Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[NH:17][CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=[CH2:27])[CH:21]=1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:27][CH2:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:28])[F:29])[CH:21]=1)[C:6]1[CH2:11][C@@H:12]3[NH:17][C@H:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1
Reactant: C=Cc1cccc(C(F)(F)F)c1
Product: Cc1ccc2c(c1)c1c(n2CCc2cccc(C(F)(F)F)c2)C[C@H]2CCC[C@@H]1N2

Procedure:
The coupling of 2-methyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110 mg, 0.486 mmol; Example 118A) and 1-(trifluoromethyl)-3-vinylbenzene (167 mg, 1.00 mmol; Aldrich) was performed according to the procedure described in Example 114B to afford the title compound as a racemic mixture. Individual enantiomers were obtained by preparative chiral supercritical fluid chromatography (ChiralPak® OD-H 5 μm column, 21×250 mm, 35° C., 10-50% gradient of CH3OH—CO2 containing 0.1% diethylamine, 20 minutes) to afford the title compound as the first-eluting enantiomer: 1H NMR (300 MHz, methanol-d4) δ ppm 0.97-1.14 (m, 1H), 1.23-1.43 (m, 2H), 1.62 (dd, J=13, 2 Hz, 1H), 1.75-1.97 (m, 2H), 2.09 (d, J=17 Hz, 1H), 2.40 (s, 3H), 2.90 (dd, J=17, 7 Hz, 1H), 3.10-3.25 (m, 2H), 3.49 (t, J=5 Hz, 1H), 4.27-4.42 (m, 3H), 6.93 (dd, J=8, 1 Hz, 1H), 7.14 (s, 1H), 7.18-7.24 (m, 2H), 7.29 (s, 1H), 7.35 (t, J=8 Hz, 1H), 7.42-7.48 (m, 1H); MS (DCI/NH3) m/z 399 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F-:14].[K+]>O1CCOCC1.O>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([F:14])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1cccc(S(=O)(=O)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 86.4 %

Procedure:
3-Nitrobenzenesulphonyl chloride (10 g) was dissolved in 1,4-dioxane (30 ml) and stirred at room temperature. To this solution was added a solution of potassium fluoride (3.9 g) in water (5 ml) and the stirring continued at room temperature for 5 hours. The reaction mixture was allowed to stand at room temperature overnight and was poured into ice/water. The product was extracted into dichloromethane, the solvent was dried (MgSO4) and evaporated under reduced pressure to give the title compound (8 g). This material was sufficiently pure for the next stage of the synthesis.
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:20]([C:28](=[CH:34][NH:35][C:36]1[N:40]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[N:39]=[C:38]([CH3:47])[CH:37]=1)[C:29]([O:31]CC)=O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>O>[OH:31][C:29]1[C:28]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:27])=[CH:34][N:35]=[C:36]2[N:40]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[N:39]=[C:38]([CH3:47])[C:37]=12
Reactant: CCOC(=O)C(=CNc1cc(C)nn1-c1ccccn1)C(=O)c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O
Product: Cc1nn(-c2ccccn2)c2ncc(C(=O)c3ccccc3)c(O)c12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 33.3 %

