Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([N:7]2[NH:11][CH:10]=[C:9]([C:12]3[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=3)[S:8]2)[CH2:6]CC[CH2:3][CH2:2]1.CNCC[OH:25].N1CCCCC1>>[OH:25][CH2:3][CH2:2][N:1]([CH3:6])[N:7]1[NH:11][CH:10]=[C:9]([C:12]2[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=2)[S:8]1
Reactant: Cn1c([N+](=O)[O-])cnc1C1=CNN(N2CCCCC2)S1
Reactant: CNCCO
Solvent: C1CCNCC1
Product: CN(CCO)N1NC=C(c2ncc([N+](=O)[O-])n2C)S1

Procedure:
The preparation of the above compound is carried out essentially as described for the 2-piperidino derivative (Example 28), an equivalent of N-methylethanolamine replacing the piperidine. The pure compound melts at 158°-160° C. after recrystallization from methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([OH:7])=O.[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])=[CH:9][N:10]=1)[C:5]([NH:28][CH2:27][CH2:26][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:7]
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Product: O=C(NCCN1CCOCC1)c1cc(Br)ncc1Nc1ccc(I)cc1F

Procedure:
2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-N-(2-morpholin-4-yl-ethyl)-isonicotinamide was synthesized according to the General Method 3 starting with 145 mg (0.33 mmol) of 2-bromo-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid and 108 mg (0.83 mmol) of 2-morpholin-4-yl-ethylamine. Yield: 95 mg, 52%. LC/MS: [7.08 min, 550, 552 (M+1)]
Reaction SMILES: [CH2:1]([N:5]1[C:12](=[O:13])[CH2:11][C:9](=[O:10])[N:8]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S([N:29]=[N+:30]=[N-])(=O)=O)=CC=1.C(N(CC)CC)C.ClCCl>C(#N)C>[CH2:1]([N:5]1[C:12](=[O:13])[C:11](=[N+:29]=[N-:30])[C:9](=[O:10])[N:8]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CCCCN1C(=O)CC(=O)N(C2CCCCC2)C1=O
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCN1C(=O)C(=[N+]=[N-])C(=O)N(C2CCCCC2)C1=O
Temperature: 2 °C
Reaction time: 1 h

Procedure:
80 mL of reagent grade acetonitrile and 6.65 gm (0.025 mole) of 1-(1-butyl)-3-cyclohexylbarbituric acid were added to a dry 250 mL 3-neck round bottom flask equipped with a thermometer, pressure equalizing dropping funnel capped by a drying tube, nitrogen inlet and magnetic stirrer. The stirred solution was cooled to 2° C. in an ice bath. Then a solution of 5.75 gm (0.029 mole) of p-toluenesulfonyl azide in 20 mL of acetonitrile was added to the reaction flask. A solution of 3.20 gm (0.0317 mole) of triethylamine in 20 mL of reagent grade dichloromethane was placed in the dropping funnel and slowly added to the reaction flask, while keeping the temperature below 3° C. The flask temperature was kept below 3° C. for 1 hour. The stirred reaction flask was allowed to warm to room temperature (20° C.) and kept at room temperature for 12 hours.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:4]=2[N:5]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:6](=[O:18])[CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[N:8]=1.[O:33]=[C:34]1[N:51](C(OC(C)(C)C)=O)[C:37]2=[N:38][CH:39]=[C:40](B3OC(C)(C)C(C)(C)O3)[CH:41]=[C:36]2[N:35]1[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].[Li+]>O1CCOCC1.O>[Cl:32][C:30]1[CH:29]=[CH:28][C:4]2[N:5]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:6](=[O:18])[CH:7]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[N:8]=[C:2]([C:40]3[CH:41]=[C:36]4[N:35]([C:59]([O:61][C:62]([CH3:63])([CH3:64])[CH3:65])=[O:60])[C:34](=[O:33])[NH:51][C:37]4=[N:38][CH:39]=3)[C:3]=2[CH:31]=1
Reactant: COc1ccc(CN2C(=O)C(CCc3ccccc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Reactant: CC(C)(C)OC(=O)n1c(=O)n(C(=O)OC(C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN2C(=O)C(CCc3ccccc3Cl)N=C(c3cnc4[nH]c(=O)n(C(=O)OC(C)(C)C)c4c3)c3cc(Cl)ccc32)cc1
Temperature: 80 °C
Yield: 26.1 %

