Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].[CH2:11]([Si:14](OC)([O:17][CH3:18])[O:15][CH3:16])[CH2:12][CH3:13]>CCOCC>[CH3:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH3:9])[C:3]=1[Si:14]([CH2:11][CH2:12][CH3:13])([O:17][CH3:18])[O:15][CH3:16]
Reactant: CCC[Si](OC)(OC)OC
Reactant: Cc1cccc(C)c1Br
Agent: [Mg]
Solvent: CCOCC
Product: CCC[Si](OC)(OC)c1c(C)cccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 41.2 %

Procedure:
A 500 mL round bottomed flask was charged with magnesium powder (2.1 g, 86 mmol, Aldrich) and ether (250 mL, Aldrich). 2-Bromo-m-xylene (9.0 mL, 68 mmol, Aldrich) was added over a 25 minute period. The contents were refluxed overnight (18 hours). The brown solution was cooled to room temperature and propyl-trimethoxysilane (17.8 mL, 101 mmol) was added over 20 minutes. A white precipitate formed. The contents were stirred at room temperature overnight (18 hours). The reaction was poured into 0.2N aqueous HCI (500 mL), the layers were separated and the product extracted into ether (3×150 mL). The combined organic portions were dried (MgSO4), filtered, and the solvent removed via rotary evaporation (13.5 g crude). Distillation under reduced pressure (b.p. 57° C., 0.04 mm Hg) provided (2,6-dimethylphenyl)-propyl-dimethoxysilane (6.8 g, 28 mmol, 41% yield); C13H22SiO2 (Mw=238.40); 1H NMR (CDCl3) δ7.2 (t, 1H), 7.0 (d, 2H), 3.6 (s, 6H), 2.5 (s, 6H), 1.4 (m, 2H), 1.0 (t, 3H), 0.9 (t, 2H); 13C NMR (CDCl3) δ145.2, 131.0, 129.6, 128.0, 49.8, 23.4, 17.9, 16.7, 16.3; MS m/z (relative abundance) 238 (8), 195 (100), 165 (22), 133 (12), 119 (10), 105 (13), 91 (9), 59 (16).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl.N1C=CC=CC=1>[NH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:16]([C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a solution of o-phenylenediamine (4 mmol) in DCM (20 mL) and pyridine (4 mL) at 0° C., 4-chlorobenzenesulfonyl chloride (4.4 mmol) was added in small portions. The reaction mixture was then gradually warmed to RT with stirring continued until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with water (2×20 mL) and 20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to give 960 mg of N-(2-aminophenyl)-4-chlorobenzenesulfonamide. LC: Tr 0.92 min, MS: 284.0 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([F:14])([F:13])[CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]([F:14])([F:13])[CH2:6][N:7]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(F)(F)CNC1CCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 103.8 %

Procedure:
A solution of 3.6 g (0.016 mole) of 3-cyclopentylamino-2,2-difluoro-propanoic acid ethyl ester in 3 mL of ethyl acetate was added over 5 minutes to a cooled (0 degrees) mixture of 3.2 g (0.016 mole) of 2,4-dichloro-5-nitro-pyrimidine, 5.47 g (0.064 mole) of sodium bicarbonate and 36 mL of ethyl acetate. The cooling bath was removed and the mixture stirred for 17 hours at room temperature. Activated charcoal was added and after stirring briefly, the mixture was filtered through a pad of Celite, washing the filter pad with ethyl acetate. The filtrate was concentrated under reduced pressure to give 6.29 g of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2,2-difluoro-propanoic acid ethyl ester (IV-100) as a yellow thick oil, which contained a small portion of a regioisomer. This material was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([Mg]Br)[CH2:13][CH2:12]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[CH:11]1([C:2]2[C:3]3[CH:10]=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:13][CH2:12]1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Br[Mg]C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Product: c1nc(C2CC2)c2cc[nH]c2n1
Temperature: 60 °C
Yield: 99.4 %

