Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH2:2][CH:3]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]([CH2:16][C:17]([OH:19])=[O:18])[C:4]1=[O:20].[CH2:21]([CH2:28][C:29](=O)[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([BH3-])#N.[Na+].Cl>C(O)(=O)C.CO>[C:17]([CH2:16][N:5]1[C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[CH2:8][CH2:9][CH2:10][CH2:11][CH:3]([NH:2][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:4]1=[O:20])([OH:19])=[O:18]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: NC1CCCCc2ccccc2N(CC(=O)O)C1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccccc1)NC1CCCCc2ccccc2N(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-amino-1-carboxymethyl-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one sodium salt (13.2 g) and ethyl benzylpyruvate (30 g) in acetic acid (100 ml) and methanol (75 ml) is stirred at room temperature under an atmosphere of dry nitrogen for one hour. A solution of sodium cyanoborohydride (3.5 g) in methanol (30 ml) is then added dropwise during 4 hours. The reaction mixture is stirred at room temperature for 18 hours. Concentrated hydrochloric acid (10 ml) is added dropwise and the reaction mixture stirred at room temperature for 1 hour. The solvents are removed under reduced pressure and the residue partitioned between water (400 ml) and ether (100 ml). The pH is adjusted to 9 by the addition of 40% aqueous sodium hydroxide, and the ether layer is discarded. The pH of the aqueous phase is adjusted to 4.3 by the addition of concentrated hydrochloric acid, and the solution is extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts are combined and dried over magnesium sulfate and the solvent removed under reduced pressure. The residue is dissolved in dichloromethane (150) (ml) and hydrogen chloride gas is bubbled in for five minutes. The solvent is evaporated and the residue is recrystallized to give 1-carboxymethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][N:3]=1.[C:13]([Cl:19])(=O)[CH2:14][C:15]([Cl:17])=O>C(#N)C.O>[Cl:17][C:15]1[CH:14]=[C:13]([Cl:19])[N:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:6]=[C:2]2[N:1]=1
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Reactant: O=C(Cl)CC(=O)Cl
Solvent: CC#N
Solvent: O
Product: Clc1cc(Cl)n2nc(-c3ccccc3)cc2n1
Reaction time: 2 h
Yield: 10 %

Procedure:
There was dissolved, in acetonitrile (20 mL), 3-amino-5-phenyl-pyrazole (1.00 g, 6.28 mM) in an argon gas atmosphere, malonyl chloride (672 μL, 6.91 mM) was added to the resulting solution with ice-cooling and the mixture was stirred for 2 hours. To this reaction liquid, there was further added malonyl chloride (210 μL, 2.15 mM) followed by stirring the mixture for one hour. This reaction liquid was diluted with water and then extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate and the solvent was then distilled off. After the addition of phosphoryl chloride (10 mL) to the resulting solid with ice-cooling, the resulting suspension was stirred for 4 hours, while refluxing the same with heating. The phosphoryl chloride was distilled off from the reaction liquid, the residue thus obtained was diluted with water and then extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate, the solvent was distilled off and then the resulting residue was purified by the silica gel column chromatography (ethyl acetate/hexane=1:10) to thus give the title compound (168 mg, yield: 10%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:27])[CH:23]([CH3:26])[CH2:24][CH3:25])[CH2:18][CH2:17]1>C(Cl)Cl>[CH3:26][CH:23]([CH2:24][CH3:25])[C:22]([N:19]1[CH2:18][CH2:17][CH:16]([NH:15][C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=2)=[O:12])[CH2:21][CH2:20]1)=[O:27]
Reactant: CCC(C)C(=O)N1CCC(N)CC1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: CCC(C)C(=O)N1CCC(NC(=O)Nc2ccc(OC(F)(F)F)cc2)CC1
Reaction time: 12 h
Yield: 895.9 %

