Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].O.[N-:17]=[N+:18]=[N-].[Na+]>C(O)(C(F)(F)F)=O>[N:1]([C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc2ccncc2c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: [N-]=[N+]=Nc1ccc2ccncc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.8 %

Procedure:
To a solution of 7-aminoisoquinoline (7.0 g) in TFA (35 mL) at 0° C. was added sodium nitrite (4.02 g) portionwise over a period of 30 minutes. The reaction was stirred at 0° C. to room temperature for 1.5 h. Water (3.5 mL) was added followed by portionwise addition of sodium azide (3.48 g) at 0° C. over a period of 30 minutes. After the addition, the reaction was slowly warmed up to room temperature and stirred for 1 h. Two third of TFA was evaporated and the residue was cooled to 0° C. Sodium bicarbonate (sat. in water) was added dropwisely to the residue until the pH was abouty 8–9. After extraction with methylene chloride (4×60 mL), the organic phase was combined, washed with water, brine, dried over sodium sulfate, filtered and concentrated to leave 7-azidoisoquinoline (7.5 g) as a dark brown solid. CI mass spectrum z (rel. intensity) 171 (M+H, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[CH2:11]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1)[CH3:12].[Si](C#N)(C)(C)C.[N:28]1([C:33](N2C=CN=C2)=[O:34])C=CN=[CH:29]1>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:18]([C:17]4[CH:20]=[CH:21][C:14]([O:13][CH2:11][CH3:12])=[CH:15][CH:16]=4)[CH2:29][NH:28][C:33]3=[O:34])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: CCOc1ccc(C=O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc2nc[nH]c2c1
Agent: C[Si](C)(C)C#N
Product: CCOc1ccc(C2CNC(=O)N2c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 4-ethoxybenzaldehyde (0.601 g, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (0.98 mL, 7.0 mmol), di-(imidazol-1-yl)methanone (0.622, 3.84 mmol) as described in method 2.
Reaction SMILES: O=[O+][O-].[C:4]12[CH2:10][C:7](=[CH:8][CH:9]=1)[C:6]1[CH:11]=[CH:12][CH:13]=[CH:14][C:5]2=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)=O.[H][H]>CO.[Pt]>[CH2:15]([N:22]1[CH2:9][CH:4]2[CH2:10][CH:7]([C:6]3[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=32)[CH2:8]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: C1=C2CC(=C1)c1ccccc12
Reactant: NCc1ccccc1
Agent: [Pt]
Agent: O=[O+][O-]
Solvent: CO
Solvent: O=CO
Product: c1ccc(CN2CC3CC(C2)c2ccccc23)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stream of ozone was bubbled through a solution of 4.00 g of benzonorbornadiene (1,4-dihydro-1,4-methanonaphthalene) (28.1 mmol, 1.0 equivalent) in 80 mL of methanol at −78° C. Once the solution developed a blue color, ozone generation was stopped after another few minutes and then oxygen was bubbled through for five minutes to dispel the blue color. Then the solution was purged with nitrogen for 20 to 40 minutes to deoxygenate the solution. To the cold solution was added 0.199 g of 5% platinum on carbon, 55% wet by weight, (.0281 mmol, 0.001 equivalent). The system was passivated with hydrogen, pressurized to 40 psi of hydrogen, and gradually warmed to room temperature. Once the ozonide was reduced completely (within 45-60 minutes), an additional 0.798 g of 5% platinum on carbon (0.112 mmol, 0.004 equivalent) was added to the reaction mixture at 0° C., followed by 3.07 mL of benzylamine (28.1 mmol, 1.0 equivalent) and 0.561 mL of 96% formic acid (14.0 mmol, 0.50 equivalent). The system was repressurized to 50 psi of hydrogen and allowed to warm to room temperature. After 4 hours, the reaction mixture was removed from the reactor and filtered through a pad of Celite, washing with 20 mL of methanol. This reaction mixture was used in the next step (Example 59B), but isolation of the intermediate was carried out as follows: the filtrate was concentrated in vacuo and partitioned between 40 mL of methylene chloride and 30 mL of a saturated aqueous solution of sodium carbonate; the aqueous layer was extracted with another 30 mL of methylene chloride; the combined organic layers were dried over anhydrous sodium sulfate and concentrated; the residue was dissolved in 10 mL of 9:1 hexane/ethyl acetate and passed through a plug of silica gel; and after concentrating the filtrate, the title compound was obtained as an oil (3.34 g, 48%): 1H NMR (400 MHz, CD3OD): δ 7.22-7.19 (m, 7H), 6.93 (d, J=8.0 Hz, 2H), 3.52 (s, 2H), 3.13-3.11 (m, 2H), 2.85 (d, J=9.5 Hz, 2H), 2.47 (d, J=9.5 Hz, 2H), 2,32-2,29 (m, 1H), 1.71 (d, J=10.0 Hz, 1H).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:4]=1[CH:5]=[N:6]2.[N:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]1[N:30]3[N:31]=[CH:32][CH:33]=[CH:34][C:29]3=[N:28][C:21]=1[CH:22]=[N:23]2>>[CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:4]=1[C:5]([NH2:18])=[N:6]2.[N:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[C:20]1[N:30]3[N:31]=[CH:32][CH:33]=[CH:34][C:29]3=[N:28][C:21]=1[C:22]([NH2:6])=[N:23]2
Reactant: c1ccc2c(c1)ncc1nc3cccnn3c12
Reactant: c1cnc2c(c1)ncc1nc3cccnn3c12
Product: Nc1nc2ccccc2c2c1nc1cccnn12
Product: Nc1nc2cccnc2c2c1nc1cccnn12

