Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:42])/[CH:26]=[CH:27]/[CH:28]=[CH:29]/[C:30]3[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=3)[CH2:21][CH:20]2[C:43]([OH:45])=O)=[O:18])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:59][NH:60][OH:61].C(N(CC)CC)C.Cl>CN(C)C=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5](/[CH:13]=[CH:14]/[CH:15]=[CH:16]/[C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25](=[O:42])/[CH:26]=[CH:27]/[CH:28]=[CH:29]/[C:30]3[CH:31]=[C:32]([O:40][CH3:41])[C:33]([O:38][CH3:39])=[C:34]([O:36][CH3:37])[CH:35]=3)[CH2:21][CH:20]2[C:43]([N:60]([CH3:59])[OH:61])=[O:45])=[O:18])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(/C=C/C=C/C(=O)N2CCN(C(=O)/C=C/C=C/c3cc(OC)c(OC)c(OC)c3)C(C(=O)O)C2)cc(OC)c1OC
Reactant: CNO
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(/C=C/C=C/C(=O)N2CCN(C(=O)/C=C/C=C/c3cc(OC)c(OC)c(OC)c3)C(C(=O)N(C)O)C2)cc(OC)c1OC
Reaction time: 0.25 h
Yield: 86.1 %

Procedure:
Added to a solution of 148 mg (0.24 mmol) of 1,4-bis[5-(3,4,5-trimethoxyphenyl)penta-(2E,4E)-dienoyl]-piperazine-2-carboxylic acid synthesized by the process of Example 34 in anhydrous dimethylformamide (0.5 ml) was 44.9 mg (0.28 mmol) of 1,1′-carbonyldiimidazole. After the mixture was stirred for 15 minutes, 24.9 mg (0.30 mmol) of N-methylhydroxyamine hydrochloride and 0.050 ml (0.36 mmol) of triethylamine were added, and the mixture was stirred for an additional 15 minutes. Added to the reaction mixture was 3 ml of 0.5N hydrochloric acid to conduct extraction with chloroform. An organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resultant crude oil (179 mg) was purified by column chromatography on silica gel to obtain 134.6 mg (yield: 87%) of the title compound as pale yellow amorphous powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([CH:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:20][CH:21]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:36][Si:37]([CH2:40][CH2:41][O:42][CH2:43]Cl)([CH3:39])[CH3:38]>CN(C=O)C.[NH4+].[Cl-].CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([C:17]2[N:18]([CH2:43][O:42][CH2:41][CH2:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[C:19]([CH:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:20][CH:21]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(C2CCN(C(=O)OCc3ccccc3)CC2)[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(C2CCN(C(=O)OCc3ccccc3)CC2)n1COCC[Si](C)(C)C
Reaction time: 0.08 h
Yield: 32.1 %

Procedure:
4-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-piperidine-1-carboxylic acid benzyl ester (6.8 g, 14.9 mmol) in DMF (115 mL) was treated with NaH (60% dispersion in mineral oil, 655 mg, 16.4 mmol) in one portion. After 5 min, the mixture was treated with SEMCl (2.75 mL, 15.7 mmol) in 0.1 mL portions over 10 min. The reaction was stirred for 3 hours and diluted with saturated NH4Cl solution (50 mL) and EtOAc (100 mL). The organic layer was washed with H2O (3 50 mL) and brine (50 mL). The solution was dried over MgSO4 and subjected to a 120 g SiO2 COMBIFLASH column (0-100% EtOAc-hexanes followed by 0-20% MeOH-EtOAc gradient) to afford 4-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-piperidine-1-carboxylic acid benzyl ester (2.8 g, 32%): MS (ESI) m/z 585 [M+H]+.
Reaction SMILES: B.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH2:17][CH2:18][NH:19][C:20](=O)[CH:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)[OH:22])[CH:13]=[CH:14][C:15]=1[OH:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O)(=O)CC>O1CCCC1>[CH2:30]([O:29][C:26]1[CH:25]=[CH:24][C:23]([CH:21]([OH:22])[CH2:20][NH:19][CH2:18][CH2:17][C:12]2[CH:13]=[CH:14][C:15]([OH:16])=[C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:11]=2)=[CH:28][CH:27]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(NCCc1ccc(O)c(OCc2ccccc2)c1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: B
Solvent: CCC(=O)O
Solvent: C1CCOC1
Product: Oc1ccc(CCNCC(O)c2ccc(OCc3ccccc3)cc2)cc1OCc1ccccc1

