Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[Cl:27])[N:23]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:22]=[C:21]2[NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40]>O.O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][C:26]=2[Cl:27])[N:23]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:35])[CH3:33])[N:22]=[C:21]3[NH:36][C:37](=[O:41])[CH2:38][CH2:39][CH3:40])=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(Br)cc12
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc(F)cc3)cc12

Procedure:
470 mg of 4-fluorophenylboronic acid, 593 mg of sodium carbonate in 40 cm3 of water and 155 mg of tetrakis(triphenylphosphine)palladium are added to 1 g of N-[5-bromo-6-chloro-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described in Example 58, in 40 cm3 of dioxane. The mixture is refluxed for 18 hours and the reaction medium is filtered through a sinter funnel packed with Celite. 60 cm3 of ethyl acetate and 50 cm3 of distilled water are added to the filtrate. The organic phase is washed with 2×20 cm3 of saturated aqueous sodium chloride solution and then separated out after settling of the phases has taken place and dried over magnesium sulphate. After filtration, the filtrate is concentrated to dryness under reduced pressure (2 kPa; 50° C.) and the residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (90/10 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 0.75 g of N-[5-(4-fluorophenyl)-6-chloro-1-[(2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide is thus obtained in the form of a yellow wax.
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[CH2:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH2:30][CH3:31]>C1COCC1>[CH2:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:2]#[N:3])=[CH:34][CH:33]=1)[CH2:30][CH3:31]
Reactant: CCCc1ccc(C=O)cc1
Reactant: N#CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCc1ccc(C=CCCCCCC#N)cc1
Yield: 67.3 %

Procedure:
This compound was synthesized from 6-cyanohexyltriphenylphosphonium bromide (9.05 g, 20 mmol) and p-propylbenzaldehyde (2.96 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation afforded the product (3.25 g, 67%) as a colorless liquid (bp 144-148° C./0.05 torr). IR 2290 cm-1 ; 1H-NMR: 0.95 (t, 3H), 1.55 (m, 8H), 2.40 (m, 6H), 5.60 (m, 1H), 6.40 (d, 1H), 7.10 (s, 4H).
Reaction SMILES: [H-].[Na+].Br[C@H:4]1[C@H:9](O)[C:8]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:7]=2[O:6][C:5]1([CH3:18])[CH3:17].C(O)C.[OH-:22].[NH4+:23]>O1CCCC1>[NH2:23][C@@H:9]1[C:8]2[CH:11]=[C:12]([C:15]#[N:16])[CH:13]=[CH:14][C:7]=2[O:6][C:5]([CH3:18])([CH3:17])[C@H:4]1[OH:22]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Reactant: [NH4+]
Reactant: [OH-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium hydride (80% dispersion in oil, 13.7 g) was added in portions over 1 h to a stirred solution of (±)-trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-benzopyran-4-ol (124.3 g) in tetrahydrofuran (250 ml) kept under a dry nitrogen atmosphere. The mixture was stirred for an additional 0.5 h after which a solution of the 3,4-epoxide resulted. Ethanol (620 ml) followed by 0.880 ammonium hydroxide (375 ml) were added, and the resulting mixture stirred at 60°-65° C. for 12 h before cooling to room temperature. The organic solvents were evaporated off and the aqueous residue acidified with 5N hydrochloric acid (125 ml). The mixture was then washed well with dichloromethane (total used=1.0 L) before basifying with 40% aq. sodium hydroxide (80 ml). It was then re-extracted with dichloromethane (4×250 ml) and the combined extracts washed once with brine and then dried (Na2SO4). Evaporation afforded the product as a gum which crystallised. This was broken up and triturated with a mixture of isopropyl ether and dichloromethane before filtering off and washing with further isopropyl ether. The product was dried under suction and finally under vacuum.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([C:9]1[CH:13]=[C:12]([CH:14]([C:18]#[N:19])[CH:15]([CH3:17])[CH3:16])[S:11][CH:10]=1)#[N:8].[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21]>CN(C=O)C>[C:18]([C:14]([C:12]1[S:11][CH:10]=[C:9]([C:7]#[N:8])[CH:13]=1)([CH:15]([CH3:16])[CH3:17])[CH2:1][CH2:21][C:20]([O:23][CH2:24][CH3:25])=[O:22])#[N:19]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)C(C#N)c1cc(C#N)cs1
Reactant: CCOC(C)=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCC(C#N)(c1cc(C#N)cs1)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 60 %

