Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25].Cl>CN(C)C=O.O>[CH2:27]([O:26][C:24](=[O:25])[C:23]([S:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:15])[CH:3]=1)([CH3:30])[CH3:29])[CH3:28]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(S)cc1C
Reactant: CCOC(=O)C(C)(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Sc1cc(C)c(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-mercapto-2-methyl-5-nitrobenzoate (1.17 g) in N,N-dimethyl-formamide (20 ml) were added potassium carbonate (1.42 g), ethyl 2-bromoisobutyrate, and the mixture was stirred at 80° C. for 4 hours. After the reaction was complete, water and 2N hydrochloric acid were added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure. The obtained residue was purified by column chromatography to give a crude product of the title compound (3.56 g).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH2:14][CH3:15])[C:9]([CH3:16])=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>C(O)C>[CH2:14]([O:13][C:10]1[C:9]([CH3:16])=[CH:8][N:7]=[C:6]([CH2:5][OH:4])[C:11]=1[CH3:12])[CH3:15]
Reactant: CCOc1c(C)cnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1c(C)cnc(CO)c1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
32.9 g of (4-ethoxy-3,5-dimethyl-2-pyridyl)methyl acetate were dissolved in 190 ml of ethanol. 95 ml of 3N sodium hydroxide solution were then added dropwise thereto at 0° and the mixture was stirred at room temperature for a further 3 hours. The ethanol was subsequently removed in vacuo and the residual aqueous solution was extracted three times with 200 ml of methylene chloride. The organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue crystallized from petroleum ether and there was obtained 4-ethoxy-3,5-dimethyl-2-pyridylmethanol of melting point 58°-59°.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[OH-].[K+].[C:28](=O)=[O:29]>C(O)CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([O:24][CH2:25][CH2:28][OH:29])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Reactant: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Product: COC12C(CO)C3=C(C(=O)C(C)=C(OCCO)C3=O)N1CC1NC12
Product: NC(=O)O

Procedure:
A solution of mitomycin A (200 mg) in 10 ml of ethylene glycol was stirred at room temperature and under nitrogen for 45 minutes with 480 mg of a 1.6% solution of KOH in ethylene glycol. The reaction mixture was decomposed with excess dry ice while immersing the flask into a water bath at room temperature. The reaction mixture was chromatographed on a column packed with neutral alumina using CHCl3 -MeOH 8:2 as the solvent. This process separates the reaction products which are pink in color from ethylene glycol. The product from the pink fraction was rechromatographed on a silica gel plate with acetone to give two major bands. The product obtained from the second band was rechromatographed on a silica gel plate with a mixture of chloroform and methanol 9:1 to give the desired product. This procedure gave 64 mg (29%) of the desired product, having a melting point of 72°-74° C. (decomposition) and providing the following analysis:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11].[CH:14]([C:16]1[N:17]=[CH:18][NH:19][CH:20]=1)=O.[BH4-].[Na+].C(O)(=O)C>CO.C(Cl)(Cl)Cl>[NH:19]1[CH:20]=[C:16]([CH2:14][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[N:17]=[CH:18]1
Reactant: COC(=O)/C=C/c1ccccc1N
Reactant: O=Cc1c[nH]cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)/C=C/c1ccccc1NCc1c[nH]cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
A solution of methyl (E)-3-(2-aminophenyl)propenoate (531.6 mg) and 4-formylimidazole (317.1 mg) in methanol. (7.0 ml) was stirred at ambient temperature for 18 hours. To the reaction mixture was added sodium borohydride (56.5 mg) under stirring and cooling in an ice-bath. After the mixture was stirred for 2 hours at ambient temperature, sodium borohydride (56.5 mg) was added thereto. The mixture was stirred for 2 hours at ambient temperature. To the reaction mixture was added acetic acid in order to decompose the excess sodium borohydride and the methanol was removed under reduced pressure. To the residue were added diluted hydrochloric acid and ethyl acetate under stirring. The separated aqueous layer was basified with aqueous sodium bicarbonate and extracted twice with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated to give a residue, which was subjected to column chromatography on silica gel with an eluent of a mixture of chloroform and methanol (20:1) to afford pure methyl (E)-3-[2-(4-imidazolylmethylamino)phenyl]propenoate (0.7 g) as an oil.
Reaction SMILES: C([CH:4]([CH2:10][C:11]([O-:13])=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)C.[C:14](O)(=O)[CH3:15].[CH:18]([NH2:20])=[NH:19].C[O-].[Na+]>C(O)C>[OH:13][C:11]1[C:10]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:14]([CH3:15])[N:20]=[CH:18][N:19]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)C(CC(=O)[O-])C(C)=O
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1c(C)ncnc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
216.24 g (1.0 mol) of ethyl acetylsuccinate and 104.11 g (1.0 mol) of formamidine acetate were placed in 500 ml of ethanol, and 360.13 g (2.0 mol) of 30% methanolic sodium methylate solution were added dropwise at 0° C. The mixture was stirred at room temperature for 6 hours and concentrated and the residue was taken up in toluene/water. The aqueous phase was brought to a pH of 3-4 with conc. hydrochloric acid and extracted by stirring a number of times with dichloromethane. Drying and concentration of the combined dichloromethane phases left a resinous solid. This solid was stirred with a mixture of diisopropyl ether and ethyl acetate (2:1) which was then filtered with suction to leave 55.6 g (28.3% of theory) of colorless crystals of m.p. 148° to 149° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([NH2:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[NH2:15][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][CH:10]=1)[NH:5][CH2:4][CH2:3][CH2:2][CH2:8][CH2:7][CH3:6]
Reactant: Nc1cccc(Br)c1
Reactant: CCCCCCN
Product: CCCCCCNc1cccc(N)c1
Yield: 80.1 %

