Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][C:11]=2[CH2:12][N:13]([CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)[C:14]2[N:15]=[N:16][N:17]([CH2:19][CH2:20][O:21][Si](C(C)(C)C)(C)C)[N:18]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CC1CCCO1>[CH3:1][O:2][C:3]1([C:10]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:49])[F:50])=[CH:44][C:11]=2[CH2:12][N:13]([CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:33]=[C:32]([C:40]([F:42])([F:41])[F:43])[CH:31]=2)[C:14]2[N:15]=[N:16][N:17]([CH2:19][CH2:20][OH:21])[N:18]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCO[Si](C)(C)C(C)(C)C)n2)CCCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC1CCCO1
Product: COC1(c2ccc(C(F)(F)F)cc2CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(CCO)n2)CCCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
To a solution of N-(2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzyl)-N-(3,5-bis(trifluoromethyl)benzyl)-2-(2-(tert-butyldimethylsilyloxy)ethyl)-2H-tetrazol-5-amine (42 mg, 0.056 mmol) in 2-methyltetrahydrofuran (1.5 mL) was added tetrabutylammonium fluoride (0.1 mL; 0.1 mmol; 1.0M in tetrahydrofuran). Reaction was stirred at room temperature for 1.5 hours. The reaction was concentrated in vacuo. The residue was purified by 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10-40% ethyl acetate in heptane) to give 34 mg (95% yield) of a gum. MS (ES+): Calc: 639.5, Found: 640.5 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.74 (s, 2H), 7.45 (m, 3H), 5.10 (s, 2H), 4.81 (s, 2H), 4.61 (t, J=4.98 Hz, 2H), 4.11 (q, J=6.22, 5.8 Hz 1, 2H), 2.94 (s, 3H), 2.44 (t, J=6.64, 6.22 Hz, 1H), 2.11 (m, 2H), 2.19 (m, 2H), 1.82-1.45(m, 8H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=2)[NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C1(N=C=NC2CCCCC2)CCCCC1>CC(C)=O.C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([CH:30]([CH2:29][CH2:28][NH2:27])[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[O:26])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:23])[CH:21]=2)[NH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CCCN
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C(CCN)C(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)OCc1ccccc1
Yield: 95 %

Procedure:
85 mmol of N-benzyloxycarbonyl-5-hydroxy-L-tryptophan and 85 mmol of tert.-butyl γ-aminobutyrate are dissolved in 170 ml of acetone and 300 ml of pure chloroform. A solution of 17.7 g (86 mmol) of dicyclohexylcarbodiimide in 80 ml of chloroform is then added and the mixture is stirred at ordinary temperature until the condensation has ended. After evaporation, taking up with ethyl acetate and the customary treatment, 40 g of a crude product are obtained, which are purified by chromatography on a silica column, elution being carried out with a methylene chloride/acetone mixture. This gives 48% of a pure product showing a single spot in TLC on Kieselgel in the system chloroform 20/acetone 6, of Rf=0.45. The NMR spectrum is recorded in solution in CDCl3 : 8.4 ppm (s) (1H) --OH; 7.3 ppm (s) (5H) benzyl; 7.2 to 6.6 ppm (m) (4H) arom; 6.4 ppm (m) (1H) and 5.9 ppm (d) (1H) --NH; 5 ppm (s) (2H) CH2 --Ph; 4.4 ppm (m) (1H) CH(NH)--CO; 3.1 ppm (m) (4H) CH2 --CH(--NH)CO and NH CH2 ; 2.1 to 1.8 ppm (m) 4H: CH2 --CH2 ; 1.4 ppm (s) (9H) tert.-butyl.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18](O)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[OH:19][CH2:18][C@@H:12]1[CH2:13][C@@H:14]([O:16][CH3:17])[CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CO[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Solvent: C1CCOC1
Product: CO[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution of borane-tetrahydrofuran complex in THF (1M, 53.0 mL, 53.0 mmol, 3.50 equiv) was added to a solution of (2S,4R)-1-[(benzyloxy)carbonyl]-4-methoxy-2-pyrrolidinecarboxylic acid (3-2, 4.23 g, 15.1 mmol, 1 equiv) in THF (200 mL) at 0° C. The resulting mixture was warmed to 23° C. and stirred for 1 h. Excess borane was carefully quenched with water. The mixture was then partitioned between a 1:1 mixture of saturated sodium carbonate solution and brine (300 mL) and ethyl acetate (300 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (100% hexane initally, grading to 100% EtOAc) to provide benzyl (2S,4R)-2-(hydroxymethyl)-4-methoxy-1-pyrrolidinecarboxylate (3-3) as a colorless oil. 1H NMR (300 MHz, CDCl3) major rotamer: δ7.37-7.25 (br m, 5H), 5.18 (d, 1H, J=12.4 Hz), 5.13 (d, 1H, J=12.2 Hz), 4.51 (dd, 1H, J=8.3,2.2 Hz), 3.86 (m, 1H), 3.78 (dd, 1H, J=11.7, 2.2 Hz), 3.72 (br d, 1H, J=11.7 Hz), 3.61 (ddd, 1H, J=9.8, 7.4, 2.2 Hz), 3.44 (dd, 1H, J=12.2, 4.4 Hz), 3.30 (s, 3H), 2.18 (m, 1H), 1.64 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:23][N:24]=[C:25]=[O:26]>C(Cl)Cl>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:10]2[CH2:15][CH2:14][N:13]([C:25]([NH:24][CH3:23])=[O:26])[CH2:12][CH2:11]2)=[CH:21][CH:20]=1
Reactant: CN=C=O
Reactant: Fc1ccc(NC(c2ccc(F)cc2)C2CCNCC2)cc1
Solvent: ClCCl
Product: CNC(=O)N1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
A mixture of 1.91 g (6.25 mmol) of the N,α-bis(4-fluorophenyl)-4-piperidinemethanamine and 0.45 g (7.9 mmol) of methyl isocyanate in 300 mL of CH2Cl2 was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was subjected to flash column chromatography (silica gel, gradiently eluted with 1 to 4% CH3OH in CH2Cl2) to give 1.54 g (68.6%) of white solid, mp 86°-90° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[S:22][N:21]=[C:20]([CH3:23])[N:19]=4)[CH2:14][CH2:13]3)[N:10]=[C:4]2[CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:23][C:20]1[N:19]=[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9]3[N:10]=[C:4]4[CH:3]=[C:2]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH:7]=[CH:6][N:5]4[N:8]=3)[CH2:13][CH2:14]2)[S:22][N:21]=1
Reactant: Cc1nsc(N2CCC(Nc3nc4cc(Br)ccn4n3)CC2)n1
Reactant: OB(O)c1ccccc1
Product: Cc1nsc(N2CCC(Nc3nc4cc(-c5ccccc5)ccn4n3)CC2)n1

