Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][C@@H:14]1[S:20][C@@H:19]([C:21]([OH:23])=O)[CH2:18][C:17]2[CH:24]=[C:25]3[O:30][CH2:29][O:28][C:26]3=[CH:27][C:16]=2[C:15]1=[O:31].[NH2:32][C:33]1[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][CH:34]=1.ON1C2C=CC=CC=2N=N1>ClCCl.CN(C)C=O.O>[CH2:43]([O:42][P:38]([CH2:37][C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:21]([C@H:19]2[CH2:18][C:17]3[CH:24]=[C:25]4[O:30][CH2:29][O:28][C:26]4=[CH:27][C:16]=3[C:15](=[O:31])[C@H:14]([CH3:13])[S:20]2)=[O:23])=[CH:47][CH:46]=1)([O:39][CH2:40][CH3:41])=[O:45])[CH3:44]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: C[C@@H]1S[C@@H](C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOP(=O)(Cc1ccc(NC(=O)[C@H]2Cc3cc4c(cc3C(=O)[C@H](C)S2)OCO4)cc1)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.6 %

Procedure:
A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.39 g) in dichloromethane (7 ml) was added drop by drop to a solution of (2R,4S)-(-)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepine-2-carboxylic acid (0.47 g) as obtained in Reference Example 2 (0.41 g) and diethyl 4-aminobenzylphosphonate (0.41 g) in N,N-dimethylformamide (DMF) (7 ml) at 0° C., followed by the addition of 1-hydroxybenzotriazole (HOBt) (0.28 g). After being stirred at 0° C. for 1 hour and at room temperature (25° C.) for 15 hours, the mixture was poured over water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residual crystal was collected by filtration, and recrystallized from ethyl-hexane acetate and methanol-hexane to yield compound A (0.37 g, 44%) in the form of a colorless prism.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1F>C(#N)C>[F:8][C:9]1[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=[CH:13][C:14]=1[N:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCNC1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCCNCC2)c(F)c1
Yield: 77.3 %

Procedure:
To homopiperazine (5 g, 0.05 mol) in acetonitrile (30 mL), 3.4-difluoronitrobenzene (3.17 g, 0.02 mol) was added and the reaction mixture was heated to reflux for 4 hrs. Then the solvent was evaporated and the residue taken in EtOAc and washed with water and brine solution. The EtOAc layer was dried over anhyd Na2SO4 and evaporated in vacuo. The residue was digested with ether-hexane (1:20), decanted and dried in vacuo to get 3.7 g of final product.
Reaction SMILES: C([O:3][C:4](=[O:14])[C:5]([C:7]1[CH:11]=[C:10]([Cl:12])[S:9][C:8]=1[Cl:13])=[O:6])C.[OH-].[Na+].Cl>O>[Cl:13][C:8]1[S:9][C:10]([Cl:12])=[CH:11][C:7]=1[C:5](=[O:6])[C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)C(=O)c1cc(Cl)sc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C(=O)c1cc(Cl)sc1Cl
Yield: 97.4 %

Procedure:
(2,5-Dichlorothiophen-3-yl)-oxo-acetic acid ethyl ester (4.51 g, 17.8 mmol) was stirred in a mixture of 100 ml water and 10 N NaOH (10 ml, 100 mmol) at room temperature for 20 hours. The reaction mixture was then acidified with 3N HCl, and extracted with ethyl acetate (3×50 ml). The combined ethyl acetate extracts were dried over Na2SO4 and concentrated under vacuum to provide (2,5-dichlorothiophen-3-yl)-oxo-acetic acid (3.90 g, 97%). MS (M−H)−: 223.02; 1H NMR (300 MHz, DMSO-d6) δ7.54 (s).
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].C([Li])CCC.CCCCCC.[CH3:17][C:18]1([CH3:32])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]1[C:27](OCC)=[O:28]>C1(C)C=CC=CC=1>[CH2:1]([NH:5][C:27]([CH:19]1[C:18]([CH3:32])([CH3:17])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1)=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: CCOC(=O)C1Nc2ccccc2C1(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCNC(=O)C1Nc2ccccc2C1(C)C
Reaction time: 3 h

