Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([CH3:20])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=2)=[CH:7][CH:6]=1.[CH2:22]([NH:29][CH2:30][CH2:31][O:32][C:33]1[CH:41]=[C:37]([C:38]([NH2:40])=[O:39])[C:36]([OH:42])=[CH:35][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[CH2:22]([N:29]([CH2:30][CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([OH:42])=[C:37]([C:38](=[O:39])[NH2:40])[CH:41]=1)[CH2:21][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]([CH3:20])[CH:13]=[C:14]([C:16]([F:17])([F:19])[F:18])[N:15]=2)=[CH:9][CH:10]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC(=O)c1cc(OCCNCc2ccccc2)ccc1O
Reactant: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC2CO2)cc1
Solvent: CC(C)O
Product: Cn1cc(C(F)(F)F)nc1-c1ccc(OCC(O)CN(CCOc2ccc(O)c(C(N)=O)c2)Cc2ccccc2)cc1

Procedure:
A solution of 5 g of 2-[4-(2,3-epoxypropoxy)-phenyl]-1-methyl-4-(trifluoromethyl)-imidazole and 4.7 g of 5-[2-(benzylamino)-ethoxy]-salicylamide in 100 ml of isopropanol is heated under reflux for 15 hours and the solvent is subsequently removed in a rotary evaporator. The crude 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-[1-methyl-4-(trifluoromethyl)-imidazol-2-yl]-phenoxy]-2-propanol, obtained in the form of an oil, is further processed in that form.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12]([NH:14][N:15]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]2[C:21]([O:23]C)=O)=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:25]>O.CCOC(C)=O>[Cl:20][C:17]1[CH:18]=[CH:19][N:15]2[C:16]=1[C:21]([OH:23])=[N:25][C:12]([C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:11][CH2:10]1)=[N:14]2
Reactant: N
Reactant: COC(=O)c1c(Cl)ccn1NC(=O)C1(NC(=O)OC(C)(C)C)CC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2nc(O)c3c(Cl)ccn3n2)CC1
Temperature: 110 °C
Yield: 46.3 %

Procedure:
A stirred solution of methyl 1-(1-((tert-butoxycarbonyl)amino)cyclopropanecarboxamido)-3-chloro-1H-pyrrole-2-carboxylate (500 mg, 1.40 mmol) in water (12 mL) was purged with NH3 gas for 5 minutes. The sealed pressure tube was heated at 110° C. for 12 h. The reaction mixture was dissolved in EtOAc (100 mL) and washed with water (50 mL). The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using CombiFlash ISCO (REDISEP®, SiO2, 12 g, 50% EtOAc/petroleum ether) to give tert-butyl (1-(5-chloro-4-hydroxypyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)carbamate (210 mg, 46.3%) as a off-white solid. LCMS Condition B-16: retention time 0.91 min, [M+1]=325.1. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.06-1.10 (m, 2H), 1.37-1.45 (m, 2H), 1.41 (s, 9H), 6.57 (d, J=2.4 Hz, 1H), 7.31 (br s, 1H), 7.51 (d, J=2.4 Hz, 1H), 11.32 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[O:6][CH2:5][CH2:4][O:3]1.CCN(CC)CC.C(Cl)(=O)C(C)(C)C.[O:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33].[Li]CCCC.[Li]>C(OCC)(=O)C.C1COCC1>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([N:30]2[CH2:31][CH2:32][O:28][C:29]2=[O:33])=[O:13])[O:3][CH2:4][CH2:5][O:6]1
Reactant: O=C1NCCO1
