Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])[NH:8]2)=[CH:4][C:3]=1[C:29]([O:31]CC)=[O:30].B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:16])([F:15])[F:17])[NH:8]2)=[CH:4][C:3]=1[C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(NC(c1cccc(C(F)(F)F)c1)C(F)(F)F)c1cc2cc(C(=O)O)c(Cl)cc2[nH]1
Temperature: -10 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
Ethyl 6-chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate (2.90 g, 5.0 mmol, 85% pure) was dissolved in 5 ml of dichloromethane and a solution of boron tribromide in dichloromethane (27.5 ml, 27.5 mmol) was added dropwise at −10° C. The reaction mixture was stirred at −10° C. for 1 h and then at room temperature for 2 h. Water was added and the precipitated solid was filtered off with suction and dried. 1.85 g (79% of theory) of 6-chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylic acid were obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([OH:14])=[CH:6][C:4]1=[O:5])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH2:1]([N:3]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([OH:14])=[C:6]([N+:15]([O-:17])=[O:16])[C:4]1=[O:5])[CH3:2]
Reactant: CCn1c2c(c(O)cc1=O)CCCC2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCn1c2c(c(O)c([N+](=O)[O-])c1=O)CCCC2
Temperature: 100 °C

Procedure:
A suspension of 1-ethyl-4-hydroxy-5,6,7,8-tetrahydrocarbostyril (1.74 g; 0.009 mole) in glacial acetic acid (10 ml) was solubilised with concentrated nitric acid (2.5 ml; d 1.42) and the mixture heated for a few minutes at 100° C. After cooling and dilution with water a yellow crystalline solid separated. On recrystallisation from ethanol it had m.p. 152° - 154° C (d).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:15]([C:16](=[O:18])[CH3:17])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)C)C.O.CO[CH:35](OC)[N:36]([CH3:38])[CH3:37]>>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)[C:15]([C:16](=[O:18])/[CH:17]=[CH:35]/[N:36]([CH3:38])[CH3:37])=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)cccc12
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)/C=C/C(=O)c1c(-c2ccc(F)cc2)nn2c(NC3CCCC3)cccc12
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (3.1 g, 9.2 mmol) in N,N-dimethylformamide dimethyl acetal (25 mL) was heated to reflux for 6 days. The mixture was cooled to room temperature, ethylacetate was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (ethyl acetate) provided (2E)-1-[7-(cyclopentylamino)-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (3.6 g, 99%) as a tinted oil. 1H NMR (CDCl3): δ 7.73-7.61 (m, 4 H), 7.32 (t, 1 H), 7.14 (t, 2 H), 6.03 (d, 1 H), 5.96 (d, 1 H), 5.05 (d, 1 H), 3.99 (m, 1 H), 5.15-2.42 (broad, 6 H), 2.19-2.08 (m, 2 H), 1.86-1.62 (m, 6 H); 19F NMR (CDCl3) δ −113.75; MS m/z 393 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.O.[Cl-].[NH4+]>C(O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[C:4]([OH:11])[CH:3]=[C:2]([Br:1])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)cc(Br)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(O)cc(Br)c1

