Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH2:2][C@H:3]1[CH2:7][NH:6][C:5](=[O:8])[CH2:4]1.Cl[C:10]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[C:22]([O:33][CH3:34])[CH:21]=2)[CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2.CC(N(C)C)=[O:37]>>[CH3:34][O:33][C:22]1[CH:21]=[C:20]([C:18]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[N:15]3)=[C:10]([O:37][CH2:2][C@H:3]3[CH2:7][NH:6][C:5](=[O:8])[CH2:4]3)[N:19]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: CC(=O)N(C)C
Reactant: NC[C@H]1CNC(=O)C1
Reactant: COc1cc(-c2cc3ncccc3c(Cl)n2)ccc1OC1CCOCC1
Product: COc1cc(-c2cc3ncccc3c(OC[C@H]3CNC(=O)C3)n2)ccc1OC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
91 mg (R)-4-Hydroxymethyl-pyrrolidine-2-one (2.2) was placed in 1 mL of dimethylacetamide at ambient temperature under nitrogen. The reaction was stirred for 10 min before 210 mg 5-chloro-7-[3-methoxy-4-(tetrahydro-pyran-4-yloxy)-phenyl]-[1,6]naphthyridine (6.36) as a solution in 1.5 mL dimethylacetamide was introduced. The reaction was stirred overnight at ambient temperature and then heated to 70° C. where it was maintained for 2 h. After this time the mixture was cooled to ambient temperature and it was partitioned between water and ethyl acetate. The aqueous layer was separated and it was extracted with additional ethyl acetate (×2). The combined organic fractions were dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification by silica gel chromatography (ethyl acetate/methanol: 100:0 to 92:8) gave the title compound.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[N+:10]([O-:13])(O)=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][N+:16]=1[O-:22]>OS(O)(=O)=O>[Cl:14][C:15]1[CH:20]=[C:19]([N+:10]([O-:13])=[O:11])[C:18]([Cl:21])=[CH:17][N+:16]=1[O-:22]
Reactant: [O-][n+]1cc(Cl)ccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=[N+]([O-])c1cc(Cl)[n+]([O-])cc1Cl
Temperature: 25 °C

Procedure:
At 0° C., 30% oleum (13 mL) is added slowly to fuming HNO3 (22 mL) and the resulting mixture is added slowly to the solution of 2,5-dichloro-pyridine 1-oxide (5.2 g, 31 mmol) in concentrated H2SO4. After addition, the reaction mixture is warmed to room temperature over 1 hr, then heated to 80° C. for 2 hr. After cooling to room temperature, the mixture is poured into ice (120 g) and precipitate is formed gradually. The solid is collected by filtration and washed with water. The product is obtained as yellow solid. 1H NMR (CDCl3) δ 8.46 (s, 1H), 8.25 (s, 1H).