Reactant: CC1(CCCCC(=O)O)OCCO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(CCCCC(=O)N2CCOC2=O)OCCO1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-2 (16.0 g, 85.5 mmol), NEt3 (13.1 ml, 94.1 mmol) and THF (400 mL) at -78° C. was added pivaloyl chloride (11.6 ml, 94.1 mmol). The mixture was warmed to 0° C. for 1.0 h and then recooled to -78° C. To a stirred solution of 2-oxazolidinone (9.3 g, 106.9 mmol) and THF (200 ml) at -78° C. was added nBuLi (43.0 ml, 106.9 mmol, 2.5M in hexanes) dropwise over 10 minutes. After 20 minutes, the lithium reagent was transferred to the mixed anhydride via cannula. After 10 minutes, the reaction was warmed to 0° C. for 1.0 h. The mixture was diluted with ethyl acetate, washed with sat. NaHCO3, brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 40%-50% EtOAc/hexanes) to give 2-3 as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C@:13]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([NH2:17])[CH2:14][CH:15]=[CH2:16])[CH3:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:14]([C@:13]1([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH2:12][CH2:11][N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH3:9])[C:33](=[O:35])[NH:17]1)[CH:15]=[CH2:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CC[C@@](N)(CCN[C@@H](C)c1ccc(Br)cc1)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)N1
Reaction time: 3 h
Yield: 20.3 %

Procedure:
To a solution of (R)—N1—((S)-1-(4-bromophenyl)ethyl)-3-(4-fluorophenyl)hex-5-ene-1,3-diamine (12 g, 31 mmol) in CH2Cl2 (100 mL) and Et3N (36 g, 0.36 mmol) was added triphosgene (3.50 g, 11.8 mmol) at 0° C. The resulting mixture was stirred for 3 h. The mixture was washed with water. The organic layer was separated, and concentrated to give the crude product, which was purified by column chromatography to afford (R)-4-allyl-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (1.0 g, 8%). 1H NMR (CDCl3): δ=1.49 (t, 3H), 2.00 (m, 2H), 2.35 (m, 2H), 2.76 (m, 2H), 5.18 (m, 2H), 5.31 (m, 2H), 5.72 (q, 1H), 6.95 (m, 4H), 7.18 (m, 2H), 7.254 (m, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:12]=[C:11]([C:13]([Cl:18])=[O:15])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc(-c2ccccc2)n1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cccc(-c2ccccc2)n1
Temperature: 40 °C
Reaction time: 13 h

Procedure:
A 2-L three neck round bottomed flask equipped with an overhead stirrer, thermocouple, heating mantle with digital temperature controller, condenser and nitrogen inlet/outlet was charged with 100.0 g (0.502 mol) of 6-phenyl-2-pyridinecarboxylic acid and 1500 mL of toluene (Kf<0.02 wt %) then warmed to 40° C. Thionyl chloride (110 mL; 1.51 mol, 3 eq) was then added to the thin slurry via addition funnel over 20 minutes. The thin slurry was heated to 75° C. and stirred overnight (typically 10-16 hr), until it became a clear solution. Reaction was assayed via HPLC for conversion as the methyl ester derivative. After cooling the reaction mixture to room temperature the solvent and excess thionyl chloride were removed in vacuo as follows: Reaction mixture was stripped under full vacuum at 40° C. (bath temperature) to approximately ⅓ its original volume (˜500 ml) and then (1000 ml) of fresh toluene was added. Concentration was continued, again stripping to ⅓ original volume (˜500 ml) followed by re-dilution with 1000 ml of fresh toluene. The total amount of toluene removed was ˜2000 mL.
