1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CO
Product: O=C1C=C(Nc2cccc(C(F)(F)F)c2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ytterbiumtriflate (138 mg; 0.223 mmol) is added to a solution of m-trifluoromethylaniline (5.55 mL; 44.6 mmol) and 1,3-cyclohexanedione (5.0 g; 44.6 mmol) and the mixture is stirred at room temperature for 1 h. Methanol is added to the suspension until everything is dissolved. Water is added and the precipitate is filtered off, washed with water and dried. Yield: 10.35 g. ESI mass spectrum: [M+H]+=256; Retention time HPLC: 0.47 min (X012_S01).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.Br[C:24]1[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH3:30])[CH:25]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1cc(Br)ccn1
Reactant: CON(C)C(=O)C[C@@H](c1ccc(Br)cc1)c1ccccc1C
Product: Cc1cc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccccc2C)ccn1

Procedure:
In analogy to example 74, step 5, from (S)-3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 142, step 1) and 4-bromo-2-methylpyridine was prepared the title compound as white solid, MS (ESI+): m/z=394.0 ([M+H]+, 1Br).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([O-:11])(=[O:10])[C:7]([CH3:9])=[O:8].[Na+].[C:13]([O-:17])(=[O:16])[CH:14]=[O:15].[Na+]>>[OH:8][CH:7]([C:6]([OH:11])=[O:10])[CH2:9][C:14](=[O:15])[C:13]([OH:17])=[O:16]
Reactant: O=CC(=O)[O-]
Reactant: CC(=O)C(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)C(=O)CC(O)C(=O)O
Reaction time: 16 h

Procedure:
Pseudomonas putida ATCC 795 strain was inoculated into 9 ml of L medium and cultured for 16 hours at 30° C. with shaking. Whole amount of this culture was then inoculated into 300 ml of GMS medium in 2 liter volume Erlenmeyer flask and cultured for 20 hours at 30° C. with shaking. The resulting culture was centrifuged, the collected cells were resuspended in 60 ml of the reactant solution (b), and the suspension was stirred in 300-ml beaker while maintaining pH at 6.5 with 1N sulfuric acid. After 6 hours, 3 ml of 2M sodium pyruvate and 3 ml of 2M sodium glyoxylate were added. After 24 hours from the starting point of this reaction, the cells were removed from the suspension by centrifugation, and the amount of 4-hydroxy-2-ketoglutaric acid formed in the supernatant was determined by HPLC. The amount of L-4-hydroxy-2-ketoglutaric acid was determined to be 150 mM and D-form was not detected.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:14][N:15]([CH3:33])[C:16]([C:18]1[CH2:19][N:20]([CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[C:21](=[O:24])[C:22]=1[OH:23])=[O:17]>ClCCl.N1C=CC=CC=1.ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:34]=[CH:35][C:36]=1[Cl:37])[CH2:14][N:15]([CH3:33])[C:16]([C:18]1[CH2:19][N:20]([CH2:25][CH2:26][N:27]2[CH2:28][CH2:29][N:30]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:31][CH2:32]2)[C:21](=[O:24])[C:22]=1[OH:23])=[O:17]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCNCC2)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN2CCN(C(=O)c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.2 %

Procedure:
To a solution of benzoyl chloride (0.023 mL, 0.23 mmol) in dichloromethane (1 mL) cooled to 0° C. was added dropwise a solution of 4-hydroxy-5-oxo-1-(2-piperazin-1-yl-ethyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (0.10 g, 0.20 mmol) in pyridine/dichloromethane (4 mL, 1:1). The resulting mixture was stirred at room temp 18 h and quenched with 1N HCl. The organic phase was washed with 1N HCl (3 times). The aqueous washings were combined and purified by preparative HPLC (C18, ODS-A, S-75 μm, 30% acetonitrile/water/0.5% TFA) to give the title compound as a white powder (0.0215 g, 20% yield). HRMS (M+H) calcd for C26H29N4Cl2O4: 531.1566; found: 531.1563.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]4[O:29][CH:30]5[CH2:35][NH:34][CH2:33][CH:31]5[N:32]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([NH:27][C:28]4[O:29][CH:30]5[CH2:35][N:34]([C:36](=[O:38])[CH3:37])[CH2:33][CH:31]5[N:32]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC5=NC6CNCC6O5)cc34)cc2C)cn1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CC2N=C(Nc3ccc4ncnc(Nc5ccc(Oc6ccc(C)nc6)c(C)c5)c4c3)OC2C1

