Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[C:5]=2[CH2:17]O)[CH2:3][CH2:2]1.P(Br)(Br)[Br:20]>ClCCl>[Br:20][CH2:17][C:5]1[C:6]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: BrP(Br)Br
Reactant: OCc1c(-c2c(Cl)cccc2Cl)noc1C1CC1
Solvent: ClCCl
Product: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Temperature: 25 °C
Yield: 81.2 %

Procedure:
To a 0° C. solution of (5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazol-4-yl)-methanol (0.124 g, 0.44 mmol) in dichloromethane (4 mL) is added phosphorous tribromide (0.261 g, 0.963 mmol). The ice bath is removed after 20 minutes and the reaction is allowed to stir for an additional twenty minutes at room temperature. The reaction is quenched with pH 7 buffer and is extracted with dichloromethane several times. The organic layers are combined, washed with brine, and dried over sodium sulfate. The reaction is filtered and concentrated under reduced pressure to yield the title compound (0.124 g, 82%). 1H-NMR (400 MHz CDCl3) δ 7.45-7.33 (m, 3H), 4.20 (s, 2H), 2.09 (m, 1H), 1.27 (m, 2H), 1.16 (m, 2H)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([CH:10]=O)=[CH:7][CH:8]=[CH:9][C:2]1=2.O.[C:13]([O:16][CH2:17]C)(=O)C>O1CCCC1>[CH3:13][O:16][CH:17]=[CH:10][C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1cccc2sccc12
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC=Cc1cccc2sccc12
Temperature: -60 °C
Reaction time: 8 h

Procedure:
In an atmosphere of nitrogen, 4.85 g of (methoxymethyl)triphenylphosphonium chloride is suspended in 40 mL of tetrahydrofuran. Then, 1.5 mL of diisopropylamine is added to the suspension, and cooled to −60° C. After dropwise adding thereto 6.6 mL of 1.6 mol/L solution of n-butyllithium in hexane, the mixture thus obtained is stirred for 30 minutes at an ice-cooled temperature. Then, the reaction mixture is cooled to −60° C., a solution of 1.72 g of benzo[b]thiophene-4-carboaldehyde in 15 mL of tetrahydrofuran is dropwise added, and the resulting mixture is allowed to stand overnight at ambient temperature. The reaction mixture is introduced into a mixture of water and ethyl acetate, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, the residue is treated with diethyl ether, and the deposited crystal is filtered off. The solvent is distilled off from the filtrate under reduced pressure, and the residue thus obtained is purified by column chromatography (eluent: n-hexane:ethyl acetate=100:1 to 50:1) to obtain 1.04 g of 2-benzo[b]thiophen-4-yl-1-ethenyl methyl ether as an oily product.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:20][CH3:21])=[C:7]([NH2:19])[CH:8]=[C:9]([C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:22]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][C:31]=1F)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.[F:57][P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O.CN(C=O)C>[CH2:22]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:19][C:7]2[CH:8]=[C:9]([C:11]3[C:12]([O:17][CH3:18])=[N:13][CH:14]=[CH:15][CH:16]=3)[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=2[O:20][CH3:21])=[O:35])=[C:32]([F:57])[CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: F[P-](F)(F)(F)(F)F
Reactant: COc1ncccc1-c1cc(N)c(OC)c(C(C)(C)C)c1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncccc1-c1cc(NC(=O)c2ccc(OCc3ccccc3)cc2F)c(OC)c(C(C)(C)C)c1
Yield: 85 %