Procedure:
A mixture of methanesulfonic acid (30 mL) and phosphorus pentoxide (6 g) was heated at 100° C. The mixture was stirred thoroughly at the temperature, with gradual addition of powdery ethyl 2-benzoyl-3-[[3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]-2-propenoate (3.0 g, 8.0 mmol). The mixture was further heated and stirred at the temperature for 30 minutes. The solution was cooled to room temperature, iced water was added thereto. The solution was neutralized by the addition of an aqueous sodium hydroxide solution, and organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Purification of the residue by basic silica gel column chromatography (chloroform) gave the title compound (880 mg, 34% yield).
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([O:25][CH3:26])=[CH:5][C:6]2[CH2:15][CH:14]3[N:9]([CH2:10][CH2:11][C:12]4[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:13]=43)[CH2:8][C:7]=2[CH:24]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH:32]=[CH:33][C:34](Cl)=[O:35]>N1C=CC=CC=1>[CH3:23][O:22][C:17]1[C:18]([O:20][CH3:21])=[CH:19][C:12]2[CH2:11][CH2:10][N:9]3[CH:14]([CH2:15][C:6]4[CH:5]=[C:4]([O:25][CH3:26])[C:3]([O:2][C:34](=[O:35])[CH:33]=[CH:32][C:31]5[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:29]([O:28][CH3:27])[CH:30]=5)=[CH:24][C:7]=4[CH2:8]3)[C:13]=2[CH:16]=1
Reactant: COc1ccc(C=CC(=O)Cl)cc1OC
Reactant: COc1cc2c(cc1O)CN1CCc3cc(OC)c(OC)cc3C1C2
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)Oc2cc3c(cc2OC)CC2c4cc(OC)c(OC)cc4CCN2C3)cc1OC
Yield: 37.4 %

Procedure:
1.9 g of 10-hydroxy-2,3,11-trimethoxy-5,6,13,13a-tetrahydro-8H-dibenzo[a, g]quinolizine hydrochloride was treated in the same manner as described in Example 6, using 2.0 g of 3,4-dimethoxycinnamoyl chloride and 20 ml of anhydrous pyridine and there was obtained 1.0 g (38.4% yield) of 5,6,13,13a-tetrahydro-2,3,11-trimethoxy-10-(3', 4'-dimethoxycinnamoyloxy)-8H-dibenzo[a, g] quinolizine as a pale brown powder. The methiodide derived from this compound was found to be in agreement with the methiodide of the compound obtained in Example 4 as determined from the melting point and IR spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.[BH-](O[C:31]([CH3:33])=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:8][C@@H:7]([C:31]2[CH:33]=[CH:12][CH:11]=[CH:4][CH:3]=2)[CH3:6])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1ncc(C=O)cc1-c1ccc(C(F)(F)F)cc1
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ncc(CN[C@H](C)c2ccccc2)cc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
R-α-Methyl benzylamine (0.12 mL, 0.928 mmol) and 6-methoxy-5-(4-(trifluoromethyl)phenyl)-3-pyridinecarbaldehyde (0.261 g, 0.928 mmol) were dissolved in 3.0 mL of 1,2-dichloroethane in a 10 mL round bottom flask. The solution was allowed to stir at 25° C. for 1 h, at which point NaBH(OAc)3 (0.295 g, 1.39 mmol) was added in one portion. The reaction was then stirred for 16 h at 25° C. The reaction was quenched by adding 5N NaOH (1.5 mL) and stirring vigorously for 30 min. The layers were separated and the aqueous layer was washed with DCM (3×2.0 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give crude product, which was then purified by silica gel chromatography (1:1 hexane-EtOAc) to afford (1R)—N-((6-methoxy-5-(4-(trifluoromethyl)phenyl)-3-pyridinyl)methyl)-1-phenylethanamine 1. MS m/z: 387 (MH+).
Reaction SMILES: [N:1]([CH:4]([C:8]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](=[O:25])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][N:14]=2)[N:9]=1)[CH:5]([CH3:7])[CH3:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:1][CH:4]([C:8]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](=[O:25])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][N:14]=2)[N:9]=1)[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)C(N=[N+]=[N-])c1nc2nccnc2c(=O)n1Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)C(N)c1nc2nccnc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
Formula 107 where R2 and R3 are H; R5 is Benzyl; R6 is Isopropyl; R6′ is H; X and Y are —C═; and W and Z are —N═: To a solution of THF (100 mL), 2-(1-azido-2-methyl-propyl)-3-benzyl-3H-pteridin-4-one (3.75 mmol) and triphenylphosphine (0.984 g, 3.75 mmol) was added 2N HCL (15 mL). The reaction mixture was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The residue was purified by flash silica gel chromatography using EtOAc-MeOH (50:1 to 10:1) as eluent to give the desired amino product of Formula 107, 2-(1-amino-2-methyl-propyl)-3-benzyl-3H-pteridin-4-one (0.880 g, 76% from Formula 105). MS (Cl) M/E: 310.2.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[CH:4][C:5](=[O:21])[N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:18])=[O:17])[C:11]([O:13]CC)=[O:12])[CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([F:33])[CH:25]=1.CC1CCCO1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Li+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:3]2[C:2]([F:1])=[CH:7][N:6]([CH2:8][CH2:9][C@@:10]([CH3:20])([S:16]([CH3:19])(=[O:17])=[O:18])[C:11]([OH:13])=[O:12])[C:5](=[O:21])[CH:4]=2)=[C:26]([F:33])[CH:25]=1
Reactant: CCOC(=O)[C@@](C)(CCn1cc(F)c(I)cc1=O)S(C)(=O)=O
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CC1CCCO1
Solvent: O
Product: C[C@@](CCn1cc(F)c(-c2ccc(Cl)cc2F)cc1=O)(C(=O)O)S(C)(=O)=O
Temperature: 75 °C
Yield: 74 %

