Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:28])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7][CH2:6]2)#[N:2].Cl.[NH2:30][OH:31].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:5](=[C:4]([CH3:28])[C:3]([C:1]([NH:30][OH:31])=[NH:2])=[CH:12][CH:11]=2)[CH2:6][CH2:7][N:8]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:20]
Reactant: CCOC(=O)CCCC1c2ccc(C#N)c(C)c2CCN1C(=O)OC(C)(C)C
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCCC1c2ccc(C(=N)NO)c(C)c2CCN1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 32 h
Yield: 86.4 %

Procedure:
A mixture of 1,1-dimethylethyl 6-cyano-1-[4-(ethyloxy)-4-oxobutyl]-5-methyl-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Preparation 26; 533 mg, 1.38 mmol), hydroxylamine hydrochloride (575 mg, 8.27 mmol) and sodium bicarbonate (695 mg, 8.27 mmol) in ethanol (15 ml) was stirred at 80° C. for 32 h. More hydroxylamine hydrochloride and sodium bicarbonate (3 equivalent of each) were added, and heating was continued at 80° C. overnight. More hydroxylamine hydrochloride and sodium bicarbonate (3 equivalent of each) were added, and heating was continued at 80° C. for 5.5 h. More hydroxylamine hydrochloride and sodium bicarbonate (3 equivalent of each) were added, and heating was continued at 80° C. overnight. The mixture was cooled to room temperature and the solid was filtered off and washed with ethanol. The filtrate and washings were combined, most of the solvent removed, and the residue dissolved in ethyl acetate. The solution was washed with brine, dried over MgSO4 and concentrated in vacuo to give the title compound (500 mg) as a pale yellow foam.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Br:14])[CH:5]1[CH2:15][C:16]([O:18]C)=O)(=[O:3])[CH3:2].C([N:23]1C=CC2C(=CC=CC=2Br)C1CC(OC)=O)(=O)C.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[Br:14][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][CH2:13][N:4]1[C:1](=[O:3])[CH2:2][NH:23][C:16](=[O:18])[CH:15]=[C:5]12
Reactant: COC(=O)CC1c2cccc(Br)c2CCN1C(C)=O
Reactant: COC(=O)CC1c2cccc(Br)c2C=CN1C(C)=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: O=C1C=C2c3cccc(Br)c3CCN2C(=O)CN1
Temperature: 25 °C

Procedure:
methyl 2-(2-acetyl-5-bromo-1,2,3,4-tetrahydroisoquinolin-1-yl)acetate. A stirred solution of methyl 2-(2-acetyl-5-bromo-1,2-dihydroisoquinolin-1-yl)acetate (147 g, 453 mmol), triethylsilane (388 g, 3333 mmol) and trifluoroacetic acid (266 mL, 3446 mmol) in 1,2-dichloroethane (1100 mL) was stirred at 80° C. for 3 h. The reaction mixture was cooled to rt and the solvent was evaporated under reduced pressure. The remaining volatile components were evaporated under high vacuo and 40° C. bath temperature. To the resulting yellow residue saturated aqueous NaHCO3 (500 mL) was added while stirring and the mixture was extracted with DCM (3×400 mL). The organic layer was washed with saturated aqueous NaHCO3 (300 mL) and brine (300 mL). The organic layer was treated with charcoal, then dried with sodium sulfate, filtered through a pad of Hyflo and the solvent was removed under reduced pressure. The crude product was crystallized from diethyl ether (300 mL) to yield the title compound as white crystals (90 g). UPLC-MS: MS 326.0/328.0 (M+H+); UPLC rt 0.94 min.
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH2:4]1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>C(#N)C>[CH2:12]([NH:19][CH2:2][CH:3]1[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH2:4]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: BrCC1Cc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: c1ccc(CNCC2Cc3ccccc3O2)cc1
Yield: 73 %