Reaction SMILES: C([O-])(=O)C.[C:5]([NH:8][CH:9]1[CH2:14][CH2:13][NH2+:12][CH2:11][CH2:10]1)(=[O:7])[CH3:6].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C>CN(C=O)C>[N+:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:5](=[O:7])[CH3:6])[CH2:10][CH2:11]1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(=O)NC1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 5 %

Procedure:
To a flask was added 4-acetylamino-piperidinium acetate (as prepared in the previous step) (800 mg, 4.00 mmol), DMF (40 mL), 2-fluoro-1-nitrobenzene (422 μL, 4.00 mmol), triethylamine (836 μL, 6.00 mmol) and the mixture stirred at RT for 17 h. The solvents were removed in vacuo and the residue was purified by silica gel preparative TLC eluting with dichloromethane/hexane/acetonitrile (47.5/47.5/5 v:v:v) yielded 55 mg (5%) of the title compound as a crystalline orange solid. 1H-NMR (400 MHz, CDCl3): δ 8.18 (m, 1H), 8.09 (br d, 1H, J=7.2 Hz), 7.45 (m, 1H), 6.88 (m, 1H), 6.67 (m, 1H), 4.38 (m, 1H), 3.86-3.74 (m, 1H), 3.32 (m, 1H), 3.07 (m, 1H), 2.14 (s, 3H), 1.67-1.52 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([F:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:17]([Si](C)(C)C)#[CH:18].O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO.[Cu]I>[C:17]([C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([F:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1)#[CH:18]
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cc1F
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: C#Cc1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a degassed solution of 4-(2-chloropyridin-4-yloxy)-2-fluoroaniline from Example A1 (0.801 g, 3.36 mmol) in DMF (2 mL) and TEA (2 mL) was added ethynyltrimethylsilane (0.929 ml, 6.71 mmol), trans-dichloro-bis(triphenyl phosphine) palladium(0) (0.236 g, 0.336 mmol) and copper (I) iodide (0.064 g, 0.336 mmol) and the mixture was stirred at 90° C. for 16 h. Water (60 ml) was added to the mixture, product was extracted with EtOAc (2×45 ml) and the combined organics were washed with brine, dried (Na2SO4) and concentrated to afford crude product. The product was dissolved in methanol (10 ml), K2CO3 (0.5 g) was added and the mixture was stirred at RT for 2 h. Solvent was removed, water (60 mL) and EtOAc (40 ml) were added, the layers were separated and the aqueous layer was extracted with EtOAc (1×30 mL). The combined organic layer was washed with brine, dried (Na2SO4), concentrated and purified by column chromatography (ethylacetate/hexanes) to afford 4-(2-ethynylpyridin-4-yloxy)-2-fluorobenzenamine as a thick residue (0.56 g, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.37 (d, J=6.0 Hz, 1H), 6.98 (dd, J=8.0 Hz, 2.4 Hz, 1H), 6.95 (d, J=6.0 Hz, 1H), 6.87 (dd, J=6.0 Hz, 2.4 Hz, 1H), 6.81-6.73 (m, 2H), 5.20 (brs, 2H), 4.03 (s, 1H); MS (ESI) m/z: 229.1 (M+H+).
Reaction SMILES: C(C1C=CC(C2C3C(=CC=C(C#C[C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=4)C=3)SC(C)(C)C=2)=CC=1)C.[OH-].[Na+].Cl>C1COCC1.CCO>[C:25]([OH:27])(=[O:26])[C:24]1[CH:30]=[CH:31][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]ethynyl]-benzoate (940.0 mg. 2.08 mmol) in 10.0 mL THF and 5.0 mL EtOH was added NaOH (416.0 mg, 10.4 mmol, 5.2 mL of a 2M aqueous solution). The resulting solution was stirred overnight at room temperature. The reaction was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 786.0 mg (89%) of 4-[[4-(4-ethylphenyl)-2,2-dimethyl-2H)-thiochromen-6-yl]-ethynyl]-benzoic acid as a colorless solid. 1H NMR (300 MHz, d5 acetone) δ: 8.01 (2H, d, J=8.3 Hz), 7.60 (2H, d, J=8.5 Hz), 7.42 (2H, m), 7.29 (2H, m), 7.22 (3H, m), 5.94 (1H, s), 2.69 (2H, 1, J=7.7 Hz), 1.47 (6H, s), 1.25 (3H, t, J=7.7 Hz). This compound is hereinafter designated as AGN 194310.