Procedure:
In steps (6) and (7) of Reaction Scheme III, a pyridazino[1′,6′:1,2]imidazo[4,5-c]quinoline or pyridazino[1′,6′:1,2]imidazo[4,5-c][1,5]naphthyridine of Formula XLIV is oxidized and then aminated to provide a pyridazino[1′,6′:1,2]imidazo[4,5-c]quinolin-6-amine or pyridazino[1′,6′:1,2]imidazo[4,5-c][1,5]naphthyridin-6-amine of Formula XLV, a subgenus of Formula I. The steps can be carried out using the methods described in steps (5) and (6) of Reaction Scheme I.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:5][CH:4]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:27]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=4)[CH:14]=3)=[CH:5][CH:4]=2)[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(CCl)cc3)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(Cn4ccnc4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.4 %

Procedure:
In DMF (3 ml) was dissolved (E)-N-[4-(chloromethyl)phenyl]-3-(4-methylphenyl)cinnamamide (200 mg), and to the solution were added imidazole (49 mg) and potassium carbonate (382 mg). The mixture was stirred at room temperature for 18 hours, and to the mixture was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropylether to give (E)-N-[4-[(imidazol-1-yl)methyl]phenyl]-3-(4-methylphenyl)-cinnamamide (Compound 65) (90 mg) as colorless crystals.
Reaction SMILES: N1CCCCC1.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]1=[O:16].[I:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=O)[CH:25]=2)[NH:20][N:19]=1>CCO>[I:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH:27]=[C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[NH:7][C:8]3=[O:16])[CH:25]=2)[NH:20][N:19]=1
Reactant: O=Cc1ccc2[nH]nc(I)c2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccccc2C1=Cc1ccc2[nH]nc(I)c2c1
Temperature: 75 °C
Reaction time: 14 h
Yield: 63.1 %

Procedure:
Piperidine (0.01 mL, 0.1 mmol) was added to a suspension of oxindole (72 mg, 0.54 mmol) and 3-iodo-1H-indazole-5-carbaldehyde (146 mg, 0.54 mmol) in EtOH (10 mL). On heating to 75° C., the suspended solid dissolved, and a new precipitate formed. Heating was continued at 75° C. for 14 hrs. After the mixture was cooled to room temperature, suction filtration and rinsing with EtOH (4×2 mL) gave 3-((3-iodo-1H-indazol-5-yl)methylene)indolin-2-one (yellow solid, 131.9 mg, 63%). 1H NMR (400 MHz, d6-DMSO) δ 13.75 (br. s, 1H), 10.61 (br. s, 1H), 7.84 (s, 1H), 7.77 (m, 2H), 7.69 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 7.23 (m, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.84 (m, 1H); MS ESI 388.0 [M+H]+, calcd for [C16H10IN3O+H]+ 388.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[CH:10]1([C:13](Cl)=O)[CH2:12][CH2:11]1.Cl[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:13]([CH:10]3[CH2:11][CH2:12]3)[N:8]([C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[C:5]2=[N:6][CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(Br)cnc1N
Reactant: CC(C)COC(=O)Cl
Product: CC(C)COC(=O)n1c(C2CC2)nc2cc(Br)cnc21

