Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[CH2:18]1[CH2:22][O:21][CH2:20][CH2:19]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:22]([O:21][CH2:20][C:6]#[C:7][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:15])[CH:18]=[CH:19][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Product: O=C(C#CCOCC=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
To a flame-dried two-neck 50 mL round-bottomed flask equipped with an argon inlet adapter, a septum, and a stir bar was added PdCl2(PPh3)2 (0.024 g, 0.034 mmol), THF (6 mL), triethylamine (0.29 mL, 2.06 mmol), and benzoyl chloride (0.24 mL, 2.06 mmol). The solution was stirred for 10 min at rt, and copper(I) iodide (0.013 g, 0.069 mmol) was added all at once through the sidearm turning the reaction from cloudy yellow to clear orange. The reaction was stirred for 10 min, and enyne S16 (0.296 g, 1.72 mmol) in THF (0.5 mL) was added all at once via syringe. The reaction was stirred for 4 h until complete by TLC, in which time the reaction became cloudy and orange. Water was added to the reaction, and the aqueous layer was separated and extracted with EtOAc (2×). The combined organic layers were washed with 1 M hydrochloric acid, sat'd aq ammonium chloride, and brine, dried over magnesium sulfate, gravity filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (50 g silica cartridge, 0-10% ethyl acetate/hexanes) to yield product 5n as a yellow oil (0.330 g, 69%).
Reaction SMILES: Br[CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5].[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][SH:16].CN(C)C=O>C(OCC)(=O)C>[CH2:15]([S:16][CH2:2][C:3](=[CH2:7])[C:4]([OH:6])=[O:5])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CCCCCCCCS
Reactant: C=C(CBr)C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=C(CSCCCCCCCC)C(=O)O

Procedure:
A mixture of 2-bromomethylacrylic acid (1.0 g, 6.0 mmol), n-octylthiol (1.2 mL, 6.6 mmol), and dimethylformamide (10 mL) is refluxed overnight. The mixture is then transferred to ethyl acetate and extracted with aqueous 10% hydrochloric acid and distilled water. The organic phase is concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:7]2[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][N:4]=1.[Br:18][CH2:19][CH2:20]Br.[OH-].[Na+]>O>[Br:18][CH2:19][CH2:20][O:15][C:10]1[CH:9]=[CH:8][C:7]2[C:3]([C:2]([F:1])([F:16])[F:17])=[N:4][O:5][C:6]=2[C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: BrCCBr
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1c(OCCBr)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
3-Trifluoromethyl-7-propyl-6-hydroxy-benzisoxazole (1 g, 4.1 mmol) prepared in Example 24, 1,2-dibromoethane (3.7 g, 18.3 mmol) and NaOH (6 M aqueous solution, 1 mL, 6.0 mmol) were combined and stirred under reflux for 4.5 h. A second portion of NaOH (6 M aqueous solution, 0.43 mL, 2.6 mmol) was added, and stirring under reflux was continued for 4 h. Upon cooling to rt, water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×). The combined organic phases were washed with NaOH (5 M aqueous solution, 2×) and water (3×). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (EtOAc/hexanes (v/v) 1:9) to obtain 550 mg (38%) of the title compound as colorless crystals. 1H NMR (300 MHz, CDCl3): δ 0.99 (t, 3H), 1.72 (dt, 2H), 2.94 (t, 2H), 3.70 (t, 2H), 4.42 (t, 2H), 7.03 (d, 1H), 7.58 (d, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.[P:27](Cl)([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[S:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:22]=[C:20]1[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17][C:16]([C:14]2[N:15]=[C:10]([CH2:9][NH:8][P:27]([O:32][CH2:33][CH3:34])([O:29][CH2:30][CH3:31])=[S:28])[CH:11]=[CH:12][CH:13]=2)=[N:21]1
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: CCOP(=S)(Cl)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOP(=S)(NCc1cccc(-c2nc(=O)c3ccccc3s2)n1)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (400 mg, 1.0 mmol) and diethyl chlorothiophosphate (410 mg, 2.2 mmol) were dissolved in acetonitrile (15 ml), and potassium carbonate (430 mg, 3.1 mmol) was added thereto. The mixture was stirred at room temperature for 2 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:2, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (362 mg, 82%) as white crystals.
Reaction SMILES: [CH2:1]=[CH:2][C@@H:3]([OH:8])[CH2:4][CH2:5][C:6]#[CH:7].C(N(CC)CC)C.O([Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])S(C(F)(F)F)(=O)=O.O>C(Cl)Cl>[C:27]([Si:24]([CH3:26])([CH3:25])[O:8][C@H:3]([CH:2]=[CH2:1])[CH2:4][CH2:5][C:6]#[CH:7])([CH3:30])([CH3:29])[CH3:28]
Reactant: C#CCC[C@H](O)C=C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCC[C@@H](C=C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
The crude (S)-hept-1-en-6-yne-3-ol (3a) was dissolved in DCM and cooled to 0° C. Triethylamin (1.55 mL, 1.132 g, 11.182 mmol) and tert-Butyldimethylsilyl triflate (2.15 mL, 2.475 g, 9.362 mmol) were added and the solution was stirred for 1 hour at 0° C. before it was warmed to room temperature. After stirring for another hour water was added and the solution was extracted with DCM (3×). The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo. Chromatography (pentane/ether 200/1) furnished 489 mg of compound (4a) as clear colourless oil with 58% yield.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1CCCNCC1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCCCCC1

