Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18](NC3SC=CN=3)=O)[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.Br[C:28]1[C:29](Cl)=[C:30]([N+]([O-])=O)C(N)=N[CH:33]=1.CCN(C(C)C)C(C)C.Cl.C1(N2CCNCC2)C=CC=CC=1>C(O)(C)C>[Br:26][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:30]=[CH:29][CH:28]=[CH:33][CH:18]=3)[CH2:13][CH2:12]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Agent: Cl
Agent: c1ccc(N2CCNCC2)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(c3ccccc3)CC2)c1[N+](=O)[O-]
Yield: 91 %

Procedure:
This was prepared using the same procedure as for 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide, but here using 5-bromo-4-chloro-3-nitropyridin-2-amine (300 mg, 1.19 mmol), DIPEA (3.5 eq, 4.16 mmol, 0.72 mL), isopropanol (7 mL) and 1-phenylpiperazine hydrochloride (1.1 eq, 1.31 mmol, 260 mg). After 18 h the precipitate was filtered and washed with cold water (2×3 mL) to give the product (407 mg, 91%) as an orange solid; 1H-NMR (500 MHz, DMSO-d6) 3.20 (br s, 4H, piperazine N(CH2)2), 3.30 (hidden by DMSO peak, 4H, piperazine N(CH2)2), 6.83 (t, J=7.5 Hz, 1H, phenyl H-4), 6.98 (d, J=8.4 Hz, 2H, phenyl H-2 & H-6), 7.04 (br s, 2H, NH2), 7.25 (t, J=7.9 Hz, 2H, phenyl H-3 & H-5), 8.21 (s, 1H, pyridine H-6);
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[C:6]([CH:12]2[CH2:14][CH2:13]2)[CH:5]=1.[OH-].[Na+]>C1COCC1.C(O)C>[CH:12]1([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:11])[CH:7]=2)[C:3]([OH:15])=[O:2])[CH2:13][CH2:14]1
Reactant: COC(=O)c1cc(OC)cc(C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc(C2CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
The above prepared 3-cyclopropyl-5-methoxy-benzoic acid methyl ester (0.221 g, 1.07 mmol) was dissolved in 3.6 ml of THF/ethanol=1/1 and treated with 1.79 ml of aq. NaOH (3M, 5 eq.). The mixture was stirred for 1.5 h at ambient temperature and was then poured onto crashed ice/AcOEt/HCl dil.; the organic layer was washed with water, dried over sodium sulfate, and evaporated to dryness to leave 0.202 g of the title compound as white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[NH2:18][C:19]1[C:26]([OH:27])=[C:25]([F:28])[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH3:35])[C:20]=1[C:21]#[N:22].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C:10]([NH:18][C:19]1[C:26]([OH:27])=[C:25]([F:28])[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:23]([CH3:35])[C:20]=1[C:21]#[N:22])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: O=C(Cl)COCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C#N)c(NC(=O)COCc2ccccc2)c(O)c(F)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.2 %