Procedure:
4-(Trifluoromethoxy)phenylisocyanate (100 mg, 0.49 mmol) and 1-(4-aminopiperidin-1-yl)-2-methylbutan-1-one (90 mg, 0.49 mmol) was dissolved in CH2Cl2 (100 mL) and stirred for 12 h. The reaction was quenched by addition of water. The organic layer was isolated and the aqueous layer was extracted with EtOAc for 4 times. The combined organic layer was concentrated under vacuo and was further purified by flash chromatography (EtOAc:Hex/1:1) yielding final product (168 mg, 4.39 mmol, 89%). H-NMR (DMSO-d6) ∂ 0.80 (m, 3H), 0.97 (m, 3H), 1.28 (m, 3H), 1.53 (m, 1H), 1.85 (tbr, 2H), 2.71 (m, 1H), 2.78 (m, 1H), 3.16 (t, J=12 Hz, 1H), 3.71 (m, 1H), 3.88 (d, J=12 Hz, 1H), 4.21 (br, 1H), 6.26 (tbr, 1H), 7.22 (d, J=9 Hz, 2H), 7.47 (d, J=9 Hz, 2H), 8.55 (d, J=9 Hz, 2H).
Reaction SMILES: [S:1]([NH:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:4])(=[O:3])=[O:2].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C[O-].[Na+]>[CH2:16]([N:5]([S:1]([CH3:4])(=[O:2])=[O:3])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: COc1ccc(CONS(C)(=O)=O)cc1
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(CON(Cc2ccccc2)S(C)(=O)=O)cc1
Yield: 65.3 %

Procedure:
9.25 g (40 mmoles) of N-mesyl-O-(p-methoxybenzyl)hydroxylamine prepared as described in Reference Example 5 was added to sodium methoxide (prepared from 150 ml of absolute methanol and 1.2 g of sodium metal), and 6 g of benzyl chloride was then added to the mixture. The resulting mixture was heated under refluxing for 3 hours. The solvent was distilled off, and 150 ml of ethyl acetate and 50 ml of water were added to the residue. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to obtain 8.4 g (65.6% yield) of N-benzyl-N-mesyl-O-(p-methoxybenzyl)hydroxylamine having a melting point of 85°-87° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[N:14][CH:15]=[CH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[NH:9][CH3:10].[ClH:31].O1CCOCC1>CO>[ClH:31].[ClH:31].[ClH:31].[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:14][CH:15]=[CH:16][N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]([NH:9][CH3:10])=[O:11]
Reactant: CNC(=O)c1ccc(-c2nccnc2C2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(-c2nccnc2C2CCNCC2)cc1F
Temperature: 25 °C
Reaction time: 96 h
Yield: 100 %

Procedure:
To a RBF was added tert-butyl 4-(3-(3-fluoro-4-(methylcarbamoyl)phenyl)pyrazin-2-yl)piperidine-1-carboxylate (2.40 g, 5.79 mmol) and methanol (20 mL) was added 4M HCl in dioxane (5 mL, 20.00 mmol). The solution was stirred at room temperature. After 96 h, the reaction was concentrated in vacuo to give 2-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide trihydrochloride (2.46 g, 5.81 mmol, 100% yield), as a yellow foam. The 3 HCl equivalent was determined from the weight of the compound, without further characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.C[O:45][C:46](=[O:62])[C@@H:47]([NH2:61])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][N:58]=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][C:41]=1[Cl:42])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([NH:61][C@@H:47]([CH2:48][C:49]5[CH:54]=[CH:53][C:52]([C:55]6[CH:56]=[CH:57][N:58]=[CH:59][CH:60]=6)=[CH:51][CH:50]=5)[C:46]([OH:62])=[O:45])=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:11][CH:12]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccncc2)cc1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccncc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3