Procedure:
The procedure of Example 24 is followed using ethyl 2-phenylquinazoline-4-carboxylate (3 g), 2,3,4,5,6,7-hexahydroazepine (2.8 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (20 ml) as the starting materials. After recrystallisation from ethanol, 2,3,4,5,6,7-hexahydro-1-[(2-phenylquinazolin-4-yl)-carbonyl]-azepine (2 g), melting at 140° C., is obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH:8](C(OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[Cl-].[Na+].CS(C)=O>O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCC(=O)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CC1CCCC(=O)C1
Temperature: 180 °C
Yield: 110.8 %

Procedure:
A solution of 1,3-diethyl 2-(3-oxocyclohexyl)propanedioate (28.50 g, 111.20 mmol, 1.00 equiv) and sodium chloride (7.02 g, 1.10 equiv) in a mixture of water (4 mL)/DMSO (80 mL) was heated for 24 h at 180° C. in an oil bath. After cooled down to r.t, the reaction was then diluted with water, extracted with 3×300 mL of ethyl acetate. The organic layers were combined, washed with water and brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give ethyl 2-(3-oxocyclohexyl)acetate (22.7 g, crude) as yellow oil which was used for next step without purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([CH3:13])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([OH:22])[CH3:21]>>[CH2:20]([O:22][CH2:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([CH3:13])[CH:4]=1)[CH3:21]
Reactant: Cc1cc(CBr)cc(C)c1[N+](=O)[O-]
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOCc1cc(C)c([N+](=O)[O-])c(C)c1

Procedure:
The product from Step A (19.0 g) is dissolved in ethanol (600 ml) and anhydrous potassium carbonate (32 g) is added. The reaction mixture is stirred at reflux until the reaction is complete by tlc (two hours). The mixture is cooled, and the solids are filtered, washed, and discarded. The filtrate and washings are evaporated to a residue and purified by column chromatography on silica gel, using as eluant cyclohexane/ethyl acetate (97:3 v/v). The desired product, 4-ethoxymethyl-2,6-dimethylnitrobenzene (10.4 g) is isolated as a colorless oil.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1>ClCCl.CN(C=O)C>[CH3:26][O:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:19]([C:16]2[CH:17]=[C:18]3[C:13]([CH2:12][CH2:11][N:10]3[S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:14][CH:15]=2)=[O:20])=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccc2c(c1)N(S(=O)(=O)c1ccccc1)CC2
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2ccccc2)CC3)cc1
Reaction time: 2 h

