Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].N1C=CC=CC=1.[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:3]([O:4][CH3:5])[CH3:2])=[O:18])=[CH:15][CH:14]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To N,O-dimethylhydroxylamine hydrochloride (27.7 g, 284 mmol) in DCM (660 mL) was added pyridine (45.8 mL, 569 mmol) followed by 4-fluorobenzoyl chloride (31.0 mL, 258 mmol). The resulting suspension was stirred at room temperature for 20 hours, then was filtered to remove a white solid precipitate. The solid was washed with DCM and the filtrate was washed with 1 N aqueous HCl (2×), then water. The organic phase was dried (Na2SO4), filtered, and concentrated, yielding the crude title compound which was used without further purification.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1.[Cl:12]([O-])(=O)=O.[K+]>O>[Cl:12][C:8]1[C:3]([OH:2])=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: [O-][Cl+2]([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(Cl)c1
Temperature: 53 °C

Procedure:
Concentrated hydrochloric acid (239 g) was added to 2-hydroxy-5-nitropyridine (40.0 g). The resulting slurry was heated to 53° C., and stirred until all the solids dissolved. To this was slowly added a solution of potassium chlorate (14.0 g) in water (250 g), while maintaining the temperature between 55° C. and 59° C. The resulting mixture was stirred at 58-62° C. for about 1 hour. The reaction was then cooled to room temperature, stirred for 12 hours and then filtered. After washing the wet cake with water, the product was dried in a vacuum oven. 1H NMR (400 MHz/DMSO-d6) δ 8.64 (d, J=2.9 Hz, 1H), 8.35 (d, J=2.9 Hz, 1H)
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:26])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1.[Sn](Cl)(Cl)(Cl)Cl>C(=S)=S>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Cc2cc3ccccc3s2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: S=C=S
Product: COc1ccc(C(=O)c2c(Cc3ccccc3)sc3ccccc23)cc1
Yield: 85 %

Procedure:
The known compound, 2-benzyl-benzo[b]thiophene (CA reg. no. 3407-15-6) was acylated with one equilvalent of anisoyl chloride using one equivalent of a tin (IV) chloride promoter in carbon disulfide solvent to afford (2-benzyl-benzo[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone (85% yield). This compound was demethylated using six equivalents of pyridinium hydrocholide at 228° C. to afford (2-benzyl-benzo[b]thiophen-3-yl)-(4-hydroxy-phenyl)-methanone (90% yield). This compound was brominated according to the procedure in Example 4 to afford the tide compound as a white solid (95% yield): mp 155.5-156.5; MS m/e 500 (M)+;
Reaction SMILES: C[O:2][CH2:3][C:4]([O:6][CH3:7])=O.[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([Mg]Br)[CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC>[CH2:8]([O:15][C:16]1[CH:21]=[C:20]([C:3](=[O:2])[CH2:4][O:6][CH3:7])[CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br[Mg]c1cccc(OCc2ccccc2)c1
Reactant: COCC(=O)OC
Solvent: CCOCC
Product: COCC(=O)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 13.8 %

Procedure:
To a solution of methyl methoxyacetate (available from Aldrich) (0.48 mL, 4.8 mmol) in ether (20 mL) was added 3-benzyloxyphenylmagnesium bromide (1.0 M in THF) (available from Aldrich) (5.0 mL, 5.0 mmol) dropwise at −78° C. The mixture was warmed to room temperature overnight, quenched with 1 N HCl, and diluted with EtOAc. The organic layers were washed with water and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford 102.A (0.17 g, 14% yield) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[OH-].[NH4+:13]>>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH2:13]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [OH-]
Product: Nc1ccc([N+](=O)[O-])cc1F
Temperature: 135 °C

Procedure:
A mixture of 10.0 grams (0.063 mole) of 3,4-difluoronitrobenzene and 40 mL of aqueous 29% ammonium hydroxide was placed in a pressure bottle and sealed. The mixture was stirred and heated at 135° C. for about 18 hours. The bottle and contents were then cooled and the bottle opened. A solid was collected by filtration and washed, first with water and then with petroleum ether. The solid was dried, yielding 9.4 grams of 2-fluoro-4-nitroaniline.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH:8]1([NH2:11])[CH2:10][CH2:9]1>C(O)C>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][CH2:3][N:11]([CH:8]1[CH2:10][CH2:9]1)[CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: NC1CC1
Solvent: CCO
Product: CCOC(=O)CCN(CCC(=O)OCC)C1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.7 %

