Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][N:6]([CH:11]([CH3:13])[CH3:12])[CH2:5]2.[Mg].II.[B:17](OC)([O:20]C)[O:18]C>O1CCCC1>[CH3:12][CH:11]([N:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([B:17]([OH:20])[OH:18])[CH:3]=2)[CH2:7]1)[CH3:13]
Reactant: CC(C)N1Cc2ccc(Br)cc2C1
Reactant: COB(OC)OC
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)N1Cc2ccc(B(O)O)cc2C1
Temperature: 5 °C

Procedure:
A solution of 5-bromo-2-(1-methylethyl)-2,3-dihydro-1H-isoindole (Intermediate 6, 20 g) in dry tetrahydrofuran (THF) (200 mL) was added to magnesium turnings (3.04 g). To this was added a crystal of iodine and the reaction mixture was heated at reflux for 4 hours. The reaction mixture was cooled to 5° C. and to this was added trimethyl borate (11.17 mL). After 1 hour the reaction was quenched with 2N hydrochloric acid (200 mL). The aqueous phase was extracted with ethyl acetate (3×200 mL), with each extraction was added triethylamine (50 mL). The combined organics were dried over magnesium sulphate and evaporated in vacuo to give a brown foam. This was triturated with TBME (300 mL) and the solid was collected by filtration to give the title compound (9.0 g) as an off-white solid.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([CH2:23][S:24]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:15]=2)[CH2:9]1)C1C=CC=CC=1.[CH2:37]([O:44][C:45](Cl)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[OH-].[Na+]>C1C=CC=CC=1>[CH2:37]([O:44][C:45]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([CH2:23][S:24]([C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:15]=2)[CH2:9]1)=[O:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=[N+]([O-])c1ccc(OC2CCN(Cc3ccccc3)C2)cc1CS(=O)(=O)c1cccc2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(Oc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)C1
Reaction time: 3 h
Yield: 70 %

Procedure:
A solution of 1-benzyl-3-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-pyrrolidine (4.2 g, 8.4 mmol) and benzylchloroformate (12.0 mL, 84 mmol in 2 equal portions) in benzene was heated at reflux temperature, under nitrogen, for 3 hours, cooled to ambient temperatures, poured into 2.5 N sodium hydroxide and extracted with ethyl acetate. The extracts were combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by flash chromatography using 40-50% ethyl acetate in hexane to afford 3-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-pyrrolidine-1-carboxylic acid benzyl ester as a buff foam, 3.2 g (70% yield), Mass spectrum (+EI, [M+H]+) m/z 547. 1HNMR (500 MHz, DMSO-d6): δ8.46 (d, 1H, J=7.44 Hz), 8.27 (d, 1H, J=8.06 Hz), 8.06-8.08 (m, 1H), 7.94-7.99 (m, 2H), 7.57-7.68 (m, 3H), 7.26-7.39 (m, 5H), 7.09 (dd, 1H, J=9.15 Hz and 2.68 Hz), 6.77 (s, 1H), 5.19-5.26 (m, 2H), 5.01-5.10 (m, 2H), 4.90 (s, 1H), 3.42-3.59 (m, 2H), 3.31-3.36 (m, 1H), 1.98-2.10 (m, 1H), 1.79-1.86 ppm (m, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:39]=[CH:38][C:12]([O:13][CH2:14][C:15]3([CH3:37])[CH:24]=[CH:23][C:22]4[C:17](=[C:18]([CH3:36])[C:19]([CH3:35])=[C:20]([O:26][CH2:27][C:28]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[O:29])[C:21]=4[CH3:25])[O:16]3)=[CH:11][CH:10]=2)[S:3]1>[Pd].C(O)C>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]3([CH3:37])[CH2:24][CH2:23][C:22]4[C:17](=[C:18]([CH3:36])[C:19]([CH3:35])=[C:20]([O:26][CH2:27][C:28]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[O:29])[C:21]=4[CH3:25])[O:16]3)=[CH:38][CH:39]=2)[S:3]1
Reactant: COCCOC(=O)COc1c(C)c(C)c2c(c1C)C=CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: [Pd]
Solvent: CCO
Product: COCCOC(=O)COc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reaction time: 10 h

