Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([NH:15][CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[CH:4][C:5]([NH:8]C(=O)C(C)(C)C)=[N:6][CH:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[CH3:22][N:19]1[CH2:18][CH2:17][CH:16]([NH:15][C:3]2[C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:7][N:6]=[C:5]([NH2:8])[CH:4]=2)[CH2:21][CH2:20]1
Reactant: CN1CCC(Nc2cc(NC(=O)C(C)(C)C)ncc2Cl)CC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CN1CCC(Nc2cc(N)ncc2-c2ccccc2)CC1
Temperature: 130 °C
Yield: 238.6 %

Procedure:
A solution of the N-(5-chloro-4-(1-methylpiperidin-4-ylamino)pyridin-2-yl)pivalamide (Synthesis 153-C) (0.187 g, 0.57 mmol), phenyl boronic acid (0.140 g, 1.15 mmol), sodium carbonate (0.153 g, 1.43 mmol) and Bedford catalyst (0.003 g, 0.005 mmol) in a mixture of actonitrile/water (4/1, 3.1 mL) was heated under microwave irradiation for 30 min at 130° C. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (1 g) eluting with methanol/dichloromethane (1/1), then 2M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. The crude mixture was used without further purification. A solution of the protected amine in 6 M HCl (3 mL) was heated under microwave irradiation at 105° C. for 50 min. The solution was basified with Na2CO3 and extracted with ethyl acetate (3×10 mL). The crude mixture was purified by flash chromatography on silica, eluting with methanol and dichloromethane (1/9), to give the title compound as a colourless solid (0.384 g, 73%).
Reaction SMILES: C([SiH](CC)CC)C.[CH3:8][O:9][C:10](=[O:33])[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)O)=[CH:13][CH:12]=1.O>C(#N)C>[CH3:8][O:9][C:10](=[O:33])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(Cc2ccccc2OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
In a nitrogen stream, triethylsilane (2.27 mL, 13.5 mmol) and a boron trifluoride-diethyl ether complex (1.52 mL, 11.88 mmol) were added to a solution of 4-[(2-benzyloxyphenyl)-hydroxymethyl]benzoic acid methyl ester (4.15 g, 11.9 mmol) in acetonitrile (22.7 mL) at −40° C. and the mixture solution was stirred at the same temperature for 1.5 hours and further at 0° C. for 30 minutes. Water was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (2.39 g, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7]
Reactant: NCc1ccccc1
Reactant: Nc1cc(C(=O)O)ccn1
Product: Nc1cc(C(=O)NCc2ccccc2)ccn1

Procedure:
The title compound was prepared from 2-aminoisonicotinic acid (L. W. Deady, O. L. Korytsky, J. E. Rowe, Aust. J. Chem., 1982, 35, 2025) and benzylamine:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].[CH3:21][C:22]1[S:26][C:25]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:24][C:23]=1[C:33]([F:36])([F:35])[F:34]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][CH:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:26][C:22]([CH3:21])=[C:23]([C:33]([F:36])([F:34])[F:35])[N:24]=3)[CH2:28][CH2:29]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: Cc1sc(N2CCNCC2)nc1C(F)(F)F
Reactant: CC(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Product: Cc1sc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC(C)C(F)(F)F)CC2)nc1C(F)(F)F
Yield: 61 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A2) and 1-(5-methyl-4-trifluoromethyl-thiazol-2-yl)-piperazine (Example 54(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as a white crystalline solid (yield 61%). MS (m/e): 546.3 (M+H+, 100%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]Cl)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH:17](=O)[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[OH:20]>>[O:20]1[C:2]([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]4[O:20][C:19]5[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=5[CH:17]=4)=[CH:11][CH:10]=3)=[CH:5][CH:4]=2)=[CH:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]1=2
Reactant: O=Cc1ccccc1O
Reactant: ClCc1ccc(-c2ccc(CCl)cc2)cc1
Product: c1ccc2oc(-c3ccc(-c4ccc(-c5cc6ccccc6o5)cc4)cc3)cc2c1

