Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]2([NH:26]S(C(C)(C)C)=O)[CH2:25][O:24][CH2:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.Cl.CCOCC>C1CCCCC1>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C:22]2([NH2:26])[CH2:23][O:24][CH2:25]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C4(NS(=O)C(C)(C)C)COC4)ccc3c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C4(N)COC4)ccc3c2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid {3-[6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-oxetan-3-yl}-amide (86 mg, 0.19 mmol) in methylene chloride (2 mL, 30 mmol) was added 2.0 M of hydrogen chloride in ether (0.188 mL, 0.376 mmol) and was stirred 10 min. A precipitate formed and cyclohexane was added to dilute the mixture. After removal of solvent, the residue was dissolved in methylene chloride, 1 M aq. NH4OH was added and the extracted organic layer was dried and chromatographed with MeOH/CH2Cl2 (20-40%) to give 3-(6-(trans-4-tert-butylcyclohexyloxy)naphthalen-2-yl)oxetan-3-amine as a solid (44.8 mg, 67%). LCMS: Rf=1.55 min 337.20 ([M−16]). 1H NMR (400 MHz, CHLOROFORM-d) δ=7.84 (d, J=1.4 Hz, 1H), 7.81-7.70 (m, 2H), 7.66 (d, J=1.9 Hz, 1H), 7.22-7.12 (m, 2H), 5.09 (d, J=6.7 Hz, 2H), 4.81 (d, J=6.7 Hz, 2H), 4.29 (tt, J=4.2, 10.8 Hz, 1H), 2.29 (d, J=13.2 Hz, 2H), 1.91 (d, J=12.5 Hz, 2H), 1.56-1.39 (m, 2H), 1.29-1.02 (m, 3H), 0.91 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:8]([F:14])([F:13])[CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:5][C:4]=2[C:3]=1[OH:23].[CH2:24]([CH:29]1[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]1)[CH2:25][CH2:26][CH2:27][CH3:28].C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:24]([CH:29]1[CH2:30][CH2:31][CH:32]([C:35]([O:23][C:3]2[C:4]3[CH2:5][CH2:6][CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:8]([F:13])([F:14])[C:9]=3[CH:10]=[C:11]([F:12])[C:2]=2[F:1])=[O:36])[CH2:33][CH2:34]1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCC1CCc2c(cc(F)c(F)c2O)C1(F)F
Reactant: CCCCCC1CCC(C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCCCCCCCC1CCc2c(cc(F)c(F)c2OC(=O)C2CCC(CCCCC)CC2)C1(F)F

Procedure:
From 2,3,5,5-tetrafluoro-6-octyl-5,6,7,8-tetrahydronaphthalen-1-ol and 4-pentylcyclohexanecarboxylic acid by means of DCC esterification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([F:16])[CH:11]=[C:12]([F:15])[CH:13]=2)[C:8]([S:17]([CH2:20][C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[O:22])(=[O:19])=[O:18])=[CH:7]1.C([N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:40]1[CH:44]=[C:43]([C:2]2[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=2)[CH2:5][N:6]2[C:14]3[C:9](=[C:10]([F:16])[CH:11]=[C:12]([F:15])[CH:13]=3)[C:8]([S:17]([CH2:20][C:21]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[O:26][N:25]=3)=[O:22])(=[O:18])=[O:19])=[CH:7]2)[CH:42]=[N:41]1
Reactant: Cc1cc(NC(=O)CS(=O)(=O)c2cn(Cc3cccc(Br)c3)c3cc(F)cc(F)c23)no1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)CS(=O)(=O)c2cn(Cc3cccc(-c4cn[nH]c4)c3)c3cc(F)cc(F)c23)no1
Temperature: 80 °C
Reaction time: 8 h
Yield: 2.1 %