Procedure:
Potassium tert-butoxide (35 mg) was suspended in DMF (5 ml), and a DMF solution (5 ml) of 3-cyano-5-(1-cyano-2-methylpropyl]thiophene (0.60 g) was added thereto. After stirring at room temperature for 3.5 hours, ethyl acetate was added. The mixture was washed with an aqueous saturated ammonium chloride and further brine, dried over anhydrous magnesium sulfate and then evaporated. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound as a pale yellow oil (0.55 g, 60%).
Reaction SMILES: O1CCN(S(F)(F)[F:8])CC1.[N:11]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][C@H:24](O)[CH2:23][C@H:12]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C(Cl)Cl.O>[CH2:16]([O:15][C:13](=[O:14])[C@H:12]1[CH2:23][C@H:24]([F:8])[CH2:26][N:11]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OCc1ccccc1
Reactant: FS(F)(F)N1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Morpholinosulfur trifluoride (morph-DAST; 3.5 mL, 29 mmol) was added by syringe to a solution of 1 (6.5 g, 20 mmol) in dry CH2Cl2 (200 mL) under Ar(g) at −78° C. The solution w allowed to warm to room temperature and stirred overnight. Following a quench with methanol, the reaction mixture was washed with 2×100 mL saturated NaHCO3(aq). An emulsion resulted, so the mixture was diluted with H2O and CH2Cl2 and filtered through Celite. The biphasic filtrate was separated, and the organic layer was washed with water, dried over MgSO4(s), and concentrated by rotary evaporation under reduced pressure. The resulting oil was purified by flash chromatography (1.5% v/v MeOH in CH2Cl2), which afforded 11 (3.1 g, 9.6 mmol, 48%) as a yellow oil. An additional 2.32 g of 11 that were contaminated with a minor impurity, as indicated by TLC, were also obtained from the column.
Reaction SMILES: CC(C)([O-])C.[C:6]([OH:9])(=[S:8])[CH3:7].[CH2:10]([O:13][C:14]([N:16]1[CH2:20][C@H:19](OS(C)(=O)=O)[CH2:18][C@H:17]1[CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][C:28]1=[O:34])=[O:15])[CH:11]=[CH2:12].O>CN(C)C=O>[C:6]([S:8][C@@H:19]1[CH2:20][N:16]([C:14]([O:13][CH2:10][CH:11]=[CH2:12])=[O:15])[C@H:17]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][C:28]2=[O:34])[CH2:18]1)(=[O:9])[CH3:7]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCN(C)CC1=O
Reactant: CC(O)=S
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CN1CCN(C)CC1=O

Procedure:
To a solution of pottasium t-butoxide (1.24 g) in N,N-dimethylformamide (15 ml) was dropwise added thioacetic acid (0.85 ml) under ice cooling with stirring. The mixture was stirred at the same temperature for 30 minutes. To the solution of (2S,4R)-1-allyloxycarbonyl-2-(2-oxo-4-methylpiperazin-1-yl) methyl-4-(methanesulfonyloxy)pyrrolidine (3.19 g) in N,N-dimethylformamide (15 ml) was added the mixture obtained above at ambient temperature with stirring. The mixture was stirred at 80°-90° C. for 1.5 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1 v/v) to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(2-oxo-4-methylpiperazin-1-yl) methylpyrrolidine (3.24 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH:9]([OH:24])[CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[C:25]([OH:30])(=[O:29])[C:26]([OH:28])=[O:27]>C(OCC)(=O)C>[C:25]([O-:30])(=[O:29])[C:26]([O-:28])=[O:27].[CH2:1]([NH+:4]([CH2:8][CH:9]([OH:24])[CH2:10][CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH2:1]([NH+:4]([CH2:8][CH:9]([OH:24])[CH2:10][CH:11]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: O=C(O)C(=O)O
Reactant: CCCN(CCC)CC(O)CC(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: CCC[NH+](CCC)CC(O)CC(c1ccccc1)c1ccccc1
Product: O=C([O-])C(=O)[O-]

