Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[N:13]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[F:29][C:30]([F:42])([F:41])[C:31]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([OH:34])[C:32]#[CH:33].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[NH2:1][C:2]1[N:3]([CH2:27][CH3:28])[C:4]2[C:9]([C:10](=[O:25])[C:11]=1[C:12]1[N:13]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[CH:15][N:16]=1)=[CH:8][CH:7]=[C:6]([C:33]#[C:32][C:31]([OH:34])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([F:29])([F:41])[F:42])[N:5]=2
Reactant: CCn1c(N)c(-c2nccn2COCC[Si](C)(C)C)c(=O)c2ccc(Cl)nc21
Reactant: C#CC(O)(c1ccccc1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c(N)c(-c2nccn2COCC[Si](C)(C)C)c(=O)c2ccc(C#CC(O)(c3ccccc3)C(F)(F)F)nc21
Yield: 27.1 %

Procedure:
Same procedure as that described in example 5, stage 5.4, starting from 0.4 g (0.95 mmol) of 2-amino-7-chloro-1-ethyl-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-1H-[1,8]naphthyridin-4-one, 0.4 g (1.9 mmol) 1,1,1-trifluoro-2-phenyl-but-3-yn-2-ol, 33 mg (0.05 mmol), bis(triphenylphosphine)palladium(II) dichloride, 18 mg (0.1 mmol) copper (I) iodide, 3 ml DMF (degassed), 3 ml triethylamine (degassed). 0.15 g of the title compound is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)CO.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:29]([SH:31])[CH3:30]>C(O)(C)C.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([S:31][CH2:29][CH3:30])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCS
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: OCCO
Solvent: CC(C)O
Product: CCSc1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Temperature: 120 °C
Reaction time: 1 h

Procedure:
Lit. Org. Lett. 2002, 4(20), 3517-3520. To a stirred suspension of 0.66 mmol 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) in 5 ml isopropanol were added 1.32 mmol ethylene glycol, 0.07 mmol copper(I) iodide, 1.32 mmol cesium carbonate, 0.13 mmol 1,20-phenanthroline and 3.29 mmol ethyl mercaptan and the reaction mixture was stirred at 120° C. for 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid. MS (m/e): 260.0 ({37Cl}[M+H− Me2C═CH2]+, 42%), 258.1 ({35Cl}[M+H− Me2C═CH2]+, 100%).
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6](=[O:9])[CH2:7][CH3:8].[C:10]([O:17][CH2:18][CH3:19])(=[O:16])[C:11]([O:13]CC)=O>>[O:13]=[C:11]([CH2:5][C:6](=[O:9])[CH2:7][CH3:8])[C:10]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)CC
Temperature: -5 °C
Reaction time: 8 h

Procedure:
To a solution of sodium ethoxide (2.33 g, 34 mmol) in absolute alcohol (40 mL) was added a mixture of 2-butanone (2.45 g, 34 mmol) and diethyl oxalate (5 g, 34 mmol) dropwise at −5° C. The reaction mixture was stirred at −5° C. overnight and then concentrated. The resulting residue was partitioned between water (20 mL) and ethyl acetate (70 mL*3). The aqueous layer was acidified to pH 2 with dilute H2SO4 and then extracted with ethyl acetate (50 ml*3). The combined organic phase was dried over anhydrous Na2SO4, The organic solvent was evaporated in vacuo, and the residue was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH3:34][C:35](OC(C)=O)=[O:36]>CCO.Cl[Ni]Cl>[CH2:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[N:25]=[CH:26][C:27]([CH2:28][NH:29][C:35](=[O:36])[CH3:34])=[CH:30][CH:31]=3)[CH2:20][CH2:19]2)=[N:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Reactant: CC(=O)OC(C)=O
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)NCc1ccc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)CC2)nc1
Reaction time: 2 h
Yield: 52 %