Procedure:
The title compound (19 mg) was prepared from (3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (30 mg) and (S)-2-amino-3-(4-pyridin-4-yl-phenyl)-propionic acid methyl ester hydrochloride according to General Procedures L and B. LCMS (m/z): 829.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C@:20]3([CH3:31])[C:25]([CH3:27])([CH3:26])[C:24](=[O:28])[N:23]([CH3:29])[C:22]([NH2:30])=[N:21]3)[CH:14]=2)[CH:5]=1.[Li+].[OH-]>C1COCC1.CO.O>[NH2:30][C:22]1[N:23]([CH3:29])[C:24](=[O:28])[C:25]([CH3:26])([CH3:27])[C@:20]([C:15]2[CH:14]=[C:13]([NH:12][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=3[O:10][CH3:11])[C:3]([OH:32])=[O:2])[CH:18]=[CH:17][C:16]=2[F:19])([CH3:31])[N:21]=1
Reactant: COC(=O)c1ccc(OC)c(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)cc1Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (S)-methyl-3-(3-(2-amino-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydropyrimidin-4-yl)-4-fluorophenylamino)-4-methoxybenzoate (example 122, 0.05 mmol) in THF (1 ml), MeOH (0.3 ml) and H2O (0.3 ml) was added LiOH (1N, 0.1 mmole) and the reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated in vacuo and the residue diluted with aqueous HCl (0.5N) until pH=5 and extracted with dichloromethane. The organic phase was dried, evaporated and the residue triturated with Et2O to give the title compound as a white solid. MS (ESI): m/z=429.2 [M+H]+.
Reaction SMILES: [Na].[CH3:2][C:3]([CH2:11][CH3:12])([CH2:7][CH2:8][CH2:9][CH3:10])[C:4](Cl)=[O:5].[CH3:13][CH2:14][O-:15].[Na+]>C(O)C>[CH3:2][C:3]([CH2:11][CH3:12])([CH2:7][CH2:8][CH2:9][CH3:10])[C:4]([O:15][CH2:14][CH3:13])=[O:5]
Reactant: CCCCC(C)(CC)C(=O)Cl
Reactant: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCCC(C)(CC)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
11.5 gm (0.5 mole ) of sodium were dissolved in 150 ml of ethanol. 44 gm (0.25 mole) of 2-methyl-2-ethyl-hexanoyl chloride were slowly added under agitation to the solution of sodium ethylate at O° to 5° C. The mixture was subsequently agitated for 3 hours at room temperature, filtered, absorbed in ether, washed neutral with water, dried, reduced, and fractionated in vacuo. The ethyl 2-methyl-2-ethyl-hexanoate was obtained in the form of a colorless oil having a fruity/fresh odor with a fragrance of apple and camomile.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([OH:19])=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O.C(Cl)Cl>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]([Cl:23])=[O:19])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cn(Cc2ccccc2)c2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cn(Cc2ccccc2)c2ccccc12
Yield: 100 %

Procedure:
A mixture of 1-benzyl-1H-indole-3-carboxylic acid (3.36 g, 13.37 mmol), oxalyl chloride (5.83 mL, 66.85 mmol), 100 mL methylene chloride and a catalytic amount of DMF was stirred at room temperature under nitrogen for 18 h (overnight). The solvent was removed under reduced pressure. To remove excess oxalyl chloride benzene was added and the solvent removed under reduced pressure to give 1-benzyl-1H-indole-3-carbonyl chloride as a brown oil (13.37 mmol) which was immediately used in step 2 without additional purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[N-:15]=[C:16]=[S:17].[K+].BrBr.O>C(O)(=O)C>[NH2:15][C:16]1[S:17][C:7]2[CH:6]=[C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=2[N:1]=1
Reactant: [N-]=C=S
Reactant: CCOC(=O)C(C)c1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)c1ccc2nc(N)sc2c1
Yield: 48.4 %