Procedure:
148 ml of 1.67M boron hydride in tetrahydrofurane were added to a solution of 11.3 g of N-[2-(3-benzyloxy-4-hydroxyphenyl)-ethyl]-4-benzyloxy-mandelamide (obtained as described in example 67) in 100 ml of tetrahydrofurane. After 3 hours under reflux, the mixture was cooled and 6.93 g of propionic acid were added. The mixture was refluxed again for 1 hour and then evaporated to dryness. The resulting oil was dissolved in methylene chloride, washed with water and diluted sodium hydroxide, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel column using methylene chloride/methanol/ammonium hydroxide=97/3/0.3 as eluent. N-[2-(4-Benzyloxyphenyl)-2-hydroxyethyl]-3-O-benzyldopamine was thus obtained, m.p. 124°-125° C. (from ethanol).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[N:8][C:6]=2[N:7]=1.[N:19]1([C:25]([CH3:30])([CH3:29])[C:26]([NH2:28])=[O:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:22]3[CH2:21][CH2:20][N:19]([C:25]([CH3:30])([CH3:29])[C:26]([NH2:28])=[O:27])[CH2:24][CH2:23]3)=[N:8][C:6]=2[N:7]=1
Reactant: CC(C)(C(N)=O)N1CCNCC1
Reactant: O=Cc1nc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C(N)=O)N1CCN(Cc2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidine-2-carbaldehyde (250 mg, 0.88 mmol), 2-piperazin-1-yl-isobutyramide (173 mg, 1.01 mmol) and 4 Å molecular sieves (1.0 g) in 1,2-dichloroethane (15 mL) was stirred at RT under nitrogen atmosphere for 4 h. Sodium triacetoxyborohydride (280 mg, 1.32 mmol) was added and the resulting reaction mixture was stirred at RT for 16 h. The solvent was reduced in vacuo and the residue was loaded on an Isolute® SCX-2 cartridge (25 g). The cartridge was washed with DCM/MeOH and the desired product was subsequently eluted using a mixture of 2 M NH3 in MeOH and DCM. The resulting residue was further purified by column chromatography (Si—PCC, MeOH:DCM: gradient 0:100 to 6:94). The solvents were reduced in vacuo to afford the title compound as a yellow solid (275 mg, 60%). LCMS (Method H): RT 2.41 min, [M+H]+ 440. 1H NMR (400 MHz, CDCl3): δ 7.04 (1 H, br s), 5.22 (1 H, br s), 3.97-3.95 (6 H, m), 3.85 (4 H, t, J=4.80 Hz), 2.67 (8 H, m), 1.25 (6 H, s)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: C1=COCCC1
Reactant: O=C(O)CCCCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To a solution of 12-hydroxydodecanoic acid (10.0 g, 0.046 mol) in 150 mL THF, p-toluenesulfonic acid (0.087 g, 0.01 eq) was added followed by 3,4-dihydro-2H-pyran (5.95 g, 0.070 mol). After stirring this homogeneous reaction mixture for 16 hours at room temperature under a nitrogen atmosphere, NaHCO3 saturated solution was added to the mixture. The mixture was then extracted with methylene chloride, dried (MgSO4), and concentrated in vacuo (30° C.) to yield 13.0 g (0.043 mol, 94%) of the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8](O)=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14].[Cl-:15]>>[CH3:1][C:2]1[C:7]([C:8]([Cl:15])=[O:9])=[C:6]([F:11])[C:5]([F:12])=[C:4]([F:13])[C:3]=1[F:14]
Reactant: [Cl-]
Reactant: Cc1c(F)c(F)c(F)c(F)c1C(=O)O
Product: Cc1c(F)c(F)c(F)c(F)c1C(=O)Cl

Procedure:
To 6-methyl-2,3,4,5-tetrafluorobenzoic acid (5.60 g) is added thiony chloride (9.8 ml) and the mixture is refluxed for 1 hour. After concentrating, 6-methyl-2,3,4,5-tetrafluorobenzoyl chloride (5.20 g) is obtained as a colorless oil, b.p. 82° C./23 mmHg.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][C:6]1[N:7]([CH3:22])[C:8]([C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[C:9]([O:11][CH3:12])[CH:10]=1)C.[OH-].[Na+]>C(O)C.O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([C:8]2[N:7]([CH3:22])[C:6]([CH2:5][C:4]([OH:23])=[O:3])=[CH:10][C:9]=2[O:11][CH3:12])=[O:21])=[CH:19][CH:18]=1
Reactant: CCOC(=O)Cc1cc(OC)c(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(CC(=O)O)n(C)c1C(=O)c1ccc(Cl)cc1
Yield: 88.9 %

