Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][C:5]([C:7]2[C:8]([CH:16]3[CH2:19][CH2:18][CH2:17]3)=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=2)[C:12]#[N:13])=[N:4][N:3]=1.[OH-].[K+].Cl.[CH3:23][CH2:24]O>>[CH:16]1([C:8]2[C:7]([C:5]3[NH:1][C:2]([O:6][CH2:23][CH3:24])=[N:3][N:4]=3)=[CH:14][C:11]([C:12]#[N:13])=[C:10]([CH3:15])[CH:9]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cc(C2CCC2)c(-c2nnc(N)o2)cc1C#N
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCOc1nnc(-c2cc(C#N)c(C)cc2C2CCC2)[nH]1
Temperature: 85 °C

Procedure:
To a solution of 5-(5-amino-1,3,4-oxadiazol-2-yl)-4-cyclobutyl-2-methylbenzonitrile (219.6, 0.5 g, 2.0 mmol) in EtOH (40 ml) was added KOH (1.11 g, 20.0 mmol). The mixture was heated at 85° C. overnight. After cooling to ambient temperature, the mixture was neutralized to pH 7 with 1N HCl at 0° C. and then extracted with EtOAc (×2). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified using column (silica gel) chromatography (hexanes:EtOAc 1:1 to EtOAc). Yield: 0.2 g, white solid, 34%. m/z (ES+) 283 (M+H)+. 1H NMR (400 MHz, Chloroform-d) δ 7.84 (s, 1H), 7.35 (s, 1H), 4.48 (t, 2H), 4.19-4.10 (m, 1H), 2.58 (s, 3H), 2.30-2.19 (m, 2H), 2.11-1.95 (m, 3H), 1.85-1.76 (m, 1H), 1.45 (t, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.[C:11]([C@H:14]1[CH2:18][N:17]([C@H:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:29])[CH2:15]1)(=[O:13])[CH3:12]>C1COCC1>[OH:13][C@@:11]([C@H:14]1[CH2:18][N:17]([C@H:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH3:20])[C:16](=[O:29])[CH2:15]1)([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:12].[OH:13][C@:11]([C@H:14]1[CH2:18][N:17]([C@H:19]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)[CH3:20])[C:16](=[O:29])[CH2:15]1)([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: COc1ccc([C@H](C)N2C[C@H](C(C)=O)CC2=O)cc1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc([C@H](C)N2C[C@H]([C@@](C)(O)c3nccs3)CC2=O)cc1
Product: COc1ccc([C@H](C)N2C[C@H]([C@](C)(O)c3nccs3)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of thiazole (3.13 mL, 44 mmol) in THF (50 mL) at −78° C. was added nBuLi at such a rate that the internal temperature did not exceed −65° C. The reaction mixture was stirred for 15 minutes, and then a solution of (4R)-4-acetyl-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one (10 g, 38.3 mmol) in THF (50 mL) was added via canula at such a rate that the internal temperature did not exceed −65° C. The mixture was stirred for 1 hour, quenched with saturated aqueous ammonium chloride (50 mL), and warmed to room temperature. EtOAc (50 mL) and water (50 mL) were added. The layers were separated, and the aqueous layer was extracted a second time with EtOAc (50 mL). The organic layers were combined, dried over MgSO4, filtered, absorbed on silica, and purified by silica gel chromatography to afford (4R)-4-[(1S)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-1-[(1S)-1-(4-methoxyphenyl)ethyl]pyrrolidin-2-one and (4R)-4-[(1R)-1-hydroxy-1-(1,3-thiazol-2-yl)ethyl]-1-[(1S)-1(4-methoxyphenyl)ethyl]pyrrolidin-2-one.
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH2:15])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[C:16](Cl)(=[O:19])[O:17][CH3:18]>ClCCl>[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: CCC(N)C1CCC2(CC1)OCCO2
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCC(NC(=O)OC)C1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
Into a 50 mL round-bottom flask was placed a solution of 1-1,4-dioxaspiro[4.5]decan-8-ylpropan-1-amine hydrochloride (as prepared in the previous step, 50 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (10 mL) and TEA (42.8 mg, 0.42 mmol, 2.00 equiv). This was followed by the addition of methyl carbonochloridate (23.9 mg, 0.25 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2×20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound as a yellow oil.
Reaction SMILES: [ClH:1].O1CCOCC1.[C:8]([C:10]1([CH2:23][OH:24])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1)#[N:9]>O1CCOCC1>[ClH:1].[OH:24][CH2:23][C:10]1([C:8]#[N:9])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(CO)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N#CC1(CO)CCNCC1
Reaction time: 1 h

