Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4])=[CH2:2].[CH2:12]([C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH:1]([C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:17]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:18][CH:19]=2)=[CH:9][CH:10]=1)=[O:4])=[CH2:2]
Reactant: CCCCCc1ccc(C(=O)O)cc1
Reactant: C=CC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)c1ccc(OC(=O)c2ccc(CCCCC)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 19.9 %

Procedure:
A mixture of 4-hydroxyphenyl vinyl ketone (c) (1.0 g), 4-pentylbenzoic acid (1.2 g), DCC (1.9 g), DMAP (0.1 g) and methylene chloride (30 mL) was stirred at room temperature for 12 hours. The white solid precipitated was filtrated out, and the solvent was evaporated away from the filtrate. The residue was dissolved in ethyl acetate, and washed with aqueous 2 M NaOH solution and then with water. The residue was purified through column chromatography (eluent: toluene) and then through recrystallization (ethanol) to obtain 0.4 g of colorless crystals, compound (1-5-11). The NMR and MS spectra of the compound well support the structure thereof.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12](F)[C:11]([F:15])=[CH:10][C:3]=1[C:4]([O:6][CH2:7][C:8]#[CH:9])=[O:5].[CH2:16]([OH:19])[C:17]#[CH:18].[H-].[Na+].Cl>CN(C=O)C>[Cl:1][C:2]1[CH:13]=[C:12]([O:19][CH2:16][C:17]#[CH:18])[C:11]([F:15])=[CH:10][C:3]=1[C:4]([O:6][CH2:7][C:8]#[CH:9])=[O:5]
Reactant: C#CCOC(=O)c1cc(F)c(F)cc1Cl
Reactant: C#CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCOC(=O)c1cc(F)c(OCC#C)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 129.4 %

Procedure:
To a mixture of 150 ml of DMF, 12.7 g of 2-propynyl 2-chloro-4,5-difluorobenzoate and 3.4 g of propargyl alcohol was added 2.4 g of 60% sodium hydride (oily) under ice-cooling. The reaction mixture was stirred at room temperature overnight. Hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The resulting organic layer was washed sequentially with water and an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and 19 g of 2-propynyl 2-chloro-5-fluoro-4-(2-propynyloxy)benzoate was obtained.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.Cl[C:11]1[N:16]=[N:15][C:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)=[CH:13][CH:12]=1>>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([C:14]2[N:15]=[N:16][C:11]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[CH:12][CH:13]=2)=[CH:18]1
Reactant: OC1CN2CCC1CC2
Reactant: Clc1ccc(-c2c[nH]c3ccccc23)nn1
Product: c1ccc2c(-c3ccc(OC4CN5CCC4CC5)nn3)c[nH]c2c1

Procedure:
3-Quinuclidinol (Aldrich, 254 mg, 2 mmol) was coupled with 3-(6-chloropyridazin-3-yl)-1H-indole (Bionet, 458 mg, 2 mmol) at 60° C. for 16 hours according to the procedure of Example 7A. The title compound was purified by preparative HPLC (Xterra™, column, Xterra RP-18, 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O (NH4HCO3, 0.1 M, pH=10), (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (400 mg, 63%). 1H NMR (MeOH-D4, 300 MHz) 1.50-1.64 (m, 1H), 1.71-1.93 (m, 2H), 2.00-2.15 (m, 1H), 2.29-2.36 (m, 1H), 2.78-3.04 (m, 5H), 3.43-3.55 (m, 1H), 5.24-5.32 (m, 1H), 7.12-7.25 (m, 3H), 7.42-7.48 (m, 1H), 7.87 (s, 1H), 8.01 (d, J=9.2 Hz, 1H), 8.26-8.33 (m, 1H) ppm. MS (DCI/NH3) m/z 321 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10]
Reactant: NCCc1ccco1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)NCCc1ccco1
Yield: 41 %

Procedure:
In close analogy to the procedure described above, 2-Furan-2-yl-ethylamine is reacted with acetic anhydride to provide the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:8]=[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)=[N:21][CH:22]=3)[N:6]2[CH:36]=1.Cl[C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1>>[O:14]1[CH2:13][CH2:12][N:11]([C:10]2[C:5]3[N:6]([CH:36]=[C:3]([CH2:2][O:1][C:38]4[N:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[N:4]=3)[C:7]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]4)=[N:21][CH:22]=3)=[CH:8][N:9]=2)[CH2:16][CH2:15]1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(CO)cn34)cn2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(COc5ncccn5)cn34)cn2)CC1