Procedure:
4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 0.452 g, 2.94 mmol), cyclopropylmagnesium bromide (43, 31.4 mL, 0.50 M in tetrahydrofuran, 15.7 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.240 g, complex 1:1 with dichloromethane, 0.294 mmol) were mixed with 15.4 mL of toluene. The reaction was heated at 60° C. overnight, then quenched with 1 M aqueous hydrochoric acid to pH 4 and filtered through a bed of celite. The layers of the filtrate were separated and the aqueous layer extracted with ethyl acetate: The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and hexane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (44, 0.465 g). MS (ESI) [M+H+]+=160.1.
Reaction SMILES: [Se](=O)=[O:2].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][CH:6]=1>O1CCOCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH:12]=[O:2])=[O:13])=[CH:7][CH:6]=1
Reactant: O=[Se]=O
Reactant: CC(=O)c1ccc(F)cc1
Solvent: C1COCCO1
Product: O=CC(=O)c1ccc(F)cc1
Temperature: 50 °C
Yield: 79 %

Procedure:
Thus, 18.5 g of selenium dioxide was dissolved in 100 mL of dioxane by warming to 50° C. and stirring until all was in solution. To this solution was added. 23 g of 4′-fluoroacetophenone and the reaction was refluxed for 4 h. The hot solution was decanted from the solid selenium and the dioxane and water were removed by distillation through a short column at atmospheric pressure. Distillation of the residue at reduced pressure afforded 20 g of 4-fluorophenylglyoxal as a thick yellow oil which was contaminated by some starting 4′-fluoroacetophenone. This can be used directly or, more preferably, it can be converted to pure hydrate (see the last paragraph of the reference and note 5). A portion was boiled in water for 0.5 h and the aqueous layer was decanted from an oily residue and then allowed to cool. The hydrate is obtained as a white solid after filtration and air drying.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[CH2:13][CH2:14][C:15]([OH:17])=O>C(Cl)Cl>[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:7]=1[CH2:13][CH2:14][C:15]2=[O:17]
Reactant: O=C(O)CCc1ccc(Cl)cc1Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1CCc2c(Cl)cc(Cl)cc21

Procedure:
Thionyl chloride (36.9 g) was added dropwise at 40° C. to a solution of 3-(2,4-di-chlorophenyl)propionic acid (43.8 g) in methylene chloride (200 ml).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][Li].O>CCOCC>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH3:15])([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: O
Solvent: CCOCC
Product: CC1(O)CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h
Yield: 86.8 %

Procedure:
To a solution of 1-benzyl-4-piperidone (5.00 mL, 27.0 mmol, 1.00 equiv, Aldrich) in anhydrous ether at −78° C. under argon was added methyllithium (1.4 M in Et2O, 54.0 mL, 53.9 mmol, 2.00 equiv). Stirring was continued at −78° C. for 1.5 hours. Ether (200 mL) and water (40 mL) were added, and the two phases were separated. The aqueous solution was extracted with Et2O (3×50 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc to EtOAc-MeOH 9:1) to give 4.81 g (87%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].ClC1C(CC2SC(C3OC=CC=3)=NN=2)=CC([C@H]2[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O2)=C(OC)C=1.OS(C(F)(F)F)(=O)=O.C1C(=O)N([Br:57])C(=O)C1>C(#N)C>[Br:57][C:7]1[C:8]([OH:10])=[CH:9][C:2]([Cl:1])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: COc1cc(Cl)c(Cc2nnc(-c3ccco3)s2)cc1[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Product: N#Cc1cc(Br)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
To a solution of 2-chloro-4-hydroxybenzonitrile (compound 86, 10.0 g, 65.1 mmol) in acetonitrile (200 mL) was added triflic acid (10.0 mL, 71.6 mmol) and NBS (16.2 g, 91.2 mmol) at −30° C. The solution was allowed to warm up to room temperature and stirred overnight prior to quenching with saturated sodium bisulfite. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography (5-40% EtOAc/hexanes) to yield title compound (9.80 g, 65%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20]>C(OCC)(=O)C.C(O)(=O)CC>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCC(=O)O
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 92 °C
Yield: 84.4 %

Procedure:
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 8 ml ethyl acetate and 5.0 ml of propionic acid is heated to its boiling point and maintained at this temperature (92° C.) for 2 hours. After completion of the reaction, the mixture is cooled and filtered. The product is washed with ethyl acetate. After drying, 0.92 g of raw deferasirox is obtained, i.e. 84% of the theory, with an HPLC purity of 99.7% and a melting temperature of 258 to 263° C.
Reaction SMILES: [S:1](=[O:5])(=O)(O)[OH:2].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[OH:12][C:6]1[CH:11]=[CH:10][C:9]([S:1]([C:9]2[CH:10]=[CH:11][C:6]([OH:12])=[CH:7][CH:8]=2)(=[O:5])=[O:2])=[CH:8][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: Oc1ccccc1
Product: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 180 °C
Reaction time: 0.03 h
Yield: 57.9 %

