Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[C:12]2[CH:13]=[C:14]([C:17]([O:19]CC)=O)[CH:15]=[CH:16][C:11]=2[O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](C1C2C=C(CO)C=CC=2OC1)C1C=CC=CC=1>>[C:7]1([CH2:2][CH2:1][CH:8]2[C:12]3[CH:13]=[C:14]([CH2:17][OH:19])[CH:15]=[CH:16][C:11]=3[O:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:22]=1
Reactant: CCOC(=O)c1ccc2c(c1)C(Cc1ccccc1)CO2
Reactant: OCc1ccc2c(c1)C(Cc1ccccc1)CO2
Product: OCc1ccc2c(c1)C(CCc1ccccc1)CO2

Procedure:
Analogously, starting from ethyl 3-benzyl-2,3-dihydro-1-benzofuran-5-carboxylate the 3-benzyl-2,3-dihydro-1-benzofuran-5-yl-methanol was obtained in 62% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[OH:19].[C:20]([O-])([O-])=O.[K+].[K+].IC>>[Br:1][C:2]1[CH:7]=[C:6]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[CH:5]=[C:4]([CH2:17][CH3:18])[C:3]=1[O:19][CH3:20]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)cc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCc1cc(C(=O)c2ccccc2Cl)cc(Br)c1OC
Reaction time: 48 h
Yield: 66 %

Procedure:
At ambient temperature, to a stirred mixture containing 2-bromo-4-(2-chlorobenzoyl)-6-ethylphenol (14.56 g, 42.82 mmol) and K2CO3 (8.90 g, 64.5 mmol) in N,N-DMF (11.6 mL) was added iodomethane (3.98 mL, 64.4 mmol). After 48 h, the reaction was quenched with H2O (300 mL) and extracted with hexane. The organic extracts were washed with H2O (2×100 mL), brine (1×100 mL), dried (Na2SO4) and concentrated. Purification on Biotage KP-Sil eluting with a 0, 2.5 & 5% EtOAc/hexane step gradient gave 10.0 g (66%) of the title compound. 1H NMR: consistent. mass spectrum (EI) m/z 352 (M+). Anal. Calcd. for C16H14BrClO2.0.2H2O: C, 53.79; H, 4.06; N, 0.00. Found: C, 53.89; H, 3.91; N, 0.08.
Reaction SMILES: [F:1][C:2]1C=[CH:8][CH:7]=[CH:6][C:3]=1C=O.[CH3:10][O:11][C:12]([O:15][CH3:16])(C)[CH3:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[CH3:10][O:11][CH:12]([O:15][CH3:16])[C:13]1[CH:8]=[CH:7][CH:6]=[CH:3][C:2]=1[F:1]
Reactant: COC(C)(C)OC
Reactant: O=Cc1ccccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: COC(OC)c1ccccc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 12.2 g of 2-fluorobenzaldehyde, 15 ml of 2,2-dimethoxypropane and 0.1 g of 4-toluenesulphonic acid was stirred at room temperature. After 24 hours, diethyl ether was added and the resultant solution washed with saturated sodium bicarbonate solution. Drying and evaporation of the organic phase gave the crude acetal. Distillation under vacuum at 90°-95° C./0.08 mm yielded the title compound as a colourless oil.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([OH:27])=[CH:20][C:13]=3[C:14]=2[C:15]([O:17]CC)=[O:16])=[CH:6][CH:5]=1>CCO.C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([OH:27])=[CH:20][C:13]=3[C:14]=2[C:15]([OH:17])=[O:16])=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(O)cc12
Temperature: 64 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
Excess NaOH (11 ml, 11.00 mmol, 1M aq) was added to a stirring solution of ethyl 2-(4-fluorophenyl)-5-hydroxy-6-nitrobenzofuran-3-carboxylate (1.9 g, 5.50 mmol) in EtOH (55 ml) and THF (55 ml) and was allowed to stir at 64° C. overnight. The mixture was concentrated and diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated to give the titled compound (1.7 g, quant.). 1H NMR (300 MHz, DMSO-D6) δ ppm 7.31-7.48 (m, 2 H) 7.71 (s, 1 H) 8.00-8.14 (m, 2 H) 8.29 (s, 1 H) 10.80 (s, 1 H) 13.35 (s, 1 H). LC-MS retention time: 0.99 min; m/z (MH−): 416. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: O=[C:2]1[C:19]2[C:20]3[C:5](=[C:6]4[C:21]5[C:14]([C:15]=3[CH:16]=[CH:17][CH:18]=2)=[CH:13][CH:12]=[CH:11][C:10]=5[C:9](=O)[CH:8]=[CH:7]4)[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]1=2>[Zn].N1C=CC=CC=1.C(O)(=O)C>[CH:11]1[C:10]2[C:21]3[C:14]([C:15]4[CH:16]=[CH:17][CH:18]=[C:19]5[C:20]=4[C:5]([C:6]=3[CH:7]=[CH:8][CH:9]=2)=[C:4]2[CH:23]=[CH:24][CH:25]=[CH:26][C:3]2=[CH:2]5)=[CH:13][CH:12]=1
Reactant: O=c1ccc2c3c1cccc3c1cccc3c(=O)c4ccccc4c2c31
Agent: [Zn]
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: c1ccc2c(c1)cc1cccc3c4cccc5cccc(c54)c2c13

