Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([Br:17])=[C:12]([CH3:18])[N:11]=1>CN(C=O)C.CCOC(C)=O.[Cl-].[Na+].O>[Br:17][C:13]1[C:12]([CH3:18])=[N:11][C:10]([N:4]2[CH:5]=[CH:6][C:2]([CH3:1])=[N:3]2)=[CH:15][C:14]=1[CH3:16]
Reactant: Cc1cc(Cl)nc(C)c1Br
Reactant: Cc1cc[nH]n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccn(-c2cc(C)c(Br)c(C)n2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
To a solution of 3-methylpyrazole (156 mg, 1.90 mmol) in DMF (2 ml) was added NaH (60% dispersion in oil, 76 mg, 1.9 mmol) and the reaction stirred at room temperature for 30 min. before adding 2-chloro-5-bromo-4,6-dimethylpyridine (227 mg, 1.03 mmol) as a solid in one portion. The mixture was heated to 85° C. for 2 d then cooled and diluted with EtOAc (35 ml) and brine (20 ml). The organic layer was washed with brine (2×15 ml) and water (1×10 ml), dried (Na2SO4), concentrated and purified by column chromatography on silica gel (Hexanes/Et2O, 9:1) to afford 3-bromo-2,4-dimethyl-6-(3-methyl-pyrazol-1-yl)-pyridine (172 mg, 63%) as a white crystalline solid. 1H NMR (CDCl3) δ 2.36 (s, 3H), 2.44 (s, 3H), 2.65 (s, 3H), 6.23 (d, 1H, J=3 Hz), 7.62 (s, 1H), 8.41 (d, 1H, J=3 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]#[CH:5])[CH3:2].C([Li])CCC.CN(P(N(C)C)(N(C)C)=O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:4]([O:3][C:1]#[C:2][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:5]
Reactant: C#COCC
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC#CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of ethoxy acetylene (9.95 g of 50% w/w. solution in hexanes, 70 mmol) in THF (100 ml) at −78° was added n-butyl lithium (31 ml of 2.5M solution in hexanes, 78 mmol). The mixture was stirred at this temperature for 2 h. prior to the addition of HMPA (20 ml), stirring was continued for a further 15 min. before the addition of benzyl bromide (9.2 ml). The reaction mixture was allowed to warm to room temperature overnight before partitioning between EtOAc (300 ml) and water (200 ml). The organics were separated, washed with water (5×200 ml), brine (200 ml), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a mobile brown oil (11.1 g, 99%). δH (300 MHz, CDCl3) 7.15-7.57 (5H, m), 4.12 (2H, q, J 7.1 Hz), 3.60 (2H, s), 1.41 (3H, t, J 7.1 Hz); m/z (ES+, 70V) MH+ 161.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]=[CH2:14])[C:9](O)=[O:10])=[CH:4][CH:3]=1.[CH3:15][N:16](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]=[CH2:14])[C:9]([NH:16][CH3:15])=[O:10])=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C=CCC(C(=O)O)c1ccc(F)cc1
Agent: CN
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC(C(=O)NC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
2-(4-Fluorophenyl)pent-4-enoic acid (Bioorg. Med. Chem. Lett. 2000, 1893; 4.20 g, 21.6 mmol) was dissolved in CH2Cl2 (75 mL) and to the resultant solution was added TBTU (7.29 g, 22.7 mmol). The mixture was stirred at RT for 15 min and then methylamine (11.9 mL of 2M THF solution, 23.8 mmol) and DIPEA (11.2 g, 86.5 mmol) were added. The reaction mixture was stirred at room temperature for 3 h, subsequently diluted with CH2Cl2 (50 mL) and then washed several times with water. The solvent was removed by evaporation and the residue flash chromatographed on silica gel (heptane-ethyl acetate, 1:1). There was obtained 3.5 g (78%) of 2-(4-fluorophenyl)-N-methylpent-4-enamide as an oil, which shortly after crystallized. 1H NMR (400 MHz, CDCl3): 2.5 (qn, 1H), 2.7 (d, 3H), 2.9 (qn, 1H), 3.4 (t, 1H), 4.9-5.1 (m, 2H), 5.6-5.8 (m, 1H), 6.0-6.2 (b, 1H), 7.0 (m, 2H), 7.3 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[CH3:12].ClC(C)[CH2:26][NH:27]C1C(C)=CC=CC=1C.FC(F)(F)C1C=C(C=CC=1)N.Cl.FC(F)(F)C1C=C(C=CC=1)N>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH2:10][CH:11]([CH3:12])[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[CH:15]=2)[C:26]1=[NH:27]