Procedure:
5,7-Dichloro-3-(2-chlorophenethyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (245 mg) and di-tert-butyl 2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-imidazo[4,5-b]pyridine-1,3(2H)-dicarboxylate (255 mg, 1.1 eq) were dissolved in dioxane/water (2 mL:0.65 mL), and cesium carbonate (327 mg, 2 eq) was added followed by lithium chloride (64 mg, 3 eq). The mixture was degassed with nitrogen and then tetrakis-triphenylphosphine palladium (0) (58 mg, 0.1 eq) was added. The mixture was degassed again, and the reaction was then heated to 80° C. for three hours. The crude mixture was partitioned between water and EtOAc and the organic fraction was then washed with brine, then dried over sodium sulfate and concentrated onto silica gel and purified by chromatography (gradient: 9:1 hexanes:EtOAc to EtOAc) delivering both the product 90 mg, 23% yield). MS (ES+) m/z 707.9 (M+Na) and m/z 807.9 (M+Na+Boc) and doubly Boc-protected material.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6](=[O:8])[CH3:7])[CH2:5][CH2:4]1.[C:9]([S:13][CH3:14])([S:11][CH3:12])=S>CN(C=O)C>[CH:3]1([C:6](=[O:8])[CH:7]=[C:9]([S:13][CH3:14])[S:11][CH3:12])[CH2:5][CH2:4]1
Reactant: CC(=O)C1CC1
Reactant: CSC(=S)SC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSC(=CC(=O)C1CC1)SC

Procedure:
To a mixture of NaH (240 mg, 6.0 mmol, 60% in mineral oil) and 1-cyclopropylethanone (168.2 mg, 2.0 mmol) in DMF (1 mL) was added dimethyl carbonotrithioate (304.3 mg, 2.2 mmol) at rt. The reaction was quenched with water after 3 h and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to yield crude 1-cyclopropyl-3,3-bis(methylthio)prop-2-en-1-one 30 which was purified by flash chromatography on silica with 15% EtOAc in hexanes as eluant. 1H NMR (400 MHz, CDCl3) δ 6.14 (s, 1H), 2.41 (s, 3H), 2.40 (s, 3H), 1.81 (m, 1H), 1.00 (m, 2H), 0.77 (m, 2H). MS m/z 189.0 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]([CH3:22])([CH3:21])[C:17](OC)=[O:18])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]([CH3:22])([CH3:21])[CH2:17][OH:18])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: COC(=O)C(C)(C)Oc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)Oc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-((4-(2-fluoro-4-nitrophenoxy)quinolin-7-yl)oxy)-2-methylpropanoate (3 g, 7.5 mmol) in THF (25 mL) was added LiAlH4 (0.34 g, 9 mmol) in portions at 0° C. The reaction was stirred at 0° C. for 4 hours and then quenched with H2O (30 mL). The organic solvent was removed in vacuo and the residue was diluted with DCM (100 mL). The organic phase was separated, dried over Na2SO4 and concentrated in vacuo. The title compound was obtained as a yellow solid (0.95 g, 34.1%).
Reaction SMILES: OC1C=C2C(=CC=1)C=C(C(OC(CCCCCC)C(F)(F)F)=O)C=C2.FC1C=C(O)C=CC=1C(OC(CCCCCC)C(F)(F)F)=O.C(O[C:57]1[CH:62]=C[C:60]([C:63]2C=C[C:66]([C:69]([O:71][C:72]3[CH:77]=[CH:76][C:75]([C:78]([O:80]C(CCCCCC)C(F)(F)F)=[O:79])=[C:74](F)[CH:73]=3)=[O:70])=[CH:65][CH:64]=2)=[CH:59][CH:58]=1)CCCCCCC>O1CCCC1>[CH2:66]([C:69]([O:71][C:72]1[CH:77]=[CH:76][C:75]([C:78]([OH:80])=[O:79])=[CH:74][CH:73]=1)=[O:70])[CH2:65][CH2:64][CH2:63][CH2:60][CH2:59][CH2:58][CH2:57][CH3:62]
Reactant: CCCCCCCCOc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)OC(CCCCCC)C(F)(F)F)c(F)c3)cc2)cc1
Agent: CCCCCCC(OC(=O)c1ccc(O)cc1F)C(F)(F)F
Agent: CCCCCCC(OC(=O)c1ccc2cc(O)ccc2c1)C(F)(F)F
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1