Procedure:
The N,N-di-n-propyl-4,4-diphenyl-2-hydroxybutylamine from Example 1 above was dissolved in 50 ml. of ethyl acetate and oxalic acid was added to the solution. The precipitated product was collected by filtration and was recrystallized from ethyl alcohol. Colorless crystalline N,N-di-n-propyl-4,4-diphenyl-2-hydroxybutylaminium oxalate was collected by filtration and dried. M.P. 121°-122° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1F.[CH3:11][S-:12].[Na+]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:12][CH3:11]
Reactant: C[S-]
Reactant: COc1ccc(F)c(F)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)c(SC)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
1,2-Difluoro-4-methoxy-benzene (100 mg, 0.69 mmol) and sodium methanethiolate (148 mg, 2.08 mmol) were dissolved in N,N-dimethylformamide (2 mL) and the reaction mixture stirred at 60° C. for 18 hours. Additional sodium methanethiolate (99 mg, 139 mmol) was added and the reaction mixture heated to 100° C. for 18 hours. The reaction mixture was diluted with water and extracted with ether (×2). The ether extracts were washed with water (×2), dried over magnesium sulphate and concentrated in vacuo. The residue was taken up in pentane:ether 1:1 mixture (2 mL) and filtered through a plug of silica in a pipette, washing through with pentane:ether 1:1 mixture (5 mL). The reaction mixture was concentrated in vacuo to yield the title product as a colourless oil, 135 mg.
Reaction SMILES: [NH:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].C(#N)[CH:14]([CH2:16][C:17]#[N:18])O.[NH:20]1CCCCC1>C(O)C>[C:17]([C:16]([C:14]#[N:20])=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([NH:1][C:2](=[O:3])[CH3:4])=[CH:6][CH:7]=1)#[N:18]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: C1CCNCC1
Reactant: N#CCC(O)C#N
Solvent: CCO
Product: CC(=O)Nc1ccc(C=C(C#N)C#N)cc1
Temperature: 25 °C

Procedure:
311.4 g (1.9 mol) of 4-acetaminobenzaldehyde and 131 g (1.99 mol) of malonitrile are initially introduced in 1 330 ml of ethanol, and 6 ml of piperidine are then added. The mixture is stirred under reflux for 30 minutes. After cooling down to room temperature, the crystals are filtered off with suction and dried.
Reaction SMILES: [CH3:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[C:5]([CH3:10])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CCCCCC>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[O:22][C:6]1[C:5]([CH3:10])=[CH:4][C:3]([N+:11]([O-:13])=[O:12])=[C:2]([CH3:1])[C:7]=1[Cl:8]
Reactant: Cc1ccc(O)c(C)c1
Reactant: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1ccc(Oc2c(C)cc([N+](=O)[O-])c(C)c2Cl)c(C)c1
Yield: 69.6 %

Procedure:
Into a round bottom reaction flask equipped with a magnetic stirrer. condenser, thermometer and nitrogen inlet was added 50.0 grams (0.23 mol) of 2,5-dimethyl-3,4-dichloronitrobenzene. 38.5 grams (0.32 mol) of 2,4-dimethylphenol, So grams (0.36 mol) of potassium carbonate and 125 milliliters of dimethylformamide. The reaction mixture was heated to a temperature of 90° C.-100° C. and maintained at this temperature for a period of 72 hours. The reaction mixture was then cooled, filtered and concentrated to give a dark oil. The dark oil was partitioned between toluene (300 milliliters) and 4% sodium hydroxide (250 milliliters) and then separated. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to give a dark oil. The dark oil was trituated with hexane and a solid was formed. The solid was washed with cold hexane and vacuum dried to give 47.8 grams (0.16 mol) of 4-(2.4-dimethylphenoxy) 2,5-dimethyl-3-chloronitrobenzene as a tan powder having a melting point of 78° C.-80° C. Elemental analysis of the tan powder indicated the following:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]=1[NH:12][C:13]1[CH2:17][CH2:16][CH2:15][N:14]=1.[ClH:18].C(OCC)C>CO.C(O)(C)C>[ClH:18].[ClH:18].[CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:11])[C:3]=1[NH:12][C:13]1[CH2:17][CH2:16][CH2:15][N:14]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1NC1=NCCC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: CC(C)O
Product: Cc1cc(N)cc(C)c1NC1=NCCC1