Procedure:
Under nitrogen atmosphere, benzyloxyacetyl chloride (489 μl, 3.10 mmol) was dropwise added to a tetrahydrofuran solution (10 ml) of 2-amino-5-phenyl-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-41) (500 mg, 2.06 mmol) and sodium hydrogencarbonate (520 mg, 6.19 mmol) cooled with ice, followed by stirring at room temperature for 18 hours. Ethyl acetate was added to the reaction liquid, followed by washing with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was recrystallized and purified with n-hexane/ethyl acetate to obtain the entitled compound (621 mg, 1.59 mmol, 77%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].CCN(C(C)C)C(C)C.[C:20]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([Si:24]([CH3:26])([CH3:25])[O:10][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1cc(Cl)ccc1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Cl)cc1C=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-chloro-2-hydroxy-benzaldehyde (9.3 g) in DMF (45 mL) was added DIPEA (20 mL) and tert-butyl-chloro-dimethyl-silane (19 g). The mixture was stirred at room temperature for 1.5 h. Then the mixture was poured into ice water (200 mL), extracted with ether (2×100 mL). The combined organic layers were washed with brine, dried over Na2SO4. The solvent was removed to give the title compound which was used directly for next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[CH:21][CH:20]=3)[CH2:12][CH2:13][CH2:14][CH2:15]SC)=[C:8]([CH3:36])[C:7]=2[CH:37]=1.Cl[C:39]1C=CC=C(C(OO)=O)C=1.[S:49]([O-:52])([O-])=[O:50].[Na+].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:26])=[CH:23][CH:24]=3)[CH2:12][CH2:13][CH2:14][CH2:15][S:49]([CH3:39])(=[O:52])=[O:50])=[C:8]([CH3:36])[C:7]=2[CH:37]=1
Reactant: O=S([O-])[O-]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CCCCSC)c2oc3ccc(OC)cc3c2C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CCCCS(C)(=O)=O)c2oc3ccc(OC)cc3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a solution (10 mL) of ethyl 3-{[(4-{[1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-5-(methylsulfanyl)pentyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (263 mg) synthesized in Example A121(1) in acetone was added m-chloroperbenzoic acid (water-containing, purity 69-75%) (344 mg) at 0° C., and the mixture was stirred overnight at room temperature. Saturated aqueous sodium sulfite solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane), then by NH silica gel column chromatography (ethyl acetate) to give the title object compound (104 mg, 37%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([I:8])[CH:7]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:11].O=P(Cl)(Cl)Cl>C(Cl)Cl>[Cl:11][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([I:8])=[CH:5][N:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Oc1ncc(I)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1cc(I)cnc1Cl
Temperature: 130 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A 100 ml 3-necked round bottom flask, fitted with a condenser topped with a N2 inlet, a mechanical stirrer and a thermometer, was charged with 17.2 g (0.0673 mole) of 3-chloro-2-hydroxy-5-iodopyridine, 14.85 g (0.0713 mole) of PCl5, and 1 ml (1.68 g; 0.0109 mole) of POCl3. The reaction mixture, containing solids, was slowly stirred and slowly heated to 130° C. The reaction mixture was stirred under N2 for 5 hours after which it was cooled to room temperature and allowed to stand overnight. The reaction mixture was cautiously poured into crushed ice and allowed to stand for 1 hour. Methylene chloride (200 ml) was added to the reaction mixture to dissolve the solids present in it. The layers was separated and the organic phase was washed with dilute base, water and saturated NaCl. After drying over anhydrous MgSO4 and filtration, the solvent was evaporated leaving 11.8 g of a yellow solid. The solid was recrystallized from methanol resulting in 6.60 g of solid that had spectral and physical properties identical to the product obtained in Example 1, STEP D.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5](=O)[CH:6]([O:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])[CH3:7].C(O)C>C(Cl)(Cl)Cl.O1CCCC1.CN(C)C1C=CN=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:9]=1[O:8][CH:6]([C:5]1[NH:4][CH2:3][CH2:2][N:1]=1)[CH3:7]
Reactant: CC(Oc1c(Cl)cccc1Cl)C(=O)NCCN
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(Oc1c(Cl)cccc1Cl)C1=NCCN1

Procedure:
58.6 (0.3089 mols) of titanium tetrachloride are dissolved in a mixture of 700 ml of absolute chloroform and 25 ml of tetrahydrofuran at 0° C. and are mixed with 35.0 g (0.1263 mols) of (-)-2-(2,6-dichlorophenoxy)-propionic acid-N-(2-aminoethyl)-amide. A solution of 74.0 g (0.6056 mols) of 4-dimethylaminopyridine is then added dropwise very slowly at 0° C. with stirring and the mixture is further stirred for 36 hours at room temperature after the solution has been added. After working up and after purification by column chromatography (silica gel-dry column, eluant: chloroform/tetrahydrofuran 3:1), 21.0 g of (-)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene C11H12Cl2N2O [259.1], are obtained, Mp.: 126°-127° C.: [α]D20 =-80.2° (c=1/ethanol).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Br[C:10]([CH3:17])([CH3:16])[C:11](OCC)=[O:12].C(NC(C)C)(C)C>CN(C=O)C>[CH3:16][C:10]1([CH3:17])[NH:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:7][C:11]1=[O:12]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC1(C)Nc2ccccc2NC1=O
Reaction time: 8 h