Procedure:
Using Paar's hydrogenation apparatus, a mixture of 260 mg of 2-methoxyethyl α-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethyl-2H-chromen-6-yloxy}acetate (prepared as described in Example 39), 300 mg of 10% w/v palladium-on-carbon and 50 ml of ethanol was stirred for 10 hours under a hydrogen pressure of 3-5 atmospheres. The palladium-on-carbon was then filtered off, and the filtrate was condensed by evaporation under reduced pressure, to give the title compound as a colorless oily substance.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][N:15]3C(=O)C4=CC=CC=C4[C:16]3=O)=[C:12]([CH3:26])[N:11]=[C:10]2[CH2:27][N:28]([CH3:30])[CH3:29])=[C:5](C(C2C=CC=CN=2)=O)[CH:4]=1.O.NN.[CH2:44](O)[CH3:45]>>[F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[CH:5][C:6]2[N:9]3[C:10]([CH2:27][N:28]([CH3:30])[CH3:29])=[N:11][C:12]([CH3:26])=[C:13]3[CH2:14][N:15]=[C:16]([C:45]3[CH:44]=[CH:4][CH:5]=[CH:6][N:9]=3)[C:7]=2[CH:8]=1
Reactant: CCO
Reactant: Cc1nc(CN(C)C)n(-c2ccc(C(F)(F)F)cc2C(=O)c2ccccn2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Product: Cc1nc(CN(C)C)n2c1CN=C(c1ccccn1)c1cc(C(F)(F)F)ccc1-2

Procedure:
In the manner given in Example 4, N-[[1-[4-trifluoromethyl-2-(2-pyridylcarbonyl)phenyl]-2-[(dimethylamino)-methyl]-4-methylimidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 8-trifluoromethyl-6-(2-pyridyl)-1-[(dimethylamino)methyl]-3-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH3:24])=[C:16]3[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][C:17]=23)=[O:12])=[CH:4][C:3]=1[CH3:25].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[CH3:8][C:7]1[CH:6]=[C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH3:24])=[C:16]3[CH2:21][C:20]([CH3:22])([CH3:23])[CH2:19][CH2:18][C:17]=23)=[O:12])[CH:4]=[C:3]([CH3:25])[C:2]=1[O:1][CH2:26][CH:28]1[CH2:29][O:30]1
Reactant: ClCC1CO1
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1OCC1CO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.3 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (200 mg, 0.561 mmol) in isopropanol (5 mL) and 3 N aq. NaOH (2 mL) is treated with epichlorohydrine (210 mg, 1.68 mmol) and the mixture is stirred at rt for 6 h before it is diluted with diethyl ether, washed with sat. aq. NaHCO3 solution followed by water, dried over MgSO4 and evaporated. The crude product is purified on prep. TLC plates with heptane:EA 1:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (135 mg) as a yellow oil; LC-MS: tR=1.19 min, [M+1]=413.26.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[Mg].II.[CH2:14]([O:21][C:22]1[CH:35]=[CH:34][C:25]([CH:26]=[N:27][CH2:28][CH:29]([O:32][CH3:33])[O:30][CH3:31])=[CH:24][C:23]=1[O:36][CH3:37])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[NH4+]>C(OCC)C.O>[CH2:14]([O:21][C:22]1[CH:35]=[CH:34][C:25]([CH:26]([NH:27][CH2:28][CH:29]([O:30][CH3:31])[O:32][CH3:33])[CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:24][C:23]=1[O:36][CH3:37])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1cc(C=NCC(OC)OC)ccc1OCc1ccccc1
Reactant: COc1cccc(CCl)c1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: COc1cccc(CC(NCC(OC)OC)c2ccc(OCc3ccccc3)c(OC)c2)c1
Reaction time: 1 h

Procedure:
3-Methoxybenzylchloride (7.26 mL, 50 mmol) was dissolved in diethyl ether (50 mL) and magnesium metal (1.28 g, 52.5 mmol) was added without stirring. Several crystals of iodine were added to the magnesium “pile”. When the reaction begins, stirring is started and external cooling is applied as necessary to maintain gentle refluxing. Once the initial reaction was complete, the mixture was refluxed for 1 h to complete the reaction. The resulting gray/green mixture was cooled in an ice-bath and (4-benzyloxy-3-methoxy-benzylidene)-(2,2-dimethoxy-ethyl)-amine (6.58 g, 20 mmol) in diethyl ether (30 mL) was added dropwise (a precipitate forms with each drop). After addition was complete, the resulting suspension was heated at reflux for 2 hours. The mixture was cooled in an ice-bath and saturated ammonium chloride solution (50 mL) was carefully added dropwise. The mixture was stirred at 0° C. for 15 minutes and then room temperature for 1 h. Water (50 mL) was added, and the mixture was filtered. The organic layer was separated, washed with water (50 mL), saturated aqueous sodium chloride solution (40 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford [1-(4-benzyloxy-3-methoxy-phenyl)-2-(3-methoxy-phenyl)-ethyl]-(2,2-dimethoxy-ethyl)-amine as a light tan solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17](I)[CH:18]([CH3:20])[CH3:19]>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CC(C)CI
Reactant: Clc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(Cl)nc2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 96 %