Procedure:
4 M hydrochloric acid/dioxane solution (15 ml) was added to a solution of tert-butyl 4-cyano-4-(hydroxymethyl)piperidine-1-carboxylate (886 mg) in dioxane (5 ml), and stirring was performed for one hour at room temperature. The reaction mixture was concentrated under reduced pressure, and 4-(hydroxymethyl)piperidine-4-carbonitrile hydrochloride (663 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8](F)[N:7]=1)=[O:4].[NH3:20].O>CC(O)C>[NH2:20][C:8]1[N:7]=[C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:19])([CH3:18])[CH3:1])[CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1ccc(NC(=O)C(C)(C)C)nc1F
Reactant: N
Solvent: CC(C)O
Solvent: O
Product: CCOC(=O)c1ccc(NC(=O)C(C)(C)C)nc1N
Temperature: 70 °C
Yield: 55 %

Procedure:
To a stirred solution of ethyl 6-[(2,2-dimethylpropanoyl)amino]-2-fluoronicotinate (M. C. Coldwell et al., Bioorg. Med. Chem. Lett., 1995, 39, 5, 1.5 g, 5.59 mmol) in 2-propanol (16 mL) was added 25% aqueous ammonia (4 mL) and the mixture was heated in a sealed tube at 70° C. for 4.5 h. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The separated organic layer was concentrated in vacuo and the residue was chromatographed on a column of silica gel eluting with ethyl acetate/pentane (1:6 to 1:2) to give 810 mg (55%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][CH:9]([C:22]([OH:24])=[O:23])[CH:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[OH-].[K+].Cl[C:28](OC1C=CC=CC=1)=[O:29].Cl>O1CCCC1.O>[O:29]=[C:28]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:10]([C:11]([OH:13])=[O:12])[C@@H:9]([C:22]([OH:24])=[O:23])[N:8]1[CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: O=C(O)C(NCc1ccccc1)C(NCc1ccccc1)C(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 30 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
220 g (0.67 mol) of meso-2,3-bis(benzylamino)succinic acid were placed under a nitrogen atmosphere in a 2 l flask fitted with two dropping funnels, a pH electrode, and a stirrer. The meso-2,3-bis(benzylamino)succinic acid was then suspended, while stirring, in 800 ml of tetrahydrofuran and 400 ml of deionized water and brought into solution by the addition of 108 ml of a 50% potassium hydroxide solution. 200 ml of 2.4 mole q. phenyl chloroformate were added dropwise to the solution within 3.5 hours. The pH was maintained between 9 and 11 during the addition of phenyl chloroformate by the successive addition of a 50% potassium hydroxide solution, and the internal temperature was maintained between 30° C. and 35° C. After the addition was completed, the mixture was stirred at about 30° C. for 2 hours and the pH was adjusted to about 7-8 with concentrated hydrochloric acid. The aqueous solution was then extracted twice with toluene and 500 ml of tetrahydrofuran were added to the combined aqueous phases. The mixture was adjusted to a pH of 1.0 with 37% hydrochloric acid and the aqueous phase was separated off. 400 ml of toluene were added to the tetrahydrofuran phase and the tetrahydrofuran was distilled off under reduced pressure. The remaining water was removed azeotropically with toluene. The residual brownish, oily solution was seeded and the crystalline solid was filtered off and washed twice with toluene. After drying to constant weight under reduced pressure, there were obtained 181.5 g (76% yield) of 2-oxo-1,3-dibenzyl-cis-4,5-imidazolidinedicarboxylic acid, with a melting point of 172.8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C:5]=1[NH:6]2.[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C:32]2[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)(=O)=O)=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]2[C:3]=1[C:4]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][C:5]=1[N:6]2[CH2:30][CH2:31][C:32]1[CH:33]=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=1
Reactant: CN1CCc2c([nH]c3c(Cl)ccc(Cl)c23)C1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCn2c3c(c4c(Cl)ccc(Cl)c42)CCN(C)C3)cn1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,8-dichloro-2,3,4,9-tetrahydro-2-methyl-1H-pyrido[3,4-b]indole (200 mg, 0.78 mmol) in DMF (2 mL), sodium hydride (94 mg, 2.36 mmol) was added. After stirring at 60° C. for 30 min., 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (572 mg, 1.96 mmol) was added to the reaction mixture and stirred at the same temperature for 40 min. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to get the residue that was purified by reverse phase HPLC to obtain the 5,8-dichloro-2,3,4,9-tetrahydro-2-methyl-9-(2-(6-methylpyridin-3-yl)ethyl)-1H-pyrido[3,4-b]indole.
Reaction SMILES: C(O)=O.C([N:8]1[C:12]([NH:13][C:14](=[O:31])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[CH:11][C:10]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=2)=[N:9]1)(C)(C)C>>[CH3:41][O:40][C:36]1[CH:35]=[C:34]([CH2:33][CH2:32][C:10]2[NH:9][N:8]=[C:12]([NH:13][C:14](=[O:31])[C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[CH:11]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: COc1cccc(CCc2cc(NC(=O)c3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)n(C(C)(C)C)n2)c1
Solvent: O=CO
Product: COc1cccc(CCc2cc(NC(=O)c3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)n[nH]2)c1
Yield: 18.9 %