Procedure:
A mixture of ethyl acrylate (300 mmol) and cyclopropyl amine (149 mmol) in absolute ethanol (45 mL) was stirred for 24 h at room temperature. The crude mixture was purified by fractionated distillation in vacuo (20 mbar). One fraction was collected (boiling point: 135° C. at 20 mbar), yielding to 20.58 g of the desired product as a colorless oil. MS (m/e): 274.3 (MH+, 100%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C@:18]34[O:24][C@H:19]3[CH2:20][CH2:21][CH2:22][CH2:23]4)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[CH2:30][Mg]Cl>O1CCCC1>[C:1]1([C:7]2[N:8]=[C:9]([C@@:18]3([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:30][C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([O:26][CH3:25])[CH:28]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc([C@@]34CCCC[C@@H]3O4)oc2-c2ccccc2)cc1
Reactant: COc1cccc(C[Mg]Cl)c1
Solvent: C1CCOC1
Product: COc1cccc(C[C@@H]2CCCC[C@]2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.4 %

Procedure:
To a solution of (1R,2S)-1-(4,5-diphenyloxazol-2-yl)-1,2-epoxycyclohexane (20 g) and CuBr (3.0 g) in tetrahydrofuran (400 ml) was dropwise added a solution of 3-methoxybenzylmagnesium chloride [prepared from 3-methoxy-benzylchloride (50 g) and Mg (9.2 g)] in tetrahydrofuran (500 ml) at −78° C. under N2. The mixture was stirred for 2 hours at the room temperature and partitioned between ethyl acetate and water. The organic layer was washed with 1N-HCl, water, sat. NaHCO3 and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (1R,2S)-1-(4,5-diphenyloxazol-2-yl)-1-hydroxy-2-(3-methoxybenzyl)cyclohexane (29.2 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][SH:4].[C:5]1([C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(C(F)(F)F)=O>[C:11]([S:4][CH2:3][CH2:2][NH2:1])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCCS
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cysteamine (commercial) (900 mg, 11.67 mmol) was added to a stirred solution of triphenylmethanol (commercial) (3.037 g, 11.67 mmol) in TFA (10 ml) and the mixture stirred at RT for 3 hours. The mixture was then concentrated under reduced pressure and the residue partitioned between DCM (20 mL) and water (20 mL). The mixture was basified by the slow addition of solid K2CO3. The aqueous phase was extracted with DCM (2×20 mL), the combined organic phases passed through a hydrophobic frit and the solvent evaporated under reduced pressure. The material was used without further purification.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6]Cl)[CH3:3].[CH3:10][C:11]1([CH3:32])[CH:20]=[C:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[C:18]2[C:13](=[CH:14][C:15]([OH:31])=[CH:16][CH:17]=2)[O:12]1>>[CH2:2]([N:4]([CH2:8][CH3:9])[CH2:5][CH2:6][O:31][C:15]1[CH:14]=[C:13]2[C:18]([C:19]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)=[CH:20][C:11]([CH3:32])([CH3:10])[O:12]2)=[CH:17][CH:16]=1)[CH3:3]
Reactant: CC1(C)C=C(c2ccc3ccccc3c2)c2ccc(O)cc2O1
Reactant: CCN(CC)CCCl
Agent: Cl
Product: CCN(CC)CCOc1ccc2c(c1)OC(C)(C)C=C2c1ccc2ccccc2c1
Yield: 49 %