Procedure:
In accordance with a conventional manner, 7,14-dioxo-7,14-dihydrobenzo[a]perylene was treated in zinc powder contained in pyridine, and then, treated in 80% acetic acid. The resultant was refined in a conventional manner to thereby obtain a target material, benzo[a]perylene
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:9]([CH3:28])=[C:10]([NH:14][C:15](=[O:27])[CH2:16][C:17]23[CH2:26][CH:21]4[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]4)[CH2:18]2)[CH2:24]3)[CH:11]=[CH:12][CH:13]=1.I[CH2:30][CH2:31][CH2:32][N:33](C)[C:34](=O)OC(C)(C)C.[ClH:42]>C(#N)C.CO>[ClH:42].[CH3:34][NH:33][CH2:32][CH2:31][CH2:30][O:7][C:8]1[C:9]([CH3:28])=[C:10]([NH:14][C:15](=[O:27])[CH2:16][C:17]23[CH2:26][CH:21]4[CH2:20][CH:19]([CH2:25][CH:23]([CH2:22]4)[CH2:24]2)[CH2:18]3)[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1c(O)cccc1NC(=O)CC12CC3CC(CC(C3)C1)C2
Reactant: CN(CCCI)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CO
Product: CNCCCOc1cccc(NC(=O)CC23CC4CC(CC(C4)C2)C3)c1C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Dry dichloromethane (40 ml), triphenylphosphine (3.28 g), imidazole (1.05 g) and iodine (3.85 g) were combined in that order. A solution of tert-butyl N-(3-hydroxypropyl)-N-methylcarbamate (1.90 g, J. Org. Chem., 1988, 53(10), 2229) in dichloromethane (10 ml) was added and the resulting reaction mixture stirred at room temperature for 1 hour. An aqueous solution of sodium hydrogen sulphite (6 g in 100 ml of water) was then added and the organic layer separated. The latter was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with iso-hexane:ether (7:3) to give tert-butyl N-(3-iodopropyl)-N-methylcarbamate (2.54 g) which was used immediately. Caesium carbonate (0.655 g) was added to a suspension of N-(3-hydroxy-2-methylphenyl)-tricyclo[3.3.1.13,7]decane-1-acetamide (0.453 g, Example 26) in acetonitrile (35 ml) and the mixture heated at 100° C. for 10 minutes. After cooling to room temperature a solution of tert-butyl N-(3-iodopropyl)-N-methylcarbamate (0.600 g) in acetonitrile (5 ml) was added and the reaction heated at reflux for 90 minutes. The reaction was concentrated under reduced pressure and the residue partitioned between dichloromethane (100 ml) and water (100 ml). The organic layer was dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane:ethyl acetate (9:1) to give a solid that was dissolved in methanol (10 ml). A solution of hydrogen chloride (generated by slow addition of acetyl chloride (12 ml) to methanol (15 ml) at 0° C. CARE—Very Exothermic) was then added to the latter solution and the reaction stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give a gum that was scratched under ether:hexane (1:1) (20 ml) to give the title compound as a pale yellow powder (0.477 g).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([Cl:13])=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:14]1[CH:28]=[CH:27][C:17]([CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:16][CH:15]=1.[C:29]([OH:32])(=O)[CH3:30]>N1C=CC=CC=1>[Cl:13][C:7]1[CH:6]=[C:5]2[C:10]([C:11](=[O:12])[N:2]([NH:1][C:29](=[O:32])[CH3:30])[CH:3]([C:14]3[CH:15]=[CH:16][C:17]([CH2:18][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:27][CH:28]=3)[N:4]2[NH:2][C:11](=[O:12])[CH3:10])=[CH:9][CH:8]=1
Reactant: CCOP(=O)(Cc1ccc(-c2nc3cc(Cl)ccc3c(=O)n2N)cc1)OCC
Reactant: CC(=O)O
Solvent: c1ccncc1
Product: CCOP(=O)(Cc1ccc(C2N(NC(C)=O)C(=O)c3ccc(Cl)cc3N2NC(C)=O)cc1)OCC
Temperature: 25 °C
Yield: 123.7 %

