Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([Br:14])=[C:10]([Cl:15])[CH:9]=2)[C:3]=1[C:16]([NH2:18])=[O:17].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>CCO.N1CCCCC1>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:4]2[C:3]([C:16]([NH2:18])=[O:17])=[C:2]([N:1]=[CH:24][C:23]3[CH:26]=[CH:27][C:20]([OH:19])=[CH:21][CH:22]=3)[NH:6][N:5]=2)=[CH:9][C:10]=1[Cl:15]
Reactant: O=Cc1ccc(O)cc1
Reactant: NC(=O)c1c(Nc2ccc(Br)c(Cl)c2)n[nH]c1N
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2ccc(Br)c(Cl)c2)n[nH]c1N=Cc1ccc(O)cc1

Procedure:
5-amino-3-((4-bromo-3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in 8 mL EtOH and 4-hydroxybenzaldehyde (194 mg, 1 eq.) and piperidine (4 drops) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((4-bromo-3-chlorophenyl)amino)-5-((4-hydroxybenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH to remove any excess 4-hydroxybenzaldehyde. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:11]=1[N:12]1[CH2:43][CH2:42][C:15]([CH3:44])([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([CH3:41])[O:22][C:23]2[CH:24]=[C:25]([F:40])[CH:26]=[CH:27][C:28]=2[CH2:29][CH:30]=[CH:31]3)[CH2:14][CH2:13]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C@@H:6]([C:10]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:11]=1[N:12]1[CH2:13][CH2:14][C:15]([CH3:44])([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([CH3:41])[O:22][C:23]2[CH:24]=[C:25]([F:40])[CH:26]=[CH:27][C:28]=2[CH2:29][CH2:30][CH2:31]3)[CH2:42][CH2:43]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1CC=C3
Agent: [Pd]
Agent: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1C/C=C/3
Solvent: CCOC(C)=O
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)ccc1CCC3
Reaction time: 16 h
Yield: 73.5 %

Procedure:
To a mixture of (2S)-2-(tert-butoxy)-2-[(10E,20S)-16-fluoro-4,20,26-trimethyl-19,25-dioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,10,13(18),14,16-octaen-3-yl]acetic acid (30 mg, 0.049 mmol) in ethyl acetate (1.5 mL) was added 10% Pd/C (5.24 mg, 4.93 μmol) and the resulting mixture was stirred under hydrogen balloon atmosphere for 16 h. At this point LCMS indicates completion of reaction. Mixture was then filtered and concentrated to afford (2S)-2-(tert-butoxy)-2-[(20S)-16-fluoro-4,20,26-trimethyl-19,25-dioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13(18),14,16-heptaen-3-yl]acetic acid (23 mg, 0.036 mmol, 72.6% yield) as white solid. 1H NMR (600 MHz, DMSO-d6) δ 7.14 (t, J=7.5 Hz, 1H), 6.88 (d, J=11.4 Hz, 1H), 6.61 (t, J=7.7 Hz, 1H), 6.23 (s, 1H), 5.62 (br. s., 1H), 4.60 (br. s., 1H), 4.31 (t, J=12.1 Hz, 1H), 2.79-2.73 (m, 1H), 2.70 (t, J=8.1 Hz, 2H), 2.56 (d, J=11.4 Hz, 1H), 2.46 (s, 3H), 2.20 (br. s., 1H), 1.91 (s, 1H), 1.84-1.75 (m, 3H), 1.70-1.62 (m, 5H), 1.56-1.44 (m, 3H), 1.18 (d, J=5.5 Hz, 3H), 1.16 (s, 3H), 1.13 (s, 9H). 4 piperidine hydrogens are missing. LCMS (M+H)=611.4.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([N+:17]([O-])=O)[CH:16]=1)[CH2:7][O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])([O-])=O.C([O-])(O)=O.[Na+]>CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([NH2:17])[CH:16]=1)[CH2:7][O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)COCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)COCc1cc(N)cc(N)c1
Yield: 64.3 %