Reaction SMILES: C1CC(S)CC1.[CH:7]1([S:13]([C:16]2[CH:37]=[CH:36][CH:35]=[CH:34][C:17]=2[CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[N:21]([CH2:29][C:30]([OH:32])=[O:31])[C:20]=2[CH3:33])(=[O:15])=[O:14])[CH2:12][CH2:11][CH2:10]C[CH2:8]1>>[CH:7]1([S:13]([C:16]2[CH:37]=[CH:36][CH:35]=[CH:34][C:17]=2[CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[N:21]([CH2:29][C:30]([OH:32])=[O:31])[C:20]=2[CH3:33])(=[O:15])=[O:14])[CH2:8][CH2:10][CH2:11][CH2:12]1
Reactant: Cc1c(Cc2ccccc2S(=O)(=O)C2CCCCC2)c2cc(F)ccc2n1CC(=O)O
Agent: SC1CCCC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)C2CCCC2)c2cc(F)ccc2n1CC(=O)O

Procedure:
Cyclopentylthiol was used as starting material in Procedure A, otherwise this compound was prepared in a similar manner to Compound 1, using Procedures A, B, K & L.
Reaction SMILES: [CH2:1]([C@@H:4]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])[CH:2]=C.C1(C)C=CC=CC=1.I([O-])(=O)(=O)=[O:31].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH2:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][C@H:4]([CH2:1][CH:2]=[O:31])[CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CC[C@@H](CCCCOCc1ccccc1)CCC(=O)OC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC[C@@H](CC=O)CCCCOCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of methyl (S)-4-allyl-8-(benzyloxy)-octanoate (2.37 g, 7.8 mmol) in tetrahydrofuran (70 ml) and water (24 ml) is added a solution of 10 mg/ml of osmium tetroxide in toluene (9.4 ml, 0.37 mmol). Sodium periodate (3.57 g, 16.7 mmol) is added in small portions over a period of 0.5 hour. The mixture is allowed to stir for 1 hour and then poured on water and extracted with ether (3×30 ml). The combined organic extracts are dried, filtered and evaporated to give crude methyl (S)-8-(benzyloxy)-4-(formylmethyl)octanoate; IR (CH2Cl2): 2727, 1724, 1202, 1100 cm-1.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][C:25]4[S:26][C:27]5[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=5[N:29]=4)=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:35]>C(Cl)Cl.O1CCOCC1>[ClH:35].[ClH:35].[S:26]1[C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=[C:25]1[O:24][C:20]1[CH:19]=[C:18]2[C:23]([C:15]([CH2:14][N:11]3[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]3)=[CH:16][NH:17]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC1CCN(Cc2c[nH]c3cc(Oc4nc5ccccc5s4)ccc23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of {1-[6-(benzothiazol-2-yloxy)-1H-indol-3-ylmethyl]-piperidin-4-yl}-carbamic acid tert-butyl ester (500 mg, 1.04 mmol) in DCM (20 mL) was added 4 M HCl in dioxane (20 mL) and the resulting reaction mixture was stirred (rt, 4 h). The reaction mixture was concentrated in vacuo to provide the title compounds as a tan solid (470 mg, 100%). MS (ESI): mass calcd. for C21H22N4OS, 378.5; m/z found, 379.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:55]([C:58]1[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH3:65])[CH:59]=1)=[C:56]=[O:57]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:56]([NH:55][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH3:65])[CH:59]=2)=[O:57])[CH2:49][CH2:48]1
Reactant: COc1cccc(N=C=O)c1
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(NC(=O)N2CCC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)CC2)c1
Yield: 26 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-Chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 1-isocyanato-3-methoxybenzene as starting materials in 26% yield. LCMS for C32H34ClN8O3 (M+H)+: m/z=613.2.