Procedure:
Using the general procedure, 3-bromoaniline (172 mg, 1.0 mmol) was coupled with n-hexylamine (198 μL, 1.5 mmol). Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (2:1) as eluent afforded the desired product as a colorless oil (154 mg, 80% yield). Rf=0.4 (hexane/ethyl acetate=2:1).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([CH2:18][C:19]([O:21]C)=O)=[C:13]([CH3:23])[CH:12]=1.[Si]([O:31][C:32]([O:34][CH3:35])=[CH2:33])(C(C)(C)C)(C)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Br:10][C:11]1[CH:12]=[C:13]([CH3:23])[C:14]([CH2:18][CH:19]([OH:21])[CH2:33][C:32]([O:34][CH3:35])=[O:31])=[C:15]([CH3:17])[CH:16]=1
Reactant: COC(=O)Cc1c(C)cc(Br)cc1C
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CC(O)Cc1c(C)cc(Br)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
DIBAL-H (8.66 mL, 12.99 mmol) was added dropwise to a solution of methyl 2-(4-bromo-2,6-dimethylphenyl)acetate (3.18 g, 12.37 mmol) in CH2Cl2 (60 mL) at −78° C. and stirred for 1 h. 1-(tert-Butyldimethylsilyloxy)-1-methoxyethene (4.05 mL, 18.55 mmol) followed by BF3.OEt2 (1.959 mL, 15.46 mmol) were added. The reaction was stirred at −78° C. for 20 min and then allowed to warm to rt. The reaction was quenched by the addition of 10 mL of 1.0 M HCl, extracted with dichloromethane. The combined organics were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (loading in chloroform, 0% to 50% ethyl acetate in hexane over 15 min using a 40 g silica gel cartridge) to yield 2A (2.5 g, 8.30 mmol, 67.1% yield) as a clear oil. 1H NMR (500 MHz, chloroform-d) δ ppm 7.18 (2H, s), 4.20-4.28 (1H, m), 3.72 (3H, s), 2.91 (1H, dd, J=14.03, 8.25 Hz), 2.72-2.78 (2H, m), 2.53-2.57 (2H, m), 2.55 (2H, dd, J=40.03, 6.19 Hz), 2.33 (6H, s), 1.58 (2H, br. s.).
Reaction SMILES: Cl.[CH2:2]([NH:5][C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:18]C)[C:12]=2[O:16]C)[CH2:7]1)[CH2:3][CH3:4].[BrH:20]>>[BrH:20].[CH2:2]([NH:5][C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:18])[C:12]=2[OH:16])[CH2:7]1)[CH2:3][CH3:4]
Reactant: CCCN[C@H]1CCc2c(ccc(OC)c2OC)C1
Agent: Br
Agent: Cl
Product: CCCN[C@H]1CCc2c(ccc(O)c2O)C1
Temperature: 130 °C