Procedure:
To a solution of 3-bromo-5-nitro-phenol (16.9 g, 77.52 mmol, commercially available [CAS 116632-23-6 {Specs}]) in ethanol (300 ml) and water (100 ml) was added solid ammonium chloride (16.59 g, 310 mmol) and then powdered electrolytic iron (34.4 g, 698 mmol). The material was heated from ambient to reflux temperature (oil bath). The material was refluxed for 3 hours and then filtered, hot, through a plug of celite, washing well with several volumes of hot EtOAc. The solvent was stripped and the remainder was taken up in EtOAc (150 ml) and water (150 ml) and the material shaken. The organic phase was collected and washed with brine (150 ml). The aqueous phases were back extracted with EtOAc (2×100 ml). The organics were combined, dried (MgSO4), filtered and stripped to provide a crude oil. The material was adsorbed onto silica (50 g) and purified by silica gel chromatography, eluting with 15% to 50% ethyl acetate in hexanes to afford 10.35 g of 3-amino-5-bromo-phenol as a dark golden-brown viscous oil.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([NH:5][CH2:6][CH2:7][O:8][CH2:9][C:10]#[C:11][CH2:12][C:13]1[C:14](=[O:27])[NH:15][C:16](=[O:26])[N:17]([CH:25]=1)[C@@H:18]1[O:24][C@H:21]([CH2:22][OH:23])[CH2:20][CH2:19]1)=[O:4].O=P(Cl)(Cl)Cl.[P:35](OC)([O:39]C)([O:37]C)=[O:36]>>[P:35]([O:23][CH2:22][C@H:21]1[O:24][C@@H:18]([N:17]2[CH:25]=[C:13]([CH2:12][C:11]#[C:10][CH2:9][O:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:28])([F:1])[F:29])[C:14](=[O:27])[NH:15][C:16]2=[O:26])[CH2:19][CH2:20]1)([OH:39])([OH:37])=[O:36]
Reactant: COP(=O)(OC)OC
Reactant: O=C(NCCOCC#CCc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(NCCOCC#CCc1cn([C@H]2CC[C@@H](COP(=O)(O)O)O2)c(=O)[nH]c1=O)C(F)(F)F
Reaction time: 2.5 h

Procedure:
To a solution of 5 (30 mg, 0.0738 mmol) in P(O)(OCH3)3 (0.5 mL) was treated with POCl3 (70 μL, 0.73 mmol) at 0° C., followed by stirring at r.t for 2-3 h and then evaporating solvent under reduced pressure and purification by preparative reverse phase HPLC to afford the corresponding mono phosphate 6. 31P NMR (CD3OD, 121.4 MHz) δ 0.79 (s); 19F NMR (CDCl3, 282.2 MHz) δ −77.37 (s, CF3). To a dried solution of 6 in DMF (1 mL) were added 1,1′-carbonyldiimidazole (CDI, 33 mg, 0.21 mmol), followed by stirring at r.t. for 5 h and then quenching with MeOH (8 μL, 0.21 mmol). A solution of tetrabutylammonium pyrophosphate (TBAPP, 143.0 mg, 0.33 mmol) and tributyl amine (0.15 mL, 0.66 mmol) in DMF (1.5 mL) was added to the above solution at r.t under Ar, followed by stirring overnight and then quenched with 2.0 M TEAB. After evaporating solvent, the organic residue was purified by preparative reverse phase HPLC with 100 mM TEAA/AcCN (0 to 50% gradient) to give the corresponding triphosphate 7. 1H NMR (D2O, 300 MHz) δ 7.74 (s, 1H, H6), 5.95 (dd, 1H, H1′, J=3.3 and 6.3 Hz), 4.29-4.20 (m, 1H, H4′), 4.18-4.07 (m, 3H, CH2 and H5′), 4.02-3.92 (m, 1H, H5′), 3.58 (t, 2H, CH2, J=5.1 Hz), 3.38 (t, 2H, CH2, J=5.1 Hz), 3.20 (s, 2H, CH2), 2.35-2.22 (m, 1H, H2′), 2.10-1.92 (m, 3H, H2′ and 2H3′). 31P NMR (D2O, 121.4 MHz) δ −10.52 (d, J=19.2 Hz), −10.95 (d, J=20.3 Hz), −22.96 (t, J=20.3 Hz); 19F NMR (D2O, 282.2 MHz) δ −76.37 (s, CF3). Removal of trifluro acetate (TFA) protecting group was accomplished by treatment with NH4OH (33%, 500 μL) at 60° C. for 20 min and then at r.t for 1 h to give the corresponding triphosphate 8 (17 mM, 500 μL).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]([O:15][CH3:16])=[O:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[S:41]([C:45]1[CH:46]=[N:47][CH:48]=[C:49]([CH:53]=1)[C:50](O)=[O:51])(=[O:44])(=[O:43])[NH2:42]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:7]1([C:4]2[CH:5]=[CH:6][N:2]([NH:1][C:50](=[O:51])[C:49]3[CH:53]=[C:45]([S:41](=[O:43])(=[O:44])[NH2:42])[CH:46]=[N:47][CH:48]=3)[C:3]=2[C:13]([O:15][CH3:16])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)c1c(-c2ccccc2)ccn1N
Reactant: NS(=O)(=O)c1cncc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2)ccn1NC(=O)c1cncc(S(N)(=O)=O)c1
Reaction time: 0.25 h
Yield: 32.4 %

