Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][C:8]1[C:9]([C:23](=O)[NH:24][CH3:25])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2.C[Si]([N:31]=[N+:32]=[N-:33])(C)C.N>C1(C)C=CC=CC=1>[Cl:7][C:8]1[C:9]([C:23]2[N:24]([CH3:25])[N:33]=[N:32][N:31]=2)=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CNC(=O)c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N
Solvent: Cc1ccccc1
Product: COc1nc2cc(Cl)c(Cl)c(-c3nnnn3C)c2nc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
Phosphorous pentachloride (0.136 g, 0.65 mmol) was added to a solution of 6,7-dichloro-2,3-dimethoxy-5-(N-methylcarbamoyl)quinoxaline (Preparation 7, 0.197 g, 0.62 mmol) in toluene (7 mL) and the mixture was heated under reflux under nitrogen for 1 hour. The reaction was cooled to room temperature and trimethylsilyl azide (123 μL, 0.107 g, 0.93 mmol) was added. After stirring at room temperature for 18 hours, dilute aqueous ammonia solution (20 mL) was added and the mixture was extracted with dichloromethane (3×50 mL). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with dichloromethane to give the title compound (0.080 g, 38%) as a white solid.
Reaction SMILES: C1CO[C:3]2([CH2:8][CH2:7][CH:6]([N:9]3[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]4[C:17]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[N:18][N:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=45)=[N:10]3)[CH2:5][CH2:4]2)[O:2]1.Cl.O1CCOCC1>O>[O:2]=[C:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]3[C:17]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=34)=[N:10]2)[CH2:5][CH2:4]1
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C1CCC(n2nc(-c3c(-c4ccccc4)nn4ccccc34)ccc2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 3-[2-(4,4-ethylenedioxycyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]-pyridine (0.68 g), 1N hydrochloric acid (5 ml), and dioxane (10 ml) was stirred at room temperature for 1 hour and heated at 50° C. for 2 hours. The reaction mixture was poured into 50 ml of water and the mixture was extracted with ethyl acetate (20 ml×2). The combined extracts were sequencially washed with saturated aqueous sodium bicarbonate (30 ml) and brine (30 ml), dried over anhydrous sodium sulfate. Evaporation of the solvent gave yellow crystals of 3-[2-(4-oxocyclohexyl)-3-oxo-2,3-dihydropyridazin-6-yl]-2-phenylpyrazolo[1,5-a]pyridine (610 mg).
Reaction SMILES: [CH2:1]([N:10]=[C:11]=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]=[C:8]=[O:9].[CH3:13][N:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH:15]1[CH:20]([CH3:22])[CH3:21]>C(OCC)(=O)C>[CH2:1]([NH:10][C:11]([N:16]1[CH2:17][CH2:18][CH2:19][N:14]([CH3:13])[CH:15]1[CH:20]([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([N:16]1[CH2:17][CH2:18][CH2:19][N:14]([CH3:13])[CH:15]1[CH:20]([CH3:22])[CH3:21])=[O:9]
Reactant: O=C=NCCCCCCN=C=O
Reactant: CC(C)C1NCCCN1C
Solvent: CCOC(C)=O
Product: CC(C)C1N(C)CCCN1C(=O)NCCCCCCNC(=O)N1CCCN(C)C1C(C)C
Reaction time: 8 h

Procedure:
A mixture of 84 g of hexamethylene diisocyanate and 100 g of ethyl acetate is slowly added at temperatures of from 25° to 35° C. to 142 g of N-methyl-2-isopropylhexahydropyrimidine ##STR17## in 150 ml of ethyl acetate. Stirring is continued for 8 hours at room temperature after the reaction has been completed and the ester is finally removed on a rotary evaporator at 100° C. and at 25 mbar.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=O)[C:6]([CH2:14][CH2:15][CH2:16][Cl:17])=[N:5]2.O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:7]1[C:6]([CH2:14][CH2:15][CH2:16][Cl:17])=[N:5][C:4]2[C:9](=[CH:10][C:11]([Cl:12])=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=c1[nH]c2cc(Cl)c(Cl)cc2nc1CCCCl
Reactant: O=P(Cl)(Cl)Cl
Product: ClCCCc1nc2cc(Cl)c(Cl)cc2nc1Cl
Yield: 21 %