Reaction SMILES: C(OC(=O)[N:10]([CH2:26][CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([CH3:46])([CH3:45])[C:38](=[O:44])[N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH:35]=2)[NH:30][C:29]=1[C:47]1[CH:52]=[C:51]([CH3:53])[CH:50]=[C:49]([CH3:54])[CH:48]=1)[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=1)C1C=CC=CC=1.C(O)C.[H][H].[NH4+].[OH-]>[OH-].[OH-].[Pd+2].C(O)(=O)C.C(OCC)(=O)C>[CH3:46][C:37]([C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:47]1[CH:52]=[C:51]([CH3:53])[CH:50]=[C:49]([CH3:54])[CH:48]=1)=[C:28]2[CH2:27][CH2:26][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][S:22]([CH3:25])(=[O:23])=[O:24])=[CH:19][CH:20]=1)([CH3:45])[C:38](=[O:44])[N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: [H][H]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4CCCC4)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)C(=O)OCc2ccccc2)c1
Agent: [Pd+2]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4CCCC4)cc3c2CCNCCCCc2ccc(NS(C)(=O)=O)cc2)c1

Procedure:
A mixture of 52.6 mg (0.069 mmol) of [2-[5-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-ylethyl)-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]-[4-(4-methanesulfonylaminophenyl)butyl]carbamic acid benzyl ester (from Step 1), 25 mg of 20% palladium hydroxide on carbon, 2.5 mL of ethanol, 2.5 mL of ethyl acetate, and 0.010 mL of glacial acetic acid was shaken with hydrogen (approx. 45 psig) in a pressure vessel for 1.8 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC on 4 Analtech tapered silica gel GF plates (developed in 92.5:7.5:0.75 CH2Cl2-MeOH-concd. NH4OH; product band extracted with the same solvent) yielded 38.4 mg (88%) of cream-colored, stiff foam; homogeneous by TLC in in 92.5:7.5:0.75 CH2Cl2-MeOH-concd. NH4OH. 500 MHz 1H NMR (CDCl3) was consistent with the assigned structure. Mass spectrum (ESI): m/e 629.6 (M+H)+.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[N:16]=[C:15]([OH:17])[CH:14]=[CH:13][N:12]=2)=[CH:8][N:9]=1)(=O)C.O1CCCC1.Cl>C(O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[N:16]=[C:15]([OH:17])[CH:14]=[CH:13][N:12]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2nccc(O)n2)s1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ncc(Sc2nccc(O)n2)s1
Yield: 14.4 %

Procedure:
A mixture of 2-acetylamino-5-(4-hydroxypyrimidin-2-ylthio)thiazole (3.7 g) in a mixture of ethanol (100 ml), tetrahydrofuran (40 ml) and aqueous 6N-hydrochloric acid (20 ml) was refluxed for 6.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate. The precipitates were collected by filtration, washed with water and dried in vacuo to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 250 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(4-hydroxypyrimidin-2-ylthio)thiazole (0.45 g, yield: 14.5%). mp: 210°-220° C. (dec.) IR (Nujol): 3450, 3350, 3125, 1675, 1510,1230 cm-1
Reaction SMILES: C(OC([N:11]1[CH2:17][C@H:16]2[C@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][C@H:15]2[CH3:18])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:23]([O:22][C:20]([NH:19][C@:13]12[CH2:14][C@@H:15]([CH3:18])[C@H:16]1[CH2:17][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: [H][H]
Reactant: C[C@@H]1C[C@]2(NC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@H]12
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C[C@]2(NC(=O)OC(C)(C)C)CNC[C@H]12
Yield: 85.4 %

Procedure:
(1R,5S,6R)-1-tert-Butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylic acid benzyl ester (180 mg, 0.59 mmol) was dissolved in a methanol (5 mL). A small amount of 10% palladium-carbon (50% wet) was added, and the mixture was stirred in a hydrogen atmosphere for one hour. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 114 mg (85%) of the title compound as a colorless oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][O:29][C@@H:30]1[CH2:34][CH2:33][C@@H:32]([CH2:35][C:36](OC)=[O:37])[CH2:31]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:36](=[O:37])[CH2:35][C@@H:32]5[CH2:33][CH2:34][C@@H:30]([O:29][CH3:28])[CH2:31]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: COC(=O)C[C@@H]1CC[C@@H](OC)C1
Agent: Cl
Product: CO[C@@H]1CC[C@@H](CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)C1

Procedure:
The title compound, white solid (14 mg, 42%), MS (ISP) m/z=472.6 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (25.8 mg, 0.070 mmol) and methyl 2-((1R,3R)-3-methoxycyclopentyl)acetate
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[C@@H:4]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:65]1([C@H:71](O)[CH2:72][CH3:73])[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:45])[C@@H:4]([N:32]([S:33]([C:36]1[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=1)(=[O:35])=[O:34])[C@H:71]([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)[CH2:72][CH3:73])[CH2:5][C:6]1[CH:31]=[CH:30][C:9]2[O:10][C@@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=4)=[CH:18][CH:19]=3)[CH2:12][O:13][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: CC[C@@H](O)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC[C@@H](c1ccccc1)N([C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2)C(=O)OC)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(S)-3-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxin-6-yl}-2-(4-nitro-benzenesulfonylamino)-propionic acid methyl ester (1.6 g) was dissolved in 4 mL dry THF and 1247 mg triphenylphosphine and 650 μL (R)-(+)-1-phenyl-1-propanol were added. The mixture was stirred at 0° C. for 10 min, then 933 μL DIAD was added over 2 min. The reaction stirred at rt for 5 h, then was evaporated. The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc) to give 1.8 g desired product after drying. 1H NMR (400 MHz, acetone-d6): 8.35(m, 2H), 7.96 (m, 2H), 7.72 (d, 1H), 7.62 (d, 1H), 7.51-7.42 (m, 3H), 7.29 (m, 5H), 7.10 (m, 2H), 6.88-6.80 (m, 3H), 5.21 (s, 2H), 5.11 (m, 1H), 4.82 (m, 1H), 4.45 (m, 1H), 4.36 (m, 1H), 4.03 (m, 1H), 3.49 (m, 1H), 3.35 (s, 3H), 3.04 (m, 1H), 2.31 (m, 1H), 1.81 (m, 1H), 0.77 (t, 3H).
Reaction SMILES: [CH3:1][CH2:2][CH:3]1[O:8][CH:7]=[C:6](CO)[C:4]1=[O:5].[C:11]([O:16]C(=O)CCC)(=[O:15])[CH2:12][CH2:13][CH3:14].Cl.N1C=CC=C[CH:24]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:11]([O:16][C:6]1[C:4](=[O:5])[CH:3]([CH2:2][CH3:1])[O:8][C:7]=1[CH3:24])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: c1ccncc1
Reactant: CCC1OC=C(CO)C1=O
Reactant: CCCC(=O)OC(=O)CCC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCC(=O)OC1=C(C)OC(CC)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2(or 5)-Ethyl-4-hydroxy-5(or 2)-methyl-3(2H)-furanone (1.0 g) and 4-dimethylaminopyridine (0.05 g) were dissolved in a mixture solution of pyridine (10 ml) and methylene chloride (10 ml) under an argon stream in a 50 ml two-necked flask. To the resulting solution, butyric anhydride (1.26 ml) was added dropwise under cooling with ice and the mixture was stirred at room temperature for 12 hours. The reaction mixture solution was mixed with a 0.5N ice-cooled aqueous solution of HCl (10 ml) and subjected to extraction with diethyl ether (30 ml). The ether-extraction was repeated 3 times. The ether layer was washed 3 times with a 0.5N aqueous solution of HCl twice with a saturated aqueous solution of sodium bicarbonate and once with a saturated saline solution and dried over sodium sulfate. The ether layer was then concentrated under a reduced pressure and applied to a silica gel column for separation and purification. Thus, a mixture (1.28 g) of 4-butyryloxy-2-ethyl-5-methyl-3(2H)-furanone (major) and 4-butyryloxy-5-ethyl-2-methyl-3(2H)-furanone (minor) was obtained.