Reaction SMILES: N/C(/C#N)=C(\N[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[F:18])=[O:8])/C#N.FC1C=C(OC)C=CC=1N.C(Cl)(=O)OC(Cl)(Cl)Cl.CCOC(C)=O>C1(C)C=CC=CC=1>[F:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[N:9]=[C:7]=[O:8]
Reactant: COc1ccc(NC(=O)N/C(C#N)=C(\N)C#N)c(F)c1
Agent: COc1ccc(N)c(F)c1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(N=C=O)c(F)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
(Z)-1-(2-Amino-1,2-dicyanovinyl)-3-(2-fluoro-4-methoxyphenyl)urea. In a 100 mL round-bottomed flask was added 2-fluoro-4-methoxyaniline (0.79 g, 5.60 mmol) and trichloromethyl carbonochloridate (0.68 mL, 5.60 mmol) in toluene (6 mL) to give a purple suspension. The mixture was then stirred at 110° C. for 3 h. Upon heating, the suspension becomes a homogeneous solution. After 3 h, no starting material remained (TLC, 3:1 hex/EtOAc). The reaction mixture was concentrated to afford 2-fluoro-1-isocyanato-4-methoxybenzene (0.936 g, 5.6 mmol, quant.) as a green oil. The intermediate 2-fluoro-1-isocyanato-4-methoxybenzene (0.936 g, 5.6 mmol) was then dissolved in acetonitrile (20 ml) and reacted with 2,3-diaminomaleonitrile (0.605 g, 5.60 mmol) according to General Procedure A. The product was filtered to give the title compound (1.36 g, 88%). MS (ESI) m/z 276.3[M+1]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6](=[O:20])[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([N+:17]([O-])=O)[CH:8]=1>CCOC(C)=O.[Pd]>[NH2:17][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=1)[C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:20]
Reactant: COCCNC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCCNC(=O)c1cc(N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 924 %

Procedure:
To a stirred solution of N-(2-methoxyethyl)-3-nitro-5-(trifluoromethyl)benzamide (760 mg, 0.26 mmol) in EtOAc (20 mL) was added Pd on carbon (10% wt, 76 mg). The mixture was allowed to stir at rt overnight under an atmosphere of hydrogen. The mixture was diluted with EtOAc and filtered through Celite. The filtrate was evaporated and the residue was purified by column chromatography (SiO2, MeOH/DCM) to yield the title compound as a white solid (630 mg, 92%). LCMS: (FA) ES+ 263.2 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][C:7](=[O:20])[C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16](N)=[O:17])[CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1.C(O)(=[O:25])C.Cl>O>[F:1][C:2]1[CH:22]=[CH:21][C:5]2[CH2:6][C:7](=[O:20])[C:8]3[CH:14]=[C:13]([CH:15]([CH3:19])[C:16]([OH:25])=[O:17])[CH:12]=[CH:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1ccc(F)cc1S2
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1ccc(F)cc1S2
Temperature: 100 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a mixture of 300 mg of 2-(10,11-dihydro-7-fluoro-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide and 3 ml of acetic acid was added 3 ml of hydrochloric acid, and the resulting mixture was stirred at 100° C. for 2 hours. After cooling, to this was added water, and the mixture was extracted with ethyl acetate. The extract was re-extracted with a dilute sodium hydroxide solution. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by distillation to obtain yellow crystals, which were recrystallized from benzene, thereby obtaining 200 mg (yield: 67%) of 2-(10,11-dihydro-7-fluoro-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as colorless crystals having a melting point of 147.5°-148° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][CH2:8][C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:12]=3[C:13]=2[CH3:14])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH2:8][C:9]2[O:10][C:11]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:30][CH:29]=[CH2:28])[C:12]=3[C:13]=2[CH3:14])=[CH:20][CH:21]=1
Reactant: C=CCBr
Reactant: COc1ccc(CCc2oc3cccc(O)c3c2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cccc2oc(CCc3ccc(OC)cc3)c(C)c12
Yield: 60.7 %

Procedure:
A mixture of 2-(p-methoxyphenethyl)-3-methyl-4-hydroxybenzofuran (1.3 gm; 4.6 mmoles), potassium carbonate (1.38 gm, 10 mmoles), and allyl bromide (1.2 gm, 10 mmoles) in acetone (50 mL) was refluxed for a period of 5 hours. The solids were filtered off and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 15% ethylacetate in hexane to yield 0.9 gm of 2-(p-methoxyphenethyl)-3-methyl-4-allyloxybenzofuran, which was used as such for the next step.