Procedure:
A solution of formic acid (5 mL, 130.36 mmol) and N-(1-tert-butyl-3-(3-methoxyphenethyl)-1H-pyrazol-5-yl)-4-(4-(methylsulfonyl)piperazin-1-yl)benzamide (255 mg, 0.47 mmol) was stirred at 85° C. for 2 h. The reaction mixture was cooled and evaporated to dryness. The crude product was purified by reverse phase prep. HPLC (basic) using a 36-46% gradient of acetonitrile in water, containing 1% 0.880 ammonia. The clean fractions were combined and evaporated to afford the title compound (43.0 mg, 18.82%) as a white solid; 1H NMR (499.9 MHz, DMSOd6+CD3CO2D) δ 2.87 (3H, s), 2.88-2.92 (4H, m), 3.28-3.32 (4H, m), 3.39-3.42 (4H, m), 3.73 (3H, s), 6.30 (1H, s), 6.71-6.74 (1H, m), 6.77 (1H, s0, 6.80 (2H, d), 6.94-6.98 (2H, m), 7.16 (1H, t), 7.85-7.89 (2H, m).
Reaction SMILES: Cl.N1C=CC=CC=1N1CCN(CC[CH2:16][CH2:17][N:18]2[C:27](=[O:28])[C:26]3[CH:29]=[CH:30][CH:31]=[C:24]4[C:25]=3[C:20](=[CH:21][CH:22]=[CH:23]4)[C:19]2=[O:32])CC1.[Br:33][CH2:34][CH2:35][CH2:36][CH2:37]CCBr.BrCCCCBr>>[Br:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:16][CH2:17][N:18]1[C:19](=[O:32])[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:25]=2[C:26](=[CH:29][CH:30]=[CH:31]3)[C:27]1=[O:28]
Reactant: BrCCCCCCBr
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCN(c2ccccn2)CC1
Agent: Cl
Solvent: BrCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr

Procedure:
Following the procedure of part (a) of example 46 but substituting 1,6-dibromohexane for the 1,4-dibromobutane, one obtains 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 95°-96°.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]([CH3:17])([CH3:16])[C:13](Cl)=[O:14])=[CH:9][CH:8]=1.Cl>CC#N.[Cl-].[Na+].O>[Br:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]([CH3:16])([CH3:17])[C:13]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:14])=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(Oc1ccc(Br)cc1)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.3 %

Procedure:
Pyrrolidine (1.54 g, 21.6 mmol) in anhydrous MeCN (10 mL) was added with stirring to 2-(4-bromophenoxy)-2-methylpropanoyl chloride (2 g, 7.2 mmol) in anhydrous MeCN (10 mL) at 0° C. The mixture was stirred at room temperature for 18 h and acidified with HCl (aq. 1M, 40 mL). Brine was added and the mixture was extracted with CH2Cl2. The combined extracts were washed with NaHCO3 (aq. sat) and brine, dried (Na2SO4), and concentrated to give the sub-title compound (2.12 g, 94%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CN(C=O)C.[C:25]([O:29][C:30](=[O:39])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38])([CH3:28])([CH3:27])[CH3:26]>C(N(CC)CC)C>[C:25]([O:29][C:30](=[O:39])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][C:17](=[O:19])/[CH:16]=[CH:15]/[C:12]1[CH:13]=[CH:14][N:10]([S:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:8])=[O:9])[CH:11]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Reaction time: 0.5 h