Procedure:
The said starting material was also prepared by dissolving 154.6 g of ethyl 2-(p-aminophenyl)propionate [Arzneim. Forsch, Vol. 23, p. 1090 (1973)] in 95% acetic acid and 261 g of potassium isothiocyanate were added with stirring. A solution of 149.4 g of Br2 in 750 ml of 95% acetic acid was then added dropwise at 18°-25° C. over 2 hours and the mixture was stirred for an extra half hour, then poured into 8 liters of water. The mixture was filtered through celite and then neutralized to pH 5-6 using 6+ liters of 20% Na2CO3 solution. The product was then extracted with CH2Cl2 and the organic layer was separated, washed with water, dried over MgSO4 and finally filtered and evaporated to dryness. The crude product was dissolved in 300 ml of hot ethyl acetate and an equal volume of petroleum ether (40°-60° C.) was added. On cooling, cream colored crystals were formed which were filtered off, washed with ethyl acetate/petroleum ether and dried to obtain 97 g (48.5% yield) of the ethyl 2-amino-α-methylbenzothiazole-6-acetate melting at 146° C. A second crop of 29 g was obtained from the mother liquors for a total yield 63%.
Reaction SMILES: P(Cl)(Cl)(OCl)=O.[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=2)[CH:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].CN(C)[CH:32]=[O:33]>>[CH2:7]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=2)[C:16]([CH:32]=[O:33])=[CH:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)C=O
Reactant: COC(=O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Agent: O=P(Cl)(Cl)OCl
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)Cc1ccc2c(C=O)cn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
18 mg (0.12 mmol) of phosphoryl oxychloride was added gradually to 4 ml of a solution of 25 mg (0.09 mmol) of methyl (1-benzylindol-6-yl)acetate, as obtained in a) above, in dimethyl formamide, at room temperature, and the resulting mixture was stirred for 30 minutes. After this time, an excess of a 2N aqueous solution of sodium hydroxide was added to the mixture, which was then stirred for 10 minutes. The aqueous layer was extracted with methylene chloride and the extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then the solvent was removed by evaporation under reduced pressure. The residue was subjected to column chromatography (eluent: a 25% v/v solution of ethyl acetate in hexane) to yield 23 mg (83%) of the title compound as an oil.
Reaction SMILES: Cl.Cl.[CH2:3]([N:5]([CH2:30][CH3:31])[CH2:6][CH2:7][O:8][CH:9]1[C:14](OC)([O:15]C)[CH2:13][CH2:12][N:11]([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:10]1)[CH3:4].S(=O)(=O)(O)O>O>[CH2:30]([N:5]([CH2:3][CH3:4])[CH2:6][CH2:7][O:8][CH:9]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:10]1)[CH3:31]
Reactant: CCN(CC)CCOC1CN(CCCOc2ccc(F)cc2)CCC1(OC)OC
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCN(CC)CCOC1CN(CCCOc2ccc(F)cc2)CCC1=O
Yield: 75 %

Procedure:
A mixture of 14.07 parts of N,N-diethyl-2-[[1-[3-(4-fluorophenoxy)propyl]-4,4-dimethoxy-3-piperidinyl]-oxy]ethanamine dihydrochloride, 7.36 parts of a sulfuric acid solution 96% and 500 parts of water was stirred and refluxed for 17 hours. The reaction mixture was allowed to cool and washed with 2,2'-oxybispropane. The aqueous phase was separated and alkalized with sodium carbonate. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated, yielding 8.0 parts (75%) of 3-[2-(diethylamino)ethoxy]-1-[3-(4-fluorophenoxy)propyl]-4-piperidinone as a residue (intermediate 120).
Reaction SMILES: S=[C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[NH:3]1.[OH-].[Na+].OO.[CH2:29](N)[CH:30]([CH3:32])[CH3:31]>CN(C)C=O>[CH3:29][CH:30]([CH3:32])[CH2:31][C:2]1[N:12]2[C:13]3[N:8]([C:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)=[CH:10][CH2:11]2)[N:7]=[CH:6][C:5]=3[C:4](=[O:24])[N:3]=1
Reactant: CC(C)CN
Reactant: O=c1[nH]c(=S)n2c3c1cnn3C(c1cccc(C(F)(F)F)c1)=CC2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)Cc1nc(=O)c2cnn3c2n1CC=C3c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 500 mg of 4,5-dihydro-5-thioxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one (prepared as described in Example 8) in 10.0 ml of N,N-dimethylformamide was added 1.5 ml of 1N sodium hydroxide. The reaction mixture was cooled to 0° C. in an ice bath, then 0.5 ml of 30% hydrogen peroxide was added to the mixture dropwise. The reaction mixture was stirred at 0° C. for 30 minutes, then 1.0 ml of isobutylamine was added in one portion and the mixture was allowed to warm to room temperature, then was stirred for 2 hours. The solid was collected by filtration and washed with water, then ether to give 223 mg of the product of the example as a white solid, m.p. 266°-268° C. Following the procedure of Example 14 and reacting, 4,5-dihydro-5-thioxo-8-[3-(trifluoromethyl)phenyl]3H ,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one with the appropriate primary aliphatic amine or cyclic secondary amine, the products of Examples 15-27 were obtained as set forth in Table III.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([S:27]([NH:30][C:31]1[C:32](=[O:42])[N:33]([CH2:38][CH2:39][CH2:40]O)[C:34]([CH3:37])=[CH:35][CH:36]=1)(=[O:29])=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Br)(Br)(Br)[Br:44]>CN(C=O)C>[CH2:20]([S:27]([NH:30][C:31]1[C:32](=[O:42])[N:33]([CH2:38][CH2:39][CH2:40][Br:44])[C:34]([CH3:37])=[CH:35][CH:36]=1)(=[O:29])=[O:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.2 %