Procedure:
The title compound was prepared by the method of Example 9 using 10.5 g of the product compound of Example 10, except that no hydrochloric acid was added during hydrogenation. The crude product was dissolved in methanol and acidified with HCl in isopropyl alcohol. Addition of diethyl ether induced precipitation of 11.6 g of the title compound. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: N[CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].N[CH2:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:39])[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH:27]=CC=1>>[F:38][C:35]1[CH:34]=[CH:33][C:32]([C:31]([NH:30][C:26]2[CH:27]=[C:2]([CH:23]=[CH:24][CH:25]=2)[CH2:3][NH:4][C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[NH:19][CH:20]=[CH:21][C:14]=23)=[O:6])=[O:39])=[CH:37][CH:36]=1
Reactant: NCc1cccc(NC(=O)c2ccc(F)cc2)c1
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Product: O=C(Nc1cccc(CNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)c1)c1ccc(F)cc1

Procedure:
This compound was prepared in an analogous manner as 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide using N[3-(aminomethyl)phenyl]-4-fluorobenzamide instead of tert-butyl-2-amino ethyl carbamate. LCMS (ESI) 486 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (1H, s) 10.39 (1H, s) 10.26 (1H, s) 8.66-8.78 (1H, m) 8.02 (4H, dt, J=5.48, 2.70 Hz) 7.81 (1H, d, J=5.42 Hz) 7.68 (2H, d, J=8.20 Hz) 7.51 (1H, d, J=5.47 Hz) 7.24-7.40 (5H, m) 7.06 (1H, d, J=7.42 Hz) 6.86 (1H, d, J=5.52 Hz) 6.43 (1H, dd, J=3.54, 1.93 Hz) 4.47 (2H, d, J=5.86 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1.C(N(CC)CC)C.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>ClCCl>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([C:34]([NH:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)[CH:7]=2)=[O:35])=[CH:37][CH:38]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.2 %