Procedure:
To a stirred solution of methyl 1-amino-3-phenyl-1H-pyrrole-2-carboxylate (2.00 g, 9.25 mmol) in DMF (20 mL) was added DMAP (3.39 g, 27.7 mmol) and HATU (10.6 g, 27.7 mmol). The reaction mixture was stirred for 15 minutes and a solution of 5-sulfamoylnicotinic acid (3.74 g, 18.5 mmol) dissolved in DMF was added. The reaction mixture was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure to remove DMF and saturated solution of citric acid was added to the residue until the pH was 3. The solution was extracted with CH2Cl2 and the organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using CombiFlash (REDISEP®, neutral alumina, 40 g, 13% methanol in CH2Cl2) to afford methyl 3-phenyl-1-(5-sulfamoylnicotinamido)-1H-pyrrole-2-carboxylate (1.20 g, 32.4%). LCMS Condition B-39: retention time 1.79 min, [M−1]=399.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.54 (s, 3H), 6.34 (d, J=3.2 Hz, 1H), 7.32-7.44 (m, 7H), 7.80 (br s, 2H), 8.68 (t, J=2.0 Hz, 1H), 9.20 (d, J=2.0 Hz, 1H), 9.30 (d, J=2.0 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.Cl.C1C[O:19][CH2:18][CH2:17]1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:13][C:6]1([CH3:14])[C:5]2[C:10](=[CH:11][C:2]([C:18](=[O:19])[CH3:17])=[CH:3][CH:4]=2)[C:9](=[O:12])[CH2:8][CH2:7]1
Reactant: C1CCOC1
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)c1ccc2c(c1)C(=O)CCC2(C)C
Reaction time: 0.17 h

Procedure:
A solution of 4,4-dimethyl-7-bromo-3,4-dihydronaphthalen-1(2H)one (Compound G) (1.78 g, 7 mmol), 1-ethoxyyinyltributyltin (EVTB) (3.3 g, 9.12 mmol), bis(triphenylphosphine)palladium(II)chloride (260 mg, 0.23 nmol) in THF (25 mL) was refluxed for 24 h under argon atmosphere. To the reaction, additional EVTB (1.5 g, 4.1 mmol) and bis(triphenylphosphine)palladium(II)chloride (200 mg, 0.2 mmol) were added and the mixture was and refluxed for an additional 24 h. The reaction mixture was cooled to room temeperature and 10% hydrochloric acid (10 ml) was added. After 10 min, the mixture was extracted with ether (3×50 mL), the combined organic layer was washed with water (10 mL), 10% sodiumbicarbonate (10 mL), brine (10 mL), dried with magnesium sulfate. Solvent was removed under reduced pressure, and after purification by flash chromatography the title compound was obtained as a white solid.
Reaction SMILES: C([N:8]([C:20](=[O:54])[CH2:21][CH2:22][C:23]1[C:28]([CH3:29])=[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([P:42]([CH2:46][CH3:47])([CH2:44][CH3:45])=[O:43])[P:36]([CH2:40][CH3:41])([CH2:38][CH3:39])=[O:37])[C:26]([CH3:48])=[CH:25][C:24]=1[O:49][C:50](=[O:53])[CH2:51][CH3:52])[C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:50]([O:49][C:24]1[CH:25]=[C:26]([CH3:48])[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]([P:36]([CH2:38][CH3:39])([CH2:40][CH3:41])=[O:37])[P:42]([CH2:44][CH3:45])([CH2:46][CH3:47])=[O:43])=[C:28]([CH3:29])[C:23]=1[CH2:22][CH2:21][C:20]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:54])(=[O:53])[CH2:51][CH3:52]
Reactant: CCC(=O)Oc1cc(C)c(OCCCCC(P(=O)(CC)CC)P(=O)(CC)CC)c(C)c1CCC(=O)N(Cc1ccccc1)[C@@H](Cc1ccccc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(=O)Oc1cc(C)c(OCCCCC(P(=O)(CC)CC)P(=O)(CC)CC)c(C)c1CCC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 3 h