Procedure:
To a solution of the 1,1,1-trifluoro-2-octyl 6-hydroxynaphthalene-2-carboxylate (0.6 g) obtained in (1) above and the 4-n-nonylcarbonyloxybenzoic acid (0.45 g) obtained in (2) above in tetrahydrofuran (40 ml) were added dicyclohexylcarbodiimide (0.45 g) and dimethylaminopyridine (0.05 g). The solution was stirred overnight and distilled to remove the solvent. The residue was dissolved in dichloromethane (40 ml) and washed with dilute aqueous hydrochloric acid solution and water, in this order. The solution was dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was purified by silica-gel column chromatography (developer: hexane/ethyl acetate=20/1) to obtain the titled compound (0.05 g) having specific rotation, [α]D20 =+42.86°.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1([CH3:13])[NH:12][CH2:11][CH2:10][O:9]1.C(N(CC)CC)C.[C:21](Cl)(=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>O>[CH3:7][C:8]1([CH3:13])[N:12]([C:21](=[O:28])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:11][CH2:10][O:9]1
Reactant: CC1(C)NCCO1
Reactant: CCCCCCC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCC(=O)N1CCOC1(C)C

Procedure:
Sixteen and one-half (16.5 ml.) milliliters of a benzene solution containing 4.6 g. of 2,2-dimethyl oxazolidine was added to 50 ml. of benzene and 4.1 g. of triethylamine. To this mixture 6 g. of n-heptanoyl chloride was added dropwise with stirring and cooling in an ice bath. The mixture was poured into water and the benzene layer extracted, dried over magnesium sulfate and the benzene removed under vacuum. Yield was 7.5 g. of an oil, nD30 =1.4598.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:17])[CH2:9][C:10](=[O:16])[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)(C)(C)C.[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22]>C(Cl)Cl>[F:19][C:20]([F:25])([F:24])[C:21]([OH:23])=[O:22].[NH2:7][C@H:8]([CH3:17])[CH2:9][C:10]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:16]
Reactant: C[C@H](CC(=O)N1CCCC1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)CC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ((R)-1-methyl-3-oxo-3-pyrrolidin-1-yl-propyl)-carbamic acid tert-butyl ester (crude from step 1, 189 mg, 0.74 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (2.0 mL, 27.0 mmol). The reaction mixture was stirred at room temperature for 2 h then concentrated to give (R)-3-amino-1-pyrrolidin-1-yl-butan-1-one trifluoroacetate as a pale yellow oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:19].[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH2:25])[CH3:21].C(N(CC)CC)C.CS(ON1C2C=CC=CC=2N=N1)(=O)=O>C(Cl)(Cl)Cl.C(OCC)(=O)C.O>[ClH:19].[CH2:20]([O:22][C:23](=[O:26])[CH2:24][NH:25][C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:21]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CN
Agent: CS(=O)(=O)On1nnc2ccccc21
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)CNC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reaction time: 20 h
Yield: 58.8 %