Procedure:
6,7-Dichloro-3-(3-chloropropyl)-1H-quinoxalin-2-one (0.68 g, 2.33 mmol) was added to POCl3 (10 ml) and the resulting mixture was heated under reflux for 0.5 hours. The reaction mixture was poured onto ice and extracted with dichloromethane (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and evaporate in vacuo. The resulting oil was purified by flash column chromatography (dichloromethane) to yield 21% of 2,6,7-trichloro-3-(3-chloropropyl)quinoxaline as a colourless oil.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.I[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:13]([N:9]1[CH2:8][CH2:7][CH:6]([C:4]([OH:3])=[O:5])[CH2:11][CH2:10]1)[CH3:14]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCN1CCC(C(=O)O)CC1
Temperature: 25 °C

Procedure:
To ethylpiperidine-4-carboxylate (1 eq) in ethanol was added iodoethane (1.1 eq) and potassium carbonate (2 eq) and the resulting mixture was refluxed for 16 h. The mixture was then cooled to room temperature and filtered. Ethanol was concentrated and partitioned between methylene chloride and water. The organic layer was then washed with saturated sodium chloride solution, dried with sodium sulfate and concentrated. To it was then added concentrated hydrochloric acid and water (2:1) and the mixture was refluxed for 5 h. The resulting 1-(ethyl)piperidine-4-carboxylic acid was then azeotroped with toluene. MS: MH+=158.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.C([Li])CCC.[CH:25]([C:27]1[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH:28]=1)=[O:26]>C1COCC1>[C:15]([O:14][C:13]([NH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([CH:25]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:40])[CH:28]=2)[OH:26])=[CH:3][CH:4]=1)=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)c2ccccc12
Reactant: CC(C)(C)OC(=O)Nc1cc(C=O)ccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(C(O)c2ccc(NC(=O)OC(C)(C)C)c3ccccc23)ccn1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of tert-butyl (4-bromonaphthalen-1-yl)carbamate (WO 2006/010082) (2.09 g, 6.48 mmol) in dry THF (50 mL) under N2 at −78° C. was added n-butyllithium (2.5 M in hexanes, 5.5 mL, 13.8 mmol) over 15 mins. The resulting mixture was maintained at −78° C. for 1.5 hr and then treated with a solution of tert-butyl (4-formylpyridin-2-yl)carbamate (WO 2004/000831) (960 mg, 4.30 mmol) in dry THF (10 mL) in one portion. The reaction mixture was stirred at −78° C. for a further 1 hr and then warmed to RT for 18 hr. The mixture was cooled to 0° C. and the reaction was quenched by the addition of MeOH (5.0 mL), then warmed to RT and partitioned between EtOAc and water. The aq layer was separated and was extracted twice with EtOAc and the combined organic extracts were washed with brine and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 80 g, EtOAc in isohexane, 0-60%, gradient elution) to afford the title compound, Intermediate F1, as a pale yellow solid (1.13 g, 88% purity (LCMS), 49%); Rt 2.22 min (Method 2); m/z 466 (M+H)+ (ES+). The material so obtained was used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][OH:3].O.[OH-].[Na+].[CH2:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16](=O)[CH3:17])[CH:13]=[CH:12][N:11]=1)[CH3:8]>CO>[CH2:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16](=[N:2][OH:3])[CH3:17])[CH:13]=[CH:12][N:11]=1)[CH3:8]
Reactant: NO
Reactant: CCNc1cc(C(C)=O)ccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCNc1cc(C(C)=NO)ccn1
Yield: 87 %

Procedure:
To a mixture of 7 g. (0.1 mole) of hydroxylamine hydrochloride in 40 ml. of water and 50 ml. of 2 N sodium hydroxide was added 11.5 g. (70 mmoles) of 1-(2-ethylamino-4-pyridyl)-1-ethanone, and the resulting mixture heated to boiling. Methanol was carefully added until the mixture became homogeneous. Heating was continued until the mixture became cloudy. The mixture was cooled and the resulting precipitate filtered, washed with water and dried. Recrystallization from toluene gave 10.9 g. (87%) of the desired product, m.p. 155°-156° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][CH:12]([C:14]2[CH:15]=[C:16]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH3:13])[CH:9]=[CH:8][CH:7]=1)#[N:6]
Reactant: N#Cc1cccc(N)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(Nc1cccc(C#N)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 49.3 %

