Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[O:16][N:15]=2)=[CH:10][CH:9]=1)(C)(C)C.C(OC(=O)NC1C=CC(C(=N)NO)=CC=1)(C)(C)C.FC(F)(F)OC1C=CC(C=O)=CC=1>C(O)(=O)C.C(Cl)(Cl)Cl>[F:29][C:26]([F:27])([F:28])[O:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[O:16][N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][CH:10]=3)[N:18]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2noc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: CC(C)(C)OC(=O)Nc1ccc(C(=N)NO)cc1
Agent: O=Cc1ccc(OC(F)(F)F)cc1
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1ccc(-c2noc(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 15 %

Procedure:
{4-[5-(4-Trifluoromethoxyphenyl)-[1,2,4]oxadiazol-3-yl]-phenyl}-carbamic acid tert-butyl ester. To a stirred solution of tert-butyl-4-(N-hydroxycarbamimidoyl)-phenylcarbamate (Ace Synthesis) (500 mg; 1.99 mmol) dissolved in 2.5 mL of acetic acid was added 4-trifluoromethoxybenzaldehyde (1.7 mL; 11.94 mmol), and the reaction mixture was stirred at room temperature for 4 d. The mixture was diluted with CHCl3 (20 mL) and filtered through a pad of Celite®. The pad was washed with CHCl3 (20 mL). Heptane (20 mL) was then added to the solution and the solution was concentrated under reduced pressure. This procedure was repeated twice. The residue was purified via radial chromatography using a 3:1 hexane/EtOAc solution as the eluent. Two fractions were isolated. The first fraction isolated (Rf=0.42) was shown to be the title compound (127 mg; 15%). 1H NMR (300 MHz, CDCl3) δ 8.26 (d, J=8.9 Hz, 2H), 8.09 (d, J=8.9 Hz, 2H), 7.52 (d, J=8.6 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 6.70 (s, 1H), 1.54 (s, 9H); EI/MS 421 [M]+. The second fraction isolated (Rf=0.11) was shown to be the 4,5-dihydro-1,2,4-oxadiazole (96 mg; 11%). 1H NMR (300 MHz, CDCl3) δ 8.40 (d, J=8.9 Hz, 2 H), 8.00 (d, J=8.9 Hz, 2 H), 7.51 (d, J=8.9 Hz, 2 H), 7.22-7.31 (m, 3 H), 6.87 (s, 1 H), 1.54 (s, 9 H); EI/MS 423 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-:17])=[O:26])=[CH:5][CH:4]=1
Reactant: COc1ccc(CSc2cccc[n+]2[O-])cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(CS(=O)c2cccc[n+]2[O-])cc1

Procedure:
The procedure employed is identical to that of Example 68 using 7 gm (0.028 mol) 2-(4-methoxyphenylmethylthio)pyridine N-oxide in 50 ml of chloroform and 5.6 gm (0.028 mol) MCPBA in 100 ml chloroform.
Reaction SMILES: O1CCOCC1.[CH:7]1([C:13]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)(=[O:31])=[O:30])=[CH:25][C:24]=4[O:39][CH3:40])=[N:17][C:16]=3[N:15]([CH3:41])[N:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[ClH:42].O1CCOCC1>CCOCC>[Cl-:42].[CH:7]1([C:13]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)(=[O:30])=[O:31])=[CH:25][C:24]=4[O:39][CH3:40])=[N:17][C:16]=3[N:15]([CH3:41])[N:14]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: Cl
Agent: COc1cc(S(=O)(=O)N2CCN(C)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Solvent: C1COCCO1
Solvent: CCOCC
Product: [Cl-]

Procedure:
To a 2 ml dioxane solution of 87 mg (0.17 mmol) of the compound obtained in Example 49, 0.1 ml (0.4 mmol) of a 4M dioxane hydrochloride solution was added. Ether was added to the resulting solution, and precipitated solids were collected by filtration. The solids were purified by recrystallization (ethanol) to obtain 52.1 mg (56%) of the captioned compound.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5].[Br-].[Mg].C([O:12][CH3:13])=O>C1COCC1.O>[F:5][C:4]([F:7])([F:6])[CH2:3][CH2:2][CH:13]([OH:12])[CH2:2][CH2:3][C:4]([F:7])([F:6])[F:5]
Reactant: COC=O
Reactant: FC(F)(F)CCBr
Agent: [Br-]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: OC(CCC(F)(F)F)CCC(F)(F)F
Temperature: 0 °C

