Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH:9]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[CH:14][CH:13]=1)([CH3:11])[CH3:10]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: Brc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)c1ccc(-c2ccncc2)cc1

Procedure:
Part A. A solution of 4-bromopyridine hydrochloride (1.0 g, 6.3 mmol) in acetonitrile-water (50 mL/20 mL) is treated with 4-isopropylbenzeneboronic acid (1.04 g, 6.3 mmol) and sodium carbonate (2.1 g, 25.2 mmol). The mixture is degassed twice, and a catalytic quantity of tetrakis(triphenylphosphine)palladium is added. The mixture is heated to reflux for 12 h., then cooled and poured into water (50 mL). The mixture is filtered and extracted with ethyl acetate (3×50 mL). The extracts are combined, washed with brine, dried over magnesium sulfate, filtered and evaporated to afford 1.01 g of sufficiently pure product, 4-(4-isopropyl-phenyl)-pyridine.
Reaction SMILES: [C:1]1([C:7]([OH:9])=[O:8])([C:4](O)=[O:5])[CH2:3][CH2:2]1.CCN(CC)CC.S(Cl)(Cl)=O.[F:21][C:22]1[CH:29]=[CH:28][C:25]([NH:26][CH3:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([N:26]([CH3:27])[C:4]([C:1]2([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]2)=[O:5])=[CH:24][CH:23]=1
Reactant: CNc1ccc(F)cc1
Reactant: O=C(O)C1(C(=O)O)CC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CN(C(=O)C1(C(=O)O)CC1)c1ccc(F)cc1
Yield: 80.6 %

Procedure:
Using a procedure analogous to Example B1, 1,1-cyclopropanedicarboxylic acid (2 g, 15.37 mmol), Et3N (2.14 mL, 15.4 mmol), thionyl chloride (1.12 mL, 15.4 mmol), and 4-fluoro-N-methylaniline (1.83 g, 14.6 mmol) were combined to provide 1-((4-fluorophenyl)(methyl)carbamoyl)cyclopropanecarboxylic acid (2.79 g, 72% yield). MS (ESI) m/z: 260.0 (M+Na+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([Cl:28])[C:20]=1[NH2:21].[H-].[Na+]>O=S(Cl)Cl.C1COCC1>[Cl:18][C:19]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[C:22]([Cl:28])[C:20]=1[NH:21][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:9]=[CH:10][C:2]=1[F:1]
Reactant: COc1ccc(Cl)c(N)c1Cl
Reactant: O=C(O)c1cc(-c2cccc(F)c2)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
A solution of 2-fluoro-5-(3-fluorophenyl)benzoic acid (intermediate III(a)) (1.6 g, 7 mmol, 3.0 eq) in SOCl2 (20 mL) was heated at reflux for 3 h. The excess thionyl chloride was removed in vacuo and the residue obtained dissolved in THF (10 mL) and added dropwise to a solution of 2,6-dichloro-3-methoxy-aniline (450 mg, 2.3 mmol, 1.0 eq) and NaH (85 mg, 3.4 mmol, 1.5 eq) in THF (10 mL). The reaction was stirred at room temperature for 2 h then quenched by addition of aqueous NH4Cl. The mixture was extracted with EtOAc and the combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:4) to give the title compound (200 mg, 21%).
Reaction SMILES: Br[CH2:2][C:3]1[C:15]2[C:14]3[CH:13]=[C:12]([F:16])[CH:11]=[CH:10][C:9]=3[N:8]([CH2:17][O:18][CH3:19])[C:7]=2[C:6](=[O:20])[N:5]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:4]=1.[C-:27]#[N:28].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl.O>[F:16][C:12]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:17][O:18][CH3:19])[C:7]3[C:6](=[O:20])[N:5]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:4]=[C:3]([CH2:2][C:27]#[N:28])[C:15]=3[C:14]=2[CH:13]=1
Reactant: COCn1c2ccc(F)cc2c2c(CBr)nn(-c3ccccc3)c(=O)c21
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCn1c2ccc(F)cc2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Yield: 86.6 %