Procedure:
Following the procedures described in Example 22, Step A, the title compound was prepared from compound 23a and 2-chloropyrimidine. Mass Spectrum (LCMS, ESI pos.) Calcd. for C29H35N9O4: 574.3 (M+H). Found 574.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=O)[CH2:3]1.C(N)CN.[N+:16]([CH3:19])([O-:18])=[O:17]>>[N+:16]([CH2:19][C:4]1[CH2:3][C:2]([CH3:11])([CH3:1])[CH2:7][C:6]([CH3:9])([CH3:8])[CH:5]=1)([O-:18])=[O:17]
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: C[N+](=O)[O-]
Solvent: NCCN
Product: CC1(C)C=C(C[N+](=O)[O-])CC(C)(C)C1
Yield: 61 %

Procedure:
A solution of 3,3,5,5-tetramethylcyclohexanone (2-13) (1.54 g, 10 mmol) and ethylenediamine (60 mg) in nitromethane (45 ml) was refluxed in argon atmosphere for 25 h. Excess of nitromethane was then removed in vacuo and the residue was purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (6:1). 1.2 g (61%) of 6 was obtained as an oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:22])[C:7]([CH2:19][C:20]#[N:21])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[NH2:29][CH:1]([C:4]1[CH:5]=[C:6]([Cl:22])[C:7]([CH2:19][C:20]#[N:21])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c(CC#N)c(C#N)c1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc(Cl)c(CC#N)c(C#N)c1-c1cccc(F)c1
Temperature: 65 °C