Procedure:
Synthesized according to the method of reagent preparation 19 by using 5-bromo-2,3-diaminopyridine and acylation with cyclopropylcarbonyl chloride in step 1 and treatment with isobutyl chloroformate in step 3. MS (EI) for C14H16BrN3O2: 339 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21](CC2C=CC(OC)=CC=2)[C:22](=[O:24])[CH3:23])[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.[C@H:34]1([NH2:41])[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1.O>CN1C(=O)CCC1>[C:22]([NH:21][C:4]1[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=[C:2]([NH:40][C@H:37]2[CH2:38][CH2:39][C@H:34]([NH2:41])[CH2:35][CH2:36]2)[CH:3]=1)(=[O:24])[CH3:23]
Reactant: COc1ccc(CN(C(C)=O)c2cc(Cl)nn3c(C(=O)Nc4ccncc4F)cnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)Nc1cc(N[C@H]2CC[C@H](N)CC2)nn2c(C(=O)Nc3ccncc3F)cnc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 6-chloro-N-(3-fluoropyridin-4-yl)-8-(N-(4-methoxybenzyl)acetamido)imidazo[1,2-b]pyridazine-3-carboxamide 19B (30 mg, 0.064 mmol) and trans-cyclohexane-1,4-diamine (14.61 mg, 0.128 mmol) in NMP (0.5 mL) was heated at 70° C. for 2.5 h, and then cooled to room temperature. Water was added. The mixture was extracted with EtOAc for three times, the combined extracts were washed with H2O and brine, and then concentrated. The resulting residue was treated with MeOH. The solid was filtered off, and the filtrate was purified by preparative HPLC. The desired fraction was concentrated to dryness and then dissolved in TFA (1 mL). The solution was stirred at 70° C. for 6 h and then concentrated. The residue was treated with MeOH/DCM, and concentrated again to give a solid, which was triturated with ether. The solid was collected by filtration, rinsed with ether, and dried under vacuum to give 19C (7.3 mg, 21%) as an off white solid. [M+H]=427. HPLC Peak Rt=2.018 minutes. (Chromolith column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm.)
Reaction SMILES: [C:1]([CH:3]1[CH:8]2[CH:4]1[CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7]2)#[N:2].F[C:17]1C=CC=C[N:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:33]1(C)C=C[CH:36]=[CH:35][CH:34]=1>>[C:12]([O:11][C:9]([N:6]1[CH2:5][CH:4]2[CH:8]([C:3]2([C:17]#[N:18])[C:1]2[CH:36]=[CH:35][CH:34]=[CH:33][N:2]=2)[CH2:7]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CC2C(C#N)C2C1
Reactant: Fc1ccccn1
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CC2C(C1)C2(C#N)c1ccccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To a solution of 3 (700 mg, 3.36 mmol) in toluene (16 mL) at 0° C. was added 2-fluoropyridine (326 mg, 3.36 mmol) and a solution of KHMDS (0.5M in toluene, 6.72 mL, 3.36 mmol). The reaction was warmed to room temperature and stirred for 18 h. The crude reaction was purified by column chromatography using 0 to 60% EtOAc in hexanes to afford 10 (390 mg, 41%) as a clear oil; 1H-nmr (400 MHz, CDCl3) δ 8.46 (d, J=4.0 Hz, 1H), 7.75-7.66 (m, 2H), 7.17 (td, J=7.0, 1.5 Hz, 1H), 3.95 (d, J=12.5 Hz, 1H), 3.86 (d, J=12.5 Hz, 1H), 3.81-3.71 (m, 2H), 2.69 (s, 2H), 1.88 (d, J=5.0 Hz, 4H), 1.48 (s, 9H); LC-MS (214 nM) 2.96 min (>98%), m/z 286.1 [M+H].
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=O)[CH2:12][C:13]#[N:14])=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>CCO.O.CCOC(C)=O>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:12]=[C:13]([NH2:14])[O:23][N:22]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: N#CCC(=O)c1ccc2cnccc2c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccc3cnccc3c2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.3 %