Procedure:
1.07 g (5.0 mmol) of compound 001C, which had been prepared in Step C of Reference Example 1, was dissolved in 11 ml of acetonitrile. To the resultant solution were added 1.64 ml (15.0 mmol) of benzylamine and 2.07 g (15.0 mmol) of potassium carbonate. The resultant mixture was stirred at 80° C. for 8 hours to effect a reaction. To the resultant reaction mixture was added 100 ml of chloroform to obtain a mixture. The obtained mixture was successively washed with 100 ml of water and 100 ml of saturated saline, to thereby form a chloroform layer containing the desired compound 002A, followed by separation of the chloroform layer. The chloroform layer thus separated was dehydrated by means of a Whatman 1PS filter paper and then, concentrated in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was applied to a column of 50 g of silica gel (Art. 9385, manufactured and sold by E. Merck, Darmstadt, Germany) and eluted with chloroform, to thereby obtain 873 mg of compound 002A as a yellow oily substance (yield: 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:21])[N:11]([C:18](Cl)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[N:22]1([CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.N1C=CC=CC=1>C1COCC1>[OH:32][CH:29]([CH2:28][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH2:30][O:31][C:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:21])=[O:19]
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Reactant: OCC(O)CN1CCOCC1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)CN3CCOCC3)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
A reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (150 mg, 0.5 mmol), 3-morpholin-4-yl-propane-1,2-diol, and pyridine in 3.0 mL of THF was stirred at room temperature for 15 min and filtered. The solid was then washed with ethyl acetate and ether to give 116 mg (55%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-3-morpholin-4-yl-propyl ester as an orange solid. 1HNMR (400 MHz, DMSO-d6) δ 12.06 (s, br, 1H, NH-1′), 10.47 (s, br, 1H, OH), 7.86–7.88 (m, 1H, H-4), 7.79–7.81 (m, 1H, H-7), 7.66 (s, 1H, H-vinyl), 7.19–7.23 (m, 2H, H-5, 6), 6.12 (d, J=2.34 Hz, 1H, H-4′), 4.35–4.45 (m, 3H), 3.75–3.98 (m, 4H), 3.26–3.51 (m, 7H), 2.37 (s, 3H, CH3), and 2.34 (s, 3H, CH3).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8]O>C(Cl)(Cl)(Cl)Cl>[Cl:5][C:6]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][Cl:3]
Reactant: CC(C)c1cccc(CO)c1Cl
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1cccc(CCl)c1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.7 %

Procedure:
At room temperature, 29.8 g of thionyl chloride is carefully dripped into 35 g of 2-chloro-3-isopropylbenzyl alcohol in 80 ml of carbon tetrachloride. The mixture is stirred for 15 hours at 25° C. and then evaporated down. Distillation (bp 0.3 :76°-78° C.) gives 33 g of 2-chloro-3-isopropylbenzyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:24]=[CH:25][CH3:26])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:24]=[CH:25][CH3:26])=[C:20]([NH:23][C:28]([O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[O:29])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC=Cc1c(N)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC=Cc1c(NC(=O)OCc2ccccc2)ccc2c1OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a solution of {(2R)-7-amino-8-[1-propenyl]-2,3-dihydro-1,4-benzo-dioxin-2-yl}methyl 4-methylbenzenesulfonate (4.20 g, 11.2 mmole) in ethyl acetate (150 mL) was added benzyl chloroformate (8.00 mL, 56.0 mmole). The reaction mixture was stirred under nitrogen for 0.5 hour, then a solution of N,N-diisopropylethylamine (9.75 mL, 56 mmole) in ethyl acetate (75 mL) was added dropwise over a period of 0.5 hour. The mixture was stirred at room temperature under nitrogen overnight. The reaction was diluted in volume to 350 ml and was then washed with 2N HCl (2×100 mL), saturated sodium bicarbonate (150 mL) and brine (100 mL), dried over magnesium sulfate, filtered and evaporated to an oil. The crude oil was column chromatographed on silica gel with 10% ethyl acetate/hexane to remove impurities and the product eluted with 60% ethyl acetate/hexane to give the (R)-enantiomer of the title compound as a yellow oil (4.5 g, 79%). 1H (CDCl3) doublet 7.8 δ (2 ); multiplet 7.4 δ (7H); doublet 6.7 δ (2H); multiplet 6.0-6.2 δ (2H); singlet 5.2 δ (2H); multiplet 4.4 δ (1H); multiplet 4.2 δ (3H); multiplet 4.0 δ (1H); singlet 2.4 δ (3H); doublet 1.9 δ (3H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH:33]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=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>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][CH2:8][C:5]2[N:4]=[N:3][C:2]([C:28]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH:29]=3)=[CH:7][CH:6]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(OCc2ccc(Cl)nn2)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(COc3ccc(S(C)(=O)=O)cc3)nn2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 13.8 %

Procedure:
To a solution of 3-chloro-6-(4-methanesulfonylphenoxymethyl)pyridazine (79 mg, 0.26 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (82 mg, 0.26 mmol) in dry N,N-dimethylformamide (3 mL) was added tetrakis(triphenylphosphine)palladium (9.0 mg, 7.9 μmol) and cesium carbonate (129 mg, 0.397 mmol). The mixture was stirred at 80° C. for 2 hours, allowed to cool to room temperature, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate=10/1 and hexane/ethyl acetate=1/2) to give the title compound as a white crystal (16 mg, yield 14%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13](=[O:15])[CH3:14].O.[C:17]([OH:21])(=[O:20])[CH:18]=O>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]/[C:13](=[O:15])/[CH:14]=[CH:18]/[C:17]([OH:21])=[O:20]
Reactant: COc1ccc(/C=C/C(C)=O)c(OC)c1
Reactant: O=CC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(/C=C/C(=O)/C=C/C(=O)O)c(OC)c1