Procedure:
Reaction of 2-diethylaminoethylchloride hydrochloride with 2,2-dimethyl-4-(2-naphthyl)-2H-chromen-7-ol by an analogous method to that described in Preparation 18 (c) gave the title compound as a colourless oil in 49% yield.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, 0° C. solution of (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (10.4 g, 55.5 mmol) and triethylamine (15.5 mL, 0.1111 mole) in CH2Cl2 (150 mL) was added dropwise methanesulfonyl chloride (5.2 mL, 0.06665 mole). When the addition was complete, the reaction mixture was allowed to warm to room temperature, then stirred overnight. The reaction mixture was concentrated under reduced pressure to give a residue that was partitioned between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100% hexane to 70:30 hexane/ethyl acetate). Fractions containing product were combined and concentrated under reduced pressure to give (S)-tert-butyl 3-(methylsulfonyloxy)pyrrolidine-1-carboxylate. 1H NMR (300 MHz, CD3OD) δ ppm 1.47 (s, 9H), 2.14-2.29 (m, 2H), 3.12 (s, 1H), 3.36-3.67 (m, 4H), 5.24-5.30 (m, 1H); MS (DCI/NH3) m/z 266 (M+H)+, 283 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[CH2:9]([C:16]([C:18]([F:21])([F:20])[F:19])=O)[C:10]([C:12]([F:15])([F:14])[F:13])=O.[OH-].[NH4+]>P(=O)(O)(O)O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]2[C:4](=[N:8][C:10]([C:12]([F:13])([F:14])[F:15])=[CH:9][C:16]=2[C:18]([F:19])([F:21])[F:20])[N:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)C(F)(F)F
Reactant: Nc1cccc(N)n1
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Nc1ccc2c(C(F)(F)F)cc(C(F)(F)F)nc2n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A mixture of 2,6-diaminopyridine (5.2 g., 47.6 mmole), 1,1,1,5,5,5-hexafluoroacetylacetone (10.0 g., 48.0 mmole) and 85% phosphoric acid (50 ml.) are stirred for six hours in an oil-bath at 90°-95° C. then left overnight at ambient temperature. The reaction mixture is poured into ice water and neutralized with ammonium hydroxide to pH 7, the solid collected, washed with water and dried to provide 9.0 g. (67%) of product, m.p. 198-204° C. Upon recrystallization from benzene, purified product separates in the form of pale yellow needles, m.p. 204°-206° C.
Reaction SMILES: [C:1]1([C:9]([O:11]CC)=[O:10])([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:3][CH2:2]1.[OH-].[K+]>C(O)C.O>[CH2:7]([O:6][C:4]([C:1]1([C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C1(C(=O)OCC)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
To a solution of diethyl cyclopropane-1,1-dicarboxylate (4.77 g, 25.6 mmol) in ethanol (40 mL) was added KOH (1.43 g, 25.6 mmol) in H2O (8 mL), and the reaction mixture was stirred at room temperature overnight. The ethanol was removed under reduced pressure. The residue was neutralized with HCl (6 mL, 5 mol/L), then extracted with EtOAc (100 mL×3). The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give the title compound as a white solid (3.58 g, 88.4%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].C([Li])(C)(C)C.[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.[OH-].[Na+]>O1CCCC1.O>[F:10][C:9]([F:12])([F:11])[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:18]([OH:23])[OH:19]
Reactant: FC(F)(F)Oc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1ccccc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of 2 g (9.5 mmol) of 1-bromo-2-trifluoromethoxy benzene in 28 mL of tetrahydrofuran (THF) at −78° C., was carefully added 5.9 mL of a 1.7 M solution of t-butyl lithium in hexanes (9.5 mmol). This reaction mixture was stirred at −78° C. for 45 min. To this reaction mixture at −78° C. was added 2.58 mL (11.1 mmol) of tri-isopropyl borate, followed by slow warming of the mixture to room temperature (RT) over a period of 16 h. The reaction mixture was diluted with water and made basic with 2N NaOH solution. The mixture was then washed with EtOAc. The aqueous fraction was acidified with 2N HCl solution and stirred for 1 h at RT. The reaction mixture was extracted with EtOAc and the organic fractions were washed with water and saturated NaCl solution (brine), dried over Na2SO4 and filtered. The filtrate was concentrated to give the title compound as a white solid. 1H NMR (CDCl3) (δ, ppm): 7.96 (dd, J=7.2, 1.6 Hz, 1 H), 7.53 (ddd, J=9.1, 7.3, 1.8 Hz, 1 H), 7.38 (td, J=7.3, 0.7 Hz, 1 H), 7.28 (d, J=8.2 Hz, 1 H), 5.25 (br s, 2H). MS (M+H): 206.9.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH2:16]O)[CH:13]=[CH:14][CH:15]=2)=[N:7][CH:8]=1.S(Cl)([Cl:22])=O.C1(C)C=CC=CC=1>ClCCl>[Cl:22][CH2:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(Oc2cccc(CCl)c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
[3-(5-Trifluoromethyl-pyridin-2-yloxy)-phenyl]-methanol from Step 1 (4.68 g, 17.4 mmol), in dichloromethane (46 mL), was cooled to 0° C., and treated dropwise with thionyl chloride (1.40 mL, 19.1 mmol). The reaction mixture was allowed to warm to ambient temperature and was stirred for 30 min. Toluene (10 mL) was added and the mixture was concentrated by evaporation to form a residue. The residue was evaporated again from toluene and dried under high vacuum to afford the desired product (4.88 g, 98% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.60 (s, 2H) 7.03 (d, J=8.70 Hz, 1H) 7.11 (ddd, J=8.09, 2.35, 0.94 Hz, 1H) 7.20 (t, J=2.03 Hz, 1H) 7.26-7.31 (m, 1H) 7.42 (t, J=7.88 Hz, 1H) 7.91 (dd, J=8.67, 2.53 Hz, 1H) 8.44 (dd, J=1.51, 0.90 Hz, 1H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.S(Cl)([Cl:12])=O>C(OCC)C>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccncc1
Solvent: CCOCC
Product: O=C(Cl)c1ccncc1