Procedure:
To a solution of 3-(isoquinolin-6-yl)-3-oxopropanenitrile (2.1 g, 11 mmol) in 60 mL of EtOH was added sodium acetate (5.3 g, 64 mmol) and hydroxylamine hydrochloride (3.7 g, 54 mmol) in 60 mL of water. The mixture was heated to reflux. After 3 hours, the reaction mixture was cooled to room temperature and diluted with 300 mL of EtOAc. The mixture was transferred to a separatory funnel and washed three times with 50 mL of water and once with 50 mL of brine. The remaining liquid was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (1 to 5% MeOH/CH2Cl2), affording 3-(isoquinolin-6-yl)isoxazol-5-amine (0.96 g, 42% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.35 (s, 1H), 8.56 (d, J=6.5 Hz, 1H), 8.36 (s, 1H), 8.19 (d, J=8.6 Hz, 1H), 8.04 (dd, J=1.4 Hz, 8.5 Hz, 1H), 7.91 (d, J=5.9 Hz, 1H), 6.92 (s, 2H), 5.60 (s, 1H).
Reaction SMILES: [C:1]([S@@:5](/[N:7]=[CH:8]/[C:9]1[S:13][C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:11][CH:10]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].C(=O)=O.[CH2:24]([Mg]Br)[CH:25]([CH3:27])[CH3:26]>ClCCl>[CH3:2][C:1]([CH3:4])([S@@:5]([NH:7][C@@H:8]([C:9]1[S:13][C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:11][CH:10]=1)[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:6])[CH3:3].[CH3:2][C:1]([CH3:4])([S@@:5]([NH:7][C@H:8]([C:9]1[S:13][C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:11][CH:10]=1)[CH2:24][CH:25]([CH3:27])[CH3:26])=[O:6])[CH3:3]
Reactant: CC(C)C[Mg]Br
Reactant: CC(C)(C)OC(=O)c1ccc(/C=N/[S@@](=O)C(C)(C)C)s1
Agent: O=C=O
Solvent: ClCCl
Product: CC(C)C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(C(=O)OC(C)(C)C)s1
Product: CC(C)C[C@H](N[S@@](=O)C(C)(C)C)c1ccc(C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(S,E)-tert-Butyl 5-((tert-butylsulfinylimino)methyl)thiophene-2-carboxylate (1 g, 3.17 mmol) was dissolved in dichloromethane (15.85 ml) and chilled to −45° C. in an acetone bath to which dry ice had been added to achieve the desired temperature. Isobutylmagnesium bromide (2.0M in diethyl ether; 3.17 ml, 6.34 mmol) was added dropwise over ˜5 minutes. The mixture was stirred for 4 hours keeping the temperature between −40° C. and −50° C. by periodic addition of dry ice and then warmed to room temperature overnight. The mixture was quenched with saturated ammonium chloride (exothermic, bubbling) and extracted with dichloromethane (three times; considerable emulsion formed). The organic extracts were dried with sodium sulfate, filtered, concentrated and chromatographed to provide both tert-butyl 5-((R)-1-((S)-1,1-dimethylethylsulfinamido)-3-methylbutyl)thiophene-2-carboxylate and tert-butyl 5-((S)-1-((S)-1,1-dimethylethylsulfinamido)-3-methylbutyl)thiophene-2-carboxylate as separate compounds.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[CH2:14][CH2:15][C:16]2=[O:21].Br[CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][O:26][CH3:27].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:9][O:8][C:7]1[C:2]([O:1][CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][O:26][CH3:27])=[C:3]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:4]=[CH:5][C:6]=1[O:10][CH3:11]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Reactant: COCC(C)(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC)c1OC
Temperature: 100 °C

Procedure:
Compound 303 (0.02 g, 0.07 mmol) and 1-bromo-3-methoxy-2,2-dimethyl-propane (0.12 g, 0.56 mmol) were dissolved in dry DMF (0.8 mL). K2CO3 (0.1 g, 0.68 mmol) were added. The suspension was heated at 100° C. for 18 h. H2O was added and the mixture was extracted with EtOAc (×2). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC afforded the title compound as an oil.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[CH3:11][CH2:12][CH2:13][CH2:14][CH:15]=[O:16].N1C=CC=CC=1.[Cl:23]CCCl>>[C:2](=[O:3])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:16][CH:15]([Cl:23])[CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCCC=O
Reactant: ClCCCl
Solvent: c1ccncc1
Product: CCCCC(Cl)OC(=O)Oc1ccccc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Phenyl chloroformate (2.0 g, 12.8 mmol) and n-valeraldehyde (1.3 g, 15.1 mmol) were dissolved in 1,2-dichloroethane (10 ml) and pyridine (0.06 g, 0.76 mmol) was added dropwise to the stirred solution. Stirred at 80° C. for 1 day. Washed with water (10 ml), dried (MgSO4) and concentrated. Purified by flash chromatography (Silikagel 60, petroleum ether/ethyl acetate 95:5). Yield: 0.26 g GC/MS: 242.0 (M+).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH:16]=[CH:17]2)[C@H:13]2[C@H:4]1[C:5]1[CH:6]=[CH:7][C:8]([OH:21])=[CH:9][C:10]=1[CH2:11][CH2:12]2.N1C=CC=CC=1.[CH2:28]([Si:30]([CH2:34][CH3:35])([CH2:32][CH3:33])Br)[CH3:29].O>C(OC)(C)(C)C>[CH3:1][O:2][C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH:16]=[CH:17]2)[C@H:13]2[C@H:4]1[C:5]1[CH:6]=[CH:7][C:8]([O:21][Si:30]([CH2:34][CH3:35])([CH2:32][CH3:33])[CH2:28][CH3:29])=[CH:9][C:10]=1[CH2:11][CH2:12]2
Reactant: CC[Si](Br)(CC)CC
Reactant: CO[C@H]1C[C@]2(C)C=CC[C@H]2[C@@H]2CCc3cc(O)ccc3[C@H]21
Solvent: O
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: CC[Si](CC)(CC)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2[C@@H](OC)C[C@]2(C)C=CC[C@@H]12
Reaction time: 1 h