Procedure:
Butylamine (15 ml) in toluene (40 ml) was cooled to −78° C. and a 2.5M solution of butyllithium in hexane (12.91 ml, 31.5 mmol) was added dropwise. After half an hour, ethyl 3,3-dimethylindoline-2(R/S)-carboxylate (4.600 g, 21 mmol) was added to the solution and this mixture was stirred under nitrogen for three hours. The mixture was then poured into a water/ice mixture (50 ml) and extracted with ethyl acetate; the extracts were dried over magnesium sulphate and the solvent was removed to give a brown oil. This was purified by chromatography on a column of silica gel, using a 7/3 petroleum ether/ethyl acetate mixture as eluent in order to give a yellow solid.
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:12][C:13]([OH:15])=O)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:18]([O:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:22])[CH3:19].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>CN(C)C=O.C(OCC)(=O)C>[CH2:18]([O:20][C:21]([CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[N:29]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1)[C:13](=[O:15])[CH2:12][C:7]1[NH:6][C:5]2[CH:16]=[CH:17][C:2]([I:1])=[CH:3][C:4]=2[S:9](=[O:10])(=[O:11])[N:8]=1)=[O:22])[CH3:19]
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Reactant: CCOC(=O)C1CCCCC1NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCCC1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 24b, 2.62 g, 7.16 mmol) was dissolved in anhydrous N,N-dimethylformamide (30 mL). 2-(4-Fluoro-benzylamino)-cyclohexanecarboxylic acid ethyl ester (2.0 g, 7.16 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g, 7.52 mmol). Then N-methylmorpholine (1.52 g, 15.04 mmol) was added into the above reaction mixture. The mixture stirred at 25° C. for 24 h. The solution was diluted with ethyl acetate (200 mL), washed with 1.0 M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and saturated aqueous brine solution. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the crude product, 2-{(4-fluoro-benzyl)-[2-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohexanecarboxylic acid ethyl ester, as a yellow oil, which was used directly in the next step without further purification. LC-MS (ESI) calcd for C25H27FIN3O5S 627.07, found 628.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH3:11])=[C:4]([CH2:12][CH3:13])[CH:3]=1.[N:14]([C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21])=[C:15]=[O:16]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:11])[C:15]([NH:14][C:17]2[CH:24]=[CH:23][CH:22]=[C:19]([C:20]#[N:21])[CH:18]=2)=[O:16])=[C:4]([CH2:12][CH3:13])[CH:3]=1
Reactant: N#Cc1cccc(N=C=O)c1
Reactant: CCc1cc(Br)ccc1CCNC
Solvent: ClCCl
Product: CCc1cc(Br)ccc1CCN(C)C(=O)Nc1cccc(C#N)c1
Yield: 62.8 %

Procedure:
A solution of 36C (250 mg, 1.03 mmol) and 3-isocyanatobenzonitrile (164 mg, 1.03 mg) in CH2Cl2 (10 mL) was refluxed for 30 min. The solution was concentrated in vacuo and purified by flash chromatography (0% to 100% EtOAc in hexanes) to afford 36D (250 mg, 63%) as a yellow solid. MS (ESI) m/z 386.04/388.05 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:19])[CH:8]=2)[N:3]=1.O.[NH2:21][NH2:22]>>[Cl:19][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:21][NH2:22])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18]
Reactant: NN
Reactant: Clc1ccc2nc(Cl)cc(-c3ccccc3Cl)c2c1
Solvent: O
Product: NNc1cc(-c2ccccc2Cl)c2cc(Cl)ccc2n1

Procedure:
In the manner given in Example 1, 2,6-dichloro-4-(o-chlorophenyl)quinoline is reacted at reflux with hydrazine hydrate to give 6-chloro-4-(o-chlorophenyl)-2-hydrazinoquinoline.
Reaction SMILES: [OH2:1].O.O.[N+]([O-])(O)=O.[C:8]([O:11][CH:12]1[CH2:20][CH2:19][CH:18]2[CH:13]1[CH2:14][CH2:15][C:16](=[O:21])[CH2:17]2)(=[O:10])[CH3:9]>C(O)(=O)C>[C:8]([O:11][CH:12]1[CH2:20][CH2:19][CH:18]2[CH:13]1[CH2:14][CH2:15][CH:17]2[C:16]([OH:21])=[O:1])(=[O:10])[CH3:9]
Reactant: CC(=O)OC1CCC2CC(=O)CCC21
Reactant: O
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)OC1CCC2C(C(=O)O)CCC12
Yield: 12.2 %