Procedure:
123 g (1 mol) of isonicotinic acid are placed in a 1 liter round-bottomed flask equipped with a condenser and a calcium chloride drying tube, and 250 ml of thionyl chloride are added all at once, whilst cooling with an ice bath. The exothermic reaction lasts about ten minutes. The mixture is then heated under reflux on an oil bath for one and a half hours. The excess thionyl chloride is driven off and the crystalline residue is taken up in 100 ml of dry diethyl ether. The mixture is stirred and the white precipitate which forms is filtered off, washed again with 50 ml of diethyl ether and dried to yield 171 g of isonicotinoyl chloride in the form of the hydrochloride. 92 g (0.516 mole) of this are placed in a 2 liter three-necked flask equipped with a thermometer, a stirrer, a condenser and a calcium chloride drying tube, and 300 ml of anhydrous toluene are added. The mixture is cooled to 10° C., 262 g (1.96 mol) of ground aluminium chloride are added in small portions and the mixture is stirred for 2 hours at ambient temperature. The dark red solution is then transferred to a dropping funnel and added dropwise to 2.5 liters of iced water cooled with an ice bath. 800 ml of ethyl acetate are then added, followed by the addition of 1 liter of sodium carbonate solution (d=1.33), with cooling. This gives a solution from which the organic phase is decanted. The aqueous phase is extracted a further three times with 500 ml of ethyl acetate, the organic phases are combined, washed with water and dried and the solvent is evaporated off in vacuo in a water bath. The residue is triturated with 100 ml of ethanol, whilst cooling in an ice bath. It is isolated by filtration and dried to give 80 g of 4-(4-methylbenzoyl)-pyridine. 42.6 ml of hydrazine hydrate and 18.4 ml of water are then added, followed by 420 ml of ethylene glycol and then by 103.5 g of sodium hydroxide pellets. The mixture is heated under reflux for 2 hours and cooled and 1 liter of water is added. The supernatant oil is extracted with diethyl ether (4×250 ml). The ether phase is washed with water, dried and evaporated. This gives 72 g of 4-(4-methylbenzyl)-pyridine in the form of an oil which crystallises.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(N1C=CN=C1)([N:15]1C=CN=C1)=O.[NH4+].[OH-]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH2:15])=[O:12]
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1cc2ccccc2[nH]1

Procedure:
Add to the 2-indole carboxylic acid (31.0 mmol) dissolved in anhydrous THF (50 ml), carbonyldiimidazole (1.10 equiv, 5.5 g, 34.0 mmol) and stir 1 h. Then add concentrated NH4OH (50 mL) in one portion and stir the reaction at rt. After 16 hours collect the solid that separates by filtration, wash with H2O and dry under vacuum at 40° C. to afford the desired 2-indole carboxamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]#[N:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.CO.[Br:14]Br>[OH-].[Na+]>[Br:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]#[N:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: N#Cc1ccc2[nH]ncc2c1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc2[nH]nc(Br)c2c1
Temperature: 40 °C
Yield: 47 %