Procedure:
A two-phase mixture of 2.8 g (6.7 mmol) of 1-(bromomethyl)-8-fluoro-5-(methoxymethyl)-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-one, of 1.3 g (26 mmol) of sodium cyanide and of 0.23 g (0.7 mmol) of tetrabutylammonium bromide in 100 ml of dichloromethane and 100 ml of water is stirred vigorously for 12 h. The organic phase is separated, washed several times with water, dried over magnesium sulphate and concentrated under reduced pressure. Diethyl ether is added and the precipitate is collected by filtration and dried under reduced pressure. 2.1 g (5.8 mmol) of solid are isolated, which solid is used as is in the following stage.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3Br)=[CH:14][N:15]2[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([O:38]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:37].Cl>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:35])[N:7]([C:9]1[CH:17]=[C:16]2[C:12]([C:13]([S:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:36](=[O:38])[CH3:37])=[CH:14][N:15]2[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2c(Sc3ccccc3Br)cn(Cc3cc(F)cc(F)c3)c2c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1ccccc1Sc1cn(Cc2cc(F)cc(F)c2)c2cc(N(C)C(=O)OC(C)(C)C)ccc12
Reaction time: 1 h
Yield: 26.2 %

Procedure:
i)—A solution of [3-(2-bromo-phenylsulfanyl)-1-(3,5-difluoro-benzyl)-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (Example 6, method 2, step i; 1.00 g, 1.79 mmol) in toluene (oxygen-free, 25 ml), containing dichlorobis(triphenylphosphine)palladium(II) (0.076 g, 0.0672 mmol) and (1-ethoxyvinyl)tributyltin (0.824 ml, 2.44 mmol) was heated under reflux overnight. After cooling, hydrochloric acid (2M, 15 ml) was added and the mixture was stirred for 1 h. The mixture was quenched with a saturated aqueous solution of sodium hydrogencarbonate and the product was extracted into ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography (heptane/ethyl acetate 9:1→85:15) afforded [3-(2-acetyl-phenylsulfanyl)-1-(3,5-difluoro-benzyl)-1H-indol-6-yl]-methyl-carbamic acid tert-butyl ester (0.245 g).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=O)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]([O:26][CH3:27])=[O:25])[CH2:20][CH2:19]1)=[O:17])[CH:9]=[CH:8]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2cc(C(=O)O)ccc2c1
Reactant: COC(=O)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(C(=O)c2ccc3cc(OC(C)=O)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 129.7 %

Procedure:
A mixture of 6-acetoxy-2-naphthoic acid (1 g, 4.34 mmol, 1.0 eq), methyl piperidine-4-carboxylate (684 mg, 4.78 mmol, 1.1 eq), HBTU (2.47 g, 6.51 mmol, 1.5 eq) and TEA (658 mg, 6.51 mmol, 1.5 eq) in DCM (20 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (200 mL). The combined organic layers were washed with water (100 mL*2) and brine (100 mL), dried over Na2SO4 and concentrated to give methyl 1-(6-acetoxy-2-naphthoyl)piperidine-4-carboxylate as a yellow oil (2 g, yield: 100%). ESI-MS: 356.0 (M+H)+. 1HNMR (400 MHz, DMSO-d6) δ: 8.05 (d, 1H), 8.01-7.96 (m, 2H), 7.73 (s, 1H), 7.53-7.51 (m, 1H), 7.40-7.37 (m, 1H), 3.63 (s, 3H), 3.18-2.95 (m, 2H), 2.71-2.65 (m, 3H), 2.34 (s, 3H), 1.97-1.76 (m, 2H), 1.61-1.50 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:4][C:3]=1[O:18][CH3:19].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:25][C:26]=1[CH3:27]>>[CH3:19][O:18][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][CH2:10][CH:11]2[O:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:2]=1[O:1][CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:25][C:26]=1[CH3:27]
Reactant: COc1cc(CCCC2OC(=O)NC2=O)ccc1O
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)sc1C