Procedure:
In a 5 mL microwave vial, 2-((1-(3-bromobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(5-methyl-isoxazol-3-yl)acetamide (20 mg, 0.38 mmol), prepared in Example 1, was dissolved in DMF (2 mL). PdCl2(PPh3)2 (1.0 mg, 0.001 mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (20 mg, 0.68 mmol), and 2 N aqueous sodium carbonate (1 mL) were added and stirred at 80° C. overnight. The reaction was cooled to ambient temperature. Water (2 mL) was added and the mixture was extracted with ethyl acetate (2×3 mL). The organics were combined, dried over magnesium sulfate and concentrated in vacuo to give an oily residue which was purified on a Gilson Prep HPLC system (5-95% acetonitrile:water (0.1% TFA) over 6 min) to afford the title compound (4.0 mg, 0.008 mmol, 21% yield) as a white solid. LCMS>98% 220 nm, RT=0.79 min, m/z=512 (m+1). 1H NMR (400 MHz, DMSOD6) 12.97 (s, 1H), 11.33 (s, 1H), 8.38 (s, 1H), 8.16, (s, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 7.49-7.55 (m, 2H), 7.28 (t, J=8.0 Hz, 1H), 7.18 (d, J=10.8 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.48 (s, 1H), 5.52 (s, 2H), 4.48 (s, 2H), 2.35 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([C:23](=O)[CH2:24][CH3:25])=[CH:4][CH:3]=1.Cl.[CH3:28][O:29][NH2:30].N1C=CC=CC=1>C(O)C>[CH3:28][O:29]/[N:30]=[C:23](\[C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)/[CH2:24][CH3:25]
Reactant: CON
Reactant: CCC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC/C(=N/OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 80 °C
Reaction time: 26 h

Procedure:
A mixture of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-one (630 mg, 1.54 mmol), O-methylhydroxylamine hydrochloride (386 mg, 4.62 mmol) and pyridine (3.9 mL) in ethanol (16 mL) was stirred at 80° C. for 26 hr. The mixture was concentrated in vacuo, diluted with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethanol/ethyl acetate to give the title compounds as a colorless crystal respectively (E (Example 121): 266 mg, 0.608 mmol, 39%, Z (Example 122): 159 mg, 0.363 mmol, 24%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:21])[CH3:20]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH:19]([CH3:21])[CH3:20])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 22 °C
Reaction time: 24 h
Yield: 94.9 %

Procedure:
A suspended orange mixture of 5-fluoro-2-nitrophenol (XVIII, 10.0 g, 63.6 mmol), potassium carbonate (8.84 g, 64.0 mmol) and 2-bromopropane (6.00 mL, 63.6 mmol) in dimethyiformamide (63.0 mL) was stirred at 22° C. under argon. After 1 d, an additional 2.0 mL of 2-bromopropane was added and the resultant mixture was heated at 60° C. for 1 do The reaction mixture was then partitioned between methylene chloride and 3N NaOH. The organic layer was separated and the basic aqueous layer was extracted with additional methylene chloride. The combined organic solution was washed with water (5×200 mL), dried (MgSO4), filtered and concentrated to provide 12.02 g (95%) of an orange oil, 95% pure by GC, which was carried on without further purification. The structure was supported by MS and 90 MHz 1H NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[NH2:26])[C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]1=2)=[O:7].C(N(CC)C(C)C)(C)C.[CH3:36][C:37]1[CH:45]=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](Cl)=[O:40]>C(Cl)Cl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:23]=[CH:24][C:25]([NH:26][C:39](=[O:40])[C:38]4[CH:42]=[CH:43][CH:44]=[CH:45][C:37]=4[CH3:36])=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1N
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)ccc1NC(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.6 %

Procedure:
A mixture of 1.0 g of 5-(3-methoxy-4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.47 g of N,N-diisopropylethylamine and 0.56 g of 2-methylbenzoyl chloride in 25 ml of methylene chloride is stirred at room temperature for 18 hours. The reaction mixture is washed with water and saturated NaHCO3, dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. Hexane is added at the boil to give 1.27 g of the desired product as a crystalline solid, m.p. 209°-210° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[O:12][C@@H:13]([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CNN>C(Cl)Cl>[NH2:3][O:12][C@@H:13]([CH3:21])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: C[C@H](ON1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: CNN
Solvent: ClCCl
Product: C[C@H](ON)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-tert-butyl 2-((1,3-dioxoisoindolin-2-yl)oxy)propanoate (73.3 mg, 0.252 mmol) in DCM (Volume: 500 μL) at 0° C. was added methyl hydrazine (13.5 μL, 0.252 mmol). After stirring for 3 h at 0° C., the solids were filtered off and the filtrate was concentrated in vacuo, affording the title compound (assumed quantitative) as a clear oil.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][OH:9])=[CH:6][C:5]([F:10])=[C:4]([Cl:11])[N:3]=1.CCN(CC)CC.C(O)=O>O1CCOCC1.O.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>[Cl:11][C:4]1[N:3]=[CH:2][C:7]([CH2:8][OH:9])=[CH:6][C:5]=1[F:10]
Reactant: OCc1cc(F)c(Cl)nc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O=CO
Product: OCc1cnc(Cl)c(F)c1
Temperature: 110 °C
Yield: 55.1 %