Procedure:
A solution of (S)-N-propyl-5,6-dimethoxy-1,2,3,4-tetrahydro-2-naphthylamine hydrochloride (22 g; 76.9 mmoles), prepared as described in example 2, in 48% hydrobromic acid (220 ml) was heated under reflux (about 130° C.) for 3 hours. The solvent was evaporated to dryness under vacuum and the residue was taken twice with toluene, by evaporating to dryness each time. The resultant crude was collected with ethyl acetate and filtered obtaining (S)-N-propyl-5,6-dihydroxy-1,2,3,4-tetrahydro-2-naphthylamine hydrobromide (23 g). m.p. 219°-222° C. [α]D =-54.59° (1% in methanol)
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:14]=[C:13]([O:28][CH3:29])[N:12]=2)[CH:8]=[CH:7][C:6]=1[Cl:30])C.[OH-].[Na+]>CO.O>[ClH:30].[Cl:30][C:6]1[CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[C:15]([NH:17][CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[N:14]=[C:13]([O:28][CH3:29])[N:12]=2)=[CH:10][C:5]=1[C:4]([OH:31])=[O:3]
Reactant: CCOC(=O)c1cc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CCNc2cc(-c3ccc(Cl)c(C(=O)O)c3)nc(OC)n2)cc1
Product: Cl
Yield: 166.1 %

Procedure:
A solution of 2-chloro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzoic acid ethyl ester [120 mg, 0.27 mmol, Example 35(z)] and sodium hydroxide (2 mL, 4 mmol, 2M) in MeOH (8 mL) and water (2 mL) is stirred for 15 hours at 60° C. The mixture is concentrated, and diluted with water and ethyl acetate. The mixture is acidified with dilute hydrochloric acid to pH, 3, and extracted with ethyl acetate. The combined extracts are dried over magnesium sulfate, filtered, and concentrated. The residue is treated with saturated hydrogen chloride in EtOAc and concentrated to afford 2-chloro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzoic acid hydrochloride salt [101 mg, 82%, Example 23(e)]. LCMS: RT=2.47 minutes, MS: 414 (M+H).
Reaction SMILES: [Mg].[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][Cl:11])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:14][N:15]([CH:17]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C:19]1=[O:24])[CH3:16].[Cl-].[NH4+]>CCOCC>[ClH:11].[C:2]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][C:19]2([OH:24])[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]2[CH:17]([N:15]([CH3:14])[CH3:16])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Reactant: CC(C)(C)c1ccc(CCl)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)Cc1ccc(C(C)(C)C)cc1
Product: Cl
Temperature: 25 °C
Yield: 39.9 %

Procedure:
0.33 g (13.5 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.46 g (13.5 mmole) of 4-tert.butylbenzyl chloride dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (13.0 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 10 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 60 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.18 g of crude base (98.1% of theory) were obtained. 2.16 g of 1-(4-tert.-butylbenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride (46.2% of theory) with a melting point of 227-229° C. were obtained from the crude base according to the procedure described in Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH2:12][OH:13])[CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>ClCCl>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH:12]=[O:13])[CH:4]=1
Reactant: COc1cc(CO)cc2c1OCO2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C=O)cc2c1OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
(7-Methoxybenzo[3,4-d]1,3-dioxolan-5-yl)methan-1-ol prepared in Step 4(7.0 g, 38.42 mmol) was dissolved in dichloromethane(150 ml), pyridiniumchlorochromate(16.6 g, 76.84 mmol) was added thereto, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was filtered through cellite, filtered under reduced pressure and the filtrate was concentrated. The residue was subjected to silica gel column chromatography(eluent: ethyl acetate/n-hexane=1/3, v/v) to give the title compound(5.68 g, Yield 82%) as a white solid.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[F:4][C:5]([F:23])([F:22])[C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10](Cl)[CH:9]=[C:8]([C:18]([F:21])([F:20])[F:19])[N:7]=1.[O-:24]CC.[Na+].[Na].C1C=C(Cl)C=C(C(OO)=O)C=1>C(O)C>[F:4][C:5]([F:23])([F:22])[C:6]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([S:3]([CH2:1][CH3:2])=[O:24])[CH:9]=[C:8]([C:18]([F:21])([F:20])[F:19])[N:7]=1
Reactant: CC[O-]
Reactant: CCOC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: CCS
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1c(S(=O)CC)cc(C(F)(F)F)nc1C(F)(F)F
Temperature: 5 °C

