Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([O:14]C)[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.N.CO>ClCCl>[Br:1][C:2]1[CH:13]=[C:12]([OH:14])[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COc1cc(Br)cc2ncn(C3CC3)c12
Agent: BrB(Br)Br
Agent: N
Solvent: ClCCl
Solvent: CO
Product: Oc1cc(Br)cc2ncn(C3CC3)c12
Temperature: 35 °C
Reaction time: 5 h

Procedure:
5-bromo-1-cyclopropyl-7-methoxy-1H-benzo[d]imidazole (0.54 g, 2.01 mmol) was dissolved in dichloromethane (12 mL) under N2. A 1M BBr3 solution in DCM (12 mL, 12 mmol) was added dropwise over 1 min. The resulting stirred suspension was heated to 35° C. After 5 h, the reaction mixture was cooled in an ice water bath. A 7M ammonia in MeOH solution (7.5 mL, 53 mmol) was then added over 2 min via syringe. The mixture was stirred 5 min and was removed from the ice bath. After an additional 10 min, the mixture was concentrated in vacuo, and the crude product was dissolved in MeOH (30 mL) and was concentrated in vacuo. The resulting crude solids were suspended in 20% MeOH in DCM (30 mL) and were filter through a short pad of silica, eluting with 20% MeOH in DCM. Filtrate was concentrated in vacuo, and the crude product was adsorbed onto silica gel. Purification by silica gel chromatography (0-20% MeOH in DCM) gave 5-bromo-1-cyclopropyl-1H-benzo[d]imidazol-7-ol (2.73). LCMS-ES r (m/z): [m+H]+ calcd for C10H10BrN2O: 253.00; found: 253.14.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:35](=[O:37])[CH3:36])[C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][C@@H:26]2[OH:34])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.I[CH3:40].[H-].[Na+]>CN(C=O)C.Cl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:38])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][N:24]([C:35](=[O:37])[CH3:36])[C@@H:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27][C@@H:26]2[O:34][CH3:40])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CI
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@@H]2c3ccccc3C[C@@H]2O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@@H]2c3ccccc3C[C@@H]2OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (2′-{[acetyl-((1R,2S)-2-hydroxy-indan-1-yl)-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.163 g, 0.31 mmol) and iodomethane (0.02 mL, 0.34 mmol) in DMF (1.6 mL) was added sodium hydride (60% in mineral oil; 0.015 g, 0.37 mmol), and the mixture was stirred at room temperature for 1 hour. Once minimal starting material was seen by analytical LCMS, the solution was diluted with aqueous 1N HCl and CH2Cl2. The organic layer was separated, dried over MgSO4., filtered, and concentrated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH3:12])[N:3]=1.[F:13][C@@H:14]1[C@@H:18]([CH2:19][OH:20])[O:17][C@@H:16](N2C=CC(=O)NC2=O)[CH2:15]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:16]2[O:17][C@H:18]([CH2:19][OH:20])[C@@H:14]([F:13])[CH2:15]2)=[C:4]([NH:11][CH3:12])[N:3]=1
Reactant: CNc1nc(Cl)nc2[nH]cnc12
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CNc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 216 h
Yield: 17.6 %