Procedure:
A mixture of 4.1 g (E)-3-[1-(5-bromo-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid with 200 ml DMF and 1.8 g HOBtxH2O and 16.0 ml triethylamine is stirred for 0.5 h. Then it is added 6.6 g EDCxHCL and stirred for 0.5 h. After that 2.4 g (2-amino-phenyl)-carbamic acid tert-butyl ester are added and the suspension is stirred at ambient temperature for 24 h. The DMF is evaporated and the residue is extracted with ethyl acetate and water. The organic layer is dried over sodium sulfate and evaporated. The title product is isolated by flash chromatography. By this method 3.7 g of a colorless solid is obtained.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:3].[N+:9]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C(O)=O)([O-:11])=[O:10].C([N:31](CC)CC)C.[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[CH2:22]([O:21][C:20]1[CH:19]=[CH:18][C:14]([NH:31][C:2]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:3])=[CH:13][C:12]=1[N+:9]([O-:11])=[O:10])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCN(CC)CC
Reactant: CCCCOC(=O)Cl
Reactant: O=C(O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CCCCOC(=O)Nc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Temperature: -5 °C

Procedure:
12.4 ml (93.6 mmol) of butyl chloroformate in 80 ml of acetone are added to a solution of 24.3 g of 3-nitro4-benzyloxybenzoic acid (J. Med. Chem. 1967 (10) 462) and 8.7 g (86.4 mmol) of triethylamine in 200 ml of acetone at 0° C. The mixture was stirred at -5° C. for a further hour, 7.0 g (108 mmol) of sodium azide in 100 ml of water are then added dropwise and the mixture is stirred at 0° C. for 2 hours. The mixture is subsequently introduced onto 800 ml of ice-water and the precipitate which has separated out is filtered off with suction and then introduced into 300 ml of boiling n-butanol.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[CH:12][N:11]=2)=O)=[C:4]([O:26][CH3:27])[CH:3]=1.O=P(Cl)(Cl)Cl>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]2[N:11]3[CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=4)[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: COc1ccc(-c2ccc(NNC(=O)c3ccc(Cl)cc3OC)nc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2ccc3nnc(-c4ccc(Cl)cc4OC)n3c2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
A flask was charged with the crude 4-chloro-2-methoxy-N′-(5-(4-methoxyphenyl)pyridin-2-yl)-benzohydrazide and POCl3 (13 mL), and the mixture was stirred at 80-100° C. overnight. The mixture was evaporated and the residue was adjusted to pH=9 with aqueous Na2CO3, then it was extracted with ethyl acetate (50 mL×4). The extract was dried over anhydrous Na2SO4 and the solvent was removed by evaporation. The crude product was purified by chromatography on silica (petroleum ether:ethyl acetate=1:1 to 0:1) to give the title compound as white solids (208 mg, 75.0% yield). 1H NMR (DMSO-d6): 8.17 (m, 1H), 7.92 (dd, J=9.6 and 1.2 Hz, 1H), 7.77 (dd, J=9.6 and 1.8 Hz, 1H), 7.68-7.62 (m, 3H), 7.40 (d, J=2.1 Hz, 1H), 7.25 (dd, J=8.1 and 2.1 Hz, 1H), 7.04 (d, J=6.6 Hz, 2H), 3.88 (s, 3H), 3.80 (s, 3H). MS: m/z 366.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>>[F:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:24]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: NC(=O)c1c(N)ncn1CCCc1ccccc1
Product: NC(=O)c1c(NC(=O)c2cccc(F)c2)ncn1CCCc1ccccc1
Yield: 88 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 22, using 2.00 g (8.19 mmol) of 4-amino-1-(3-phenylpropyl)-5-imidazolecarboxamide prepared in the same manner as in Example 114 and 3-fluorobenzoyl chloride instead of benzoyl chloride to obtain 2.63 g of 4-(3-fluorobenzoylamino)-1-(3-phenylpropyl)-5-imidazolecarboxamide (yield 88%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](O)=[O:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24].ON1C2C=CC=CC=2N=N1.CN(C)CCCCN=C=NCC.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=[O:19])[NH:21][CH2:22][C:23](=[O:24])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)O
Reactant: NCC(=O)c1ccccc1
Agent: CCN=C=NCCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)NCC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
3,4-Dihydro-1H-isoquinoline-2,3-dicarboxylic acid-2-tertbutyl ester (2.77 g, 10 mmol) and 2-amino-1phenyl-ethanone (1.71 g, 10 mmol), and HOBT (1-hydroxybenzo-triazole) (2.70 g, 20 mmol) were dissolved in dichloromethane (100 ml). The solution was cooled to 0° C. and then (4-dimethylamino-butyl)-ethyl-carbodiimide (2.29 g, 12 mmol) was added followed by NMM (N-methyl-morpholine) (1.31 g, 13 mmol). The reaction mixture was then warmed to room temperature. After 72 hours the reaction mixture was extracted with water, and the organic phase extracted consecutively with saturated NaHCO3, 2N citric acid and NaHCO3, dried over MgSO4, filtered and concentrated to yield the title product as a yellow foam. Liquid chromatography (LC) indicated the compound was 86% pure (214 nm), and was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[H-].[Na+].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21]OC1C=C(S([O-])(=O)=O)C=CC=1C>CN(C)C=O>[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][N:4]1[C:3](=[O:8])[C:2]([CH3:9])([CH3:1])[NH:6][C:5]1=[O:7]
Reactant: COCCOCCOCCOc1cc(S(=O)(=O)[O-])ccc1C
Reactant: CC1(C)NC(=O)NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOCCN1C(=O)NC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
5,5-Dimethylhydantoin (1.32 g, 10.3 mmol) was dissolved in N,N-dimethylformamide (100 ml). To the stirring room temperature solution was added sodium hydride (60%, 412 mg, 10.2 mmol). After an additional one hour of stirring at room temperature, [2-[2-(2-methoxyethoxy)ethoxy]ethoxy]p-toluenesulfonate (3.28 g, 10.3 mmol) was slowly added to the basic solution over a 20 minute period. The reaction mixture was stirred for an additional 18 hours at room temperature. The reaction mixture was concentrated under high vacuum. The solid material was dissolved in dichloromethane and the solution was filtered to remove any solid material. The organic layer was concentrated in vacuo, and crude material was purified by preparative-high pressure liquid chromatography to give 900 mg (31%) of the title compound. 1H NMR (D2O, 400 MHz) δ 3.56-3.51 (m, 12H), 3.37 (s, 3H), 1.42 (s, 6H); LRMS (ESI/APCI) m/z 275 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH2:11]([C:13]1[S:17][C:16]2[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:15]=2[C:14]=1[S:23](Cl)(=[O:25])=[O:24])[CH3:12]>C1COCC1>[Br:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:23]([C:14]1[C:15]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:16]=2[S:17][C:13]=1[CH2:11][CH3:12])(=[O:24])=[O:25]
Reactant: CCc1sc2ccc(C)cc2c1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1sc2ccc(C)cc2c1S(=O)(=O)Nc1onc(C)c1Br