Procedure:
In a 100 ml, round-bottom flask equipped with a stir bar, 6-[4-(4-Benzyl-phthalazin-1-yl)-piperazin-1-yl]-nicotinonitrile (150 mg, 0.362 mmol) is dissolved in anhydrous EtOH (7 mL) followed by the addition of NiCl2 (0.398 mmol). NaBH4 (0.723 mmol) is added in portions and the reaction is stirred for 2 h under a N2 atmosphere. The septum is removed and Ac2O (1.08 mmol) is added. The reaction is capped again and stirred for one additional hour. LC/MS shows full conversion to the acylated product. The reaction is filtered through a Celite pad and rinsed with 50 ml of MeOH. The final compound is purified by preparative HPLC using a C-18 column and propanol as the modifier (85 mg, 52% yield).
Reaction SMILES: [CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:22]([O:27][C@@H:28]([C:30]1[N:35]=[C:34](OS(C)(=O)=O)[CH:33]=[CH:32][N:31]=1)[CH3:29])(=[O:26])[CH2:23]CC>ClCCl>[C:22]([O:27][C@@H:28]([C:30]1[N:31]=[C:32]([N:11]2[CH2:12][CH2:13][C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)([OH:14])[CH2:9][CH2:10]2)[CH:33]=[CH:34][N:35]=1)[CH3:29])(=[O:26])[CH3:23]
Reactant: CCCC(=O)O[C@H](C)c1nccc(OS(C)(=O)=O)n1
Reactant: OC1(Cc2ccccc2)CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H](C)c1nccc(N2CCC(O)(Cc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-benzyl-4-hydroxypiperidine (0.95 g, 5.0 mmol) and triethylamine (0.51 g, 5.0 mmol) in dichloromethane (10 mL) was added (R)-1-(4-methanesulfonyloxy-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Eight, 123 g, 4.0 mmol) and stirred at ambient temperature for 18 h. The mixture was washed once with water, once with saturated aqueous sodium chloride and the organic layer was dried over sodium sulfate and filtered. The filtrate was evaporated to an oil which was purified by flash chromatography (95:5 dichloromethane:methanol) to give the title compound of Example 174, Step A as a viscous oil, 0.99 g (52%). 1H NMR (CDCl3, 300 MHz) δ 0.95 (t, 3H), 1.53 (d, 3H), 1.65-1.78 (m, 4H), 1.88 (m, 2H), 2.08 (m, 2H), 2.48 (t, 2H), 3.45 (m, 2H), 4.42 (br s, 1H), 5.68 (q, 1H), 6.41 (d, 1H), 7.30-7.48 (m, 5H), 8.18 (d, 1H); MS (CI) 384 (MH+).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5]P(=O)(OC)OC.[CH3:19][O:20][C:21](=[O:37])[CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:33](=[O:34])[CH2:32][CH2:31][CH2:30][C@@H:29]1[CH:35]=O>C1COCC1>[CH3:19][O:20][C:21](=[O:37])[CH2:22][O:23][CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C@@H:29](/[CH:35]=[CH:5]/[C:4](=[O:3])[CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:30][CH2:31][CH2:32][C:33]1=[O:34]
Reactant: COP(=O)(CC(=O)Cc1ccccc1)OC
Reactant: COC(=O)COCCCCN1C(=O)CCC[C@@H]1C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
Sodium hydride (60% dispersion in oil, 14 mg, 0.35 mmol) was added to a solution of dimethyl 2-oxo-3-phenylpropylphosphonate (83 mg, 0.34 mmol) in THF (1.0 mL) at 0° C. After 1 h at 0° C., [4-((R)-2-formyl-6-oxo-piperidin-1-yl)-butoxy]-acetic acid methyl ester (94 mg, 0.35 mmol) in THF (1 mL) was added via cannula. The reaction was allowed to warm to rt. After 22 h at rt, the reaction was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (30% →50% EtOAc/CH2Cl2, gradient) afforded 42 mg (31%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]2[CH2:14][OH:15])=[C:6]([O:16][CH3:17])[CH:5]=[C:4]([O:18][CH3:19])[C:3]=1[C:20](=[O:22])[CH3:21].CO[C:25](=O)[C:26]1[CH:31]=[C:30]([N:32]([CH3:34])[CH3:33])[CH:29]=[CH:28][C:27]=1[Cl:35].[H-].[Na+]>CN(C=O)C>[Cl:35][C:27]1[CH:28]=[CH:29][C:30]([N:32]([CH3:34])[CH3:33])=[CH:31][C:26]=1[C:25]1[O:1][C:2]2[C:3]([C:20](=[O:22])[CH:21]=1)=[C:4]([O:18][CH3:19])[CH:5]=[C:6]([O:16][CH3:17])[C:7]=2[C@@H:8]1[CH2:12][CH2:11][N:10]([CH3:13])[C@H:9]1[CH2:14][OH:15]
Reactant: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2CO)c(O)c1C(C)=O
Reactant: COC(=O)c1cc(N(C)C)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)cc(-c3cc(N(C)C)ccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO

Procedure:
Compound of example 6 (0.8 g, 2.58 mmol) in dry DMF (15 mL) was reacted with methyl-2 chloro-5-dimethylaminobenzoate (1.65 g, 7.7 mmol) in the presence of NaH (50%, 0.62 g, 12.9 mmol) as described in example 16 to obtain the title compound.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[C:8]([CH2:19][CH2:20][CH3:21])=[CH:9][C:10]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:22].F[C:24]1[CH:33]=[CH:32][C:27]([C:28]([NH:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.C1CCN2C(=NCCC2)CC1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:31][NH:30][C:28](=[O:29])[C:27]1[CH:32]=[CH:33][C:24]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:10]3[CH:9]=[C:8]([CH2:19][CH2:20][CH3:21])[C:6]4[O:7][CH:2]([CH3:1])[C:3](=[O:22])[NH:4][C:5]=4[CH:11]=3)[CH2:18][CH2:17]2)=[CH:25][CH:26]=1
Reactant: CCCc1cc(CN2CCNCC2)cc2c1OC(C)C(=O)N2
Reactant: CNC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1cc(CN2CCN(c3ccc(C(=O)NC)cc3)CC2)cc2c1OC(C)C(=O)N2
Temperature: 120 °C
Reaction time: 4 h
Yield: 18.6 %

Procedure:
In a 20 mL scintillation vial was added 2-methyl-6-(piperazin-1-ylmethyl)-8-propyl-2H-benzo[b][1,4]oxazin-3(4H)-one 358E (67 mg, 0.221 mmol) and 4-fluoro-N-methylbenzamide (50.7 mg, 0.331 mmol) in DMSO (1.104 mL) and stirred at 120° C. for 4 h. DBU (0.133 mL, 0.883 mmol) was added and the reaction mixture was stirred at 120° C. for 18 h. The reaction was concentrated in vacuo to remove DBU, and then K2CO3 (61.0 mg, 0.442 mmol) was added. The mixture was heated overnight at 120° C. The reaction was subsequently filtered and the crude material was purified by prep HPLC 20-45% acetonitrile in water. The appropriate fractions were collected and concentrated in vacuo to give the title compound as a yellow solid (18 mg, 0.041 mmol, 18.67% yield). 1H NMR (DMSO-d6, 400 MHz): δ=10.89 (s, 1H), 10.73 (br. s., 1H), 8.04 (br. s., 1H), 7.75 (d, J=8.8 Hz, 1H), 7.24 (s, 1H), 7.11 (s, 1H), 6.95-7.04 (m, 2H), 6.87 (d, J=2.0 Hz, 1H), 4.66-4.72 (m, 1H), 4.64 (d, J=6.6 Hz, 2H), 3.26 (t, J=7.1 Hz, 2H), 3.03 (q, J=6.7 Hz, 2H), 2.30-2.45 (m, 3H), 1.61-1.67 (m, 2H), 1.55 (d, J=6.8 Hz, 5H), 1.40 (d, J=6.8 Hz, 3H), 0.86-0.93 ppm (m, 3H). ESI-MS: m/z 437.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:16]3[N:20]=[C:19]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[O:18][N:17]=3)[CH:15]=[C:10]2[N:9]=[CH:8]1.FC(F)(F)C(O)=O>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:16]3[N:20]=[C:19]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[O:18][N:17]=3)[CH:15]=[C:10]2[N:9]=[CH:8]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(-c5noc(C6CCN(C(=O)OC(C)(C)C)CC6)n5)cnc43)cc2OC)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(COc2ccc(Cn3cnc4cc(-c5noc(C6CCNCC6)n5)cnc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a stirred solution of tert-butyl 4-(3-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (0.14 g, 0.22 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (0.20 g, 1.79 mmol). The reaction mixture was allowed to stir at room temperature. After 1 h, the mixture was diluted with cold saturated sodium carbonate solution. The phases were separated, and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to provide 0.067 g (57%) of the product as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 9.02 (d, J=1.5 Hz, 1H), 8.75 (s, 1H), 8.58 (d, J=2.0 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 7.75 (dd, J=8.5, 2.0 Hz, 1H), 7.16 (d, J=1.5 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.89 (dd, J=8.0, 2.0 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 5.48 (s, 2H), 4.98 (s, 2H), 3.84 (s, 3H), 3.74 (s, 3H), 3.26-3.21 (m, 1H), 3.02-3.00 (m, 2H), 2.65-2.61 (m, 2H), 2.02-2.00 (m, 2H), 1.75-1.67 (m, 2H) ppm; (M+1)=528.
Reaction SMILES: [CH2:1]([C:4]1(O)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([B:14]3[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]3)[CH:12]=2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCCl>[CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([B:14]3[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]3)[CH:12]=2)[O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(O)CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCC1CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
A stirred solution of 4-allyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-4-ol (1.80 g, 5.69 mmol) and triethylsilane (7.27 ml, 45.5 mmol) in DCE (30 ml) was treated with TFA (14.03 ml, 182 mmol) by rapid addition at ambient temperature. The reaction was stirred for 10 min, then carefully quenched with sat'd. aq. NaHCO3 (200 mL). The organic layer was concentrated and the residue was purified by biotage (80 g SiO2, 0% (3 CV), 0-60% (15 CV), 60% (2 CV), EtOAc in hexanes) to afford the desired product (0.942 g, 3.14 mmol, 55.1% yield) as a viscous clear oil. 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.56 (dd, J=8.2, 1.4 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 5.90-5.76 (m, 1H), 5.15-5.04 (m, 2H), 4.23-4.14 (m, 2H), 2.89 (dq, J=10.0, 5.0 Hz, 1H), 2.75-2.62 (m, 1H), 2.35-2.22 (m, 1H), 2.09-1.96 (m, 1H), 1.92-1.81 (m, 1H), 1.34 (s, 12H). LCMS (M+H)=301.3.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH2:36])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]>C(#N)C>[CH2:20]([N:23]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:34][CH2:35][NH:36][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:24][CH2:25][CH3:26])[CH2:21][CH3:22]
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Reactant: CCCN(CCC)CC1CCCCN1CCN
Solvent: CC#N
Product: CCCN(CCC)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2cccnc21
Yield: 66 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 2-[2-[(dipropylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 66% of theory. Colourless crystals, m.p. 149°-151° C. (acetonitrile).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)=[CH:5][CH:4]=1.[OH-].[Na+].[C:24]([O:28][CH2:29][CH3:30])(=[O:27])[CH:25]=[CH2:26]>O1CCCC1.CN(C)C=O>[O:19]=[C:14]1[CH2:13][CH2:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:20])[F:21])=[CH:8][CH:7]=3)[CH:10]=2)[N:15]1[CH2:26][CH2:25][C:24]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: C=CC(=O)OCC
Reactant: O=C1CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1C(=O)CCc2cc(-c3ccc(C(F)(F)F)cc3)ccc21
Reaction time: 4 h
Yield: 58 %