Procedure:
3-Bromo-1,1,1-trifluoropropane (31 g, 0.175 mol) was dissolved in THF (175 mL). Mg (4.2 g, 0.175 mol) was placed in a 1 L, 3-necked round-bottom flask equipped with a condenser, nitrogen inlet and thermometer. The bromide solution (10 mL) was added to cover the magnesium and upon stirring a mild exotherm commenced. The temperature was kept <40° C. by immersing the flask in a bowl of water. The bromide was added slowly to maintain this mild exothermic reaction. When the exotherm had subsided the mixture was cooled in ice-water and methyl formate (7 mL, 0.11 mol) in THF (175 mL) was added. The mixture was stirred for 30 min and then quenched with NH4Cl (aq.soln. 100 mL). The mixture was extracted with ethyl acetate. The organic extracts were washed with brine, dried (MgSO4) and evaporated.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]1[C:19]([C:20]2[NH:21][C:22](=[O:39])[C:23]3[C:24](=[C:26]([CH2:36][CH2:37][CH3:38])[N:27]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[N:28]=3)[N:25]=2)=[CH:18][C:17]([S:40]([N:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH3:50])[CH2:45][CH2:44]2)(=[O:42])=[O:41])=[CH:16][N:15]=1)[CH3:12]>OCC1C=COC=1>[CH2:49]([N:46]1[CH2:47][CH2:48][N:43]([S:40]([C:17]2[CH:18]=[C:19]([C:20]3[NH:21][C:22](=[O:39])[C:23]4[C:24](=[C:26]([CH2:36][CH2:37][CH3:38])[N:27]([CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=5)[N:28]=4)[N:25]=3)[C:14]([O:13][CH2:11][C:12]3[CH:12]=[CH:11][O:13][CH:14]=3)=[N:15][CH:16]=2)(=[O:41])=[O:42])[CH2:44][CH2:45]1)[CH3:50]
Reactant: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC)[nH]c(=O)c2nn1Cc1ccccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: OCc1ccoc1
Agent: [K+]
Product: CCCc1c2nc(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCc3ccoc3)[nH]c(=O)c2nn1Cc1ccccn1
Yield: 62.7 %

Procedure:
Potassium bis(trimethylsilyl)amide (176 mg, 0.88 mmol) was added to a stirred suspension of the title compound of Example 26 (100 mg, 0.17 mmol) in 3-hydroxymethylfuran (4 ml) and the reaction mixture heated under reflux for 24 hours then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel, using dichloromethane:methanol (95:5) as eluant, to furnish the title compound (33 mg, 31%) as a pale yellow foam. δ (CDCl3) 0.93 (3H, t), 1.04 (3H, t), 1.72 (2H, m), 2.41 (2H, q), 2.55 (4H, m), 2.99 (2H, t), 3.14 (4H, m), 5.63 (2H, s), 5.68 (2H, s), 6.60 (1H, s), 7.09 (1H, d), 7.22 (1H, m), 7.44 (1H, s), 7.64 (2H, m), 8.57 (1H, d), 8.68 (1H, s), 9.02 (1H, s), 10.53 (1H, s). LRMS: m/z 619 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH3:20])[CH2:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O.CO>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: CCCN1CC=C(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN1CCC(c2ccc(N)c(OC)c2)CC1
Yield: 84.6 %