Procedure:
A mixture of 6-acetyl-4-chloro-3-(cyanomethyl)-3′-fluorobiphenyl-2-carbonitrile (0.020 g, 0.064 mmol) and ammonium acetate (49 mg, 0.64 mmol) in methanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65° C. in a sealed tube for 30 min. The mixture was cooled to room temperature and sodium cyanoborohydride (8 mg, 0.13 mmol) was added. The reaction was heated at 65° C. for another 4 hours, cooled to room temperature, quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step (20 mg, 100%). LCMS calculated for C17H14ClFN3 (M+H)+: m/z=314.1. found: 313.9.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([F:32])[CH:26]=2)=[N:4][C:5]([N:8]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][C:19]([CH3:24])([CH3:23])[CH2:18]2)C(=O)OC(C)(C)C)=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:25]2[C:30]([Cl:31])=[CH:29][N:28]=[C:27]([F:32])[CH:26]=2)=[N:4][C:5]([NH:8][CH2:16][CH:17]2[CH2:22][CH2:21][O:20][C:19]([CH3:23])([CH3:24])[CH2:18]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CC1CCOC(C)(C)C1)c1ccc(Cl)c(-c2cc(F)ncc2Cl)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(CNc2ccc(Cl)c(-c3cc(F)ncc3Cl)n2)CCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3,5′-dichloro-2′-fluoro-2,4′-bipyridin-6-yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate (8 mg, 0.017 mmol), DCM (1 mL) and TFA (0.1 mL, 1.3 mmol) were combined in a 4 mL screw cap vial. The vial was capped and the reaction mixture mixture was stirred at ambient temperature for 1 hour. The solvent was evaporated under vacuum and the residual material was converted to the free base using sodium bicarbonate. (5.8 mg, 91%). LCMS (m/z): 3484.2/386.1/388.2 (M+H), retention time=1.07 min.
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[F:24][C:25]1[C:26](F)=[C:27]2[O:32][CH2:31][C@H:30]([CH3:33])[N:29]3[CH:34]=[C:35]([C:40]([OH:42])=[O:41])[C:36](=[O:39])[C:37]([CH:38]=1)=[C:28]23>C(#N)C>[F:24][C:25]1[C:26]([N:10]2[CH2:11][CH2:12][CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[N:3]3)[CH2:8][CH2:9]2)=[C:27]2[O:32][CH2:31][C@H:30]([CH3:33])[N:29]3[CH:34]=[C:35]([C:40]([OH:42])=[O:41])[C:36](=[O:39])[C:37]([CH:38]=1)=[C:28]23
Reactant: C[C@H]1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: c1cn(C2CCNCC2)nn1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1COc2c(N3CCC(n4ccnn4)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-(1,2,3-triazol-1-yl)piperidine hydrochloride (100 mg) and DBU (80 mg) were added to a suspension of (-)-9,10-difluoro-3(S)-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]-1,4-benzoxazine-6-carboxylic acid in acetonitrile (5 ml). The reaction mixture was refluxed for 48 hrs followed by stirring at room temperature for an additional 48 hrs. The reaction mixture was concentrated and the residue was diluted with water. The separated solid was filtered, washed with water and dried to yield 30 mg of desired product. m.p. 254°-255° C. (dec). 1H NMR (TFA) δ: 9.4 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.16 (d, 11.43Hz, 1H), 5.6-5.1 (m, 2H), 5.0-4.7 (m, 2H), 4.45-4.05 (m, 4H), 3.1-2.6 (m, 4H), 1.86 (d, 6.3Hz, 3H). Anal. calcd. for C 20 H20FN5O4 . H2O; C, 55.68; H, 5.14; N, 16.23.Found C, 55.88; H, 4.762; N, 15.92.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([CH:17]([OH:33])[C:18]4[C:19]([F:32])=[C:20]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:21]=[CH:22][C:23]=4[F:24])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:18]4[C:19]([F:32])=[C:20]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[CH:21]=[CH:22][C:23]=4[F:24])=[O:33])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of 632 (ca. 386 mM) in 1,4-dioxane was added 2,3-dichloro-5,6-dicyanobenzoquinone (83.8 g, 502 mM) followed by water (final 4.8%). The resulting mixture was stirred 2 hours at room temperature and then quenched with one volume of saturated sodium bicarbonate. The mixture was evaporated in vacuo to remove 1,4-dioxane and extracted 3× with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated in vacuo to give a crude solid that was purified on a silica-gel column with 94:5:1 dichloromethane/methanol/ammonium hydroxide as eluent to give P-0956 (approximately 50% yield for 3 steps) as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18].[Cl-].[NH4+]>CN(C)C=O>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:14])[F:15])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH2:3][CH2:4][OH:5]
Reactant: CNCCO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CN(CCO)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(Methylamino)ethanol (17.3 g, 231 mmol) was added dropwise to a solution of 4-chloro-3-nitrobenzotrifluoride (26.0 g, 115 mmol) in N,N-dimethylformamide (100 ml) at 0° C. After the reaction temperature was raised to room temperature, the reaction mixture was stirred at room temperature for 1 hour, poured into a saturated aqueous ammonium chloride solution, and then extracted twice with ethyl acetate. The organic layer was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol = 97/3) to obtain an oil of 4-[N-methyl-N-(2-hydroxy-ethyl) amino]-3-nitrobenzotrifluoride.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([C:39](=[O:40])[CH2:38][CH2:37][CH:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[C:19]3[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=3)=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)CCC1CCCC1
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(C(=O)OCC)cc3)cc2)cc1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc(C(=O)OCC)cc3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure B using ethyl 4-({4-[(4-butylphenyl)ethynyl]benzyl}amino)benzoate and 3-cyclopentylpropanoyl chloride as a yellow oil (79%). 1H NMR (CDCl3, 300 MHz) δ 8.01 (d, J=8.3 Hz, 2H), 7.41 (m, 4H), 7.14 (m, 4H), 7.04 (d, J=8.3 Hz, 2H), 4.89 (s, 2H), 4.39 (q, J=6.8 Hz, 2H), 2.61 (t, J=7.7 Hz, 2H), 2.09 (m, 2H), 1.80-1.25 (m, 16H), 1.00-0.88 (m, 5H). M+ (ESI): 536.9. HPLC, Rt: 6.58 min (Purity: 98.7%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)=[O:4].FC(F)(F)C1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31]NCC2)=C([N+]([O-])=O)C=1>C(#N)C>[Cl:12][C:10]1[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:27]2[CH2:24][CH2:25][CH2:26][CH2:31][CH2:32]2)[CH:11]=1
Reactant: O=C(CBr)Nc1cc(Cl)nc(-c2ccccc2)n1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCNCC1
Solvent: CC#N
Product: O=C(CN1CCCCC1)Nc1cc(Cl)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide (100 mg) was dissolved in acetonitrile (5 ml) and (4-trifluromethyl-2-nitrophenyl)piperazine (253 mg) added. The solution was stirred overnight at room temperature. After this time the solvent was removed in vacuo. Purification by flash chromatography on silica gel eluting with a mixture of dichloromethane and methanol (98:2, then 93:7 v/v) afforded the title compound. m/z (ES+) 521 (MH)+
Reaction SMILES: [C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH2:30])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].I[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[C:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[C:27]([F:28])=[CH:26][C:25]([F:29])=[C:24]([NH:30][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:20]=3[C:21](=[O:23])[CH:22]=2)=[CH:13][C:12]=1[F:31])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CCCCCCI
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCNc1c(F)cc(F)c2oc(-c3ccc(N(CC(=O)OCC)C(C)=O)c(F)c3)cc(=O)c12
Temperature: 25 °C
Reaction time: 1.7 h
Yield: 28 %