Procedure:
step 1—A solution of 100 (100 mg, 0.349 mmol, 4-benzyloxy-3-fluoro-benzoic acid (86 mg, 0.349 mmol), HATU (146 mg, 0.384 mmol, DIPEA (0.122 mL, 0.698 mmol), and DMF (3 mL) is stirred at 50° under Ar overnight. The reaction was cooled, diluted with H2O and extracted with EtOAc. The combined extracts were washed with H2O, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 eluting with 20% EtOAc/hexane to afford 0.125 g (85%) of 4-benzyloxy-N-[3-tert-butyl-2-methoxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-2-fluoro-benzamide (322) which could be recrystallized from EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:17])[CH:5]=[C:6]([N:8]([CH3:16])[CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:7]=1.[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1>[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:17][C:4]1[CH:5]=[C:6]([N:8]([CH3:16])[CH:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[CH:7]=[C:2]([F:1])[CH:3]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CN1CCC(N(C)c2cc(N)cc(F)c2)CC1
Solvent: C1COCCO1
Product: CN1CCC(N(C)c2cc(F)cc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Combine 5-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 29, 0.036 g, 0.15 mmol), 2-chloro-4-fluoro-benzoyl chloride (0.044 g, 0.23 mmol) and 1,4-dioxane (2 mL), stir and heat at reflux. After 3 hr, cool to ambient temperature. Load on a SCX column (10 g), wash with methanol, elute with 2M ammonia-methanol. Concentrate eluent to obtain 0.059 g (100%) the title compound as a free base. Dissolve this material in dichloromethane (5 mL) and treat with 1M hydrochloric acid in ether (0.15 mL, 0.15 mmol). Concentrate to give the title compound as a brown powder: high resolution mass spectrum: Obs. m/z 394.1495; Calc. m/z 394.1497; 1H NMR (CDCl3) of free base: 7.8 (bs, 1H), 7.7 (m, 1H), 7.2 (m, 1H), 7.1 (m, 1H), 6.8 (s, 1H), 6.7 (m, 1H), 6.2 (m, 1H), 3.5 (m, 1H), 2.9 (m, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 2.1 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]5[NH:23][C:24]([NH:32][C:19]=5[CH:18]=4)=[C:25]4[CH:31]=[CH:30][C:28](=[O:29])[CH:27]=[CH:26]4)[NH:16][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[CH:33]1(N=C=NC2CCCCC2)CCCC[CH2:34]1.C(O)(=O)CCC(O)=O>C(Cl)(Cl)Cl>[CH3:33][CH2:34][O:29][C:28]1[CH:30]=[CH:31][C:25]([C:24]2[NH:32][C:19]3[CH:18]=[C:17]([C:15]4[NH:16][C:10]5[CH:9]=[C:8]([N:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)[CH:13]=[CH:12][C:11]=5[N:14]=4)[CH:22]=[CH:21][C:20]=3[N:23]=2)=[CH:26][CH:27]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CN1CCN(c2ccc3nc(-c4ccc5c(c4)NC(=C4C=CC(=O)C=C4)N5)[nH]c3c2)CC1
Agent: O=C(O)CCC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOc1ccc(-c2nc3ccc(-c4nc5ccc(N6CCN(C)CC6)cc5[nH]4)cc3[nH]2)cc1
Yield: 80 %

Procedure:
A solution of bisbenzimidazole (6 g; 0.01 mol) dicyclohexylcarbodiimide (0.05 mol) and Succinic acid (0.01 mol) in 100 mL chloroform is stirred overnight for 18-24 hrs. During this time, a white precipitate is formed. The precipitate is filtered and washed with chloroform (2×50 mL). The chloroform washes are combined and concentrated under vacuum in a rotary evaporator and the residue purified by flash column chromatography. The fractions containing the product are combined and concentrated under vacuum in a rotary evaporate to afford bisbenzimide succinnate ester (80%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H].O>CN(C=O)C.CC#N.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[C:22]([OH:24])=[O:23])=[CH:15][CH:14]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccccc1Nc1ccc(CCCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: Nc1ccc(CCCc2ccc(Nc3ccccc3C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.8 %