Procedure:
1-(2-{4-[3-Methyl-4-(6-methylpyridin-3-yloxy)-phenylamino]-quinazolin-6-ylamino}-3a,4,6,6a-tetrahydropyrrolo[3,4-d]oxazol-5-yl)-ethanone is prepared from N4-[3-methyl-4-(6-methylpyridin-3-yloxy)-phenyl]-N6-(4,5,6,6a-tetrahydro-3aH-pyrrolo[3,4-d]oxazol-2-yl)-quinazoline-4,6-diamine by standard acetylation methods using acetic anhydride in a mixture of pyridine and methylene chloride. MS APCI (+) m/z 510 (M+1) detected; 1H NMR (400 mHz, CD3OD) δ 8.44 (s, 1H), 8.26 (d, 1H), 8.13 (d, 1H), 7.71 (m, 2H), 7.63 (m, 2H), 7.28 (m, 2H), 7.00 (d, 1H), 5.28 (m, 1H), 4.89 (m, 1H), 4.15 (d, 0.5H), 4.03 (m, 1H), 3.84 (d, 0.5H), 3.75 (m, 1H), 3.47 (m, 1H), 2.50 (s, 3H), 2.27 (s, 3H), 2.09 (d, 3H).
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[N:27]=[C:20]3[C:21]([CH3:26])=[N:22][CH:23]=[C:24]([CH3:25])[N:19]3[N:18]=2)=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH3:28][N:29](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH3:25][C:24]1[N:19]2[N:18]=[C:17]([C:3]3[C:2]([C:28]#[N:29])=[CH:7][N:6]4[CH:8]=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[N:10]=[C:5]4[CH:4]=3)[N:27]=[C:20]2[C:21]([CH3:26])=[N:22][CH:23]=1
Reactant: Cc1ncc(C)n2nc(-c3cc4nc(-c5ccccc5)cn4cc3Br)nc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1ncc(C)n2nc(-c3cc4nc(-c5ccccc5)cn4cc3C#N)nc12
Reaction time: 1.25 h

Procedure:
A 2-dram pressure rated scintillation vial was charged with 2-(6-bromo-2-phenylimidazo[1,2-a]pyridin-7-yl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (20 mg, 0.048 mmol) and suspended in DMF (477 mL). To that stirring solution was added zinc cyanide (5.60 mg, 0.048 mmol). The vial was sealed and degassed using dry argon and sonication for 1 minute. Tetrakis(triphenylphosphine)palladium(0) (16.5 mg, 0.014 mmol) was then added in one portion. The vial was resealed, flushed with argon, and placed in a reaction block preheated to 90° C. After 1.25 hours, LCMS showed complete conversion of starting material to a major peak with the desired product (m/z=366 [M+H]+). Upon cooling, a solid began to form. The crude material was purified by HPLC method 10. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (1H, s), 8.65 (1H, s), 8.46 (1H, s), 8.14 (1H, s), 8.09 (2H, d, J=7.28 Hz), 7.50-7.56 (2H, m), 7.40-7.46 (1H, m), 2.88 (3H, s), 2.78 (3H, s). Mass found 366 [M+H]+.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[NH:4][N:3]=1.C([Li])CCC.CCCCCC.[CH2:31]1[CH:39]2[N:34]([CH2:35][CH2:36][C:37](=[O:40])[CH2:38]2)[CH2:33][CH2:32]1.C(=O)([O-])O.[Na+]>O1CCCC1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[NH:4][N:3]=[C:2]([C:37]3([OH:40])[CH2:38][CH:39]4[N:34]([CH2:33][CH2:32][CH2:31]4)[CH2:35][CH2:36]3)[C:6]=2[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:14][CH:15]=1
Reactant: O=C1CCN2CCCC2C1
Reactant: Fc1ccc(-c2[nH]nc(Br)c2-c2ccncc2)cc1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC1(c2n[nH]c(-c3ccc(F)cc3)c2-c2ccncc2)CCN2CCCC2C1
Reaction time: 0.17 h
Yield: 21.9 %