Procedure:
Prepared in analogy to example 66c from (7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-[1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine and phenyl boronic acid. The title compound was obtained as off-white foam.
Reaction SMILES: [NH4+].[Cl-].[CH3:3][C:4]1([CH3:20])[O:8][C@H:7]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=2)[CH2:6][O:5]1.O>C(O)(C)C.[Fe]>[CH3:3][C:4]1([CH3:20])[O:8][C@H:7]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[NH2:17])[CH2:6][O:5]1
Reactant: CC1(C)OC[C@@H](COc2cccc([N+](=O)[O-])c2)O1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: CC1(C)OC[C@@H](COc2cccc(N)c2)O1
Yield: 79 %

Procedure:
A mixture of Fe powder (2.38 g, 42.5 mmol), NH4Cl (2.27 g, 42.5 mmol) and (R)-2,2-dimethyl-4-((3-nitrophenoxy)methyl)-1,3-dioxolane 104 (1.80 g, 7.09 mmol) in isopropanol (30 mL)/H2O (10 mL) was heated at reflux for 18 h. The crude material was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure. The resulting aqueous layer was extracted with dichloromethane (3×15 mL). The combined organic layers were dried with Na2SO4, and concentrated under reduced pressure to afford 105 (1.25 g, 76% yield). The acetonide protecting group could be removed after coupling with the appropriate aniline by treatment with EtOH/3 N HCl (4:1) at reflux for 12 h.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[S:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[C:27](O)(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[OH:3][C:2]1[CH2:4][S:5][C:6](=[O:7])[C:1]=1[C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]\[CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: O=C1CSC(=O)C1
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)C1=C(O)CSC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
To a stirring solution of 695 mg (6.04 mmol) of thiotetronic acid in 10 mL of dimethylformamide is added 902 μL (6.47 mmol) of triethylamine and 240 mg (1.97 mmol) of 4-dimethylaminopyridine at 0° C. Next, 1.37 g (7.13 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.0 g (7.19 mmol) of γ-linolenic acid are added and the reaction mixture is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted three times with diethyl ether. The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was subjected to HPLC chromatography (2 inch Dynamax silica gel column, 25 mL/min) eluting with 100% ethyl acetate to give 1.8 g (79%) of 4-hydroxy-3-[(Z,Z,Z)-1-oxo-6,9,12-octadecatrienyl]-2(5H)-thiophenone as an oil.
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:2]([CH3:4])[CH3:3])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 22 h
Yield: 98.6 %