Procedure:
Benzenesulfonyl-2,3-dihydro-1H-indole-6-carboxylic acid (40 mg, 0.13 mmol) was added to a solution of thionyl chloride (63 mg, 0.53 mmol, 4 equiv.) in dichloromethane (5 ml) and DMF (1 ml). The reaction mixture was stirred for 2 hours, then the solvent was removed. The crude acyl chloride was redissolved in dichloromethane (5 ml) and treated with 4-amino benzoic acid methyl ester (80 mg, 0.53 mmol, 4 equiv.). The mixture was stirred for 30 min. at room temperature, then the solvent was removed. The residue was purified by flash chromatography, yielding 4-[(1-benzenesulfonyl-2,3-dihydro-1H-indole-6-carbonyl)-amino]-benzoic acid methyl ester as a white solid, 42 mg (73%). MS (ISP): m/e=437.3 (M+H+.), δH (300 MHz; CDCl3) 8.02-8.09 (4H, m), 7.82 (2H, d), 7.77 (2H, d), 7.45-7.61 (4H, m), 7.21 (2H, d), 3.98 (2H, t), 3.92 (3H, s), 2.97 (2H, t).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]([NH:19][CH3:20])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[N+:16]([O-])=O.[ClH:21]>C(O)C.O.[Fe]>[ClH:15].[ClH:21].[NH2:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[CH2:8][CH:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[CH3:1])[NH:19][CH3:20]
Reactant: CNC(Cc1ccc(Cl)cc1[N+](=O)[O-])c1sccc1C
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNC(Cc1ccc(Cl)cc1N)c1sccc1C

Procedure:
A solution of 10 g of α-(3-methyl-2-thienyl)-N-methyl-4-chloro-2-nitrobenzeneethana mine in 150 ml of 95% ethanol and 40 ml water was treated with 22 g of reduced electrolytic iron and 1 ml of concentrated hydrochloric acid, and the mixture was refluxed for 0.5 hr, with stirring. The resulting mixture was filtered, and the filter cake was washed with 95% ethanol. The filtrate was basified with 10% sodium hydroxide solution, extracted with dichloromethane and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue was accomplished by preparative HPLC (Water's Associates Prep LC/System 500A, silica gel, eluted with methanol, flow rate of 200 ml/min, Gow-Mac Model 80-800 UV detector). The appropriate fractions were collected, combined and concentrated. The residue was dissolved in ether, the solution was filtered, and the filtrate was concentrated. The residue was dissolved in methanol, a few drops of ethereal hydrogen chloride was added followed by anhydrous ethyl ether dropwise until a precipitate appeared. The precipitate was collected, and the filter cake was recrystallized from methanol and anhydrous ether to afford 8.4 g of product.
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:11]1[C:23]2[CH:22]([CH2:24][O:25][C:26](Cl)=[O:27])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1>O1CCOCC1>[CH:11]1[C:23]2[CH:22]([CH2:24][O:25][C:26]([NH:1][C:2]3([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)=[O:27])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: NC1(C(=O)O)CCCCC1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: C1COCCO1
Product: O=C(NC1(C(=O)O)CCCCC1)OCC1c2ccccc2-c2ccccc21
Temperature: 20 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
To a chilled (ice bath) suspension of aminocyclohexanecarboxylic acid (2.51 g, 17.5 mmol) in alumina-filtered dioxane (17 mL) were added 10% Na2CO3 (35 mL) and a solution of 9-fluorenylmethylchloroformate (4.57 g, 17.7 mmol) in 26 mL of dioxane (added slowly). The reaction mixture was allowed to warm to about 20° C. and stirred overnight under N2. The reaction mixture was poured into ~300 mL of ice water and washed with anhydrous ether (some product went into the ether layer). The aqueous layer was chilled in an ice bath and acidified with concentrated hydrochloric acid to pH about 2. The aqueous layer was then extracted with ethyl acetate (3×100 mL). The combined ethyl acetate layers were washed with 0.1N HCl and H2O. The ether and ethyl acetate layers were dried over anhydrous MgSO4, combined and concentrated. The resulting compound was flash chromatographed with a gradient of 40-50% EtOAc/Hexane to yield 0.383 g (1.05 mmol, 6.0% yield) of the title compound as a white foam DEI M+@m/z=365.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([Br:12])[CH:6]=1)=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.CC(C)([O-])C.[K+].O>CS(C)=O>[Br:12][C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][C:8]=1[O:20][C:17]1[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=1)[C:3]([OH:2])=[O:4].[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][C:8]([O:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)=[C:7]([Br:12])[CH:6]=1
Reactant: COC(=O)c1ccc(F)c(Br)c1
Reactant: Oc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(Oc2ccc(Cl)cc2)c(Br)c1
Product: O=C(O)c1ccc(Oc2ccc(Cl)cc2)c(Br)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a solution of methyl-3-bromo-4-fluoro benzoate (20 g, 86 mmol) and 4-chlorophenol (11.0 g, 171 mmol) in dimethylsulfoxide (500 mL) was added potassium tert-butoxide (19.3 g, 171 mmol) and the reaction mixture was stirred at 120° C. for 16 hours and then poured into 500 mL of water and extracted with dichloromethane (3×100 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified via column chromatography on silica gel (1:1 petroleum ether:EtOAc) to yield 18 g (55 mmol) of 3-bromo-4-(4-chlorophenoxy)-benzoic acid and 2 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([F:9])[CH:3]=1.[Mg].[B:11]([O:20]C(C)C)([O:16]C(C)C)[O:12]C(C)C.S(=O)(=O)(O)O>O1CCCC1>[F:9][C:4]1[CH:3]=[C:2]([O:12][B:11]([OH:20])[OH:16])[CH:7]=[CH:6][C:5]=1[F:8]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(Br)cc1F
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)Oc1ccc(F)c(F)c1
Temperature: -65 °C
Reaction time: 1 h