Procedure:
To a 3 L flask with mechanical stirring was added ethyl (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate, T2 (100 g, 225 mmol), (4-chloro-2-fluorophenyl)boronic acid (25.5 g, 146 mmol) and Pd(dppf)2Cl2 (4.93 g, 6.74 mmol). The flask was purged with N2, then degassed 2-methyltetrahydrofuran (1 L) and 3 M aq K3PO4 (225 mL, 674 mmol) were added. The reaction mixture was heated to 75° C. and stirred at this temperature for 30 min. Additional (4-chloro-2-fluorophenyl)boronic acid (25.5 g, 146 mmol) was added and the reaction was allowed to heat for 1.5 h. The mixture was allowed to cool to rt and the aqueous layer was separated. The organic layer was passed through a celite pad and placed back in the reaction vessel. Lithium hydroxide (28 g, 667 mmol) in water (700 mL) was added and the mixture was heated to 50° C. and stirred at this temperature for 1 h. The mixture was allowed to cool and the aqueous layer separated. Celite was added to the aqueous layer and the mixture was filtered through a plug of celite. The filtrate was placed in a flask with overhead stirrer and carefully acidified with 4 M aq HCl and heated to 50° C. with stirring until a precipitate formed. The solid was collected via filtration and dried under vacuum to afford the title compound as a tan solid (68.7 g, 74%). MS (LCMS) m/z 420.6 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (s, 3 H) 2.18 (ddd, J=13.17, 10.24, 5.07 Hz, 1 H) 2.41-2.45 (m, 1 H) 3.10-3.19 (s, 3 H) 3.87-4.08 (m, 2 H) 6.47 (d, J=7.02 Hz, 1 H) 7.42 (dd, J=8.39, 1.95 Hz, 1 H) 7.48-7.56 (m, 1 H) 7.60 (dd, J=9.95, 1.95 Hz, 1 H) 8.06 (d, J=6.05 Hz, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2nc[nH]c(=O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2ncnc(Cl)c2cc1OC

Procedure:
Specifically, 4,5-dimethoxy-2-nitrobenzoic acid (compound 1) was treated with thionyl chloride to form acid chloride, followed by reacting with ammonia to yield 4,5-dimethoxy-2-nitrobenzamide (compound 2). Compound 2 was reduced with sodium borohydride in the presence of catalytic amounts of copper sulphate to give 4,5-dimethoxy-2-aminobenzamide (compound 3), which was directly refluxed with formic acid to yield 6,7-dimethoxyquinazoline-4(3H)-one (compound 4). Compound 4 was refluxed with phosphorus oxytrichloride to give 4-chloro-6,7-dimethoxyquinazoline (compound 5) in good yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[C:11]([CH2:15][OH:16])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I(C1C=CC=CC=1C(O)=O)(=O)=O.O>CS(C)=O>[CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[C:11]([CH:12]=[CH:13][CH:14]=1)[CH:15]=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(CO)cccc1OCc1ccccc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Solvent: CS(C)=O
Product: Cc1c(C=O)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a solution of (3-(benzyloxy)-2-methylphenyl)methanol (228 mg) in DMSO (5.0 mL) was added 2-iodoxybenzoic acid (280 mg), and the mixture was stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (200 mg) as a yellow oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=[O:15])[NH:8]2)[CH3:2]>C(O)C.[Pd]>[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:15])[NH:8]2)[CH3:2]
Reactant: CCc1cc2[nH]c(=O)ccc2c(CC)n1
Agent: [Pd]
Solvent: CCO
Product: CCc1cc2c(c(CC)n1)CCC(=O)N2
Reaction time: 30 h
Yield: 95.1 %