Procedure:
2-Chloro-6-methylamino-9H-purine (0.48 g 2.6 moles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 50 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.). and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added and the suspension was stirred at 45° C. After 9 days, 100 ml MeOH was added to the reaction mixture. The resulting mixture was filtered through Celite. The filtrate was flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:methanol (96:4). Solvent was removed and lyophilization yielded 0.117 g of 2-chloro-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-(methylamino)-9H-purine (18%): mp 181°-182° C.; TLC Rf 0.70 (silica ge, MeCN:15N NH4OH:H2O/85:5:10); [α]D20 -18.6 (c=0.5, DMF); UV λmax (ε×10-3) at pH 7, 269 (17.6); at pH 13, 269 (16.8); 1H NMR (400 MHz, DMSO-d6) δ8.35 (s, 1H, H8), 8.32 (b, 1H, NH), 6.30 (dd, 1H, H1', J=9.1 Hz, J=5.7 Hz), 5.41 (dd, 1H, H3', J=53.5 Hz, J=4.1 Hz), 5.16 (t, 1H, OH5', J=5.7 Hz), 4.16-4.24 (m, 1H, H4'), 3.57 (t, 2H, H5' and H5", J=5.2 Hz), 2.83-3.00 (m, 4H, NCH3 and H2') and 2.60-2.73 (m, 1H, H2"); MS (ci) 302 (M+1), 282 (M-F), 184 (MH2 --C5H8FO2).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH2:29]([C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]>>[CH2:29]([C:31]1[N:32]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: CCc1nc2ccccc2n1Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1
Yield: 63 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 2-ethylbenzimidazole, the title compound was isolated as a yellow solid in 63% yield (96% purity by HPLC).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][N:10]2[C:15](=[O:17])[CH3:16].C(=O)(O)[O-].[Na+]>S(=O)(=O)(O)O>[F:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][N:10]2[C:15](=[O:17])[CH3:16]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1CCc2c(F)cccc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(=O)N1CCc2c1ccc([N+](=O)[O-])c2F
Temperature: 0 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
Fuming nitric acid (0.22 mL) was added dropwise to a solution of 1-(4-fluoro-indolin-1-yl)ethanone (1 g, 5.58 mmol) in concentrated sulfuric acid (10 mL) at −15° C. to 0° C. The reaction mixture was stirred at 0° C. for 2 h and then the resulting mixture was basified with sodium bicarbonate solution (100 mL). The reaction mixture was partitioned between chloroform (100 mL) and water (100 mL). The organic layer was separated and the aqueous layer was extracted with chloroform (5×30 mL). The combined organic layers were washed with water (3×20 mL), brine (3×20 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to give the crude product. Purification by column chromatography over neutral alumina using 10-12% ethyl acetate in hexane as eluent afforded 1-(4-fluoro-5-nitro-indolin-1-yl)ethanone (0.56 g, 45%) as a yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][O:14][CH3:15])C.[OH-].[Na+]>CO>[CH3:15][O:14][CH2:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)Cc1ccccc1OCOC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCOc1ccccc1CC(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
To 20 mL of a methanol solution containing 0.69 g of ethyl-(2-methoxymethoxyphenyl)acetate, 16 mL of 1M aqueous sodium hydroxide solution was added and stirred at room temperature for 5 hours. From the reaction liquid the solvent was distilled off under reduced pressure and the residue was rendered acidic with 2M aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate and thereafter the solvent therein was distilled off under reduced pressure to provide 0.47 g (yield: 77%) of the title compound as an oily substance.
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=1[NH2:6])[CH2:2][CH3:3].Cl[CH2:13][CH:14]=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH2:1]([C:4]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:5]=1[NH:6][CH2:13][CH:14]=[O:15])[CH2:2][CH3:3]
Reactant: CCCc1ccc(F)cc1N
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCc1ccc(F)cc1NCC=O
Temperature: 150 °C

Procedure:
2-Propyl-5-fluoroaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at about 150° C. for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-propyl-5-fluoroanilino)actaldehyde.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([CH2:11][CH2:12][CH:13]([CH3:17])[CH2:14][CH2:15][Br:16])C(OCC)=O)C.Br.C1C=CC=CC=1>O>[Br:16][CH2:15][CH2:14][CH:13]([CH3:17])[CH2:12][CH2:11][CH2:5][C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C(CCC(C)CCBr)C(=O)OCC
Agent: Br
Solvent: c1ccccc1
Solvent: O
Product: CC(CCBr)CCCC(=O)O