Procedure:
284 mg (1 mmol) of 11β-methoxy-estra-1,3,5(10),16-tetraen-3-ol is reacted in 10 ml of tert-butylmethyl ether and 1 ml of pyridine with 0.6 ml of triethylbromosilane. After 1 hour, 30 ml of water is added to the reaction suspension. The organic phase is separated, washed, dried and concentrated by evaporation in a vacuum. The oily product that is thus obtained is used immediately in the next stage (hydroboration). Yield: 380 mg (95% of theory)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:9](C)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[OH:8].[C:20](=O)([O-])[O-].[K+].[K+].Br[C:27](Br)([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>CC(C)=O>[C:14]([O:13][C:12]([NH:11][C@H:10]([CH3:20])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]2[O:8][C:27]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:28]([O:30][CH2:31][CH3:32])=[O:29])[O:1][C:2]=2[CH:3]=1)=[O:18])([CH3:15])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Reactant: O=C([O-])[O-]
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)c1ccc(O)c(O)c1
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(C[C@@H](C)NC(=O)OC(C)(C)C)cc2O1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of (R)-2-(3,4-dihydroxyphenyl)propylcarbamic acid, t-butyl ester. (1.07 g, 4 mMol) in acetone (25 ml) containing potassium carbonate (3 equiv, 1.66 g, 12 mMol) was stirred at 60° C. under an argon atmosphere for 1 hour. After cooling to ambient temperature, a solution of diethyl dibromomalonate (1.27 g, 4 mMol) in acetone (7 ml) was added and the reaction was stirred at ambient temperature for 18 hours. The suspension was filtered and the residue was washed with ethyl acetate. The filtrates were combined, evaporated and the residue was partitioned between ethyl acetate (200 ml) and dilute hydrochloric acid (100 ml, pH5). The organic layer was separated, washed with water (2×100 ml) and brine (100 ml), dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluting with 25% ethyl acetate in n-hexane giving the title compound as an oil;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:42])[N:18]([CH2:19][C:20](=O)[O:21]C3C(F)=C(F)C(F)=C(F)C=3F)[C:17](=[O:34])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH:43][C:44]1[CH:45]=[C:46]2[C:67](=[CH:68][CH:69]=1)[CH2:66][C@:48]1([C:56]3[C:51](=[N:52][CH:53]=[CH:54][CH:55]=3)[N:50]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:63])[CH3:62])[C:49]1=[O:65])[CH2:47]2.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:42])[N:18]([CH2:19][C:20](=[O:21])[O:43][C:44]3[CH:45]=[C:46]4[C:67](=[CH:68][CH:69]=3)[CH2:66][C@:48]3([C:56]5[C:51](=[N:52][CH:53]=[CH:54][CH:55]=5)[N:50]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:62])([CH3:63])[CH3:64])[C:49]3=[O:65])[CH2:47]4)[C:17](=[O:34])[C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)C(=O)C12CCCC2
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(Cc3ccc(O)cc3C2)c2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(CC(=O)Oc2ccc3c(c2)C[C@@]2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C(=O)C12CCCC2
Temperature: 150 °C

Procedure:
A mixture of tert-butyl (8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-9-[2-oxo-2-(pentafluorophenoxy)ethyl]-6,9-diazaspiro[4.5]decane-6-carboxylate from Step A (119 mg, 0.197 mmol), (2R)-5-hydroxy-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (77 mg, 0.201 mmol, described in Intermediate 35), and N,N-diisopropylethylamine (0.17 mL, 0.98 mmol) in DMF (0.5 mL) was heated at 150° C. in a microwave reactor for 30 min. The reaction mixture was cooled and partitioned between saturated aqueous NaHCO3 (20 mL) and EtOAc (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified on silica gel, eluting with a gradient of hexanes:EtOAc—100:0 to 0:100, to provide the title compound. MS: m/z=803.7 (M+1).