Procedure:
The compound obtained in Example 57 (3.0 g) and anhydrous acetic acid (2.2 g) were suspended in 20 ml of pyridine and refluxed at room temperature for 18 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was diluted with dichloromethane and washed with distilled water. The organic layer was dried over anhydrous magnesium sulfate and condensed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol=50:1) and recrystallized from dichloromethane-n-hexane to provide 2.3 g of the desired compound as colorless crystals. Table 3 shows the chemical structure and property (melting point) of the compound obtained.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:6]=1)=O.[SH:17][C:18]1[NH:19][N:20]=[CH:21][C:22](=[O:24])[N:23]=1>C(O)C>[C:13]([C:7]1[CH:6]=[C:5]([C:3]2[N:19]3[N:20]=[CH:21][C:22](=[O:24])[N:23]=[C:18]3[S:17][CH:2]=2)[CH:10]=[C:9]([CH3:11])[C:8]=1[OH:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=c1cn[nH]c(S)n1
Reactant: Cc1cc(C(=O)CBr)cc(C(C)(C)C)c1O
Solvent: CCO
Product: Cc1cc(-c2csc3nc(=O)cnn23)cc(C(C)(C)C)c1O

Procedure:
A solution of 28.5 g (0.1 mol) of 2-bromo-1-(3-tert.butyl-5-methyl-4-hydroxyphenyl)-ethanone from step (a1) and 12.9 g (0.1 mol) of 3-mercapto-2H-1,2,4-triazin-5-one was refluxed for 8 hours in 250 ml of ethanol. After the solvent had been removed in vacuo, the solid residue was dissolved in 200 ml of boiling ethyl acetate and filtered while hot. On concentration of the filtrate, colorless crystals were produced which were again recrystallized from isopropanol.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:21]1([N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[C:21]1([N:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)=[O:29])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: c1ccc(Nc2ccncc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(N(c1ccccc1)c1ccccc1)N(c1ccccc1)c1ccncc1

Procedure:
A solution of 8.51 g (0.05 mol) of N-phenyl-4-pyridinamine in 400 ml of chloroform is mixed with 11.5 g (0.11 mol) of triethylamine. To this mixture is added, dropwise with stirring, a solution of 11.6 G (0.05 mol) of diphenylcarbamic chloride in chloroform.
Reaction SMILES: [C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O.[OH-].[K+]>C(Cl)Cl>[CH3:3][CH:2]([CH3:4])[C:1]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5]
Reactant: CC(C)C(=O)Nc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-(4-aminophenyl)-1-piperidinecarboxylate (8.20 g, 29.7 mmol) and triethylamine (8.4 mL, 60 mmol) in dry THF (100 mL) at 0° C. was slowly added a solution of 2-methylpropanoyl chloride (3.84 g, 36.0 mmol) in THF (50 mL). The reaction mixture was then warmed up to room temperature and stirred for 2 h. After removing the solvent in vacuo, the crude product was purified by recrystallization (hexane/THF), affording the desired amide, tert-butyl 4-[4-(isobutyrylamino)phenyl]-1-piperidinecarboxylate, as a white solid (8.60 g, 84%). The tert-butyl 4-[4-(isobutyrylamino)phenyl]-1-piperidinecarboxylate was dissolved in CH2Cl2 (50 mL) at room temperature, TFA (13.68 g, 120 mmol, 5 equiv.) was added by syringe. The reaction mixture was stirred for 3 or 4 h and another 5 equivalents of TFA was added and the mixture was stirred for 2 or 3 more hours. The reaction solution was then basified to pH >14 by KOH (aq, 2 M). The solution was extracted with CH2Cl2 K2CO3. Removal of solvent under reduced pressure gave the free amine, 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide, as a brownish solid (5.99 g, 98%). 1H NMR (400 MHz, CDCl3) δ 7.55-7.35 (m, 2H), 7.35-6.9 (m, 3H), 3.26-2.98 (m, 2H), 2.84-2.64 (m, 2H), 2.64-2.53 (m, 1H), 2.53-2.32 (m, 1H), 1.90-1.68 (m, 2H), 1.68-1.36 (m, 3H), 1.22 (d, 6H, J=6.0 Hz); ESMS m/e: 247.1 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[NH2:18])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:27](Cl)(=[O:36])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:20]=[CH:19][C:8]([C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[NH:18][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cnccc2N)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)Nc2ccncc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 12.5 %