Procedure:
A solution of 19 g (92 mmol) of (E)-4-(2,4-dimethoxyphenyl)but-3-en-2-one and 8.4 g (92 mmol) of glyoxylic acid monohydrate in 24 ml of acetic acid was heated at reflux for 20 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was extracted twice with 3N sodium hydroxide solution. The combined aqueous phases were treated with 3N hydrochloric acid to produce a strongly acidic reaction and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated. Crystallization of the residue from methylene chloride/ether/hexane yielded (E,E)-6-(2,4-dimethoxyphenyl)-4-oxo-2,5-hexadienoic acid of melting point 195°-200°.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:11]([CH2:12][N:13]=[N+]=[N-])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CCN(CC)CC.Cl[Sn]Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=2)=[CH:18][CH:19]=1
Reactant: [N-]=[N+]=NCc1ccc(COc2ccc(Cl)cc2)cc1
Agent: Cl[Sn]Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: NCc1ccc(COc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
4-(4-Chloro-phenoxymethyl)-benzylazide (3.2 g, 11.7 mmol) was dissolved in MeOH (50 mL). NEt3 (11.35 mL, 81.9 mmol) and SnCl2×2H2O (5.28 g, 23.4 mmol) were added and the exothermic reaction was stirred under reflux. When boiling ceased the mixture was heated to reflux for additional 45 min. After cooling to r.t. the mixture was filtered and the filtrate was evaporated to dryness. The residue was dissolved in CH2Cl2 (300 mL) and this solution was washed with sat. aq. NaHCO3-solution (1×100 mL), dried over Na2SO4, filtered and evaporated to dryness to give the title compound, pure enough for further reaction.
Reaction SMILES: [OH-].[K+:2].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([O:34]CC)=[O:33].[K+].CN1C2C(=CC(NC(C3C(C4C=CC=CC=4)=CC=C(C(F)(F)F)C=3)=O)=CC=2)C=C1C([O-])=O>O.CC(O)C>[K+:2].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]([C:16]3[C:17]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][CH:23]=4)=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:10][CH:11]=2)[CH:6]=[C:5]1[C:32]([O-:34])=[O:33]
Reactant: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1C
Agent: Cn1c(C(=O)[O-])cc2cc(NC(=O)c3cc(C(F)(F)F)ccc3-c3ccccc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cn1c(C(=O)[O-])cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
A solution of potassium hydroxide (54.1 g) in water (600 mL) was added over 15 minutes to a suspension of ethyl 1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylate (300 g), from the previous step, in propan-2-ol (4500 mL) at 60° C. and the resulting mixture was heated to reflux for an hour. The solution was seeded with product (1-methyl-5-[4-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid potassium salt) and the mixture granulated at 60-70° C. for two hours. The mixture was slowly cooled to 0-5° C. and the product potassium salt collected by filtration, washing with a chilled 90/10 mixture of propan-2-ol and demineralized water (510 mL total volume). The product solids were dried, yielding 1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid potassium salt 2.6 hydrate (287.4 g, 85% correcting for water content of 9.1% by weight). Anhydrous Mol wt of parent acid (calc) 438.41, MS: 439.3 (MH+), 437.3 (M−). 1H NMR (DMSO-d6): δ 3.99 (s, 3H), 6.53 (s, 1H), 7.12-7.76 (complex, 11H), 10.05 (broad), HPLC retention time 9.30 minutes. The preferred solid form of the product is characterized by the pXRD (powder X-ray diffraction) pattern shown in FIG. 7.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[N+:27](C1C=CC(C2CCC3C(=CC=C(O)C=3)O2)=CC=1)([O-:29])=[O:28]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: O=[N+]([O-])c1ccc(C2CCc3cc(O)ccc3O2)cc1
Product: O=[N+]([O-])c1ccc(C2CCc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3O2)cc1

Procedure:
5-Nitro-2-[2-(4-nitrophenyl)chroman-6-yloxy]pyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 2-(4-nitrophenyl)chroman-6-ol. 1H NMR (300 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1, 2.9 Hz), 8.29 (d, 2H, J 6.9 Hz), 7.76 (d, 2H, J 6.9 Hz), 7.21 (d, 1H, J 9.1 Hz), 6.98-7.02 (m, 3H), 5.35 (dd, 1H, J 9.9, 2.2 Hz), 2.96-3.05 (m, 1H), 2.73-2.78 (m, 1H), 2.24-2.29 (m, 1H), 1.96-2.04 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH:10][C@@H:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:9])[S:5][C:6]=1[Cl:7].C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:45]2[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=2)OC1>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:7][C:6]1[S:5][C:4]([C:8]([NH:10][C@@H:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:9])=[CH:3][C:2]=1[C:45]1[N:49]([CH3:50])[N:48]=[CH:47][CH:46]=1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Reactant: CC(C)(C)OC(=O)NC[C@H](Cc1ccccc1C(F)(F)F)NC(=O)c1cc(Br)c(Cl)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CNC(=O)OC(C)(C)C)Cc2ccccc2C(F)(F)F)sc1Cl
Reaction time: 12 h
Yield: 25.9 %