Procedure:
To a solution of (2,6-dichloro-5-fluoro-3-pyridinyl)methanol (4.4 g, 22.45 mmol) in 1,4-dioxane (20 ml) was added Et3N (3.42 ml, 24.69 mmol), formic acid (0.947 ml, 24.69 mmol) and Pd(PPh3)4 (1.297 g, 1.122 mmol). The mixture was then heated at 110° C. for 6 h in a pressure tube. The crude was diluted with H2O and extracted twice with EtOAc. The combined organic phases were washed with H2O and sat. NaCl, dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography using Flashmaster II, a 70 g spherical silica gel cartridge and DCM/MeOH 98:2 as eluent to give 2.0 g (41%) of the title compound pure enough to be used in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=O)[CH2:8][C:9](=O)[CH3:10])[CH:2]=1.O.[NH2:14][NH2:15]>CO>[CH3:10][C:9]1[CH:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[NH:14][N:15]=1
Reactant: NN
Reactant: CC(=O)CC(=O)c1cccnc1
Solvent: CO
Solvent: O
Product: Cc1cc(-c2cccnc2)[nH]n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Pyridin-3-yl-butane-1,3-dione (step 1) (500 mg, 3.06 mmol) was dissolved in MeOH (20 ml). Hydrazine monohydrate (230 mg, 223 μl, 4.60 mmol) was added and the resulting mixture was stirred at RT for 1 hour. After cooling to RT, the solvent was removed in vacuo. The crude residue was dissolved in DCM, dried over (MgSO4) filtered and concentrated in vacuo to afford the title compound which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:27])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([O:17][C:18]([NH:20][C:21]([CH2:23][Cl:24])=[O:22])=[O:19])[C@H:10]1[O:25][CH3:26])[CH3:8].[ClH:28]>CO>[Cl:24][CH2:23][C:21]([NH:20][C:18]([O:17][CH:11]1[CH2:12][CH2:13][C:14]([CH2:15][Cl:28])([OH:16])[CH:9]([C:6]2([CH3:8])[O:7][CH:5]2[CH2:4][CH:3]=[C:2]([CH3:1])[CH3:27])[CH:10]1[O:25][CH3:26])=[O:19])=[O:22]
Reactant: Cl
Reactant: CO[C@@H]1[C@H](OC(=O)NC(=O)CCl)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Solvent: CO
Product: COC1C(OC(=O)NC(=O)CCl)CCC(O)(CCl)C1C1(C)OC1CC=C(C)C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of O-(chloroacetylcarbamoyl)fumagillol (100 mg) in methanol (2 ml) was added 0.4N hydrochloric acid (1 ml), which was stirred for one hour at room temperatures. Resulting precipitates were collected by filtration and recrystallized from methanol-water to afford 4-O-(chloroacetylcarbamoyl)-2(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1,4-cyclohexanediol (96 mg, yield 90%) colorless crystals.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][C:15]2([CH2:21][CH:22]=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=[C:8]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:7]=1)(=[O:3])[CH3:2].[NH:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=2)[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(O)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][C:15]2([CH2:21][CH2:22][N:29]3[CH2:34][CH2:33][CH:32]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=4)[CH2:31][CH2:30]3)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:9]=[C:8]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CC=O)CCCCC2)c1
Reactant: Cc1ccc(NC2CCNCC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(=O)OCc1cc(COC(C)=O)cc(OCCC2(CCN3CCC(Nc4ccc(C)cn4)CC3)CCCCC2)c1
Reaction time: 0.75 h
Yield: 82.8 %