Procedure:
102 g (1.0 mole) of 96% sulfuric acid and 546 g (6.0 moles) of phenol were simultaneously fed dropwise over a period of 30 minutes to a vertical glass tube (length 80 cm, diameter 4 cm) heated at 180° C. and packed with glass balls (diameter 4 mm). The residence time of the reaction mixture in the packed column was about 1 to 3 minutes. The effluent reaction mixture was collected and excess phenol was distilled off. The residue was dissolved in 5-10% sodium hydroxide solution and bis(4-hydroxyphenyl) sulfone was then precipitated therefrom by the addition of sulfuric acid to a pH of from 6.5 to 7.0. After filtration and drying, there were obtained 145 g (58%) of bis(4-hydroxyphenyl) sulfone 98.5% pure.
Reaction SMILES: C(N(CC)CC)C.NCCCN1C=CN=C1.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([NH:31][CH2:32][CH3:33])=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[O:34]1CCCC1>>[CH2:32]([NH:31][C:24]1[CH:23]=[C:22]2[C:27]([C:18](=[O:34])[NH:19][CH:20]=[N:21]2)=[CH:26][C:25]=1[N+:28]([O-:30])=[O:29])[CH3:33]
Reactant: C1CCOC1
Reactant: CCNc1cc2ncnc(Cl)c2cc1[N+](=O)[O-]
Agent: NCCCn1ccnc1
Solvent: CCN(CC)CC
Product: CCNc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]

Procedure:
Triethylamine (10 ml, 71.7 mmol) and 1-(3-aminopropyl)imidazole (5 ml, 41.9 mmol) were added to a tetrahydrofuran solution (10 ml) of 4-chloro-7--ethylamino-6-nitroquinazoline obtained from 7-ethylamino-6-nitro-4(3H)-quinazolone (610.3 mg, 2.61 mmol) in Reference Example 13 under ice-cooling. The mixture was stirred at room temperature for 19 hours and at 50° C. for 12 hours. After the solvent was distilled off, the residue was purified by silica gel column chromatography (elution with chloroform:methanol=30:1) to give Solid A (800 mg, 89.9%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[Br:16]Br>>[Br:16][C:7]1[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15]
Reactant: BrBr
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Product: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.8 %

Procedure:
To a solution of 2,4-di-t-butylphenol (Aldrich, 2.0 g, 9.7 mmol) in 2 ml of HOAC was added Br2 (0.5 ml, 9.7 mmol). The reaction mixture was stirred at room temperature for 12 hours. Solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate/hexane 1/20) to yield the desired product (2.54 g) as a white solid. 1H NMR δ 7.33 (d, J=2.3 Hz, 1H), 7.24 (d, J=2.3 Hz, 1H), 1.41 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[Br:20][CH2:21][CH2:22]Br>CN(C=O)C>[Br:20][CH2:21][CH2:22][O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: BrCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(2-Bromoethoxy)phthalimide was synthesised by a modification of the procedure of Bauer and Suresh (Bauer et al 1963). N-Hydroxyphthalimide (80 g, 0.49 mol), triethylamine (150 mL, 1.08 mol), and 1,2-dibromoethane (175 mL, 2.30 mol) were combined in DMF (575 mL) and stirred at room temperature overnight. Solids were filtered and washed with DMF and the filtrate was diluted with water (4.0 L) and the resulting precipitate filtered, dissolved in EtOAc (500 mL), and washed with 1 N HCl (2×100 mL), water (1×100 mL), and dried over MgSO4. Volatiles were removed in vacuo, and the resulting solid recrystallised from 95% EtOH to give (9) as a white solid (87.1 g, 70%): mp. 94-96° C.; lit. mp. 94-96° C. 1H NMR (CDCl3): δ 7.82 (m, 4H), 4.49 (t, 2H, J=6.9 Hz), 3.65 (t, 2H, J=6.9 Hz).
Reaction SMILES: [Li][C@H]1CC(C(O)=O)N([Li])C1=O.[Li]CCCC.[CH3:17][C:18]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:19]1[CH:23]=[CH:22][CH:21]=[CH:20]1>CCOCC>[CH:19]1([CH:18]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH3:17])[CH:23]=[CH:22][CH:21]=[CH:20]1
Reactant: CC(=C1C=CC=C1)c1ccccc1
Agent: [Li]CCCC
Agent: [Li][C@H]1CC(C(=O)O)N([Li])C1=O
Solvent: CCOCC
Product: CC(c1ccccc1)C1C=CC=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
To a solution of 0.77 mL of dilithio (s)-(-)-2-pyrrolidone-5-carboxylic acid (6 mmol) in 40 mL of ether was added 7.8 mL of n-BuLi (1.6M solution in hexanes, 13 mmol) at 0° C. This solution was stirred for 30 min at room temperature. 6-Methyl-6phenylfulvene, 1.0 g, (6 mmol) was added dropwise at 0° C. and the solution warmed to room temperature. The organic layer was separated and washed with aqueous NaHCO3, H2O and then dried over MgSO4. Removal of solvent gave 1.0 g (99% yield) of 1-cyclopentadienyl-1-phenylethane as a light yellow oil. [α]D =0.0° (CHCl3).
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].Br[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[N:7]=1>C1(C)C=CC=CC=1.O>[Br:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:1][CH2:2][CH3:3])[N:7]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1cccc(Br)n1