Procedure:
To a solution of 1,1-dimethylethyl {(2S)-2-{[(4-bromo-5-chloro-2-thienyl)carbonyl]amino}-3-[2-(trifluoromethyl)phenyl]propyl}carbamate (750 mg, 1.38 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (762 mg, 5.52 mmol), tetrakistriphenylphosphine Pd(0) (80 mg, 69 umol), and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (373 mg, 1.8 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 2 h where additional tetrakistriphenylphosphine Pd(0) (80 mg, 69 umol) and 5-(5,5-dimethyl-1,3,2-dioxaborinane-2-yl)-1-methyl-1H-pyrazole (373 mg, 1.8 mmol) were added. After 12 h, the solution was poured onto H2O (100 mL) and extracted with DCM. The organics were dried (Na2SO4), concentrated under vacuum, and purified on silica gel (hexanes/EtOAc, 1:1) to give the title compound (194 mg, 26%) as a white solid: LC-MS (ES) m/z=544.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[Br-].[C:15]1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li]CCCC>>[CH2:15]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: C=C1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.05 h

Procedure:
The title compound was prepared according to the procedure of Intermediate 71 starting from tert-butyl 3-oxopyrrolidine-1-carboxylate (0.8 g, 4.3 mmol), triphenylphosphonium bromide (2.31 g, 6.5 mmol) and n-BuLi (1.8 M; 2.4 mL, 6.5 mmol). Yield: 0.23 g (29%) after purification by flash chromatography with DCM as eluent. HPLC purity 99%, RT=2.28 min (System A; 10-97% MeCN over 3 min); 99%, RT=2.21 min (System B; 10-97% MeCN over 3 min). 1H NMR (400 MHz, CDCl3) δ ppm 1.23-1.40 (m, 9H) 2.42 (t, J=6.78 Hz, 2H) 3.31 (t, J=7.40 Hz, 2H) 3.71-3.85 (m, 2H) 4.74-4.91 (m, 2H). MS (ESI+) for C10H17NO2 m/z 128 (M-C4H8)+. *Previously reported in Tetrahedron 1997, 53, 539-556.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.[CH3:33][NH:34][O:35][CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OC(=O)C)C>CN(C)O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([N:34]([O:35][CH3:36])[CH3:33])=[O:16])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:24])([F:25])[F:23])[O:11][N:10]=1
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10.8 g (22.2 mmol) 3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid, 2.17 g (1 eq) N,O-Dimethylhydroxylamine and 8.42 g (1 eq) HBTU in dimethylhydroxylamine 3.68 mL DIPEA were added. The mixture was stirred overnight at r.t. The solvent was removed in the vacuum. The residue was resolved in ethylacetate and extracted with sodium hydrogen carbonate (5%, aq) and citric acid (5%, aq). The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in the vacuum. TLC (6:4 petrolether:ethylacetate) showed residual educt. The product was isolated by column chromatoghraphy (6:4) petrolether:ethylacetate). The product (example I-63) was dried under vacuum to yield 2.28 g (19%). Result of LC/MS MH+: 528.8; 1H NMR (DMSO-d6; CCl4): 3.08 (3H, s, CH3), 3.36 (3H, s, CH3), 7.40-7.81 (7H, m, CH-arom.), 8.39 (1H, s, CH-pyraz.)
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:19][C:20]([C@@H:22](/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C@@:23]([OH:34])([CH2:31][CH2:32][OH:33])[C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])[C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:54])C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C.O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:19][C:20]([C@H:22]([C@@:23]([OH:34])([CH2:31][C:32]([OH:33])=[O:54])[C:24]([OH:26])=[O:25])/[CH:35]=[CH:36]/[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43](=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:21])[C:14](=[O:18])[N:15]([CH3:16])[CH3:17])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)N(C)C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Solvent: O
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(=O)O)C(=O)O)C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
tert-Butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-dimethylcarbamoyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate (96.8 mg, 0.133 mmol) was dissolved in acetonitrile (2.0 mL) and water (0.6 mL), and 4-acetamide-2,2,6,6-tetramethylpiperidine-1-oxyl (4.3 mg, 19.9 μmol) and diacetoxyiodobenzene (85.7 mg, 0.266 mmol) were added. The mixture was stirred at room temperature for 4 hours. An aqueous solution of citric acid was added to the reaction mixture, which was followed by extraction with ethyl acetate. The organic extract was washed with sodium thiosulfate and a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in formic acid (4.0 mL) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified with preparative HPLC to obtain the title compound (43.2 mg).