Procedure:
30 g of (5-bromo-3-methylpentyl)-malonic acid diethyl ester were heated to the boil, while stirring, with 15 ml of 48% HBr and 15 ml of HBr/glacial acetic acid, whereby the low-boiling products were distilled off. After 7 hours the cooled reaction solution was distributed between benzene and water and the organic phase was evaporated with MgSO4 after drying and distilled off.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[CH:10]12[CH2:16][CH:13]([CH:14]=[CH:15]1)[CH2:12][CH:11]2[CH:17]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH3:33])[CH:27]=1)[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=1.C(N(CC)CC)C.C(O)=O>C(OCC)(=O)C.CN(C=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]2[CH2:15][CH:10]3[CH2:16][CH:13]2[CH2:12][CH:11]3[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH3:25])[CH:19]=2)[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([CH3:33])[CH:27]=2)=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(C(c2ccc(O)c(C)c2)C2CC3C=CC2C3)ccc1O
Reactant: Cc1cc(Br)ccc1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=CO
Product: Cc1cc(C2CC3CC2CC3C(c2ccc(O)c(C)c2)c2ccc(O)c(C)c2)ccc1O
Temperature: 75 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
Under a nitrogen atmosphere, 4-Bromo-2-methylphenol (4.69 g, 25.1 mmol), (tris-o-tolylphosphine)2PdCl2 (0.377 g; 0.480 mmol), and 4,4′-(bicyclo[2.2.1]hept-5-en-2-ylmethylene)bis(2-methylphenol) (5.14 g; 16.0 mmol) were charged to an appropriately sized and equipped reaction vessel. DMF (80 mL) was added to this reactant mixture to give a suspension. Triethylamine (11.0 mL, 78.9 mmol) and formic acid (2.30 mL, 60.9 mmol) were added to this suspension and then heated to 75° C. in an oil bath. The reaction mixture turned from its original orange suspension to pale yellow and became clear. During, the course of the reaction, the temperature of the reaction mixture rose to 82° C. and turned darker, and a gas evolved very slowly. Alter the initial exothermic reaction ceased, the reaction mixture was stirred overnight at 75° C. After this time, the reaction mixture was a clear, pale yellow solution with black particles. The cooled reaction mixture was diluted with ethyl acetate (80 mL) and washed with water (160 mL) to remove DMF. The organic layer was dried over anhydrous MgSO4. The crude mixture was purified by preparative TLC using a hexanes/ethyl acetate mixture (50:50) as developer to afford 3.7 g of 4,4′-((5-(4-hydroxy-3-methylphenyl)bicyclo[2.2.1]heptan-2-yl)methylene)-bis(2-methylphenol) (54% yield). The identity of the product as PP429 was confirmed by LC-MS (ESI) and proton NMR.
Reaction SMILES: CCO.[C:4]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])=[O:10])([CH3:7])([CH3:6])[CH3:5].[NH2:32][C:33]1[N:38]=[C:37](Cl)[CH:36]=[C:35]([Cl:40])[N:34]=1.C(=O)=O>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[NH2:32][C:33]1[N:38]=[C:37]([C:20]2[CH:19]=[CH:18][C:17]([CH2:16][C@H:12]([NH:11][C:9]([O:8][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:10])[C:13]([OH:15])=[O:14])=[CH:22][CH:21]=2)[CH:36]=[C:35]([Cl:40])[N:34]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(Cl)nc(N)n2)cc1)C(=O)O
Temperature: 15 °C
Reaction time: 0.25 h
Yield: 82 %