Procedure:
In substantially the same manner as in Working Example 9, 5-[3-(4-hydroxy-3-methoxyphenyl)propyl]-2,4-oxazolidinedione was reacted with 4-chloromethyl-5-methyl-2-phenylthiazole to obtain 5-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-thiazolylmethoxy]phenyl]propyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-chloroform to give colorless prisms, m.p.128-129° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])[CH2:4][CH:5]([OH:16])[CH2:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)[CH3:2].C1(C)C=CC(S(O)(=O)=[O:31])=CC=1.ClC1C=CC=C(C(OO)=O)C=1>C(O)C>[CH2:1]([N:3]([CH2:17][CH2:18][CH2:19][S:20]([CH2:21][CH2:22][CH3:23])=[O:31])[CH2:4][CH:5]([OH:16])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCSCCCN(CC)CC(O)COc1ccc(C#N)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Product: CCCS(=O)CCCN(CC)CC(O)COc1ccc(C#N)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
2.45 g of 4-[3-[ethyl[3-(propylthio)propyl]amino]-2-hydroxypropoxy]-benzonitrile and 1.4 g p-toluenesulfonic acid were mixed in 50 ml of ethanol. The mixture was cooled to -10° C. and 1.7 g of m-chloroperbenzoic acid was added in small protions. The mixture was stirred for 0.5 hour at -10° C. and one hour at room temperature and then evaporated. The residue was dissolved in dichloromethane and washed with three portions of sodium carbonate and twice with water and thereafter dried over sodium sulfate, filtrated and evaporated. The residue, 2.3 g yellow oil, was purified by column chromatography. Yield: 1.4 g of the title compound.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[O:16])[O:15][C:11]=3[CH:10]=2)[CH2:5][CH2:4]1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[C:21]=1[CH2:28][CH2:29][CH:30]=O.Cl>>[F:27][C:22]1[CH:23]=[C:24]([F:26])[CH:25]=[C:20]([F:19])[C:21]=1[CH2:28][CH2:29][CH2:30][N:2]([CH3:1])[C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[O:16])[O:15][C:11]=3[CH:10]=2)[CH2:7][CH2:8]1
Reactant: O=CCCc1c(F)cc(F)cc1F
Reactant: CN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Agent: Cl
Product: CN(CCCc1c(F)cc(F)cc1F)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1

Procedure:
Condensation of 15 (460 mg, 1.9 mmol) and 3-(2,4,6-trifluorophenyl)-propionaldehyde (360 mg, 1.9 mmol), following the procedure described in Example 45, Step 2, followed by conversion to the HCl salt, gave 6-(trans-4-{[3-(2,4,6-trifluorophenyl)propyl]methylamino}cyclohexyl)-3H-benzoxazol-2-one (275 mg, 32%), as a white solid: mp 235-238° C.; IR (KBr): 2949, 1772, 1632, 1603 cm−1; 1H NMR (300 MHz, DMSO-d6): δ 11.54 (s, 1H), 9.78 (s, 1H), 7.26-7.18 (m, 3H), 7.00 (s, 2H), 3.32-3.27 (m, 1H), 3.26-3.04 (m, 2H), 2.71 (d, J=5 Hz, 3H), 2.58-2.54 (m, 1H), 2.66-2.62 (m, 2H), 2.12-1.86 (m, 6H), 1.68-1.48 (m, 4H); ESI (m/z): 419 [M+H]+; HPLC: method A, 6.30 minutes (98.8%); Anal. Calcd for C23H25F3N2O2.HCl: C, 60.73; H, 5.76; N, 6.16. Found: C, 60.43; H, 5.71; N, 5.99.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Cl:1][C:2]1[C:3]([C:15](=[O:16])[CH2:14][Cl:13])=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC(=O)Nc1cc(Cl)ccc1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1cc(Cl)c(C(=O)CCl)cc1C
Yield: 75.7 %

Procedure:
To N-(5-Chloro-2-methyl-phenyl)-acetamide (30 g, 163.37 mmol) in carbondisulfide (1200 mL) was added chloroacetylchloride (19.50 mL, 245.05 mmol) followed by anhydrous aluminum chloride powder (65.35 g, 490.11 mmol) in one portion at rt. The reaction was heated to reflux for 3 h after which the reaction was cooled and the solvent decanted. The remaining residue was carefully hydrolyzed with cold H2O (500 mL) with vigorous stirring to give a white/gray solid suspension which was collected by filtration and dried in vacuo to give desire product (32.15 g, 123.6 mmol). Yield=76%; 1H NMR (400 MHz, CDCl3) δ 8.28 (bs, 1H, NH), 7.47 (s, 1H), 7.24 (s, 1H), 4.73 (s, 2H), 2.25 (s, 3H).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]([C:20]2[O:30][C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)[C:9]2[O:19][C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:3][CH:2]=1.[O:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[K]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[O:19]=[C:9]([NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=1[C:17]([O:31][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:18])[C:8](=[CH:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:20]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=1[C:28]([O:31][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])=[O:30]
Reactant: CC(C)(C)O[K]
Reactant: O=c1oc(C(=Cc2ccccc2)c2nc3ccccc3c(=O)o2)nc2ccccc12
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccccc1NC(=O)C(=Cc1ccccc1)C(=O)Nc1ccccc1C(=O)OC(C)(C)C
Yield: 59 %