Procedure:
N-Benzyloxycarbonyl-L-valine (1.26 g), glycine ethyl ester hydrochloride (0.70 g) and triethylamine (1.40 ml) are dissolved in anhydrous chloroform (10 ml), and thereto is added 1-methanesulfonyloxy-1,2,3-benzotriazole (1.05 g) with stirring under ice-cooling. After stirrig at room temperature for 20 hours, to the reaction mixture are added water and ethyl acetate. The ethyl acetate layer is separated, washed and dried. After drying, the solvent is distilled off to give N-(N-benzyloxycarbonyl-L-valyl)glycine ethyl ester hydrochloride (1.1 g), melting point: 162°-165° C.
Reaction SMILES: [Cl:1][C:2]([Cl:38])([Cl:37])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:36])[C@@H:14]([NH:21][C:22](=[O:35])[C@@H:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:24]([CH3:26])[CH3:25])[CH2:15]N2C=CC=N2)[NH:8]1)=[O:6].ClC(Cl)(Cl)[CH2:41][O:42]C([C@@H]1CCCN(C(=O)[C@@H](NC(OC(C)(C)C)=O)COC)N1)=O>>[Cl:37][C:2]([Cl:38])([Cl:1])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:36])[C@@H:14]([NH:21][C:22](=[O:35])[C@@H:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:24]([CH3:25])[CH3:26])[CH2:15][O:42][CH3:41])[NH:8]1)=[O:6]
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cn1cccn1)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Product: COC[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Yield: 77 %

Procedure:
Compound 117b was prepared in the same manner as (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-pyrazol-1-yl-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester using (S)-1-((S)-2-tert-butoxycarbonylamino-3-methoxy-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (750 mg, 1.62 mmol) instead of (S)-1-((S)-2-tert-butoxycarbonylamino-3-pyrazol-1-yl-propionyl)-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester to afford the title compound as a viscous oil (700 mg, 77%) and as a 1:1 mixture of two diastereoisomers. LCMS (m/z) 563.3 [M+H], Tr=2.81 min.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])([O:3][CH3:4])=[O:2].Br[CH2:13][CH2:14][CH:15]1[O:20][CH2:19][CH2:18][CH2:17][O:16]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:16]1[CH2:17][CH2:18][CH2:19][O:20][CH:15]1[CH2:14][CH2:13][C:5]1([C:1]([O:3][CH3:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11]
Reactant: BrCCC1OCCCO1
Reactant: COC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(CCC2OCCCO2)CCCCC1=O

Procedure:
A solution of 2-carbomethoxycyclohexanone in DMF is reacted with 2-(2-bromoethyl)-1,3-dioxane and potassium carbonate by the method of Example 102 to generate the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10](C3C=CC=CC=3)=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:19][CH2:20][O:21]S(C1C=CC(C)=CC=1)(=O)=O.[CH2:32]([O:34][C:35](=[O:56])[C:36]([O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([CH3:48])[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][CH:39]=1)[CH3:33]>C(O)C>[CH2:32]([O:34][C:35](=[O:56])[C:36]([CH3:48])([O:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[CH2:37][C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]([O:21][CH2:20][CH2:19][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:40][CH:39]=1)[CH3:33]
Reactant: CCOC(=O)C(C)(Cc1cccc2ccccc12)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccccc12)Oc1ccccc1
Temperature: 55 °C
Yield: 2 %