Procedure:
To a solution of 2-{4-[3-(4-nitrophenyl)propyl]phenylamino}benzoic acid (Example 158) (3.0 g, 7.97 mmol) in DMF (40 mL) was added 10% Pd—C (300 mg) at room temperature under argon atmosphere. Hydrogen gas (1 atm) was introduced into the flask and the mixture was stirred for 14 hours at room temperature. The reaction mixture was filtered through a Celite pad to remove Pd—C and concentrated in vacuo. The residue was diluted with MeOH (ca. 50 mL) and concentrated in vacuo. This operation was repeated 3 times to remove any trace of DMF. The residue was diluted with McOH again, and insoluble stuff was removed by filtration. Removing the solvent of the filtrate in vacuo afforded an oil, which was diluted with CH3CN (50 mL) and added dropwise water (100 mL) slowly. The precipitate formed was filtered and dried at 60° C. in vacuo, affording the title compound as a white solid (2.34 g, 85% yield). mp 110-112° C. MS (Fab): 347 (MH+).
Reaction SMILES: [P:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:32][C:33]4[N:34]=[C:35]([C:38]5[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([C:45]([F:48])([F:47])[F:46])[CH:39]=5)[O:36][CH:37]=4)=[CH:26][CH:27]=3)[O:22][CH:21]=2)=[CH:16][CH:15]=1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].FC(F)(F)C(O)=O>C(Cl)Cl>[P:1]([OH:3])([OH:8])([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:32][C:33]4[N:34]=[C:35]([C:38]5[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([C:45]([F:46])([F:47])[F:48])[CH:39]=5)[O:36][CH:37]=4)=[CH:26][CH:27]=3)[O:22][CH:21]=2)=[CH:16][CH:15]=1)=[O:2]
Reactant: CC(C)(C)OP(=O)(Oc1ccc(-c2coc3cc(OCc4coc(-c5cc(F)cc(C(F)(F)F)c5)n4)ccc3c2=O)cc1)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1c(-c2ccc(OP(=O)(O)O)cc2)coc2cc(OCc3coc(-c4cc(F)cc(C(F)(F)F)c4)n3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-{4-[bis(tert-butoxy)phosphinooxy]phenyl}-7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)chromen-4-one prepared in Step 2 in methylene chloride (60 ml) was added trifluoroacetic acid (0.15 ml, 1.99 mmol). The reaction mixture was stirred at room temperature overnight, the solid filtered off, and washed with methylene chloride, to afford 100% pure (by HPLC) 4-[7-({2-[5-fluoro-3-(trifluoromethyl)phenyl](1,3-oxazol-4-yl)}methoxy)-4-oxochromen-3-yl]phenyl dihydrogen phosphate.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([CH3:24])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[OH:25]O.[OH-].[Na+]>CO.ClCCl.O>[O:25]1[C:11]23[C@:16]([CH3:17])([CH2:15][CH2:14][C:13](=[O:23])[CH:12]12)[C@@H:18]1[C@H:8]([C@H:7]2[C@:21]([CH3:22])([CH2:20][CH2:19]1)[C@@H:4]([C@H:3]([CH3:24])[CH2:2][OH:1])[CH2:5][CH2:6]2)[CH2:9][CH2:10]3
Reactant: OO
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
A solution of (20S)-21-hydroxy-20-methylpregn-4-en-3-one (12.8 mmole) in methanol (55 mL) and dichloromethane (11 mL) was cooled to 12° C. and treated in one portion with 30% aqueous hydrogen peroxide (3.3 mL) followed by dropwise addition of an aqueous sodium hydroxide solution prepared by dissolving sodium hydroxide (0.38 g) in water (2.2 mL). After one hour, the cooling bath was removed and the reaction was stirred for an additional 3 hours. Most of the solvent was then removed in vacuo. The residue was dissolved in dichloromethane and purified by flash chromatography (hexane-20% ethyl acetate and hexane-40% ethyl acetate) to give (20S)-4,5-epoxy-21-hydroxy-20-methylpregnan-3-one (73.1%). This material was a mixture of the 4α,5α- and 4β,5β-isomers and it was used as is in further reactions.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13](=[O:32])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH:25]2[O:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[CH:18][CH:17]=1.C(O)C.[BH4-].