Procedure:
A solution of 5,7-diethyl-1,6-naphthyridin-2(1H)-one (10.0 g) in ethanol (100 ml) was catalytically hydrogenated over 10% palladium on carbon (1 g) at 50° C. and a pressure of 20 atmospheres for 30 hours. The catalyst was removed by filtration through diatomaceous earth and the filtrate was concentrated under vacuum to give 5,7-diethyl-1,2,3,4-tetrahydro-1,6-naphthyridin-2-one (9.6 g), m.p. 90°-94° C.; NMR: 1.2-1.3(m, 6H), 2.6-2.85(m, 6H), 3.05(t, 2H), 6.5(s, 1H), 8.9(br s, 1H).
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[N:11][N:12]=[C:13]2O)=[CH:8][CH:7]=1)[C:3]([CH3:5])=[O:4].O=P(Cl)(Cl)[Cl:26].C([O-])(O)=O.[Na+]>C(#N)C.O>[NH:2]([C:6]1[CH:15]=[C:14]2[C:9]([C:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[N:11][N:12]=[C:13]2[Cl:26])=[CH:8][CH:7]=1)[C:3]([CH3:5])=[O:4]
Reactant: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)Nc1ccc2c(Cc3ccncc3)nnc(Cl)c2c1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
Under a nitrogen atmosphere, a suspension of 2.24 g (7.6 mmol) 7-acetamino-1-hydroxy-4-(4-pyridylmethyl)phthalazine hydrochloride (≡1-oxo-4-[pyridyl-(4′)-methyl]-7-acetamino-1,2-dihydrophthalazine hydrochloride: for preparation see German Auslegeschrift no. 1 061 788 [published Jul. 23, 1959]) in 22 ml acetonitrile is spiked with 1.74 ml (19 mmol) phosphoroxychloride and heated for 4 h to 95° C. The mixture is cooled to 10° C., and 7.5 g NaHCO3 in 30 ml water is added. The deep-red suspension is stirred for 15 min, filtered, and washed out with water. Drying under HV yields the title compound: HPLC: tRet(Grad5-40)=10.2; FAB MS (M+H)+=313.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C.O>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCC=Cc1ccccc1
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: NC(=O)c1cccc(OCC=Cc2ccccc2)c1

Procedure:
3-hydroxybenzamide (0.5 g 3.6 mmol) was dissolved in dry acetonitrile (50 ml). To this was added potassium carbonate (0.503 g; 3.6 mmol) and cinnamyl chloride (0.5 ml; 3.6 mmol). This was left to reflux for 3.5 hours. The acetonitrile was removed under reduced pressure yielding a white sold which was dissolved in water (80 ml). The organics were extracted in dichloromethane (3×30 ml), dried over magnesium sulphate, filtered and the solvent removed under reduced pressure leaving a white solid. The solid was recrystallised from ethyl acetate and petrol (45%).
Reaction SMILES: ClC1C=CC2N(C(CC3C(F)=C4C(=CC=3F)N(C)N=C4)=CN=2)N=1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC.[F:42][C:43]1[C:51]([CH:52]([C:54]2[N:58]3[N:59]=[C:60]([C:63]([O:65]CC)=[CH2:64])[CH:61]=[CH:62][C:57]3=[N:56][CH:55]=2)C)=[C:50]([F:68])[CH:49]=[C:48]2[C:44]=1[CH:45]=[N:46][N:47]2[CH3:69]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:42][C:43]1[C:51]([CH2:52][C:54]2[N:58]3[N:59]=[C:60]([C:63](=[O:65])[CH3:64])[CH:61]=[CH:62][C:57]3=[N:56][CH:55]=2)=[C:50]([F:68])[CH:49]=[C:48]2[C:44]=1[CH:45]=[N:46][N:47]2[CH3:69]
Reactant: C=C(OCC)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cn1ncc2c(F)c(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Product: CC(=O)c1ccc2ncc(Cc3c(F)cc4c(cnn4C)c3F)n2n1
Yield: 71.3 %