Procedure:
To a solution of 6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-2(1H)-one, prepared as described above (90 mg, 0.31 mmol) in anhydrous tetrahydrofuran (3 mL) was added at room temperature 20-40 mesh beads of sodium hydroxide (48 mg, 1.20 mmol) and ethyl acrylate (1.200 g, 1.20 mmol) in anhydrous N,N-dimethylformamide (1 mL). The reaction mixture was stirred for 4 hours under an atmosphere of dry N2, followed by addition of a second portion of sodium hydroxide (96 mg, 2.40 mmol). The reaction was followed by LCMS and stirring was continued until all of the starting material had disappeared. Solvent was removed from the reaction mixture under reduced pressure, diluted with ethyl acetate (20 mL), and aqueous Na2SO3 (10 mL) added. The aqueous phase was extracted with ethyl acetate (3×20 mL), and the combined organic phase successively washed with 2N sodium carbonate (20 mL), 30% ammonium chloride (20 mL), brine (20 mL), and dried over magnesium sulfate. Evaporation of the solvent gave a crude mixture that was purified by reverse phase HPLC with a gradient of acetonitrile/water (2% to 98%) to afford ethyl 3-(2-oxo-6-(4-(trifluoromethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)propanoate (65 mg, 0.18 mmol, 58%). LCMS mz 364.0 (M+H), 386.0 (M+Na), anal HPLC>99% in purity. 1H NMR (400 MHz; CD3CN) δ7.87 (d, J=8.2 Hz, 2H); 7.81 (d, J=8.6 Hz, 2H); 7.66 (d, J=2.3 Hz, 1H); 7.63 (m, 1H); 7.26 (d, J=8.6 Hz, 1H); 4.25 (m, 2H); 3.02 (m, 2H); 2.67 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][O:20][C:21](=[O:25])[CH2:22][CH2:23][NH2:24].C(N(CC)CC)C.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:19][O:20][C:21](=[O:25])[CH2:22][CH2:23][NH:24][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: COC(=O)CCN
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCNC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
To a mixture of 4-benzyloxybenzoic acid (8.92 g, 39.08 mmol) and 3-amino-propionic acid methyl ester hydrochloride (6.00 g, 42.98 mmol) in CH2Cl2 (100 mL) was added DMAP (catalytic), triethylamine (6.60 mL, 47.35 mmol), and EDCI (9.00 g, 46.94 mmol). The mixture was stirred at RT for 12 h. The mixture was diluted with CH2Cl2. The organics were washed with 1N HCl, 2N NaOH, water, and brine (1×100 mL each), and dried with MgSO4 to yield 11.28 g (92%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[O:3][CH2:2]1.C([Mg]Cl)(C)C.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19](=[O:27])[C:20](=[O:26])[NH:21]2>O1CCCC1>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[C:19]([OH:27])([C:7]1[C:8]([OH:10])=[CH:9][C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=1)[C:20](=[O:26])[NH:21]2
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C1Nc2cccc(Cl)c2C1(O)c1cc2c(cc1O)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of 1,3-benzodioxol-5-ol (4.86 g, 22.0 mmol) in anhydrous tetrahydrofuran (100 mL) was added dropwise a solution of isopropyl magnesium chloride (49.6 mmol, 24.8 mL, 2.0 M solution in tetrahydrofuran) over 10 min at 0° C. The reaction mixture was stirred for 30 min upon which time 4-chloroisatin (4.00 g, 22.0 mmol) was added in one portion. The reaction mixture was stirred at ambient temperature for 2 h and quenched by the addition of 10% aqueous hydrochloric acid (25.0 mL) and the mixture was concentrated in vacuo to dryness. The residue was diluted with ethyl acetate (100 mL), washed with saturated ammonium chloride (3×30.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was triturated with hot diethyl ether to afford 4-chloro-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (6.70 g, 95%) as a beige solid: mp 250-253° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.30, (s, 1H), 9.04 (s, 1H), 7.20 (s, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.74 (d, J=8.2 Hz, 1H), 6.70 (d, J=7.7 Hz, 1H), 6.45 (s, 1H), 6.17 (s, 1H), 5.88 (d, J=6.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 178.1, 148.6, 147.0, 145.6, 139.6, 130.6, 130.1, 129.6, 122.3, 118.6, 108.9, 108.4, 101.1, 97.4, 75.8; MS (ES−) m/z 304.2 (M−17), 302.2 (M−17).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([CH3:13])=[O:12]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:10][C:11](=[O:12])[CH:13]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)=O
Product: O=C(C=Cc1ccc(F)cc1)C=Cc1ccc(F)cc1