Procedure:
Thallic nitrate trihydrate (133 g) was added to a stirred solution of 7-acetoxybicyclo[4,3,0]nonan-3-one (57 g; prepared as described in Reference Example 4) in glacial acetic acid (290 ml). After 30 minutes the resulting solid was filtered off and the filtrate was heated at reflux for 30 minutes. The acetic acid was distilled off under reduced pressure and the residue was neutralised by treatment with aqueous sodium hydroxide solution to pH 5 and then with aqueous sodium bicarbonate solution to neutral. The resulting solution was washed with diethyl ether, and then it was acidified by treatment with concentrated hydrochloric acid and extracted with chloroform. The combined chloroform extracts were washed with saturated aqueous sodium chloride solution, then dried over magnesium sulphate, and concentrated under reduced pressure. The residue was purified by medium pressure, short column chromatography on silica gel, eluting with a mixture of ethyl acetate, hexane, and acetic acid (45:55:1 by volume), to give 6-acetoxy-2-carboxybicyclo[3,3,0]octane (7.55 g), predominantly in the 2β-configuration.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:14]([CH2:22][CH2:23][N:24]=3)[C:15]([NH2:21])=[N:16][C:17]=2[C:18]=1[O:19][CH3:20])C1C=CC=CC=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>CO>[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[F:28][C:27]([F:30])([F:29])[C:25]([OH:31])=[O:26].[NH2:21][C:15]1[N:14]2[CH2:22][CH2:23][N:24]=[C:13]2[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[C:18]([O:19][CH3:20])[C:17]=2[N:16]=1
Reactant: COc1c(OCc2ccccc2)ccc2c1N=C(N)N1CCN=C21
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1c(O)ccc2c1N=C(N)N1CCN=C21
Temperature: 60 °C
Reaction time: 17 h
Yield: 100 %

Procedure:
3-(Benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline (Step 7, 30 g, 93 mmol) was added portionwise over 1 h to a round bottom flask containing TFA (400 mL) precooled with an ice bath. The reaction mixture was heated to 60° C. and allowed to stir at this temperature for 17 h at which time it was cooled to rt and the reaction mixture concentrated under reduced pressure. The resulting residue was taken up in DCM and hexanes and concentrated under reduced pressure. The material thus obtained was dissolved in MeOH and DCM (250 mL, 1:1) and concentrated under reduced pressure. The resulting solid was dried overnight under vacuum with low heat to give the title compound (100%): 1H NMR (DMSO-d6) δ: 7.61 (1H, m), 6.87 (1H, m), 4.15 (2H, br t), 4.00 (2H, m), 3.64 (3H, s).
Reaction SMILES: CN1C=CN=C1.[OH:7][CH2:8][CH:9]1[CH2:13][O:12][C:11](=[O:14])[NH:10]1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:7][CH2:8][CH:9]2[CH2:13][O:12][C:11](=[O:14])[NH:10]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: O=C1NC(CO)CO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cn1ccnc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COC(=O)N2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
N-methylimidazole (360 ml, 4.5 mmol, 1.5 eq) is added to a cooled suspension of 4-(hydroxymethyl)-1,3-oxazolidin-2-one a90 (0.35 g, 3 mmol, 1 eq) in dichloromethane (20 ml). p-Toluenesulfonyl chloride a40 (0.63 g, 3.3 mmol, 1.1 eq) in dichloromethane (5 ml) is then added, dropwise. The mixture is stirred at 0° C. for 5 hours then at room temperature for 24 hours. The mixture is then quenched under vigorous stirring with 0.5 ml of water and taken up in chloroform (100 ml). The organic phase is washed with a saturated aqueous solution of sodium hydrogenocarbonate (2×25 ml), with a 1N solution of hydrochloric acid (2×25 ml), with brine, and is dried over magnesium sulfate. The organic layer is concentrated in vacuo to afford 0.61 g of (2-oxo-1,3-oxazolidin-4-yl)methyl 4-methylbenzenesulfonate a91 as a white solid.
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH3:15])[CH2:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[Cl:14].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][N:3]([CH:4]([CH3:15])[CH2:5][C:6]1[C:7]([Cl:14])=[CH:8][C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)Cc1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
To a solution of O-methyl-N-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-hydroxylamine (12.3 g, 0.046 mol) prepared as described in example P5a in Xylene (90 g) was added triethylamine (5.6 g, 0.055 mol) followed by addition of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (40.1 g, 0.046 mol) at 70° C. during 2 hours. After complete addition of acid chloride the mixture was stirred 2 hours at 70° C. The solution was washed twice with water and the volatiles were removed from the organic layer under reduced pressure. The resulting crude mass 23.6 g (sticky dark brown oil) was purified by crystallization from a mixture of 16 g xylene and 36 g methylcyclohexene to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-2-(2,4,6-trichloro-phenyl)-ethyl]-amide (17.0 g, 91.5%) as off white solid. m.p: 115-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:13][C:14]([C@@H:16]([NH2:21])[CH2:17][C:18]([OH:20])=[O:19])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl.[CH3:23][C:24]([CH3:29])([CH3:28])[CH2:25][CH:26]=O.C(=O)([O-])O.[Na+]>CO.[Pd]>[CH3:23][C:24]([CH2:25][CH2:26][NH:21][C@H:16]([C:14]([NH:13][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15])[CH2:17][C:18]([OH:20])=[O:19])([CH3:29])[CH3:28]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Reactant: CC(C)(C)CC=O
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NCCC(C)(C)C
Reaction time: 48 h
Yield: 90 %

