Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][CH2:16]OC.C(OCC)(=O)C.Cl>[Ti](Cl)(Cl)(Cl)Cl.O>[Cl:15][CH2:16][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:6][CH:5]=1
Reactant: COCCl
Reactant: N#Cc1ccccc1-c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccccc1-c1ccc(CCl)cc1
Yield: 48.3 %

Procedure:
To vigorously stirred 2-phenylbenzonitrile (68.1 g) under ice-cooling was added titanium tetrachloride (432 g) dropwise for 30 minutes. The precipitated crystals were pulverized and then chloromethyl-methyl ether (61 g) was added dropwise for 20 minutes with stirring under ice-cooling. After stirring at 60° C. for 2 hours, additional chloromethyl-methyl ether (15.3 g) was added and the mixture was stirred for an additional hour. To the reaction mixture was added ethyl acetate (200 ml) dropwise with stirring under ice-cooling. Then ice was added until hydrogen chloride gas development ceased and iced water (400 ml) was added before stirring for a while. The precipitated crystals were filtered and dried. The filtrate was extracted with ethyl acetate, washed with water, and concentrated to dryness in vacuo. The resulting residue was purified by column chromatography on silica gel to give crystals which were combined with the previously obtained crystal and recrystallized from methanol to yield pale yellow prisms (41.8 g, 48%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:16]([O:18][CH:19]=[CH2:20])=[O:17]>ClCCCl>[CH:19]([O:18][C:16](=[O:17])[O:14][CH2:13][CH:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[CH2:20]
Reactant: C=COC(=O)Cl
Reactant: OCC1CCN(Cc2ccccc2)C1
Solvent: ClCCCl
Product: C=COC(=O)OCC1CCN(Cc2ccccc2)C1
Yield: 70.7 %

Procedure:
A solution of (1-benzyl-pyrrolidin-3-yl)-methanol (prepared as described by Y.-H. Wu and R. F. Feldkamp, Pyrrolidines I, 1961, 26, 1519-1524) (455 mg, 2.38 mmol) and vinyl chloroformate (0.40 mL, 4.7 mmol) in 1,2-dichloroethane (10 mL) was heated to reflux for 2 h then concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (5% MeOH/CH2Cl2) gave a yellow oil (440 mg, 71%). 1H NMR (CDCl3) δ 1.84 (m, 1H), 2.26 (m, 1H), 3.03 (m, 5H), 4.01 (br s, 2H), 4.23 (m, 2H), 4.61 (dd, 1H, J=6.2, 2.3 Hz), 4.93 (dd, 1H, J=14, 2.1 Hz), 7.06 (dd, 1H, J=14, 6.3 Hz), 7.41 (m, 3H), 7.53 (m, 2H).
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[Br:37][C:38]1[C:46]2[O:45][C:44]([C:47](=O)[CH3:48])=[CH:43][C:42]=2[CH:41]=[C:40]([O:50][CH3:51])[CH:39]=1.[OH-].[K+]>C(O)C>[Br:37][C:38]1[C:46]2[O:45][C:44]([C:47]3[CH:48]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)=[CH:43][C:42]=2[CH:41]=[C:40]([O:50][CH3:51])[CH:39]=1
Reactant: COc1cc(Br)c2oc(C(C)=O)cc2c1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Br)c2oc(-c3ccc4cc(-c5nc6cc(C(=O)O)ccc6n5C5CCCCC5)ccc4n3)cc2c1
Yield: 17 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(7-bromo-5-methoxy-benzofuran-2-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound, 17% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:9][CH2:8]1
Reactant: COC(=O)CCCC1CCNCC1
Reactant: BrCCOCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCC1CCN(CCOCc2ccccc2)CC1
Yield: 37.7 %