Reactant: Cc1cccc(C)c1NCC(C)Cl
Reactant: Cc1cccc(C)c1NCC(C)Nc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: Nc1cccc(C(F)(F)F)c1
Product: Cc1cccc(C)c1N1CC(C)N(c2cccc(C(F)(F)F)c2)C1=N
Yield: 42.4 %

Procedure:
1-(2',6'-Dimethylphenyl-amino)-2-(3'-trifluoromethylphenyl-amino)-propane, applied as starting substance, is prepared by reacting N-(β-chloropropyl)-2,6-dimethyl-aniline, a compound prepared as described in Example 3, Method (b), point (a), with 3-trifluoromethyl-aniline. The reaction is performed as described in Example 16, point (c) with the difference that crystalline 3-trifluoromethyl-aniline hydrochloride is separated from the reaction mixture by trituration with benzene. The aimed product is obtained with a yield of 42.4%; m.p.: 160°-166° C. (dihydrochloride).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CCN(C(C)C)C(C)C.[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=2)[CH2:23][CH2:22]1>C1COCC1>[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH:29][C:2]3[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=3[N+:9]([O-:11])=[O:10])[CH:25]=2)[CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(F)cc1Nc1cc(C2CC2)[nH]n1
Temperature: 80 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (1.76 g, 11.1 mmol) and DIEA (1.93 ml, 11.1 mmol) in THF (20 ml) was added dropwise a solution of 5-cyclopropyl-1H-pyrazol-3-amine (0.91 g, 7.39 mmol) in THF (5 ml) at 25° C. After addition, the reaction mixture was stirred at 80° C. for 48 hours. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane:DCM:EtOAc=2:1:1) to give the title compound as a yellow solid (0.62 g, 32%). NMR (400 MHz) 12.37 (s, 1H), 9.83 (s, 1H), 8.25 (m, 1H), 7.98 (d, J=11.2 Hz, 1H), 6.75 (m, 1H), 5.95 (s, 1H), 1.90 (m, 1H), 0.96 (m, 2H), 0.72 (m, 2H).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:2]=1.[NH2:25][C:26]1[CH:31]=[C:30]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH:29]=[CH:28][C:27]=1[NH:37]C(=O)OC(C)(C)C.C(N(CC)CC)C>S(Cl)(Cl)=O.CN(C=O)C>[NH2:37][C:27]1[CH:28]=[CH:29][C:30]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[CH:31][C:26]=1[NH:25][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([NH:7][C:3]1[CH:2]=[C:1]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: O=C(O)CCCCCCC(=O)Nc1cccc(-c2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Nc1ccc(-c2cccs2)cc1NC(=O)CCCCCCC(=O)Nc1cccc(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
Acid 183 (0.103 g, 0.32 mmol) in thionyl chloride (3 mL) with a few drops of DMF was stirred at room temperature for 15 min then concentrated, diluted with dry THF (10 mL), cooled to 0° C. then treated with amine 4 (0.12 g, 0.41 mmol) and triethylamine (0.086 mL, 0.61 mmol). The reaction mixture was stirred at 0° C. for 30 min then quenched with aqueous NH4Cl, extracted with AcOEt, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (eluent: 50% AcOEt-hexane) to give the title compound 184 (0.111 g, 52% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:7]=2[N:8]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([C:19]([NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[O:21])[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:7]=2[N:8]=1
Reactant: Nc1ccccc1
Reactant: CSc1ncc2c(n1)CCN(c1cccc(C(=O)O)n1)C2
Product: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3ccccc3)n1)C2

Procedure:
In a manner similar to that described in Example 108, a mixture of 6-[2-(methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]pyridine-2-carboxylic acid and aniline were converted to the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([CH3:29])[CH:23]=[CH:22]2>>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[C:24]([CH3:29])[CH:23]=[CH:22]4)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Cc1ccc2cc(Br)ccc2n1
Reactant: Fc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc2cc(-n3c4c(c5cc(F)ccc53)CN3CCC4CC3)ccc2n1

Procedure:
The reaction of 9-fluoro-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (230 mg, 1.0 mmol; Example 161) and 6-bromo-2-methylquinoline (333 mg, 1.5 mmol; Oakwood) was performed as described in Example 68 to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 1.94-2.20 (m, 4H) 2.78 (s, 3H) 2.89-2.96 (m, 1H) 3.08-3.30 (m, 4H) 4.30 (s, 2H) 6.84 (td, J=9, 2 Hz, 1H) 7.04 (dd, J=9, 4 Hz, 1H) 7.11 (dd, J=9, 3 Hz, 1H) 7.54 (d, J=9 Hz, 1H) 7.67 (dd, J=9, 2 Hz, 1H) 7.90 (d, J=2 Hz, 1H) 8.14 (d, J=9 Hz, 1H) 8.33 (d, J=8 Hz, 1H); MS (DCI/NH3) m/z 372 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[N:8]([CH3:18])[C:7](=[O:19])[C:6]3([CH3:24])[CH2:20][O:21][CH2:22][CH2:23][N:5]3[C:4]=2[N:3]=1.[CH3:25][NH:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)=[O:28].C(=O)(O)[O-].[Na+]>O1CCOCC1.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]>[CH3:18][N:8]1[C:7](=[O:19])[C:6]2([CH3:24])[CH2:20][O:21][CH2:22][CH2:23][N:5]2[C:4]2[N:3]=[C:2]([C:33]3[CH:32]=[CH:31][C:30]([NH:29][C:27]([NH:26][CH3:25])=[O:28])=[CH:35][CH:34]=3)[N:11]=[C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[C:9]1=2
Reactant: CNC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN1C(=O)C2(C)COCCN2c2nc(Cl)nc(N3CCOCC3)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CNC(=O)Nc1ccc(-c2nc(N3CCOCC3)c3c(n2)N2CCOCC2(C)C(=O)N3C)cc1
Temperature: 100 °C
Yield: 17.4 %

Procedure:
2-Chloro-5,6a-dimethyl-4-morpholino-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (23 mg, 0.065 mmol), 1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (21.54 mg, 0.078 mmol), PdCl2(dppf) (9.51 mg, 0.013 mmol) and sodium bicarbonate (1.5 mL, sat.) were mixed in 1,4-dioxane (3 mL). The suspension was heated by microwave irradiation at 100° C. for 30 minutes. After filtration, the solution was purified by mass-triggered preparative HPLC eluted with 20-25% of ACN (containing 0.035% TFA) in water (containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mm column) to give the title compound (5.3 mg 17% yield) as a pale yellow solid. 1H NMR (400 MHz, MeOD) δ ppm 1.57 (s, 3H) 2.70 (s, 3H) 2.80 (s, 3H) 3.34 (m, 1H) 3.64 (m, 1H) 3.72-3.86 (m, 9H) 4.10 (m, 2H) 4.25 (m, 1H) 7.51 (d, J=8 Hz, 2H) 7.62 (d, J=8 Hz, 2H). MS [M+H] Found 468.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.Cl[C:10]1[CH:19]=[N:18][C:17]2[C:12](=[CH:13][C:14]([O:22][CH3:23])=[C:15]([O:20][CH3:21])[CH:16]=2)[N:11]=1>C(O)C>[CH3:21][O:20][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][C:14]=1[O:22][CH3:23])[N:11]=[C:10]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1)[CH:19]=[N:18]2
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Reactant: N[C@H]1CC[C@@H](O)CC1
Solvent: CCO
Product: COc1cc2ncc(N[C@H]3CC[C@@H](O)CC3)nc2cc1OC
Temperature: 180 °C

Procedure:
A mixture of cis-4-aminocyclohexanol (400 mg, 3.48 mmole) and 2-chloro-6,7-dimethoxyquinoxaline (450 mg, 2 mmole) in 5 mL of ethanol is placed in sealed tube and then heated at 180° C. for 3 hours. The dark-brown mixture is chromatographed on silica gel and eluted with ethyl acetate to provide the desired product (m.p. 65-67° C.). Anal. Calcd. for C16H21N3O3.0.6H2O: C, 61.17; H, 7.12; N, 13.37; Found: C, 61.22; H, 7.19; N, 12.19.