Procedure:
The title compound as a light yellow solid (350 mg, 71.3%) was synthesized from 6-chloro-3-((4,6-difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine (360 mg, 1.079 mmol), tributyl(1-ethoxyvinyl)stannane (1.095 mL, 3.24 mmol) and Pd(PPh3)4 (374 mg, 0.324 mmol) using the same procedure as described in the synthesis of compound 51.3 and 51.4. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.09 (s, 1H), 8.07 (s, 1H), 7.78 (d, 1H), 7.71 (s, 1H), 7.26 (d, 1H), 4.59 (s, 2H), 4.02 (s, 3H), 2.74 (s, 3H). LCMS (method B): [MH]+=342.0, tR=2.39 min.
Reaction SMILES: C[C@@H](N)CC.BrC1C=C(C#N)C(N[C@H](C)CC)=CC=1C(OCC)=[O:10].[C:25]([C:27]1[C:37]([NH:38][C@H:39]([CH3:42])[CH2:40][CH3:41])=[CH:36][C:30]([C:31]([O:33]CC)=[O:32])=[C:29]([NH:43][CH2:44][CH3:45])[CH:28]=1)#[N:26]>>[NH2:26][C:25]([C:27]1[C:37]([NH:38][C@H:39]([CH3:42])[CH2:40][CH3:41])=[CH:36][C:30]([C:31]([OH:33])=[O:32])=[C:29]([NH:43][CH2:44][CH3:45])[CH:28]=1)=[O:10]
Reactant: CCOC(=O)c1cc(N[C@H](C)CC)c(C#N)cc1Br
Reactant: CCNc1cc(C#N)c(N[C@H](C)CC)cc1C(=O)OCC
Agent: CC[C@@H](C)N
Product: CCNc1cc(C(N)=O)c(N[C@H](C)CC)cc1C(=O)O