Procedure:
The compound 52 (1.0 g, 2.5 mmol) obtained in the same manner as in Example 21 (b) was dissolved in dry benzene (80 ml), treated with KOC(CH3)3 (684 mg, 6.1 mmol), and heated under reflux for 1 hour. After completion of the reaction, the solvent was evaporated and the residue was dried and suspended by adding a small amount of water under ice cooling. The aqueous layer was made neutral with 0.5N.HCl, and the residue was dissolved by adding chloroform. The mixed layer was removed to a separating funnel. After the solid was completely dissolved, water was added to wash the solution so as to make the chloroform layer neutral or weak acidic. The chloroform layer was separated, washed with saturated aquecus NaCl solution and dried over magnesium sulfate. The solvent was evaporated to give a white solid. The product was dissolved in chloroform and purified by silica gel column chromatography (developing solvent: benzene:ethyl acetate=4:1) to give the desired compound as white solid (801 mg, crude yield 58%). Recrystallization from the mixed solvent of methanol and water gave white crystals (654 mg, yield, 47%). m.p., 117°-118° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[C:26]([O:30][C:31]([C:33]1[CH:34]=[N:35][C:36]([NH2:39])=[CH:37][CH:38]=1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[C:14]([NH:39][C:36]3[N:35]=[CH:34][C:33]([C:31]([O:30][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:32])=[CH:38][CH:37]=3)=[O:15])=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)c1ccc(N)nc1
Reactant: O=C(O)C(Nc1ccc(F)cc1F)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Nc2ccc(F)cc2F)c2ccc(S(=O)(=O)C3CC3)cc2)nc1
Yield: 14 %

Procedure:
The compound of example A8 was obtained by similar method described in example A1 using 2-(4-cyclopropylsulfonylphenyl)-2-(2,4-difluoroanilino)acetic acid (Preparation 3, 0.150 g, 0.408 mmol), 6-aminopyridine-3-carboxylic acid tert-butyl ester (preparation 54, 0.095 g, 0.49 mmol), HOBT (0.082 g, 0.612 mmol), and EDCl (0.116 g, 0.612 mmol), N-methyl morpholine (0.103 g, 1.02 mmom) in DCM (4 mL) to provide the title compound (0.031 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[O-:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>[Cu]>[CH3:9][O:8][C:5]1[C:4](=[CH:3][C:2]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[O:10][CH3:11]
Reactant: [O-]c1ccccc1
Reactant: COc1ccc(I)cc1OC
Agent: [Cu]
Agent: [Na+]
Product: COc1ccc(Oc2ccccc2)cc1OC

Procedure:
R = 4-phenoxy. Heating a mixture of 4-iodoveratrol (Janssen et al., J. Org. Chem. 20, 1326 (1955)), sodium phenoxide and a catalytic amount of copper powder at about 200° C. for about 4 hours, then pouring the mixture over ice, extracting the mixture with an organic solvent such as ether, drying the extract, stripping the solvent and distilling the residue to give 4-phenoxycatechol dimethyl ether. Treating this product with an anhydrous aluminum chloride/sodium chloride melt (Janssen et al., supra), pouring the resulting mixture into ice-hydrochloric acid, extracting the mixture with an organic solvent, stripping the solvent under reduced pressure and fractionally distilling the residue gives the desired 4-phenoxycatechol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[C:15]1([O:21][C:22](=[O:23])[NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccncc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4 aminopyridine (0.6 g, 6.37 mmol) in dichloromethane (15 ml) is treated with triethylamine (0.89 ml, 6.37 mmol) followed by phenylchloroformate (0.80 ml, 6.37 mmol) and then stirred at room temperature for 3 days. The reaction mixture is partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase is dried over magnesium sulphate and evaporated to afford pyridin-4-yl-carbamic acid phenyl ester.
Reaction SMILES: [CH:1](=[N:8][CH2:9][P:10](=[O:15])([O:13][CH3:14])[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([Li])C=CC=CC=1.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:25]>O1CCCC1>[CH:1](=[N:8][CH:9]([P:10]([O:13][CH3:14])([O:11][CH3:12])=[O:15])[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COP(=O)(CN=Cc1ccccc1)OC
Reactant: COc1ccc(COC(=O)Cl)cc1
Agent: [Li]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)C(N=Cc2ccccc2)P(=O)(OC)OC)cc1