Procedure:
Sodium ethoxide (1.5 g, 63 mmol sodium, in ethanol (30 ml)) was added to 2,6-dibromopyridine (15 g, 63 mmol) in toluene (150 ml) at ambient temperature under nitrogen, and the reaction heated under reflux for 5 hours. The cooled mixture was diluted with water (100 ml), and extracted with ethyl acetate (2×100 ml). The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel using pentane/ethyl acetate (100:0 to 95:5) as eluant to give the title compound as a yellow oil, (quantitative).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12]Br>C(Cl)(Cl)Cl.CO>[Br:12][C:11]1[CH:10]=[C:5]([CH:4]=[CH:3][C:2]=1[OH:1])[C:6]([O:8][CH3:9])=[O:7]
Reactant: BrBr
Reactant: COC(=O)c1ccc(O)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(O)c(Br)c1
Reaction time: 2 h

Procedure:
Methyl 4-hydroxybenzoate (25.00 g) was dissolved in chloroform (225 mL) and methanol (25 mL), and a chloroform (30 mL) solution of bromine (8.5 mL) was added dropwise to the solution, and then the mixture was stirred for 2 hours. The reaction solution was diluted with chloroform, washed with water, an aqueous 10% sodium thiosulfate solution and saturated brine and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (37.81 g) as a colorless crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH:7]([CH:15](C(C)=O)[C:16]([O:18]CC)=[O:17])[CH:8](C(C)=O)[C:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(O)C.[OH-].[Na+].COC1C=CC(C(C(C(C)=O)C([O-])=O)C(C(C)=O)C([O-])=O)=CC=1>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([CH2:15][C:16]([OH:18])=[O:17])[CH2:8][C:9]([OH:11])=[O:10])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C(C)=O)C(c1ccc(OC)cc1)C(C(C)=O)C(=O)[O-]
Agent: COc1ccc(C(C(C(C)=O)C(=O)[O-])C(C(C)=O)C(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(CC(=O)O)CC(=O)O)cc1
Yield: 16.1 %

Procedure:
A mixture of ethyl 2,2'-(4-methoxybenzal)-bis-acetoacetate (30 g), ethanol (450 ml) and 50% sodium hydroxide (450 g) is refluxed vigorously for 1.0 hour. Water (150 ml) is added and most of the ethanol is removed by distillation in vacuo. The concentrate is acidified with concentrated hydrochloric acid and is extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried, evaporated and the residue is crystallized from benzene-methanol to afford 3.3 g of 3-(4-methoxyphenyl)glutaric acid, melting point 147°-150° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].O1CCCC1.[N+:30]([O-:33])([OH:32])=[O:31]>C(#N)C>[CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].[N+:30]([O-:33])([O-:32])=[O:31]
Reactant: O=[N+]([O-])O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Solvent: CC#N
Solvent: C1CCOC1
Product: O=[N+]([O-])[O-]