Procedure:
1,3-Diacetoxymethyl-5-[2-[1-(formylmethyl)cyclohexyl]ethoxy]benzene (synthesized in Example 32) (215 mg) and 2-(piperidin-4-ylamino)-5-methylpyridine (synthesized in Preparation Example 4-3) (126 mg) were dissolved in 1,2-dichloroethane (5 mL). To this was added acetic acid (0.04 mL) at room temperature. The solution was stirred for 45 minutes. Sodium triacetoxyborohydride (295 mg) was added to the solution at room temperature and it was stirred for 3 hours. Saturated aqueous sodium bicarbonate solution was added to the solution and it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, chloroform-methanol (10:1)] to give the title compound (258 mg).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[CH:27]=[C:26]([CH3:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[CH3:28][C:26]1[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][N:23]=[C:22]([NH:21][CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH:27]=1.[ClH:32]
Reactant: Cc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NC2CCNCC2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (1 mL) is added to a solution of 4-(4-methyl-5-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (170 mg; 0.51 mmol, prepared in accordance with Example 69) in dichloromethane (5 mL) under stiffing and the resulting mixture is stirred for 30 minutes at room temperature. The mixture is then concentrated under reduced pressure and co-evaporated with dichloromethane (2×10 mL). The residue obtained is diluted in dioxane (3 mL) and a 4N solution of hydrochloric acid in dioxane (3 mL) is added. The precipitate formed is filtered and is triturated with a small volume of acetone and dried under high vacuum to afford the desired product as hydrochloride (120 mg; 0.44 mmol).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:29])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[NH:20][C:19]2=[O:28])[CH:12]=1.CO.[Li+].[OH-].Cl>O>[F:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:28])[C:18]2=[CH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[C:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])=[O:29]
Reactant: COC(=O)CCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
6-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)hexanoic acid methyl ester (410 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (289 mg, 73% yield) as a brown solid. LC-MS (m/z) 397 (M+1).
Reaction SMILES: [NH2-].[Li+].N.[Li].Cl[CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([C:20]1[CH:28]=[CH:27][C:23]([CH2:24][C:25]#[CH:26])=[CH:22][CH:21]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:12]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][C:25]#[C:26][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:27][CH:28]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C#CCc1ccc(CCCCCCCC)cc1
Reactant: O=C(O)CCCCl
Agent: N
Agent: [Li+]
Agent: [Li]
Product: CCCCCCCCc1ccc(CC#CCCCC(=O)O)cc1

Procedure:
A solution of lithium amide in liquid ammonia is prepared by the addition of lithium metal (2 mmoles) to liquid ammonia containing a trace amount of ferrous sulfate. To this solution is added 4-chlorobutyric acid (1 mmole) and p-(n-octyl)benzylacetylene (1 mmole, prepared as described in paragraph B of this example). After a suitable time at refluxing liquid ammonia temperatures, the ammonia is removed by evaporation and the residue dissolved in 10% sodium hydroxide solution. After extraction with ether, the aqueous layer is acidified to a pH of 2-3 with concentrated hydrochloric acid, and extracted with methylene chloride. The methylene chloride layer is separated and the solvent removed by evaporation to give a residue. This residue is purified either by column chromatography or molecular distillation under reduced pressure to afford the desired title product, 7-[p-(n-octyl)phenyl]hept-5-ynoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=3[CH3:24])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](Cl)=[O:39]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[C:21]([NH:23][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][CH:43]=[C:35]([Cl:34])[CH:36]=4)[CH:20]=[CH:19][C:18]=3[CH3:24])[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cncc2c(COc3cc(N)ccc3C)csc12
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1cncc2c(COc3cc(NC(=O)c4cccc(Cl)c4)ccc3C)csc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(5-amino-2-methyl-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (346.7 mg, 1.01 mmol) (from Example 23 supra) in THF (20 mL) were added diisopropylethylamine (258 mg, 2.03 mmol) (Aldrich) and then 3-chlorobenzoyl chloride (265 mg, 1.51 mmol) (Aldrich). The reaction was stirred at room temperature for 30 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (200 mL), washed with aqueous 1N NaOH (15 mL), brine (2×15 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (CH2Cl2/MeOH, 99/1 to 95/5) to give 3-[5-(3-chloro-benzoylamino)-2-methyl-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 468 mg, 97%).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[C:19]([C:22]([O:24][CH3:25])=[O:23])[CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br.CCCCCC.[K+].[Br-]>O>[C:22]([C:19]1[CH:20]=[CH:21][C:13]2[O:12][CH:11]([CH2:10][CH2:9][OH:1])[C:16](=[O:17])[N:15]([CH2:30][C:29]3[CH:32]=[CH:33][CH:34]=[C:27]([Cl:26])[CH:28]=3)[C:14]=2[CH:18]=1)([O:24][CH3:25])=[O:23]
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(CCO[Si](C)(C)C(C)(C)C)O2
Reactant: Clc1cccc(CBr)c1
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Product: COC(=O)c1ccc2c(c1)N(Cc1cccc(Cl)c1)C(=O)C(CCO)O2