Procedure:
A 2-L round bottomed flask was charged with 1H-indazole-5-carbonitrile (17.6 g, 123 mmol), 333 mL methanol (MeOH), 333 mL of 2.0 M aq. NaOH, and a solution of bromine (Br2, 54.7 g, 344 mmol, 2.80 equiv.) in 166 mL of 2.0 M aq. NaOH. The mixture was warmed on an oil bath to 40° C. (external temperature) for 6 h, and then cooled to room temperature in a water bath. The pH of the solution adjusted to ca. 5.5 with 103 mL of 4.0 M aq. HCI. The resulting precipitate was collected by filtration, washed with 200 mL of H2O, and dried. The product was purified by chromatography on 265 g of silica gel using 30–40% EtOAc in hexanes. This afforded the title compound (12.83 g, 47% yield): ES-MS (m/z) 222 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C([Cl:23])=O>ClCCl.CN(C)C=O>[Cl:23][C:13]([C:12]1[CH:16]=[CH:17][C:9]([CH2:8][C:7]2[CH:18]=[CH:19][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1)=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Nitrobenzyl)-benzoic acid (1.03 g, 4 mmol) was dissolved in dichloromethane (40 mL). Oxalyl chloride (0.42 mL, 1.2 eq) was added to the mixture, followed by 1 drop of N,N-dimethylformamide. The mixture was stirred for 1 hour at room temperature and the solvents evaporated to give 4-(4-chlorocarbonylbenzyl)-nitrobenzene (1.10 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>ClCCl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([Cl:20])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(OCc2ccccc2)cc1

Procedure:
To a mixture of 4benzyloxybenzoic acid (2.28 g, 10 mmole) in 20 ml dried dichloromethane were added five drops of DMF and 2.5 ml thionyl chloride. The mixture was refluxed for three hours and evaporated under reduced pressure. Yield: 2.45 g=100%
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].[C:10]([OH:14])(=[O:13])[CH:11]=[CH2:12].C([O-])([O-])=O.[Na+].[Na+]>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][CH2:12][CH2:11][C:10]([OH:14])=[O:13]
Reactant: C=CC(=O)O
Reactant: Sc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CCSc1cccc(Cl)c1Cl
Temperature: 50 °C
Reaction time: 3 h
Yield: 55.2 %

Procedure:
2,3-Dichiorothiophenol (4.94 g, 28 mmol) was added to acrylic acid (2.11 g, 29 mmol) and stirred at 50° C. for 3 hours. The reaction mixture was poured into 10% Na2CO3 and extracted with ether. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ether, washed with brine, dried over MgSO4, and concentrated in vacuo to give the 3-(2,3-dichlorophenylthio)propanoic acid (3.88 g), contaminated with some acrylic acid, as a clear oil which was used without further purification in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>>[CH2:14]([O:13][C:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCCCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1

Procedure:
The first step was to protect 6-aminocaproic acid using benzyl chloroformate to give N-benzyloxycarbonyl-6-aminocaproic acid. This first step was carried out as follows. A solution of 6-aminocaproic acid (32.8 g, 0.25M) in 75 mL of H2O and 42 mL of 6N NaOH was cooled in a salt-ice bath to below 10° C. With stirring, benzyl chloroformate, 46.9 g, 0.275M) and 2N NaOH (138 mL) were alternatively added in small portions over 90 min. After the addition was complete, the solution was brought to room temperature, and stirring was continued for an additional 1 hr. The product was precipitated by lowering the pH to 2 with concentrated HCL, and H2O was added as required to keep the suspension stirring. The white precipitate was filtered, then resuspended and triturated with 1 liter of water. The solid was filtered, washed with water, compressed and then washed with hexane. The solid was then thoroughly dried in a vacuum desiccator to yield 55 grams (83% yield) of N-benzyloxycarbonyl-6-aminocaproic acid.