Procedure:
The compound is prepared startaing from an Ampicillin solution (2 g, 5.72 rmoles) in a mixture formed by acetonitrile (30 ml) and tetrahydrofuran (20 ml), by adding a 65% nitric acid solution (0.450 ml) in acetonitrile (5 ml) and following the procedure reported in Example 5. Ampicillin nitrate as amorphous solid is obtained. Yield 55%.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>CO>[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:17]1[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH:16]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CN1CCC(=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1CC=C(c2c[nH]c3ccc(Br)cc23)CC1
Temperature: 20 °C
Yield: 83.6 %

Procedure:
A solution of KOH (6.7 g, 118.45 mmol) in methanol (60 mL) was added to 5-bromo-1H-indole (10 g, 50.51 mmol) in a 250 mL 3-necked round bottom flask. 1-methylpiperidin-4-one (7.7 g, 67.46 mmol) was then added dropwise with stirring, while cooling to a temperature of 20° C. The resulting solution was allowed to react, with stirring, for 4 hours while the temperature was maintained at 73° C. The reaction mixture was then cooled to 15° C. and filtered. The filter cake was washed with water (3×50 mL). The product was purified by recrystallization from ethanol to afford 12.3 g (83%) of 5-bromo-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole as a white solid.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:13]([N:16](C(C)C)[CH2:17]C)(C)C.CC(C)(C)C(Cl)=O.CNC>ClCCl>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([N:16]([CH3:17])[CH3:13])=[O:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1cc(I)cc(F)c1F
Agent: CC(C)(C)C(=O)Cl
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(I)cc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
2,3-Difluoro-5-iodo-benzoic acid (7.20 g, 25.35 mmol), di-iso-propylethylamine (4.5 ml, 25.83 mmol), trimethylacetyl chloride (3.2 ml, 25.98 mmol), and dichloromethane (100 ml) were combined and stirred at room temperature for 1 hour. Dimethylamine (2 M in tetrahydrofuran, 22.0 ml, 44.00 mmol) was added to the reaction, and the combined mixture was stirred for an addition 18 hours at room temperature. The mixture was concentrated in vacuo, and the crude product was purified by flash chromatography on silica gel (0 to 40% ethyl acetate in hexanes) to afford 7.17 g (91%) of 2,3-difluoro-5-iodo-N,N-dimethyl-benzamide. 1H-NMR (250 MHz, d6-DMSO) δ 8.02-7.90 (m, 1H), 7.60-7.54 (m, 1H), 2.99 (s, 3H), 2.84 (s, 3H); LCMS m/z 400.0 (M+H+); MS: m/z 312.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[OH:11])[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:24][C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1)[CH:6]=[O:7]
Reactant: BrCc1ccccc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C=O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a solution of 3-methoxy-4-hydroxy benzaldehyde (10.0 g; 64.9 mmol) in dry acetone (80 ml), potassium carbonate (17.9 gm, 129.8 mmol) and BnBr (11.5 ml, 97.30 mmol) were added and stirred in room temperature for 18 hours. Potassium carbonate was filtered, acetone concentrated and the residue purified on silica gel to give the title compound as a crystalline solid 14 gm, 88%). 1H NMR (CDCl3, 200 MHz): δ 3.9 (s, 3H), 5.2 (s, 2H), 6.95 (d, J=8.37 HZ, 1H), 7.4 (m, 7H), 9.8 (s, 1H); Mass (m/z): M+242, mp: 58° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Br[C:13]1[S:14][CH:15]=[CH:16][N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(O)cc1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Oc1ccc(Oc2nccs2)cc1
Yield: 91.4 %

Procedure:
A mixture of Example 1A (15.5 g, 0.1 mol), 2-bromothiazole (18.2 g, 0.11 mol) and potassium carbonate (15.2 g, 0.11 mol) in dimethylsulfoxide was heated at 160° C. under nitrogen for six hours. After cooling and treating with water, the aqueous phase was extracted with dichloromethane. The organic layer was washed with brine, dried, and concentrated to give 27.5 g of the crude as a dark brown oil, which was purified on a silica gel (ethyl acetate/hexane 5-35%) to afford 21.5 g of the product as a brown oil (91% yield) 1H NMR (500 MHz, CDCl3) δ ppm 1.32-1.36 (m, 6H) 1.34 (none, 6H) 1.34 (none, 5 H) 4.45-4.57 (m, 1H) 6.76 (d, J=3.91 Hz, 1H) 6.87-6.93 (m, 2H) 7.15-7.20 (m, 2H) 7.21 (d, J=3.91 Hz, 1H). MS (ESI): m/z 236 (M+H).