Procedure:
A mixture of 1,2-phenylenediamine (II, 7.55 g), ethyl 2-bromoisobutyrate (III, 12.8 ml), diisopropylamine (15.5 ml) and DMF (30 ml) is heated at 110° for 5 hr, after which an additional ethyl bromoisobutyrate (III, 0.5 ml) and diiopropylethylamine (0.8 ml) is added. After heating for 2 more hours, the reaction is cooled and the DMF is removed in under reduced pressure. The residue is stored overnight in the freezer and then partitioned between ethyl acetate, water, and saline. The phases are separated and the organic phase is dried over magnesium sulfate, the organic phase is removed under reduced pressure. The residue is chromatographed eluting with ethyl acetate/dichloromethane (20/80). The product crystallizes out in the column. The product is recrystallized from dichloromethane/hexane to give the title compound, mp 173°-174°; NMR (CDCl3) 1.41, 3.72, 6.67, 6.76, 6.87 and 8.50 δ.
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21]Cl)[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:7].[ClH:5].[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][SH:3])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1
Reactant: NC(N)=S
Reactant: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 75 %

Procedure:
Utilizing the procedure described in Example 1(b), 6.0 g of thiourea, was reacted with 25.2 g of 1-(4-chlorobenzyl-4-(3-chloropropyl)piperazine dihydrochloride and 8.7 g of triethylamine in 200 ml of reagent ethanol. The hydrolysis was effected with 5.0 g of sodium hydroxide in 50 ml of water. Work-up as described above gave 16.6 g (75% of theory) of 3-[4-(4-chlorobenzyl)piperazine-1-yl]propanethiol dihydrochloride as an off-white crystalline solid, M.p. 257°-260° C.
Reaction SMILES: [N:1]([C:4]1[C:9]([CH:10]=O)=[CH:8][C:7](OC)=[C:6](OC)[CH:5]=1)=[N+:2]=[N-].NC1C=CC=CC=1.C(O)(=O)C>CN(C)C=O>[NH:1]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[N:2]1
Reactant: COc1cc(C=O)c(N=[N+]=[N-])cc1OC
Solvent: CC(=O)O
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: c1ccc2[nH]ncc2c1
Reaction time: 1 h
Yield: 169.3 %

Procedure:
A solution containing 51.8 g (0.25 mole) 6-azidoveratraldehyde (Example XII), 26.0 g (0.28 mole) aniline, 4 ml galcial acetic acid, and 300 ml dimethylformamide was stirred at 90°-100° for 1 hr, then refluxed for 1 hr until the gaseous evolution was complete. After the mixture was cooled and poured slowly in 1.5 1. iced water, the product was filtered, washed with two 150 ml portions cold water, and air dried to give 50 g of crude indazole, m.p. 130°-138°. Recrystallization from ethyl acetate -- hexane followed by ethyl acetate gave 26 g (41%) of the product, m.p. 149°-152°. Recrystallization from ethyl acetate -- hexane gave the analytical sample, m.p. 149°-152° .
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O.NN>C(O)C>[F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCN1CCC(Cc2ccc(F)cc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCN1CCC(Cc2ccc(F)cc2)CC1

Procedure:
A solution of 2-{2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethyl}-isoindole-1,3-dione (0.087 g, 0.24 mmol) in ethanol (20 ml) is treated with hydrazine hydrate (1.0 ml, 2 mmol) and heated under reflux for 1.5 hours. Most of the solvent is evaporated and the resultant solution is ice cooled for 0.5 hours. The precipitate is filtered off and the filtrate is evaporated to afford 2-[4-(4-fluoro-benzyl)-piperidin-1-yl]-ethylamine which is used directly, without further characterisation, in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11](=[O:22])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21].[CH3:23][NH2:24].O>CN(C)C=O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]1[CH2:12][C:11](=[O:22])[CH2:10][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:24]1[CH3:23]
Reactant: COc1ccccc1C=CC(=O)C=Cc1ccccc1OC
Reactant: CN
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1C1CC(=O)CC(c2ccccc2OC)N1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.6 %