Procedure:
In accordance with the statements of German Offenlegungsschrift No. 2,238,734, 4,4'-bis-(chloromethyl)biphenyl (42) is reacted with salicylaldehyde to give 4,4'-bis-(benzo[b]furan-2-yl)-biphenyl and this product is reacted further with oleum to give a mixture of the corresponding tri- and tetra-sulphonic acids. This mixture can also be used for the optical brightening of cotton and polyamide.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:5]1)=[N+:2]=[N-:3].C(O[Na])(C)=O.[Br:23]Br>C(O)(=O)C>[N:1]([C@@H:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:23])[CH:11]=2)[N:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: BrBr
Reactant: COC(=O)N1C[C@H](N=[N+]=[N-])Cc2ccccc21
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: COC(=O)N1C[C@H](N=[N+]=[N-])Cc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of azide 12 (120 mg, 0.52 mmol) in acetic acid (2 ml) were successively added anhydrous AcONa (212 mg, 1.9 mmol) and Br2 (0.3 mL, 0.52 mmol). The mixture was stirred at 25° C. for 1 h and then quenched with water (30 mL). The resulting solution was extracted with CH2Cl2 (2×30 mL). The combined organic layers were dried with anhydrous Na2SO4 and concentrated in vacuo. The residue was purified over column chromatography with petroleum ether/EtOAc (9:1 v/v) to give bromo azide 13 (153 mg) as thick liquid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1.CS[C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16]>>[N+:15]([NH:14][C:13]([NH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[O:7][CH:8]=[CH:9][N:10]=1)=[NH:18])([O-:17])=[O:16]
Reactant: NCCCSc1ncco1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCCSc1ncco1)N[N+](=O)[O-]

Procedure:
Reacting 2-(3-aminopropylthio)oxazole with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[3-(2-oxazolyl)thiopropyl]guanidine. Similarly, reaction of the same starting material with N,S-dimethyl-N'-nitroisothiourea by the procedure of Example 2(iii) gives N-methyl-N'-nitro-N"-[3-(2-oxazolyl)thiopropyl]guanidine.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[N:8]=[CH:9][N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:11]=1)=[O:6].C(N(CC)CC)C.CS(Cl)(=O)=O.O>O1CCCC1>[CH:11]1[N:10]=[CH:9][N:8]2[CH2:2][CH2:3][CH2:4][C:5](=[O:6])[C:7]=12
Reactant: O=C(CCCO)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1CCCn2cncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.2 %

Procedure:
4-Hydroxy-1-(1-trityl-1H-imidazol-4-yl)butan-1-one (25.22 g) was dissolved in tetrahydrofuran (120 ml). Triethylamine (0.021 ml) and methanesulfonyl chloride (0.012 ml) were added and the mixture was stirred at room temperature for 1 h. Water (100 ml) was added under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Acetonitrile (100 ml) was added and the mixture was refluxed under heating for 2 h. The reaction mixture was concentrated to dryness and the residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=20:1→5:1) and washed with diethyl ether to give the title compound (2.10 g) as a pale-brown powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[N:7]([CH3:20])[CH2:8][CH2:9][O:10][C:11]1[C:12](Cl)=[N:13][C:14]([Cl:18])=[N:15][C:16]=1[Cl:17])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:8][CH2:9][O:10][C:11]1[C:16]([Cl:17])=[N:15][C:14]([Cl:18])=[N:13][C:12]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH3:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCOc1c(Cl)nc(Cl)nc1Cl)C(=O)OC(C)(C)C
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(CCOc1c(Cl)nc(Cl)nc1N1CCOCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl-[2-(2,4,6-trichloro-pyrimidin-5-yloxy)-ethyl]-carbamic acid tert-butyl ester (1.50 mmol), morpholine (130 μL, 1.50 mmol) and triethylamine (417 μL, 3.00 mmol) in ethanol (5 mL) was stirred at RT for 1 hour then partitioned between ethyl acetate and water. The aqueous phase was extracted with further ethyl acetate and the combined organic extracts dried (Na2SO4) and concentrated in vacuo affording [2-(2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (quantitative). LCMS: RT=3.89 min, [M-CH2CH2NMeBoc+H]+=250/252/254.
Reaction SMILES: C([BH3-])#[N:2].[Na+].O=[C:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][S:14][C:15]2[NH:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH2:8][CH2:7]1.C([O-])(=O)C.[NH4+]>CO>[NH2:2][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][S:14][C:15]2[NH:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH2:8][CH2:7]1
Reactant: O=C1CCN(CCSc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCN(CCSc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 65 h
Yield: 49.9 %