Procedure:
A mixture of 2.1 (5.0 g, 18.5 mmol), SnCl2 dihydrate (48.0 g, 212.7 mmol) in 60 mL of methanol was refluxed for 40 minutes. The resulting dark solution was cooled (ice bath) and cautiously neutralized by adding saturated NaHCO3. The solid precipitate was filtered off and washed with methanol and CH2Cl2 until no product was found (by TLC) in the washings. The filtrate and washings were combined and evaporated in vacuo to give crude diamine 2.2. Chromatography on a silica gel column (4.5×20 cm) eluting with ethyl acetate afforded the title compound as a yellow oil (2.5 g, 64%), which slowly crystallized upon drying in vacuo: 1H NMR (CDCl3) δ 6.11 (d, J=2 Hz, 1H, C4 --H), 5.96 (t, J=2 Hz, 2H, C2 --H), 4.44 (s, 2H, CH2), 4.07 (s, 2H, CH2), 3.75 (s, 3H, CH3), 3.59 (br s, 4H, NH2); 13C NMR (CDCl3) δ 170.96, 147.78, 139.33, 105.51, 101.41, 73.31, 66.85, 51.89.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([CH:22]=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25](C3N=CN(C)C=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1)[CH2:2][CH3:3].Cl.[OH2:36]>C(#N)C.OO>[CH3:3][CH2:2][CH2:1][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([OH:23])=[O:36])=[CH:14][CH:15]=2)[C:7]2[CH:24]=[C:25]([C:4]3[N:8]([CH3:9])[C:7]4[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=4[N:5]=3)[CH:26]=[C:27]([CH3:28])[C:6]=2[N:5]=1
Reactant: O
Reactant: CCCc1nc2c(C)cc(-c3cn(C)cn3)cc2n1Cc1ccc(-c2ccccc2C=O)cc1
Agent: Cl
Agent: OO
Solvent: CC#N
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reaction time: 1.5 h

Procedure:
A solution of 156 mg of NaClO2.4H2O in 1 mL of water was added dropwise by canilla to a stirred mixture of 4′-[(2-n-propyl-4-methyl-6-(1-methyl-imidazol-4-yl)-benzimidazol-1-yl)methyl]-biphenyl-2-carboxaldehyde (230 mg) in 1 mL of acetonitrile, 0.16 ml of 10 solution of NaH2PO4 in water and 0.23 mL of 30% H2O2 at the temperature 10° C. pH of the mixture was adjusted to 2 with concentrated hydrochloric acid. Stirring was continued for 1.5 h at room temperature. Reaction mixture was poured in 1.2 mL of water, stirred for 15 minutes, product filtered, washed with water and dried in vacuo to yield 210 mg of telmisartan.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.C([Li])(C)(C)C.[Br-].[Mg+2].[Br-].Br[C:25]1[CH2:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2>CCOCC>[C:12]([C:4]1[CH:3]=[C:2]([C:25]2[CH2:33][C:32]3[C:27]([CH:26]=2)=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: BrC1=Cc2ccccc2C1
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Agent: [Br-]
Agent: [Li]C(C)(C)C
Agent: [Mg+2]
Solvent: CCOCC
Product: CC(C)(C)c1cc(C2=Cc3ccccc3C2)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
1-Bromo-3,5-di-t-butylbenzene (47.2 g, 0.175 mol) was dissolved in ether (500 mL) and cooled to −70° C. t-Butyllithium (200 mL of 1.7 M solution in pentane, 0.34 mol) was added at −70° C. over a two hour period. The solution was allowed to warm to room temperature slowly. Magnesium bromide etherate (46.5 g, 0.18 mol) was added and the slurry was stirred for one hour. The mixture was then cooled to 5° C. and 2-bromoindene (34.2 g, 0.18 mol) was added. The mixture was warmed to room temperature and then refluxed for three hours. The solution was cooled to room temperature and the reaction was quenched carefully with water. The layers were separated and the organics washed with salt brine and dried over magnesium sulfate. The solvents were evaporated and the product was distilled twice and recrystallized from hexane to give 37.1 g of product (70%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH2:9])[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:16][NH:17][C@H:18]([CH3:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC#N>[Cl:8][C:6]1[N:5]=[C:4]([NH2:9])[N:3]=[C:2]([N:17]([CH3:16])[C@H:18]([CH3:26])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=1
Reactant: CN[C@H](C)Cc1ccccc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@H](Cc1ccccc1)N(C)c1cc(Cl)nc(N)n1
Temperature: 140 °C
Reaction time: 2 h
Yield: 53.9 %