Procedure:
A Grignard reagent solution prepared from 46.8 g of 1-bromo-3,4-difluorobenzene and 6 g of magnesium in 150 ml of tetrahydrofuran is added dropwise at -65° C. under nitrogen to a solution of 72.8 ml of triisopropyl borate in 200 ml of tetrahydrofuran. The mixture is stirred at -65° C. for 1 hour, warmed to 14°-20° C., treated dropwise with 100 ml of 10 percent (v/v) sulphuric acid, left to stand overnight and the separated salt is filtered off. The aqueous phase of the filtrate is separated and extracted with diethyl ether. The organic phases are combined, washed with sodium chloride solution, dried over sodium sulphate and evaporated. After boiling with hexane the residue gives 22.1 g of colourless 3,4-difluorophenylboric acid m.p. 275°-277.5° C. (sublimed).
Reaction SMILES: Br[C:2]([CH3:4])=[CH2:3].[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:10]2[O:11][CH2:12][CH2:13][O:14][C:9]=2[C:8]=1B(O)O.[C:20]([O-])([O-])=O.[K+].[K+]>COCCOC.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>[C:2]([C:8]1[C:9]2[O:14][CH2:13][CH2:12][O:11][C:10]=2[CH:15]=[CH:16][C:7]=1[O:6][CH3:5])([CH3:4])=[CH2:3].[CH2:10]=[CH:15][C:16](=[CH2:7])[CH3:20]
Reactant: C=C(C)Br
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(c1B(O)O)OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: COCCOC
Product: C=C(C)c1c(OC)ccc2c1OCCO2
Product: C=CC(=C)C

Procedure:
To a solution of 2-bromopropene (5.4 ml, 59 mmol) in 200 mL DME was added Pd(Ph3P)4 (3.116, 2.8 mmol). After 30 min 6-methoxy-2,3-dihydro-benzo[1,4]dioxin-5-yl-boronic acid (13.320 g, 58.6 mmol) and K2CO3 (8.099 g, 58.6 mmol) was added. The mixture was warmed to reflux. After 16 hours the mixture was cooled, filtered through a pad of celite and concentrated in vacuo. The residue was dissolved in H2O and extracted with ethyl acetate. The combined organics were washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated in vacuo. Purification via flash chromatography afforded isoprene 5-isopropenyl-6-methoxy-2,3-dihydro-benzo[1,4]dioxine (5.542 g, as an inseparable mixture of product/sm 1:1) as an oil.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)=[O:4].[CH2:15]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(CC)=O>[CH2:23]([N:22]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:2][C:3]([C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)=[O:4])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(=O)c1cc(C(=O)CBr)ccc1O
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CCC(C)=O
Product: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Yield: 45 %

Procedure:
5-Bromoacetyl salicylamide (515 g) was added to a stirred solution of dibenzylamine (750 g) in ethyl methyl ketone (3.0 l). The mixture was heated at reflux for one hour and the dibenzylamine hydrobromide was filtered and dried. The filtrate was allowed to cool, when the crude product crystallised. This was filtered off, dried, and recrystallised from ethyl acetate, (5 l), to give 5-(N,N-dibenzylglycyl)salicylamide as an off-white solid (336 g), m.p. 168°.
Reaction SMILES: C(OC(=O)C[C:6]1[C:15]([C:16]([OH:18])=[O:17])=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)C.O=P(Cl)(Cl)[Cl:22].CN(C=O)C>ClCCl>[Cl:22][C:6]1[C:15]([C:16]([OH:18])=[O:17])=[N:14][C:13]2[C:8]([N:7]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: CCOC(=O)Cc1nc2ccccc2nc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(O)c1nc2ccccc2nc1Cl
Temperature: 75 °C
Reaction time: 1 h