Reaction SMILES: C(O)(=O)C=CC=CC=C.N1C2C(=CC=CC=2)C=CC=1.[Br:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[NH:29][C:28](=O)[CH2:27][CH2:26]2.B.CSC>>[Br:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:30]=1[NH:29][CH2:28][CH2:27][CH2:26]2
Reactant: O=C1CCc2cccc(Br)c2N1
Agent: B
Agent: C=CC=CC=CC(=O)O
Solvent: c1ccc2ncccc2c1
Solvent: CSC
Product: Brc1cccc2c1NCCC2

Procedure:
An example for a compound in accordance with Formula 2 is 4-iso-propylaniline that serves as the starting material for the presently preferred compounds of the invention. The aniline derivative of Formula 2 is reacted with an acryloyl chloride derivative of Formula 2A in a basic solvent, such as pyridine, to provide the phenyl amide derivative of the acryloic acid of Formula 3. An example of the acryloyl chloride derivative of Formula 2A that is used for the synthesis of the presently preferred compounds of the invention is commercially available 3,3-dimethylacryloyl chloride. The acryloic acid amide derivative of Formula 3 is cyclized under Friedel Crafts conditions to provide the 1,2,3,4-tetrahydro-quinolin-2-one derivative of Formula 4. The 1,2,3,4-tetrahydro-quinolin-2-one derivative of Formula 4 is reacted with bromine in acetic acid to provide the 8-bromo-1,2,3,4-tetrahydro-quinoline-2-one derivative of Formula 5. The numbering of the quinoline ring system and of the heptatrienoic acid moiety that is attached to it in the 8 position of the quinoline nucleus in the compounds of the invention, is shown in Formula 1. The endocyclic oxo function of the 8-bromo-1,2,3,4-tetrahydro-quinoline-2-one derivative of Formula 5 is reduced by treatment with borane-methyl sulfide to give the 8-bromo-1,2,3,4-tetrahydro-quinoline derivative of Formula 6. An alkyl group, designated R3, where R3 is defined as in connection with Formula 1, is introduced to the nitrogen of the quinoline nucleus by treatment of the compound of Formula 6 with an alkylating agent, such as R3-I, in the presence of base, to give the 1-alkyl-8-bromo1,2,3,4-tetrahydro-quinoline compound of Formula 7. The 1-alkyl-8-bromo1,2,3,4-tetrahydro-quinoline compound of Formula 7 is reacted with dimethylformamide (DMF) in the presence of strong base, such as n-butyl lithium to give a 1-alkyl-1,2,3,4-tetrahydro-quinoline-8-carbaldehyde of Formula 8. The carbaldehyde of Formula 8 is reacted with a Grignard reagent of the formula R5MgBr, where R5 is defined as in connection with Formula 1, to provide a (1-alkyl-1,2,3,4-tetrahydro-quinoline-8-yl)-alkan-1-ol of Formula 9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[C:3]=1[O:10][CH3:11].[C:12]([NH2:23])(=[O:22])[C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15](N)=[O:16].[K]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH2:8][N:23]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(Br)cccc1CBr
Reactant: NC(=O)c1ccccc1C(N)=O
Agent: [K]
Solvent: CN(C)C=O
Product: COc1c(Br)cccc1CN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Yield: 51.4 %

Procedure:
To a solution of 1-bromo-3-(bromomethyl)-2-(methyloxy)benzene (41.4 g, 0.15 mol) in DMF (350 mL), Potassium Phthalamide (PhtK) (28.8 g, 0.16 mol) was added, and the mixture was heated to 90° C. over night. Then the solvent was removed under reduced pressure. The residue was dissolved in CHCl3 (300 mL), and filtered. The filtrate was washed with H2O (100 mL×2), brine (100 mL), and dried over Na2SO4. After removing the solvent, the residue was recrystallized with EtOH (200 mL). 26.7 g of the product was obtained as white solid. Yield: 52.1%. 1H NMR (400 MHz, CDCl3) δ 3.98 (s, 3 H), 4.95 (s, 2H), 6.93 (t, J=8.0 Hz, 1 H), 7.20 (d, J=0.8 Hz, 1 H), 7.45 (d, J=8.0 Hz, 1 H), 7.72-7.87 (m, 4 H).