Procedure:
To a suspension of 4,6-dichloro-2-pyrimidinamine (1.0 g, 6.10 mmol) and K2CO3 (1.69 g, 12.2 mmol) in CH3CN (6.0 mL) was added (2R)—N-methyl-1-phenyl-2-propanamine (1.09 g, 7.32 mmol), and the reaction mixture was heated at 140° C. under microwave conditions with stirring for 2 hours. The mixture was filtered and washed by EtOAc (50 mL). The solution was concentrated, and the resulting residue was purified by reversed phase chromatography using CH3CN in water from 45% to 55% (0.5% ammonium hydrogen carbonate in water) to afford the title compound (910 mg) as a white solid. LC-MS (ES) m/z=277 [M+H]+.
Reaction SMILES: NC1C=CC(C(=O)C)=CC=1.Cl.C(OC(CC(OCC)=O)=N)C.[NH4+].[Cl-].[CH2:25]([O:27][C:28]([CH2:39][C:40]([O:42]CC)=O)=[N:29][C:30]1[CH:35]=[CH:34][C:33]([C:36](=[O:38])[CH3:37])=[CH:32][CH:31]=1)[CH3:26].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>C(Cl)Cl>[C:36]([C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([O:27][CH2:25][CH3:26])[CH:39]=[C:40]2[OH:42])(=[O:38])[CH3:37]
Reactant: CCOC(=O)CC(=Nc1ccc(C(C)=O)cc1)OCC
Agent: CC(=O)c1ccc(N)cc1
Agent: CCOC(=N)CC(=O)OCC
Agent: Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccc(-c2ccccc2)cc1
Product: CCOc1cc(O)c2cc(C(C)=O)ccc2n1
Yield: 65 %

Procedure:
A mixture of 14.5 gm. (0.107 moles) of p-aminoacetophenone and 19.0 gm. (0.097 moles) of ethyl (1-ethoxyformimidoyl)acetate hydrochloride (Chem. Ber., 100, 1428 (1967)) in 500 ml. of dry CH2Cl2 was stirred at 22° C. for 18 hours. The reaction, containing a precipitate of NH4Cl, was washed successively with ice cold aqueous solutions of 1 N HCl (2×100 ml), in Na2CO3 (2×100 ml) and saturated NaCl, and dried over Na.SO4. Filtration and evaporation yielded 20 gm. of crude ethyl [1-ethoxy(N-p-acetylphenyl)formimidoyl]acetate. This crude material was stirred and heated at 250° in 150 ml. of Dowtherm A for 30 minutes. Cooling dilution with 400 ml. of 1:1 ether-hexane and filtration of the precipitate yielded 12 gm. of the title compound. By base extraction of the filtrate and acidification, a further 2.5 gm. of product was obtained, mp. 210°-219° C. (65% yield).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[S:22][C:21]([C:23]([O:25]CC)=[O:24])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH-].[Na+]>C(O)C>[CH2:1]([NH:17][C:18]1[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)s1