Procedure:
A solution of 2 (2.00 g, 10.8 mmol), (2-bromoethoxymethyl)benzene (2.31 g, 10.8 mmol), and triethylamine (4.5 ml, 32.4 mmol) in dichloromethane (30 mL) was stirred at room temperature overnight. Solvent was evaporated and the residue was purified by Flash™ chromatography (BIOTAGE, Inc) (9.3:0.7 dichloromethane/methanol, v/v) to provide 3a (1.3 g, 42%) as a yellow oil. 1H NMR (300 MHz, CD3OD) δ 1.30 (m, 5H), 1.66 (m, 2H), 1.87 (d, 2H), 2.37 (m, 2H), 2.58 (m, 2H), 3.04 (m, 2H), 3.39 (m, 2H), 3.65 (s, 3H), 3.80 (m, 2H), 4.55 (s, 2H), 7.37 (m, 5H). m/z (ESI): 320 [C19H29NO3+H]+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][OH:13])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][O:16]1)[O:11][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][O:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(O)COCc1ccccc1
Reactant: BrCCCCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COCC(COCCCCCCOC2CCCCO2)OCCCCCCOC2CCCCO2)cc1
Reaction time: 0.75 h
Yield: 41.2 %

Procedure:
To a cooled solution, 0° C., of 1-benzylglycerol (3.00 g) in dimethylformamide (165 ml) was added sodium hydride (60% dispersion in mineral oil, 3.95 g) and the reaction stirred for 45 minutes. 1-Tetrahydropyran-2-yloxy-6-bromohexane (13.10 g) was added and the reaction stirred at 20° C. for 19 hours. The reaction was quenched by the portionwise addition of methanol(10 ml) over 30 minutes at 0° C. The solvent was removed in vacuo and the residue partitioned between water (125 ml) and dichloromethane(125 ml). The organic layer was washed with brine (150 ml), dried and the solvent removed in vacuo. This was purified by column chromatography on silica gel (Biotage) eluting with 8% ethyl acetate in cyclohexane to give the title compound as a pale yellow oil (3.74 g).
Reaction SMILES: COC([CH:5]1[CH2:10][C:9]([C:17]#[N:18])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6]1=[O:19])=O>OS(O)(=O)=O.C(O)(=O)C.O>[C:17]([C:9]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][C:6](=[O:19])[CH2:5][CH2:10]1)#[N:18]
Reactant: COC(=O)C1CC(C#N)(c2ccccc2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: N#CC1(c2ccccc2)CCC(=O)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
5-Cyano-2-oxo-5-phenylcyclohexanecarboxylic acid methyl ester (7.71 g, 0.03 mol) was dissolved in 10 per cent strength H2SO4 and concentrated acetic acid (240 ml). The reaction mixture was stirred at 100° C. for 24 h. The course of the reaction was monitored by TLC. For working up, the mixture was diluted with water (400 ml), while cooling with ice, and extracted with ethyl acetate (3×100 ml). The organic phase was then washed thoroughly with water (6×100 ml), saturated sodium bicarbonate solution (10×100 ml) and saturated sodium chloride solution (1×100 ml). After drying with Na2SO4, the solvent was distilled off on a rotary evaporator. It was possible to isolate the desired product in a yield of 5.46 g (92%) with a melting point of 106-107° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([OH:10])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH3:2].[C:14]([O-])([O-])=O.[K+].[K+].CI.O>CS(C)=O.C(OCC)C>[CH2:1]([C:3]1[CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[C:6]([O:10][CH3:14])=[CH:7][C:8]=1[F:9])[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])c(O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CI
Product: CCc1cc([N+](=O)[O-])c(OC)cc1F
Yield: 83.4 %

Procedure:
4-Ethyl-5-fluoro-2-nitrophenol (5.72 g, 30.9 mmol) was dissolved in 60 mL of DMSO with stirring. K2CO3 (6.41 g, 46.4 mmol) was added. Methyl iodide (2.5 mL, 40 mmol) was added via syringe. The reaction was stirred overnight and poured into H2O and diethyl ether. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 5.13 g (83%) of the title compound of step C. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=7.9 Hz, 1H), 7.23 (d, J=12.1 Hz, 1H), 3.86 (s, 3H), 2.56 (q, J=7.6 Hz, 2H), 1.11 (t, J=7.5 Hz, 3H).
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([CH:11]([CH2:30][CH:31]=[CH2:32])[CH2:12][O:13][SiH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22]C(C)(O)CC(C)C)=[CH:17][CH:16]=1)[CH:9]=[CH2:10].[OH-].[Na+]>C(Cl)Cl>[CH2:30]([CH:11]([CH2:8][CH:9]=[CH2:10])[CH2:12][O:13][SiH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1)[CH:31]=[CH2:32]
Reactant: C=CCC(CC=C)CO[SiH2]c1ccc(C#CC(C)(O)CC(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C#Cc1ccc([SiH2]OCC(CC=C)CC=C)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 5.6 %