Procedure:
3-aminobenzonitrile (96 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (0.1 g, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(3-cyanophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (44 mg, 48%) as a white solid. Mass Spectrum: M+H+ 447.
Reaction SMILES: [C:1]([C:4]1[C:9](=[O:10])[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)(=[O:3])[CH3:2].C(O[CH:27](OCC(C)(C)C)[N:28]([CH3:30])[CH3:29])C(C)(C)C>>[CH3:27][N:28]([CH3:30])[CH:29]=[CH:2][C:1]([C:4]1[C:9](=[O:10])[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)=[O:3]
Reactant: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Reactant: CCOC(=O)c1cc(C(C)=O)c(=O)[nH]c1C(=O)OCC
Product: CCOC(=O)c1cc(C(=O)C=CN(C)C)c(=O)[nH]c1C(=O)OCC
Temperature: 25 °C
Yield: 70 %

Procedure:
Diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3pyridinedicarboxylate, (25 g, 0.089 mol) and N,N-dimethylformamide dineopentyl acetal (50 mL, 98%, 40.62 g, 0.176 mol) are heated for 30 minutes at 80°-100° C. After cooling to room temperature, the product is obtained as a precipitate and is filtered and washed with hexane to yield 23.4 g, 70% yield, of solid which is recrystallized from isopropanol to give a pure product, melting point 182°-183° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([Sn](CCCC)(CCCC)CCCC)=[N:6][C:7]=2[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Br[C:44]1[C:49]2[CH:50]=[CH:51][NH:52][C:48]=2[CH:47]=[CH:46][N:45]=1>>[CH3:1][N:2]1[C:10]([CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:16][CH2:17]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([C:44]1[C:49]3[CH:50]=[CH:51][NH:52][C:48]=3[CH:47]=[CH:46][N:45]=1)=[N:6][C:7]=2[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Brc1nccc2[nH]ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2nc(CN3CCC(N4CCOCC4)CC3)n(C)c2n1
Product: Cn1c(CN2CCC(N3CCOCC3)CC2)nc2c(N3CCOCC3)nc(-c3nccc4[nH]ccc34)nc21

Procedure:
Following the procedures to prepare 124, 4-(1-((9-Methyl-6-morpholino-2-(tributylstannyl)-9H-purin-8-yl)methyl)piperidin-4-yl)morpholine and 4-bromo-1H-pyrrolo[3,2-c]pyridine were reacted to give 133. LCMS: M+H+=518.3. 1H-NMR (400 MHz, DMSO-d6): δ 11.55 (s, 1H), 8.30 (d, 1H), 7.51 (d, 1H), 7.48 (d, 1H), 7.20 (d, 1H), 4.30 (m, 4H), 3.80 (s, 3H), 3.78 (m, 6H), 3.55 (m, 4H), 2.88 (m, 2H), 2.44 (m, 4H), 2.09 (m, 2H), 1.77 (m, 2H), 1.40 (m, 3H)
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1)[NH2:24]>CN1CCCC1=O.C(OCC)(=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:3]3[N:10]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=4)[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:25]=[CH:26][C:27]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=1
Reactant: OCc1ccc(Cn2ccc3ncnc(Cl)c32)cc1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: OCc1ccc(Cn2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c32)cc1
Temperature: 140 °C
Yield: 93 %

Procedure:
{4-[(4-Chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]phenyl}methanol (354 mg) and 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (488 mg) were dissolved in 1-methyl-2-pyrrolidone (2.58 mL), and the mixture was stirred with heating at 140° C. for 2 hrs. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (80 mL) and partitioned with saturated aqueous sodium hydrogen carbonate (30 mL). The organic layer washed with saturated brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) to give the title compound (588 mg) as a powder.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[CH2:13][CH:14]([CH3:16])[CH3:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.C(OCC)(=O)C>[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:25][C:17](=[O:19])[C@H:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.6 %