Procedure:
A mixture of 0.1 g. of ethyl 5-hexadecylamino-2-thiophenecarboxylate, 10 ml. of absolute ethanol and 10 ml. of 0.5 N sodium hydroxide is refluxed for 3 hours. The reaction mixture is cooled and then concentrated. The pH of the solution is adjusted to 5.3 and the resulting solid filtered and dried to yield the product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH2:24]O)=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[C:11]([CH2:24][Br:29])=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1c2ccc(-c3ccccc3)cc2C(CO)=CC1(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1c2ccc(-c3ccccc3)cc2C(CBr)=CC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-tert-butyloxycarbonyl-1,2-dihydro-2,2-dimethyl-4-hydroxymethyl-6-phenylquinoline (structure 11, where R1=phenyl) (230 mg, 0.630 mmol) and carbon tetrabromide (220 mg, 0.662 mmol) in 5 mL of dichloromethane at 0° C. was added triphenylphosphine (174 mg, 0.662 mmol) in 2 mL of dichloromethane. The reaction mixture was allowed to warm to rt and stirred for 1 h. The mixture was concentrated in vacuo to a residue that was subjected to flash chromatography (silica gel, hexane/ethyl acetate, 9:1) to give structure 12, where R1=phenyl (72 mg, 27%). 1H NMR (acetone d6) 7.67 (m, 3H), 7.52 (dd, J=8.7, 2.1, 1H), 7.45 (t, 2 H), 7.32 (m, 2H), 6.07 (s, 1H), 4.60 (s, 2H), 1.55 (s, 6H) 1.53 (s, 9H).
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(OC(C)(C)C)=O)CC1.[CH:30]1([C:33]2[C:34]([O:47][CH2:48][CH:49]3[CH2:54][CH2:53][C:52]([CH3:56])([CH3:55])[CH2:51][CH2:50]3)=[CH:35][C:36]([F:46])=[C:37]([CH:45]=2)[C:38]([O:40]C(C)(C)C)=[O:39])[CH2:32][CH2:31]1>>[CH:30]1([C:33]2[C:34]([O:47][CH2:48][CH:49]3[CH2:54][CH2:53][C:52]([CH3:56])([CH3:55])[CH2:51][CH2:50]3)=[CH:35][C:36]([F:46])=[C:37]([CH:45]=2)[C:38]([OH:40])=[O:39])[CH2:32][CH2:31]1
Reactant: CC1(C)CCC(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CC1
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: CC1(C)CCC(COc2cc(F)c(C(=O)O)cc2C2CC2)CC1

Procedure:
Following the procedure as described in Example 158 step 4, and making variations as required to replace tert-butyl 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoate with tert-butyl 5-cyclopropyl-4-((4,4-dimethylcyclohexyl)-methoxy)-2-fluorobenzoate, the title compound was obtained as a colorless solid (0.356 g, 20%): MS (ES+) m/z 321.2 (M+1).
Reaction SMILES: [OH-:1].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].[CH2:7]([CH:17]1[O:22][C:20](=[O:21])[CH2:19][CH2:18]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[OH:22][CH:17]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][C:20]([O-:21])=[O:1].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CCCCCCCCCCC1CCC(=O)O1
Agent: C[N+](C)(C)C
Product: CCCCCCCCCCC(O)CCC(=O)[O-]

Procedure:
Using the procedure of Example 3, 13 g of a 25% aqueous solution of tetramethylammonium hydroxide is allowed to react with 6.79 grams of gamma-n-decyl-gamma-butyrolactone. After removal of water and extraction by n-hexane, a quantitative yield of purified tetramethylammonium gamma-hydroxytetradecanoate is obtained. This white solid product has good detergent properties even in hard water.
Reaction SMILES: [Na+].[CH2:2]([P:4]([OH:11])([CH2:6][CH2:7][C:8]([O-:10])=[O:9])=[O:5])[CH3:3].S(=O)(=O)(O)O>O>[CH2:2]([P:4]([OH:11])([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:3]
Reactant: CCP(=O)(O)CCC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCP(=O)(O)CCC(=O)O
Yield: 97.9 %