Procedure:
To a solution of 2-chloro-benzoimidazole (1.0 eq.) in DMF was added K2CO3 (2.0 eq.) and isobutyl iodide (1.5 eq.). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was poured into ice-water. The mixture was extracted with ethyl acetate (3×100 mL), washed with brine, dried over Na2SO4, concentrated to get a residue, which was purified by column chromatography to afford 4 g (96%) of 2-chloro-1-isobutyl-benzoimidazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[C:5](=[C:6]3[C:11](=[CH:12][N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7]3)[CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1.CSC.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[N+:13]([O-:25])=[CH:12][C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]=2[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2ncc3c(c2c1)CCCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CSC
Product: COc1ccc2c(c1)c1c(c[n+]2[O-])CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a solution of Compound 273 (91.80 g, 430 mmol) in dichloromethane (500 mL) cooled at zero degrees C. was added a solution of mCPBA (55 percent, 161.7 g, 516 mmol) in dichloromethane (900 mL), and the resulting mixture was stirred at 25° C. for 1 hour. Dimethyl sulfide (6.95 mL, 94.6 mmol) was added and stirring was continued for 15 minutes followed by addition of saturated aqueous sodium bicarbonate solution (1000 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (500 mL). The combined organic layers were dried (MgSO4), filtered through a 3 cm×3 cm plug of silica, and evaporated in vacuo. The residue was purified by recrystallization from benzene-cyclohexane to give a total of 88.34 g (90 percent) of the N-oxide Compound 280a: off-white crystalline solid; mp 167°-169° C.; Rf =0.31 (silica, 20 percent methanol in ethyl acetate); IR (CHCl3) νmax 2943, 1617, 1512, 1459, 1428, 1379, 1108 cm-1 ; 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J=9.5 Hz, 1 H, H4), 8.18 (s, 1 H, H 6), 7.30 (dd, J=9.5, 2.6 Hz, 1 H, H3), 7.10 (d, J=2.6 Hz, 1 H, H1), 2.95 (t, J=6.2 Hz, 2 H, H10), 2.77 (t, J=6.2 Hz, 2 H, H7), 1.99-1.94 and 1.89-1.85 (m, 2 H each, H8 and H9); 13C NMR (125 MHz, CDCl3 ) δ 159.1, 134.8, 134.3, 131.4, 130.8, 121.7, 120.3, 101.8, 55.5, 27.0, 24.7, 22.1, 21.8; MS (FAB+) m/e (rel intensity) 230 (M+H, 100), 213 (10); HRMS for C 14 H16NO2 (M+H), calcd 230.1181, found 230.1194.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([N:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[C:10]2[CH:16]=[CH:15][N:14](S(C3C=CC=CC=3)(=O)=O)[C:11]2=[N:12][CH:13]=1.C1COCC1.CO.[Li+].[OH-]>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([N:26]2[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]2)=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3F)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2c(-c3ccccc3F)cnc3[nH]ccc23)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
tert-Butyl 4-(5-(2-fluorophenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.100 g, 0.186 mmol) was placed in 1:1 THF:MeOH (6 mL). LiOH (0.621 mL, 1.86 mmol) was then added, and the reaction was stirred at 50° C. for 1 hour. The reaction was then poured into water and extracted into DCM. The organic fractions were combined, dried, filtered and concentrated to give the crude product tert-butyl 4-(5-(2-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (0.066 g, 89.3% yield) that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][C:14]([CH:43]([NH:45][CH:46]([CH3:48])[CH3:47])[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].C(O)(C(F)(F)F)=O.OS(C(F)(F)F)(=O)=O.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH:43]([NH:45][CH:46]([CH3:48])[CH3:47])[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)NC(C)C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C(C)NC(C)C)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 80 °C
Yield: 79 %