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-6-carbomethoxy-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 3-chlorobenzyl bromide, in 70% overall yield as a white solid, after trituration with hexane, IR (KBr) 3468, 2952, 1688, 1452, 1285, 1260, 765 cm-1 ; 1H NMR (CDCl3) δ 1.61 (br s, 1H plus HDO), 2.17-2.39 (m, 2H), 3.86 (s, 3H), 3.93 (t, J=5.7 Hz, 2H), 4.94 (dd, J=7.6, 5.5 Hz, 1H), 5.16 (s, 2H), 7.04 (d, J=8.4, 1H), 7.15-7.33 (m, 4H), 7.59 (d, J=1.8 Hz, 1H), 7.71 (dd, J=8.4, 1.8 Hz, 1H); MH+ at m/z=376; Anal. Calc'd for C19 H18ClNO5.0.1 H2O: C, 60.44; H, 4.86; N, 3.71. Found: C, 60.26; H, 4.60; N, 3.58.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:22])[Cl:21])[CH:14]=[C:13]([Cl:23])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH:11]=O.Cl.[Cl:25][C:26]([Cl:31])=[CH:27][CH2:28][O:29][NH2:30].Cl>N1C=CC=CC=1>[Cl:25][C:26]([Cl:31])=[CH:27][CH2:28][O:29][N:30]=[CH:11][CH2:10][O:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:13]([Cl:23])=[CH:14][C:15]([O:17][CH2:18][CH:19]=[C:20]([Cl:21])[Cl:22])=[CH:16][C:2]=1[Cl:1]
Reactant: NOCC=C(Cl)Cl
Reactant: O=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: ClC(Cl)=CCON=CCOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.6 %

Procedure:
To a mixture of 0.37 g of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyl-oxy)phenoxy)butyloxyacetaldehyde and 10 ml of pyridine was added 0.20 g of O-(3,3-dichloro-2-propenyl)hydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.39 g (yield, 74%) of 4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde O-(3,3-dichloro-2-propenyl)oxime, nD24.0 1.5489.
Reaction SMILES: C([O:5][C:6](=[O:32])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])=[CH:18][N:17]=2)=[C:11]([F:31])[CH:10]=1)CCC.[OH-].[Na+]>CCO>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:12]2[CH:13]=[CH:14][C:9](/[CH:8]=[CH:7]/[C:6]([OH:32])=[O:5])=[CH:10][C:11]=2[F:31])=[N:17][CH:18]=1
Reactant: CCCCOC(=O)/C=C/c1ccc(Oc2ccc(OCc3ccccc3Cl)cn2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)/C=C/c1ccc(Oc2ccc(OCc3ccccc3Cl)cn2)c(F)c1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
To an EtOH (40 mL) solution of the ester was added 5 M NaOH (6.9 mL), and stirred for 2.5 hours at 50° C., then EtOH was evaporated. The residue was dissolved in water, and acidified with 6 M HCl. The resulting precipitate was collected by filtration and dried to afford (E)-3-[4-({5-[(2-Chlorobenzyl)oxy]pyridin-2-yl}oxy)-3-fluorophenyl]prop-2-enoic acid as a white powder (2.78 g).