Procedure:
Step 4): Sodium cyanoborohydride (0.06 g, 9.5 mmol) was added to solution of 2-[2-(4-oxopiperidin-1-yl)ethyl]thio-4,5-diphenylimidazole (0.34 g, 0.91 mmol), powdered 3A molecular sieves (0.268 g) and ammonium acetate (0.73 g, 9.5 mmol) in methanol (10 ml). The mixture was stirred at room temperature under nitrogen atmosphere for 65 hours and then filtered and washed with methanol. The filtrate was concentrated. The residue was dissolved in 10% NaOH solution and ethyl acetate. The organic layer was washed with water and saturated NaCl solution, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (0.8% NH4OH in chloroform/methanol) to give 2-[2-(4-aminopiperidin-1-yl)ethyl]thio-4,5-diphenylimidazole (172 mg, 49.9%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][C:12](=O)[C:11]=2[C:10]([CH3:18])=[C:9]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.CO>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[C:10]([CH3:18])=[C:9]1[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1
Reactant: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(Cl)cc1)CCNC2=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c2c(n(-c3ccccc3Cl)c1-c1ccc(Cl)cc1)CCNC2
Temperature: 25 °C
Yield: 34.8 %

Procedure:
To a solution of 1-(2-chlorophenyl)-2-(4-chlorophenyl)-3-methyl-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (2.84 g, 7.64 mmol, prepared as in Scheme 2 and in a similar manner to Example 22) in tetrahydrofuran (38 mL) was added borane-tetrahydrofuran complex (1 M, 76 mL) at 0° C. over 20 minutes. The mixture was heated at reflux for 3 h. The mixture was cooled to rt, methanol was added, and then the solvent was evaporated off. The residue was purified by silica gel chromatography. Elution first with ethyl acetate, followed by 10% methanol in methylene chloride, gave a colorless gum (950 mg, 34.8%). LC-MS m/z (MH+) 357.1, retention time 2.78 min (method 2).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][N:7]1[C:12](=[O:13])[C:11]2[S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:10]=2[NH:9][C:8]1=[O:21].[Br:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31]Br>>[Br:28][C:29]1[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=1[CH2:31][N:9]1[C:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[S:14][C:11]=2[C:12](=[O:13])[N:7]([OH:6])[C:8]1=[O:21]
Reactant: COc1ccc(COn2c(=O)[nH]c3c(sc4ccccc43)c2=O)c(OC)c1
Reactant: BrCc1ccccc1Br
Product: O=c1c2sc3ccccc3c2n(Cc2ccccc2Br)c(=O)n1O

Procedure:
Following general procedure B2 and D1, 3-(2,4-Dimethoxy-benzyloxy)-1H-benzo[4,5]thieno[3,2-d]pyrimidine-2,4-dione was alkylated with 2-bromobenzyl bromide and subsequently deprotected to provide the title compound as a white solid. 1H NMR (d6-DMSO, 300 MHz) δ 5.58 (s, 2H); 7.16-7.19 (m, 1H); 7.25-7.31 (m, 2H); 7.34-7.43 (m, 1H); 7.48-7.57 (m, 2H); 7.78-7.81 (m, 1H); 8.43 (d, J=8 Hz, 1H); 11.10 (br s, 1H); Ret. time=2.87 min., m/z=403.0.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6](F)[NH:5][C:4]=2[CH:3]=1.Cl.[CH3:15][C:16]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[S:10][C:9]2[S:8](=[O:12])(=[O:11])[N:7]=[C:6]([NH:21][C:16]3([CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]3)[NH:5][C:4]=2[CH:3]=1
Reactant: CC1(N)CCCC1
Reactant: O=S1(=O)N=C(F)Nc2cc(Cl)sc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1(NC2=NS(=O)(=O)c3sc(Cl)cc3N2)CCCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
A mixture of 6-chloro-3-fluoro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (0.60 g, 2.5 mmol), 1-methylcyclopentylamine hydrochloride (0.5 g, 3.7 mmol) and triethylamine (1.03 ml, 7.4 mmol) in ethanol (2.5 ml) was stirred for 16 h at 50° C. and then for 24 h at 65° C. in a sealed flask. The cooled mixture was concentrated in vacuo and the residue was triturated with water followed by adjustment to pH <2 with 1M hydrochloric acid. The crude product was isolated by filtration, dried and recrystallised from acetic acid to give 208 mg (26%) of the title compound; mp >300° C. (dec.); 1H-NMR (DMSO-d6): δ1.43 (s, 1H), 1,53-1.72 (m, 6H), 1.92-2.10 (m, 2H), 6.91 (br s, 1H), 7.10 (s, 1H), 10.52 (br s, 1H).
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Cl[CH2:14][C:15]([F:18])([F:17])[F:16]>CN(C)C=O>[F:16][C:15]([F:18])([F:17])[CH2:14][S:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccccc1S
Reactant: FC(F)(F)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1SCC(F)(F)F
Temperature: 100 °C
Yield: 23.1 %