Procedure:
Firstly, dist. toluene (5 mL) was added to and dissolved in 1-(diallylethoxysilyl)-4-(3,5-dimethyl-3-hydroxy-hexynyl)benzene (125 mg, 0.35 mmol) obtained in Synthesis example 10. The resultant mixture was added with NaOH (9.9 mg, 0.25 mmol), and then was stirred under a nitrogen atmosphere at 80° C. for 16 hours to obtain a reaction mixture. Then, the reaction mixture was diluted with CH2Cl2, and an organic layer was washed with dist. H2O and sat. NaCl. The organic layer thus collected was dried with MgSO4, and the dried organic layer was filtered and concentrated to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography (hexane/EtOAc=5/1) to obtain 1-(diallylethoxysilyl)-4-ethynylbenzene (5 mg, 6% yield).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]#[N:23])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[NH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]#[N:23])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Add trifluoroacetic acid (23 mL, 34.7 g, 304 mmol) to 4-cyanomethylpiperidine-1-carboxylic acid t-butyl ester (5.43 g, 24.21 mmol) in DCM (25 mL) and stir at room temperature for 18 hr. Remove the solvent in vacuo and dissolve in methanol (50 mL) and pour onto an SCX-2 column. Elute with 2 M ammonia in methanol and evaporate the eluent to give piperidin-4-ylacetonitrile as an oil which solidifies on standing (2.78 g, 92%). MS (m/z): 125.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[O:7])=[CH:4][C:3]=1[N+:19]([O-])=O.C(=O)([O-])[O-].[Na+].[Na+].[H][H]>[Pd].ClCCCl>[NH2:19][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:2]=1)[C:6]([C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=1)=[O:7]
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: Nc1ccc(C(=O)c2cccc(N)c2)cc1
Temperature: 70 °C
Reaction time: 10 h

Procedure:
To an autoclave there are added 30.7 g (0.1 moles) of 4-chloro-3,4'-dinitro benzophenone, 10.6 g (0.1 moles) of sodium carbonate, 1 g of 5% palladium/alumina catalyst (available from Nihon-Engelhardt Co.) and 250 ml of 1,2-dichloro ethane. With the mixture being stirred at 30°-35° C., the reaction is carried out at a constant pressure for 10 hours by introducing hydrogen into the mixture. After completion of the reaction, the reaction mixture is heated up to 70° C. to be subjected to filtering for removing the catalyst. Then, on cooling, there is obtained 3,4'-diamino benzophenone in the form of yellow needle-like crystals. The crystals are filtered, washed with 20 ml of 1,2-dichloro ethane and dried. Yield 17.6 g (83%). M.P. 121°-122° C. Recrystallization from ethanol gives yellow needle-like pure crystals of said benzophenone. M.P. 122°-122.5° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:22][S:19]([C:5]1[CH:4]=[CH:3][C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][C:6]=1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(F)cc1Nc1cccc2ccccc12
Reactant: C1CNCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1Nc1cccc2ccccc12
Yield: 18.5 %

Procedure:
N-(5-Fluoro-2-(methylsulfonyl)phenyl)naphthalen-1-amine (0.56 g, 1.7 mmol), piperazine (0.46 g, 5.3 mmol), N,N-diisopropylethylamine (0.89 g, 6.8 mmol) were stirred at 80° C. in dry acetonitrile (5 mL) for 48 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 10% methanol in dichloromethane to afford the title compound (120 mg, 18% yield). 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.89 (d, 1H), 7.83 (d, 1H), 7.66 (d, 1H), 7.62 (m, 1H), 7.39 (m, 4H), 6.35 (d, 1H), 6.26 (s, 1H), 3.09 (s, 3H), 2.98 (m, 4H), 2.79 (m, 4H); MS (ESI) m/z: Calculated for C21H24N3O2S: 382.2; Observed: 382.4 (M+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:30])[CH3:9])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>>[O:30]=[C:11]1[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccccc2)OC1=O
Reactant: OB(O)c1cccnc1
Product: C[C@@H](c1ccc(-c2cccnc2)cc1)N1CC[C@](CCCNS(C)(=O)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamide and pyridine-3-boronic acid following procedures analogous to those described in Example 1 Step 2. LC-MS Method 2 tR=1.466 min, m/z=497.3; 1H NMR (CDCl3) 1.33 (m, 1H), 1.53 (d, 3H), 1.63 (m, 1H), 1.84-2.03 (m, 2H), 2.18 (m, 1H), 2.30 (m, 2H), 2.84 (s, 3H), 2.93 (m, 1H), 3.02 (t, 2H), 4.30 (s, 1H), 5.64 (m, 1H), 7.02 (d, 2H), 7.22 (m, 2H), 7.31 (m, 5H), 7.77 (m, 1H), 7.80 (d, 1H), 8.71 (d, 1H), 8.93 (s, 1H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][NH:11]2)[CH:6]=[CH:7][C:8]=1[F:9].CCN(C(C)C)C(C)C.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]([CH:10]2[CH2:15][CH:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][N:11]2[C:30]([O:32][CH3:33])=[O:31])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(F)c(F)c2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.4 %