Procedure:
Palladium on carbon (10% by weight, 2.5 g) was added to a nitrogen-flushed Fischer-Porter vessel. At least a portion of the 4-(3-methoxy-4-nitrophenyl)-1-propyl-1,2,3,6-tetrahydropyridine from Step B was combined with additional 4-(3-methoxy-4-nitrophenyl)-1-propyl-1,2,3,6-tetrahydropyridine prepared by substantially the same method. Then, a solution of the 4-(3-methoxy-4-nitrophenyl)-1-propyl-1,2,3,6-tetrahydropyridine (9.20 g, 33.3 mmol) in Ethyl acetate (150 mL) followed by methanol (50 mL) were added to the vessel. The reaction was purged and then kept under a hydrogen pressure of 60 psi for 2 d. The pressure was released and the reaction was purged with nitrogen. The reaction was filtered through celite and concentrated to afford 2-methoxy-4-(1-propylpiperidin-4-yl)aniline as a white solid (7.0 g, 85% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.86 (t, J=7.5 Hz, 3 H), 1.44 (dt, J=7.4, 7.4 Hz, 2 H), 1.52-1.63 (m, 2 H), 1.63-1.70 (m, 2 H), 1.90 (td, J=11.6, 2.4 Hz, 2 H), 2.20-2.25 (m, 2 H), 2.30 (tt, J=11.9, 4.0 Hz, 1 H), 2.89-2.94 (m, 2 H), 3.74 (s, 3 H), 4.45 (s, 2 H), 6.53 (s, 2 H), 6.65 (s, 1 H). ESIMS (M+H)+=249.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13](=[O:16])[CH:14]=[CH2:15])[CH3:11]>CCO>[CH2:10]([O:12][C:13](=[O:16])[CH2:14][CH2:15][NH:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11]
Reactant: C=CC(=O)OCC
Reactant: NCCc1ccccc1
Solvent: CCO
Product: CCOC(=O)CCNCCc1ccccc1

Procedure:
Phenylethyl amine (10 g) was dissolved in EtOH (50 ml) and then treated with acrylic acid ethyl ester (8.3 g) dropwise under argon at RT. The resulting mixture was allowed to stir over night and was evaporated and dried in vacuo. The residue (18.9 g) was used without further purification. Colorless liquid, MS (ESI): 222.3 (MH+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH3:4].[CH3:5][N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1>>[Br-:1].[CH3:5][N+:6]1[CH:10]=[CH:9][N:8]([CH2:2][CH2:3][CH3:4])[CH:7]=1
Reactant: CCCBr
Reactant: Cn1ccnc1
Product: CCCn1cc[n+](C)c1
Product: [Br-]
Temperature: 70 °C
Yield: 94.9 %

Procedure:
450 g of 1-bromopropane (3.66 mol) are loaded into a 1 l glass reactor. The mixture is heated to 70° C. and then 200 g of 1-methylimidazole (2.44 mol) are poured in dropwise, with stirring. The mixture is left to react for 1 h at 70° C. After returning to room temperature, the mixture is separated by decantation. The bottom ionic liquid phase is recovered, washed with toluene (1×100 ml), and then evaporated under vacuum. 475 g of 1-methyl-3-propylimidazolium bromide are obtained in the form of a yellow liquid. The product is used as a base without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][C:16]#N)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.C[OH:26].Cl.[C:28](=O)(O)[O-:29].[Na+]>O.CCOCC>[CH3:28][O:29][C:16](=[O:26])[CH2:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][C:6]=3[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:8][CH2:9][C:10]2=[N:14][N:13]=1
Reactant: CO
Reactant: O=C([O-])O
Reactant: N#CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COC(=O)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-acetonitrile (1.00 g., 0.003 mole) methanol (2 ml.) and ether (6 ml.) is cooled in a salt-ice bath saturated with a stream of anhydrous hydrogen chloride during 15 minutes. The mixture is allowed to warm slowly to ambient temperature and stand for 18 hours; it is then poured into water. This mixture is neutralized with sodium bicarbonate and extracted with chloroform. The extract is washed with brine, dried over anhydrous magnesium sulfate and then concentrated. The residue is crystallized from methanol to give 0.149 g. of a by-product of melting point 184.5°-188° C. (d). The mother liquor is crystallized from methanol-ethyl acetate to give 0.126 g. of a by-product of melting point 205.5°-207.5° C. (d). The mother liquor from this crystallization is concentrated and chromatographed on silica gel (50 g.) with 2% methanol-98% chloroform. The first compound eluted from the column is crystallized from methanol-ethyl acetate to give 8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-acetic acid methyl ester in two crops: 0.169 g. of melting point 202°-203.5° C. (d.) and 0.125 g. of melting point 200.5°-202.5° C. (d.). The analytical sample had a melting point of 202°-203° C.
Reaction SMILES: I/[CH:2]=[CH:3]/[C@@H:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17]C2CCCCO2)=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:24][C:25]1[CH:30]=[CH:29][C:28](S([O-])(=O)=O)=[CH:27][CH:26]=1.C1C=C[NH+]=CC=1>CCO>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([C@H:4](/[CH:3]=[CH:2]/[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CCOC(=O)C[C@@H](/C=C/I)c1ccc(OC2CCCCO2)cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CCOC(=O)C[C@@H](/C=C/Cc1ccccc1)c1ccc(O)cc1
Reaction time: 16 h