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[CH:17]([C:19]1[S:20][CH:21]=[CH:22][C:23]=1[C:24]1[C:25](=[O:42])[N:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:29]=1)=O.O>O1CCCC1>[CH2:13]([O:12][C:10]([CH:9]=[CH:17][C:19]1[S:20][CH:21]=[CH:22][C:23]=1[C:24]1[C:25](=[O:42])[N:26]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:29]=1)=[O:11])[CH3:14]
Reactant: O=Cc1sccc1-c1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1sccc1-c1cc(-c2ccccn2)cn(-c2ccccc2)c1=O
Yield: 33.5 %

Procedure:
To a solution of 7.5 mg of ethyl diethylphosphonoacetate in tetrahydrofuran was added 1.3 mg of sodium hydride in nitrogen atmosphere under ice-cooling, followed by the dropwise addition of a solution of 10 mg of 3-(2-formylthiophen-3-yl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one in tetrahydrofuran. After stirring the mixture at room temperature for 1 hour in nitrogen atmosphere, water was added thereto. Then, it was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 4 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:29]3[CH2:33][CH2:32][CH2:31][NH:30]3)=[N:9][C:10]=2[C:11]2[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]3[S:19][C:20]4[CH2:26][CH2:25][CH2:24][CH2:23][C:21]=4[N:22]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:34](O)(=[O:38])[C:35]#[C:36][CH3:37]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:29]3[CH2:33][CH2:32][CH2:31][N:30]3[C:34](=[O:38])[C:35]#[C:36][CH3:37])=[N:9][C:10]=2[C:11]2[CH:28]=[CH:27][C:14]([C:15]([NH:17][C:18]3[S:19][C:20]4[CH2:26][CH2:25][CH2:24][CH2:23][C:21]=4[N:22]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC#CC(=O)O
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4nc5c(s4)CCCC5)cc3)c12
Product: CC#CC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3nc4c(s3)CCCC4)cc2)c2c(N)nccn12
Yield: 19.2 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)benzamide (intermediate 15) and 2-butynoic acid, to afford the title compound (7 mg, 19.2%). Data: UPLC (C) Rt: 2.41 min; m/z 526.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH2:16][C:15](=[O:17])[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[C:24](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:24][N:8]1[C:9]2[C:14](=[CH:13][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:11][CH:10]=2)[C:15](=[O:17])[CH:16]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC(c1ccccc1)=N2
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)c(=O)cc(-c1ccccc1)n2C
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 2 grams of methyl 2-phenyl-4-quinolone-6-carboxylate (obtained in Example 1), 16 ml of methyl iodide, 2 grams of potassium carbonate and 50 ml of dimethyl formamide is stirred for four hours at 60° C. After cooling, the mixture is poured into water and extracted with ethyl acetate. From the extract ethylacetate is evaporated, the residue is purified by silica chromatography, and 1.8 grams of methyl 1-methyl-2-phenyl-4-quinolone-6-carboxylate, colorless powder, melting point 174° to 176° C., is obtained.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5].[F:26][C:27]1[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34]>C1COCC1>[F:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[CH:7]=1)=[O:5]
Reactant: CON(C)C(=O)c1cn(Cc2cccc(C)n2)c2ccccc2c1=O
Reactant: COc1ccc([Mg]Br)cc1F
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C)n3)c3ccccc3c2=O)cc1F