Procedure:
2-Bromopropane (4.51 mL, 5.90 g, 48 mmol) was added to a mixture of 4-benzyloxy-2-nitrophenol (J.Biol.Chem., 1985, 260, 3440, 2.94 g, 12 mmol) and potassium carbonate (9.95 g, 72 mmol) in dimethylformamide (20 mL) and the mixture was stirred at 50° C. for 22 h. The mixture was cooled, diluted with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with aqueous sodium hydroxide (1M, 4×100 mL) and brine (100 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as an orange oil (3.40 g, 99%). 1H NMR (360 MHz, CDCl3) δ 7.41-7.33 (6H, m), 7.12 (1H, dd, J 9.1, 3.1 Hz), 7.02 (1H, d, J 9.1 Hz), 5.05 (2H, s), 4.52 (1H, hept, J 6.1 Hz), and 1.35 (6H, d, J 6.1 Hz).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]([F:23])([F:22])[O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1.I[CH2:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[CH:26]1([CH2:25][CH:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:22])([F:23])[F:9])=[CH:17][CH:16]=2)[C:19]([OH:21])=[O:20])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: ICC1CCCC1
Reactant: O=C(O)Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(OC(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 30.3 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (23 mL of a 0.31M stock solution, 7.13 mmol) cooled to −78° C. was treated with (4-trifluoromethoxy-phenyl)-acetic acid (0.74 g, 3.39 mmol) in tetrahydrofuran/ 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8.5 mL, 3:1). The resulting solution was stirred at −78° C. for 45 min. At this time, the reaction was treated with a solution of iodomethylcyclopentane (0.78 g, 3.73 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 18 h. The reaction mixture was then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (10 mL). The resulting mixture was concentrated in vacuo to remove the excess solvent. The residue was diluted with water (100 mL) and acidified to pH=1 with a 1N aqueous hydrochloric acid solution. This solution was extracted with ethyl acetate (3×50 mL). The organics were washed with a saturated aqueous lithium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-trifluoromethoxy-phenyl)-propionic acid (0.31 g, 30.6%) as a tan solid: mp 62-64° C.; EI-HRMS m/e calcd for C15H17F3O3 (M+) 302.1129 found 302.1131.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH:22]1([CH2:21][N:11]2[C:12]3[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=3[C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:8]=[C:9]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:10]2=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Temperature: 25 °C
Yield: 21.8 %