Procedure:
1.20 g (2.76 mmol) of 2-[4-(N-acetyl-N-ethoxycarbonylmethylamino)-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 44 was dissolved in 20 ml of dimethylformamide under argon atmosphere, 111 mg of sodium hydride (60% oil dispersion) and 0.82 ml of 1-iodohexane were added under ice-cooling and the mixture was stirred at room temperature for 1.7 hours. 33 mg of sodium hydride was added and the mixture was stirred for additional 40 minutes. A 10% aqueous solution of citric acid was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetonitrile=10:1) to give 433 mg (28%) of 2-[4-(N-acetyl-N-ethoxycarbonylmethylamino)-3-fluorophenyl]-6,8-difluoro-5-hexylamino-4H-1-benzopyran-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].[Br:14][C:15]1[S:23][C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:25]#[N:26])[C:21]=2Cl)[CH:16]=1>O1CCCC1>[Br:14][C:15]1[S:23][C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:25]#[N:26])[C:21]=2[NH:4][C:3]2[CH:5]=[C:6]([O:10][CH3:11])[C:7]([Cl:9])=[CH:8][C:2]=2[Cl:1])[CH:16]=1
Reactant: N#Cc1cnc2cc(Br)sc2c1Cl
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(Br)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 48.6 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (221.8 mg, 1.16 mmol) and 60% sodium hydride (46.2 mg, 1.16 mmol) in 6 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 2-bromo-7-chlorothieno[3,2-b]pyridine-6-carbonitrile (150 mg, 0.55 mmol) is added. The resulting reaction mixture is heated at reflux for 5 hours, cooled to room temperature, and then partitioned between dichloromethane and water. The organic layer is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative thin layer chromatography developing with 40% ethyl acetate in hexane to provide 114.6 mg of 2-bromo-7-[(2,4-dichloro-5-methoxyphenyl)amino]-thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 228-229° C.; 1H NMR (DMSO-d6) δ 3.86 (s, 3H), 7.40 (s, 1H), 7.71 (s, 1H), 7.80 (s, 1H), 8.61 (s, 1H), 9.80 (s, 1H); MS 426.0, 428.0 (M−H)−.
Reaction SMILES: I[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1.[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)[CH3:21].C(#N)C>C(=O)([O-])[O-].[Na+].[Na+].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>[CH2:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][C:13]([C:15]([O:17][CH3:18])=[O:16])=[CH:14][C:9]=3[O:8][CH2:7][CH2:6][N:5]2[CH:19]=1)[CH3:21]
Reactant: CCOc1ccccc1B(O)O
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(I)nc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOc1ccccc1-c1cn2c(n1)-c1ccc(C(=O)OC)cc1OCC2
Yield: 11.4 %

Procedure:
Methyl 2-iodo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (80 mg, 1 eq), 2-ethoxyphenylboronic acid (66 mg, 1.75 eq), and tetrakis(triphenylphosphine)palladium (10 mg, 0.05 eq), in 1.0 M aqueous sodium carbonate (1.0 mL) and acetonitrile (1.0 mL) were heated to 140° C. for 10 min in a sealed microwave reactor. The crude reaction mixture was concentrated and purified using reverse phase HPLC to yield 295 (9 mg). ESI-MS 365.1 (M)+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].CO.[CH2:8]=[C:9]([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11]>O>[F:11][C:10]([F:13])([F:12])[CH:9]([C:14]([F:17])([F:16])[F:15])[CH2:8][NH:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:8][CH:9]([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11]
Reactant: C=C(C(F)(F)F)C(F)(F)F
Reactant: NCCCN
Solvent: CO
Solvent: O
Product: FC(F)(F)C(CNCCCNCC(C(F)(F)F)C(F)(F)F)C(F)(F)F