Procedure:
Toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.132 mmol) (see Ex. 1, Part I) was added to a one dram, screw-cap vial and diluted with ethanol (0.5 mL). To this solution are added 2-phenoxy-3-(naphthalen-1-yl)-2-methylpropionic acid ethyl ester (0.5 mL of a 0.264 M solution in ethanol, 0.132 mmol) and polystyrene bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (100–125 mg, 2.6 mmol/g) and the vial was tightly closed. The reaction vessel was heated in a block heater for 24–48 h at 55° C., or until TLC or MS analysis indicates the disappearance of starting materials. The suspension was filtered while warm and the residue washed with ethanol (1 mL). The solution was treated with aqueous NaOH (5N solution, 100 μl) and the vial resealed tightly. The solution was heated in a block heater at 55° C. for 3–16 h, or until MS analysis indicates the completion of the hydrolysis. The solvents are removed with a stream of nitrogen or under reduced pressure and the residue dissolved in 1 mL water. The solution was acidified with aqueous HCl (5N solution, 150 μl), often causing precipitation of product. The suspension was diluted with dichloromethane (3 mL) and the resultant biphasic solution was filtered through a Chrom-Elut column to remove water. The filtrate was concentrated in vacuo and the resultant residue was purified by mass-directed HPLC to produce a white solid (2%). MS [EI+] 584 (M+H)+, [EI−] 582 (M−H)+
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[CH:9][NH:10][C:6]=2[CH:5]=[C:4]([NH:11][C:12]2[NH:13][CH2:14][CH2:15][N:16]=2)[CH:3]=1.[Br:17]Br.CO.CCOC(C)=O>CC(O)=O>[Br:17][C:5]1[C:6]2[NH:10][CH:9]=[N:8][C:7]=2[C:2]([Br:1])=[CH:3][C:4]=1[NH:11][C:12]1[NH:13][CH2:14][CH2:15][N:16]=1
Reactant: BrBr
Reactant: Brc1cc(NC2=NCCN2)cc2[nH]cnc12
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Brc1cc(NC2=NCCN2)c(Br)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 136.4 %

Procedure:
To a solution of 7-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (0.6 g, 2.10 mmol) in 10 ml of AcOH was added Br2 (0.057 ml, 1.1 mmol) in a portion. The resulting reaction mixture was stirred for 1 h at 25° C. Concentration of reaction mixture in vacuo yields a brown oil which was subjected to column chromatography (30% NH_sat'd MeOH/EtOAc) to provides 0.28 g (1.5 mmol, 71%) of the desired product. The product obtained was recrystallized from MeOH to afford 0.22 g (56%) of the product as a light brown solid: mp320-321° C.; Anal. Calc. for C10H9N5Br2 requires C, 33.45; H, 2.53; N, 19.51. Found: C, 33.93; H, 4.05; N, 19.01.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH:3]=1.Cl[CH2:19][CH:20]=O>O.C(O)(C)C>[N:1]1[CH:19]=[CH:20][N:7]2[C:2]=1[CH:3]=[C:4]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH:5]=[N:6]2
Reactant: COC(=O)c1cccc(-c2cnnc(N)c2)c1
Reactant: O=CCCl
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1cccc(-c2cnn3ccnc3c2)c1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of methyl 3-(6-aminopyridazin-4-yl)benzoate (0.20 g, 0.87 mmol) and chloroacetaldehyde in water (0.3 mL, 50%) in isopropyl alcohol (3.0 mL) was stirred at 100° C. for 4 h. The solvent was removed and the residue was dissolved in ethyl acetate, washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in methylene chloride (0-30%) to afford the desired product (0.18 g). LCMS (M+H)+: m/z=254.1
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:15])[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:15])[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][CH:3]=1)(=[O:18])[CH3:17]
Reactant: CCn1c(=O)c(=O)[nH]c2ccc(N)cc21
Reactant: CC(=O)OC(C)=O
Product: CCn1c(=O)c(=O)[nH]c2ccc(NC(C)=O)cc21
Temperature: 0 °C
Yield: 86 %