Procedure:
Methyl 2-(3,4-difluorophenyl)piperidine-4-carboxylate hydrochloride (6.1 g, 20.91 mmol) and DIPEA (9.13 mL, 52.28 mmol) were dissolved in DCM (30 mL). Methyl chloroformate (1.944 mL, 25.09 mmol) was added and the reaction stirred at room temperature for 1.5 h. DCM (170 mL) was added. The organic phase was washed with 0.1 M HCl (2×200 mL), satd NaHCO3 (200 mL), dried with a phase separator and evaporated in vacuo yielding dimethyl 2-(3,4-difluorophenyl)piperidine-1,4-dicarboxylate (6.58 g, 100%) as a dark oil. MS m/z 314 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:32]3[CH2:31][CH2:30][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[Cl:22])[CH2:34][CH2:33]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Clc1ccccc1N1CCNCC1
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(c2ccccc2Cl)CC1

Procedure:
The the hydrochloride of title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(2-chlorophenyl)piperazine. Drying in vacuo at 50° C. for 3½ h gave the title compound; 1H NMR (DMSO-d6): δ8.61-8.55 (br, 1H), 8.29-8.20 (dd-like, 1H), 7.53-7.41 (m, 1H), 7.39-7.17 (m, 7H), 7.14-7.03 (m, 1H), 4.58 (br s, NH+water), 3.85-3.55 (br m, 4H), 3.12-2.99 (br m, 4H); HPLC-MS: m/z=478 (M+H); IR (KBr): ν 1733 (C═O) cm−1.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6].[C:9](#N)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[Br-].[Zn+2].[Br-]>[CH3:6][S:5][CH2:4][CH2:3][C@@H:2]1[CH2:7][O:8][C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:1]1
Reactant: CSCC[C@@H](N)CO
Reactant: N#Cc1ccccc1
Agent: [Br-]
Agent: [Zn+2]
Product: CSCC[C@@H]1COC(c2ccccc2)=N1
Temperature: 120 °C
Reaction time: 90 h
Yield: 48.6 %

Procedure:
A mixture of (R)-methioninol (4.95 g), benzonitrile (8.3 mL) and zinc bromide (250 mg) was stirred at 120° C. for 90 hours under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was washed with water and brine, dried over magnesium sulfate and filtered again. The filtrate was concentrated in vacuo, and the resultant crude product was purified by column chromatography on silica gel (solvent; hexane/ethyl acetate=5/1 to 3/1) to give (R)-4-(2-methylthioethyl)-2-phenyl-4,5-dihydrooxazole (3.94 g, yield: 48.6%) as a colorless oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[C:8]([CH:10]=1)[OH:9])([CH3:3])[CH3:2].[CH:12]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)([CH3:14])[CH3:13].[ClH:22]>C(O)(=O)C>[ClH:22].[CH:12]([N:15]1[CH2:16][CH:17]=[C:18]([C:7]2[C:8]([OH:9])=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=2[OH:11])[CH2:19][CH2:20]1)([CH3:14])[CH3:13]
Reactant: CC(C)N1CCC(=O)CC1
Reactant: CC(C)c1cc(O)cc(O)c1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)c1cc(O)c(C2=CCN(C(C)C)CC2)c(O)c1
Yield: 50 %