Procedure:
N-Cbz-L-leucine (Chemical Dynamics) (1.32 g, 4.97 mmol), L-leucine methyl ester hydrochloride (Aldrich) (0.99 g, 5.47 mmol), 1-hydroxybenzotriazole (0.14 g, 1.0 mmol) and 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (1.05 g, 5.47 mmol) were combined, dissolved in 25 mL of DMF and stirred at room temperature for 15 h. The solution was diluted with ethyl acetate (250 mL) and washed successively with water, 0.1 N HCl, saturated aqueous NaHCO3 and saturated brine, then dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on 230-400 mesh silica gel, eluting with 1:3 ethyl acetate hexanes, to give the title compound as a white solid (1.28 g, 66%). 1H NMR (400 MHz, CDCl3) δ7.37-7.32 (m, 5H), 6.28 (d, 1H), 5.28 (m, 3H), 4.6-4.58 (m, 1H), 4.20 (m, 1H), 3.74 (s, 3H), 1.69-1.54 (m, 6H), 0.96-0.92 (m, 12H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7]>C(O)C>[CH2:2]([C:3]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=1)[CH2:1][CH2:6][CH3:5]
Reactant: Nc1ccccc1N
Solvent: CCO
Product: CCCCc1nc2ccccc2[nH]1
Temperature: 25 °C
Yield: 138 %

Procedure:
To a solution of o-phenylenediamine (0.171 g, 1.58 mmol) in absolute ethanol (8 ml), ethyl valerylimidate (0.313 g, 1.9 mmol) was added, and the mixture was refluxed overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated NaHCO3. The organic phase was separated and the aqueous layer was extracted with ethyl acetate (3×20 ml). The organic layers were combined and washed with brine, dried (MgSO4), and then concentrated in vacuo. The crude product, thus obtained, was purified by medium pressure liquid chromatography (MPLC) on silica-gel using ethyl acetate-hexane (1:1) to give cream colored crystalline solid (0.19 g, 69%). NMR (CDCl3): δ0.92 (t, J=7 Hz, 3H), 1.42(m, 2H), 1.86(m, 2H), 2.95(t, J=7Hz, 2H), 7.22(m, 2H), 7.58(m, 2H); FAB-MS: m/e 174 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=[O:20])=[CH:14][CH:13]=1.Cl>C(Cl)Cl.N1C=CC=CC=1>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([CH:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])=[O:20])=[CH:14][CH:13]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(C(=O)Cc2ccc(F)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid, 8.0 g, 56 mmol) dissolved in anhydrous methylene chloride (100 mL) and pyridine (11 mL), at 0° C. under nitrogen atmosphere, was slowly added 2-(4-fluorophenyl)acetyl chloride (7.6 mL, 9.6 g, 56 mmol). The red solution was stirred at 0° C. for 1.5 h. The reaction mixture was treated with 1 N HCl (13 mL) and diluted with methylene chloride (200 mL). The layers were separated and the organic layer was washed with saturated aqueous sodium chloride, dried and concentrated in vacuo to give 5-(2-(4-fluorophenyl)acetyl)-2,2-dimethyl-1,3-dioxane-4,6-dione. The crude intermediate was suspended in absolute EtOH (150 mL) and the resulting mixture was refluxed for 4 hours. The solvent was then removed in vacuo and the residue was purified by flash column chromatography (SiO2, 230-400 mesh, 8:1 hexane-ethyl acetate gradient elution) to afford the desired product (4.6 g, 37%). 1H NMR (CDCl3) δ 7.23-7.15 (m, 2H), 7.05-6.98 (m, 2H), 4.18 (q, 2H, J=7.0 Hz), 3.81 (s, 2H), 3.46 (s, 2H), 1.26 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 225 (M+H)+.
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][C:16](=[O:18])[N:15]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29](=[O:36])[NH:28][N:27]=3)[CH:22]=[CH:21][C:20]=2[F:37])[C:14](=[O:38])[CH2:13]1)C1C=CC=CC=1.CO>O.[Pd]>[F:37][C:20]1[CH:21]=[CH:22][C:23]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29](=[O:36])[NH:28][N:27]=2)=[CH:24][C:19]=1[N:15]1[C:14](=[O:38])[CH2:13][NH:12][CH2:17][C:16]1=[O:18]
Reactant: O=C1CN(Cc2ccccc2)CC(=O)N1c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: O=C1CNCC(=O)N1c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Temperature: 25 °C