Procedure:
Ethanethiol (5.33 ml, 0.072 mol) followed by 14.72 g (0.046 mol) of product of Example 19 was added to a solution of sodium ethoxide prepared from 1.66 g (0.072 mol) of sodium in 100 ml of ethanol and stirred at reflux overnight. The reaction mixture was filtered, poured into 200 ml of water, extracted with ether, washed with 10% NaOH, dried (MgSO4) and concentrated in vacuo to 9.45 g of yellow oil. This oil in 150 ml of CH2Cl2 was cooled to 5° C. and 3.73 g (0.022 mol) of MCPBA was added. Reaction was monitored by TLC. The reaction mixture was filtered, washed with NaHCO3, dried (MgSO4) and concentrated in vacuo to give 5.06 g of yellow oil. This was purified by HPLC using 10% ethyl acetate/cyclohexane as eluting solvent to give 3.81 g (65.6%) of an oil. A portion (1.71 g) of this oil was kugelhohr distilled at 22 Pa, pot temperature 95° C., affording 1.45 g of product as a clear oil, nD25 1.4575.
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C:9]1[CH:17]=[CH:16][C:12]2[N:13]=[CH:14][NH:15][C:11]=2[CH:10]=1.[F:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:20]=1[CH:21]=O.[Si](C#N)(C)(C)C.[N:34]1([C:39](N2C=CN=C2)=[O:40])C=CN=[CH:35]1>>[NH:13]1[C:12]2[CH:16]=[CH:17][C:9]([N:8]3[CH:21]([C:20]4[C:19]([F:18])=[CH:26][CH:25]=[CH:24][C:23]=4[F:27])[CH2:35][NH:34][C:39]3=[O:40])=[CH:10][C:11]=2[N:15]=[CH:14]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=Cc1c(F)cccc1F
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])C(F)(F)F
Product: O=C1NCC(c2c(F)cccc2F)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized as trifluoroacetate salt starting from 5-aminobenzimidazole (0.585 g, 4.4 mmol), 2,6-difluorobenzaldehyde (0.431 mL, 4 mmol), TMSCN (0.5 mL, 4 mmol), PdC (10%, 0.02 g), TEA (1.15 mL, 8.22 mmol), di-(imidazol-1-yl)methanone (0.730, 4.5 mmol) as described in method 2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.Cl.[CH3:25]N(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOC(C)=O>[CH3:25][O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][NH:14][C:15]1[C:20]([NH2:21])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)NC(CNc1ncccc1N)C(=O)O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(CNc1ncccc1N)NC(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 66.6 %

Procedure:
A solution of (2S) 2-tert-Butoxycarbonylamino-3-(3-aminopyridin-2-ylamino)-propionic acid (360 mg, 1.21 mmol) and MeOH (59 mg, 1.82 mmol) in anhydrous CH2Cl2 (20 ml) was treated with 4-dimethylaminopyridine (DMAP, 163 mg, 1.33 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (280 mg, 1.45 mmol). The reaction was stirred for 18 h, diluted with EtOAc (150 ml), washed with water (2×), sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4 and concentrated in vacuo. Chromatography (flash, SiO2, 0 to 5% MeOH/CH2Cl2) gave 250 mg (67%) of the title compound as a light tan solid.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25]([Br:28])(=[O:27])[CH3:26]>O1CCOCC1>[BrH:28].[CH2:2]([N:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[C:25](=[O:27])[CH3:26])[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Br
Reactant: O=[N+]([O-])c1ccccc1NC1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Br
Product: CC(=O)N(c1ccccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1