Procedure:
[2-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (319 mg, 1.28 mmol) was dissolved in dichloromethane (5 mL). Triethylamine (117 μL, 1.40 mmol) and 4-tert-butylbenzoyl chloride (274 μL, 1.40 mmol) were added and the reaction was stirred at room temperature for 10 minutes. The crude mixture was absorbed onto silica and purified by column chromatography to give the title compound as an off-white solid (274 mg, 52% yield). MS (ES+) m/e=411. 1H NMR (CDCl3) δH 1.36 (12H, s), 1.39 (9H, s), 4.10 (3H, s), 7.55 (2H, d), 7.86 (2H, d), 8.28 (1H, s), 8.36 (1H, br s), 9.07 (1H, s).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].N1C=CN=C1.[C:21]([Si:25](Cl)([CH3:27])[CH3:26])([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([O:15][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:27])[CH3:26])[CH3:14]
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
4-Bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (intermediate A2, 5 g, 18.658 mmol) was dissolved in DCM (50 ml); imidazole (2.54 g, 37.3 mmol) and tert-butyl(chloro)dimethylsilane (5.624 g, 37.3 mmol) were added and the mixture was stirred at RT for 1 hr. The mixture was washed with brine, the organic phase was dried over sodium sulfate and solvent removed under reduced pressure to afford a crude which was purified by flash chromatography on silica gel Biotage column (cyclohexane:EtOAc=95:5 to 60:40) affording title compound as a white solid (6.5 g, 16.97 mmol, 91%).
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:29]=[CH:28][CH:27]=[CH:26][C:6]=1[CH2:7][C:8]1[N:12]2[N:13]=[CH:14][CH:15]=[CH:16][C:11]2=[C:10]([C:17]2[N:22]=[C:21]([NH2:23])[C:20]([NH2:24])=[C:19]([NH2:25])[N:18]=2)[N:9]=1.Cl[C:31]([O:33][CH3:34])=[O:32]>N1C=CC=CC=1>[CH:31]([OH:33])=[O:32].[NH2:25][C:19]1[C:20]([NH:24][C:31](=[O:32])[O:33][CH3:34])=[C:21]([NH2:23])[N:22]=[C:17]([C:10]2[N:9]=[C:8]([CH2:7][C:6]3[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=3[F:4])[N:12]3[C:11]=2[CH:16]=[CH:15][CH:14]=[N:13]3)[N:18]=1
Reactant: Nc1nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc(N)c1N
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)Nc1c(N)nc(-c2nc(Cc3ccccc3F)n3ncccc23)nc1N
Product: O=CO
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1.84 g (4.642 mmol) of the compound prepared in Example 9A were initially charged in pyridine (35 ml), 0.359 ml (4.642 mmol) of methyl chloroformate was added at 0° C. and the mixture was stirred at 0° C. for 10 min. After 16 hours of stirring at 20° C., the reaction mixture was poured into ice-water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (mobile phase:gradient dichloromethane:methanol 100:5 to dichloromethane:methanol 2:1). This gave 1.13 g of the target compound (53% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([O:8][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of 3-bromophenol (50 g, 289 mmol) in 340 mL DMF was added Et3N (35 g, 347 mmol) and tert-butyldimethylsilyl chloride (52 g, 347 mmol). The mixture was stirred for 0.5 h, and then diluted with Et2O (2 L). The organic phase was washed with 5% aqueous HCl and brine, and dried over MgSO4. Flash chromatography using hexane:EtOAc (95:5) gave 80.1 g (96%) of product.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][C@H:5]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:3]12[CH3:4])=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[C:22]([O-:25])(O)=O.[Na+].N1C=CC=C[CH:28]=1>C(OC(=O)C)(=O)C>[C:22]([O:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][C@H:5]2[C@H:9]3[C:18]([CH2:19][CH2:20][C@:3]12[CH3:4])=[C:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)(=[O:25])[CH3:28]
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@]2(C)[C@H]1O
Reactant: c1ccncc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)O[C@H]1[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@@]21C

Procedure:
A solution of 7.8 g of 17β-hydroxy-16α-methyl-4,9(10)-estradien-3-one in 25 ml of pyridine and 8 ml of acetic anhydride is stirred for 6 hours at 50° C. under argon. After cooling the mixture is poured into saturated NaHCO3 solution and extracted with ethyl acetate. The ethyl acetate extracts are washed in succession with water, 2 N hydrochloric acid, and saturated NaCl solution, dried over sodium sulfate, and concentrated. Crystallization from ether yields 6.6 g of 17β-acetoxy-16α-methyl-4,9(10)-estradien-3-one, m.p. 124°-126° C.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].[O:10]1[CH:14]=[CH:13][C:12]([CH:15](O)[CH3:16])=[N:11]1.C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1>[CH3:1][S:2]([O:5][CH:15]([C:12]1[CH:13]=[CH:14][O:10][N:11]=1)[CH3:16])(=[O:4])=[O:3]
Reactant: CC(O)c1ccon1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(OS(C)(=O)=O)c1ccon1
Reaction time: 18 h

Procedure:
Methanesulfonic anhydride (825 mg, 4.74 mmol) was added to a solution of 1-isoxazol-3-ylethanol (C6 from the previous step, 536 mg) and triethylamine (0.90 mL, 6.5 mmol) in THF (10 mL), and the reaction mixture was stirred for 18 hours. After addition of ethyl acetate, the mixture was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The reaction was judged to be incomplete by proton NMR spectroscopy, so this material was resubjected to the reaction conditions, using two equivalents of methanesulfonic anhydride, and worked up in the same manner. The crude material was purified by silica gel chromatography (Eluants: 25% ethyl acetate in heptane followed by 50% ethyl acetate in heptane) to provide the product as a colorless oil. Yield: 276 mg, 1.44 mmol, 14% over 2 steps. 1H NMR (400 MHz, CDCl3) δ 1.81 (d, J=6.6 Hz, 3H), 3.01 (s, 3H), 5.93 (q, J=6.6 Hz, 1H), 6.50 (d, J=1.8 Hz, 1H), 8.45 (d, J=1.7 Hz, 1H).