[Na+].Cl>O1CCCC1.O>[OH:32][CH:13]([C:3]1[N:4]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:6][C:2]=1[CH3:1])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH:25]2[O:29][C:28](=[O:30])[NH:27][C:26]2=[O:31])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(CCCC2OC(=O)NC2=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1C(O)COc1ccc(CCCC2OC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a solution of 5-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]phenyl]propyl]-2,4-oxazolidinedione (0.2 g) in tetrahydrofuran (THF) (5 ml) - ethanol (5 ml) was added sodium borohydride (0.03 g). The mixture was stirred for one hour at room temperature. To the reaction mixture were added 2N HCl and water, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), then the solvent was distilled off. The oily residue was subjected to a silica gel column chromatography. From the reactions eluted with chloroform-methanol (50:1, v/v) was obtained 5-[3-[4-[2-hydroxy-2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-phenyl]propyl]-2,4-oxazolidinedione (0.16 g, 80%). Recrystallization from dichloromethane--isopropyl ether gave colorless needles, m.p.146°-147° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.C(OC)(OC)OC.[CH:21]([NH2:24])([CH3:23])[CH3:22].[BH4-].[Na+]>C1COCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH:24][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)N
Reactant: O=Cc1cccc(-c2nccs2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: C1CCOC1
Product: CC(C)NCc1cccc(-c2nccs2)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
To a solution of 3-(1,3-thiazol-2-yl)benzaldehyde (15 g, 81 mmol, 1.0 eq) in THF (100 mL) was added trimethyl orthoformate (9.0 mL, 8.6 g, 81 mmol, 1.0 eq) followed by isopropyl amine (11 mL, 7.3 g, 120 mmol, 1.5 eq) and the resulting reaction was stirred at 23° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in methanol (100 mL). Sodium borohydride (6.1 g, 160 mmol, 2.0 eq) was added portionwise over 30 minutes and after addition was complete the reaction was stirred for an additional 30 minutes at 23° C. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate (200 mL) and 1M aqueous potassium carbonate solution. The aqueous layer was separated and extracted with ethyl acetate (50 mL×2) and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to yield N-[3-(1,3-thiazol-2-yl)benzyl]propan-2-amine (15 g, 80%) as a white solid. 1H NMR (400 MHz, DMSO): δ 7.91-7.86 (m, 2 H); 7.77-7.72 (m, 2 H); 7.39 (d, J=5.4 Hz, 2 H); 3.72 (s, 2 H); 2.73-2.63 (m, 1 H); 0.98 (d, J=6.2 Hz, 6 H). LRMS m/z (M+H) 233.2 found, 233.1 required.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][S:11]([OH:14])(=O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][S:11]([Cl:17])(=[O:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)CCOCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)CCOCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 2-(benzyloxy)ethanesulfonic acid (4.0 g) was added thionyl chloride (13.5 ml) dropwise at ambient temperature for 15 minutes and the mixture was stirred at the same temperature for 10 minutes. To the mixture was added dropwise N,N-dimethylformamide (0.072 ml) at ambient temperature. The mixture was stirred at the same temperature for 20 minutes and refluxed for 1 hour. After cooling down to room temperature, the mixture was evaporated under reduced pressure to give 2-(benzyloxy)ethanesulfonyl chloride (4.1 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:22]([O-])([OH:24])=[O:23].O>ClCCl>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[C:6]([N+:22]([O-:24])=[O:23])[C:5]=1[OH:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(C)=O)c(O)c1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A mixture of N-(4-acetyl-3-hydroxyphenyl)acetamide (9.66 g, 50 mmol) and acetic anhydride (14.2 ml, 15.3 g, 150 mmol) in dichloromethane (150 ml) was cooled to 5° C. and nitric acid (90%, d 1.49, 4.70 ml, 7.00 g, 100 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour, poured into water (150 ml) and extracted with dichloromethane (3×150 ml). The combined organic fractions were dried (Na2SO4) and evaporated under reduced pressure and the residue was purified by repeated flash column chromatography on silica gel, eluting with hexane/30% ethyl acetate then hexane/50% ethyl acetate. The first isomer to elute was N-(4-acetyl-5-hydroxy-2-nitrophenyl)acetamide as a yellow solid (3.87 g, 33%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH:11]([Mg]Cl)=[CH2:12].[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:8][CH:12]=[CH:11]2
Reactant: C=C[Mg]Cl
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1cccc2cc[nH]c12
Temperature: -50 °C
Reaction time: 1 h