Procedure:
A solution of triphenylphosphine (0.46 g, 1.75 mmol) in DMF (5 mL) was added to a mixture of 1-5 (0.49 g, 1.46 mmol) and carbon tetrabromide (0.68 g, 2.05 mmol) in DMF (5 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and allowed to stir for 12 hours. The mixture was then concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using ethyl acetate and hexane (3:1 to 2:1 gradient) as eluants to afford the title compound 1-6 (0.38 g, 66% yield) as a yellow solid. MS (m/e): 399. TLC: Rf (0.35) (EA/Hex); 1H NMR (400 MHz, CDCl3): δ 2.23 (m, 2H), 2.4 (s, 3H), 3.5 (t, 2H), 4.2 (t, 2H), 4.3 (s, 2H), 6.0 (d, 1H), 7.2(d, 1H), 7.3(m, 5H).
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][N:14]=1>C1COCC1>[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH3:8])[CH2:20][O:21]2)=[CH:15][N:14]=1
Reactant: C[S+](C)C
Reactant: CC(=O)c1cnc(C)nc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1ncc(C2(C)CO2)cn1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents stirred for 10 min. after which the solution of 1-(2-methylpyrimidin-5-yl)ethanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. The reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([N:52]([CH2:57][CH2:58][CH3:59])[CH2:53][CH2:54][CH2:55][NH2:56])[CH2:50][CH3:51]>CN(C=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:56][CH2:55][CH2:54][CH2:53][N:52]([CH2:57][CH2:58][CH3:59])[CH2:49][CH2:50][CH3:51])=[O:21])=[CH:22][CH:23]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CCCN(CCC)CCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)CCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (190 mg) obtained in Example 2-2 was dissolved in DMF (3.0 ml) and added with DCC (189 mg), HOBt (124 mg), and the compound (96.9 mg) obtained in Example 22-3, followed by stirring overnight at room temperature. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform, followed by separating the solution into layers by the addition of 1 mol/l hydrochloric acid. The aqueous layer was made basic with a 1 mol/l sodium hydroxide aqueous solution. Then, the solution was subjected to extraction with chloroform. The extract was washed with saturated saline solution and the organic layer was then dried with anhydrous sodium sulfate. The solvent was distilled off. Subsequently, the residue was treated with hydrochloric acid and then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (84.8 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:26])[NH:15][C@:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1([C:33]2[CH:42]=[C:41](O)[C:40]3[C:35](=[CH:36][C:37]([O:44][CH3:45])=[CH:38][CH:39]=3)[N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][C@H:11]([O:13][C:41]2[C:40]3[C:35](=[CH:36][C:37]([O:44][CH3:45])=[CH:38][CH:39]=3)[N:34]=[C:33]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:42]=2)[CH2:10][C@H:9]1[C:14](=[O:26])[NH:15][C@:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C@H:17]1[CH:19]=[CH2:20])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 0 °C
Reaction time: 48 h
Yield: 67.8 %

Procedure:
Compound 34 (73 mg, 0.199 mmol) was dissolved in dry THF (4 mL) and 2-phenyl-7-methoxy-4-quinolinol (86 mg, 0.342 mmol) and triphenylphosphine (141 mg, 0.538 mmol) were added. The mixture was cooled to 0° C. and DIAD (0.567 mmol) dissolved in 1 mL THF was added dropwise. The mixture was stirred for 48 h at room temperature. The solvent was evaporated and the crude product was purified by flash column chromatography gradient elution (toluene/EtOAc 9:1, 6:1, 4:1) to give compound 35 (81 mg, 68%).