Procedure:
A mixture of 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanone (Example 271, 0.270 g, 0.443 mmol), titanium (iv) isopropoxide (0.519 mL, 1.772 mmol) and isopropylamine (0.152 mL, 1.772 mmol) in 3 mL THF was sealed and heated to 60° C. overnight. The reaction was cooled, diluted with 3 mL DCM and treated with sodium triacetoxyborohydride (0.375 g, 1.772 mmol). After 1 h, sodium cyanoborohydride (0.111 g, 1.772 mmol) was added. After 3 h, the reaction was complete. The reaction was treated with ice, water, conc. NH4OH, and DCM. The organic layer was removed. Upon attempted extraction, only an emulsion was possible, so the material was filtered through celite. The aq. layer was extracted 1×DCM. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give 0.331 g of an orange oil containing impure 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(isopropylamino)ethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine. m/z (ESI, +ve ion) 653 (M+H)+. The impure material was treated with 2 mL TFA and triflic acid (0.197 mL, 2.214 mmol) in a sealed vessel, and was heated to 80° C. for 30 min. The reaction was cooled and poured onto ice, and basified with 10N NaOH. The material was extracted with DCM, three times, and 10% iPrOH/DCM once. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was suspended in MeOH and filtered, rinsing with MeOH. The solid was dried in vacuo to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(isopropylamino)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.145 g, 0.352 mmol, 79% yield) as an orange solid. m/z (ESI, +ve ion) 413 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.91 (s, 1H), 8.77 (br. s., 1H), 8.28-8.49 (m, 3H), 7.89 (br. s., 1H), 7.74 (br. s., 1H), 3.93 (s, 3H), 3.76-3.91 (m, 1H), 3.26-3.32 (m, 1H), 2.44 (s, 3H), 1.27 (br. s., 3H), 0.84-1.08 (m, 6H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:16]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=3[C:6](=[CH:5][CH2:4][CH2:3][N:2]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:1])[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)CBr
Reactant: CNCCC=C1c2ccccc2C=Cc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(C)CCC=C1c2ccccc2C=Cc2ccccc21
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 2.61 g of 5-[3-(methylamino)propylidene]-5H-dibenzo[a,d]cycloheptene, 2.00 g of ethyl bromoacetate, 1.38 g of potassium carbonate, and 13 ml of N,N-dimethylformamide was stirred at 70° C. for 4 hours. After the reaction was completed, water was added to the reaction mixture and the mixture was then extracted with diethyl ether. The ether layer was washed with water and dried, and then the solvent was removed by distillation. The residue was purified by column chromatography on aluminum oxide [n-hexane-diethyl ether (1:1)] to give 1.88 g of slightly yellow viscous liquid.
Reaction SMILES: [C:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:13]=[C:14]([O:21][CH3:22])[CH:15]=[CH:16][C:17]=4[C:18]=3[CH2:19][CH2:20][C@:4]12[CH3:5])#[CH:2].C(=O)([O-])[O-].[Ca+2].[H][H]>C1C=CC=CC=1>[CH2:1]([C@:3]1([OH:23])[CH2:8][CH2:7][C@H:6]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:13]=[C:14]([O:21][CH3:22])[CH:15]=[CH:16][C:17]=4[C:18]=3[CH2:19][CH2:20][C@:4]12[CH3:5])[CH3:2]
Reactant: C#C[C@]1(O)CC[C@H]2C3=C(CC[C@@]21C)c1ccc(OC)cc1CC3
Reactant: [H][H]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccccc1
Product: CC[C@]1(O)CC[C@H]2C3=C(CC[C@@]21C)c1ccc(OC)cc1CC3
Yield: 63.5 %

Procedure:
Add dl-17α-ethynyl-3-methoxyestra-1,3,5(10),8-tetraen-17-ol (7 g) in benzene (75 ml) to a suspension of prehydrogenated 2% palladised calcium carbonate (3 g) in benzene (50 ml), and shake in an atmosphere of hydrogen until two molecular equivalents of hydrogen (1.030 ml) have been absorbed. Filter the catalyst, evaporate the solvent and recrystallize the residue twice from methanol to obtain dl-17α-ethyl-3-methoxyestra-1,3,5(10),8-tetraen-17-ol (4.5 g), m.p. 105°-120°; ultraviolet absorption maximum 278 mμ (ε12,000); infrared absorption peaks at 295 μ, 6.25 μ.
Reaction SMILES: CN(C)C=O.C(N(CC)CC)C.[C:13]([C:17]#[CH:18])([CH3:16])([CH3:15])[CH3:14].[CH2:19]([N:21]([CH3:32])[CH:22]=[N:23][C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][C:25]=1[CH3:31])[CH3:20]>[Cu](I)I.C(OCC)(=O)C.O>[CH2:19]([N:21]([CH3:32])[CH:22]=[N:23][C:24]1[CH:29]=[CH:28][C:27]([C:18]#[C:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:26][C:25]=1[CH3:31])[CH3:20]
Reactant: CCN(C)C=Nc1ccc(I)cc1C
Reactant: C#CC(C)(C)C
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C)C=Nc1ccc(C#CC(C)(C)C)cc1C
Temperature: 80 °C
Reaction time: 12 h
Yield: 23.6 %