Procedure:
Ethyl-5-(p-chlorobenzoyl)-4-methoxy-1-methylpyrrole-2-acetate (145 mg, 0.475 mmole) is dissolved in 1 ml hot ethanol under nitrogen. Subsequently, 2 ml of 2.5 N aqueous sodium hydroxide is added dropwise. The solution is heated at 95° for about 5 min. The reaction solution is then diluted with water, the product precipitated with 2.5 ml of 2.5 N hydrochloric acid. The resulting precipitate is filtered, washed with water and dried in vacuo to yield 130 mg of 5-(p-chlorobenzoyl)-4-methoxy-1-methylpyrrole-2-acetic acid, m.p. 148 (dec).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14](OCC)(=[O:23])[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16]>>[C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:23])[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[OH:16]
Reactant: CCOC(=O)C(O)c1ccccc1
Reactant: CCCCCCCCCCCCO
Product: CCCCCCCCCCCCOC(=O)C(O)c1ccccc1
Temperature: 60 °C
Yield: 62.3 %

Procedure:
A mixture of Novozym® 435 (2.21 g), molecular sieves (18.60 g), 1-dodecanol (3.76 g), and ethyl mandelate (3.61 g) in a 150 mL beaker was maintained at 60° C. in a convection oven for 28 hours. Upon work-up, 4.0 g of lauryl mandelate (56% yield) was obtained as a clear viscous liquid. The purity of the product was >95% as assessed by HPLC-DAD.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:22]=[C:23]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:32]=4)[C:24]4[S:29][CH:28]=[CH:27][C:25]=4[N:26]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]3[N:22]=[C:23]([O:30][C:31]4[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=4)[C:24]4[S:29][CH:28]=[CH:27][C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc3ccsc23)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCNCC4)cc3)nc3ccsc23)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
The compound (600 mg, 1.05 mmol) obtained in Step 1 was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1.62 mL, 21.0 mmol) was added thereto, followed by stirring at room temperature for 1 hour. After the reaction was complete, the reaction mixture was distilled under a reduced pressure to remove solvent, alkalify (pH 8) with sat. NaHCO3 aqueous solution, and extracted with chloroform 2 times. The organic layer was separated, washed with water and sat. brine, dried with anhydrous sodium sulfate, and then filtered and distilled under a reduced pressure. The residue was separated by column chromatography (chloroform:methanol=10:1 (volume ratio)) to obtain the title compound (yield: 316 mg, 72%).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[O:9])=[C:6]([CH3:17])[CH:5]=1.ClN1C(=O)CCC1=O.[Cl:26][C:27]1[CH:28]=[C:29]([C:35]([C:37]([F:40])([F:39])[F:38])=[CH2:36])[CH:30]=[C:31]([Cl:34])[C:32]=1[Cl:33].C(=O)([O-])O.[K+]>COCCOC.O>[CH3:17][C:6]1[CH:5]=[C:4]([C:3]2[CH2:36][C:35]([C:29]3[CH:30]=[C:31]([Cl:34])[C:32]([Cl:33])=[C:27]([Cl:26])[CH:28]=3)([C:37]([F:40])([F:39])[F:38])[O:1][N:2]=2)[CH:16]=[CH:15][C:7]=1[C:8]([NH:10][C:11](=[O:14])[O:12][CH3:13])=[O:9]
Reactant: COC(=O)NC(=O)c1ccc(C=NO)cc1C
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)NC(=O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 23.7 %

Procedure:
In a solution of 45 mg of methyl N-[4-hydroxyiminomethyl-2-methylbenzoyl]carbamate in 10 mL of 1,2-dimethoxyethane, 40 mg of N-chlorosuccinimide was added, and stirred at 60° C. for 45 minutes. Then, the reaction mixture was left and cooled to room temperature, and then 68 mg of 3,4,5-trichloro-1-(1-trifluoromethylethenyl)benzene, 40 mg of potassium hydrogen carbonate and 5 drops of water were added, and continued to stir at room temperature further for 15 hour. After the completion of the reaction, the reaction mixture was poured in 10 mL of water, and extracted with ethyl acetate (15 mL×2). The combined organic phases were dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 1:2 to 1:1) to obtain 23 mg of the aimed product as colorless resinous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH2:29]([O:31][C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:39]=1[F:40])=[O:33])[CH3:30]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[CH2:29]([O:31][C:32](=[O:33])[C:34]1[CH:35]=[C:36]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)[CH:37]=[CH:38][C:39]=1[F:40])[CH3:30]
Reactant: CCOC(=O)c1cc(B(O)O)ccc1F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)ccc1F