Procedure:
A solution of N3-(4-tert-butylbenzoyl)-3,4-pyridinediamine (400 mg, 1.49 mmol), pyridine (0.264 mL), and p-anisoyl chloride (0.254 mL, 1.49 mmol) in toluene (12 mL) was heated at reflux for 3 h. The mixture was filtered and the filtrate poured into a mixture of ethyl acetate and water. The organic layer was washed three times with water, once with saturated sodium chloride solution, dried, and filtered. Concentration in vacuo and purification of the residue by recrystallization (methanol/ethyl acetate/hexanes) followed by flash chromatography (silica gel, ethyl acetate/methylene chloride) yielded 75 mg (13%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].CS(O[CH:13]1[CH2:30][CH2:29][C:16]2([CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:15][CH2:14]1)(=O)=O>CN(C=O)C.O>[N:1]1([CH:13]2[CH2:30][CH2:29][C:16]3([CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:20][CH2:21]3)[CH2:15][CH2:14]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(OS(C)(=O)=O)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(n3ccnc3)CC2)CC1
Reaction time: 0.33 h
Yield: 59 %

Procedure:
Imidazole (1.17 g, 17.3 mmol, 3.0 eq.) was added to a stirred suspension of NaH (20.16 mmol, 3.5 eq.) in DMF (10 ml) at 0° C. and the reaction mixture was allowed to stir at the same temperature for 20 min. A solution of tert-butyl 9-(methylsulfonyloxy)-3-azaspiro[5.5]undecane-3-carboxylate (2.0 g, 5.76 mmol, 1.0 eq.) in DMF (5 ml) was added to the reaction mixture at 0° C. and it was stirred at RT for 16 h. The reaction mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (60 ml) and dried over sodium sulfate. The solvent was evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (silica gel; 3% MeOH/MC) to yield the desired product as a colorless oil. Yield: 59% (1.10 g, 3.45 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=[O:19].[CH2:21](I)[CH3:22]>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCI
Reactant: Nc1c(CC(=O)O)cccc1C(=O)c1ccc(Br)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(C(=O)c2ccc(Br)cc2)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 74 %

Procedure:
A slurry of 35.6 g (0.1 mole) of 2-amino-3-(4-bromobenzoyl)benzeneacetic acid in 500 ml of dimethylformamide was treated with 32.0 g (0.2 mole) of ethyl iodide and stirred at ambient temperature for 24 hours. The mixture was filtered and the filtrate was poured into 3.5 liters of water. The solid which precipitated was collected by filtration, washed with water and recrystallized from absolute ethanol to give 26.8 g (74%) of title compound, gold needles, m.p. 107°-109° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[C:18]([F:20])[C:17]([F:21])=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1cc(F)c(F)cc1F
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1cc(F)c(F)cc1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,4,5-triflouroaniline to yield 2-[(2,4,5-triflourophenyl)amino]phenylacetic acid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C(C)=CC=CC=1C>>[CH2:16]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(O)c(Cc2ccccc2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Product: COc1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
Trifluoromethanesulfonic anhydride (10.0 mL, 60 mmol) was added over 3 min to a solution of 2-benzyl-4-methoxyphenol (10.71 g, 50 mmol; prepared according to J. Am. Chem. Soc. 1949, 71, 64) and anhydrous 2,6-lutidine (12.0 mL, 100 mmol) in anhydrous CH2C2 (250 mL) at -78° C. under argon. The reaction was stirred at -78° C. for 0.5 h, then was warmed to RT. After 1 h, the reaction was diluted with hexanes (250 mL) and washed sequentially with 1.0 N HCl (2×100 mL), 1.0 N NaOH (2×50 mL), H2O (100 mL) and brine (50 mL). Drying (Na2SO4), concentration, and silica gel chromatography (10% EtOAc/hexanes) gave the title compound as a light yellow solid (16.65 g, 96%): TLC Rf 0.51 (10% EtOAc/hexanes); 1H NMR (250 MHz, CDCl3) δ 7.10-7.40 (m, 6H), 6.77 (dd, J=9.0, 3.1 Hz, 1H), 6.66 (d, J=3.1 Hz, 1H), 4.03 (s, 2H), 3.73 (s, 3H); FTIR (CCl4) 1492, 1423, 1405, 1249, 1216, 1161, 1144, 1039, 869 cm 1 ; MS (ES) m/e 369 (M+Na)+, 364.0 (M+NH4)+, 347.0 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[C:6]([F:16])=[C:7]2[C:12](=[CH:13][C:14]=1[F:15])[N:11]=[CH:10][CH:9]=[CH:8]2.O.[NH2:19][NH2:20]>C(O)C>[F:16][C:6]1[C:5]([CH2:4][C:3]([NH:19][NH2:20])=[O:2])=[C:14]([F:15])[CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: NN
Reactant: COC(=O)Cc1c(F)cc2ncccc2c1F
Solvent: O
Solvent: CCO
Product: NNC(=O)Cc1c(F)cc2ncccc2c1F
Temperature: 30 °C
Reaction time: 24 h