Procedure:
Aspartame hydrochloride salt (10 mmol) and 3,3-dimethylbutyraldehyde (10 mmol) were dissolved in methanol (100 ml) in a hydrogenation vessel. Sodium hydrogen carbonate (NaHCO3, 12 mmol) and 5% palladium on carbon (100 mg) were added. The mixture was hydrogenated at 30-40 psi for 2 days at room temperature. After completion of the reaction, the catalyst was removed from the reaction mixture by filtration and washed with methanol (3×20 ml). The combined organic solvent was removed under reduced pressure below 40° C., and the residue was extracted using methylene chloride. The wet product was dried over sodium sulfate, and the solvent was removed in vacuo below 40° C. to give neotame in 90% yield.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][CH2:7][C:8]#[N:9])C.[C:13]([O:17][C:18]([NH:20][C@H:21]([C:29]([OH:31])=O)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:22]([C@H:21]1[C:29](=[O:31])[N:6]([CH2:7][C:8]#[N:9])[CH:5]=[CH:4][N:20]1[C:18]([O:17][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:19])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(CNCC#N)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C=CN(CC#N)C(=O)[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a mixture of 3.0 g of 2,2-diethoxyethylaminoacetonitrile, 4.85 g of N-t-butoxycarbonyl-L-phenylalanine and 50 ml of methylene chloride was added 3.6 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, which was stirred for 4 hours at room temperature. The reaction mixture was concentrated under reduced pressure. To the concentrate were added 100 ml of ethyl acetate and 50 ml of water. The mixture was shaken. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate and, then, concentrated under reduced pressure. The concentrate (7.0 g) was dissolved in 100 ml of ethyl acetate. To the solution was added 0.5 g of p-toluenesulfonic acid, and the mixture was stirred for 4 hours at 75° to 85° C. The reaction mixture was cooled and washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by means of a silica-gel column chromatography (eluent: hexane-ethyl acetate=3:1), followed by recrystallization from ethyl acetate to afford 3.7 g of colorless prisms, m.p.160°-162° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29]>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:35]2[CH2:34][CH2:33][N:32]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)[CH2:37][CH2:36]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1cc(N2CCN(C(=O)Nc3nc4ccc(C)cc4nc3OC)CC2)cc(OC)c1OC
Yield: 91 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 2.49 (s, 3H), 3.16-3.23 (m, 4H), 3.71-3.95 (m, 4H), 3.80 (s, 3H), 3.86 (s, 6H), 4.13 (s, 3H), 6.19 (s, 2H), 7.08-7.62 (m, 3H), 7.72 (d, J=8.6 Hz, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=O)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>>[C:25]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:21])[CH2:12][CH2:11]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Reactant: NCC(F)(F)F
Agent: Cl
Product: O=C(NCC(F)(F)F)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
The procedure of step (d) of Example 1 was repeated using the compound prepared in step (c) of Example 1, except that 2,2,2-trifluoroethylamine hydrochloride was used instead of N-methylbenzylamine. Thus, 3-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]-N-(2,2,2-trifluoroethyl)benzamide was prepared.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([CH3:30])=[C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[C:10]2[N:11]([N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[N:15]=2)[CH:12]=1)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[NH:41][NH2:42])[C:36]#[N:37]>>[C:36]([C:35]1[CH:38]=[CH:39][C:40]([N:41]2[C:5]([C:7]3[C:8]([CH3:30])=[C:9]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=4)[C:10]4[N:11]([N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[N:15]=4)[CH:12]=3)=[CH:4][CH:3]=[N:42]2)=[C:33]([F:32])[CH:34]=1)#[N:37]
Reactant: N#Cc1ccc(NN)c(F)c1
Reactant: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)C=CN(C)C)cn2n1
Product: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(-c3ccnn3-c3ccc(C#N)cc3F)cn2n1