Procedure:
1,5-Bis(2-methoxyphenyl)-1, 4-pentadien-3-one (20c, 0.26 g, 0.9 mmol) was dissolved in dimethyl formamide (5 ml). Methylamine (51, 0.40 ml, 4.6 mmol, 40% in water) was added and the mixture stirred for 24 hr at room temperature. The mixture was poured into water (50 ml) and stirred for 24 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The solid was recrystallized twice from ethanol to give 0.16 g (55%) of a white solid: mp 146-148° C.; 1H NMR δ 1.89 (s, 3H), 2.50 (d, 2H, J=13.7 Hz), 2.65 (t, 2H, J=11.9 Hz), 3.82 (s, 6H), 4.11 (d, 2H, J=11.5 Hz), 6.87 (d, 2H, J=8.3 Hz), 7.03 (t, 2H, J=7.2 Hz), 7.23 (t, 2H, J=5.8 Hz), 7.72 (d, 2H, J=7.6 Hz); 13C NMR: δ 40.3, 49.2, 55.4, 61.2, 110.7, 121.0, 127.6, 127.8, 131.5, 156.3, 208.1; Exact mass calcd for C20H23NO3: 325.1678, observed (M+H) 326.1754.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:11][CH2:12][CH2:13][CH3:14]>C(#N)C>[Br-:11].[CH2:12]([N+:2]([CH3:1])([CH2:9][CH3:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:13][CH3:14]
Reactant: CCN(C)c1ccccc1
Reactant: CCCBr
Solvent: CC#N
Product: CCC[N+](C)(CC)c1ccccc1
Product: [Br-]

Procedure:
100 mmol of N-methyl-N-ethylaniline (Aldrich) were quaternized with 100 mmol of bromopropane (Aldrich) at reflux in 100 ml of acetonitrile for 48 hours. After evaporation of the solvent, the N-propyl-N-methyl-N-ethylanilinium bromide (PMEA.Br) obtained was purified by washing with ether. 50 mmol of KBFST were added to 50 mmol of PMEA.Br in 100 ml of water, and then the solution was extracted with twice 50 ml of dichloromethane. After evaporation of the solvent and drying under vacuum, PMEA.BFST was obtained. The two optical isomer forms of this salt were separated on a chiral column. The two optical isomers isolated serve as a chiral reaction medium.
Reaction SMILES: O[CH:2]([NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1)[C:3]([Cl:6])([Cl:5])[Cl:4].S(Cl)(Cl)=O.ClC(NC(=O)C1C=CC=NC=1)C(Cl)(Cl)Cl.[CH3:35][O:36][CH2:37][CH2:38][NH2:39].C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.C1C=CC=CC=1>[CH3:35][O:36][CH2:37][CH2:38][NH:39][CH:2]([NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1)[C:3]([Cl:6])([Cl:5])[Cl:4]
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1cccnc1
Reactant: COCCN
Agent: O=C(NC(Cl)C(Cl)(Cl)Cl)c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COCCNC(NC(=O)c1cccnc1)C(Cl)(Cl)Cl
Reaction time: 8 h
Yield: 41.3 %