Procedure:
5-Isopropyl resorcinol (5.40 g), N-isopropyl-4-piperidone (5.00 g) and 12 ml acetic acid was treated with HCl as described in Example I to give 5.48 g product (50% yield); m.p. 247°-248°.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]([C:7]([O:9]CC)=[O:8])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[OH-].[Na+]>CO>[Cl:1][C:2]1[NH:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc([N+](=O)[O-])c(Cl)[nH]1

Procedure:
A stirred solution of 0.40 gram (0.0018 mole) of ethyl 5-chloro-4-nitropyrrole-2-carboxylate and 10 mL (excess) of an aqueous solution of 10% sodium hydroxide in 25 mL of methanol was warmed to 80° C. where it was maintained during a 1.5-hour period. After this time the reaction mixture was cooled and the methanol was removed under reduced pressure. The concentrate was diluted with 50 mL of water and 50 mL of ethyl acetate, and acidified to a pH of about 2.0. The organic layer was separated, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue. The yield of the subject compound was 0.34 gram. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: FC1C=CC(CN2C(=O)C(CN3CCN(C)CC3)=CC(C3C=CC4OCCC=4C=3)=N2)=CC=1.[C:33]([C:36]1[C:37](=[O:59])[N:38]([CH2:51][C:52]2[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=2)[N:39]=[C:40]([C:42]2[CH:43]=[CH:44][C:45]3[O:49][CH2:48][CH2:47][C:46]=3[CH:50]=2)[CH:41]=1)(O)=[O:34]>>[Cl:58][C:55]1[CH:54]=[CH:53][C:52]([CH2:51][N:38]2[C:37](=[O:59])[C:36]([CH2:33][OH:34])=[CH:41][C:40]([C:42]3[CH:43]=[CH:44][C:45]4[O:49][CH2:48][CH2:47][C:46]=4[CH:50]=3)=[N:39]2)=[CH:57][CH:56]=1
Reactant: O=C(O)c1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(Cl)cc2)c1=O
Agent: CN1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(Cc3ccc(F)cc3)c2=O)CC1
Product: O=c1c(CO)cc(-c2ccc3c(c2)CCO3)nn1Cc1ccc(Cl)cc1
Yield: 32.7 %

Procedure:
The general procedure of Example 1 (4) was repeated by use of 4-carboxy-2-(4-chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one, to thereby yield the title compound as a pale yellow powder (yield: 32.7%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[NH:29][C:30](=[O:42])[CH2:31][CH:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33]([OH:35])=O>CC(N(C)C)=O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:28])[NH:20][N:19]=2)=[CH:13][C:12]=1[N:29]1[C:30](=[O:42])[CH2:31][CH:32]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:33]1=[O:35]
Reactant: O=C(CC(C(=O)O)c1ccccc1)Nc1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC(c2ccccc2)C(=O)N1c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C
Reaction time: 65 h
Yield: 76.4 %

Procedure:
O-Benzotriazol-1-yl-N,N,N′N′-tetramethyluronium tetrafluoroborate (0.726 g, 2.26 mmol) and diisopropylethylamine (0.494 g, 3.8 mmol) were added sequentially at ambient temperature to a stirred solution of N-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-2-phenylsuccinamic acid (0.775 g, 1.7 mmol) in dimethylacetamide (4 ml), the mixture was stirred at ambient temperature for 65 hours, then it was added dropwise to ice-cold water (40 ml). The resulting solid was collected by filtration, washed with water (3 ml), then dried in vacuo. The crude product was dissolved in hot methanol (8 ml), the solution was filtered through a small plug of cotton wool, then the filtrate was added to water (30 ml). The resulting solid was collected by filtration and dried in vacuo to give 1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]-3-phenylpyrrolidine-2,5-dione (0.555 g) as an off-white solid, m.pt. 114–120° C.; 250 MHz 1H-nmr (CDCl3) δ (ppm): 2.8–3.0 (m, 1H) (—CHHCHPh), 3.2–3.4 (m, 1H) (—CHHCHPh), 4.1–4.3 (m, 1H+2H) (—CHPh- and ArCH2—), 7.0–7.4 (m, 8H) (8×ArH), 7.6–7.8 (m, 3H) (3×ArH), 8.4 (d, 1H) (ArH), 10.65 (s, 1H) (CONH); m/z (M+H)+. 428, 92.1% purity.