Procedure:
To a stirred solution of 84.4 (156.9 mg, 0.398 mmol, MW 394.50) in EtOH (5 mL) at 23° C. was added PPTS (catalytic). Stirring was continued for 16 hours. The reaction was concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0 to 20% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated providing a colorless oil. The desired product was contaminated (˜5%) with a further olefinic product (believed to contain a terminal double bond) and was used without further purification.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:19]N(C)P(N(C)C)(N(C)C)=O.[H-].[Na+].IC>C1COCC1>[CH3:19][O:1][CH2:2][C@H:3]([N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17])[CH2:4][CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)C[C@H](CO)N1C(=O)c2ccccc2C1=O
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@@H](CC(C)C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
(R)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (example 9c) (5.88 g, 23.87 mmol) was dissolved in dry THF (25 mL) and hexamethyl-phosphoramide (30 mL) and the solution cooled to 0° C. Sodium hydride (60% in mineral oil, 1.15 g, 28.65 mmol) was added and after 10 minutes iodomethane (7.43 ml, 119.35 mmol) was added dropwise and the solution was warmed up slowly to room temperature and stirred over night. The reaction mixture was poured into ice/water, extracted with EtOAC, washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified on silica gel (20% EtOAC in hexane) to give 3.92 g of (R)-2-(1-methoxy-4-methylpentan-2-yl)isoindoine-1,3-dione (63%).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[C:6]([C:16](=[O:28])[C:17]([NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:18])=[CH:5]1)([CH3:3])[CH3:2].O.O.[Cl:31][Sn]Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[ClH:31].[NH2:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:16](=[O:28])[C:17]([NH:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[O:18])=[CH:5][N:4]2[CH:1]([CH3:3])[CH3:2])=[CH:8][CH:9]=1
Reactant: CC(C)n1cc(C(=O)C(=O)NCCN2CCCCC2)c2ccc([N+](=O)[O-])cc21
Reactant: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)n1cc(C(=O)C(=O)NCCN2CCCCC2)c2ccc(N)cc21
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
The title compound was prepared according to the following procedure: 2-(1-isopropyl-6-nitro-1H-indol-3-yl)-2-oxo-N-(2-(piperidin-1-yl)ethyl)acetamide (500 mg, 1.29 mmol) was dissolved in EtOAc. SnCl2.2H2O (1.39 g, 6.50 mmol) was added portionwise and the mixture was heated at reflux for 8 hr. The reaction mixture was then cooled and treated with sat. NaHCO3. After stirring at RT for 30 min., the reaction mixture was extracted with EtOAc, dried over MgSO4, concentrated down and then converted to the HCl salt to yield the title compound (350 mg, 76% yield): 1H NMR (400 MHz, DMSO-d6): δ 10.30 (NH2 and NH+, br, s, 3H), 9.04 (s, 1H), 8.87 (s, 1H), 8.26 (s, 1H), 7.67 (s, 1H), 7.25 (s, 1H), 4.77 (m, 1H), 3.60 (m, 2H), 3.17 (m, 2H), 2.86 (m, 2H), 1.74 (m, 4H), 1.50 (d, 6H), 1.28 (m, 2H), 1.04 (m, 2H); MS (ESI) m/z: Calculated for C20H28N4O2: 356.2. Found: 357.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][C:17]([O:19]CC)=[O:18])=[N:12][N:11]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[C:1]([C:4]1[CH:23]=[CH:22][C:7]([CH2:8][S:9][C:10]2[S:14][C:13]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[N:12][N:11]=2)=[C:6]([CH2:24][CH2:25][CH3:26])[C:5]=1[OH:27])(=[O:3])[CH3:2]
Reactant: CCCc1c(CSc2nnc(SCC(=O)OCC)s2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCc1c(CSc2nnc(SCC(=O)O)s2)ccc(C(C)=O)c1O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
In 7.8 ml of 90% methanol was dissolved 0.98 g of ethyl [[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4- thiadiazol-2-yl]thio]acetate obtained in Example 1 with heating at 60° C. Further 6.1 ml of a 1N aqueous sodium hydroxide solution was added to the solution followed by stirring at 60° C. for 30 minutes. A 1N aqueous sodium hydroxide solution and ethyl acetate were added to the reaction mixture to fractionate. The aqueous phase was made acidic with a 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with, in sequence, water, a saturated aqueous sodium chloride solution and water and then, dried over anhydrous magnesium sulfate. The solvent was then distilled off. Recrystallization of the thus obtained solid from isopropyl alcohol gave 0.75 g of [[5-[(4-acetyl-3-hydroxy-2-propylbenzyl)thio]-1,3,4-thiadiazol-2-yl]thio]-acetic acid.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([CH2:11][CH3:12])[CH2:9][C@H:8]2[C@H:13]3[C:22]([CH:23]=[CH:24][C@:6]12[CH3:7])=[C:21]1[C:16](=[CH:17][C:18](=[O:25])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:11]([C@@H:10]1[CH2:9][C@H:8]2[C@H:13]3[C:22]([CH:23]=[CH:24][C@:6]2([CH3:7])[C@H:5]1[OH:4])=[C:21]1[C:16](=[CH:17][C:18](=[O:25])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)[CH3:12]
Reactant: CC[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3C=C[C@]2(C)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3C=C[C@]2(C)[C@H]1O
Reaction time: 4 h
Yield: 86.7 %