Procedure:
In this reference example, 1.67 g of 1-benzyl-4-(2-nitroanilino)-piperidine hydrochloride is suspended in 30 ml of dioxane. The suspension is mixed with 13 ml of acetyl bromide and refluxed for 4 hours. The resultant reaction mixture is cooled and then the deposited crystals are separated by filtration. The crystals are washed with ether and then dried to obtain 1.96 g of crude crystals. The crude crystals are recrystallized from 25 ml of ethanol to obtain 1.33 g of the desired product.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10]([NH2:13])[CH2:11][NH2:12]>C(O)C>[CH:1](=[N:12][CH2:11][CH2:10][N:13]=[CH:1][C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: NCCN
Reactant: O=Cc1ccccc1O
Solvent: CCO
Product: Oc1ccccc1C=NCCN=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a stirred solution of salicylaldehyde (12.21 g/10.62 mL) in 70° C. ethanol (100 mL) was added ethylenediamine (3.01 g/3.33 mL). A yellow crystalline material immediately formed, and the reaction mixture was allowed to cool to room temperature with stirring. The solution was filtered, and the crystals were washed with cold ethanol. The ethanol layers were combined and reduced to approximately 20 mL and allowed to stand at 0° C. overnight. The resulting crystals were collected by vacuum filtration and washed with water. The collected solids were dried in vacuo to obtain 13.15 g (98%) N,N′-bis(salicylidene)ethylenediamine as yellow platelets with a melting point of 126° C. (literature value (24) 127-128° C.). 1H NMR (DMSO-d6) δ8.57 (s 2H, HC═N), 7.42 (d, 2H aromatic, J=7.3 Hz), 7.31 (t, 2H, aromatic, J=9.0 Hz), 6.88 (t, 4H, aromatic, J=8.3, 16.1 Hz), 3.89 (s, 4H, CH2). 13C NMR (DMSO-d6) δ166.94 (2C, CO), 160.57 (2C, HC+N), 132.38 (2C, aromatic), 131.69 (4C, aromatic), 118.59 (2C, aromatic), 116.51 (2C, aromatic), 58.88 (2C, CH2).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=O)=[CH:5][CH:4]=1)[CH3:2].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1.ClC1C=C(Cl)C=CC=1C1[C:36]([C:37]2[NH:38][CH:39]=[CH:40][N:41]=2)=[CH:35][N:34]=[C:33]([NH:42][CH2:43][CH2:44][NH:45]C2C=CC([N+]([O-])=O)=CN=2)[N:32]=1>>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]2[C:36]([C:37]3[NH:38][CH:39]=[CH:40][N:41]=3)=[CH:35][N:34]=[C:33]([NH:42][CH2:43][CH2:44][NH:45][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=3)[N:32]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)Cl)cc1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: CCc1ccc(-c2nc(NCCNc3ccc(C(F)(F)F)cn3)ncc2-c2ncc[nH]2)cc1

Procedure:
[4-(4-ethylphenyl)-5-imidazol-2-ylpyrimidin-2-yl](2-{[5-(trifluoromethyl)(2-pyridyl)]amino}ethyl)amine was prepared from 4-ethylbenzoyl chloride and 2-chloro-5-(trifluoromethyl)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH:1]1([S:7]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH:11][S:12]([C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)(=[O:14])=[O:13])[CH3:10].C(N(CC)CC)C>CN(C)C=O.C(Cl)(Cl)Cl>[CH:1]1([S:7][N:11]([CH2:9][CH3:10])[S:12]([C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)(=[O:13])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCNS(=O)(=O)c1nc2ccccc2s1
Reactant: ClSC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(SC1CCCCC1)S(=O)(=O)c1nc2ccccc2s1
Temperature: 0 °C

Procedure:
7.8 grams (0.0517 mole) of cyclohexyl chlorosulfide prepared as in Example 1 is added over a 60-minute period to a stirred solution of 12 grams (0.0495 mole) of N-ethyl benzothiazole-2-sulfonamide, 5.5 grams of triethylamine (0.0495 mole) in 200 ml anhydrous dimethylformamide and 200 ml chloroform. The temperature is maintained between about 15° and 20° C. The reaction mixture is poured into 2 liters of ice water. The solvent layer is well washed, dehydrated with anhydrous sodium sulfate and any remaining solvent is removed by vacuum distillation.
Reaction SMILES: [OH:1][CH:2]([C:4]1([CH3:23])[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](Cl)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].C(N(CC)CC)C.[CH2:31]([NH2:34])[CH2:32][CH3:33]>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH:2]([C:4]1([CH3:23])[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([NH:34][CH2:31][CH2:32][CH3:33])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3]
Reactant: CCCN
Reactant: CC(O)C1(C)C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCNC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C)(C(C)O)C2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of benzyl 6-(1-hydroxyethyl)-6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (50 mg) in anhydrous DMF (1 ml) is cooled in an ice-bath and stirred while triethylamine (28 μl) and propylamine (12.4 μl) are added. The resulting solution is allowed to slowly warm to room temperature and kept at room temperature for 1 hr. The solution is diluted with ethyl acetate (10 ml), washed with water (5×2 ml), pH 3 phosphate buffer (2 ml), 5% NaHCO3 (2 ml), and brine, dried with MgSO4, filtered, and evaporated in vacuo to give benzyl 6-(1-hydroxyethyl)-6-methyl-3-propylamino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.