Procedure:
5.5 g (27 mmol) of 7-amino-1-ethyl-2,3(1H,4H)-quinoxalinedione were refluxed in 75 ml of acetic anhydride for 1 h. The mixture was then poured into ice-water and filtered. The filtrate was concentrated under reduced pressure to yield 5.7 g (86%) of the product. Melting point 303°-304° C. (decomposition).
Reaction SMILES: C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[F:23][C:24]([F:37])([F:36])[S:25]([O:28]S(C(F)(F)F)(=O)=O)(=[O:27])=[O:26].[Cl:38][C:39]1[CH:48]=[C:47]2[C:42]([C:43](O)=[C:44]([C:50]3[CH:55]=[C:54]([CH3:56])[CH:53]=[C:52]([CH3:57])[CH:51]=3)[C:45](=[O:49])[NH:46]2)=[CH:41][C:40]=1[N+:59]([O-:61])=[O:60]>>[Cl:38][C:39]1[CH:48]=[C:47]2[C:42]([C:43]([O:28][S:25]([C:24]([F:37])([F:36])[F:23])(=[O:27])=[O:26])=[C:44]([C:50]3[CH:55]=[C:54]([CH3:56])[CH:53]=[C:52]([CH3:57])[CH:51]=3)[C:45](=[O:49])[NH:46]2)=[CH:41][C:40]=1[N+:59]([O-:61])=[O:60]
Reactant: Cc1cc(C)cc(-c2c(O)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Product: Cc1cc(C)cc(-c2c(OS(=O)(=O)C(F)(F)F)c3cc([N+](=O)[O-])c(Cl)cc3[nH]c2=O)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 7-chloro-3-(3,5-dimethylphenyl)-4-hydroxy-6-nitro-1H-quinolin-2-one (1.0 g in 50 mL dry methylene chloride) was added 0.455 ml diazabicycloundecene and the mixture cooled to -78° C. To this was added trifluoromethanesulfonic anhydride (0.51 mL) dropwise via syringe and the mixture stirred at low temperature. After 1 hour, the reaction was quenched by the addition of saturated ammonium chloride (35 mL) and extracted with ethyl acetate (3×75 mL). The organics were washed with water (50 mL) and brine (50 mL) then dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 3:2) gave the title compound (629 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14](OC)=[O:15])=O)(=[O:3])[CH3:2].O.[NH2:30][NH2:31].[OH-].[Na+]>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([C:10]2[CH2:12][CH2:13][C:14](=[O:15])[NH:30][N:31]=2)[CH:18]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC(O)CNC(C)(C)C
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1

Procedure:
A solution of methyl 3-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate (0.21g) and hydrazine hydrate (0.12 ml) in glacial acetic acid (5 ml) was heated under reflux of 16 hours. Evaporation of the reaction mixture under reduced pressure gave a glassy residue to which was added sodium hydroxide solution (2N, 10 ml). The resulting solution was extracted well with chloroform, the combined organic phases washed with water, dried and evaporated to give a white brittle residue which was recrystallised from isopropanol/ether to give 6-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid (0.16g, 80% m.p. 102°-109° C; M+, 376, M 376).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:17]([N:21]([CH2:31][CH2:32][CH2:33][N:34]1C(=O)C2C(=CC=CC=2)C1=O)[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH:18]([CH3:20])[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN>C(O)C>[NH2:34][CH2:33][CH2:32][CH2:31][N:21]([C@@H:17]([C:9]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=1)[CH:18]([CH3:19])[CH3:20])[C:22](=[O:30])[C:23]1[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=1
Reactant: CC(C)C(c1nc2ccccc2n1Cc1ccccc1)N(CCCN1C(=O)c2ccccc2C1=O)C(=O)c1ccc(Cl)cc1
Agent: NN
Solvent: CCO
Product: CC(C)[C@H](c1nc2ccccc2n1Cc1ccccc1)N(CCCN)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
To a solution of N-[1-(1-benzyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-4-chloro-benzamide (180 mg, 0.302 mmol) in ethanol at room temperature, was added hydrazine (0.19 ml, 6 mmol). The reaction was stirred at room temperature for 1 hour. The crude product was purified via reverse phase chromatography to give N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-chlorobenzamide 5 (129 mg, yield 91%).