Procedure:
Dimethyl N-benzylidene-aminomethylphosphonate (22.72 g) is dissolved in anhydrous tetrahydrofuran (500 ml) under nitrogen. The solution is cooled to -78°, and phenyllithium (45 ml of a 2.3 M solution in benzene-ether) is added with stirring. The solution is stirred an additional 15 minutes at -78°. and then treated dropwise over 45 minutes with p-methoxybenzyl chloroformate (10.03 g) in tetrahydrofuran (100 ml). After stirring for 2 hours at -78°, the reaction mixture is allowed to warm to 0° over 30 minutes. The solvent is evaporated in vacuo and the residue is partitioned between ether (500 ml) and 0.5 M pH 3 phosphate buffer (100 ml). The ether portion is washed with water and saturated brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to dryness. Chromatography of the residue on silica gel affords p-methoxybenzyl N-benzylidene-α-amino-dimethylphosphonoacetate.
Reaction SMILES: C(O[C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:27])[CH2:6]1)[C@:19]1([CH3:20])[C:14]([C:15]([CH3:26])=[C:16]([O:24]C)[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=O)C.[CH:28]#[CH:29].Cl>CO.O>[C:28]([C@:7]1([OH:27])[CH:6]=[CH:5][C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]12[CH3:9])[C@:19]1([CH3:20])[C:14](=[C:15]([CH3:26])[C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)#[CH:29]
Reactant: C#C
Reactant: COC1=C(C)C2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: Cl
Solvent: CO
Solvent: O
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=C(C)C(=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
3.5 g of 15α-acetoxy-3-methoxy-4-methylandrosta-3,5-dien-17-one is reacted with acetylene analogously to Example 5. The resultant 17α-ethynyl-3-methoxy-4-methylandrosta-3,5,15-trien-17β-ol is allowed to react, as described in Example 5, with concentrated hydrochloric acid in a mixture of methanol/water. After the crude product has been chromatographed on silica gel with a hexane-ethyl acetate gradient, 1.3 g of 17α-ethynyl-17β-hydroxy-4-methylandrosta-4,15-dien-3-one is obtained as a foam.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>ClCCl>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](=[O:21])[CH2:8][CH2:7][CH2:6][C:5]1[CH:4]=[CH:3][CH:2]=[CH:1][N:9]=1
Reactant: COc1ccccc1C(=O)Cl
Reactant: NCCc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1C(=O)CCCc1ccccn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 0.5 gm of phenethylamine (4.12 mmol) in 5 mL of dichloromethane and 0.978 mL of pyridine (8.2 mmol) at 0° C. was added 1.39 gm of 2-methoxybenzoyl chloride (1.14 mL, 8.2 mmol). The reaction was allowed to warm to room temperature and was stirred for 4 hr. The reaction mixture was concentrated, 5mL of heptane were added and the mixture was evaporated to dryness this being repeated one more time. The residue was purified by HPLC (RCM SepPak, silica 25×100, 3.6% CH3CN, 14.4% tBuOCH3, 82% hexane) to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:32]([N:39]1[CH2:44][CH2:43][CH:42](O)[CH2:41][CH2:40]1)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:42]2[CH2:43][CH2:44][N:39]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:40][CH2:41]2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: COC(=O)c1ccc(O)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 2,4-dihydroxybenzoate (5.1 g, 30.33 mmol) and triphenylphosphine (9.52 g, 36.3 mmol) were stirred in THF (200 ml) under nitrogen. The mixture was cooled in an ice bath and treated with a solution of 1-Boc-4-hydroxypiperidine (6.8 g, 33.8 mmol) and diethyl azodicarboxylate (5.73 ml, 6.34 g, 36.4 mmol) in THF (100 ml) added dropwise over 30 min. The mixture was stirred at ambient temperature for 18 hours, then diluted with ethyl acetate and washed with 1M NaOH, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 10% ethyl acetate in hexane, and the product fractions were evaporated to dryness in vacuo to give methyl 2-hydroxy-4-(1-Boc-4-piperidyloxy)benzoate.