Procedure:
In analogy to Example 5, 6-[(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (63 mg) was reacted with 3-ethoxycarbonyl-4-fluorophenylboronic acid, copper-(II)-acetate and pyridine to give the title compound (25 mg) as a white solid. MS (m/e)=582.0 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:12]=[CH:13][O:14]C)=[CH:7]2.Cl.CCOCC.O>O1CCCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH:13]=[O:14])=[CH:7]2
Reactant: COC=Cc1ccc2c(Br)cccc2c1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=CCc1ccc2c(Br)cccc2c1
Yield: 105.6 %

Procedure:
The methyl 5-bromo-2-naphthylvinyl ether (2.8 g) dissolved in tetrahydrofuran (55 ml) was stirred with concentrated hydrochloric acid (10 ml) for 1 hour at room temperature. Ether and water were added and the organic solution separated and washed with water, saturated sodium bicarbonate and saturated sodium chloride solutions. Evaporation gave a liquid (2.8 g), nD20 =1.6444.
Reaction SMILES: P(Br)(Br)([Br:3])=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[CH:15]=[C:16]([N+:21]([O-:23])=[O:22])[C:17](=O)[NH:18][CH:19]=2)=[CH:9][CH:8]=1.CN(C=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Br:3][C:17]1[C:16]([N+:21]([O-:23])=[O:22])=[CH:15][C:14]([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=2)=[CH:19][N:18]=1
Reactant: O=P(Br)(Br)Br
Reactant: O=c1[nH]cc(Cc2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Cc2ccc(F)cc2)cnc1Br
Temperature: 25 °C

Procedure:
A solution of POBr3 (227 g, 0.79 mol) in toluene (900 mL) was added slowly to a stirred suspension of 5-[(4-fluorophenyl)methyl]-3-nitro-2(1H)-pyridinone (179 g, 0.72 mol) in toluene (900 mL). The mixture was heated to reflux; then cooled to rt and DMF (56 mL, 0.72 mol) was added slowly; the mixture was again heated to reflux and then allowed to cool to rt overnight. After cooling the mixture in an ice-bath, water (500 mL) was added slowly followed by dropwise addition 4 N NaOH (450 mL, 1.76 mol). All insoluble material was removed by filtration and the two liquid phases were separated. The organic layer was concentrated at reduced pressure to afford the product as a beige solid: 1H NMR (d6-DMSO) δ 8.62 (1H, d, J=2 Hz), 8.37 (1H, d, J=2 Hz), 7.33 (2H, m), 7.12 (2H, m), 4.05 (2H, s); ES+ MS: 313 (M+H+, 100), 311 (M+H+, 100).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]1([CH:14]=[C:12]([OH:13])[CH:11]=[C:9]([OH:10])[CH:8]=1)[OH:7].CN1CCOCC1>O1CCCC1>[CH3:1][S:2]([O:7][C:6]1[CH:14]=[C:12]([O:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[C:9]([O:10][S:2]([CH3:1])(=[O:4])=[O:3])[CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1cc(O)cc(O)c1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CS(=O)(=O)Oc1cc(OS(C)(=O)=O)cc(OS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
39.8 g (0.33 mol) of methanesulfonic acid chloride were added dropwise at 0° C. within the course of 30 minutes to a solution of 12.6 g (0.10 mol) of phloroglucinol and 101 g (1.0 mol) of N-methylmorpholine in 200 ml of dry tetrahydrofuran in such a way that the temperature did not rise above 10° C. After the dropwise addition, the ice bath was removed, and the mixture was warmed to room temperature and stirred for 2 hours at this temperature. The mixture was then slowly added dropwise with continuous stirring to 3 l of ice water, and the resulting precipitate was filtered off with suction and washed until neutral with water. After drying, this gave 32.9 g (91%) of a colorless powder of melting point 145 to 149° C. Recrystallization from an isopropanol/acetone solvent mixture gave colorless, highly light-refracting platelets of melting point 150° C.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][C@@:20]2([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@H:19]2[S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:15]2[C@@:6]1([F:32])[C@:7]1([CH3:31])[C:12]([CH2:13][CH2:14]2)=[CH:11][C:10](=[O:30])[CH:9]=[CH:8]1)(=O)C.[OH-].[Na+].C(Cl)(Cl)Cl.C(OCC)(=O)C>O1CCCC1.CO>[F:32][C@:6]12[C@@H:5]([OH:4])[CH2:22][C@@:20]3([CH3:21])[C@@H:16]([CH2:17][CH2:18][C@H:19]3[S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:15]1[CH2:14][CH2:13][C:12]1[C@:7]2([CH3:31])[CH:8]=[CH:9][C:10](=[O:30])[CH:11]=1
Reactant: CC(=O)O[C@H]1C[C@]2(C)[C@H](Sc3ccccc3)CC[C@H]2[C@@H]2CCC3=CC(=O)C=C[C@]3(C)[C@@]12F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@]12C[C@H](O)[C@@]3(F)[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1CC[C@H]2Sc1ccccc1
Reaction time: 8 h