Procedure:
Synthesized according to the method of reagent preparation 50 by using (1R)-1-methylpropylamine in step 1 then following step 2 with the conversion of ethyl 2-bromo-4-cyano-5-{[(1R)-1-methylpropyl]amino}benzoate to ethyl 4-cyano-2-(ethylamino)-5-{[(1R)-1-methylpropyl]amino}benzoate according to the method described in step 1 then proceeding through steps 3 and 4. MS (EI) for C14H21N3O3: 280 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][C:11]=1[C:26](OCC)=[O:27]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:8][C:4]1[N:3]=[C:2]([NH:1][C:26]([C:11]2[C:10](=[O:9])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)=[O:27])[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1=C(O)c2ccccc2N(c2ccccc2)C1
Reactant: Cc1cccc(N)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1cccc(NC(=O)c2cn(-c3ccccc3)c3ccccc3c2=O)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.49 g of 2-amino-6-methylpyridine and 10 g of 1,2-dihydro-4-hydroxy-1-phenyl-3-quinolinecarboxylic acid, ethyl ester in 500 ml of toluene was refluxed for 24 hours in a soxhlet apparatus containing 10 g of 4 Å molecular sieves. The solution was filtered and evaporated. The residue was purified by means of high pressure liquid chromatography (silica gel: dichloromethane as the eluent) to afford 9.8 g of 1,2-dihydro-4-hydroxy-N-(6-methyl-2-pyridyl)-1-phenyl-3-quinolnecarboxamide which was dissolved in chloroform, treated with 35 g of activated manganese dioxide and stirred for three hours at room temperature.
Reaction SMILES: [N:1]1([C:7]2[C:12](/[CH:13]=[CH:14]/[C:15](O)=[O:16])=[CH:11][CH:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br.[Cl:29][C:30]1[C:39]([OH:40])=[C:38]([OH:41])[C:37]([Cl:42])=[C:36]2[C:31]=1[CH2:32][CH2:33][NH:34][CH2:35]2.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CN(C1C=CN=CC=1)C.O>[Cl:29][C:30]1[C:39]([OH:40])=[C:38]([OH:41])[C:37]([Cl:42])=[C:36]2[C:31]=1[CH2:32][CH2:33][N:34]([C:15](=[O:16])/[CH:14]=[CH:13]/[C:12]1[C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:8][C:9]([C:18]([F:21])([F:20])[F:19])=[CH:10][CH:11]=1)[CH2:35]2
Reactant: O=C(O)/C=C/c1ccc(C(F)(F)F)nc1N1CCCCC1
Reactant: Oc1c(O)c(Cl)c2c(c1Cl)CCNC2
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(/C=C/c1ccc(C(F)(F)F)nc1N1CCCCC1)N1CCc2c(Cl)c(O)c(O)c(Cl)c2C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23.7 %

Procedure:
(E)-3-(2-(piperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)acrylic acid (150.0 mg, 0.50 mmol) was suspended in dry THF (7.0 mL). DMAP (111.4 mg, 0.91 mmol) and caesium carbonate (296.0 mg, 0.91 mmol) were added and the mixture was stirred at rt for 15 minutes. 5,8-Dichloro-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide (143.0 mg, 0.45 mmol), EDC.HCl (130.6 mg, 0.68 mmol), HOBt (69.8 mg, 0.45 mmol) were then added. The mixture was stirred at rt overnight. Water (100 mL) was added and the product extracted with EtOAc. Combined organic extracts were dried (MgSO4), filtered and concentrated. Purification was done first using flash column chromatography (CH2Cl2/MeOH 98/2→95/5) and then by size exclusion (Sephadex LH20; CHCl3/MeOH 1/1) to yield 55.0 mg (24%) of the title product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[NH:5]2.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[N:5]2[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1
Reactant: CC1Nc2cc(F)ccc2-n2cccc21
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)N2c3cc(F)ccc3-n3cccc3C2C)c1

Procedure:
7-Fluoro-5-(3-methoxybenzoyl)-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from the product of Example 47 and m-anisoyl chloride according to the procedure of Example 106, Step 2. MS (ESI) m/z 337.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].N1C=CC=CC=1.[Cl:18][CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.Cl>C1C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][C:20]([CH2:19][Cl:18])=[CH:21][CH:22]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Oc1ccc2ccccc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(Oc1ccc2ccccc2c1)c1ccc(CCl)cc1

Procedure:
This ester was prepared by Method C by placing 72.1 g (0.5 mole) of β-naphthol, suspended in 150 ml of benzene, and 0.5 ml of pyridine in the vessel, adding all at once, at room temperature, a solution of 95 g (0.5 mole) of p-chloromethylbenzoyl chloride in 80 ml of benzene, and refluxing this reaction mixture for 6 hours, while passing a weak current of nitrogen through the apparatus. The HCl cleavage began at about 40° C., and at an internal temperature of 50° C., a clear, homogeneous solution had formed. After the end of the reaction time the benzene was substantially removed by distillation. The residue crystallized to a grayish pink crystal mass, the yield of which was quantitative (147.5 g). The raw ester melted at 90°-96° C. It was recrystallized from 2.5 liters of isopropanol with the addition of decolorizing carbon, yielding colorless, pearly, shiny flakes of a melting point of 102°-103.5° C.