Reaction SMILES: [CH3:1][C@@:2]12[C@H:12]3[CH2:13][CH2:14][C@:15]4([CH3:22])[C@:19]([OH:21])([CH3:20])[CH2:18][CH2:17][C@H:16]4[C@@H:11]3[CH2:10][CH2:9][C@H:8]1[CH2:7][C:5](=[O:6])[CH2:4][CH2:3]2.I(C1C=CC=CC=1C(O)=O)(=O)=O>C1(C)C=CC=CC=1.CS(C)=O>[CH3:20][C@:19]1([OH:21])[CH2:18][CH2:17][C@H:16]2[C@H:11]3[C@H:12]([CH2:13][CH2:14][C@:15]12[CH3:22])[C@:2]1([CH3:1])[C@H:8]([CH2:7][C:5](=[O:6])[CH:4]=[CH:3]1)[CH2:9][CH2:10]3
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: C[C@]12C=CC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(C)O
Temperature: 67.5 °C

Procedure:
A mixture of mestanolone (55.3 g, 0.182 mol) and IBX (76.5 g, 0.273 mol, 1.5 eq.) in 1800 ml toluene:DMSO (2:1) was heated at 65-70° C. for 48 h after which time the beginning clear solution turned into a suspension. TLC (thin layer chromatography) indicated the disappearance of starting mestanolone and the appearance of the desired product and two by-products. After cooling to RT (room temperature), the reaction mixture was filtered on a frit and solid washed with ethyl acetate (2×200 ml). The filtrate was diluted with 1000 ml of ethyl acetate and the resulting organic phase was washed with 1000 ml each of 5% NaHCO3, water, and brine. After drying over sodium sulfate, removal of the solvents on a rotavapor gave ˜56.0 g of a crude products mixture containing the required product (i.e., 17α-methyl-17β-hydroxy-5α-androst-1-en-3-one) along with two minor by-products.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:31])[C:11]#[C:12][C:13]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:14]=2/[C:15](=[CH:23]/[C:24]2[NH:25][CH:26]=[CH:27][C:28]=2[O:29][CH3:30])/[C:16](=[O:22])[NH:17]3)=[CH:6][CH:5]=1.O[Li].O>C1COCC1.O>[CH3:30][O:29][C:28]1[CH:27]=[CH:26][NH:25][C:24]=1/[CH:23]=[C:15]1\[C:16](=[O:22])[NH:17][C:18]2[C:14]\1=[C:13]([C:12]#[C:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:32])=[O:2])=[CH:9][CH:8]=1)[OH:31])[CH:21]=[CH:20][CH:19]=2
Reactant: COC(=O)c1ccc(C(O)C#Cc2cccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(C(=O)O)cc3)c21

Procedure:
Using Method F above, 4-[1-hydroxy-3-[3-(3-methoxy-1H-pyrrol-2-ylmethylene)-2-oxo-2,3-dihydro-1H-indol-4-yl]-prop-2-ynyl]-benzoic acid methyl ester (30 mg, 0.07 mmol) (from Example 12 above) was hydrolyzed with LiOH.H2O (13 mg, 2.7 mmol) in THF (1 mL) and water (1 mL) at room temperature for 18 h, to yield rac-(Z)-4-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-1-hydroxy-2-propynyl]benzoic acid. (Yield 21 mg, 72%).