Procedure:
A solution of ammonium formate (0.55 g, 8.8 mmol) in water (5 ml) was added to a stirred mixture of 4-benzyl-1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]piperazine-2,6-dione (1 g, 2.2 mmol; prepared in a manner similar to that described in Example 31), 10% palladium on carbon catalyst (0.33 g) and methanol (15 ml), the mixture was heated under reflux for 1 hour, then it was cooled to ambient temperature and filtered through a pad of Celite filter aid. The filter pad was washed with methanol (50 ml), then the combined filtrate and washings were concentrated in vacuo. The residue was diluted with water (20 ml), the product was extracted into ethyl acetate (4×20 ml), the combined extracts were dried (MgSO4) and the solvent was removed in vacuo to give 1-[2-fluoro-5-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]piperazine-2,6-dione (0.8 g) as a pale brown solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 3.3 (2× overlapping d, 4H) (2×ring CH2), 4.25 (s, 2H) (ArCH2—), 6.95–7.2 (m, 2H) (2×ArH), 7.7–7.9 (m, 3H) (3×ArH), 7.95 (d, 1H) (ArH), 8.2 (d, 1H) (ArH), 9.7 (s, 1H) (piperazine NH), 12.6 (s, 1H) (CONH).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:10][CH2:11][CH3:12])=[O:9]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][C:4](=[CH:13][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)C=C1CCOCC1
Yield: 56.4 %

Procedure:
A solution of tetrahydo-4H-pyran-4-one (5 g, 50 mmol) in CH2Cl2 (500 mL) was treated with (carbethoxymethylene)triphenylphosphorane (19.29 g, 55 mmol) stirred at reflux for 24 h, concentrated and purified via silica gel column chromatography eluting with 10% ethyl acetate/hexane to give 4.8 g of the title compound. MS (APCI): m/z 188 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH2:7]Br.[CH3:11][NH:12][CH2:13][CH2:14][CH:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC1(C)CCCC(C)(C)N1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH2:7][N:12]([CH2:13][CH2:14][CH:15]([OH:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:11])[CH:9]=1
Reactant: Fc1ccc(Cl)cc1CBr
Reactant: CNCCC(O)c1ccccc1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CC#N
Product: CN(CCC(O)c1ccccc1)Cc1cc(Cl)ccc1F
Yield: 73.2 %

Procedure:
A solution of 5-chloro-2-fluorobenzyl bromide (10.5 g) in acetonitrile (100 ml) was added dropwise to a mixture of N-methyl-3-hydroxy-3-phenylpropylamine (7.7 g), 2,2,6,6-tetramethylpiperidine (8 ml) and acetonitrile (100 ml) After 12 h the mixture was filtered, the filtrate evaporated and the residue chromatographed on silica (Woelm Grade 1) using ether as eluant to give the title compound as an oil (10.5 g), b.p. 160°/0.5 mm.
Reaction SMILES: C([BH3-])#N.[Na+].Cl.[CH3:6][C:7]1[C:11]([CH3:12])=[C:10]([NH:13][S:14]([C:17]2[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[O:30][CH:31]=[CH:32][N:33]=4)=[CH:25][C:24]=3[CH2:34][NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[O:9][N:8]=1.[CH:41](=O)[CH3:42]>CO>[CH3:6][C:7]1[C:11]([CH3:12])=[C:10]([NH:13][S:14]([C:17]2[C:18]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[O:30][CH:31]=[CH:32][N:33]=4)=[CH:25][C:24]=3[CH2:34][N:35]([CH2:41][CH3:42])[CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])[O:9][N:8]=1
Reactant: CC=O
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(-c3ncco3)cc2CNCC(F)(F)F)c1C
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCN(Cc1cc(-c2ncco2)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C)CC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
Sodium cyanoborohydride (13 mg; 0.20 mmol) was added to a mixture of N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-[[(2,2,2-trifluoroethyl)amino]methyl][1,1'-biphenyl]-2-sulfonamide, monohydrochloride (55 mg; 0.10 mmol, prepared as in Example 45), 100 mg of 3 Å molecular sieves and acetaldehyde (0.10 ml; 1.80 mmol) in 1 ml of methanol at room temperature. After stirring for 18 hours at room temperature, the reaction mixture was filtered through a nylon syringe filter. The filtrate was concentrated and the residue was partitioned between EtOAc (20 ml) and saturated NaHCO3 solution (20 ml), the aqueous layer was extracted with EtOAc (20 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO4) and concentrated. The residue was chromatographed on a 2.5×6 cm silica gel column, using EtOAc:Hex, 1:1 as the mobile phase. The pure fractions were concentrated to an oil that was dissolved in ~0.2 ml of MeOH. Water (3 ml) was added and the turbid mixture was frozen. Lyophilization afforded 24 mg (49%) of the title compound of this Example as a white solid.