Procedure:
Compound 135 (272 mg, 0.335 mmol) was treated with a 50% v/v solution of TFA in CH2Cl2 (4 mL). After stirring for 3 hr the reaction mixture was concentrated to dryness and coevaporated with toluene. After drying under vacuum, acid 136 was obtained as a colorless liquid (304 mg, 120%) and was used without purification. 1H NMR (400 MHz, CDCl3) δ 1.25 (t, J=7.3, 3H), 1.32-1.37 (m, 12H), 1.70-1.81 (m, 4H), 1.93-2.02 (m, 2H), 2.13 (s, 3H), 2.20 (s, 3H), 2.20-2.29 (m, 2H), 2.47 (tt, J=5.8, 24.5, 1H), 2.57 (q, J=7.7, 2H), 2.74-2.81 (m, 1H), 2.87-2.93 (m, 1H), 3.01 (dd, J=6.2, 14.0, 1H), 3.15 (dd, J=5.5, 14.0, 1H), 3.66 (t, J=6.8, 2H), 4.14-4.22 (m, 8H), 4.75-4.80 (m, 1H), 6.12 (d, J=7.6, 1H), 6.67 (s, 1H), 7.06-7.09 (m, 2H), 7.14-7.24 (m, 3H): 31P (162 MHz, CDCl3) δ 24.35 (s, 1 P), 24.39 (s, 1 P).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[CH2:32][OH:33])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:27][CH3:28])=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:23])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH2:24][CH2:25][CH3:26])[CH:13]=1.[CH2:34]([Mg]Br)[CH3:35]>>[CH2:27]([C:11]1[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH2:34][CH3:35])([OH:23])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH2:24][CH2:25][CH3:26])=[CH:13][C:8]([O:7][CH2:6][C:5]2[CH:29]=[CH:30][C:31]([CH2:32][OH:33])=[C:3]([CH2:2][OH:1])[CH:4]=2)=[CH:9][CH:10]=1)[CH3:28]
Reactant: CC[Mg]Br
Reactant: CCCc1cc(C(=O)CC)ccc1-c1cc(OCc2ccc(CO)c(CO)c2)ccc1CC
Product: CCCc1cc(C(O)(CC)CC)ccc1-c1cc(OCc2ccc(CO)c(CO)c2)ccc1CC

Procedure:
In a manner similar to that of Example 1(q), by reacting 830 mg (1.9 mmol) of 1-{5′-[3,4-bis(hydroxymethyl)benzyloxy]-2′-ethyl-2-propylbiphenyl-4-yl}-1-propanone with 5.1 ml (15.2 mmol) of ethylmagnesium bromide (3M/ether), and after purification by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (40/60), 700 mg (77%) of {4-[6-ethyl-4′-(1-ethyl-1-hydroxypropyl)-2′-propylbiphenyl-3-yloxymethyl]-2-hydroxymethylphenyl}methanol are obtained in the form of white crystals with a melting point of 101° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccncc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccnc(N2CCOCC2)c1
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of 2-chloro, 4-nitropyridine (0.2 g, 1.27 mmol) in THF (3 mL) was added morpholine (328 mg, 38.1 mmol). The reaction was heated to 80 C and stirred overnight. The solvent was evaporated and the residue purified by column chromatography (2/1 Hex/EtOAc) to yield 150 mg of the target compound.
Reaction SMILES: Cl.[CH3:2][C@:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][NH:4]1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:2][C@:3]1([C:8]([O:10][CH3:11])=[O:9])[CH2:7][CH2:6][CH2:5][N:4]1[CH2:18][C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:22])[F:23])=[CH:21][CH:20]=1
Reactant: COC(=O)[C@@]1(C)CCCN1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)[C@@]1(C)CCCN1Cc1ccc(C(F)(F)F)cc1