Procedure:
A two-necked flask was charged under nitrogen with 45 ml of dimethylformamide and 16 g of a 50% strength by weight aqueous sodium hydroxide solution. After addition of 15 g of 2-mercaptobenzoic acid, 18 g of chlorotrifluoroethane were passed in at 0° C. and the reaction mixture was then transferred into a stirred autoclave. The mixture was heated at 100° C. for 12 hours (maximum pressure: 2.5 bar), allowed to cool and the crude product was then precipitated by addition of concentrated hydrochloric acid. The dried crude product was recrystallized from hot formic acid, giving 5.3 g of 2-(2',2',2'-trifluoroethylthio)benzoic acid having a melting point of 226°-227° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:6]=1
Reactant: Ic1cn[nH]c1
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCn1cc(I)cn1
Reaction time: 0.17 h

Procedure:
A solution of 4-iodopyrazole (11.25 g, 6.44 mmol) in DMF (20 mL) at room temperature was treated with 60% NaH (271 mg, 6.77 mmol), stirred for 10 minutes, treated with 1-bromooctane (1.22 mL, 7.08 mmol), stirred for 30 minutes, poured into water, and extracted three times with ether/hexanes. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(+)) m/e 307 (M+H)+.
Reaction SMILES: [CH3:1][C:2](=[CH2:34])[C@@H:3]([N:20]1[C:26](=[O:27])[C@H:25]2[C@@H:21]1[O:22][C:23]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[N:24]2)[C:4]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:35]Cl.N1C=CC=CC=1>C(OCC)(=O)C.C(Cl)(Cl)(Cl)Cl>[C:28]1([C:23]2[O:22][C@H:21]3[C@H:25]([C:26](=[O:27])[N:20]3[C@H:3]([C:2]([CH2:1][Cl:35])=[CH2:34])[C:4]([O:6][CH:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:5])[N:24]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCl
Reactant: C=C(C)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=C(CCl)[C@H](C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H]2N=C(c3ccccc3)O[C@@H]21

Procedure:
A solution of 100 mg of Compound (1a) in ethyl acetate is reacted with a solution (2.0 molar equivalents) of chlorine in carbon tetrachloride at room temperature. The obtained product is treated with 1.2 equivalents of pyridine for 45 minutes under ice cooling, instead of chromatography of silica gel, to yield 110 mg of Compound (7).
Reaction SMILES: [OH:1][C:2]([CH2:28][CH2:29][CH3:30])([CH2:25][CH2:26][CH3:27])[CH2:3][NH:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH:8]=[CH:9][CH:10]=1.O.NN>C(O)C>[NH2:14][CH2:13][CH2:12][CH2:11][C:7]1[CH:6]=[C:5]([NH:4][CH2:3][C:2]([OH:1])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH:10]=[CH:9][CH:8]=1
Reactant: CCCC(O)(CCC)CNc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCCC(O)(CCC)CNc1cccc(CCCN)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(3-(3-(2-hydroxy-2-propylpentylamino)phenyl)propyl)isoindoline-1,3-dione (0.22 g, 0.71 mmol) and hydrazine hydrate (0.1 ml, 1.6 mmol) in ethanol was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure. Purification by column chromatography (5% to 10% MeOH—CH2Cl2 gradient) gave 4-((3-(3-aminopropyl)phenylamino)methyl)heptan-4-ol as a light yellow semisolid. Yield (0.06 g, 18%); 1H NMR (400 MHz, DMSO-d6) δ 6.93 (t, J=7.6 Hz, 1H), 6.44-6.41 (m, 2H), 6.35 (d, J=7.6 Hz, 1H), 4.92 (t, J=5.2 Hz, 1H), 4.19 (bs, 1H), 2.87 (d, J=5.2 Hz, 2H), 2.54-2.50 (m, 2H), 2.44 (t, J=7.6 Hz, 2H), 1.55-1.62 (quintet, J=7.2 Hz, 2H), 1.42-1.33 (m, 4H), 1.32-1.27 (m, 4H), 0.85 (t, J=7.2 Hz, 6H); RP-HPLC (Method 3) tR=4.44 min, 97.48% (AUC); ESI MS m/z 279.31 [M+H]+.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]1C=CC=CC=1.S(Cl)(Cl)=O.CO>C(Cl)Cl>[C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([O:18][CH3:20])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccccc1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
In a reaction flask with mechanical stirring and reflux condenser, 263 g of 2-(3-benzoylphenyl)propionic acid (VI with R1 =CH3 and R2 =H) were suspended in 1L of dry benzene. Then 154 g of thionyl chloride were added and the mixture was heated under reflux for 5 hours. After cooling at room temperature, benzene and unreacted thionyl chloride were eliminated under vacuum. To the resulting residue (corresponding to the acid chloride) 400 mL of absolute methanol were added with care. The resulting solution was heated under reflux for 5 hours. After cooling at room temperature, the solvent was eliminated under vacuum and the residue was dissolved in 250 mL methylene chloride. The solution was washed and neutralized by treating it three times with 200 mL of a 5% solution of sodium hydrogencarbonate and then with water. After being dried, the solvent was evaporated under vacuum and 256 g of an oily residue was obtained (92% yield), used without further purification in the reaction of the following example. After 24 hours of drying, a white solid of m.p. 50-2° C. was obtained. After recrystalization from cyclohexane, experimental m.p. was 51-2° C. and the solid was identified as the title compound. By following analogous procedures, compounds Vc of Table 1 were prepared.
Reaction SMILES: [N+:1]([CH:4]([CH:10]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])([O-])=O.Cl.[Cl:25]CCl>C(O)C.[Pd]>[ClH:25].[NH2:1][CH:4]([CH:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: ClCCl
Reactant: CCOC(=O)C(C1c2ccccc2Oc2ccccc21)[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)C1c2ccccc2Oc2ccccc21