Procedure:
3-Bromo-5-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (3.18 g (10 mmol), prepared as described in 1)) was dissolved in tetrahydrofuran (32 ml). To the solution was added a solution of 1.6 M butyl lithium/hexane (13.75 ml, 13.75 mmol) at −78° C., and the resulting mixture was stirred for 10 minutes. To the mixture was added 1,2,3,5,6,7,8,8a-octahydroindolizin-7-one (1.53 g, 11 mmol) at −78° C., and the resulting mixture was stirred first at −78° C. for 2 hours, then at room temperature for 1 hour. At the end of this time, the reaction mixture was added to a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, ethyl acetate:methanol:isopropylamine=20:1:1), to give the title compound (830 mg) as a pale yellow powder (yield 22%).
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[N:17]2[CH3:20])=[CH:13][CH:12]=1>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:16]([C:21]([O:23][CH3:24])=[O:22])[N:17]2[CH3:20])=[CH:13][CH:12]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COC(=O)c1cc2ccc(Cl)cc2n1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)CC(=O)c1c(C(=O)OC)n(C)c2cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 6.2 ml (48.4 mmol) of ethyl 3-chloro-3-oxopropanoate in 70 ml of 1,2-dichloroethane is cooled to 0° C. In small portions 5.3 ml (48.3 mmol) of titanium tetrachloride are added and the mixture is stirred at 0° C. for 30 minutes. A solution of 4.3 g (19.2 mmol) of methyl 6-chloro-1-methyl-1H-indole-2-carboxylate in 35 ml of 1,2-dichloroethane is added and the mixture is stirred at ambient temperature for 12 h. It is poured into ice water and extracted with dichloromethane. The organic phase is separated off, washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column (eluent: cyclohexane/ethyl acetate: 90/10 to 80/20). This gives a yellow solid, which is triturated in heptane and then in diisopropyl ether.
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[OH:14][C@:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>CCO>[OH:14][C@:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][N:18]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[O:11][CH2:12][CH2:13][C:3]=23)[CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Temperature: 110 °C
Reaction time: 15 h
Yield: 65.7 %

Procedure:
To a vial containing 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (59 mg, 0.20 mmol) and tert-butyl [(3R,4R,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (46 mg, 0.19 mmol) was added EtOH (2.0 mL), followed by DIPEA (100 mg, 0.772 mmol). The mixture was stirred at 110° C. for 15 h. After cooling to the room temperature, the reaction was concentrated under reduced pressure. The resulting residue was purified on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a yellow foamy solid (51 mg, 67%). LCMS calc. for C19H29N4O6 (M+H)+: m/z=409.2. found 409.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH3:29])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])=[CH:8][C:7]=1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.O1CCOCC1>O1CCOCC1>[CH3:1][O:2][C:3](=[O:30])[C@H:4]([CH3:29])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][C:7]=1[C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)[C@H](C)Nc1ccc(OCC(=O)OC(C)(C)C)cc1C(=O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](C)Nc1ccc(OCC(=O)O)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-t-butoxycarbonylmethoxy-N-(2-benzoylphenyl)alanine methyl ester (1.4 g), 4N hydrogen chloride/dioxane (10 ml) and dioxane (10 ml) was stirred at room temperature for 3 hours and allowed to stand overnight. The reaction mixture was concentrated under reduced pressure. To the residue was added toluene and the mixture was concentrated under reduced pressure. The residue was chromatographed on a silica gel column (LiChroprepDIOL (Merck)) using hexane: ethyl acetate=2:1−1:1 as the eluant to afford the title compound (0.87 g, Rf=0.53: thin layer chromatography on a silica gel plate using hexane: ethyl acetate=3:2 as the eluant).
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:14]=[CH:15][C:16]2[O:20][CH:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]=2[CH:27]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[N+:28]([O-:33])([N+]([O-])=O)=[O:29].[OH-].[Na+].Cl>ClCCl.C(OCC)C>[N+:28]([C:19]1[O:20][C:16]2[CH:15]=[CH:14][C:13]([CH:2]([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:27][C:17]=2[C:18]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([O-:33])=[O:29]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: CCCCCCCCCCC(O)c1ccc2occ(-c3ccccc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCCCC(O)c1ccc2oc([N+](=O)[O-])c(-c3ccccc3)c2c1
Reaction time: 16 h