Procedure:
630 g (3 mol) of 3-(ethylhydroxyphosphinyl)propionic acid sodium salt (produced as in Example 16) are dissolved in 860 g of water and initially charged into a 5 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel and neutralized by addition of about 147 g (1.5 mol) of concentrated sulfuric acid. The water is subsequently distilled off in vacuo. The residue is taken up in ethanol and the insoluble salts are filtered off. The solvent of the filtrate is removed in vacuo to leave 488 g (98% of theory) of 3-(ethylhydroxy-phosphinyl)propionic acid as a solid material.
Reaction SMILES: N12[CH2:11][CH2:10][CH2:9][N:8]=[C:7]1[CH2:6][CH2:5][CH2:4][CH2:3]C2.[N+](C1CCCCC=1)([O-])=O.[CH2:21]([O:23][C:24](=[O:28])C[N+]#[C-])[CH3:22].Cl>CC(O)C.C1COCC1.CCOC(C)=O>[CH2:21]([O:23][C:24]([C:7]1[NH:8][CH:9]=[C:10]2[C:6]=1[CH2:5][CH2:4][CH2:3][CH2:11]2)=[O:28])[CH3:22]
Reactant: C1CCC2=NCCCN2CC1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: Cl
Agent: O=[N+]([O-])C1=CCCCC1
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]cc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,8-Diazabicyclo[5.4.0]-undec-7-ene (6.2 mL, 41.5 mmol) in 2-propanol (45 mL) was added by addition funnel over ˜25 minutes to a stirring solution of 1-nitrocyclohexene (5.0441 g, 39.67 mmol) and ethylisocyanoacetate (4.3340 g, 37.16 mmol) in THF (45 mL). The reaction was judged complete after stirring overnight at room temperature. 2N HCl (˜100 mL) and EtOAc (˜50 mL) were added. The organic layer was removed, then washed with H2O, 5% NaHCO3, and H2O. The crude product was dried with Na2SO4, filtered, concentrated, and purified by silica gel chromatography (Combiflash column, 100% CH2Cl2) to obtain 171 contaminated with a minor impurity. Attempts to recrystallize from hexanes were unsuccessful at removing the impurity, so the product was carried on to the next step with no further purification. 1H (CDCl3, 400 MHz): δ 9.01 (1H, broad s), 6.64 (1H, s), 4.31 (3H, q, J=7.2 Hz), 2.82 (2H, t, J=5.6 Hz), 2.55 (2H, t, J=5.6 Hz), 1.80-1.68 (4H, m), 1.36 (3H, t, J=7.2 Hz) ppm. 13C (CD3OD, 100 MHz): 6161.71, 128.06 and 127.84, 121.98 and 121.96, 118.74 and 118.55, 118.03 and 117.71, 59.62, 23.41 and 23.39, 23.36 and 23.33, 23.16 and 23.13, 21.88 and 21.86, 14.48 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 14.48; CH2 carbons: 59.62, 23.41 and 23.39, 23.36 and 23.33, 23.16 and 23.13, 21.88 and 21.86; CH carbons: 118.74 and 118.55 ppm. HPLC: 10.689 min.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][Cl:7])=[O:3].[Cl:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[C:11]([NH2:19])[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1>[Cl:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([N+:16]([O-:18])=[O:17])=[C:11]([NH:19][C:2](=[O:3])[O:4][CH2:5][CH2:6][Cl:7])[CH:10]=1
Reactant: O=C(Cl)OCCCl
Reactant: Nc1cc(Cl)c(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1cc(Cl)c(O)cc1[N+](=O)[O-])OCCCl
Temperature: 90 °C
Yield: 95 %

Procedure:
21 ml of β-chloroethyl chloroformate are added dropwise to 37.7 g (0.2 mole) of 6-chloro-3-nitro-4-aminophenol and 12 g of sodium carbonate in 130 ml of dioxane at 70° C. and the mixture is then heated at 90° C. for a further hour. After addition of 500 ml of water and stirring until cold, the mixture is extracted 3 times with methylene chloride and the extracts are dried and concentrated completely, after which 56 g (95%) of the product are obtained as a dark red oil, which crystallises completely, after some time, by trituration with toluene.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=2[F:17])=[N:6][O:7][C:8]=1[CH3:9])([OH:3])=O.C(Cl)(=O)C(Cl)=O.[NH2:24][C:25]1[CH:26]=[C:27]([CH2:31][C:32]([NH:34][C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl.CN(C)C=O>[CH3:42][O:41][C:39]1[CH:40]=[C:35]([NH:34][C:32](=[O:33])[CH2:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([NH:24][C:1]([C:4]3[C:5]([C:10]4[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=4[F:17])=[N:6][O:7][C:8]=3[CH3:9])=[O:3])[CH:26]=2)[CH:36]=[C:37]([O:45][CH3:46])[C:38]=1[O:43][CH3:44]
Reactant: COc1cc(NC(=O)Cc2cccc(N)c2)cc(OC)c1OC
Reactant: Cc1onc(-c2ccc(Br)cc2F)c1C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(=O)Cc2cccc(NC(=O)c3c(-c4ccc(Br)cc4F)noc3C)c2)cc(OC)c1OC
Yield: 65.9 %