Procedure:
Ethyl α-nitro-9H-xanthene-9-acetate (7.5 g, 24 mmol) is dissolved in 150 mL of ethanol and 2 mL of concentrated hydrochloric acid and hydrogenated over 1.0 g of 20% palladium on carbon (53 hours, 51 pounds per square inch (psi)). The filtered solution is stripped or solvent and washed with dichloromethane. This gives 4.83 g of the title compound. An additional crop, 0.61 g is obtained after cooling the dichloromethane wash. The crops are combined and used in the next step.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>O.C1COCC1.C(=O)([O-])[O-].[Cu+2]>[C:11]([NH:7][CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCCC[C@H](N)C(=O)O
Agent: [Cu+2]
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](CCCCNC(=O)c1ccccc1)C(=O)O
Temperature: 5 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
This compound was synthesized by a modified procedure of Kurtz et al.93. Copper (II) carbonate, basic (16.3 g, 74.0 mmoles) was added to a hot (80° C.) solution of L-lysine (15 g, 82.0 mmoles) in distilled water (250 mL). Excess copper carbonate was removed by gravity filtration while the mixture was still warm. The epsilon amino group of L-lysine was benzoylated by the dropwise addition of benzoyl chloride (14 g, 99.0 mmoles) in THF (35 mL) to the above solution after being cooled to 5° C. Sodium bicarbonate was added in small portions (total 14 g, 167.0 mmoles) to maintain the pH of the aqueous solution above 7 (pH was monitored with neutral litmus paper). The cold solution was maintained at 5° C. for 4 h and 2 d at room temperature. A hot (80° C.) solution (1 L) of EDTA (14.6 g, 0.25 moles) was added to the reaction mixture, stirred for 1 h and cooled to 10° C. The precipitate collected by vacuum filtration was washed with water and 30 mL of 95% ethanol. The powder, containing the product was purified by first adding the powder to 1×10-1M hydrochloric acid (300 mL) and filtering off the sediment. The filtrate was slowly neutralized with 0.01N sodium hydroxide and the precipitate collected by gravity filtration. The latter was then air-dried to give 13 g (57 mmoles) (69.5% yield) of a white powder, mp 232°-234° C. (lit.93 mp 230°-233° C.). 1H-NMR (DMSO-d6) δ 1.36-190(6Ha,m); 3.20(2Hb,m); 4.20-4.53(1Hc,m); 7.16(1Hd,m, rotamer of amide -NH); 7.43(2He,e', app. dd, Jef =8Hz, Jee,=2Hz); 7.63(1Hf, app. dd, Jfe =8Hz, Jfg =2Hz); 8.03(2Hf,f', app dd, Jge =8Hz, Jgf =2Hz); 9.50(1Hh,s)ppm. IR (Nujol) 3330, 3030, 1687, 1270, 735, 695 cm-1.