Procedure:
From crude 16d, with a changed ratio of 1 g 16d: 0.8 mL POCl3: 1.6 mL DMF. The reaction mixture was heated, with moisture exclusion, at 75° C. for 16 h, then cooled, diluted with cold dichloromethane, and kept at −18° C. for 1 h. The brick red solid was filtered and washed exhaustively, with thorough stirring, with cold dichloromethane to give the dione (22% from 3-chloroquinoxaline-2-carboxylic acid), mp 133-139° C. 1H NMR (d6-DMSO): δ 3.27 (s, 3H, NCH3), 3.57 (s, 3H, NCH3), 7.66 (ddd, J=8.3, 6.6, 1.6 Hz, 1H), 7.81-7.92 (m, 2-H), 8.04 (d, J=7.8 Hz, 1H), 8.66 (s, 1H, ═HCNMe2). 13C NMR (d6-DMSO): δ 45.0 (CH3), 48.3 (CH3), 87.0 (C), 127.2 (CH), 128.3 (CH), 130.3 (CH), 133.3 (C), 133.7 (CH), 139.4 (C), 143.2 (C), 150.3 (C), 157.6 (C), 159.7 (C), 161.1 (CH).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([OH:19])=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:9])(=[O:3])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:1]([O:4][C:5]1[C:6]([O:19][CH3:20])=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[O:9])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCC(=O)c1cccc(OC(C)=O)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC(=O)CCC(=O)c1cccc(OC(C)=O)c1OC

Procedure:
A stirred mixture of methyl 3-(3-acetoxy-2-hydroxybenzoyl)-propionate, potassium carbonate, methyl iodide, and dry acetone, was heated under reflux for 24 hours. Evaporation of the filtered solution gave methyl 3-(3-acetoxy-2-methoxybenzoyl)-propionate.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=2)O1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>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>[N+:24]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[C:9]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH:10]=1)([O-:26])=[O:25]
Reactant: CC1(C)OB(C2=CC(=O)CCC2)OC1(C)C
Reactant: O=[N+]([O-])c1cnccc1Cl
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
Product: O=C1C=C(c2ccncc2[N+](=O)[O-])CCC1
Temperature: 120 °C
Yield: 60.2 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-one (6.0 g, 27 mmol) and 4-chloro-3-nitropyridine (2.4 g, 15 mmol) in 1,4-dioxane (60 mL), 2.0 N aq. Na2CO3 (12 mL, 24 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.8 g, 1.5 mmol) were added. The reaction mixture was heated at 120° C. for 1 h. The reaction mixture was filtered through diatomaceous earth, which was washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluting with 10-100% EtOAc in hexanes) to give the sub-title compound as a brown solid (1.97 g, 87%). LCMS calc. for C11H11N2O3 (M+H)+: m/z=219.1. Found: 219.0.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([O:22][CH3:23])[CH2:20][C@@:19]2([CH3:24])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:25])[CH2:16][C@@:15]2([CH3:26])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[BrH:27].BrBr.O>CO.C(O)(=O)C>[Br:27][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:26])[C@H:8]([C@H:7]3[C@H:18]([C:17](=[O:25])[CH2:16]2)[C@:19]2([CH3:24])[C@H:4]([CH2:3][C@H:2]([OH:1])[C@@H:21]([O:22][CH3:23])[CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Reactant: Br
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)CBr)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Temperature: 25 °C

Procedure:
A solution of 3α-hydroxy-2β-methoxy-5α-pregnane-11,20-dione (2 g.) in methanol (15 ml.) was treated with hydrobromic acid in glacial acetic acid (3 drops). The mixture was stirred at room temperature and bromine (530 mg.) in methanol (1.45 ml.) was added dropwise over a period of 30 minutes. The mixture was stirred for a further 30 minutes and poured into water, stirred, filtered, washed with water and dried. Purification by preparative t.l.c., followed by crystallisation from ethyl acetate and petrol gave title compound (250 mg.) as colourless plates; m.p. 185°-188°; [α]D + 104°.