Procedure:
2-Fluoro-1-nitrobenzene (20.0 g, 0.142 mol) was dissolved in dry tetrahydrofuran (400 ml) and cooled to −50° C. Vinylmagnesium chloride (288 ml, 15% wt/vol) was added at −45° C. and stirred at this temperature for 1 hr. The reaction mixture was then poured onto saturated ammonium chloride (600 ml), separated and the aqueous layer extracted with diethyl ether (2×200 ml) then dried (MgSO4), filtered and concentrated in vacuo to yield a dark oil which was purified by column chromatography on silica using toluene as mobile phase. Fractions concentrated to yield a crystalline solid. (Tetrahedron Lett. (1989), 30(16), 2129-32)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]2[CH:23]=[CH:22][NH:21][N:20]=2)[CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([C:19]2[CH:23]=[CH:22][N:21]([C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[NH:8][CH:9]=[CH:10][C:3]=34)[N:20]=2)[CH:13]=1
Reactant: Oc1ccc(F)cc1-c1cc[nH]n1
Reactant: Brc1ccnc2[nH]ccc12
Product: Oc1ccc(F)cc1-c1ccn(-c2ccnc3[nH]ccc23)n1
Temperature: 25 °C

Procedure:
4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.050 g, 0.00025 mol) and 4-fluoro-2-(1H-pyrazol-3-yl)phenol (0.150 g, 0.000842 mol) were heated neat to 160° C. for 5 h. The reaction was allowed to cool to rt and the residue was purified by prep LC-MS on a C-18 column eluting with a water/ACN gradient containing 0.2% TFA to give the title compound, (0.052 g, 20%, as an amorphous white solid, LC/MS (M+H)+ 295, 1H NMR (DMSO-d6) δ 12.01 (bs, 1H), 10.25(bs, 1H), 8.81(s, 1H), 8.35(d, 1H, J=5.5), 7.77(d, 1H, J=9.5), 7.64(m, 1H), 7.59(d, 1H, J=5.5), 7.32(s, 1H), 7.09(m, 1H), 7.05(m, 1H), 7.01(m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][CH:5]([Br:9])[C:6]([CH3:8])=[O:7].COC(=O)CCC(CBr)=O.COC(=O)CC(Br)C(CBr)=O.COC(=O)CCC(C)=O>CO.[H][H]>[BrH:9].[CH3:1][O:2][C:3](=[O:10])[CH2:4][CH2:5][C:6]([CH3:8])=[O:7]
Reactant: [H][H]
Reactant: COC(=O)CC(Br)C(C)=O
Agent: COC(=O)CC(Br)C(=O)CBr
Agent: COC(=O)CCC(=O)CBr
Agent: COC(=O)CCC(C)=O
Solvent: CO
Product: Br
Reaction time: 5 h

Procedure:
Distillation of the solvent from the combined mother liquors obtained from the low-temperature crystallisation of 5-bromolevulinic acid methyl ester according to Example 1 in vacuo afforded a mixture consisting of 3-bromolevulinic acid methyl ester (61%), 5-bromolevulinic acid methyl ester (23%), 3,5-dibromolevulinic acid methyl ester (8%) and levulinic acid methyl ester (8%). The mixture (5 g) was dissolved in bulk grade methanol (20 ml), a hydrogen catalyst (palladium on carbon) was then added and the mixture was hydrogenated for 5 h while passing in hydrogen at a pressure of 20 bar at 20–25° C. By monitoring the hydrogenation, it was found that the reaction was completed after 5 h (1H-NMR, 13C-NMR) and besides hydrogen bromide only levulinic acid methyl ester has been formed. Water was added (20 ml) and the resulting mixture was extracted with dichloro methane (3×20 ml). The combined organic extracts were washed with saturated aqueous sodium hydrogen carbonate (3×10 ml) and saturated aqueous sodium chloride. Drying of the organic layer with Na2SO4, followed by distillation of the solvent in vacuo yielded 2.5 g (80%) levulinic acid methyl ester. The obtained product may be used for the preparation of 5-bromolevulinic acid methyl ester according to Example 2. The further purification of the obtained levulinic acid methyl ester by distillation is not necessary, so that the raw-product may be directly lead back to the bromination step after removing the hydrogen bromide for the most part.
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)CCC>C1(C)C=CC=CC=1.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:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: O=C(c1ccc(I)cc1)N1Cc2cccn2Cc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2ccccn2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 120 °C
Yield: 81.6 %

Procedure:
To a solution of 2.0 g of 10,11-dihydro-10-(4-iodobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 4.39 g of 2-[(tri-n-butyl)stannyl]pyridine in 30 ml of toluene under nitrogen is added 0.2 g of tetrakis(triphenylphosphine)palladium and the mixture heated to 120° C. for 16 hours. The toluene is evaporated in vacuo and the oily residue diluted with 50 ml of chloroform and washed with water, dried(Na2SO4), filtered through diatomaceous earth and evaporated in vacuo to give a residue which is columned on silica gel by elution with 7:1 to 1:1 ethyl acetate:hexane to give 1.44 g of the desired product as a solid, m.p. 170°-172° C.; M+H=366.1; M+Na=388.1.