Procedure:
Dimethylformamide (10 ml), 10 ml of triethylamine, 0.27 g of tert-butylacetylene, 0.11 g of palladium chloride-ditriphenylphosphine complex, and 0.03 g of copper iodide were added to 0.50 g of the N-ethyl-N-methyl-N′-(4-iodo-2-methylphenyl)formamidine (Compound 2-2) produced in Reference Example 2, and the mixture was stirred at 80° C. for 12 hours. After completion of the reaction, water was added to the reaction solution, and extraction was performed 3 times with ethyl acetate. The organic layer was collected, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), thereby obtaining 0.10 g of N-ethyl-N-methyl-N′-[2-methyl-4-(3,3-dimethyl-1-butynyl)phenyl]formamidine (Compound 66).
Reaction SMILES: [CH:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>[Fe].O>[CH:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccccc1SC1CCCCC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Nc1ccccc1SC1CCCCC1
Temperature: 90 °C
Yield: 98.3 %

Procedure:
A mixture of 8.5 g of 2-(cyclohexylthio)nitrobenzene, 9.6 g of iron powder, 0.61 g of ammonium chloride and 22 ml of water was stirred on heating at 90° C. for 3 hours. The temperature of the reaction solution was returned to room temperature, the reaction solution was filtered by Selite and extracted with dichloromethane. The dichloromethane layer was washed, in turn, with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated to give 7.3 g of 2-(cyclohexylthio)aniline as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=1)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8](Br)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C([NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)(=O)C>CN(C)C=O>[CH3:1][C:2]([CH3:23])([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=1)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:7]=1
Reactant: CC(=O)Nc1ccccc1
Reactant: CCOc1ccc(C(C)(C)COCc2ccc(F)c(Br)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(C(C)(C)COCc2ccc(F)c(Nc3ccccc3)c2)cc1
Temperature: 140 °C
Reaction time: 40 h

Procedure:
2.37 Grams of 3-bromo-4-fluorobenzyl 2,2-dimethyl-2-(4-ethoxyphenyl)ethyl ether, 0.95 g of potassium carbonate, 1.01 g of acetanilide, 10 ml of dimethylformamide and 250 mg of cuprous chloride were mixed and stirred at 140° C. for 40 hours in a nitrogen stream. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium chloride liquor, and after removing the solvent by evaporation, the residual oil was dissolved in a 20% ethanol solution of potassium hydroxide (2 times by mole) and refluxed for 30 minutes. The reaction solution was then poured into ice water and extracted with ether. The ether layer was washed with an aqueous sodium chloride liquor and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation. The residual oil was separation-purified by column chromatography on silica gel to obtain 1.05 g of 3-anilino-4-fluorobenzyl 2,2-dimethyl-2-(4-ethoxyphenyl)ethyl ether.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2.[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[N:8]([CH:9]=[C:10]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=3)[N:11]=1)[CH2:7][CH2:6][O:5]2)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc1OCC2
Temperature: 100 °C
Yield: 93.1 %

Procedure:
A mixture of 12-bromo-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (200 mg, 0.53 mmol), 2-(N-tert-butylsulfamoyl)phenylboronic acid (274 mg, 1.07 mmol), Pd(dppf)Cl2 (38.9 mg, 0.0530 mmol), and CS2CO3 (350 mg, 1.07 mmol) in 1,4-dioxane (5 mL) was heated to 100° C. for 8 h. After filtration, the filtrate was purified by reverse phase combiflash eluting with a 0-70% gradient of CH3CN in 0.3% NH4HCO3 to afford N-tert-butyl-2-{4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}benzene-1-sulphonamide (250 mg, 93% yield) as white solid. LCMS (ESI) m/z: 507.2 [M+H+]