Procedure:
A solution of 2.5 g of 17β-acetoxy-16α-ethyl-4,9,11-estratrien-3-one in 120 ml of methanol and 5 ml of water is stirred, after adding 6.0 g of potassium carbonate, for 4 hours at room temperature. The mixture is then poured into water and extracted with ethyl acetate. Crystallization of the crude product from ethyl acetate yields 1.9 g of 16α-ethyl-17β-hydroxy-4,9,11-estratrien-3-one, m.p. 139°-141° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][CH2:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][C:12]=2[Cl:21])=[O:9])=[CH:4][CH:3]=1.[CH2:24]=O>C(O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:6]2[CH2:7][C:8](=[O:9])[N:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][C:12]=3[Cl:21])[CH2:24]2)=[CH:22][CH:23]=1
Reactant: C=O
Reactant: NS(=O)(=O)c1ccc(NC(=O)CNc2ccc(Cl)cc2)c(Cl)c1
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccc(N2CN(c3ccc(Cl)cc3)CC2=O)c(Cl)c1

Procedure:
2-(p-Chloroanilino)-N-(2-chloro-4-sulphamoylphenyl)-acetamide (3g)was dissolved in ethanol (40 ml) and paraformaldehyde (0.5g) in water (80 ml) added thereto. The mixture was refluxed for 3 hours, cooled and filtered to yield the title product (2.1g), m.p. 222°-225°(ethanol).
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25](I)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:30]1[CH2:34][CH2:33][O:32][CH:31]1[C:35]1[O:39][C:38]([Sn](CCCC)(CCCC)CCCC)=[CH:37][CH:36]=1>CCOC(C)=O>[ClH:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([C:38]5[O:39][C:35]([CH:31]6[O:32][CH2:33][CH2:34][O:30]6)=[CH:36][CH:37]=5)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Reactant: Ic1ccc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5cc(-c6ccc(C7OCCO7)o6)ccc45)ccc32)cc1