Procedure:
A mixture of 1-cyclohexylmethyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (41 mg, 0.087 mmol), β-alanine (623 mg, 7.0 mmol) and NaOMe solution (10 mL, 5.2 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (5-90% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 10 mg of the title compound as a white solid. MS: (+) m/z 527.45 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1SC.[N+:9]([CH2:12][C:13]([O:15]C)=[O:14])([O-:11])=[O:10]>[Cl-].[Zn+2].[Cl-]>[CH3:1][N:2]1[CH2:6][CH2:5][NH:4][C:3]1=[C:12]([N+:9]([O-:11])=[O:10])[C:13]([OH:15])=[O:14]
Reactant: CSC1=NCCN1C
Reactant: COC(=O)C[N+](=O)[O-]
Agent: [Cl-]
Agent: [Zn+2]
Product: CN1CCNC1=C(C(=O)O)[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
19.5 g of 1A, 17.8 g of methyl nitroacetate and a small amount of zinc chloride were mixed and the mixture heated to 100°-105°. After 30 minutes, the solid reaction mixture was washed with ether, then with hot methanol. The mixture then was filtered to give the methyl ester of (1-methyl-2-imidazolidinylidene)nitroacetic acid (1B) as a tan solid, m.p.: 209°-210°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:55])[NH:15][C@@H:16]([C:28](=[O:54])[N:29]([C@@H:31]([C:43]2[O:47][N:46]=[C:45]([C:48](OCCC)=[O:49])[N:44]=2)[CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH3:30])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:56][NH2:57]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:55])[NH:15][CH:16]([C:28](=[O:54])[N:29]([CH:31]([C:43]2[O:47][N:46]=[C:45]([C:48](=[O:49])[NH:57][CH3:56])[N:44]=2)[CH2:32][C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=2)[CH3:30])[CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN
Reactant: CCCOC(=O)c1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: CCO
Product: CNC(=O)c1noc(C(Cc2ccc3ccccc3c2)N(C)C(=O)C(Cc2ccc3ccccc3c2)NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
4-((1R)-1-{N-[(1R)-1-(3-Propoxycarbonyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (0.80 g, 1.07 mmol) was dissolved in 33% methylamine in ethanol and stirred at 90° C. for 18 h in a closed reaction vessel. The reaction mixture was concentrated in vacuo and the residue was chromatographed on silica (60 g) using ethyl acetate and heptane (7:3) as eluent to give 0.15 g of 4-(1-{-N-[1-(3-methylcarbamoyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)-ethyl]-N-methylcarbamoyl}-2-(2-naphthyl)ethylcarbamoyl)piperidine-1-carboxylic acid tert butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=[O:20])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][O:15][C:14]=2[C:13]([Br:19])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:2].[F:22][C:23]([Si](C)(C)C)([F:25])[F:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH2:1]([O:3][C:4](=[O:21])[C:5]([OH:20])([C:23]([F:25])([F:24])[F:22])[CH2:6][C:7]([C:10]1[C:18]2[O:17][CH2:16][O:15][C:14]=2[C:13]([Br:19])=[CH:12][CH:11]=1)([CH3:9])[CH3:8])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(C)(C)c1ccc(Br)c2c1OCO2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(O)(CC(C)(C)c1ccc(Br)c2c1OCO2)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
300 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid and 0.1 ml of sulfuric acid (96%) in 5 ml of ethanol are heated for 4 hours to 70° C. Then, the batch is concentrated by evaporation in a vacuum and added to water. It is extracted with ethyl acetate, washed with brine, dried and concentrated by evaporation in a vacuum. 272 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-4-methyl-2-oxo-valeric acid-ethyl ester is obtained as a yellow oil. This ester and 0.32 ml of trifluoromethyl-trimethylsilane in 4 ml of THF are mixed with 0.14 ml of a tetrabutylammonium fluoride solution (1 M in THF) at −70° C. It is stirred for 1 hour at −70° C., for 1.5 hours at −0° C., for 1 hour a and for 2 hours at room temperature. Another spatula-tip full of tetrabutylammonium fluoride is added, and after stirring is continued for 20 minutes, it is added to water. It is extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 297 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid-ethyl ester is obtained as a yellow oil. This oil is mixed in 5 ml of ether at 0° C. with 29 mg of lithium aluminum hydride, and stirred for 1 hour at 0° C. and for another 10 hours at room temperature. The batch is added to dilute hydrochloric acid, extracted with ethyl acetate, washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. 164 mg of 4-(7-bromo-1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentan-1-ol is obtained as a yellow oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([B:11]([OH:13])[OH:12])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[N+:14]([O-])([OH:16])=[O:15]>C(OC(=O)C)(=O)C>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([B:11]([OH:13])[OH:12])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: O=[N+]([O-])O
Reactant: CC(C)Cc1ccc(B(O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: CC(C)Cc1ccc(B(O)O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-isobutyl-phenylboronic acid (0.9 g, 5.05 mmol) in acetic anhydride (9 mL) at -10° C., fuming nitric acid (0.4 mL) was added over 10 minutes. The mixture was stirred for 1 hour, warmed to room temperature and stirred for an additional 1.5 hours. The clear orange solution was added to 100 mL of ice, stirred for 3 hours and azeotroped with water (4×100 mL). The residue was partitioned between 25 mL each of ether and water and the ether layer was dried and evaporated to provide 0.75 g of yellow solid. The solid was dissolved in ethyl acetate (25 mL) and the solution was extracted with 1N aqueous sodium hydroxide (2×25 mL). The combined aqueous extracts were acidified to pH 2 using 2N aqueous hydrochloric acid and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed once with water, dried and evaporated to provide 0.63 g of light yellow solid. Reverse phase preparative HPLC on a 30×500 mm ODS S10 column using 76% solvent A (90% MeOH, 10% H2O, 0.1% TFA) and 24% solvent B (10% MeOH, 90% H2O, 0.1% TFA) provided 0.16 g of compound A as light yellow solid.
Reaction SMILES: [C:1]([CH:3]([CH2:7][CH2:8][CH3:9])[C:4]([OH:6])=[O:5])#[N:2].[OH-].[Na+:11]>O>[Na+:11].[C:1]([CH:3]([CH2:7][CH2:8][CH3:9])[C:4]([O-:6])=[O:5])#[N:2]
Reactant: CCCC(C#N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(C#N)C(=O)[O-]

Procedure:
An initiator solution of cyanovaleric acid sodium salt was prepared in a round bottomed flask under nitrogen by taking cyanovaleric acid (6.2 g), sodium hydroxide aq solution (33.2 ml, 1 moldm-3) and water (84cm3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][OH:14])=[N:11][CH:12]=1.[Mn]([O-])(=O)(=O)=[O:19].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]([OH:19])=[O:14])=[N:11][CH:12]=1
Reactant: OCc1ccc(OCc2cccc(Cl)c2)cn1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(OCc2cccc(Cl)c2)cn1

Procedure:
The mixture of 13.1 g of 5-(m-chloro-benzyloxy)-2-pyridinemethanol and 250 ml of water is stirred vigorously at 25°. To this mixture is added 11.5 g of potassium permanganate in several portions. Then the mixture is filtered, the precipitated manganese dioxide washed with hot water, the washing is combined with the filtrate, concentrated to a small volume and then acidified with aqueous hydrochloric acid. The precipitated product is collected and recrystallized from ethyl acetate to yield 5-(3-chloro-benzyloxy)-2-pyridinecarboxylic acid melting at 176°-177°.