Procedure:
The title compound was prepared from N-[6-(3-dimethylamino-acryloyl)-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 25, 85 mg, 0.197 mmol) and 3-fluoro-4-hydrazino-benzonitrile (45 mg, 0.298 mmol) using similar methods to those employed in Example 40, Step 4 and Example 26, Step 1 (22 mg).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O-])=[O:12])[CH2:2]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]1[C:10]([CH2:11][OH:12])=[CH:14][CH:15]=[CH:16][N:17]=1)[CH2:4]2
Reactant: O=C([O-])c1cccnc1N1CC2CCC(C1)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccnc1N1CC2CCC(C1)O2
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a cooled (0° C.) solution of 2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)nicotinate (0.10 g, 0.40 mmol) in THF (5 mL) was added a solution of lithium aluminum hydride (1.2 mL, 1M in THF). The reaction mixture was stirred for 1 h and then 20 μL of H2O was added followed by 20 μL of 15% NaOH (aq) and then 60 μL of additional H2O. The slurry was stirred for 1 h, filtered and the resulting residue was washed with ether. The combined organic layers were dried over MgSO4 and concentrated in vacuo to yield (2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyridin-3-yl)methanol (0.070 g, 79% yield). MS (ES) for C12H16N2O2: 221 (MH+).
Reaction SMILES: [CH3:1][C:2]1O[C:4](=[O:15])[C:5]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:16][CH:17]1[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]1=[O:24]>>[CH3:1][C:2]1[N:16]([CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[C:4](=[O:15])[C:5]2[C:6](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:12]([O-:14])=[O:13])[N:7]=1
Reactant: NC1CCC(=O)NC1=O
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1C1CCC(=O)NC1=O

Procedure:
In certain embodiments, the solvent in step (a) (reacting 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one and 3-aminopiperidine-2,6-dione or a salt thereof to form 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione) is petroleum ether, pentane, hexane(s), heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin, cumene, dichloromethane (DCM), 1,2-dichloroethane, 1,1-dichloroethene, 1,2-dichloroethene, chloroform, trichloroethane, trichloroethene, carbon tetrachloride, chlorobenzene, trifluoromethylbenzene, methanol, ethanol, isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, t-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, ethyleneglycol, diethyl ether, diisopropyl ether, methyl t-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bi(2-methoxyethyl)ether, 1,1-dimethoxymethane, 2,2-dimethoxypropane, anisole, acetone, butanone, methyl ethyl ketone (MEK), methyl isopropyl ketone, methyl butyl ketone, methyl isobutyl ketone (MIBK), methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, ethylene carbonate, propylene carbonate, formamide, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, acetonitrile (ACN), dimethyl sulfoxide (DMSO), sulfolane, nitromethane, nitrobenzene, N-methyl pyrrolindone, 2-methyl tetrahydrofuran, tetrahydrofuran (THF), dioxane, pyridine, formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, hexamethylphosphoramide, carbon sulfide, water; or a mixture thereof.