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[CH:20]=[CH:19][C:18]2[S:17](=[O:22])(=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10](C(OC(C)(C)C)=O)[C:9]=2[CH:8]=1)=O)C.[F:30][C:31]1([F:39])[CH2:36][CH2:35][CH:34]([CH2:37]I)[CH2:33][CH2:32]1.FC1(F)CCC(C(OCC)=O)CC1.[I-].[CH3:54][O:55][C:56]1[N:61]=[C:60]2[S:62][C:63]([NH2:65])=[N:64][C:59]2=[CH:58][CH:57]=1>>[F:30][C:31]1([F:39])[CH2:36][CH2:35][CH:34]([CH2:37][CH:6]([C:7]2[CH:20]=[CH:19][C:18]3[S:17](=[O:22])(=[O:21])[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[CH:8]=2)[C:4]([NH:65][C:63]2[S:62][C:60]3[C:59]([N:64]=2)=[CH:58][CH:57]=[C:56]([O:55][CH3:54])[N:61]=3)=[O:3])[CH2:33][CH2:32]1
Reactant: COc1ccc2nc(N)sc2n1
Reactant: FC1(F)CCC(CI)CC1
Reactant: CCOC(=O)Cc1ccc2c(c1)N(C(=O)OC(C)(C)C)c1ccccc1S2(=O)=O
Agent: CCOC(=O)C1CCC(F)(F)CC1
Agent: [I-]
Product: COc1ccc2nc(NC(=O)C(CC3CCC(F)(F)CC3)c3ccc4c(c3)Nc3ccccc3S4(=O)=O)sc2n1

Procedure:
Analogously to Example 36 and Example 44, tert-butyl 2-ethoxycarbonylmethyl-5,5-dioxo-5H-phenothiazine-10-carboxylate, 1,1-difluoro-4-iodomethylcyclohexane (prepared from commercially available ethyl 4,4-difluorocyclohexanecarboxylate analogously to the synthesis of the iodide described in Example 40) and 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine give 3-(4,4-difluorocyclohexyl)-2-(5,5-dioxo-5,10-dihydrophenothiazin-2-yl)-N-(5-methoxythiazolo[5,4-b]pyridin-2-yl)propionamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14]O)=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:17][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: OCc1ccccc1-c1ccc(F)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(-c2ccccc2CBr)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of (4′-fluorobiphenyl-2-yl)-methanol (2.58 g, 12.8 mmol) in CH2Cl2 (100 mL), carbon tetrabromide (7.40 g, 22.3 mmol) is added. The solution is cooled to 0° C. and then triphenylphosphine (7.53 g, 28.7 mmol) is added portionwise. The reaction is stirred at 0° C. for 1.5 h and then at room temperature for 90 h before the solvent is removed. The resulting residue is partitioned between Et2O and water and then filtered. The layers are separated and the aqueous layer is extracted with Et2O. The combined organic layers are washed with water, brine and dried over Na2SO4. After concentration, the residue is purified by flash chromatography (hexane) to give 2-bromomethyl-4′-fluorobiphenyl as an oil. (an alternative preparation appears in J. Med. Chem. 2004, 47(22), 5441) 1H NMR (400 MHz, CDCl3) δ 7.53-7.50 (m, 1H), 7.43-7.31 (m, 4H), 7.24-7.21 (m, 1H), 7.15-6.80 (m, 2H), 4.42 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].OO.C(O)C>ClCCl.O>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]1[NH:13][C:11](=[O:12])[C:10]2[C:9](=[C:17]([O:18][CH3:19])[CH:16]=[CH:15][CH:14]=2)[N:8]=1)[CH3:2]
Reactant: CCOc1ccccc1C(=O)Nc1c(OC)cccc1C(N)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCOc1ccccc1-c1nc2c(OC)cccc2c(=O)[nH]1

Procedure:
A stirred mixture of 2-(2-ethoxybenzamido)-3-methoxybenzamide (2.6 g, 0.0083 mol), anhydrous potassium carbonate (2.33 g, 0.017 mol), hydrogen peroxide (30%, 4 ml), ethanol (40 ml) and water (80 ml) was heated under reflux for 1 hour. The mixture was allowed to cool and poured into a mixture of water (200 ml) and dichloromethane (100 ml), then the aqueous phase separated, acidified to pH 4 by the addition of 2N hydrochloric acid and extracted with dichloromethane (2×100 ml). The organic solutions were combined, dried (MgSO4) and evaporated under vacuum to give the title compound, which crystallized from ethyl acetate as a colourless solid (2.8 g, 83%), m.p. 198-199° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.N1C=CC=CC=1.[I:16]Cl.O1CCOCC1.[C:24]([O:28][C:29]([O:31]C(OC(C)(C)C)=O)=O)([CH3:27])([CH3:26])[CH3:25].CN(C)CCN>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:24]([O:28][C:29]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([I:16])=[CH:2]1)=[O:31])([CH3:27])([CH3:26])[CH3:25]
Reactant: ClI
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: c1cnc2[nH]ccc2c1
Agent: CN(C)CCN
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1cc(I)c2cccnc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1H-Pyrrolo[2,3-b]pyridine (2.00 g, 0.0169 mol; Aldrich) was dissolved in pyridine (17 mL, 0.21 mol; Acros) and cooled in an ice bath. A solution of 1.00 M of iodine monochloride in methylene chloride (18.6 mL; Aldrich) was added over 5 min. After 15 min the cooling bath was removed, and after another 30 min the solution was diluted with 200 mL of ethyl acetate. The organic solution was washed sequentially with 1 N hydrogen chloride and 1 N sodium hydroxide, dried over magnesium sulfate, and concentrated. The material was dissolved in 1,4-dioxane (85 mL, 1.1 mol; Acros) and treated with di-tert-butyldicarbonate (4.07 g, 0.0186 mol; Aldrich) and 4-dimethylaminopyridine (0.216 g, 0.00177 mol; Aldrich). The mixture was stirred at room temperature for 3 days. Excess di-tert-butyldicarbonate was destroyed by the addition of N,N-dimethyl-1,2-ethanediamine (1.7 mL, 0.015 mol). After stirring for 30 min, the solution was evaporated to dryness, taken up in ethyl acetate, then washed with dilute HCl and then saturated NaCl, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography produced the title compound in 2.03 g (35%) yield. MS m/z=345.01 (M+1). 1H NMR (400 MHz, CDCl3)™ ppm 8.527 (dd, J=4.8, 1.5 Hz, 1H) 7.796 (s, 1H) 7.717 (dd, J=7.9, 1.5 Hz, 1H) 7.276 (dd, J=7.9, 4.8 Hz, 1H) 1.671 (s, 9H). TLC Rf=0.50 in 3:1 hexanes/ethyl acetate.
Reaction SMILES: [C:1]1([N:7]2[C:10](=[O:11])[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][NH2:20]>C(#N)C>[CH3:19][NH:20][C:10]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([NH:9][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:18])=[O:11]
Reactant: CN
Reactant: O=C1N(c2ccccc2)C(=O)N1c1ccccc1
Solvent: CC#N
Product: CNC(=O)N(C(=O)Nc1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 76 %

Procedure:
In 30 ml of acetonitrile, 6.0 g (0.025 mol) of 1,3-diphenyl-1,3-diazetidine-2,4-dione was added. Then 3.9 ml (0.05 mol) of aqueous solution (40%) of methylamine was added dropwise thereinto with stirring. The reaction was continued at 50° C. for 0.5 hours, then the solvent was removed by distillation under a reduced pressure. The residue thus obtained was recrystallized from ethanol to obtain 5.1 l g (yield 76%) of 1-methyl-3,5-diphenylbiuret having a melting point of 145°-147° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.ClC1C=CC(S(N[C@H]2CC[C@H](C(OC)=O)CC2)(=O)=O)=CC=1[N+]([O-])=O>>[CH2:15]([NH:22][S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Agent: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Product: O=S(=O)(NCc1ccccc1)c1ccc(C(F)(F)F)cc1

Procedure:
4-(Trifluoromethyl)benzene-1-sulfonyl chloride (1 gm) was coupled to benzylamine using conditions analogous to those used to prepare intermediate 1. Purification by chromatography yielded N-benzyl-4-(trifluoromethyl)benzenesulfonamide (770 mg). Rf=0.38 by TLC eluting with 30% ethyl acetate in heptane. MS MH+ 316.2
Reaction SMILES: [OH:1][C:2]1[C:19]([I:20])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:21])[CH2:10][CH2:9]4)[C@@H:6]([OH:22])[CH2:5][C:4]=2[CH:3]=1.CC([O-])C.CC([O-])C.CC([O-])C.[Al+3]>C1(C)C=CC=CC=1.C1(=O)CCCCC1>[OH:1][C:2]1[C:19]([I:20])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:21])[CH2:10][CH2:9]4)[C:6](=[O:22])[CH2:5][C:4]=2[CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4cc(I)c(O)cc4C[C@H](O)[C@H]3[C@@H]1CCC2=O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: Cc1ccccc1
Solvent: O=C1CCCCC1
Product: C[C@]12CC[C@@H]3c4cc(I)c(O)cc4CC(=O)[C@H]3[C@@H]1CCC2=O
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
A solution of 206 mg (0.5 mmol) of 3,7β-dihydroxy-2-iodo-estra-1,3,5(10)-trien-17-one 14 in 15 ml of toluene and 4 ml of cyclohexanone was heated to 140° C. (oil bath temperature), and a solution of 400 mg of aluminum isopropylate in 10 ml of toluene was added drop by drop. In the meantime, a portion of the reaction mixture was distilled off. After complete addition of the aluminum isopropylate, it was refluxed for still another 5 hours. Then, the reaction solution was cooled and diluted with 80 ml of dichloromethane and 30 ml of potassium/sodium tartrate solution, and the resulting mixture was first stirred vigorously for 30 minutes before the organic phase was separated from the aqueous phase. The aqueous phase was finally extracted with dichloromethane (3×30 ml), and the combined organic phases were washed with a saturated NaCl solution, dried on sodium sulfate and concentrated by evaporation in a rotary evaporator. Flash chromatography (cyclohexane/ethyl acetate) yielded 129 mg (63%) of colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:39]([CH3:40])[CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:41])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:43]=[C:44]([CH:51]=[CH:52][CH:53]=2)[CH2:45][O:46]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[NH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>C1COCC1>[CH:45]([OH:46])=[O:66].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:35]([CH3:41])[CH2:36][CH2:37][CH2:38][C@@H:39]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:53]=[CH:52][CH:51]=[C:44]([CH2:45][N:63]3[CH2:68][CH2:67][O:66][CH2:65][CH2:64]3)[CH:43]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CN5CCOCC5)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 50 °C
Reaction time: 24 h
Yield: 37.8 %

Procedure:
To a solution of Intermediate 130b (0.17 mmol) in THF (2 mL) was added DIPEA (122 μL, 0.70 mmol) and morpholine (62 μL, 0.70 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% (2M NH3 in MeOH) in DCM, followed by MDAP (Method 7) purification, to give the title compound (25 mg, 19%). LCMS (Method 5): Rt 3.75 min, m/z 732 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.55 (3H, d, J=6.2 Hz), 0.58 (3H, d, J=6.2 Hz), 1.23 (9H, s), 1.35-1.53 3H, m), 1.63-1.68 (2H, m), 1.72-1.86 (2H, m), 1.86-1.92 (1H, m), 2.01-2.07 (2H, m), 2.32 (4H, t, J=4.1 Hz), 308-3.20 (2H, m), 3.46 (2H, s), 3.50 (4H, t, J=4.5 Hz), 4.78 (1H, td, J=8.6, 5.9 Hz), 5.47 (1H, t, J=4.2 Hz), 6.28 (1H, s), 6.98 (1H, d, J=8.6 Hz), 7.15 (1H, dd, J=9.8, 2.1 Hz), 7.17-7.23 (2H, m), 7.25-7.31 (3H, m), 7.32-7.44 (3H, m), 7.61 (1H, d, J=9.7 Hz), 7.83 (1H, d, J=1.8 Hz), 8.05 (1H, s), 8.12 (1.6H, s).