Procedure:
To a 5-L three-necked flask with a thermometer controller, a mechanical stirrer, and a condenser protected under N2 was charged EtOH (570 g), THF (1330 g), boronic acid 7 (100 g, 255.6 mmol, 1.0 eq.), 2-amino-4,6-dichloropyrimidine 126 g (768.3 mmol, 3.0 eq.), PPh3 (0.87 g, 3.32 mmol, 1.3 mol %) and Pd(OAc)2 (0.373 g, 1.66 mmol, 0.65 mol %). The flask was then degassed by three vacuum/nitrogen fill cycles and stirred at about 10-20° C. for about 10-20 minutes. To the stirring solution was added an aqueous solution of KHCO3 (92 g, 918.9 mmol, 3.6 eq in 579 g of water) over about 30-50 minutes to control the evolution of CO2 gas). The flask was then degassed again by three vacuum/nitrogen fill cycles. The resulting solution was then refluxed at about 68˜72° C. for 21˜23 hours and the reaction was determined to be complete base on HPLC analysis. The reaction mixture was concentrated to ˜750 mL under reduced pressure at 35˜40° C. and then flushed with water (300 mL×2). The concentrated solution was diluted with water (600 g) and stirred for 15˜30 minutes at 20˜25° C. After filtration, the filter cake was washed with water (200 g×2). The filtrate was extracted with EtOAc (500 g×2). The combined EtOAc layer was washed with water (300 g). THF (1000 g) and toluene (730 g) were then added to the combined aqueous layer and the mixture was acidified to pH 2.5˜3.5 with 6 N HCl (−100 g) at 20˜25° C. The layers were separated and NaCl (500 g) was added to the aqueous layer then extracted with EtOAc (400 g). The combined organic layer was treated with active carbon (50 g) at 65˜68° C. for 8˜10 hours twice. The resulting mixture was concentrated under vacuum to ˜300 mL at 30˜40° C. and then flushed with toluene (500 g). The resulting mixture was cooled to 0˜5° C. and stirred for 60˜80 minutes at 0˜5° C., and then filtered. The wet cake was washed with toluene (43 g) and dried in vacuum oven at 40˜45° C. for 12 hours to afford 82.3 g of the monochloride toluene solvate 8 as an off-white solid in 66% yield corrected for 80 w % purity (96.3 A %).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:18][CH2:19][C:20]3(C(F)(F)F)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:6][C:7]([F:17])=[C:8]([CH:16]=2)[C:9]([O:11]C(C)(C)C)=[O:10])[CH2:3][CH2:2]1.C1(COC2C(C3CC3)=CC(C(OC(C)(C)C)=O)=C(F)C=2)CCCCC1>>[CH:20]1([CH2:19][O:18][C:5]2[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:16][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:17])[CH:6]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F
Product: O=C(O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F

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 4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoate, the title compound was obtained as a colorless solid (6.64 g, 58%): MS (ES−) m/z 291.3 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21]CC2C=CC=CC=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1COc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of the product from step 1, in THF (11 ml), EtOH (25 ml), Pd—C (1.17 g, 10% wt) in a round bottom flask was charged with H2-balloon after flushing with hydrogen 3 times. The resulting solution was stirred overnight at rt. The reaction mixture was then filtered, washed with THF (30 ml), EtOH (25 ml) and dried over anhydrous MgSO4. After removal of the solvent in vacuo, the product was obtained as an orange oil (1.0 g, 95%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2nccs2)cc1
Temperature: 95 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
To a stirred solution of (4-fluorophenyl)boronic acid (10 g, 60.9 mmol) in toluene (70 mL) and ethanol (200 mL) was added 2-bromothiazole (12.7 g, 91.4 mmol), followed by Pd(PPh3)4 (3.5 g, 3.04 mmol). The reaction mixture was purged with argon for 20 min, Na2CO3 solution (2M, 100 mL, 19.39 g) added, and the reaction mixture stirred at 95° C. for 5 h. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution (2×100 mL), and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with ice-cold water (2×100 mL) followed by brine solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtained crude product. The crude product was purified by column chromatography (100-200 mesh silica gel) using 10% ethyl acetate in hexane to obtain 2-(4-fluorophenyl)thiazole as white solid (9.0 g, 82% yield). 1H NMR (400 MHz, DMSO): 7.98 (dd, 2H, J=6.8 & 14.0 Hz), 7.88 (d, 1H, J=4.8 Hz), 7.91 (d, 1H, J=2.8 Hz), 7.88 (d, 1H, J=4.8 Hz), 7.31 (t, 2H, J=8.8 & 17.2 Hz).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O.O>[F:1][C:2]1[C:3]2[O:10][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:5][C:4]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)CBr
Reactant: O=Cc1cccc(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cccc(F)c2o1
Temperature: 100 °C
Yield: 51.9 %