Procedure:
To a solution of (5,7-difluoro-quinolin-6-yl)-acetic acid methyl ester (1.023 g, 4.32 mmol) in ethanol (15 mL) was added hydrazine monohydrate (2 mL) and the mixture was stirred at 30° C. for 24 h. The solvent was removed in vacuo to afford 1.024 g of the title compound as white solid, which was used without further purification. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.33 (s, 1H), 8.97 (d, 1H), 8.46 (d, 1H), 7.67 (d, 1H), 7.61 (dd, 1H), 4.27 (s, 2H). LCMS (method A): [MH]+=238, tR=3.24 min. (5,7-difluoroquinolin-6-yl)-acetic acid methyl ester was synthesized using the method described in WO2008/144767 p 108 (intermediate 2), followed by the method described for Intermediate 12, step 1 WO2008/144767 p 114.
Reaction SMILES: Br[C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([F:21])([F:20])([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:8].O1CCCCC1[N:35]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=[N:36]1>>[OH:28][C@@H:25]1[CH2:26][CH2:27][N:23]([C:3]2[C:2]([C:37]3[NH:36][N:35]=[CH:39][CH:38]=3)=[CH:22][C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([S:16]([F:20])([F:19])([F:21])([F:17])[F:18])=[CH:14][CH:15]=3)=[O:8])=[CH:5][N:4]=2)[CH2:24]1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(S(F)(F)(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: O=C(Nc1ccc(S(F)(F)(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 8 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(pentafluorosulfanyl)phenyl)nicotinamide (Stage 17.1) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to afford a beige solid. HPLC (Condition 4) tR=4.68 min, UPLC-MS (Condition 3) tR=0.92 min, m/z=476.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.91 (m, 2H) 2.93 (d, J=11.73 Hz, 1H) 3.19-3.34 (m, 2H) 3.36-3.49 (m, 1H) 4.12-4.24 (m, 1H) 4.81 (d, J=3.13 Hz, 1H) 6.38 (s, 1H) 7.73-7.89 (m, 3H) 7.92-8.09 (m, 3H) 8.73 (d, J=1.96 Hz, 1H) 10.37 (s, 1H) 12.82-13.17 (m, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[CH:5]=[C:6]([N+:9]([O-])=O)[C:7]=1[NH2:8].[CH3:22][O:23][CH2:24][C:25]#[CH:26]>>[CH3:22][O:23][CH2:24][CH2:25][CH2:26][C:2]1[C:7]([NH2:8])=[C:6]([NH2:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[CH:3]=1
Reactant: Nc1c(I)cc(-c2ccccc2C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C#CCOC
Product: COCCCc1cc(-c2ccccc2C(F)(F)F)cc(N)c1N

Procedure:
The title compound was prepared from 3-iodo-5-nitro-2′-trifluoromethyl-biphenyl-4-ylamine (as prepared in Example 9, step A) and 3-methoxy-propyne according to the procedures described in Example 10, steps A and B.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[Br:25]CCO.S(=O)(=O)(O)O.C(=O)(O)[O-].[K+]>CCOCC>[Br:25][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: OCCBr
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOCC
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](Br)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Temperature: 25 °C

Procedure:
2α, 3α-Epoxy-5α-pregnane-11,20-dione (660 mg.) was dissolved in ether (70 ml.) and 2-bromoethanol (1 ml.) added to the solution. Concentrated sulphuric acid (0.5 ml.) was then added and the mixture stirred at room temperature for one-half hour. 10% Potassium bicarbonate solution (18 ml.) was added and when effervescence had ceased the aqueous layer was removed and extracted with ether (20 ml.). The combined organic extracts were washed with water (100 ml.), dried over anhydrous sodium sulphate and evaporated in vacuo to a pale yellow oil (794 mg.) which was purified by preparative tlc. The main band (RF ~ 0.3) gave 2β-bromo-3α-hydroxy-5α-pregnane-11,20-dione (230 mg.), m.p. 172°-3°C identical with a previously prepared sample.