Procedure:
The title compound (D80) (50 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from (R)-methyl 2-methylpyrrolidine-2-carboxylate hydrochloride (D50) (60 mg) and 4-(Trifluoromethyl)benzyl bromide (0.126 ml). (Na2CO3: 4 eq; reaction time 18 hrs; 68° C.)
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].CO.Cl>C1COCC1>[CH2:23]([O:22][C:20](=[O:21])[NH:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][OH:12])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CCCCCNC(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCCCCCCO)OCc1ccccc1
Reaction time: 4 h
Yield: 76.4 %

Procedure:
To a solution of diisobutylaluminum hydride (49 mL, 1.5 M in toluene) in THF (150 mL) cooled to −78° C. was added a solution of 6-benzyloxycarbonylamino-hexanoic acid methyl ester (10 g, 37 mmol) in THF (100 mL) . The reaction mixture was stirred for 4 h and methanol (2.5 mL) was added carefully at −78 to −75° C. After 2 h, the mixture was poured to 250 mL of 1 N HCl solution cooled in ice-bath, extracted with ethyl acetate (300 mL), washed with brine (3×100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, 50% ethyl acetate in hexane) to yield the titled compound (7.1 g, 80%); white solid, mp 67-68° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][N+]([O-])=O)[CH2:3][C:4]([O:6][CH3:7])=[O:5].C[O-].[Na+].[O:15]=[O+][O-]>CO>[CH3:1][CH:2]([CH:8]=[O:15])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: O=[O+][O-]
Reactant: COC(=O)CC(C)C[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CC(C)C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of methyl 3-methyl-4-nitrobutanoate (96 g, 0.596 m) in methanol (30 ml) is added dropwise to a solution of sodium methoxide (34.5 g, 0.638 m) in methanol (1 l) at room temperature under nitrogen. The resulting mixture is stirred for 1 hr., cooled to -78° C. and treated with one equivalent of ozone. The reaction mixture is then allowed to warm to room temperature and most of the solvent is removed in vacuo. The residue is filtered and the filtrate is treated with ether (500 ml). The organic phase is washed with water (3×200 ml), dried (Na2SO4) and the solvent is removed in vacuo to give the crude product, methyl 3-methyl-4-oxo-butanoate (86.3 g). This material is used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([Br:11])[C:3]=1[Br:12].[N:13]1[C:20](Cl)=[N:19][C:17](Cl)=[N:16][C:14]=1Cl>>[Br:1][C:2]1[C:7]([O:8][C:14]2[N:16]=[C:17]([O:8][C:7]3[C:2]([Br:1])=[C:3]([Br:12])[C:4]([Br:11])=[C:5]([Br:10])[C:6]=3[Br:9])[N:19]=[C:20]([O:8][C:7]3[C:6]([Br:9])=[C:5]([Br:10])[C:4]([Br:11])=[C:3]([Br:12])[C:2]=3[Br:1])[N:13]=2)=[C:6]([Br:9])[C:5]([Br:10])=[C:4]([Br:11])[C:3]=1[Br:12]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Oc1c(Br)c(Br)c(Br)c(Br)c1Br
Product: Brc1c(Br)c(Br)c(Oc2nc(Oc3c(Br)c(Br)c(Br)c(Br)c3Br)nc(Oc3c(Br)c(Br)c(Br)c(Br)c3Br)n2)c(Br)c1Br