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-ethyl-5-methylbenzo[b]thiophene-3-sulfonamide was prepared in the same manner as described in Example 41. Reaction of 4-bromo-3-methyl-5-aminoisoxazole (1.0 mmole, 0.18 g), NaH (2.5 mmoles, 0.10 g), and 2-ethyl-5-methylbenzo[b]thiophene-3-sulfonylchloride (1.3 mmoles, 0.36 g) in THF (6 ml) yielded, after recrystallization from chloroform and hexanes, 0.25 g (60%) of a light brown crystalline solid, m.p. 176-178° C.
Reaction SMILES: S1[CH2:5][CH2:4][N:3]([C:6]([O:8][C@@H:9]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[O:7])[CH2:2]1.ClC1C=CC=C(C(OO)=O)C=1.[S:38]([O-:41])([O-])=[O:39].[Na+].[Na+]>C(Cl)Cl>[O:39]=[S:38]1(=[O:41])[CH2:5][CH2:4][N:3]([C:6]([O:8][C@@H:9]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11])=[O:7])[CH2:2]1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCSC1
Reactant: O=S([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCS(=O)(=O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of benzyl 2(S)-(3-thiazolidine-carbonyloxy)-3-phenylpropionate (371 mg) in methylene chloride (7 ml) was added 80% m-chloroperbenzoic acid (431 mg). The mixture was stirred at ambient temperature for 2 days. Then 10% sodium sulfite aqueous solution and methylene chloride were added thereto, and the mixture was separated. The aqueous layer was extracted with methylene chloride. The combined extract was washed with saturated sodium hydrogen carbonate solution 2 times and saturated sodium chloride solution successively, dried over magnesium sulfate, and concentrated under reduced pressure to give benzyl 2(S)-(1,1-dioxothiazolidine-3-carbonyloxy)-3-phenylpropionate (330 mg).