Procedure:
Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-(7-iodoquinazolin-4-yl)-amine hydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tri-n-butylstannyl)furan; tlc Rf, 0.25 (100% EtOAc on silica); m/z (M+1+) 490.
Reaction SMILES: [CH3:1][O-:2].[Na+].S(O)(O)(=O)=O.[CH3:9][O:10][C:11]([NH2:13])=[NH:12].[C:14]([O:22]C)(=O)[CH2:15][C:16]([O:18]OC)=O>C(O)C>[CH3:9][O:10][C:11]1[N:13]=[C:14]([OH:22])[C:15]([O:2][CH3:1])=[C:16]([OH:18])[N:12]=1
Reactant: C[O-]
Reactant: COOC(=O)CC(=O)OC
Reactant: COC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: COc1nc(O)c(OC)c(O)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
9.7 g (180 mmoles) of sodium methylate is added to a solution of 9 g (52 mmoles) of methoxyformamidine sulphate in 100 ml of ethanol cooled down to 0° C. and the mixture is stirred for 15 minutes; then a solution of 6.5 ml (46.8 mmoles) of methyl methoxy malonate in 50 ml of ethanol is added, followed by stirring overnight at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa). The residue is taken up in 100 ml of a saturated solution of sodium chloride and extracted with 800 and 200 ml of n-butanol. The organic phases are dried over sodium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa). 7 g of expected product is obtained in the form of a white solid.
Reaction SMILES: C1COCC1.[C:6]1([CH3:14])[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Mg]Cl.Cl[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1CC=CCCC=C1.C1CC=CCCC=C1.[Ni]>[C:6]1([C:14]2[CH:20]=[CH:21][CH:16]=[CH:17][C:18]=2[CH3:19])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1ccccc1[Mg]Cl
Reactant: Clc1ccccc1
Agent: [Ni]
Agent: C1=C\CC/C=C\CC/1
Solvent: C1=CCCC=CCC1
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccccc1
Reaction time: 0.17 h
Yield: 57 %

Procedure:
In the drybox, 54.0 mg (0.303 mm) of (Me3C)2PH(S) (from Experiment 18), 83.4 mg (0.303 mm) of Ni(COD)2 and 10.0 mL of THF were loaded into a reactor (20 mL) equipped with a magnetic stir bar. The resulting mixture was stirred at room temperatureover a period of 10 min. After addition of 1.126 g (10.0 mm) of chlorobenzene, the resulting mixture was stirred for 5 min until the catalytic reaction was initiated by dropwise addition of 15 mL (15.0 mm, 1.0 M in THF) of o-tolylmagnesium chloride at room temperature over a period of 5 min. The resulting mixture was stirred at room temperature over 12 h before the reaction was quenched with 10.0 mL of H2O, and the mixture was diluted with 300 mL of Et2O. After separation of organic and aqueous phases, the organic phase was washed with 2×100 mL of H2O, and 100 mL of brine, then dried over mgSO4, filtered and concentrated by rotary evaporation. The crude product was purified by column chromatography on silica gel (100:1-hexane:methyl t-butyl ether) to afford 0.96 g (57% yield) of 2-phenyltoluene.
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:53]=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[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([N:61]=[C:62]=[O:63])[CH:56]=1>>[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:53]=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[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:62]([NH:61][C:57]2[CH:58]=[CH:59][CH:60]=[C:55]([F:54])[CH:56]=2)=[O:63])[CH2:51][CH2:52]1
Reactant: O=C=Nc1cccc(F)c1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(F)c1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-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-nonaene tris(trifluoroacetate) and 1-fluoro-3-isocyanatobenzene as the starting materials in 60% yield. LCMS for C31H32ClFN7O2 (M+H)+: m/z=588.1.