Procedure:
Tris-(pentabromophenoxy)-s-triazine was prepared from pentabromophenol and cyanuric chloride using the process described in Example 1, above. The compound was found to have a melting point of 320°-325°C.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][OH:20])=[O:16])=[C:4]([I:23])[C:3]=1[NH:24][C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26].[OH-].[Na+].Br[CH2:54][CH2:55][OH:56]>O>[I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH2:12][OH:13])=[O:9])=[C:6]([I:14])[C:5]([C:15]([NH:17][CH:18]([CH2:21][OH:22])[CH2:19][OH:20])=[O:16])=[C:4]([I:23])[C:3]=1[N:24]([CH2:54][CH2:55][OH:56])[C:25]([NH:27][C:28]1[C:33]([I:34])=[C:32]([C:35]([NH:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40])=[O:36])[C:31]([I:43])=[C:30]([C:44]([NH:46][CH2:47][CH2:48][OH:49])=[O:45])[C:29]=1[I:50])=[O:26]
Reactant: OCCBr
Reactant: O=C(Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NC(CO)CO)c1I)Nc1c(I)c(C(=O)NCCO)c(I)c(C(=O)NC(CO)CO)c1I
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NCCO)c1c(I)c(NC(=O)N(CCO)c2c(I)c(C(=O)NCCO)c(I)c(C(=O)NC(CO)CO)c2I)c(I)c(C(=O)NC(CO)CO)c1I
Reaction time: 20 h

Procedure:
N,N'-bis[2,4,6-triiodo-3-(2-hydroxyethylaminocarbonyl)-5-(1,3-dihydroxyprop-2-ylaminocarbonyl)-phenyl]urea (0.27 g, 0.2 mmol) from Example 4 was dissolved in water (7 ml) containing 2M aqueous NaOH (1.0 ml) and 2-bromoethanol (0.084 ml, 1.2 mmol). After stirring for 20 h, the solution was neutralized with a strongly acidic cation exchange resin and evaporated to dryness. The residue was purified by preparative HPLC. Yield 138 mg (50%).
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH3:15])([CH3:6])([CH3:5])[CH3:4].Br[CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>O1CCCC1>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:9][C:8]=1[O:14][CH3:15])([CH3:6])([CH3:4])[CH3:5]
Reactant: COc1cc(O)ccc1C(C)(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(OCC(=O)OC(C)(C)C)ccc1C(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a suspension of 60% sodium hydride (96 mg, 2.4 mmol) in tetrahydrofuran (THF) (10 ml) was added 4-tert-butyl-3-methoxyphenol (360 mg, 2 mmol) at 0° C., followed by additional stirring for 30 minutes. Then, tert-butyl bromoacetate (468 mg, 2.4 mmol) was added and the mixture was refluxed at 80° C. for 1 hour. The reaction was then quenched with saturated aqueous solution of ammonium chloride and the crude product was extracted with ethylacetate. The organic layer was separated, washed with brine, dried over magnesium sulfate. Then, filtration, evaporation to remove the solvent under reduced pressure gave the residue, which was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and ethylacetate (20/1 to 4/1) to furnish 466 mg (79% yield) of the title compound as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=2[F:22])[C@@H:11]([CH3:23])[N:10]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:9]1=[O:29])(C)(C)C.[ClH:31]>CCOC(C)=O>[ClH:31].[NH2:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=2[F:22])[C@@H:11]([CH3:23])[N:10]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:9]1=[O:29]
Reactant: C[C@@H]1[C@H](c2c(F)ccc(F)c2F)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1[C@H](c2c(F)ccc(F)c2F)C[C@H](N)C(=O)N1CC(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl[(3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]carbamate (122 mg, 0.277 mmol) in EtOAc (10 mL) was saturated with HCl (g) and aged for 30 min. The resulting mixture was concentrated in vacuo to give the title compound. MS: m/z=341.1 (M+1); 1H NMR (500 MHz, CD3OD) δ 7.33 (qd, 1H, J=9.3, 4.9 Hz), 7.05 (tdd, 1H, J=9.8, 3.7, 2.2 Hz), 4.78 (dq, 1H, J=15.4, 9.3 Hz), 4.22 (dd, 1′-1, J=12.2, 6.6 Hz), 4.06 (ddd, 1H, J=13.3, 4.5, 2.7 Hz), 3.97 (m, 1H), 3.73 (dq, 1H, J=15.4, 8.8 Hz), 2.91 (qt, 1H, J=12.7, 3.1 Hz), 2.36 (ddd, 1H, J=12.7, 6.4, 2.0 Hz), 1.22 (d, 3H, J=6.6 Hz).