Procedure:
A mixture of 3-fluoro-2-hydroxybenzaldehyde (5.00 g, 35.7 mmol), potassium carbonate (9.85 g, 71.4 mmol), and ethyl bromoacetate (4.30 ml, 39.3 mmol) in N,N-dimethylformamide (70 mL) was heated at 100° C. for 16 h. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (3×150 mL). The combined organic solution was washed with brine (150 mL), dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo. The residue was purified by column chromatography (hexanes/ethyl acetate, 49/1→9/1) to afford ethyl 7-fluorobenzofuran-2-carboxylate (3.86 g, 52%) as a yellowish oil: 1H NMR (300 MHz, CDCl3) δ7.56-7.54 (m, 1H), 7.47-7.42 (m, 1H), 7.28-7.14 (m, 2H), 4.46 (q, J=7.1 Hz, 2H), 1.43 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[OH:20][CH:21]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1)[C:22](O)=[O:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([C:22](=[O:23])[CH:21]([OH:20])[C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=5)[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)C(O)c1cccc(C(F)(F)F)c1
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(C(O)c1cccc(C(F)(F)F)c1)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the product from Example 54F (0.05 g, 0.168 mmol) and 2-hydroxy-2-(3-(trifluoromethyl)phenyl)acetic acid (0.035 g, 0.160 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.070 g, 0.185 mmol) and N-methylmorpholine (0.056 mL, 0.505 mmol). The resulting mixture was stirred at room temperature for 90 minutes and was then partitioned between water and ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-10% methanol in dichloromethane. The title compound was obtained as a colorless solid (73 mg, 94%). 1H NMR (300 MHz, CDCl3) δ ppm 0.87-0.99 (m, 4 H) 1.23-3.25 (m, 9H) 3.48-3.73 (m, 2 H) 4.57-4.84 (m, 2 H) 5.20-5.37 (m, 2 H) 7.45-7.64 (m, 4 H) 7.87-8.05 (m, 2 H); MS (ESI) m/z 463 (M+H)+.
Reaction SMILES: [OH:1][C@:2]1([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:25]=[CH:24][C:23]([CH:26]([OH:28])[CH3:27])=[CH:22][CH:21]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1.[C:37]([O:41][C:42]([NH:44][C@@H:45]([CH3:49])[C:46](O)=[O:47])=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[OH:1][C@:2]1([C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[C@:18]2([CH3:19])[C@H:5]([C@H:6]3[C:15]([C@@H:16]([C:20]4[CH:21]=[CH:22][C:23]([CH:26]([O:28][C:46](=[O:47])[C@@H:45]([NH:44][C:42]([O:41][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:43])[CH3:49])[CH3:27])=[CH:24][CH:25]=4)[CH2:17]2)=[C:14]2[C:9](=[CH:10][C:11](=[O:29])[CH2:12][CH2:13]2)[CH2:8][CH2:7]3)[CH2:4][CH2:3]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(O)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Product: CC(OC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1ccc([C@H]2C[C@@]3(C)[C@@H](CC[C@@]3(O)C(F)(F)C(F)(F)F)[C@@H]3CCC4=CC(=O)CCC4=C32)cc1
Yield: 73 %

Procedure:
In analogy to Example 5, 300 mg (0.59 mmol) of (8S,11R,13S,14S,17S)-17-hydroxy-11-[4-((RS)-1-hydroxyethyl)phenyl]-1 3-methyl-17-pentafluoroethyl-1,2,6,7,8,11,12,13,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one were converted using (S)-2-tert-butoxycarbonylaminopropionic acid and, after workup and purification, 294 mg (73%) of the title compounds were isolated as a colourless foam.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12].C(O)CC>ClC>[NH:11]([C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][N:3]=1)[NH2:12]
Reactant: NN
Reactant: Fc1cnc(F)c(F)c1
Agent: CCl
Solvent: O
Solvent: CCCO
Product: NNc1ncc(F)cc1F
Yield: 85.6 %

Procedure:
6.65 g of the compound obtained in Step 3 and 4.6 ml of hydrazine monohydrate were added to 100 ml of n-propanol. The resulting mixture was refluxed for 6 hours, and distilled under a reduced pressure to remove the solvent. The residue thus obtained was dissolved in 80 ml of chloromethane, washed with water, and dried over anhydrous magnesium sulfate. The resulting organic layer was concentrated under a reduced pressure to obtain 6.20 g (yield: 85.6%) of the title compound.