Procedure:
To a mixture of 1,3-diaminopropane (3.5 g) and methanol (4 mL) was added HFIB in several portions over a period of about 0.5 h until a gentle reflux of HFIB was observed which did not dissipate. A dry-ice condenser was used to obtain the gentle reflux of HFIB at 20° C. for 15 h. The mixture was poured into water (100 mL) and the bottom layer washed with water to provide 1,3-di-(2-trifluoromethyl-3,3,3-trifluoropropylamino)propane (13 g): MS (m/e) 402 (M+, 0.5%), 251 (12%), 221 (82%), 208 (23%),194 (100%); 1H NMR (CDCl3): 1.66 (quintet, J=6.5 Hz, 2H), 2.72 (t, J=6.5 Hz, 4H), 3.08 (m, 6H) ppm.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[CH3:7][S:8][C:9]1[N:14]=[C:13](SC)[C:12]2=[N:17][CH:18]=[C:19]([C:20]#[N:21])[N:11]2[N:10]=1>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:7][S:8][C:9]1[N:14]=[C:13]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C:12]2=[N:17][CH:18]=[C:19]([C:20]#[N:21])[N:11]2[N:10]=1
Reactant: CSc1nc(SC)c2ncc(C#N)n2n1
Reactant: NCC(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CSc1nc(NCC(F)(F)F)c2ncc(C#N)n2n1
Temperature: 120 °C

Procedure:
(I3A): 2,2,2-trifluoroethanamine (1252 mg, 12.64 mmol) was added to a solution of 2,4-bis(methylthio)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (I2A), 300 mg, 1.264 mmol) in NMP (3 mL) and the resulting mixture was heated at 120° C. for 5 h. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography on silica gel using an automated ISCO system (40 g column, eluting with 0-40% ethyl acetate/dichloromethane). 2-(methylthio)-4-((2,2,2-trifluoroethyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (363 mg) was obtained as a white solid.
Reaction SMILES: [C:1]([NH:9][C:10](=[CH:15][N:16]([CH3:18])C)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:26]=[CH:25]C(N)=[CH:22][CH:21]=1.Cl>C(O)(C)C>[C:1]([NH:9][C:10](=[CH:15][NH:16][C:18]1[CH:25]=[CH:26][C:20]([F:19])=[CH:21][CH:22]=1)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)C(=CN(C)C)NC(=O)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)C(=CNc1ccc(F)cc1)NC(=O)c1ccccc1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
10g (39.5 mmol) of methyl 2-benzoylamino-3-dimethylaminoacrylate and 11.4 ml (118 mmol) of 4-fluoroaniline were dissolved in 200 ml of isopropanol at 40° C. The solution was admixed with 3.6 ml (43.5 mmol) of concentrated hydrochloric acid within 5 minutes (min) and stirred for a further 30 min. The suspension was cooled to 10° C. and the crystallized product was filtered off. Yield: 12.4 g (94% of theory) 1H NMR: 3.62 (s, 3H); 7.05-7.24 (m, 4H); 7.48-7.52 (m, 3H); 7.88 (d, 1H); 8.00-8.04 (m, 2H); 8.90 (d, 1H); 9.15 (s, 1H)
Reaction SMILES: [OH-].[Na+].O.[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([O:30]CC)=[O:29])[N:22]=3)[N:20]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:5].Cl>C(O)C>[CH2:4]([O:6][C:7]1[CH:8]=[C:9]([C:16]2[S:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([C:28]([OH:30])=[O:29])[N:22]=3)[N:20]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:5]
Reactant: CCOC(=O)c1nc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(-c2nc(-c3ccc(O)c(C(=O)O)n3)cs2)cc1OCC
Yield: 47.7 %

Procedure:
A solution of 0.32 g of sodium hydroxide dissolved in 20 ml of ethanol and 20 ml of water was added to 0.54 g of 2-(3,4-diethoxyphenyl)-4-(5-hydroxy-6-ethoxycarbonyl-2-pyridyl)thiazole. The mixture was refluxed for 2.5 hours. To the reaction mixture was added 100 ml of water. The mixture was made acidic with concentrated hydrochloric acid and subjected to extraction four times with 70 ml of ethyl acetate. The solvent in the extract was removed and the resulting residue was recrystallized from ethyl acetate-diethyl ether to obtain 0.24 g of 2-(3,4-diethoxyphenyl)-4-(5-hydroxy-6-carboxy-2-pyridyl)thiazole. m.p.: 161.4°-162° C.