Procedure:
150 ml of benzene was added to 5.0 g of N-(1-hydroxy-2,2,2-trichloroethyl)nicotinamide. 2.6 g of thionyl chloride was added dropwise to the mixture under stirring and the obtained mixture was heated under stirring at 60° to 80° C. for about 5 h to complete the production of N-(1,2,2,2-tetrachloroethyl)nicotinamide. The reaction solution was cooled to a temperature of 30° C. or below. 1.4 g of 2-methoxyethylamine was added thereto and then 3.7 g of triethylamine was added dropwise to the liquid mixture kept at 5° C. After stirring at room temperature for 3 h, the mixture was left to stand at room temperature overnight. The reaction solution was poured in an aqueous sodium bicarbonate solution. A benzene layer thus separated was washed with a saturated aqueous common salt solution and water and dried over anhydrous sodium sulfate. After concentration, the residue was recrystallized from a solvent mixture of n-hexane and ethyl acetate to obtain 2.5 g of N-(2-methoxyethylamino-2,2,2-trichloroethyl)nicotinamide. m.p. 75° to 77° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].C[Li].C([Li])(C)(C)C.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C>O1CCCC1.C(OCC)C.CCCCC>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[B:24]([OH:25])[OH:23]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
3-Bromo-4-methoxybenzoic acid (2.00 g) is dissolved in tetrahydrofuran (50 ml), and the mixture is cooled to −78° C., and thereto is added dropwise a 1.1M methyllithium in diethyl ether (7.7 ml). The mixture is stirred at −78° C. for 5 minutes, and thereto is added dropwise a 1.6M tert-butyllithium in n-pentane (13.2 ml), and the mixture is stirred at −78° C. for 15 minutes, and the mixture is allowed to warm to −45° C., and the mixture is stirred for 45 minutes, and then again cooled to −78° C. Thereto is added dropwise triisopropylborate, and the mixture is stirred at −78° C. for 15 minutes, and the mixture is allowed to warm to room temperature. The mixture is stirred at room temperature for 1.5 hours, and the mixture is concentrated under reduced pressure, and thereto are added water and hexane. The aqueous layer is adjusted to pH 4 by addition of a 6N-hydrochloric acid and a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate and methanol twice. The organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. To the resulting residue is added diethyl ether, and the resulting solids are collected by filtration to give 2-methoxy-5-carboxyphenylboronic acid (1.37 g) as a crude product.
Reaction SMILES: [S:1]([NH:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][C:18]2=O)=[CH:14][CH:13]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[C:22]([O:29][CH2:30][CH3:31])(=[O:28])[C:23](OCC)=O.[O-]CC.[Na+].[C:36]1([NH:42][NH2:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(O)C.C(O)(=O)C>[C:36]1([N:42]2[C:18]3[C:19]4[C:15]([CH2:16][C:17]=3[C:23]([C:22]([O:29][CH2:30][CH3:31])=[O:28])=[N:43]2)=[CH:14][CH:13]=[C:12]([NH:11][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])[CH:20]=4)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NNc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc3c(c2)C(=O)CC3)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1nn(-c2ccccc2)c2c1Cc1ccc(NS(=O)(=O)c3ccc(C)cc3)cc1-2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Tosylamino-indan-1-one, m.p. 202°-204° C., (4.2 g) is reacted with diethyl oxalate (20.5 g) in anhydrous ethanol (125 ml) containing sodium ethoxide (3.75 g) under stirring in inert atmosphere at room temperature for 2 hours. The reaction mixture is diluted with ice water and extracted with hexane. The aqueous phase is acidified to pH 3 with N HCl and extracted with ethyl acetate. The organic solution is washed with water until neutral and then is evaporated to dryness in vacuo to give crude 2-ethoxalyl-6-tosylamino-indan-1-one, which is reacted with phenylhydrazine (1.65 g) in acetic acid (60 ml) at 60° C. for 2 hours. The reaction mixture is diluted with ice water and the precipitate is filtered, washed with water, dissolved in CHCl3 and evaporated to dryness in vacuo. Purification over a SiO2 column using hexane/ethyl acetate 7/3 as eluent yields pure 1,4-dihydro-1-phenyl-7-tosylamino -indeno[1,2-c]pyrazole-3-carboxylic acid, ethyl ester (3.3 g), which is reacted with acetonitrile (12 ml) in anhydrous dioxane (50 ml) in the presence of 50% sodium hydride (1.1 g) under stirring at 60° C. for 4 hours. After cooling the reaction mixture is diluted with ice water and acidified to pH 4 with citric acid. The precipitate is extracted with ethyl acetate, washed with 5% NaHCO 3 aqueous solution and then with water. By concentration to a small volume in vacuo the product crystallizes. The precipitate is filtered and washed with ethyl acetate to yield pure 3-(1,4-dihydro-1-phenyl-7-tosylamino-indeno [1,2-c]pyrazol-3-yl)-3-oxo-propanenitrile (2.1 g), which is reacted with phenyl isocyanate (0.55 g) in dimethylformamide (15 ml) in the presence of triethylamine (0.65 ml) at room temperature for 30 minutes. The reaction mixture is diluted with ice water and acidified to pH 2 with 2N HCl.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:19]=1.[CH3:20]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>O>[CH3:20][O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=[CH:15][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:19]=1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc(O)cc1C=C2
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1ccc2c(c1)C=Cc1ccc(C(=O)O)cc1S2

Procedure:
1 G. 8-hydroxydibenzo[b,f]thiepin-3-carboxylic acid is stirred in 50 cc. dimethylformamide with 1.5 g. potassium carbonate and 3 cc. methyl iodide. 100 CC. water is added to the reaction mixture, heated for three hours and then extracted with ethyl acetate, and the aqueous layer acidified. The precipitated solid is filtered, washed with water and a small volume of cold methanol, and dried. Yield of the desired material 700 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[C:10]([Br:12])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc2c(c1)C(=O)CC2
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1Br)C(=O)CC2
Reaction time: 1 h

Procedure:
A solution of 6-aminoindanone (12 g, 81.6 mmol) in N,N-dimethylformamide (220 ml) is treated with N-bromosuccinimide (14.5 g, 81.6 mmol) in portions over a period of one hour and stirred for one hour. Evaporation of the solvent and water/dichloromethane workup followed by purification by chromatography with EtOAc/hexane (1:3) as eluent gives the product 6-amino-7-bromoindanone; LC/MS: 226/228 (M+1)+.