Procedure:
In a fashion similar to that described for preparation 35, 4-carboxy-5-methyl-3-(2-fluoro-4-bromophenyl)isoxazole (119 mg, 0.40 mmol), oxalyl chloride (0.070 ml, 0.80 mmol), dimethylformamide (0.010 ml), dichloromethane (5 ml), 2-(3-aminophenyl)-N-(3,4,5-trimethoxyphenyl)acetamide (110 mg, 0.35 mmol), triethylamine (0.111 ml, 0.80 mmol), DMAP (5 mg), dimethylformamide (1 ml), dichloromethane (5 ml) gave the title compound (138 mg, 66%) after column chromatography (silica gel, hexanes/ethyl acetate gradient).
Reaction SMILES: [OH:1][C:2]([CH3:27])([CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25]O)=[CH:20][CH:19]=1)[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:15])[CH:7]=1)=[O:4].COCCN(S(F)(F)[F:38])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:38][CH2:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:2]([OH:1])([CH3:27])[C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:15])[CH:7]=2)=[O:4])=[CH:19][CH:20]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: Cc1cc(NC(=O)C(C)(O)COc2ccc(CCO)cc2)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(NC(=O)C(C)(O)COc2ccc(CCF)cc2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2-hydroxy-3-[4-(2-hydroxyethylphenoxy]-2-methyl-N-(3-methyl-4-nitrophenyl)propionamide (prepared in Example 20, 300 mg, 0.0008012 mol) in dry CH2Cl2 (3 ml) was treated with Deoxo-Fluor® (195 mg, 0.0008813 mol) in dry CH2Cl2 (1 ml) at −15 to −10° C. The solution was stirred for 2 h at 0° C. and then for 3 days at room temperature. The saturated NaHCO3 solution was added and the mixture was extracted with dichloromethane. The combined extracts were washed with water, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography using dichloromethane as an eluent. Crystallization from toluene afforded the desired compound as pure crystals: m.p. 102-105° C. 1H NMR (400 MHz, DMSO-d6): 1.43 (3H, s), 2.53 (3H, s), 2.88 (2H, dt, 3JHF=24.4 Hz, 3J=6.4 Hz), 3.95 (1H, d, 2Jgem=9.8 Hz), 4.18 (1H, d, 2Jgem=9.5 Hz), 4.56 (2H, dt, 2JHF=47.4 Hz, 3J=6.4 Hz), 6.18 (1H, broad s, —OH), 6.85 (2H, d, 3J=8.5 Hz), 7.15 (2H, d, 3J=8.4 Hz), 7.88 (1H, d, 3J=9.0 Hz), 7.93 (1H, s), 8.03 (1H, d, 3J=9.0 Hz), 10.13 (1H, broad s, —NHCO—).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:17][CH:16]=1>CN(C=O)C>[CH:29]1([CH:21]([C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:5]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])=[CH:16][CH:17]=2)[C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Agent: [K]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(c1ccc(CN2C(=O)c3ccccc3C2=O)cc1)C1CCCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under argon, 6.49 g (35 mmol) of potassium phthalimide were initially charged in 60 ml of DMF, 15 g (31.8 mmol) of tert-butyl(+/−)-2-(4-(bromomethyl)phenyl)-2-cyclopentylacetate were added and the mixture was stirred at 80° C. overnight. A further 0.5 equivalent of potassium phthalimide was then added, and the mixture was stirred at 80° C. for another 6 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with ethanol and the solid was filtered off with suction, washed with ethanol and dried under high vacuum. This gave 8.5 g (about 96% pure, 61% of theory) of the target compound.