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 120 mg (0.36 mmol) of 1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 2 mL THF and 1.6 mL 0.5M 3-fluoro-4-methoxyphenylmagnesium bromide. Yield: 95 mg of a white solid. LC-MSD, m/z for C24H19FN2O3 [M+H]+=403.1; HPLC retention time: 1.9 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](OC)=[O:12])[N:6]=1)=[O:4].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.C1COCC1.C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.O=[Mn]=O>[CH:11]([C:7]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]=[CH:9][CH:8]=1)=[O:12]
Reactant: COC(=O)c1cccc(C(=O)OC)n1
Agent: O=[Mn]=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(C=O)n1
Temperature: 75 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
A suspension of dimethylpyridine-2,6-dicarboxylate (1.0 g, 5.12 mmol) in methanol (8 mL) and THF (3 mL) was heated at 75° C. until the solid was dissolved. NaBH4 (184 mg, 4.87 mmol) was then added portion-wise. The mixture was stirred at 70° C. for 1 h. The mixture was cooled to room temperature and 10% citric acid (1.6 mL) was added. The solution was filtered and the filtrate was evaporated to dryness, taken up in dichloromethane, dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by silica gel chromatography, eluting with 0-100% EtOAc in isohexane, to provide a colourless oil which was then dissolved in toluene (20 mL) and chloroform (20 mL). MnO2 (194 mg, 22.2 mmol) was added and the mixture was stirred at room temperature for 18 h. The mixture was filtered through a pad of fluorosil, eluting with chloroform (30 mL) and the solvent was removed in vacuo to provide the title compound (249 mg, 29%) as white solid.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)(=O)=O.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCOC(C)=O.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>CC#N.[O-][Mo]([O-])(=O)=O>[CH2:14]([NH:21][CH2:6][C@@H:7]1[CH2:11][O:10][C:9]([CH3:12])([CH3:13])[O:8]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(C)OC[C@@H](COS(C)(=O)=O)O1
Reactant: NCc1ccccc1
Agent: O=[Mo](=O)([O-])[O-]
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)OC[C@@H](CNCc2ccccc2)O1
Yield: 81.1 %

Procedure:
The title compound was prepared in the same way as that method described for preparing the (S)-enantiomer (M. Lemaire, F. Posada, J.-G. Gourcy and G. Jeminet, Synlett, 1995, 627). A solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (3.0 g, 14.27 mmol) and benzylamine (6.23 ml, 57.1 mmol) were refluxed together in CH3CN (38 ml) for 48 h. Tlc (EtOAc-hex 8:2) showed a new product (uv/molybdate or ninhydrin) with Rf ˜0.3 together with a little higher running sm. The solvent was evaporated and the residue dissolved in EtOAc and washed with aqueous sat. NaHCO3, dried and the solvent evaporated. The residue was chromatographed (EtOAc-hex, 6:4 then 8:2) to give (R)—N-benzyl-1-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (2.56 g, 11.57 mmol, 81% yield) as a yellow oil. [α]D21 −3.7 (c, 0.885, CHCl3). 1H NMR (CDCl3, 300 MHz), δ ppm, 7.32-7.20 (m, 5H), 4.25, (m, 1H), 4.03 (dd, 1H, J 8.0, 6.4 Hz), 3.82 (s, 2H), 3.68 (dd, 1H, J 8.0, 6.8 Hz), 2.74 (d, 2H, J 5.7 Hz), 1.40 (s, 3H), 1.35 (s, 3H). 13C NMR (CDCl3, 75.5 MHz), δ ppm, 140.6, 128.8, 128.4, 127.3, 109.5, 75.8, 67.9, 54.4, 52.1, 27.3, 25.8.