Procedure:
To a stirred mixture of (11β,17α)-11-(acetyloxy)-9-fluoro-17-(phenylthio)androsta-1,4-dien-3-one (300 mg) in tetrahydrofuran (12.0 ml) and methanol (6.0 ml) (in a nitrogen atmosphere) was added 1.5 ml of a 12% sodium hydroxide solution. TLC (7:3, chloroform:ethyl acetate) taken after 1 hour showed the reaction to be complete. After a total of 1.5 hours at room temperature, the reaction was quenched with water and extracted with chloroform (3×50 ml). The chloroform extracts were pooled, dried over anhydrous magnesium sulfate and evaporated to a yellow oil. This was dissolved in 10.0 ml of boiling dichloromethane, cooled, and a few drops of petroleum ether were added. The solution was left in the freezer overnight, yielding fine, light green needle-like crystals (57 mg) of an analytical specimen with consistent spectral data and melting point 248°-252° C. (with decomposition).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[N:32]([CH3:34])[CH:31]=[C:30]4[CH2:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]>ClCCl>[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[N:32]([CH3:34])[CH:31]=[C:30]4[CH2:35][CH2:36][C:37]([OH:39])=[O:38])[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)cn(C)c34)no2)cc1C#N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)cn(C)c34)no2)cc1C#N
Reaction time: 0.75 h
Yield: 75.4 %

Procedure:
Trifluoroacetic acid (0.475 mL) was added to a solution of 1,1-dimethylethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoate (D10) (60 mg) in dichloromethane (1 mL) at RT. The resulting solution was stirred for 45 min. The reaction mixture was concentrated. The residue was recrystallized from ether/hexane to afford 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]propanoic acid (E4) (40 mg) as a pale yellow solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.63 (2H, t), 2.97 (2H, t), 3.64 (3H, s), 4.99 (1H, m), 7.18 (1H, t), 7.21 (1H, s), 7.44 (1H, m), 7.57 (1H, d), 7.81 (1H, dd), 8.43 (1H, dd), 8.55 (1H, d), 12.12 (1H, br s). MS (ES): C24H22N4O4 requires 430; found 431.0 (M+H+).
Reaction SMILES: C([O:8]/[N:9]=[C:10]1\[CH2:11][CH2:12][C:13]2[C:18]\1=[CH:17][CH:16]=[C:15]([C:19]1[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[N:21][N:22]([CH2:24][CH2:25][OH:26])[CH:23]=1)[CH:14]=2)C1C=CC=CC=1.Cl.[H][H]>CO.[OH-].[Pd+2].[OH-]>[OH:26][CH2:25][CH2:24][N:22]1[CH:23]=[C:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[C:10](=[N:9][OH:8])[CH2:11][CH2:12]3)[C:20]([C:27]2[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=2)=[N:21]1
Reactant: OCCn1cc(-c2ccc3c(c2)CC/C3=N\OCc2ccccc2)c(-c2ccncc2)n1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: OCCn1cc(-c2ccc3c(c2)CCC3=NO)c(-c2ccncc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
To (E)-5-(1-(2-hydroxyethyl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl)-2,3-dihydroinden-1-one O-benzyl oxime (31.9 mg; Example 4, Step 4) in 5 mL methanol was added 38 μL 6M hydrochloric acid and about 5 mg palladium hydroxide (20% by weight on carbon). A hydrogen-filled balloon was attached to the reaction vessel and the mixture was stirred at ambient temperature for 1 hour. The mixture was filtered through celite, the celite was washed with methanol, and the filtrate treated with a small amount of saturated aqueous sodium bicarbonate. The filtrate was concentrated under vacuum and the residue was purified by chromatography, eluting with a 10:1 mixture of dichloromethane-methanol to yield 13.2 mg (53% yield) of a white solid. 1H NMR (CDCl3) was consistent with the desired structure 110. LC/MS showed one peak with a M+1 molecular ion of m/z 335.4 by positive ESI.