Procedure:
Commercially available 4-fluorobenzaldehyde of formula V-1 is condensed with acetone, under basic conditions, to provide 1,5-Bis-(4-fluorophenyl)-penta-1,4-dien-3-one of formula V-2. The dienone is reduced with magnesium in methanol to provide the ketone of formula V-3. The ketone of formula V-3 is converted to dihydropyrone products of formula V-8 using chemistry analogous to that described in Chart U for the sequence of reactions from U-3 to U-8.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].Cl[CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:31]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[C:30]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:31]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: ClCc1cncc(-c2ccccc2)c1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cncc(-c4ccccc4)c3)cc2)nc1OCC
Temperature: 80 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (700 mg), 3-chloromethyl-5-phenylpyridine (500 mg), potassium carbonate (500 mg) and N,N-dimethylformamide (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-(5-phenyl-3-pyridylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (720 mg, yield: 67%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]2[N:9]([CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[N:7]=[C:6]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]=2[CH2:4][CH2:3]1>[Pd].C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]2[CH:5]([CH:6]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:7][C:8](=[O:15])[N:9]2[CH:12]([CH3:14])[CH3:13])[CH2:4][CH:3]=1
Reactant: CC1CCc2c(-c3ccccc3)nc(=O)n(C(C)C)c2C1
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: CC1=CCC2C(=C1)N(C(C)C)C(=O)NC2c1ccccc1

Procedure:
To 14 g. of 7-methyl-1-isopropyl-4-phenyl-5,6,7,8-tetrahydro 2(1H)-quinazolinone in 280 ml. xylene is added 0.35 g. palladium on charcoal catalyst (10%) and the mixture refluxed for 24 hours. The catalyst is then removed by filtration and the filtrate evaporated to leave a crystalline residue which crystallizes from ethyl acetate to yield 7-methyl-1-isopropyl-4-phenyl-4,5-dihydro 2(1H)-quinazolinone.