Procedure:
To the solution of product from step A is added 2 g. of dinitrogen tetraoxide dissolved in dichloromethane, and the mixture is stirred for about 16 hours. Evaporation provides a residue which is mixed with ice and 10 percent sodium hydroxide solution. The mixture is stirred for 15 minutes, then cold 6N hydrochloric acid and diethyl ether are added. The ether layer is separated, then washed with saturated sodium chloride solution and dried. The solution is chromatographed on silica gel, eluting first with carbon tetrachloride, then dichloromethane. The later fractions are evaporated to provide 1-(2-nitro-3-phenyl-5-benzofuranyl)undecan-1-ol as a yellow solid, m.p. 84°-85° C. after recrystallization from hexane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]([OH:14])=O)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:56][CH2:57][C:58]1[CH:59]=[C:60]([OH:64])[CH:61]=[CH:62][CH:63]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:14])[NH:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([OH:64])[CH:59]=2)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: CCc1cc(C(=O)O)sc1C(=O)OC
Reactant: NCc1cccc(O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)NCc2cccc(O)c2)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.5 %

Procedure:
To a solution of 3-Ethyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (250 mg, 1.17 mmol) in anhydrous DMF (10 mL) was added triethylamine (0.50 mL, 3.51 mmol), HBTU (0.67 g, 1.76 mmol), HOBT (190 mg, 1.40 mmol), and 3-Aminomethyl phenol (160 mg, 1.29 mmol). The mixture was stirred at room temperature 2 d, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-50% EtOAc in hexane to afford the desired product (0.140 g, 38% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH2:9])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18].[OH-].[Na+]>ClCCl>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:17](=[O:19])[CH3:18])[CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cccc(Br)n1
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1cccc(Br)n1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of C-(6-Bromo-pyridin-2-yl)-methylamine (5440 mg, 29.08 mmol) in dichloromethane (100 mL) at room temperature was added triethylamine (5886 mg, 58.17 mmol) and acetyl chloride (2511 mg, 31.99 mmol). The reaction mixture was heated at 40° C. for 3 h and cooled down to room temperature. A solution of sodium hydroxide (1N) was added and the reaction was stirred for 1 h at room temperature. The layers were separated and the organic phase was concentrated under reduced pressure. The crude mixture was dissolved in EtOH (50 mL) and concentrated hydrochloric acid (10 mL) was added. The mixture was stirred for 30 min and benzene was added followed by sodium hydroxide pellets until pH 10 was reached. The phases were separated and the organic layer was washed with an aqueous solution of ammonium chloride and the volatiles were removed in vacuo. The crude material was purified by column chromatography with a gradient of 0 to 5% methanol/dichloromethane to give N-(6-Bromo-pyridin-2-ylmethyl)-acetamide as viscous orange oil. MS ES (MH+ 229.1/231.0).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:16]2[CH:17]=[CH:18][C:13]([Br:12])=[CH:14][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(Br)cc1

Procedure:
The subtitle compound was prepared by the method of example 2 step (i) using 4-fluorobenzenesulfonyl chloride and bromobenzene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([C:11]#[N:12])[CH2:6][C:7](=[O:10])[CH2:8][CH3:9])[CH3:2].[CH2:14](O)[CH2:15][OH:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([C:11]#[N:12])[CH2:6][C:7]1([CH2:8][CH3:9])[O:16][CH2:15][CH2:14][O:10]1)[CH3:2]
Reactant: OCCO
Reactant: CCOC(=O)C(C#N)CC(=O)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(C#N)CC1(CC)OCCO1
Temperature: 25 °C

Procedure:
In a 500 mL flask equipped with a reflux condenser and Dean-Stark trap were combined 40.0 g (218 mmol) of 2-cyano-4-oxohexanoic acid ethyl ester, 20.3 g (327 mmol) of ethylene glycol, 0.83 g (4.3 mmol) of p-toluenesulfonic acid monohydrate, and 100 mL of benzene. The reaction was heated to reflux until approximately 4.5 mL of water had been collected in the trap. The reaction was cooled to ambient temperature, washed with 50 mL of water, 50 mL of saturated δsodium bicarbonate solution and dried over sodium sulfate. The mixture was then concentrated to 46.0 g (93%) of α-cyano-2-ethyl-1,3-dioxolane-2-propanoic acid ethyl ester as a light tan oil. An NMR of the crude product showed less than 10% residual ketone remained and the crude product was used without further purification. nmr (500 MHz, CDCl3) δ0.92 (t, J=7.5 Hz, 3H), 1.31 (t, J=7.2 Hz, 3H), 1.64 (q, J=7.5 Hz, 2H), 2.29 (dd, J=6.8, 14.6 Hz, 1H), 2.41 (dd, J=6.3, 14.6 Hz, 1H), 3.59 (dd, J=6.3, 6.8 Hz, 1H), 3.59 (m, 4H), 4.24 (q, J=7.2 Hz, 2H).